TW200800871A

TW200800871A - Novel catechol derivatives pharmaceutical compositions containing the sane and their uses

Info

Publication number: TW200800871A
Application number: TW095143900A
Authority: TW
Inventors: Takehiro Ishikawa; Toshihiro Nishimura; Hitoshi Inoue; Nobuyuki Tanaka; Muranaka Hideyuki
Original assignee: Kissei Pharmaceutical
Priority date: 2005-11-29
Filing date: 2006-11-28
Publication date: 2008-01-01
Also published as: JP5210637B2; WO2007063789A1; JPWO2007063789A1

Abstract

The present invention provides a compound represented by general formula(I):or pharmaceutically acceptable salts thereof, wherein R1 and R2 are each independently hydrogen, lower acyl, lower alkoxycarbonyl or the like; R3 is nitro or cyano; R4 and R5 are each independently hydrogen, lower alkyl or the like; R6, R7, R8, R9 and R10 are each independently hydrogen, halogen, lower alkyl, halo-lower alkyl, lower alkenyl, lower alkoxy, halo-lower alkoxy, carboxy, lower alkoxycarbonyl, lower acyl, lower alkylsulfonyl, cyano or the like, which exhibits potent COMT inhibitory activities. The present invention also provides pharmaceutical compositions containing said compound, and uses thereof.

Description

200800871 九、發明說明：【發明所屬技術領域】本發明係關於具有兒⑽+轉甲基酶（eatechQi_ 〇 - methy 1 transf erase)抑制作用之新穎兒茶酚衍生物、含有其之醫藥組成物及該等之用途。【先前技術】巴金森氏症（Parkinson，s disease)係好發於中高年齡層之進行性神經變異疾病，隨高齡化社會之進展，其患者人數正增加中。巴金森氏症以靜止時震顫(“出叫 pernor)、肢體僵直（rigidity)、運動不能、反射障礙（disturbance 〇f posture)等協同性運動功能障礙為主要症狀之疾病，其病因認為係中腦愛性神經細胞變異導致粒線體多巴胺之缺乏所引起、。因此，巴金森氏症之治療藥係使用左多巴（L_ D〇pA)及多巴胺受體刺激藥等。左多巴為多巴胺（d〇pamine)之前驅物（precurs〇r)，在腦中被代謝成多巴胺而表現效果之藥劑，但其缺點為在血液中之半衰期極短。因此，左多巴通常與屬於左多巴代謝酵素抑制劑之末端性芳香族L—胺基酸脫羧酶抑制劑及/ 或兒茶紛-0 -轉曱基酶抑制劑共同使用。兒茶酚—〇 —轉甲基酶（以下簡稱C0MT)已知為催化由其辅媒s -腺苷一 L甲石”L版酉文轉送甲基至兒命盼基質之酵素，而抑制此酵素之結果能夠抑制左多巴代謝成3 - 0 -甲基左多巴，使左多巴在血液中之半衰期增加，進而增加穿透腦部腦血管 312XP/發明說明書(補件)/96-03/95143900 6 200800871 P早壁(Blood-brain barrier)之左多巴量。藉由將此種 C0MT抑制劑與左多巴一起投予’已知可增加左多巴之生體内利用率，延長其作用時間（如參照非專利文獻丨）。又，C0MT抑制劑具有促進***尿中鈉之作用，故期望可用於作為高血壓症之治療藥（如參照非專利文獻2)。又，C0MT抑制劑期望可用於作為憂鬱症之治療藥（如參照非專利文獻3)。200800871 IX. OBJECTS OF THE INVENTION: 1. Field of the Invention The present invention relates to novel catechol derivatives having an inhibitory effect on eatechQi_ 〇- methy 1 transf erase, pharmaceutical compositions containing the same, and The use of such. [Prior Art] Parkinson's disease is a progressive neurodegenerative disease that occurs in the middle and high age groups. As the aging society progresses, the number of patients is increasing. Parkinson's disease is characterized by tremor at rest ("pernor", limb rigidity, dysmotility, disturbance 〇f posture, etc.). Love neuronal cell variability is caused by the lack of mitochondrial dopamine. Therefore, the treatment of Parkinson's disease uses levo-dopa (L_D〇pA) and dopamine receptor stimulating drugs, etc. Levodopa is dopamine ( D〇pamine) is a drug that is metabolized into dopamine in the brain to express its effects, but its shortcoming is that the half-life in the blood is extremely short. Therefore, levo-dopa is usually associated with metabolism of levo-dopa. A terminally aromatic L-amino acid decarboxylase inhibitor of an enzyme inhibitor and/or a catechin-trans-thiolase inhibitor. Catechol-〇-transmethylase (hereinafter referred to as C0MT) It is known to catalyze the enzyme which transfers the methyl group to the parental hope matrix by its auxiliary medium s-adenosyl-L-methyl"L version, and the inhibition of this enzyme can inhibit the metabolism of levo-dopa into 3 - 0 - A Quitodopa, making left dopa in the blood The half-life is increased, thereby increasing the brain penetration of cerebrovascular 312XP / present specification (complement member) / 96-03 / 95143900 6 200800871 P earlier wall (Blood-brain barrier) Zhizuo dopa amount. By administering such a C0MT inhibitor together with levo-dopa, it is known to increase the utilization rate of levodopa and to prolong its action time (see, for example, Non-Patent Document). Further, since the C0MT inhibitor has an action of promoting excretion of sodium in urine, it is expected to be useful as a therapeutic drug for hypertension (see, for example, Non-Patent Document 2). Further, a C0MT inhibitor is expected to be useful as a therapeutic drug for depression (see, for example, Non-Patent Document 3).

近年報告有各種C0MT抑制劑。至今已知最強之c〇MT抑制劑為多加邦（Tolcapone、3,4 -二羥基—4，—甲美一 5 -硝基二苯甲酮、參照專利文獻丨）及安達=邦 (Entacapone、（Ε) - 2 -氰基-ν，Ν -二乙基—3 — (3 4 一二羥基-5 -硝苯基）丙烯醯胺、參照專利文獻2)，此2 種C劑已被使用於巴金森氏症。但多加邦被確認有重度肝功能損害’故必須在嚴格之肝功能監控下進行投予。又安達加邦存在有其效果較多加邦低、作用持續時間較短等問題。在此情形下，期望出現安全性高、作用持續時間長之新穎C0MT抑制劑。Various C0MT inhibitors have been reported in recent years. The strongest c〇MT inhibitors known to date are Tokacapone (3,4-dihydroxy-4, 5-methyl 5-nitrobenzophenone, see patent literature) and Entacapone. (Ε) - 2 -Cyano-ν,Ν-diethyl- 3 - (3 4 -dihydroxy-5-nitrophenyl) acrylamide, refer to Patent Document 2), these two C agents have been used In Parkinson's disease. However, Toga is confirmed to have severe liver damage, so it must be administered under strict liver function monitoring. And there are problems in Andagabang that have more effects, less state, and shorter duration of action. Under this circumstance, it is desirable to have a novel C0MT inhibitor with high safety and long duration of action.

Borgulya J.等人報告了具有C0MT抑制作用之作為兒条酚衍生物的5 -甲續醯基-3 -硝苯基—1，2 —二醇（如參照非專利文獻4)。但該化合物之C0MT抑制活性及作用持續時間並不充分。非專利文獻 1 · Nutt J· G·等，「Lancet」，1998 年，351 卷，9111 號，ρ· 1221-1222 非專利文獻 2 ·· Eklof A· C·等，「Kidney Int·」，1997 年，52 312XP/發明說明書(補件)/96_03/95143900 7 200800871 * 卷，3 號，ρ· 742-747 非專利文獻 3 : Moreau J· L.等，「Behav· Pharmacol.」， 1994 年，5 卷，3 號，p. 344-350 非專利文獻 4: Borgulya J·等，「Helvetica Chimica Acta」， 1989 年，72 卷，p. 952-968 非專利文獻 5 · Koga，Κ·等，「Eur· J· Pharmacol·」，2000 年，408 卷，ρ· 249-255 _專利文獻1 :歐洲專利申請公開第237929號說明書專利文獻2 ·英國專利申請公開第2200109號說明書【發明内容】 (發明所欲解決之問題）本發明之目的為提供具有強大c〇MT抑制作用，且最好具有高安全性及作用持續時間長之新穎化合物。 (解決問題之手段）本發明者為解決上述課題而一再精心研读鲁一般式（I)表示之兒茶酚衍生物係具有優異作用，且具有高安全性及長作用持續時間，^ ，且具有高安全性及長作用持續時間亦即，亦即，本發明係關於以一般式（I)表示理學上容許之鹽： [化1] 一再精心研究，結果發現以分係具有優異之C0MT抑制 1持續時間，遂完成本發明。式（I)表示之化合物或其藥Borgulya J. et al. reported 5-carboxymethyl-3-nitrophenyl-1,2-diol as a catechol derivative having a C0MT inhibitory action (see Non-Patent Document 4). However, the C0MT inhibitory activity of the compound and the duration of action are not sufficient. Non-Patent Document 1 · Nutt J. G. et al., "Lancet", 1998, 351, 9111, ρ·1221-1222 Non-Patent Document 2 ·· Eklof A·C·, etc., “Kidney Int·”, 1997 Year, 52 312XP/Invention Manual (supplement)/96_03/95143900 7 200800871 * Volume, No. 3, ρ· 742-747 Non-Patent Document 3: Moreau J. L. et al., "Behav· Pharmacol.", 1994, 5, No. 3, p. 344-350 Non-Patent Document 4: Borgulya J. et al., "Helvetica Chimica Acta", 1989, Vol. 72, p. 952-968 Non-Patent Document 5 · Koga, Κ, et al., Eur·J· Pharmacol·”, 2000, vol. 408, pp. 249-255 _ Patent Document 1: European Patent Application Publication No. 237929, Patent Document 2, British Patent Application Publication No. 2200109, Problem to be Solved The object of the present invention is to provide a novel compound which has a strong c〇MT inhibitory effect and which preferably has high safety and a long duration of action. (Means for Solving the Problems) The present inventors have repeatedly studied the catechol derivatives represented by the general formula (I) in order to solve the above problems, and have excellent effects, high safety and long duration of action, and have High safety and long duration of action, that is, the present invention relates to a salt which is physiologically acceptable in the general formula (I): [Chemical 1] has been carefully studied, and it has been found that the fraction has excellent C0MT inhibition 1 For the duration, the present invention has been completed. a compound represented by the formula (I) or a drug thereof

3_發明說明書(補件)/96-03/95143900 8 200800871 [式中： R1及R2分別獨立為氫原子、低級醯基、低級烷氧羰基、一 C(0)NRnR12，或 R1 及 R2 共同形成—c(〇) 一； R3為硝基或氰基； R及R分別獨立為氫原子、顧素原子、低級烧基、函化低級烧基、氰基、低級酿基；立為以下之a)〜ah) R6、R7、R8、R9 及 R"分別獨 a )氫原子，3_Invention Manual (Supplement)/96-03/95143900 8 200800871 [In the formula: R1 and R2 are each independently a hydrogen atom, a lower sulfhydryl group, a lower alkoxycarbonyl group, a C(0)NRnR12, or a combination of R1 and R2. Forming -c(〇)1; R3 is a nitro group or a cyano group; R and R are each independently a hydrogen atom, a ruthenium atom, a lower alkyl group, a functional lower alkyl group, a cyano group, and a lower aryl group; a)~ah) R6, R7, R8, R9 and R" respectively a) hydrogen atom,

b )鹵素原子， c)低級烧基， d)鹵化低級烷基， e )低級烯基， Ο低級炔基， g )環烧基， h)環烷基低級烷基， • i )低級烧氧基， j) 鹵化低級烷氧基， k) 經基， l) 羥基低級烷基， m) 羧基， η)低級烷氧羰基，〇)環烷基氧羰基， Ρ)低級醯基， q)低級烷磺醯基， 312XP/發明說明書(補件)/96-03/95143900 9 200800871 r) 氰基， s) 硝基， t) - A1 - NRUR12， u) - C(0)NR"R12， v) - S〇2NR"R12， w) - N(R13) C(0)R14， x) _ N(R13) S〇2R15， y) 被選自氰基、低級烷氧基、低級烷氧羰基及_ C(0)-® NRUR12所構成群中之基取代之低級烷基， z) 被選自氰基、低級烷氧基、低級烷氧羰基及_ c(0) -NRnR12所構成群中之基取代之低級烷氧基， aa) 被選自氰基、低級烷氧羰基及—以〇) — NRUR12所構成群中之基取代之低級烯基， ab) 未被取代之芳基，或環被自_素原子、低級烧基、鹵化低級烷基、低級烷氧基、氰基、低級醯基及低級烷氧 _羰基獨立選擇之1〜3個基取代之芳基， ac) 未被取代之芳烷基，或環被自鹵素原子、低級烷基、鹵化低級烷基、低級烷氧基、氰基、低級醯基及低級烷氧羰基獨立選擇之1〜3個基取代之芳烧基， ad) 未被取代之芳氧基，或環被自鹵素原子、低級烷基、鹵化低級烷基、低級烷氧基、氰基、低級醯基及低級烷氧幾基獨立選擇之1〜3個基取代之芳氧基， ae) 未被取代之芳烷氧基，或環被自_素原子、低級烷基、鹵化低級烷基、低級烷氧基、氰基、低級醯基及低級 312XP/發明說明書(補件)/96-03/95143900 10 200800871 烷氧羰基獨立選擇之i〜3個基取代之芳烷氧基， af) 未被取代之芳醯基，或環被自_素原子、低級烷基、鹵化低級烧基及低級烧氧基獨立選擇之1〜3個基取代之芳醯基， ag) 未被取代之芳磺醯基，或環被自鹵素原子、低級烷基、齒化低級烷基及低級烷氧基獨立選擇之丨〜3個基取代之芳磺醯基， 1 ah) 未被取代之雜芳基，或環被自S素原子、低級烷基、鹵化低級烷基及低級烷氧基獨立選擇之丨〜3個基取代之雜芳基，或“、^及1^。中之2個相鄰時，其等鍵結形成以-0(ch2)„0 -、- (CH2)n 一、_ c(0) - NH _ c(〇) 一、_ CH = CH- CH=CH -或-c(0) - (CH2)p -表示之基； R11及R12分別獨立為氫原子、低級烷基或芳烷基，或r11 及Rl2與其等所鍵結之氮原子共同形成環狀胺基； Φ Rl3為氫原子、低級烷基； R14為氫原子、低級烧基、未被取代之芳基，或環被自函素原子、低級烷基、_化低級烷基、低級烷氧基、氰基、低級醯基及低級烷氧羰基獨立選擇之〗〜3個基取基；土方 R為低級烷基、未被取代之芳基，或環被自齒素原子、低級烷基、幽化低級烷基、低級烷氧基、氰基、低級醯基及低級烷氧羰基獨立選擇之1〜3個基取代之芳美· 土 A1為鍵結或低級伸烧基； 312XP/發明說明書(補件)/96-03/95143900 11 200800871 m為1或2 ; η為3或4 ; ρ為2〜4之整數。] 又，本發明係關於含有一般式⑴表示之化合物或理學上容許之鹽作為有效成分之醫藥組成物。卞又’本發明係關於含有一般式⑴表示之化合物或其玲理學上容許之鹽作為有效成分之兒茶紛-0 -轉曱基酶Γρ 制劑。 ρ 又’本發明係關於將由-般式⑴表示之化合物或其藥理學上容許之鹽、與選自左多巴及芳香族L_胺基酸脫魏酶抑制劑中之至少1種組合而成之醫藥。又’本發明係關於含有一般式⑴表示之化合物或理學上容許之鹽作為有效成分之巴金森氏症、憂營症或高金壓症之治療或預防劑。又’本發明係關於用於萝造巴今蟲、衣匕巴至林氏症、憂鬱症或高血 £症之治療或預防劑之一般式（1)表學上容許之鹽的使用。化口物或其樂理又，本發㈣關於巴金森氏症、㈣症或高療或預防方法，該方法包含投予有效量之―铲川^二之化合物或其藥理學上容許之鹽的步驟。又示於上述一般式（I)表示之化合物中，之意義，除非另有說明。下逃用語具有以下於本說明書，所謂「低級」意指具有i〜6 除非另有說明。们杈原子數， 312XP/發明說明書(補件)/96·03/95143900 12 200800871 6「_子」為氟原子、氯原子、漠原子或蛾原子。於 R、R、R8、R9及中以氟原子或氯原子較適合。低級烷基」為直鏈狀或支鏈狀之碳原子數1〜6之烷基’如甲基、乙基、丙基、異丙基、丁基、異丁基、第二丁基、第三丁基、戊基、異戊基、新戊基、第三戊基、工一甲基丁基、2 -甲基丁基、u —二甲基丙基、己基、里己b) a halogen atom, c) a lower alkyl group, d) a halogenated lower alkyl group, e) a lower alkenyl group, a lower alkynyl group, g) a cycloalkyl group, h) a cycloalkyl lower alkyl group, • i) a lower calcination oxygen Base, j) halogenated lower alkoxy, k) thiol, l) hydroxy lower alkyl, m) carboxyl, η) lower alkoxycarbonyl, 〇) cycloalkyloxycarbonyl, Ρ) lower fluorenyl, q) lower Alkylsulfonyl, 312XP/Invention Manual (supplement)/96-03/95143900 9 200800871 r) Cyano, s) Nitro, t) - A1 - NRUR12, u) - C(0)NR"R12, v ) - S〇2NR"R12, w) - N(R13) C(0)R14, x) _ N(R13) S〇2R15, y) is selected from the group consisting of cyano, lower alkoxy, lower alkoxycarbonyl and _ C(0)-® NRUR12 is a group-substituted lower alkyl group, z) is selected from the group consisting of cyano, lower alkoxy, lower alkoxycarbonyl and _c(0)-NRnR12 a lower alkoxy group substituted by a group, aa) a lower alkenyl group substituted with a group selected from the group consisting of a cyano group, a lower alkoxycarbonyl group and a group of NRUR12, ab) an unsubstituted aryl group, or a ring From a sulphur atom, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group , cyano group, lower fluorenyl group and lower alkoxy-carbonyl group independently selected from 1 to 3 groups of substituted aryl groups, ac) unsubstituted aralkyl group, or ring derived from halogen atom, lower alkyl group, halogenated lower alkane a aryl group, an unsubstituted aryloxy group, or a ring derived from a halogen atom, a lower order, independently selected from the group consisting of a aryl group, an alkyl group, a lower alkoxy group, a cyano group, a lower alkyl group and a lower alkoxycarbonyl group. An alkyl group, a halogenated lower alkyl group, a lower alkoxy group, a cyano group, a lower fluorenyl group and a lower alkoxy group independently selected from 1 to 3 groups of substituted aryloxy groups, ae) an unsubstituted aralkyloxy group, Or a ring derived from a silane atom, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group, a cyano group, a lower fluorenyl group, and a lower 312XP/invention specification (supplement)/96-03/95143900 10 200800871 alkoxycarbonyl independent Selecting i~3 base-substituted aralkyloxy groups, af) unsubstituted aryl fluorenyl group, or ring independently selected from _ _ atom, lower alkyl group, halogenated lower alkyl group and lower alkyloxy group a three-substituted arylsulfonyl group, ag) an unsubstituted arylsulfonyl group, or a ring derived from a halogen atom, a lower alkyl group, The dentate lower alkyl group and the lower alkoxy group are independently selected 丨~3 groups substituted aryl sulfonyl group, 1 ah) unsubstituted heteroaryl group, or the ring is derived from S atom, lower alkyl group, halogenated lower stage The alkyl group and the lower alkoxy group are independently selected from 丨3 groups substituted heteroaryl groups, or ", ^ and 1^. When two of them are adjacent, their linkages are formed with -0(ch2) „0 -, - (CH2)n I, _ c(0) - NH _ c(〇) I, _ CH = CH- CH=CH - or -c(0) - (CH2)p - represents the base; R11 and R12 is independently a hydrogen atom, a lower alkyl group or an aralkyl group, or r11 and Rl2 together with a nitrogen atom bonded thereto form a cyclic amine group; Φ Rl3 is a hydrogen atom, a lower alkyl group; R14 is a hydrogen atom, a lower stage An alkyl group, an unsubstituted aryl group, or a ring independently selected from a self-determining atom, a lower alkyl group, a lower alkyl group, a lower alkoxy group, a cyano group, a lower alkyl group, and a lower alkoxycarbonyl group. The base R is a lower alkyl group, an unsubstituted aryl group, or the ring is derived from a dentin atom, a lower alkyl group, a quiet lower alkyl group, a lower alkoxy group, a cyano group, a lower sulfhydryl group, and a lower stage. Alkoxycarbonyl independent selection 1 to 3 groups of substituted meimei · soil A1 is a bonding or lower stretching base; 312XP / invention specification (supplement) / 96-03/95143900 11 200800871 m is 1 or 2; η is 3 or 4; ρ An integer of 2 to 4. Further, the present invention relates to a pharmaceutical composition containing a compound represented by the general formula (1) or a salt which is physiologically acceptable as an active ingredient. Further, the present invention relates to a catechin-0-transferase Γρ preparation containing a compound represented by the general formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient. ρ 。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。 Chengzhi Medicine. Further, the present invention relates to a therapeutic or preventive agent for Parkinson's disease, sorrow or high blood pressure which contains a compound represented by the general formula (1) or a salt which is physiologically acceptable as an active ingredient. Further, the present invention relates to the use of a salt of the general formula (1) which is a therapeutically or prophylactic agent for a therapeutic or prophylactic agent for the treatment of P. sinensis, sylvestre to Lin's disease, depression or hyperemia. The oral substance or its music theory, the fourth (4) regarding the Parkinson's disease, the (4) disease or the high-therapy or prevention method, the method comprises administering an effective amount of the compound of the shovel Chuan 2 or its pharmacologically acceptable salt. step. Further, it is shown in the above-mentioned compound represented by the general formula (I), unless otherwise stated. The following terms are used in this specification, and the term "lower" means having i~6 unless otherwise stated. Atomic number, 312XP/Invention manual (supplement)/96·03/95143900 12 200800871 6 "_子" is a fluorine atom, a chlorine atom, a desert atom or a moth atom. It is preferred to use a fluorine atom or a chlorine atom in R, R, R8, and R9. The lower alkyl group is a linear or branched alkyl group having 1 to 6 carbon atoms such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, second butyl group, and the like. Tributyl, pentyl, isopentyl, neopentyl, third amyl, monomethyl butyl, 2-methylbutyl, u-dimethylpropyl, hexyl, hexyl

AmmR'r、Ri2、RliRl4/Ci4 中，以低級烧基較適合，甲基更適合。「鹵化低級烷基」係指被〗〜3個相同或相異之鹵素原子取代之低級烷基，可舉例如氟甲基、二氟甲基、三氟甲基、2, 2, 2 -三氟乙基等，以二氟甲基或三氟曱基較適合。「低級烯基」係指至少具有丨個雙鍵之直鏈狀或支鏈狀之石厌原子數2〜6之不飽和烴，如乙烯基、丙烯基等。 &「低級炔基」係指至少具有丨個三鍵之直鏈狀或支鏈狀之碳數2〜6個之不飽和烴，如乙炔基、丙炔基等。「環烷基」係指3〜7員環之飽和環狀烴，如環丙基、環丁基、環戊基、環己基及環庚基等。「環烷基低級烷基」係指被環烷基取代之低級烷基。「低級烷氧基」係指直鏈狀或支鏈狀之碳原子數丨〜6 之烷氧基，如甲氧基、乙氧基、丙氧基、異丙氧基、丁氧基、異丁氧基、第二丁氧基、第三丁氧基、戊氧基、己氧基等。於R6、R7、R8、& Rl。中，以Ci μ低級烷氧基較適合，曱氧基更適合。鹵化低級烧氧基」係指被1〜3個相同或相異之鹵素 312XP/發明說明書(補件)/96-03/95143900 13 200800871 原子取代之低級烷氧基，如二氟甲氧基、三氟甲氧基、 2, 2, 2 -三氟乙氧基等。「羥基低級烷基」為被羥基取代之低級烷基，如羥甲基、1 -羥乙基、1 -羥基—L j —二甲基甲基、2 —羥乙基、 2-羥基-2-甲基丙基、3一羥丙基等。低級烷氧羰基」係指以（低級烷氧基）-C0 -表示之Among AmmR'r, Ri2, and RliRl4/Ci4, a lower alkyl group is suitable, and a methyl group is more suitable. The "halogenated lower alkyl group" means a lower alkyl group substituted with ~3 identical or different halogen atoms, and examples thereof include a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, and 2, 2, 2 - three. Fluoroethyl or the like is preferably a difluoromethyl or trifluoromethyl group. The "lower alkenyl group" means a linear or branched linear hydrocarbon having 2 to 6 ring atoms, such as a vinyl group or a propylene group, having at least one double bond. & "Lower alkynyl group" means a linear or branched hydrocarbon having 2 to 6 carbon atoms having at least one triple bond, such as an ethynyl group, a propynyl group or the like. "Cycloalkyl" means a saturated cyclic hydrocarbon of 3 to 7 membered rings such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. "Cycloalkyl lower alkyl" means a lower alkyl group substituted by a cycloalkyl group. "Lower alkoxy" means a linear or branched alkoxy group having a carbon number of 丨~6, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso Butoxy, second butoxy, tert-butoxy, pentyloxy, hexyloxy and the like. On R6, R7, R8, & Rl. Among them, a Ci μ lower alkoxy group is more suitable, and a decyloxy group is more suitable. Halogenated lower alkoxy group means a lower alkoxy group substituted by 1 to 3 identical or different halogens 312XP / invention specification (supplement) / 96-03/95143900 13 200800871 atom, such as difluoromethoxy, Trifluoromethoxy, 2, 2, 2-trifluoroethoxy, and the like. "Hydroxy lower alkyl" is a lower alkyl group substituted by a hydroxy group such as hydroxymethyl, 1-hydroxyethyl, 1-hydroxy-L j-dimethylmethyl, 2-hydroxyethyl, 2-hydroxy-2 -methylpropyl, 3-hydroxypropyl, and the like. Lower alkoxycarbonyl" means (lower alkoxy)-C0-

基’如甲氧羰基、乙氧羰基、丙氧羰基、氧無基、異丁氧羰基、第二丁氧羰基、第異丙氧羰基、丁三丁氧羰基、戊氧羰基、己氧羰基等。於r6、r7、r8、尺9及RlG中，以（Ch 低級烷氧基）-C0-較適合，甲氧羰基最適合。「環烷基氧羰基」係指以（環烷基）—〇 —⑶—表示之基，如環戊基氧羰基、環己基氧羰基等。低、、及L基」係指以Η — c(0)-或（低級烧基）—c(〇) -表示之基，如甲醯基、乙醯基、丙醯基、丁醯基、異丁醯a group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, oxy-free, isobutoxycarbonyl, second butoxycarbonyl, isopropoxycarbonyl, butadibutoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc. . Among r6, r7, r8, caliper 9 and RlG, (Ch lower alkoxy)-C0- is more suitable, and methoxycarbonyl is most suitable. The "cycloalkyloxycarbonyl group" means a group represented by (cycloalkyl)-oxime-(3)-, such as a cyclopentyloxycarbonyl group, a cyclohexyloxycarbonyl group or the like. "Low, and L-based" means a radical represented by Η-c(0)- or (lower alkyl)-c(〇)-, such as methyl, ethyl, propyl, butyl, butyl醯

基、二曱基乙醯基、戊醯基、異戊醯基等。於R6、、R8、 R及1^中，以乙醯基、丙醯基較適合，乙醯基更適合。「低級烷磺醯基」係指以（低級烷基）—s〇2 —表示之基，如曱伽基、乙伽基、丙磺酿基、了續基、戊石黃醯基、己磺醯基等，而以甲磺醯基較適合。「芳基」係指碳原子數6〜10之芳香族烴，如苯基、工一奈基 2秦基寻’而以苯基較適合。「芳烷基」係指被芳基取代之低級烷基，如苄基、乙氧苯基、1-苯乙基、3 -苯丙基、4 -苯丁基、萘甲基等。「芳氧基」係指以（芳基）_〇_表示之基，如苯氧基、工一 312XP/發明說明書(補件)/96-〇3/95143900 14 200800871 奈乳基、2 -蔡氧基笼「# 寺，而以苯氧基較適合。方说乳基」係指以（芳燒基）_ 〇基、乙氧苯氧基、丨__笼不之基，如苄氧氧基較適合。虱土 3苯丙氧基等，而以苄基芳酿基」係指以（芳基）_c〇一表 1-萘羰基、2〜茨羰^ μ 基，如苯曱醯 , /丁、扠基4，而以苯甲醯基較適人。方石頁酗基」係指以（芳基）_s〇2_表示、口子雜方基」係指含有卜5個碳原子〜硫原子所構成群中獨立選擇之卜4個^原子、^ 員環單環式芳㈣雜環。但此㈣不含，石=子。此種雜芳基可舉例如対基、吱喃基”塞吩基、土、吼峻基、0号唾基、異0等唾基”等二唾&、四唑基、嘆唾基、異售結、嗟二絲、三嗤基、响 °密咬基及料基等。此等雜環包含之所有位置異構^如 2 一吡啶基、3 -吡啶基、4 -吡啶基等）。「環狀胺基」係指環内可含有—丽—、—〇 —或—s —之 5〜7員環環狀胺，如丨—吡嘻唆基、痕啶基、哌畊基、咮啉基、噻咮啉基等。該環狀胺基可因應需要而被丨〜2個低級烷基所取代。低級伸烷基」係指具有1〜6個碳原子之2價之直鏈狀或支鏈狀的飽和烴鏈。該低級伸烷基之具體可舉例如一 CH2-、——CH2CH2-、-CH(CH3)-、-CH(CH3)CH2-、-CH2CH(CH3) -、- C(CH3)2 -、_ C(CH3)2CH2 -、- CH2 C(CH3)2 -、-CH2CH2CH2-、-C(CH3)2CH2CH2-、-C(CH3)2CH2CH(CH3)等之基。 312XP/發明說明書(補件)/96·〇3/95 M3900 15 200800871 於本發明之上述一般式⑴表示之化合物中，存在i個们個以上之不對稱碳原子時，本發明亦包含各種不對稱石反原子為R組態（configurati〇n)之化合物、5組態之化合物、及此等任意組合之化合物。又此等之消旋化合物、消旋混合物、單-鏡像異構物、非鏡像異構物混合物亦包含於本發明之範圍。又’於本發明之一般式⑴表示之化合物中，存在幾何學異構物時，本發明則包含任何其之幾何學異構物。再者，本發明之上述一般式⑴表示之化合物中，亦包含水合物或與乙醇等醫藥品所容許之溶劑的溶劑合物。本發明之上述一般式（丨）表示之化合物，可以鹽之形態存在。此種鹽可舉例如與鹽酸、溴化氫酸、碘化氫酸、硫酸、硝酸、磷酸等之無機酸的酸加成鹽，甲酸、醋酸、三氟醋酸、曱磺酸、苯磺酸、對甲苯磺酸、丙酸、檸檬酸、琥珀酸、酒石酸、富馬酸、丁酸、草酸、丙二酸、順丁烯 ⑩一酸、乳酸、蘋果酸、碳酸、穀胺酸、天冬胺酸等之有機酸的酸加成鹽，鈉鹽、鉀鹽、鈣鹽等之無機鹼之鹽，三乙胺、哌啶（piperidine)、咮啉、離胺酸等之有機鹼的加成鹽。於本發明之一般式（I)表示之化合物的一實施態樣中： R1與R2以氫原子較佳， R3以硝基較佳， R4與R5以氫原子較佳，或 R6、R7、R8、R9及R1Q以分別獨立為氫原子、函素原子、低級烷基、il化低級烷基、低級烷氧基、低級烷氧羰基、 312XP/發明說明書(補件)/96-03/95143900 16 200800871 低級醯基或氰基較佳。於本發明之較佳實施態樣中： R3為硝基。於本發明之更佳實施態樣中： R1與R2為氫原子； R3為确基。於本發明之再更佳實施態樣中： R1、R2、R4及R5為氫原子； • R3為硝基。於本發明之再更佳之實施態樣中： R1、R2、R4及R5為氫原子， R3為確基^ R6、R7、R8、R9及R1G分別獨立為以下之a)〜h): a) 氫原子， b) 鹵素原子， φ c)低級烧基， d )鹵化低級烧基’ e) 低級烧氧基， f) 低級烧氧幾基， g) 低級醯基，或 h) 氰基。於本發明之特佳實施態樣中： R1、R2、R4及R5為氫原子， R3為硝基， 312XP/發明說明書(補件)/96-03/95143900 17 200800871 R為鹵素原子、低級烷基、_化低級烷基、低級烷氧基、低級烷氧羰基、低級醯基或氰基， R7及R9為氫原子， R及R为別獨立’為氫原子、鹵素原子、低級烷基、鹵化低級烷基、低級烷氧基、低級烷氧羰基、低級醯基或氰基。於本發明之另一特佳之實施態樣中： R1、R2、R4及R5為氫原子， • R3為硝基， R6為氫原子、齒素原子、低級烷基、鹵化低級烷基、低級烧氧基、低級烷氧羰基、低級醯基或氰基， R及R分別獨立為_素原子、低級烷基、鹵化低級烷基、低級烷氧基、低級烷氧羰基、低級醯基或氰基， R8及為氫原子。於本發明之另一特佳之實施態樣中： • Rl、R2、R4及R5為氫原子， R3為硝基， R為低級烷氧羰基、低級醯基或氰基， R7及R9為氫原子， R及Rl°分別獨立為鹵素原子或低級烷基。本發明之較佳之實施態樣之具體例，為選自以下所構成群中之化合物或其藥理學上容許之鹽·· 5 一一氟一 6一三氟曱基苯石黃醯基）- 3-硝基苯-1，2 -二醇； 312XP/發明說明書(補件)/96-03/95143900 18 200800871 1，2 (4 -氟-2 - 二氟▼基苯磺醯基）一 3 確基苯二5 經基_5_硝基苯石黃酸基）苯甲猜； 1，2 1 /—乳-4—氟苯磺酿基）~3-石肖基苯一 5 —氯-3-(34 - 一絲甘 p. 甲基苯曱腈；，— 5_硝基苯磺醯基)_2- 酸基）- 5-氟-3 - 2 - (3, 4 -二羥基_ 5 —硝基苯碏甲基苯甲腈； ' 說基—1 —硝基苯磺醯基）-4 - 氯一 5 -（3, 4- 二甲基苯甲腈；醯基）-3,5-二氟苯 2 -（3,4-二羥基一 5—硝基苯碏甲腈； /' 苯- 1，2 一（2 -二氟甲基—4, β -二醇；氟苯磺醯基）-3 -硝基氟苯 &基_ 5 ~硝基苯磺醯基）苯 - [3-氣 - 5 -（3, 4 - 二羥基 5 -硝基苯磺醯基)苯基] 312ΧΡ/發明說明書(補件)/96-03/95143900 19 1 曱腈乳—2 — (3, 4 —二經基—1 —確基苯磺醢基）-3- (2氯2 —曱基苯磺醯基）—3 —硝基苯—ι 2 2 2，4 - .—氣 - 6 -（3，4 曱酸乙酯； 5 -（3, 5 -二氯-2 ~甲氧基笨磺醯基）一 3 一硝基苯 1，2 - 二醇； 200800871 乙酮；硝基苯磺醯基）—3, 5 一 5 -硝基苯磺醯基）一 2 一（3, 4 - 二羥基一 5 一甲酸乙酯； 1 一 [2 〜（3, 4 -二羥基 3 -甲基苯基]乙酮；Base, dimercaptoethyl, pentamidine, isopentenyl and the like. Among the R6, R8, R and 1^, the ethyl hydrazide group and the propyl fluorenyl group are more suitable, and the acetamino group is more suitable. "Lower alkanesulfonyl" means a group represented by (lower alkyl)-s〇2 - such as 曱基, 乙伽, propyl sulfonyl, contiguous, pentane fluorenyl, hexyl sulfonyl Etc., and the methanesulfonyl group is more suitable. The "aryl group" means an aromatic hydrocarbon having 6 to 10 carbon atoms, such as a phenyl group, a phenylene group, and a phenyl group. "Aralkyl" means a lower alkyl group substituted by an aryl group such as benzyl, ethoxyphenyl, 1-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, naphthylmethyl and the like. "Aryloxy" means a group represented by (aryl)_〇_, such as phenoxy, gong 312XP/invention specification (supplement)/96-〇3/95143900 14 200800871 奈乳, 2 - 蔡The oxygen cage "# temple, and the phenoxy group is more suitable. The term "milk base" refers to (aryl) thiol, ethoxyphenoxy, 丨__ cage base, such as benzyloxy oxygen The base is more suitable. Alumina 3 phenylpropoxy group, etc., and benzyl aryl aryl group means (aryl)_c 〇 a 1-naphthalenecarbonyl group, 2 to carbonyl group, such as benzoquinone, / butyl, fork Base 4, and the benzamidine group is more suitable. "方石页酗基" means a group consisting of (aryl)_s〇2_, and a heteronuclear group means an independent choice of four carbon atoms to a sulfur atom. Ring monocyclic aryl (tetra) heterocycle. But this (four) does not contain, stone = child. Examples of such a heteroaryl group include a sulfhydryl group, a fluorenyl group, a thiophene group, a soil, a sulfhydryl group, a thiol group, a sulfonyl group, and the like, and a di-salt & Different sales, bismuth, triterpene, ringing, and base. These heterocycles contain all of the isomeric groups such as 2-pyridyl, 3-pyridyl, 4-pyridyl and the like. "Cyclic amine group" means a 5- to 5-membered cyclic amine such as fluorenyl-pyridinyl, pyridyl, piperidinyl, porphyrin which may contain -Li-, --- or -s- in the ring. Base, thioporphyrin group and the like. The cyclic amine group can be substituted with 丨~2 lower alkyl groups as needed. The lower alkylene group means a divalent straight or branched saturated hydrocarbon chain having 1 to 6 carbon atoms. Specific examples of the lower alkylene group include CH2-, -CH2CH2-, -CH(CH3)-, -CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2-, _C (CH3) 2CH2 -, - CH2 C(CH3)2 -, -CH2CH2CH2-, -C(CH3)2CH2CH2-, -C(CH3)2CH2CH(CH3) or the like. 312XP/Invention Manual (Supplement)/96·〇3/95 M3900 15 200800871 In the compound represented by the above general formula (1) of the present invention, when there are more than one asymmetric carbon atoms, the present invention also includes various The symmetrical stone anti-atoms are compounds of the R configuration (configurati〇n), compounds of the 5 configuration, and compounds of any combination thereof. Further, such racemic compounds, racemic mixtures, mono-mirrranomers, and non-imagewise isomer mixtures are also included within the scope of the invention. Further, in the compound represented by the general formula (1) of the present invention, when a geometric isomer is present, the present invention encompasses any geometrical isomer thereof. Further, the compound represented by the above formula (1) of the present invention also contains a hydrate or a solvent mixture of a solvent which is acceptable to a pharmaceutical such as ethanol. The compound represented by the above general formula (丨) of the present invention may exist in the form of a salt. Such salts may, for example, be acid addition salts with inorganic acids such as hydrochloric acid, hydrogen bromide, hydrogen iodide, sulfuric acid, nitric acid, phosphoric acid, etc., formic acid, acetic acid, trifluoroacetic acid, sulfonic acid, benzenesulfonic acid, P-toluenesulfonic acid, propionic acid, citric acid, succinic acid, tartaric acid, fumaric acid, butyric acid, oxalic acid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid, glutamic acid, aspartame An acid addition salt of an organic acid such as an acid, a salt of an inorganic base such as a sodium salt, a potassium salt or a calcium salt, or an addition salt of an organic base such as triethylamine, piperidine, porphyrin or lysine; . In one embodiment of the compound of the general formula (I) of the present invention, R1 and R2 are preferably a hydrogen atom, R3 is preferably a nitro group, R4 and R5 are preferably a hydrogen atom, or R6, R7 or R8. , R9 and R1Q are each independently a hydrogen atom, a functional atom, a lower alkyl group, a lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group, 312XP/invention specification (supplement)/96-03/95143900 16 200800871 Lower sulfhydryl or cyano is preferred. In a preferred embodiment of the invention: R3 is a nitro group. In a further preferred embodiment of the invention: R1 and R2 are hydrogen atoms; R3 is a confirming group. In still another preferred embodiment of the invention: R1, R2, R4 and R5 are hydrogen atoms; and R3 is a nitro group. In still another preferred embodiment of the present invention: R1, R2, R4 and R5 are hydrogen atoms, and R3 is an exact group; R6, R7, R8, R9 and R1G are each independently a) to h): a) a hydrogen atom, b) a halogen atom, φ c) a lower alkyl group, d) a halogenated lower alkyl group 'e) a lower alkoxy group, f) a lower aerobic group, a g) a lower sulfhydryl group, or a h) a cyano group. In a particularly preferred embodiment of the invention: R1, R2, R4 and R5 are a hydrogen atom, R3 is a nitro group, 312XP/Invention Manual (Supplement)/96-03/95143900 17 200800871 R is a halogen atom, a lower alkane a group, a lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group, a lower alkyl group or a cyano group, R7 and R9 are a hydrogen atom, and R and R are independently a hydrogen atom, a halogen atom, a lower alkyl group, Halogenated lower alkyl, lower alkoxy, lower alkoxycarbonyl, lower fluorenyl or cyano. In another preferred embodiment of the present invention: R1, R2, R4 and R5 are a hydrogen atom, • R3 is a nitro group, R6 is a hydrogen atom, a dentate atom, a lower alkyl group, a halogenated lower alkyl group, a lower-grade burn. An oxy group, a lower alkoxycarbonyl group, a lower fluorenyl group or a cyano group, and R and R are each independently a _ s atom, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group, a lower fluorenyl group or a cyano group. , R8 and are hydrogen atoms. In another preferred embodiment of the present invention: • R1, R2, R4 and R5 are a hydrogen atom, R3 is a nitro group, R is a lower alkoxycarbonyl group, a lower fluorenyl group or a cyano group, and R7 and R9 are a hydrogen atom. R and Rl are each independently a halogen atom or a lower alkyl group. A specific example of a preferred embodiment of the present invention is a compound selected from the group consisting of a pharmacologically acceptable salt thereof, and a pharmacologically acceptable salt thereof, which are selected from the group consisting of the following: 5-monofluoro-6-trifluorodecylphenidinyl) 3- Nitrobenzene-1,2-diol; 312XP/invention specification (supplement)/96-03/95143900 18 200800871 1,2 (4-fluoro-2 -difluoro-based phenylsulfonyl)-3 Benzene 5 via _5_nitrophenylphosphonate) Benzene guess; 1,2 1 /-milk-4-fluorobenzenesulfonate)~3-Shishylbenzene-5-chloro-3-(34 - a glycerol p. methyl benzoquinonitrile;, - 5 nitrobenzene sulfonyl) 2 - oxy) 5-fluoro-3 - 2 - (3, 4 - dihydroxy -5 - nitrophenyl hydrazine Methyl benzonitrile; 'sayyl-1 nitrophenylsulfonyl)-4 -chloro-5-(3,4-dimethylbenzonitrile; fluorenyl)-3,5-difluorobenzene 2 -(3,4-dihydroxy-5-nitrophenylhydrazine); /' Benzene-1,2-(2-difluoromethyl-4,β-diol; fluorophenylsulfonyl)-3 Nitrofluorobenzene & yl-5-nitrophenylsulfonyl)benzene-[3-Gas-5-(3,4-dihydroxy-5-nitrophenylsulfonyl)phenyl] 312ΧΡ/Invention Manual ( Supplement)/96-03/95143900 19 1 曱Nitrile emulsion - 2 - (3, 4-di-diyl-1 - phenylsulfonyl)-3-(2chloro-2-indolylsulfonyl)-3-nitrobenzene-ι 2 2 2, 4-(-)-gas- 6-(3,4 decanoic acid ethyl ester; 5-(3,5-dichloro-2-methoxy oxasulfonyl)-3-nitrobenzene 1,2-diol; 200800871 Ethyl ketone; nitrophenylsulfonyl)-3,5-5-nitrophenylsulfonyl)-2-one (3,4-dihydroxy-5-carboxylic acid ethyl ester; 1 [2 ~ (3, 4-dihydroxy-3-methylphenyl]ethanone;

2 -（ 3，4 - 甲酸甲酯；經基〜5 ~硝基苯磺醯基）—3, 5 一鼠苯 5 一氟-2 -( 3,4 - methyl formate; base ~5 ~ nitrophenylsulfonyl) - 3, 5 a benzene benzene 5 - fluoro

3 一二氟甲基- 5 -基）—4 -甲基苯甲腈； 2 -（3, 4 -二羥基一甲基苯甲酸甲醋； (3, 4 _二羥基_ 5 -硝基苯磺醯 5-確基苯續醯基）_ 5一氟一 3_ 1 - [2- (3,4-二羥基氟苯基]乙g同； -硝基苯磺醯基）—3, 5 一二 1 [2 (3, 4 —二羥基—5 -硝基苯磺醯基）—3, 5 —二氟苯基]丙-1 -酮；及氯5 (3, 4 -二羥基一 5 -硝基苯磺醯基）一 4 一甲基苯曱腈。本卷明之以一般式Q)表示之化合物，可依製程圖1〜e 所示方法製造。 [化2]3-difluoromethyl-5-yl)-4-methylbenzonitrile; 2-(3,4-dihydroxymethylbenzoic acid methylacetate; (3,4-dihydroxy-5-nitrobenzene) Sulfonium 5-n-phenylbenzene sulfhydryl)_5-fluoro-3_ 1 - [2-(3,4-dihydroxyfluorophenyl]ethylg;-nitrophenylsulfonyl)-3, 5 11 [2 (3,4-dihydroxy-5-nitrophenylsulfonyl)-3,5-difluorophenyl]propan-1-one; and chloro 5 (3,4-dihydroxy-5- Nitrobenzenesulfonyl)-4-methylbenzonitrile The compound represented by the general formula Q) can be produced according to the process shown in Schemes 1 to e. [Chemical 2]

312XP/發明說明書(補件)/96-〇3/95143900 20 200800871312XP/Invention Manual (supplement)/96-〇3/95143900 20 200800871

(式中mmm。如同上述定義， L:。為漠原子、碘原子、氯原子、三氟甲磺醯氧基等脫離基， R為低級醯基、低級烷氧羰基或—c⑽rUr12。） <步驟1 - 1 > 在惰性溶劑中，於鹼類、鈀觸媒及磷配位子存在下，；化合物（X)與亞磺酸衍生物（XI)進行縮合，製得磺酸衍= 物（XII)。本反應所使用之惰性溶劑可舉例如甲苯、N N — 二甲基曱酿胺、1，2-二甲氧基乙烧等。鹼類可舉例如碳酸鉀、碳酸铷、碳酸铯等。觸媒可舉例如參（二苯亞甲美丙酮）二鈀（0)、碘化銅（1)、雙[三氟甲磺酸（1)銅]苯錯= 物等。配位子可舉例如9，9 _二曱基_ 4，5 _雙（二一[Ν，Ν，-二甲基乙二胺等。反應溫度通常為80。二 ii〇°c，反應時間因使用原料物質、溶劑、反應溫度等而異’但-般為1小時〜24小時。又，本反應亦可因應須要加入四丁基氣化銨、氯化鋰等添加劑進行反應。〈步驟1 - 2> " 在N性洛劑中，使用脫曱基化劑，將磺酸衍生物（XI j) 進仃脫甲基作用，製得化合物（Ia)。本反應所使用之惰性 /容劑可舉例如醋酸乙酯、吡啶、丨，4 —二碍烧等。脫甲基化劑可舉例如氯化紹—σ比咬等。反應溫度通常為㈣〜 312χρ/發明說明書(補件)/96-03/95143900 21 200800871 質、溶劑、反應溫度等而 12 0 C ’反應時間因使用原料物異，但一般為1小時〜24小時〈步驟1 - 3> 使用醯化劑，將化合物（ L ^ 1 a)進仃醯化作用，製得化合物 r H f &化為本業者所習知，例如可依T. W. Greene & in Organic tS，「 ProtectiVe Groups Synthesis」第3版記载之方法進行。 [化3](wherein mmm. As defined above, L: is a leaving group such as a desert atom, an iodine atom, a chlorine atom, or a trifluoromethanesulfonyloxy group, and R is a lower fluorenyl group, a lower alkoxycarbonyl group or -c(10)rUr12.) < Step 1 - 1 > In an inert solvent, in the presence of a base, a palladium catalyst and a phosphorus ligand, the compound (X) is condensed with a sulfinic acid derivative (XI) to obtain a sulfonic acid derivative. (XII). The inert solvent used in the reaction may, for example, be toluene, N N -dimethylamine, or 1,2-dimethoxyethane. The base may, for example, be potassium carbonate, cesium carbonate or cesium carbonate. The catalyst may, for example, be ginseng (diphenylmethyleneacetone) dipalladium (0), copper iodide (1) or bis[trifluoromethanesulfonate (1) copper] benzene. The ligand may, for example, be 9,9 _dimercapto-4,5 bis (di-[[Ν, Ν,-dimethylethylenediamine, etc. The reaction temperature is usually 80. ii 〇 °c, reaction time) It may vary from 1 hour to 24 hours depending on the starting material, solvent, reaction temperature, etc. Further, the reaction may be carried out by adding an additive such as tetrabutylammonium hydride or lithium chloride. - 2>" In the N-type agent, the sulfonic acid derivative (XI j) is demethylated by deamination using a demethylating agent to prepare the compound (Ia). The inertness/capacity used in the reaction. The agent may, for example, be ethyl acetate, pyridine, hydrazine, 4-disulfide, etc. The demethylating agent may, for example, be a chlorinated-sigma ratio bite or the like. The reaction temperature is usually (4) to 312 χ ρ / invention specification (supplement) /96-03/95143900 21 200800871 Quality, solvent, reaction temperature, etc. and 12 0 C 'reaction time varies depending on the starting materials, but generally 1 hour to 24 hours <Step 1 - 3> Using a deuterating agent, the compound ( L ^ 1 a) Inhibition, the preparation of the compound r H f & is known to the industry, for example, according to TW Greene & in Organic tS, the method described in the third edition of "CertiVe Groups Synthesis" is carried out. [Chem. 3]

製程2 R4Process 2 R4

(式中’ R4、R5、R6、R7、V、r9、n Ll如同上述定義〈步驟2 - 1 > 下，將在惰性溶劑中，於鹼類、鈀觸媒及磷配位子存在 312XP/發明說明書(補件)/96-03/95143900 22 200800871 亞石黃酸衍生物（XIII)與化合物（XIV)進行縮合，製得石黃酸衍生物（XV)。本反應所使用之惰性溶劑可舉例如曱苯、 N，N-二甲基甲酸胺、U-二甲氧基乙烧等。驗類可舉例如碳酸鉀、碳酸铷、碳酸绝等。觸媒可舉例如參（二苯亞曱基丙酮）二鈀（0)、碘化鋼（1)、雙[三氟曱磺酸（1)銅] 苯錯合物等。配位子可舉例如9,9 —二曱基—4,5_雙（二苯膦基)…N，N，—二甲基乙二胺等。：應溫度通又常為 ⑩80C〜11(TC，反應時間因使用原料物質、溶劑、反應溫度等而異，但-般為1小時〜24小時。又，本反應亦可因應須要加入四丁基氯化銨、氯化鋰等添加劑進行反應。〈步驟2 - 2> 與步驟2 - 1相同，可由化合物（χνι)及亞磺酸衍生物 (XVII)製得磺酸衍生物（XV)。〈步驟2 - 3 > 在惰性溶劑中，使用脫甲基化劑，將磺酸衍生物（XV) 馨進行脫曱基作用，製得酚衍生物（χνιη)。本反應所使用之惰性溶劑可舉例如Ν，Ν -二甲基甲醯胺、1，2 -二甲氧基乙烧、一甲基亞颯等。脫曱基化劑可舉例如氰化鈉、氰化卸等。反應溫度通常為80°C〜150°C，反應時間因使用原料物質、溶劑、反應溫度等而異，但一般為1小時〜24 小時0 〈步驟2 - 4> 在惰性溶劑中使用硝化劑，將酚衍生物（XVIII)進行硝化作用’製得硝基酚衍生物（χΐχ)。本反應所使用之惰性 3_發明說明書(補件)/96·〇3/951439〇〇 23 200800871 溶劑可舉例如二氯曱烷、1，2 -二氯乙烷、醋酸乙酯、醋酸 '四氫σ夫喃等。硝化劑可舉例如硝酸、發煙破酸、四氟硼酸硝鏘（Nitroniumtetrafluroborate)等。反應溫度通常為一20 °C〜8 0°C，反應時間因使用原料物質、溶劑、反應溫度等而異，但一般為5分鐘〜12小時。〈步驟2 - 5> 與步驟1 - 2相同，將硝基酚衍生物（XIX)進行脫曱基作用，製得化合物（Ic)。(wherein R4, R5, R6, R7, V, r9, n Ll are as defined above <Step 2 - 1 >, in an inert solvent, in the presence of a base, a palladium catalyst and a phosphorus ligand in the 312XP /Invention Manual (Supplement)/96-03/95143900 22 200800871 The arsenic acid derivative (XIII) is condensed with the compound (XIV) to obtain a crude acid derivative (XV). The inert solvent used in the reaction. For example, benzene, N,N-dimethylformate, U-dimethoxyethane, etc. may be mentioned, for example, potassium carbonate, cesium carbonate, carbonic acid, etc. The catalyst may, for example, be benzene (diphenyl). Mercaptoacetone) dipalladium (0), iron iodide (1), bis[trifluorosulfonium (1) copper] benzene complex, etc. The ligand may, for example, be 9,9-didecyl- 4,5_bis(diphenylphosphino)...N,N,-dimethylethylenediamine, etc.: The temperature should be often 1080C~11 (TC, reaction time due to the use of raw materials, solvents, reaction temperatures, etc. However, it is generally 1 hour to 24 hours. Further, the reaction may be carried out by adding an additive such as tetrabutylammonium chloride or lithium chloride. <Step 2 - 2> is the same as Step 2 - 1. Can be The sulfonic acid derivative (XV) is obtained by the compound (χνι) and the sulfinic acid derivative (XVII). <Step 2 - 3 > The sulfonic acid derivative (XV) is used in an inert solvent using a demethylating agent. The bismuth is desulfonated to obtain a phenol derivative (χνιη). The inert solvent used in the reaction may, for example, be hydrazine, hydrazine-dimethylformamide, 1,2-dimethoxyacetone, or one For example, the deacetylation agent may, for example, be sodium cyanide or cyanide. The reaction temperature is usually from 80 ° C to 150 ° C, and the reaction time varies depending on the starting materials, solvent, reaction temperature, etc., but Generally, it is 1 hour to 24 hours 0 <Step 2 - 4> The nitrophenol derivative (χΐχ) is obtained by subjecting the phenol derivative (XVIII) to nitrification using an nitrating agent in an inert solvent. The inertness used in the reaction. 3_Inventive specification (supplement)/96·〇3/951439〇〇23 200800871 The solvent may, for example, be dichlorosilane, 1,2-dichloroethane, ethyl acetate or acetic acid 'tetrahydro-sulphur. The nitrating agent may, for example, be nitric acid, fuming acid, Nitronium tetrafluroborate, etc. The reaction temperature is usually a 20 C to 80 ° C, the reaction time varies depending on the starting material, solvent, reaction temperature, etc., but is usually from 5 minutes to 12 hours. <Step 2 - 5> The same as Step 1 - 2, the nitrophenol derivative (XIX) Deprotection is carried out to obtain a compound (Ic).

[化4][Chemical 4]

脫苄基化: 步驟34Debenzylation: Step 34

(式中，R4、R5、R6、R7、R8、R9、R1。及L1如同上述定義 Bn為苄基。）〈步驟3 - 1及步驟3 - 2> 312χρ/發明說明書(補件)/96-03/95143900 24 200800871 在惰性溶劑中，於鹼類、金屬觸媒及配位子存在下，將芳硫醇（XX)與化合物（XIV)進行縮合，製得硫醚衍生物 (XXI)。本反應所使用之惰性溶劑可舉例如丨，4 _二哼烷、(wherein R4, R5, R6, R7, R8, R9, R1, and L1 are as defined above, and Bn is a benzyl group.) <Step 3 - 1 and Step 3 - 2> 312 χ ρ / Invention Specification (Supplement) / 96 -03/95143900 24 200800871 The aryl thiol (XX) is condensed with the compound (XIV) in the presence of a base, a metal catalyst and a ligand in an inert solvent to obtain a thioether derivative (XXI). The inert solvent used in the reaction may, for example, be hydrazine, 4 dioxane,

◎-二曱基曱醯胺、1，2_二甲氧基乙烷、甲苯等。驗類 :舉例如第二丁醇鈉、第三丁醇鉀、碳酸鉀、二異丙基乙胺、三正丁胺等。金屬觸媒可舉例如醋酸鈀、參（二苯亞甲基丙酮）二鈀（0)、碘化銅（1)等。配位子可舉例如（氧基 2，1_伸苯基）雙（二笨膦）、1，1， _雙（二苯膦基）二茂鐵"雙（二異丙膦基）二茂鐵、反式_ 1，2_環己一女等反應/JQn度通常為8 0 °C〜11 〇 °c，反應時間因使用原料物質、溶劑、反應溫度等而異，但一般為i小時〜 24小時。以相同方法，可由化合物UXII)與芳硫醇（ΧΧΠΙ) B成硫醚衍生物（XXI)。又，化合物（XIV)中之R6、R8及γ之至少1個為羧基、 =、及ι基或鼠基時，將化合物與化合物(X⑺於惰性 :劑中、驗類存在下進行縮合，製得硫㈣生物（XXI)。一反應所使用之惰性溶劑可舉例如U一二巧烧、Μ』— ^ 土甲g皿胺、1 2 —二甲氧基乙烷、四可舉例如第三丁_、第三了醇鉀、碳酸料。〈步驟3 - 3> 惰性溶劑中使用氧化劑，將硫_衍生物⑽）進行氧乍用’製得石黃酸衍生物（W 了 V )。g _ 劑可舉例如物（mv)本反應所使用之惰性溶一虱甲烷、丙酮、水等。氧化劑可舉例如過氧 312轉明說明書(補件)/96彻51439〇〇 200800871 反應溫溶劑、間苯甲酿氯、Gx_(註冊商標）、過氧度通常為（TC〜8(TC，反應時間因使 j尺4 沒雍、、田泠笙品里, JU使用原料物質反應/皿度寺而異’但一般為5分鐘〜 • 匕 4 夕 J、〇〈步驟3 - 4> 在惰性溶劑(如乙醇、N，N、甲基甲酿胺、四◎-Dimercaptoamine, 1,2-dimethoxyethane, toluene, and the like. Test: For example, sodium second butoxide, potassium t-butoxide, potassium carbonate, diisopropylethylamine, tri-n-butylamine, and the like. The metal catalyst may, for example, be palladium acetate, stilbene (diphenylmethyleneacetone) dipalladium (0) or copper iodide (1). The ligand may, for example, be (oxy 2,1_phenylene) bis(diphenylphosphine), 1,1, bis(diphenylphosphino)ferrocene "bis(diisopropylphosphino)di Molybdenum, trans _ 1, 2 _ cyclohexyl female and other reactions / JQn degree is usually 80 ° C ~ 11 〇 ° c, the reaction time varies depending on the use of raw materials, solvents, reaction temperatures, etc., but generally i Hours ~ 24 hours. In the same manner, the thiol derivative (XXI) can be formed from the compound UXII) and the aryl thiol (oxime) B. Further, when at least one of R6, R8 and γ in the compound (XIV) is a carboxyl group, a =, and an i group or a murine group, the compound (X(7) is condensed in the presence of an inert: agent; Sulfur (IV) organism (XXI). The inert solvent used in the reaction may, for example, be a U-batch, a Μ--, a dimethylamine, a dimethoxyethane, or a third, for example, a third. D-, third potassium alkoxide, carbonic acid. <Step 3 - 3> An oxidizing agent is used in an inert solvent, and the sulfur-derivative (10) is subjected to oxonium to obtain a rhein derivative (W is V). The g _ agent may, for example, be an inert solution of methane, acetone, water or the like used in the reaction. The oxidizing agent may, for example, be a peroxygen 312 transcript (supplement)/96 gram 51439 〇〇 200800871 reaction temperature solvent, m-benzoic chlorinated chlorine, Gx_ (registered trademark), and the degree of peroxygen is usually (TC~8 (TC, reaction) The time is such that the j-foot 4 is not 雍, and the 泠笙泠笙 ,, JU uses the raw material reaction / the dish is different, but it is usually 5 minutes ~ • 匕 4 夕 J, 〇 <Step 3 - 4> In an inert solvent (such as Ethanol, N, N, methyl amylamine, four

:環境下及金相媒（如μ、氧錢等）存在二生物(XXIV)之节基脫去，可㈣衍生物 ⑽⑴。反應溫度通常為室溫〜8(rc，反應時間因使用原枓物質、溶劑、反應溫度等而異’但一般為3 〜 12小時。又，亦可在惰性溶劑（如二氯甲烧、甲苯等）中使用酸或路以士酸（Lewisacid)(如溴化氫、氯化鋁、四氯化鈦等）處理磺酸衍生物（XXIV)以進行脫节基化。反應溫度通常為 0 C 8 〇 C，反應時間因使用原料物質、溶劑、反應溫度等而異，但一般為15分鐘〜24小時。 _〈步驟3 - 5> 與步驟2 - 4相同，將酚衍生物（χνιπ)進行硝化作用，製得硝基酚衍生物（XIX)。〈步驟3 - 6〉與步驟1 - 2相同，將硝基酚衍生物（XIX)進行脫甲基作用’製得化合物（I c)。 [化5] 312ΧΡ/發明說明書(補件)/96-03/95143900 26 200800871: In the environment and in the presence of metallographic media (such as μ, oxygen, etc.), the second organism (XXIV) is removed, and the (four) derivative (10) (1). The reaction temperature is usually room temperature to 8 (rc, the reaction time varies depending on the use of the original hydrazine, the solvent, the reaction temperature, etc.) but is usually 3 to 12 hours. Alternatively, it may be in an inert solvent (e.g., methylene chloride, toluene). The sulfonic acid derivative (XXIV) is treated with an acid or a Lewis acid (such as hydrogen bromide, aluminum chloride, titanium tetrachloride, etc.) for de-synmentation. The reaction temperature is usually 0 C. 8 〇C, the reaction time varies depending on the starting material, solvent, reaction temperature, etc., but is generally 15 minutes to 24 hours. _ <Step 3 - 5> The same as Step 2 - 4, the phenol derivative (χνιπ) is carried out. Nitrification to obtain a nitrophenol derivative (XIX) <Step 3 - 6> The same as Step 1-2, the nitrophenol derivative (XIX) is subjected to demethylation to obtain a compound (I c). [Chemical 5] 312 ΧΡ / invention manual (supplement) / 96-03/95143900 26 200800871

(式中，R4、R5、R6、R7、R8、R9、R1Q及Bn如同上述定義。）〈步驟4 - 1 > 在惰性溶劑中，於驗類及16觸媒存在下，將硼酸衍生物 (XXV)與磺醯氯衍生物（XXVI)進行縮合，製得磺酸衍生物 (XXV11)。本反應所使用之惰性溶劑可舉例如丙酮與水之混合溶劑等。驗類可舉例如碳酸钟等。觸媒可舉例如氯化 _鈀等。反應溫度通常為0°C〜20°c，反應時間因使用原料物質、溶劑、反應溫度等而異，但一般為15分鐘〜2小時。〈步驟4 - 2> 與步驟3 - 4相同，將磺酸衍生物（XXVII)進行脫节基作用，製得化合物（Ic)。 [化6] 製程5·(wherein R4, R5, R6, R7, R8, R9, R1Q and Bn are as defined above.) <Step 4 - 1 > Boric acid derivative in an inert solvent in the presence of a catalyst and 16 catalyst (XXV) is condensed with a sulfonium chloride derivative (XXVI) to obtain a sulfonic acid derivative (XXV11). The inert solvent to be used in the reaction may, for example, be a mixed solvent of acetone and water. The test may be, for example, a carbonic acid clock or the like. The catalyst may, for example, be chlorinated palladium or the like. The reaction temperature is usually from 0 ° C to 20 ° C, and the reaction time varies depending on the starting materials, solvent, reaction temperature, etc., but it is usually from 15 minutes to 2 hours. <Step 4 - 2> The same as Step 3 - 4, the sulfonic acid derivative (XXVII) is subjected to a debenzylation to obtain a compound (Ic). [Chemical 6] Process 5·

200800871200800871

(式中 ’ R4、r5、r6、 R8、R9及R1(J如同上述定義。〈步驟5 - i > 鱼步驟 1 一〇丄(wherein ' R4, r5, r6, R8, R9 and R1 (J are as defined above. <Step 5 - i > Fish Step 1 1 〇丄

厂 2相同，將化合物（XV)進行脫甲基作月得兒茶酚衍生物（XXVIII)。〈步驟5 - 2> 、j惰性溶劑中，使用溴化劑，將兒茶酚衍生物（XXVI Π) 進行廣化作用，製得漠化兒茶紛衍生物（XXIX)。本反應所 =用之惰性溶劑可舉例如二氯曱烷、醋酸乙酯、L 4 -二咢烧專、/臭化劑可舉例如溴、三溴化ϋ比略咬顚I等。反應溫 _度通常為-啊〜峨，反應時間因使用原料物質、溶劑、反應溫度等而異，但一般為3〇分鐘〜丨2小〈步驟5 - 3> 在N性溶劑中使用苄基化劑，將兒茶紛衍生物（XXIX) 進行苄基化作用，製得化合物（χχχ)。本反應所使用之惰性溶劑可舉例如ν，ν -二甲基甲醯胺、丙酮等。苄基化劑可舉例如苄基溴化物、苄基氯化物等。反應溫度通常為室，〜110°C，反應時間因使用原料物質、溶劑、反應溫度等而異，但一般為15分鐘〜24小時。 312XP/發明說明書(補件)/96-03/95143900 28 200800871 〈步驟5 - 4> 在N性☆㈣巾’於氰化劑、纪觸媒及配位子存在化合物（XXX)進行縮合，製得乙腈衍生物（則）。本反: 所使用之惰性溶劑可舉例如i 甲酸胺：1，2—二甲氧基乙统、卜甲基-2-四氣终; 酮等1化劑可舉例如氰化銅⑴、氰化鉀等。觸媒可舉例如苓（一苯亞曱基丙酮）二鈀（〇)等。配位子可舉例如 1，1’。-雙（二苯膦基）二茂鐵等。反應溫度通常為8〇它〜 110 C ’反應時間因使用原料物質、溶劑、反應溫度等而 /、仁瓜為1小時〜24小時。又，本反應亦可因應須要加入氰化四乙銨等添加劑進行反應。、〈步驟5 - 5> 與步驟3_ 4相同，將乙腈衍生物（XXXI)進行脫苄基作用，製得化合物（Id)。 [化7] 製程6 R4 R6 R7In the same manner as in the factory 2, the compound (XV) was demethylated to give a catechol derivative (XXVIII). In the step 5 - 2 >, j, a brominating agent is used to broaden the catechol derivative (XXVI Π) to obtain a desertified catechin derivative (XXIX). The inert solvent to be used in the present reaction may, for example, be dichlorosilane, ethyl acetate or L 4 -bifluorene, and the odorant may be, for example, bromine or ruthenium tribromide. The reaction temperature _ degree is usually - ah ~ 峨, the reaction time varies depending on the starting material, solvent, reaction temperature, etc., but generally 3 〇 minutes ~ 丨 2 small <Step 5 - 3> Benzyl group is used in the N solvent The chelating agent (XXIX) is subjected to benzylation to prepare a compound (χχχ). The inert solvent used in the reaction may, for example, be ν, ν-dimethylformamide, acetone or the like. The benzylating agent may, for example, be a benzyl bromide or a benzyl chloride. The reaction temperature is usually room temperature, ~110 ° C, and the reaction time varies depending on the starting materials, solvent, reaction temperature, etc., but it is usually from 15 minutes to 24 hours. 312XP/Inventive Manual (Supplement)/96-03/95143900 28 200800871 <Step 5 - 4> Condensation in the presence of compound (XXX) in N-type ☆ (four) towel's cyanide agent, catalyst and ligand An acetonitrile derivative (then) is obtained. The reverse inert solvent to be used may, for example, be an amine formic acid: 1,2-dimethoxyethane, or a methyl-2-tetraxene; and a ketone or the like may, for example, be copper cyanide (1) or potassium cyanide. Wait. The catalyst may, for example, be fluorene (monophenylarhenylidene) dipalladium (ruthenium) or the like. The ligand may be, for example, 1,1'. - bis(diphenylphosphino)ferrocene or the like. The reaction temperature is usually 8 Torr. It is ~ 110 C 'reaction time due to the use of the starting materials, solvent, reaction temperature, etc. /, and the melon is 1 hour to 24 hours. Further, the reaction may also be carried out by adding an additive such as tetraethylammonium cyanide. <Step 5 - 5> The acetonitrile derivative (XXXI) was subjected to debenzylation in the same manner as in Step 3 to 4 to obtain a compound (Id). [Chem. 7] Process 6 R4 R6 R7

Βγ2 H3CO R5 R10 (XVIII) R4 R6 R7Βγ2 H3CO R5 R10 (XVIII) R4 R6 R7

H3CO Rd r1〇 r9 (XXXII) 步驟64H3CO Rd r1〇 r9 (XXXII) Step 64

(式中，R4、R5、R6、R7、R8、R9及R10如同上述定義。）〈步驟6 - 1> 與步驟5 - 2相同，將酚衍生物（XV iii)進行溴化作用， 312XP/發明說明書(補件)/96-03/95143900 29 200800871 製得溴化酚衍生物（χχχΗ)。〈步驟6 - 2> 與步驟5 — 4相同，將溴化酚衍生物（XXXII)進行氰化作用’製得乙腈衍生物（XXXIII)。〈步驟6 - 3 > ，與步驟1 - 2相同，將乙腈衍生物（χχχπι)進行脫甲基作用’製得化合物（I d)。上述製程圖係例示幾種製造本發明之化合物或其製造中間物之方法，從業當可輕易明白此種製程圖可做各種改變。本1明之一般式（I)表示之化合物及為了製造該化合物斤使用之中間物，可視需要藉由本領域之從業者所習知之 t離、精製方法，例如溶劑萃取、結晶化、再結晶、色層刀析法、分取咼速液體色層分析法等之操作，以實施分離、精製。、如此製成之本發明之化合物，由於具有優異之⑶MT抑 2作用，故可用於作為巴金森氏症之治療或預防藥，並適 I夕巴（L —D0PA)組合使用。又，本發明之化合物亦可與芳香族L -胺基酸去羧基酶抑制劑組合使用。能夠與本發明之化合物組合使用之芳香族L—胺基酸去幾基酶抑制劑，可舉例如卡比多巴（Carbidopa)、Benserazide(苯思樂塞）等。又因應須要亦可再組合使用C0MT抑制劑及左多巴以外之巴金森氏症治療劑。此種巴金森氏症治療劑可舉例如 312ΧΡ/^___/% 猶 5143_ 30 200800871(wherein R4, R5, R6, R7, R8, R9 and R10 are as defined above.) <Step 6 - 1> In the same manner as in Step 5-2, the phenol derivative (XV iii) is subjected to bromination, 312XP/ Description of the Invention (Repair) / 96-03/95143900 29 200800871 A brominated phenol derivative (χχχΗ) is obtained. <Step 6 - 2> The acetonitrile derivative (XXXIII) was obtained by subjecting the brominated phenol derivative (XXXII) to cyanidation in the same manner as in Step 5-4. <Step 6 - 3 > In the same manner as in Step 1-2, the acetonitrile derivative (χχχπι) was subjected to demethylation to give a compound (I d). The above process diagrams illustrate several methods of making the compounds of the present invention or intermediates therefor, and it will be readily apparent that such process maps can be modified in various ways. The compound represented by the general formula (I) of the present invention and the intermediate compound used for the production of the compound can be optionally subjected to a method of separation and purification, such as solvent extraction, crystallization, recrystallization, coloration, which is known to those skilled in the art. The layer knife analysis method, the idling liquid chromatography method, and the like are performed to perform separation and purification. The compound of the present invention thus produced can be used as a therapeutic or prophylactic agent for Parkinson's disease because of its excellent (3) MT inhibitory action, and is preferably used in combination with L-DPA. Further, the compound of the present invention can also be used in combination with an aromatic L-amino acid decarboxylase inhibitor. The aromatic L-amino acid de-molease inhibitor which can be used in combination with the compound of the present invention may, for example, be Carbidopa or Benserazide. In addition, it is also necessary to use a combination of a C0MT inhibitor and a treatment for Parkinson's disease other than Zuodopa. Such a therapeutic agent for Parkinson's disease can be, for example, 312 ΧΡ/^___/% 犹 5143_ 30 200800871

Droxidopa(多樂多巴）、Melevodopa(美佛多巴）、L -threo - D0PS(L-絲胺酸D0PS);多巴胺D2受體促效劑（如 Cabergoli η(加倍格林）、布克丁甲磺醯鹽（Bromocriptine mesylate) 、 Terguride(特古利）、Talipexole dihydrochloride(鹽酸大力比索）、鹽酸力必平 (Ropinirole HC1)、Perg〇iide mesylate(甲磺酸巴格利）、Pramipexole(普拉米索）、R〇tig〇tine(樂得定）等）；鲁抗膽驗劑（如Profenamine(普樂佛胺）、Trihexyphenidyl hydrochlorideC 鹽酸三己芬得）、Mazaticol hydrochloride(鹽酸馬查可）、Piperidene(吡定）、鹽酸Droxidopa, Doleopa, L-threo-D0PS (L-serine D0PS); Dopamine D2 receptor agonist (eg Cabergoli η (Big Green), Bukectin Bromocriptine mesylate, Terguride, Talipexole dihydrochloride, Ropinirole HC1, Perg〇iide mesylate, Pramipexole Cable, R〇tig〇tine, etc.; Lu anti-biliary test (such as Profenamine, Trihexyphenidyl hydrochloride C trihexifene hydrochloride), Mazaticol hydrochloride, Piperidide ( Pyridine), hydrochloric acid

Piroheptine hydrochloride(鹽酸比樂定）、Metixine hydrochloride(鹽酸美第幸）等）；腺苷Aza拮抗劑（如 Istradefylline(依斯特拉第佛靈）等）；丽拮抗劑（如 Budipine(普第平）等）；單胺氧化酶b抑制劑（如 Selegiline hydrochloride(鹽酸西樂吉林）、RasagiUne 攀mesylate(甲磺酸拉沙吉林）、Safinamidemesylate(曱磺酸沙芬醯胺等）；Zonisamide(左納醯胺）；鹽酸金剛烷胺 (Amantadine HC1)等。又’本發明之化合物可用於作為憂鬱症之治療或預防藥。又，本發明之化合物由於具有促進尿中鈉之***作用，故可用於作為高血壓症之治療藥。含有本發明之-般式⑴表示之化合物或其藥理學上容許之鹽作為有效成分之醫藥組成物，可因應用法而使用各種劑型。此種劑型如散劑、顆粒劑、細粒劑、乾糖漿劑、 312XP/發明說明書(補件)/96-〇3/95143900 31 200800871 貼附劑鍵劑、膠囊劑、注射劑、液劑、軟膏劑、栓塞劑、等，並以、誕口或非經口方式投予。此等％藥組成物，因應其劑型藉由調劑學上習知之方法，與適當之賦形劑、分解劑、黏合劑、潤滑劑、稀釋劑、緩衝劑、等滲透壓劑、防腐劑、濕潤劑、乳化劑、分散劑、 L疋剑助’谷劑專醫樂品添加物適當混合或稀釋·溶解而進行調劑。曰般式（I)表示之化合物或其藥理學上容許之鹽之投予置丄係，患者之年齡、性別、體重、疾病及治療程度等而，田决疋，經口投予時成人每日以約10mg〜約2000mg之範圍投予，非經口投予時成人每日以約5mg〜約1 000mg 之辄圍投予，並可依1日1次或分成數次適當投予。臨本發明之-般式⑴表示之化合物或其藥理學上容許之 ;:與廷自左多巴與芳香族L-胺基酸脫羧酶抑制劑中之 =1種組合而成之醫藥，可將同時含有此等有效成分^ =進、或以此等有效成分各別製劑化又：二別製劑化時’此等製劑可分別或同時投=仃如各別製劑化時，則使用μ莖混合後同時投可使用稀釋劑等進行之：本：：之一般式⑴表示之化合物或其藥理學上容’ 之鹽、與選自左多巴蛊予工谷开之至u # 胺基酸脫叛酶抑制劑中齡、醫藥’其藥劑配合比可依患者之年虹症狀、投予時間、劑型、投予方丰^ 〇劑組合等而適當選擇。扠予方法、樂 312XP/發明說明書(補件)/96-03/95143900 32 200800871 (發明效果）Piroheptine hydrochloride (Metidine hydrochloride, Metixine hydrochloride, etc.); adenosine Aza antagonists (such as Istradefylline (Istraflayl), etc.); Li antagonists (such as Budipine (Pudiping) )); monoamine oxidase b inhibitors (such as Selegiline hydrochloride), RasagiUne climbing mesylate (rasagicin mesylate), Safinamidemesylate (salbenyl sulfonate, etc.); Zonisamide (left amide); Amantadine hydrochloride (Amantadine HC1), etc. Further, the compound of the present invention can be used as a therapeutic or prophylactic agent for depression. Further, the compound of the present invention can be used as a hypertension because it has a function of promoting excretion of sodium in urine. The pharmaceutical composition containing the compound represented by the general formula (1) of the present invention or a pharmacologically acceptable salt thereof as an active ingredient can be used in various dosage forms depending on the application method. Such a dosage form such as a powder, a granule, or a fine granule Agent, dry syrup, 312XP/invention manual (supplement)/96-〇3/95143900 31 200800871 patching agent, capsule, injection, liquid, soft Ointment, embolic agent, etc., administered in a blistering or non-oral manner. These % drug compositions are formulated according to the methods known in the art, and appropriate excipients, decomposers, and adhesives. Agent, lubricant, diluent, buffer, etc. osmotic pressure agent, preservative, wetting agent, emulsifier, dispersing agent, L疋剑助's glutinous specialty medicine additive, mixing or diluting and dissolving The compound represented by the formula (I) or the pharmacologically acceptable salt thereof is administered to the sputum system, the age, sex, weight, disease and treatment degree of the patient, and the adult is administered orally. It is administered in a range of from about 10 mg to about 2000 mg per day, and is administered per day from about 5 mg to about 1 000 mg per day for oral administration, and may be administered once or several times a day. A compound represented by the general formula (1) or a pharmacologically acceptable one thereof; a medicine which is combined with a compound of 1 and a mixture of zdopa and an aromatic L-amino acid decarboxylase inhibitor; Will also contain these active ingredients ^ = into, or such active ingredients are formulated separately: When the formulation is not formulated, the preparations may be administered separately or simultaneously. For example, when the preparation is separately formulated, the mixture of the mu stems may be used, and the diluent may be used at the same time: the compound represented by the general formula (1) or the compound thereof The pharmacological content of the salt, and the selected from the left Dopa 蛊工开至 u u u u u u u u u u u u u u u 、、、、、、、、、、、、、、、、、、、、、、 Time, dosage form, administration of Fang Feng ^ sputum combination, etc. are appropriately selected. Fork method, music 312XP/invention manual (supplement)/96-03/95143900 32 200800871 (invention effect)

本發明之化合物具有強大之c〇MT抑制作用。又，本發明之化合物對肝臟之影響輕微，具有高安全性。再者，本發明之化合物具有較長作用持續時間。因此，本發明之化合物f用於作為巴金森氏症、憂鬱症及高血壓症之治療或預防樂，尤其藉由組合使用本發明之化合物與左多巴，能夠增加左多巴之生體内利用率並延長其作用時間，故適合於巴金森氏症之治療或預防。【實施方式】以下述參考例、實施例及試驗例再詳細說明本發明之内谷’但本發明不受此等内容之限定。 (實施例） (參考例1 - 1) 4 -胺基- 3, 5 -二氯苯曱腈在至溫下’將30%過氧化氫水（4· 〇mL)加入至4 -胺基笨 _曱腈（2· 00g)、濃鹽酸（5· 65mL)及曱醇（3〇mL)之混合物中，迴流攪拌該混合物整夜。待冷卻後，於此反應混合物中加入亞硫酸鈉水溶液，以2mo 1 /L氫氧化鈉水溶液調整為驗性。其有機液層用無水硫酸鎂乾燥後，在減壓下進行濃縮’得目標化合物（3 · 4 7 g)。 4-丽R(CDCl3)6ppm : 5.00(2H，brs)，7.48(2H，s) 依參考例1 - 1相同方法，並使用對應之苯胺以代替4〜月女基本曱猜’合成付茶考例1 - 2〜务考例1 - 4。將此等不於表1。 312XP/發明說明書(補件)/96-03/95143900 33 200800871 [表1 ]The compounds of the invention have potent c〇MT inhibition. Further, the compound of the present invention has a slight effect on the liver and is highly safe. Furthermore, the compounds of the invention have a longer duration of action. Therefore, the compound f of the present invention is useful for the treatment or prevention of Parkinson's disease, depression and hypertension, and in particular, by using the compound of the present invention in combination with letrodopa, it is possible to increase the body of the left dopa. It is suitable for the treatment or prevention of Parkinson's disease because it utilizes and prolongs its action time. [Embodiment] The inner portion of the present invention will be described in detail with reference to the following Reference Examples, Examples and Test Examples. However, the present invention is not limited thereto. (Example) (Reference Example 1-1) 4-Amino-3,5-dichlorobenzonitrile was added to a 4-amino group at a temperature of '30% hydrogen peroxide water (4·mL) In a mixture of acetonitrile (2.0 g), concentrated hydrochloric acid (5·65 mL) and decyl alcohol (3 〇mL), the mixture was stirred under reflux overnight. After cooling, an aqueous solution of sodium sulfite was added to the reaction mixture, which was adjusted to a 2 mol / L aqueous sodium hydroxide solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (3·47 g). 4-Li R (CDCl3) 6ppm: 5.00 (2H, brs), 7.48 (2H, s) According to the same method as in Reference Example 1-1, and using the corresponding aniline instead of 4~ month female basic 曱 guess 'synthetic tea Example 1 - 2 ~ Exams 1 - 4. This is not the same as Table 1. 312XP/Invention Manual (supplement)/96-03/95143900 33 200800871 [Table 1]

參考例1 - 2〜參考例1 - 4之物性值係如下示。 *(參考例1-2) 4-丽R(CDCl〇 6 ppm:4.79(2H，br s)，7.75(2H，s) (參考例1-3) iH-NMRCCDCh) ppm : 4· 27(2H, br s)，7· 00(2H，d, J=8· 1Hz) (參考例1-4) iH-NMR(CDC13) 3 ppm:2.24(3H，s)，3,99(2H，brs)，6.63(lH，s)， 7.37(lH，s) φ (參考例2-1) 2 -氯- 5 -曱氧基苯胺將1 -氯-4 _甲氧基-2 -硝基苯（2· 〇〇g)、鋅粉末 (5· 57g)、氣化銨（〇· 63g)、乙醇（2〇mL)、水（i〇mL)及四氳呋喃（1 OmL)之混合物迴流攪拌2小時。濾除不溶物後，將滤液用醋酸乙醋與水進行分液。有機液層依次以水及食鹽水洗滌，用無水硫酸鎂乾燥後在減壓下進行濃縮，得目標化合物（1· 76g)。 •H - NMRCCDCh) 5 ppm : 3. 74(3H, s), 6. 27(1H, dd, J = 312XP/發明說明書(補件)/96-03/95143900 34 200800871 8· 8, 2· 8Hz)，6· 32(ih d j 8.8Hz) 5 2·8Ηζ)，7· i2(lH，d，J = — ^同方法，使用對應之硝基苯以代替1 - 2-3。此；合成參考W參考例 [表2]The physical property values of Reference Examples 1 - 2 to Reference Examples 1 - 4 are as follows. * (Reference Example 1-2) 4-Li R (CDCl〇6 ppm: 4.79 (2H, br s), 7.75 (2H, s) (Reference Example 1-3) iH-NMRCCDCh) ppm : 4· 27 (2H , br s), 7· 00 (2H, d, J=8·1 Hz) (Reference Example 1-4) iH-NMR (CDC13) 3 ppm: 2.24 (3H, s), 3, 99 (2H, brs) , 6.63 (lH, s), 7.37 (lH, s) φ (Reference Example 2-1) 2-Chloro-5-nonyloxyaniline 1-chloro-4-methoxy-2-nitrobenzene (2 · Mixture of 〇〇g), zinc powder (5·57g), ammonium sulfate (〇·63g), ethanol (2〇mL), water (i〇mL) and tetrahydrofuran (1OmL) under reflux for 2 hours . After the insoluble matter was filtered off, the filtrate was separated with ethyl acetate and water. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (1·76 g). • H - NMRCCDCh) 5 ppm : 3. 74(3H, s), 6. 27(1H, dd, J = 312XP / invention specification (supplement) /96-03/95143900 34 200800871 8· 8, 2· 8Hz ), 6· 32 (ih dj 8.8Hz) 5 2·8Ηζ), 7· i2 (lH, d, J = - ^ the same method, using the corresponding nitrobenzene instead of 1 - 2-3. This; synthesis reference W reference example [Table 2]

^-NMRCCDCh) S DDm . 9 〇AiQU λ PPm · 2· 34(3H，s)，6· 60-6· 70(2H，m)，^-NMRCCDCh) S DDm . 9 〇AiQU λ PPm · 2· 34(3H,s),6· 60-6·70(2H,m),

6 · 9 0 - 7 · 0 0 (1Η，m ) (參考例2-3) 臓（CDCIO c5Ppm:2.22(3H，s)，3 93(2H brs) 6 4〇 -6.59(lH,m), 6. 55-6. 65(1H, n〇, 7. 25-7. 30( 1H, m) (參考例3 - 1) 5-氣-2-羥基一 3一曱氧基苯曱腈在室溫下，將羥基胺鹽酸鹽（2 〇9g)加入至5-氯—2一羥基-3 -曱氧基苯曱醛（3· 73g)及甲酸（3〇mL)之混合物中。在迴流下攪拌50小時後，加水（4〇mL)，再攪拌1〇分 312XP/發明說明書(補件)/96-03/95143900 35 200800871 鐘。濾取固體，用水（1 OmL)洗满：5次，得目標化合物 (2·69g)。 4 -丽R(D1S0 - de) 6 ppm : 3.88(3H，s),7.29(lH，d，J = 2· 5Hz)，7· 31(1H，d，J= 2· 5Hz)，10· 76(lH，br) (參考例4- 1) 4 -溴- N，N -二曱基-3-三氟曱基苯磺醯胺在冰浴攪拌下，將三乙胺（1.05mL)及50%二曱胺水溶液 (5.0mL)依次加入至4 -溴-3 -三氟曱基苯磺醯氯（1.62g) 及四氫σ夫喃（15mL)之混合物中。此混合物在室溫下授拌 30分鐘後，用醋酸乙酯及水稀釋。分離有機液層後，將水層以醋酸乙酯進行萃取。合併有機液層，以食鹽水洗滌 2 -人，用播水硫酸鎂乾爍，最後在減壓下進行濃縮，得目標化合物（1 · 62g)。 Η -丽R(CDC13) 6 ppm ·· 2· 76(6H，s)，7· 78(1H，dd，J = 8·5,2·2Ηζ)， 7.91(lH5d5J = 8. 5Hz), 8. 06( 1H, d, J = φ 2. 2Hz) 依麥考例4 - 1相同方法，使用對應之磺醯氯及胺以代替4 -溴-3 _二氟曱基苯磺醯氯及二曱胺，合成參考例 4 - 2〜參考例4-3。此等示於表3。6 · 9 0 - 7 · 0 0 (1Η,m ) (Reference Example 2-3) 臓 (CDCIO c5Ppm: 2.22(3H, s), 3 93(2H brs) 6 4〇-6.59(lH,m), 6. 55-6. 65(1H, n〇, 7. 25-7. 30( 1H, m) (Reference Example 3 - 1) 5-Gas-2-hydroxy-3 methoxy benzoquinone in the chamber Hydrogenamine hydrochloride (2 〇 9 g) was added to a mixture of 5-chloro-2-hydroxy-3-nonyloxybenzaldehyde (3.33 g) and formic acid (3 〇 mL) at reflux. After stirring for 50 hours, add water (4 〇 mL), and then stir 1 〇 312XP / invention manual (supplement) / 96-03/95143900 35 200800871 clock. Filter solids, wash with water (1 OmL): 5 times The target compound (2·69g) was obtained. 4 -Li R(D1S0 - de) 6 ppm : 3.88(3H,s), 7.29 (lH,d,J = 2·5Hz), 7·31(1H,d, J = 2· 5 Hz), 10· 76 (lH, br) (Reference Example 4- 1) 4 -Bromo-N,N-dimercapto-3-trifluorodecylbenzenesulfonamide, stirred in an ice bath, Triethylamine (1.05 mL) and a 50% aqueous solution of decylamine (5.0 mL) were sequentially added to 4-bromo-3-trifluorodecylbenzenesulfonyl chloride (1.62 g) and tetrahydro-sulphur (15 mL). In the mixture, the mixture was mixed for 30 minutes at room temperature and diluted with ethyl acetate and water. After the organic layer was separated, the aqueous layer was extracted with ethyl acetate. The organic layer was combined, washed with brine, washed with sodium sulfate, and concentrated under reduced pressure to give the title compound ( 1 · 62g) Η - Li R (CDC13) 6 ppm ·· 2· 76(6H, s), 7·78 (1H, dd, J = 8·5, 2·2Ηζ), 7.91 (lH5d5J = 8. 5Hz), 8. 06( 1H, d, J = φ 2. 2Hz) In the same way as the wheat test 4-1, the corresponding sulfonium chloride and amine are used instead of 4-bromo-3-difluorodecylbenzenesulfonate. Chlorochloride and diamine were synthesized in Reference Example 4-2 to Reference Example 4-3. These are shown in Table 3.

312XP/發明說明書(補件)/96-03/95143900 36 200800871 參考例4 - 2〜參考例4 - 3之物性值係如下示。 (參考例4-2) iH-NMRCCDCh) (5 ppm: 2.95(6H，s)，7.63(2H，s) 參考例4-3 iH-MIKCDCh) (5 ppm:3.09(3H，s)，6.63(lH，br)，6·92-6·95(1Η，πι)，7·36-7·40(1Η，πι)，7.65-7.66(lH，m)，7.82 -7· 84(1Η，m) (參考例5- 1 ) • 2 - (2 -溴苯基）-5 -曱基十坐在室溫下’將1 -胺基丙_ 2 -醇（466mg)加入至2 -溴苯曱醯氯（l.OOg)、三乙胺（〇· 95mL)及醋酸乙酯（3〇mL)之混合物中，並攪拌整夜。濾除不溶物後，在減壓下進行濃縮，其殘留物以石夕膠中壓管柱色析法進行精製（洗提液：醋酸乙酯），得2 -溴-N - (2 -羥丙基）苯曱醯胺（1. 19g)。在室溫下’將三乙胺（2· 56mL)加入至三氧化硫·吡啶錯攀合物（2.20g)及二曱基亞砜（3、3mL)之混合物中，並攪拌 30分鐘。在冰浴下，將2 -溴-N - (2 -羥丙基）苯曱醯胺 (1· 19g)及一曱基亞颯（3. 3mL)之混合物加入至反應混合物中，在室溫下攪拌30分鐘。將混合物用醋酸乙酯與水進行分液。有機液層依次以水及食鹽水洗滌，用無水硫酸鎂乾燥後’在減壓下進行濃縮，得粗製之3 -溴_ n - (2 -氧丙基）苯曱醯胺。將粗製之3 -溴-N - (2 -氧丙基）苯曱醯胺及磷醯氣 (4. 93g)之混合物在迴流下攪拌3小時。將混合物冷卻至 312XP/發明說明書(補件)/96-03/95143900 37 200800871 室溫後，倒入至冰水中，用醋酸乙酯與水進行分液。將有機液層在減壓下進行濃縮，殘留物以矽膠中壓管挺進行精製（洗提液：己烷/醋酸乙酯= 5/1)，得目標化合物 (〇·89g)。 4 -丽R(CDCls) 5 ppm:2· 40-2· 45(3H，m)，6. 90-6. 95 (lH，m)，7· 35-7· 45(lH，m)，7· 65-7· 75(lH，m)，7· 85〜?· 95( lH，m) (參考例5 - 2) 2 -（ 3 -溴苯基）-5 -曱基u等唾依參考例5 - 1相同方法，使用3 -溴苯曱醯氯以代替 2 -溴笨曱醯氯，合成得目標化合物。 !H - NMR(CDCh) (5 ppm : 2. 35-2. 45(3H, m), 6. 80-6. 90 OH，m)，7· 25-7· 35(1H，m)，7· 50-7· 60(1H, m)，7· 90-7· 95( lH，m)，8· 10-8· 20(lH，m) (參考例6- 1) 1，3 -二氯- 5_碘- 2-曱氧基茴香醚在室溫下，將N -碘琥珀醯亞胺（2· 7〇g)加入至2,6 -二氯紛（1· 63g)及N，N -二曱基曱醯胺（3〇mL)之混合物中。在相同溫度下攪拌後，加入2mol/L鹽酸（lOOmL)於此反應混合物，再用醋酸乙酯稀釋。分離有機液層後，水層以醋酸乙酯萃取。將合併之有機液層以食鹽水洗滌，用無水硫酸鎂乾燥後，在減壓下進行濃縮，得粗2, 6-二氯-4一蛾盼。在氬氣環境及冰浴攪拌下，將碳酸鉀及氯曱基甲醚 312XP/發明說明書(補件)/96-03/95143900 38 200800871 (1.14mL)加入至粗製之2,6_二氯碘酚及n，n_二甲基曱醯胺（20mL)之混合物中。此混合物在室溫下攪拌3 小時後’用醋酸乙醋稀釋再注入至水中。分離有機液層後，水層以醋酸乙酯萃取。合併有機液層，依次以飽和碳酸氫鈉水溶液、硫代硫酸鈉水溶液、食鹽水洗滌，用盔水硫酸鈉乾燥。在減壓下進行濃縮，其殘留物以矽膠管^色析法進行精製（洗提液：從己烷自1〇%醋酸乙酯_己烷以梯度洗提），得目標化合物（3· i9g)。 • *Η- NMR(CDCla)(5ppm : 3. 67(3H, s), 5. 16(2H s) 7 63 (2H, s) 5 (參考例7 - 1 ) N - (3-蛾苯基）- N -甲基乙醯胺在〇°c下，將吡啶（0.61mL)及醋酸酐（〇 57mL)加入至 3-碘苯胺（0.60mL)及二氯甲烷（15mL)之混合物中。在室 μ下攪拌3小b守後，將反應混合物用冷甲醇（5此）及醋酸 φ乙酉曰稀釋’再/主入至2mo 1 /L鹽酸中。水層以醋酸乙酉旨萃取，有機液層依次以2mol/L氫氧化鈉水溶液、飽和碳酸氫鈉水溶液、食鹽水洗滌，用無水硫酸鎂乾燥後，在減壓下進行/辰縮。其殘留物與己烧一起進行粉碎，用己烧濾取固體，得粗製之N - (3 -碘苯基）乙醯胺。制在氬氣環境及〇它下，將氫化鈉（60%、275mg)加入至粗製之N- (3-碘苯基）乙醯胺及N，N_二曱基曱醯胺（i5mL) 之混合物中。在相同溫度下攪拌1〇分鐘後，在室溫下加入碘化甲基（〇· 86mL)。在8(TC攪拌2小時後，加入水（50mL) 312XP/發明說明書(補件)/96-03/95143900 39 200800871 及醋酸乙醋於此反應混合物中，水層以醋酸乙醋萃機液層依次以水、飽和碳酸氫鈉水溶液、食臨水洗浐無水疏酸鎮乾燥後，其殘留物以謂管柱^^進=精= (洗提液：己烷/醋酸乙醋= 得目標化合物（i i = 丽R(CDCl3)(5ppm : 1.89(3H，s)，3.24(3h s) ? ^ U9(2H，m)，7.55-7.6(KlH，m)，7.68(1H,d，J=’6.9Hd~ (茶考例8 - 1) 甲苯-4-石黃酸2,4-二氯-6_氰基苯酯在室溫下，將3,5-二氯-2-經基苯甲猜（1._加入至氫化鈉（55%、30_及N’ N _ : ψ基甲㈣⑽L)之混合物中，在相同溫度下擾拌5分鐘。於此反應混合物中加入對甲苯續醯氯U. 43g)，在相同溫度下授拌14小時。反應混合物用水(29mL)稀釋後以二***萃取。有機液層用硫酸鈉乾燥後在減壓下進行濃縮。其殘留物與己烧一起進行粉碎，得目標化合物（1· 78g)。 lH1MR(CDCl3)<5ppm:2.5G(3H，S)，7.35-7.45(2H，m) 7.54(lH,d,J=2.5Hz),7.69(lH,d,J=2. 5Hz),7.90- 8· 00(2H，m) (參考例9 - 1) 三氟甲磺酸4—氣—2-氰基〜6—甲氧基苯酯在0 C，將吡啶（〇· 65mL)及三氟甲磺酸酐（L 〇〇mL)加入 ^ 5-氯-2-羥基一 3一曱氧基苯甲腈（734mg)及二氯曱 ^(20mL)之混合物中。在相同溫度下攪拌i小時後，將此反應混合物用醋酸乙酯稀釋，在〇。〇下注入2m〇1/L鹽酸 312XP/發明說明書(補件)/9卜〇3/95143900 40 200800871 中，水層以醋酸乙酯萃取。右 _水溶液 '飽和碳酸氫納、、^/^ 在減壓下進行濃二膠一⑽酸乙…)’得目標化 H NMR(DMS0 - do) ppra ： 4. 〇〇(3H5 s), 7. 87(1H, d, J = 2. 5Hz), 7. 91(1H, d, J= 2. 5Hz) (參考例9 ~ 2) 氟甲广、敲2、（4 -苄氧基-3 -甲氧基苯亞磺醯基）—4 -氰基- β—二氟甲基苯酯依參考例9 - 1相同方法，使用3 — (4_苄氧基—3 —甲氧基苯亞績醯基）—5 —二氟甲基-4 -經基苯甲腈（參考例60 i)以替代5 -氯-2-羥基—3 -甲氧基苯甲腈，合成得目標化合物。 4 -丽R(DMS0 - d6) 3 ppm ·· 3· 78(3H，s)，5. 15(2H，s、 ❿ 7.08-7.51(9H，m)，7.64-7.68(lH，m)，8·1"·22(1Η，πι) (參考例10 - 1) 5 3, 5 -二氯- 2 -碘苯曱酸乙酯在氬氣環境及0°C下，將碳酸鉀（2.89g)及峨化甲基 (1 · 6mL)連縯加入至2 -胺基- 3，5 -二氯苯甲酸（3· 92g) 及N，N -二曱基甲醯胺（20mL)之混合物中。在室溫下授掉 2小時後，加入水（60mL)於此反應混合物中。此反應混人物注入於二***中後，其水層用二***萃取。有機液層依次以飽和碳酸氫鈉水溶液、食鹽水洗滌，用無水硫酸^美乾 312XP/發明說明書(補件)/96-03/95143900 41 200800871 燥後在減壓下進行濃縮。纟〇ΐ下緩緩加入亞石肖酸納 (1.58g)之水（5mL)溶液於其殘留物與2m〇1/L鹽酸（2〇mL) 及醋酸（20inL)之混合物中。在室溫下擾摔3〇分鐘後，在 0C下將碘化鉀（4.74g)及水（5mL)之混合物以1〇分鐘時間加入其中。在室溫下激烈攪拌2小時後，再加入2⑽亞硫酸鈉水溶液（6〇mL)。此反應混合物以己烷稀釋，其水層用己烷萃取。有機液層依次以2m〇1/L鹽酸、2m〇1/L氫氧鲁化鈉水溶液、飽和碳酸氫鈉水溶液、食鹽水洗滌，用無水硫酸鎂乾燥後在減壓下進行濃縮。其殘留物之醋酸乙酯/ 己烷= 1/4溶液中加入胺丙基矽膠（5g)。將此混合物攪拌 1小時後，通過Celite(註冊商標）矽藻土層過濾並用相同溶劑洗提。濾液在減壓下進行濃縮，得目標化合物 (4.40g)。 ^ - NMR(CDCl3)(5ppin ： 1.42(3H, t, J = 7. OHz), 4. 22 (2H, q, J = 7. OHz), 7. 44(1H, d5 J = 2. 5Hz), 7. 56(1H, d, J = φ 2.5Hz) ，， (參考例11 - 1) 2, 4, 6 -三氯苯甲酸乙酯在室溫下，將吡啶（1.6mL)加入2, 4, 6 -三氯苯曱醯氯 (1 · 6mL)及乙醇（2〇1111〇之混合物中。在相同溫度下擾摔6 小時後’反應混合物用一***稀釋，注入至2mo 1 /l鹽酸中。水層以二***萃取，有機液層依次以飽和碳酸氫鈉水溶液、食鹽水洗滌，用無水硫酸鎂乾燥後在減壓下進行濃縮，得目標化合物（2· 25g)。 312XP/發明說明書(補件)/96-03/95143900 42 200800871 ]11 - NMRCCDCla) δ ppm : 1. 41 (3Η, t, J = 7. 3Hz), 4. 45 (2H，q，J= 7· 3Hz)，7· 35(2H，s) (參考例12 - 1) 4 -溴- 2, 6 -二氯苯胺在室溫下，將溴（1, 〇4mL)加入至2, 6 -二氯苯胺（3· 0〇g) 及二氯曱烷（300mL)之混合物中並攪拌3〇分鐘。待冷卻後，加入至亞硫酸鈉水溶液，並以2mol/L氫氧化鈉水溶312XP/Invention Manual (Supplement)/96-03/95143900 36 200800871 The physical property values of Reference Example 4-2 to Reference Example 4-3 are as follows. (Reference Example 4-2) iH-NMRCCDCh) (5 ppm: 2.95 (6H, s), 7.63 (2H, s) Reference Example 4-3 iH-MIKCDCh) (5 ppm: 3.09 (3H, s), 6.63 ( lH, br), 6.92-6·95 (1Η, πι), 7·36-7·40 (1Η, πι), 7.65-7.66 (lH, m), 7.82 -7· 84 (1Η, m) (Reference Example 5-1) • 2 - (2-Bromophenyl)-5-fluorenyl 10 is placed at room temperature to add 1-aminoprop-2-ol (466 mg) to 2-bromophenylhydrazine. A mixture of chlorine (1.0 g), triethylamine (〇·95 mL) and ethyl acetate (3 mL) was stirred overnight. After insolubles were filtered off and concentrated under reduced pressure. Refining by using a gas chromatography column chromatography (eluent: ethyl acetate) to give 2-bromo-N-(2-hydroxypropyl)benzamide (1. 19 g). 'Triethylamine (2.65 mL) was added to a mixture of sulfur trioxide pyridine pyridine (2.20 g) and dimethyl sulfoxide (3, 3 mL) and stirred for 30 minutes. A mixture of 2-bromo-N-(2-hydroxypropyl)benzamide (1·19 g) and monodecylphosphonium (3.3 mL) was added to the reaction mixture, and stirred at room temperature for 30 minutes. Ethyl acetate The water was separated, and the organic layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give crude 3-bromo-n-(2-ethoxypropyl)benzamide. A mixture of the crude 3-bromo-N-(2-oxopropyl)benzoguanamine and phosphonium (4.93 g) was stirred under reflux for 3 hours. The mixture was cooled to 312XP/invention manual (supplement) /96-03/95143900 37 200800871 After room temperature, pour into ice water and separate with ethyl acetate and water. The organic layer is concentrated under reduced pressure, and the residue is refined with a medium pressure tube. (Eluent: hexane/ethyl acetate = 5/1), the target compound (〇·89g) was obtained. 4 - Li R (CDCls) 5 ppm: 2· 40-2· 45 (3H, m), 6 90-6. 95 (lH,m),7· 35-7· 45(lH,m),7· 65-7·75(lH,m),7·85~?·95( lH,m) (Reference Example 5 - 2) 2 -( 3 -Bromophenyl)-5 -fluorenyl u, etc. In the same manner as in Reference Example 5-1, 3-bromobenzoquinone chloride was used instead of 2-bromo alum , the target compound was synthesized. !H - NMR (CDCh) (5 ppm : 2. 35-2. 45 (3H, m), 6. 80-6. 90 OH, m), 7 · 25-7 · 35 ( 1H m),7· 50-7· 60(1H, m), 7· 90-7· 95( lH,m), 8· 10-8· 20(lH,m) (Reference Example 6-1) 3-Dichloro-5-iodo-2-oxo-anisole Ether added N-iodosuccinimide (2.7 g) to 2,6-dichloro (1·63 g) at room temperature And a mixture of N,N-dimercaptodecylamine (3 〇 mL). After stirring at the same temperature, 2 mol/L hydrochloric acid (100 mL) was added to the reaction mixture, followed by dilution with ethyl acetate. After separating the organic layer, the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give crude 2,6-dichloro-4. Potassium carbonate and chlorohydrin methyl ether 312XP / invention instructions (supplement) / 96-03/95143900 38 200800871 (1.14mL) were added to the crude 2,6-dichloroiodine under argon atmosphere and ice bath stirring. A mixture of phenol and n,n-dimethyl decylamine (20 mL). The mixture was stirred at room temperature for 3 hours and then diluted with ethyl acetate and poured into water. After separating the organic layer, the aqueous layer was extracted with ethyl acetate. The organic layer was combined, washed with a saturated aqueous solution of sodium hydrogencarbonate, aqueous sodium thio sulfate and brine, and dried over sodium sulfate. Concentration under reduced pressure, and the residue was purified by a gelatin chromatography method (eluent: eluted from hexane from 1% by weight of ethyl acetate-hexane) to give the title compound (3·i9g) ). • *Η-NMR (CDCla) (5ppm: 3.67(3H, s), 5. 16(2H s) 7 63 (2H, s) 5 (Reference Example 7 - 1 ) N - (3-Mothyl) - N-methylacetamide pyridine (0.61 mL) and acetic anhydride (〇57 mL) were added to a mixture of 3-iodoaniline (0.60 mL) and dichloromethane (15 mL) at EtOAc. After stirring at room μ for 3 hours, the reaction mixture was diluted with cold methanol (5) and acetonitrile acetate. The mixture was further extracted into 2 mol / L hydrochloric acid. The aqueous layer was extracted with ethyl acetate. The mixture was washed successively with a 2 mol/L aqueous sodium hydroxide solution, a saturated aqueous sodium hydrogencarbonate solution and brine, dried over anhydrous magnesium sulfate, and then dried under reduced pressure. The residue was pulverized with hexane and filtered. The solid was taken to give the crude N-(3-iodophenyl)acetamide. Under a argon atmosphere and under sodium, sodium hydride (60%, 275 mg) was added to the crude N-(3-iodophenyl). a mixture of acetaminophen and N,N-didecylguanamine (i5 mL). After stirring at the same temperature for 1 minute, methyl iodide (〇·86 mL) was added at room temperature. After stirring the TC for 2 hours, add water (50 mL) 312XP/invented Instructions (supplement)/96-03/95143900 39 200800871 and ethyl acetate in this reaction mixture, the water layer is washed with water, saturated sodium bicarbonate solution, water and saturated water in the ethyl acetate vinegar extract layer. After the town is dried, the residue is referred to as the column column = fine = (eluent: hexane / ethyl acetate = the target compound (ii = Li R (CDCl3) (5ppm: 1.89 (3H, s), 3.24(3h s) ? ^ U9(2H,m), 7.55-7.6(KlH,m), 7.68(1H,d,J='6.9Hd~ (Tea Test 8 - 1) Toluene-4-Rhein 2,4-Dichloro-6-cyanophenyl at room temperature, 3,5-dichloro-2-pyrimidin (1._ added to sodium hydride (55%, 30_ and N' In a mixture of N _ : mercapto (4) (10) L), it was stirred at the same temperature for 5 minutes. To the reaction mixture was added p-toluene chloride (U. 43 g), and the mixture was stirred at the same temperature for 14 hours. The mixture was diluted with diethyl ether, and the organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was triturated with hexane to give the title compound (1·78 g). lH1MR(CDCl3) <5 ppm :2.5G(3H,S), 7.35-7.45(2H,m) 7.54(lH,d,J=2.5Hz) , 7.69 (lH, d, J = 2. 5 Hz), 7.90 - 8 · 00 (2H, m) (Reference Example 9 - 1) Trifluoromethanesulfonic acid 4-carbon- 2-cyano~6-methoxy Phenyl ester at 0 C, pyridine (〇·65 mL) and trifluoromethanesulfonic anhydride (L 〇〇 mL) were added to 5-chloro-2-hydroxy-3-methoxybenzonitrile (734 mg) and dichloropurine. In a mixture of (20 mL). After stirring at the same temperature for 1 hour, the reaction mixture was diluted with ethyl acetate in hydrazine. Under the armpit, 2 m 〇 1 / L hydrochloric acid 312XP / invention manual (supplement) / 9 〇 3 / 95143900 40 200800871, the aqueous layer was extracted with ethyl acetate. Right _aqueous solution 'saturated sodium bicarbonate, ^ / ^ under reduced pressure, concentrated di- y (10) acid B...) 'targeted H NMR (DMS0 - do) ppra: 4. 〇〇 (3H5 s), 7 87(1H, d, J = 2. 5Hz), 7. 91(1H, d, J= 2. 5Hz) (Reference Example 9 ~ 2) Fluoromethyl, Knockout 2, (4-Benzyloxy-3) -Methoxy sulfinyl)-4-cyano-β-difluoromethylphenyl ester In the same manner as in Reference Example 9-1, 3-(4-benzyloxy-3-methoxybenzophenone) was used. The desired compound was synthesized by substituting 5-bromomethyl-4-p-benzonitrile (Reference Example 60 i) in place of 5-chloro-2-hydroxy-3-methoxybenzonitrile. 4 - Li R (DMS0 - d6) 3 ppm ·· 3·78(3H,s), 5. 15(2H,s, ❿ 7.08-7.51(9H,m), 7.64-7.68(lH,m),8 ·1"·22(1Η,πι) (Reference Example 10 - 1) 5 3,5-Dichloro-2-iodobenzoate ethyl ester Potassium carbonate (2.89g) under argon atmosphere at 0 °C And deuterated methyl (1.6 mL) was added to a mixture of 2-amino-3,5-dichlorobenzoic acid (3.92 g) and N,N-dimercaptocaramine (20 mL). After being allowed to stand at room temperature for 2 hours, water (60 mL) was added to the reaction mixture. After the reaction mixture was poured into diethyl ether, the aqueous layer was extracted with diethyl ether. Wash with salt water, use anhydrous sulfuric acid ^ Meigan 312XP / invention manual (supplement) / 96-03/95143900 41 200800871 After drying, concentrate under reduced pressure. Slowly add yttrium succinate (1.58) g) Water (5 mL) solution in a mixture of 2 m 〇 1 / L hydrochloric acid (2 〇 mL) and acetic acid (20 inL). After 3 minutes of shaking at room temperature, potassium iodide was added at 0 C ( A mixture of 4.74 g) and water (5 mL) was added over 1 minute. After stirring for 2 hours, 2 (10) aqueous sodium sulfite solution (6 〇 mL) was added. The reaction mixture was diluted with hexane, and the aqueous layer was extracted with hexane. The organic layer was successively 2 m 〇 1 / L hydrochloric acid, 2 〇〇 1 / L hydrogen The aqueous solution of sodium oxysulfide, saturated aqueous sodium hydrogencarbonate and brine were washed with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was ethyl acetate / hexane = 1/4 solution (5 g) After the mixture was stirred for 1 hour, it was filtered through Celite (registered trademark) celite layer and eluted with the same solvent. The filtrate was concentrated under reduced pressure to give the title compound (4.40 g). ) (5ppin : 1.42(3H, t, J = 7. OHz), 4. 22 (2H, q, J = 7. OHz), 7. 44(1H, d5 J = 2. 5Hz), 7. 56( 1H, d, J = φ 2.5Hz) ,, (Reference Example 11 - 1) 2, 4, 6 - Trichlorobenzoic acid ethyl ester pyridine (1.6 mL) was added to 2, 4, 6 - 3 at room temperature Chlorobenzoquinone chloride (1.6 mL) and ethanol (2〇1111〇 mixture. After 6 hours of disruption at the same temperature, the reaction mixture was diluted with diethyl ether and injected into 2 mol of hydrochloric acid. The water layer was Diethyl ether extraction, there is Layers were sequentially washed with saturated aqueous sodium bicarbonate solution brine, dried over anhydrous magnesium sulfate for concentrated under reduced pressure to give the title compound (2 · 25g). 312XP/Invention Manual (supplement)/96-03/95143900 42 200800871 ]11 - NMRCCDCla) δ ppm : 1. 41 (3Η, t, J = 7. 3Hz), 4. 45 (2H,q,J= 7 · 3 Hz), 7 · 35 (2H, s) (Reference Example 12 - 1) 4 -Bromo-2,6-dichloroaniline Add bromine (1, 〇4 mL) to 2, 6 - 2 at room temperature A mixture of chloroaniline (3.0 g) and dichlorodecane (300 mL) was stirred for 3 minutes. After cooling, add to the aqueous sodium sulfite solution and dissolve in water at 2 mol/L sodium hydroxide.

液調整為驗性。有機液層用無水硫酸鎂乾燥。在減壓行濃縮，得目標化合物（4. 75g)。The liquid is adjusted for inspection. The organic layer was dried over anhydrous magnesium sulfate. Concentration under reduced pressure gave the title compound ( 4.75 g).

!H - NMR(CDCla) δ ppm ： 4 46(2H • v ，-〜，* · 依參考例12 - 1相同方法，使用對應 ’ 2，δ_二氯苯胺，合成參考例12_ 2〜參考女以代曰等示於表4。 2 - η。此 [表4]!H-NMR (CDCla) δ ppm : 4 46 (2H • v , -~,* · According to the same method as in Reference Example 12-1, using the corresponding '2, δ-dichloroaniline, Synthesis Reference Example 12_ 2~ Reference Female This is shown in Table 4. 2 - η. This [Table 4]

F 312ΧΡ/發明說明書(補件)/96-03/95143900 43 200800871F 312ΧΡ/Invention Manual (supplement)/96-03/95143900 43 200800871

(參考例12-2) ^-NMRCCDCh) 5 ppm ： 4. 11(2H5 br s)? 6. 95-7. 05(1H, m)5 7·20-7·25(1H，m) * (參考例12-3) ^-NMRCCDCh) (5 ppm： 7. 40(1H, d5 J-9. 2Hz), 8, 30C1H, d, J:9·2Hz) (參考例12 - 4) 4-丽R(CDC13) (5ppm:4.11(2H，br，s)，6·96-7·05(1Η，π〇, 7. 20-7. 25(1H, m) (參考例12-5) φ ^-NMRCCDCh) (5 ppm：2. 19(3Η, s), 6. 99(1H, d? J-2. 1Ηζ)? 7· 29(1H，d，J = 2· 1Hz) (參考例12-6) ^-NMRCCDCh) (5 ppm ： 2. 27(3H, s), 3. 96(2H, br s), 6.65(lH，s)，7.38(lH，s) (參考例12 - 7) !H-NMR(CDCl3) 5 ppm ： 2. 10(3H, s), 2. 27(3H, s), 3.52 (2H，br s)，6· 54(1H，s)，7· 17(1H，s) (參考例12-8) 312XP/發明說明書(補件)/96-03/95143900 44 200800871 丽R(CDCh) 5ppm: 2.57(3H，s)，5.08(2H，brs)，7·48 (lH，s) (參考例12-9) 4-丽R(CDCls) (5ppm:2.19(3H，s)，2.56(3H，s)，7.23 (lH，s) (參考例12-10) 4-丽R(CDCh) 6ppm: 2.21(3H，s)，3.88(2H，br s), 6. 75-6. 85(1H, m), 7. 00-7. 10(1H, m) * (參考例12-11) 丽R(CDCh) 5ppm:2.54(3H，s)，4.91(2H，brs)， 7. 39(1H，s) (參考例13 - 1) 2,6-二氯-4-曱基苯胺將4 -漠-2，6 _二氣本胺（參考例12 - 1) (2 · 0 0 g)、四曱基錫（2.3mL)、肆（三苯基膦）鈀（〇.96g)及N，N -二曱基鲁曱醯胺（15mL)之混合物，在攪拌下照射微波，以i8〇〇c加熱5分鐘。待冷卻後將反應混合物用二乙驗稀釋，依次以水、食鹽水洗滌，用無水硫酸鎂乾燥。在減壓下進行濃縮，得目標化合物（1. 17g)。 !Η - NMRΓCDT1 ^ Λ DDm : 9 91 r qu ^\ r, _____(Reference Example 12-2) ^-NMRCCDCh) 5 ppm : 4. 11(2H5 br s)? 6. 95-7. 05(1H, m)5 7·20-7·25(1H,m) * ( Reference Example 12-3) ^-NMRCCDCh) (5 ppm: 7.40 (1H, d5 J-9. 2Hz), 8, 30C1H, d, J: 9·2Hz) (Reference Example 12 - 4) 4-Li R(CDC13) (5ppm: 4.11(2H, br, s), 6.96-7·05 (1Η, π〇, 7. 20-7. 25(1H, m) (Reference Example 12-5) φ ^ -NMRCCDCh) (5 ppm: 2.19 (3Η, s), 6. 99 (1H, d? J-2. 1Ηζ)? 7· 29 (1H, d, J = 2·1Hz) (Reference Example 12- 6) ^-NMRCCDCh) (5 ppm : 2. 27 (3H, s), 3. 96 (2H, br s), 6.65 (lH, s), 7.38 (lH, s) (Reference Example 12 - 7)! H-NMR (CDCl3) 5 ppm : 2. 10(3H, s), 2. 27(3H, s), 3.52 (2H, br s), 6. 54 (1H, s), 7·17 (1H, s) (Reference Example 12-8) 312XP/Invention Manual (Supplement)/96-03/95143900 44 200800871 Li R (CDCh) 5ppm: 2.57(3H, s), 5.08(2H, brs), 7·48 ( lH, s) (Reference Example 12-9) 4-Li R (CDCls) (5ppm: 2.19(3H, s), 2.56(3H, s), 7.23 (lH, s) (Reference Example 12-10) 4- R (CDCh) 6ppm: 2.21(3H, s), 3.88(2H, br s), 6. 75-6. 85(1H, m), 7. 00-7. 10(1H, m) * (Reference Example 12-11) Li R (CDCh) 5ppm: 2.54 (3H, s), 4.91 (2H, br s), 7. 39(1H, s) (Reference Example 13 - 1) 2,6-Dichloro-4-mercaptoaniline 4-is--2,6-di-halogen amine (Reference Example 12 - 1) a mixture of (2 · 0 0 g), tetradecyltin (2.3 mL), hydrazine (triphenylphosphine) palladium (〇.96 g) and N,N-dimercaptolide (15 mL), stirring The microwave was irradiated and heated for 5 minutes at i8 〇〇c. After cooling, the reaction mixture was diluted with diethylbenzene, washed with water and brine, and dried over anhydrous magnesium sulfate. The title compound (1.17 g) was obtained. !Η - NMRΓCDT1 ^ Λ DDm : 9 91 r qu ^\ r, _____

(參考例13 - 2) 4-氯- 2 -氟- 6-曱基苯胺國化本以代替參考例13 - 3。 312XP/發明說明書(補件)/96·03/95143900 45 200800871 4 -丽R(CDC13) (5 ppm ·· 2.16(3H，s)，3.62(2H，br s)， 6· 80-6. 95(2H，m) (參考例13 - 3) 3 -（4-苄氧基一 3 一甲氧基苯亞磺醯基）一 5 一二氟曱基-4-曱基苯甲腈 !H- NMRCCDCh) 5 ppm : 2. 48(3H, s), 3. 88(3H, s), 5. 22 (2H，s)，6· 78(1H，t，54· 9Hz)，6· 95-7· 11(4H，m)， 7·30-7.49(5H，m)，7.53 - 7.57(lH，m) ® (參考例14 - 1) 3-溴-5-氯- 2-甲基苯甲腈在冰浴攪拌下，將濃鹽酸（1 〇mL)加入至4 _胺基-3 - 漠- 5 -氯-2 -甲基苯甲腈（參考例12 _ 8)(5. 24g)及醋酸（30mL)之混合物中，再滴加亞硝酸鈉〇· 92g)之水（15mL) 洛液。將此混合物攪拌丨小時後，在室溫下小心滴加於氧化銅（I)(12.2g)之乙醇（50mL)混合物中。此反應混合物以 6〇°C加熱15分鐘。待冷卻後將此反應混合物用醋酸乙酯萃取。有機液層以食鹽水洗務，用纟水硫酸鎂乾燥。在減壓下進行濃縮，其殘留物以石夕膠中壓管柱色析法進行精製 ^洗提液：己烧/醋酸乙酯=1()/1)，得目標化合物（3 33g)。 Η - NMR(CDCla) (5 ppm ： 2. 61 (3H, s), 7. 56(1H d J = 2.2Hz), 7.78(lH,d, J=2.2Hz) ’ ’ 依參考例14 - 1相同方法，使用對庫尬I 4應之本胺以代替4 - 胺基-3 -溴_ 5_氯-2_甲基苯甲腈，入 2〜參考例14-3。此等示於表5。。成4考例14- 312XP/發明說明書(補件)/96-03/95143900 46 200800871 [表5](Reference Example 13 - 2) 4-Chloro-2-fluoro-6-mercaptoaniline Nationalization was used instead of Reference Example 13-3. 312XP/Invention Manual (supplement)/96·03/95143900 45 200800871 4 - Li R (CDC13) (5 ppm ·· 2.16(3H,s), 3.62(2H,br s), 6·80-6. 95 (2H,m) (Reference Example 13 - 3) 3 -(4-Benzyloxy-1,3-methoxysulfoximine)-5-difluorodecyl-4-mercaptobenzonitrile! H- NMRCCDCh) 5 ppm : 2. 48(3H, s), 3. 88(3H, s), 5. 22 (2H, s), 6. 78 (1H, t, 54·9Hz), 6· 95-7 · 11(4H,m), 7·30-7.49(5H,m), 7.53 - 7.57(lH,m) ® (Reference Example 14 - 1) 3-bromo-5-chloro-2-methylbenzonitrile Concentrated hydrochloric acid (1 〇mL) was added to 4 -amino-3 - oxa- 5 - chloro-2-methylbenzonitrile (Ref. 12 _ 8) (5.24 g) and acetic acid under stirring in an ice bath. In a mixture of (30 mL), water (15 mL) of sodium nitrite (92 g) was added dropwise. After the mixture was stirred for a few hours, it was carefully added dropwise to a mixture of copper (I) oxide (12.2 g) in ethanol (50 mL) at room temperature. The reaction mixture was heated at 6 ° C for 15 minutes. After cooling, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. Concentration was carried out under reduced pressure, and the residue was purified by a gas chromatography column chromatography. The eluent: hexanes / ethyl acetate = 1 () / 1) to give the title compound (3 33 g). Η - NMR (CDCla) (5 ppm : 2. 61 (3H, s), 7. 56 (1H d J = 2.2Hz), 7.78 (lH, d, J = 2.2Hz) ' ' by reference example 14 - 1 In the same manner, the amine of the formula I 4 is used instead of 4 -amino-3 -bromo-5-chloro-2-methylbenzonitrile, and 2 to Reference Example 14-3. 5. 4 test case 14- 312XP / invention manual (supplement) / 96-03/95143900 46 200800871 [Table 5]

參考例14 _ 2〜參考例14 - 3之物性值如下。 ⑩(參考例14-2) l-NMIKCDCh) 5ppm: 2.33(3H，s)，2.58(3H，s)，7·37 (lH，s)，7·59(1Η, s) (參考例14-3) 4-丽R(CDCl3) 5 ppm: 2. 54(3H，s), 7· 62(1H，d, J二 1· 6Hz) 7· 76(1H，d，J = l. 6Hz) (參考例15 - 1) _ 2-胺基- 5-氯- 3-三氟曱基苯曱腈將2 -溴-4 -氯- 6 -三氟曱基苯胺（參考例工2、 3)(4· 35g)、氰化銅（1)(1. 70g)、氰化鉀（1 24g)及 1 〜曱基-2 -吼咯啶酮（15mL)之混合物，在攪拌下照射微波，以240 C加熱1小時。將反應混合物用醋酸乙酯與水進行分液，其有機液層用無水硫酸鎂乾燥後在減壓下進行濃縮，其殘留物以石夕膠管枝色析法進行精製（洗提液：己烧/ 醋酸乙酯=3/1)，得目標化合物（2· 63g)。丽R(CDCl3)(5ppm : 4.95(2H，br s)，7 55(1H，d，j = 312XP/發明說明書(補件)/96-03/95143900 47 200800871 2.4Hz)，7.61(lH，d，j” … ^ , 2·4Hz) 依爹考例15 - 1相H + n , 叫方法，使用對應之鹵化苯以代替 2 - 溴-4-氯—6一：一〜氣甲基苯胺，合成參考例15- 2〜參考例15- 8。此等示於表6。The physical property values of Reference Example 14 _ 2 to Reference Example 14 - 3 are as follows. 10 (Reference Example 14-2) l-NMIKCDCh) 5 ppm: 2.33 (3H, s), 2.58 (3H, s), 7.37 (lH, s), 7·59 (1Η, s) (Reference Example 14- 3) 4-Li R (CDCl3) 5 ppm: 2. 54(3H, s), 7· 62 (1H, d, J 2·6Hz) 7· 76(1H,d,J = l. 6Hz) ( Reference Example 15 - 1) _ 2-Amino- 5-chloro-3-trifluorodecyl benzoquinone 2-bromo-4-chloro-6-trifluorodecyl phenylamine (References 2, 3) 4·35g), a mixture of copper cyanide (1) (1.70g), potassium cyanide (1 24g) and 1~mercapto-2-oxaridone (15mL), irradiated with microwave under stirring, to 240 C was heated for 1 hour. The reaction mixture was partitioned with ethyl acetate and water, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was purified by the ash ash tube chromatography (eluent: hexane) /ethyl acetate = 3/1) to give the title compound (2· 63 g). R (CDCl3) (5ppm: 4.95 (2H, br s), 7 55 (1H, d, j = 312XP / invention manual (supplement) / 96-03/95143900 47 200800871 2.4Hz), 7.61 (lH, d , j" ... ^ , 2 · 4Hz) Depending on the test case 15 - 1 phase H + n , called the method, use the corresponding halogenated benzene instead of 2 - bromo-4-chloro-6: one ~ gas methyl aniline, Synthesis Reference Example 15-2 to Reference Example 15-8. These are shown in Table 6.

(參考例15 - 2) ^-NMRCCDCh) 5ppm： 4, 51(2H5br s), 7. 15-7. 25(2H, m) (參考例15 - 3) ^-NMRCCDCla) (5ppra： 2.17(3H, s), 4.37(2H,br), 7.19-7· 25(2H，m) (參考例15-4) 'H-NMRCCDCh) (5 ppm ： 2.41(3H>S), 4.46(2H,br s), 6.61(lH，s)，7.46(lH，s) 312XP/發明說明書(補件)/96-03/95143900 48 200800871 (參考例15-5) ^-NMRCCDCla) (5 ppm ： 2. 11(3H, s), 2. 40(3H, s)5 3. 98 (2H，br s)，6.50(lH，s)，7.24(lH，s) (參考例15 - 6) ^-NMRCCDCh) (5ppm ： 2. 19(3H5 s), 4. 23(2H, br s), 6. 95-7· 05(2H，m) (參考例15 - 7) ^-NMRCCDCls) (5 ppm ： 2.38(3H, s)? 4. 82(2H, br s), 6.63 (1H，d，J = 7· 9Hz)，7· 22(1H，d，J = 7· 9Hz) (參考例15 - 8) 'H-NMRCCDCh) 5 ppm ： 5. 21(2H, s), 6. 83-7. 10(2H, m), 7· 35-7· 45(5H，m)，7· 67-7· 76( 1H，m)，7· 86-7· 90(1 H，m) (參考例16 - 1 ) 5-氣-2-碘- 3 一曱基苯曱腈在冰浴攪拌下，將濃鹽酸（12mL)加入至2_胺基—5一氯- 3 -曱基苯曱腈（參考例15 — 3χ4· 2〇g)及醋酸（5〇mL) 之混合物中後，再滴加亞硝酸鈉（1.92g)之水（12mL)溶液。此此合物攪拌1小時後，在室溫下小心滴加碘化鉀 (12· 6g)之水（i2mL)溶液。將此反應混合物在室溫下攪拌 15分鐘’再以6(rc加熱15分鐘。待冷卻後力认亞硫酸納 ^溶液:再用甲笨萃取。有機液層依次以飽和碳酸氫鈉水 :液〶""水洗滌，用無水硫酸鎂乾燥。在減壓下進行濃 (6 3g)。 ” 一/、丙基醚—起粉碎，濾取得目標化合物 312XP/發明說明書(補件)辄〇3/951439〇〇 49 200800871 iH-NMfKCDClO i^ppm : 2·50(3Η，s)，7.40-7· 43(2H，m) 依參考例16 - 1相同方法，使用對應之苯胺以代替2-胺基-5 -氯-3 -甲基苯甲腈，合成參考例16 - 2〜參考例16 - 17。此等示於表7。(Reference Example 15 - 2) ^-NMRCCDCh) 5 ppm: 4, 51 (2H5br s), 7. 15-7. 25 (2H, m) (Reference Example 15 - 3) ^-NMRCCDCla) (5ppra: 2.17 (3H) , s), 4.37(2H,br), 7.19-7·25(2H,m) (Reference 15-4) 'H-NMRCCDCh) (5 ppm : 2.41(3H>S), 4.46(2H,br s ), 6.61 (lH, s), 7.46 (lH, s) 312XP / invention specification (supplement) / 96-03 / 95143900 48 200800871 (Reference Example 15-5) ^-NMRCCDCla) (5 ppm : 2. 11 ( 3H, s), 2. 40(3H, s)5 3. 98 (2H, br s), 6.50 (lH, s), 7.24 (lH, s) (Reference Example 15 - 6) ^-NMRCCDCh) (5ppm : 2. 19(3H5 s), 4. 23(2H, br s), 6. 95-7· 05(2H,m) (Reference Example 15 - 7) ^-NMRCCDCls) (5 ppm : 2.38 (3H, s)? 4. 82(2H, br s), 6.63 (1H,d,J = 7·9Hz), 7·22(1H,d,J = 7· 9Hz) (Reference Example 15 - 8) 'H- NMRCCDCh) 5 ppm : 5. 21(2H, s), 6. 83-7. 10(2H, m), 7· 35-7· 45(5H,m), 7·67-7· 76( 1H, m),7·86-7·90(1 H,m) (Reference Example 16 - 1 ) 5-Gas-2-iodo-3 mercaptobenzonitrile The concentrated hydrochloric acid (12 mL) was stirred under ice bath. Add to 2_amino-5-chloro-3-indolylbenzonitrile (Reference Example 15-3χ4·2〇g) and acetic acid (5〇mL) After the composition, and then solution of sodium nitrite (1.92 g of) water (12 mL) solution. After the mixture was stirred for 1 hour, a solution of potassium iodide (12.6 g) in water (i2 mL) was carefully added dropwise at room temperature. The reaction mixture was stirred at room temperature for 15 minutes and then heated at 6 (rc for 15 minutes. After cooling, the sodium sulfite solution was applied: the mixture was extracted with a solution. The organic layer was successively saturated with sodium bicarbonate: 〒""Water washing, drying with anhydrous magnesium sulfate. Concentration (6 3g) under reduced pressure. " One /, propyl ether - pulverized, filtered to obtain target compound 312XP / invention specification (supplement) 3/951439〇〇49 200800871 iH-NMfKCDClO i^ppm : 2·50(3Η, s), 7.40-7·43(2H,m) According to the same method as in Reference Example 16-1, the corresponding aniline is used instead of 2- Amino-5-chloro-3-methylbenzonitrile, Synthesis Reference Example 16-2 to Reference Examples 16-17. These are shown in Table 7.

312XP/發明說明書(補件)/96-03/95143900 50 200800871 [表7] 參考例構造式參考例構造式 16-1 16-10 V。、 α 16-2 16-11 A, 16-3 Ό〇 16-12 F 16-4 16-13 Υ 16-5 C>/N Cl 16-14 F 16-6 C,^F Cl 16-15 /0 16-7 or 16»! 6 16-8 o\ 16-17 16-9 Cl 參考例16 - 2〜參考例16 - 17之物性值係如下示。 (參考例16-2) lH-NMR(CDCl3) (5 ppm ： 2. 45(3H, s)5 6. 80-6. 90 ( 1H, m), 7.15-7.25(lH，m)，7.65 - 7.75(lH，m) (參考例16-3) 51 312XP/發明說明書(補件)/96-03/95143900 200800871 'H-NlIKCDCls) 5 ρρπι:1·95-2·10(2Η，πι)，2·80—2.95 (4Η，m)， 6. 98(1Η，d，J二7. 8Ηζ)， 7· 44( 1Η，d，J = 7. 8Hz)， 7· 56(1Η，s) (參考例16-4) j-NMIKCDCh) 6 ppm : 7· 35-7· 45(lH，m)，7.50-7. 60 (lH，m)，7·60 - 7.70(lH，m) (參考例16-5) 4-丽R(CDC13) 6 ppm:7.59(2H，s) ® (參考例16-6) j-NMIKCDCh) 5 ppm:7.50(2H，s) (參考例16-7) ^-NMRCCDCh) 5 ppm ： 7. 17(2H, d, J = 8. 2Hz) (參考例16-8) 4-丽吖00(：13)(5??111:2.25(3!1，3)，2.47(311，3)，6.90-7.00(lH，m)，7·05-7·15(1Η，ιη) φ (參考例16-9) 丽R(CDCh) (5 ppm:2.28(3H，s)，7.17(2H，s) (參考例16-10) 4-丽R(CDCls) (5 ppm:3.79(3H，s)，6.96(2H，s) (參考例16-11) ^-NMRCCDCh) (5 ppm ： 2. 50(3H, s), 7. 10-7. 15( 1H, m), 7· 25-7· 35(1H，m) (參考例16-12) !H-NMR(CDCl3) (5 ppm ： 2. 46(3H, s)5 6. 85-6. 95( 1H5 m), 312XP/發明說明書(補件)/96-03/95143900 52 200800871 7· 05-7· 10(lH，m) (參考例16-13) W-NMIKCDCIO 6 ppm: 7· 70 - 7.75(lH，m)，7.75-7.85 (lH，m) (參考例16-14) (參考例16-15) ^-NMRCCDCh) δ ppm： 3.79(3H, s), 6. 80( 1H3 dd, J = 8. 8, •2.8Hz), 7.15(lH,d, J=2.8Hz), 7. 33( 1H, d, J = 8. 8Hz) (參考例16-16) 4-丽R(CDC13) ppm:2.52(3H，s)，7·15 —7·25(2Η，π〇 (參考例16-17) iH-raR(CDCl3) 5 ppm:i.4i(3H，t，j = 7 3Hz)，2 51(3H，s) 4· 41(2H，q，J = 7· 3Hz)，7· 08-7· 15(2H，m) (參考例17 - 1) φ 2-曱氧基-4-硫氰基酚在0C下，將溴加入漠化卸⑴5g)及甲醇 (lOOmL)之混合物中。在〇。口，將此混合物加入至2_甲氧基酚⑽)、硫氰酸鈉(19.6g)及甲醇(7〇mL)之混合物中在0C下授拌30分鐘後’加入飽和碳酸氮納水溶液於此混合物中。其溶劑之大部分在減壓下進行濃縮。其殘留物用醋酸乙酿與水進行分液，將有機液層以食鹽水洗滌，用無水硫酸鎂乾燥後在減壓下進行濃縮，得目標化合物 Π1 。 312ΧΡ/發明說明書(補件)/96·03/9Μ43900 53 200800871 Η - NMRCCDCh) ppm ： 3, 95(3Η, s), 6. 96(1Η, d, J = 8. 2Hz)， 7· 06(1H，d，J = 2· 1Hz)，7· 11(1H，dd，J = 8· 2, 2· 1Hz) (參考例17 - 2) 2-甲氧基-5-曱基硫氰基酚依參考例Π- 1相同方法，使用2—甲氧基甲基驗以代替2-甲氧基齡，合成目標化合物。 _ H-NMR(CDCh)5ppm : 2·40〜2·45(3Η，πι)，3·85-3.95 (3Η，m)，6· 85-6· 90(1H，m)，7· 〇5一7· 10(1H，m) (參考例18 - 1) 1 -节氧基-2 -甲氧基—4〜硫氰基苯在室溫下，將2 -甲氧基〜4 —硫氣基紛（參考例n l)(11.3g)、节基漠化物（16 5g)、碳酸钟（16.7g)及 -曱基曱義（2GGmL)之混合物擾拌2小時。於此反應液中加入N，N-二曱基乙一跄上a 〜312XP/Invention Manual (Supplement)/96-03/95143900 50 200800871 [Table 7] Reference example Structure Reference example Structure 16-1 16-10 V. , α 16-2 16-11 A, 16-3 Ό〇 16-12 F 16-4 16-13 Υ 16-5 C>/N Cl 16-14 F 16-6 C, ^F Cl 16-15 / 0 16-7 or 16»! 6 16-8 o\ 16-17 16-9 Cl The physical property values of Reference Example 16 - 2 to Reference Example 16 - 17 are as follows. (Reference Example 16-2) lH-NMR (CDCl3) (5 ppm: 2. 45 (3H, s) 5 6. 80-6. 90 (1H, m), 7.15-7.25 (lH, m), 7.65 - 7.75(lH,m) (Reference Example 16-3) 51 312XP/Invention Manual (supplement)/96-03/95143900 200800871 'H-NlIKCDCls) 5 ρρπι:1·95-2·10(2Η,πι), 2·80—2.95 (4Η,m), 6. 98(1Η,d,J 2 7. 8Ηζ), 7· 44( 1Η,d,J = 7. 8Hz), 7· 56(1Η,s) ( Reference Example 16-4) j-NMIKCDCh) 6 ppm : 7· 35-7· 45 (lH, m), 7.50-7. 60 (lH, m), 7.60 - 7.70 (lH, m) (Reference example) 16-5) 4-Li R (CDC13) 6 ppm: 7.59 (2H, s) ® (Reference Example 16-6) j-NMIKCDCh) 5 ppm: 7.50 (2H, s) (Reference Example 16-7) ^- NMRCCDCh) 5 ppm : 7. 17(2H, d, J = 8. 2Hz) (Reference Example 16-8) 4-丽吖00(:13)(5??111:2.25(3!1,3), 2.47 (311, 3), 6.90-7.00 (lH, m), 7·05-7·15 (1Η, ιη) φ (Reference Example 16-9) Li R (CDCh) (5 ppm: 2.28 (3H, s ), 7.17 (2H, s) (Reference Example 16-10) 4-Li R (CDCls) (5 ppm: 3.79 (3H, s), 6.96 (2H, s) (Reference Example 16-11) ^-NMRCCDCh) (5 ppm : 2. 50(3H, s), 7. 10-7. 15( 1H, m), 7· 25-7· 35(1H,m) (Reference Example 16-12) !H-NMR( CDCl3) (5 ppm 2. 46(3H, s)5 6. 85-6. 95( 1H5 m), 312XP/Invention Manual (supplement)/96-03/95143900 52 200800871 7· 05-7· 10(lH,m) ( Reference Example 16-13) W-NMIKCDCIO 6 ppm: 7·70 - 7.75 (lH, m), 7.75-7.85 (lH, m) (Reference Example 16-14) (Reference Example 16-15) ^-NMRCCDCh) δ Ppm: 3.79(3H, s), 6. 80( 1H3 dd, J = 8. 8, •2.8Hz), 7.15(lH,d, J=2.8Hz), 7. 33( 1H, d, J = 8 8 Hz) (Reference Example 16-16) 4-Li R (CDC13) ppm: 2.52 (3H, s), 7·15 — 7·25 (2Η, π〇 (Reference Example 16-17) iH-raR (CDCl3 5 ppm: i.4i (3H, t, j = 7 3Hz), 2 51(3H, s) 4· 41 (2H, q, J = 7· 3Hz), 7· 08-7· 15 (2H, m) (Reference Example 17-1) φ 2-decyloxy-4-thiocyanophenol At 0 C, bromine was added to a mixture of (1) 5 g) and methanol (100 mL). Here. The mixture was added to a mixture of 2-methoxyphenol (10)), sodium thiocyanate (19.6 g) and methanol (7 mL), and the mixture was stirred for 30 minutes at 0 C. In this mixture. Most of the solvent was concentrated under reduced pressure. The residue was subjected to liquid separation with ethyl acetate, and the organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the desired compound Π1. 312ΧΡ/Invention Manual (supplement)/96·03/9Μ43900 53 200800871 Η - NMRCCDCh) ppm : 3, 95(3Η, s), 6. 96(1Η, d, J = 8. 2Hz), 7· 06( 1H,d,J = 2·1 Hz), 7·11 (1H, dd, J = 8· 2, 2·1 Hz) (Reference Example 17 - 2) 2-Methoxy-5-mercaptothiocyanophenol The target compound was synthesized by the same procedure as in Reference Example-1 using a 2-methoxymethyl group instead of 2-methoxyl. _ H-NMR (CDCh) 5 ppm : 2·40~2·45 (3Η, πι), 3·85-3.95 (3Η, m), 6·85-6· 90(1H,m), 7· 〇5 a 7·10(1H,m) (Reference Example 18-1) 1-Hydroxy-2-methoxy-4~thiocyanobenzene 2-methoxy~4-sulfur at room temperature A mixture of base (reference example nl) (11.3 g), node-based desertification (16 5 g), carbonic acid clock (16.7 g) and -mercaptopurine (2 GGmL) was scrambled for 2 hours. To the reaction solution, N,N-dimercaptoethylidene was added to a~

月女（35· 5g)，在室溫下攪拌j小時。將反應㈣二乙鍵與切行分液，其有機液層依次以水、lmol/L鹽酸法路。田t^ ^ ^ 、 “、、水硫酸錢乾餘後在減壓下進行濃縮，得目標化合物（22· 6g)。 NMRCCDCh) d ppm ： 3. 91 (3H, s), 5. 17(2H, s), 6 88 ⑽ d，J=8.6Hz)’7.〇5 —7.1〇(2H，m)7.25_7.45(5H.m) e依餐考例t1相同方法，使用對應线以代替2_甲氧土瓜氰基齡’並用對應之鹵化芳燒化物，合成參考例18_ 2〜灸土 ' «卞暴溟可別B 2〜參考例18_4。此等示於表卜 312XP/發明說明書(補件)/96_〇3/951439〇〇 54 200800871Moon female (35·5g), stirred for j hours at room temperature. The reaction (4) and the di-ethyl bond are separated and cut into liquid, and the organic liquid layer is sequentially treated with water and 1 mol/L hydrochloric acid. Tian t ^ ^ ^, ",, water sulfuric acid, and then concentrated under reduced pressure to obtain the target compound (22 · 6g). NMRCCDCh) d ppm : 3. 91 (3H, s), 5. 17 (2H , s), 6 88 (10) d, J=8.6Hz) '7.〇5 —7.1〇(2H,m)7.25_7.45(5H.m) e The same method as the meal test t1, using the corresponding line instead 2_Methoxy guana cyanide age' and use the corresponding halogenated aromatic compound, synthesis reference example 18_ 2~ moxibustion soil « «卞暴溟 can be B 2 ~ reference example 18_4. These are shown in Table 312XP / invention manual (supplement)/96_〇3/951439〇〇54 200800871

鲁1Η-腫⑽⑶）6 ppm : 2.42(3H，S)，3.89(3H，s) 5.15(2H，s)，6.81(1H，s)，7.10(1H，s)，7.25-7 45 (5H，m) (參考例18 - 3) (參考例18 - 2) 4 - NMR(CDCjh) 6 PPm:5.11(2H，s)，6·81-7·08(2Η，πι) 7·33 — 7·42(5Η，πι)，7·46 —7·51(1Η，πι)，7.69(lH，d，J = 2. 2Ηζ) 馨(蒼考例18 - 4 ) 4-丽R(CDCls) 5 ppm:2.12-2.18(2H，m)，2·91(2Η，ΐ J =7· 3Ηζ)，4· 00(2Η，t，J = 6· ΟΗζ)，6· 68-6· 77(2Η，m)， 7· 19-7· 30(6H，m)，7· 77-7· 79(lH，m) (參考例19- 1) 4 -苄氧基-3 -曱氧基苯硫醇在室溫下，將磷酸二氳_ (41 mg)之水（15mL)溶液加入至 1-节氧基-2 -甲氧基-4 -硫氰基苯（參考例a 1)(22· 6g)及乙醇（120mL)之混合物中。再加入二硫蘇糖广 312XP/發明說明書(補件)/96-03/95143900 55 200800871 (dithiothreitol、3 飧 —、上 •讣g)後，在迴流下攪拌2小時。待冷卻後在減壓下進行澧验。# & ~ t 辰、、、侣於所侍殘留物中加水（8〇mL) 稀釋。固體用水洗滌得目標化合物（2.21g)。 lH—歷(CDCl3)<5pPm : 3.G4(1H，s)，3.87(3H，s)，5.11(2h，s)， 6.76(lH,d,J = 8.2HZ),7.05-7.10(2H,m),7.25-7.45(5H,m) (參考例19 - 2) 4-苄氧基-5-曱氧基_ 2_曱基苯硫醇魯依參考例19-1相同方法，使用^节氧基甲氧基一 5 —曱基一 4 一硫氰基苯（參考例18 - 2)以代替1一苄氧基-2 -甲氧基-4-硫氰基苯，合成目標化合物。 NMR(CDCh)(5ppm ： 2. 25(3H, s), 3. 16(1H, s), 3. 85 (3H, s), 5. 10 (2H, s), 6. 73(1H, s), 6. 87(1H, s), 7. 25- 7· 40(3H，m)，7· 40-7· 50(2H，m) (參考例20 - 1) 4 -苄氧基-3 -甲氧基苯亞磺酸鈉·ι氫氧化納 • 在室溫下，將30%過氧化氫水（3· 3mL)加入至4—节氧基-3 -曱氧基苯硫醇（參考例19_ 1 )(3 63g)、lm〇i/L氫氧化鈉水溶液（41· 3mL)及乙醇（40mL)之混合物中。在室溫下攪拌3 0分鐘後，將此反應液在減壓下進行濃縮。將混合物用鹽酸調整為酸性後，用二***與水進行分液。其有機液層以lmol/L氫氧化鈉水溶液（5mL)萃取2次，在減壓下進行濃縮，得目標化合物（2. 43g)。 Η - NMR(DMS〇-de) 5 ppm : 3·78(3H，s)，5·〇6(2H s) 6· 90-7· 00(2H，m)，7· 10-7· 15(lH，m)，7· 25-7· 5〇(5H，m) 312XP/發明說明書(補件)/96-03/95143900 56 200800871 (參考例21 - 1) 二曱基硫代胺基曱酸-2, 3, 6-三氯苯酯將 2,3,6-^ΐΚ2.39—ΜΜ_3〇5ιη§)4 U4mL)溶液中，冷卻至代並攪拌1Q分鐘。於此反應混合物中加入二甲基硫代胺基甲醯氯(ι.响)之四氫呋喃 (4.5IHL)溶液，在室溫下攪拌15小時。加入lm〇1/L氫氧化鈉水溶液（28mL)並攪拌10分鐘。濾取固體用水洗滌，得目標化合物（1. 22g)。Lu 1Η-swollen (10)(3)) 6 ppm : 2.42 (3H, S), 3.89 (3H, s) 5.15 (2H, s), 6.81 (1H, s), 7.10 (1H, s), 7.25-7 45 (5H, m) (Reference Example 18 - 3) (Reference Example 18 - 2) 4 - NMR (CDCjh) 6 PPm: 5.11 (2H, s), 6·81-7·08 (2Η, πι) 7·33 — 7· 42(5Η,πι),7·46 —7·51(1Η,πι), 7.69(lH,d,J = 2. 2Ηζ) Xin (Cang test case 18 - 4 ) 4-Li R(CDCls) 5 ppm : 2.12-2.18(2H,m),2·91(2Η,ΐ J =7· 3Ηζ), 4· 00(2Η,t,J = 6· ΟΗζ),6· 68-6· 77(2Η,m ), 7· 19-7· 30(6H,m),7· 77-7·79(lH,m) (Reference Example 19-1) 4-Benzyloxy-3-nonyloxybenzenethiol in the chamber a solution of dioxonium phosphate (41 mg) in water (15 mL) was added to 1-oxy-2-methoxy-4-thiocyanobenzene (Reference Example a 1) (22·6 g) and In a mixture of ethanol (120 mL). After further adding dithiothreitol 312XP/invention specification (supplement)/96-03/95143900 55 200800871 (dithiothreitol, 3 飧 -, upper 讣g), it was stirred under reflux for 2 hours. After cooling, perform the test under reduced pressure. # & ~ t 辰,,,,,,,,,,,,,,,,,,,,,,,,,,,, The solid was washed with water to give the title compound ( 2.21. lH—calendar (CDCl3)<5pPm: 3.G4(1H,s), 3.87(3H,s), 5.11(2h,s), 6.76(lH,d,J=8.2HZ),7.05-7.10(2H , m), 7.25-7.45 (5H, m) (Reference Example 19-2) 4-Benzyloxy-5-decyloxy-2-phenylsulfonylthiol Ruyi The same method as in Example 19-1, using ^ The target compound was synthesized by substituting a methoxymethoxy-5-fluorenyl-4-phosphazenebenzene (Reference Example 18-2) in place of 1-benzyloxy-2-methoxy-4-thiocyanobenzene. NMR (CDCh) (5ppm: 2. 25(3H, s), 3. 16(1H, s), 3. 85 (3H, s), 5. 10 (2H, s), 6. 73(1H, s ), 6. 87(1H, s), 7. 25- 7·40(3H,m), 7· 40-7· 50(2H,m) (Reference Example 20 - 1) 4 -Benzyloxy-3 -Sodium methoxybenzenesulfinate sodium iota hydride • Add 30% hydrogen peroxide water (3.3 mL) to 4-tertoxy-3-methoxy thiol at room temperature (Ref. Example 19-1) (3 63 g), a mixture of lm〇i/L aqueous sodium hydroxide solution (41·3 mL) and ethanol (40 mL). After stirring at room temperature for 30 minutes, the reaction mixture was evaporated under reduced pressure. After concentration, the mixture was acidified with hydrochloric acid, and then separated with diethyl ether and water. The organic layer was extracted twice with 1 mol/L aqueous sodium hydroxide (5 mL) and concentrated under reduced pressure to give the title compound. (2. 43g) Η - NMR(DMS〇-de) 5 ppm : 3·78(3H,s),5·〇6(2H s) 6· 90-7· 00(2H,m),7· 10-7· 15(lH,m),7· 25-7· 5〇(5H,m) 312XP/Invention Manual (supplement)/96-03/95143900 56 200800871 (Reference Example 21 - 1) Thioamine phthalic acid-2,3,6-trichlorophenyl ester will be 2,3,6-^ΐΚ2.39-ΜΜ_3〇5ιη§) 4 U4 mL) solution, cooled to generation and stirred for 1Q minutes. To the reaction mixture was added a solution of dimethylthioaminomethionine chloride (m.) in tetrahydrofuran (4.5 IHL), and stirred at room temperature for 15 hours. A solution of lm〇1/L sodium hydroxide (28 mL) was added and stirred for 10 minutes. The solid was collected by filtration to give the title compound (1. 22 g).

NMR(CDCl3)^ppm ： 3. 42(3H, s), 3. 49(3H, s), 7. 25-7. 35(2H，s) (參考例22 - 1) 二曱基硫代胺基曱酸-S - 2, 3, 6 -三氯苯基將二曱基硫代胺基甲酸-〇 — 2, 3, 6 -三氯苯酯（參考例 21- l)(1.21g)在攪拌下照射微波，以23(TC加熱30分鐘。加入己烷：二***=1 : 1之混合溶液後進行粉碎， φ得目標化合物（1· 〇7g)。 - NMRCCDCh) (5 ppm : 3. 04(3H, brs), 3. 17(3H, brs), 7. 39(1H，d，J= 8· 9Hz)，7· 46(1H，d，J= 8. 9Hz) (參考例23- 1) 2, 3, 6 -三氯苯硫醇在0°C下，將氫化鋁鋰（Imol/L四氫呋喃溶液、2. 4mL) 加入二甲基硫代胺基甲酸_ S - 2, 3, 6 -三氯苯酯（參考例 22 - l)(569mg)及四氫呋喃（8. OmL)之混合物中，在相同溫度下攪拌1小時。於反應混合物加入lmol/L鹽酸（12mL) 312XP/發明說明書(補件)/96-03/95143900 57 200800871 後用一***（1 OroL)萃取。其有機液層以無水硫酸納乾燥後’在減屋下進行》辰縮’得目標化合物（415mg )。 4 -丽R(CDC13) 5 ppm : 4.77(lH，s)，7.19(lH，d，J = 8· 9Hz)，7· 26(1H，d, J= 8· 9Hz)NMR(CDCl3)^ppm : 3. 42(3H, s), 3. 49(3H, s), 7. 25-7. 35(2H,s) (Reference Example 22 - 1) Dimercaptothioamine Base acid-S-2,3,6-trichlorophenyl group of dimercaptothiocarbamic acid-indole-2,3,6-trichlorophenyl ester (Reference Example 21-l) (1.21 g) The microwave was irradiated with stirring, and heated at 23 (TC for 30 minutes. The mixed solution of hexane: diethyl ether = 1 : 1 was added, followed by pulverization, and φ was obtained to obtain the target compound (1· 〇 7 g). - NMRCCDCh) (5 ppm : 3. 04(3H, brs), 3. 17(3H, brs), 7. 39(1H,d,J= 8· 9Hz), 7·46(1H,d,J= 8. 9Hz) (Reference Example 23- 1) 2,3,6-trichlorobenzenethiol lithium hydride (Imol/L tetrahydrofuran solution, 2.4 mL) was added to dimethylthiocarbamic acid _S-2, 3 at 0 °C. A mixture of 6-trichlorophenyl ester (Reference Example 22-1) (569 mg) and tetrahydrofuran (8.0 mL) was stirred at the same temperature for 1 hour. To the reaction mixture was added 1 mol/L hydrochloric acid (12 mL) 312XP/Invention Manual (Repair)/96-03/95143900 57 200800871 After extraction with diethyl ether (1 OroL), the organic liquid layer is dried under anhydrous sodium sulfate and then dried under reduced house to obtain the target compound (415 mg). 4 - Li R (CDC13) 5 ppm : 4.77 (lH, s), 7.19 (lH, d, J = 8·9Hz), 7·26 (1H, d, J = 8·9Hz)

(參考例24- U 3 - (4-苄氧基-3 -甲氧基苯亞磺醯基）_5_氯苯甲腈在100°C下，將4 -苄氧基-3 -曱氧基苯硫醇（參考例 19 - 1)(3· 20g)、3 -溴-5 -氯苯甲腈（3· 38g)、參（二苯亞甲基丙酮）二I巴（〇)(597mg)、（氧基二-2，1-伸苯基）雙（二苯基膦）（702mg)、第三丁醇鉀（2· 19g)及甲苯（65mL) 之混合物攪拌2小時。待冷卻至室溫後，將此反應混合物通過Celite(註冊商標）矽藻土層進行過濾，用醋酸乙酯洗提。濾液在減壓下進行濃縮後，其殘留物以矽膠中壓管柱色析法進行精製（洗提液：己烷/醋酸乙酯=9/；[至了八之梯度洗提），得目標化合物（3. I6g)。 φ 'H- NMR(CDCh) 5 ppm : 3. 88(3H, s)5 5. 21 (2H, s), 6. 90-7· 00(lH，m)，7· 00-7· 10(2H，m)，7· 10-7· 20(lH，m), 7. 20-7.30(lH，m)，7.30 - 7.50(6H，m) 依參考例24 - 1相同方法，使用對應之鹵化苯以代替 3 - >臭-5 -氯苯曱腈，合成參考例24 - 2〜參考例24 - 7。此等示於表9。 312ΧΡ/發明說明書(補件)/96-03/95143900 58 200800871 構造式參考例構造式 24-1 crW 24-δ 24-2 24-6 24-3 24-7 r° 24-4(Reference Example 24-U 3 -(4-Benzyloxy-3-methoxyphenylsulfinyl)-5-chlorobenzonitrile 4-Obenzyloxy-3-decyloxy at 100 ° C Phenyl mercaptan (Reference Example 19-1) (3·20g), 3-bromo-5-chlorobenzonitrile (3·38g), ginseng (diphenylmethyleneacetone) di Ib (〇) (597mg) a mixture of (oxydi-2,1-phenylene)bis(diphenylphosphine) (702 mg), potassium butoxide (2·19 g) and toluene (65 mL) was stirred for 2 hours. After the temperature, the reaction mixture was filtered through Celite (registered trademark) diatomaceous earth layer and eluted with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography. (Eluent: hexane/ethyl acetate = 9/; [to a gradient of eight), to give the target compound (3. I6g). φ 'H-NMR (CDCh) 5 ppm : 3. 88 (3H , s)5 5. 21 (2H, s), 6. 90-7· 00(lH,m),7· 00-7· 10(2H,m),7· 10-7· 20(lH,m ), 7. 20-7.30 (lH, m), 7.30 - 7.50 (6H, m) In the same manner as in Reference Example 24-1, the corresponding halogenated benzene was used instead of 3 - > odor-5-chlorobenzonitrile, Synthesis Reference Example 24 - 2~ Exams 24 - 7. These are shown in Table 9. 312 ΧΡ / invention manual (supplement) / 96-03/95143900 58 200800871 Structural reference example construction formula 24-1 crW 24-δ 24-2 24-6 24- 3 24-7 r° 24-4

參考例24 - 2〜參考例24 - 7之物性值係如下示。 (參考例24-2) 'H-NMRCCDCh) (5 ppm ： 2. 43(3H, s), 3. 83(3H, s), 5.10 (2H，s)，6.65(lH，dd，J = 8.3，2·2Ηζ)，6.76(lH，d，J = 8·3Ηζ)，6·86(1Η，（1，】 = 2·2Ηζ)，7·27-7·41(5Η，ιη)，7·45-7·46(1Η，πι)，7·54 - 7.56(lH，m)The physical property values of Reference Examples 24 - 2 to Reference Examples 24 - 7 are as follows. (Reference 24-2) 'H-NMRCCDCh) (5 ppm : 2. 43(3H, s), 3. 83(3H, s), 5.10 (2H, s), 6.65 (lH, dd, J = 8.3 , 2·2Ηζ), 6.76 (lH, d, J = 8·3Ηζ), 6·86 (1Η, (1,] = 2·2Ηζ), 7·27-7·41 (5Η, ιη), 7· 45-7·46(1Η,πι),7·54 - 7.56(lH,m)

(參考例24-3) 'H-NMRCCDCh) 5 ppm ·· 3.87(3H，s)， 5. 20(2H, s), 6. 90-6. 95(lH,m), 7. 00-7. 10(2H, m), 7. 25-7. 50(9H, m) (參考例24-4) ^-NMRCCDCh) δ ppm· 3.67(3H, s), 3.88(3H, s), 5.19- 5· 26(4H，m)， 6. 82-7· 08(5H，m)， 7. 3卜7· 50(5H，m)， 7. 62-7. 66(lH,m) (參考例24-5) ^-NMRCCDCh) ά ppm ： 3. 11(3H, s)? 3. 29(3H, s), 3.86 312XP/發明說明書(補件)/96-03/95143900 59 200800871 6·8〇〜6.84(lH，m)，6·91-6·93 ，m)，7·13 - 7.17(2H，m)，7·31 - (3H，s)，5.18(2H，s)， (1H，m)，7·03-7·05(2H 7.46(6H，m) (參考例24-6) t臓（CDC13) d ppm : 3 86(3Hs)， 5 19(2Hs)， 6.71 6.73(lH,m), 6· 92-6. 98(2H, m), 7. 06-7. 10(3H, m), 7. 31-7· 52(6H，m) (參考例24-7)(Reference Example 24-3) 'H-NMRCCDCh) 5 ppm ·· 3.87 (3H, s), 5. 20(2H, s), 6. 90-6. 95(lH,m), 7. 00-7 10(2H, m), 7. 25-7. 50(9H, m) (Reference 24-4) ^-NMRCCDCh) δ ppm· 3.67(3H, s), 3.88(3H, s), 5.19- 5·26(4H,m), 6. 82-7· 08(5H,m), 7. 3Bu 7·50(5H,m), 7. 62-7. 66(lH,m) (Reference example) 24-5) ^-NMRCCDCh) ά ppm : 3. 11(3H, s)? 3. 29(3H, s), 3.86 312XP/invention manual (supplement)/96-03/95143900 59 200800871 6·8〇 ~6.84(lH,m),6·91-6·93,m),7·13 - 7.17(2H,m),7·31 - (3H,s),5.18(2H,s), (1H, m), 7·03-7·05 (2H 7.46(6H,m) (Reference Example 24-6) t臓(CDC13) d ppm : 3 86(3Hs), 5 19(2Hs), 6.71 6.73(lH, m), 6· 92-6. 98(2H, m), 7. 06-7. 10(3H, m), 7. 31-7· 52(6H,m) (Reference Example 24-7)

〗Η-臓（CDCh) 5 ppm : 3 84(3h，s)，5 17(2H s)， 6.88-7.10(6H,m), 7. 20^7. 22(1H, ra), 7. 30-7. 45( 1 OH, m) (參考例25 - 1) 2 - (4-苄氧基-3_甲氧基笨亞磺醯基）_3,5_二氟苯甲醛在冰浴授拌下，將第三丁醇卸（617mg)力认4_节氧基一 3 -曱氧基苯硫醇（參考例19_ 1)(123g)及N，N_二曱基 ❿曱醯胺（6mL)之混合物中並攪拌5分鐘。加入2,3,5_三氟苯甲醛（0.68mL)後在相同溫度下攪拌3〇分鐘。於反應此合物中加入水後攪拌1 〇分鐘。濾取固體，用水洗滌5 次後減壓乾燥，得目標化合物（1· 84g)。 'H- NMR(CDCh) 5 ppm : 3. 83(3H, s), 5. 10(2H, s), 6.65-6. 80 (2H, m)? 6. 85-6. 90(1H, m), 7. 05-7. 15(1H, m), 7. 25- 7·45(5Η，ηι)，7·45-7· 55(lH，m)，10· 72(lH，d，J=3.4Hz) (參考例25 - 4) 2 -（4-苄氧基- 3-甲氧基苯亞磺酿基）一 3, 5 一二氟 312XP/發明說明書(補件)/96-03/95143900 60 200800871 苯甲酸甲醋在冰浴攪拌下，將第三丁醇鉀（522mg)加入至4—苄氧基—3 -甲氧基苯硫醇（參考例19 一 1)(1· 〇知）、2, & 5 一三氟苯曱酸甲酯（804邶）及n，n -二曱基甲醯胺（5 3mL)之混合物中後，在室溫_15小時。於混合物中加入水 ⑵mL)後用醋酸乙g|萃取。其有機液層以無水硫酸鋼乾燥後在減G下進行》辰縮，其殘留物膠管柱色析法進行精製（洗提液：0%至20%醋酸乙醋一己烷之梯度洗提 7 標化合物（520mg)。依麥考例25 - 1相同方法，使用對應之苯甲盤以代錢 2,3, 5 —二氟苯曱醛，合成參考例25 - 2、25 - 3、25〜曰及25 — 6。此等示於表1〇。 5 [表 10] 參考例構造式參考例. 構造式 ^ 25-1 ΟγΗ 一 s ‘ JL 25-4 25-2 25-5 °Y〇vJ^3 Cr私 25 - 3 25-6 cr^ 麥考例25 - 2〜參考例25 - 6之物性值係如下示。 (參考例25-2) 4-丽r(cdci3) 5 ppm:3.82(3H，s), 51〇(2H，s)，6·7〇 312ΧΡ/發明說明書(補件)/96-03/95143900 61 200800871 6.80(2H，m)，6.85-6.9〇(lH，m)，7·20-7·45(6Η，ιη)，7.45 - 7.55(lH，m), 7.75-7.85(lH，m)，10.73(lH，d，J = (K7Hz) (參考例25-3) 4-丽R(CDCh) 6 ppm:3.85(3H，s)，5.17(2H，m)，6·85-7· 00(3H，m)，7.〇5-7.10(lH，m)，7.10-7.20(lH，m)，7·25 -7.50(5H，m)，7·50 - 7·60(1Η，π〇，10.39(lH，d，J = 1.9Hz) (參考例25-4) 丽R(CDCM (5 ppm:3.83(3H，s)，3.90(3H，s)，5·11 ⑩（2H，s)，6·70-6.80(lH，m)，6·80-6.90(lH，m)，6·90-7.00(2H，m)，7·15 - 7.25(lH，m)，7·25 - 7.50(5H，m) (參考例25-5) imMIKCDCh) 5 ppm :3.84(311,3), 5.19(2H，s)，5· 45 (2H，s)，6·80-7.〇〇(3H，m)，7·25-7·45(8Η，ιη)，7·45 -7·50(2Η，η〇，7·55 - 7·60-(2H，m) (參考例25-6) 鲁1H-NMR(CDC13) (5 ppm:3.85(3H，s)，5.19(2H，s)，6·92 -6· 95(2H，m)， 7· 04-7· 06(2H，m)， 7· 25-7· 46(7H，m), 7· 82-7· 84(1H，m)，10· 33(1H，s) (參考例26 - 1) 1 - [3 -（4 -苄氧基一 3一甲氧基苯亞磺醯基）一 5 -氯苯基]乙酮在一78 C及攪拌下，將曱基鋰-二***溶液（L 61mL) 加入3 - (4 -苄氧基—3 -甲氧基苯亞磺醯基）—5_氯苯曱腈（麥考例24 - l)(549mg)及四氫呋喃（5mL)之混合物 312XP/發明說明書(補件)/96-03/95143900 62 200800871 中。於混合物攪拌丨小時後，升溫至〇它再攪拌1小時。加入4mol/L氯化氫—醋酸乙酯溶液（〇· 62mL)於此混合物中以停止反應，並加水後，以5〇。〇加熱攪拌。待冷卻至室溫後，將混合物用醋酸乙酯與lm〇1/L鹽酸分液，其有機液層以無水硫酸鈉乾燥後在減壓下進行濃縮。其殘留物以矽膠中壓管柱色析法進行精製（洗提液：己烷/醋酸乙酯 —9/1至5/1之梯度洗提），得目標化合物（259mg)。 ^ 'H- NMR(CDCl3) (5 ppm ： 2. 51 (3H, s), 3. 87(3H, s), 5. 19 (2H，s)，6· 90-6· 95(1H，m)，7· 〇〇-7· 10(2H，m)，7· 15-7· 25(lH，m)，7· 25-7· 35 (lH，m)，7· 35-7. 50(4H，m)，7· 55- 7· 70(2H，m) (參考例26 - 2) 1 - [2 -（4-苄氧基一 3 —甲氧基苯亞磺醯基5 一氟- 3 -甲基苯基]乙酮依參考例26 - 1相同方法，使用2 — (4 —苄氧基—3 — 擊曱氧基苯亞磺醯基）—5 -氟-3-甲基苯曱腈（參考例 56 - 1)以代替3 - (4-苄氧基—3 —甲氧基苯亞磺醯基）— 5 -氯苯甲腈，合成目標化合物。 NMR(CDCl3)^ppm ： 2. 36(3H, s), 2. 51 (3H, s), 3. 79〖Η-臓(CDCh) 5 ppm : 3 84(3h, s), 5 17(2H s), 6.88-7.10(6H,m), 7. 20^7. 22(1H, ra), 7. 30 -7. 45( 1 OH, m) (Reference Example 25 - 1) 2 - (4-Benzyloxy-3_methoxy oxasulfinyl)_3,5-difluorobenzaldehyde was mixed in an ice bath Next, the third butanol was unloaded (617 mg) to recognize 4-hydroxyl 3-methoxy thiol mercaptan (Reference Example 19-1) (123 g) and N,N-didecylguanamine (6 mL). The mixture was stirred for 5 minutes. After adding 2,3,5-trifluorobenzaldehyde (0.68 mL), it was stirred at the same temperature for 3 minutes. After adding water to the reaction mixture, the mixture was stirred for 1 minute. The solid was collected by filtration, washed with water for five times and dried under reduced pressure to give the title compound (1· 84 g). 'H-NMR (CDCh) 5 ppm : 3. 83(3H, s), 5. 10(2H, s), 6.65-6. 80 (2H, m)? 6. 85-6. 90(1H, m ), 7. 05-7. 15(1H, m), 7. 25- 7·45(5Η, ηι), 7·45-7· 55(lH,m),10·72(lH,d,J =3.4 Hz) (Reference Example 25 - 4) 2 -(4-Benzyloxy-3-methoxybenzosulfinyl)-3,5-Difluoro 312XP/Invention Manual (supplement)/96-03 /95143900 60 200800871 Potassium tert-butoxide (522 mg) was added to 4-benzyloxy-3-methoxybenzenethiol under stirring in an ice bath (Reference Example 19-1) (1· 〇 After a mixture of methyl trifluorobenzoate (804 邶) and n, n-dimercaptocarboxamide (5 3 mL), it was allowed to stand at room temperature for -15 hours. Water (2) mL) was added to the mixture and extracted with ethyl acetate. The organic liquid layer is dried with anhydrous sulfuric acid steel and then subjected to reduction by G. The residue is purified by a rubber column chromatography method (eluent: 0% to 20% acetic acid ethyl acetate-hexane gradient elution) Compound (520 mg). In the same manner as in the test example 25-1, the corresponding benzotriene disk was used to replace the 2,3,5-difluorobenzaldehyde, and the synthesis reference example 25 - 2, 25 - 3, 25 ~ 曰And 25-6. These are shown in Table 1. 5 [Table 10] Reference example structural reference example. Structural formula ^ 25-1 ΟγΗ One s ' JL 25-4 25-2 25-5 °Y〇vJ^ 3 Cr private 25 - 3 25-6 cr^ Wheat test 25 - 2 ~ Reference examples 25 - 6 The physical property values are as follows (Reference Example 25-2) 4-Li r (cdci3) 5 ppm: 3.82 (3H ,s), 51〇(2H,s),6·7〇312ΧΡ/Invention Manual (supplement)/96-03/95143900 61 200800871 6.80(2H,m), 6.85-6.9〇(lH,m),7 · 20-7·45 (6Η, ιη), 7.45 - 7.55 (lH, m), 7.75-7.85 (lH, m), 10.73 (lH, d, J = (K7Hz) (Reference Example 25-3) 4- R (CDCh) 6 ppm: 3.85 (3H, s), 5.17 (2H, m), 6·85-7· 00 (3H, m), 7. 〇 5-7.10 (lH, m), 7.10-7.20 (lH,m), 7.25 -7.50 (5H,m),7·50 - 7· 60 (1 Η, π 〇, 10.39 (lH, d, J = 1.9 Hz) (Reference Example 25-4) Li R (CD ppm (5 ppm: 3.83 (3H, s), 3.90 (3H, s), 5·11 10(2H,s),6·70-6.80(lH,m),6·80-6.90(lH,m),6·90-7.00(2H,m),7·15 - 7.25(lH,m) , 7.25 - 7.50 (5H, m) (Reference Example 25-5) imMIKCDCh) 5 ppm : 3.84 (311, 3), 5.19 (2H, s), 5· 45 (2H, s), 6·80- 7.〇〇(3H,m),7·25-7·45(8Η,ιη),7·45 -7·50(2Η,η〇,7·55 - 7·60-(2H,m) ( Reference Example 25-6) Lu 1H-NMR (CDC13) (5 ppm: 3.85 (3H, s), 5.19 (2H, s), 6.92 -6· 95 (2H, m), 7·04-7· 06(2H,m), 7· 25-7· 46(7H,m), 7· 82-7· 84(1H,m),10·33(1H,s) (Reference Example 26 - 1) 1 - [3-(4-Benzyloxy-1,3-methoxybenzosulfinyl)-5-chlorophenyl]ethanone a solution of decyllithium-diethyl ether (L 61 mL) with stirring at 78 C Add a mixture of 3-(4-benzyloxy-3-methoxybenzylsulfinyl)-5-chlorobenzonitrile (Mc. 24-1) (549 mg) and tetrahydrofuran (5 mL) 312XP/Invention Manual (Supplement) /96-03/95143900 62 200800871. After the mixture was stirred for a few hours, it was warmed to 〇 and stirred for an additional 1 hour. 4 mol/L of a hydrogen chloride-ethyl acetate solution (〇·62 mL) was added to the mixture to stop the reaction, and after adding water, it was 5 Torr. 〇 Heat and stir. After cooling to room temperature, the mixture was partitioned between ethyl acetate and EtOAc (EtOAc). The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate - 9/1 to 5/1 gradient elution) to give the title compound (259 mg). ^ 'H-NMR (CDCl3) (5 ppm : 2. 51 (3H, s), 3. 87(3H, s), 5. 19 (2H, s), 6· 90-6· 95 (1H, m ),7· 〇〇-7· 10(2H,m),7·15-7· 25(lH,m),7· 25-7· 35 (lH,m),7·35-7. 50( 4H,m),7·55- 7·70(2H,m) (Reference Example 26-2) 1 - [2-(4-Benzyloxy-3-methoxybenzylsulfinyl-5-fluoro- 3-methylphenyl]ethanone according to the same procedure as in Reference Example 26-1, using 2-(4-benzyloxy-3-anthraceneoxyphenylsulfinyl)-5-fluoro-3-methylbenzene The title compound was synthesized by substituting nitrile (Reference Example 56-1) for 3-(4-benzyloxy-3-methoxybenzylsulfinyl)-5-chlorobenzonitrile. NMR (CDCl3) 2. 36(3H, s), 2. 51 (3H, s), 3. 79

(3H，s)，5· 08(2H，s)，6· 46(1H，dd，J= 8· 4, 2· 0Hz)，6· 68 (1H，d，J= 2· 2Hz)，6· 73(1H，d，J = 8· 3Hz)，6. 89(1H，dd，J =8· 1，2· 8Hz)，7· 04(1H，dd, J= 8· 9, 2· 9Hz)，7· 25-7· 45 (5H，m) (參考例27 - 1) 312XP/發明說明書(補件)/96-03/95143900 63 200800871 3-(4_苄氧基一3_甲氧基苯亞磺醯基）_5_氣苯甲酸甲酯在80°C下，將3 - (4 -苄氧基-3 -曱氧基苯亞磺醯基）-5 -氯苯甲腈（參考例24- i)(458mg)、甲醇·· i，4 一二’烧=3 : 2之混合溶劑（3〇mL)及2 m〇1/L氫氧化鈉水溶液（6· OmL)之混合物加熱攪拌3〇小時。待冷卻至室溫後，於反應混合物中加入1 m〇 1 /L鹽酸（13mL)，再用水稀(3H, s), 5· 08 (2H, s), 6 · 46 (1H, dd, J = 8 · 4, 2· 0Hz), 6· 68 (1H, d, J = 2· 2Hz), 6 · 73 (1H, d, J = 8 · 3Hz), 6. 89 (1H, dd, J = 8 · 1, 2 · 8Hz), 7 · 04 (1H, dd, J = 8 · 9, 2 · 9Hz ), 7· 25-7· 45 (5H, m) (Reference Example 27 - 1) 312XP/Invention Manual (supplement)/96-03/95143900 63 200800871 3-(4-Benzyloxy-3_methoxy 3-(4-Benzyloxy-3-indolyl sulfinyl)-5-chlorobenzonitrile at 80 ° C (reference) Example 24 - i) (458 mg), methanol · · i, 4 - 2 'steam = 3: 2 mixed solvent (3 〇 mL) and 2 m 〇 1 / L sodium hydroxide aqueous solution (6 · OmL) mixture Stir for 3 hours. After cooling to room temperature, 1 m 〇 1 /L hydrochloric acid (13 mL) was added to the reaction mixture, and then diluted with water.

釋後攪拌5分鐘。濾取沈澱物，用水洗滌後減壓乾燥，得 3 -（4 -苄氧基-3 -甲氧基苯亞石黃醯基）_ 5 -氯苯甲酸 (443mg) ° 在室溫攪拌下，將碳酸鉀（229mg)及碘化甲基（〇. 341 mL) 加入3- (4-苄氧基—3—曱氧基苯亞磺醯基）—5—氯苯曱酸（439mg)及N，N -二曱基曱醯胺（3.6mL)之混合物中。將此/%合物授拌1 · 5小時後用水稀釋反應混合物。濾取沈澱物，用水洗滌後減壓乾燥，得目標化合物（463mg)。 φ 'H - NMR(CDCh) 5 ppm : 3. 86(3H, s), 3. 89(3H, s), 5. 19 (2H，s)，6·90-6·95(1Η，ιη)，7·00-7·10(2Η，ιη)，7·15-?·25 (1Η, m)，7· 30-7· 35(1Η, m), 7· 35-7· 50(4Η，m)，7· 70-7 80 (2H，m) (參考例27 - 2) 2 -（4-苄氧基- 3 -曱氧基苯亞磺醯基）一 5一氯— 3 -曱基苯曱酸乙酯依參考例2 7 - 1相同方法’使用2- (4 -节氧基—3 曱氧基苯亞磺醯基）-5_氯-3 -甲基苯曱腈（參考例 312XP/發明說明書(補件)/96-03/95143900 64 200800871 24- 2)以代替3- (4-苄氧基-3-甲氧基苯亞磺醯基）一 5 -氯苯甲腈，合成目標化合物。 4-丽 R(CDCl3)(5ppm :1.43(3H，t，J=7.2Hz)，2 48 (3H，s)，3· 93 (3H，s)，4· 47(2H，q，J= 7· 2Hz)，5· 20 (2H, s), 6. 94(1H, d, J= 8. 6Hz), 7. 25-7. 42(5H, m), 7. 61 (1H, dd，J= 8· 6, 2· 2Hz)，7. 67(1H，d，J= 2. 2Hz) (參考例28 - 1) 3 (4苄氧基3甲氧基苯亞石夤酿基）一 5 -氯苯甲酸在0C及攪拌下，將l.()m〇i/L二異丁基氫化鋁—曱苯溶液（DIBAL)(2. 4mL)滴加於3 - (4 -节氧基-3 —甲氧基苯亞磺醯基）-5 -氯苯曱腈（參考例24 — 1 )(765mg)及四氫呋喃（20mL)之混合物中。將此混合物攪拌丨· 5小時後在室溫下攪拌13小時。再滴加DIBAL(2 4mL)，將反應混合物攪拌4小時後，最後再滴加DIBAL(12mL)，將此混合物攪拌30分知。加入lmol/L鹽酸（30mL)後，所得混合物修用二***萃取。將有機液層以無水硫酸鈉乾燥後，在減壓下進行濃縮。其殘留物以矽膠中壓管柱色析法進行精製 (洗提液：己烷/醋酸乙酯= 9/1至7/1之梯度洗提），得目標化合物（291mg)。 NMRCCDCh) ^ ppm ： 3. 87(3H, s), 5. 20(2H, s), 6. 90~ 7· 00 (1H，m)，7· 00-7. 05(lH，m)，7· 05-7· 10(1H，m)，7· 20-7· 30(lH，m)，7· 30-7· 50(6H，m)，7· 55-7· 60(lH,m)，9· 85 (1H，S) ，， (參考例29 - 1) 312XP/發明說明書(補件)/96-03/95143900 65 200800871 1_· (4-苄氧基-3-甲氧基苯亞磺醯基）_3 一氣— 5 - 一鼠甲苯Stir for 5 minutes after release. The precipitate was collected by filtration, washed with water and dried under reduced pressure to give 3-(4-benzyloxy-3-methoxybenzodiazepine)-5-chlorobenzoic acid (443 mg). Potassium (229 mg) and methyl iodide (〇. 341 mL) were added 3-(4-benzyloxy-3-methoxybenzylsulfinyl)-5-chlorobenzoic acid (439 mg) and N,N a mixture of dimercaptoguanamine (3.6 mL). The /% compound was stirred for 1.5 hours and the reaction mixture was diluted with water. The precipitate was collected by filtration, washed with water and evaporated to dry φ 'H - NMR (CDCh) 5 ppm : 3. 86(3H, s), 3. 89(3H, s), 5. 19 (2H, s), 6·90-6·95 (1Η, ιη) ,7·00-7·10(2Η,ιη),7·15-?·25 (1Η, m),7· 30-7· 35(1Η, m), 7· 35-7· 50(4Η, m),7·70-7 80 (2H,m) (Reference Example 27-2) 2 -(4-Benzyloxy-3-oxalylsulfinyl)-5-chloro-3-indolyl Ethyl benzoate was used in the same manner as in Reference Example 2-7 - '2-(4-oxo-3 methoxy sulfinyl)-5-chloro-3-methylbenzonitrile (Reference example) 312XP/Invention Manual (supplement)/96-03/95143900 64 200800871 24- 2) Instead of 3-(4-benzyloxy-3-methoxyphenylsulfinyl)-5-chlorobenzonitrile, Synthesis of the target compound. 4-Li R (CDCl3) (5ppm: 1.43 (3H, t, J = 7.2Hz), 2 48 (3H, s), 3.93 (3H, s), 4· 47 (2H, q, J= 7 · 2Hz), 5· 20 (2H, s), 6. 94(1H, d, J= 8. 6Hz), 7. 25-7. 42(5H, m), 7. 61 (1H, dd, J = 8· 6, 2· 2 Hz), 7.67 (1H, d, J = 2. 2 Hz) (Reference Example 28 - 1) 3 (4 benzyloxy 3 methoxyphenyl ruthenium ruthenium)-5 -chlorobenzoic acid at 0 ° with stirring, l. () m〇i / L diisobutylaluminum hydride - benzene solution (DIBAL) (2.4 mL) was added dropwise to 3 - (4-ethoxyl group - a mixture of 3-methoxybenzylsulfinyl)-5-chlorobenzonitrile (Ref. 24-1) (765 mg) and tetrahydrofuran (20 mL). The mixture was stirred for 5 hours at room temperature. After stirring for 13 hours, DIBAL (24 mL) was added dropwise, the reaction mixture was stirred for 4 hours, and finally DIBAL (12 mL) was added dropwise, and the mixture was stirred for 30 minutes. After adding 1 mol/L hydrochloric acid (30 mL), the mixture was obtained. The mixture was extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by gel column chromatography (eluent: hexane / ethyl acetate = Gradient elution from 9/1 to 7/1 The target compound (291 mg) was obtained. NMR CCD Ch) ^ ppm : 3. 87 (3H, s), 5. 20 (2H, s), 6. 90~ 7· 00 (1H, m), 7· 00-7 05(lH,m),7· 05-7· 10(1H,m),7· 20-7· 30(lH,m),7· 30-7· 50(6H,m),7·55 -7· 60(lH,m),9· 85 (1H,S) ,, (Reference Example 29 - 1) 312XP/Invention Manual (supplement)/96-03/95143900 65 200800871 1_· (4-Benzyloxy) 3-methoxyphenylsulfinyl)_3 one gas — 5 - one mouse toluene

在室溫授拌下，將雙（2_甲氧乙基）胺基三氟化硫 (〇.468mL)=入至3- (4 —苄氧基—3 -甲氧基苯亞磺醯基）—5 —氯苯甲醛（參考例28 - l)(577mg)之二氯甲烷 (〇·6π^)溶液中，並攪拌4·5小時。將反應混合物注入於飽和碳酸氫鈉水溶液中後用二氯甲烷萃取。其有機液層以無水硫酸鎂乾燥後在減壓下進行濃縮。其殘留物以矽膠中壓官柱色析法進行精製（洗提液：己烷/醋酸乙酯= 9/1至 7/1之梯度洗提），得目標化合物（528mg)。 Η - NMR(CDCla) 5 ppm ； 3. 87(3H, s), 5. 20(2H, s), 6. 50 OH, t, J=56^ 2Hz), 6. 90-6. 95(lH,m), 7. 00-7. 15(4H,m), 7. 20-7. 25(1H, m)5 7. 30-7. 50(5H, m) 依麥考例29 - 1相同方法，使用對應之苯曱醛以代替 3 一（4-苄氧基一 3-曱氧基苯亞磺醯基）一 5一氯苯曱醛，合成參考例29 - 2〜參考例29 - 6。此等示於表U。 [表 11] 參考例構造式參考例構造式 29-1 29-4 fXh jTYsyS 0^/0 Cl 〇r°T Uf 29-2 〇P〇Jp"FXiF 29-5 ΒΌ 29-3 29-6 312XP/發明說明書(補件)/96-03/95143900 66 200800871 參考例29 - 2〜參考例29 — 6之物性值係如下示。 (參考例29-2) ^-NMRCCDCh) 5 ppm ： 3.82C3H, s), 5.1〇(2H,s), 6. 70- 6.80(2H，m)，6·85-6·90(ΐΗ，η〇，6·95-7·05(1Η，πι) 7 10 -7.45(7H，m) ’ ’ · (參考例29-3) 疆（CDC10 占 ppm:3 81(3H，s)，51〇(2H，s)，nAdd bis(2-methoxyethyl)aminosulfur trifluoride (〇.468mL) = 3-(4-benzyloxy-3-methoxyphenylsulfinyl) at room temperature -5-Chlorobenzaldehyde (Reference Example 28-1) (577 mg) in dichloromethane (〇·6π^) solution and stirred for 4.5 hours. The reaction mixture was poured into a saturated aqueous solution of sodium hydrogencarbonate and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate = 9/1 to 7/1 gradient) to give the title compound (528 mg). Η - NMR (CDCla) 5 ppm ; 3. 87(3H, s), 5. 20(2H, s), 6. 50 OH, t, J=56^ 2Hz), 6. 90-6. 95(lH ,m), 7. 00-7. 15(4H,m), 7. 20-7. 25(1H, m)5 7. 30-7. 50(5H, m) The same as the McCormian 29 - 1 By the method, the corresponding phenylfurfural is used instead of 3-(4-benzyloxy-3-methoxyphenoxysulfonyl)-5-chlorophenylfurfural, and the synthesis of Reference Example 29-2 to Reference Example 29-6 . These are shown in Table U. [Table 11] Reference example Construction formula Reference example Structure 29-1 29-4 fXh jTYsyS 0^/0 Cl 〇r°T Uf 29-2 〇P〇Jp"FXiF 29-5 ΒΌ 29-3 29-6 312XP /Invention Manual (Supplement)/96-03/95143900 66 200800871 The physical property values of Reference Example 29-2 to Reference Example 29-6 are as follows. (Reference Example 29-2) ^-NMRCCDCh) 5 ppm : 3.82C3H, s), 5.1〇(2H, s), 6. 70- 6.80(2H,m),6·85-6·90(ΐΗ,η 〇,6·95-7·05(1Η,πι) 7 10 -7.45(7H,m) ' ' (Reference Example 29-3) Xinjiang (CDC10 in ppm: 3 81 (3H, s), 51〇 ( 2H, s), n

6.80(2H，m)，6·85-6·90(ιη，π〇，7·10-7·45(7Η m) 7 4R -7.60(2H，m) ’ ’ · b (參考例29-4) 4-丽 R(CDC13) 6· 85(2H，m)，6 -7· 45(7H，m) 占 PPm : 3.83(3H，s), 5· 14(2H，s)，• 85-6· 90(ih，m)，6· 90-7· 20(2H，m) 6· 80-7. 20 (參考例29-5) lH-NMR(CDCl3) ^ ppm：6.91(lH5 t, J = 55.0Hz), 7.30^7 5〇 _ (2H，m)，7·55〜7.7〇(2H，m) · (參考例29-6) ^^NMRCCDCls) ^ ppm ： 6.69-6.97(2H,m)5 7. 40-7. 48 (1H，m)，7· 56〜7· 58(1H，m) ‘ (參考例30- 1) [3 312XP/發明說明書(補件)/96-03/95143900 67 200800871 乙酿1(參考例26 - l)(258mg)及二氯曱烷（6.5mL)之混合物中’在室溫下攪拌1小時。此反應混合物用醋酸乙酯與水進行为液’有機液層依次以1 mo 1 /L硫代硫酸鈉水溶液、 2mol/L氫氧化鈉水溶液、食鹽水洗滌，用無水硫酸鈉乾燥後’在減壓下進行濃縮，得目標化合物（277mg)。 NMRCCDCh) (5 ppm :2e 62(3H5 s), 3. 94(3Η, s), 5. 20 (2Η，s)，6· 95-7. 〇〇(ιη，m)，7· 25-7· 45(6Η，m)，7· 45-7· 55 (1Η，m)，8· 00 —8· 1〇(2Η，m)，8· 25-8· 35(1Η，m) ·(參考例30 — 9) 2 一（4 一苄氧基—3 一甲氧基苯磺醯基）- 3, 5 -二氟苯曱酸曱酯在至溫授摔下’將過氧間苯曱酸氯（965mg)加入至2-(4 -苄氧基-3 -曱氧基苯亞磺醯基）—3, 5 _二氟苯曱酸曱酯（茶考例25 - 4)(495mg)及二氣甲烷（11· 9mL)之混合物中亚授摔3小時。於混合物中加水（llmL)後用醋酸乙酯書（48mL)萃取有機液層依次以im〇i/L硫代硫酸納水溶液 (llmL)、2mol/L氫氧化鈉水溶液（llmL)2次、食鹽水洗條’用無水硫酸納乾燥後在減壓下進行濃縮，得目標化合物（504mg)。 (參考例30 - 10) 1 [2 (4 —节氧基-3 -甲氧基苯磺醯基）—3, 5 -二氟苯基]乙酮在室溫，摔下’將過氧間苯曱酸氯（965mg)加入至1 - [2 -（4 -苄氧基-3〜甲氧基苯亞磺醯基）_ 3, 5 一二氟苯 312XP/發明說明書(補件)/96·03/951439〇〇 68 200800871 基]乙_ (參考例62 — l)(486mg)及二氯甲烷（12· ImL)之混合物中並攪拌12小時。於混合物加入水u〇. 8mL)後用醋酉文乙g曰（47mL)萃取。有機液層依次以im〇1/L硫代硫酸鈉谷液（10· 8mL)、2mol/L氫氧化鈉水溶液（10. 8mL)2次、良鹽水洗條’用無水硫酸鈉乾燥後在減壓下進行濃縮，得目才示化合物（545mg)。依芩考例30 - 1相同方法，使用對應之二苯硫以代替 1 [3 — (4 —苄氧基—3 —甲氧基苯亞磺醯基）-5 -氯笨基]乙酮，合成麥考例2〜參考例3〇 - 8及3〇 — “〜 30 - 14。此等示於表12。6.80(2H,m),6·85-6·90(ιη,π〇,7·10-7·45(7Η m) 7 4R -7.60(2H,m) ' ' · b (Reference Example 29-4 ) 4-Li R (CDC13) 6· 85 (2H, m), 6 -7· 45 (7H, m) occupies PPm: 3.83 (3H, s), 5· 14 (2H, s), • 85-6 · 90 (ih, m), 6· 90-7· 20 (2H, m) 6· 80-7. 20 (Reference Example 29-5) lH-NMR (CDCl3) ^ ppm: 6.91 (lH5 t, J = 55.0 Hz), 7.30^7 5〇_ (2H, m), 7·55~7.7〇(2H,m) · (Reference Example 29-6) ^^NMRCCDCls) ^ ppm : 6.69-6.97(2H,m) 5 7. 40-7. 48 (1H, m), 7· 56~7· 58(1H,m) ' (Reference Example 30-1) [3 312XP/Invention Manual (supplement)/96-03/95143900 67 200800871 Stirring at room temperature for 1 hour in a mixture of B. 1 (Reference Example 26-1) (258 mg) and dichloromethane (6.5 mL). The reaction mixture was washed with ethyl acetate and water as a liquid. The organic layer was washed successively with 1 mol / L aqueous sodium thiosulfate solution, 2 mol / L aqueous sodium hydroxide solution, brine, and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave the title compound (277 mg). NMRCCDCh) (5 ppm : 2e 62 (3H5 s), 3. 94 (3Η, s), 5. 20 (2Η, s), 6· 95-7. 〇〇 (ιη, m), 7· 25-7 · 45(6Η,m),7· 45-7· 55 (1Η,m),8· 00 —8· 1〇(2Η,m),8· 25-8· 35(1Η,m) ·(Reference Example 30 — 9) 2 I(4-benzyloxy-3 methoxyphenylsulfonyl)-3,5-difluorobenzoate decyl ester under the temperature drop to 'peroxide isophthalic acid Chlorine (965 mg) was added to 2-(4-benzyloxy-3-indolyl sulfinyl)-3,5-difluorobenzoic acid decyl ester (Tea Test 25 - 4) (495 mg) and A mixture of dioxane methane (11.9 mL) was subliminated for 3 hours. Water (llmL) was added to the mixture, and the organic layer was extracted with ethyl acetate (48 mL) to give an aqueous solution of im〇i/L sodium thiosulfate. llmL), 2mol/L sodium hydroxide aqueous solution (llmL) twice, and the salt-washing strip was dried with anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (504 mg). (Reference Example 30 - 10) 1 [2 (4 - hydroxy-3-methoxyphenylsulfonyl)-3,5-difluorophenyl]ethanone fell at room temperature, adding peroxyisophthalic acid chloride (965 mg) to 1 - [2 -(4-benzyloxy-3~A Benzosulfinyl)_3,5-difluorobenzene 312XP/Invention Manual (supplement)/96·03/951439〇〇68 200800871 Base]B_ (Reference Example 62-1) (486mg) and Dichloro A mixture of methane (12·1 mL) was stirred for 12 hours, and water (5 mL) was added to the mixture, and then extracted with EtOAc (EtOAc). The organic layer was sequentially treated with im〇1/L sodium thiosulfate solution (10·8 mL), 2 mol/L sodium hydroxide aqueous solution (10. 8 mL) twice, and brine was washed with anhydrous sodium sulfate. Concentration under reduced pressure gave the compound (545 mg). In the same manner as in Test Example 30-1, the corresponding diphenyl sulfide was used instead of 1 [3 - (4-benzyloxy-3-methoxybenzylsulfinyl)-5-chlorophenyl]ethanone. Synthetic wheat test 2 to reference examples 3 〇 - 8 and 3 〇 - "~ 30 - 14. These are shown in Table 12.

312XP/發明說明書(補件)/96-03/95143900 69 200800871 [表 12] 參考例構造式參考例構造式 30-1 30-8 30-2 30-9 30-3 (Τ夕太 30-10 30-4 30-11 30-5 hXf 30-12 cr^ 30-6 30-13 30-7 hXf j0rs^ Cr°T 30-14 0,¾^1 cr^ 參考例30 - 2〜參考例30 - 14之物性值係如下示。 (參考例30-2) ^-NMRCCDCh) 5 ppm ： 3, 94(3H, s), 3.95(3H,s), 5.20 (2H，s)，6.95-7.00(lH，m)，7.25-7.45(6H，m)，7.45-7.55(lH?m), 8. 00-8. 10(1H, m), 8. 10-8. 20(1H? m), 8.40 312XP/發明說明書(補件)/96-03/95143900 70 200800871 -8· 45(1H，m) (參考例30-3) 'H-丽R(CDC13) (5 ppm:l.43(3H，1:，J = 7.2Hz)，2.48(3H，s)， 3.93(3H，s)，4.47(2H，q，J = 7.2Hz)，5.20(2H，s)，6.94 (lH，d，J = 8.6Hz)，7·25-7·42(5Η，πι)，7.61(lH，dd，J = 8·6,2·2Ηζ)，7.67(lH，d，J = 2.2Hz) (參考例30-4) ^-NMRCCDCla) 5 ppm ： 3. 95(3H, s), 5.21(2H,s)5 6.65 ⑩（lH，t，J = 55.9Hz)，6.95-7. 00(lH，m)，7.25 —7·45(6Η，πι)， 7. 45-7. 55(lH, m), 7. 60-7. 70(1H, m), 7. 90-7. 95(1H, m), 7. 95-8. 00(lH,m) (參考例30-5) NMR(CDC13) δ ppm : 3.92(3H，s)， 5.21(2H，s)， 6. 90-7. 00(2H,m), 7. 25-7. 45(6H, m), 7. 50-7. 55(1H, m), 7· 55-7· 65(1H，m)，7· 94(1H，t，J = 54· 9Hz) 鲁（參考例30-6) 4-NMR(CDCh) 5 ppm:3.93(3H，s)，5.21(2H，s)，6·95-7·00(1Η，ηι)，7·20-7·30(1Η，πι)，7·30-7·45(5Η，ιη)，7·50 -7· 75(4Η，m)，7· 98(1Η，t，J = 54· 9Ηζ) (參考例30-7) 7· 00(lH，m)， 7· 20-7· 50(8H，m)， 7· 50-7· 85(2Η，m)， 8· 05-8· 15(lH，m) (參考例30-8) 312XP/發明說明書(補件)/96-03/95143900 71 200800871 NMR(CDCh) ά ppm : 3. 95(3H，s)， 5· 21(2H，s)， 6. 95-7. 00(1H, m), 7. 25-7. 45(6H, m), 7. 45-7. 55(1H, m), 7.60-7·70(1Η，ιη)，7·75 - 7.85(lH，m)，8.10-8.20(2H，m) (參考例30-9) 1-丽R(CDCh) (5 ppm:3.96(3H，s)，4.04(3H，s)，5.22 (2H，s)，6·85-7·05(3Η，ιη)，7·25-7·50(5Η，ιη)，7.55-7· 70(2H，m) (參考例30-10) ⑩1Η-丽R(CDC13) (5 ppm : 2.72(3H，s)， 3· 97(3H，s), 5· 21(2H，s)， 6· 70-6· 80(1H，m)， 6. 80-6, 90(lH,m), 6·95-7·00(1Η，ηι)，7·30-7·35(1Η，πι)，7·35-7.45(4H，m)， 7. 45-7. 55(1 H, m), Ί. 55-7. 60(1 Η, m) (參考例30-11) 4-丽{?(〇0(：13)(5??111:1.30(311，1:，】二7.3112)，2.99 (2H，q，J = 7.3Hz)，3.98(3H，s)，5.21(2H，s)，6·65-6·75 • (lH，m)，6.80-6.90(lH，m)，6.90-7.00(lH，m)，7.25-7.45(5H，m)，7·45 - 7.60(2H，m) (參考例30-12) iH-NMRCCDCls) (5 ppm:2.86(3H，s)，2.87(3H，s)，3·94 (3H,s), 5.22(2H,s), 6. 97( 1H, d, J-8, 2Hz), 7.29-7. 44 (7H，m)，7·51-7·65(3Η，π〇，8·07-8.〇9(lH，m) (參考例30-13) 1H-NMR(CDCl3) (5 ppm ： 3, 97(3H, s), 5.19(2^,8), 6.92 (lH，d，J = 8.5Hz)，7.29-7.59(9H，m)，7.73(lH，d，J = 312XP/發明說明書(補件)/96-03/95143900 72 200800871 2.2Hz)，7.76-7.81(2H，m)，7.93-7.95(2H，m)，8.33-8·37(1Η，π〇，8·50 - 8.53(lH，m) (參考例30-14) lH-NMR(CDCh) (5 ppm： 3. 20(1H5 d, J = 3. 8Hz), 3. 86(3H, s), 5.20(2H，s)，6.65(lH，d，J = 3.8Hz)，6.91(lH，d，J = 8.6Hz), 7. 11-7. 13(2H5m), 7. 21-7. 27(4H, m), 7.31-7.50(9H,m), 8. 07-8. 08(1H, m) (參考例31 - 1) 1 - [3 -氯-5 - (4 -羥基-3-甲氧基苯磺醯基）苯基] 乙酮在室溫攪拌下’將四氯化鈦（〇 · 14mL)加入至1 - [ 3 - (4 -苄氧基-3 -甲氧基苯石黃醯基）—5 -氯苯基]乙酮（參考例30- l)(276mg)及二氯曱烷（107mL)之混合物中，並312XP/Invention Manual (supplement)/96-03/95143900 69 200800871 [Table 12] Reference example Construction formula Reference example Structure 30-1 30-8 30-2 30-9 30-3 (Τ夕太30-10 30-4 30-11 30-5 hXf 30-12 cr^ 30-6 30-13 30-7 hXf j0rs^ Cr°T 30-14 0,3⁄4^1 cr^ Reference example 30 - 2~ Reference example 30 - The physical property values of 14 are as follows (Reference Example 30-2) ^-NMRCCDCh) 5 ppm : 3, 94 (3H, s), 3.95 (3H, s), 5.20 (2H, s), 6.95-7.00 (lH , m), 7.25-7.45 (6H, m), 7.45-7.55 (lH?m), 8. 00-8. 10(1H, m), 8. 10-8. 20(1H? m), 8.40 312XP /Inventive Manual (Supplement)/96-03/95143900 70 200800871 -8· 45(1H,m) (Reference Example 30-3) 'H-Li R (CDC13) (5 ppm: l.43(3H,1 :, J = 7.2 Hz), 2.48 (3H, s), 3.93 (3H, s), 4.47 (2H, q, J = 7.2 Hz), 5.20 (2H, s), 6.94 (lH, d, J = 8.6 Hz), 7·25-7·42 (5Η, πι), 7.61 (lH, dd, J = 8·6, 2·2Ηζ), 7.67 (lH, d, J = 2.2 Hz) (Reference Example 30-4 ^-NMRCCDCla) 5 ppm : 3. 95(3H, s), 5.21(2H,s)5 6.65 10(lH,t,J = 55.9Hz), 6.95-7. 00(lH,m),7.25 — 7·45(6Η,πι), 7. 45-7. 55(lH, m), 7. 60-7. 70(1H, m), 7. 90-7. 95(1H, m), 7. 95-8. 00(lH,m) (Reference Example 30-5) NMR(CDC13) δ ppm : 3.92(3H,s), 5.21 (2H, m), 7. 90-7. 00(2H,m), 7. 25-7. 45(6H, m), 7. 50-7. 55(1H, m), 7· 55-7 · 65 (1H, m), 7. 94 (1H, t, J = 54· 9 Hz) Lu (Reference Example 30-6) 4-NMR (CDCh) 5 ppm: 3.93 (3H, s), 5.21 (2H, s),6·95-7·00(1Η,ηι),7·20-7·30(1Η,πι),7·30-7·45(5Η,ιη),7·50 -7· 75( 4Η,m),7·98(1Η,t,J=54·9Ηζ) (Reference Example 30-7) 7· 00(lH,m), 7· 20-7· 50(8H,m), 7· 50-7·85(2Η,m), 8· 05-8· 15(lH,m) (Reference Example 30-8) 312XP/Invention Manual (Supplement)/96-03/95143900 71 200800871 NMR(CDCh) ά ppm : 3. 95(3H,s), 5· 21(2H,s), 6. 95-7. 00(1H, m), 7. 25-7. 45(6H, m), 7. 45 -7. 55(1H, m), 7.60-7·70(1Η,ιη), 7.75 - 7.85(lH,m), 8.10-8.20(2H,m) (Reference Example 30-9) 1-Li R(CDCh) (5 ppm: 3.96 (3H, s), 4.04 (3H, s), 5.22 (2H, s), 6.85-7.05 (3Η, ιη), 7·25-7·50 ( 5Η, ιη), 7.55-7·70(2H,m) (Reference Example 30-10) 101Η-丽R(CDC13) (5 ppm : 2.72(3H,s) , 3· 97(3H,s), 5· 21(2H,s), 6· 70-6· 80(1H,m), 6. 80-6, 90(lH,m), 6·95-7 ·00 (1Η, ηι), 7·30-7·35 (1Η, πι), 7·35-7.45(4H,m), 7. 45-7. 55(1 H, m), Ί. 55- 7. 60(1 Η, m) (Reference Example 30-11) 4-Li{?(〇0(:13)(5??111:1.30(311,1:,=2 7.3112), 2.99 (2H, q, J = 7.3 Hz), 3.98 (3H, s), 5.21 (2H, s), 6·65-6·75 • (lH, m), 6.80-6.90 (lH, m), 6.90-7.00 (lH , m), 7.25-7.45 (5H, m), 7.45 - 7.60 (2H, m) (Reference Example 30-12) iH-NMRCCDCls) (5 ppm: 2.86 (3H, s), 2.87 (3H, s ),3·94 (3H,s), 5.22(2H,s), 6. 97( 1H, d, J-8, 2Hz), 7.29-7. 44 (7H,m),7·51-7· 65(3Η,π〇,8·07-8.〇9(lH,m) (Reference Example 30-13) 1H-NMR(CDCl3) (5 ppm : 3, 97(3H, s), 5.19(2^ , 8), 6.92 (lH, d, J = 8.5Hz), 7.29-7.59 (9H, m), 7.73 (lH, d, J = 312XP / invention specification (supplement) / 96-03/95143900 72 200800871 2.2 Hz), 7.76-7.81 (2H, m), 7.93-7.95 (2H, m), 8.33-8.37 (1Η, π〇, 8.50 - 8.53 (lH, m) (Reference Example 30-14) lH -NMR (CDCh) (5 ppm: 3. 20 (1H5 d, J = 3. 8Hz), 3. 86(3H, s), 5.20 (2H, s), 6.65 (lH, d, J = 3.8 Hz), 6.91 (lH, d, J = 8.6 Hz), 7. 11-7. 13(2H5m), 7. 21-7. 27(4H , m), 7.31-7.50(9H,m), 8. 07-8. 08(1H, m) (Reference Example 31 - 1) 1 - [3 -Chloro-5 - (4-hydroxy-3-methoxy) Addition of titanium tetrachloride (〇·14 mL) to 1-[3-(4-benzyloxy-3-methoxybenzoquinone) at room temperature with stirring a mixture of 5-chlorophenyl]ethanone (Ref. 30-l) (276 mg) and dichloromethane (107 mL), and

攪拌17为叙。於反應混合物中加入1 m〇 1 /l鹽酸後激烈攪拌。分離有機液層後，用無水硫酸鈉乾燥後在減壓下'進行濃縮。其殘留物以石夕膠管柱色析法進行精製（洗提液：己烷/醋酸乙酯=2/1至 (194mg) 〇 1 /1之梯度洗提），得目標化合物 iH-NMRCCDClsjdppm : 2 。η。/ s), 3. 98(3H, s),6.10 (1H，s)，7· 00-7· 10(1H，m) 7 7 yj r, t 口、 Α「4ϋ-7·45(1Η，πι)，7·50 — 7·60 (lH,m), 8. 00-8. 10(2H,m), 8. 30-8. 35(1H m) (參考例31 - 8) ’ 甲氧基苯磺醯基）苯甲 3，5-二氟-2 -（4-經基—3 酸甲酯 312XP/發明說明書(補件)/96-03/95143900 73 200800871 在室溫攪拌下，將四氯化鈦（〇· 245mL)加入2 - (4 -节氧基-3-曱氧基苯磺酿基3,5 -二氟苯曱酸曱酯（參考例30 - 9)(501 mg)及二氯曱烷（18· 6mL)之混合物中並擾拌20分鐘。於混合物加入lmol/L鹽酸（i6mL)，用無水硫酸納乾燥後在減壓下進行濃縮。其殘留物以矽膠管柱色析法進行精製（洗提液：〇%至40%醋酸乙酯-己烷之梯度洗 k) ’得目標化合物（318mg)。 (參考例31 - 9) 馨 1 - [3，5-二氟-2 -（4-經基-3 -曱氧基苯石黃醒基）苯基]乙酮在室溫攪拌下，將四氯化鈦（〇·275ιηΙ〇加入至1 - [2-(4 -苄氧基-3 -曱氧基苯磺醯基）-3, 5 -二氟苯基]乙酉同（芩考例30- l〇)(542mg)及二氯甲烷（20.9inL)之混合物中並攪拌18分鐘。於混合物中加入im〇i/L鹽酸 (18· 9mL)，用無水硫酸鈉乾燥後在減壓下進行濃縮。其殘 _留物用水（5mL)進行粉碎，濾取其固體並用水（5mL)洗滌5 次後減壓乾燥，得目標化合物（390^)。依參考例31 - 1相同方法，使用對應之二苯砜以代替 1 - [3 - (4-苄氧基—3 -曱氧基苯磺醯基）-5 -氯苯基] 乙酮，合成參考例31 - 2〜參考例31 - 7及31 - 10〜31 -12。此寻不於表13。 312XP/發明說明書(補件)/96_〇3/95143900 74 200800871 [表 13] 參考例構造式參考例構造式 3卜1 /0 CI 31-7 hXf /0 31-2 €ί 31-8 31-3 /0 31-9 H〇J?& /0 31-4 V Ρ hWh /0 Cl 31-10 /0 31-5 Λ /〇 3M1 、x 〇、 3卜6 HnLf /0 31 -12 〇,βΡ ΗΟ^ 0、Stir 17 for the narrative. After 1 m 〇 1 /l hydrochloric acid was added to the reaction mixture, the mixture was vigorously stirred. After separating the organic layer, it was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by a Shih-Hui column chromatography (eluent: hexane/ethyl acetate = 2/1 to (194 mg) 〇1 /1 gradient elution) to give the target compound iH-NMRCCDClsjdppm : 2 . η. / s), 3. 98(3H, s), 6.10 (1H, s), 7· 00-7· 10(1H,m) 7 7 yj r, t mouth, Α "4ϋ-7·45 (1Η, Πι),7·50 — 7·60 (lH,m), 8. 00-8. 10(2H,m), 8. 30-8. 35(1H m) (Reference Example 31 - 8) 'Methoxy Benzosulfonyl)benzazole 3,5-difluoro-2 -(4-carbyl-3-carboxylate 312XP/Invention Manual (supplement)/96-03/95143900 73 200800871 Stir at room temperature, Titanium tetrachloride (〇·245 mL) was added to 2-(4-oxo-3-oxobenzenesulfonyl aryl 3,5-difluorobenzoate (Example 30-9) (501 mg) And a mixture of dichloromethane (18. 6 mL) and spoiled for 20 minutes. Add 1 mol / L hydrochloric acid (i6mL) to the mixture, dry with anhydrous sodium sulfate and concentrate under reduced pressure. Purification by color analysis (eluent: 〇% to 40% ethyl acetate-hexane gradient washing k) 'The target compound (318 mg). (Reference Example 31 - 9) Xin 1 - [3,5-II Fluorine-2 -(4-carbazhen-3-methoxybenzophenone) phenyl]ethanone Titanium tetrachloride (〇·275ιηΙ〇 added to 1 - [2-(4- Benzyloxy-3-indolylbenzenesulfonyl)-3, 5 - two A mixture of phenyl]acetamidine (芩 30 30-l〇) (542 mg) and dichloromethane (20.9 inL) was stirred for 18 minutes. Im 〇i/L hydrochloric acid (18·9 mL) was added to the mixture. After drying over anhydrous sodium sulfate and concentrating under reduced pressure, the residue was crystallized from water (5 mL), and the solid was filtered, washed with water (5 mL) 5 times and dried under reduced pressure to give the title compound (390^). In the same manner as in Reference Example 31-1, the corresponding diphenyl sulfone was used instead of 1-[3-(4-benzyloxy-3-methoxysulfonyl)-5-chlorophenyl]ethanone. Example 31 - 2 to Reference Examples 31 - 7 and 31 - 10 to 31 -12. This is not found in Table 13. 312XP / Invention Manual (supplement) / 96_〇 3/95143900 74 200800871 [Table 13] Reference example construction Formula Reference Formula 3 Bu 1 /0 CI 31-7 hXf /0 31-2 €ί 31-8 31-3 /0 31-9 H〇J?& /0 31-4 V Ρ hWh /0 Cl 31-10 /0 31-5 Λ /〇3M1 , x 〇, 3 卜 6 HnLf /0 31 -12 〇, βΡ ΗΟ^ 0,

參考例31 - 2〜參考例31 - 12之物性值係如下示。 (參考例31 -2) ^-NMRCCDCh) (5 ppm ： 3, 95(3H, s), 3. 98(3H,s), 6,09 (lH，s)，7\ 00-7.05(lH，m)，7.35-7.45(lH，m)，7.50-7.60(lH，m)，8.00-8·10(1Η，πι)，8·10-8·20(1Η，πι)，8·40 -8· 45(1Η，m) (參考例31-3) !Η-NMR(CDCh) (5 ppm:1.43(3H，t，J = 7.2Hz)，2.49(3H，s)， 312XP/發明說明書(補件)/96-03/95143900 75 200800871 3.96(3H，s)，4.48(2H，q，J 二 7·2Ηζ)，6.08(lH，s)，7·00 (lH，d，J = 8.2Hz)，7·26-7·29(2Η，π〇，7,65(lH，dd，J二8.2, 2.0Hz), 7. 69(1H, d, J-2. 0Hz) (參考例31 -4) 4-丽R(CDCh) ά ppm ·· 3· 98(3H，s)， 6· 12(1H，s)， 6.65(lH，t，J二 55.8Hz)，7.00-7.10(lH，m)，7.35 -7· 45(1H，m)， 7· 50-7. 55(1 H, m)， 7. 65-7. 70(lH,m), 7· 90-7· 95(lH，m)，7· 95-8. 00(lH，m) 馨（參考例3卜5) !Η-丽R(CDC13) (5 ppm : 3· 96(3H，s)， 6· 12(1H，s)， 6·90-7.05(2H，m)，7.40-7.45(lH，m)，7: 50—7.55(lH，m)， 7· 55-7· 65(1H，m)，7· 95(1H，t，J = 54· 9Hz) (參考例31 -6) 4-丽R(CDCh) 5 ppm:3.96(3H，s)，6.12(lH，s)，7·00 -7. 05(1H，m)， 7. 20-7. 30(lH,ra), 7. 50-7. 60(lH,m), φ 7. 60-7. 75(3H,m)5 7. 98(1H, t, J = 55. 1Hz) (參考例31-7) 丽R(CDCh) 5 ppm : 3· 95(3H，s)， 6· 09(1H，s)， 6. 95-7. 05(lH,m), 7. 25-7. 35(1H, m), 7. 35-7. 40(1H, m), 7. 40-7. 50(1Η>Πι)5 7. 50-7. 85(2H,m), 8. 10-8. 20(1H, m) (參考例31-8) 丽R(CDC13) 5 ppm:3.99(3H，s)，4.05(3H，s)，6·12 (lH，s)，6·85 - 7·00(2Η，ιη)，7·00-7.10(lH，m)，7·55-7·70(2Η，m) 312ΧΡ/發明說明書(補件)/96-03/95143900 76 200800871 (參考例31-9) 4-NMR(CDC13) (5 ppm : 2· 73(3H，s)， 4· 00(3H，s)， 6· 10(1H，s)， 6· 70-6· 80(1H，m)， 6· 80-6· 90(1 H，m)， 7·00-7.05(lH，m)，7·45-7、55(lH，m)，7·55-7·65(1Η，πι) (參考例31-10) (2H，q，J = 7.2Hz)，4.00(3H，s)，6.10(lH，s)，6.70-6.75 (lH,m), 6. 80-6. 90(lH,m), 7. 00-7. 05(1H, m), 7.45-⑩ 7. 55(lH，m)，7· 55-7. 65(lH，m) (參考例31-11) 4-丽R(CDC13) 6ppm:2.90(3H，s)，2.95(3H，s)，3.98 (3H，s)，6.12(lH，s)，7.02(lH，d，J = 8.5Hz)，7.43- 7. 65(5H,m)? 8, 10-8. I2(1H, m) (參考例31-12) 4-丽R(CDC13) δ ppm ： 4· 00(3H, s)， 6· 07(1H，s)， _ 6· 97(1H，d，J = 8· 2Hz)，7· 46-7· 60(4H，m)，· 78-7· 81(3H，m )，7. 93-7· 95(2H，m)，8· 35-8· 38(1H，m)，8· 49-8· 53(1H，m) (參考例32 - 1) 3 -（4 -經基-3 -曱氧基苯績醯基）笨曱酿胺在室溫攪拌下，將30%溴化氫-醋酸溶液（5. 2mL)加入至3-(4-苄氧基-3-曱氧基苯磺醯基）苯甲腈（參考例 30 - 8)(582mg)及二氣曱烷（15. 6mL)之混合物中並擾掉2 小時。於反應混合物中加入水後用醋酸乙酯與水進行分液。有機液層用水洗滌3次後，用無水硫酸納乾燥，在減 312XP/發明說明書(補件)/96-03/95143900 77 200800871 壓下進行濃縮。其殘留物以矽膠管柱色析法進行精製（洗提液：己烷/醋酸乙酯= 1/1至1/4之梯度洗提），得目標化合物（152mg)。 'H - NMR(CDCls) δ ppm : 3. 85(3H, s), 6. 90-7. 〇〇(1Η, m), 7.35-7.50 (2H，m)，7.64(lH，brs)，7.65-7.75(lH，m) 8.05-8.15(2H，m)，8.27(lH，brs)，8.35 — 8.45(lH，m)， 10.33(1H，s) ’ (參考例33 - 1) ⑩ 3- (4-經基-3 -甲氧基苯石黃醯基）—n，N -二甲基苯曱醯胺將4 -卞氧基-3 -曱氧基苯硫醇（參考例19 一 1)(1. 〇〇g)、3 -碘苯甲酸乙酯（1· 46g)、三（二苯亞甲基丙酉同）一把(0)二氯甲烧加成物（2〇3mg)、（氧基二—2 1 一伸苯基）雙（二苯基膦）（235mg)、第三丁醇鉀（684mg)及曱苯 U〇mL)之混合物在1()(rC攪拌8小時。將反應混合物待冷鲁郃後通過Celite(註冊商標）矽藻土層過濾，用醋酸乙酯洗提。濾液以食鹽水洗滌，用無水硫酸鎂乾燥後在減壓^ 進行浪縮，得粗製之3 - (4 -苄氧基—3_曱氧基苯亞碏醯基）苯曱酸乙酯。〃在〇°C下，將〇xone(註冊商標）（7 49g)加入至丙酮 (20mL)、水（4mL)、粗製之3_(4_节氧基—3_甲氧基苯亞磺醯基）苯曱酸乙酯及碳酸氫鈉（2 73g)之混合物中=將此混合物升溫至室溫’授拌3〇分鐘。此反應混合物用醋酸乙醋稀f睪，食鹽水洗蘇’無水硫酸鎮乾燥後在減壓下^ 312XP/發明說明書(補件)/96-03/95143900 78 200800871 行濃縮。其殘留物以石夕膠中壓瞢*The physical property values of Reference Examples 31 - 2 to Reference Examples 31 - 12 are as follows. (Reference Example 31 - 2) ^-NMRCCDCh) (5 ppm : 3, 95 (3H, s), 3. 98 (3H, s), 6,09 (lH, s), 7\ 00-7.05 (lH, m), 7.35-7.45 (lH, m), 7.50-7.60 (lH, m), 8.00-8·10 (1Η, πι), 8·10-8·20 (1Η, πι), 8·40 -8 · 45 (1Η, m) (Reference Example 31-3) !Η-NMR (CDCh) (5 ppm: 1.43 (3H, t, J = 7.2Hz), 2.49 (3H, s), 312XP / invention manual (complement) ())/96-03/95143900 75 200800871 3.96 (3H, s), 4.48 (2H, q, J 2·7Ηζ), 6.08 (lH, s), 7·00 (lH, d, J = 8.2Hz) ,7·26-7·29(2Η,π〇,7,65(lH,dd,J=8.2, 2.0Hz), 7. 69(1H, d, J-2. 0Hz) (Reference Example 31 -4 ) 4-Li R(CDCh) ά ppm ·· 3· 98(3H,s), 6· 12(1H,s), 6.65(lH,t,J 2 55.8Hz), 7.00-7.10(lH,m) , 7.35 -7· 45(1H,m), 7· 50-7. 55(1 H, m), 7. 65-7. 70(lH,m), 7· 90-7· 95(lH,m ), 7·95-8. 00(lH,m) Xin (Reference Example 3 Bu 5) !Η-丽R(CDC13) (5 ppm : 3· 96(3H,s), 6·12(1H,s ), 6·90-7.05(2H,m), 7.40-7.45(lH,m),7:50-7.55(lH,m), 7·55-7·65(1H,m),7·95( 1H, t, J = 54· 9Hz) (Reference Example 31 -6) 4-Li R (CDCh) 5 Ppm: 3.96 (3H, s), 6.12 (lH, s), 7·00 -7. 05 (1H, m), 7. 20-7. 30 (lH, ra), 7. 50-7. 60 ( lH,m), φ 7. 60-7. 75(3H,m)5 7. 98(1H, t, J = 55. 1Hz) (Reference Example 31-7) Li R(CDCh) 5 ppm : 3· 95(3H,s), 6· 09(1H,s), 6. 95-7. 05(lH,m), 7. 25-7. 35(1H, m), 7. 35-7. 40( 1H, m), 7. 40-7. 50(1Η>Πι)5 7. 50-7. 85(2H,m), 8. 10-8. 20(1H, m) (Reference Example 31-8) R (CDC13) 5 ppm: 3.99 (3H, s), 4.05 (3H, s), 6·12 (lH, s), 6.85 - 7·00 (2Η, ιη), 7·00-7.10 ( lH,m),7·55-7·70(2Η,m) 312ΧΡ/Invention Manual (supplement)/96-03/95143900 76 200800871 (Reference Example 31-9) 4-NMR (CDC13) (5 ppm : 2· 73(3H,s), 4· 00(3H,s), 6· 10(1H,s), 6· 70-6· 80(1H,m), 6· 80-6· 90(1 H , m), 7·00-7.05 (lH, m), 7·45-7, 55 (lH, m), 7·55-7·65 (1Η, πι) (Reference Example 31-10) (2H, q, J = 7.2 Hz), 4.00 (3H, s), 6.10 (lH, s), 6.70-6.75 (lH, m), 6. 80-6. 90 (lH, m), 7. 00-7. 05(1H, m), 7.45-10 7. 55(lH,m),7·55-7. 65(lH,m) (Reference Example 31-11) 4-Li R(CDC13) 6ppm: 2.90 (3H , s), 2.95 (3H, s) 3.98 (3H, s), 6.12 (lH, s), 7.02 (lH, d, J = 8.5 Hz), 7.43 - 7. 65 (5H, m)? 8, 10-8. I2(1H, m) ( Reference example 31-12) 4-Li R (CDC13) δ ppm : 4· 00(3H, s), 6· 07(1H, s), _ 6· 97 (1H, d, J = 8· 2Hz), 7· 46-7· 60(4H,m),· 78-7· 81(3H,m ), 7. 93-7· 95(2H,m),8· 35-8· 38(1H,m) ,8· 49-8· 53(1H,m) (Reference Example 32 - 1) 3 -(4 -transyl-3-oxophenoxyphenyl) Asterile amine at room temperature with stirring, 30 % hydrogen bromide-acetic acid solution (5.2 mL) was added to 3-(4-benzyloxy-3-indolylbenzenesulfonyl)benzonitrile (Reference Example 30-8) (582 mg) and dioxane The mixture of alkane (15.6 mL) was disturbed for 2 hours. Water was added to the reaction mixture, followed by partitioning with ethyl acetate and water. The organic layer was washed 3 times with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure 312 XP / invention specification (supplement) / 96-03/95143900 77 200800871. The residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate = 1/1 to 1/4 gradient) to give the title compound (152 mg). 'H-NMR (CDCls) δ ppm : 3. 85(3H, s), 6. 90-7. 〇〇(1Η, m), 7.35-7.50 (2H,m), 7.64(lH,brs),7.65 -7.75(lH,m) 8.05-8.15(2H,m), 8.27(lH,brs),8.35 — 8.45(lH,m), 10.33(1H,s) ' (Reference Example 33 - 1) 10 3- ( 4-Phenyl-3-methoxyphthalide xanthyl)-n,N-dimethylbenzamide 4-leudecyloxy-3-nonyloxybenzenethiol (Reference Example 19-1) (1) 〇〇g), ethyl 3-iodobenzoate (1·46g), tris(diphenylmethylene propyl hydrazine), one (0) chloroformate adduct (2〇3mg), (oxygen) A mixture of bis- 2 1 phenyl) bis(diphenylphosphine) (235 mg), potassium t-butoxide (684 mg) and hydrazine Benzene 〇mL) was stirred at 1 () for 8 hours at rC. After being cold-cold, it was filtered through Celite (registered trademark), and washed with ethyl acetate. The filtrate was washed with brine, dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure to obtain a crude 3 - ( 4-Benzyloxy-3-nonyloxybenzylidene)ethyl benzoate 〃〇xone (registered trademark) (7 49 g) was added to acetone (20 mL), water at 〇 °C. 4mL), crude In a mixture of 3-(4-hydroxy-3-methoxysulfonyl) benzoic acid ethyl ester and sodium hydrogencarbonate (2 73 g) = the mixture was allowed to warm to room temperature and stirred for 3 minutes. The reaction mixture was diluted with acetic acid ethyl acetate, washed with sodium chloride and dried over anhydrous sulfuric acid, and then concentrated under reduced pressure. 312XP/invention specification (supplement)/96-03/95143900 78 200800871 concentrated. Pressure in the glue*

i e柱色析法進行精製（洗提液·己烷/醋酸乙酯=2/10)，楫q ( A 丁 -苄氧基一 3-甲氧基苯磺醯基）苯甲酸乙酯（j · 35g)。將3 - (4 - ¥氧基-3 —甲氧基苯續酿基）苯甲酸乙醋 (1.35g)、2mol/L氫氧化納水溶液及四氫π夫喃⑽l)之混合物迴流2小時。將反應混合物待冷卻至室溫後以濃鹽酸調整為酸性’用醋酸乙㈣釋。有機液層以食鹽水洗條，Purification by column chromatography (eluent, hexane/ethyl acetate = 2/10), 楫q (A-benzyloxy-3-methoxyphenylsulfonyl) benzoic acid ethyl ester (j · 35g). A mixture of 3-(4-valentoxy-3-methoxybenzoic acid) benzoic acid ethyl acetate (1.35 g), a 2 mol/L aqueous sodium hydroxide solution, and a tetrahydro π-propanol (10) 1) was refluxed for 2 hours. The reaction mixture was allowed to cool to room temperature and then adjusted to acidic with concentrated hydrochloric acid. The organic layer is washed with saline solution,

以無水硫酸鎂乾燥後，在減壓下進行濃縮，得粗製之3一 (4卞氧基-3 -曱氧基苯石黃酸基）苯甲酸。將1乙基3 (3 — —曱胺丙基）碳化二亞胺鹽酸鹽 (217mg)加入至粗製之3 - (4 -苄氧基—3 —曱氧基苯磺醯基）苯甲酸、二曱胺鹽酸鹽（123mg)、1 —羥基苯并*** (153mg)、三乙胺（22911^)及二氯曱烷（3〇1111〇之混合物中，在室溫下攪拌2小時。有機液層以水洗滌，以無水硫酸鎂乾燥後在減壓下進行濃縮。其殘留物以石夕膠中壓管柱色析法進行精製（洗提液：醋酸乙酯），得3 - (4 -苄氧基—3 ~ 曱氧基苯磺醯基）-N，N -二甲基苯曱醯胺（241 mg)。在氫氣環境及室溫下，將3 - (4 -苄氧基-3 -曱氧基苯石黃醯基）-N，N -二曱基苯曱酿胺（241 mg)、1 〇%把碳 (20mg、含水50%)及四氫吱喃（20mL)之混合物擾拌2小時。將反應混合物經過濾去除不溶物後，在減壓下濃縮濾液，得目標化合物（206mg)。 NMRCCDCh) 5 ppm : 2. 96(3H, s), 3. 12(3H5 s), 3. 93 (3H，s)，6· 98(1H，d，J= 8· 5Hz)，7· 36(1H，d，J= 2· 2Hz)， 312XP/發明說明書(補件)/96-03/95143900 79 200800871 7. 46(1H, dd, J= 8. 4, 2. 0Hz), 7. 53-7. 61(2H, m), 7. 90-7. 99(2H,m) (參考例33 - 2) 4-氯- 3 -（4-羥基一 3 一甲氧基苯磺醯基）一 n，n 一二甲基苯甲醯胺依與參考例33 - 1相同方法，使用4_氯_ 3_破苯甲酸以代替3-碘苯甲酸乙酯，合成目標化合物。 NMR(DMS0- de) (5 ppm ： 2. 92(3H, s) 3 0K3H s) • 3.34(3H，s)，6.97(lH，d，J=8.2Hz)，7.36_7.47(2H，m)， 7. 63-7. 78(2H，m)，8· 19(lH，d, J=2· 〇Hz) (參考例34 - 1) 4 -（4 -乙基苯石黃醯基）—2 -甲氧基紛將4 -苄氧基-3 -曱氧基笨硫醇（參考例19 一 1 )(370mg)、1-乙基-4 -峨苯（382mg)、參（二苯亞甲基丙酮）二鈀（〇)(69mg)、(氧基二_ 2, 1 -伸苯基）雙（二苯基 _膦）（8111^)、第三丁醇鉀（253mg)及甲苯（6mJL)之混合物在 10 0 C下攪拌整夜。將反應混合物待冷卻後用醋酸乙酯稀釋，依次以lmol/L鹽酸、飽和碳酸氫鈉水溶液及食鹽水洗滌。其有機液層用無水硫酸鎂乾燥後在減壓下進行濃縮。其殘留物以矽膠中壓管柱色析法進行精製（洗提液：己烧/醋酸乙酯= 20/1至3/1之梯度洗提），得1-爷氧基4 (4 -乙基本亞石頁酸基）-2_甲氧基苯（362mg)。在室溫攪拌下’將過氧間苯甲醯氯（5〇mg)加入1 -节氧基- 4 - (4-乙基苯亞石黃醯基）一 2-甲氧基苯（3 “mg)及 312ΧΡ/發明說明書(補件)/96-03/95143900 80 200800871 二氯曱烧（5mL)之混合物中並攪拌1小時。此反應混合物用醋酸乙酷稀釋後通過胺丙基石夕膠進行過濾，再用醋酸乙酯洗提。濾液在減壓下進行濃縮，得1 —苄氧基—4 — (4一乙基苯磺醯基）-2 -曱氧基苯（380mg)。在冰浴攪拌下，將四氯化鈦（392mg)加入1 -苄氧基一 4- (4 -乙基苯磺醯基）-2 —甲氧基苯（38〇mg)及二氣甲烧（30mL)之混合物中，並攪拌23分鐘。將反應混合物以 lmol/L鹽酸洗滌，用無水硫酸鎂乾燥後在減壓下進行濃縮。其殘留物以矽膠管柱色析法進行精製（洗提液：己烷/ 醋酸乙酯= 5/5)，得目標化合物（26〇mg)。丽R(CDCh)5ppm : 1·24(3Η，ΐ，】=7·7Ηζ)，2·71 (2Η, q5 J= 7. 6Hz), 4. 00(3H, s), 7. 36(2H, d, J= 8. 5Hz), 7· 57(1H，d，J= 1· 9Hz)，7· 85(2H，d，J = 8· 5Hz)，8· 32 (1H，d，J= 2· 2Hz)，11· 〇8(lH，s) (參考例34 - 42) 籲 5 -氟- 2 - (4—羥基- 3 -甲氧基苯磺醯基）一 3 —甲基苯甲腈將4 -苄氧基—3 -甲氧基苯硫醇（參考例j 9 一 l)(1.0g)、5 -氟-2 -碘-3 -曱基苯甲腈（參考例16一 16) (1· 4g)、參（二苯亞曱基丙酮）二|巴（〇)(2〇5mg)、（氧基一 —2，1 -伸笨基）雙（二苯基膦）（235mg)、第三丁醇鉀 (685mg)及甲苯（40mL)之混合物在10〇cc下攪拌2小時。將混合物待冷卻後通過Ce life (註冊商標）矽藻土層進行過濾，在減壓下進行濃縮，得粗製之2 _ (4 -苄氧基—3 一 312XP/發明說明書(補件)/96-03/95143900 81 200800871 曱氧基苯亞磺醯基)_5_氟_3_甲基苯甲腈。在室溫攪，下’將過氧間苯甲醯氯(3. 5g)加入至粗製之 2 (4苄氧基-曱氧基苯亞礦醯基）_5_氟_3_曱基苯甲腈及二氯甲燒（2QmL)之混合物中並攪拌整夜。將反應混合物通過胺丙基㈣進行過濾、，再用二氯甲烧洗提。濾液在減壓下進行濃縮，得粗製之2 - (4 -苄氧基_ 3 _ 甲氧基苯磺醯基）一 5_氟_ 3_甲基苯甲腈。平土After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure to give a crude tris(4-methoxy-3-decyloxyphthalic acid) benzoic acid. 1-Ethyl 3 (3-amidopropyl)carbodiimide hydrochloride (217 mg) was added to the crude 3-(4-benzyloxy-3-methoxyphensulfonyl)benzoic acid, The mixture of diammonium hydrochloride (123 mg), 1-hydroxybenzotriazole (153 mg), triethylamine (22911^) and dichloromethane (3〇1111) was stirred at room temperature for 2 hours. The organic layer is washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by a column chromatography (eluent: ethyl acetate) to obtain 3 - ( 4-Benzyloxy-3~nonylbenzenesulfonyl)-N,N-dimethylbenzamide (241 mg) 3-(4-benzyloxy) under hydrogen atmosphere and room temperature -3 - nonyloxyphenyl fluorenyl)-N,N-dimercaptobenzoic acid (241 mg), 1% by weight mixed with carbon (20 mg, 50% aqueous) and tetrahydrofuran (20 mL) After the reaction mixture was filtered to remove the insoluble material, the filtrate was concentrated under reduced pressure to give the title compound (206 mg). NMR CCD Ch) 5 ppm: 2. 96 (3H, s), 3. 12 (3H5 s), 3. 93 (3H, s), 6. 98 (1H, d, J = 8 · 5Hz), 7 · 36 (1H, d, J = 2· 2Hz), 312XP/Invention Manual (supplement)/96-03/95143900 79 200800871 7. 46(1H, dd, J= 8. 4, 2. 0Hz), 7. 53-7. 61(2H, m), 7. 90-7. 99(2H,m) (Reference Example 33-2) 4-Chloro-3-(4-hydroxy-1,3-methoxyphenylsulfonyl)-n, n-dimethyl The benzylideneamine was synthesized in the same manner as in Reference Example 33-1 using 4-chloro-3-benzoic acid in place of ethyl 3-iodobenzoate to synthesize the target compound. NMR (DMS0-de) (5 ppm : 2. 92(3H, s) 3 0K3H s) • 3.34 (3H, s), 6.97 (lH, d, J = 8.2 Hz), 7.36_7.47 (2H, m ), 7. 63-7. 78(2H,m),8· 19(lH,d, J=2· 〇Hz) (Reference Example 34 - 1) 4 -(4-Ethylpyrene)-2 -Methoxy groups of 4-benzyloxy-3-indolyl thiol (Reference Example 19-1) (370 mg), 1-ethyl-4-indenylbenzene (382 mg), ginseng (diphenylmethylene) Acetone) dipalladium (〇) (69 mg), (oxy-2,1-phenylene)bis(diphenylphosphine) (8111^), potassium butoxide (253 mg) and toluene (6 mJL) The mixture was stirred at 10 0 C overnight. After the reaction mixture was cooled, it was diluted with ethyl acetate, and washed with 1 mol/L hydrochloric acid, saturated aqueous sodium hydrogen carbonate and brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by silica gel medium pressure column chromatography (eluent: hexane/ethyl acetate = 20/1 to 3/1 gradient elution) to obtain 1-yoloxy 4 (4-B) Basic sulphate)-2-methoxybenzene (362 mg). Adding peroxybenzhydryl chloride (5 〇 mg) to 1-hydroxy-4-(4-ethylphenyl sulfite) 2-methoxybenzene (3"mg) with stirring at room temperature And 312 ΧΡ / invention manual (supplement) / 96-03/95143900 80 200800871 Dichlorohydrazine (5mL) mixture was stirred for 1 hour. The reaction mixture was diluted with ethyl acetate and filtered through amine propyl sulfite. The extract was extracted with ethyl acetate. The filtrate was concentrated under reduced pressure to give 1-benzyloxy-4-(4-ethylbenzenesulfonyl)-2- methoxybenzene (380 mg). Next, titanium tetrachloride (392 mg) was added to 1-benzyloxy-4-(4-ethylbenzenesulfonyl)-2-methoxybenzene (38 〇mg) and dimethylacetate (30 mL). The mixture was stirred for 23 minutes, and the reaction mixture was washed with 1 mol/L hydrochloric acid, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by gel column chromatography (eluent: hexane / ethyl acetate = 5/5), the target compound (26 〇 mg) was obtained. R (CDCh) 5 ppm : 1 · 24 (3 Η, ΐ, 】 = 7 · 7 Ηζ), 2 · 71 (2 Η, q5 J = 7. 6Hz), 4. 00(3H, s), 7. 36(2H, d, J= 8. 5 Hz), 7· 57 (1H, d, J = 1·9 Hz), 7·85 (2H, d, J = 8·5 Hz), 8·32 (1H, d, J = 2· 2 Hz), 11· 〇8(lH,s) (Reference Examples 34-42) 5- 5-fluoro-2-(4-hydroxy-3-methoxyphenylsulfonyl)-3-methylbenzonitrile 4- 4-benzyloxy —3-methoxybenzenethiol (Reference Example j 9-1) (1.0 g), 5-fluoro-2-iodo-3-indenylbenzonitrile (Reference Example 16-16) (1.4 g),参(diphenylarhenylidene)di-bar (〇) (2〇5mg), (oxy--2,1-extended base) bis(diphenylphosphine) (235mg), potassium butoxide A mixture of (685 mg) and toluene (40 mL) was stirred at 10 ° C for 2 hours. The mixture was cooled, filtered through a Celite (registered trademark) diatomaceous earth layer, and concentrated under reduced pressure to give a crude product. (4-benzyloxy-3 312XP/invention specification (supplement)/96-03/95143900 81 200800871 decyloxy sulfinyl)_5_fluoro_3_methylbenzonitrile. Stir at room temperature , the next 'toluene meta-benzoyl chloride (3.5 g) was added to the crude 2 (4 benzyloxy-decyloxybenzonitrile) _5_fluoro_3_mercaptobenzonitrile and dichloride Stir-fry (2QmL) mixture Night. The reaction mixture was filtered through an amine propyl group (tetra) and then washed with dichloromethane. The filtrate was concentrated under reduced pressure to give crude 2-(4-benzyloxy-3 methoxyphenylsulfonyl)-5-fluoro-3-methylbenzonitrile as crude. Flat soil

在室溫攪拌下，將四氯化鈦（1.54g)加入粗製之2_ (4_ ¥氧基-3 -甲氧基苯磧醯基）_5_氟_3_；甲基苯甲猜及二氣曱烧（3GmL)之混合物中並攪拌1()分鐘。於混合物中力二入lmol/L鹽酸，其有機液層用無水硫酸鎮乾燥^在減壓下進行濃縮。其殘留物时膠管柱色析法進行精製 (洗提液：己烷/醋酸乙酯=丨/丨），得目標化合物。依參考例34- 1相同方法，使用4 1氧基_卜甲氧基-2-曱基苯硫醇以代替4_苄氧基_3__曱氧基苯碚醇，及使用對應之_化苯以代替丨_乙基碘苯，人成參考例34- 2〜參考例34- 41及34 - 43〜34 - 96。此等示於表14。 312XP/發明說明書(補件)/96-03/95143900 82 200800871 [表 14] 參考例構造式參考例構造式 34-1 〆0 34-9 34-2 34-10 ：Xr5i 34-3 co^。、 0 34-11 :X^X 34-4 〇“〇、1 :：CrsX^。 34-12 34-5 〇,.〇 Y C〇rsTi 34-13 :：xy;^F 34-6 34-14 ；〇xx"xx 34-7 iyys^0 34-15 0 V Cl 34-8 v P 34-16 Λ U CotcrTitanium tetrachloride (1.54 g) was added to the crude 2_(4_¥oxy-3-methoxyphenylindenyl)_5_fluoro_3_ under stirring at room temperature; methamphetamine The mixture was burned (3GmL) and stirred for 1 () minutes. The mixture was neutralized with 1 mol/L hydrochloric acid, and the organic layer was dried over anhydrous sulfuric acid and concentrated under reduced pressure. The residue was purified by a hose column chromatography (eluent: hexane / ethyl acetate = hydrazine / hydrazine) to give the title compound. In the same manner as in Reference Example 34-1, 4 1 oxy-p-methoxy-2-mercaptobenzenethiol was used instead of 4-benzyloxy_3__nonoxyphenyl decyl alcohol, and the corresponding _ Benzene is substituted for hydrazine-ethyl iodide, and humans are referred to as Examples 34-2 to Reference Examples 34-41 and 34-43-34-96. These are shown in Table 14. 312XP/Invention Manual (Supplement)/96-03/95143900 82 200800871 [Table 14] Reference example Structure Reference example Structure 34-1 〆0 34-9 34-2 34-10 : Xr5i 34-3 co^. , 0 34-11 :X^X 34-4 〇"〇, 1 ::CrsX^. 34-12 34-5 〇,.〇YC〇rsTi 34-13 ::xy;^F 34-6 34-14 ;〇xx"xx 34-7 iyys^0 34-15 0 V Cl 34-8 v P 34-16 Λ U Cotcr

312XP/發明說明書(補件)/96-03/95143900 83 200800871 [表14(續）]312XP/Invention Manual (supplement)/96-03/95143900 83 200800871 [Table 14 (continued)]

參考例構造式參考例構造式 34-17 34-24 34-1S η V c 34-25 ；:»γχ9 34-19 〇、、◊〇 :xw、 34-26 34-20 :瑪 F十F 34-27 34-21 F 34-28 ；°〇Χ^'4 34-22 ;：xivyc, H 34-29 〇 V ；Χ^Χ〇 34-23 34 -30 312XP/發明說明書(補件)/96-03/95143900 84 200800871 [表14(續）]Reference example Structural formula Reference example Structure 34-17 34-24 34-1S η V c 34-25 ;:»γχ9 34-19 〇, ◊〇: xw, 34-26 34-20 : Ma F 十 F 34 -27 34-21 F 34-28 ;°〇Χ^'4 34-22 ;:xivyc, H 34-29 〇V ;Χ^Χ〇34-23 34 -30 312XP/invention manual (supplement)/96 -03/95143900 84 200800871 [Table 14 (continued)]

參考例讎式參考例構造式 34-31 :分V CI 34-38 34-32 34-39 ΟγίΟ 34-33 :峨Ν 34-40 C〇^c, N 34-34 ff 34-41 n 34-35 ::儀 34-42 34-36 34-43 H 34-37 34 - 44 0% ,0 /0 p 312XP/發明說明書(補件)/96-03/95143900 85 200800871 [表14(續）]Reference example 参考 Reference example Structure 34-31: Sub-V CI 34-38 34-32 34-39 ΟγίΟ 34-33 :峨Ν 34-40 C〇^c, N 34-34 ff 34-41 n 34- 35 ::Instrument 34-42 34-36 34-43 H 34-37 34 - 44 0% , 0 /0 p 312XP / Invention Manual (supplement) /96-03/95143900 85 200800871 [Table 14 (continued)]

312XP/發明說明書(補件)/96-03/95143900 86 200800871 [表14(續厂312XP/Invention Manual (supplement)/96-03/95143900 86 200800871 [Table 14 (Renewal)

312XP/發明說明書(補件)/96-03/95143900 87 200800871 [表14(續）]312XP/Invention Manual (supplement)/96-03/95143900 87 200800871 [Table 14 (continued)]

參考例構造式參考例構造式 34-73 34-80 34-74 34-81 hXp /O F 34-75 34-82 ca众 o^o 1 34 - 76 /0 34-83 34-77 34-84 ::你 Ci 34-78 〆〇 34-85 Cl 34-79 34-86 Cx^x 312XP/發明說明書(補件)/96-03/95143900 88 200800871 [表14(續）] 參考例構造式參考例構造式 34-87 34-92 34-88 34-93 H〇X^sXX0. 34-89 34-94 34-90 Η 34-95 34-91 HO人〆 34-96Reference example Structural formula Reference example Structure 34-73 34-80 34-74 34-81 hXp /OF 34-75 34-82 ca all o^o 1 34 - 76 /0 34-83 34-77 34-84 : : You Ci 34-78 〆〇34-85 Cl 34-79 34-86 Cx^x 312XP/Invention Manual (supplement)/96-03/95143900 88 200800871 [Table 14 (continued)] Reference Example Construction Reference Example Structural formula 34-87 34-92 34-88 34-93 H〇X^sXX0. 34-89 34-94 34-90 Η 34-95 34-91 HO 〆 34-96

參考例3 4 - 2〜參考例3 4 - 9 6之物性值係如下示。 (蒼考例3 4 - 2 ) 'H-NMRCCDCl) δ ppm:3.86 (3H, s), 4.00 (3H, s), 6.95 (1H, d, J=8.4Hz), 7.12-7. 3 23 (1H, m), 7.57-7.63 (1H, m), 7.68 (1H, d, J=2.0Hz)5 8.14 (1H, dd, 1=7.9, L6Hz), 8.43 (1H, d, j=2.1Hz), 11.09 (1H, s) (參考例34 - 3) ^-NMRiCDa ) δ ppm :3.94 (3H, s), 3.96 (3H, s), 7.01 (1H, d, J=8.2Hz), 7.40 (1 H, d, J=1.9Hz), 7.53 (1H, dd, J=8.5, 2.2Hz), 7.98 (1H, d, J=8.5Hz), 8.14 (1H5 d, J= 8·5Ηζ) 89 312XP/發明說明書(補件 V96-〇3/95143900 200800871 (參考例34-4) ^-NMRiCDCl) δ ppm :3.95 (3H, s), 3.96 (3H, s), 7.01 (1H, d, J=8.4Hz), 7.43 (1 3 H, d, J=2.1Hz), 7.53 (1H, dd, J=8.4, 2.2Hz), 7.59 (lHy t, J=7.8Hz), 8.05-8.15 (1H, m), 8.18-8.25 (1H, m), 8.51-8.61 (1H, m) (參考例34-5) 'h-NMRCCDCO δ ppm:3e96 (3H, s), 3.98 (3H, s), 7〇00 (1H, d, J=8.8Hz), 7.47-7. 66 (5H, m), 8.00-8.06 (1H, m) (參考例34 - 6)Reference Example 3 4 - 2 to Reference Example 3 The physical property values of 4 - 9 6 are as follows. (Cang test example 3 4 - 2 ) 'H-NMRCCDCl) δ ppm: 3.86 (3H, s), 4.00 (3H, s), 6.95 (1H, d, J=8.4Hz), 7.12-7. 3 23 ( 1H, m), 7.57-7.63 (1H, m), 7.68 (1H, d, J=2.0Hz)5 8.14 (1H, dd, 1=7.9, L6Hz), 8.43 (1H, d, j=2.1Hz) , 11.09 (1H, s) (Reference Example 34 - 3) ^-NMRiCDa ) δ ppm : 3.94 (3H, s), 3.96 (3H, s), 7.01 (1H, d, J=8.2Hz), 7.40 (1 H, d, J=1.9Hz), 7.53 (1H, dd, J=8.5, 2.2Hz), 7.98 (1H, d, J=8.5Hz), 8.14 (1H5 d, J= 8·5Ηζ) 89 312XP/ Disclosure of the Invention (Repair V96-〇3/95143900 200800871 (Reference Example 34-4) ^-NMRiCDCl) δ ppm : 3.95 (3H, s), 3.96 (3H, s), 7.01 (1H, d, J=8.4Hz ), 7.43 (1 3 H, d, J=2.1Hz), 7.53 (1H, dd, J=8.4, 2.2Hz), 7.59 (lHy t, J=7.8Hz), 8.05-8.15 (1H, m), 8.18-8.25 (1H, m), 8.51-8.61 (1H, m) (Reference Example 34-5) 'h-NMRCCDCO δ ppm:3e96 (3H, s), 3.98 (3H, s), 7〇00 (1H , d, J=8.8Hz), 7.47-7. 66 (5H, m), 8.00-8.06 (1H, m) (Reference Examples 34 - 6)

'H-NMRCCDCl) 6 ppm:2.35 (6H, s), 3.96 (3H, s), 6.99 (1H, d, J=8.5Hz), 7.15 (1 3 H, s), 7.41 (1H, d, J=2.2Hz), 7。49 (1H, dd, J=8.4, 2·0Ηζ)，7。51 (2H，s) (參考例34 - 7) ^-NMRCCDCl) δ ppm:3.95 (3H, s), 6.20 (1H, s), 7.00 (1H, d, J=8.5Hz), 7.08-7. 3 14 (1H, m), 7.27-7.32 (1H, m, J=7.7, 7.7Hz), 7.50-7.58 (3H, m), 8.07 (1H, d, J=1.6 Hz) (參考例34-8) ^-NMR^DGl) δ ppm:3.96 (3H, s), 7.01 (1H, d, J=8.4Hz), 7.17-7.26 (1H, m), 7. 3 40 (1H, d, J=2.1Hz), 7.44-7.55 (2H? m), 7.58-7.64 (1H, m), 7.68-7.73 (1H, m) (參考例34 - 9) "H'NMRCCDCI ) δ ppm :3.95 (3H, s), 6.08 (1H, s), 7.00 (1H, d, J=8.4Hz), 7.13-7； 3 20 (3H, m), 7.39 (IH, d5 J=2„lHz), 7.49 (2H, dd, j=8.4, 2.1Hz), 7.89-7.96 (3H, m) (參考例34-10) 'H-NMRiCDCl) δ ppm:3.93-3.97 (3H, m), 6.98 (1H, d, J=8.5Hz), 7.32-7.45 (2H, 3 m), 7.54 (1H, dd, J=9〇0, 2.7Hz), 8.41 (1H, dd) 312XP/發明說明書(補件)/96-03/95143900 90 200800871 (參考例34-11) 'H-NMRCCDCO δ ppm:3.83-4e〇3 (3Η, m), 6.99 (1H, d5 J=8.5Hz), 7.28-7.46 (3H, m), 7.50-7.59 (1H, m), 8.37-8.47 (1H, m) (參考例34-12) 1H~NMR(CDC1). δ ppm:3.96-4.01 (3H, m), 7.02 (1Ή, dd, J-8.4, 1.4Hz), 7.06 (1H, t, J=9.0Hz), 7.47-7.53 (2H, m), 7.57 (1H, d, J-8.5Hz), 8.01*8.07 (1H, m) (參考例34-13)'H-NMRCCDCl) 6 ppm: 2.35 (6H, s), 3.96 (3H, s), 6.99 (1H, d, J=8.5Hz), 7.15 (1 3 H, s), 7.41 (1H, d, J =2.2 Hz), 7.49 (1H, dd, J=8.4, 2·0Ηζ), 7.51 (2H, s) (Reference Example 34 - 7) ^-NMRCCDCl) δ ppm: 3.95 (3H, s) , 6.20 (1H, s), 7.00 (1H, d, J=8.5Hz), 7.08-7. 3 14 (1H, m), 7.27-7.32 (1H, m, J=7.7, 7.7Hz), 7.50- 7.58 (3H, m), 8.07 (1H, d, J=1.6 Hz) (Reference 34-8) ^-NMR^DGl) δ ppm: 3.96 (3H, s), 7.01 (1H, d, J=8.4 Hz), 7.17-7.26 (1H, m), 7. 3 40 (1H, d, J=2.1Hz), 7.44-7.55 (2H? m), 7.58-7.64 (1H, m), 7.68-7.73 (1H , m) (Reference Example 34 - 9) "H'NMRCCDCI ) δ ppm : 3.95 (3H, s), 6.08 (1H, s), 7.00 (1H, d, J=8.4Hz), 7.13-7; 3 20 (3H, m), 7.39 (IH, d5 J=2„lHz), 7.49 (2H, dd, j=8.4, 2.1Hz), 7.89-7.96 (3H, m) (Reference 34-10) 'H -NMRiCDCl) δ ppm: 3.93-3.97 (3H, m), 6.98 (1H, d, J=8.5Hz), 7.32-7.45 (2H, 3 m), 7.54 (1H, dd, J=9〇0, 2.7 Hz), 8.41 (1H, dd) 312XP/Invention Manual (supplement)/96-03/95143900 90 200800871 (Reference Example 34-11) 'H-NMRCCDCO δ ppm: 3.83-4e〇3 (3Η, m), 6.99 (1H, d5 J=8.5Hz), 7.28-7 .46 (3H, m), 7.50-7.59 (1H, m), 8.37-8.47 (1H, m) (Reference 34-12) 1H~NMR(CDC1). δ ppm:3.96-4.01 (3H, m) , 7.02 (1Ή, dd, J-8.4, 1.4Hz), 7.06 (1H, t, J=9.0Hz), 7.47-7.53 (2H, m), 7.57 (1H, d, J-8.5Hz), 8.01* 8.07 (1H, m) (Reference Example 34-13)

'H-NMRiCDCl) δ ppm:3.98 (3H, s), 6.15 (1H, s), 7.04 (1H5 ds J=8e5Hz), 7.18-7. 3 26 (1H, m), 7.47-7.53 (1H, m), 7.59 (1H, d, J=8.5Hz), 7.79-7.87 (1H, m)s 8.32-8.4 2 (1H，m) (茶考例3 4 -14) ^-NMRCCDCO δ ppm:2.39 (3H, s), 3.96 (3H, s), 6.05 (1HS s), 6.91 (1H, d, J=ll e〇Hz), 6.99 ClH, d, J=8.5Hz), 7.09 (1H, d, J=7.3Hz), 7.48-7^56 (2H, m), 7.93 (1H, t ,J=7〇9Hz) (參考例34-15) 馨 ^-NMRiCDCl) δ ppm :2.54 (3H, s),, 3.93 (3H, s), 6.11 (1H, s), 7.00 (1H, d, J=8. 3 5Hz), 7.29-7.36 (2H, m), 7.39 (1H, dd, J=8.4, 2.0Hz), 7.59 (1H, d, J=7.9Hz), 8.08 ( 1H，d, J=7.9Hz) (參考例34-16) 'H-NMRiCDCl) δ ppm :2.44 (3H, s), 3.95 (3H, s), 6.09 (1H, s), 7〇01 (1H, d, J=8. 3 5Hz), 7.17 (1H, d, J=8.2Hz), 7.35 (1H, d, J=2.2Hz), 7.40-7.47 (2H, m), 8.14 (1H, d ,J=2.2Hz) (參考例34-17) 91 312XP/發明說明書(補件)/96-03/95143900 200800871 'H-NMRXCDCI ) δ ppm :2.47 (3H, s), 3.93 (3H, s), 6.05 (1HS s), 6.94 (1H, d, J=9. 3 5Hz), 6.99 (1H, d, J=8e2Hz), 7.02-7.09 (1H, m), 7.33-7.40 (2H, m)5 8J5-8.20 (1H, m) (參考例34-18) "H-NMR(CDC1) δ ρριη:2·44 (3H，s)，3·94 (3H，s), 6.15 (1H, s)，7。01 (1H，d, J=8. 3 ' 5Hz), 7.14-7.22 (2H, m), 7.32-7.38 (1H, m), 7.43 (1H, dd, J=8e4, 2.0Hz), 7.86 (1H, dd，J:8.5, 2·8Ηζ) (參考例34-19)'H-NMRiCDCl) δ ppm: 3.98 (3H, s), 6.15 (1H, s), 7.04 (1H5 ds J=8e5Hz), 7.18-7. 3 26 (1H, m), 7.47-7.53 (1H, m ), 7.59 (1H, d, J=8.5Hz), 7.79-7.87 (1H, m)s 8.32-8.4 2 (1H,m) (Tea test 3 4 -14) ^-NMRCCDCO δ ppm: 2.39 (3H , s), 3.96 (3H, s), 6.05 (1HS s), 6.91 (1H, d, J=ll e〇Hz), 6.99 ClH, d, J=8.5Hz), 7.09 (1H, d, J= 7.3 Hz), 7.48-7^56 (2H, m), 7.93 (1H, t, J=7〇9Hz) (Reference Example 34-15) 馨^-NMRiCDCl) δ ppm :2.54 (3H, s),, 3.93 (3H, s), 6.11 (1H, s), 7.00 (1H, d, J=8. 3 5Hz), 7.29-7.36 (2H, m), 7.39 (1H, dd, J=8.4, 2.0Hz) , 7.59 (1H, d, J=7.9Hz), 8.08 ( 1H,d, J=7.9Hz) (Reference Example 34-16) 'H-NMRiCDCl) δ ppm :2.44 (3H, s), 3.95 (3H, s), 6.09 (1H, s), 7〇01 (1H, d, J=8. 3 5Hz), 7.17 (1H, d, J=8.2Hz), 7.35 (1H, d, J=2.2Hz), 7.40-7.47 (2H, m), 8.14 (1H, d, J=2.2Hz) (Reference 34-17) 91 312XP/Invention Manual (supplement)/96-03/95143900 200800871 'H-NMRXCDCI δ ppm : 2.47 (3H, s), 3.93 (3H, s), 6.05 (1HS s), 6.94 (1H, d, J=9. 3 5Hz), 6.99 (1H, d, J=8e2Hz), 7.02-7.09 ( 1H, m), 7.33-7.40 (2H, m)5 8J5-8 .20 (1H, m) (Reference Example 34-18) "H-NMR(CDC1) δ ρριη: 2·44 (3H, s), 3·94 (3H, s), 6.15 (1H, s), 7.01 (1H,d, J=8. 3 '5Hz), 7.14-7.22 (2H, m), 7.32-7.38 (1H, m), 7.43 (1H, dd, J=8e4, 2.0Hz), 7.86 (1H, dd, J: 8.5, 2·8Ηζ) (Reference Example 34-19)

^-NMRCCDCl) δ ppm :3.89 (3H, s), 3.96 (3H, s), 6.99 (1H, d, J=8.2Hz), 7.02 (1 3 H? dd, J=8.7, 3.0Hz), 7.31 (1H, d, J=8.5Hz), 7.49 (2H, td, J=9„0, 2〇2Hz), 7〇84 (1H, d, J=3.2Hz) (參考例34-20) ^-NMRiCDCl) δ ppm:3.99 (3H, s), 7.04 (1H, d, J=8.4Hz), 7.35-7.46 (2H, m), 7. 3 49-7。60 (2H, m), 7.78-7.86 (1H，m), 8.25-8.35 (1H, m) (參考例34-21) 1H-NMR(CDC1 ) δ ppm:2〇39 (3H, d, J=2.2Hz), 3.94 (3H, s), 6.09 (1H, s), 7.00 (1 3 H, d, J=8.4Hz), 7.15-7.26 (1H, m), 7.31-7.43 (3H, m), 7.94 (1H, d, J=7.9Hz) (參考例34-22) ^-NMRCCDCl ) δ ppm:3.99 (3H, s), 7.06 (1H, d, J=8.4Hz), 7.38 (1H, d, J=2〇lHz 3 ),7.53 (1H, dd, J=8.4, 2.1Hz), 7.74-7.80 (1H, m), 8.03^8.06 (1H, m), 8,09~8〇12 (1 H, m) (參考例34-23) —NMR(CDC13) δ ppm:4.01 (3H; s)，6·17 (1H, s), 7·02 (1H, d, J=8.5Hz)，7。42—7· 53 (2H, m), 7〇73 (1H, d, J=2.1Hz), 8.30-8.35 (1H, m) 92 312XP/發明說明書(補件)/96-03/95143900 200800871 (參考例34-24) 'H-NMRCCDCU δ ppm:2.54 (3Η, s), 3.91-3.96 (3H, m), 7.00-7.05 (1H, m), 7.27 -7.35 (1H, m), 7Α0-7Λ7 (1H, m), 7.49-7.56 (1H, m), 7.66 (1H, d, J=8e2Hz), 8Λ8-8.23 (1H, m) (參考例34-25) 1H-NMR(CDC〇 δ ppm: 1.68-1.73 (4H, m), 2.78 (2H, s), 2.92 (2H, s), 3.92 (3H, s ),6.98 (1H, d, J=8„5Hz), 7.35 (1H, d, J=2.2Hz), 7.38 (1H, dd, J=8.4, 2〇0Hz), 7〇96 ( 1H, d, J=7.6Hz) ⑩（參考例34-26) ^-NMRiCDCl ) δ ppm:2.45 (3H, s), 3.93 (3H, s), 6.99 (1H, d, J=8.2Hz), 7.23 (1 3 H, d, J=L6Hz), 7〇33 (1H, d, J=2.2Hz), 7.35 (1H, dd, J=8.5, 2.2Hz), 7.40 (1H, dd, J =8·5, 2·2Ηζ), 8.08 (1H, d, J二8·5Ηζ) (參考例34-27) ^-NMRiCDCl ) δ ppm:2.37 (3H, s), 3.94 (3H, s), 6.12 (1H, s), 6.98 (1H, d, J=8. 3 2Hz), 7β36 (1H? t, J=7.7Hz), 7.44-7.50 (3H, m), 8.18 (1H, dd, J=7.9, l〇3Hz)^-NMRCCDCl) δ ppm : 3.89 (3H, s), 3.96 (3H, s), 6.99 (1H, d, J=8.2Hz), 7.02 (1 3 H? dd, J=8.7, 3.0Hz), 7.31 (1H, d, J=8.5Hz), 7.49 (2H, td, J=9„0, 2〇2Hz), 7〇84 (1H, d, J=3.2Hz) (Reference Example 34-20) ^- NMRiCDCl) δ ppm: 3.99 (3H, s), 7.04 (1H, d, J=8.4Hz), 7.35-7.46 (2H, m), 7. 3 49-7.60 (2H, m), 7.78-7.86 (1H,m), 8.25-8.35 (1H, m) (Reference Example 34-21) 1H-NMR (CDC1) δ ppm: 2〇39 (3H, d, J=2.2Hz), 3.94 (3H, s) , 6.09 (1H, s), 7.00 (1 3 H, d, J=8.4Hz), 7.15-7.26 (1H, m), 7.31-7.43 (3H, m), 7.94 (1H, d, J=7.9Hz (Reference Example 34-22) ^-NMRCCDCl ) δ ppm: 3.99 (3H, s), 7.06 (1H, d, J=8.4Hz), 7.38 (1H, d, J=2〇lHz 3 ), 7.53 ( 1H, dd, J=8.4, 2.1Hz), 7.74-7.80 (1H, m), 8.03^8.06 (1H, m), 8,09~8〇12 (1 H, m) (Reference 34-23) —NMR(CDC13) δ ppm:4.01 (3H; s),6·17 (1H, s), 7·02 (1H, d, J=8.5Hz), 7.42—7· 53 (2H, m) , 7〇73 (1H, d, J=2.1Hz), 8.30-8.35 (1H, m) 92 312XP/Invention Manual (supplement)/96-03/95143900 200800871 (Reference Example 34-24) 'H-NMRCCDCU δ ppm: 2.54 (3Η, s), 3.91-3.96 (3H, m), 7.00-7.0 5 (1H, m), 7.27 -7.35 (1H, m), 7Α0-7Λ7 (1H, m), 7.49-7.56 (1H, m), 7.66 (1H, d, J=8e2Hz), 8Λ8-8.23 (1H , m) (Reference Example 34-25) 1H-NMR (CDC 〇 δ ppm: 1.68-1.73 (4H, m), 2.78 (2H, s), 2.92 (2H, s), 3.92 (3H, s), 6.98 (1H, d, J=8„5Hz), 7.35 (1H, d, J=2.2Hz), 7.38 (1H, dd, J=8.4, 2〇0Hz), 7〇96 ( 1H, d, J=7.6 Hz) 10 (Reference Example 34-26) ^-NMRiCDCl ) δ ppm: 2.45 (3H, s), 3.93 (3H, s), 6.99 (1H, d, J=8.2Hz), 7.23 (1 3 H, d , J=L6Hz), 7〇33 (1H, d, J=2.2Hz), 7.35 (1H, dd, J=8.5, 2.2Hz), 7.40 (1H, dd, J =8·5, 2·2Ηζ) , 8.08 (1H, d, J 2·8Ηζ) (Reference Example 34-27) ^-NMRiCDCl ) δ ppm: 2.37 (3H, s), 3.94 (3H, s), 6.12 (1H, s), 6.98 ( 1H, d, J=8. 3 2Hz), 7β36 (1H? t, J=7.7Hz), 7.44-7.50 (3H, m), 8.18 (1H, dd, J=7.9, l〇3Hz)

(茶考例3 4 - 2 8 ) 'H-NMRiCDCl) δ ppm:2.52 (3H, s), 4.01 (3H, s), 6.19 (1H, s), 7.01 (1H, d, J=8. 3 5Hz), 7.45 (1H, d, J=7.6Hz), 7.52 (1H, dd, J=8.5, 2.2Hz), 7.67 (1H, d, J=7.9Hz), 7e 76 (1H, d, J=2.2Hz), 8.10 (1H, s) (參考例34-29 ) ^-NMRiCDCO δ ppm :2.05-2.13 (2H, m), 2.89-2.96 (4H, m, J=7.4, 7.4, 3.8Hz), 3.95 (3H, s), 6.98 (1H, d, J=8.2Hz), 7.31 (1H, d, J=7.9Hz), 7.41 (1H, d, J=2.2Hz), 7 .49 (1H, dd, J=8.4, 2ΌΗζ), 7.70 (1H, d, J=7.9Hz), 7.73 (1H, s) (參考例34-30 ) 93 3 ΠΧΡ/發明說明書(補件)/96-03/95143900 200800871 1H~NMR(CDC1) δ ppm:L75~1.81 (4H, m), 2.75-2«81 (4H, m), 3.94 (3H, s), 6.16 3 (1H, s), 6.98 (1H, d, J=8e5Hz), 7.15 (1H, d, J=7.6Hz), 7.36-7.43 (1H, m), 7.48 (1H5 d, J=7.9Hz), 7.57-7.63 (2H, m) (參考例34-31) 'H-NMRCCDCl) 6 ppm:2〇39 (3H, s), 3.97 (3H, s), 6,07 (1H, s), 7.02 (1H, d, J=8. 3 4Hz), 7.30-7.35 (1H? m), 7β39 (1H, d, J=2.1Hz), 7.50 (1H, dd, J=8.4, 2.1Hz), 7.56-7.62 (1H, m), 7.67-7.70 (1H, m) (參考例34-32)(Tea test 3 4 - 2 8 ) 'H-NMRiCDCl) δ ppm: 2.52 (3H, s), 4.01 (3H, s), 6.19 (1H, s), 7.01 (1H, d, J=8. 3 5Hz), 7.45 (1H, d, J=7.6Hz), 7.52 (1H, dd, J=8.5, 2.2Hz), 7.67 (1H, d, J=7.9Hz), 7e 76 (1H, d, J= 2.2 Hz), 8.10 (1H, s) (Reference Example 34-29) ^-NMRiCDCO δ ppm : 2.05-2.13 (2H, m), 2.89-2.96 (4H, m, J=7.4, 7.4, 3.8Hz), 3.95 (3H, s), 6.98 (1H, d, J=8.2Hz), 7.31 (1H, d, J=7.9Hz), 7.41 (1H, d, J=2.2Hz), 7.49 (1H, dd , J=8.4, 2ΌΗζ), 7.70 (1H, d, J=7.9Hz), 7.73 (1H, s) (Reference Example 34-30) 93 3 ΠΧΡ/Invention Manual (supplement)/96-03/95143900 200800871 1H~NMR(CDC1) δ ppm: L75~1.81 (4H, m), 2.75-2«81 (4H, m), 3.94 (3H, s), 6.16 3 (1H, s), 6.98 (1H, d, J=8e5Hz), 7.15 (1H, d, J=7.6Hz), 7.36-7.43 (1H, m), 7.48 (1H5 d, J=7.9Hz), 7.57-7.63 (2H, m) (Reference Example 34- 31) 'H-NMRCCDCl) 6 ppm: 2〇39 (3H, s), 3.97 (3H, s), 6,07 (1H, s), 7.02 (1H, d, J=8. 3 4Hz), 7.30 -7.35 (1H? m), 7β39 (1H, d, J=2.1Hz), 7.50 (1H, dd, J=8.4, 2.1Hz), 7.56-7.62 (1H, m), 7.67-7.70 (1H, m ) (Reference Example 34-32)

^-NMRiCDCl) δ ppm:3〇94 (3H, s), 6.99 (1H, d, J=8.5Hz), 7.53-7.64 (2H, m), 7. 3 69 (1H, d, J=7.9Hz), 7.92 (1H, d, J-8.2Hz) (參考例34-33) 'H-NMRiCDCl) δ ppm:3.98 (3H, s), 7.04 (1H, d, J=8〇5Hz), 7.55-7.65 (2H, m), 7〇 3 70 (2H, s) (參考例34-34) 'H-NMRiCDCO δ ppm:3.98 (3H, s), 6.18 (1H, br), 7.03 (1H, d, J=8.4Hz), 7.61 (1 H, d, J=2.1Hz), 7.65-7.70 (3H, m) (參考例34-35) iH-NMI^CDCl) δ ρρπι:3·97 (3H, s), 6·12 (1H, br)，7β〇2 (1H, d, J=8.5Hz)，7e20 (1 3 H, d, J=7.8Hz), 7.55-7.70 (2H,m) (參考例34-36) 'H-NMRCCDCl) δ ppm:2.31 (3H, s), 2.81 (3H, s), 3.95 (ίΗ, s), 6〇51 (1Ή, d, J=8. 3 5Hz), 7.00-7.05 (1H, m), 7.10-7 J5 (1H, m), 7.39 (1H, dd, J=8.5, 2.1Hz), 7.52 (1H, d, J=2.1Hz) (參考例34-37) 94 312XP/發明說明書(補件)/96-03/95143900 200800871 "H-NMRCCDCO δ ppm:2.40-2.45 (3H, m), 3.96 (3H, s), 6.85-6.90 (1H, m), 7.01 (1H, d, J=8.5Hz), 7.40-7.50 (1H, m), 7.50-7.60 (2H, m), 7.90-8.00 (1H, m), 8.15-8 .20 (1H, m), 8.50-8.55 (1H, m) (參考例34-38) 1H-NMR(CDC1) δ ppm:0.90~l〇00 (3H, m), 1.40-L55 (2H, m), L70-L85 (2H, m), 3 3.98 (3H, s), 4.35-4.45 (2H, m), 6.99 (1H, d, J=8.3Hz), 7.45-7〇65 (5H, m), 7.95-8. 05 (1H, m) (參考例34-39)^-NMRiCDCl) δ ppm: 3〇94 (3H, s), 6.99 (1H, d, J=8.5Hz), 7.53-7.64 (2H, m), 7. 3 69 (1H, d, J=7.9Hz ), 7.92 (1H, d, J-8.2Hz) (Reference Example 34-33) 'H-NMRiCDCl) δ ppm: 3.98 (3H, s), 7.04 (1H, d, J=8〇5Hz), 7.55- 7.65 (2H, m), 7〇3 70 (2H, s) (Reference Example 34-34) 'H-NMRiCDCO δ ppm: 3.98 (3H, s), 6.18 (1H, br), 7.03 (1H, d, J=8.4Hz), 7.61 (1 H, d, J=2.1Hz), 7.65-7.70 (3H, m) (Reference Example 34-35) iH-NMI^CDCl) δ ρρπι:3·97 (3H, s ), 6·12 (1H, br), 7β〇2 (1H, d, J=8.5Hz), 7e20 (1 3 H, d, J=7.8Hz), 7.55-7.70 (2H, m) (Reference example) 34-36) 'H-NMRCCDCl) δ ppm: 2.31 (3H, s), 2.81 (3H, s), 3.95 (ίΗ, s), 6〇51 (1Ή, d, J=8. 3 5Hz), 7.00 -7.05 (1H, m), 7.10-7 J5 (1H, m), 7.39 (1H, dd, J=8.5, 2.1Hz), 7.52 (1H, d, J=2.1Hz) (Reference Example 34-37) 94 312XP/Invention Manual (supplement)/96-03/95143900 200800871 "H-NMRCCDCO δ ppm: 2.40-2.45 (3H, m), 3.96 (3H, s), 6.85-6.90 (1H, m), 7.01 (1H, d, J=8.5Hz), 7.40-7.50 (1H, m), 7.50-7.60 (2H, m), 7.90-8.00 (1H, m), 8.15-8 .20 (1H, m), 8.50 -8.55 (1H, m) (Reference Example 34-38) 1H- NMR (CDC1) δ ppm: 0.90~l〇00 (3H, m), 1.40-L55 (2H, m), L70-L85 (2H, m), 3 3.98 (3H, s), 4.35-4.45 (2H, m), 6.99 (1H, d, J=8.3Hz), 7.45-7〇65 (5H, m), 7.95-8. 05 (1H, m) (Reference 34-39)

'H-NMR^DCO δ ppm:L35-1.50 (1H, m), 1.55-1.90 (5H, m), 3.10-3.25 (2H, m), 3.60-3.70 (2H, m), 3.95-4.00 (3H, m), 6.90-7.00 (1H, m), 7.40-7J5 (4H, m), 7.95 -8.00 (1H, m) (參考例34-40) 1H~NMR(CDC1) δ ppm:2.67 (3H, s), 3.96 (3H, s), 7.03 (1H, d, J=8.2Hz), 7.33 (1 3 H, d, J=2.2Hz), 7.42 (1H, dd, J=8.4, 2.1Hz), 7.78 (1H, d, 8.36 (1H, d, J= 2.2Hz) •(參考例34-41) ^-NMRCCDCl) 6 ppm:2.46 (3H, s), 2.64 (3H, s), 3.95 (3H, s), 7.01 (1H, d, J=8. 3 2Hz), 7.30-7.40 (2H，m), 7.60-7.65 (1H, m)，8·20_8·25 (1H, m) (參考例34_42) ^-NMRCCDCI) δ ppm: 2.73 (3H, s), 3.97 (3H, s), 7.02 (1H, d, J=8e5Hz), 7.21 (1 3 H, dd, J=8.5, 2.5Hz), 7.44 (1H, dd, J=7.6, 2.5Hz), 7.50-7.60 (1H, m), 7.63 (1H, s) (參考例34-43) ^-NMRCCDCl) δ ppm :2.63 (3H, s), 3.97 (3H, s), 7.05 (1H, d, J=8〇2Hz), 7.31 (1 3 H, d, J=1.9Hz), 7.69 (1H, dd, J=8.3, 2.0Hz), 7.85 (1H, d, J=L6Hz), 7.32 (1H, d, J= I. 6Hz) 95 312XP/發明說明書(補件)/96-03/95143900 200800871 (參考例34-44) 'H-NMRCCDCl) δ ppm:3.97 (3Η, s), 6.08 (1H, s), 7.00-7.05 (1H, m)s 7.35^7.45 ( 3 1H，m)，7。50-7·60 (1H, m), 7.70-7。80 (2H, m), 8.00-8.10 (2H, m) (參考例34-45) 1H-NMR(CDC1) δ ppm:3.97 (3H, s), 6.09 (1H, s), 7.00-7.10 (1H, m), 7.40-7.45 ( 3 1H, m)，7.50-7.60 (1H, m)，7·60-7.70 (1H, m)，7.75-7·85 (1H, m)，8·0515 (1H， m)，8。15-8。25 (1H，m) (參考例34-46)'H-NMR^DCO δ ppm: L35-1.50 (1H, m), 1.55-1.90 (5H, m), 3.10-3.25 (2H, m), 3.60-3.70 (2H, m), 3.95-4.00 (3H , m), 6.90-7.00 (1H, m), 7.40-7J5 (4H, m), 7.95 -8.00 (1H, m) (Reference Example 34-40) 1H~NMR(CDC1) δ ppm: 2.67 (3H, s), 3.96 (3H, s), 7.03 (1H, d, J=8.2Hz), 7.33 (1 3 H, d, J=2.2Hz), 7.42 (1H, dd, J=8.4, 2.1Hz), 7.78 (1H, d, 8.36 (1H, d, J = 2.2Hz) • (Reference Example 34-41) ^-NMRCCDCl) 6 ppm: 2.46 (3H, s), 2.64 (3H, s), 3.95 (3H, s), 7.01 (1H, d, J=8. 3 2Hz), 7.30-7.40 (2H, m), 7.60-7.65 (1H, m), 8·20_8·25 (1H, m) (Reference 34_42) ^-NMRCCDCI) δ ppm: 2.73 (3H, s), 3.97 (3H, s), 7.02 (1H, d, J=8e5Hz), 7.21 (1 3 H, dd, J=8.5, 2.5Hz), 7.44 ( 1H, dd, J=7.6, 2.5Hz), 7.50-7.60 (1H, m), 7.63 (1H, s) (Reference 34-43) ^-NMRCCDCl) δ ppm : 2.63 (3H, s), 3.97 ( 3H, s), 7.05 (1H, d, J=8〇2Hz), 7.31 (1 3 H, d, J=1.9Hz), 7.69 (1H, dd, J=8.3, 2.0Hz), 7.85 (1H, d, J=L6Hz), 7.32 (1H, d, J= I. 6Hz) 95 312XP/Invention Manual (supplement)/96-03/95143900 200800871 (Reference Example 34-44) 'H-NMRCCDCl) δ ppm: 3.97 (3Η, s), 6.08 (1H, s), 7.00-7.05 (1H, m)s 7.35^7.45 (3 1H, m), 7.50-7.60 (1H, m), 7.70-7.80 (2H, m), 8.00 -8.10 (2H, m) (Reference 34-45) 1H-NMR (CDC1) δ ppm: 3.97 (3H, s), 6.09 (1H, s), 7.00-7.10 (1H, m), 7.40-7.45 ( 3 1H, m), 7.50-7.60 (1H, m), 7·60-7.70 (1H, m), 7.75-7·85 (1H, m), 8·0515 (1H, m), 8.15- 8.25 (1H, m) (Reference Example 34-46)

'H-NMRCCDCl) δ ppm :2.40 (3H, s), 3.96 (3H, s), 6.02 (1H, s), 6.95-7.05 (1H, m 3 )? 7.30-7.45 (3H, m), 7.45-7.55 (1H, m), 7.65-7.80 (2H, m) (參考例34-47) 1H-NMR(CDCI) δ ppm :2.48 (3H, s), 3〇93 (3H, s), 6.05 (1H, s), 6.95-7.05 (1H, m 3 ),7〇20-7.30 (1H, m), 7.30-7.50 (4H, m), 8.10-8.20 (1H, m) (參考例34-48) 1H-NMR(CD30D) δ ppm:3.88 (3H, s), 6.85-6.95 (1H, m), 7.30-7.45 (2H, m), 7.7 5-8。00 (3H，m), 8.25-8.40 (1H，m) (參考例34-49) 'H-NMRCCDCl) δ ppm: 3.93 (3H, s), 5.99 (1H, s), 6.90-7.00 (1H, m), 7.40-7.65 ( 3 5H, m), 7.85-7.95 (1H, m), 8.05-8.15 (1H, m), 8.40-8.50 (1H, m), 8:65-8.70 (1H, m) (參考例34-50) 'H-NMRXCDa ) § ppm: 3.99 (3H, s), 6.12 (1H, s), 7.00-7.10 (1H, m), 7.35-7.45 ( 1H, m), 7.50-7.55 (1H, m), 7.60-7.70 (1H, m), 7.75-7.85 (1HS m), 8.10-8.20 (2H, m) 96 312XP/發明說明書(補件)/96-03/95143900 200800871 (參考例34_51) 'H-NMRiCDCl) δ ppm:3.97 (3H, s), 6.12 (1H, s), 7.00-7.10 (1H, m), 7.35-7Λ5 ( 3 1H, m), 7.50-7.55 (1H, m), 7.75-7.85 (2H, m), 7.95-8.05 (2H, m) (參考例34-52) 'H-NMRCCDCl) δ ppm:4.02 (3H, s), 6.12 (1H, s), 6.95-7.05 (1H, m), 7,50-7.60 ( 3 1H, m), 7.60-7.70 (1H, m), 7.70-7.85 (3H, m), 8.25-8.35 (1H, m) (參考例34-53)'H-NMRCCDCl) δ ppm : 2.40 (3H, s), 3.96 (3H, s), 6.02 (1H, s), 6.95-7.05 (1H, m 3 )? 7.30-7.45 (3H, m), 7.45- 7.55 (1H, m), 7.65-7.80 (2H, m) (Reference 34-47) 1H-NMR (CDCI) δ ppm : 2.48 (3H, s), 3〇93 (3H, s), 6.05 (1H , s), 6.95-7.05 (1H, m 3 ), 7〇20-7.30 (1H, m), 7.30-7.50 (4H, m), 8.10-8.20 (1H, m) (Reference 34-48) 1H -NMR (CD30D) δ ppm: 3.88 (3H, s), 6.85-6.95 (1H, m), 7.30-7.45 (2H, m), 7.7 5-8.00 (3H, m), 8.25-8.40 (1H , m) (Reference Example 34-49) 'H-NMRCCDCl) δ ppm: 3.93 (3H, s), 5.99 (1H, s), 6.90-7.00 (1H, m), 7.40-7.65 ( 3 5H, m) , 7.85-7.95 (1H, m), 8.05-8.15 (1H, m), 8.40-8.50 (1H, m), 8:65-8.70 (1H, m) (Reference Example 34-50) 'H-NMRXCDa § ppm: 3.99 (3H, s), 6.12 (1H, s), 7.00-7.10 (1H, m), 7.35-7.45 (1H, m), 7.50-7.55 (1H, m), 7.60-7.70 (1H, m), 7.75-7.85 (1HS m), 8.10-8.20 (2H, m) 96 312XP/Invention Manual (supplement)/96-03/95143900 200800871 (Reference Example 34_51) 'H-NMRiCDCl) δ ppm: 3.97 ( 3H, s), 6.12 (1H, s), 7.00-7.10 (1H, m), 7.35-7Λ5 ( 3 1H, m), 7.50-7.55 (1H, m), 7.75-7.85 (2H, m), 7 . 95-8.05 (2H, m) (Reference Example 34-52) 'H-NMRCCDCl) δ ppm: 4.02 (3H, s), 6.12 (1H, s), 6.95-7.05 (1H, m), 7,50- 7.60 ( 3 1H, m), 7.60-7.70 (1H, m), 7.70-7.85 (3H, m), 8.25-8.35 (1H, m) (Reference 34-53)

XH-NMR(CDC1) δ ppm:3.97 (3H, s), 6.11 (1H, s), 6^95-7.05 (1H, m), 7.35-7.40 ( 3 1H, m), 7.40-7.55 (3H, m), 8.25*8.35 (1H, m) (參考例34-54) ^-NMRiCDCl) δ ppm:3.98 (3H, s), 6.11 (1H, s), 7〇00-7.10 (1H, m), 7.35-7.40 ( 3 1H, m), 7.45-7.55 (2H, m), 7.77 (2H, d, J=L9Hz) (參考例34-55) 'H-NMRiCDCl) δ ppm:2.29 (3H, s), 4.00 (3H, s), 5〇96 (1H, s), 6.76 (1H, s), 7.45 3 -7.65 (3H, m), 7·77 (1H, s), 7.80-7.90 (2H, m) 着（參考例34-56) 'H-NMRiCDCl) δ ppm :3.99 (3H, s), 6.15 (1H, s), 7〇05-7.10 (1H, m), 7.40-7.45 ( 3 1H, m), 7.50-7.60 (1H, m), 8.04 (1H, s), 8.35 (2H, s) (參考例34-57) ^-NMRCCDCl) δ ppm:3.95 (3H, s), 6.10 (1H, s), 6.95-7.05 (1H, m), 7.40-7.50 ( 3 4H, m), 8.20-8,30 (1H, m) (參考例34-58) ^-NMRCCDCl) δ ppm: 3.97 (3H, s), 6.10 (1H, s), 7,00-7.05 (1H, m), 7.3〇-7〇35 ( 3 1H, m), 7.40-7〇50 (2H, m), 7.60-7.70 (2H, m) 97 312XP/發明說明書(補件)/96-03/95143900 200800871 (參考例34-59) ^-NMRiCDCO δ ppm:3.97 (3Η, s), 6.13 (1H, br s), 6.95-7.05 (1H, m), 7.35-7.5 0 (2H, m), 7.90-8.05 (2H, m), 8.66 (1H, s) (參考例34-60) "H-NMRCCDCl) δ ppm :3.96 (3H, s), 6.01 (1H, br s), 6.95-7.05 (1H, m), 7.45-7.5 3 0 (1H, m), 7.50-7J0 (3H, m), 7.80-7.85 (1H, m), 7^85-7.90 (1H, m), 7.90-7.95 (1 Hy m), 7.95-8.00 (1H, m), 8.50-8.60 (1H, m) (蒼考例3 4 - 61 )XH-NMR (CDC1) δ ppm: 3.97 (3H, s), 6.11 (1H, s), 6^95-7.05 (1H, m), 7.35-7.40 (3 1H, m), 7.40-7.55 (3H, m), 8.25*8.35 (1H, m) (Reference Example 34-54) ^-NMRiCDCl) δ ppm: 3.98 (3H, s), 6.11 (1H, s), 7〇00-7.10 (1H, m), 7.35-7.40 ( 3 1H, m), 7.45-7.55 (2H, m), 7.77 (2H, d, J=L9Hz) (Reference 34-55) 'H-NMRiCDCl) δ ppm: 2.29 (3H, s) , 4.00 (3H, s), 5〇96 (1H, s), 6.76 (1H, s), 7.45 3 -7.65 (3H, m), 7·77 (1H, s), 7.80-7.90 (2H, m ) (Reference Example 34-56) 'H-NMRiCDCl) δ ppm : 3.99 (3H, s), 6.15 (1H, s), 7〇05-7.10 (1H, m), 7.40-7.45 ( 3 1H, m ), 7.50-7.60 (1H, m), 8.04 (1H, s), 8.35 (2H, s) (Reference 34-57) ^-NMRCCDCl) δ ppm: 3.95 (3H, s), 6.10 (1H, s ), 6.95-7.05 (1H, m), 7.40-7.50 ( 3 4H, m), 8.20-8,30 (1H, m) (Reference 34-58) ^-NMRCCDCl) δ ppm: 3.97 (3H, s ), 6.10 (1H, s), 7,00-7.05 (1H, m), 7.3〇-7〇35 ( 3 1H, m), 7.40-7〇50 (2H, m), 7.60-7.70 (2H, m) 97 312XP/Invention Manual (supplement)/96-03/95143900 200800871 (Reference Example 34-59) ^-NMRiCDCO δ ppm: 3.97 (3Η, s), 6.13 (1H, br s), 6.95-7.05 ( 1H, m), 7 .35-7.5 0 (2H, m), 7.90-8.05 (2H, m), 8.66 (1H, s) (Reference 34-60) "H-NMRCCDCl) δ ppm :3.96 (3H, s), 6.01 (1H, br s), 6.95-7.05 (1H, m), 7.45-7.5 3 0 (1H, m), 7.50-7J0 (3H, m), 7.80-7.85 (1H, m), 7^85-7.90 (1H, m), 7.90-7.95 (1 Hy m), 7.95-8.00 (1H, m), 8.50-8.60 (1H, m) (Cang test example 3 4 - 61)

'H-NMRCCDCl) δ ppm:3.97 (3H, s), 6.10 (1H, s), 7.00-7.05 (1H, m), 7.44 (2H, s 3 ),7.55-7.60 (1H, m), 7.60-7.70 (1H, m) (參考例34-62) ^-NMRCCDCI ) δ ppm :3.97 (3H, s), 6.13 (1H, s), 7.00-7.05 (1H, m), 7.45-7.50 ( 3 1H, m), 7.50-7.55 (1H, m), 7.55-7.60 (1H, m), 7.70~7〇80 (1H, m), 8.55-8.65 (1H, m) (參考例34-63) 1H-NMR(CDC1) δ ppm:3.95 (3H, s), 6.09 (1H, s), 6.95-7.05 (1H, m), 7.10-7.25 ( 3 2H, m), 7.40-7.50 (2H, m), 8.30-8.40 (1H, m) (參考例34-64) 1H-NMR(CDC1) δ ppm :3.96 (3H, s), 6.09 (1H, s), 6β95-7β〇5 (1H, m), 7.35-7.40 ( 3 1H, m), 7.40-7.45 (1H, m), 7.65-7.75 (1H, m), 7.75-7.85 (1H5 m), 8.25-8.35 (1H, m) (參考例34-65) 'H-NMRCCDQ ) δ ppm :3.97 (3H, s), 6.13 (1H, s), 6.95-7.05 (1H, m), 7.35-7.50 ( 2H, m), 7.95-8.05 (1HS m), 8.07 (1H, s), 8.45-8.55 (1H, m) 98 3 UXP/發明說明書(補件)/96-03/95143900 200800871 (參考例34-66) 'H-NMRCCDCl) δ ppm:3.97 (3Η, s), 6.11 (1H, s), 7.00-7.05 (1H, m), 7.39 (1H, d 3 ,J=8.8Hz), 7.54 (1H, d, J=8„8Hz), 7.55-7.70 (2H, m) (參考例34-67) 'H-NMRCCDCI ) δ ppm: 3.96 (3H, s), 6J2 (1H, s), 6.95-7.05 (1H, m), 7.35-7.40 ( 3 1H, m), 7.40-7.55 (3H, m), 8.10-8.15 (1H, m) (參考例34-68) 'H-NMRCCDCl) δ ppm:2.39 (3H, s), 3.95 (3H, s), 6.05 (1H, s), 6.95-7.00 (1H, m'H-NMRCCDCl) δ ppm: 3.97 (3H, s), 6.10 (1H, s), 7.00-7.05 (1H, m), 7.44 (2H, s 3 ), 7.55-7.60 (1H, m), 7.60- 7.70 (1H, m) (Reference Example 34-62) ^-NMRCCDCI ) δ ppm : 3.97 (3H, s), 6.13 (1H, s), 7.00-7.05 (1H, m), 7.45-7.50 ( 3 1H, m), 7.50-7.55 (1H, m), 7.55-7.60 (1H, m), 7.70~7〇80 (1H, m), 8.55-8.65 (1H, m) (Reference 34-63) 1H-NMR (CDC1) δ ppm: 3.95 (3H, s), 6.09 (1H, s), 6.95-7.05 (1H, m), 7.10-7.25 (3 2H, m), 7.40-7.50 (2H, m), 8.30- 8.40 (1H, m) (Reference Example 34-64) 1H-NMR (CDC1) δ ppm : 3.96 (3H, s), 6.09 (1H, s), 6β95-7β〇5 (1H, m), 7.35-7.40 ( 3 1H, m), 7.40-7.45 (1H, m), 7.65-7.75 (1H, m), 7.75-7.85 (1H5 m), 8.25-8.35 (1H, m) (Reference 34-65) 'H -NMRCCDQ ) δ ppm : 3.97 (3H, s), 6.13 (1H, s), 6.95-7.05 (1H, m), 7.35-7.50 ( 2H, m), 7.95-8.05 (1HS m), 8.07 (1H, s), 8.45-8.55 (1H, m) 98 3 UXP/Invention Manual (supplement)/96-03/95143900 200800871 (Reference Example 34-66) 'H-NMRCCDCl) δ ppm: 3.97 (3Η, s), 6.11 (1H, s), 7.00-7.05 (1H, m), 7.39 (1H, d 3 , J=8.8Hz), 7.54 (1H, d, J=8„8Hz), 7.55-7.70 (2H, m)(Reference Example 34-67) 'H-NMRCCDCI) δ ppm: 3.96 (3H, s), 6J2 (1H, s), 6.95-7.05 (1H, m), 7.35-7.40 ( 3 1H, m), 7.40- 7.55 (3H, m), 8.10-8.15 (1H, m) (Reference 34-68) 'H-NMRCCDCl) δ ppm: 2.39 (3H, s), 3.95 (3H, s), 6.05 (1H, s) , 6.95-7.00 (1H, m

3 )，7.20-7.30 (2H，m), 7.40-7.50 (2H, m)，8· 15-&20 (1HS m) (參考例34-69) h-NMR(CDC1) δ ppm:2.43 (3H，s)，3·96 (3H，s)，6.07 (1H，s)，6e95-7。05 (1H, m 3 )，7。25-7.35 (2H，m)，7.45-7.55 (2H，m), 8.10-8.15 (1H，m) (參考例34-70) h—NMiUCDCl) δ ppm:2.71 (3H，s)，4·01 (3H，s)，6.05 (1H，s)，6.95-7力5 (1H，m 3 ),7,25-7.30 (1H, m), 7.45-7.50 (1H, m), 7.50-7.65 (3H, m), 7.95-8.00 (1H, m) φ (參考例34-71) 'H-NMRiCDCl) δ ppm :3.97 (3H, s), 6.15 (1H, s), 7.00-7.05 (1H, m), 7.45-7.55 ( 3 > 2H, m), 7.65-7.70 (1H, m), 8.20^8.30 (1H, m) (參考例34-72) ^-NMRiCDCl) δ ppm:3.81 (6H, s), 3.95 (3H, s), 6.02 (1H, s), 6〇57 (1H, t, J=2.2 33), 7.20-7.30 (2H, m), 7.40-7.50 (2H, m), 8·15 & 20 (1HS m) (Reference Example 34-69) h-NMR (CDC1) δ ppm: 2.43 ( 3H, s), 3·96 (3H, s), 6.07 (1H, s), 6e95-7. 05 (1H, m 3 ), 7. 25-7.35 (2H, m), 7.45-7.55 (2H, m), 8.10-8.15 (1H, m) (Reference Example 34-70) h-NMiUCDCl) δ ppm: 2.71 (3H, s), 4·01 (3H, s), 6.05 (1H, s), 6.95- 7 force 5 (1H, m 3 ), 7, 25-7.30 (1H, m), 7.45-7.50 (1H, m), 7.50-7.65 (3H, m), 7.95-8.00 (1H, m) φ (Reference Example 34-71) 'H-NMRiCDCl) δ ppm : 3.97 (3H, s), 6.15 (1H, s), 7.00-7.05 (1H, m), 7.45-7.55 (3 > 2H, m), 7.65- 7.70 (1H, m), 8.20^8.30 (1H, m) (Reference Example 34-72) ^-NMRiCDCl) δ ppm: 3.81 (6H, s), 3.95 (3H, s), 6.02 (1H, s), 6〇57 (1H, t, J=2.2 3

Hz), 6.99 (1H, d, J=8.5Hz), 7.03 (2H, d, J=2.2Hz), 7.35-7.45 (1H, m), 7.45-7.55 (1 H,m) (參考例34-73) 'H-NMRiCDCl ) 6 ppm :3.87 (3H, s), 3.89 (6H, s), 3.96 (3H, s), 6.02 (1H, s), 6.95 3 -7.05 (1H, m), 7.13 (2H, s), 7.35-7.45 (1H, m), 7.45-7.55 (1H, m) 312XP/發明說明書(補件)/96-03/95143900 99 200800871 (參考例34_74) 'H-NMRCCDCI) δ ppm :2.29 (3H, s), 2.60 (6H, s), 3.94 (3H, s), 5.97 (1H, s), 6.90 3 -7.00 (3H, m)5 7.20-7.25 (1H, m), 7^35-7.40 (1H, m) (參考例34-75) 'H-NMRCCDCI ) δ ppm :3.96 (3H, s), 6.07 (1H, s), 6.95-7.05 (1H, m), 7.25-7.35 ( 3 1H, m), 7.40-7.50 (2H, m), 7.50-7.55 (1H, m), 7.55-7.65 (1H, m), 8.20-8.30 (1H, m) (參考例34-76)Hz), 6.99 (1H, d, J=8.5Hz), 7.03 (2H, d, J=2.2Hz), 7.35-7.45 (1H, m), 7.45-7.55 (1 H,m) (Reference Example 34- 73) 'H-NMRiCDCl ) 6 ppm : 3.87 (3H, s), 3.89 (6H, s), 3.96 (3H, s), 6.02 (1H, s), 6.95 3 -7.05 (1H, m), 7.13 ( 2H, s), 7.35-7.45 (1H, m), 7.45-7.55 (1H, m) 312XP/Invention Manual (supplement)/96-03/95143900 99 200800871 (Reference Example 34_74) 'H-NMRCCDCI) δ ppm : 2.29 (3H, s), 2.60 (6H, s), 3.94 (3H, s), 5.97 (1H, s), 6.90 3 -7.00 (3H, m)5 7.20-7.25 (1H, m), 7^ 35-7.40 (1H, m) (Reference Example 34-75) 'H-NMRCCDCI δ ppm : 3.96 (3H, s), 6.07 (1H, s), 6.95-7.05 (1H, m), 7.25-7.35 ( 3 1H, m), 7.40-7.50 (2H, m), 7.50-7.55 (1H, m), 7.55-7.65 (1H, m), 8.20-8.30 (1H, m) (Reference 34-76)

'H-NMRXCDCO δ ppm:3.96 (3H, s), 6.08 (1H, s), 7.00-7.05 (1H, m), 7.35-7.45 ( 2H，m)，7.50-7.60 (2H, m), 7.75-7。80 (1H, m)，7.80-7·85 (1H, m) (參考例34-77) ^-NMRXCDCl) δ ppm :2.84 (3H, s), 3.96 (3H, s), 6.06 (1H, s)5 6.95-7.00 (1H, m )，7.20-7.25 (1H, m)，7·3(Κ7β35 (1H，m)，7.35-7.45 (1H, m), 7·45-7·55 (1H，m) (參考例34-78) ^-NMRiCDCl) δ ppm:3.95 (3H, s), 6.00-6.35 (2H, m), 6.95-7.00 (1H, m), 7.35 3 -7.50 (4H9 m), 7.55-7.65 (1H, m), 8.15-8.20 (1H, m) (參考例34-79) ^-NMRCCDCl) δ ppm:3.96 (3H, s), 5.80-6.05 (1H, m), 6.07 (1H, s), 7.00-7.05 ( 3 1H, m), 7.35-7.45 (2H, m), 7.50-7.55 (2H? m), 7,75-7.85 (2H, m) (參考例34-80) ^-NMRiCDCO δ ppm:3.95 (3H, s), 6.06 (1H, s), 6.95-7.05 (1H, m), 7〇35-7.45 ( 1H, m), 7.45-7.50 (1H, m), 7.60-7.90 (4H, m), 8.05-8.10 (1H, m) (參考例34-81) 100 312XP/發明說明書(補件)/96-03/95143900 200800871 1H-NMR(CDC13) δ ppm:3.96 (3H, s), 6.12 (1H5 s), 7.00-7.10 (1H, m), 7.30-7.45 (2H, m), 7.45-7.55 (1H, m), 7.60-7.90 (3H, m) (參考例34-82) 'H-NMRiCDCl) δ ppm:3.84 (3H, s)s 3.95 (3H, s), 6.09 (1H, s), 6.99 (1H, d, J=8e 3 5Hz), 7.06 (1H, dd, J=8.2, 2.5Hz), 7.37-7.44 (3H, m), 7.48 (1H, d, J=7.6Hz)s 7.51 ( 1H, dd, J=8〇4, 2.0Hz) (參考例34_83)'H-NMRXCDCO δ ppm: 3.96 (3H, s), 6.08 (1H, s), 7.00-7.05 (1H, m), 7.35-7.45 (2H, m), 7.50-7.60 (2H, m), 7.75- 7.80 (1H, m), 7.80-7·85 (1H, m) (Reference 34-77) ^-NMRXCDCl) δ ppm : 2.84 (3H, s), 3.96 (3H, s), 6.06 (1H , s)5 6.95-7.00 (1H, m ), 7.20-7.25 (1H, m), 7·3 (Κ7β35 (1H, m), 7.35-7.45 (1H, m), 7·45-7·55 ( 1H,m) (Reference Example 34-78) ^-NMRiCDCl) δ ppm: 3.95 (3H, s), 6.00-6.35 (2H, m), 6.95-7.00 (1H, m), 7.35 3 -7.50 (4H9 m ), 7.55-7.65 (1H, m), 8.15-8.20 (1H, m) (Reference 34-79) ^-NMRCCDCl) δ ppm: 3.96 (3H, s), 5.80-6.05 (1H, m), 6.07 (1H, s), 7.00-7.05 ( 3 1H, m), 7.35-7.45 (2H, m), 7.50-7.55 (2H? m), 7,75-7.85 (2H, m) (Reference Example 34-80 ^-NMRiCDCO δ ppm: 3.95 (3H, s), 6.06 (1H, s), 6.95-7.05 (1H, m), 7〇35-7.45 (1H, m), 7.45-7.50 (1H, m), 7.60-7.90 (4H, m), 8.05-8.10 (1H, m) (Reference 34-81) 100 312XP/Invention Manual (supplement)/96-03/95143900 200800871 1H-NMR (CDC13) δ ppm: 3.96 (3H, s), 6.12 (1H5 s), 7.00-7.10 (1H, m), 7.30-7.45 (2H, m), 7.45-7.55 (1H, m), 7.60-7.90 (3H, m) (Reference Example 34-82) 'H-NMRiCDCl) δ ppm: 3.84 (3H, s)s 3.95 (3H, s), 6.09 (1H, s), 6.99 (1H, d, J=8e 3 5Hz), 7.06 (1H, dd, J=8.2, 2.5Hz), 7.37-7.44 (3H, m), 7.48 (1H, d, J=7.6Hz)s 7.51 ( 1H, dd, J=8〇4, 2.0Hz) ( Reference example 34_83)

1H-NMR(CDC1) δ ppm: 1.09 (3H, t, J=7.4Hz), 2.92 (2H, q, J=7.5Hz), 3〇93 (3H, s) 3 ,6.98 (1H, d, J=8.2Hz), 7.31-7.40 (4H, m)5 7.47-7.54 (1H, m), 8.11 (1H, dd, J=8〇0, 1.4Hz) (蒼考例3 4 _ 8 4 ) 'H-NMRiCDCl) δ ppm :3.95 (3H, s), 6.10 (1H, s), 7.00 (1H, d, J=9.1Hz), 7.41 (1 3 H, t, J=8.0Hz), 7.46-7.49 (2H, m), 7.68 (1H, dd, J=7.9, 1.6Hz), 8.26 (1HS dd, J=7〇9 ,1.6Hz) (參考例34-85) ^-NMRiCDCl ) δ ppm :3,97 (3H, s), 6.09 (1H, s), 7.02 (1H, d, J=8.2Hz), 7.38 (1 3 H, d, J=L9Hz), 7.50 (1H, dd, J=8.4, 2.0Hz), 7.56 (1H, d, J=8.5Hz), 7.72 (1H, dd, J =8.2, 2.2Hz), 7.98 (1H, d, J=2.2Hz) (參考例34-86) ^-NMRiCDCO δ ppm:2.29 (3H, s), 2.30 (3H,s), 3〇95 (3H, s), 6.00 (1H, s), 6.98 (1H, d, J=8,3Hz)? 7.23 (1H, d, J=7.8Hz), 7.41 (1H, d, J=2.0Hz), 7.48 (1H, dd, J=8.3 ,2.0Hz), 7.62-7.67 (2H, m) (參考例34-87) 101 312XP/發明說明書(補件)/96-03/95143900 200800871 'H-NMRiCDCO δ ppm :2.40 (3H, s), 2.41 (3H,s), 3,94 (3H, s), 6.02 (IH, s), 6.97 -6.99 (1H, m), 7.11 (1H, d, J=7.4Hz), 7.25-7.28 (2H, m)s 7.37-7.40 (2H, m), 7.97 ( 1H, br) (麥考例3 4 - 8 8 ) ^-NMRiCDCl) δ ppm:2.28 (3H, s), 2.39 (3H,s), 3〇93 (3H, s), 6.02 (1H, s), 6.98 3 (1H, d, J=8.2Hz), 7.24-7.27 (2H, m), 7.36-7.39 (3H? m), 7.97 (1H, br d, J=7.7Hz) (參考例34-89) ^-NMRCCDCO δ ppm :2.36 (3H, s), 2.43 (3H, s), 3〇92 (3H, s), 6.97 (1H, d, J=8. 5Hz), 7.04 (1H，s), 7Λ6 (1H, d, J二8·2Ηζ), 7.35-7.40 (2H, m)，8·03 (1H, d, J=8.2Hz ) (麥考例3 4 - 9 0 ) 'H-NMRCDMSO-d ) δ ppm:3.88 (3H, s), 6.97 (1H, d, J=8.3Hz), 7.51 (1H, d, ]=2. 6 3Hz), 7.54 (2H, dd, J=8.3, 2.3Hz), 8.72 (1H, t, J=1.4Hz), 8.78 (2H, d, J=1.4Hz), 10 .45 (1H, br) (參考例34-91)1H-NMR (CDC1) δ ppm: 1.09 (3H, t, J=7.4Hz), 2.92 (2H, q, J=7.5Hz), 3〇93 (3H, s) 3 ,6.98 (1H, d, J =8.2Hz), 7.31-7.40 (4H, m)5 7.47-7.54 (1H, m), 8.11 (1H, dd, J=8〇0, 1.4Hz) (Cang test example 3 4 _ 8 4 ) 'H -NMRiCDCl) δ ppm : 3.95 (3H, s), 6.10 (1H, s), 7.00 (1H, d, J=9.1Hz), 7.41 (1 3 H, t, J=8.0Hz), 7.46-7.49 ( 2H, m), 7.68 (1H, dd, J=7.9, 1.6Hz), 8.26 (1HS dd, J=7〇9, 1.6Hz) (Reference Example 34-85) ^-NMRiCDCl ) δ ppm :3,97 (3H, s), 6.09 (1H, s), 7.02 (1H, d, J=8.2Hz), 7.38 (1 3 H, d, J=L9Hz), 7.50 (1H, dd, J=8.4, 2.0Hz ), 7.56 (1H, d, J = 8.5 Hz), 7.72 (1H, dd, J = 8.2, 2.2 Hz), 7.98 (1H, d, J = 2.2 Hz) (Reference Example 34-86) ^-NMRiCDCO δ Ppm: 2.29 (3H, s), 2.30 (3H, s), 3〇95 (3H, s), 6.00 (1H, s), 6.98 (1H, d, J=8, 3Hz)? 7.23 (1H, d , J=7.8Hz), 7.41 (1H, d, J=2.0Hz), 7.48 (1H, dd, J=8.3, 2.0Hz), 7.62-7.67 (2H, m) (Reference Example 34-87) 101 312XP /Invention (Repair)/96-03/95143900 200800871 'H-NMRiCDCO δ ppm : 2.40 (3H, s), 2.41 (3H, s), 3,94 (3H, s), 6.02 (IH, s) , 6.97 -6.99 (1H, m), 7.11 (1H, d, J=7.4Hz), 7.25-7 .28 (2H, m)s 7.37-7.40 (2H, m), 7.97 ( 1H, br) (Mc. 3 4 - 8 8 ) ^-NMRiCDCl) δ ppm: 2.28 (3H, s), 2.39 (3H ,s), 3〇93 (3H, s), 6.02 (1H, s), 6.98 3 (1H, d, J=8.2Hz), 7.24-7.27 (2H, m), 7.36-7.39 (3H? m) , 7.97 (1H, br d, J=7.7Hz) (Reference Example 34-89) ^-NMRCCDCO δ ppm : 2.36 (3H, s), 2.43 (3H, s), 3〇92 (3H, s), 6.97 (1H, d, J=8. 5Hz), 7.04 (1H, s), 7Λ6 (1H, d, J 2·8Ηζ), 7.35-7.40 (2H, m), 8·03 (1H, d, J =8.2Hz ) (McC3 3 - 9 0 ) 'H-NMRCDMSO-d ) δ ppm: 3.88 (3H, s), 6.97 (1H, d, J=8.3Hz), 7.51 (1H, d, ] =2. 6 3Hz), 7.54 (2H, dd, J=8.3, 2.3Hz), 8.72 (1H, t, J=1.4Hz), 8.78 (2H, d, J=1.4Hz), 10.45 (1H , br) (Reference Example 34-91)

'H-NMRCCDCI ) 5 ppm:2.73 (3H, s), 3.99 (3H, s), 6.15 (1H, s), 7.03 (1H, d, J=8. 3 2Hz), 7.46-7.47 (1H, m), 7.55 (1H, dd, J=8.2, 2.2Hz), 7.66 (1H, d, J=2.2Hz), 7.69 ( 1H, d, J=2.2Hz). (參考例34-92) 'H-NMRCCDCU δ ppm :3.94 (3H, s), 6.99 (1H, d, J=8e5Hz), 7.41 (1H, d, J=2.2Hz ),7.45-7.60 (4H, m)，7.85—7.95 (2H，m) (參考例34_93) 'H-NMRiCDCO δ ppm:3.34 (3H, s), 3.94 (3H, s), 6.90-7.00 (3H5 m), 7.35-7.50 ( 2H, m), 7.80-7.90 (2H, m) 102 312XP/發明說明書(補件)/96-03/95143900 200800871 (參考例34-94) 'H-NMRiCDCl) 6 ppm:2e01-2〇07 (2Η, m), 2.77 (2Η, t, J=7.6Hz)s 3.83 (3H, s), 3. 3 94 (2H, t, J=6.4Hz), 5.99 (1H, s), 6.84 (1H, d, J=8.1Hz), 6.95 (1H, d, J=8.5Hz), 7.0 6-7J0 (1H, m), 7.17-7.21 (3H, m), 7.27-7.30 (2H, m), 7.44-7.53 (3H, m), 8.15-8.1 7 (1H, m) (參考例3 4 - 9 5 ) 1H-NMR(CDC1) δ ppm:3.73 (3H, s), 5.99 (1H, s), 6.76-6.79 (3H, m), 6.92-6.94 ( 3'H-NMRCCDCI 5 ppm: 2.73 (3H, s), 3.99 (3H, s), 6.15 (1H, s), 7.03 (1H, d, J=8. 3 2Hz), 7.46-7.47 (1H, m ), 7.55 (1H, dd, J=8.2, 2.2Hz), 7.66 (1H, d, J=2.2Hz), 7.69 (1H, d, J=2.2Hz). (Reference 34-92) 'H- NMRCCDCU δ ppm : 3.94 (3H, s), 6.99 (1H, d, J=8e5Hz), 7.41 (1H, d, J=2.2Hz), 7.45-7.60 (4H, m), 7.85-7.95 (2H, m (Reference Example 34_93) 'H-NMRiCDCO δ ppm: 3.34 (3H, s), 3.94 (3H, s), 6.90-7.00 (3H5 m), 7.35-7.50 ( 2H, m), 7.80-7.90 (2H, m) 102 312XP/Invention Manual (supplement)/96-03/95143900 200800871 (Reference Example 34-94) 'H-NMRiCDCl) 6 ppm: 2e01-2〇07 (2Η, m), 2.77 (2Η, t, J=7.6Hz)s 3.83 (3H, s), 3. 3 94 (2H, t, J=6.4Hz), 5.99 (1H, s), 6.84 (1H, d, J=8.1Hz), 6.95 (1H , d, J=8.5Hz), 7.0 6-7J0 (1H, m), 7.17-7.21 (3H, m), 7.27-7.30 (2H, m), 7.44-7.53 (3H, m), 8.15-8.1 7 (1H, m) (Reference Example 3 4 - 9 5 ) 1H-NMR (CDC1) δ ppm: 3.73 (3H, s), 5.99 (1H, s), 6.76-6.79 (3H, m), 6.92-6.94 ( 3

1H, m), 7.12-7.15 (1H, m), 7.20-7.23 (1H, m), 7.27-7.31 (2H, m), 7.42-7.46 (1H, m), 7.50-7.52 (2H, m), 8.20-8.22 (1H, m) (參考例34-96) 'H-NMRCCDa ) δ ppm:L2D-L29 (5H, m), 1.42-1.44 (2H, m), L71-1.74 (3H, m), 3.37-3.42 (1H, m), 3.93 (3H, s), 6〇01 (1H, s), 6.98 (1H, d, J=8〇2Hz)s 7.32-7.40 (4 H, m), 7.51-7.54 (1H, m), 8Λ6~8Λ8 (1H, m) (參考例35 - 1) 5 -氯-2 - (4-羥基—3_甲氧基苯磺醯基）苯甲腈在冰浴攪拌下’將第三丁醇鉀（254mg)加入苄氧美— 3-甲氧基苯硫醇（參考例19_ 1)(4吻）及二曱亞石風（^) ，混合物中並攪拌5分鐘。加入5一氯_ 2_1苯曱腈 (376mg)後，將混合物徐徐升溫至室溫並_ 4q分鐘。此反應混合物以水稀釋1 lm〇1/L氫氧化納水溶液⑽ 调整為鹼性後’攪拌5分鐘。濾取固體減壓乾燥，得2 - (4—节氧基_ 3 _甲^其/洗條5 — 人後 5-氣苯甲腈。 ⑽3甲平飞基笨亞續醯基)— 在冰浴_下，將過氧間苯f醯氯（l53g)以少量分批 312XP/發明說明書(補件)/96·〇3/95143900 ⑽ 200800871 加入2 - (4 _苄氧基-3_甲氧基苯亞磺醯基）-5 -氯苯甲腈及二氯曱烧（19mL)之混合物中，將混合物升溫至室溫後攪拌3小時。此反應混合物以水稀釋，用醋酸乙酯萃取。其有機液層依次以lm〇l/L硫代硫酸鈉水溶液、2m〇l/L 氫氧化鈉水溶液、食鹽水洗滌，用無水硫酸鎂乾燥後在減壓下進行濃縮，得粗製之2 - (4 -苄氧基-3 -曱氧基苯磺醯基）-5_氯苯甲腈。在冰浴攪拌下，將四氯化鈦（392mg)加入至粗製之2 -(4 -苄氧基-3 -甲氧基苯磺醯基）-5 -氯苯曱腈及二氯曱烷（30mL)之混合物中並攪拌23分鐘。此反應混合物以 lmol/L鹽酸洗滌，用無水硫酸鎂乾燥後在減壓下進行濃細。其殘留物以矽膠管柱色析法進行精製（洗提液：己烷/ 醋酸乙S旨=5/5)，得目標化合物（5Umg)。 H-NMR(CDCh)(5ppm ·· 4.01(3H，s)，6.15(1H，s)，7.00 -7· 〇5 (1H，m)，7· 45-7. 55(1H，m)，7· 70-7· 80(3H，m)， φ 8. 20-8. 30(lH,m) 依參考例35 - 1相同方法，使用對應之鹵化苯以代替 5-氯-2-氟苯甲腈，合成參考例35— 2〜參考例35一 16。此等示於表15。 312XP/發明說明書(補件)/96-03/95143900 104 200800871 [表 15] 參考例構造式參考例構造式 N 〇〇| 八Ί 35 -1 35-9 i 1 35-2 .JprO 35-10 HOiX0 j T HO Tn^ pXF l 〇** ·,〇 i 35-3 35-11 及SA< 〆〇〆〇 F N a 〇f "f 35-4 35-12 〆〇 J N 〇〇? N 〇 of 35-5 /0 35-13 .γ：Α Ο 0 Υ°Ύ^Ί 35-6 ΧΎ^0 35-14 J o o V°Y" 35-7 J?# 35-15 〆〇 35-8 義 35-16 /〇 /〇參考例35 - 2〜參考例35 - 16之物性值係如下示。 105 312XP/發明說明書(補件)/96-03/95143900 200800871 (參考例35-2) 'H-NMRiCDCl) δ ppm :4.02 (3Η, s), 6.17 (1H, s), 7.00-7.10 (1H, m), 7.50-7.60 ( 3 1H, m), 7.60-7.65 (1H, m), 7J0-7.80 (2H, m), 8.25-8.30 (1H, m) (參考例35 - 3) 1H-NMR(CDC1) δ ppm:4e〇l (3H, s), 6·17 (1H，s), 7·00—7·10 (1H，m), 7·70-7·90 ( 3 3H, m), 8.05-8.10 (1H, m), 8.10-8.15 (1H, m) (參考例35 - 4) ^-NMR^DCl) δ ppm:2〇44 (3H, s), 4.01 (3H, s), 6.11 (1H, s), 6.95-7.05 (1H, m1H, m), 7.12-7.15 (1H, m), 7.20-7.23 (1H, m), 7.27-7.31 (2H, m), 7.42-7.46 (1H, m), 7.50-7.52 (2H, m), 8.20-8.22 (1H, m) (Reference Example 34-96) 'H-NMRCCDa ) δ ppm: L2D-L29 (5H, m), 1.42-1.44 (2H, m), L71-1.74 (3H, m), 3.37-3.42 (1H, m), 3.93 (3H, s), 6〇01 (1H, s), 6.98 (1H, d, J=8〇2Hz)s 7.32-7.40 (4 H, m), 7.51- 7.54 (1H, m), 8Λ6~8Λ8 (1H, m) (Reference Example 35 - 1) 5 -Chloro-2-(4-hydroxy-3-methoxyphenylsulfonyl)benzonitrile was stirred in an ice bath Next 'potassium tert-butoxide (254 mg) was added to benzyloxet-3-methoxybenzenethiol (Reference Example 19-1) (4 kisses) and diterpene stone (^), and the mixture was stirred for 5 minutes. . After the addition of 5-chloro-2-phenylbenzonitrile (376 mg), the mixture was slowly warmed to room temperature for _4q min. This reaction mixture was adjusted to be basic with water diluted with 1 lm 〇 1 /L aqueous sodium hydroxide solution (10), and stirred for 5 minutes. The solid was collected by filtration under reduced pressure to give 2 - (4-hydroxyl_3__^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ In the bath_, the peroxy-m-benzene fluorene (l53g) is added in small amounts in batches 312XP/Invention Manual (supplement)/96·〇3/95143900 (10) 200800871 Add 2 - (4 _benzyloxy-3_methoxy In a mixture of benzylsulfinyl)-5-chlorobenzonitrile and dichlorohydrazine (19 mL), the mixture was warmed to room temperature and stirred for 3 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic liquid layer was washed successively with lm〇l/L aqueous sodium thiosulfate solution, 2 m 〇l/L aqueous sodium hydroxide solution and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a crude 2-( 4-Benzyloxy-3-indolylbenzenesulfonyl)-5-chlorobenzonitrile. Titanium tetrachloride (392 mg) was added to the crude 2-(4-benzyloxy-3-methoxyphenylsulfonyl)-5-chlorobenzonitrile and dichloromethane as stirring under ice-cooling ( A mixture of 30 mL) was stirred for 23 minutes. This reaction mixture was washed with 1 mol/L hydrochloric acid, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by a silica gel column chromatography (eluent: hexane / ethyl acetate) to give the title compound (5 Umg). H-NMR (CDCh) (5 ppm · · 4.01 (3H, s), 6.15 (1H, s), 7.00 -7 · 〇 5 (1H, m), 7·45-7. 55(1H, m), 7 · 70-7· 80(3H,m), φ 8. 20-8. 30(lH,m) According to the same method as in Reference Example 35-1, the corresponding halogenated benzene is used instead of 5-chloro-2-fluorobenzamide. Nitrile, Synthesis Reference Example 35-2 to Reference Example 35-16. These are shown in Table 15. 312XP/Invention Manual (Supplement)/96-03/95143900 104 200800871 [Table 15] Reference Example Construction Reference Reference Structure N 〇〇| Gossip 35 -1 35-9 i 1 35-2 .JprO 35-10 HOiX0 j T HO Tn^ pXF l 〇** ·,〇i 35-3 35-11 and SA< 〆〇〆〇 FN a 〇f "f 35-4 35-12 〆〇JN 〇〇? N 〇of 35-5 /0 35-13 .γ:Α Ο 0 Υ°Ύ^Ί 35-6 ΧΎ^0 35-14 J oo V°Y" 35-7 J?# 35-15 〆〇35-8 义35-16 /〇/〇 Reference Example 35 - 2~ Reference Examples 35 - 16 The physical property values are as follows: 105 312XP/Invention Instruction manual (supplement)/96-03/95143900 200800871 (Reference Example 35-2) 'H-NMRiCDCl) δ ppm : 4.02 (3Η, s), 6.17 (1H, s), 7.00-7.10 (1H, m), 7.50-7.60 ( 3 1H, m), 7.60-7.65 (1H, m), 7J0-7.80 (2H, m), 8.25-8.30 (1H, m) (Reference Example 35 - 3) 1H-NMR ( CDC1) δ ppm: 4e〇l (3H, s), 6·17 (1H, s), 7·00—7·10 (1H, m), 7·70-7·90 ( 3 3H, m), 8.05-8.10 (1H, m), 8.10-8.15 (1H, m) (Reference Example 35 - 4) ^-NMR^DCl) δ ppm: 2〇44 (3H, s), 4.01 (3H, s), 6.11 (1H, s), 6.95-7.05 (1H, m

3 ),7.45-7:65 (3HS m), 7J0-7.80 (1H, m), 8.15-8.20 (1H, m) (參考例35-5) 1H-NMR(CDC1) δ ppm:4〇00 (3H, s), 6.18 (1H, s), 7.00-7.10 (1H, m), 7.35-7.45 ( 3 1H, m), 7.60-7.75 (4H, m) (參考例35-6) 'H-NMRiCDCO δ ppm:4e〇3 (3H, s), 6.18 (1H, s), 7.00-7.05 (1H, m), 7.45-7.55 ( 1H, m), 7.65-7.75 (2H, m), 7.75-7.80 (1H, m), 8.20-8.30 (1H, m) Φ (參考例35-7) 'H-NMRiCDCl) δ ppm:4.03 (3H, s), 6.19 (1H, s), 7.00-7.05 (1H, m), 7.45-7.55 ( 3 1H, m), 7.75-7.85 (1H, m), 7.85-7.95 (1H, m), 7.95-8.05 (1H, m), 8.50-8.60 (1H, m) (參考例35-8) ^-NMRiCDCl) δ ppm:3〇96 (3H, s), 6.16 (1H, s), 7.00-7.05 (1H, m), 7.40^7.55 ( 3 2H, m), 7.70-7.80 (2H, m), 8.40-8.45 (1H, m) (參考例35-9) 106 312XP/發明說明書(補件)/96·03/95143900 200800871 'H-NMR^DCl) δ ppm:3.99 (3H, s), 6.17 (1H, s), 7.00-7.10 (1H, m), 7.50-7.60 ( 3 1H, m), 7·65-7·75 (3H，m)，7。80-7·85 (1H, m) (參考例35-10) 'H-NMRiCDCl) δ ppm:4e〇3 (3H, s), 6.23 (1H, s), 7.05-7J5 (1H, m), 7.70-7.90 ( 3 3H, m), 8.05 (2H, d, J=7e9Hz) (參考例35-11) ^-NMRiCDCl) δ ppm:4.00 (3H, s), 6.22 (1H, s), 7.05-7.10 (1H, m), 7.65-7.70 ( 3 1H, m), 7.70-7.75 (1H, m), 7〇9〇-7β95 (1H, m), 8.00-8.05 (1H, m) ® (參考例35-12) ^-NMRCCDCl) δ ppm:3.99 (3H, s), 6Λ9 (1H, s), 7.00-7JO (1H, m), 7.60-7.75 ( 3 3H, m), 7.75-7.80 (1H, m) (參考例35-13) ^-NMRiCDCl) δ ppm:4.00 (3H? s), 6.19 (1H, s), 7.00-7.10 (1H, m), 7.10-7.20 ( 3 1H, m), 7.35-7.45 (1H, m), 7.55-7.65 (1H, m), 7.65-7.75 (1H, m) (參考例35-14)3), 7.45-7:65 (3HS m), 7J0-7.80 (1H, m), 8.15-8.20 (1H, m) (Reference Example 35-5) 1H-NMR (CDC1) δ ppm: 4〇00 ( 3H, s), 6.18 (1H, s), 7.00-7.10 (1H, m), 7.35-7.45 (3 1H, m), 7.60-7.75 (4H, m) (Reference Example 35-6) 'H-NMRiCDCO δ ppm: 4e〇3 (3H, s), 6.18 (1H, s), 7.00-7.05 (1H, m), 7.45-7.55 (1H, m), 7.65-7.75 (2H, m), 7.75-7.80 ( 1H, m), 8.20-8.30 (1H, m) Φ (Reference Example 35-7) 'H-NMRiCDCl) δ ppm: 4.03 (3H, s), 6.19 (1H, s), 7.00-7.05 (1H, m ), 7.45-7.55 ( 3 1H, m), 7.75-7.85 (1H, m), 7.85-7.95 (1H, m), 7.95-8.05 (1H, m), 8.50-8.60 (1H, m) (Reference example) 35-8) ^-NMRiCDCl) δ ppm: 3〇96 (3H, s), 6.16 (1H, s), 7.00-7.05 (1H, m), 7.40^7.55 (3 2H, m), 7.70-7.80 ( 2H, m), 8.40-8.45 (1H, m) (Reference Example 35-9) 106 312XP/Invention Manual (supplement)/96·03/95143900 200800871 'H-NMR^DCl) δ ppm: 3.99 (3H, s), 6.17 (1H, s), 7.00-7.10 (1H, m), 7.50-7.60 ( 3 1H, m), 7·65-7·75 (3H, m), 7. 80-7·85 ( 1H, m) (Reference Example 35-10) 'H-NMRiCDCl) δ ppm: 4e〇3 (3H, s), 6.23 (1H, s), 7.05-7J5 (1H, m), 7.70-7.90 ( 3 3H , m), 8.05 (2H, d, J= 7e9Hz) (Reference Example 35-11) ^-NMRiCDCl) δ ppm: 4.00 (3H, s), 6.22 (1H, s), 7.05-7.10 (1H, m), 7.65-7.70 ( 3 1H, m), 7.70 -7.75 (1H, m), 7〇9〇-7β95 (1H, m), 8.00-8.05 (1H, m) ® (Reference Example 35-12) ^-NMRCCDCl) δ ppm: 3.99 (3H, s), 6Λ9 (1H, s), 7.00-7JO (1H, m), 7.60-7.75 ( 3 3H, m), 7.75-7.80 (1H, m) (Reference Example 35-13) ^-NMRiCDCl) δ ppm: 4.00 ( 3H? s), 6.19 (1H, s), 7.00-7.10 (1H, m), 7.10-7.20 ( 3 1H, m), 7.35-7.45 (1H, m), 7.55-7.65 (1H, m), 7.65 -7.75 (1H, m) (Reference Example 35-14)

^-NMRCCDCO δ ppm:L20-L7O (6H, m), 1.75-1.90 (2H, m), 2.05-2.15 (2H, m), 3.98 (3H, s), 5.10-5.20 (1H, m), 6.10 (1H, s), 6.85-6.95 (2H, m), 7.00-7.05 (1H, m), 7.60-7.65 (1H, m), 7.65-7.75 (1H, m) (參考例35-15) "H-NMRCCDCl) δ ppm: 1.45 (3H, s), 1.46 (3H, s), 3.98 (3H, s), 5.30-5.45 (1H, m 3 ),6.09 (1H, s), 6.85-6.95 (2H, m), 7.00-7.05 (1H, m), 7.60-7.65 (1H5 m), 7〇65-7.7 5 (1H, m) (參考例35-16) 107 312XP/發明說明書(補件)/96-03/95143900 200800871 'H-NMRiCDCO δ ppm: 1.46 (3H, t5 J=7e2Hz), 3.98 (3H, s), 4.51 (2H, q, J=7.2Hz) ,6.11 (1H, brs), 6.85-7.00 <2H, m), 7.00-7.05 (1H, m), 7.60-7.65 (1H? m), 7〇65-7. 70 (1H, m) (參考例36 - 1) 4 -（4 -乙基苯磺醯基）一 2 一甲氧基一 6 一硝基酚在至溫攪拌下，將發煙硝酸（〇〇44mL)加入至4- (4〜乙基苯磺醯基）-2 -曱氧基酚（參考例34- l)((K26g)及一氣曱烷（5mL)之混合物中並攪拌15分鐘。此反應混合物以食鹽水洗滌，用無水硫酸鎂乾燥後在減壓下進行濃縮。其殘留物通過SCX離子交換管柱（Argonaute公司製、gg) 進行過濾，再用1%曱醇-二氯曱烷溶液洗提後，濾液在減壓下進行濃縮。其殘留物以矽膠中壓管柱色析法進行精製（洗提液··二氯曱烷至2%曱醇-二氯甲烷），得目標化合物（0· 24g)。 'H- NMR(CDCh) 5 ppm : 1. 24(3H, t, J = 7. 7Hz), 2. 71 φ (2H, q, 7. 6Hz), 4. 00(3H, s), 7. 36(2H, d, g. 5Hz), 7· 57(1H，d，J = 1· 9Hz), 7· 85(2H，d，J= 8· 5Hz)，8· 32 (1H，d，2· 2Hz)，11· 〇8(lH，s) (參考例36 - 45) 5 -氟-2 - (4 _羥基-3 -甲氧基_ 5 -硝基笨磺醯基）-3 -曱基苯曱腈在0C下’將發煙硝酸（〇.467mL)及二氯甲烧（4mL)之混合物加入至5-氟-2-(4-羥基-3-甲氧基苯磺醯基）- 3 -甲基苯甲腈（參考例34 — 42)(3g)及二氯甲烧 312XP/發明說明書(補件)/96-03/95143900 108 200800871 (180mL)之混合物中，在相同溫度下攪拌15分鐘。於混合物中加入Imol/L鹽酸（6mL)。分取有機液層，用無水:二鎂乾燥後在減壓下進行濃縮。其殘留物與二***一起進行粉碎，減壓乾燥，得目標化合物（2. 859g)。 (參考例36 - 118) 3 ’ 5 -二氟-2 - (4 -經基-3 -曱氧基_ 5 _硝基苯石蔷醯基）苯甲酸曱酯在0 C下，將發煙硝酸（〇· 〇4mL)加入至3，5 -二氟-2 -馨（4 -經基U氧基苯磺醯基）苯甲酸甲酯（參考例3卜 8) (316mg)及二氯甲烷（8.8mL)之混合物中，在相同溫度下攪拌24分鐘。於混合物中加入水（13mL)。分取有機液層，用無水硫酸鈉乾燥後在減壓下進行濃縮。其殘留物與二***（2mL)—起進行粉碎，濾取固體，用二***（imL) 洗滌5次後以50°C減壓乾燥，得目標化合物（264mg)。 (參考例36 - 124) _ 1 - [3, 5 -二氟-2 -（4 -羥基- 3 -甲氧基- 5 一硝基苯磺醯基）苯基]乙酮在室溫檟:拌下’將發煙硝酸（〇 · 〇 5 5mL)加入至1—[3,5一二氟-2 - (4~羥基-3 -甲氧基苯磺醯基）苯基]乙酮（參考例31 _ 9)(390mg)及二氯甲烷（11.4mL)之混合物中，在相同溫度下攪拌24分鐘。此反應混合物加入水 (16. 9mL)。分取有機液層，用無水硫酸鈉乾燥後在減壓下進行濃縮，得目標化合物（456mg)。依與參考例36 - 1相同方法，使用對應之2 —曱氧基酚 312XP/發明說明書(補件)/96-03/95143900 109 200800871 以代替4 - (4 -乙基苯磺醯基）-2 -曱氧基酚，合成參考例 36 - 2〜36-44、36 - 46〜36 - 117、36 - 119〜36 - 123 及36 - 125。此等示於表16。 [表 16 ]^-NMRCCDCO δ ppm: L20-L7O (6H, m), 1.75-1.90 (2H, m), 2.05-2.15 (2H, m), 3.98 (3H, s), 5.10-5.20 (1H, m), 6.10 (1H, s), 6.85-6.95 (2H, m), 7.00-7.05 (1H, m), 7.60-7.65 (1H, m), 7.65-7.75 (1H, m) (Reference 35-15) " H-NMRCCDCl) δ ppm: 1.45 (3H, s), 1.46 (3H, s), 3.98 (3H, s), 5.30-5.45 (1H, m 3 ), 6.09 (1H, s), 6.85-6.95 (2H , m), 7.00-7.05 (1H, m), 7.60-7.65 (1H5 m), 7〇65-7.7 5 (1H, m) (Reference Example 35-16) 107 312XP/Invention Manual (supplement)/96 -03/95143900 200800871 'H-NMRiCDCO δ ppm: 1.46 (3H, t5 J=7e2Hz), 3.98 (3H, s), 4.51 (2H, q, J=7.2Hz), 6.11 (1H, brs), 6.85- 7.00 <2H, m), 7.00-7.05 (1H, m), 7.60-7.65 (1H? m), 7〇65-7. 70 (1H, m) (Reference Example 36 - 1) 4 -(4 - Ethylbenzenesulfonyl)-2-methoxy-6-nitrophenol was added to 4-(4~ethylphenylsulfonyl)-2 with stirring nitric acid (〇〇44 mL) under stirring. a mixture of methoxyphenol (Reference Example 34-1) ((K26g) and monooxane (5 mL) and stirred for 15 minutes. The reaction mixture was washed with brine, dried over anhydrous magnesium sulfate The residue was filtered through an SCX ion exchange column (manufactured by Argonaute Co., gg), and eluted with a 1% methanol-dichloromethane solution, and the filtrate was concentrated under reduced pressure. The phthalocyanine medium pressure column chromatography method was used for purification (eluent · dichloro decane to 2% decyl alcohol - dichloromethane) to give the title compound (0·24 g). 'H-NMR (CDCh) 5 ppm : 1. 24(3H, t, J = 7. 7Hz), 2. 71 φ (2H, q, 7. 6Hz), 4. 00(3H, s), 7. 36(2H, d, g. 5Hz) , 7· 57(1H,d,J = 1· 9Hz), 7·85(2H,d,J= 8· 5Hz), 8· 32 (1H,d,2· 2Hz),11·〇8(lH , s) (Reference Example 36 - 45) 5 -Fluoro-2 - (4 _ hydroxy-3 -methoxy-5-nitro oxasulfonyl)-3 -mercaptobenzonitrile at 0C 'will be issued A mixture of nicotinic acid (〇.467mL) and methylene chloride (4mL) was added to 5-fluoro-2-(4-hydroxy-3-methoxyphenylsulfonyl)-3-methylbenzonitrile (Reference) Example 34 - 42) (3g) and methylene chloride 312XP / invention instructions (supplement) / 96-03 / 95143900 108 200800871 (180mL) mixture was stirred at the same temperature for 15 minutes. Imol/L hydrochloric acid (6 mL) was added to the mixture. The organic layer was separated, dried over anhydrous: magnesium sulfate and concentrated under reduced pressure. The residue was pulverized with diethyl ether and dried under reduced pressure to give title compound (2. 859 g). (Reference Examples 36 - 118) 3 ' 5 -Difluoro-2 -(4-carbyl-3 -nonyloxy-5-nitrophenylphosphonium) benzoate oxime at 0 C, will emit fumes Nitric acid (〇·〇4mL) was added to methyl 3,5-difluoro-2-antimony (4-hydroxyisooxybenzenesulfonyl)benzoate (Reference Example 3, 8) (316 mg) and dichloromethane (8.8 mL) of the mixture was stirred at the same temperature for 24 minutes. Water (13 mL) was added to the mixture. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was pulverized with diethyl ether (2 mL), and the solid was filtered, washed twice with diethyl ether (imL) and dried under reduced pressure at 50 ° C to give the title compound (264 mg). (Reference Example 36 - 124) _ 1 - [3,5-Difluoro-2-(4-hydroxy-3-methoxy-5-nitrophenylsulfonyl)phenyl]ethanone at room temperature: Mix with 'Fume nitric acid (〇·〇5 5mL) to 1-[3,5-difluoro-2-(4-hydroxy-3-methoxyphenylsulfonyl)phenyl]ethanone (Ref. A mixture of Example 31-9(390 mg) and dichloromethane (11.4 mL) was stirred at the same temperature for 24 min. The reaction mixture was added with water (16.9 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. In the same manner as in Reference Example 36-1, the corresponding 2-methoxyphenol 312XP/invention specification (supplement)/96-03/95143900 109 200800871 was used instead of 4-(4-ethylbenzenesulfonyl)- 2-Hydroxyphenol, Synthesis Reference Examples 36 - 2 to 36-44, 36 - 46 to 36 - 117, 36 - 119 to 36 - 123 and 36 - 125. These are shown in Table 16. [Table 16]

312XP/發明說明書(補件)/96-03/95143900 110 200800871 [表16](續）312XP/Invention Manual (supplement)/96-03/95143900 110 200800871 [Table 16] (continued)

312XP/發明說明書(補件)/96-03/95143900 111 200800871 [表16](續）312XP/Invention Manual (supplement)/96-03/95143900 111 200800871 [Table 16] (continued)

312XP/發明說明書(補件)/96·03/95143900 112 200800871 [表16](續）312XP/Invention Manual (supplement)/96·03/95143900 112 200800871 [Table 16] (continued)

參考例構造式參考例構造式 36-43 v 1 36-50 t Lf u F 36_44 v I 0”0 36-51 〇\ 36-45 0、ν·0- N 36-52 〆〇 36-46 0、v.0· {[丨 36-53 〆〇 35 - 47 cdsxr 36-54 36 - 48 N 36-55 〇^f'VN 36 - 49 l： V 36-56 S: vo 。:y久 312XP/發明說明書(補件)/96-03/95143900 113 200800871 [表1 6 ](續）Reference example Construction reference example Construction formula 36-43 v 1 36-50 t Lf u F 36_44 v I 0"0 36-51 〇\ 36-45 0, ν·0- N 36-52 〆〇36-46 0 , v.0· {[丨36-53 〆〇35 - 47 cdsxr 36-54 36 - 48 N 36-55 〇^f'VN 36 - 49 l: V 36-56 S: vo .:y long 312XP/ Invention specification (supplement)/96-03/95143900 113 200800871 [Table 1 6] (continued)

312XP/發明說明書(補件)/96-03/95143900 114 200800871 [表16](續）312XP/Invention Manual (supplement)/96-03/95143900 114 200800871 [Table 16] (continued)

參考例構造式參考例構越 36 - 71 /Ο F 36-78 〆〇 36-72 36-79 36-73 35-80 /〇 36 - 74 36-81 分古σ 〆〇 36-75 i v〇 ? 〆〇 1 36-82 °3^4^ /Ο 36-76 36-δ3 36-77 Jo σ 36-84 /〇 312XP/發明說明書(補件)/96-03/95143900 115 200800871 [表16](續）Reference example Structural formula Reference structure 36 - 71 /Ο F 36-78 〆〇36-72 36-79 36-73 35-80 /〇36 - 74 36-81 分 σ 〆〇36-75 iv〇? 〆〇1 36-82 °3^4^ /Ο 36-76 36-δ3 36-77 Jo σ 36-84 /〇312XP/Invention Manual (supplement)/96-03/95143900 115 200800871 [Table 16] ( Continued)

參考例構造式參考例構造式 36-85 36-92 /〇 36-86 36-93 /〇 36-87 辨, 36-94 36-88 /〇 36-95 / F 36-S9 36-96 〆〇 36-90 °：w;、 36-97 /〇 36-91 。料 36-98 ?' 〇、、,， 312XP/發明說明書(補件)/96-03/95143900 116 200800871 [表16](續）Reference example Construction reference example Construction formula 36-85 36-92 /〇36-86 36-93 /〇36-87 Identification, 36-94 36-88 /〇36-95 / F 36-S9 36-96 〆〇 36-90 °: w;, 36-97 / 〇 36-91. Material 36-98 ?' 〇,,,, 312XP/Invention Manual (supplement)/96-03/95143900 116 200800871 [Table 16] (Continued)

312XP/發明說明書(補件)/96-03/95143900 117 200800871 [表16](續）312XP/Invention Manual (supplement)/96-03/95143900 117 200800871 [Table 16] (Continued)

參考例構造式參考例構造式 36-113 Or '0 36-120 /〇 36-114 0、“。-丨 :Λ:ώ d 36-121 〇5^5Γ /〇 36-115 O' :知. 36-122 36-116 %^°· If 人 36-123 破 36-117 〇s 36-124 °分’& 〆〇 36-118 /° 36-125 〆〇 36-119 /〇 3 UXP/發明說明書(補件)/96-03/95143900 118 200800871 參考例3 6 - 2〜參考例3 6 - 12 5之物性值係如下示。 (參考例36-2) 2H, m), 7.49-7.54 (1H, m), 7»57 (1H, d, J=2.0Hz), 8.33 (1H, d, J=2,lHz), 1L10 (1 H, s) (參考例36 - 3)Reference example Construction reference example Structure 36-113 Or '0 36-120 /〇36-114 0, ".-丨:Λ:ώ d 36-121 〇5^5Γ /〇36-115 O' : Know. 36-122 36-116 %^°· If person 36-123 break 36-117 〇s 36-124 ° '& 〆〇36-118 /° 36-125 〆〇36-119 /〇3 UXP/invention Specification (supplement)/96-03/95143900 118 200800871 Reference Example 3 6 - 2 to Reference Example 3 The physical property values of 6 - 12 5 are as follows (Reference Example 36-2) 2H, m), 7.49-7.54 ( 1H, m), 7»57 (1H, d, J=2.0Hz), 8.33 (1H, d, J=2, lHz), 1L10 (1 H, s) (Reference Example 36 - 3)

'H-NMRCCDCO δ ppm:3〇81 (3H, s), 3.94 (3H, s), 6.06 (1H, s), 6.91 (1H, d, J=8. 2Hz), 6.97 (1H, d, J=8e5Hz), 7.06-7.13 (1H, m), 7.48-7.55 (2H, m), 8.12 (1H, dd, J'H-NMRCCDCO δ ppm: 3〇81 (3H, s), 3.94 (3H, s), 6.06 (1H, s), 6.91 (1H, d, J=8. 2Hz), 6.97 (1H, d, J =8e5Hz), 7.06-7.13 (1H, m), 7.48-7.55 (2H, m), 8.12 (1H, dd, J

(參考例36 - 4) ^-NMRiCDCO δ ppm:3.95 (3H, s), 4,01 (3H, s), 7.56 (1H, d, J=1.9Hz), 8.02 (2 H, d, J=8.8Hz), 8.17-8.23 (2H, m), 8.36 (1H, d, J=L9Hz), 11.13 (1H, s) (參考例36-5) 1H-NMR(CDC〇 δ ppm:3.97 (3H, s), 4.02 (3H, s), 7.58 (1H, d, J=2.1Hz), 7.66 (1 H, t, J=7.9Hz), 8.11-8.18 (1H, m), 8.24-8.32 (1H, m), 8.36 (1H, d, J=2.1Hz), 8.59 ( 1H, t, J=1.7Hz) (參考例36-6) ^-NMRiCDCO δ ppm:4.01 (3H, s), 4.05 (3H, s), 7.56-7.61 (1H, m), 7.64-7.71 ( 2H, m), 7.86 (1H, d, J=L9Hz), 8.11-8.17 (1H, m), 8.40 (1H, d, J=1.9Hz), 11.12 (1 H, s) (參考例36 - 7) 'H-NMRiCDCl) δ ppm:2.38 (6H, s), 4.01 (3H, s), 7.22 (1H, s), 7.54 (2H, s), 7.57 3 (1H, d, J=1.9Hz), 8.32 (1H, d, J=2.2Hz), 1L09 (1H, s) 119 312XP/發明說明書(補件)/96-03/95143900 200800871 (參考例36-8) "H-NMRiCDCl) δ ppm:2e98 (3Η, s), 3.14 (3H, s), 4〇00 (3H, s), 6.76 (1H, s), 7.53 3 (1H, d, J=1.9Hz), 7.56-7〇69 (2H, m), 7.99 (1H, d, J=L6Hz), 8.35 (1H, d, J=2.2Hz), 10.99-11.21 (lH,m) (參考例3 6 — 9) 1H-NMR(CDC1) δ ppm:4e〇2 (3H, s), 7.16 (2H, ts J=9.5Hz), 7.37 (2H, t, J=7.7Hz) 3 ,7.61-7.66 (1H, m), 7.70 (2H, s), 8.10 (1H, t, J=7.4Hz), 8.38 (1H, s), 11.11 Qh, s) (參考例36-10)(Reference Example 36 - 4) ^-NMRiCDCO δ ppm: 3.95 (3H, s), 4,01 (3H, s), 7.56 (1H, d, J=1.9Hz), 8.02 (2 H, d, J= 8.8 Hz), 8.17-8.23 (2H, m), 8.36 (1H, d, J=L9Hz), 11.13 (1H, s) (Reference Example 36-5) 1H-NMR (CDC〇δ ppm: 3.97 (3H, s), 4.02 (3H, s), 7.58 (1H, d, J=2.1Hz), 7.66 (1 H, t, J=7.9Hz), 8.11-8.18 (1H, m), 8.24-8.32 (1H, m), 8.36 (1H, d, J = 2.1 Hz), 8.59 (1H, t, J = 1.7 Hz) (Reference Example 36-6) ^-NMRiCDCO δ ppm: 4.01 (3H, s), 4.05 (3H, s), 7.56-7.61 (1H, m), 7.64-7.71 ( 2H, m), 7.86 (1H, d, J=L9Hz), 8.11-8.17 (1H, m), 8.40 (1H, d, J=1.9 Hz), 11.12 (1 H, s) (Reference Example 36 - 7) 'H-NMRiCDCl) δ ppm: 2.38 (6H, s), 4.01 (3H, s), 7.22 (1H, s), 7.54 (2H, s), 7.57 3 (1H, d, J=1.9Hz), 8.32 (1H, d, J=2.2Hz), 1L09 (1H, s) 119 312XP/invention manual (supplement)/96-03/95143900 200800871 (Reference Example 36-8) "H-NMRiCDCl) δ ppm: 2e98 (3Η, s), 3.14 (3H, s), 4〇00 (3H, s), 6.76 (1H, s), 7.53 3 (1H , d, J=1.9Hz), 7.56-7〇69 (2H, m), 7.99 (1H, d, J=L6Hz), 8.35 (1H, d, J=2.2Hz), 10.99-11.21 (lH,m (Reference Example 3 6 - 9) 1H-NMR (CDC1) δ ppm: 4e〇2 (3H, s), 7.16 (2H, ts J=9.5Hz), 7.37 (2H, t, J=7.7Hz) 3 , 7.61 - 7.66 (1H, m), 7.70 (2H, s ), 8.10 (1H, t, J=7.4Hz), 8.38 (1H, s), 11.11 Qh, s) (Reference Example 36-10)

^-NMRCCDCl) δ ppm:4.01 (3H, s), 7.31 (1H, d, J=2.5Hz), 7.51-7.58 (2H, m), 7. 3 65 (1Ή, d, J=7.9Hz), 7.75 (1H, d, J=7.9Hz), 8.33 (1H, d, J=2.2Hz), 11.08 (1H, br s) (參考例36-11) 'H-NMRiCDCl) δ ppm:4.00 (3H, s), 7.20-7.26 (2H, m), 7〇55 (1H, d, J=1.9Hz), 7. 3 95-8.03 (2H, m), 8.31 (1H, d, J=2.2Hz), 1L08 (1H, s) (參考例36-12) ^-NMRCCDa) 6 ppm :3.96-4.02 (3H, m), 7.48-7.54 (1H, m), 7.54-7.62 (2H, m), 8Λ6 (1H, d, J=2.1Hz), 8.49-8.57 (1H, m) (參考例36-13) ^-NMRiCDCO δ ppm: 3.98-4.03 (3H, m), 7.28-7.43 (2H, m), 7.45-7.64 (1H, m), 8.12-8.19 (1H, m), 8.48-8.59 (1H, m), 10.92-11.25 (1H, m) (參考例36-14 ) 'H-NMRCCDCy δ ppm:4.03 (3H, s), 7.11 (1H, t, J=9.0Hz), 7.51-7.61 (1H, m), 7. 67 (2H, s), 8.07 (1H, dd, J=6e〇, 2.5Hz), 8.40 (1H, s), 1L16 (1H, s) (參考例36-15) 312XP/發明說明書(補件)/96·03/95143900 120 200800871 1H-NMR(CDa ) δ ppm:4.04 (3H, s), 7〇30 (1H, t, J=9.0Hz)5 7.68 (1H, s), 7.85-7. 96 (1H, m), 8.39 (1H, d, J=6〇0Hz)s 8.43 (1H, s), 1L15-1L22 (1H, m) (參考例36-16) ^-NMRiCDCl) δ ppm:2.42 (3H, s), 4,01 (3H, s), 6.96 (1H, d, J=11.0Hz), 7.15 (1 3 H, d, J=8.2Hz), 7.69 (1H, s), 7.95 (1H, t, J=7.9Hz), 8.36 (1H, s), 1L09-11.16 (1H, m) (參考例36_17)^-NMRCCDCl) δ ppm: 4.01 (3H, s), 7.31 (1H, d, J=2.5Hz), 7.51-7.58 (2H, m), 7. 3 65 (1Ή, d, J=7.9Hz), 7.75 (1H, d, J=7.9Hz), 8.33 (1H, d, J=2.2Hz), 11.08 (1H, br s) (Reference Example 36-11) 'H-NMRiCDCl) δ ppm: 4.00 (3H, s), 7.20-7.26 (2H, m), 7〇55 (1H, d, J=1.9Hz), 7. 3 95-8.03 (2H, m), 8.31 (1H, d, J=2.2Hz), 1L08 (1H, s) (Reference Example 36-12) ^-NMRCCDa) 6 ppm : 3.96-4.02 (3H, m), 7.48-7.54 (1H, m), 7.54-7.62 (2H, m), 8Λ6 (1H , d, J = 2.1 Hz), 8.49-8.57 (1H, m) (Reference Example 36-13) ^-NMRiCDCO δ ppm: 3.98-4.03 (3H, m), 7.28-7.43 (2H, m), 7.45- 7.64 (1H, m), 8.12-8.19 (1H, m), 8.48-8.59 (1H, m), 10.92-11.25 (1H, m) (Reference Example 36-14) 'H-NMRCCDCy δ ppm: 4.03 (3H , s), 7.11 (1H, t, J=9.0Hz), 7.51-7.61 (1H, m), 7. 67 (2H, s), 8.07 (1H, dd, J=6e〇, 2.5Hz), 8.40 (1H, s), 1L16 (1H, s) (Reference Example 36-15) 312XP/Invention Manual (Supplement)/96·03/95143900 120 200800871 1H-NMR (CDa) δ ppm: 4.04 (3H, s) , 7〇30 (1H, t, J=9.0Hz)5 7.68 (1H, s), 7.85-7. 96 (1H, m), 8.39 (1H, d, J=6〇0Hz)s 8.43 (1H, s), 1L15-1L22 (1H, m) (reference Example 36-16) ^-NMRiCDCl) δ ppm: 2.42 (3H, s), 4,01 (3H, s), 6.96 (1H, d, J=11.0Hz), 7.15 (1 3 H, d, J= 8.2 Hz), 7.69 (1H, s), 7.95 (1H, t, J=7.9Hz), 8.36 (1H, s), 1L09-11.16 (1H, m) (Reference Example 36_17)

^-NMRCCDCl) δ ppm :2.56 (3H, s), 3.98 (3H, s), 7.38 (1H, t, J=8e〇Hz), 7.45-7. 3 53 (1H, m), 7.65 (1H, d, J=8e2Hz), 8.15 (1H, d, J=8.2Hz), 8.21-8.27 (1H, m), 11.11 (1H, s) (參考例36-18) 'H-NMRCCDCO δ ppm:2.47 (3H, s), 3.99 (3H, s), 7.22 (1H, d, J=8.2Hz), 7.47-7. 53 (2H, m), 8.17 (1H, d, J=2.2Hz)s 8.27 (1H, d, J=1.9Hz), 11.12 (1H, s) (參考例3 6 -19) "H-NMRCCDCl) δ ppm:2.50 (3H, s), 3.98 (3H, s), 6.99 (1H, dd, J=9.1? 2.5Hz), 7. 3 07-7.15 (1H, m), 7.49 (1H, d, J=L9Hz), 8.18-8.25 (2H, m), 11.10 (1H, s) (參考例3 6 - 2 0) 'H-NMR(CDC1) δ ppm:2.50 (3H，s), 3·98 (3H, s)，6。99 (1H, dd，风1，2„5Hz)，7. 3 07-7J5 (1H, m), 7.49 (1H, d, J=L9Hz), 8.18-8.25 (2H, m), 11.10 (1H? s) (參考例36-21) ^-NMRiCDCl) δ ppm:3.85-3.94 (3H, m), 3.96-4.03 (3H, m), 7β〇4-7.11 (1H, m), 3 7。31 -7。39 (1H, m), 7.64-7·70 (1H, m), 7.81-7.89 (1H, m), 8·22-8〇37 (1H，m), 11.0 4-11.16 (1H, m) (參考例3 6 - 2 2) 121 312XP/發明說明書(補件)/96-03/95143900 200800871 "H-NMRCCDCI) δ ppm :4.04 (3H, s), 7〇50 (1H, s), 7J1 (1H, s), 7.87-7.94 (1H, m 3 ),8.31-8.35 (1H, m), 8.35-8.42 (1H, m), 11.17 (1H, br s) (參考例36-23) 1H-NMR(CDC1) δ ppm:2.42 (3H, d, J=1.9Hz), 3.98 (3H, s), 7.32 (1H, t, J-8e5Hz) 3 ,7〇36-7〇45 (1H, m), 7.51 (1H, d, J=L9Hz), 8.00 (1H, d, J=7.3Hz), 8.22-8.28 (1H, m), 11.11 (1H, s) (參考例36-24) ^-NMRiCDCl) δ ppm:4.05 (3H, s), 7〇53 (1H, d, J=2.1Hz), 7.84-7.88 (1H, m), 8,^-NMRCCDCl) δ ppm : 2.56 (3H, s), 3.98 (3H, s), 7.38 (1H, t, J=8e〇Hz), 7.45-7. 3 53 (1H, m), 7.65 (1H, d, J=8e2Hz), 8.15 (1H, d, J=8.2Hz), 8.21-8.27 (1H, m), 11.11 (1H, s) (Reference Example 36-18) 'H-NMRCCDCO δ ppm: 2.47 ( 3H, s), 3.99 (3H, s), 7.22 (1H, d, J=8.2Hz), 7.47-7. 53 (2H, m), 8.17 (1H, d, J=2.2Hz)s 8.27 (1H , d, J=1.9Hz), 11.12 (1H, s) (Reference Example 3 6 -19) "H-NMRCCDCl) δ ppm: 2.50 (3H, s), 3.98 (3H, s), 6.99 (1H, Dd, J=9.1? 2.5Hz), 7. 3 07-7.15 (1H, m), 7.49 (1H, d, J=L9Hz), 8.18-8.25 (2H, m), 11.10 (1H, s) (Reference Example 3 6 - 2 0) 'H-NMR (CDC1) δ ppm: 2.50 (3H, s), 3·98 (3H, s), 6.99 (1H, dd, wind 1, 2 „ 5 Hz), 7 3 07-7J5 (1H, m), 7.49 (1H, d, J=L9Hz), 8.18-8.25 (2H, m), 11.10 (1H? s) (Reference Example 36-21) ^-NMRiCDCl) δ ppm :3.85-3.94 (3H, m), 3.96-4.03 (3H, m), 7β〇4-7.11 (1H, m), 3 7.31 -7.39 (1H, m), 7.64-7·70 ( 1H, m), 7.81-7.89 (1H, m), 8·22-8〇37 (1H, m), 11.0 4-11.16 (1H, m) (Reference Example 3 6 - 2 2) 121 312XP/Invention Manual (supplement)/96-03/95143900 200800871 "H-NMRCC DCI) δ ppm : 4.04 (3H, s), 7〇50 (1H, s), 7J1 (1H, s), 7.87-7.94 (1H, m 3 ), 8.31-8.35 (1H, m), 8.35-8.42 (1H, m), 11.17 (1H, br s) (Reference Example 36-23) 1H-NMR (CDC1) δ ppm: 2.42 (3H, d, J = 1.9 Hz), 3.98 (3H, s), 7.32 ( 1H, t, J-8e5Hz) 3 ,7〇36-7〇45 (1H, m), 7.51 (1H, d, J=L9Hz), 8.00 (1H, d, J=7.3Hz), 8.22-8.28 ( 1H, m), 11.11 (1H, s) (Reference Example 36-24) ^-NMRiCDCl) δ ppm: 4.05 (3H, s), 7〇53 (1H, d, J=2.1Hz), 7.84-7.88 ( 1H, m), 8,

3 06-8.11 (1H, m), 8.12-8.17 (1H, m), 8.36 (1H, d, J=2.1Hz), 11.18 (1H, br s) (參考例36-25) ^-NMRiCDCl) δ ppm:4.07 (3H, s), 7.50-7.59 (2H, m), 7.95-7.98 (1H, m), 8.30 3 (1H, d, J=2.1Hz), 8.36-8.42 (1H, m), 11.13 (1H, s) (參考例3 6 - 2 6)3 06-8.11 (1H, m), 8.12-8.17 (1H, m), 8.36 (1H, d, J=2.1Hz), 11.18 (1H, br s) (Reference Example 36-25) ^-NMRiCDCl) δ Ppm: 4.07 (3H, s), 7.50-7.59 (2H, m), 7.95-7.98 (1H, m), 8.30 3 (1H, d, J=2.1Hz), 8.36-8.42 (1H, m), 11.13 (1H, s) (Reference Example 3 6 - 2 6)

'H-NMRCDMSO-d ) δ ppm :2.53 (5H, s), 3.97 (4H, s), 7.55 (1H, s), 7.95-8.04 (3H 6 · ，m)，8.26 (1H，d, J=8.2Hz) φ (參考例36-27) ^-NMRiCDCl) δ ppm: 1.70-1.77 (4H, m), 2.81 (2H, s), 2.89 (2H, s), 3.98 (3H, s 3 ),7.33 (2H, d, J=14.5Hz), 7.50 (1H, d, J=L6Hz), 8.03 (1H, d), 8.22 (1H, d, J=2.2H z), 11.11 (1H, br s) (參考例36-28) 'H-NMRiCDCl) 5 ppm :2.48 (3H, s), 3.98 (3H, s), 7.27-7.30 (1H, m), 7.41 (1H, d 3 ,J=8.5Hz), 7.45-7.51 (1H, m), 8.13 (1H, d, J=8.5Hz), 8.22-8.27 (1H, m), 1L09-1L 15 (1H, m) 122 312XP/發明說明書(補件)/96-03/95143900 200800871 (參考例36_29) 'H-NMRiCDa) δ ppm:2.36-2.42 (3H, m), 3.95-4.02 (3H, m, J=3.2Hz), 7.40-7.4 8 (1H, m), 7.53 (1H, ds J=7.6Hz), 7.66 (1H, d, J=2.8Hz), 8.20-8.26 (1H, m), 8.29-8 .34 (1H, m), 1L09-1L16 (1H, m) (參考例36-30) 'H-NMRiCDCl) δ ppm:2.57 (3H, s), 4.08 (3H, s), 7.52 (1H, d, J=6.9Hz), 7.72 (1 3 H, d, J=7.9Hz), 8.02 (1H, d, J=1.9Hz), 8.15 (1H, s), 8.30 (1H, d, J=2.2Hz), 1L11 (1 H, s) 馨（參考例36-31) ^-NMRiCDCl) δ ppm:2.09-2.16 (2H, m), 2.93-2.98 (4H, m), 4.00 (3H, s), 7„36 (1H, d, J=7e9Hz), 7.58 (1H, d, J=1.9Hz), 7.73 (1H, d, J=7.9Hz), 7.75 (1H, s), 8〇31 ( 1H, d, J=2.2Hz), 1L07 (1H, s) (參考例3 6 - 3 2 ) 'H-NMR^DCl) δ ppm: 1.77-1.86 (4H, m), 2.81 (4H, d, J=6.0Hz), 4.00 (3H, s), 7. v 3'H-NMRCDMSO-d ) δ ppm :2.53 (5H, s), 3.97 (4H, s), 7.55 (1H, s), 7.95-8.04 (3H 6 · , m), 8.26 (1H,d, J= 8.2 Hz) φ (Reference Example 36-27) ^-NMRiCDCl) δ ppm: 1.70-1.77 (4H, m), 2.81 (2H, s), 2.89 (2H, s), 3.98 (3H, s 3 ), 7.33 (2H, d, J=14.5Hz), 7.50 (1H, d, J=L6Hz), 8.03 (1H, d), 8.22 (1H, d, J=2.2H z), 11.11 (1H, br s) ( Reference Example 36-28) 'H-NMRiCDCl) 5 ppm : 2.48 (3H, s), 3.98 (3H, s), 7.27-7.30 (1H, m), 7.41 (1H, d 3 , J=8.5Hz), 7.45-7.51 (1H, m), 8.13 (1H, d, J=8.5Hz), 8.22-8.27 (1H, m), 1L09-1L 15 (1H, m) 122 312XP/invention specification (supplement)/96 -03/95143900 200800871 (Reference Example 36_29) 'H-NMRiCDa) δ ppm: 2.36-2.42 (3H, m), 3.95-4.02 (3H, m, J=3.2Hz), 7.40-7.4 8 (1H, m) , 7.53 (1H, ds J=7.6Hz), 7.66 (1H, d, J=2.8Hz), 8.20-8.26 (1H, m), 8.29-8 .34 (1H, m), 1L09-1L16 (1H, m) (Reference Example 36-30) 'H-NMRiCDCl) δ ppm: 2.57 (3H, s), 4.08 (3H, s), 7.52 (1H, d, J=6.9Hz), 7.72 (1 3 H, d , J=7.9Hz), 8.02 (1H, d, J=1.9Hz), 8.15 (1H, s), 8.30 (1H, d, J=2.2Hz), 1L11 (1 H, s) Xin (Refer to Example 36) -31) ^-NMRiCDCl) δ p Pm:2.09-2.16 (2H, m), 2.93-2.98 (4H, m), 4.00 (3H, s), 7„36 (1H, d, J=7e9Hz), 7.58 (1H, d, J=1.9Hz ), 7.73 (1H, d, J=7.9Hz), 7.75 (1H, s), 8〇31 ( 1H, d, J=2.2Hz), 1L07 (1H, s) (Reference Example 3 6 - 3 2 ) 'H-NMR^DCl) δ ppm: 1.77-1.86 (4H, m), 2.81 (4H, d, J=6.0Hz), 4.00 (3H, s), 7. v 3

21 (IH, d, J=8.5Hz)? 7〇57 (1H, d, J=1.9Hz)> 7.62 (2H, t, j=3*9, 2.4Hz), 8.30 (1H, d, J=1.9Hz), 1L04-1L10 (1H, m) (參考例3 6 - 3 3) ^-NMRiCDQ) δ ppm:3.03 (3H, s), 3.16 (3H, s), 4.00 (3H, s), 7.54 (1H, d, J=8. 2Hz), 7.59 (1H, s), 7.65 (IH, dd, J=8.2, 1.9Hz), 8.35-8.41 (2H, m) (參考例3 6 - 3 4) "H-NMRCCDCO δ ppm:2.42 (3H, s), 4.02 (3H, s), 7.39 (1H, s), 7.55 (1H, d, J=2. 2Hz), 7.62 (1H, s), 7；72 (1H, s), 8.33 (1H, d, J=1.9Hz), 11.11 (1H, s) (參考例36-35) 123 312XP/發明說明書(補件)/96-03/95143900 200800871 'H-NMRCCDCl) δ ppm:3.99 (3H, s), 7.63^7.70 (1H, m), 7.71-7.77 (2H, m), 7.97 3 (1H, d, J=7.9Hz), 8.44 (1H, d, J=2.2Hz), 11.16 (1H, s) (參考例36-36) ^-NMRCCDCl) δ ppm :4.03 (3H, s), 7.70-7.80 (3H, m), 8.49 (1H, d, j=2.1Hz), 1 3 1.22 (1H, s) (參考例36-37) ^-NMRiCDCl) δ ppm:4.03 (3H, s), 7.26 (1H, s), 7.72 (1H, s), 7.77 (1H, d, J=2. 3 1Hz), 8.50 (1H, d, J=2.1Hz), 11.20 (1H, s) 修（參考例36-38) 'H-NMRiCDCl) δ ppm:4.02 (3H, s), 7.25-7.30 (2H, m), 7β76 (1H, d, J=2.1Hz), 8. 3 46 (1H, d, J=2.1Hz) (參考例36-39) 'H-NMRCCDCO δ ppm:2.34 (3H, s), 2.84 (3H, s), 4.01 (3H, s), 7.05-7； 10 (1H, m ),7.15-7.20 (1H, m), 7.70 (1H, d, J=2.1Hz), 8.19 (1H, d, J=2.1Hz), 11.09 (1H, br) (參考例36-40)21 (IH, d, J=8.5Hz)? 7〇57 (1H, d, J=1.9Hz)> 7.62 (2H, t, j=3*9, 2.4Hz), 8.30 (1H, d, J = 1.9 Hz), 1L04-1L10 (1H, m) (Reference Example 3 6 - 3 3) ^-NMRiCDQ) δ ppm: 3.03 (3H, s), 3.16 (3H, s), 4.00 (3H, s), 7.54 (1H, d, J=8. 2Hz), 7.59 (1H, s), 7.65 (IH, dd, J=8.2, 1.9Hz), 8.35-8.41 (2H, m) (Reference example 3 6 - 3 4 "H-NMRCCDCO δ ppm: 2.42 (3H, s), 4.02 (3H, s), 7.39 (1H, s), 7.55 (1H, d, J=2. 2Hz), 7.62 (1H, s), 7;72 (1H, s), 8.33 (1H, d, J=1.9Hz), 11.11 (1H, s) (Reference Example 36-35) 123 312XP/Invention Manual (supplement)/96-03/95143900 200800871 'H-NMRCCDCl) δ ppm: 3.99 (3H, s), 7.63^7.70 (1H, m), 7.71-7.77 (2H, m), 7.97 3 (1H, d, J=7.9Hz), 8.44 (1H, d, J = 2.2 Hz), 11.16 (1H, s) (Reference Example 36-36) ^-NMRCCDCl) δ ppm : 4.03 (3H, s), 7.70-7.80 (3H, m), 8.49 (1H, d, j=2.1Hz), 1 3 1.22 (1H, s) (Reference Example 36-37) ^-NMRiCDCl) δ ppm: 4.03 (3H, s), 7.26 (1H, s), 7.72 (1H, s), 7.77 (1H, d, J=2. 3 1Hz), 8.50 (1H, d, J=2.1Hz), 11.20 (1H, s) Revision (Reference Example 36-38) 'H-NMRiCDCl) δ ppm: 4.02 (3H , s), 7.25-7.30 (2H, m), 7 76 (1H, d, J=2.1Hz), 8. 3 46 (1H, d, J=2.1Hz) (Reference Example 36-39) 'H-NMRCCDCO δ ppm: 2.34 (3H, s), 2.84 (3H , s), 4.01 (3H, s), 7.05-7; 10 (1H, m ), 7.15-7.20 (1H, m), 7.70 (1H, d, J=2.1Hz), 8.19 (1H, d, J =2.1Hz), 11.09 (1H, br) (Reference Example 36-40)

'H-NMRiCDCl) δ ppm:2.40-2.45 (3H, m), 4.02 (3H, s), 6.85-6.90 (1H, m), 7.55 3 -7.70 (2H, m), 7.90-8.00 (1H, m), 8.20-8.30 (1H, m), 8.38 (1H, d, J=2.1Hz), 8.50-8.60 (1H, m), 1L12(1H, br) (參考例36-41) ^-NMRiCDCl) δ ppm:0.95-l〇05 (3H, m), 1.40-1.55 (2H, m), L70-1.85 (2H, m), 3 4.05 (3H, s), 4.35-4.40 (2H, m), 7.50-7.60 (1H, m), 7.60-7.70 (2H, m), 7.85-7.95 (1H, m), 8.10-8.15 (1H, m), 8.35-8.45 (1H, m) (參考例36-42) 124 312XP/發明說明書(補件)/96-03/95143900 200800871 ^-NMRiCDa ) δ ppm:L35-L50 (1H, m), 1.55Ί.90 (6H, m)? 3J5-3.25 (2H, m), 3.60-3.70 (2H, m), 3.85-4.00 (1H, m), 4.05 .(3H,s), 7.25-7.35 (1H, m), 7.50-7.70 (2H, m), 8.00-8.10 (2H, m), 8.45 (1H, d, J=2.1Hz), 11.10 (1H, br) (參考例36_43) 'H-NMRCCDCl) δ ppm :2.70 (3H, s), 4.02 (3H, s), 7.48 (1H, d, J=2.2Hz), 7.85 (1 3 H, d, J=2〇2Hz), 8.26 (1H, d, J=2.2Hz)i 8.41 (1H, d, J=2.2Hz), 11.17 (1H, s) (參考例36-44)'H-NMRiCDCl) δ ppm: 2.40-2.45 (3H, m), 4.02 (3H, s), 6.85-6.90 (1H, m), 7.55 3 -7.70 (2H, m), 7.90-8.00 (1H, m ), 8.20-8.30 (1H, m), 8.38 (1H, d, J=2.1Hz), 8.50-8.60 (1H, m), 1L12(1H, br) (Reference Example 36-41) ^-NMRiCDCl) δ Ppm: 0.95-l〇05 (3H, m), 1.40-1.55 (2H, m), L70-1.85 (2H, m), 3 4.05 (3H, s), 4.35-4.40 (2H, m), 7.50- 7.60 (1H, m), 7.60-7.70 (2H, m), 7.85-7.95 (1H, m), 8.10-8.15 (1H, m), 8.35-8.45 (1H, m) (Ref. 36-42) 124 312XP/Invention Manual (supplement)/96-03/95143900 200800871 ^-NMRiCDa ) δ ppm: L35-L50 (1H, m), 1.55Ί.90 (6H, m)? 3J5-3.25 (2H, m), 3.60-3.70 (2H, m), 3.85-4.00 (1H, m), 4.05 .(3H,s), 7.25-7.35 (1H, m), 7.50-7.70 (2H, m), 8.00-8.10 (2H, m), 8.45 (1H, d, J=2.1Hz), 11.10 (1H, br) (Reference Example 36_43) 'H-NMRCCDCl) δ ppm : 2.70 (3H, s), 4.02 (3H, s), 7.48 ( 1H, d, J=2.2Hz), 7.85 (1 3 H, d, J=2〇2Hz), 8.26 (1H, d, J=2.2Hz)i 8.41 (1H, d, J=2.2Hz), 11.17 (1H, s) (Reference Example 36-44)

'H-NMRiCDCl) δ ppm:2.50 (3H, s), 2.67 (3H, s), 4.01 (3H, s), 7.52 (1H, d, J=2. 3 1Hz), 7.65-7.70 (1H, m), 8.20-8.30 (2H, m) (參考例36-45) 'H-NMRiCDCl) δ ppm:2.81 (3H, s), 4.05 (3H, s), 7.17 (1H, dd, J=7e3, 2〇5Hz), 7. 3 90 (1H, d, J=1.9Hz), 8.34 (1H, d, J=2.2Hz), 11.14 (1H, br) (參考例36-46) ^H-NMRiCDCl ) δ ppm:2.64 (3H, s), 4.01 (3H, s), 7.45 (1H, d, J=2.2Hz), 7.92 (1 3 H, d, J=1.6Hz), 8.29 (1H, dd, J=L9Hz), 8.40 (1H, d, J=L6Hz), 11.18 (1H, br) (參考例36-47) 'H-NMRCCDCl) δ ppm:2.42 (3H, s), 3.99 (3H, s), 7.30-7.40 (2H, m), 7.50-7.60 ( 3 1H, m), 7β80-7.90 (2H, m), 8〇25~8〇35 (1H, m), 11.06 (1H, s) (參考例36-48) 'H-NMRCCDCO δ ppm :2.79 (3H, s), 4.05 (3H, s), 7.53-7.54 (1H, m), 7.73 (1H, d ,J=2.2Hz), 7.89 (1H, d, J=1.8Hz), 8.34 (1H, d, J=2.2Hz), 11.13 (1H, s) 125 312XP/發明說明書(補件)/96-03/95143900 200800871 (參考例36-49) 'H-NMRCCDCI ) δ ppm:4.02 (3Η, s)5 7.50-7.60 (1H, m), 7.75-7.85 (2H, m), 8.05 3 -8.15 (2H，m)，8.30-8·40 (1H, m)，11.13 (1H，s) (參考例36-50) 1H-NMR(CDC1) δ ppm:4.02 (3H, s)s 7.50-7.60 (IH, m), 7,65-7.80 (1H, m), 7.85 3 -7.95 (IH, m), 8.10-8.20 (1H, m), 8.20-8.25 (IH, m), 8.35-8.40 (IH, m)s 1L15 (1 H, s) •(參考例36-51) ^-NMRfCDCl) δ ppm:2.43 (3H, s), 4.01 (3H, s), 7.35-7.50 (2H, m), 7.50^7.65 ( 3 IH, m), 7.70-7.80 (2H, m), 8.25-8.40 (IH, m), 11.08 (IH, br s) (參考例36-52) 'H-NMR^DCO δ ppm :2.51 (3H, s), 3.98 (3H, s), 7.25-7.35 (IH, m), 7.40-7.60 ( 3H, m), 8.15-8.30 (2H, m), 11.11 (IH, s) (參考例36-53)'H-NMRiCDCl) δ ppm: 2.50 (3H, s), 2.67 (3H, s), 4.01 (3H, s), 7.52 (1H, d, J=2. 3 1Hz), 7.65-7.70 (1H, m ), 8.20-8.30 (2H, m) (Reference Example 36-45) 'H-NMRiCDCl) δ ppm: 2.81 (3H, s), 4.05 (3H, s), 7.17 (1H, dd, J=7e3, 2 〇5Hz), 7. 3 90 (1H, d, J=1.9Hz), 8.34 (1H, d, J=2.2Hz), 11.14 (1H, br) (Reference Example 36-46) ^H-NMRiCDCl ) δ Ppm: 2.64 (3H, s), 4.01 (3H, s), 7.45 (1H, d, J=2.2Hz), 7.92 (1 3 H, d, J=1.6Hz), 8.29 (1H, dd, J= L9Hz), 8.40 (1H, d, J=L6Hz), 11.18 (1H, br) (Reference Example 36-47) 'H-NMRCCDCl) δ ppm: 2.42 (3H, s), 3.99 (3H, s), 7.30 -7.40 (2H, m), 7.50-7.60 ( 3 1H, m), 7β80-7.90 (2H, m), 8〇25~8〇35 (1H, m), 11.06 (1H, s) (Ref. 36) -48) 'H-NMRCCDCO δ ppm : 2.79 (3H, s), 4.05 (3H, s), 7.53-7.54 (1H, m), 7.73 (1H, d, J=2.2Hz), 7.89 (1H, d , J=1.8Hz), 8.34 (1H, d, J=2.2Hz), 11.13 (1H, s) 125 312XP/Invention Manual (supplement)/96-03/95143900 200800871 (Reference Example 36-49) 'H -NMRCCDCI ) δ ppm: 4.02 (3Η, s)5 7.50-7.60 (1H, m), 7.75-7.85 (2H, m), 8.05 3 -8.15 (2H, m), 8.30-8·40 (1H, m ), 11.13 (1H, s) (Reference Example 36-50) 1H-NMR (CDC1) δ ppm: 4.02 (3H, s)s 7.50-7.60 (IH, m), 7,65-7.80 (1H, m), 7.85 3 -7.95 (IH, m), 8.10-8.20 (1H, m), 8.20-8.25 (IH, m), 8.35-8.40 (IH, m)s 1L15 (1 H, s) • (Reference Example 36-51) ^-NMRfCDCl) δ Ppm: 2.43 (3H, s), 4.01 (3H, s), 7.35-7.50 (2H, m), 7.50^7.65 (3 IH, m), 7.70-7.80 (2H, m), 8.25-8.40 (IH, m), 11.08 (IH, br s) (Reference Example 36-52) 'H-NMR^DCO δ ppm : 2.51 (3H, s), 3.98 (3H, s), 7.25-7.35 (IH, m), 7.40 -7.60 ( 3H, m), 8.15-8.30 (2H, m), 11.11 (IH, s) (Reference Example 36-53)

1H-NMR(CDC1) δ ppm:3.93 (3H, s), 7.40-7.50 (IH, m), 7.80-8.00 (3H, m), 8.00 3 -8.10 (IH, m), 8.40-8.50 (IH, m) (參考例36-54) 'H-NMRCCDCl) δ ppm:3.96 (3H, s), 7.55-7JO (4H, m), 7.90-8.00 (IH, m)s 8e10 3 -8.20 (IH, m), 8〇30-8.40 (IH, m), 8.50-8.55 (IH, m), 8.60-8.70 (IH, m), 11.07 (1 H, s) (參考例36-55) i一NMR(CDC1) δ ppm:4.04 (3H, s), 7·50—7.60 (IH, m), 7.65-7.75 (IH, m), 7.85 3 «7.95 (IH, m), 8.15-8.25 (2H, m), 8.30-8.40 (IH, m), 11.16 (IH, s) 126 312XP/發明說明書(補件)/96-03/95143900 200800871 (參考例36-56) ^-NMRiDMSO-d ) δ ppm:3.97 (3Η, s), 7〇60~7.70 (1H, m), 8.05-8.15 (3H, m), 8〇 6 20-8.30 (2H, m), 1L82 (IH, br) (參考例36-57) 1H-NMR(DMSO~d ) δ ppm: 3.97 (3H, s), 7»60-7.80 (3H, m), 8.05-8.10 (1H, m), 8«, 6 10-8.25 (2H, m), 8.27 (1H, br s), 8.40-8.50 (1HS m), 11.88 (1H, br) (參考例36-58)1H-NMR (CDC1) δ ppm: 3.93 (3H, s), 7.40-7.50 (IH, m), 7.80-8.00 (3H, m), 8.00 3 -8.10 (IH, m), 8.40-8.50 (IH, m) (Reference Example 36-54) 'H-NMRCCDCl) δ ppm: 3.96 (3H, s), 7.55-7JO (4H, m), 7.90-8.00 (IH, m)s 8e10 3 -8.20 (IH, m ), 8〇30-8.40 (IH, m), 8.50-8.55 (IH, m), 8.60-8.70 (IH, m), 11.07 (1 H, s) (Reference Example 36-55) i-NMR (CDC1) δ ppm: 4.04 (3H, s), 7·50—7.60 (IH, m), 7.65-7.75 (IH, m), 7.85 3 «7.95 (IH, m), 8.15-8.25 (2H, m), 8.30-8.40 (IH, m), 11.16 (IH, s) 126 312XP/Invention Manual (supplement)/96-03/95143900 200800871 (Reference Example 36-56) ^-NMRiDMSO-d ) δ ppm: 3.97 (3Η , s), 7〇60~7.70 (1H, m), 8.05-8.15 (3H, m), 8〇6 20-8.30 (2H, m), 1L82 (IH, br) (Reference Example 36-57) 1H -NMR (DMSO~d) δ ppm: 3.97 (3H, s), 7»60-7.80 (3H, m), 8.05-8.10 (1H, m), 8«, 6 10-8.25 (2H, m), 8.27 (1H, br s), 8.40-8.50 (1HS m), 11.88 (1H, br) (Reference Examples 36-58)

"H-NMRiCDCl) 6 ppm:4.08 (3H, s), 7.70-7.80 (1H, m), 7.80-7.90 (2H, m), 8.00 3 -8.05 (1HS m), 8.25-8.35 (1H, m), 8.35-8.40 (1H, m), 11.13 (1H, br s) (參考例36-59) 1H-NMR(CDC〇 δ ppm:4.02 (3H, s), 7.35-7.45 (1H, m), 7.50-7.60 (1H, m), 7.60 -7.70 (1H, m)5 8.30-8.35 (1H, m), 8.35-8.40 (1H, m), 11.16 (1H, d, J=0〇6Hz) (參考例36-60) 'H-NMRCCDCO δ ppm:4.03 (3H, s), 7.50-7〇55 (1H, m), 7.55-7.60 (1H, m), 7J5 -7.85 (2H, m), 8.30-8.40 (1H, m), 11.16 (1HS s) (參考例36-61) 'H-NMRCCDCl) δ ppm:2.29 (3H, s), 4.08 (3H, s), 6J5 (1H, br s), 7.50-7.70 (3H, 3 m), 7.80-7.90 (2H, m), 7.95 (1H, s) (參考例36-62) ^-NMRiCDCl^) δ ppm :4.04 (3H, s), 7.50-7.60 (1H, m), 8.11 (1H, s), 8.35-8,45 ( 3H, m), 11.19 (1H, s) (參考例36-63) 127 312XP/發明說明書(補件)/96-03/95143900 200800871 ^-NMRCCDCl) δ ppm:4.00 (3H, s), 7.45-7.55 (2H, m), 7.60-7.65 (1H, m), 8.25 3 -8.35 (2H,m)，11.15 (lH，s) (參考例36-64) ^-NMRCCDCO δ ppm:4.02 (3H, s), 7.35-7.45 (1H, m), 7.45-7.55 (2H, m), 7.75 -7.85 (1H, m), 8.45-8〇50 (1H, m), 11.17 (1H, s) (參考例36-65) 1H-NMR(CDC〇 δ ppm:4e〇l (3H, s), 7.55-7.65 (1H, m), 8.00-8.10 (2H, m), 8.20 -8.25 (1H, m), 8.75 (1H, s), 1L13 (1H, s) * (參考例36-66) ^-NMRCCDCl) δ ppm :4.00 (3H, s), 7.60-7.75 (3H, m), 7.80-8.05 (4H, m), 8.35 3 -8.45 (1H, m), 8.55-8.60 (1H, m), 11.07 (1H, s) (參考例36-67) 1H-NMR(CDC1) δ ppm :4.01 (3H, s), 7.49 (2H, s), 7.70-7.80 (1H, m), 8.40-8.50 ( 3 1H, m), 11.16 (1H, s) (麥考例3 6 - 6 8)"H-NMRiCDCl) 6 ppm: 4.08 (3H, s), 7.70-7.80 (1H, m), 7.80-7.90 (2H, m), 8.00 3 -8.05 (1HS m), 8.25-8.35 (1H, m ), 8.35-8.40 (1H, m), 11.13 (1H, br s) (Reference Example 36-59) 1H-NMR (CDC〇δ ppm: 4.02 (3H, s), 7.35-7.45 (1H, m), 7.50-7.60 (1H, m), 7.60 -7.70 (1H, m)5 8.30-8.35 (1H, m), 8.35-8.40 (1H, m), 11.16 (1H, d, J=0〇6Hz) (Reference Example 36-60) 'H-NMRCCDCO δ ppm: 4.03 (3H, s), 7.50-7〇55 (1H, m), 7.55-7.60 (1H, m), 7J5 -7.85 (2H, m), 8.30- 8.40 (1H, m), 11.16 (1HS s) (Reference Example 36-61) 'H-NMRCCDCl) δ ppm: 2.29 (3H, s), 4.08 (3H, s), 6J5 (1H, br s), 7.50 -7.70 (3H, 3 m), 7.80-7.90 (2H, m), 7.95 (1H, s) (Reference Example 36-62) ^-NMRiCDCl^) δ ppm : 4.04 (3H, s), 7.50-7.60 ( 1H, m), 8.11 (1H, s), 8.35-8, 45 ( 3H, m), 11.19 (1H, s) (Reference Example 36-63) 127 312XP/Invention Manual (supplement)/96-03/ 95143900 200800871 ^-NMRCCDCl) δ ppm: 4.00 (3H, s), 7.45-7.55 (2H, m), 7.60-7.65 (1H, m), 8.25 3 -8.35 (2H, m), 11.15 (lH, s) (Reference Example 36-64) ^-NMRCCDCO δ ppm: 4.02 (3H, s), 7.35-7.45 (1H, m), 7.45-7.55 (2H, m), 7.75 -7. 85 (1H, m), 8.45-8〇50 (1H, m), 11.17 (1H, s) (Reference Example 36-65) 1H-NMR (CDC〇δ ppm: 4e〇l (3H, s), 7.55 -7.65 (1H, m), 8.00-8.10 (2H, m), 8.20 -8.25 (1H, m), 8.75 (1H, s), 1L13 (1H, s) * (Reference Example 36-66) ^-NMRCCDCl δ ppm : 4.00 (3H, s), 7.60-7.75 (3H, m), 7.80-8.05 (4H, m), 8.35 3 -8.45 (1H, m), 8.55-8.60 (1H, m), 11.07 ( 1H, s) (Reference Example 36-67) 1H-NMR (CDC1) δ ppm : 4.01 (3H, s), 7.49 (2H, s), 7.70-7.80 (1H, m), 8.40-8.50 ( 3 1H, m), 11.16 (1H, s) (Mc. 3 6 - 6 8)

"H-NMRCCDCl) δ ppm:4.01 (3H, s), 7.60-7.70 (2H, m), 7.75-7.85 (1H, m), 8.35 3 -8.45 (1H, m), 8.60-8。65 (1H，m), 11.17 (1H, s) (參考例36-69) 'H-NMRiCDCl) 6 ρρΐϊΐ:4β〇0 (3H, s), 7.20-7.30 (2H, m), 7.60-7.70 (1H, m), 8.30 3 -8.35 (1H, m), 8.35-8.45 (1H, m), 11.13 (1H, d, J=0.6Hz) (參考例36-70) 'H-NMRCCDCl) δ ppm:4.01 (3H, s), 7.60 (1H, s), 7.75-7.90 (2H, m), 8.15-8.20 ( 3 1H, m)，8.40-8.45 (1H，m)，11.10 (1H, d, J=0.6Hz) (參考例36-71) 128 312XP/發明說明書(補件)/96-03/95143900 200800871 一NMR(CDC13) δ ppm:4.02 (3H，s)，7·62 (1H，s)，8.05-8·15 (2H，m)，8·15-8.25 ( 1H, m), 8.60-8.70 (1H, m), 11.12 (1H, d, J=0.6Hz) (參考例36-72) 1H-NMR(CDC1) δ ppm:1.45 (3H, t, J=7.2Hz), 2.54 (3H, s), 4.02 (3H, s), 4.49 (2 3 H, q, J=7.2Hz), 7.32 (2H, s), 8.01 (1H, d, J=1.8Hz), 8.52 (1H, d, J=L8Hz), 11.15 (1 H, br) (參考例36-73) 'H-NMRiCDCl) δ ppm:4e〇l (3H, s), 7.40-7.60 (2H, m), 7.65-7.70 (1H, m), 8.15 3 -8.20 (1H, m), 8.30-8.35 (1H，m), 11.15 (1H, d, J=0.6Hz) (參考例36-74)"H-NMRCCDCl) δ ppm: 4.01 (3H, s), 7.60-7.70 (2H, m), 7.75-7.85 (1H, m), 8.35 3 -8.45 (1H, m), 8.60-8.65 ( 1H,m), 11.17 (1H, s) (Reference Example 36-69) 'H-NMRiCDCl) 6 ρρΐϊΐ: 4β〇0 (3H, s), 7.20-7.30 (2H, m), 7.60-7.70 (1H, m), 8.30 3 -8.35 (1H, m), 8.35-8.45 (1H, m), 11.13 (1H, d, J=0.6Hz) (Reference Example 36-70) 'H-NMRCCDCl) δ ppm: 4.01 ( 3H, s), 7.60 (1H, s), 7.75-7.90 (2H, m), 8.15-8.20 (3 1H, m), 8.40-8.45 (1H, m), 11.10 (1H, d, J=0.6Hz (Reference Example 36-71) 128 312XP/Invention Manual (Supplement)/96-03/95143900 200800871 One NMR (CDC13) δ ppm: 4.02 (3H, s), 7.62 (1H, s), 8.05- 8·15 (2H, m), 8·15-8.25 (1H, m), 8.60-8.70 (1H, m), 11.12 (1H, d, J=0.6Hz) (Reference Example 36-72) 1H-NMR (CDC1) δ ppm: 1.45 (3H, t, J=7.2Hz), 2.54 (3H, s), 4.02 (3H, s), 4.49 (2 3 H, q, J=7.2Hz), 7.32 (2H, s), 8.01 (1H, d, J=1.8Hz), 8.52 (1H, d, J=L8Hz), 11.15 (1 H, br) (Reference Example 36-73) 'H-NMRiCDCl) δ ppm: 4e〇 l (3H, s), 7.40-7.60 (2H, m), 7.65-7.70 (1H, m), 8.15 3 -8.20 (1H, m), 8.30-8.35 (1H, m), 11.15 (1H, d, J =0.6Hz) (Reference Example 36-74)

1H-NMR(CDC1) 5 ppm:2.42 (3H, s), 4.00 (3H, s), 7.25-7.35 (2H, m), 7.60-7.70 ( 3 1H, m), 8.20-8.25 (1H, m), 8.25-8.35 (1H, m), 11.12 (1H, s) (參考例36-75) 1H-NMR(CDC1) δ ppm:2.47 (3H, s), 4.01 (3H, s), 7.30-7.40 (2H, m), 7.65-7.75 ( 3 1H, m), 8.10-8.20 (1H, m), 8.25-8.35 (1H, m), 11.12 (1H, s) (參考例36-76) ^-NMRiCDCl) δ ppm:4.07 (3H, s), 7.75-7.85 (2H, m), 7.95-8.00 (1H, m), 8.25 3 -8.35 (2H, m), 11.14 (1H, s) (參考例36-77) "H-NMRiCDCl) δ ppm:4.08 (3H, s), 7.65-7.75 (1H, m), 7.75-7〇80 (1H, m), 7.95 3 -8.00 (1H, m), 8.30-8.40 (2H, m), 11.17 (1H, s) (參考例36-78) 1H-NMR(DMS〇-d ) 8 ppm:3e94 (3H, s), 7.60-7.70 (1H, m), 8.05-8J5 (2H, m), 8. 6 35-8^45 (1H, m), 8.45-8.50 (1H, m) (參考例36-79) ^-NMRCCDCO δ ppm :2.44 (3H, s), 4.07 (3H, s), 7.55-7.70 (2H, m), 7.95-8.05 ( 129 312XP/發明說明書(補件)/96-03/95143900 200800871 1H, m)，8·20-8·25 (1H, m)，8.25-8。35 (1H，m)，11.11 (1H，s) (參考例36-80) 'H-NMRCCDCl) δ ppm:4.05 (3H, s), 7.40-7.50 (1H, m), 7.65-7.80 (2H, m), 7.81 3 (1H, s), 8.45-8.55 (1H, m), 1L21 (1H, s) (參考例36-81) 'H-NMRCCDCl) δ ppm :4.09 (3H, s), 7.75-7.80 (2H, m), 8.00-8.05 (1H, m), 8.25 3 * -8.35 (2H, m), 11.14 (1H, s) * (參考例36-82) "H-NMRiCDCl) δ ppm :4.09 (3H, s), 7.95-8.10 (3H, m), 8.25-8.35 (1H, m), 8.60 3 -8.70 (1H，m), 11.15 (1H, d，J=0.7Hz) (參考例36-83) ^-NMRiDMSO-d ) δ ppm:3.94 (3H, s), 7.55-7.60 (1H, m), 8.00-8.10 (1H, m), 8. 6 10-8.20 (1H, m)> 8.25-8.35 (1H, m), 8.35-8.45 (1H, m) (參考例36-84)1H-NMR (CDC1) 5 ppm: 2.42 (3H, s), 4.00 (3H, s), 7.25-7.35 (2H, m), 7.60-7.70 (3 1H, m), 8.20-8.25 (1H, m) , 8.25-8.35 (1H, m), 11.12 (1H, s) (Reference Example 36-75) 1H-NMR (CDC1) δ ppm: 2.47 (3H, s), 4.01 (3H, s), 7.30-7.40 ( 2H, m), 7.65-7.75 ( 3 1H, m), 8.10-8.20 (1H, m), 8.25-8.35 (1H, m), 11.12 (1H, s) (Reference Example 36-76) ^-NMRiCDCl) δ ppm: 4.07 (3H, s), 7.75-7.85 (2H, m), 7.95-8.00 (1H, m), 8.25 3 -8.35 (2H, m), 11.14 (1H, s) (Reference Example 36-77 "H-NMRiCDCl) δ ppm: 4.08 (3H, s), 7.65-7.75 (1H, m), 7.75-7〇80 (1H, m), 7.95 3 -8.00 (1H, m), 8.30-8.40 (2H, m), 11.17 (1H, s) (Reference Example 36-78) 1H-NMR (DMS〇-d) 8 ppm: 3e94 (3H, s), 7.60-7.70 (1H, m), 8.05-8J5 (2H, m), 8. 6 35-8^45 (1H, m), 8.45-8.50 (1H, m) (Reference Example 36-79) ^-NMRCCDCO δ ppm :2.44 (3H, s), 4.07 ( 3H, s), 7.55-7.70 (2H, m), 7.95-8.05 (129 312XP/invention manual (supplement)/96-03/95143900 200800871 1H, m), 8·20-8·25 (1H, m ), 8.25-8. 35 (1H, m), 11.11 (1H, s) (Reference Example 36-80) 'H-NMRCCDCl) δ ppm: 4.05 (3H, s), 7.40-7.50 (1H, m), 7. 65-7.80 (2H, m), 7.81 3 (1H, s), 8.45-8.55 (1H, m), 1L21 (1H, s) (Reference Example 36-81) 'H-NMRCCDCl) δ ppm : 4.09 (3H , s), 7.75-7.80 (2H, m), 8.00-8.05 (1H, m), 8.25 3 * -8.35 (2H, m), 11.14 (1H, s) * (Reference Example 36-82) "H -NMRiCDCl) δ ppm : 4.09 (3H, s), 7.95-8.10 (3H, m), 8.25-8.35 (1H, m), 8.60 3 -8.70 (1H, m), 11.15 (1H, d, J=0.7 Hz) (Reference Example 36-83) ^-NMRiDMSO-d ) δ ppm: 3.94 (3H, s), 7.55-7.60 (1H, m), 8.00-8.10 (1H, m), 8. 6 10-8.20 ( 1H, m)> 8.25-8.35 (1H, m), 8.35-8.45 (1H, m) (Reference Example 36-84)

'H-NMRXDMSO-d ) δ ppm:3.96 (3H, s), 7.55-7.65 (1H, m), 7.85-7.95 (1H, m), 7. 6 95-8.05 (1H, m), 8.05-8.15 (1H, m), 8.15-8.20 (1H, m) (參考例36-85) 'H-NMRCDMSO-dJ δ ppm:3〇95 (3H, s), 7〇67 (1H, d, J=2.1Hz), 8.05 (1H, t, J=7e9 Hz), 8.18 (1H, d, J=2.1Hz), 8.44 (2H, d, J=7.9Hz) (參考例36-86) ^-NMRCCDCl) δ ppm:2.72 (3H, s), 4〇08 (3H, s), 7.30-7.40 (1H, m)s 7.55-7.70 ( 3 2H, m), 7.70-7.80 (1H, m), 8.00^8.10 (1H, m), 8.35-8.40 (1H, m), 11Λ1 (1H, s) (參考例36-87) 312XP/發明說明書(補件)/96-03/95143900 130 200800871 iH-NMR(DMSO-d ) δ ppm :3.95 (3H, s), 7„60-7·65 (1H，m)，8.10-8.15 (1H，m)，8· 6 25-8.35 (2H，m) (蒼考例3 6 - 8 8) ^-NMRiCDCl) δ ppm:4.02 (3H, s)5 7.44 (1H, d, J=8.8Hz), 7.61 (1H, d, j=8e8Hz 3 ),7.75-7.80 (1H, m), 8.45-8.50 (1H, m), 1L16 (1H, s) (參考例36-89) 'H-NMRCCDCO δ ppm:3.83 (6H, s), 4.00 (3H, s), 6〇63 (1H, t, J=2.2Hz), 7.04 (2 H, d, J=2.2Hz), 7.55-7.60 (1H, m), 8.30-8.35 (1H, m), 11.08 (1H, d, J=0.6Hz) ® (參考例36-90) 'H-NMRCCDCI ) δ ppm :3.89 (3H, s), 3.92 (6H, s), 4.01 (3H, s), 7.15 (2H, s), 7.55 3 -7·60 (1H, m), 8.30-05 (1H, m), 11.07 (1H，d，J=〇e7Hz) (參考例36-91) 1H-NMR(CDC1) δ ppm:2.32 (3H, s), 2.62 (6H, s), 3.98 (3H, s), 6.98 (2H, s), 7.50 3 -7.55 (1H, m), 8.00-8.10 (1H, m), 11.03 (1H? s) (參考例36-92) 'h-NMR^DCI ) 6 ppm:4.01 (3H, s), 7.30-7〇40 (1H, m), 7.45-7.55 (1H, m), 7.65 3 -7.75 (2H, m), 8.25-8.35 (2H, m), 11.11 (1H, d, J=0.6Hz) (參考例36-93) ^-NMRiCDCl) δ ppm:4.01 (3H, s), 7.40-7.50 (1H, m), 7.50-7.65 (2H, m), 7.75 3 -7.85 (1H, m), 7.85-7.95 (1H, m), 8.30-8.40 (1H, m), 11.11 (1H, s) (參考例36-94) "H-NMRiCDCU δ ppm:2.87 (3H, s), 4.01 (3H, s), 7.25-7.35 (1H, m), 7.35-7.40 ( 1H, m)，7.65-7.70 (1H, m), 8·20-8·25 (1H，m)，11·09 (1H, s) 131 312XP/發明說明書(補件)/96-03/95143900 200800871 (參考例36-95) 4-NMR(CDC1) δ ppm:4.05 (3H，s)，7·80-7·85 (1H, m)，7·95-8·00 (1H，m), 8·05 3 -8.10 (1H, m), 8.50-8.60 (1H, m), 11.22 (1H, d, J=0.7Hz) (參考例36-96) ^NMRiCDCl) δ ppm:4.04 (3H, s), 7.70-7.75 (1H, m), 7.75-7.85 (2H, m), 8,45 3 -8.55 (1H, m), 1L20 (1H, s) (參考例36-97)'H-NMRXDMSO-d ) δ ppm: 3.96 (3H, s), 7.55-7.65 (1H, m), 7.85-7.95 (1H, m), 7. 6 95-8.05 (1H, m), 8.05-8.15 (1H, m), 8.15-8.20 (1H, m) (Reference Example 36-85) 'H-NMRC DMSO-dJ δ ppm: 3〇95 (3H, s), 7〇67 (1H, d, J=2.1 Hz), 8.05 (1H, t, J=7e9 Hz), 8.18 (1H, d, J=2.1Hz), 8.44 (2H, d, J=7.9Hz) (Reference Example 36-86) ^-NMRCCDCl) δ Ppm: 2.72 (3H, s), 4〇08 (3H, s), 7.30-7.40 (1H, m)s 7.55-7.70 ( 3 2H, m), 7.70-7.80 (1H, m), 8.00^8.10 ( 1H, m), 8.35-8.40 (1H, m), 11Λ1 (1H, s) (Reference Example 36-87) 312XP/Invention Manual (Supplement)/96-03/95143900 130 200800871 iH-NMR (DMSO-d δ ppm : 3.95 (3H, s), 7„60-7·65 (1H, m), 8.10-8.15 (1H, m), 8· 6 25-8.35 (2H, m) (Cang test example 3 6 - 8 8) ^-NMRiCDCl) δ ppm: 4.02 (3H, s)5 7.44 (1H, d, J=8.8Hz), 7.61 (1H, d, j=8e8Hz 3 ), 7.75-7.80 (1H, m) , 8.45-8.50 (1H, m), 1L16 (1H, s) (Reference Example 36-89) 'H-NMRCCDCO δ ppm: 3.83 (6H, s), 4.00 (3H, s), 6〇63 (1H, t, J=2.2Hz), 7.04 (2 H, d, J=2.2Hz), 7.55-7.60 (1H, m), 8.30-8.35 (1H, m), 11.08 (1H, d, J=0.6Hz) ® (Reference Example 36-90) 'H-NMRCCDC I) δ ppm : 3.89 (3H, s), 3.92 (6H, s), 4.01 (3H, s), 7.15 (2H, s), 7.55 3 -7·60 (1H, m), 8.30-05 (1H , m), 11.07 (1H, d, J = 〇e7Hz) (Reference Example 36-91) 1H-NMR (CDC1) δ ppm: 2.32 (3H, s), 2.62 (6H, s), 3.98 (3H, s ), 6.98 (2H, s), 7.50 3 -7.55 (1H, m), 8.00-8.10 (1H, m), 11.03 (1H? s) (Reference Example 36-92) 'h-NMR^DCI) 6 ppm :4.01 (3H, s), 7.30-7〇40 (1H, m), 7.45-7.55 (1H, m), 7.65 3 -7.75 (2H, m), 8.25-8.35 (2H, m), 11.11 (1H , d, J = 0.6 Hz) (Reference Example 36-93) ^-NMRiCDCl) δ ppm: 4.01 (3H, s), 7.40-7.50 (1H, m), 7.50-7.65 (2H, m), 7.75 3 - 7.85 (1H, m), 7.85-7.95 (1H, m), 8.30-8.40 (1H, m), 11.11 (1H, s) (Reference Example 36-94) "H-NMRiCDCU δ ppm: 2.87 (3H, s), 4.01 (3H, s), 7.25-7.35 (1H, m), 7.35-7.40 (1H, m), 7.65-7.70 (1H, m), 8·20-8·25 (1H, m), 11·09 (1H, s) 131 312XP/Invention Manual (supplement)/96-03/95143900 200800871 (Reference Example 36-95) 4-NMR (CDC1) δ ppm: 4.05 (3H, s), 7·80 -7·85 (1H, m), 7·95-8·00 (1H, m), 8·05 3 -8.10 (1H, m), 8.50-8.60 (1H, m), 11.22 (1H, d, J=0.7Hz) (Reference Example 36-96) ^NMRiCDCl) δ ppm: 4.04 (3H, s), 7.70-7.75 (1H, m), 7.75-7.85 (2H, m), 8,45 3 -8.55 (1H, m), 1L20 (1H, s) (Reference Example 36-97)

'H-NMRCCDCl) δ ppm:4.05 (3H, s), 7.15-7.25 (1H, m), 7.40-7.50 (1H, m), 7.75 3 -7.80 (1H, m), 8.45-8.50 (1H, m), 11.20 (1H, s) (參考例36-98) ^-NMRCCDCO δ ppm:3.99 (3H, s), 6.05-6.35 (1H, m), 7.40-7.55 (2H, m), 7.55 -7.65 (1H, m), 7.65-7.75 (1H, m), 8.20-8.35 (2H, m), 1L12 (1H, s) (參考例36-99) ^-NMRXCDCI) δ ppm:4.01 (3H, s), 5.80-6.10 (1H, m), 7.45-7.50 (1H, m), 7.50 3 -7.65 (2H, m), 7.75-7.90 (2H, m), 8.30-8.40 (1H, m), 11.13 (1H, s) 參(參考例36-1 00) 'H-NMRiCDCO δ ppm:4.00 (3H, s), 7.55-7.95 (5H, m), 8.15-8.25 (1H, m), 8.25 -8.35 (1H, m), 11.12 (1H, s) (參考例36-101) 1H-NMR(CDC1) δ ppm:4〇00 (3H, s), 7.35-7.50 (1H, m), 7；55-7.60 (1H, m), 7.70 3 v (1H, t, J=55.0Hz), 7.85-7.95 (2H, m), 8,30-8.35 (1H, m), 1L13 (1H, s) (餐考例3 6 -1 0 2) 'H-NMRiCDCl ) δ ppm:4.00 (3H, s), 7.00-7.10 (1H, m), 7.45-7.50 (1H, m), 7.65 3 -7.75 (1H, m), 7.90 (1H, t, J=54.7Hz), 8.40-8.50 (1H, m), 1L17 (1H, s) 132 312χΡ/發明說明書(補件)/96-03/95143900 200800871 (參考例36-103) ^-NMRiCDCl) δ ppm:2.65 (3Η, s), 4.03 (3H, s), 7.55-7.60 (1H, m), 8.05-8.10 ( 3 1H, m), 8.10-8.15 (1H, m), 8.30-8.40 (2H, m), 11.13 (1H, s) (參考例36-104) 'H-NMRiCDCU δ ppm:3.98 (3H, s), 4.03 (3H, s), 7.55-7.60 (1H, m), 8.05-8.15 ( 1H, m), 8.20-8.25 (1H, m), 8.35-8.40 (1H, m), 8.40-8.50 (1H, m), 11.15 (1H, s) (參考例36-1 05)'H-NMRCCDCl) δ ppm: 4.05 (3H, s), 7.15-7.25 (1H, m), 7.40-7.50 (1H, m), 7.75 3 -7.80 (1H, m), 8.45-8.50 (1H, m ), 11.20 (1H, s) (Reference Example 36-98) ^-NMRCCDCO δ ppm: 3.99 (3H, s), 6.05-6.35 (1H, m), 7.40-7.55 (2H, m), 7.55 -7.65 ( 1H, m), 7.65-7.75 (1H, m), 8.20-8.35 (2H, m), 1L12 (1H, s) (Reference Example 36-99) ^-NMRXCDCI) δ ppm: 4.01 (3H, s), 5.80-6.10 (1H, m), 7.45-7.50 (1H, m), 7.50 3 -7.65 (2H, m), 7.75-7.90 (2H, m), 8.30-8.40 (1H, m), 11.13 (1H, s) Reference (Reference Example 36-1 00) 'H-NMRiCDCO δ ppm: 4.00 (3H, s), 7.55-7.95 (5H, m), 8.15-8.25 (1H, m), 8.25 -8.35 (1H, m ), 11.12 (1H, s) (Reference Example 36-101) 1H-NMR (CDC1) δ ppm: 4〇00 (3H, s), 7.35-7.50 (1H, m), 7; 55-7.60 (1H, m), 7.70 3 v (1H, t, J=55.0Hz), 7.85-7.95 (2H, m), 8,30-8.35 (1H, m), 1L13 (1H, s) (Meal test case 3 6 - 1 0 2) 'H-NMRiCDCl ) δ ppm: 4.00 (3H, s), 7.00-7.10 (1H, m), 7.45-7.50 (1H, m), 7.65 3 -7.75 (1H, m), 7.90 (1H , t, J=54.7Hz), 8.40-8.50 (1H, m), 1L17 (1H, s) 132 312χΡ/Invention Manual (supplement)/96-03/95143900 200800871 (Reference Example 36-103) ^ -NMRiCDCl) δ ppm: 2.65 (3Η, s), 4.03 (3H, s), 7.55-7.60 (1H, m), 8.05-8.10 ( 3 1H, m), 8.10-8.15 (1H, m), 8.30- 8.40 (2H, m), 11.13 (1H, s) (Reference Example 36-104) 'H-NMRiCDCU δ ppm: 3.98 (3H, s), 4.03 (3H, s), 7.55-7.60 (1H, m), 8.05-8.15 ( 1H, m), 8.20-8.25 (1H, m), 8.35-8.40 (1H, m), 8.40-8.50 (1H, m), 11.15 (1H, s) (Reference Example 36-1 05)

'H-NMRiCDCO δ ppm:4.03 (3H, s), 6.68 (1H, t, J=55.7Hz), 7.50-7.60 (1H, m), 7.70-7.75 (1H, m), 7.90-8.00 (1H, m), 8.00-8.05 (1H, m), 8.30-8.40 (1H, m), 11.16 (1H, s) (參考例36-106) 'H-NMRCCDCI ) 6 ppm:4.00 (3H, s), 7.25-7.35 (1H, m), 7.65-7.80 (3H, m), 7.93 3 (1H, t, J=54.8Hz), 8.45-8.50 (1H, m), 11.19 (1H, s) (參考例36-107) ^-NMRCCDCl ) δ ppm:4.00 (3HS s), 7.35-7.45 (1H, m), 7.55-7.85 (3H, m), 8.20 3 -8,25 (1H, m), 8.25-8.30 (1H, m), 1L12 (1H, s) (參考例36-108) 'H-NMRiCDCl) δ ppm:3.84 (3H5 s), 3.94 (3H, s), 7.37-7.41 (1H, m), 7.46 (1H, d 3 d, J=8.4, 2.0Hz), 7.84 (1H, d, J=9elHz) (參考例36-1 09) 'H-NMRiCDCl) δ ppm: L16 (3H, t, J^T.eHz), 2.91 (2H, q, J=7.4Hz), 3.97 (3H, s) 3 ，7.36 (1H, d, J二7·6Ηζ), 7,40-7.45 (1H, m), 7·51 (1H, d, J=1.9Hz)，7。55-7.61 (1H， m), 8.16 (1H, dd, J=8.2, 1.3Hz), 8.23 (1H, d, J=2.2Hz), 11.09 (1H, s) (參考例36-110) 133 312XP/發明說明書(補件)/96-03/95143900 200800871 "H-NMRCCDCl) δ ppm :4.01 (5HS s), 7A9 (1H, t, J=8.0Hz), 7.66 (1H, d, J=2.2Hz) 3 ,7.75 (1H, dd, J=7.9, L6Hz), 8e3i (2H, td, J=3.9, L6Hz), 11.12 (1H, s) (參考例36-111) ^-NMR^DCl) δ ppm:4.02 (3H, s), 7.53 (1H, d, J=2.2Hz), 7.63 (1H, d, J=8.2Hz 3 ),7.77 (1H, dd, J=8.5, 2.2Hz), 8.02 (1H, d, J=2.2Hz), 8.33 (1H, d, J=2.2Hz), 11.12 (1H, br s) (參考例36-112)'H-NMRiCDCO δ ppm: 4.03 (3H, s), 6.68 (1H, t, J=55.7Hz), 7.50-7.60 (1H, m), 7.70-7.75 (1H, m), 7.90-8.00 (1H, m), 8.00-8.05 (1H, m), 8.30-8.40 (1H, m), 11.16 (1H, s) (Reference Example 36-106) 'H-NMRCCDCI ) 6 ppm: 4.00 (3H, s), 7.25 -7.35 (1H, m), 7.65-7.80 (3H, m), 7.93 3 (1H, t, J=54.8Hz), 8.45-8.50 (1H, m), 11.19 (1H, s) (Reference Example 36- 107) ^-NMRCCDCl ) δ ppm: 4.00 (3HS s), 7.35-7.45 (1H, m), 7.55-7.85 (3H, m), 8.20 3 -8,25 (1H, m), 8.25-8.30 (1H , m), 1L12 (1H, s) (Reference Example 36-108) 'H-NMRiCDCl) δ ppm: 3.84 (3H5 s), 3.94 (3H, s), 7.37-7.41 (1H, m), 7.46 (1H , d 3 d, J=8.4, 2.0 Hz), 7.84 (1H, d, J=9elHz) (Reference Example 36-1 09) 'H-NMRiCDCl) δ ppm: L16 (3H, t, J^T.eHz ), 2.91 (2H, q, J=7.4Hz), 3.97 (3H, s) 3 , 7.36 (1H, d, J 2·6Ηζ), 7,40-7.45 (1H, m), 7·51 ( 1H, d, J=1.9Hz), 7.55-7.61 (1H, m), 8.16 (1H, dd, J=8.2, 1.3Hz), 8.23 (1H, d, J=2.2Hz), 11.09 (1H , s) (Reference Example 36-110) 133 312XP/Invention Manual (supplement)/96-03/95143900 200800871 "H-NMRCCDCl) δ ppm : 4.01 (5HS s), 7A9 (1H, t, J=8.0 Hz), 7.66 (1H, d, J=2.2Hz) 3 , 7.75 (1H, dd, J=7.9, L6Hz), 8e3i (2H, td, J=3.9, L6Hz), 11.12 (1H, s) (Reference Example 36- 111) ^-NMR^DCl) δ ppm: 4.02 (3H, s), 7.53 (1H, d, J=2.2Hz), 7.63 (1H, d, J=8.2Hz 3 ), 7.77 (1H, dd, J =8.5, 2.2Hz), 8.02 (1H, d, J=2.2Hz), 8.33 (1H, d, J=2.2Hz), 11.12 (1H, br s) (Reference Example 36-112)

'H-NMRCCDCl) δ ppm:2e31 (3H, s), 2.32 (3H,s), 4.00 (3H, s), 6.02 (1H, s), 7.29 3 (1H, d, J=8.7Hz), 7.57 (1H, d, J=L9Hz), 7.66-7.69 (2H, m), 8.30 (1H, d, J=1.9Hz), 11.06 (lH,s) (參考例36-113) ^-NMRCCDCl) δ ppm:2e44 (6H, s), 3.98 (3H, s), 6.02 (1H, s), 7.16 (1H, d, J=7. 3 5Hz), 7〇33 (1H, d, J=7〇5Hz), 7〇53 (1H, d, J=2.1Hz), 8.00 (1H, s), 8.22 (1H, d, J=2.1 Hz), 11.08 (1H, s) (參考例36-114) 'H-NMRiCDCl) δ ppm :2.30 (3H, s), 2.41 (3H, s), 3.97 (3H, s), 6.02 (IH, s), 7.32- 3 (1H, t, J=7.6Hz), 7.44 (1H, d, J=7e6Hz), 7〇51 (1H, d, j=2.1Hz), 8.07 (1H, d, J=7.6 Hz), 8.22 (1H, d, j=7.6, 2.1Hz), 1L08 (1H, s) (參考例36-115) ^-NMRiCDCl) δ ppm :2.39 (3H, s), 2.45 (3H, s), 3.97 (3H, s), 7.08 (1H, s), 7.22 3 (1H, d, J=7.9Hz), 7.51 (1H, d, J=1.9Hz), 8.07 (1H, d, J=8.2Hz), 8.22 (1H, d, J=1.9 Hz), 11.07 (1H, s) (參考例36-116) 'H-NMRCDMSO-d ) δ ppm :3.99 (3H, s), 7.71 (1H, d, J=2.2Hz), 8.19 (1H, d, J=2〇 6 2Hz), 8.77 (1H, t, J=1.4Hz), 8.88 (2H, d, J=L4Hz) 312XP/發明說明書(補件)/96-03/95143900 134 200800871 (參考例36-117) "H-NMRCCDCI ) δ ppm:L80 (6Η, s), 2.45 (3HS s), 3〇95 (3H, s), 5.67 (1H, s), 6.92 3 -6.94 (1H, m), 7.21-7.23 (1H, m), 7.85 (1H, d, J=2e2Hz), 8,32 (1H, d, J=2.2Hz), 11 .09 (1H, br) (參考例36-118) h-NMR(CDCl ) δ ppm:A04 (3H, s)，4·08 (3H，s), 6.90-7.05 (2H，m)，7.80-7·90 ( 3 1H, m), 8,50-8.55 (1H, m), 11.19 (1H, s) _ (參考例36-119) 'H-NMRCCDCl) δ ppm:L20-1.75 (6H, m), L75-L90 (2H, m), 2.05-2.15 (2H, m), 3 4·04 (3H，m), 5.10-5.20 (1H，m), 6·90-7·00 (2H，m), 7·85-7·95 (1H, m)，8.50-8.60 (1H, m), 1L18 (1H, s) (參考例36-120) 'H-NMRXCDCl) δ ppm: 1.46 (3H, s), 1.48 (3H, s), 4.04 (3H, s), 5.35-5.45 (1HS m 3 ),6.90-7.00 (2H, m), 7.85-7；90 (1H, m), 8.50-8,60 (1H, m), 11.17 (1H, s) Φ (參考例36-121) 'H-NMRCCDCl) δ ppm:L48 (3H, t, J=7.2Hz), 4.04 (3H, s), 4.53 (2H, q, J=7.2Hz) 3 ,6.90-7.05 (2H, m), 7.80-7.90 (1H, m), 8.50-8.55 (1H, m), 11.17 (1H, s) (參考例36-122) 'H-NMRiCDCO δ ppm :2.79 (3H, s), 4.01 (3H, s), 6.77 (1H, t, J=55.8 Hz), 7.48 ( 1H, d, J=1.8Hz), 8.00-8.05 (1H, m), 8.27 (1H, d, J=L8Hz), 8.55-8.60 (1H, m) (參考例36-123) ^-NMRiDMSO-d ) δ ppm :3.93 (3H, s), 7.45-7.60 (1H, m), 7.60-7.75 (2H, m), 8. 6 05-8.15 (1H, m), 14.24 (1H, br) 135 312XP/發明說明書(補件)/96-03/95143900 200800871 (參考例36-124) 1H-NMR(CDC1) δ ppm:2.74 (3Η, s), 4.06 (3H, s), 6.75-6^85 (1H, m), 6.90-7.00 ( 3 1H, m)，7.65-7.75 (1H，m)，8.45-8.50 (1H, m)，11.19 (1H，s) (參考例36-125) "H-NMRiCDCO δ ppm: 1.32 (3H, t, J=7.1Hz), 3.01 (2H, q, J=7.1Hz), 4.07'(3H, s) ,.6.75-6.85 (1H, m), 6.85-7.00 (1H, m), 7.65-7.75 (1H, m), 8.45-8,50 (1H, m), 11. 21 (1H, s) (參考例37 - 1) 1，2 - —曱乳基- 4 -（曱苯-4 -石黃酿基）苯鲁在氬氣環境下，將甲苯亞磺酸鈉4水合物（1. 〇〇g)、4-溴藜蘆醚（0· 29mL)、參（二苯亞曱基丙酮）二鈀 (0)(93mg)、9, 9 -二曱基-4, 5 -雙（二苯膦基）4 嗟 (115mg)、碳酸鉋（1· 30g)及曱苯（7mL)之混合物以lire 攪拌39小時。此反應混合物待冷卻後通過celite(註冊商標）矽藻土層進行過濾，用醋酸乙酯洗提。濾液以食鹽水洗滌，用無水硫酸鎂乾燥後在減壓下進行濃縮。其殘留眷物以矽膠中壓管柱色析法進行精製（洗提液：己烷/醋酸乙酉旨=3 / 2 ) ’得目標化合物（51 〇mg )。 'H - NMR(CDCls) (5 ppm : 2. 39(3H, s), 3. 91 (3H, s), 6. 85 -6· 95 1H，m)，7· 20-7· 35(2H，m)，7· 35-7· 4〇(1H，m)，7· 50-7· 60(1H，m)，7. 75-7· 85(2H，m) (參考例38 - 1) 2-甲氧基- 4 -（甲苯-4-磺醯基）酚將1，2 -二甲氧基- 4-(甲苯-4-磺酿基）苯（參考例 37 - 1)(219mg)、氣化納（183nig)及二曱亞石風（3mL)之混合 312XP/發明說明書(補件)/96-03/95143900 136 200800871 物在12 0 °C攪拌2 0小時。將反應混合物待冷卻後加入 lmol/L鹽酸及水（7mL)，用醋酸乙酯與水進行分液，其有機液層依次以lmol/L鹽酸及食鹽水洗滌，用無水琉酸鎮乾燥。在減壓下進行濃縮，其殘留物以矽膠中壓管柱色析法進行精製（洗提液：己烧/醋酸乙g旨=1 /1 )，得目標化人物（156mg)。 NMR(CDCh)6ppm : 2.38(3H，s)，3.95(3H，s)，6.90 -7· 05 (lH，m)，7· 20-7· 35(2H，m)，7· 35-7· 45(lH，m)，7· 45 ® 55(lH,m), 7. 75-7. 85(2H? m) (參考例39 - 1) 4 -苯磺醯基-1，2 -二甲氧基苯在氬氣環境下，將苯亞磺酸鈉2水合物（5· 00g)、4 -漠藜蘆醚（2· 17g)、參（二苯亞甲基丙酮）二鈀（〇)(5〇〇mg)、 9, 9 -二曱基-4, 5 -雙（二苯膦基）咄。星（577mg)、碳酸铯 (6.52g)及曱苯（20mL)之混合物以1〇〇。(3攪拌2日。將反書應混合物待冷卻後通過Celite(註冊商標）矽藻土層進行過濾，用醋酸乙酯洗提。濾液以食鹽水洗滌，用無水硫酸鎂乾燥後在減壓下進行濃縮。其殘留物以矽膠中壓管柱色析法進行精製（洗提液：己烧/醋酸乙酯=5 /1 )，得目標化合物（2· 04g)。 4 - MR(CDCl3)6ppm : 3.91(3H，s)，3.92(3H，s)，6.93 (1H, d, J= 8. 5Ηζ), Ί. 39(1H, d, J= 2. 2Hz), Ί. 45-7. 60 (5H，m)，7· 90-7· 95(lH，m) (參考例40 - 1) 312XP/發明說明書(補件)/96-03/95143900 137 200800871 L 2 -雙苄氧基-3-溴-5 -苯基甲苯磺醯基苯在室溫下，將三溴化硼（lm〇l/L二氯甲烷溶液、6.4mL) 加入至4-苯磺醯基—；ι，2—二曱氧基苯（參考例㈣一 l)(2.04g)及二氯甲烷（2〇mL)之混合物中。將混合物在室溫下攪拌2小時。加入曱醇（5mL)在室溫下攪拌3〇分鐘。將混合物在減壓下進行濃縮，得粗製之4 —苯磺醯基苯S — 1，2 -二醇。將溴（0· 45mL)加入至粗製之4 -苯磺醯基笨—2 -一 •醇及二氯甲烷（5mL)之混合物中。此混合物在室溫下攪拌整夜。繼之加入飽和亞硫酸氫鈉水溶液（5mL)、二氯甲燒 (10mL)及甲醇（imL)。將混合物以二氯曱烷與水進行分液，其有機液層在減壓下進行濃縮，得5—苯磺醯基—3一溴本-1，2 -二醇（1 · 5 4 g)。在室溫下，將5 -苯磺醯基-3 -溴苯-1，2 -二醇 (833mg)、溴曱苯（〇· 9mL)、碳酸鉀（1· 26g)及 N，Μ ~ 二甲 _基曱醯胺（lOmL)之混合物攪拌2小時。此反應混合物以二 ***與水進行分液，其有機液層以水洗滌，用無水硫酸鎂乾燥後在減壓下進行濃縮，得目標化合物（72〇mg)。 lH- NMR(CDCl3)^ppm : 5. 〇9(2H, s), 5. 17(2H, s), 7. 25- 7·65 (14Η，ιη)，7·73(1Η，d，J=2.0Hz)，7:80-7·90(2Η，ιη) (參考例41 - 1 ) 5 -苯磺醯基- 2, 3 -雙苄氧基苯曱腈將1，2-雙苄氧基-3-溴—5-苯基曱苯磺醯基笨（參考例40 - l)(720mg)、氰化銅（1)(387呢）、參（二苯亞甲 312XP/發明說明書(補件)/96-03/95143900 138 200800871 基丙酮）二鈀（〇)(49mg)、氰化四乙銨（I69mg)、1，1，一雙 (二苯膦基）二茂鐵（120mg)及1>4—二噚烷（1〇mL)之混合物I20 C下攪拌整夜。將反應混合物濾除不溶物後，在減壓下進行濃縮，其殘留物以矽膠管柱色析法進行精製 ι(洗提液··己烷/醋酸乙酯=3/1)，得目標化合物。 Η - NMR(CDCh) 6 ppm : 5· 20(2H, s), 5. 33(2H, s), 7. 25 -7· 45 (11H，m)，7· 45-7· 65(3H，m)，7· 65-7· 70(1H，m)， 7· 80-7· 85(2H，m) ，， _ (參考例42 - i) 1 -苄氧基-2 -甲氧基-4— (4 —曱氧基苯磺醯基）苯在氬氣環境下，將4 -苄氧基-3_曱氧基苯亞磺酸鈉一氫氧化鈉（參考例20_ 1)(1·〇2§)、1—溴—4 —曱氧基苯 (0.25mL)、三（二苯亞曱基丙酮）二鈀（〇)二氯甲烷加成物 (lOOmg)、9, 9 -二曱基-4, 5 —雙（二苯膦基）。山σ星 (115mg)。、碳酸铯（1· 30g)、甲苯（7mL)及水（5mL)之混合物籲以100 C攪拌整夜。將反應混合物待冷卻後通過 Cel ite(注冊商標）矽藻土層進行過濾，用醋酸乙酯洗提。濾液以食鹽水洗滌，用無水硫酸鎂乾燥後在減壓下進行濃縮。其殘留物以矽膠中壓管柱色析法進行精製（洗提液：己烷/醋酸乙酯= 1/1)，得目標化合物（457mg)。 NMR(CDCl3)6PPm : 3.83(3H，s)，3.91(3H，s)，5.17 (2H，s)，6· 94(2H，d，J= 8· 7Ηζ)，7· 25-7· 55(8H，m)，7· 82 (2H，d，J=8,7Hz) ’ (參考例43- 1) . 312XP/發明說明書(補件)/96-03/95143900 139 200800871 4 -苯磺SI基-2 -曱氧基-6 -石肖基酴將4 -溴-2 -曱氧基-6 -硝基酚（6· 17g)、硫酸二曱酯（9· 41g)、碳酸氫鈉（8.36替）及丙酮（12〇11^)之混合物在迴流下攪拌整夜。將反應混合物待冷卻後以水與醋酸乙酯進行分液，其有機液層用無水硫酸鎂乾燥後在減壓下進行濃縮。其殘留物以胺丙基矽膠中壓管柱色析法進行精製 (洗提液：己烷/醋酸乙酯=3/1)，得5-溴-1，2-二甲乳基-3 -硝基苯（4.78g)。鲁在氬氣環境下，將苯亞磺酸鈉（300mg)、5 -溴-1，2 -二曱氧基-3 -硝基苯（262mg)、參（二苯亞甲基丙酮）二鈀 (〇)二氯曱烧加成物（50mg)、9, 9 -二曱基-4, 5 -雙（二苯膦基 >山嗟（58mg)、碳酸鉋（652mg)及曱苯（5〇mL)之混合物以10 0 C攪拌8小時。將反應混合物待冷卻後通過石夕藻土 Ce 1 i te(注冊商標）層進行過濾，用醋酸乙酯洗提。濾液以食鹽水洗滌，用無水硫酸鎂乾燥後在減壓下進行濃縮。其肇殘留物以矽膠中壓管柱色析法進行精製（洗提液：二氯曱烧/曱醇=10/1)，得目標化合物（98mg)。丽R(CDCl3)(5PPm ·· 4.01(3H，s)，7 5〇 — 7 7〇(4H，m)， 7·90-8.00(2H，m)，8.30-8.40(lH，m) (參考例44 - 1) 1H-四唆- 5-基）苯 -硝基苯磺醯基）苯曱化鈉（158mg)、三曱胺 2-曱氧基- 4 - [3-(1 一甲基一磺醯基]-6 -硝基酚將3 - (4 -羥基- 3 -曱氧基一 5 腈（參考例 36 _ 55) ( 20〇mg)、疊 ^ 312XP/發明說明書(補件)/96-03/95143900 140 200800871 鹽酸鹽(172mg)及1 —甲基—2 一吡咯啶酮（15mL)之混合物，在攪拌下照射微波，以2〇(rc加熱1〇分鐘。此反應混合物用一***與水進行分液。其有機液層依次以水、食鹽水洗滌，用热水硫酸鎂乾燥後在減壓下進行濃縮，得粗製之2一曱氧基—6一硝基-4-[3 -（1H-四唑-5-基）苯磺醯基]酚。’ 在室溫下，將粗製之2 —曱氧基—6 -硝基—4-[3一 (1H -四唑-5 -基）苯磺醯基]酚、N，N -二曱基甲醯胺 (10mL)、碘化曱基（11〇11^)及碳酸鉀（124邶）之混合物攪拌 1小時。此反應混合物用二***與水進行分液，其有機液層依次以水、食鹽水洗滌，用無水硫酸鎂乾燥後在減壓下進行濃縮，得目標化合物（252mg)。 NMR(CDCl3)5ppm ： 4. 02(3H3 s), 4. 43(3H, s), 7. 62 (lH，d，J = 1·9Ηζ)，7·65-7·75(1Η，ηι)，7·95-8·10(2Η，πι)， 8· 35-8· 40(1H，m)，8· 65-8· 75(lH，m)，11· n(iH，s) 春(參考例45 - 1) 2 -曱氧基- 6 -頌基- 4 - (4 - °比嘻咬一 1 —基苯石黃醯基）紛將4 - (4 -氟苯磺醯基）-2 -曱氧基—6 —硝基酚（參考例36 - ll)(265mg)、吡咯啶（288mg)及Ν，Ν -二曱基曱醯胺（10mL)之混合物，在攪拌下照射微波，以2〇(rc加熱5 分鐘。此反應混合物用醋酸乙酯與水進行分液，其有機液層依次以水、食鹽水洗滌，用無水硫酸鎂乾燥後在減壓下進行濃縮，得目標化合物（162mg)。 312XP/發明說明書(補件)/96-03/95143900 141 200800871 'H- NMR(CDCh) 5 ppm ： 3. 40-3. 46(4H, m)5 3. 47-3. 53'H-NMRCCDCl) δ ppm: 2e31 (3H, s), 2.32 (3H, s), 4.00 (3H, s), 6.02 (1H, s), 7.29 3 (1H, d, J=8.7Hz), 7.57 (1H, d, J=L9Hz), 7.66-7.69 (2H, m), 8.30 (1H, d, J=1.9Hz), 11.06 (lH, s) (Reference Example 36-113) ^-NMRCCDCl) δ ppm :2e44 (6H, s), 3.98 (3H, s), 6.02 (1H, s), 7.16 (1H, d, J=7. 3 5Hz), 7〇33 (1H, d, J=7〇5Hz) , 7〇53 (1H, d, J=2.1Hz), 8.00 (1H, s), 8.22 (1H, d, J=2.1 Hz), 11.08 (1H, s) (Reference Example 36-114) 'H- NMRiCDCl) δ ppm : 2.30 (3H, s), 2.41 (3H, s), 3.97 (3H, s), 6.02 (IH, s), 7.32- 3 (1H, t, J=7.6Hz), 7.44 (1H , d, J=7e6Hz), 7〇51 (1H, d, j=2.1Hz), 8.07 (1H, d, J=7.6 Hz), 8.22 (1H, d, j=7.6, 2.1Hz), 1L08 ( 1H, s) (Reference Example 36-115) ^-NMRiCDCl) δ ppm : 2.39 (3H, s), 2.45 (3H, s), 3.97 (3H, s), 7.08 (1H, s), 7.22 3 (1H , d, J=7.9Hz), 7.51 (1H, d, J=1.9Hz), 8.07 (1H, d, J=8.2Hz), 8.22 (1H, d, J=1.9 Hz), 11.07 (1H, s (Reference Example 36-116) 'H-NMRCDMSO-d ) δ ppm :3.99 (3H, s), 7.71 (1H, d, J=2.2Hz), 8.19 (1H, d, J=2〇6 2Hz) , 8.77 (1H, t, J=1.4Hz), 8.88 (2H, d, J=L4Hz) 312XP/Invention Manual (Supplement )/96-03/95143900 134 200800871 (Reference Example 36-117) "H-NMRCCDCI ) δ ppm: L80 (6Η, s), 2.45 (3HS s), 3〇95 (3H, s), 5.67 (1H , s), 6.92 3 -6.94 (1H, m), 7.21-7.23 (1H, m), 7.85 (1H, d, J=2e2Hz), 8,32 (1H, d, J=2.2Hz), 11 . 09 (1H, br) (Reference Example 36-118) h-NMR (CDCl) δ ppm: A04 (3H, s), 4·08 (3H, s), 6.90-7.05 (2H, m), 7.80-7 ·90 ( 3 1H, m), 8,50-8.55 (1H, m), 11.19 (1H, s) _ (Reference Example 36-119) 'H-NMRCCDCl) δ ppm: L20-1.75 (6H, m) , L75-L90 (2H, m), 2.05-2.15 (2H, m), 3 4·04 (3H,m), 5.10-5.20 (1H,m), 6·90-7·00 (2H,m) , 7·85-7·95 (1H, m), 8.50-8.60 (1H, m), 1L18 (1H, s) (Reference Example 36-120) 'H-NMRXCDCl) δ ppm: 1.46 (3H, s) , 1.48 (3H, s), 4.04 (3H, s), 5.35-5.45 (1HS m 3 ), 6.90-7.00 (2H, m), 7.85-7; 90 (1H, m), 8.50-8,60 ( 1H, m), 11.17 (1H, s) Φ (Reference Example 36-121) 'H-NMRCCDCl) δ ppm: L48 (3H, t, J=7.2Hz), 4.04 (3H, s), 4.53 (2H, q, J=7.2Hz) 3 , 6.90-7.05 (2H, m), 7.80-7.90 (1H, m), 8.50-8.55 (1H, m), 11.17 (1H, s) (Reference Example 36-122) ' H-NMRiCDCO δ ppm : 2.79 (3H, s), 4.01 (3H, s), 6.77 (1H, t, J=55.8 Hz), 7.48 ( 1H, d, J=1.8Hz), 8.00-8.05 (1H, m), 8.27 (1H, d, J=L8Hz), 8.55-8.60 (1H, m) (Reference Example 36-123) ^-NMRiDMSO-d ) δ ppm : 3.93 (3H, s), 7.45-7.60 (1H, m), 7.60-7.75 (2H, m), 8. 6 05 -8.15 (1H, m), 14.24 (1H, br) 135 312XP/Invention Manual (supplement)/96-03/95143900 200800871 (Reference Example 36-124) 1H-NMR (CDC1) δ ppm: 2.74 (3Η, s), 4.06 (3H, s), 6.75-6^85 (1H, m), 6.90-7.00 ( 3 1H, m), 7.65-7.75 (1H, m), 8.45-8.50 (1H, m), 11.19 (1H, s) (Reference Example 36-125) "H-NMRiCDCO δ ppm: 1.32 (3H, t, J=7.1Hz), 3.01 (2H, q, J=7.1Hz), 4.07'(3H, s ) , .6.75-6.85 (1H, m), 6.85-7.00 (1H, m), 7.65-7.75 (1H, m), 8.45-8,50 (1H, m), 11. 21 (1H, s) ( Reference Example 37 - 1) 1,2-anthracene-yl- 4 -(indolyl-4 -offhoxyl)benzeneluene Under argon, sodium toluenesulfinate tetrahydrate (1. 〇〇 g), 4-bromofurose (0. 29 mL), ginseng (diphenylarbenium acetonide) dipalladium (0) (93 mg), 9,9-dimercapto-4,5-bis(diphenylphosphine) a mixture of 4 嗟 (115 mg), carbonate planer (1·30 g) and toluene (7 mL) as lir e Stir for 39 hours. After the reaction mixture was cooled, it was filtered through a Celite (registered trademark) layer of celite and eluted with ethyl acetate. The filtrate was washed with brine, dried over anhydrous magnesium sulfate and evaporated. The residual sputum was purified by silica gel column chromatography (eluent: hexane/acetate = 3 / 2 ) to give the target compound (51 〇mg). 'H-NMR (CDCls) (5 ppm : 2. 39(3H, s), 3. 91 (3H, s), 6. 85 -6· 95 1H, m), 7· 20-7· 35 (2H , m), 7· 35-7· 4〇(1H,m), 7· 50-7· 60(1H,m), 7. 75-7·85(2H,m) (Reference Example 38 - 1) 2-methoxy-4-(-toluene-4-sulfonyl)phenol 1,2 -dimethoxy-4-(toluene-4-sulfonic acid)benzene (Reference Example 37-1) (219 mg) Mixture of gasification nano (183nig) and bismuth stone (3mL) 312XP / invention manual (supplement) / 96-03/95143900 136 200800871 Stir at 20 ° C for 20 hours. After the reaction mixture was cooled, 1 mol/L hydrochloric acid and water (7 mL) were added, and the mixture was partitioned with ethyl acetate and water. The organic liquid layer was washed successively with 1 mol/L hydrochloric acid and brine, and dried with anhydrous citric acid. Concentration was carried out under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexanes/ethyl acetate = 1 /1) to give a target compound (156 mg). NMR (CDCh) 6 ppm: 2.38 (3H, s), 3.95 (3H, s), 6.90 -7· 05 (lH, m), 7·20-7· 35 (2H, m), 7·35-7· 45(lH,m),7· 45 ® 55(lH,m), 7. 75-7. 85(2H? m) (Reference Example 39 - 1) 4 -Benzenesulfonyl-1,2-dimethyl Sodium phenyl sulfinate 2 hydrate (5.0 00g), 4-diclofenac (2.71g), ginseng (diphenylmethylene acetonide) dipalladium (〇) under argon atmosphere (5 〇〇 mg), 9, 9 -dimercapto-4,5-bis(diphenylphosphino) fluorene. A mixture of star (577 mg), cesium carbonate (6.52 g) and toluene (20 mL) was 1 Torr. (3, stirring for 2 days. The anti-book mixture was cooled, and then filtered through Celite (registered trademark) diatomaceous earth layer, and extracted with ethyl acetate. The filtrate was washed with brine, dried over anhydrous magnesium sulfate and then evaporated. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate = 5 /1) to give the title compound (2·04 g). 4 - MR (CDCl3) 6 ppm : 3.91(3H,s), 3.92(3H,s), 6.93 (1H, d, J= 8. 5Ηζ), Ί. 39(1H, d, J= 2. 2Hz), Ί. 45-7. 60 (5H,m),7·90-7·95(lH,m) (Reference Example 40-1) 312XP/Invention Manual (supplement)/96-03/95143900 137 200800871 L 2 -Bisbenzyloxy-3 -Bromo-5-phenyltoluenesulfonylbenzene Add boron tribromide (lm〇l/L dichloromethane solution, 6.4 mL) to 4-phenylsulfonyl-; Mixture of dimethoxybenzene (Reference Example (4)-1) (2.04g) and dichloromethane (2〇mL). The mixture was stirred at room temperature for 2 hours. Add sterol (5 mL) and stir at room temperature. The mixture was concentrated under reduced pressure to give a crude 4-benzenesulfonylbenzene S-1,2-diol. Bromine (0.55 mL) was added to a mixture of crude 4- benzenesulfonyl succinyl-2-ol and dichloromethane (5 mL). This mixture was stirred overnight at room temperature. An aqueous solution of sodium hydrogensulfate (5 mL), methylene chloride (10 mL) and methanol (imL). The mixture was partitioned between dichloromethane and water, and the organic layer was concentrated under reduced pressure to give 5-benzenesulfon. Mercapto-3 bromo-1,2-diol (1 · 5 4 g). 5-Benzenesulfonyl-3-bromobenzene-1,2-diol (833 mg), at room temperature, A mixture of bromopyrene (〇·9 mL), potassium carbonate (1·26 g), and N, dimethyl decylamine (10 mL) was stirred for 2 hours. The reaction mixture was partitioned between diethyl ether and water. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and evaporated to drynessielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielielieliel 17(2H, s), 7. 25- 7·65 (14Η, ιη), 7.73 (1Η, d, J=2.0Hz), 7:80-7·90(2Η, ιη) (Reference Example 41 - 1 ) 5-Benzenesulfonyl- 2,3-bisbenzyloxybenzonitrile, 1,2-bisbenzyloxy-3-bromo-5-phenylsulfonylsulfonyl Reference Example 40 - l) (720 mg), copper cyanide (1) (387), gin (diphenylmethylene 312XP / invention specification (supplement) / 96-03/95143900 138 200800871 base acetone) dipalladium (〇 a mixture of (49 mg), tetraethylammonium cyanide (I69 mg), 1,1, bis(diphenylphosphino)ferrocene (120 mg) and 1>4-dioxane (1 〇mL) under I20 C Stir overnight. After the reaction mixture was filtered, the insoluble material was filtered, and the residue was concentrated under reduced pressure, and the residue was purified by EtOAc EtOAc (EtOAc/EtOAc/EtOAc. . Η - NMR (CDCh) 6 ppm : 5 · 20 (2H, s), 5. 33 (2H, s), 7. 25 -7· 45 (11H, m), 7· 45-7· 65 (3H, m),7· 65-7·70(1H,m), 7·80-7·85(2H,m) ,, _ (Reference Example 42 - i) 1-Benzyloxy-2-methoxy- 4-(4-oxobenzenesulfonyl)benzene 4-Abenzyloxy-3_decyloxybenzenesulfinate sodium-sodium hydroxide under argon (Ref. 20-1) (1· 〇2§), 1-bromo-4-oxooxybenzene (0.25mL), tris(diphenylarbenium acetonide) dipalladium (〇) dichloromethane adduct (100mg), 9, 9 - di Base-4,5-bis(diphenylphosphino). Mountain σ star (115mg). A mixture of cesium carbonate (1·30 g), toluene (7 mL) and water (5 mL) was stirred at 100 C overnight. The reaction mixture was cooled and filtered through a Celite (registered trademark) celite layer and eluted with ethyl acetate. The filtrate was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1 / 1) to give the title compound (457 mg). NMR (CDCl3) 6PPm: 3.83 (3H, s), 3.91 (3H, s), 5.17 (2H, s), 6.94 (2H, d, J = 8·7Ηζ), 7·25-7·55 ( 8H,m),7·82 (2H,d,J=8,7Hz) ' (Reference Example 43-1) . 312XP/Invention Manual (Supplement)/96-03/95143900 139 200800871 4 -Benzenesulfonyl SI -2 -decyloxy-6-succinyl hydrazide 4-bromo-2-methoxy-6-nitrophenol (6·17g), dinonyl sulfate (9·41g), sodium bicarbonate (8.36) A mixture of acetone (12 〇 11 ^) was stirred under reflux overnight. The reaction mixture was cooled to dryness with water and ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The residue was purified by an amine propyl sulfonium medium pressure column chromatography (eluent: hexane / ethyl acetate = 3 / 1) to give 5-bromo-1,2-dimethyllacyl-3 - Nitrobenzene (4.78 g). Sodium benzenesulfinate (300mg), 5-bromo-1,2-dimethoxy-3-nitrobenzene (262mg), bis(diphenylmethyleneacetone) dipalladium under argon atmosphere (〇) Dichlorohydrazine calcined adduct (50 mg), 9,9-dimercapto-4,5-bis(diphenylphosphino)> hawthorn (58 mg), carbonic acid planer (652 mg) and toluene (5 The mixture of 〇mL) was stirred for 8 hours at 10 0 C. After the reaction mixture was cooled, it was filtered through a layer of celite, Ce 1 i te (registered trademark), and eluted with ethyl acetate. The filtrate was washed with brine. After drying over anhydrous magnesium sulfate, the residue was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloropyrene / decyl alcohol = 10/1) to give the title compound (98 mg) Li R (CDCl3) (5PPm · · 4.01 (3H, s), 7 5〇 - 7 7〇 (4H, m), 7·90-8.00 (2H, m), 8.30-8.40 (lH, m) (Reference Example 44 - 1) 1H-tetrakis- 5-yl)benzene-nitrophenylsulfonyl) sodium benzoate (158 mg), tridecylamine 2-decyloxy-4 - [3-(1 Methylsulfonyl]-6-nitrophenol 3-(4-hydroxy-3-oxooxy-5 nitrile (Reference Example 36 _ 55) (20 〇mg), stack 312XP/ Instructions (Supplement) / 96-03/95143900 140 200800871 A mixture of hydrochloride (172 mg) and 1-methyl-2-pyrrolidone (15 mL), irradiated with microwave under stirring, heated at 2 〇 (rc heating 1 The reaction mixture was partitioned with diethyl ether and water. The organic layer was washed with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure. 6-Nitro-4-[3 -(1H-tetrazol-5-yl)benzenesulfonyl]phenol. ' At the room temperature, the crude 2-oxooxy-6-nitro-4-[ 3-(1H-tetrazol-5-yl)benzenesulfonyl]phenol, N,N-dimercaptocarboxamide (10 mL), sulfonium iodide (11〇11^) and potassium carbonate (124邶) The mixture was stirred for 1 hour, and the mixture was combined with diethyl ether and water. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (252 mg). NMR (CDCl3) 5 ppm: 4. 02 (3H3 s), 4. 43 (3H, s), 7. 62 (lH, d, J = 1·9Ηζ), 7·65-7·75 (1Η, ηι) ,7·95-8·10(2Η,πι), 8· 35-8· 40(1H,m),8· 65-8· 75(l H, m), 11 · n (iH, s) Spring (Reference Example 45 - 1) 2 - decyloxy - 6 - fluorenyl - 4 - (4 - ° than bite - 1 - phenylene sulphate) 4-(4-Fluorophenylsulfonyl)-2-methoxyl-6-nitrophenol (Reference Example 36-ll) (265 mg), pyrrolidine (288 mg) and hydrazine, hydrazine-dimercaptopurine A mixture of amines (10 mL) was irradiated with microwaves under stirring and heated at 2 Torr for 5 minutes. The reaction mixture was partitioned between ethyl acetate and water, and the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (162 mg). 312XP/Invention Manual (supplement)/96-03/95143900 141 200800871 'H-NMR (CDCh) 5 ppm : 3. 40-3. 46(4H, m)5 3. 47-3. 53

UH，m)，3· 95—4· 01(3H，m)，6· 54(2H，d，9· 1Hz)，7· 56 (1H，d，J = 2· 2Hz)，7· 73(2H，d，J = 8· 8Hz)，8· 24(1H，d，J =1. 9Hz) ’ (參考例4 6 - 1) 2-曱氧基- 4 -（2 ~甲基一 6-三氟曱基苯磺醯基）酚在冰》合攪拌下，將第三丁醇鉀（494mg)加入至4 -苄氧基-3 -曱氧基苯硫醇（參考例19 — i)(985mg)及N，n〜二春曱基曱&胺（6mL)之混合物中並攪拌5分鐘。加入2 -氟〜 3-二氟曱基苯曱醛（〇· 61mL)後，將此混合物在室溫下授拌2小時。此反應混合物用醋酸乙酯與2111〇1/；1鹽酸進行分液，其有機液層依次以2mol/L氫氧化鈉水溶液、飽和碳酸氳納水溶液、食鹽水洗滌，用無水硫酸鎂乾燥。在減壓下進行濃縮，得粗製之2- (4 -苄氧基-3 -曱氧基笨亞磺醯基）-3 -三氟曱基笨曱醛。 • 在冰浴攪拌下，將硼氳化納（151 mg)加入至粗製之2 -(4-苄氧基-3 -曱氧基苯亞磺醯基）-3 —三氟曱基笨甲酸、甲醇（10mL)及四氫呋喃（l〇mL)之混合物中並攪拌5分 1里。在至溫下攪拌15分鐘後小心加入2mo 1 /L鹽酸以處理反應。所得混合物用醋酸乙醋稀釋，分離有機液層。水層則再用醋酸乙酯萃取。合併有機液層，依次以飽和碳酸氫納水溶液、食鹽水洗滌，用無水硫酸鎂乾燥後在減壓下進行濃縮，得粗製之[2- (4-苄氧基-3 -甲氧基苯亞磺醯基）-3 -三氟曱基苯基]曱醇。 312XP/發明說明書(補件)/96-〇3/95143900 142 200800871 在氬氣環境及冰浴攪拌下，將四溴化碳（199g)及三苯基膦（1.57g)加入至粗製之[2 — (4 —苄氧基-3—曱氧基苯亞石頁酿基）一 3 -三氟曱基苯基]曱醇及二氯曱烷（2〇mL) 之混合物中後，在室溫下攪拌90分鐘。此反應混合物在減壓下進行濃縮，其殘留物通過矽膠過濾，並用3〇%醋酸乙酯-己烷洗提。濾液在減壓下進行濃縮，得粗製之i 一苄氧基-4 - (2-溴曱基—6 -三氟甲基苯亞磺醯基）一 2 -甲氣基苯。在冰浴攪拌下，將氫化鋁鋰（152mg)小心加入至粗製之卞氧基 4 (2 -演甲基-6-三氟曱基苯亞石黃醢基）一 2 -曱氧基苯及四氫呋喃（1〇mL)之混合物中。在7〇 C擾摔3小時後，在室溫下再小心加入氫化鋁鋰 (304mg)。在迴流下攪拌3小時後，滴加水於此反應液中，再加入2mol/L鹽酸。此混合物用二***萃取，有機液層依次以飽和碳酸氫鈉水溶液、食鹽水洗滌，用無水硫酸鎂乾燥。在減壓下進行濃縮，得粗製之1 -苄氧基-2 -曱氧基-4- (2 -甲基—6 —三氟曱基苯亞磺醯基）苯。在室溫攪拌下，將過氧間苯曱醯氯（3· 2g)加入至粗製之氧基一/一甲氧基一 4-（2-甲基-6-三氟甲基苯亞石兴fe基）笨及二氯曱烧（3〇此）之混合物中並攪拌I〗小時。此反應混合物用醋酸乙酯與2m〇1/；L氳氧化鈉水溶液進行分液，有機液層依次以飽和碳酸氫鈉水溶液、食鹽水洗滌，用無水硫酸鎂乾燥，在減壓下進行濃縮，得粗製之 1 -苄氧基-2 -甲氧基一 4一（2 一曱基一 6 一三氟甲基苯 3 UXP/發明說明書(補件)/%-〇3/951439〇〇 143 200800871 石黃酿基）苯。在室溫攪拌下，將27%溴化氫_醋酸溶液（5 〇mL)加入粗製之1-节氧基-2_甲氧基_4_(2_曱基_6_三氟曱基苯石黃醯基）苯及二氯曱燒（15mL)之混合物中，並擾掉 4小時。於此反應混合物加人水及醋酸乙g|後激烈授摔。分離有機液層，水層用醋酸乙醋萃取。合併有機液層，以食鹽水洗滌2次後，用無水硫酸鈉乾燥，在減壓下進行濃縮。其殘留物以石夕膠中壓管柱色析法進行精製（洗提液：攀20〜_醋酸乙醋-己燒之梯度洗提），得目標化合物 (733mg)。 NMR(CDCh)(5ppra ： 2. 59(3H, s), 3. 93(3H, s), 6. 07 (1H, s), 6. 97(1H, d, J = 8. 6Hz), 7. 39(1H, dd, J=8. 6, 2. 2Hz) 7. 44 (1H, d, J= 2. 2Hz), 7. 47(1H, d, J= 7. 9Hz), 1. 57 ’ (1H，t，J= 7· 9Hz)，7.85(lH，d，J=7· 9Hz) (麥考例4 7 - 1 ) φ 3 - U -羥基-3 _甲氧基苯磺醯基）苯甲酸將4 -苄氧基_ 3 -甲氧基苯硫醇（參考例i 9 _ l)(l.〇〇g)、3 -碘苯甲酸乙酯（1.46g)、參（二苯亞甲基丙酮）二鈀（0)二氯甲烷加成物（203mg)、（氧基二_ 2>1 :伸苯基）雙（二苯基膦）（235mg)、第三丁醇鉀（684mg)及甲苯 (30niL)之混合物在l〇(rC攪拌8小時。將反應混合物待冷卻通過Celite(註冊商標）矽藻土層過濾後用醋酸乙酯= 提。濾液以食鹽水洗滌，用無水硫酸鎂乾燥後在減壓下進行濃縮，得粗製之3_ (4-苄氧基_ 3_甲氧基苯亞磺醯 312XP/發明說明書(補件)/96-03/95143900 144 200800871 基）苯曱酸乙酯。在0°C下，將Oxone(註冊商標）（7.49g)加入粗製之3-(4 -苄氧基-3 -曱氧基苯亞磺醯基）苯曱酸乙酯、丙酮 (20mL)、水（4mL)及碳酸氫鈉（2. 73g)之混合物中後，將此混合物升溫至室溫並攪拌30分鐘。此反應混合物用醋酸乙酯稀釋，以食鹽水洗滌，用無水硫酸鎂乾燥，在減壓下進行濃縮。其殘留物以矽膠中壓管柱色析法進行精製（洗提液：己烷/醋酸乙酯二2/10)，得3 - (4 -苄氧基-3-•曱氧基苯磺醯基）苯曱酸乙酯（1.35g)。將3 - (4 -苄氧基-3 -曱氧基苯磺醯基）苯曱酸乙酯 (1. 35g)、2mol / L氫氧化鈉水溶液及四氳吱喃（40mL)之混合物迴流2小時。將反應混合物待冷卻至室溫後以濃鹽酸調整為酸性，用醋酸乙酯稀釋，以食鹽水洗滌，用無水硫酸鎂乾燥，在減壓下進行濃縮得粗製之3- (4-苄氧基-3-曱氧基苯磺醯基）苯曱酸（827mg)。 φ 在氳氣環境下，將粗製之3 - (4 -苄氧基-3 -甲氧基苯石黃醯基）苯甲酸（250 mg)、10% I巴碳（20 mg、含水量50%) 及四氫呋喃（20mL)之混合物在室溫下攪拌1小時。過濾此反應混合物以去除不溶物後，濾液在減壓下進行濃縮，得目標化合物（209mg)。 ^ - NMR(CDCh) 5 ppm : 3. 98(3H, s), 7. 02(1H, d? J = 8· 5Hz), 7_ 44(lH，d，J=l· 9Hz)，7· 55(1H，dd，J = 8. 5, 1. 9Hz)， 7· 63(1H，t，7· 7Hz)，8· 16(1H，d，J= 8· 2Hz)，8· 26 (1H，d，J= 7· 9Hz)，8· 62(1H，s) 312XP/發明說明書(補件)/96-03/95143900 145 200800871 (簽考例4 8 - 1) 3-二氟曱基-4 -羥基笨曱腈在氫氣環境下，將3 -二氟曱基—4 —羥基苯甲腈（參考例15 - 8)(8· 37g)、10%鈀碳（1· 6g、含水量5〇%)及四氳呋嚼（lOOmL)之混合物在室溫下攪拌3〇分鐘。過濾此反應混合物以去除不溶物後，濾液在減壓下進行濃縮，得目標化合物（4· 87g)。、 Η - NMR(DMS0 - de) 5 ppm · β· 94-7· 19(2H，m)，7· 79-7 83 • (lH,m), T.87-7.91(lH,m)511.52(lH,brs) (參考例49 - 1) 5-二氟甲基- 4-經基-3 一蛾苯甲腈將N -破玻拍酿亞胺（1· i23g)加入至5 -二氟甲基一 4-羥基苯曱腈（參考例48- l)(563mg)及N，N_二曱^曱醯胺（20mL)之混合物中，在室溫下攪拌3〇分鐘。此反應混合物用二***與水進行分液。分取有機液層，依次以籲水、食鹽水洗滌，用無水硫酸鎂乾燥，在減壓下進行濃縮，得目標化合物（1· 〇64g)。、 4 - NMR(CDC13) d ppm ·· 6· 91(1H，t，H4· 7Hz)，7. 80- 7· 85(1H，m)，8· 05-8· 10(1H，m) (參考例50 - 1) 2_胺基- 5-氟- 3-甲基苯甲酸乙酯在10 C下，將溴（2· 7mL)加入2 -胺基-5—氟苯甲酸乙醋（7.95g)及二氯τ烷（8〇mL)之混合物中。此混合物在相同溫度下授拌10分鐘後在室溫下攪拌4小時。繼之在1〇 312XP/發明說明書(補件)/96·〇3/95143900 146 200800871 C下將10%亞硫酸氫鈉水溶液（15()mL)加入此反應混合物中。將混合物注入醋酸乙酯中。其水層再以醋酸乙酯萃取。合併有機液層，依次以水、飽和碳酸氬鈉水溶液、食鹽水洗滌，用無水硫酸鎂乾燥後在減壓下進行濃縮，其殘留物以矽膠管柱色析法進行精製（洗提液：3%醋酸乙酯/ 己烷）’付2 -胺基—3 —溴一 5_氟苯曱酸乙酯（1〇. 3知）。在氬氣環境下，將2 -胺基—3 —溴—5 —氟苯甲酸乙酯 (4· 28g)、四甲基錫（n· 3mL)、氯化雙（三苯基膦）鈀 (II)(1.14g)及甲苯（4〇mL)之混合物以11〇。〇攪拌9〇小時。此反應混合物待冷卻後用醋酸乙酯稀釋，加入 Florisil(註冊商標、和光純藥製）（5g)，在室溫下攪拌工小時。將反應混合物通過Cel ite(註冊商標）矽藻土層進行過濾後用醋酸乙酯洗提。濾液在減壓下進行濃縮，其殘留物以矽膠管柱色析法進行精製（洗提液：1〇%醋酸乙酯/ 己烧）’得目標化合物（2.96g)。馨1H-丽R(CDCl3)5ppm: i.38(3H，t，J=7.3Hz)，2.17 (3Η，s)，4· 33 (2Η，q，J= 7· 3Hz)，5· 66(2H，br)，6· 96-6· 99 (1Η，m)，7· 45-7· 48(1Η，m) (參考例51 - 1) 2, 3, 5 -三氟苯曱酸異丙酯將1-乙基-3- (3-二曱胺丙基）碳二亞胺鹽酸鹽 (749mg)加入2, 3, 5 -三氟苯甲酸（529mg) ' 2 —丙醇 (0.689mL)、4 -二甲基胺基吡啶（183mg)及N，N —二甲基曱醯胺（6mL)之混合物中，在室溫下攪拌2〇小時。此反應 312XP/發明說明書(補件)/96-03/95143900 147 200800871 混合物加入水（5OmL)後用二***萃取。有機液層依次以 lmol/L鹽酸、水洗滌，用無水硫酸鎂乾燥後在減壓丁進行濃縮，得目標化合物（481 mg)。 ~ NMR(CDCh) δ ppm : 1. 38(3H, s), 1. 39(3H, s)? 5 20-5· 35(lH，m)，7· 05-7· 15(lH，m)，7. 35-7· 45(lH，m) (參考例51 - 2) 2, 3, 5 -三氟苯曱酸環己酯依與參考例51 - 1相同方法，使用環己醇代替2 —丙馨酵’合成得目標化合物。 H~NMR(CDCl3)(5ppm： 1. 〇5-2. 00(10H5m), 5.00-5 15 (lH，m)，7· 05-7· 15(1Η，π〇, 7· 35-7· 45(1H，m) (參考例52 -1) 2, 3, 5 -三氟苯曱酸苄酯在至/皿下’將石炭酸鉀（622mg)及苄基溴化物（〇· 428mL) 依次加入2,3,5 -三說苯甲酸（772mg)及N，N -二甲基甲鲁醯胺之混合物中。此混合物在室溫下攪拌2〇小時。加入水（24mL)並攪拌30分鐘。濾取固體，以水洗滌8次，在減壓下進行乾燥，得目標化合物（772mg)。咜-丽R(CDC13) (5 ppm:5.40(2H，s)，7.05-7.20(lH，m)， 7. 30-7. 50(6H, m) (參考例53- 1) 3 —氟甲基-5 -峨-4 -甲氧基甲氧苯甲腈將5 —二氟甲基_ 4 -羥基-3 -碘苯甲腈（參考例49 一 1)(1. 02g)、氯甲基甲醚（418mg)、N，N —二異丙基乙胺 312XP/發明說明書(補件 y96_〇3/951439()() 148 200800871 (894mg)及醋酸乙酯（20mL)之混合物在室溫下攪拌i小時。此反應混合物用醋酸乙酯與水進行分液，有機液層以' 食鹽水洗務，用無水硫酸納乾燥。在減壓下進行潫縮，其殘留物以矽膠管柱色析法進行精製（洗提液：己烧酸/乙酯=10/1)，得目標化合物（94〇mg)。 'H - NMR(CDCh) 5 ppm ： 3. 65(3H, s), 5. 18(2H, s), 6. 95 (1H，t，J= 54· 9Hz)，7. 90-7· 92(1H，m)，8· 19-8· 21(1H，m) (參考例54 - 1) ’ • 3，，4，—二氫-8，-硬螺[1，3 -二.等咮一 2，Γ (2，Η)萘] 將 8 -碘-3,4 -二氫-2Η-萘-1-酮（i.7g)、乙二醇 (1· 16g)、對甲苯磺酸（5〇mg)及甲苯（i〇〇mL)之混合物，以 Dien_ Stark裝置在迴流下攪拌整夜。用醋酸乙酯稀釋，依次以飽和碳酸氫鈉水溶液、食鹽水洗滌，用無水硫酸鎂乾燥後在減壓下進行濃縮，其殘留物以石夕膠管柱色析法進 _行精製（洗提液：己烷至30%醋酸乙酯/己烷之梯度洗提），得目標化合物（773mg)。 - NMRCCDCls) (5 ppm ： 1. 81-1. 89( 1H, m), 1. 94-2. 02 (2H，m)，2· 80 —2· 87(2H，m)，4· 11—4. 21(2H，m)，4· 39 —4· 44 (2H，m)，6· 85(1H，t，J = 7. 7Hz), 7. 08(1H, dd, J ^ 7-6，1.3Hz)，7.86(lH，d，J=7.3Hz) (參考例55 - 1) N- (2-蛾苯基）一 N-甲基甲石黃醯胺在冰浴下’將氫化納（55%、502mg)加入N - (2 -峨苯基） 312XP/發明說明書(補件)/96-03/95143900 149 200800871 曱磺醯胺（2.85g)及N，N -二甲基曱醯胺（2〇mL)之混合物中，在相同溫度下攪拌20分鐘。於混合物中加入碘化甲基（1.19mL)後在室溫下攪拌2小時。此反應混合物在冰浴授拌下加入水（40mL)及醋酸乙酯（50mL)。分離之有機液層依次以水、飽和碳酸氫鈉水溶液、食鹽水洗滌，用無水硫酸鎂乾燥後在減壓下進行濃縮，其殘留物以矽膠管柱色^ 法進行精製（洗提液：10至50%醋酸乙酯/己烷之梯度洗提），得目標化合物（2. 6 g)。馨1Η - NMR(CDCh) 5 ppm : 3· 09(3H, s)，3· 25(3H，s)，7· 〇5-7·09 (lH，m)，7.39-7· 42(1 H，m)，7· 48-7· 50(1 H，m)， 7· 91 -7· 93(lH，m) (參考例56 - 1) 2 - [2 -（4-苄氧基- 3-曱氧基苯亞磺醯基5 — 氟- 3-甲基苯基]丙-2-醇在〇°C下，將溴化曱基鎂（3.0m〇l/L二***溶液、17此）書加入5 -氟-2 -碘-3 -甲基苯甲酸乙酯（參考例16 — 17)(441mg)及四氫呋喃（l〇mL)之混合物中。在室溫下授掉 1小時後加入氯化銨水溶液，用醋酸乙酯萃取。有機液層依次以碳酸氫鈉水溶液、食鹽水洗滌，用無水硫酸鎂乾燥後在減壓下進行濃縮，其殘留物以矽膠管柱色析法進行^ 製（洗提液：5%至20%醋酸乙酯/己烷之梯度洗提），得目標化合物（418mg)。 4 - NMR(CDCl3)6ppm: 1.69(6H，s)，2.29(3iI，s)，3 76 (3H，s)，4· 40(1H，s), 5· 07(2H，s)，6· 38(1H，dd，J = 8. 5, 2. 2Hz) 3 GXP/發明說明書(補件)/96-03/95143900 150 200800871 6· 61(1H，d，J= 2· 2Hz)，6· 73(1H，d，J= 8· 5Hz)，6· 92-6. 95 (1Η，π〇,7·22 —7.40(6H，m) (參考例57 - 1) 2 - (4-节氧基- 3 -甲氧基苯亞石黃酿基）- 5 -氟—3 — 甲基苯甲腈在氬氣流下，將5 -氟-2 -蛾-3 -曱基苯甲腈（來考例1 6 - 1 6)(500mg)、4 -苄氧基-3 -甲氧基苯硫醇（參考例 19 - l)(472mg)、碘化銅（I)(365mg)、反-1，2 —環己籲二胺（437mg)、碳酸鉀（529mg)及 1，4 -二，烧（i3mL)之混合物以10 0 °C攪拌15分鐘。將反應混合物待冷卻至室溫後加入2mol/L鹽酸（5mL)。此混合物在室溫下攪拌3〇分鐘後，通過Celite(註冊商標）矽藻土層進行過濾，依次以28%氣水與食鹽水之混合物2次、食鹽水、2m〇i 鹽酸、食鹽水洗滌，用無水硫酸鎂乾燥後在減壓下進行濃縮，其殘留物以矽膠管柱色析法進行精製（洗提液：己烷至5〇% _醋酸乙酯/己烷之梯度洗提），得目標化合物（553mg)。 lH - NMRCCDCh) (5 ppm ： 2. 46(3H, s), 3. 83(3H, s), 5. 10 (2H, s), 6. 63(lH,dd, J = 8. 2, 2. 2Hz), 6. 75(1H, d, J=8. 5Hz), 6. 85(1H, d, J= 2. 2Hz), 7. 21(1 H, dd5 J= 8. 8, 2. 8Hz), 7· 28-7. 41 (6H，m) (參考例58 - 1) [2 —苄氧基-3 -甲氧基苯亞磺醯基5 —氟一 3 -甲基苯基]甲醇將5氟2礙—3 -甲基苯甲酸乙酯（參考例μ- 3 ΠΧΡ/發明說明書(補件)/96_〇3/95143900 151 200800871 Π)(4· Og)、4 -苄氧基—3 -甲氧基苯硫醇（參考例19 一 l)(2.13g)、^(二苯亞甲基丙商…二鈀“^乃^幻^氧基二-2，1 -伸苯基）雙（二苯基膦）（932mg)、第三丁醇鉀 (1· 46g)及曱苯（6〇mL)之混合物在1〇〇〇c下攪拌4〇分鐘。將反應混合物待冷卻後用醋酸乙酯稀釋，加入 Florisil(註冊商標、和光純藥製）（1〇g)，在室溫下攪拌 1小時。此反應混合物通過Celite(註冊商標）矽藻土層進灯過濾，用醋酸乙酯洗提。濾液以食鹽水洗滌，用無水硫酸鎂乾燥，在減壓下進行濃縮，其殘留物以矽膠管枉色析法進行精製（洗提液：5%至20%醋酸乙酯/己烷之梯度洗提）’得2 -（4-苄氧基一 3-甲氧基苯亞磺醯基）_5-氟- 3 -曱基苯甲酸乙酯（2· 4gg)。在〇 C下’將氳化|呂鐘（11 gmg)加入2-(4 -节氧基一 3 -甲氧基苯亞磺醯基）—5 -氟—3 -甲基苯甲酸乙酯 (1· lg)及四氫呋喃（2〇mL)之混合物中。在相同溫度下攪拌 2 0分麵後’在〇它下加入水。此反應混合物用二***稀釋。將此混合物注入於2mo 1 /L鹽酸中，其水層用二*** 萃取。有機液層依次以水、飽和碳酸氫鈉水溶液、食鹽水洗務’用無水硫酸鎂乾燥，在減壓下進行濃縮，其殘留物以石夕膠管柱色析法進行精製（洗提液·· 5%至30%醋酸乙酯/ 己烧之梯度洗提），得目標化合物（90Omg)。 4-丽R(CDC13) 5 ppm: 2· 10(1H，t，J= 6· 3Hz)，2· 41(3H，s)， 3· 77(3H，s)，4· 78(2H，d，6· 3Hz)，5· 07(2H，s)，6. 32 (1H，dd，J=8· 2, 2· 2Hz)，6. 59(1H, d，J=2· 2Hz)，6· 71 312XP/發明說明書(補件)/96-03/95143900 152 200800871 (1H，d，J= 8· 2Έζ)，6· 96-6· 99(1H，m)，7· 14-7· 17(1H，m)， 7.27-7.40(5H，m) ’ ’ (參考例59 - 1) 2 - (4 -苄氧基—3 —曱氧基苯亞磺醯基）_ j —溴曱基- 5-氟- 3-甲苯將5-氟-2-碘- 3-甲基苯甲酸乙酯（參考例16 一 17)(4. 0g)、4 -苄氧基—3 —甲氧基苯硫醇（參考例19一 1)(2· 13g)、麥（二苯亞甲基丙酮）二鈀（〇)(792呢）、（氧基一 2’1伸本基）雙（一苯基膦）（932mg) '第三丁醇鉀 (1.46g)及曱苯（60mL)之混合物在i〇(TC攪拌4〇分鐘。此反應混合物待冷卻後用醋酸乙酯稀釋，加入F1〇risil(註冊商標、和光純藥製）（1 〇g)，在室溫下攪拌丨小時。此反應混合物通過Ceiite(註冊商標）矽藻土層進行過濾，用醋3文乙i曰洗知：。濾液以食鹽水洗務，用無水硫酸鎂乾燥，在減壓下進行濃縮，其殘留物以矽膠管柱色析法進行精製書（洗提液：5%至20%醋酸乙酯/己烷之梯度洗提），得2一 (4-苄氧基-3-甲氧基苯亞磺醯基）-5 一氟- 3-甲基苯甲酸乙酯（2.48g)。在0C下，將氫化銘链（1〇 5mg)加入至2 - (4 -节氧基一 3 -甲氧基苯亞磺醯基）-5 -氟-3 -甲基苯曱酸乙醋 (9 8 5mg)及四氫咬喃（2 0mL)之混合物中。在相同溫度下授拌2 0分鐘後，在〇 °c加入水。此反應混合物用二乙_稀釋。將此混合物注入於2m〇 1 /L鹽酸中，其水層用二乙鍵萃取。其有機液層依次以水、飽和碳酸氫鈉水溶液、食鹽 312XP/發明說明書(補件)/96-03/95143900 153 200800871 水洗滌，用無水硫酸鎂乾燥，在減壓下進行濃縮，得粗製之[2-(4-苄氧基-3 -曱氧基苯亞磺醯基）_5_氟— 3 -曱基苯基]曱醇。在0°C下，將四溴化碳（1· I5g)及三苯基膦（9〇9mg)依序加入至粗製之[2 - (4-节氧基—3 —甲氧基苯亞磺醯基）-5 -氟-3 -曱基苯基]甲醇及二氯甲烷（2〇mL)之混合物中。此混合物在相同溫度下攪拌丨小時後，在減壓下UH,m),3·95—4· 01(3H,m),6·54(2H,d,9·1Hz),7·56 (1H,d,J=2·2Hz),7·73( 2H,d,J = 8·8 Hz), 8·24 (1H, d, J = 1. 9 Hz) ' (Reference Example 4 6 - 1) 2-decyloxy-4 -(2 ~methyl-6- Potassium tert-butoxide (494 mg) was added to 4-benzyloxy-3-indolyl thiol (with reference to Example 19-i) under stirring with trifluoromethanesulfonyl phenol. 985 mg) and a mixture of N, n~dioxanylamine &amine (6 mL) and stirred for 5 minutes. After adding 2-fluoro-1,3-difluoromercaptophenylfurfural (〇·61 mL), the mixture was stirred at room temperature for 2 hours. The reaction mixture was partitioned between ethyl acetate and 2111 〇 1 / 1 hydrochloric acid, and the organic layer was washed successively with 2 mol/L aqueous sodium hydroxide, saturated aqueous sodium carbonate and brine, and dried over anhydrous magnesium sulfate. Concentration under reduced pressure gave crude 2-(4-benzyloxy-3-indolyl sulfinyl)-3trifluorodecyl cumene. • Add borohydride (151 mg) to the crude 2-(4-benzyloxy-3-indolyl sulfinyl)-3trifluorodecyl benzoic acid under stirring in an ice bath. A mixture of methanol (10 mL) and tetrahydrofuran (10 mL) was stirred for 5 minutes and 1 liter. After stirring for 15 minutes at the temperature, 2 mol of 1 / L hydrochloric acid was carefully added to treat the reaction. The resulting mixture was diluted with ethyl acetate and the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The organic layer was combined, washed with saturated aqueous NaHCO3 and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give [2-(4-benzyloxy-3-methoxybenzene). Sulfomethyl)-3-trifluorodecylphenyl]nonanol. 312XP/Invention Manual (Supplement)/96-〇3/95143900 142 200800871 Carbon tetrabromide (199g) and triphenylphosphine (1.57g) were added to the crude [2] under argon atmosphere and ice bath [2] —(4-Benzyloxy-3-decyloxyphenyl ruthenium) a mixture of 3-trifluorodecylphenyl]nonanol and dichlorodecane (2〇mL), at room temperature Stir under 90 minutes. The reaction mixture was concentrated under reduced pressure and the residue was filtered and evaporated eluting The filtrate was concentrated under reduced pressure to give crude i-benzyloxy-4-(2-bromoindol-6-trifluoromethylphenylsulfinyl)-2-carbobenzene. Lithium aluminum hydride (152 mg) was carefully added to the crude oxirane 4 (2-methyl-6-trifluorodecyl phenyl fluorinyl)-2-nonyloxybenzene and tetrahydrofuran under stirring in an ice bath. 1 〇mL) in a mixture. After 3 hours of disruption at 7 ° C, lithium aluminum hydride (304 mg) was carefully added at room temperature. After stirring under reflux for 3 hours, water was added dropwise to the reaction mixture, and then 2 mol/L hydrochloric acid was added. The mixture was extracted with diethyl ether. Concentration under reduced pressure gave crude 1-benzyloxy-2-indole-4-(2-methyl-6-trifluorodecylbenzenesulfinyl)benzene. Peroxydiphenylphosphonium chloride (3.2 g) was added to the crude oxy-/monomethoxy-4-(2-methyl-6-trifluoromethylphenyl sulfite) under stirring at room temperature. Fe base) Stirred and dichlorohydrin (3 〇) mixture and stirred for 1 hour. The reaction mixture was separated with ethyl acetate and aq. EtOAc (EtOAc). 1 -Benzyloxy-2-methoxy- 4-(2-fluorenyl- 6-trifluoromethylbenzene 3 UXP/inventive specification (supplement)/%-〇3/951439〇〇143 200800871 Stone yellow base) benzene. Add 27% hydrogen bromide-acetic acid solution (5 〇mL) to the crude 1-hydroxy-2-phenyloxy_4_(2_fluorenyl-6-trifluoromethyl phthalite) with stirring at room temperature A mixture of benzene and dichlorohydrazine (15 mL) and was disturbed for 4 hours. After the reaction mixture was added with human water and ethyl acetate, it was drastically dropped. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer was combined, washed twice with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by a celite gel column chromatography (eluent: gradient 20~_ethyl acetate-hexane) eluted to give the title compound (733 mg). NMR (CDCh) (5ppra: 2. 59(3H, s), 3. 93(3H, s), 6. 07 (1H, s), 6. 97(1H, d, J = 8. 6Hz), 7 39(1H, dd, J=8. 6, 2. 2Hz) 7. 44 (1H, d, J= 2. 2Hz), 7. 47(1H, d, J= 7. 9Hz), 1. 57 ' (1H,t,J= 7· 9Hz), 7.85 (lH,d,J=7·9Hz) (McC4 4 7 - 1 ) φ 3 - U -hydroxy-3 _methoxybenzenesulfonyl Benzoic acid 4- 4-benzyloxy-3-methoxybenzenethiol (Reference Example i 9 _ l) (l.〇〇g), ethyl 3-iodobenzoate (1.46g), ginseng (diphenyl) Methylene acetonide) dipalladium (0) dichloromethane adduct (203 mg), (oxy bis 2 > 1 : phenyl) bis (diphenyl phosphine) (235 mg), potassium t-butoxide ( A mixture of 684 mg) and toluene (30 mM) was stirred at rt for 8 hours. The reaction mixture was cooled and filtered through Celite (registered trademark) celite and filtered with ethyl acetate. After drying over magnesium sulfate, the residue was concentrated under reduced pressure to give crude 3-(4-benzyloxy-3-methoxyphenylsulfinium 312XP/invention specification (supplement)/96-03/95143900 144 200800871 base) benzene Ethyl citrate. Add Oxone (registered trademark) (7.49g) at 0 °C. After a mixture of crude 3-(4-benzyloxy-3-indolyl sulfinyl) benzoate, acetone (20 mL), water (4 mL) and sodium bicarbonate (2. 73 g) The mixture was warmed to room temperature and stirred for 30 minutes. The reaction mixture was diluted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Purification by analytical method (eluent: hexane/ethyl acetate 2/10) to give ethyl 3-(4-benzyloxy-3-•nonoxyphenylsulfonyl)benzoate (1.35 g) a mixture of ethyl 3-(4-benzyloxy-3-indolylbenzenesulfonyl)benzoate (1.35 g), 2 mol/L aqueous sodium hydroxide and tetrafuran (40 mL) After the reaction mixture was refluxed for 2 hours, the reaction mixture was cooled to room temperature, then was acidified with concentrated hydrochloric acid, diluted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate and evaporated. -benzyloxy-3-decyloxybenzenesulfonyl)benzoic acid (827 mg). φ In a helium atmosphere, the crude 3-(4-benzyloxy-3-methoxybenzoquinone) Benzoic acid (250 mg), A mixture of 10% I bar carbon (20 mg, 50% water content) and tetrahydrofuran (20 mL) was stirred at room temperature for 1 hour. After filtering the reaction mixture to remove the insoluble material, the filtrate was concentrated under reduced pressure to give the title compound (209 mg). ^ - NMR (CDCh) 5 ppm : 3. 98(3H, s), 7. 02(1H, d? J = 8· 5Hz), 7_ 44(lH,d,J=l· 9Hz),7·55 (1H, dd, J = 8. 5, 1. 9Hz), 7· 63 (1H, t, 7·7Hz), 8·16 (1H, d, J= 8· 2Hz), 8·26 (1H, d, J = 7· 9 Hz), 8· 62 (1H, s) 312XP / invention manual (supplement) / 96-03/95143900 145 200800871 (test case 4 8 - 1) 3-difluorodecyl-4 -Hydroxyl hydrazine nitrile in a hydrogen atmosphere, 3-difluorodecyl-4-hydroxybenzonitrile (Reference Example 15-8) (8.33 g), 10% palladium on carbon (1.6 g, water content 5 〇 A mixture of %) and tetrahydrofuran (100 mL) was stirred at room temperature for 3 minutes. After the reaction mixture was filtered to remove insoluble material, the filtrate was concentrated under reduced pressure to give the title compound (4·87 g). , Η - NMR (DMS0 - de) 5 ppm · β· 94-7· 19(2H,m), 7· 79-7 83 • (lH,m), T.87-7.91(lH,m)511.52( lH,brs) (Reference Example 49 - 1) 5-Difluoromethyl-4-trans-yl-3-mothenzonitrile N-Born-Born-Imine (1·i23g) was added to 5-difluoromethyl A mixture of 4-hydroxybenzoic acid nitrile (Reference Example 48-1) (563 mg) and N,N-dioxane (20 mL) was stirred at room temperature for 3 min. This reaction mixture was partitioned with diethyl ether and water. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (1· 〇 64 g). , 4 - NMR (CDC13) d ppm · · 6· 91 (1H, t, H4 · 7Hz), 7. 80- 7· 85 (1H, m), 8· 05-8· 10(1H, m) ( Reference Example 50 - 1) 2-Amino-5-fluoro-3-methylbenzoic acid ethyl ester Bromine (2.7 mL) was added to 2-amino-5-fluorobenzoic acid ethyl acetate (7.95) at 10 C. g) and a mixture of dichlorohethane (8 〇 mL). This mixture was stirred at the same temperature for 10 minutes and then stirred at room temperature for 4 hours. A 10% aqueous solution of sodium hydrogen sulfite (15 () mL) was then added to the reaction mixture at 1 312 XP/Inventive Manual (supplement)/96·〇3/95143900 146 200800871 C. The mixture was poured into ethyl acetate. The aqueous layer was extracted with ethyl acetate. The organic layer was combined, washed with water, a saturated aqueous solution of sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was purified by gel column chromatography (eluent: 3 % ethyl acetate / hexane) '2'-amino-3-bromo-5-fluorobenzoic acid ethyl ester (1〇. 3). 2-Amino-3-bromo-5-fluorobenzoic acid ethyl ester (4·28g), tetramethyltin (n·3mL), bis(triphenylphosphine)palladium chloride (under argon) A mixture of II) (1.14 g) and toluene (4 〇 mL) was 11 Torr. Stir for 9 hours. The reaction mixture was diluted with ethyl acetate, and added to Florisil (registered trademark, manufactured by Wako Pure Chemical Industries, Ltd.) (5 g), and stirred at room temperature for several hours. The reaction mixture was filtered through a Celite (registered trademark) layer of celite and eluted with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: 1% ethyl acetate / hexane) to give the title compound (2.96 g). Xin 1H-Li R (CDCl3) 5ppm: i.38 (3H, t, J = 7.3Hz), 2.17 (3Η, s), 4· 33 (2Η, q, J= 7· 3Hz), 5· 66 ( 2H, br), 6· 96-6· 99 (1Η, m), 7· 45-7· 48 (1Η, m) (Reference Example 51 - 1) 2, 3, 5-trifluorobenzoic acid isopropyl The ester was added 1-ethyl-3-(3-diamidinopropyl)carbodiimide hydrochloride (749 mg) to 2,3,5-trifluorobenzoic acid (529 mg) '2-propanol (0.689 mL) And a mixture of 4-dimethylaminopyridine (183 mg) and N,N-dimethylguanamine (6 mL) was stirred at room temperature for 2 hours. This reaction 312XP / invention specification (supplement) / 96-03 / 95143900 147 200800871 The mixture was added with water (5OmL) and extracted with diethyl ether. The organic layer was washed successively with 1 mol/L hydrochloric acid and water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (481 mg). ~ NMR(CDCh) δ ppm : 1. 38(3H, s), 1. 39(3H, s)? 5 20-5· 35(lH,m),7· 05-7· 15(lH,m) , 7. 35-7· 45 (lH, m) (Reference Example 51 - 2) 2, 3, 5-trifluorobenzoic acid cyclohexyl ester in the same manner as in Reference Example 51-1, using cyclohexanol instead of 2 - Acetin's synthesis of the target compound. H~NMR (CDCl3) (5ppm: 1. 〇5-2. 00(10H5m), 5.00-5 15 (lH,m),7·05-7·15(1Η,π〇, 7· 35-7· 45(1H,m) (Reference Example 52-1) 2,3,5-trifluorobenzoic acid benzyl ester was added to / under the dish's potassium silicate (622 mg) and benzyl bromide (〇·428 mL). 2,3,5 -3, a mixture of benzoic acid (772 mg) and N,N-dimethylcarbamate. The mixture was stirred at room temperature for 2 hr. Water (24 mL) was added and stirred for 30 min. The solid was collected by filtration, washed with water (3×), and dried under reduced pressure to give the title compound (772mg). 咜丽 R (CDC13) (5 ppm: 5.40 (2H, s), 7.05-7.20 (lH, m) , 7. 30-7. 50(6H, m) (Reference Example 53-1) 3 —Fluoromethyl-5-indole-4-methoxymethoxybenzonitrile 5- 5 -Difluoromethyl _ 4 - Hydroxy-3-iodobenzonitrile (Reference Example 49-1) (1. 02g), chloromethyl methyl ether (418mg), N,N-diisopropylethylamine 312XP/Invention Manual (supplement y96_〇 3/951439()() 148 200800871 (894mg) and a mixture of ethyl acetate (20mL) were stirred at room temperature for 1 hour. The reaction mixture was partitioned with ethyl acetate and water, and the organic layer was washed with brine. Drying with anhydrous sodium sulfate, collapsing under reduced pressure, and purifying the residue by gel column chromatography (eluent: hexane acid/ethyl ester = 10/1) to obtain the target compound (94 〇) Mg). 'H-NMR (CDCh) 5 ppm : 3. 65(3H, s), 5. 18(2H, s), 6. 95 (1H,t,J= 54· 9Hz), 7. 90- 7· 92(1H,m),8· 19-8· 21(1H,m) (Reference Example 54 - 1) ' • 3,,4,-Dihydro-8,-Hard snail [1,3 - II . equivalent to 2, Γ (2, Η) naphthalene] 8-iodo-3,4-dihydro-2-indole-naphthalen-1-one (i.7g), ethylene glycol (1·16g), p-toluene A mixture of sulfonic acid (5 〇 mg) and toluene (i 〇〇 mL) was stirred overnight under reflux with a Dien_Stark apparatus, diluted with ethyl acetate, washed successively with saturated aqueous sodium bicarbonate, brine, and anhydrous After the magnesium is dried, it is concentrated under reduced pressure, and the residue is purified by a chromatography method (elution: hexane to 30% ethyl acetate/hexane gradient) to obtain the target compound. (773mg) - NMRCCDCls) (5 ppm : 1. 81-1. 89( 1H, m), 1. 94-2. 02 (2H,m), 2· 80 —2· 87(2H,m), 4·11—4. 21(2H,m),4 39 —4· 44 (2H,m),6·85(1H,t,J = 7. 7Hz), 7. 08(1H, dd, J ^ 7-6,1.3Hz), 7.86(lH,d, J = 7.3 Hz) (Reference Example 55 - 1) N-(2-Mothylphenyl)-N-methylmethionine was added to N - (2) by hydrogenation (55%, 502 mg) in an ice bath -峨Phenyl) 312XP/Invention Manual (Supplement)/96-03/95143900 149 200800871 In a mixture of sulfonamide (2.85g) and N,N-dimethyl decylamine (2〇mL), Stir at the same temperature for 20 minutes. After adding methyl iodide (1.19 mL) to the mixture, the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added water (40 mL) and ethyl acetate (50 mL). The separated organic layer was washed successively with water, a saturated aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was purified by a gel column chromatography (eluent: 10 The title compound (2.6 g) was obtained by eluting with a gradient of 50% ethyl acetate/hexane.馨1Η - NMR(CDCh) 5 ppm : 3· 09(3H, s), 3· 25(3H,s),7· 〇5-7·09 (lH,m),7.39-7·42(1 H , m), 7· 48-7· 50(1 H,m), 7· 91 -7· 93(lH,m) (Reference Example 56 - 1) 2 - [2- (4-Benzyloxy-3) - methoxy sulfinyl sulfonyl 5 - fluoro-3-methylphenyl] propan-2-ol 曱溴溴 ( ( (3.0 m 〇 l / L diethyl ether solution, 17 this at 〇 ° C The book was added to a mixture of ethyl 5-fluoro-2-iodo-3-methylbenzoate (Ref. 16-17) (441 mg) and tetrahydrofuran (10 mL), and added at room temperature for 1 hour. The aqueous solution of ammonium chloride was extracted with ethyl acetate. The organic layer was washed successively with aqueous sodium hydrogencarbonate and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure, and the residue was subjected to gel column chromatography. Preparation (Eluent: 5% to 20% ethyl acetate / hexane gradient elution) to give the title compound (418 mg). 4 - NMR (CDCl3) 6 ppm: 1.69 (6H, s), 2.29 (3iI, s ), 3 76 (3H, s), 4 · 40 (1H, s), 5 · 07 (2H, s), 6 · 38 (1H, dd, J = 8. 5, 2. 2Hz) 3 GXP / invention Instruction manual (supplement)/96-03/95143900 150 200800871 6· 61 (1H d, J = 2· 2 Hz), 6·73 (1H, d, J = 8·5 Hz), 6· 92-6. 95 (1Η, π〇, 7.22 — 7.40 (6H, m) (Reference example) 57 - 1) 2 - (4-Ethoxy-3-methoxyphenyl fluorite) 5- 5 -fluoro-3-methylbenzonitrile 5-argon-2 - moth under argon flow -3 - mercaptobenzonitrile (example 1 6 - 16) (500 mg), 4-benzyloxy-3-methoxybenzenethiol (Reference Example 19-1) (472 mg), copper iodide A mixture of (I) (365 mg), trans-1,2-cyclohexyldiamine (437 mg), potassium carbonate (529 mg) and 1,4 -di, calcined (i3 mL) was stirred at 10 ° C for 15 minutes. After the reaction mixture was cooled to room temperature, 2 mol/L hydrochloric acid (5 mL) was added. The mixture was stirred at room temperature for 3 minutes, and then filtered through a Celite (registered trademark) diatomaceous earth layer, followed by 28% gas water and salt. The mixture of water was washed twice with brine, 2 ml of hydrochloric acid and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was purified by gel column chromatography (eluent: hexane) The title compound (553 mg) was obtained from EtOAc (EtOAc) elute lH - NMRCCDCh) (5 ppm : 2. 46(3H, s), 3. 83(3H, s), 5. 10 (2H, s), 6. 63(lH,dd, J = 8. 2, 2 2Hz), 6. 75(1H, d, J=8. 5Hz), 6. 85(1H, d, J= 2. 2Hz), 7. 21(1 H, dd5 J= 8. 8, 2. 8 Hz), 7· 28-7. 41 (6H, m) (Reference Example 58-1) [2-Benzyloxy-3-methoxyphenylsulfinyl-5-fluoro-3-methylphenyl] Ethyl 5-fluoro-2-methyl-benzoic acid ethyl ester (Reference example μ-3 ΠΧΡ/Invention manual (supplement)/96_〇3/95143900 151 200800871 Π) (4·Og), 4-benzyloxy Benz-3-methoxybenzenethiol (Reference Example 19-1) (2.13g), ^(diphenylmethylenepropene...di-palladium)^^^^^^^^^^^^^ A mixture of bis(diphenylphosphine) (932 mg), potassium butoxide (1·46 g) and toluene (6 〇mL) was stirred at 1 ° C for 4 minutes. The reaction mixture was allowed to cool. After it was diluted with ethyl acetate, Florisil (registered trademark, manufactured by Wako Pure Chemical Industries, Ltd.) (1 〇g) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered through a Celite (registered trademark) diatomaceous earth layer. The ethyl acetate was eluted. The filtrate was washed with brine and dried over anhydrous magnesium sulfate. Concentration under reduced pressure, and the residue was purified by hydrazine gel chromatography (eluent: 5% to 20% ethyl acetate / hexane gradient elution) to give 2-(4-benzyloxy- Ethyl 3-methoxyphenylsulfinyl)-5-fluoro-3-indenylbenzoate (2·4 gg). Under 〇C, '氲化| 吕钟(11 gmg) was added to 2-(4- a mixture of ethyl p-oxy-3-methoxybenzylsulfinyl)-5-fluoro-3-methylbenzoate (1·lg) and tetrahydrofuran (2〇mL). Stir at the same temperature 2 After 0 面面, 'water was added under 〇. The reaction mixture was diluted with diethyl ether. The mixture was poured into 2 mol / L hydrochloric acid, and the aqueous layer was extracted with diethyl ether. The sodium aqueous solution and the saline solution were dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel column chromatography (eluent 5% to 30% ethyl acetate / hexane) Gradient elution), the target compound (90Omg) was obtained. 4-Li (CDC13) 5 ppm: 2·10 (1H, t, J = 6·3Hz), 2·41(3H, s), 3· 77 (3H, s), 4·78 (2H, d, 6·3Hz), 5· 07 (2H , s), 6. 32 (1H, dd, J=8· 2, 2· 2Hz), 6. 59 (1H, d, J=2· 2Hz), 6·71 312XP/invention specification (supplement)/ 96-03/95143900 152 200800871 (1H,d,J= 8· 2Έζ),6·96-6· 99(1H,m),7·14-7·17(1H,m), 7.27-7.40(5H , m) ' ' (Reference Example 59 - 1) 2 - (4-Benzyloxy-3-methoxybenzylsulfinyl)_j-bromomethyl- 5-fluoro-3-toluene 5-Fluoro Ethyl 2-iodo-3-methylbenzoate (Reference Example 16-17) (4.0 g), 4-benzyloxy-3-methoxybenzenethiol (Reference Example 19-1) (2· 13g), wheat (dibenzylideneacetone) dipalladium (〇) (792?), (oxy-2'1 extended base) bis(monophenylphosphine) (932mg) 'potassium butoxide ( A mixture of 1.46 g) and toluene (60 mL) was stirred at 4 ° for 4 min. After the reaction mixture was cooled, it was diluted with ethyl acetate, and added to F1〇risil (registered trademark, manufactured by Wako Pure Chemical Industries, Ltd.) (1 〇g), and stirred at room temperature for 丨 hours. This reaction mixture was filtered through a Ceiite (registered trademark) diatomaceous earth layer and washed with vinegar. The filtrate was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by gel column chromatography (eluent: 5% to 20% ethyl acetate/hexane gradient) Elution) gave 2-(4-benzyloxy-3-methoxyphenylsulfinyl)-5-fluoro-3-methylbenzoic acid ethyl ester (2.48 g). Hydrogenation chain (1 〇 5 mg) was added to 2-(4-oxo-1,3-methoxyphenylsulfinyl)-5-fluoro-3-methylbenzoic acid ethyl acetonate at 0C. 9 8 5 mg) and a mixture of tetrahydrotetramine (20 mL). After 20 minutes of incubation at the same temperature, water was added at 〇 °c. This reaction mixture was diluted with diethyl _. This mixture was poured into 2 m 〇 1 /L hydrochloric acid, and the aqueous layer was extracted with a double bond. The organic layer is washed with water, saturated sodium hydrogen carbonate aqueous solution, salt 312XP/invention specification (supplement)/96-03/95143900 153 200800871, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a crude [2-(4-Benzyloxy-3-meroxyphenylsulfinyl)-5-fluoro-3-indenylphenyl]nonanol. Carbon tetrabromide (1·I5g) and triphenylphosphine (9〇9mg) were sequentially added to the crude [2-(4-hydroxy-3-methoxybenzosulfin) at 0 °C. A mixture of fluorenyl)-5-fluoro-3-nonylphenyl]methanol and dichloromethane (2 〇 mL). The mixture was stirred at the same temperature for a few hours and then under reduced pressure.

濃縮溶劑，其殘留物以矽膠管柱色析法進行精製（洗提液：2%至15%醋酸乙酯/己烷之梯度洗提），得目標化合物 (1.〇〇g) ° Η - NMR(CDCh) δ ppm · 2.36(3H, s),3.77(3H,s),4 75 (2H，s)，5· 08 (2H，s)，6· 41(1H，dd，J= 8· 5, 2· 2HZ)，6· 64 (1H，d，J= 2· 2Hz)，6.72 (lH，d，J=8.5Hz)，6.97-6.99 (lH，m)，7.13-7.16(lH，m)，7·27-7·40 (5H，m) (爹考例6 0 - 1 ) φ 3 - (4 -苄氧基-3 -曱氧基苯亞磺醯基）—5 —二氟〗基-4-羥基苯甲腈將3- (4-苄氧基-3-甲氧基苯亞磺醯基）—5-二氟曱基-4 -甲氧曱氧基苯甲腈（628mg)(參考例24 —4)、濃鹽酸（lmL)及四氫呋喃（i〇mL)之混合物在7(rc攪拌整夜。此反應混合物用醋酸乙酯與水進行分液。其有機液層用無水硫酸鎂乾燥，在減壓下進行濃縮，得目標化合物 C417mg) ° 丽R(CDC13) 5 ppm : 3· 85(3H，s)，5· 14(2H，s)，6· 72- 312XP/發明說明書(補件)/96-03/95143900 154 200800871 7. 〇7(4H, m), 7. 29-7. 43(5H, m), 7. 84-7. 86(2H, m) (參考例61 - i) 1 一 [2 - (4 —苄氧基一 3 -甲氧基苯亞磺醯基）一 3, 5一 -一氣本基]乙醇在〇 C下’將甲基氯化鎂（3m〇1/L四氫呋喃溶液、〇. 6mL) 滴加於2 - (4 -苄氧基_3 -曱氧基苯亞磺醯基）—3, 5 一一氟苯曱醛（參考例25 - l)(579mg)及四氫呋喃（l〇mL)之混合物中，在相同溫度下攪拌丨小時。此反應混合物加入飽和氯化銨水溶液（15mL)後用二***萃取。其有機液層用無水硫酸鎂乾燥，在減壓下進行濃縮。其殘留物以矽膠中壓管柱色析法進行精製（洗提液：0%至33%醋酸乙酯/己烷之梯度洗k ) ’得目標化合物（535mg)。 Η - NMRCCDCh) δ ppm ： 1. 41 (3H, d5 J = 6. 4Hz), 2. 03 〇H，d，JUHz)，3.82(3H，S)，5.09(2H，S)，5·45-5·60 (lH，m)，6· 50-6· 60(lH，m)，6·70-6·85(3Η，ιη)，7·20-7·45 • (6H, m) 依與參考例61 - 1相同方法，使用對應之曱酸及烧基鹵化鎂以代替2- (4-苄氧基—3-甲氧基苯亞磺醯基）一 3, 5 - 一氟本曱越及曱基氯化鎂，合成得參考例η — 2〜參考例61 - 3。此等示於表17。 312XP/發明說明書(補件)/96-03/95143900 155 200800871 [表 17]The solvent is concentrated, and the residue is purified by a silica gel column chromatography (eluent: 2% to 15% ethyl acetate / hexane gradient elution) to give the target compound (1. g) ° Η - NMR (CDCh) δ ppm · 2.36 (3H, s), 3.77 (3H, s), 4 75 (2H, s), 5· 08 (2H, s), 6. 41 (1H, dd, J = 8· 5, 2· 2HZ),6· 64 (1H,d,J= 2· 2Hz), 6.72 (lH,d,J=8.5Hz), 6.97-6.99 (lH,m),7.13-7.16(lH,m ),7·27-7·40 (5H,m) (爹考例6 0 - 1 ) φ 3 - (4-Benzyloxy-3-methoxyoxysulfinyl)-5-difluoro 3--4-Butylbenzonitrile 3-(4-Benzyloxy-3-methoxyphenylsulfinyl)-5-difluoroindol-4-methoxyoxetonitrile (628 mg) (Reference Example 24-4), a mixture of concentrated hydrochloric acid (1 mL) and tetrahydrofuran (i〇mL) was stirred overnight at 7 (rc). The reaction mixture was partitioned with ethyl acetate and water. Magnesium is dried and concentrated under reduced pressure to give the title compound C 417 mg) δ R (CDC13) 5 ppm : 3·85 (3H, s), 5·14 (2H, s), 6·72- 312XP/Invention Manual (supplement)/96-03/95143900 154 200800871 7. 〇7(4H, m ), 7. 29-7. 43(5H, m), 7. 84-7. 86(2H, m) (Reference Example 61 - i) 1 -[4 - (4-Benzyloxy-3-methoxy) Benzenesulfinyl)3,5-one-one gas base]ethanol under 〇C's methyl magnesium chloride (3m〇1/L tetrahydrofuran solution, 〇. 6mL) was added dropwise to 2 - (4-benzyloxy) a mixture of 3,5-nonylphenylsulfinyl)-3,5-fluorobenzaldehyde (reference example 25-1) (579 mg) and tetrahydrofuran (10 mL), stirred at the same temperature hour. The reaction mixture was poured into aq. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: gradient elution from 0% to 33% ethyl acetate/hexane) to give the title compound (535 mg). Η - NMRCCDCh) δ ppm : 1. 41 (3H, d5 J = 6. 4Hz), 2. 03 〇H,d,JUHz), 3.82(3H,S),5.09(2H,S),5·45- 5·60 (lH,m),6· 50-6· 60(lH,m),6·70-6·85(3Η,ιη),7·20-7·45 • (6H, m) In the same manner as in Reference Example 61-1, the corresponding citric acid and alkyl halide were used instead of 2-(4-benzyloxy-3-methoxybenzosulfinyl)-3,5-fluorobenzamide. And fluorenyl magnesium chloride, synthesized as reference example η - 2 ~ Reference Example 61 - 3. These are shown in Table 17. 312XP/Invention Manual (supplement)/96-03/95143900 155 200800871 [Table 17]

_ 參考例61 - 2〜參考例61 - 3之物性值係如下示。 (參考例61-2) 'H-NMRCCDCI ) δ ppm :0.95 (3H, t, J=7.3Hz), 1.60-L75 (2H, m), 2.02 (1H, d, 3 4.1Hz), 3.81 (3H, s), 5.10 (2H, s), 5.25-5.35 (1H, m), 6.55-6.60 (1H, m), 6J0-6.85 (3H, m), 7.15-7.25 (1H, m), 7.25-7.45 (5H, m) (參考例61-3) 1H—NMR(CDC13) δ ppm:2.46 (1H，d, J=4.1Hz), 3.78 (3H，s)，5.13 (2H，s)，6.35 (1 H，d, J=4.1Hz), 6.81 -6·83 (3H，m), 7。1卜7.18 (2H, m), 7.23-7·27 (2H，m)，7.30-7.4 3 (9H, m), 7.52-7.54 (1H, m) (參考例62- 1) 1 - [2 -（4 -苄氧基- 3 -曱氧基苯亞磺醯基）- 3, 5 -二氟苯基]乙酮在〇°C下，將三乙胺（(K 922mL)及三氧化硫•吡啶錯合物（632mg)之二曱亞颯（2· 7mL)之混合物依序加入至1 -[2 - (4 -苄氧基—3-甲氧基苯亞磺醯基）-3, 5-二氟苯· 基]乙醇（參考例61 - l)(532mg)及二甲亞颯（5· 3mL)之混 156 312XP/發明說明書(補件)/96-03/95143900 200800871 合物中。此反應混合物在室戸τ % 此占 / 、啦至7皿下攪拌1小時。於反應混合物中加入水（32mL)並攪拌3〇公供 . 、、刀麵。濾取固體，用水（3mL) 洗務5次’在減壓下進行乾择 j轧知，得目標化合物（487mg)。 H-臓（CDC1以卿：2.57(3Hs)，3.83(3h，s)5.i〇 (2H,s), B.T〇-6.80(2H,m),6.85^〇〇(3H mX7 7.45(5H?m) (參考例62 - 2)_ Reference Examples 61 - 2 to Reference Examples 61 - 3 The physical property values are as follows. (Reference Example 61-2) 'H-NMRCCDCI) δ ppm : 0.95 (3H, t, J = 7.3 Hz), 1.60-L75 (2H, m), 2.02 (1H, d, 3 4.1Hz), 3.81 (3H , s), 5.10 (2H, s), 5.25-5.35 (1H, m), 6.55-6.60 (1H, m), 6J0-6.85 (3H, m), 7.15-7.25 (1H, m), 7.25-7.45 (5H, m) (Reference Example 61-3) 1H-NMR (CDC13) δ ppm: 2.46 (1H, d, J = 4.1 Hz), 3.78 (3H, s), 5.13 (2H, s), 6.35 (1) H,d, J=4.1Hz), 6.81 -6·83 (3H,m), 7.1b 7.18 (2H, m), 7.23-7·27 (2H,m), 7.30-7.4 3 (9H, m), 7.52-7.54 (1H, m) (Reference Example 62-1) 1 - [2-(4-Benzyloxy-3-yloxyphenylsulfinyl)-3,5-difluorophenyl Ethyl ketone was added to 1 -[2] in a mixture of triethylamine ((K 922mL) and sulfur trioxide pyridine complex (632mg) of diterpenoid (2.7mL) at 〇 °C. - (4-Benzyloxy-3-methoxybenzylsulfinyl)-3,5-difluorophenyl-yl]ethanol (Reference Example 61-l) (532 mg) and dimethyl sulfoxide (5.3 mL) In the mixture 156 312XP / invention manual (supplement) / 96-03/95143900 200800871. The reaction mixture was stirred at room τ ° % / 到 to 7 liters for 1 hour. Add water to the reaction mixture 32 mL), and the mixture was stirred for 3 ounces, and the surface was removed. The solid was collected by filtration and washed with water (3 mL) for 5 times. The title compound (487 mg) was obtained by dry-drying under reduced pressure. H-臓 (CDC1) Essence: 2.57 (3Hs), 3.83 (3h, s) 5.i〇(2H, s), BT〇-6.80(2H,m), 6.85^〇〇(3H mX7 7.45(5H?m) (Reference example) 62 - 2)

1- [2 - (4 -苄氧基 - 3 - -一氣苯基]丙-1-酉同甲氧基苯亞磺醯基）-3, 5 - ’使用1 - [2 -（4 -苄氧 ’5 - —氣苯基]丙~ 1-醇〜曱氧基苯亞磺醯基）一依與參考例6 2 - 1相同方法基-3 -曱氧基苯亞石黃醯基）—3 代替1 - [ 2 -（ 4 -苄氧基—3 3, 5-二氟苯基]乙醇，合成目標化合物。 - NMR(CDC13) 5 ppm : 1· 18(3H，t，7· 3Hz)，2· 85 (2H, q, 7. 3Hz), 3. 83(3H, s), 5. 11(2Η, s), 6. 70-6. 801-[2-(4-Benzyloxy-3-(1-phenylphenyl)propan-1-indoleoxyphenylsulfinyl)-3,5-' using 1-[2-(4-benzyl) Oxygen '5 - - phenyl phenyl - propyl - 1 - ol - decyloxy sulfinyl sulfhydryl) - the same method as in Reference Example 6 2 - 1 -3 - decyloxy phenylene sulphate) - 3 Synthesis of the target compound by 1-[2-(4-benzyloxy-3 3,5-difluorophenyl)ethanol - NMR (CDC13) 5 ppm : 1· 18 (3H, t, 7·3 Hz), 2 · 85 (2H, q, 7. 3Hz), 3. 83(3H, s), 5. 11(2Η, s), 6. 70-6. 80

(2H，m)，6. 80-6. 95(3H，m)，7. 25-7. 45(5H，m) (參考例63 - 1) (EZ)- 3 - [2 - (4-苄氧基-3一曱氧基苯亞磺醯基）_ 5 -氟- 3 -曱基苯基]丙烯腈在氬氣環境及0°C下，將氫化鈉（6〇%、74mg)加入至氛曱基膦酸二乙酯（327mg)及四氫呋喃（6mL)之混合物中。此混合物在相同溫度下攪拌10分鐘後，加入2 — (4 —节氧基-3 -曱氧基苯亞磺醯基）-3, 5 -二氟苯曱醛（參考例 25- l)(470mg)。將混合物在室溫下攪拌1小時後加入氯 312XP/發明說明書(補件)/96-03/95143900 157 200800871 化銨水溶液。此混合物用醋酸乙酯萃取。有機液層依次以碳酸氫鈉水溶液、食鹽水洗滌，用無水硫酸鎂乾^，在減壓下進行濃縮。其殘留物與甲醇一起進行粉碎f濾取固體’用甲酵洗條’得目標化合物（376mg)。 ^ - NMR(CDCl3) 3 ppm : 2. 40-2· 45(3H，m)，3· 75-3 85 (3H,m), 5.05-5.10(2H,m),5.40-5.80(lH,m),6.3〇_6 4〇 (3H，m)，6· 50-6· 75(2H，m)，7· 05-8· 20(8H，m) (參考例6 4 - 1 ) • [2 - (4-經基-3-曱氧基苯續醢基）苯基]苯甲嗣在室溫下，將三乙胺（2. lmL)及三氧化硫•吡啶錯合物 (1 · 2Og)之二甲亞颯（3祖l)之混合物依序加入至[2 — (4 一苄氧基-3 -曱氧基苯亞磺醯基）苯基]苯甲醇（參考例 61 3)(1. 29g)及一曱亞石風（6mL)之混合物中。此混合物在相同溫度下攪拌2小時後再加入三乙胺（〇 61mL)及三氧化硫· σ比咬錯合物（479mg)。此混合物在室溫攪拌2小時， _在60°C攪拌2小時後，在室溫下加入水（3〇mL)，用醋酸乙醋（80mL)稀釋。分離之有機相依次以2m〇i/L鹽酸、水、飽和;5反酸虱鈉水溶液、食鹽水洗滌，用無水硫酸鎂乾燥，在減壓下進行濃縮，得粗製之[2- (4 —苄氧基—3 —曱氧基苯亞磺醯基）苯基]苯曱酮。在冰浴攪拌下，將過氧間苯曱醯氯（2· 4g)加入至粗製之 [2 - (4-苄氧基—3 —曱氧基笨亞磺醯基）苯基]苯甲酮及一氯曱烧（30mL)之混合物中。將混合物在室溫下攪拌小時。於混合物中加入2〇%亞硫酸氫鈉水溶液（5mL)、 312XP/發明說明書(補件)/96_〇3/95143900 158 200800871 2mol/L氫氧化鈉水溶液（30mL)及醋酸乙酯（i〇〇mL)。分離之有機液層依次以2mo 1 /L氫氧化鈉水溶液、飽和碳酸氫鈉水溶液、食鹽水洗滌，在減壓下進行濃縮。其殘留物與甲醇一起進行粉碎，濾取固體，得[2 - (4 -苄氧基-3 -甲氧基苯磺醯基）苯基]苯曱酮（955mg)。在冰冷攪拌下，將四氣化鈦（〇· 34mL)加入至[2 - (4 一节氧基-3 -甲氧基苯磺醯基）苯基]苯甲酮（955mg)及二氯 _曱烷（15mL)之混合物中，在相同溫度下攪拌15分鐘。於合物中加入2mol/L鹽酸（15mL)及醋酸乙酯（70mL)。分难有機液層依次以水、飽和碳酸氫鈉水溶液、食鹽水洗滌，用無水硫酸鎂乾燥，在減壓下進行濃縮，其殘留物以石夕膠官柱色析法進行精製（洗提液：由己烷至3〇%至7〇% 醋酸乙酯-己烷之梯度洗提），得目標化合物（773mg)。 NMR(CDCl3)(5ppm : 4.00(3H，s)，6.04(1H，s)，6.97 (lH，d’J = 8·6Ηζ)，7·27 - 7·30(1Η，πι)，7·43 — 7·63(7Η，πι)， _ 7· 78-7· 80(2H，m)，8· 09-8· 12(lH，m) (參考例6 5 - 1) 2 -（4 -苄氧基-3 -甲氧基苯亞磺醯基3, 5_二氟苯曱酸將2- (4-苄氧基-3-曱氧基苯亞磺醯基）_3,5_二氟苯曱醛（芩考例25 - l)(3g) '過氧硼酸鈉4水合物 (4.18g)及醋酸（i5、5mL)之混合物在49艽攪拌n小時。此反應混合物待冷卻至室溫後加入水（6511^)。此混合物用醋酸乙酯萃取2次，其有機液層依次以lm〇1/L硫代硫酸 312XP/發明說明書(補件)/96·03/95143900 159 200800871 鈉水&液、水洗滌3次，用無水硫酸鈉乾燥，在減壓下進行濃縮，得目標化合物（3· 25g)。 H- _(CDC13) (5 ppm : 3· 92(3H，s)，5· 17(2H，s)，6· 90-6_95(1Η，π〇，7·00 — 7·15(2Η，ιη)，7·25-7·45(6Η，πι)，7·60 — 7· 75(1H，m) (參考例66 - 1 )(2H,m), 6. 80-6. 95(3H,m), 7. 25-7. 45(5H,m) (Reference Example 63 - 1) (EZ)- 3 - [2 - (4- Benzyloxy-3-monooxyphenylsulfinyl) 5-fluoro-3-indolylphenyl]acrylonitrile sodium hydride (6〇%, 74mg) was added under argon atmosphere at 0 °C To a mixture of diethyl decylphosphonate (327 mg) and tetrahydrofuran (6 mL). After the mixture was stirred at the same temperature for 10 minutes, 2-(4-hydroxy-3-oxaoxysulfinyl)-3,5-difluorobenzofural (Reference Example 25-l) was added (Reference Example 25-l) ( 470mg). After the mixture was stirred at room temperature for 1 hour, an aqueous solution of ammonium chloride was added to the chlorine 312XP/invention specification (supplement)/96-03/95143900 157 200800871. This mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous solution of sodium hydrogencarbonate and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was pulverized with methanol, and the solid was removed by the residue to give the title compound (376 mg). ^ - NMR (CDCl3) 3 ppm : 2. 40-2· 45(3H,m),3·75-3 85 (3H,m), 5.05-5.10(2H,m),5.40-5.80 (lH,m ), 6.3〇_6 4〇(3H,m),6· 50-6· 75(2H,m),7· 05-8· 20(8H,m) (Reference Example 6 4 - 1 ) • [2 - (4-carbyl-3-indolylbenzene sulfhydryl)phenyl]benzhydrazide triethylamine (2.1 mL) and sulfur trioxide pyridine complex (1 · 2Og) at room temperature a mixture of dimethyl sulfoxide (3 祖) is added to [2-(4-benzyloxy-3-indolyl sulfinyl) phenyl] benzyl alcohol (Reference Example 6 3) ( 1. 29g) and a mixture of sulphur (6mL). This mixture was stirred at the same temperature for 2 hours, and then triethylamine (〇61 mL) and sulfur trioxide-σ ratio (479 mg) were added. This mixture was stirred at room temperature for 2 hours, and after stirring at 60 ° C for 2 hours, water (3 mL) was added at room temperature and diluted with ethyl acetate (80 mL). The separated organic phase was washed successively with 2 m 〇i / L hydrochloric acid, water, saturated; 5 aqueous sodium citrate aqueous solution, brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give crude [2- (4 - Benzyloxy-3-methoxybenzylsulfinyl)phenyl]benzophenone. Adding peroxyisophthalic chloride (2.4 g) to the crude [2-(4-benzyloxy-3-pyridyloxysulfinyl)phenyl]benzophenone under stirring in an ice bath And a mixture of monochloropyrene (30 mL). The mixture was stirred at room temperature for an hour. 2% aqueous sodium hydrogen sulfite solution (5 mL), 312XP/invention specification (supplement)/96_〇3/95143900 158 200800871 2mol/L sodium hydroxide aqueous solution (30mL) and ethyl acetate (i〇) 〇mL). The separated organic liquid layer was washed successively with a 2 mol / L aqueous sodium hydroxide solution, a saturated aqueous sodium hydrogen carbonate solution and brine, and concentrated under reduced pressure. The residue was pulverized with methanol, and the solid was filtered to give [2-(4-benzyloxy-3-methoxyphenylsulfonyl)phenyl]benzophenone (955 mg). Titanium tetraoxide (〇·34 mL) was added to [2-(4-oxo-3-methoxybenzosulfonyl)phenyl]benzophenone (955 mg) and dichloro- _ with stirring under ice-cooling A mixture of decane (15 mL) was stirred at the same temperature for 15 minutes. 2 mol/L hydrochloric acid (15 mL) and ethyl acetate (70 mL) were added to the mixture. The organic layer was washed with water, a saturated aqueous solution of sodium hydrogencarbonate and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure, and the residue was purified by chromatography. : eluted with a gradient of hexane to 3% to 7% by ethyl acetate-hexane to give the title compound (773 mg). NMR (CDCl3) (5 ppm: 4.00 (3H, s), 6.04 (1H, s), 6.97 (lH, d'J = 8.6 Ηζ), 7·27 - 7·30 (1 Η, πι), 7·43 — 7·63(7Η,πι), _ 7· 78-7· 80(2H,m),8· 09-8· 12(lH,m) (Reference Example 6 5 - 1) 2 -(4-Benzyl Oxy-3-methoxyphenylsulfinyl 3,5-difluorobenzoic acid 2-(4-benzyloxy-3-decyloxysulfinyl)_3,5-difluorobenzene Furfural (Reference Example 25 - 1) (3g) A mixture of sodium peroxodisulfate 4 hydrate (4.18g) and acetic acid (i5, 5mL) was stirred at 49 Torr for n hours. After the reaction mixture was cooled to room temperature Water (6511^) was added. The mixture was extracted twice with ethyl acetate, and the organic layer was successively taken as lm〇1/L thiosulfate 312XP/invention specification (supplement)/96·03/95143900 159 200800871 sodium water & Washing with water and water for 3 times, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (3·25 g) H- _(CDC13) (5 ppm : 3 · 92 (3H, s), 5 · 17(2H,s),6·90-6_95(1Η,π〇,7·00 — 7·15(2Η,ιη), 7·25-7·45(6Η,πι),7·60 — 7 · 75(1H,m) (Reference Example 66 - 1)

1 一 [5-氟- 2 -（4-羥基-3-曱氧基苯磺醯基）一3一曱基苯基]乙酉同在室溫攪拌下，將過氧間苯曱醯氯（1· 158g)加入至1 -[2一（4-苄氧基-3-甲氧基苯亞磺醯基）一5一氟-3一甲基笨基]乙酮（參考例26 — 2)(532mg)及二氯曱烷（2〇mL) 之此合物中並攪拌整夜。將反應混合物通過胺丙基石夕膠過慮’再用二氣曱烧洗提。濾液在減壓下進行濃縮，得粗製之1- [2 -（4-苄氧基一 3-曱氧基苯磺醯基）-5 一氟一 3-曱基苯基]乙酮。馨在至溫攪拌下，將四氯化鈦（50 9mg)加入至粗製之1 — [2 -（4 -苄氧基一 3 -甲氧基苯磺醯基）—5 一氟一 3 —曱基本基]乙酮及二氣甲烧（2〇mL)之混合物中，在室溫下攪拌10分鐘。於反應混合物加入lm〇l/L鹽酸，分取有機液層，用無水硫酸鎂乾燥，在減壓下進行濃縮。其殘留物以矽膠管柱色析法進行精製（洗提液：己烷/醋酸乙酯= 1 /1) ’得目標化合物（2 9 8mg )。 NMRCCDCls) ά ppm ： 2. 53(3H, s), 2. 72(3H, s), 3. 97 (3H，s)， 6· 80(1H，dd，J = 7· 6, 2· 5Hz), 6· 95(1H，dd，J = 312XP/發明說明書(補件)/96-03/95143900 160 200800871 B. 8,2.5Hz), 7. 〇〇 = 8. 2Hz), 7. 54( 1H, d, J = 1· 9Hz)，7. 60(1H，dd，8· 3, 2· 1Hz) 依與參考例48- 1相同方法’使用對應之二苯硫以代替 1 — [2_ (4_苄氧基—3 —甲氧基苯亞磺醯基）_ 5_氟— 3-甲基笨基]乙酮，合成得參考例66_ 2〜參考例⑽― 5。此等示於表18。「矣 ΙΟΊ L衣i δ」參考例構造式參考例構造式 • 66-1 66- 4 66-2 〇、 &δ-5 〇、 66-3 參考例66 - 2〜參考例66 - 5之物性值係如下示。 φ (參考例66-2) 'H-NMRCCDCO δ ppm: 1.81 (6H, s), 2.39 (3H, s), 3.91 (3H, s), 6.10 (1H, s), 6.17 (1H, s), 6.86-6.88 (1H, m), 6,96 (1H, d, J=8e5Hz), 7.19-7.22 (1H, in), 7.43 (l.H, dd ,J=8.5, 2.2Hz), 7.55 (1H, d, J=2.2Hz) (參考例66-3) "H-NMRiCDCl) δ ppm:2.61-2.69 (3H, m), 3.96 (3H, s), 6.79 (1H, t, J=54〇4Hz), 3 7.05 (1H, d, J=8.5Hz), 7.32 (1H, d, J=2.2Hz), 7.45 (1H, dd, J=8.4, 2.1Hz), 8.01-8.0 5 (1H, m), 8.49-8.53 (1H, m) (參考例66 - 4) 161 312XP/發明說明書(補件)/96-〇3/95143900 200800871 ^-NMRiCDCl) δ ppm:2.05-2.14 (2H? m), 2.64-2.72 (2H, m), 2.88-2.96 (2H, m), 3 3.94-3〇99 (3H, m), 6.90-6.97 (1H, m), 7.38-7.43 (1H, m), 7.47-7.53 (1H, m)5 7.57 -7.69 (2H，m)，8.28-8.34 (1H, m) (參考例66-5) 'H-NMRCCDCO δ ppm:2.50-2.70 (3H, m),3e90-4.00 (3H, m), 5.45-5〇65 (1H, m), 6.05-6.15 (1H, m), 6.90-7.45 (4H, m), 8.15-8.50 (1H, m) (參考例67-1) 4 -（4-氟-2-曱氧甲基- 6 -甲基苯磺醯基）一2一甲氧基酚在鼠氣私丨兄及0C下’將氣化納（6〇%、46mg)加入至[2 - (4-苄氧基- 3-甲氧基苯亞磺醯基）—5 一氟—3-甲基苯基]曱醇（簽考例58 - l)(40〇mg)及N，N -二甲基甲醯胺 (5mL)之混合物中。在相同溫度下攪拌1〇分鐘後，在室溫下加入碘化曱基（〇. 19mL)，並在室溫下攪拌3小時。此反應混合物加入水（5mL)，再用醋酸乙酯萃取。分離之有機液層依次以水、飽和碳酸氫鈉水溶液、食鹽水洗滌，用無 _水硫酸鎂乾燥。在減壓下進行濃縮，得粗製之2- (4 一苄氧基-3 -甲氧基苯亞磺醯基）—5 —氟—丨-曱氧甲基一 3 -甲苯。土在0 C下，將過氧間苯甲醯氯（丨· lg)加入至粗製之2 一 (4 -苄氧基-3 -甲氧苯基亞磺醯基）—5_氟一 i 一曱氧甲基-3-甲苯及二氯甲烷（1〇mL)之混合物中並攪拌12 小時。此反應混合物用醋酸乙酯與2m〇1/L氫氧化鈉水溶液進行分液，其有機液層依次以飽和碳酸氫鈉水溶液、食鹽水洗滌，用無水硫酸鎂乾燥，在減壓下進行濃縮，得粗 312XP/發明說明書(補件)/96-03/95143900 162 200800871 製之2 -（4 -苄氧基-3-甲氧基苯磺醯基）一5-氣一 i-曱氧甲基- 3 -曱苯。在〇°C下，將四氯化鈦（170mg)加入至粗製之(4 一节氧基- 3-甲氧基苯石黃酿基5一氟- 1—甲氧曱基一 3_ 曱苯及二氯甲烷（l〇mL)之混合物中，並攪拌15分鐘。於反應混合物中加入2mol/L鹽酸，再用醋酸乙酯萃取。其有機液層依次以飽和碳酸氫納水溶液、食鹽水洗務，用無水硫酸鎂乾燥。在減壓下進行濃縮，其殘留物以矽膠管柱鲁色析法進行精製（洗提液：10%至50%醋酸乙酯/己烧之梯度洗提），得目標化合物（322mg)。沱-丽R(CDC13) (5 ppm : 2· 53(3H，s)，3· 48(3H，s)，3· 93 (3H，s)，4· 99 2H，s)，6.02(lH，S)，6.87-6·89(1Η，ιη)，6·96 (1H，d，8· 5Hz)，7· 27(1H，dd，J = 8· 5, 2· 2Hz)，7· 39- 7· 42(1H,m) (參考例68 - 1) 拳 [5 -氟-2 -（4-羥基-3-曱氧基苯磺醯基）一 3一曱基苯基]乙腈在室溫下，將氰化鉀（36 Omg)加入至2 - (4 -节氧基-3 -曱氧基苯亞石黃酸基）-1 一溴甲基一 5 —氟一 3 一曱苯 (參考例59 - l)(449mg)、乙醇（l〇mL)、水（lmL)及二曱亞砜（5mL)之混合物中。此混合物在80艺攪拌3小時。於混合物加入水後用醋酸乙酯萃取。其有機液層依次以水、食鹽水洗蘇’用無水硫酸鎮乾餘。在減壓下進行濃縮，得粗製之2 -（4-苄氧基一 3-甲氧基苯亞磺醯基）一 5 一氟一 312XP/發明說明書(補件)/96-03/95143900 163 200800871 3-曱基苯基]乙腈。在〇°c下，將過氧間苯曱醯氯（67〇mg)加入至粗製之2一 (4苄氧基3甲氧苯基亞石黃酿基）-5 -氟-3-甲基笨基]乙腈及一氯甲烧（gmL)之混合物中後，在室溫下攪拌 12小時。將反應混合物於醋酸乙酯與2m〇1/L氫氧化鈉水 /合液之間進行分液，其有機液層依次以飽和碳酸氫鈉水溶液、食鹽水洗滌，用無水硫酸鎂乾燥，在減壓得粗製之2- U-节氧基-3—甲氧基苯續酿基丁): 響默-3-甲基苯基]乙腈。在Ot：下，將四氯化鈦（286mg)加入至粗製之2 — (4—苄氧基-3 -甲氧基苯磺醯基5—氟_3_甲基苯基]乙腈及二氯甲烷（10mL)之混合物中，並攪拌15分鐘。於反應混合物中加入2mol/l鹽酸，再用醋酸乙酯萃取。其有機液層依次以飽和碳酸氫鈉水溶液、食鹽水洗滌，用無水硫酸鎂乾燥。在減壓下進行濃縮，其殘留物以矽膠管柱色^ •法進行精製（洗提液：15%至45%醋酸乙酯/己烷之梯度洗提）’得目標化合物（277mg)。 Η -麵（CDC13) 6 ppm : 2· 54(3H，s), 3· 94(3H，s)，4. 44 (2H, s), 6. 08(1 Η, s), 6. 98-7. 01(2Η, m), 7. 22-7. 24 UH, m)，7· 36(1Η，dd，I = 8· 5, 2· 2Hz)，7· 4G(1H，d，J = 2.2Hz) (參考例69 - 1) 5 -氟- 2 -（4 _羥基- 3 -甲氧基苯磺醯基）一 3 一甲基苯曱酸甲酯 312ΧΡ/發明說明書(補件)/96-03/95143900 164 200800871 在氩氣環境及室溫擾拌下，將4 -节氧基-3 -甲氧基苯硫醇（參考例19- l)(4.43g)及第三丁醇鉀（3 03g)依次加入至5 -氟-2 -碘-3 -甲基苯曱酸乙酯（參考例u -17)(8.31g)、參（二苯亞甲基丙酮）二|巴（〇)(165g)、（氧基二-2，1-伸苯基）雙（二苯基膦）（1· 94g)及曱苯（6〇mL) 之混合物中。此混合物在10(rc攪拌丨小時。將反應混合物待冷卻後用醋酸乙酯稀釋，加入F1〇risil(註冊商標、和光純藥製）（15g)，在室溫下攪拌丨小時。將反應混合物通過Ce 1 i te (注冊商標）石夕藻土層過滤，用醋酸乙酯洗提。濾液以食鹽水洗滌，用無水硫酸鎂乾燥，在減壓下進行濃縮。其殘留物以矽膠管柱色析法進行精製（洗提液：3%至 15%醋酸乙酯/己烷之梯度洗提），得2 — (4 -节氧基—3- 曱氧基苯亞磺醯基）-5 -氟-3 -甲基苯甲酸乙酯 (5.42g)。在室溫下，將2 _ (4 -苄氧基-3 -曱氧基苯亞磺醯籲基）- 5 -氟-3-曱基苯甲酸乙醋（5· 42g)、2mol/L氫氧化鈉水溶液（20mL)、1，4-二嘮烷（60mL)及曱醇（20mL)之混合物攪拌6小時。於反應混合物加入醋酸乙酯及2mo 1 /l 鹽酸。分取之有機液層依次以水、食鹽水洗滌2次，用益水硫酸鎂乾燥後在減壓下進行濃縮，得粗製之2 - (4 -节氧基-3 -甲氧基苯亞磺醯基）-5 -氟-3-甲基苯甲酸。在室溫下，將碳酸鉀（323mg)及碘化曱基（(K22mL)依序加入至粗製之2 - (4 -十氧基-3 -曱氧基苯亞續酿基）— 5 -氟-3-甲基苯甲酸及N，N -二曱基曱蕴胺（5mL)之混 312XP/發明說明書(補件)/96-03/95143900 165 200800871 合物中’並在相同溫度下授拌2小時。於反應混合物加入 2m:l/L鹽酸’再用醋酸乙酯萃取。將有機液層依次以碳酸氫鈉水/合液、食鹽水洗務，用無水硫酸鎮乾燥後，在減壓下進行濃縮’得粗製之2-(4-节氧基—3—甲氧基苯亞磺醯基)—5 —氟—3 —曱基苯甲酸甲酯。在0^下，將過氧間苯甲醯氣（930mg)加入至粗製之2一 -苄氧基- 3 -曱氧基苯亞磺醯基）—5 一氟—3 一曱基馨苯甲酸甲醋及二氯曱烧（1〇mL)之混合物中後，在室溫下擾拌5小％。加入2m〇i/L氫氧化鈉水溶液及醋酸乙酯。此 /心合物用醋酸乙酯與水進行分液，其有機液層依次以飽和碳酸氫鈉水溶液、食鹽水洗滌，用無水硫酸鎂乾燥，在減壓下進行濃縮，得粗製之2 — (4_苄氧基—3_曱氧基苯磺醯基）-5 -氟-3 -曱基苯曱酸曱酯。在冰浴攪拌下，將四氯化鈦（333mg)加入至粗製之2 一 (4-苄氧基- 3-甲氧基苯磺醯基）一 5一氟_ 3一甲基苯 _曱酸甲醋及二氯曱烧（l〇mL)之混合物中，並攪拌15分鐘。此反應混合物在冰浴攪拌下注入冰水中後，用二氯甲烧稀釋。分離之有機液層依次以2mol/L鹽酸、食鹽水洗務’用热水硫酸錤乾燥。在減壓下進行濃縮，其殘留物以石夕膠管柱色析法進行精製（洗提液：30%至35%醋酸乙酯/ 己烧之梯度洗提），得目標化合物（341mg)。 'H - NMR(CDCh) d ppm ： 2. 51(3H? s)5 3. 96(3H, s), 4. 01 (3H, s), 6. 05( 1H, s), 6. 98-7. 01 (3H, m), 7. 64( 1H? dd, J-8·2,2·2Ηζ)，7.67(lH，d，J=2.2Hz) 312XP/發明說明書(補件)/96-03/95143900 166 200800871 (參考例70 - 1) 3，5 -二氟-2 -（4 -羥基-3 -甲氧基苯石黃基）苯甲酸在氳氣環境及室溫下，將2 - (4 -苄氧基-3-甲氧基本石黃醯基）-3, 5 -二氟苯曱酸苄醋（參考例25 一 5)(686mg)、10%把石炭（I40mg、含水量50%)及二氯曱燒/醋酸乙酯=1/1混合溶液（26mL)之混合物攪拌2小時。過淚此反應混合物以去除不溶物後，將濾液在減壓下進行濃 ⑩、纟佰。殘留物以一氯曱烧/己烧=2 /1混合溶液（9 mL )粉碎，其固體用己烷過濾後以二氯曱烷/己烷=1/1混合溶液 (3mL)洗滌5次，得目標化合物（412mg)。 -丽R(DMS0 - de) 6 ppm : 3· 81(3H，s)，6· 95-7· 05(lH，m)， 7· 35-7. 65(4H，m)，10· 48(1H，s)，14. 08(1H，br) (參考例71 - 1) 4 -（2 -苄基苯石黃醯基）-2 -曱氧基紛鲁在氫氣私境及室溫下’將[2 - (4 -节氧基-3 -甲氧基本石頁基）本基]苯基甲醇（參考例61 - 3) (600mg)、1 〇%把碳（300mg、含水量50%)及醋酸乙酯（15mL)之混合物授拌 14小時。將反應混合物通過Celite(註冊商標）矽藻土層過濾，在減壓下進行濃縮，得目標化合物（442mg)。 4 -丽R(CDC13) (5 ppm : 3· 83(3H，s)，4· 35(2H，s)，5· 99 (1H，s)，6· 88 -6· 92(3H，m)，7· 07-7· 20(4H，m)，7· 30-7· 47 (4H，m)，8· 19-8· 21(1H，m) (參考例72- 1) 312XP/發明說明書(補件)/96-03/95143900 167 2008008711-[5-Fluoro-2-(4-hydroxy-3-indolylbenzenesulfonyl)- 3-indolylphenyl]acetamidine with peroxyisoprene chloride at room temperature with stirring · 158g) was added to 1-[2-(4-benzyloxy-3-methoxyphenylsulfinyl)-5-fluoro-3-methylphenyl]ethanone (Reference Example 26-2) This mixture of 532 mg) and dichloromethane (2 mL) was stirred overnight. The reaction mixture was passed through an amine propyl sulfonate and then eluted with a second gas. The filtrate was concentrated under reduced pressure to give 1-[2-(4-benzyloxy-3-trimethoxyoxysulfonyl)-5-fluoro-3-indolylphenyl]ethanone as crude. Titanium tetrachloride (50 9 mg) was added to the crude 1-[2-(4-benzyloxy-3-methoxyphenylsulfonyl)-5-fluoro-3-inium under gentle stirring. The mixture of the basic group] ethyl ketone and the two gas (2 〇 mL) was stirred at room temperature for 10 minutes. The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (eluent: hexane / ethyl acetate = 1 / 1) to give the title compound (2 9 8 mg). NMRCCDCls) ά ppm : 2. 53(3H, s), 2. 72(3H, s), 3. 97 (3H, s), 6· 80 (1H, dd, J = 7· 6, 2· 5Hz) , 6· 95 (1H, dd, J = 312XP / invention manual (supplement) / 96-03/95143900 160 200800871 B. 8,2.5Hz), 7. 〇〇 = 8. 2Hz), 7. 54 ( 1H , d, J = 1· 9 Hz), 7. 60 (1H, dd, 8·3, 2·1 Hz) In the same way as in Reference Example 48-1, 'the corresponding diphenyl sulphur was used instead of 1 — [2_ (4 _Benzyloxy-3-methoxybenzylsulfinyl)-5-fluoro-3-methylphenyl]ethanone was synthesized in Reference Example 66_2 to Reference Example (10)-5. These are shown in Table 18. "矣ΙΟΊ L衣i δ" Reference example Structural formula Reference example Structure • 66-1 66- 4 66-2 〇, & δ-5 〇, 66-3 Reference Example 66 - 2 to Reference Example 66 - 5 The physical property values are as follows. φ (Reference Example 66-2) 'H-NMRCCDCO δ ppm: 1.81 (6H, s), 2.39 (3H, s), 3.91 (3H, s), 6.10 (1H, s), 6.17 (1H, s), 6.86-6.88 (1H, m), 6,96 (1H, d, J=8e5Hz), 7.19-7.22 (1H, in), 7.43 (lH, dd, J=8.5, 2.2Hz), 7.55 (1H, d , J=2.2Hz) (Reference Example 66-3) "H-NMRiCDCl) δ ppm: 2.61-2.69 (3H, m), 3.96 (3H, s), 6.79 (1H, t, J=54〇4Hz) , 3 7.05 (1H, d, J=8.5Hz), 7.32 (1H, d, J=2.2Hz), 7.45 (1H, dd, J=8.4, 2.1Hz), 8.01-8.0 5 (1H, m), 8.49-8.53 (1H, m) (Reference Example 66 - 4) 161 312XP/Invention Manual (supplement)/96-〇3/95143900 200800871 ^-NMRiCDCl) δ ppm: 2.05-2.14 (2H? m), 2.64- 2.72 (2H, m), 2.88-2.96 (2H, m), 3 3.94-3〇99 (3H, m), 6.90-6.97 (1H, m), 7.38-7.43 (1H, m), 7.47-7.53 ( 1H, m)5 7.57 -7.69 (2H,m), 8.28-8.34 (1H, m) (Reference Example 66-5) 'H-NMRCCDCO δ ppm: 2.50-2.70 (3H, m), 3e90-4.00 (3H , m), 5.45-5〇65 (1H, m), 6.05-6.15 (1H, m), 6.90-7.45 (4H, m), 8.15-8.50 (1H, m) (Reference Example 67-1) 4 - (4-Fluoro-2-indolylmethyl-6-methylphenylsulfonyl)-2-methoxyphene will be gasified in the mouse and 0C (6〇%) , 46 mg) was added to [2-(4-benzyloxy-3-methoxyphenylsulfinyl)-5-fluoro-3-methylphenyl]nonanol (Signature 58-l) (40) 〇mg) and a mixture of N,N-dimethylformamide (5mL). After stirring at the same temperature for 1 minute, cesium iodide (〇.19 mL) was added at room temperature, and stirred at room temperature for 3 hours. This reaction mixture was added to water (5 mL) and then ethyl acetate. The separated organic layer was washed with water, a saturated aqueous sodium hydrogen carbonate solution and brine, and dried over anhydrous magnesium sulfate. Concentration under reduced pressure gave crude 2-(4-benzyloxy-3-methoxyphenylsulfinyl)-5-fluoro-indole-indoleoxymethyl-3-toluene. At 0 C, the peroxymetabenzyl chloride (丨· lg) was added to the crude 2-(4-benzyloxy-3-methoxyphenylsulfinyl)-5-fluoro-i- A mixture of methoxymethyl-3-toluene and dichloromethane (1 mL) was stirred for 12 hours. The reaction mixture was separated with ethyl acetate and aq. EtOAc EtOAc.粗粗312XP/Invention Manual (Supplement)/96-03/95143900 162 200800871 Manufactured by 2-(4-benzyloxy-3-methoxyphenylsulfonyl)-5-a-i-anthoxymethyl - 3 - Benzene. Titanium tetrachloride (170 mg) was added to the crude (4 methoxy-3-methoxybenzolate 7-fluoro-1-methoxyindol-3-phenylene) at 〇 ° C Dichloromethane (10 mL) was stirred for 15 minutes. 2 mol/L hydrochloric acid was added to the reaction mixture, and then extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate and brine. It is dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue is purified by gel column chromatography (eluent: 10% to 50% ethyl acetate / hexane gradient). Compound (322 mg). 沱-Li R (CDC13) (5 ppm : 2· 53 (3H, s), 3·48 (3H, s), 3·93 (3H, s), 4·99 2H, s) , 6.02 (lH, S), 6.87-6·89 (1Η, ιη), 6.96 (1H, d, 8·5Hz), 7·27 (1H, dd, J = 8· 5, 2· 2Hz) ,7· 39- 7· 42(1H,m) (Reference Example 68 - 1) Boxing [5-Fluoro-2 -(4-hydroxy-3-indolylbenzenesulfonyl)- 3-indenylphenyl ] Acetonitrile Potassium cyanide (36 Omg) was added to 2-(4-oxo-3-oxophthalyl phthalate)-1 monobromomethyl-5-fluoro-3 at room temperatureTo a mixture of toluene (Ref. 59-l) (449 mg), ethanol (10 mL), water (1 mL) and disulfoxide (5 mL). This mixture was stirred at 80 ° for 3 hours. The mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried with anhydrous sulfuric acid. The residue was concentrated under reduced pressure to give crude 2-(4-benzyloxy- 3-methoxybenzene. Sulfosulfonyl)-5-fluoro-312XP/invention specification (supplement)/96-03/95143900 163 200800871 3-mercaptophenyl]acetonitrile. Peroxy-p-benzoquinone chloride at 〇°c 67〇mg) was added to a mixture of crude 2-(4-benzyloxy-3methoxyphenyl sulfite)-5-fluoro-3-methylphenyl]acetonitrile and monochloromethane (gmL). After stirring at room temperature for 12 hours, the reaction mixture was partitioned between ethyl acetate and 2 m〇l/L sodium hydroxide water/liquid mixture, and the organic layer was successively saturated aqueous sodium hydrogen carbonate solution and brine. After washing, it was dried over anhydrous magnesium sulfate and evaporated to dryness toield. Titanium tetrachloride (286 mg) was added to the crude 2-(4-benzyloxy-3-methoxybenzenesulfonyl 5-fluoro-3-methylphenyl)acetonitrile and dichloride under Ot: The mixture was stirred for 15 minutes with methylene chloride (10 mL). Drying. Concentration under reduced pressure, the residue was purified by column chromatography (eluent: 15% to 45% ethyl acetate/hexane gradient elution) to give the title compound (277 mg) Η-面(CDC13) 6 ppm : 2· 54(3H, s), 3· 94(3H, s), 4. 44 (2H, s), 6. 08(1 Η, s), 6. 98 -7. 01(2Η, m), 7. 22-7. 24 UH, m), 7· 36 (1Η, dd, I = 8· 5, 2· 2Hz), 7·4G (1H, d, J = 2.2Hz) (Reference Example 69 - 1) 5-Fluoro-2 -(4 _hydroxy-3-methoxyphenylsulfonyl)-methyl 3-methylbenzoate 312ΧΡ/Invention Manual (supplement) /96-03/95143900 164 200800871 4-aroxy-3-methoxybenzenethiol (Ref. 19-l) (4.43g) under argon and room temperature Potassium tert-butoxide (3 03 g) was sequentially added to ethyl 5-fluoro-2-iodo-3-methylbenzoate (Reference Example u-17) (8.31 g), ginseng (diphenylmethyleneacetone) A mixture of bis(barium) (165 g), (oxydi-2,1-phenylene)bis(diphenylphosphine) (1.99 g) and toluene (6 〇mL). The mixture was stirred for 10 hours at rc. After the reaction mixture was cooled, it was diluted with ethyl acetate, and then added to F1〇risil (registered trademark, manufactured by Wako Pure Chemical Industries, Ltd.) (15 g), and stirred at room temperature for a few hours. The mixture was filtered through Celite, and washed with ethyl acetate. The filtrate was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Purification by analytical method (eluent: 3% to 15% ethyl acetate / hexane gradient elution) to give 2-(4-hydroxy-3-trimethoxyphenylsulfinyl)-5- Ethyl fluoro-3-methylbenzoate (5.42 g). 2 _(4-Benzyloxy-3-methoxyoxysulfinyl) 5-fluoro-3-indole at room temperature A mixture of ethyl benzoic acid ethyl acetate (5·42 g), 2 mol/L aqueous sodium hydroxide solution (20 mL), 1,4-dioxane (60 mL) and decyl alcohol (20 mL) was stirred for 6 hours. Ester and 2mo 1 /l hydrochloric acid. The organic layer was separated twice with water and brine, dried with magnesium sulfate and concentrated under reduced pressure to give a crude 2-(4-ethoxy) -3 -Methoxybenzylsulfinyl)-5-fluoro-3-methylbenzoic acid. Potassium carbonate (323 mg) and sulfonium iodide (K22 mL) were added sequentially to the crude at room temperature. 2 - (4 - decaoxy-3 - decyloxyphenyl hydrazide) - 5 - fluoro-3-methylbenzoic acid and N, N - dimercaptopurine (5mL) mixed 312XP / invention In the specification (supplement)/96-03/95143900 165 200800871, the mixture was stirred for 2 hours at the same temperature. 2 m: l/L hydrochloric acid was added to the reaction mixture and extracted with ethyl acetate. Washing with sodium bicarbonate water/liquid mixture, brine, drying with anhydrous sulfuric acid, and then concentrating under reduced pressure to obtain crude 2-(4-ethoxy-3-methoxybenzylsulfinyl) -5 - Methyl fluoro-3-indenyl benzoate. Peroxybenzhydrazide (930 mg) was added to the crude 2-monobenzyloxy-3-methoxy sulfinium sulfonate at 0 ° After the mixture of 5-fluoro-3-mercaptobenzoic acid methyl vinegar and dichlorohydrazine (1 〇 mL), 5 5% of the mixture was stirred at room temperature. 2 m 〇i / L sodium hydroxide was added. Aqueous solution and ethyl acetate. This / core compound is separated with ethyl acetate and water. The organic layer was washed successively with a saturated aqueous solution of sodium hydrogencarbonate and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a crude 2-(4-benzyloxy-3- decyloxybenzenesulfonyl) -5-fluoro-3-mercaptobenzoic acid decyl ester. Titanium tetrachloride (333 mg) was added to the crude 2-(4-benzyloxy-3-methoxybenzenesulfonate) under stirring in an ice bath. Amid. a mixture of 5-fluorobenzene-3-methylbenzene-methyl citrate and dichlorohydrazine (10 mL) and stirred for 15 minutes. The reaction mixture was poured into ice water with stirring in an ice bath, and then diluted with methylene chloride. The separated organic liquid layer was washed successively with 2 mol/L hydrochloric acid and brine, and dried with hot water barium sulfate. Concentration under reduced pressure, and the residue was purified by chromatography eluting with EtOAc (EtOAc: EtOAc: EtOAc) 'H-NMR (CDCh) d ppm : 2. 51(3H? s)5 3. 96(3H, s), 4. 01 (3H, s), 6. 05( 1H, s), 6. 98- 7. 01 (3H, m), 7. 64 ( 1H? dd, J-8·2, 2·2Ηζ), 7.67 (lH, d, J=2.2Hz) 312XP/Invention Manual (supplement)/96- 03/95143900 166 200800871 (Reference Example 70-1) 3,5-Difluoro-2 -(4-hydroxy-3-methoxyphenytyl)benzoic acid in a helium atmosphere at room temperature, 2 - (4-Benzyloxy-3-methoxybenzolone)-3,5-difluorobenzoic acid benzyl vinegar (Reference Example 25-5) (686 mg), 10% charcoal (I40 mg, water content 50%) A mixture of dichlorohydrazine/ethyl acetate = 1/1 mixed solution (26 mL) was stirred for 2 hours. After the reaction mixture was passed through to remove insolubles, the filtrate was concentrated under reduced pressure. The residue was pulverized with a chloropyrene/hexane = 2/1 mixed solution (9 mL), and the solid was filtered over hexane, and washed with a mixture of dichloromethane/hexane = 1/1 (3 mL). The title compound (412 mg) was obtained. - Li R (DMS0 - de) 6 ppm : 3 · 81 (3H, s), 6 · 95-7 · 05 (lH, m), 7 · 35-7. 65 (4H, m), 10 · 48 ( 1H, s), 14.08 (1H, br) (Reference Example 71 - 1) 4 -(2-Benzyl phenylphosphite)-2 - decyloxy in the hydrogen atmosphere and at room temperature 'will [ 2-(4-oxo-3-methoxybenzyl) benzyl alcohol (Reference Example 61 - 3) (600 mg), 1 〇% carbon (300 mg, water content 50%) and acetic acid A mixture of ethyl ester (15 mL) was stirred for 14 hours. The reaction mixture was filtered through Celite (registered trademark) EtOAc. 4 - Li R (CDC13) (5 ppm : 3 · 83 (3H, s), 4 · 35 (2H, s), 5 · 99 (1H, s), 6 · 88 -6 · 92 (3H, m) ,7· 07-7· 20(4H,m),7· 30-7· 47 (4H,m),8· 19-8· 21(1H,m) (Reference Example 72-1) 312XP/Invention Manual (supplement)/96-03/95143900 167 200800871

(3 -碘-4,5 - ¥氧基苯磺醯基）_3_ 在室溫下，將N -碘琥珀醯亞胺（58〇mg)加入至5_氟甲基苯甲腈（參物中，並攪拌2 2 - (4 _羥基- 3 -曱氧基苯磺醯基）一 3 一甲基考例34 - 42)(69〇mg)及乙腈（i〇mL)之混合物中小時。將反應混合物用醋酸乙酯稀釋後加入2m〇1/L鹽酸。分取之有機液層依次以飽和碳酸氫鈉水溶液、食鹽水洗滌，用無水硫酸鎂乾燥，在減壓下進行濃縮，得粗製之 5 -氟-2- (4-羥基-3-曱氧基-5 -碘苯磺醯基 3 -曱基苯曱腈。在室溫下，將碳酸鉀（594mg)及碘化甲基（9i4mg)加入至粗製之5-氟-2 -（4-羥基- 3 -曱氧基—β 一碘笨磺醯基）-3 -曱基苯曱腈及Ν，Ν —二曱基曱醯胺（1〇mL)之混合物中，並在相同溫度下攪拌12小時。於混合物中加入 2mo 1 /L鹽酸後用醋酸乙酯稀釋。分取之有機液層依次以 _飽和碳酸氫鈉水溶液、食鹽水洗滌，用無水硫酸鎂乾燥。在減壓下進行濃縮，其殘留物以矽膠管柱色析法進行精製 (洗提液：醋酸乙酯/己烷=3/1)，得5—氟—2—(3—換_ 4,5 -二甲氧基苯磺醯基）—3 -曱基苯甲腈（939mg)。在室溫下，將三溴化硼（lm〇l/L二氯甲烧溶液、8· 加入至5 -氟-2 - (3 -破-4, 5 -二甲氧基苯磺醯基）— 3-曱基苯甲腈（939mg)及二氯甲烷（6mL)之混合物中，並擾拌60小時。加入甲醇（imL)後用醋酸乙酯稀釋，依次以水、食鹽水洗滌，在減壓下進行濃縮，得粗製之2— (3, 4一 312XP/發明說明書(補件)/96-〇3/95143900 168 200800871 二羥基-5 -碘苯磺醯基）—5 —氟_3 —甲基苯甲腈。在室溫下，將苄基溴化物（0 73mL)加入至粗製之2一 (3, 4 -二羥基-5-硪苯磺醯基）-5 -氟—3 -甲基苯甲腈、碳酸鉀（L40g)及N，N —二曱基甲醯胺（1〇mL)之混合物中並攪拌1小時。再於6(rc攪拌丨小時。於混合物中加入2mol/L鹽酸後用醋酸乙酯稀釋。分取之有機液層依次以2mol/L氫氧化鈉水溶液、飽和碳酸氫鈉水溶液、食鹽水洗滌，用無水硫酸鎂乾燥後在減壓下進行濃縮。其殘留物與甲醇（15mL)—起進行粉碎，濾取固體，用甲醇（5社) 洗滌3次，得5 -氟-2 - (3 -碘-4,5 -节氧基苯磺醯基）一 3 -曱基苯甲腈（938mg)。 NMR(CDC13) δ ppm : 2· 62(3H，s)，5· 13(2H，s)，5· 22 (2H，s)，7· 18一7· 20(1H，m)，7· 32 —7· 46(11H，m)，;· 68 (lH，d，J=2.2Hz)，7.93(lH，d，J=2.2Hz) (參考例73- 1) 5 -氟-2- (3 -氰基-4, 5-苄氧基苯磺醯基）一 3一甲基苯甲腈在氬氣環境下，將5 -氟-2 - (3—碘-4, 5 —节氧基苯磺醯基）-3 -甲基苯甲腈（參考例72 — 1 )(938mg)、氰化銅（I)(548mg)、參（二苯亞甲基丙酮）二鈀（〇)(7〇mg)、氰化四乙銨（239mg)、1，1，-雙（二苯膦基）二茂鐵（17〇nJ) 及1，4 -二哼烷（1 〇mL)之混合物在迴流下攪拌}小時。將反應混合物通過Celite(註冊商標）矽藻土層過濾，用醋酸乙酉曰洗提。濾液以食鹽水洗滌，用無水硫酸鎂乾燥後在 312XP/發明說明書(補件)/96-03/95143900 169 200800871 減壓β下進打濃縮。其殘留物以矽膠管柱色析法進行精製 (洗提液：己烧/醋酸乙醋=2/3)，得粗製生成物。殘留物與曱醇（10mL)—起進行粉碎，濾取固體，用曱醇（3mL)洗滌5次，得5 -氟-2_ (3_氰基—4, 5 —苄氧基苯磺醯基）-3 -曱基苯甲腈（494mg)。 H- NMR(CDCh) δ ppm ： 2. 64(3H5 s)5 5. 26(2H, s)5 5. 39 (2H，s)，7· 20-7· 23(1H，m)，7· 32-7· 46(11H，m)，7· 67 (1H，d，J= 2· 2Hz)，7· 88(1H，d，J= 2· 2Hz) •(實施例1 - 1) 5 -（4 -乙基苯磺醯基）_ 3 -硝基苯—i 2 _二醇（化合物 1 - 1) 在室溫攪拌下，將氯化鋁（237mg)加入至4- (4-乙基苯磺醯基）-2 -曱氧基-6 -硝基酚（參考例36 -l)(240mg)及醋酸乙酯（7mL)之混合物中，再滴加π比咬 (〇· 35mL)。此混合物加熱迴流1夜。待冷卻後將粉碎之冰書以少量分批加入至反應混合物，將不溶物加入至lm〇l/L 鹽酸中。分取之有機液層以食鹽水洗滌，用無水硫酸鎂乾燥，在減壓下進行濃縮。其殘留物通過SCX離子交換管柱 (Argonaute公司製、5g)過濾，以二氯甲烷洗提後將濾液濃縮，得目標化合物（205mg)。 !H- NMR(CDCl3) 5 ppm ： 1. 24(3H, t, J= 7. 7Hz)5 2. 71 (2H，q，J= 7· 6Hz)，7· 35(2H，d，J= 8· 2Hz)，7· 70(1H, d，J = 1· 9Hz)，7· 85(1H，d，J=8. 2Hz)，8· 30(1H，d，J=2· 2Hz)， 10. 95(1H, br s) 3UXP/發明說明書(補件)/96-03/95143900 170 200800871 (實施例1 - 2) 5 -（2 -氯- 6 -三氟甲基苯磺醯基）_ 3 -硝基笨〜 1，2 -二醇（化合物1 — 2) 將4 - (2 -氯—6 —三氟甲基苯磺醯基）—2一甲氧基、 6 -硝基酚（參考例36 - 35)(485mg)、47%溴化氫酸水二液 (2mL)及醋酸（i〇mL)之混合物在攪拌下照射微波，以 °C加熱5分鐘。此反應混合物在減壓下進行濃縮，其殘留物與醋酸乙酯一起進行粉碎後濾取得目標化合響（345mg)。 NMRCDMSO- de) 5 ppm ： 7. 42( 1H? d? J = 2. 5Hz), 7. 88^ 7· 96 (2H，m)，7. 98-8· 04(1H，m，8· 2, 1· 3Hz)，8· 14 (1H，dd，J= 8· 0, 1· 1Hz), 11· 13(ih，br) (實施例1 - 4 5 ) 2- (3,4 -二羥基-5 -硝基苯磺醯基）_ 5_氟—3_甲基苯甲腈（化合物1 - 4 5) • 在室溫攪拌下，將氯化鋁U.46g)及吡啶（2.65inL)依序加入至5-氟-2-(4-羥基-3_甲氧基_5_硝基苯磺 L基）3甲基苯曱腈（參考例36 _ 45)(2g)及醋酸乙酯 (55mL)之混合物中。此混合物在8{rc攪拌2小時。此反應混合物待冷卻至室溫後加入2m〇1/L鹽酸（2〇mL)。分取有機液層依次以2mol/L鹽酸（20mL)2次、食鹽水洗滌，用無水硫酸鎂乾燥，在減壓下進行濃縮，得目標化合物 (1.9g)。 (實施例1 - 121) 312XP/發明說明書(補件)/96·03/951439〇〇 171 200800871 2- (3,4-二羥基_ 5_硝基苯磺醯基）_ 3,5_二氟苯曱酸曱酯（化合物丨—121) 在室溫攪拌下，將氯化銘（222mg)及吼咬（0.32mL)依序力入3’5 —氟-2- (4-經基-3-甲氧基一 5 -墙基苯石黃酿基）苯甲酸甲酷（參考例36 - 1 18)(267mg)及醋酸乙醋 (6. 6mL)之混合物中。此混合物在迴流下攪拌2小時。此反應混合物待冷卻至室溫後加入2m〇1/L鹽酸（8. 3mL)。分取有機液層，用無水硫酸鈉乾燥，在減壓下進行濃縮。並殘留物用二氣甲烷/己烷=1/1混合溶液（2mL)進行粉碎了濾取固體，用二氯甲烷/己烷=1/1混合溶液洗滌5 次，得目標化合物（2iimg)。 (實施例1 - 127) 1- [2 - (3, 4~二羥基—5 -硝基苯磺醯基）—3, 5 —二氟苯基]乙酮（化合物1 — 12 7) 在室溫攪拌下，將氯化鋁（391mg)及吡啶〇· 569mL)依序 _加入至1 - [3, 5 -二氟-2 - (4 -羥基-3 -甲氧基- 5 - 硝基苯磺醯基）苯基]乙酮（參考例36 — 124)(455mg)及醋酉文乙i曰(11 · 7mL)之混合物中。此混合物在迴流下攪拌3小日守。此反應混合物待冷卻至室溫後加入2m〇1/L鹽酸 (14· 7mL)。分取有機液層，用無水硫酸鈉乾燥，在減壓下進行濃縮。其殘留物用二氣曱烷/己烷=171混合溶液（4mL) 粉碎，濾取固體，用二氯曱烷/己烷=2/1混合溶液（2mL) 洗滌5次，得目樣化合物（362mg)。依與實施例1 - 1或實施例1 — 2相同方法，使用對應之 312XP/發明說明書(補件)/96-03/95143900 172 200800871 3 -硝基苯-1，2 -二醇以代替4 - (4 -乙基苯磺醯基）-2 -曱氧基-6 -石肖基盼或4 - (2-氯- 6 -三氟曱基苯石黃醢基）-2 -曱氧基-6 -硝基紛，合成化合物1-3〜1-44、1 - 46〜1 - 120、1 - 122〜1 - 126 及 1 - 129。此等示於表19。(3 -iodo-4,5 - oxyphenylsulfonyl)_3_ N-iodosuccinimide (58 〇mg) was added to 5-fluoromethylbenzonitrile at room temperature (in the reference) And stirring 2 2 - (4 - hydroxy- 3 - methoxy oxysulfonyl) - 3 - methyl test 34 - 42) (69 〇 mg) and acetonitrile (i 〇 mL) in a mixture of hours. The reaction mixture was diluted with ethyl acetate and then 2 m 〇l/L hydrochloric acid was added. The organic layer was separated and washed with saturated aqueous sodium hydrogen carbonate and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give crude 5-fluoro-2-(4-hydroxy-3-decyloxy). -5-iodobenzenesulfonyl 3-mercaptobenzonitrile. Potassium carbonate (594 mg) and methyl iodide (9i4 mg) were added to the crude 5-fluoro-2-(4-hydroxy-) at room temperature. a mixture of 3-methoxy-β-iodosulfonyl)-3 -mercaptobenzonitrile and hydrazine, hydrazine-didecylguanamine (1 〇 mL), and stirred at the same temperature for 12 hours. The mixture was diluted with ethyl acetate, and then diluted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate and brine and dried over anhydrous magnesium sulfate. The residue was purified by gel column chromatography (eluent: ethyl acetate/hexane = 3/1) to obtain 5-fluoro-2-(3-exchange-4,5-dimethoxybenzenesulfonate).醯-) 3-mercaptobenzonitrile (939 mg). At room temperature, boron tribromide (lm〇l / L dichloromethane solution, 8 · added to 5-fluoro-2 - (3 - Broken-4,5-dimethoxybenzenesulfonyl)-3-mercaptobenzene A mixture of acetonitrile (939 mg) and dichloromethane (6 mL) was stirred for 60 hours. After adding methanol (imL), it was diluted with ethyl acetate, washed with water and brine, and concentrated under reduced pressure. Crude 2 - (3, 4 - 312XP / invention specification (supplement) / 96 - 〇 3 / 95143900 168 200800871 dihydroxy-5 - iodobenzenesulfonyl) - 5 - fluoro - 3 - methyl benzonitrile. Benzyl bromide (0 73 mL) was added to the crude 2-(3,4-dihydroxy-5-nonylsulfonyl)-5-fluoro-3-methylbenzonitrile, carbonated at room temperature Mixture of potassium (L40g) and N,N-dimercaptocaramine (1〇mL) and stir for 1 hour, then stir at 6 (rc for 丨 hours. Add 2mol/L hydrochloric acid to the mixture and use ethyl acetate The organic layer was separated and washed with a 2 mol/L aqueous sodium hydroxide solution, a saturated aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue and methanol (15 mL) The mixture was pulverized, and the solid was collected by filtration and washed three times with methanol (5) to give 5-fluoro-2-(3-iodo-4,5-oxophenylsulfonyl)-3-mercaptobenzonitrile. (938 mg). NMR (CDC13) δ ppm : 2· 62 (3H, s), 5· 13 (2H, s), 5· 22 (2H, s), 7·18·7·20 (1H, m), 7·32 —7· 46(11H,m),;· 68 (lH,d,J=2.2Hz), 7.93 (lH,d,J=2.2Hz) (Reference Example 73-1) 5 -Fluoro-2- (3) -Cyano-4,5-benzyloxybenzenesulfonyl)-3-methylbenzonitrile 5-arfluoro-2 -(3-iodo-4,5-oxybenzene) under argon Sulfomethyl)-3-methylbenzonitrile (Reference Example 72-1) (938 mg), copper (I) cyanide (548 mg), bis(diphenylmethyleneacetone) dipalladium (〇) (7〇) a mixture of mg), tetraethylammonium cyanide (239 mg), 1,1,-bis(diphenylphosphino)ferrocene (17〇nJ) and 1,4-dioxane (1 〇mL) under reflux Stir for} hours. The reaction mixture was filtered through a pad of Celite (registered trademark), and eluted with ethyl acetate. The filtrate was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure under 312 XP/Inventive Manual (supplement)/96-03/95143900 169 200800871 under reduced pressure. The residue was purified by a gel column chromatography (eluent: hexane/acetic acid ethyl acetate = 2/3) to obtain a crude product. The residue was pulverized with decyl alcohol (10 mL), and the solid was collected by filtration and washed 5 times with methanol (3 mL) to give 5-fluoro-2-(3-cyano-4,5-benzyloxybenzenesulfonyl) -3 - mercaptobenzonitrile (494 mg). H-NMR (CDCh) δ ppm : 2. 64(3H5 s)5 5. 26(2H, s)5 5. 39 (2H, s), 7· 20-7· 23(1H,m),7· 32-7·46(11H,m),7·67 (1H,d,J= 2·2Hz), 7.88 (1H,d,J=2·2Hz) • (Example 1 - 1) 5 - (4-Ethylbenzenesulfonyl)_3-nitrobenzene-i 2 diol (Compound 1-1) Aluminum chloride (237 mg) was added to 4-(4-ethyl group) with stirring at room temperature To a mixture of phenylsulfonyl)-2-oxo-6-nitrophenol (Reference Example 36-1) (240 mg) and ethyl acetate (7 mL), a π ratio (〇·35 mL) was further added dropwise. This mixture was heated to reflux for 1 night. After cooling, the pulverized ice book was added to the reaction mixture in small portions, and the insoluble matter was added to lm〇l/L hydrochloric acid. The organic layer was separated and washed with brine, dried over anhydrous magnesium sulfate and evaporated. The residue was filtered through a SCX ion exchange column (5 g, manufactured by Argonaute), eluted with dichloromethane, and the filtrate was concentrated to give the title compound (205 mg). !H-NMR (CDCl3) 5 ppm : 1. 24(3H, t, J= 7. 7Hz)5 2. 71 (2H,q,J= 7·6Hz),7·35(2H,d,J= 8·2 Hz), 7·70 (1H, d, J = 1·9 Hz), 7·85 (1H, d, J=8. 2Hz), 8·30 (1H, d, J=2· 2Hz), 10. 95(1H, br s) 3UXP/Invention Manual (Supplement)/96-03/95143900 170 200800871 (Examples 1 - 2) 5 -(2-Chloro-6-trifluoromethylbenzenesulfonyl) _ 3 -Nitrophenyl~ 1,2-diol (Compound 1-2) 4-(2-Chloro-6-trifluoromethylbenzenesulfonyl)-2-methoxy and 6-nitrophenol (Reference Examples 36 - 35) (485 mg), a mixture of 47% aqueous hydrocyanide (2 mL) and acetic acid (i 〇 mL) were irradiated with microwaves under stirring, and heated at ° C for 5 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was combined with ethyl acetate and filtered to give the desired compound (345 mg). NMRCDMSO- de) 5 ppm : 7. 42 ( 1H? d? J = 2. 5Hz), 7. 88^ 7· 96 (2H,m), 7. 98-8· 04(1H,m,8· 2 , 1·3 Hz), 8·14 (1H, dd, J=8·0, 1·1 Hz), 11·13(ih, br) (Example 1 - 4 5 ) 2- (3,4-dihydroxyl) -5-nitrophenylsulfonyl)_ 5_fluoro-3-methylbenzonitrile (Compound 1 - 4 5) • U.46g of aluminum chloride and pyridine (2.65inL) with stirring at room temperature Add to 5-fluoro-2-(4-hydroxy-3_methoxy-5-nitrophenylsulfonyl) 3-methylbenzonitrile (Ref. 36-45) (2 g) and ethyl acetate (55 mL) in a mixture. This mixture was stirred at 8 {rc for 2 hours. After the reaction mixture was cooled to room temperature, 2 m of 1/L hydrochloric acid (2 mL) was added. The organic layer was separated and washed twice with 2 mol/L hydrochloric acid (20 mL) and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (1.9 g). (Examples 1 - 121) 312XP/Invention Manual (supplement)/96·03/951439〇〇171 200800871 2- (3,4-Dihydroxy-5-nitrophenylsulfonyl)_ 3,5_2 Ethyl fluorobenzoate (Compound 丨-121) chlorinated (222mg) and bite (0.32mL) were sequentially added to 3'5-fluoro-2-(4-carbo-) A mixture of 3-methoxy-5-wall benzophenone yellow benzoic acid methyl benzoate (Reference Example 36 - 1 18) (267 mg) and ethyl acetate (6.6 mL). This mixture was stirred under reflux for 2 hours. After the reaction mixture was cooled to room temperature, 2 m of 1 / L hydrochloric acid (8.3 mL) was added. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was pulverized with a mixture of di-methane/hexane = 1/1 (2 mL). The solid was collected by filtration and washed twice with dichloromethane/hexane = 1/1 mixture to give the title compound (2 iimg). (Example 1 - 127) 1- [2-(3,4-dihydroxy-5-nitrophenylsulfonyl)-3,5-difluorophenyl]ethanone (Compound 1 - 12 7) In the chamber Aluminum chloride (391 mg) and pyridinium 569 mL) were sequentially added to 1-[3,5-difluoro-2-(4-hydroxy-3-methoxy-5-nitrobenzene) under constant stirring. A mixture of sulfonyl)phenyl]ethanone (Reference Examples 36-124) (455 mg) and acetoacetin (11. 7 mL). This mixture was stirred under reflux for 3 hours. After the reaction mixture was cooled to room temperature, 2 ml of 1/L hydrochloric acid (14.7 mL) was added. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was pulverized with a mixed solution of dioxane/hexane = 171 (4 mL), and the solid was collected by filtration, and washed twice with a mixture of dichloromethane/hexane = 2/1 (2 mL). 362mg). In the same manner as in Example 1-1 or Example 1-2, the corresponding 312XP/invention specification (supplement)/96-03/95143900 172 200800871 3-nitrobenzene-1,2-diol is used instead of 4 - (4-Ethylbenzenesulfonyl)-2-decyloxy-6-stone chopropan or 4-(2-chloro-6-trifluoromethylphenylphosphonium)-2-oxo-6-nitrate Based on the synthesis of compounds 1-3~1-44, 1-46~1-120, 1-122~1-126 and 1-129. These are shown in Table 19.

312XP/發明說明書(補件)/96-03/95143900 173 200800871 [表 19]312XP/Invention Manual (supplement)/96-03/95143900 173 200800871 [Table 19]

化合物 Να. 構造式化合物 No. 構造式 1-1 1-S :夺科、 1-2 Sr0_ Φ 1-9 0、v〇- 1-3 ο: ♦.〇 1-10 0ν〇- ::xiux ο/χο 1-4 cfvo 1-11 V ：Asi7f ο/Νο 1-5 v 1-12 :¾ 1~S 0、v°- :¾ 0^0 1-13 :偷F 0◊、0 I-T oMb 卜14 :¾^ 312XP/發明說明書(補件)/96-03/95143900 174 200800871 表19(續）Compound Να. Structural Formula No. 1-1 1-S: 克, 1-2 Sr0_ Φ 1-9 0, v〇- 1-3 ο: ♦.〇1-10 0ν〇- ::xiux ο/χο 1-4 cfvo 1-11 V :Asi7f ο/Νο 1-5 v 1-12 :3⁄4 1~S 0, v°- :3⁄4 0^0 1-13 : Stealing F 0◊, 0 IT oMb卜 14 : 3⁄4^ 312XP / invention manual (supplement) / 96-03/95143900 174 200800871 Table 19 (continued)

312XP/發明說明書(補件)/96-03/95143900 175 200800871 表19(續）312XP/Invention Manual (supplement)/96-03/95143900 175 200800871 Table 19 (continued)

31ZXP/發明說明書(補件)/96-03/95143900 176 200800871 表19(續）31ZXP/Invention Manual (supplement)/96-03/95143900 176 200800871 Table 19 (continued)

312XP/發明說明書(補件)/96-03/95143900 177 200800871 表19(續）312XP/Invention Manual (supplement)/96-03/95143900 177 200800871 Table 19 (continued)

化合物 No. 構造式化^&物 No. 構造式卜57 1-64 ?： Vl :衫 1-58 F65 1-59 M5ac, OH 1-66 1-60 1-67 。私 1-61 1-68 oh水卜62 。:w 〇h水 1-69 1-63 妙。, 1-70 312XP/發明說明書(補件)/96-03/95143900 178 200800871 表19(續）Compound No. Structural Formula ^ & No. Structural Formula 卜 57 1-64 ?: Vl : Shirt 1-58 F65 1-59 M5ac, OH 1-66 1-60 1-67 . Private 1-61 1-68 oh water Bu 62. :w 〇h water 1-69 1-63 Wonderful. , 1-70 312XP/Invention Manual (supplement)/96-03/95143900 178 200800871 Table 19 (continued)

312XP/發明說明書(補件)/96-03/95143900 179 200800871 表19(續）化合物 No. 構造式化合物 No. 構造式 1-85 1-92 OH 1-86 卜93 °Ι：Υ%ν 1-87 1-94 。: 1-88 1-95 1-89 1-96 球卜90 1-97 球 1-91 。:丨執 1-98 ΟΗ312XP/Invention Manual (Supplement)/96-03/95143900 179 200800871 Table 19 (continued) Compound No. Structural Formula No. Structural Formula 1-85 1-92 OH 1-86 卜 93 °Ι:Υ%ν 1 -87 1-94. : 1-88 1-95 1-89 1-96 Balls Bu 90 1-97 Balls 1-91. :丨执 1-98 ΟΗ

312XP/發明說明書(補件)/96-03/95143900 180 200800871 表19(續）312XP/Invention Manual (supplement)/96-03/95143900 180 200800871 Table 19 (continued)

No. 構造式化合物 m. 構造式 1-99 0H 1-106 °：〇^5 1-iOO 1-107 1-101 \-m V 卜102 1-109 I-I03 1-110 V a :如〇/'〇 1-104 ~ Ml! 0Ύ_ a :A々a 1-105 1-112 ::齡〇,、〇 312XP/發明說明書(補件)/96-03/95143900 181 200800871 表19(續）No. Structural formula m. Structural formula 1-99 0H 1-106 °: 〇^5 1-iOO 1-107 1-101 \-m V Bu 102 1-109 I-I03 1-110 V a : 如〇 /'〇1-104 ~ Ml! 0Ύ_ a :A々a 1-105 1-112 :: Age, 〇 312XP / invention manual (supplement) / 96-03/95143900 181 200800871 Table 19 (continued)

化合物 No. 構造式化合物 No. 構造式 1-113 〇% βο 1-120 OH 1-114 :祕〇，、〇 M21 OH 1-115 :ώ〇σ οό °ο 卜122 OH Ml 6 °^°" 1 1-12S OH H17 Ν 1-124 。滅 OH 1-U8 0 0 ν、# 1-125 % °V/〇 X 0H I 1-119 %-°· 门 :成A? O' 0 1-126 OH 312XP/發明說明書(補件)/96-03/95143900 182 200800871 表19(續）Compound No. Structural Formula No. Structural Formula 1-113 〇% βο 1-120 OH 1-114 : Peru, 〇M21 OH 1-115 : ώ〇σ οό °ο 卜 122 OH Ml 6 °^°&quot ; 1 1-12S OH H17 Ν 1-124 . OH OH 1-U8 0 0 ν, # 1-125 % °V/〇X 0H I 1-119 %-°· Gate: into A? O' 0 1-126 OH 312XP / invention manual (supplement) / 96 -03/95143900 182 200800871 Table 19 (continued)

化合物1 - 3〜化合物1 - 12 9之物性值係如下示。化合物1 - 3 'H-NMRiDMSO-d ) δ ppm:3e80 (3H, s), 7.15-7.23 (1H, m), 7.48 (1H, d, J=2.2Hz 6 ),7.64-7.72 (1H, m), 7.84 (1H, d, J=2.2Hz), 7.97 (1H, dd, J=7.7, L7Hz), 11.11 (1H ,br) 化合物1 - 4 ^-NMRCDMSO-d ) δ ppm:3.89 (3H, s), 7.47 (1H, d, J=2.2Hz), 7.94 (1H, d, J=2. 6 2Hz), 8.06-8.13 (1H, m, J=8.5Hz), 8.16 (1H, d, J=8.4Hz), 1L26 (1H, br) •化合物1-5 'H-NMRiDMSO-d ) δ ppmT3e92 (3H, s), 7.47-7.54 (1H, m), 7.79-7.87 (1H, m), 7 6 e94-8.02 (lH, m), 8.21-8.31 (2H, m), 8.37-8.46 (1H, m), 1L25 (1H, br) 化合物1 - 6 'H-NMRiDMSO-d ) δ ppm:3.75 (1H, d), 3.87 (3H, s), 7.50 (1H, d, J=2.2Hz), 7.64 6 -7.74 (1H, m), 7.77-7.84 (2H? m), 7.92 (1H, d, J=2.2Hz), 8.12-8.20 (1H, m), 11.21 (1H, br) 化合物1 - 7 1H-NMR(DMSO"-d ) δ ppm:2.31-2.37 (6H, m), 7.33 (1H, s), 7.43 (1H, d, J=2.2Hz 6 ),7.56 (1H, s), 7.89 (1H, d, J=2e2Hz), 11.16 (1H, br) 183 312XP/發明說明書(補件)/96-03/95143900 200800871 化合物1 - 8 'H-NMRCDMSO-d ) δ ppm :2.87 (3H, s)? 3.00 (3H, s), 7.45 (1H, d, J=2„2Hz), 7.68 6 -7J6 (1H, m), 7.92-7.97 (1H, m), 7.99-8.04 (1H, m) 化合物1 - 9 i-NMR(DMSOd ) δ ppm :7.43-7.52 (3H，m), 7.78-7.83 (1H，m)，7。87-7·90 (1H, 6 m)，8。0卜8。07 (1H，m), 11.10 (1H，br) 化合物1 -10 -NMR(DMS〇-d ) δ ppm:7.47 (1H, d，J=2.5Hz)，7.56-7.64 (1H，m)，7.65-7·73 (The physical property values of the compound 1 - 3 to the compound 1 - 12 9 are shown below. Compound 1 - 3 'H-NMRiDMSO-d ) δ ppm: 3e80 (3H, s), 7.15-7.23 (1H, m), 7.48 (1H, d, J=2.2Hz 6 ), 7.64-7.72 (1H, m ), 7.84 (1H, d, J=2.2Hz), 7.97 (1H, dd, J=7.7, L7Hz), 11.11 (1H, br) Compound 1 - 4 ^-NMRCDMSO-d ) δ ppm: 3.89 (3H, s), 7.47 (1H, d, J=2.2Hz), 7.94 (1H, d, J=2. 6 2Hz), 8.06-8.13 (1H, m, J=8.5Hz), 8.16 (1H, d, J = 8.4 Hz), 1L26 (1H, br) • Compound 1-5 'H-NMRiDMSO-d ) δ ppmT3e92 (3H, s), 7.47-7.54 (1H, m), 7.79-7.87 (1H, m), 7 6 e94-8.02 (lH, m), 8.21-8.31 (2H, m), 8.37-8.46 (1H, m), 1L25 (1H, br) Compound 1 - 6 'H-NMRiDMSO-d ) δ ppm: 3.75 ( 1H, d), 3.87 (3H, s), 7.50 (1H, d, J=2.2Hz), 7.64 6 -7.74 (1H, m), 7.77-7.84 (2H? m), 7.92 (1H, d, J =2.2 Hz), 8.12-8.20 (1H, m), 11.21 (1H, br) Compound 1 - 7 1H-NMR (DMSO "-d ) δ ppm: 2.31-2.37 (6H, m), 7.33 (1H, s ), 7.43 (1H, d, J=2.2Hz 6 ), 7.56 (1H, s), 7.89 (1H, d, J=2e2Hz), 11.16 (1H, br) 183 312XP/invention specification (supplement)/96 -03/95143900 200800871 Compound 1 - 8 'H-NMRCDMSO-d ) δ ppm : 2.87 (3H, s)? 3.00 (3H, s), 7.45 (1H, d, J=2„2Hz ), 7.68 6 -7J6 (1H, m), 7.92-7.97 (1H, m), 7.99-8.04 (1H, m) Compound 1 - 9 i-NMR (DMSOd ) δ ppm :7.43-7.52 (3H,m) , 7.78-7.83 (1H, m), 7. 87-7·90 (1H, 6 m), 8. 0 b 8.07 (1H, m), 11.10 (1H, br) Compound 1 -10 -NMR ( DMS〇-d ) δ ppm: 7.47 (1H, d, J=2.5Hz), 7.56-7.64 (1H, m), 7.65-7·73 (

6 1H, m), 7.77-7.85 (1H, m), 7.96 (1H, d, J=2.2Hz), 11.04 (1H, br) 化合物1 -11 ^-NMRCDMSO-d ) δ ppm :7.43-7.50 (3HS m), 7.88-7.96 (1H, m), 7.98-8.07 (2H, 6 m) 化合物1_ 126 1H, m), 7.77-7.85 (1H, m), 7.96 (1H, d, J=2.2Hz), 11.04 (1H, br) Compound 1 -11 ^-NMRCDMSO-d ) δ ppm :7.43-7.50 ( 3HS m), 7.88-7.96 (1H, m), 7.98-8.07 (2H, 6 m) Compound 1_ 12

^-NMRCDMSO-d ) δ ppm :7.35-7.45 (1H, m), 7.80-7.90 (2H, m), 7.98 (1H, dd, J 6 =9.2, 2.7Hz), 8.45 (1H, dd, J=9.2, 5.4Hz), 10.82 (1H, br) 0化合物1 -13 ^-NMRCDMSO-d ) δ ppm:7.43 (1H, d, J=2.2Hz), 7.84-7.92 (2H, m), 7.95-8.04 ( 6 1H, m), 8.47 (1H, dd, J=9.1, 5.4Hz), 1L24 (1H, br) 化合物1 -14 'H-NMRCDMSO-d ) δ ppm:7.49-7.55 (2H, m), 7.85-7.91 (1H, m), 7.93 (1H, d, J= 6 1.9Hz), 8.00-8.02 (1H, m), 1L16 (1H, br) 化合物1-15 'H-NMR^MSO-d ) δ ppm:7.56 (1H, d, J=1.3Hz), 7.70-7.77 (1H, m), 7.99 (1H, d 6 ,J=L9Hz), 8.23-8.31 (2H, m), 1L34 (1H, br) 184 312XP/發明說明書(補件)/90-03/95143900 200800871 化合物1 -16 ^-NMRCDMSO-d ) δ ppm:2.38 (3H, s), 7.25-7.35 (2H, m), 7〇4-7.50 (1H, m), 7-. 6 84 (1H, d, J=2.2Hz), 7.86-7.92 (1H, m), 1L20 (1H, br) 化合物1-17 ^-NMRCDMSO-d ) δ ppm:7.43-7.51 (1H? m), 7.51-7.62 (2H, m), 7〇75 (1H, d, J-8.1Hz), 7.98 (1H, d, J=7.8Hz) 化合物1 -18 'H-NMRCDMSO-d ) δ ppm :2.42 (3H, s), 7.35-7.43 (1H, m), 7.47 (2H, d, J=7.9Hz!^-NMRCDMSO-d ) δ ppm :7.35-7.45 (1H, m), 7.80-7.90 (2H, m), 7.98 (1H, dd, J 6 =9.2, 2.7Hz), 8.45 (1H, dd, J= 9.2, 5.4 Hz), 10.82 (1H, br) 0 Compound 1 -13 ^-NMRCDMSO-d ) δ ppm: 7.43 (1H, d, J = 2.2 Hz), 7.84-7.92 (2H, m), 7.95-8.04 (6 1H, m), 8.47 (1H, dd, J=9.1, 5.4Hz), 1L24 (1H, br) Compound 1 -14 'H-NMRCDMSO-d ) δ ppm: 7.49-7.55 (2H, m), 7.85-7.91 (1H, m), 7.93 (1H, d, J = 6 1.9Hz), 8.00-8.02 (1H, m), 1L16 (1H, br) Compound 1-15 'H-NMR^MSO-d ) δ ppm: 7.56 (1H, d, J=1.3Hz), 7.70-7.77 (1H, m), 7.99 (1H, d 6 , J=L9Hz), 8.23-8.31 (2H, m), 1L34 (1H, br 184 312XP/Invention Manual (supplement)/90-03/95143900 200800871 Compound 1 -16 ^-NMRCDMSO-d ) δ ppm: 2.38 (3H, s), 7.25-7.35 (2H, m), 7〇4- 7.50 (1H, m), 7-. 6 84 (1H, d, J=2.2Hz), 7.86-7.92 (1H, m), 1L20 (1H, br) Compound 1-17 ^-NMRCDMSO-d ) δ ppm :7.43-7.51 (1H? m), 7.51-7.62 (2H, m), 7〇75 (1H, d, J-8.1Hz), 7.98 (1H, d, J=7.8Hz) Compound 1 -18 'H -NMRCDMSO-d ) δ ppm :2.42 (3H, s), 7.35-7.43 (1H, m), 7.47 (2H, d, J=7.9Hz!

6 ),7.72 (1H, d? J=8.2Hz), 7.86-7.94 (1H, m), 8.07 (1H, s), 1L06 (1H, br) 化合物1 -19 'H-NMRCDMSO-d ) δ ppm:2.44 (3H, s), 7.30-7.39 (2H, m), 7β83 (1H, d, J=2.2Hz 6 ),8.10-8.19 (1H5 m), 11.09 (1H, br) 化合物1 - 2 0 'H-NMRCDMSO-d ) δ ppm:2.41 (3H, s), 7.39 (1H, d, J=2.5Hz), 7.46-7.55 (2H, m 6 ),7.86-7.94 (2H, m), 11.04 (1H, br) •化合物1 - 21 'H-NMRCDMSO-d ) 6 ppm:3.90 (3H, s), 7.32 (1H, dd, J=8.8, 3.2Hz), 7.49 (1H, d, 6 J=2.5Hz), 7.57 (1H, d, J=8.8Hz), 7.73 (1H, d, J=3e2Hz), 7.91 (1H, d, J=2e2Hz), 11. 17 (1H, br) 化合物1-22 i-NMR(DMSO-d ) δ ppm:7.51-7.58 (1H, m)，7。63-7·74 (1H，m)，7·89-7β99 (1H，· 6 m), 8.14-8.23 (1H, m), 8.33-8.39 (1H, m) 化合物1 - 2 3 ___ — -- —〜一~ --- 4-NMR(DMSOd ) δ ppm:2.24-2·35 (3H，m), 7.34 (1H, d，J=2.2Hz)，7。51-7.62 ( 6 2H, m), 7.83 (1H, d, J=2.3Hz), 7.88-7.98 (1H, m) 、 185 312XP/發明說明書(補件)/96-03/95143900 200800871 化合物1 - 2 4 'H-NMRiDMSO-d ) δ *ppm:7.51 (1H, d, J=2.2Hz), 8〇06 (1H, d, J=2.3Hz), 8.37 (1 6 H, t, J=1.8Hz), 8.40 (1H, t, J=1.8Hz), 8.49 (1H, t, J=1.4Hz) 化合物1 - 2 5 'H-NMRiDMSO-d ) δ ppm:7.52 (1H, d, J=2e3Hz), 7〇87 (1H, td, J=8.5, 2.6Hz), 7e 6 98 (1H, d, J=2e3Hz), 8.21 (1H, dd, J-8,5, 2.6Hz), 8.37 (1H, dd, J=8.9, 5.2Hz) 化合物1 - 2 66), 7.72 (1H, d? J=8.2Hz), 7.86-7.94 (1H, m), 8.07 (1H, s), 1L06 (1H, br) Compound 1 -19 'H-NMRCDMSO-d ) δ ppm :2.44 (3H, s), 7.30-7.39 (2H, m), 7β83 (1H, d, J=2.2Hz 6 ), 8.10-8.19 (1H5 m), 11.09 (1H, br) Compound 1 - 2 0 ' H-NMRC DMSO-d ) δ ppm: 2.41 (3H, s), 7.39 (1H, d, J=2.5Hz), 7.46-7.55 (2H, m 6 ), 7.86-7.94 (2H, m), 11.04 (1H , br) • Compound 1 - 21 'H-NMRCDMSO-d ) 6 ppm: 3.90 (3H, s), 7.32 (1H, dd, J=8.8, 3.2Hz), 7.49 (1H, d, 6 J=2.5Hz ), 7.57 (1H, d, J=8.8Hz), 7.73 (1H, d, J=3e2Hz), 7.91 (1H, d, J=2e2Hz), 11. 17 (1H, br) Compound 1-22 i- NMR (DMSO-d) δ ppm: 7.51-7.58 (1H, m), 7.63-7.74 (1H, m), 7·89-7β99 (1H, · 6 m), 8.14-8.23 (1H, m), 8.33-8.39 (1H, m) Compound 1 - 2 3 ___ — -- -~ One ~ --- 4-NMR (DMSOd ) δ ppm: 2.24-2·35 (3H, m), 7.34 (1H , d, J=2.2Hz), 7. 51-7.62 (6 2H, m), 7.83 (1H, d, J=2.3Hz), 7.88-7.98 (1H, m), 185 312XP/invention manual (supplement) )/96-03/95143900 200800871 Compound 1 - 2 4 'H-NMRiDMSO-d ) δ *ppm: 7.51 (1H, d, J=2.2Hz), 8〇06 (1H, d, J=2.3Hz ), 8.37 (1 6 H, t, J = 1.8 Hz), 8.40 (1H, t, J = 1.8 Hz), 8.49 (1H, t, J = 1.4 Hz) Compound 1 - 2 5 'H-NMRiDMSO-d δ ppm: 7.52 (1H, d, J=2e3Hz), 7〇87 (1H, td, J=8.5, 2.6Hz), 7e 6 98 (1H, d, J=2e3Hz), 8.21 (1H, dd, J-8,5, 2.6Hz), 8.37 (1H, dd, J=8.9, 5.2Hz) Compound 1 - 2 6

^-NMRCDMSO-d ) δ ppm:2.46-2.49 (3H, m), 7.30-7.35 (1H, m), 7〇86 (1H, d, j= 6 2.2Hz), 7.94-8.02 (2H, m), 8.19 (1H, d, J=8.2Hz), 11.15 (1H, br) 化合物H 7 ^^NMRiDMSO-d ) δ ppm: 1.61-1.69 (4H, m), 2.48-2.52 (2H, m), 2.75-2.84 (4H, 6 m), 7.30 (1H, d5 J=2〇2Hz), 7.38-7.46 (2H, m), 7.78 (1H, d, J=2.2Hz), 7.91 (1H, dd, J=7.7, L4Hz), 1L20 (1H, br) 化合物1 - 28 xH-NMR(DMSO~d ) δ ppm:2.44 (3H, s), 7.35 (1H, d, J=1.9Hz), 7.57 (1H, s), 7.60 6 (1H, d, J=8.5Hz), 7.84 (1H, d, J=1.9Hz), 8.09 (1H, d, J=8.5Hz), 11.18 (1H, br) 化合物1 - 29 'H-NMRiDMSO-d ) δ ppm:2.35 (3H, s), 7.36-7.43 (1H, m), 7.57 (1H, t, J=7.7Hz) 6 ,7.75 (1H, d, J=7.6Hz), 7.87 (1H, d, J=2.2Hz), 8.12 (1H, d, J=7e9Hz), 11.09 (1H, b r) 化合物1-30 'H-NMRCDMSO-d ) δ ppm:7.53 (1H, d, J=2.2Hz), 7.72 (1H, d, J=7.9Hz), 7.98 (1 6 H, d, J=2.2Hz), 8.02 (1H, d, J=7.9Hz), 8.12-8.17 (1H, m), 11.29 (1H, br) 化合物1 - 31 186 312XP/發明說明書(補件)/96-03/95143900 200800871 1H-NMR(DMS〇-d ) δ ppm: 1.99-2.06 (2H, m), 2.91 (4H, q, J=7〇3Hz), 7.41 (1H, d 6 ,J=2.5Hz), 7.46 (1H? d, J=7.9Hz), 7.70 (1H, dd, J=7.9, 1.9Hz), 7.74-7.78 (1H, m), 7.86 (1H, d, J=2.2Hz) 化合物1 - 3 2 'H-NMRiDMSO-d ) δ ppm: 1.72 (4H, s), 2.51 (2H, s), 2.76 (4H, s), 7.30 (1H, d, j 1 6 =7.9Hz), 7.43 (1H, s), 7.57-7.65 (2H, m), 7.87 (1H, s), 1L07 (1H, br) 化合物1 - 3 3^-NMRCDMSO-d ) δ ppm: 2.46-2.49 (3H, m), 7.30-7.35 (1H, m), 7〇86 (1H, d, j= 6 2.2Hz), 7.94-8.02 (2H, m) , 8.19 (1H, d, J=8.2Hz), 11.15 (1H, br) Compound H 7 ^^NMRiDMSO-d ) δ ppm: 1.61-1.69 (4H, m), 2.48-2.52 (2H, m), 2.75 -2.84 (4H, 6 m), 7.30 (1H, d5 J=2〇2Hz), 7.38-7.46 (2H, m), 7.78 (1H, d, J=2.2Hz), 7.91 (1H, dd, J= 7.7, L4Hz), 1L20 (1H, br) Compound 1 - 28 xH-NMR (DMSO~d) δ ppm: 2.44 (3H, s), 7.35 (1H, d, J=1.9Hz), 7.57 (1H, s ), 7.60 6 (1H, d, J=8.5Hz), 7.84 (1H, d, J=1.9Hz), 8.09 (1H, d, J=8.5Hz), 11.18 (1H, br) Compound 1 - 29 ' H-NMRiDMSO-d) δ ppm: 2.35 (3H, s), 7.36-7.43 (1H, m), 7.57 (1H, t, J=7.7Hz) 6 , 7.75 (1H, d, J=7.6Hz), 7.87 (1H, d, J=2.2Hz), 8.12 (1H, d, J=7e9Hz), 11.09 (1H, br) Compound 1-30 'H-NMRCDMSO-d ) δ ppm:7.53 (1H, d, J =2.2Hz), 7.72 (1H, d, J=7.9Hz), 7.98 (1 6 H, d, J=2.2Hz), 8.02 (1H, d, J=7.9Hz), 8.12-8.17 (1H, m ), 11.29 (1H, br) Compound 1 - 31 186 312XP / Invention Manual (supplement) /96-03/95143900 200800871 1H-NMR (DMS〇-d ) δ ppm: 1.99-2.06 (2H, m), 2.91 (4 H, q, J=7〇3Hz), 7.41 (1H, d 6 , J=2.5Hz), 7.46 (1H? d, J=7.9Hz), 7.70 (1H, dd, J=7.9, 1.9Hz), 7.74-7.78 (1H, m), 7.86 (1H, d, J=2.2Hz) Compound 1 - 3 2 'H-NMRiDMSO-d ) δ ppm: 1.72 (4H, s), 2.51 (2H, s), 2.76 (4H, s), 7.30 (1H, d, j 1 6 =7.9Hz), 7.43 (1H, s), 7.57-7.65 (2H, m), 7.87 (1H, s), 1L07 (1H, br) 1 - 3 3

^-NMRCDMSO-d ) δ ppm:2.91-2.97 (3H, m), 2.99-3.05 (3H, m), 7.45 (1H, d), 7 6 .75 (1H, d, J=8.2Hz), 7.80 (1H, dd, J=8.2, 1.9Hz), 7.95 (1H, d, J=2.2Hz), 8.24 (1H, d, J=2.2Hz), 11.14 (1H, br) 化合物1-34 'H-NMRCDMSO-d ) δ ppm:2.35-2.46 (3H, m), 7.09-8.44 (5H, m), 10.97 (1H, br) 6 化合物1 - 3 5 'H-NMRiDMSO-d^ δ ppm:3〇84 (3H, s), 7.27 (1H, dd, J=8.1s 2.5Hz), 7.38-7.60 ( 3H, m), 7.92 (1H, d, j=2.2Hz)s 1L15 (1H, br) 0化合物1-36 ^-NMRCDMSO-d ) δ ppm:7e45-7e55 (1H, m), 7.98 (1H, d, J=2e2Hz), 8,31 (2H, s 6 ) 化合物1-37 ^-NMRCDMSO-d ) δ ppm:7〇45~7e55 (1H, m), 7.99 (1H, d, J=2.2Hz), 8.14 (2H, s 6 ) 化合物1-38 1H-NMR(DMS〇-d6) δ ppm:7.50-7.60 (1H, m), 7.75-7.85 (2H, m)s 7.90-8.00 (1H, m) 187 312XP/發明說明書(補件)/96-03/95143900 200800871 化合物1 - 3 9 'H-NMRiDMSO-d ) δ ppm:2.31 (3H, s), 2.73 (3H, s), 7.25-7.30 (1H, m), 7.30-7. 6 40 (1H, m), 7.42 (1H, d, J=2〇4Hz), 8〇82 (IH, d, J=2.4Hz), 1L08 (1H? br) 化合物1 - 4 0 'H-NMRCDMSO-d ) δ ppm:2e40-2〇45 (3H, m),7.08 (1H, d, J=L3Hz), 7.46 (1H, br 6 )，7。95 (1H, d，J=2.2Hz), 8.00-8.10 (1H，m), 8.15-8.25 (1H，m), 8.30-8·40 (1H, m) 化合物1 - 41^-NMRCDMSO-d ) δ ppm: 2.91-2.97 (3H, m), 2.99-3.05 (3H, m), 7.45 (1H, d), 7 6.75 (1H, d, J=8.2Hz), 7.80 (1H, dd, J=8.2, 1.9Hz), 7.95 (1H, d, J=2.2Hz), 8.24 (1H, d, J=2.2Hz), 11.14 (1H, br) Compound 1-34 'H- NMRCDMSO-d) δ ppm: 2.35-2.46 (3H, m), 7.09-8.44 (5H, m), 10.97 (1H, br) 6 Compound 1 - 3 5 'H-NMRiDMSO-d^ δ ppm:3〇84 (3H, s), 7.27 (1H, dd, J=8.1s 2.5Hz), 7.38-7.60 ( 3H, m), 7.92 (1H, d, j=2.2Hz)s 1L15 (1H, br) 0 Compound 1 -36 ^-NMRCDMSO-d ) δ ppm: 7e45-7e55 (1H, m), 7.98 (1H, d, J=2e2Hz), 8,31 (2H, s 6 ) Compound 1-37 ^-NMRCDMSO-d ) δ ppm: 7〇45~7e55 (1H, m), 7.99 (1H, d, J=2.2Hz), 8.14 (2H, s 6 ) Compound 1-38 1H-NMR (DMS〇-d6) δ ppm: 7.50 -7.60 (1H, m), 7.75-7.85 (2H, m)s 7.90-8.00 (1H, m) 187 312XP/invention specification (supplement)/96-03/95143900 200800871 Compound 1 - 3 9 'H-NMRiDMSO -d ) δ ppm: 2.31 (3H, s), 2.73 (3H, s), 7.25-7.30 (1H, m), 7.30-7. 6 40 (1H, m), 7.42 (1H, d, J=2 〇4Hz), 8〇82 (IH, d, J=2.4Hz), 1L08 (1H? br) Compound 1 - 4 0 'H-NMRCDMSO-d ) δ ppm: 2e40-2〇45 (3H, m) , 7.08 (1H, d, J=L3Hz), 7.46 (1H, br 6 ), 7.95 (1H, d, J=2.2Hz), 8.00-8.10 (1H,m), 8.15-8.25 (1H,m ), 8.30-8·40 (1H, m) Compound 1 - 41

'H-NMRiDMSO-d ) δ ppm:〇e85-〇e95 (3H, m), 1.30-1.40 (2H, m)5 L60-1.70 (2H, 6 m)s 4.25-4.35 (2H, m), 7.45-7.50 (1H, m), 7.60-7.70 (1H, m), 7〇75-7〇95 (2H, m), 8.05-8.15 (1H, m), 8.50-8.55 (1H, m) 化合物1 - 4 2 1H-NMR(DMS〇-d ) δ ppm:L30-L70 (6H, m), 2.95-3.10 (3H, m)s 7〇35~7.45 (1H, 6 m), 7.55-7.80 (3H, m), 7.96 (1H, d, J=2.2Hz), 8.00-8.05 (1H, m), 1L08 (1H, br) 化合物1 - 4 3 'H-NMRCDMSO-d ) δ ppm:2〇59 (3H, s), 7.35-7.40 (1H, m), 7.93 (1H, d, J-2.5Hz 6 ),8.37 (1H, d, J=2.5Hz), 8.41 (1H, d, J=2.5Hz) 化合物1-44 ^-NMRCDMSO-d ) δ ppm:2.44 (3H, s), 2.57 (3H, s), 7.30-7.35 (1H, m), 7.85 (1 6 H, d, J=2e2Hz), 7.95-8.05 (1H, m), 8.20-8.25 (1H, m) 化合物1-45 'H-NMRCDMSO-d ) δ ppm :2.60 (3H, s)5 7.46 (1H, d, j=2.1Hz), 7.76 (1H, dd5 J=9 6 .3, 2,4Hz), 7.92 (1H, d, J=2.1Hz), 8.10 (1H, dd, J=8.2, 2.8Hz), 11.20 (1H? br) 化合物1-46 'H-NMRCDMSO-d^ δ ppm:2.55 (3H, s), 7A2 (1H, d, J=2.2Hz), 7e9〇-7.95 (1H, m | ),8.40-8.50 (2H, m), 11.11 (1H, br) j 312XP/發明說明書(補件)/96-03/95143卯0 188 200800871 化合物1 - 4 7 W-NMR(DMSO~d ) δ ppm:2·38 (3H，s), 7。35-7.50 (3H，m)，7.75-7.90 (3H, m)，1 6 1.07 (2H? br) 'H-NMRCDMSO-d ) δ ppm :7.25-7.30 (1H, m), 7.45-7.60 (3H, m), 7.70-7.85 (3H, 6 m), 11.00 (1H, br) 化合物1-49'H-NMRiDMSO-d ) δ ppm: 〇e85-〇e95 (3H, m), 1.30-1.40 (2H, m)5 L60-1.70 (2H, 6 m)s 4.25-4.35 (2H, m), 7.45 -7.50 (1H, m), 7.60-7.70 (1H, m), 7〇75-7〇95 (2H, m), 8.05-8.15 (1H, m), 8.50-8.55 (1H, m) Compound 1 - 4 2 1H-NMR (DMS〇-d ) δ ppm: L30-L70 (6H, m), 2.95-3.10 (3H, m)s 7〇35~7.45 (1H, 6 m), 7.55-7.80 (3H, m), 7.96 (1H, d, J=2.2Hz), 8.00-8.05 (1H, m), 1L08 (1H, br) Compound 1 - 4 3 'H-NMRCDMSO-d ) δ ppm: 2〇59 (3H , s), 7.35-7.40 (1H, m), 7.93 (1H, d, J-2.5Hz 6 ), 8.37 (1H, d, J=2.5Hz), 8.41 (1H, d, J=2.5Hz) 1-44 ^-NMRCDMSO-d ) δ ppm: 2.44 (3H, s), 2.57 (3H, s), 7.30-7.35 (1H, m), 7.85 (1 6 H, d, J=2e2Hz), 7.95- 8.05 (1H, m), 8.20-8.25 (1H, m) Compound 1-45 'H-NMRCDMSO-d ) δ ppm : 2.60 (3H, s)5 7.46 (1H, d, j=2.1Hz), 7.76 ( 1H, dd5 J=9 6 .3, 2,4 Hz), 7.92 (1H, d, J=2.1 Hz), 8.10 (1H, dd, J=8.2, 2.8 Hz), 11.20 (1H? br) Compound 1- 46 'H-NMRC DMSO-d^ δ ppm: 2.55 (3H, s), 7A2 (1H, d, J=2.2Hz), 7e9〇-7.95 (1H, m | ), 8.40-8.50 (2H, m), 11.11 (1H, br) j 312XP / invention manual (fill )/96-03/95143卯0 188 200800871 Compound 1 - 4 7 W-NMR (DMSO~d) δ ppm: 2·38 (3H, s), 7.35-7.50 (3H, m), 7.75-7.90 (3H, m),1 6 1.07 (2H? br) 'H-NMRCDMSO-d ) δ ppm :7.25-7.30 (1H, m), 7.45-7.60 (3H, m), 7.70-7.85 (3H, 6 m ), 11.00 (1H, br) Compound 1-49

'H-NMRCDMSO-d ) δ ppm:7.35-7.45 (1H, m), 7.90-8.05 (3H, m), 8.10-8.20 (2H, 6 m), 1L05 (2H, br) 化合物1-50 'H-NMRCDMSO-d ) δ ppm:7.40-7.50 (1H, m), 7.85-7.95 (1H, m)5 8e00-8e05 (1H, 6 m), 8.05-8J5 (1H, m), 8.20-8.30 (1H, m)s 11.12 (1H, br) 化合物1-51 'H-NMRCDMSO-d ) δ ppm :2,39 (3H, s), 7〇35-7.45 (1H, m), 7.45-7.55 (2H, m), 7 6 .65-7.80 (2H, m), 7.85-7.95 (1H, m), 1L12 (2H, br) 化合物1-52 士-NMR(DMSCHd ) δ ppm:2.43 (3H, s)，7。25-7。35 (1H, m), 7·35—7。45 (1H, m)，7 6 •45-7.55 (1H, m), 7.60-7.70 (1H, m), 7。75-7.85 (1H, m), 8.Ό0-8.10 (1H, m)，1L19 (2H, br) 化合物1 - 5 3 ^-NMRCDMSO-d ) δ ppm:7.35-7.45 (1H, m), 7；8〇-7.90 (1H, m), 7.90-8.10 (3H, 6 m), 8.30-8.40 (1H, m), 11.23 (2H, br) 化合物1 - 5 4 312XP/發明說明書(補件)/96-03/95143900 189 200800871 1H-NMR(DMSO~d ) δ ppm:7.35-7.45 (1H, m), 7.60-7.85 (3H, m), 7.95-8.00 (1H5 6 m), 8.10-8.20 (1H, m), 8.30-8.40 (1H，m), 8.40-8。45 (1H, m), 8.45-8.55 (1H，m), 11.01 (2H, br) 化合物1 - 5 5 ^-NMRCDMSO-d ) δ ppm:7.40-7.50 (1H, m), 7.80-7.90 (1H, m), 7.95-8.05 (1H? 6 m), 8.15-8.20 (1H, m), 8.20-8.30 (1H, m), 8.45-8.55 (1H, m), 11.12 (1H, br) 化合物1 - 5 6 'H-NMRCDMSO-d ) δ ppm:7.35-7.45 (1H, m), 7〇90-8.00 (1H, m), 8.05-8.20 (4HS 6'H-NMRCDMSO-d ) δ ppm: 7.35-7.45 (1H, m), 7.90-8.05 (3H, m), 8.10-8.20 (2H, 6 m), 1L05 (2H, br) Compound 1-50 'H -NMRCDMSO-d ) δ ppm: 7.40-7.50 (1H, m), 7.85-7.95 (1H, m)5 8e00-8e05 (1H, 6 m), 8.05-8J5 (1H, m), 8.20-8.30 (1H , m)s 11.12 (1H, br) Compound 1-51 'H-NMRCDMSO-d ) δ ppm : 2,39 (3H, s), 7〇35-7.45 (1H, m), 7.45-7.55 (2H, m), 7 6 .65-7.80 (2H, m), 7.85-7.95 (1H, m), 1L12 (2H, br) Compound 1-52 ±NMR (DMSCHd ) δ ppm:2.43 (3H, s), 7.25-7.35 (1H, m), 7·35-7.45 (1H, m), 7 6 •45-7.55 (1H, m), 7.60-7.70 (1H, m), 7.75 -7.85 (1H, m), 8.Ό0-8.10 (1H, m), 1L19 (2H, br) Compound 1 - 5 3 ^-NMRCDMSO-d ) δ ppm:7.35-7.45 (1H, m), 7; 8〇-7.90 (1H, m), 7.90-8.10 (3H, 6 m), 8.30-8.40 (1H, m), 11.23 (2H, br) Compound 1 - 5 4 312XP/Invention Manual (supplement)/96 -03/95143900 189 200800871 1H-NMR (DMSO~d) δ ppm: 7.35-7.45 (1H, m), 7.60-7.85 (3H, m), 7.95-8.00 (1H5 6 m), 8.10-8.20 (1H, m), 8.30-8.40 (1H,m), 8.40-8.45 (1H, m), 8.45-8.55 (1H,m), 11.01 (2H, br) Compound 1 - 5 5 ^-N MRCDMSO-d ) δ ppm: 7.40-7.50 (1H, m), 7.80-7.90 (1H, m), 7.95-8.05 (1H? 6 m), 8.15-8.20 (1H, m), 8.20-8.30 (1H, m), 8.45-8.55 (1H, m), 11.12 (1H, br) Compound 1 - 5 6 'H-NMRCDMSO-d ) δ ppm: 7.35-7.45 (1H, m), 7〇90-8.00 (1H, m), 8.05-8.20 (4HS 6

m), 11.12 (1H, br) 化合物1 - 5 7 'H-NMRiDMSO-d ) δ ppm:7.40-7.50 (1H, m), 7〇68 (1H, br s), 7.70-7.80 (1H, m) 6 ,7.90-8.00 (1H, m), 8.05-8.20 (2H, m), 8.30 (1H, br s), 8.35-8.45 (1H, m), 11.08 ( 1H, br) 化合物1 - 5 8 'H-NMRCDMSO-d ) δ ppm:7.45-7.55 (1H, m), 7〇85-7.95 (1H, m), 7.95-8.05 (2H, 6 m), 8.10-8.20 (1H, m), 8.25-8.35 (1H, m), 11.22 (1H, br) 化合物1 - 5 9 'H-NMRiDMSO-d ) δ ppm:7.45-7.50 (1H, m), 7.65-7.75 (1H, m), 7.80-7.90 (1HS 6 m), 7.90-8.00 (1H, m), 8.20-8.25 (1H, m), 11.14 (1H, br) 化合物1 - 6 0 'H-NMRCDMSO-d ) δ ppm: 7.40-7.50 (1H, m), 7.95-8.05 (4H, m), 11.04 (2H, br) 6 化合物1-61 'H-NMRCDMSO-d ) δ ppm:2.08 (3H, s), 7.60-7.70 (2H, m), 7.70-7.80 (2H? m), 7 6 .80-7.85 (2H, m), 1L00 (1H, br), 11.33 (1H, br) 190 312XP/發明說明書(補件)/96-03/95143%0 200800871 化合物1 - 6 2 'Η-NMR(DMSO-d ) δ ppm:7.50-7.60 (1H，m)，8.10_8。20 (1H, m)，8.54 (1H，s)，8 6 „60 (2H, s), 11.09 (1H, br) 化合物1 - 6 3 1H-NMR(DMSO~d ) δ ppm :7.35-7.45 (1H, m), 7.70-7〇80 (1HS m)9 7.85-7.95 (2H, 6 m), 8.20-8.25 (1H, m), 1L08 (1H, br) 化合物1-64 -NMR(DMSO-d ) 0 ppm:7e45-7·55 (1H, m), 7.60-7J5 (3H，m)s 7.90-8.00 (1H, 6m), 11.12 (1H, br) Compound 1 - 5 7 'H-NMRiDMSO-d ) δ ppm: 7.40-7.50 (1H, m), 7〇68 (1H, br s), 7.70-7.80 (1H, m 6 , 7.90-8.00 (1H, m), 8.05-8.20 (2H, m), 8.30 (1H, br s), 8.35-8.45 (1H, m), 11.08 ( 1H, br) Compound 1 - 5 8 ' H-NMRC DMSO-d ) δ ppm: 7.45-7.55 (1H, m), 7〇85-7.95 (1H, m), 7.95-8.05 (2H, 6 m), 8.10-8.20 (1H, m), 8.25- 8.35 (1H, m), 11.22 (1H, br) Compound 1 - 5 9 'H-NMRiDMSO-d ) δ ppm: 7.45-7.50 (1H, m), 7.65-7.75 (1H, m), 7.80-7.90 ( 1HS 6 m), 7.90-8.00 (1H, m), 8.20-8.25 (1H, m), 11.14 (1H, br) Compound 1 - 6 0 'H-NMRCDMSO-d ) δ ppm: 7.40-7.50 (1H, m), 7.95-8.05 (4H, m), 11.04 (2H, br) 6 Compound 1-61 'H-NMRCDMSO-d ) δ ppm:2.08 (3H, s), 7.60-7.70 (2H, m), 7.70 -7.80 (2H? m), 7 6 .80-7.85 (2H, m), 1L00 (1H, br), 11.33 (1H, br) 190 312XP/Invention Manual (supplement)/96-03/95143%0 200800871 Compound 1 - 6 2 'Η-NMR (DMSO-d ) δ ppm: 7.50-7.60 (1H, m), 8.10_8. 20 (1H, m), 8.54 (1H, s), 8 6 „60 (2H , s), 11.09 (1H, br) Compound 1 - 6 3 1H-NMR (DMSO~d) δ ppm :7.35-7.45 (1H, m ), 7.70-7〇80 (1HS m)9 7.85-7.95 (2H, 6 m), 8.20-8.25 (1H, m), 1L08 (1H, br) Compound 1-64 - NMR (DMSO-d ) 0 ppm :7e45-7·55 (1H, m), 7.60-7J5 (3H,m)s 7.90-8.00 (1H, 6

m), 11.08 (1H, br) 化合物1 - 6 5 i-NMRiDMSO-d ) δ ppm:7。40-7.45 (1H, m), 7.90-8.00 (1H，m)，8.25-8·35 (1H, 6 m)? 8.35-8.40 (1H, m), 8.62 (1H, s), 11.09 (1H, br) 化合物1-66 i-NMR(DMSO-de) δ ppm:7.50-7.55 (1H, m), 7.65-7。80 (2H，m), 7.85-7.95 (1H, m), 7.95-8.10 (2H, m), 8.10-8.20 (1H, m), 8.20-8.30 (1H, m), 8.65-8.75 (1H, m), 11.14 (1H, br) 化合物1 - 6 7 1H~NMR(DMS〇-d ) δ ppm :7.45-7.55 (1H, m), 7.90-8=00 (3H, m)5 11.18 (1H, br) 6 化合物1-68 'H-NMRCDMSO-d ) δ ppm:7e45-7.50 (1H, m), 7.9〇-8β〇5 (2H, m), 8.10-8.20 (1H, 6 m), 8.45-8.50 (1H, m)5 1L10 (1H, br) 化合物1 - 6 9 'H-NMRiDMSO-d ) δ ppm:7.35-7.45 (1H, m), 7.50-7.60 (1H, m), 7.70-7.80 (1H 6 9 m)，7。85-7.90 (1H, m), 8e25-8.35 (1H，m), 11.09 (1H，br) 191 312XP/發明說明書(補件)/96-03/95143900 200800871 化合物1-70 ^-NMRCDMSO-d ) δ ppm:7e30-7.40 (1Η, m), 7.80-7.90 (1H, m), 8.00-8.15 (2H, 6 m)s 8.30-8.40 (1H, m), 1L03 (1H, br) 化合物1 - 71 'H-NMRCDMSO-d ) δ ppm:7〇35-7e45 (1H5 m), 7.85-7.95 (1H, m), 8,31 (1H, s), 8 6 .35-8.40 (1H, m), 8.50-8.60 (1H, m)s 11.09 (1H, br) 化合物1 - 7 2m), 11.08 (1H, br) Compound 1 - 6 5 i-NMRiDMSO-d ) δ ppm: 7.40-7.45 (1H, m), 7.90-8.00 (1H, m), 8.25-8·35 (1H , 6 m)? 8.35-8.40 (1H, m), 8.62 (1H, s), 11.09 (1H, br) Compound 1-66 i-NMR (DMSO-de) δ ppm: 7.50-7.55 (1H, m) , 7.65-7.80 (2H,m), 7.85-7.95 (1H, m), 7.95-8.10 (2H, m), 8.10-8.20 (1H, m), 8.20-8.30 (1H, m), 8.65- 8.75 (1H, m), 11.14 (1H, br) Compound 1 - 6 7 1H~NMR(DMS〇-d ) δ ppm :7.45-7.55 (1H, m), 7.90-8=00 (3H, m)5 11.18 (1H, br) 6 Compound 1-68 'H-NMRCDMSO-d ) δ ppm: 7e45-7.50 (1H, m), 7.9〇-8β〇5 (2H, m), 8.10-8.20 (1H, 6 m ), 8.45-8.50 (1H, m)5 1L10 (1H, br) Compound 1 - 6 9 'H-NMRiDMSO-d ) δ ppm: 7.35-7.45 (1H, m), 7.50-7.60 (1H, m), 7.70-7.80 (1H 6 9 m), 7.85-7.90 (1H, m), 8e25-8.35 (1H, m), 11.09 (1H, br) 191 312XP/invention manual (supplement)/96-03/ 95143900 200800871 Compound 1-70 ^-NMRCDMSO-d ) δ ppm: 7e30-7.40 (1Η, m), 7.80-7.90 (1H, m), 8.00-8.15 (2H, 6 m)s 8.30-8.40 (1H, m ), 1L03 (1H, br) Compound 1 - 71 'H-NMRCDMSO-d ) δ ppm: 7〇35-7e45 (1H5 m), 7.85- 7.95 (1H, m), 8,31 (1H, s), 8 6 .35-8.40 (1H, m), 8.50-8.60 (1H, m)s 11.09 (1H, br) Compound 1 - 7 2

^NMRCDMSO-d ) δ ppm:L33 (3HS t, J=7.1Hz), 2.45 (3H, s), 4〇37 (2H, q, J=7.1 6^NMRCDMSO-d ) δ ppm: L33 (3HS t, J=7.1Hz), 2.45 (3H, s), 4〇37 (2H, q, J=7.1 6

Hz), 7.55 (1H, d, J=2„0Hz), 7.68-7.71 (2H, m), 7.98 (1H, d, J=2e5Hz) 化合物1-73 'H-NMRCDMSO-d ) δ ppm:7〇40-7e45 (1H, m), 7.65-7.95 (3H, m), 8.05-8.15 (1H, 6 m), 1L16 (1H, br) 化合物1-74 ^-NMRXDMSO-d^ 6 ppm :2.38 (3HS s\ 7.35-7.45 (1H, m), 7.45-7.50 (1H, m), 7 β52 (1H，s), 7·80-7·90 (1H, m), 8·10-8β15 (1H, m)，11·12 (1H, br) φ化合物1-75 ^-NMRCDMSO-d^ δ ppm :2.43 (3H, s), 7.40-7.45 (1H, m), 7.50-7.60 (2H, m) 7 。85-7。90 (1H，m), 8.05-8.15 (1H, m), 1L11 (1H, br) 化合物1 - 7 6 ^-NMRiDMSO-d^ δ ppm:7.45-7.55 (1H, m), 7.95-8.00 (1H, m), 8.05-8.10 (1H, m), 8e25-8〇30 (1H, m), 8.35-8.40 (1H, m), 1L20 (1H, br) 化合物1 - 7 7 'H-NMRCDMSO-d ) δ ppm:7；50~7e60 (1H, m), 8.00-8.10 (2Ή, m), 8.15-8»20 (1H, 6 m), 8.30-8.40 (1H, m), 11.22 (1H, br) 192 312XP/發明說明書(補件)/96-03/95143900 200800871 化合物1 - 7 8 1H-NMR(DMS〇-d6) δ ppm:7.50-7.60 (lH, m), 8.00-8.15 (2H, m), 8.35-8.45 (IH, m), 8.45-8.50 (1H, m), 11.21 (1H, br) 化合物1 - 7 9 'H-NMRCDMSO-d ) δ ppm:2.42 (3H? s)? 7.45-7.55 (1H, m), 7.75-7.85 (1H5 m), 7 6 。90-8‘。00 (2H5 m)，8.15-8.20 (1H，m)5 11。22 (1H, br) 化合物1 - 8 0 'H-NMRiDMSO-d ) δ ppm :7.50-7.60 (1H, m), 7.80-7.90 (1H, m)? 7.90-8.05 (3H, 6Hz), 7.55 (1H, d, J=2„0Hz), 7.68-7.71 (2H, m), 7.98 (1H, d, J=2e5Hz) Compound 1-73 'H-NMRCDMSO-d ) δ ppm:7 〇40-7e45 (1H, m), 7.65-7.95 (3H, m), 8.05-8.15 (1H, 6 m), 1L16 (1H, br) Compound 1-74 ^-NMRXDMSO-d^ 6 ppm :2.38 ( 3HS s\ 7.35-7.45 (1H, m), 7.45-7.50 (1H, m), 7 β52 (1H, s), 7·80-7·90 (1H, m), 8·10-8β15 (1H, m),11·12 (1H, br) φ compound 1-75 ^-NMRCDMSO-d^ δ ppm :2.43 (3H, s), 7.40-7.45 (1H, m), 7.50-7.60 (2H, m) 7 85-7.90 (1H, m), 8.05-8.15 (1H, m), 1L11 (1H, br) Compound 1 - 7 6 ^-NMRiDMSO-d^ δ ppm: 7.45-7.55 (1H, m), 7.95-8.00 (1H, m), 8.05-8.10 (1H, m), 8e25-8〇30 (1H, m), 8.35-8.40 (1H, m), 1L20 (1H, br) Compound 1 - 7 7 ' H-NMRCDMSO-d ) δ ppm:7;50~7e60 (1H, m), 8.00-8.10 (2Ή, m), 8.15-8»20 (1H, 6 m), 8.30-8.40 (1H, m), 11.22 (1H, br) 192 312XP/Invention Manual (supplement)/96-03/95143900 200800871 Compound 1 - 7 8 1H-NMR (DMS〇-d6) δ ppm: 7.50-7.60 (lH, m), 8.00- 8.15 (2H, m), 8.35-8.45 (IH, m), 8.45-8.50 (1H, m), 11.21 (1H, br) Compound 1 - 7 9 'H-NMRCDMSO-d δ ppm: 2.42 (3H? s)? 7.45-7.55 (1H, m), 7.75-7.85 (1H5 m), 7 6 .90-8'.00 (2H5 m), 8.15-8.20 (1H, m) 5 11.22 (1H, br) Compound 1 - 8 0 'H-NMRiDMSO-d ) δ ppm : 7.50-7.60 (1H, m), 7.80-7.90 (1H, m)? 7.90-8.05 (3H, 6

m), 11.27 (1H, br) 化合物1 - 81 'H-NMRCDMSO-d ) δ ppm :7.45-7.55 (1H, m), 7.95-8.05 (2H, m), 8.05-8.15 (1H? 6 m), 8.20-8.30 (1H, m), 11.27 (1H, br) 化合物1 - 8 2 W-NMR(DMSO-气)δ ppm:7.50-7.60 (lH，m)，7.95-8.05 (1H, m), 8.15-8.25 (1H， m), 8.30-8.40 (1H, m), 8.60-8.65 (1H, m), 1L22 (1H, br) φ化合物1 - 8 3 'H-NMRiDMSO-d ) δ ppm:7.40-7.45 (1H, m), 7.90-7.95 (1H, m), 8.10-8.20 (1H, 6 m), 8.25-8.35 (1H, m), 8.35-8.40 (1H, m), 1L15 (1H, br) 化合物1-84 ^-NMRCDMSO-d ) δ ppm:7.45-7.55 (1H, m), 7.85-7.95 (1H, m), 7.95-8,05 (2H, 6 m), 8.15-8.20 (1H, m), 11.19 (1H, br) 化合物1 - 8 5 'H-NMRCDMSO-d ) δ ppm :7.58 (1H, d, J=2.2Hz), 8.05 (1H, t, J=7.8Hz), 8.10 (1 6 H, d, J=2.2Hz), 8.44 (2H, d, J=7.8Hz), 11.25 (1H, br) 193 312XP/發明說明書(補件)/96-03/95143900 200800871 化合物1 - 8 6 ^-NMRCDMSO^d ) δ ppm:2.61 (3Η, s), 7〇40~7.50 (1H, m), 7.60-7.75 (2H, m), 6 , 7.75-7.85 (1H, m), 7.85-7.90 (1H, m), 8.00-8.10 (1H, m), 11.15 (1H, br) 化合物1- 8 7m), 11.27 (1H, br) Compound 1 - 81 'H-NMRCDMSO-d ) δ ppm :7.45-7.55 (1H, m), 7.95-8.05 (2H, m), 8.05-8.15 (1H? 6 m) , 8.20-8.30 (1H, m), 11.27 (1H, br) Compound 1 - 8 2 W-NMR (DMSO-gas) δ ppm: 7.50-7.60 (lH, m), 7.95-8.05 (1H, m), 8.15-8.25 (1H, m), 8.30-8.40 (1H, m), 8.60-8.65 (1H, m), 1L22 (1H, br) φ compound 1 - 8 3 'H-NMRiDMSO-d ) δ ppm: 7.40 -7.45 (1H, m), 7.90-7.95 (1H, m), 8.10-8.20 (1H, 6 m), 8.25-8.35 (1H, m), 8.35-8.40 (1H, m), 1L15 (1H, br Compound 1-84 ^-NMRCDMSO-d ) δ ppm: 7.45-7.55 (1H, m), 7.85-7.95 (1H, m), 7.95-8,05 (2H, 6 m), 8.15-8.20 (1H, m), 11.19 (1H, br) Compound 1 - 8 5 'H-NMRCDMSO-d ) δ ppm : 7.58 (1H, d, J = 2.2 Hz), 8.05 (1H, t, J = 7.8 Hz), 8.10 ( 1 6 H, d, J=2.2Hz), 8.44 (2H, d, J=7.8Hz), 11.25 (1H, br) 193 312XP/Invention Manual (supplement)/96-03/95143900 200800871 Compound 1 - 8 6 ^-NMRCDMSO^d ) δ ppm: 2.61 (3Η, s), 7〇40~7.50 (1H, m), 7.60-7.75 (2H, m), 6 , 7.75-7.85 (1H, m), 7.85- 7.90 (1H, m), 8.00-8.10 (1H, m), 11.15 (1H, br) Compound 1- 8 7

1H-NMR(DMS〇-d ) δ ppm:7.40-7.50 (1H, m), 7.95-8.00 (1H, m), 8.20-8.25 (1H 6 ,m), 8.25-8.30 (1H, m), 11.02 (1H, br) 化合物1_ 8 8 i-NMR(DMSO_d ) δ ppm:7.45-7.55 (1HS m), 7.73 (1H, d，J=8.9Hz)，7。95-8。00 61H-NMR (DMS〇-d) δ ppm: 7.40-7.50 (1H, m), 7.95-8.00 (1H, m), 8.20-8.25 (1H 6 ,m), 8.25-8.30 (1H, m), 11.02 (1H, br) Compound 1_ 8 8 i-NMR (DMSO_d ) δ ppm: 7.45-7.55 (1HS m), 7.73 (1H, d, J=8.9Hz), 7.95-8.00 6

(2H, m), 11.13 (1H, br) 化合物1 - 8 9 1H-NMR(DMS〇-d ) 8 ppm:3.81 (6H, s), 6.80 (1H, t, J=2.2Hz), 7.00 (2H, d, J=2. 6 2Hz), 7.40-7.45 (1H, m), 7.90-7.95 (1H, m), 1L08 (1H, br) 化合物1-90 1H-NMR(DMS〇-d ) δ ppm:3.72 (3H, s), 3.86 (6H, s), 7.17 (2H, s), 7.40-7.50 (1 6 H, m), 7.90-8.00 (1H, m), 11.01 (1H, br) 0化合物1 - 91 iH-NMlUDMSO-d ) δ ppm:2.28 (3H, s), 2·54 (6H，s)，7。11 (2H, s), 7.25-7.30 (1 6 H, m), 7.70-7.75 (1H, m), 1L02 (1H, br) 化合物1-92(2H, m), 11.13 (1H, br) Compound 1 - 8 9 1H-NMR (DMS 〇-d ) 8 ppm: 3.81 (6H, s), 6.80 (1H, t, J = 2.2 Hz), 7.00 ( 2H, d, J=2. 6 2Hz), 7.40-7.45 (1H, m), 7.90-7.95 (1H, m), 1L08 (1H, br) Compound 1-90 1H-NMR (DMS〇-d ) δ Ppm: 3.72 (3H, s), 3.86 (6H, s), 7.17 (2H, s), 7.40-7.50 (1 6 H, m), 7.90-8.00 (1H, m), 11.01 (1H, br) 0 Compound 1 - 91 iH-NMlUDMSO-d ) δ ppm: 2.28 (3H, s), 2·54 (6H, s), 7.11 (2H, s), 7.25-7.30 (1 6 H, m), 7.70 -7.75 (1H, m), 1L02 (1H, br) Compound 1-92

'H-NMRCDMSO-d ) δ ppm:7.35-7.45 (1H, m), 7.50-7.60 (1H, m), 7.60-7.70 (1H 6 ,m), 7.80-7.90 (2H, m), 8.15-8.25 (1H, m), 1L02 (1H, br) 化合物1 - 9 3 'H-NMRCDMSO-d ) δ ppm:7.40-7.50 (1H? m), 7.70-7.85 (2H, m), 7.90-7.95 (1H 6 ,m), 7.95-8.05 (2H, m), 10.94 (1H, br) 194 312XP/發明說明書(補件)/96-03/95143900 200800871 化合物1-94 'H-NMRCDMSO-d ) 5 ppm:2.77 (3H, s), 7β4〇-7.45 (1H, m), 7.60-7.70 (1H, m), 6 7.70-7.75 (1H, m), 7.80-7.90 (1H, m), 11.05 (1H, br) 化合物1 - 95 1H-NMR(DMS〇-d ) δ ppm:7.45-7.55 (1H, m), 8.00-8.10 (1H, m), 8.45-8.50 (1H, 6 m), 8.60-8.70 (1H, m), 10.91 (1H, br) 化合物1-96 'H-NMRCDMSO-d ) δ ppm: 7.45-7.55 (1H, m), 7.95-8^05 (1H, m), 8.25-8.30 (1H 6'H-NMRCDMSO-d ) δ ppm: 7.35-7.45 (1H, m), 7.50-7.60 (1H, m), 7.60-7.70 (1H 6 ,m), 7.80-7.90 (2H, m), 8.15-8.25 (1H, m), 1L02 (1H, br) Compound 1 - 9 3 'H-NMRCDMSO-d ) δ ppm: 7.40-7.50 (1H? m), 7.70-7.85 (2H, m), 7.90-7.95 (1H 6 , m), 7.95-8.05 (2H, m), 10.94 (1H, br) 194 312XP / invention specification (supplement) /96-03/95143900 200800871 Compound 1-94 'H-NMRCDMSO-d ) 5 ppm: 2.77 (3H, s), 7β4〇-7.45 (1H, m), 7.60-7.70 (1H, m), 6 7.70-7.75 (1H, m), 7.80-7.90 (1H, m), 11.05 (1H, br Compound 1 - 95 1H-NMR (DMS〇-d ) δ ppm: 7.45-7.55 (1H, m), 8.00-8.10 (1H, m), 8.45-8.50 (1H, 6 m), 8.60-8.70 (1H , m), 10.91 (1H, br) Compound 1-96 'H-NMRCDMSO-d ) δ ppm: 7.45-7.55 (1H, m), 7.95-8^05 (1H, m), 8.25-8.30 (1H 6

,m), 8.40-8.45 (1H, m), 1L09 (2H, br) 化合物1 - 9 7 'H-NMRCDMSO-d ) δ ppm:7.45-7.55 (IH, m), 7.90-8.05 (2H, m), 8.10-8.20 (1H 6 ,m), 11.23 (1H, br) 化合物1-98 'H-NMRCDMSO-d ) δ ppm:6.60-6.90 (1H, m), 7〇25-7〇30 (1H, m), 7.55-7.60 (1H 6 ,m), 7.60-7.65 (1H, m), 7.80-7.95 (2H, m), 8.15-8.25 (1H, m), 10.96 (1H, br) 0化合物1 - 9 9, m), 8.40-8.45 (1H, m), 1L09 (2H, br) Compound 1 - 9 7 'H-NMRCDMSO-d ) δ ppm: 7.45-7.55 (IH, m), 7.90-8.05 (2H, m ), 8.10-8.20 (1H 6 ,m), 11.23 (1H, br) Compound 1-98 'H-NMRCDMSO-d ) δ ppm: 6.60-6.90 (1H, m), 7〇25-7〇30 (1H , m), 7.55-7.60 (1H 6 ,m), 7.60-7.65 (1H, m), 7.80-7.95 (2H, m), 8.15-8.25 (1H, m), 10.96 (1H, br) 0 Compound 1 - 9 9

擎 ^-NMRCDMSO-d ) δ ppm:6.70-7.00 (1H, m), 7.40-7.50 (1HS m), 7〇60-7.70 (1H 6 ,m)s 7.70-7.85 (2H, m), 7.90-8.00 (2H, m), 11.11 (1H, br) 化合物1-100 ^-NMRCDMSO-d ) 6 ppm:7.35-7〇45 (1H, m), 7.68 (1H, t, J=54〇2Hz)? 7.80-8.00 6 (4H, m), 8.10-8.20 (1H, m), 1L06 (1H, br) 化合物1-101 ^-NMRiDMSO-d ) δ ppm:7.40-7.50 (1H, m), 7.65 (1H, t, J=54e2Hz), 7.70-7.80 6 (1H, m), 7.90-8.05 (3H, m), 11.02 (1H, br) 化合物卜102 195 M2XP/發明說明書(補件)/96-03/95143900 200800871 1H-NMR(DMS〇-d ) δ ppm:7e50-7e60 (1H, m), 7.60-7.70 (1H, m), 7 JO-8.05 (3H 6 ,m), 1U5 (1H, br) 化合物1-103 ^-NMRiDMSO-d ) δ ppm:2〇66 (3H, s), 7.45-7.50 (1H, m), 8〇00~8〇05 (1H, m), 6 8.20-8.35 (3H, m), 11.02 (1H, br) 化合物1-104 ^-NMR(DMSO-d ) δ ppm:3〇91 (3H, s), 7.40-7.50 (1H, m), 8〇00-8〇05 (1H, m), 6 8.15-8〇25 (1H, m), 8.25-8.40 (2H, m), 1L08 (1H, br) ®化合物1-105 'H-NMRCDMSO-d ) δ ppm:7〇14 (1H, t, J=55.2Hz), 7.40-7.50 (1H, m), 8.00-8.05 6 (2H, m), 8.05-8.15 (1H, m), 8.20-8.25 (1H, m), 11.12 (1H, br) 化合物1-106擎^-NMRCDMSO-d ) δ ppm: 6.70-7.00 (1H, m), 7.40-7.50 (1HS m), 7〇60-7.70 (1H 6 ,m)s 7.70-7.85 (2H, m), 7.90- 8.00 (2H, m), 11.11 (1H, br) Compound 1-100^-NMRCDMSO-d) 6 ppm: 7.35-7〇45 (1H, m), 7.68 (1H, t, J=54〇2Hz)? 7.80-8.00 6 (4H, m), 8.10-8.20 (1H, m), 1L06 (1H, br) Compound 1-101 ^-NMRiDMSO-d ) δ ppm: 7.40-7.50 (1H, m), 7.65 (1H , t, J=54e2Hz), 7.70-7.80 6 (1H, m), 7.90-8.05 (3H, m), 11.02 (1H, br) Compound Bu 102 195 M2XP/Invention Manual (supplement)/96-03/ 95143900 200800871 1H-NMR (DMS〇-d ) δ ppm: 7e50-7e60 (1H, m), 7.60-7.70 (1H, m), 7 JO-8.05 (3H 6 ,m), 1U5 (1H, br) 1-103 ^-NMRiDMSO-d ) δ ppm: 2〇66 (3H, s), 7.45-7.50 (1H, m), 8〇00~8〇05 (1H, m), 6 8.20-8.35 (3H, m), 11.02 (1H, br) Compound 1-104 ^-NMR (DMSO-d ) δ ppm: 3〇91 (3H, s), 7.40-7.50 (1H, m), 8〇00-8〇05 ( 1H, m), 6 8.15-8〇25 (1H, m), 8.25-8.40 (2H, m), 1L08 (1H, br) ® compound 1-105 'H-NMRCDMSO-d ) δ ppm:7〇14 (1H, t, J=55.2Hz), 7.40-7.50 (1H, m), 8.00-8.05 6 (2H, m), 8.05-8.15 (1H, m), 8.20-8.25 (1H, m), 11.12 (1H, br) Compound 1-106

1H-NMR(DMS〇-d ) δ ppm:7.50-7.60 (1H, m), 7.60-7.70 (1H, m)3 7.75-8.05 (4H 6 ,m), 1L15 (1H, br) 化合物1-1071H-NMR (DMS〇-d) δ ppm: 7.50-7.60 (1H, m), 7.60-7.70 (1H, m)3 7.75-8.05 (4H 6 ,m), 1L15 (1H, br) Compound 1-107

^-NMRCDMSO-d ) δ ppm:7e35-7e45 (1H, m), 7.50-7.80 (3H, m), 7.90-8.00 (1H 6 ，m)，8。20-8。30 (1H, m), 1L12 (1H，br) 化合物1-108 2Hz), 7.83-7.89 (3H, m), 11.07 (1H, br) 化合物1-109 十 —- -一 1H-NMR(CDC13) δ ppm: 1.15 (3H, t, J=7.4Hz), 2.88 (2H, q, J=7.5Hz), 7.35 (1H, d, J=7〇6Hz), 7.42 (1H, t, J=7e3Hz), 7.53-7.63 (2H, m), 8.17 (1H, dd, 1=8.2, 1.3Hz), 8.26 (1H, d? J=2.2Hz), 11.00 (1H, br s) 196 312XP/發明說明書(補件)/96-03/95143900 200800871 化合物1-110 -NMR(DMSO-d ) δ ppm:7.43 (1H，d，J=2.2Hz), 7.69 (2H，t，J=8.0Hz)，7。90 (1 6 H，d，』=2·2Ηζ), 8·04 (1H，dd, J=8.2, 1·6Ηζ)，8。25 (2H，dd，J二8·0, 1·4Ηζ)，11.06 (1H ,br s) 化合物1-111 1H-NMR(DMS〇-d ) δ ppm :7.48 (1H, d, J=2.2Hz), 7.88-7.94 (2H, m), 7.99 (1H, d 6 ,J=2.2Hz), 8.22 (1H, d, J=L9Hz), 11.00 (1H, br s) 化合物1-112^-NMRCDMSO-d ) δ ppm: 7e35-7e45 (1H, m), 7.50-7.80 (3H, m), 7.90-8.00 (1H 6 ,m), 8.20-8.30 (1H, m), 1L12 (1H, br) Compound 1-108 2Hz), 7.83-7.89 (3H, m), 11.07 (1H, br) Compound 1-109 X----1H-NMR (CDC13) δ ppm: 1.15 (3H, t, J=7.4Hz), 2.88 (2H, q, J=7.5Hz), 7.35 (1H, d, J=7〇6Hz), 7.42 (1H, t, J=7e3Hz), 7.53-7.63 (2H, m), 8.17 (1H, dd, 1=8.2, 1.3Hz), 8.26 (1H, d? J=2.2Hz), 11.00 (1H, br s) 196 312XP/invention manual (supplement)/96-03/ 95143900 200800871 Compound 1-110 - NMR (DMSO-d) δ ppm: 7.43 (1H, d, J = 2.2 Hz), 7.69 (2H, t, J = 8.0 Hz), 7.90 (1 6 H, d, 』=2·2Ηζ), 8·04 (1H, dd, J=8.2, 1·6Ηζ), 8.25 (2H, dd, J 2:8, 1·4Ηζ), 11.06 (1H, br s) Compound 1-111 1H-NMR (DMS 〇-d) δ ppm : 7.48 (1H, d, J = 2.2 Hz), 7.88-7.94 (2H, m), 7.99 (1H, d 6 , J = 2.2 Hz), 8.22 (1H, d, J=L9Hz), 11.00 (1H, br s) Compound 1-112

^-NMRCDMSO-d ) δ ppm :2.28 (3H, s\ 2.29 (3H, s), 7.36-7.41 (2H, m), 7〇65 (1 6 H, dd, J=7.9, L9Hz), 7.69-7.71 (1H, m), 7.86 (1H, d, J=2.2Hz), 10.00-1L92 (1HS m) 化合物1 -113 ^-NMRiDMSO-d ) δ ppm:2.36 (3H, s), 2〇39 (3H, s), 7.29 (1H, d, J=7e6Hz), 7.33 6 (1H, d, J=2.2Hz), 7.44 (1H, dd, J=7.7, L4Hz), 7.81 (1H, d, J=2.2Hz), 7〇90 (1H, d, J=L3Hz), 10.98 (1H, br s) 化合物1-114 ^-NMRiDMSO-d ) δ ppm:2.27 (3H, s), 2.33 (3H, s), 7.30 (1H, d, J=2.2Hz), 7.41 6 (2H, t, J=7e7Hz), 7.55 (1H, d, J=7.6Hz), 7.80 (1H, d, J=2.2Hz), 7.94 (1H, d, J=7.9^-NMRCDMSO-d ) δ ppm : 2.28 (3H, s\ 2.29 (3H, s), 7.36-7.41 (2H, m), 7〇65 (1 6 H, dd, J=7.9, L9Hz), 7.69- 7.71 (1H, m), 7.86 (1H, d, J=2.2Hz), 10.00-1L92 (1HS m) Compound 1 -113 ^-NMRiDMSO-d ) δ ppm: 2.36 (3H, s), 2〇39 ( 3H, s), 7.29 (1H, d, J=7e6Hz), 7.33 6 (1H, d, J=2.2Hz), 7.44 (1H, dd, J=7.7, L4Hz), 7.81 (1H, d, J= 2.2 Hz), 7〇90 (1H, d, J=L3Hz), 10.98 (1H, br s) Compound 1-114^-NMRiDMSO-d ) δ ppm: 2.27 (3H, s), 2.33 (3H, s) , 7.30 (1H, d, J=2.2Hz), 7.41 6 (2H, t, J=7e7Hz), 7.55 (1H, d, J=7.6Hz), 7.80 (1H, d, J=2.2Hz), 7.94 (1H, d, J=7.9

Hz), 11.01 (1H, br s) 化合物卜115 1H-NMR(DMS〇-d ) δ ppm:2.35 (3H, s), 2.37 (3H, s), 7.17-7.24 (1H, m), 7.29-7. 6 34 (2H, m), 7.78 (1H, d, J=2.2Hz), 7.96 (1HS d, J=8.2Hz), 11.25 (1H, br s)^ 化合物1-116 1H-NMR(DMS〇-d ) δ ppm:7.52 (1H, d, J=2.3Hz), 8.08 (1H, d, J=2.3Hz), 8.77 (1 6 H, t, J=L4Hz), 8.82 (2H, d, J=L4Hz) 312XP/發明說明書(補件)/96-03/95143900 197 200800871 化合物1 -117 ^-NMRCDMSO-d ) δ ppm:2.59 (3Η, s), 7.47 (1H, d, J=2.6Hz), 7.93-7.95 (2H, m 6 ),8.23 (1H, d, J=2.2Hz) 化合物1-118 'H-NMRCDMSO-d ) δ ppm:4.48 (3H, s), 7.52 (1H, d, J=2.3Hz), 7.80-7.90 (1H, m 6 ),7·98 (1H, d，J=2.3Hz)，8.10-&20 (1H，m)，8β30-8·40 (1H, m), 8.45-8.55 (1H, m) 化合物1-119 "H-NMRCDMSO-d ) δ ppm: 1.85-2.05 (2H, m)s 3.25-3.30 (2H, m), 6.62 (2H, d, J= 6Hz), 11.01 (1H, br s) Compound 115 1H-NMR (DMS〇-d ) δ ppm: 2.35 (3H, s), 2.37 (3H, s), 7.17-7.24 (1H, m), 7.29- 7. 6 34 (2H, m), 7.78 (1H, d, J=2.2Hz), 7.96 (1HS d, J=8.2Hz), 11.25 (1H, br s)^ Compound 1-116 1H-NMR (DMS 〇-d ) δ ppm: 7.52 (1H, d, J=2.3Hz), 8.08 (1H, d, J=2.3Hz), 8.77 (1 6 H, t, J=L4Hz), 8.82 (2H, d, J=L4Hz) 312XP/Invention Manual (Supplement)/96-03/95143900 197 200800871 Compound 1 -117 ^-NMRCDMSO-d ) δ ppm: 2.59 (3Η, s), 7.47 (1H, d, J=2.6Hz ), 7.93-7.95 (2H, m 6 ), 8.23 (1H, d, J = 2.2 Hz) Compound 1-118 'H-NMRCDMSO-d ) δ ppm: 4.48 (3H, s), 7.52 (1H, d, J=2.3Hz), 7.80-7.90 (1H, m 6 ), 7·98 (1H, d, J=2.3Hz), 8.10-&20 (1H,m),8β30-8·40 (1H, m ), 8.45-8.55 (1H, m) Compound 1-119 "H-NMRCDMSO-d ) δ ppm: 1.85-2.05 (2H, m)s 3.25-3.30 (2H, m), 6.62 (2H, d, J = 6

9.0Hz), 7.35 (1H, d, j=2.1Hz), 7.63 (2H, d, J=9e〇Hz), 7.76 (1H, d, J=2.2Hz) 化合物1 -12 0 'H-NMRiDMSO-d ) δ ppm: 1.72 (6H, s), 2.38 (3H, s), 5.47 (1H, br), 7.21 (1H, d, 6 J=2.2Hz), 7.22-7.25 (1H, m), 7.63-7.66 (1H, m), 7.73 (1H, d, J=2.2Hz), 11.05 (1H, br) 化合物1-121 'H-NMRCDMSO-d ) δ ppm:3.94 (3H, s), 7.45-7.55 (1H, m), T.55-7.65 (1H, m), 7〇 6 70-7.80 (1H, m), 7.90-7.95 (1H, m), 11.21 (1H, br) 化合物1-122 'H-NMRCDMSO-d ) δ ppm: 1.20-1.65 (6H, m), 1.65-1.80 (2H, m), 1.95-2.05 (2HS 6 m), 4.90-5.05 (1H, m), 7.35-7,50 (1H, m), 7.5〇-7„55 (1H, m), 7.65-7.75 (1H, m)s 7.90-8.00 (1H, m), 10.78 (1H, br) 化合物1 -12 3 'H-NMRCDMSO-d ) δ ppm:L38 (3H, s), 1.39 (3H, s), 5.15-5.30 (1H, m), 7.45-7. 6 60 (2H, m), 7.65-7.75 (1H, m), 7.90-8.00 (1H, m), 1L07 (1H, br) 化合物1-124 198 312XP/發明說明書(補件)/96-03/95143900 200800871 'H-NMRiDMSO-d ) δ ppm: 1.37 (3H, t, J=7e2Hz), 4.41 (2H, q, J=7.2Hz), 7.50-7.6 6 0 (2H, m), 7.65-7.75 (1H, m), 7.90-7.95 (1H, m), 11.22 (1H, br) 化合物1-125 'H-NMRiDMSO-d ) 5 ppm:2e56 (3H, s), 7.17-7.40 (2H, m), 7.94 (1H, d, J=2.5Hz) 6 ,8.34-8.36 (1H, m), 8.64-8.67 (1H, m) 化合物1-126 'H-NMRiDMSO-d ) δ ppm:7.45-7.55 (1H, m), 7.55-7.60 (1H, m), 7.60-7.70 (1H, 6 m), 7.95-8.00 (1H, m), 1L26 (1H, br), 14.14 (1H, br) ®化合物卜127 'H-NMRCDMSO-d ) δ ρρπι:2β65 (3H, s), 7.40-7.55 (2H, m), 7〇55~7JO <1H, m), 7. 6 85-7.90 (1H, m), 11.14 (1H, br) 化合物1-128 'H-NMRCDMSO-d ) δ ppm: L16 (3H, t, J=7.1Hz), 2.97 (2H, q, J=7.1Hz), 7.40-7.5 6 0 (2H, m), 7.55-7.70 (1H, m), 7.80-7.90 (1H, m), 1L06 (1H, br) 化合物1-129 φ 1H-NMR(DMS〇-d6) δ ppm :6.91-6.93 (1H, m), 6.99-7.03 (1H, m), 7.45-7.52 (2H, m)3 7.86-7.88 (2H, m), 10〇90 (2H, br) (實施例2) 5 - (3-氮-5 -氟苯續酿基）-3-墙基苯- 1,2-二醇 (化合物2 - 1) 將4 -节氧基-3 -曱氧基苯硫醇（參考例19 -1)(300 mg )、1-漠-4 -氟-2 -三氟曱基苯（386 mg)、參 (二苯亞甲基丙酮）二鈀（〇)·二氣甲烷加成物（62mg)、（氧基二-2, 1-伸苯基）雙（二苯基膦）（71 mg)、第三丁醇鉀 312XP/發明說明書(補件)/96·03/95143900 199 200800871 (206mg)及甲苯（50mL)之混合物在1〇〇t：攪拌8小時。將反應混合物待冷卻後通過Celite(註冊商標）矽藻土層過濾:用醋酸乙醋洗提。滤、液以食鹽水洗務，用無水硫酸鎮乾燥，在減壓下進行濃縮，得粗製之j _ (4 _苄氧基—3 一甲氧基苯亞磺醯基）-3 -氯-5-氟苯。在冰浴攪拌下，將過氧間苯甲醯氯（673mg)以少量分批加入至粗製之1- (4-节氧基_ 3_甲氧基苯亞石黃釀基 3 -氯-5 -氟苯及二氯甲烷（5〇mL)之混合物中，再將此混合物升溫至室溫並攪拌30分鐘。將反應混合物通過胺丙基矽膠層過濾，用二氯甲烷洗提。濾液在減壓下進行濃縮，得粗製之1- (4 -苄氧基_ 3 -曱氧苯基苯磺醯基）_ 3-氯- 5-氟苯。在冰浴攪拌下，將四氯化鈦（233mg)加入至粗製之夏一 (4苄氧基-3 -甲氧苯基苯石黃醯基）-3-氯-5 -氟苯及一氯甲烧（50mL)之混合物中並攪拌15分鐘。將此反應 _混合物注入於在攪拌下之冰水中後用二氣甲烷稀釋。分離之有機液層依次以lm〇l/L鹽酸、食鹽水洗滌，用無水硫酸鎂乾燥。在減壓下進行濃縮，其殘留物以矽膠管柱色析法進行精製（洗提液：己烷/醋酸乙酯=5/5)，得4 — (3 一氣- 5 -氟苯磺醯基）—2 -甲氧基酚（189mg)。在室溫攪拌下，將發煙硝酸（〇· 〇31mL)加入至4 — (3 一氯- 5 -氟苯磺醯基）-2 -甲氧基酚（I89mg)及二氯甲烷 (20mL)之混合物中並攪拌15分鐘。此反應混合物以 lmol/L鹽酸洗滌，用無水硫酸鎂乾燥，在減壓下進行濃 312XP/發明說明書(補件)/96-03/95143900 200 200800871 縮。其殘留物通過SCX離子交換管柱（Argonaute公司製、 5g)過濾，以二氯甲烷洗提後將濾液濃縮，得粗製之4 -(3 -氯-5 _氟苯石黃酿基）-2 -甲氧基_6~~石肖基酸。在室溫攪拌下，將氯化鋁（205mg)加入至粗製之4- (3-氯-5 -氟苯石黃酸基）-2 -甲氧基-6 -石肖基盼及醋酸乙酯（30mL)之混合物中後再滴加吡啶（0. 30mL)。此混合物加熱迴流1夜。此反應混合物待冷卻後加入1 mo 1 /L鹽酸。分取之有機液層以食鹽水洗滌，用無水硫酸鎂乾燥，在減 •壓下進行濃縮。其殘留物通過SCX離子交換管柱 (Argonaute公司製、5g)過濾，以二氯曱烧洗提後將濾液濃縮，得目標化合物（114mg)。 4 - NMR(DMS0-d6)5ppm:7.48(lH，d，J=2.2Hz)，7. 50 — 7· 60 (1H，m)，7· 65-7· 75(lH，m)，8· 02(1H，d，2· 2Hz) 依與實施例2相同方法，使用對應之硫醇以代替1 -溴-4 -氟-2 -三氟曱基苯，合成化合物2 - 2〜化合物 • 2 - 43。此等示於表20。 312XP/發明說明書(補件)/96-03/95143900 201 200800871 [表 20]9.0 Hz), 7.35 (1H, d, j=2.1 Hz), 7.63 (2H, d, J=9e〇Hz), 7.76 (1H, d, J=2.2Hz) Compound 1 -12 0 'H-NMRiDMSO- d ) δ ppm: 1.72 (6H, s), 2.38 (3H, s), 5.47 (1H, br), 7.21 (1H, d, 6 J=2.2Hz), 7.22-7.25 (1H, m), 7.63- 7.66 (1H, m), 7.73 (1H, d, J=2.2Hz), 11.05 (1H, br) Compound 1-121 'H-NMRCDMSO-d ) δ ppm: 3.94 (3H, s), 7.45-7.55 ( 1H, m), T.55-7.65 (1H, m), 7〇6 70-7.80 (1H, m), 7.90-7.95 (1H, m), 11.21 (1H, br) Compound 1-122 'H- NMRCDMSO-d ) δ ppm: 1.20-1.65 (6H, m), 1.65-1.80 (2H, m), 1.95-2.05 (2HS 6 m), 4.90-5.05 (1H, m), 7.35-7,50 (1H , m), 7.5〇-7„55 (1H, m), 7.65-7.75 (1H, m)s 7.90-8.00 (1H, m), 10.78 (1H, br) Compound 1 -12 3 'H-NMRCDMSO- d) δ ppm: L38 (3H, s), 1.39 (3H, s), 5.15-5.30 (1H, m), 7.45-7. 6 60 (2H, m), 7.65-7.75 (1H, m), 7.90 -8.00 (1H, m), 1L07 (1H, br) Compound 1-124 198 312XP/Invention Manual (supplement)/96-03/95143900 200800871 'H-NMRiDMSO-d ) δ ppm: 1.37 (3H, t, J=7e2Hz), 4.41 (2H, q, J=7.2Hz), 7.50-7.6 6 0 (2H, m), 7.65-7.75 (1H, m), 7.90-7.95 (1H, m), 11.22 (1H, Br ) Compound 1-125 'H-NMRiDMSO-d ) 5 ppm: 2e56 (3H, s), 7.17-7.40 (2H, m), 7.94 (1H, d, J = 2.5Hz) 6 , 8.34 - 8.36 (1H, m), 8.64-8.67 (1H, m) Compound 1-126 'H-NMRiDMSO-d ) δ ppm: 7.45-7.55 (1H, m), 7.55-7.60 (1H, m), 7.60-7.70 (1H, 6 m), 7.95-8.00 (1H, m), 1L26 (1H, br), 14.14 (1H, br) ® compound 127 'H-NMRCDMSO-d ) δ ρρπι: 2β65 (3H, s), 7.40-7.55 ( 2H, m), 7〇55~7JO <1H, m), 7. 6 85-7.90 (1H, m), 11.14 (1H, br) Compound 1-128 'H-NMRCDMSO-d ) δ ppm: L16 (3H, t, J=7.1Hz), 2.97 (2H, q, J=7.1Hz), 7.40-7.5 6 0 (2H, m), 7.55-7.70 (1H, m), 7.80-7.90 (1H, m ), 1L06 (1H, br) Compound 1-129 φ 1H-NMR (DMS〇-d6) δ ppm :6.91-6.93 (1H, m), 6.99-7.03 (1H, m), 7.45-7.52 (2H, m ) 3 7.86-7.88 (2H, m), 10〇90 (2H, br) (Example 2) 5 - (3-Nitro-5-fluorobenzene continuation)-3-wall benzene - 1,2- Diol (Compound 2 - 1) 4-tertoxy-3-methoxyoxyl mercaptan (Reference Example 19-1) (300 mg), 1-Di-4-fluoro-2-trifluorodecylbenzene (386 mg), ginseng (diphenylmethyleneacetone) dipalladium (ruthenium) di-halogen methane adduct (62 mg), (oxyl) -2, 1-phenylene) bis(diphenylphosphine) (71 mg), potassium butoxide 312XP/invention specification (supplement)/96·03/95143900 199 200800871 (206 mg) and toluene (50 mL) The mixture was stirred at 1 Torr for 8 hours. The reaction mixture was cooled and filtered through a Celite (registered trademark) layer of celite: eluted with ethyl acetate. The filtrate and the solution are washed with brine, dried over anhydrous sulfuric acid, and concentrated under reduced pressure to give a crude j _(4 _benzyloxy-3 methoxy sulfinyl)-3 - chloro-5 - Fluorobenzene. Under stirring in an ice bath, peroxybenzhydryl chloride (673 mg) was added in small portions in portions to the crude 1-(4-hydroxy-3-phenyloxyphenyl sulphate 3-chloro-5. - mixture of fluorobenzene and dichloromethane (5 〇mL), the mixture was warmed to room temperature and stirred for 30 minutes. The reaction mixture was filtered through a pad of propyl acetate and eluted with dichloromethane. Concentration under pressure to obtain crude 1-(4-benzyloxy-3-(indolylphenylphenylsulfonyl)-3-chloro-5-fluorobenzene. Titanium tetrachloride was stirred under ice bath ( 233 mg) was added to a mixture of crude Xia (4 benzyloxy-3-methoxyphenyl beterinyl)-3-chloro-5-fluorobenzene and monochloromethane (50 mL) and stirred for 15 min. The reaction mixture was poured into ice water with stirring, and then diluted with di-methane. The separated organic layer was washed with MgSO 2 /L hydrochloric acid and brine and dried over anhydrous magnesium sulfate. The residue was purified by gel column chromatography (eluent: hexane/ethyl acetate = 5/5) to give 4-(3-a- 5 -fluorophenylsulfonyl)-2-methoxy Phenol (189mg). Toluene nitric acid (〇·〇31 mL) was added to 4-(3-chloro-5-fluorophenylsulfonyl)-2-methoxyphenol (I89 mg) and dichloromethane (20 mL). The mixture was stirred for 15 minutes. The reaction mixture was washed with 1 mol/L hydrochloric acid, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure 312XP/inventive (supplement)/96-03/95143900 200 200800871. Filtration through an SCX ion exchange column (5 g, manufactured by Argonaute Co., Ltd.), elution with dichloromethane, and concentration of the filtrate to obtain a crude 4-(3-chloro-5-fluorobenzoic acid)-2-methoxy Base_6~~ succinic acid. Aluminum chloride (205 mg) was added to the crude 4-(3-chloro-5-fluorophthalic acid)-2-methoxy-6- under stirring at room temperature. Pyridine (0.30 mL) was added dropwise to a mixture of EtOAc (30 mL). The mixture was heated and refluxed for one night. The mixture was cooled and then added with 1 mol / L hydrochloric acid. It was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was filtered through a SCX ion exchange column (5 g, manufactured by Argonaute) to dichloride. After the rinsing, the filtrate was concentrated to give the title compound (114 mg). 4 - NMR (DMS0-d6) 5 ppm: 7.48 (1H, d, J = 2.2 Hz), 7. 50 - 7 · 60 (1H, m), 7· 65-7·75(lH,m),8·02(1H,d,2·2Hz) In the same manner as in Example 2, the corresponding thiol was used instead of 1-bromo-4-fluoro-2. Trifluoromethane benzene, synthetic compound 2 - 2 ~ compound • 2 - 43. These are shown in Table 20. 312XP/Invention Manual (supplement)/96-03/95143900 201 200800871 [Table 20]

312XP/發明說明書(補件)/96-03/95143900 202 200800871 表20(續）312XP/Invention Manual (supplement)/96-03/95143900 202 200800871 Table 20 (continued)

312XP/發明說明書(補件)/%-03/95143900 203 200800871 表20(續）312XP/Invention Manual (supplement)/%-03/95143900 203 200800871 Table 20 (continued)

312XP/發明說明書(補件)/96-03/95143900 204 200800871 表20(續）312XP/Invention Manual (supplement)/96-03/95143900 204 200800871 Table 20 (continued)

化合物2- 2〜化合物2 - 43之物性值係如下示。化合物2 - 2 "H-NMRiDMSO-d ) δ ppm:7.51 (1H, d, J=2〇2Hz), 7.87-7.95 (1H, m), 7.98 (1H, d 6 ,J=2.3Hz), 8.02-8.10 (1H, m), 8.14 (1H, d, J=8.0Hz) 馨化合物2-3 i-NMRDMSO-d ) δ ppm:0.65-0·75 tea m), 0.90-LOO (3H, m)，LOO—1·1〇 (2H， 6 m), L30-L45 (3H, m), 2.85-3.05 (3H, m), 7.35-7.45 (1H, m), 7.50-7.55 (1H, m), 7.60-7.80 (2H, m), 7.90-8。10 (2H，m) 化合物2 - 4 ^-NMRiDMSO-d^ δ ppm :2.60-2.95 (3H, m), 4.15-4.90 (2H, m), 7.35-7.85 (9H, m), 7.95-8.10 (2H, m)The physical property values of the compound 2-2 to the compound 2 - 43 are shown below. Compound 2 - 2 "H-NMRiDMSO-d ) δ ppm: 7.51 (1H, d, J=2〇2Hz), 7.87-7.95 (1H, m), 7.98 (1H, d 6 , J=2.3Hz), 8.02-8.10 (1H, m), 8.14 (1H, d, J=8.0Hz) 化合物 compound 2-3 i-NMR DMSO-d ) δ ppm: 0.65-0·75 tea m), 0.90-LOO (3H, m ), LOO—1·1〇(2H, 6 m), L30-L45 (3H, m), 2.85-3.05 (3H, m), 7.35-7.45 (1H, m), 7.50-7.55 (1H, m) , 7.60-7.80 (2H, m), 7.90-8.10 (2H,m) Compound 2 - 4 ^-NMRiDMSO-d^ δ ppm : 2.60-2.95 (3H, m), 4.15-4.90 (2H, m) , 7.35-7.85 (9H, m), 7.95-8.10 (2H, m)

化合物2 - 5 1H-NMR(DMS〇-d ) δ ppm:2.70 (3H, s), 3.01 (3H, s), 7.41 (1H, dd, J=7.6, 1.3Hz) 6 ,7.50-7.55 (1H, m), 7.60-7.80 (2H, m), 7.95 (1H, d, J=2.2Hz), 8.04 (1H, dd, J=7.9, 1.0Hz), 1L07 (1H, br) 化合物2-6 'H-NMRiDMSO-d ) δ ppm:2.30-2.35 (3H, m), 6.95-7.00 (1H, m), 7.30-7.40 (1H, 6 m), 7.70-7.90 (4H, m), 8.25-8.35 (1H, m) 化合物2-7 'H-NMRCDMSO-d ) δ ppm:7.51 (1H, s), 8.10 (1H, d, J=2.2Hz), 8.53 (1H, s), 8〇70 6 (1H? s), 8.83 (1H, s) 205 312XP/發明說明書(補件 V96-03/95143900 200800871 化合物2 _ 8 ^-NMRiDMSO-d ) δ ppm :2.34 (3Η, s), 7.50-7.60 (3H, m), 7.94 (1H, d, J=2.2Hz) 6 化合物2-9 i-NMR(DMS〇-d ) δ ppm:3.80-3.90 (3H，m)，7。28 (2H, m), 7.50 (1H, d, J=2«5Hz 6 ),7.91 (1H, ds J=2e5Hz) 化合物2 -10 i—NMI^DMSO—d ) δ ppm:2.67 (3H, s), 7·45-7·50 (2H, m)，7.50-7.60 (1H, m)s 7。 6 85-7.90 (1H, m) _化合物2-11 'H-NMRiDMSO-d ) δ ppm:7.50-7.55 (1H, m), 7.99 (1H, d, J=2e2Hz), 8.25 (1H, d 6 ,J=2.2Hz), 8β41 (1H, d, J=2.2Hz) 化合物2 -12 i-NMR(DMSOd ) δ ppm:7.42 (1H, d, J=2.2Hz), 7.70-7.72 (2H，m)，7·91 (1H, d 6 ,J=2.2Hz), 7.95-7.97 (2H, m), 11.19 (2H, br) 化合物2 -13Compound 2 - 5 1H-NMR (DMS 〇-d ) δ ppm: 2.70 (3H, s), 3.01 (3H, s), 7.41 (1H, dd, J=7.6, 1.3 Hz) 6 , 7.50-7.55 (1H , m), 7.60-7.80 (2H, m), 7.95 (1H, d, J=2.2Hz), 8.04 (1H, dd, J=7.9, 1.0Hz), 1L07 (1H, br) Compound 2-6 ' H-NMRiDMSO-d ) δ ppm: 2.30-2.35 (3H, m), 6.95-7.00 (1H, m), 7.30-7.40 (1H, 6 m), 7.70-7.90 (4H, m), 8.25-8.35 ( 1H, m) Compound 2-7 'H-NMRCDMSO-d ) δ ppm: 7.51 (1H, s), 8.10 (1H, d, J=2.2Hz), 8.53 (1H, s), 8〇70 6 (1H s), 8.83 (1H, s) 205 312XP/Invention Manual (Supplement V96-03/95143900 200800871 Compound 2 _ 8 ^-NMRiDMSO-d ) δ ppm : 2.34 (3Η, s), 7.50-7.60 (3H, m), 7.94 (1H, d, J = 2.2 Hz) 6 Compound 2-9 i-NMR (DMS 〇-d) δ ppm: 3.80-3.90 (3H, m), 7.28 (2H, m), 7.50 (1H, d, J=2«5Hz 6 ), 7.91 (1H, ds J=2e5Hz) Compound 2 -10 i-NMI^DMSO-d ) δ ppm: 2.67 (3H, s), 7·45-7· 50 (2H, m), 7.50-7.60 (1H, m)s 7. 6 85-7.90 (1H, m) _compound 2-11 'H-NMRiDMSO-d ) δ ppm: 7.50-7.55 (1H, m), 7.99 (1H, d, J=2e2Hz), 8.25 (1H, d 6 , J = 2.2 Hz), 8β41 (1H, d, J = 2.2 Hz) Compound 2 -12 i-NMR (DMSOd ) δ ppm: 7.42 (1H, d, J = 2.2 Hz), 7.70-7.72 (2H, m ),7·91 (1H, d 6 , J=2.2Hz), 7.95-7.97 (2H, m), 11.19 (2H, br) Compound 2 -13

1H-NMR(DMS〇-d ) δ ppm:7.46 (1H, d, J=2〇2Hz), 7.65-7.69 (1H, m), 7.79-7.81 ( 6 1H, m), 7.92-7.94 (1H? m), 7.98 (1H, d, J=2.2Hz), 8.01-8.02 (1H, m), 11.19 (2H, b 化合物2 - 1 4 'H-NMRCDMSO-d ) δ ppm:7.42 (1H, d, J=2e2Hz), 7.66-7.77 (3H, m), 7.88 (1H, d 6 ,J=2.2Hz), 8.26 (1H, dd, J=7.9, 1.6Hz), 11.20 (2H, br) 化合物2 -15 'H-NMRCDMSO-^) δ ppm:L19 (6H, d, J=6.9Hz), 2.93-3.01 (1H, m), 7.42 (1H, d ,J=2.2Hz), 7.50 (2H, d, J=8.2Hz), 7.85 (2H, d, J=8.2Hz), 7.88 (1H, d, J=2.2Hz), 11 .17 (2H, br) 206 312XP/發明說明書(補件)/96-03/95143900 200800871 化合物2-16 'H-NMRiDMSO-d ) δ ppm: 1.00 (6H, d, J=6e9Hz), 3.64-3.69 (1H, m), 7.29 (1H? d 6 ,J=2.2Hz), 7.48-7.51 (1H, m), 7.63 (1H, dd, J=7.9, 1.0Hz), 7.69-7.73 (1H, m), 7J 8 (1H, d, J=2e2Hz), 8.04 (1H, dd, J=8.2, 1.6Hz), 1L19 (2H, br) 化合物2-17 ^-NMRiDMSO-d ) δ ppm:7.45 (1H, d, J=2.2Hz), 7.65-7〇68 (2H, m), 7.83-7.95 ( 6 3H, m), 11.12 (1H, br) 化合物2 -18 1H-NMR(DMS〇-d ) δ ppm :7.48-7.49 (1H, m), 8.02-8.04 (2H, m), 8.23-8.24 (1H, 6 m),.8.35-8.37 (ΪΗ, m), 1L70 (1H, s) 化合物2 -19 ^-NMRCDMSO-d ) δ ppm:2.91 (3H, s), 7.34 (1H, d, J=2.2Hz), 7.56-7.67 (3H, m) 6 ,7.89 (1H, d, J=2.2Hz), 8.02-8.04 (1H, m), 8.21 (1H, d, J=8.5Hz), 8.83-8.85 (1H, m), 10.94 (2H, br) 化合物2 - 2 01H-NMR (DMS〇-d) δ ppm: 7.46 (1H, d, J=2〇2Hz), 7.65-7.69 (1H, m), 7.79-7.81 (6 1H, m), 7.92-7.94 (1H? m), 7.98 (1H, d, J=2.2Hz), 8.01-8.02 (1H, m), 11.19 (2H, b compound 2 - 1 4 'H-NMRCDMSO-d ) δ ppm: 7.42 (1H, d, J=2e2Hz), 7.66-7.77 (3H, m), 7.88 (1H, d 6 , J=2.2Hz), 8.26 (1H, dd, J=7.9, 1.6Hz), 11.20 (2H, br) Compound 2 - 15 'H-NMRC DMSO-^) δ ppm: L19 (6H, d, J=6.9Hz), 2.93-3.01 (1H, m), 7.42 (1H, d, J=2.2Hz), 7.50 (2H, d, J=8.2Hz), 7.85 (2H, d, J=8.2Hz), 7.88 (1H, d, J=2.2Hz), 11 .17 (2H, br) 206 312XP/invention manual (supplement)/96- 03/95143900 200800871 Compound 2-16 'H-NMRiDMSO-d ) δ ppm: 1.00 (6H, d, J=6e9Hz), 3.64-3.69 (1H, m), 7.29 (1H? d 6 , J=2.2Hz) , 7.48-7.51 (1H, m), 7.63 (1H, dd, J=7.9, 1.0Hz), 7.69-7.73 (1H, m), 7J 8 (1H, d, J=2e2Hz), 8.04 (1H, dd , J=8.2, 1.6Hz), 1L19 (2H, br) Compound 2-17 ^-NMRiDMSO-d ) δ ppm: 7.45 (1H, d, J=2.2Hz), 7.65-7〇68 (2H, m) , 7.83-7.95 ( 6 3H, m), 11.12 (1H, br) Compound 2 -18 1H-NMR (DMS〇-d ) δ ppm :7.48-7.49 (1H, m), 8.02-8.04 (2H, m) , 8.23- 8.24 (1H, 6 m), .8.35-8.37 (ΪΗ, m), 1L70 (1H, s) Compound 2 -19 ^-NMRCDMSO-d ) δ ppm: 2.91 (3H, s), 7.34 (1H, d, J=2.2Hz), 7.56-7.67 (3H, m) 6 , 7.89 (1H, d, J=2.2Hz), 8.02-8.04 (1H, m), 8.21 (1H, d, J=8.5Hz), 8.83 -8.85 (1H, m), 10.94 (2H, br) Compound 2 - 2 0

1H-NMR(DMS〇-d ) δ ppm:2J8 (3H, s), 7.42 (1H, d, J=2.2Hz), 7.46-7.59 (3H, m) 6 ,7.86 (1H, d, j=2.2Hz), 11.11 (2H, br) 化合物2 - 21 "H-NMRCDMSO-d ) δ ppm:2.58 (6H, s), 7.28-7.30 (3H, m), 7.47 (1H, t, J=7.6Hz) 6 ,7.76 (1H, d, J=2.2Hz), 1L07 (2H, br) 化合物2 - 2 2 ^NMRCDMSO-d ) δ ppm:2.28 (6H, s), 3.70 (3H, s), 7.40 (1H, d, J=2.2Hz), 7.63 6 (2H, s), 7.84 (1H, d, J=2.2Hz), 1L09 (1H, br) 化合物2 - 2 3 207 312XP/發明說明書(補件)/96-03/95143900 200800871 ^-NMR(DMS〇-d ) δ ppm:7〇46 (1H, d, J=2.2Hz), 7.66-7»77 (3H? m), 8.00 (1H, d 6 s J=2.2Hz), 11.08 (1H, br) 化合物2-24 'H-NMRCDMSO-d ) δ ppm: 7〇48~7.53 (2H, m), 7.90 (1H, d, J=2e2Hz), 7.98-8.01 ( 6 2H, m), 11.15 (1H, br) 化合物2 - 2 5 ^-NMRCDMSO-d ) δ ppm :7.46 (IH, d, J=2.2Hz), 7.58-7.60 (1H, m), 7.74-7.77 ( 6 1H, m), 7.87 (1H, d, j=2e2Hz), 8.01-8.05 (1H, m), 11.14 (1H, br) _化合物2 - 2 6 'H-NMRCDMSO-d ) δ ppm:7.44 (1H, d, J-2e2Hz), 7.79-7.83 (1H, m), 7.92 (1H, d 6 ,J=2.2Hz), 8.10-8.13 (1H, m), 8.23-8〇25 (1H, m), 11.03 (1H, br) 化合物2 - 2 7 ^-NMRiDMSO-d ) δ ppm:2.61 (3H, s), 7.46 (1H, d, J=2.2Hz), 7.76-7.80 (2H, m) 6 ,7〇95 (1H, d, J=2.2Hz), 8.02-8.04 (1H, m), 1L21 (1H, br) 化合物2-281H-NMR (DMS〇-d) δ ppm: 2J8 (3H, s), 7.42 (1H, d, J=2.2Hz), 7.46-7.59 (3H, m) 6 , 7.86 (1H, d, j=2.2 Hz), 11.11 (2H, br) Compound 2 - 21 "H-NMRCDMSO-d ) δ ppm: 2.58 (6H, s), 7.28-7.30 (3H, m), 7.47 (1H, t, J=7.6Hz 6 , 7.76 (1H, d, J=2.2Hz), 1L07 (2H, br) Compound 2 - 2 2 ^NMRCDMSO-d ) δ ppm: 2.28 (6H, s), 3.70 (3H, s), 7.40 ( 1H, d, J=2.2Hz), 7.63 6 (2H, s), 7.84 (1H, d, J=2.2Hz), 1L09 (1H, br) Compound 2 - 2 3 207 312XP/Invention Manual (supplement) /96-03/95143900 200800871 ^-NMR (DMS〇-d ) δ ppm: 7〇46 (1H, d, J=2.2Hz), 7.66-7»77 (3H? m), 8.00 (1H, d 6 s J=2.2 Hz), 11.08 (1H, br) Compound 2-24 'H-NMRCDMSO-d ) δ ppm: 7〇48~7.53 (2H, m), 7.90 (1H, d, J=2e2Hz), 7.98 -8.01 ( 6 2H, m), 11.15 (1H, br) Compound 2 - 2 5 ^-NMRCDMSO-d ) δ ppm : 7.46 (IH, d, J = 2.2 Hz), 7.58-7.60 (1H, m), 7.74-7.77 ( 6 1H, m), 7.87 (1H, d, j=2e2Hz), 8.01-8.05 (1H, m), 11.14 (1H, br) _compound 2 - 2 6 'H-NMRCDMSO-d ) δ Ppm: 7.44 (1H, d, J-2e2Hz), 7.79-7.83 (1H, m), 7.92 (1H, d 6 , J=2.2Hz), 8.10-8.13 (1H, m), 8.23-8 〇25 (1H, m), 11.03 (1H, br) Compound 2 - 2 7 ^-NMRiDMSO-d ) δ ppm: 2.61 (3H, s), 7.46 (1H, d, J=2.2Hz), 7.76-7.80 (2H, m) 6 , 7〇95 (1H, d, J=2.2Hz), 8.02-8.04 (1H, m), 1L21 (1H, br) Compound 2-28

.'H-NMRCDMSO-d ) δ ppm:7.44-7.53 (4H, m), 7.71-7.73 (2H, m), 7.90-8.02 (5H, 6 m), 11.20 (1H, br) 化合物2-29. 'H-NMRC DMSO-d ) δ ppm: 7.44 - 7.53 (4H, m), 7.71-7.73 (2H, m), 7.90-8.02 (5H, 6 m), 11.20 (1H, br) Compound 2-29

'H-NMRCDMSO-d ) δ ppm: 1.36 (3H, t, J=6〇9Hz), 4.39 (2H, q, J=6.9Hz), 7.56 (1H 6 ,d, J=2e2Hz), 7.90 (1H, d, J=2.2Hz), 8.00 (1H, d, J=2.2Hz), 8.01 (1H, d, J=2.2Hz), 11.13 (1H, br) 化合物2 - 3 0 'H-NMRCDMSO-d ) δ ppm :2.65 (6H, s), 7〇45 (IH, d, J=2.2Hz), 7.97-7.98 (3H, m) 6 ,8.19 (2H, d, J=8.2Hz), 11.16 (1H, br) 208 312XP/發明說明書(補件)/96-03/95143900 200800871 化合物2-31 ^-NMRCDMSO-d ) δ ppm:6.86-6.88 (2H, m), 6.95-6.97 (2H, m), 7.21-7.31 (4H, 6 m), 7〇72-7.76 (2H, m), 8.28 (1H, dd, j=7.9, L6Hz), 10.95 (1H, br) 化合物2-32 'H-NMRiDMSO-d ) δ ppm:4.28-4.33 (4H,m), 7.06-7.08 (1H, m), 7,38-7.40 (3H, 6 m), 7.86 (1H, d, J=2.2Hz), 11.13 (1H, br) 化合物2-33 'H-NMRCDMSO-d ) δ ppm:2.83 (6H, s), 7A2 (1H, d, J=2.2Hz), 7〇81 (1H, d, J=2.2 6'H-NMRCDMSO-d ) δ ppm: 1.36 (3H, t, J=6〇9Hz), 4.39 (2H, q, J=6.9Hz), 7.56 (1H 6 ,d, J=2e2Hz), 7.90 (1H , d, J=2.2Hz), 8.00 (1H, d, J=2.2Hz), 8.01 (1H, d, J=2.2Hz), 11.13 (1H, br) Compound 2 - 3 0 'H-NMRCDMSO-d δ ppm : 2.65 (6H, s), 7〇45 (IH, d, J=2.2Hz), 7.97-7.98 (3H, m) 6 , 8.19 (2H, d, J=8.2Hz), 11.16 (1H , br) 208 312XP/Invention Manual (supplement)/96-03/95143900 200800871 Compound 2-31 ^-NMRCDMSO-d ) δ ppm: 6.86-6.88 (2H, m), 6.95-6.97 (2H, m), 7.21-7.31 (4H, 6 m), 7〇72-7.76 (2H, m), 8.28 (1H, dd, j=7.9, L6Hz), 10.95 (1H, br) Compound 2-32 'H-NMRiDMSO-d δ ppm: 4.28-4.33 (4H, m), 7.06-7.08 (1H, m), 7,38-7.40 (3H, 6 m), 7.86 (1H, d, J=2.2Hz), 11.13 (1H, Br) Compound 2-33 'H-NMRCDMSO-d ) δ ppm: 2.83 (6H, s), 7A2 (1H, d, J=2.2Hz), 7〇81 (1H, d, J=2.2 6

Hz), 7〇94-7e99 (3H, m), 8.43-8.45 (1H, m), 11.06 (1H, br) 化合物2-34 'H-NMRCDMSO-d ) δ ppm:7.43-7〇54 (4H, m), 7.71-7.75 (3H, m), 7β93~8.02 (3H, 6 m), 8.14 (1H, dd, J=1.9, 1.6Hz), 11.10 (1H, br) 化合物2-35 'H-NMRiDMSO-d ) δ ppm:2.63 (6H, s), 7〇44 (1H, d, J=2.2Hz), 7.92 (1H, dd, J=7. 9, 7.9Hz), 7〇99 (1H, d, J=2.2Hz), 8.06-8.09 (1H, m), 8.13-8.14 (1H, m), 8.27-8〇29 (1H, m), 11.19 (1H, br)Hz), 7〇94-7e99 (3H, m), 8.43-8.45 (1H, m), 11.06 (1H, br) Compound 2-34 'H-NMRCDMSO-d ) δ ppm:7.43-7〇54 (4H , m), 7.71-7.75 (3H, m), 7β93~8.02 (3H, 6 m), 8.14 (1H, dd, J=1.9, 1.6Hz), 11.10 (1H, br) Compound 2-35 'H- NMRiDMSO-d ) δ ppm: 2.63 (6H, s), 7〇44 (1H, d, J=2.2Hz), 7.92 (1H, dd, J=7. 9, 7.9Hz), 7〇99 (1H, d, J=2.2Hz), 8.06-8.09 (1H, m), 8.13-8.14 (1H, m), 8.27-8〇29 (1H, m), 11.19 (1H, br)

化合物2-36 ^-NMRCDMSO-d ) δ ppm:2.40 (3H, s), 7〇41-7.44 (2H, m), 7.60-7.64 (2H? m), 7. 6 94 (1H, d, J=2e2Hz), 11.14 (1H, br) 化合物2-37 - -. — - — - ^-NMRiDMSO-d ) δ ppm :7.47 (1H, d, J=2.2Hz), 7.87-7.89 (1H, m), 7〇92 (1H, d 6 ,J=2.2Hz), 8.00-8.03 (1H, m), 8,23-8.26 (1H, m), 1L18 (1H, br) 化合物2-38 209 312XP/發明說明書(補件)/96-03/95143900- 200800871 ^-NMRCDMSO-d ) δ ppm:2.55 (3H, s), 7.32 (1H, d, J=2.2Hz), 7.74 (1H, dd, J=8, 6 2, 7.9Hz), 7.86 (1H, d, J=2.2Hz), 8.09 (1H, d, j=7.9Hz), 8.39 (1H, d, j=8e2Hz), 11. 20 (1H, br) 化合物2-39 ^-NMRCDMSO-d ) δ ppm:3.53 (3H, s), 7.48 (1H, d, J=2.2Hz), 7.91 (1HS d, J=2.2 6Compound 2-36 ^-NMRCDMSO-d ) δ ppm: 2.40 (3H, s), 7〇41-7.44 (2H, m), 7.60-7.64 (2H? m), 7. 6 94 (1H, d, J =2e2Hz), 11.14 (1H, br) Compound 2-37 - -. - - - - ^-NMRiDMSO-d ) δ ppm :7.47 (1H, d, J=2.2Hz), 7.87-7.89 (1H, m) , 7〇92 (1H, d 6 , J=2.2Hz), 8.00-8.03 (1H, m), 8,23-8.26 (1H, m), 1L18 (1H, br) Compound 2-38 209 312XP/Invention Instruction manual (supplement)/96-03/95143900- 200800871 ^-NMRCDMSO-d ) δ ppm: 2.55 (3H, s), 7.32 (1H, d, J=2.2Hz), 7.74 (1H, dd, J=8 , 6 2, 7.9Hz), 7.86 (1H, d, J=2.2Hz), 8.09 (1H, d, j=7.9Hz), 8.39 (1H, d, j=8e2Hz), 11. 20 (1H, br Compound 2-39 ^-NMRCDMSO-d ) δ ppm: 3.53 (3H, s), 7.48 (1H, d, J=2.2Hz), 7.91 (1HS d, J=2.2 6

Hz), 8.01-8.07 (2H, m), 8.23-8.25 (1H, m), 8.44-8.45 (1H, m), 11.06 (1H, br) 化合物2-40Hz), 8.01-8.07 (2H, m), 8.23-8.25 (1H, m), 8.44-8.45 (1H, m), 11.06 (1H, br) Compound 2-40

^-NMRCDMSO-d ) δ ppm:7.43 (1H, d, J=2e2Hz), 7.93 (1H, d, J=2.2Hz), 8.05 (1 6 H, dd, J=8.5, 1.6Hz), 8.14 (1H, d, J=1.6Hz), 8.44 (1H, d, J=8.5Hz), 11.09 (1H, br) 化合物2-41 'H-NMRCDMSO-d ) δ ppm:2.71 (6H, s), 7.42 (1H, d, J=2.2Hz), 7.90 (1H, d, J=2.2 6^-NMRCDMSO-d ) δ ppm: 7.43 (1H, d, J=2e2Hz), 7.93 (1H, d, J=2.2Hz), 8.05 (1 6 H, dd, J=8.5, 1.6Hz), 8.14 ( 1H, d, J=1.6Hz), 8.44 (1H, d, J=8.5Hz), 11.09 (1H, br) Compound 2-41 'H-NMRCDMSO-d ) δ ppm: 2.71 (6H, s), 7.42 (1H, d, J=2.2Hz), 7.90 (1H, d, J=2.2 6

Hz), 8.10 (1H, d, J=L6Hz), 8.30 (1H, dd, J=8„5, L6Hz), 8.54 (1H, d, J=8.5Hz), 1L 11 (1H, br) 化合物2-42 'H-NMRCDMSO-d ) δ ppm :7.48 (1H, d, J=2.2Hz), 8.05 (1H, d, J=2.2Hz), 8〇23 (2 6 H, s), 1L10 (ih, br) 化合物2-43 'H-NMRiDMSO^) δ ppm:2.90 (6H, s), 7.49 (1H, d, J=2.2Hz), 8.08 (1H, d, J=2.2 Hz), 8.15 (2H, s), 11.04 (1H, br) (實施例3 ) 5 -氯- 2 -（3, 4 -二羥基- 5 -硝基苯磺醯基）一 3 一三氟曱基苯曱腈（化合物3 - 1) 在冰浴攪拌下，將第三丁醇鉀（254mg)加入至4 -节氧基-3 -曱氧基苯硫醇（參考例19 — i)(446mg)及N，N—二 210 312XP/發明說明書(補件)/96-03/95143900 200800871 曱基甲醯胺（50mL)之混合物中並攪拌5分鐘。加入5 -氟-2-碘-3-三氟甲基苯曱腈（參考例16 - 1 3) (500mg) 後徐徐升溫至室溫並攪拌1夜。此反應混合物用水與二乙醚進行分液，其有機液層依次以水及食鹽水洗滌，用無水硫酸鎂乾燥，在減壓下進行濃縮，得粗製之2- (4 -苄氧基-3 -曱氧基苯亞磺醯基）-5 -氯-3-三氟曱基苯曱腈。在冰浴攪拌下，將過氧間苯曱醯氯（1. 30g)以少量分批 _加入至粗製之2-(4 -苄氧基-3-曱氧基苯亞磺醯基）-5-氯-3-三氟甲基苯曱腈及二氣甲烷（50mL)之混合物中，再將此混合物升溫至室溫並攪拌30分鐘。將反應混合物通過胺丙基矽膠層過濾，用二氯曱烷洗提。濾液在減壓下進行濃縮，得粗製之2-(4-苄氧基-3-曱氧基苯磺醯基）-5 -氯-3 -三氟曱基苯曱腈。在冰浴攪拌下，將四氯化鈦（573mg)加入至粗製之2-• (4 -苄氧基-3 -曱氧基苯磺醯基）- 5 -氯-3 -三氟曱基苯甲腈及二氯甲烷（50mL)之混合物中並攪拌15分鐘。將此反應混合物注入於在攪拌下之冰水中後用二氯曱烷稀釋。分離之有機液層以lmol/L鹽酸洗滌，在減壓下進行濃縮，其殘留物以矽膠管柱色析法進行精製（洗提液：己烧/醋酸乙酯= 5/5)，得5 -氯-2 - (4 -經基- 3 -甲氧基苯磺醯基）-3 -三氟甲基苯曱腈（223mg)。在室溫攪拌下，將發煙硝酸（0. 029mL)加入至5 -氯-2 -（4 -經基-3 -曱氧基笨磺酿基）-3 -三氟曱基苯甲 312XP/發明說明書(補件)/96-03/95143900 211 200800871 腈（223mg)及二氯曱烧（50mL)之混合物中並擾拌15分鐘。此反應混合物以lmol/L鹽酸洗滌，在減壓下進行濃縮。將殘留物通過SCX離子交換管柱（Argonaute公司製、 5g)過濾，以二氯曱烷洗提後將濾液減壓濃縮，得粗製之 5 -氯- 2 - (4 -經基- 3 -曱氧基-5 -石肖基苯石黃酿基）-3 -三氟甲基苯甲腈。在室溫攪拌下，將氯化鋁（190mg)加入至粗製之5 -氯-2 -（4 -羥基- 3 -曱氧基-5 -硝基苯磺醯基）- 3 -三氟 _曱基苯曱腈及醋酸乙酯（30mL)之混合物中後再滴加吡啶 (0 · 28mL)。此混合物加熱迴流1夜。此反應混合物待冷卻後加入1 mo 1 /L鹽酸。分取之有機液層以食鹽水洗務，用無水硫酸鎂乾燥，在減壓下進行濃縮。其殘留物通過SCX 離子交換管柱（Argonaute公司製、5g)過濾，以二氣甲烧洗提後將濾液濃縮，得目標化合物（126mg)。沱-丽R(DMS〇- d6)(5ppm : 7·50-7·55(1Η，ιη)，8·01 • (1Η，d，J= 2· 2Hz)，8. 45(1H，d，J= 1. 9Hz)，8· 72(1H，d，J = 2. 2Hz)，依與實施例3相同方法，使用對應之鹵化苯以代替5-氟-2 -蛾-3-三氟曱基苯甲腈，合成化合物3-2〜化合物3 - 5。此等示於表21。 312ΧΡ/發明說明書(補件)/96-03/95143900 212 200800871 [表 21 ]Hz), 8.10 (1H, d, J=L6Hz), 8.30 (1H, dd, J=8„5, L6Hz), 8.54 (1H, d, J=8.5Hz), 1L 11 (1H, br) Compound 2 -42 'H-NMRCDMSO-d ) δ ppm : 7.48 (1H, d, J=2.2Hz), 8.05 (1H, d, J=2.2Hz), 8〇23 (2 6 H, s), 1L10 (ih , br) Compound 2-43 'H-NMRiDMSO^) δ ppm: 2.90 (6H, s), 7.49 (1H, d, J=2.2Hz), 8.08 (1H, d, J=2.2 Hz), 8.15 (2H , s), 11.04 (1H, br) (Example 3) 5-Chloro-2-(3,4-dihydroxy-5-nitrophenylsulfonyl)- 3trifluorodecylbenzonitrile (Compound) 3 - 1) Potassium terp-butoxide (254 mg) was added to 4-tertoxy-3-nonyloxybenzenethiol (Ref. 19-i) (446 mg) and N,N- under stirring in an ice bath. 2 210 312XP / invention manual (supplement) / 96-03 / 95143900 200800871 a mixture of mercaptocarbamide (50mL) and stirred for 5 minutes. Add 5-fluoro-2-iodo-3-trifluoromethylphenylhydrazine The nitrile (Reference Example 16 - 13) (500 mg) was gradually warmed to room temperature and stirred for 1 night. The reaction mixture was partitioned between water and diethyl ether. The organic layer was washed with water and brine, Dry and concentrate under reduced pressure to give 2-(4-benzyloxy) crude 3-(methoxyphenylsulfinyl)-5-chloro-3-trifluorodecylbenzonitrile. Under stirring in an ice bath, peroxybenzoquinone chloride (1. 30g) is divided into small amounts. Batch_Add to a mixture of crude 2-(4-benzyloxy-3-indolylsulfinyl)-5-chloro-3-trifluoromethylbenzonitrile and dioxane (50 mL) The mixture was warmed to room temperature and stirred for 30 minutes. The reaction mixture was filtered with EtOAc EtOAc (EtOAc m. Oxy-3-indolylbenzenesulfonyl)-5-chloro-3-trifluorodecylbenzonitrile. Titanium tetrachloride (573 mg) was added to the crude 2-• (with stirring in an ice bath) a mixture of 4-benzyloxy-3-indolylbenzenesulfonyl)-5-chloro-3-trifluorodecylbenzonitrile and dichloromethane (50 mL) was stirred for 15 minutes. After being stirred in ice water, it is diluted with dichloromethane. The separated organic layer is washed with 1 mol/L hydrochloric acid, concentrated under reduced pressure, and the residue is purified by gel column chromatography (eluent) : hexane / ethyl acetate = 5/5), get 5-chloro-2 - (4 - Yl - 3 - methoxy benzenesulfonamide acyl) -3 - trifluoromethylbenzene Yue-carbonitrile (223mg). Toluene nitric acid (0.029 mL) was added to 5-chloro-2 -(4-carbyl-3-indolyl oxasulfonyl)-3-trifluorodecylbenzene 312XP/ under stirring at room temperature. BRIEF DESCRIPTION OF THE INVENTION (Spread)/96-03/95143900 211 200800871 A mixture of nitrile (223 mg) and dichlorohydrazine (50 mL) was scrambled for 15 minutes. This reaction mixture was washed with 1 mol/L hydrochloric acid and concentrated under reduced pressure. The residue was filtered through an SCX ion exchange column (5 g, manufactured by Argonaute Co., Ltd.), eluted with dichloromethane, and the filtrate was concentrated under reduced pressure to give crude 5-chloro-2 - (4-amino- 3 - oxime). Oxy-5-stone sulphate yellow liquor-3-3-trifluoromethylbenzonitrile. Aluminium chloride (190 mg) was added to the crude 5-chloro-2 -(4-hydroxy-3-methoxy-5-nitrophenylsulfonyl)-3trifluoro-oxime under stirring at room temperature. A mixture of phenyl phthalonitrile and ethyl acetate (30 mL) was added dropwise with pyridine (0 · 28 mL). This mixture was heated to reflux for 1 night. After the reaction mixture was cooled, 1 mol / L hydrochloric acid was added. The organic layer which was separated was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was filtered through a SCX ion exchange column (5 g, manufactured by Argonaute), and the mixture was evaporated to dryness to give the title compound (126 mg).沱-丽R(DMS〇-d6)(5ppm : 7·50-7·55(1Η,ιη),8·01 • (1Η,d,J= 2· 2Hz), 8. 45(1H,d, J = 1. 9 Hz), 8.72 (1H, d, J = 2. 2 Hz), in the same manner as in Example 3, using the corresponding halogenated benzene instead of 5-fluoro-2 - moth-3-trifluoroanthracene Benzobenzonitrile, synthetic compound 3-2 to compound 3 - 5. These are shown in Table 21. 312 ΧΡ / invention specification (supplement) / 96-03/95143900 212 200800871 [Table 21]

化合物3 - 2〜化合物3 - 5之物性值係如下示。化合物3-2 ^-NMRiDMSO-d ) δ ppm:7.51 (1H, d, J=2e2Hz), 8.01 (1H, ds J=2.2Hz)5 8〇36 (1H 6 ,dd, J=8.6, L3Hz), 8.47 (lH, d, J=8.6Hz), 8.65 (1H, d, J=1.3Hz), 11.21 (1H, br)The physical property values of the compound 3 - 2 to the compound 3 - 5 are shown below. Compound 3-2 ^-NMRiDMSO-d ) δ ppm: 7.51 (1H, d, J=2e2Hz), 8.01 (1H, ds J=2.2Hz) 5 8〇36 (1H 6 , dd, J=8.6, L3Hz) , 8.47 (lH, d, J=8.6Hz), 8.65 (1H, d, J=1.3Hz), 11.21 (1H, br)

化合物3-3Compound 3-3

'H-NMRiDMSO-d ) δ ppm:7.57 (1H, d, J=2〇2Hz), 8.10 (1H, d, J=2.2Hz)s 8.34 (1H 6 〜 ,dd, J=7e9, 1.3Hz), 8.40 (1H, d, J=7.9Hz), 8.54 (1H, d, J=1.3Hz), 11.20 (1H, br) 化合物3-4 "H—NMRiDMSO-d ) δ ppm:3.88 (3H, s), 7。51 (1H, d, J=2.2Hz), 7·71 (1H，d，J=2e2 6'H-NMRiDMSO-d ) δ ppm: 7.57 (1H, d, J=2〇2Hz), 8.10 (1H, d, J=2.2Hz)s 8.34 (1H 6 〜 , dd, J=7e9, 1.3Hz) , 8.40 (1H, d, J=7.9Hz), 8.54 (1H, d, J=1.3Hz), 11.20 (1H, br) Compound 3-4 "H-NMRiDMSO-d ) δ ppm:3.88 (3H, s), 7.51 (1H, d, J=2.2Hz), 7·71 (1H,d,J=2e2 6

Hz), 7.86 (1H, d, J=2.2Hz), 7.90 (1H, d, J=2.2Hz), 11.14 (1H, br) 化合物3 - 5 'H-NMRCDMSO-d ) δ ppm: L35 (3H, t, J=7JHz), 4.40 (2H, q, J=7.1Hz), 7A9 (1H, 6 d, J=2„2Hz), 8.01 (1H, d, J=2.2Hz), 8.19 (1H, d, J=1.9Hz), 8.21 (1H, d, J=L9Hz), 11.24 (1H, br) 312XP/發明說明書(補件)/96-03/95143900 213 200800871 (實施例4) 5 -（5 -氯- 3 -氟- 2 -曱氧基苯磺醯基）- 3 -硝基苯-1，2 -二醉（化合物4 - 1) 在室溫攪拌下，將N -碘琥珀醯亞胺（1.24g)加入至4-氯-2 -氟齡（7 3 3ing )及N，N -二曱基曱酿胺（10 mL)之混合物中。在相同溫度下擾拌8小時後加入2mol /L鹽酸 UOOmL)。此混合物用二***稀釋。其水層用二***萃取，合併有機液層依次以飽和碳酸氫納水溶液、飽和硫代硫酸 ⑩鈉水溶液、食鹽水洗滌，用無水硫酸鎂乾燥，在減壓下進行濃縮，得粗製之4-氯-2 -氟-6 -蛾盼。在室溫攪拌下，將碳酸鉀（l.〇4g)及碘化曱基（0.37mL) 相繼加入至粗製之4 -氯_ 2 _氣-6 -破紛及N，N -二曱基曱醯胺（10mL)之混合物中。在相同溫度下攪拌12小時後加入水（50mL)。此混合物用20%二***/己烷溶液稀釋。其水層用己烷萃取，合併有機液層依次以飽和碳酸氫鈉水 φ溶液、飽和硫代硫酸鈉水溶液洗滌，用無水硫酸鎂乾燥，在減壓下進行濃縮，得粗製之5 -氯-1-氟-3 -碘-2-甲氧基苯。在氬氣環境及室溫攪拌下，將4 -苄氧基-3 -曱氧基苯硫醇（參考例19- l)(616mg)及第三丁醇鉀（421mg)依序加入至粗製之5_氣-I-氟-3 -蛾-2 -曱氧基苯、參 (二苯亞曱基丙酮）二鈀（〇)(115mg)、（氧基二-2, 1 -伸苯基）雙（二苯基膦）（135mg)及曱苯（30mL)之混合物中。此混合物在90°C攪拌1小時。此反應混合物待冷卻後用醋酸 312XP/發明說明書(補件)/96-03/95143900 214 200800871 乙酯稀釋，加入Florisil(註冊商標、和光純藥製）（3g)，在室溫下㈣丨小時。將反應混合物通過註冊商標）石夕藻土層過濾、，用醋酸乙醋洗提。遽液用食鹽水洗務，用無水硫酸鎂乾燥，在減壓下進行濃縮，得粗製之丨_ 苄氧基-3 -甲氧基苯亞磺醯基）_ 5_氯_ 3_氟_ 2_ 氧基苯。在冰浴攪拌下，將過氧間苯甲醯氯（l 7〇g)以少量分批加入^至粗製之i — (4 —苄氧基—3 —甲氧基苯亞磺醯基）一飞―氯-3 -氟-2 —甲氧基苯及二氯曱烷（2〇mL)之混合物中，再將此混合物升溫至室溫並攪拌6小時。加入2m〇i/L 氫氧化納水洛液及醋酸乙醋。此混合物用醋酸乙酯與水進行分液，其有機液層依次以飽和碳酸氫鈉水溶液、食鹽水洗滌，用無水硫酸鎂乾燥，在減壓下進行濃縮，得粗製之 1 一（4-苄氧基- 3-甲氧基苯磺醯基）一 5一氯一 3一氟一 2-曱氧基苯。 • 在冰浴攪拌下，將四氯化鈦（711mg)加入至粗製之i 一 (4-苄氧基- 3-甲氧基苯磺醯基）一5一氯一 3 一氟一 2一甲氧基苯及二氯曱烷（2〇mL)之混合物中並攪拌15分鐘。將此反應混合物注入於在攪拌下之冰水中後用二氯曱烷稀釋。分離之有機液層依次以lmol/L鹽酸及食鹽水洗滌’用無水硫酸鎂乾燥。在減壓下進行濃縮，其殘留物以石夕膠管柱色析法進行精製（洗提液：己烷/醋酸乙酯= 5/5) ’得4 - (5 -氯-3 -氟- 2 -甲氧基苯磺醯基）- 2 - 曱氧基紛（53ling)。 312XP/發明說明書(補件)/96-03/95143900 215 200800871 在室溫攪拌下，將發煙硝酸（0.069inL)加入至4- (5-氯-3 -氟-2 -甲氧基苯石黃醯基）-2 -甲氧基_ (5 31 mg ) 及二氯曱烷（15mL)之混合物中並攪拌15分鐘。此反應混合物以lmol/L鹽酸洗滌，用無水硫酸鎂乾燥，在減壓下進行濃縮。其殘留物通過SCX離子交換管柱（Argonaute 公司製、5g)過濾，以二氯曱烷洗提後將濾液濃縮，得粗製之4 - (5 -氯-3 -氟- 2 -曱氧基苯磺醯基）- 2-曱氧基-6 -頌基紛。 ⑩ 在室溫攪拌下，將氯化鋁（374mg)加入至粗製之4 - (5- 氯-3 -氟-2 -曱氧基苯磺醯基）-2 -曱氧基-6 -硝基酚及醋酸乙酯（10mL)之混合物中後再滴加吡啶 (0. 91 mL) ◦此混合物加熱迴流1夜。此反應混合物待冷卻後加入1 mo 1 /L鹽酸。分取之有機液層以食鹽水洗滌，用無水硫酸鎂乾燥，在減壓下進行濃縮。將殘留物通過SCX 離子交換管柱（Argonaute公司製、5g)過濾，以二氯曱烧 0洗提後將濾液濃縮，得目標化合物（318mg)。 4-丽R(DMS0- d6)6ppm ·· 3.84(3H，d，J=2.2Hz)，7.49 (1H，d，J = 2· 2Hz)，7· 78-7. 79(1 H，m)，7· 89(1 H，d，J = 2· 2Hz)，7· 95-7· 98(1H，m)，11· 10(1H，br) 依與實施例4相同方法，使用對應之酚以代替4 -氯-2 -貌紛，合成化合物4 - 2〜化合物4 - 3。此等示於表 22。 312XP/發明說明書(補件)/96-03/95143900 216 200800871 [表 22] 化含物一 No。構造式化含物 No. 職式 4-1 4-3 4-2 齡化合物4 - 2〜化合物4 - 3之物性值係如下示。 _化合物4-2 'H-NMRCDMSO-d ) δ ppm:3.90 (3H, s), 7〇51 (1H, d, J=2.2Hz), 7.89 (1H, d, J=2.2 6Hz), 7.86 (1H, d, J=2.2Hz), 7.90 (1H, d, J=2.2Hz), 11.14 (1H, br) Compound 3 - 5 'H-NMRCDMSO-d ) δ ppm: L35 (3H , t, J=7JHz), 4.40 (2H, q, J=7.1Hz), 7A9 (1H, 6 d, J=2„2Hz), 8.01 (1H, d, J=2.2Hz), 8.19 (1H, d, J=1.9 Hz), 8.21 (1H, d, J=L9Hz), 11.24 (1H, br) 312XP/Invention Manual (supplement)/96-03/95143900 213 200800871 (Example 4) 5 -(5 -Chloro-3-fluoro- 2 -nonylbenzenesulfonyl)- 3 -nitrobenzene-1,2-didact (Compound 4 - 1) N-iodosuccinimide at room temperature with stirring (1.24 g) was added to a mixture of 4-chloro-2-fluoro (7 3 3ing) and N,N-diindenylamine (10 mL). After stirring for 8 hours at the same temperature, 2 mol / L-hydrochloric acid UOOmL). The mixture was diluted with diethyl ether. The aqueous layer was extracted with diethyl ether. The combined organic layer was washed with saturated aqueous sodium hydrogen carbonate, saturated aqueous sodium thiosulfate solution, brine, and dried over anhydrous magnesium sulfate. Concentration under reduced pressure gave crude 4-chloro-2-fluoro-6-methane. Potassium carbonate (1. 4 g) and decyl iodide (0.37 mL) were successively added to the mixture. Rough 4 -Chloro 2 _ gas-6 - a mixture of N and N-didecylguanamine (10 mL). After stirring at the same temperature for 12 hours, water (50 mL) was added. The mixture was diluted with diethyl ether/hexanes. The aqueous layer was combined with EtOAc. The crude 5-chloro-1-fluoro-3-iodo-2-methoxybenzene was obtained. Under a argon atmosphere and stirring at room temperature, 4-benzyloxy-3-anthoxybenzenethiol (reference example) 19- l) (616 mg) and potassium butoxide (421 mg) were sequentially added to the crude 5_gas-I-fluoro-3-moth-2-decyloxybenzene, ginseng (diphenylarsinylacetone) a mixture of dipalladium (115 mg), (oxydi-2,1-phenylene)bis(diphenylphosphine) (135 mg) and toluene (30 mL). The mixture was stirred at 90 ° C. After the reaction mixture is cooled, it is diluted with ethyl acetate 312XP/invention manual (supplement)/96-03/95143900 214 200800871 ethyl ester, and added to Florisil (registered trademark, manufactured by Wako Pure Chemical Industries, Ltd.) (3g) at room temperature (4) Hour. The reaction mixture was filtered through a registered trademark of Shixia, and washed with ethyl acetate. The mash was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give crude 丨 _ benzyloxy-3-methoxyphenylsulfinyl)_______________ Oxybenzene. Under stirring in an ice bath, peroxybenzhydryl chloride (17 g) was added in small portions to the crude i-(4-benzyloxy-3-methoxyphenylsulfinyl) A mixture of fly-chloro-3-fluoro-2-methoxybenzene and dichloromethane (2 mL) was added and the mixture was warmed to room temperature and stirred for 6 hours. Add 2m〇i/L sodium hydroxide solution and ethyl acetate. The mixture was separated with ethyl acetate and water, and the organic layer was washed with saturated aqueous sodium hydrogen sulfate and brine, dried over anhydrous magnesium sulfate Oxy-3-trimethoxybenzenesulfonyl)-5-chloro-3-trifluoro-2-oxooxybenzene. • Titanium tetrachloride (711 mg) was added to the crude i-(4-benzyloxy-3-methoxyphenylsulfonyl)-5-chloro-3-trifluoro-2-one under stirring in an ice bath. A mixture of oxybenzene and dichlorodecane (2 〇 mL) was stirred for 15 minutes. The reaction mixture was poured into ice water under stirring and diluted with dichloromethane. The separated organic liquid layer was washed successively with 1 mol/L hydrochloric acid and brine, and dried over anhydrous magnesium sulfate. Concentration under reduced pressure, and the residue was purified by Shixi gum column chromatography (eluent: hexane/ethyl acetate = 5/5) to give 4-(5-chloro-3-fluoro- 2 -Methoxybenzenesulfonyl)- 2 -decyloxy (53 ling). 312XP/Invention Manual (Supplement)/96-03/95143900 215 200800871 Adding fuming nitric acid (0.069 inL) to 4-(5-chloro-3-fluoro-2-methoxyphene) with stirring at room temperature A mixture of 2-methoxy-(5 31 mg) and dichloromethane (15 mL) was stirred for 15 minutes. The reaction mixture was washed with 1 mol/L hydrochloric acid, dried over anhydrous magnesium sulfate and evaporated. The residue was filtered through a SCX ion exchange column (5 g, manufactured by Argonaute Co., Ltd.), eluted with dichloromethane, and the filtrate was concentrated to give a crude 4-(5-chloro-3-fluoro-2-phenyloxybenzene). Sulfhydryl)-2-methoxy-6-indenyl. 10 Aluminium chloride (374 mg) was added to the crude 4-(5-chloro-3-fluoro-2-indolylbenzenesulfonyl)-2-methoxy-6-nitro group under stirring at room temperature. A mixture of phenol and ethyl acetate (10 mL) was added dropwise pyridine (0. 91 mL). After the reaction mixture was cooled, 1 mol / L hydrochloric acid was added. The organic layer was separated and washed with brine, dried over anhydrous magnesium sulfate and evaporated. The residue was filtered through a SCX ion exchange column (5 g, manufactured by Argonaute), eluted with dichloromethane, and the filtrate was concentrated to give the title compound (318 mg). 4-Li R (DMS0-d6) 6ppm ·· 3.84(3H,d,J=2.2Hz), 7.49 (1H,d,J = 2· 2Hz), 7·78-7. 79(1 H,m) , 7. 89 (1 H, d, J = 2· 2 Hz), 7·95-7· 98 (1H, m), 11·10 (1H, br) According to the same method as in Example 4, the corresponding phenol was used. Instead of 4-chloro-2, the compound 4-2~~4-3 was synthesized. These are shown in Table 22. 312XP/Invention Manual (supplement)/96-03/95143900 216 200800871 [Table 22] Chemical inclusion No. Structural Formulation No. Position 4-1 4-3 4-2 Age The physical property values of Compound 4 - 2 to Compound 4 - 3 are as follows. _Compound 4-2 'H-NMRCDMSO-d ) δ ppm: 3.90 (3H, s), 7〇51 (1H, d, J=2.2Hz), 7.89 (1H, d, J=2.2 6

Hz), 7.95 (1H, d, J=2.5Hz), 8.11 (1H, d, J=2.5Hz), 11.16 (1H, br) 化合物4-3 'H-NMRCDMSO-d^ δ ppm:3.89 (3H, s), 7〇51 (1H, d, J=2.2Hz), 7〇79-7〇81 (1H, m) ,7·88 (1H，d, J=2.2Hz)，7.95-7.98 (1H, m)，11.10 (1H, br) (實施例5 ) • 5 - (4-曱磺醯基苯磺醯基）-3 -硝基苯- 1,2-二醇 (化合物5 - 1) 將1-碘-4-曱基亞磺醯基苯（687mg)、4-苄氧基-3 -曱氧基苯硫醇（參考例19 - l)(616mg)、參（二苯亞甲基丙酮）二鈀（〇)(115mg)、（氧基二-2，1-伸苯基）雙（二苯基膦）（135mg)、第三丁醇鉀（421mg)及曱苯（30mL)之混 &物在8 0 C攪:掉1小時。此反應混合物待冷卻後用醋酸乙酯稀釋，加入Florisil (註冊商標、和光純藥製）（3g)，在室溫下攪拌1小時。將反應混合物通過Celite(註冊商 312XP/發明說明書(補件)/96-03/95143900 217 200800871 標）矽藻土層過濾，用醋酸乙酯洗提。濾液用食鹽水洗滌，用無水硫酸鎂乾燥，在減壓下進行濃縮，其殘留物以矽膠管柱色析法進行精製（洗提液：己烷/醋酸乙酯= 3/7)，得 1 -苄氧基- 2 -曱氧基-4 - (4 -曱磺醯基苯磺醯基）苯 (700mg) 〇在冰浴攪拌下，將過氧間苯曱醯氯（3g)以少量分批加入至1-苄氧基-2-曱氧基-4-(4-甲磺醯基苯磺醯基）苯（700mg)及二氯甲烷（20mL)之混合物中，再將此混合物馨升溫至室溫並授拌15小時。加入2mo 1 /L氫氧化鈉水溶液及醋酸乙酯。此混合物用醋酸乙酯與水進行分液，其有機液層依次以飽和碳酸氫納水溶液、食鹽水洗滌，用無水硫酸鎂乾燥，在減壓下進行濃縮，得粗製之1 -苄氧基-4 -(4-甲磺醯基苯磺醯基）-2 -甲氧基苯。在冰浴攪拌下，將四氯化鈦（721mg)加入至粗製之1 -节氧基-4 - (4 -曱苯石黃酿基苯石黃酿基）-2 -曱氧基苯及 _二氯甲烷（20mL)之混合物中並攪拌15分鐘。將此反應混合物注入於在攪拌下之冰水中後用二氯甲烷稀釋。分離之有機液層依次以lmol/L鹽酸及食鹽水洗滌，用無水硫酸鎂乾燥。在減壓下進行濃縮，其殘留物以矽膠管柱色析法進行精製（洗提液：己烧/醋酸乙醋= 1/1)，得4 - (4 -曱磺醯基苯磺醯基）-2 -甲氧基苯（423mg)。在室溫攪拌下，將發煙硝酸（0.055mL)加入至4- (4-甲磺醯基苯磺醯基）-2 -甲氧基苯（423mg)及二氯曱烷 (15mL)之混合物中並攪拌15分鐘。此反應混合物以 312XP/發明說明書(補件)/96-03/95143900 218 200800871 lmol/L鹽酸洗滌，用無水硫酸鎂乾燥，在減壓下進行濃細。其K留物通過SCX離子交換管柱（Argonaute公司製、 5g)過濾，以二氯甲烷洗提後將濾液濃縮，得粗製之4一 (4 -甲％酿基苯石黃醯基）—2 —曱氧基—β _石肖基_。在室溫擾拌下，將氯化铭（241 mg)加入至粗製之4 - (4 -甲磺醯基苯磺醯基）_ 2 -甲氧基-6 -硝基酚及醋酸乙酯 (10mL)之混合物中後再滴加吡啶（〇· 59mL)。此混合物加熱迴流1夜。此反應混合物待冷卻後加入lm〇1/L鹽酸。分 _取之有機液層以食鹽水洗滌，用無水硫酸鎂乾燥，在減壓下進行濃縮。其殘留物通過SCX離子交換管柱（Arg〇naute 公司製、5g)過濾，以二氣甲烷洗提後將濾液濃縮，得目標化合物（243mg)。其結構式示於表23。噌 - NMR(DMS0— d6) 5 ppm : 3· 29(3H，s)，7· 43(1H，d，J = 2· 2Hz)，7· 97(1H，d，J= 2· 2Hz)，8· 14-8· 17(2H，m)，8· 20- 8·23(2H，m)，11·14(1H，br) φ (實施例6) 4 -（3, 4-二羥基- 5-硝基苯磺醯基）一 2,6_二曱基苯甲腈（化合物6- 1) 在氬氣環境及o°c下，將吡啶（1 · 2mL)及苯曱醯氯（〗· 4mL) 加入至4 -硤-2,6 -二曱基酚（2 48g)及二氯曱烷（2〇mL) 之混合物中。在室溫下攪拌4小時後，將此反應混合物用二***稀釋，注入於2mol/L鹽酸中，再用二***萃取。其有機液層依次以2mo 1 /L氫氧化鈉水溶液、飽和碳酸氫鈉水溶液、食鹽水洗滌，用無水硫酸鎂乾燥，在減壓下進 312XP/發明說明書(補件)/96-03/95143900 219 200800871 行濃縮，其殘留物以矽膠管柱色析法進行精製（洗提液：己烷/醋酸乙酯=5/1)，得苯甲酸4 -碘-2,6-二甲基苯酯（3·22g)。將苯甲酸4 -碘-2, 6 -二甲基苯酯（3. 22g)、4 -苄氧基-3 -甲氧基苯硫醇（參考例19 — ix985mg)、參（二苯亞甲基丙酮）二鈀（0)二氯甲烷加成物（182mg)、（氧基二一 2, 1 -伸苯基）雙（二苯基膦）（4〇5mg)、第三丁醇鉀（673mg) 及甲笨（30mL)之混合物在8〇它攪拌2小時。此反應混合物待冷部後用醋酸乙酯稀釋，加入F1 〇r丨s丨1 (註冊商標、和光純藥製）（2g)，在室溫下攪拌i小時。將反應混合物通過Celite(註冊商標）矽藻土層過濾，用醋酸乙酯洗提。濾液以食鹽水洗滌，用無水硫酸鎂乾燥，在減壓下進行濃縮，得粗製之苯甲酸4 - (4一节氧基—3一甲氧基苯亞磺醯基）-2, 6 -二曱基苯酯。在冰浴攪拌下，將過氧間苯甲醯氯（2. 6g)以少量分批加入至粗製之苯甲酸4-([节氧基-3—甲氧基苯亞福醯基）-2,6-二甲基笨醋及二氯曱烷（4〇raL)之混合物中，再將此混合物升溫至室溫並授拌3小時。此反應混合物加入 2mol/L氫氧化鈉水溶液及醋酸乙醋。此混合物用醋酸乙酉曰與水進仃分液’其有機液層依次以飽和碳酸氫納水溶 =、=水絲’用無水錢鎂錢，在錢下進行濃縮。其歹“物與甲醇一起進行粉碎’得粗製之苯甲酸4- (4_ 卞乳基-3 - f氧基苯伽基卜2,6_二甲基苯醋。在室溫下，將2m〇1/L氫氧化納水溶液加人至粗製之苯 312XP/發明說明書(補件)/96-03/95143900 220 200800871 甲酸4 -（4-苄氧基- 3 -甲氧基苯磺醯基）- 2, 6 -二甲基苯酯、1，4 -二崎燒（20mL)及曱醇（5mL)之混合物中。在相同溫度下擾拌3小時後，將反應混合物用醋酸乙g旨稀釋，再加入2mol/L鹽酸，其水層用醋酸乙酯萃取。有機液層依次以飽和碳酸氳鈉水溶液、食鹽水洗滌，用無水硫酸鎂乾燥，在減壓下進行濃縮，得粗製之4 - (4 -苄氧基— 3 -甲氧基苯磺醯基）-2, 6 -二曱基苯酯。在0C下’將三氟曱石黃酸酐（〇.39mL)加入至粗製之4-⑩（4 -苄氧基-3 -曱氧基苯石黃醢基）-2, 6 _二甲基苯酯、 σ比咬（0· 25mL)及二氯曱烧（15mL)之混合物中。在相同溫度下攪拌1小時後，將反應混合物用醋酸乙酯稀釋，在下加入於2mol/L鹽酸中，其水層用醋酸乙酯萃取。有機液層依次以飽和碳酸氫鈉水溶液、食鹽水洗滌，用無水硫酸鎂乾燥’在減壓下進行濃縮，得粗製之三氟曱續酸4 一 (4 -苄氧基-3 -曱氧基苯磺醯基）—2, 6_二甲基苯酯。 φ 在氬氣環境下，將粗製之三氟甲磺酸4 - (4 -节氧基-3 -曱氧基苯磺醯基）-2, 6 -二甲基苯酯、氰化銅 (I)(556mg)、氰化四乙銨（243mg)、1，Γ —雙（二苯膦基）二茂鐵（172mg)、參（二苯亞甲基丙酮）二鈀（〇)(71呢）及 1，4 -二噚烷（15mL)之混合物迴流攪拌2小時。此反應混合物待冷卻後用醋酸乙酯稀釋，通過矽藻土層Celite(註冊商標）過濾，用醋酸乙酯洗提。濾液注入於2m〇1/L鹽酸中，其水層用醋酸乙酯萃取。有機液層依次以2m〇1/L氫氧化鈉水溶液、飽和碳酸氫鈉水溶液、食鹽水洗滌，用無 312XP/發明說明書(補件)/96-03/95143900 221 200800871 水硫酸鎂乾燥，在減壓下進行濃縮。其殘留物與曱醇一起進行粉碎，得粗製之4 - (4 -苄氧基-3 -甲氧基苯磺醯基)-2,6 -二曱基苯曱腈。在冰浴攪拌下，將四氯化鈦（270mg)加入至粗製之4-(4 -苄氧基-3 -曱氧基苯磺醯基）-2, 6 -二甲基苯曱腈及二氣曱烷（15mL)之混合物中並攪拌15分鐘。將此反應混合物注入於在攪拌下之冰水中後用二氯曱烷稀釋。分離之有機液層依次以1 mo 1 /L鹽酸及食鹽水洗滌，用無水硫馨酸鎂乾燥。在減壓下進行濃縮，其殘留物以矽膠管柱色析法進行精製（洗提液：己烷/醋酸乙酯= 1/1)，得4 - (4-羥基-3 -曱氧基苯磺醯基）-2, 6 -二甲基苯曱腈 (300mg) 〇在室溫攪拌下，將發煙硝酸（0.042mL)加入至4- (4-經基-3 -曱氧基苯石黃酿基）-2，6 -二曱基苯曱猜（3 0 0mg ) 及二氯甲烷（10mL)之混合物中並攪拌15分鐘。此反應混 φ合物以lmol/L鹽酸洗滌，用無水硫酸鎂乾燥，在減壓下進行濃縮。其殘留物通過SCX離子交換管柱（Argonaute 公司製、5g)過濾，以二氯甲烷洗提後將濾液於減壓下濃縮，得粗製之4 - (4-羥基-3 -曱氧基-5 -硝基苯磺醯基）-2,6-二甲基苯曱腈。在室溫攪拌下，將氯化鋁（249mg)加入至粗製之4 - (4-經基_ 3 -曱氧基-5 '瑣基苯石黃酸基）-2，6 -二曱基苯曱腈及醋酸乙酯（15mL)之混合物中後再滴加吡啶 (0· 6mL)。此混合物加熱迴流1夜。此反應混合物待冷卻 312XP/發明說明書(補件)/96-03/95143卯0 222 200800871 後加入2m〇1/L鹽酸。分取之有機液層以食鹽水洗務，用 :水硫酸鎂乾燥’在減壓下進行濃縮。其殘留物通過犯料父換管柱（Argonaute公司製、5g)過濾，以二氣甲烧洗提後將濾、液於減壓下濃縮’得目標化合物結構式示於表23。八 lH ' NMR(DMS0 * d6> ^ PPm ： 2. 55(6H, s), 7. 42(1H, d, J ^Hz), 7.95 (1H, d, J=2.5Hz), 8.11 (1H, d, J=2.5Hz), 11.16 (1H, br) Compound 4-3 'H-NMRCDMSO-d^ δ ppm:3.89 (3H , s), 7〇51 (1H, d, J=2.2Hz), 7〇79-7〇81 (1H, m), 7·88 (1H, d, J=2.2Hz), 7.95-7.98 (1H , m), 11.10 (1H, br) (Example 5) • 5 - (4-oxasulfonylbenzenesulfonyl)-3-nitrobenzene-1,2-diol (Compound 5 - 1) 1-iodo-4-mercaptosulfinylbenzene (687 mg), 4-benzyloxy-3-nonyloxybenzenethiol (Reference Example 19-1) (616 mg), ginseng (diphenylmethyleneacetone) a mixture of dipalladium (115 mg), (oxydi-2,1-phenylene)bis(diphenylphosphine) (135 mg), potassium t-butoxide (421 mg) and toluene (30 mL) & the object is stirred at 80 C: 1 hour. The reaction mixture was diluted with ethyl acetate and added to Florisil (registered trademark, manufactured by Wako Pure Chemical Industries, Ltd.) (3 g), and stirred at room temperature for 1 hour. The reaction mixture was filtered through a pad of Celite (Cert. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; The filtrate was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by gel column chromatography (eluent: hexane / ethyl acetate = 3/7). -benzyloxy-2-yloxy-4-(4-indolesulfonylbenzenesulfonyl)benzene (700 mg) 〇Peroxydiphenylphosphonium chloride (3 g) was added in small portions with stirring in an ice bath. Add in portions to a mixture of 1-benzyloxy-2-methoxy-4-(4-methylsulfonylbenzenesulfonyl)benzene (700 mg) and dichloromethane (20 mL). Allow to room temperature and mix for 15 hours. 2mo 1 / L aqueous sodium hydroxide solution and ethyl acetate were added. The mixture was partitioned between ethyl acetate and water, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give crude 1-benzyloxy- 4-(4-Methanesulfonylbenzenesulfonyl)-2-methoxybenzene. Titanium tetrachloride (721 mg) was added to the crude 1-t-ethoxy-4-(4-pynene yellow-bromophenyl fluorenyl)-2-nonyloxybenzene and _ under stirring in an ice bath. Mixture of dichloromethane (20 mL) and stir for 15 minutes. The reaction mixture was poured into ice water with stirring and diluted with dichloromethane. The separated organic layer was washed successively with 1 mol/L hydrochloric acid and brine, and dried over anhydrous magnesium sulfate. Concentration under reduced pressure, and the residue was purified by gel column chromatography (eluent: hexane/acetic acid ethyl acetate = 1/1) to give 4-(4-sulfonylbenzenesulfonyl) -2 -Methoxybenzene (423 mg). To a mixture of 4-(4-methanesulfonylbenzenesulfonyl)-2-methoxybenzene (423 mg) and dichloromethane (15 mL) was added with stirring nitric acid (0.055 mL). Stir and stir for 15 minutes. This reaction mixture was washed with 312XP / invention specification (supplement) / 96-03 / 95143900 218 200800871 lmol / L hydrochloric acid, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The K residue was filtered through an SCX ion exchange column (5 g, manufactured by Argonaute Co., Ltd.), eluted with dichloromethane, and the filtrate was concentrated to obtain a crude 4-(4-methyl-glycolylxanthyl)- 2 -anthracene. Oxy-β _ Shi Xiaoji _. Chlorination (241 mg) was added to the crude 4-(4-methanesulfonylphenylsulfonyl)-2-methoxy-6-nitrophenol and ethyl acetate at room temperature. Pyridine (〇·59 mL) was added dropwise to a mixture of 10 mL). The mixture was heated to reflux for 1 night. After the reaction mixture was cooled, lm〇1/L hydrochloric acid was added. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated. The residue was filtered through a SCX ion exchange column (5 g of Arg〇naute), and the filtrate was concentrated with methylene chloride to give the title compound (243 mg). The structural formula is shown in Table 23.噌-NMR (DMS0-d6) 5 ppm : 3· 29(3H, s), 7·43 (1H, d, J = 2· 2Hz), 7.97 (1H, d, J = 2· 2Hz), 8· 14-8· 17(2H,m),8· 20- 8·23(2H,m),11·14(1H,br) φ (Example 6) 4 -(3,4-dihydroxy- 5-nitrophenylsulfonyl)- 2,6-dimercaptobenzonitrile (Compound 6-1) Pyridine (1.2 mL) and benzoquinone chloride under argon and o°c • 4 mL) was added to a mixture of 4 -硖-2,6-dinonylphenol (2 48 g) and dichloromethane (2 mL). After stirring at room temperature for 4 hours, the reaction mixture was diluted with diethyl ether, poured over 2 mol/L hydrochloric acid, and extracted with diethyl ether. The organic liquid layer was washed successively with 2 mol 1 /L sodium hydroxide aqueous solution, saturated aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure 312XP / invention specification (supplement) / 96-03/95143900 219 200800871 Concentration, the residue was purified by gel column chromatography (eluent: hexane / ethyl acetate = 5 / 1) to give 4-iodo-2,6-dimethylphenyl benzoate (3·22g). 4-Iodo-2,6-dimethylphenyl benzoate (3.22 g), 4-benzyloxy-3-methoxybenzenethiol (Reference Example 19 - ix985 mg), ginseng (diphenylmethylene) Acetone) dipalladium (0) dichloromethane adduct (182 mg), (oxydi- 2,1-phenylene) bis(diphenylphosphine) (4 〇 5 mg), potassium t-butoxide ( A mixture of 673 mg) and methyl bromide (30 mL) was stirred at 8 Torr for 2 hours. The reaction mixture was diluted with ethyl acetate, and then added with F1 〇r丨s丨1 (registered trademark, manufactured by Wako Pure Chemical Industries, Ltd.) (2 g), and stirred at room temperature for 1 hour. The reaction mixture was filtered through a pad of Celite (registered trademark), and eluted with ethyl acetate. The filtrate was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give crude 4-benzoic acid benzoic acid 4-(4-methoxy-3-methoxybenzosulfinyl)-2,6-di Nonylphenyl ester. Under stirring in an ice bath, peroxybenzhydryl chloride (2.6 g) was added in small portions to the crude 4-([oxy-3-methoxybenzofurazyl)-2 benzoate. In a mixture of 6-dimethyl benzyl vinegar and dichloromethane (4 〇 raL), the mixture was warmed to room temperature and stirred for 3 hours. This reaction mixture was added with a 2 mol/L aqueous sodium hydroxide solution and ethyl acetate. This mixture was separated from the acetic acid by means of ethyl acetate and water. The organic liquid layer was sequentially dissolved in saturated sodium hydrogencarbonate = water = water, and concentrated under an amount of money. The 歹物物物物 ' 得得得得得得得苯苯苯 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 1/L aqueous solution of sodium hydroxide added to crude benzene 312XP / invention specification (supplement) / 96-03/95143900 220 200800871 formic acid 4-(4-benzyloxy-3-methoxyphenylsulfonyl)- a mixture of 2,6-dimethylphenyl ester, 1,4-disaki (20 mL) and decyl alcohol (5 mL). After stirring at the same temperature for 3 hours, the reaction mixture was diluted with ethyl acetate. Further, 2 mol/L hydrochloric acid was added, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give crude 4 - ( 4-Benzyloxy-3-methoxybenzylsulfonyl)-2,6-dimercaptophenyl ester. Add trifluorophthalic anhydride (〇.39mL) to the crude 4-10 at 0C. a mixture of (4-benzyloxy-3-mercaptophthalazinyl)-2,6-dimethylphenyl ester, σ specific bite (0.25 mL) and dichlorohydrazine (15 mL) at the same temperature After stirring for 1 hour, the reaction mixture was Diluted with ethyl acetate, and added to 2 mol/L hydrochloric acid, the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and brine and dried over anhydrous magnesium sulfate. Concentration, crude trifluorosulfonate 4-(4-benzyloxy-3-indolylbenzenesulfonyl)-2,6-dimethylphenyl ester. φ Under argon, crude 4-(4-hydroxy-3-oxooxybenzenesulfonyl)-2,6-dimethylphenyl trifluoromethanesulfonate, copper (I) cyanide (556 mg), tetraethylammonium cyanide (243 mg), 1, bis-bis(diphenylphosphino)ferrocene (172 mg), ginseng (diphenylmethyleneacetone) dipalladium (ruthenium) (71%) and 1,4-dioxane (15 mL) The mixture was stirred under reflux for 2 hours. The reaction mixture was cooled, diluted with ethyl acetate, filtered over Celite (registered trademark), and eluted with ethyl acetate. The filtrate was poured into 2 〇 1 / L hydrochloric acid. The aqueous layer was extracted with ethyl acetate. The organic layer was washed successively with 2 m〇l/L aqueous sodium hydroxide solution, saturated aqueous sodium hydrogencarbonate solution and brine, and used without 312XP/invention specification (supplement)/96-03/95 143900 221 200800871 The dried magnesium sulfate was concentrated under reduced pressure, and the residue was triturated with decyl alcohol to give 4-(4-benzyloxy-3-methoxyphenylsulfonyl)-2 as a crude. 6-Dimercaptobenzonitrile. Titanium tetrachloride (270 mg) was added to the crude 4-(4-benzyloxy-3-indolylbenzenesulfonyl)-2,6 under stirring in an ice bath. A mixture of dimethylbenzonitrile and dioxane (15 mL) was stirred for 15 minutes. This reaction mixture was poured into ice water under stirring, and then diluted with dichloromethane. The separated organic layer was washed successively with 1 mol / L hydrochloric acid and brine, and dried over anhydrous magnesium sulfate. Concentration under reduced pressure, and the residue was purified by gel column chromatography (eluent: hexane / ethyl acetate = 1 / 1) to give 4-(4-hydroxy-3- methoxybenzene) Sulfhydryl)-2,6-dimethylbenzonitrile (300 mg) 发Toluene nitric acid (0.042 mL) was added to 4-(4-carbazhen-3-oxetite) with stirring at room temperature A mixture of 2,6-dimercaptobenzoquinone (300 mg) and dichloromethane (10 mL) was stirred for 15 minutes. The reaction mixture was washed with 1 mol/L hydrochloric acid, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was filtered through a SCX ion exchange column (5 g, manufactured by Argonaute), eluted with dichloromethane, and the filtrate was concentrated under reduced pressure to give 4-(4-hydroxy-3-methoxyoxy-5). -Nitrophenylsulfonyl)-2,6-dimethylbenzonitrile. Aluminium chloride (249 mg) was added to the crude 4-(4-pyridyl-3-yloxy-5'-triphenylphthalic acid)-2,6-dimercaptobenzene under stirring at room temperature. Pyridine (0.6 mL) was added dropwise to a mixture of carbonitrile and ethyl acetate (15 mL). This mixture was heated to reflux for 1 night. This reaction mixture was to be cooled 312XP / invention specification (supplement) / 96-03 / 95143 卯 0 222 200800871 after adding 2m 〇 1 / L hydrochloric acid. The organic layer which was separated was washed with brine and dried over magnesium sulfate < The residue was filtered through a parental change column (5 g, manufactured by Argonaute Co., Ltd.), and the mixture was filtered with a second gas, and the filtrate was concentrated under reduced pressure to give a target compound. VIII lH ' NMR (DMS0 * d6 > ^ PPm : 2. 55(6H, s), 7. 42(1H, d, J ^

2.2Hz), ^87(2H,s),7.94(lH,d, J=2.2Hz),11 H (lH，br) * •(實施例7) 2-氯- 4- ( 3, 4 -二羥基—5 —硝基苯磺醯基）一6一甲基苯甲腈（化合物7 - 1) 將碳酸鉀（1.38g)加入至4-漠—2—氣—β—甲基紛 (j.llg)及N，N-二甲基甲醯胺（15mL)之混合物中後，在氬氣環境及o°c下加入氯甲基甲醚（0 57mL)。在室溫下攪拌6小時後，將此反應混合物用醋酸乙酯稀釋，注入於水 _中，再用醋酸乙酯萃取。有機液層依次以飽和碳酸氩鈉水溶液、食鹽水洗滌，用無水硫酸鎂乾燥，在減壓下進行濃縮，得粗製之5-溴-1-氣一 2一甲氧曱氧基—3一曱基苯。將粗製之5-溴- 1-氯一 2 -甲氧曱氧基一 3 -甲基苯、4 -苄氧基_ 3 _曱氧基苯硫醇（參考例19 一 l)(985mg)、參（二苯亞甲基丙酮）二鈀（〇)二氯甲烷加成物 (182mg)、（氧基一 -2，1 -伸苯基）雙（二苯基膦）（405mg)、第三丁醇鉀（673mg)及甲苯（5〇mL)之混合物 312XP/發明說明書(補件)/96-03/95143900 223 200800871 在iio c攪拌2小時。此反應混合物待冷卻後用醋酸乙酯稀釋加入Fl〇risi 1 (註冊商標、和光純藥製）（4g)，在室，下擾摔1小時。將反應混合物通過Celite(註冊商標） f你土層過濾，用醋酸乙酯洗提。濾液用食鹽水洗滌，用，，硫酸鎂乾燥，在減壓下進行濃縮，得粗製之5- (4- 苄氧基—曱氧基苯亞磺醯基）-1—氯—2_曱氧曱氧基一 3-甲基苯。鲁在冰浴攪拌下，將過氧間苯曱醯氣（2· 7g)以少量分批加入至^粗製之5 - (4 -苄氡基—3 -甲氧基苯亞磺醯基）一 1氯2 —曱氧甲氧基-3 -甲苯及二氯曱烷（4〇mL)之混 :物中’再將此混合物升溫至室溫並攪拌3小時。此反應混合物加入2mol/L氳氧化鈉水溶液及醋酸乙酯。此混合，用醋Ul日與水進行分液，其有機液層依次以飽和碳酸氫鈉$溶液、食鹽水洗滌，用無水硫酸鎂乾燥，在減壓下進行濃縮，其殘留物以矽膠管柱色析法進行精製（洗提鬱液：己烷/醋酸乙酯=1/1)，得（4 —苄氧基—3 —曱氧基苯石黃酿基）—卜氯—2—甲氧甲氧基—3 —甲苯 (1.27g)。在室溫攪拌下，將10—樟腦磺酸（637mg)加入至5一 U -苄氧基-3 -甲氧基苯磺醯基）一1 —素— 氧基- 3-甲基苯（h27g)、甲醇（1〇mL)及四氣咬味⑽L) 之混合物中，並在相同溫度下擾摔24小時。此反應混合物用醋酸乙酯稀釋，加入飽和碳酸氫鈉水溶液，再用醋酸乙酯萃取。有機液層以食鹽水洗滌，用無水硫酸鎂乾燥， 312XP/發明說明書(補件)/96·〇3/95ΐ43900 224 200800871 在減壓下進行濃縮。其殘留物以二氯甲烷/己烷= 1/4粉碎，固體用己烷予以過濾，得粗製之4 - (4 -苄氧基-3 - 曱氧基苯績酿基）-2_氯-6 -甲基紛。在0°C下，將三氟曱石黃酸酐（0.42mL)加入至粗製之4 - (4 -子氧基-3 -甲氧基苯石黃酿基）-2 -氯-6 -曱基驗、 °比咬（0· 27mL)及二氯曱烧（15mL)之混合物中。在相同溫度2.2 Hz), ^87 (2H, s), 7.94 (lH, d, J = 2.2 Hz), 11 H (lH, br) * • (Example 7) 2-chloro- 4- (3, 4 - two Hydroxy-5-nitrophenylsulfonyl)-6-methylbenzonitrile (Compound 7-1) Potassium carbonate (1.38g) was added to 4-Moid-2-Ga-β-methyl (j. After llg) and a mixture of N,N-dimethylformamide (15 mL), chloromethyl methyl ether (0 57 mL) was added under argon atmosphere and o. After stirring at room temperature for 6 hours, the reaction mixture was diluted with ethyl acetate, poured over water and then ethyl acetate. The organic layer was washed successively with a saturated aqueous solution of sodium hydrogencarbonate and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give crude 5-bromo-1-oxo-2-methoxymethoxy-3. Base benzene. Crude 5-bromo-1-chloro-2-methoxymethoxy-3-methylbenzene, 4-benzyloxy-3 methoxy thiol (Reference Example 19-1) (985 mg), Reference product (diphenylmethyleneacetone) dipalladium (ruthenium) dichloromethane adduct (182 mg), (oxy-1,1-phenylene) bis(diphenylphosphine) (405 mg), third Mixture of potassium butoxide (673 mg) and toluene (5 〇 mL) 312XP / invention specification (supplement) / 96-03/95143900 223 200800871 Stir at iio c for 2 hours. After the reaction mixture was cooled, it was diluted with ethyl acetate to be added to Fl〇risi 1 (registered trademark, manufactured by Wako Pure Chemical Industries, Ltd.) (4 g), and the chamber was shaken for 1 hour. The reaction mixture was filtered through Celite (registered trademark) f, and eluted with ethyl acetate. The filtrate was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to give crude 5-(4-benzyloxy-decyloxysulfinyl)-1 -chloro-2-oxoxime Alkoxy 1-methylbenzene. Lu was added to the crude 5-(4-benzylindole-3-methoxybenzylsulfinyl) in a small amount in portions with stirring in an ice bath. Mixture of 1 chloro-2-oxomethoxymethoxy-3-toluene and dichloromethane (4 〇mL): The mixture was further warmed to room temperature and stirred for 3 hours. This reaction mixture was added with a 2 mol/L aqueous solution of sodium hydride and ethyl acetate. The mixture was separated with water, and the organic layer was washed with saturated sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Purification by color analysis (extraction of sulphate: hexane / ethyl acetate = 1 / 1), which gives (4-benzyloxy-3 methoxy phenanthrene) - chloro-2-methoxy Methoxy-3-toluene (1.27 g). 10-camphorsulfonic acid (637 mg) was added to 5-U-benzyloxy-3-methoxybenzenesulfonyl)-1-oxo-oxy-3-methylbenzene (h27g) with stirring at room temperature ), a mixture of methanol (1 〇 mL) and four gas bite (10) L), and disturbed for 24 hours at the same temperature. The reaction mixture was diluted with ethyl acetate. EtOAc (EtOAc) The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure, 312 </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; The residue was pulverized with dichloromethane / hexane = 1/4, and the solid was filtered using hexane to give 4-(4-benzyloxy-3 - decyloxyphenyl)-2-chloro- 6-methyl. Add trifluorophthalic anhydride (0.42 mL) to the crude 4-(4-oxo-3-methoxybenzolate)-2-chloro-6-fluorenyl group at 0 °C A mixture of °, bite (0. 27 mL) and dichlorohydrazine (15 mL). At the same temperature

下攪拌1小時後，將反應混合物用醋酸乙酯稀釋，在〇 °C 加入於2mo 1 /L鹽酸中，其水層用醋酸乙酯萃取。有機液 ⑩層依次以飽和碳酸氫鈉水溶液、食鹽水洗滌，用無水硫酸鎂乾燥，在減壓下進行濃縮，得粗製之三氟曱續酸4 — (4 一苄氧基-3 -甲氧基苯磺醯基）-2 -氯-6 -甲基盼。在氬氣環境下，將粗製之三氟曱磺酸4- (4 -节氧基- 3 -甲氧基本石頁醯基）-2 -氯-6 -甲基紛、氰化銅 (I)(599mg)、氰化四乙銨（261mg)、1，Γ —雙（二苯麟基）二茂鐵（185mg)、參（二苯亞曱基丙酮）二鈀（〇)(76111§)及 _ 1，4_二碍烷（15mL)之混合物迴流攪拌9()分鐘。此反應混合物待冷卻後用醋酸乙酯稀釋，通過矽藻土層CeHte(註冊商標）過濾，用醋酸乙酯洗提。濾液注入於2ιη〇1几鹽酸中，其水層用醋酸乙酯萃取。有機液層依次以2m〇1/L氫氧化鈉水溶液、飽和碳酸氫鈉水溶液、食鹽水洗滌，用無水硫酸鎂乾燥，在減壓下進行濃縮。其殘留物以曱醇進行粉碎，固體用曱醇過濾。將胺丙基石夕膠（5g)加入至此固體之醋酸乙醋/二氯曱烧=3/7溶液中並授摔3〇分鐘，通過秒藻土層（註冊商標）過濾，用相同溶劑洗提，在 312XP/發明說明書(補件 V96-03/95143900 225 200800871 縮氣'粗製之4-(4,基I曱氧基 L 乳一 6-甲基苯曱腈。在冰，攪拌下，將四氯化鈦⑵㈣加入至粗製之4 — 苄氧基3 —甲氧基苯磺醯基）—2 -氣-6 -曱基苯甲睛^—氣甲燒（1GmL)之混合物中並擾拌15分鐘。將此反應二:物注入於在攪拌下之冰水中後用二氯甲烷稀釋a刀離之有機液層依次以lmol/L鹽酸及食鹽水洗滌， 2…、水坆敲鎂乾燥。在減壓下進行濃縮，其殘留物以矽膠官柱色析法進行精製（洗提液：己烷/醋酸乙酯= 1/1)，得 2 -氣- 4 - (4-羥基一3 一曱氧基苯磺醯基）一6一甲基苯甲腈（159mg)。在室溫授拌下，將發煙硝酸（0.021mL)加入至2-氯-4 (4备基-3 -曱氧基苯石黃酸基）—6 -甲基苯甲腈 U59mg)及二氯甲烷（5mL)之混合物中並攪拌15分鐘。此反應混合物以1 mo 1 /L鹽酸洗滌，用無水硫酸鎂乾燥，在 _減壓下進行濃縮。其殘留物通過sex離子交換管柱 (Argonaute公司製、5g)過濾，以二氯曱烷洗提後將濾液於減壓下濃縮，得粗製之2 -氯-4- (4 -羥基-3 -曱氧基-5 -硝基苯磺醯基曱基苯曱腈。在室溫攪拌下，將氯化銘（109mg)加入至粗製之2 -氯-4 -（4-經基-3 -甲氧基-5-硝基苯石黃醯基）- 6-曱基苯甲腈及醋酸乙酯（1 OmL)之混合物中後再滴加吼咬 (0 · 2 7mL)。此混合物加熱迴流1夜。此反應混合物待冷卻後加入lmol/L鹽酸。分取之有機液層以食鹽水洗滌，用 312XP/發明說明書(補件)/96-03/95143900 226 200800871 無水硫酸鎂乾燥，在減壓下進行濃縮。其殘留物通過SCX 離子交換管柱（Argonaute公司製、5g)過濾，以二氯甲烧洗提後將濾液濃縮，得目標化合物（126mg)。其結構式示於表23。 -丽R(DMS0 - d6) (5 ppm : 2· 59(3H，s)，7· 45(1H，d，J = 2· 2Hz)，8· 01(1H，d，J = 2· 2Hz)，8· 05(1H，d，J = 1. 〇Hz)， 8. 12(lH,d, J= 1. 〇Hz), 11.02ClH,br) (實施例8) 馨3’ -氯-5’ -（3, 4 -二羥基-5 -硝基苯磺醯基）聯苯基-3 -碳化腈（化合物8- 1) 將1，3 -二溴- 5-氯苯（3· 38g)、4 -苄氧基—3 -甲氧基苯硫醇（參考例19 - l)(1.23g)、參（二苯亞曱基丙酮）二飽（〇)(229mg)、（氧基二-2，1 -伸苯基）雙（二苯基膦）（270mg)、第三丁醇鉀（842mg)及曱苯（50mL)之混合物在110 C攪拌1小時。此反應混合物待冷卻後用醋酸乙醋鲁稀釋，加入Florisil(註冊商標、和光純藥製）（5g)，在至溫下授拌1小時。此反應混合物通過Ce 1 i te(註冊商標）石夕藻土層過濾，用醋酸乙酯洗提。濾液用食鹽水洗滌，用無水硫酸鎂乾燥，在減壓下進行濃縮，得粗製之1 — (4一节氧基- 3-甲氧基苯亞磺醯基）一 3 -溴- 5-氯苯。在冰浴攪拌下’將過氧間苯曱醢氯（2 · 7 g )以少量分批加入至粗製之1- (4 -苄氧基-3 -甲氧基苯亞磺醯基）一 3-溴-5 -氯苯及二氯甲烷（2〇mL)之混合物中，再將此混 a物升溫至室溫並攪拌12小時。加入2mo 1 /L氫氧化納水 312XP/發明說明書(補件)/96-03/95143900 227 200800871 溶液及醋酸乙s旨。此混合物用醋酸乙g旨與水進行分液，1 有機液層依次以飽和碳酸氫鈉水溶液、食鹽水洗滌，用無 K瓜I鎂乾;^，在減壓下進行濃縮。其殘留物與甲醇一起進行粉碎。於固體之醋酸乙醋/己燒= 1/1(i_l)溶液中加入胺丙基石夕膠（3g)並攪拌！小時。將反應混合物通過 (註冊商標W藻土層過濾，用相同溶劑洗提。遽液在減壓下進打濃縮，其殘留物與二***/己烷=1/4 一起進行粉碎，固體用己烷洗滌，得粗製之丨—（4 —苄氧基— 3 -曱氧基苯磺醯基）一 3—溴一 5一氣笨。土在氬氣環境及室溫下，將碳酸鈉（217mg)及肆（三苯基膦）鈀（0)(118mg)連續加入至粗製之i — (4 —苄氧基—3一甲氧基苯續酿基）-3 -演_5_氯苯、3_氰苯基硼酸 (226mg)、甲苯（5mL)及水（〇· 5mL)之混合物中。在1〇〇t：攪拌24小時後，反應混合物用醋酸乙酯稀釋並注入於 2mol/L鹽酸中，將水層用醋酸乙酯萃取。其有機液層依次以2mol/L氫氧化鈉水溶液、飽和碳酸氫鈉水溶液、食鹽水洗滌，用無水硫酸鎂乾燥，在減壓下進行濃縮。其殘留物以矽膠管柱色析法進行精製（洗提液：己烷/醋酸乙酯 = 2/3)，得5’ - (4-苄氧基-3 -曱氧基苯磺醯基）一 3 -氯聯苯基-3 -碳化腈（402mg)。在冰浴攪拌下，將四氯化鈦（〇 · 18mL)加入至5，— (4 - 苄氧基-3 -曱氧基苯磺醯基）—3，-氯聯苯基—3 —碳化腈（402mg)及二氯甲烷（i〇mL)之混合物中並攪拌15分鐘。將此反應混合物注入於在攪拌下之冰水中後用二氯甲 312XP/發明說明書(補件)/96-03/95143900 228 200800871 烧稀釋。分離之有機液層依次以Irnol/L鹽酸及食鹽水洗滌，用無水硫酸饍乾燥。在減壓下進行濃縮，其殘留物以石夕膠管柱色析法進行精製（洗提液：己烧/醋酸乙醋= 1/1)，得3’-氯-5’-(4-羥基-3-曱氧基苯磺醯基）聯苯基-3 -碳化腈（314mg)。在室溫攪拌下，將發煙硝酸（0. 035mL)加入至3’ -氯- 5’ - （4-羥基-3 -曱氧基苯磺醯基）聯苯基-3 -碳化腈（314mg)及二氯甲烷（10mL)之混合物中並攪拌15分馨鐘。此反應混合物以lmol/L鹽酸洗滌，用無水硫酸鎂乾燥，在減壓下進行濃縮。其殘留物通過SCX離子交換管柱 (Argonaute公司製、5g)過濾，以二氯曱烧洗提後將濾液於減壓下濃縮，得粗製之5’ -氯-3’ -(4-羥基-3- 曱氧基苯磺醯基）聯苯基-3 -碳化腈。在室溫攪拌下，將氯化鋁（192mg)加入至粗製之5’ - 氯-3’ -（4 -經基-3 -曱氧基-5-石肖基苯石黃醯基）聯苯 _基-3 -碳化腈及醋酸乙酯（15mL)之混合物中後再加入吡啶（0. 47mL)。此混合物在迴流下攪拌整夜。此反應混合物待冷卻後加入2mo 1 /L鹽酸。分取之有機液層以食鹽水洗滌，用無水硫酸鎂乾燥，在減壓下進行濃縮。其殘留物通過SCX離子交換管柱（Argonaute公司製、5g)過濾，以二氯甲烷洗提後將濾液濃縮，得目標化合物（259mg)。其結構式示於表23。After stirring for 1 hour, the reaction mixture was diluted with ethyl acetate. EtOAc (EtOAc m. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give crude trifluorosulfon acid 4-(4-benzyloxy-3-methoxy) Phenylsulfonyl)-2-chloro-6-methyl. Crude trifluoromethanesulfonic acid 4-(4-oxo- 3 -methoxy-based fluorenyl)-2-chloro-6-methyl hydride, copper cyanide (I) under argon atmosphere (599mg), tetraethylammonium cyanide (261mg), 1, bis-bis(diphenyl) ferrocene (185mg), ginseng (diphenylarbenium acetonide) dipalladium (〇) (76111§) and A mixture of _ 1, 4 - di-anesane (15 mL) was stirred at reflux for 9 () min. The reaction mixture was cooled, diluted with ethyl acetate, filtered through celite (EtOAc) (EtOAc) and eluted with ethyl acetate. The filtrate was poured into 2% hydrazine hydrochloride, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed successively with a 2 m 〇l/L aqueous sodium hydroxide solution, a saturated aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was pulverized with methanol and the solid was filtered with decyl alcohol. Add the aminopropyl saponin (5g) to the solid ethyl acetate/dichloropyrene = 3/7 solution and give it a drop for 3 minutes, filter through the second layer of algae (registered trademark), and elute with the same solvent. , in the 312XP / invention manual (supplement V96-03/95143900 225 200800871 shrinking gas - crude 4- (4, based I methoxy L milk a 6-methyl benzoquinone. Under ice, stirring, will be four Titanium chloride (2) (4) is added to a mixture of crude 4-benzyloxy 3-methoxyphenylsulfonyl)-2- gas-6-fluorenylbenzoquinone^-gas-fired (1GmL) and scrambled 15 In this case, the reaction mixture was poured into ice water with stirring, and then the organic layer was diluted with methylene chloride, and then washed with 1 mol/L hydrochloric acid and brine, and dried with water. Concentration under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1 / 1) to give 2 - gas - 4 - (4-hydroxy-3) Ethoxybenzenesulfonyl)-6-methylbenzonitrile (159 mg). Toluene nitric acid (0.021 mL) was added to 2-chloro-4 (4 benzyl-3-oxo) at room temperature. Benthyl phthalate)-6-methylbenzate A mixture of nitrile U59 mg) and dichloromethane (5 mL) was stirred for 15 min. The reaction mixture was washed with 1 EtOAc / EtOAc. The residue was filtered through a sep-ion exchange column (5 g, manufactured by Argonaute Co., Ltd.), eluted with dichloromethane, and the filtrate was concentrated under reduced pressure to give crude 2-chloro-4-(4-hydroxy-3).曱oxy-5-nitrobenzenesulfonylhydrazinobenzonitrile. Chloroform (109 mg) was added to the crude 2-chloro-4-(4-carbazin-3-) under stirring at room temperature. A mixture of oxy-5-nitrophenylphosphonium)- 6-mercaptobenzonitrile and ethyl acetate (1 mL) was then added dropwise (0·27 mL). After the reaction mixture was cooled, 1 mol/L hydrochloric acid was added, and the organic layer was washed with brine, dried with 312XP/invention specification (supplement)/96-03/95143900 226 200800871 anhydrous magnesium sulfate, under reduced pressure. The residue was filtered through a SCX ion exchange column (5 g, manufactured by Argonaute Co., Ltd.), and the filtrate was concentrated to give the title compound (126 mg). The structure was shown in Table 23. (DMS0 - d6) (5 ppm : 2· 59(3H, s), 7·45 (1H, d, J = 2· 2Hz), 8· 01 (1H, d, J = 2· 2Hz), 8· 05(1H,d,J = 1. 〇Hz), 8. 12(lH,d, J= 1 〇Hz), 11.02ClH,br) (Example 8) Xin 3'-chloro-5'-(3,4-dihydroxy-5-nitrophenylsulfonyl)biphenyl-3-carbonitrile Compound 8- 1) 1,3 -dibromo 5-chlorobenzene (3·38 g), 4-benzyloxy-3-methoxybenzenethiol (Reference Example 19-1) (1.23 g), ginseng (diphenylarbenium acetonide) di-succinium (229 mg), (oxydi-2,1-phenylene) bis(diphenylphosphine) (270 mg), potassium t-butoxide (842 mg) and The mixture of toluene (50 mL) was stirred at 110 C for 1 hour. After the reaction mixture was cooled, it was diluted with ethyl acetate, and Florisil (registered trademark, manufactured by Wako Pure Chemical Industries, Ltd.) (5 g) was added, and the mixture was stirred for 1 hour at the temperature. The reaction mixture was filtered through EtOAc (EtOAc) (EtOAc) (EtOAc) —(4 methoxy-3-methoxybenzylsulfinyl)-3-bromo-5-chlorobenzene. Under stirring in an ice bath, 'peroxide benzoquinone chloride (2 · 7 g ) Add a small amount to the crude 1-(4-benzyloxy-3-methoxybenzosulfinyl)-3- In a mixture of bromo-5-chlorobenzene and dichloromethane (2 mL), the mixture was warmed to room temperature and stirred for 12 hours. Add 2mo 1 /L sodium hydroxide water 312XP / invention manual (supplement) / 96-03/95143900 227 200800871 solution and acetic acid. This mixture was separated from water by using ethyl acetate, and the organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and brine, and dried over K. The residue was pulverized together with methanol. In a solid ethyl acetate / hexane = 1 / 1 (i_l) solution, add ampicillin (3g) and stir! hour. The reaction mixture was passed through a (registered trademark of W-algae layer, and eluted with the same solvent. The mash was concentrated under reduced pressure, and the residue was pulverized with diethyl ether/hexane = 1/4. After washing, the crude ruthenium-(4-benzyloxy-3-oxooxybenzenesulfonyl)-3-bromo-5-gas is stupid. The sodium carbonate (217 mg) and sodium argon in an argon atmosphere and at room temperature肆(triphenylphosphine) palladium (0) (118 mg) was continuously added to the crude i-(4-benzyloxy-3-methoxybenzene continuation)-3 - _5_chlorobenzene, 3_ a mixture of cyanophenylboronic acid (226 mg), toluene (5 mL), and water (5 mL). After stirring for 1 hour, the reaction mixture was diluted with ethyl acetate and poured into 2 mol/L hydrochloric acid. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed successively with 2mol/L aqueous sodium hydroxide, saturated aqueous sodium hydrogen carbonate and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Purification by gel column chromatography (eluent: hexane/ethyl acetate = 2/3) to give 5'-(4-benzyloxy-3-indolylbenzenesulfonyl) 3-Chlorobiphenyl-3 -carbonitrile (402 mg). Titanium tetrachloride (〇·18 mL) was added to 5, 4-(benzyloxy-3-decyloxybenzenesulfonate) with stirring in an ice bath. a mixture of 3,-chlorobiphenyl-3-carbononitrile (402 mg) and dichloromethane (i〇mL) and stirred for 15 minutes. The reaction mixture was poured into ice water under stirring. Dichloroa 312XP/Invention Manual (Supplement)/96-03/95143900 228 200800871 Dilution by dilution. The separated organic layer was washed successively with Irnol/L hydrochloric acid and brine, dried over anhydrous sulfuric acid, concentrated under reduced pressure. The residue is purified by Shixi rubber column chromatography (eluent: hexane/acetic acid ethyl acetate = 1/1) to obtain 3'-chloro-5'-(4-hydroxy-3-indolyloxy group Phenylsulfonyl)biphenyl-3-carbonitrile (314 mg). Toluene nitric acid (0.035 mL) was added to 3'-chloro-5'-(4-hydroxy-3-indole) with stirring at room temperature. A mixture of oxybenzenesulfonyl)biphenyl-3-carbonitrile (314 mg) and dichloromethane (10 mL) was stirred for 15 minutes. The reaction mixture was washed with 1 mol/L hydrochloric acid and dried over anhydrous magnesium sulfate. Under decompression The residue was filtered through a SCX ion exchange column (5 g, manufactured by Argonaute Co., Ltd.), eluted with dichlorohydrazine, and the filtrate was concentrated under reduced pressure to give crude 5'-chloro-3'-(4- Hydroxy-3-indolylbenzenesulfonyl)biphenyl-3-carbonitrile. Aluminum chloride (192 mg) was added to the crude 5'-chloro-3'-(4- Pyridine (0.47 mL) was then added to a mixture of carbazinyl-p-methoxy-5- succinyl phthalocyanine)biphenyl-yl-3-carbonitrile and ethyl acetate (15 mL). This mixture was stirred overnight under reflux. After the reaction mixture was cooled, 2 mol / L hydrochloric acid was added. The organic layer which was separated was washed with brine, dried over anhydrous magnesium sulfate and evaporated. The residue was filtered through a SCX ion exchange column (5 g, manufactured by Argonaute), eluted with dichloromethane, and the filtrate was concentrated to give the title compound (259 mg). The structural formula is shown in Table 23.

]H- NIR(DMS0- d6) 5 ppm ： 7. 53(1H, d, I-2. 2Hz), 7. 71 (1H，dd，J = 8· 1，7· 6Hz)，7. 92-7. 94(1H，m)，8· 05(1H，dd，J 312XP/發明說明書(補件)/96-03/95143900 229 200800871 =1. 9, 1. 6Hz), 8. 07 (1H, d, J = 2. 2Hz), 8. 13-8. 15(1H, m), 8.21(lH,dd,J = 1.9,1.6Hz)， 8.25(lH,dd,J = 1· 6, 1. 6Hz), 8. 35(1H, dd, J= 1. 6, 1. 6Hz), 11. 05(1H, br) (實施例9) 5- [3, 5…二氯—4 一（2 —甲氧乙氧基）苯磺醯基]—3 — 硝基苯-1，2 -二醇（化合物g — 1) 在氬氣環境及室溫攪拌下，將4-苄氧基-3 -甲氧基苯硫醇（參考例 19- l)(1.97g)、i，3—二氯-5-碘-2-曱氧甲氧基苯（參考例6 - 1)(3· 20g)及第三丁醇鉀（1· 35g) 依序加入至參（二苯亞甲基丙酮）二鈀（0)(366mg)、（氧基 =一 2，1 -伸笨基）雙（二苯基膦）（8〇lmg)及甲苯（6〇1111〇之此。物中。在90 C攪拌1小時。此反應混合物待冷卻後 2醋i欠乙稀釋，加入F1〇risil (註冊商標、和光純藥衣）（5g)在至溫下攪拌1小時。將反應混合物通過 Celite(註冊商標）石夕藻土層過濾，用醋酸乙醋洗提。濾液氯—2 -曱氧甲氧基苯 2艮孤水洗I，用I水硫酸鎂乾燥，在減壓下進行濃縮， :于，衣之5 — (4 -苄氧基-3 -曱氧基苯亞磺醯基）- 1，3 一起- 在冰浴攪拌下，將過氧間1审々备入至粗製之5_(4 P其少量分批加 ,,一 & 卞乳基—3 —甲氧基苯亞磺醯基）- 物；二二广甲氧甲氧基苯及二氯甲燒㈣)之混合 ^ ’再將此混合物升溫至室溫並則半3小時。加入 2mol/L虱氧化鈉水溶液醋與水進行分液，其有機二曰。此混合物用醋酸乙八為液層依次以飽和碳酸氫鈉水溶 312XP/發明說明書(補件)/96-03/95143900 200800871 液、食鹽水洗滌，用無水硫酸鎂乾燥，在減壓下進行濃縮。其殘留物以矽膠管柱色析法進行精製（洗提液：己烷/醋酸乙酯= 1/1)，得5 - (4 ~苄氧基—3 —甲氧基苯磺醯基）一 1，3 -二氯-2 -甲氧曱氧基苯（2· 6〇g)。在室溫下，將10 -樟腦磺酸（L 97g)加入至5 — (4 —节氧基-3 -曱氧基苯磺醯基）—ι，3 -二氯—2 -曱氧曱氧基苯（2.60g)、曱醇（2〇mL)及四氫呋喃（2〇mL)之混合物中，並在相同溫度下擾拌24小時。此反應混合物用醋酸乙酯稀釋，加入飽和碳酸氫鈉水溶液，再用醋酸乙酯萃取。有機液層以食鹽水洗滌，用無水硫酸鎂乾燥，在減壓下進行濃縮。其殘留物以20%二***/己烷進行粉碎，固體用20% 一乙_ /己烧過濾，得粗製之4 - (4 -节氧基-3 -曱氧基苯石黃醯基）-2, 6 -二氯盼。在室溫下，將碳酸鉀（315mg)及2 —溴乙基甲醚（〇16mL) 連續加入至粗製之4 - (4-苄氧基-3 -甲氧基苯磺醯鲁基）-2,6-二氯酚及N，N_二甲基甲醯胺（5mL)之混合物中。在相同溫度下攪拌i小時後在8(rc攪拌8小時，此反應混合物用醋酸乙酯稀釋後注入於水中。水層用二*** 卒取其有機液層依次以飽和碳酸氯納水溶液、食鹽水洗滌，用無水硫酸鎂乾燥，在減壓下進行濃縮，得粗製之5 一 (4-苄氧基- 3 -甲氧基苯磺醯基）—13 —二氯一 2一 (2-甲氧乙氧基）苯。在冰浴攪拌下，將四氯化鈦（432mg)加入至粗製之5 -(4专氧基-3 -甲氧基苯石黃醯基）一 1，3 一二氯一2 - 312XP/發明說明書(補件)/96-03/95143900 231 200800871 (2甲氧乙氣基）苯及二氣甲烧（1 OmL)之混合物中並授拌 15分鐘。將此反應混合物注入於在攪拌下之冰水中後用一氣曱燒稀釋。分離之有機液層依次以1 1 /l鹽酸及食鹽水洗滌，用無水硫酸鎂乾燥。在減壓下進行濃縮，其殘留物以矽膠管柱色析法進行精製（洗提液：己烷/醋酸乙酯 = 1/1)，得4 - [3, 5 -二氯-4 - (2 -甲氧乙氧基）苯磺醯基]- 2 -甲氧基酚（325mg)。在室溫攪拌下，將發煙硝酸（〇· 〇35mL)加入至4 — [3, 5 一 •二氯-4 - (2 -甲氧乙氧基）苯磺醯基]—2 —甲氧基酚 (325mg)及二氯甲烷（10mL)之混合物中並攪拌15分鐘。此反應混合物以lm〇l/L鹽酸洗滌，用無水硫酸鎂乾燥，在減壓下進行濃縮。其殘留物通過Sex離子交換管柱 (Argonaute公司製、5g)過濾，以二氯曱烷洗提後將濾液於減壓下濃縮，得粗製之4 - [3, 5 -二氯-4 - (2 -甲氧乙氧基）苯磺醯基]-2 ~甲氧基—6 —硝基酚。 • 在室溫攪拌下，將氯化鋁（195mg)加入至粗製之4一 [3,5-二氯-4- (2-甲氧乙氧基）苯磺醯基]—2一甲氧基-6 -硝基酚及醋酸乙酯（1〇mL)之混合物中後再加入吡啶（0.47mL)。此混合物加熱迴流〗夜。此反應混合物待冷卻後加入lmol/L鹽酸。分取之有機液層以食鹽水洗滌，用無水硫酸鎂乾燥，在減壓下進行濃縮。其殘留物通過 SCX離子交換管柱（Argonaute公司製、5g)過濾，以二氯甲烧洗提後將濾液於減壓下濃縮，得目標化合物 (274mg)。其結構式示於表23。 312XP/發明說明書(補件)/96-03/95143900 232 200800871 4 -丽R(DMS0 - de) δ ppm·· 3· 27(3H，s)，3. 66-3· 68(2H，m)， 4· 2卜4· 23(2H，m)，7.49(lH，d，2· 2Hz)，8· 〇2(lH，d，J = 2.2Hz)，8.07(2H，s)，11.09(lH，br) (實施例10) 4 -氯-3 - (3, 4 -二羥基-5 -硝基苯磺醯基）苯甲腈 (化合物10 - 1) 在室溫下，將亞硫醯氯（2· 2mL)及N，N -二甲基曱醯胺 (2滴）連續加入至4 -氣-3 -碘苯曱酸（1· 70g)及甲苯 _ (20mL)之混合物中。在8(rc攪拌4小時後，此反應混合物在減壓下進行濃縮，再加入曱苯進行減壓濃縮，並重複此操作2次。其殘留物在減壓下乾燥後溶解於四氫吱鳴 (15mL)中。此溶液在〇。〇下加入28%氨水。在室溫下攪拌 1小時後，於反應混合物中加入飽和碳酸氫鈉水溶液及醋酸乙酯，水層用醋酸乙酯萃取。其有機液層以食鹽水洗滌，用無水硫酸鎂乾燥，在減壓下進行濃縮。其殘留物與鲁二***/己烷=1/1粉碎，用己烷濾取固體，得4 -氯—3一峨本曱酿胺（1. 54g)。在氮氣環境及〇°c下，將三氟甲磺酸酐（0 76mL)加入 4 -氯-3-碘苯甲醯胺（844mg)、吡啶（2· 4mL)及二氯曱烷 (20mL)之混合物中。在室溫攪拌丨小時後，反應混合物用醋酸乙酯及2mol/L鹽酸稀釋，其水層用醋酸乙酯萃取。有機液層依次以飽和碳酸氫鈉水溶液、食鹽水洗滌，用無水硫酸鎮乾燥’在減壓下進行濃縮，得粗製之4 —氯—3 一碘苯曱腈。 312XP/發明說明書(補件)/96-03/95143900 233 200800871 =粗製之4 一氯一 3-碘苯曱腈、4 一苄氧基一 3 -曱氧基苯奴醇（苓考例19 — iXW.g)、參（二苯亞甲基丙酮）一鈀（〇)—氣曱燒加成物（115mg)、（氧基二- 2, 1 -伸苯基）雙（二苯基膦）（135mg)、第三丁醇鉀（421邶）及甲苯（2〇1^) 之此&物在90 C攪拌1小時。此反應混合物待冷卻後用乙s曰稀釋’加入F1〇risil(註冊商標、和光純藥製）（4g)，在室溫下攪拌丨小時。此反應混合物通過 Celite(註冊商標）矽藻土層過濾，用醋酸乙酯洗提。濾液用食鹽水洗滌，用無水硫酸鎂乾燥，在減壓下進行濃縮，得粗製之3 -（4 -节氧美〇审气装#兀廿、 ^ 卞氣基—3 -甲乳基苯亞磺醯基）-4 - 氯苯曱腈。在冰浴攪拌下，將過氧間苯甲醯氯（166g)以少量分批加^至粗製之3_ (4_节氧基_ 3一甲氧基苯亞俩基）一氯苯甲腈及二氯甲烧（2()mL)之混合物中，再將此混合物升溫至室溫並攪拌3小時。此反應混合物加入2mol/L 籲氫氧化鈉水溶液及醋酸乙酯。此混合物用醋酸乙酯與水進打分液，其有機液層依次以飽和碳酸氫鈉水溶液、食趟水洗滌，用無水硫酸鎮乾燥，在減壓下進行濃縮，得粗=之 3-U-节氧基-3-甲氧基苯_基）_4_氯苯甲猜。在〇°C下，將25%溴化氫-醋酸溶液（5mL)加入至粗製之 3- (4 - ¥氧基-3 -甲氧基苯續醯基卜4_氯苯甲猜及二氣甲烧（IGniL)之混合物中。在室溫下_ 3小時後，此反應混合物用醋酸乙酯稀釋。纟有機液層时鹽水洗滌2 次，用無水硫酸鎂乾燥，在減壓下進行濃縮，其殘留物节以 312ΧΡ/發明說明書(補件)/96-03/95143900 234 200800871 /專層石夕膠色析法進行精製（洗提液：己烧/醋酸乙酿= 1/1)，得4 -氯-3 - (4 -羥基-3 -甲氧基苯磺醯基）笨甲腈（256mg)。在室溫攪拌下’將發煙石肖酸（〇 · 〇35mL)加入至4-氯~ 3 - (4 -羥基-3 -甲氧基苯磺醯基）苯曱腈（256mg)及二氯甲烷（10mL)之混合物中並攪拌15分鐘。此反應混合物以lmol/L鹽酸洗滌，用無水硫酸鎂乾燥，在減壓下進行 /辰縮。其殘留物通過SCX離子交換管柱（Argonaute公司馨‘、5g)過濾，以一氯甲烧洗提後將濾液於減壓下濃縮，得粗製之4 -氯-3 -（4-經基- 3 -曱氧基一 5-石肖基苯石黃酿基）苯甲猜。在室溫攪拌下，將氯化紹（159mg)加入至粗製之4 -氯一 3 -（4 -經基-3 -甲氧基-5 -硝基苯石黃醯基）苯甲腈及醋酸乙酯（10mL)之混合物中後再加入吡啶（〇· 39mL)。此混合物在迴流下攪拌整夜。此反應混合物待冷卻後加入至鲁lmol/L鹽酸。分取之有機液層以食鹽水洗滌，用無水硫酸鎂乾燥，在減壓下進行濃縮。其殘留物通過Sex離子交換管柱（Argonaute公司製、5g)過濾，以二氯曱烷洗提後將濾液濃縮，得目標化合物（129mg)。其結構式示於表23。 4 -丽R(DMS0 - d〇 6 ppm : 7· 50(1H，d，J= 2· 2Hz)，7· 90 (1H，d，J = 8· 2Hz)，7· 97(1H，d，J = 2· 2Hz)，8· 22(1H，dd，J =8· 2, 1· 9Hz)，8· 65(lH，d，J = 1· 9Hz), 11· 15(lH，br) (實施例11) 3 - (3, 4 -二羥基-5 _硝基苯磺醯基）苯曱酸（化合物 312XP/發明說明書(補件)/96-03/95143900 235 200800871 11]H-NIR(DMS0-d6) 5 ppm : 7. 53(1H, d, I-2. 2Hz), 7. 71 (1H,dd,J = 8· 1,7·6Hz), 7. 92- 7. 94(1H,m),8· 05(1H,dd,J 312XP/invention specification (supplement)/96-03/95143900 229 200800871 =1. 9, 1. 6Hz), 8. 07 (1H, d, J = 2. 2Hz), 8. 13-8. 15(1H, m), 8.21(lH,dd,J = 1.9,1.6Hz), 8.25(lH,dd,J = 1· 6, 1. 6Hz), 8. 35(1H, dd, J= 1. 6, 1. 6Hz), 11. 05(1H, br) (Example 9) 5- [3, 5... Dichloro-4 I (2 — Methoxyethoxy)benzenesulfonyl]-3 nitrobenzene-1,2-diol (compound g-1) 4-benzyloxy-3-methyl under argon and stirring at room temperature Oxybenzenethiol (Reference Example 19-l) (1.97 g), i,3-dichloro-5-iodo-2-indoleoxyphenyl (Reference Example 6-1) (3·20 g) and Potassium tributoxide (1·35g) was added to the ginseng (diphenylmethyleneacetone) dipalladium (0) (366 mg), (oxy = 2,1 -extended) bis(diphenylphosphine) (8〇lmg) and toluene (6〇1111〇. This is stirred at 90 C for 1 hour. After the reaction mixture is cooled, 2 vinegar i is diluted with B, and added to F1〇risil (registered trademark, Wako Pure Chemical Industries, Ltd.) Clothing) (5g) The mixture was stirred for 1 hour at a temperature. The reaction mixture was filtered through Celite (registered trademark), and washed with ethyl acetate. The filtrate was washed with chloro-2-hydroxymethoxybenzene 2 hydrazine. Dry over magnesium sulfate and concentrate under reduced pressure: 5, (4-benzyloxy-3-indolyl sulfinyl)- 1,3 together - under stirring in an ice bath Oxygen 1 trial prepared for crude 5_(4 P with a small amount of batch addition, 1 & 卞基 — 3 -methoxy sulfinyl)-; 2 dimethyl methoxymethoxy Mixing benzene and methylene chloride (4)) ^ The mixture was allowed to warm to room temperature for a further 3 hours. A 2 mol/L aqueous solution of sodium cerium oxide was added to separate the vinegar from the water, and the organic oxime was separated. This mixture was washed with a saturated aqueous solution of sodium bicarbonate (yield) (yield) (yield) / s. The residue was purified by a gel column chromatography (eluent: hexane/ethyl acetate = 1/1) to give 5-(4-benzyloxy-3-methoxyphenylsulfonyl)- 1,3 -Dichloro-2-methoxymethoxybenzene (2.6 g). Add 10 - camphorsulfonic acid (L 97g) to 5-(4-oxo-3-oxooxybenzenesulfonyl)-m,3 -dichloro-2-oxooxoxime at room temperature A mixture of benzene (2.60 g), decyl alcohol (2 〇 mL) and tetrahydrofuran (2 〇 mL) was stirred at the same temperature for 24 hours. The reaction mixture was diluted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated. The residue was pulverized with 20% diethyl ether/hexane, and the solid was filtered over 20% EtOAc / hexane to afford crude 4-(4- ethoxy-3- methoxy phenyl fluorinyl)-2. 6 - Dichloroprene. Potassium carbonate (315 mg) and 2-bromoethyl methyl ether (〇16 mL) were continuously added to the crude 4-(4-benzyloxy-3-methoxyphenylsulfonyl)-2 at room temperature. , a mixture of 6-dichlorophenol and N,N-dimethylformamide (5 mL). After stirring at the same temperature for 1 hour, it was stirred at 8 (rc for 8 hours), and the reaction mixture was diluted with ethyl acetate and poured into water. The aqueous layer was diluted with diethyl ether and the organic layer was successively washed with saturated aqueous solution of sodium carbonate and brine. After washing, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give crude 5-(4-benzyloxy-3-methoxyphenylsulfonyl)-13-dichloro-2-one (2-methoxy). Ethoxy)benzene. Titanium tetrachloride (432 mg) was added to the crude 5-(4-polyoxy-3-methoxybenzofluorenyl)-1,3-dichloro- 2 group under stirring in an ice bath. - 312XP/Inventive Manual (supplement)/96-03/95143900 231 200800871 (2 methoxyethyl) benzene and a mixture of two gas (1 OmL) and mixed for 15 minutes. Inject this reaction mixture into After being stirred in ice water, it was diluted with a gas simmer. The separated organic layer was washed with 1 1 / 1 hydrochloric acid and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Purification by chromatography (eluent: hexane/ethyl acetate = 1/1) to give 4-[3,5-dichloro-4-(2-methoxyethoxy)benzene Sulfhydryl]-2-methoxyphenol (325 mg). Add fuming nitric acid (〇·〇35 mL) to 4 —[3,5-•dichloro-4 - (2-A) with stirring at room temperature a mixture of oxyethoxy)benzenesulfonyl]-2-methoxyphenol (325 mg) and dichloromethane (10 mL) was stirred for 15 minutes. The reaction mixture was washed with lm?l/L hydrochloric acid. The magnesium was dried and concentrated under reduced pressure, and the residue was filtered through a Seex ion exchange column (5 g, manufactured by Argonaute), eluted with dichloromethane, and the filtrate was concentrated under reduced pressure to give a crude 4-[ 3,5-Dichloro-4 -(2-methoxyethoxy)benzenesulfonyl]-2 ~methoxy-6-nitrophenol. • Aluminum chloride (195 mg) with stirring at room temperature Add to crude 4-mono[3,5-dichloro-4-(2-methoxyethoxy)benzenesulfonyl]-2-methoxy-6-nitrophenol and ethyl acetate (1 mL) Pyridine (0.47 mL) was added to the mixture. The mixture was heated to reflux overnight. After the reaction mixture was cooled, 1 mol/L hydrochloric acid was added, and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. Concentration under reduced pressure. The mixture was filtered through a SCX ion exchange column (manufactured by Argonaute Co., Ltd., 5 g), and washed with dichloromethane, and the filtrate was concentrated under reduced pressure to give the title compound (274 mg). The structure formula is shown in Table 23. 312XP/Invention Manual (supplement)/96-03/95143900 232 200800871 4 - Li R(DMS0 - de) δ ppm·· 3· 27(3H,s), 3. 66-3· 68(2H,m), 4· 2 Bu 4· 23(2H,m), 7.49 (lH,d,2·2Hz),8·〇2(lH,d,J=2.2Hz),8.07(2H,s),11.09(lH,br) ( Example 10) 4-Chloro-3-(3,4-dihydroxy-5-nitrophenylsulfonyl)benzonitrile (Compound 10-1) Thionyl chloride (2.2 mL) at room temperature And N,N-dimethyl decylamine (2 drops) was continuously added to a mixture of 4- gas-3-iodobenzoic acid (1.70 g) and toluene (20 mL). After stirring at 8 (rc for 4 hours, the reaction mixture was concentrated under reduced pressure, and then concentrated to dryness under reduced pressure, and this was repeated twice. The residue was dried under reduced pressure and dissolved in tetrahydrofuran. (15 mL). This solution was added with 28% aqueous ammonia under hydrazine. After stirring at room temperature for 1 hour, a saturated aqueous solution of sodium hydrogencarbonate and ethyl acetate were added and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized with EtOAc/hexane = 1/1. One 曱曱胺 amine (1. 54g). Add trifluoromethanesulfonic anhydride (0 76mL) to 4-chloro-3-iodobenzamide (844mg), pyridine (2) under nitrogen atmosphere and 〇°c · 4 mL) and a mixture of dichloromethane (20 mL). After stirring at room temperature for a few hours, the reaction mixture was diluted with ethyl acetate and 2 mol/L hydrochloric acid, and the aqueous layer was extracted with ethyl acetate. Saturated with aqueous sodium hydrogencarbonate solution and brine, dried over anhydrous sulfuric acid and concentrated under reduced pressure to give crude 4-Chloro-3-monoiodobenzonitrile 312XP/Invention Manual (supplement)/96-03/95143900 233 200800871 = Crude 4 Monochloro-3-iodobenzoic acid nitrile, 4-benzyloxy- 3 -曱苯苯醇苓苓苓苓苓 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 19 - phenyl) bis(diphenylphosphine) (135 mg), potassium t-butoxide (421 邶) and toluene (2 〇 1 ^) This & stirred at 90 C for 1 hour. The reaction mixture was to be cooled. After that, it was diluted with s 曰 ' ' Add F1 〇 il (registered trademark, manufactured by Wako Pure Chemical Industries, Ltd.) (4 g), and stirred at room temperature for 丨 hours. The reaction mixture was filtered through Celite (registered trademark) diatomaceous earth layer with acetic acid The ester was eluted. The filtrate was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a crude product of 3-(4 - oxysole oxime gas oxime #兀廿, ^ 卞基 -3 -methyl emulsion Phenylsulfonyl)-4 - chlorobenzonitrile. Toluene m-benzoyl chloride (166 g) was added in small portions to the crude 3_(4_hydroxyl_3) in an ice bath with stirring. Methoxy phenylene) In a mixture of benzonitrile and methylene chloride (2 () mL), the mixture was warmed to room temperature and stirred for 3 hours. The reaction mixture was added 2 mol/L aqueous sodium hydroxide solution and ethyl acetate. The mixture was washed with ethyl acetate and water, and the organic liquid layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and gargle water, dried over anhydrous sulphuric acid, and concentrated under reduced pressure to give crude = 3-U-oxygen. Base-3-methoxybenzene-yl)_4_ chlorobenz. Add 25% hydrogen bromide-acetic acid solution (5 mL) to the crude 3-(4-valent oxy-3-methoxybenzene hydrazino 4 chlorobenzene at 〇 ° C. After a lapse of 3 hours, the reaction mixture was diluted with ethyl acetate. The organic layer was washed twice with brine and dried over anhydrous magnesium sulfate. The residue section is refined by 312ΧΡ/invention specification (supplement)/96-03/95143900 234 200800871 / special layer Shixi gum color analysis method (eluent: burned / acetic acid = 1/1) 4-Chloro-3-(4-hydroxy-3-methoxyphenylsulfonyl)benzonitrile (256 mg). Add the fuming acid (〇·〇35 mL) to 4- at room temperature with stirring. A mixture of chloro- 3 - (4-hydroxy-3-methoxybenzenesulfonyl)benzonitrile (256 mg) and dichloromethane (10 mL) was stirred for 15 minutes. The reaction mixture was washed with 1 mol/L hydrochloric acid. The organic layer was dried over anhydrous magnesium sulfate and dried under reduced pressure. The residue was filtered through EtOAc EtOAc (EtOAc) Thick 4 -Chloro-3 -(4-carbyl-3-oxooxy-5-stone succinyl yellow wine) Benzene guess. Add chlorinated (159 mg) to the crude 4 with stirring at room temperature Pyridine (〇·39 mL) was added to a mixture of -chloro-3-(4-carbyl-3-methoxy-5-nitrophenylphosphonium)benzonitrile and ethyl acetate (10 mL). The mixture was stirred overnight under reflux. The reaction mixture was cooled and then added to EtOAc <RTI ID=0.0> The ion-exchanged column (5 g, manufactured by Argonaute Co., Ltd.) was filtered, and the filtrate was concentrated with dichloromethane to give the title compound (129 mg). The structure is shown in Table 23. 4 - Li R (DMS0 - d〇6) Ppm : 7· 50 (1H, d, J = 2· 2Hz), 7· 90 (1H, d, J = 8· 2Hz), 7.97 (1H, d, J = 2· 2Hz), 8.22 (1H, dd, J = 8· 2, 1·9 Hz), 8·65 (lH, d, J = 1·9 Hz), 11·15 (lH, br) (Example 11) 3 - (3, 4 -dihydroxy-5-nitrobenzenesulfonyl)benzoic acid (Compound 312XP/Invention Manual (supplement)/96-03/95143900 23 5 200800871 11

在室溫攪拌下，將發煙硝酸（0.031mL)加入至3— (4一羥基-3 -甲氧基苯磺醯基）苯甲酸（參考例47 — =二氯甲烷（20mL)之混合物中並攪拌15分鐘。此反應混合物以Imol/L鹽酸洗滌，用無水硫酸鎂乾燥，在減壓下進行濃縮。其殘留物通過scx離子交換管柱（紅名⑽仙忱 =司製、5g)過濾，以二氯甲烷洗提後將濾液濃縮，得粗赢衣之3 (4 -羥基-3-甲氧基-5 -硝基苯磺醯基）苯甲酸。在室溫攪拌下，將氯化鋁（196mg)加入至粗製之3 - (4一 L基-3 -甲氧基-5 -硝基苯磺醯基）苯甲酸及醋酸乙酯 (30mL)之混合物中後再加入吡啶（〇. 286mL)，在迴流下攪拌整夜。此反應混合物待冷卻後加入lm〇1/L鹽酸。分取之有機液層以食鹽水洗滌，用無水硫酸鎂乾燥，在減壓下進行濃縮。其殘留物通過SCX離子交換管柱（Arg〇naute 鲁公司製、5g)過濾，以二氯甲烷洗提後將濾液濃縮，得目標化合物（20mg)。其結構式示於表23。 4 一 NMR(DMS0 - d6) 5 ppm : 7· 38(1H，d，J= 2 5Hz)，7 67 — 7· 75 (1H，m)，7· 87(1H，d，2· 2Hz)，8· 10-8· 18(1H，m)， 8· 28-8· 32(lH，m) ’ 依與實施例11相同方法，使用對應之2 —甲氧基酚以代替3 - (4 -羥基-3 -甲氧基笨磺醯基）苯曱酸，合成化合物11 - 2〜化合物11 — 15。其結構式示於表23。 (實施例12) 312XP/發明說明書(補件)/96-〇3/95143900 236 200800871 5 -苯磺醯基-2, 3 -二羥基苯曱腈（化合物12 — ^ 將5-苯磺醯基-2,3-雙苄氧基苯曱腈（參考例41一 l)(90mg)及27%漠化氫-酯酸溶液（lmL)之混合物在室溫下授掉1小日守。此反應混合物用二乙鍵與水進行分液，並有機液層以水洗滌，用無水硫酸鎂乾燥，在減壓下進行^ 縮，得目標化合物（45mg)。其結構式示於表23。辰 -臟（DMSO- d6) 5 ppm:7.40-7·75(7Η，πι) 依與實施例12相同方法，使料應之节氧基苯以代替 5 -苯礦酸基-2, 3-雙节氧基苯曱猜，合成化合物12_曰2 〜化合物12 - 4。其結構式示於表23。 (實施例13) 、，一 2, 2 -三曱基丙酸5一（3 —氯—5 —氛基苯石黃酿基卜2 — 經基-3 -石肖基苯酯（化合物13 — 1) 在f浴擾拌下’將特戊酿氯⑷川加人至咪扣〇mg) 及四氫呋喃（3raL)之混合物中並攪拌15分鐘。其次，將3 —To a mixture of 3-(4-hydroxy-3-methoxyphenylsulfonyl)benzoic acid (Ref. 47) = dichloromethane (20 mL) was stirred at room temperature with stirring. After stirring for 15 minutes, the reaction mixture was washed with 1 mol/L hydrochloric acid, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was filtered through a scx ion exchange column (red name (10) 忱忱 = 司, 5 g) After eluting with dichloromethane, the filtrate was concentrated to give 3 (4-hydroxy-3-methoxy-5-nitrophenylsulfonyl)benzoic acid as a crude material. Aluminium (196 mg) was added to a mixture of the crude 3-(4-chloro-3-methoxy-5-nitrophenylsulfonyl)benzoic acid and ethyl acetate (30 mL) and then pyridine was added. 286 mL), and stirred under reflux overnight. The reaction mixture was cooled to dryness and then EtOAc EtOAc EtOAc. The product was filtered through an SCX ion exchange column (manufactured by Arg〇naute Co., Ltd., 5 g), eluted with dichloromethane, and the filtrate was concentrated to obtain the target compound. 20mg). Its structural formula is shown in Table 23. 4 NMR (DMS0 - d6) 5 ppm : 7· 38 (1H, d, J = 2 5Hz), 7 67 — 7· 75 (1H, m), 7· 87 (1H, d, 2 · 2 Hz), 8· 10-8· 18 (1H, m), 8· 28-8· 32 (lH, m) ' In the same manner as in the embodiment 11, the corresponding 2 - A methoxy phenol was used instead of 3-(4-hydroxy-3-methoxysulfonyl)benzoic acid to synthesize the compound 11-2 to the compound 11-15. The structural formula is shown in Table 23. (Example 12 312XP/Invention Manual (Supplement)/96-〇3/95143900 236 200800871 5 -Benzenesulfonyl-2,3-dihydroxybenzonitrile (Compound 12 — ^ 5-Benzenesulfonyl-2,3 a mixture of bisbenzyloxybenzonitrile (Reference Example 41-1) (90 mg) and 27% hydrogenation-ester acid solution (1 mL) was given at room temperature for 1 hour. The reaction mixture was used with 2 The bond was separated from water, and the organic layer was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to give the title compound (45 mg). The structure formula is shown in Table 23. Chen-dirty (DMSO- D6) 5 ppm: 7.40-7·75 (7Η, πι) In the same manner as in Example 12, the material should be made of oxybenzene to replace the 5-benzene ore. Base-2,3-bis-hydroxybenzoquinone, synthesize compound 12_曰2~compound 12-4. Its structural formula is shown in Table 23. (Example 13), a 2,2-tridecyl-propyl Acid 5 -(3 -chloro-5 - aryl benzophenone yellow broth 2 - carbyl - 3 - Shizoyl phenyl ester (Compound 13 - 1) in the f bath scrambled 'The special pentyl chloride (4) Chuanjia Mix to a mixture of mM mg) and tetrahydrofuran (3 raL) for 15 minutes. Secondly, will be 3 -

氯5 (3, 4 -經基-5 _確基苯石黃酿基）苯甲猜（化合物l- 24)(100mg)及四氫呋喃(lmL)之混合物滴加於上述物中後，升溫至室溫，_ 2小時。此反應混合A mixture of chloro 5 (3,4-carbazin-5-yl phenylephrine) benzoate (compound l-24) (100 mg) and tetrahydrofuran (1 mL) was added dropwise to the above, and the mixture was warmed to room. Warm, _ 2 hours. This reaction mix

物用酉a酉夂乙醋稀釋，依攻以《I 〇心B mGl/L鹽酸及食鹽水洗滌。其有機液層用無水硫酸鎂乾焊留物與二異丙基醚一起匕在，下進行濃縮。其殘 .ηΛ 、 ^ 進仃泰砰後濾取得目標化合物 (90mg)。其結構式示於表23。 Η -丽R(DMS0 - d6) 5 ppm :(2H，m)，8·1〇—8.14(2H，m) I 41(9Η，s)，7. 85-7. 87 8· 64(lH，d，J=2· ΙΗζ)，11· 07 312ΧΡ/發明說明書(補件)/96·〇3/951439〇〇 237 200800871 (lH’br) (實施例14 ) 2,2?甲基兩酸4_(3_氯_5_氰基苯磺醯基)-2-’ 2 一甲基丙醯氧基）—6 —硝基苯酯（化合物14 - 1) 在5 C下將知戊酿氣（78mg)加入至3_氯_ 5_ (3 4-二羥基—5 —硝基苯磺醯基）苯甲腈（、化合物’} _ 24)(l〇〇mg)、二乙胺（6〇mg)及四氫呋喃（3此）之混合物中亚攪拌3G分鐘。此混合物在室溫下攪拌整夜。此反應混口物用ga I乙g旨稀釋’依次以lmQl/L冑酸及食鹽水洗滌。其有機液層用無水硫酸鎂乾燥，在減壓下進行濃縮。其殘留物與二異丙基㈣—起進行粉碎後濾取得目標化合物（117mg)。其結構式示於表23。 Η _ 丽以廳〇 _ d6) 3 PPm : 1.37(9H，s),1.39(9H，s)， 7. 86-7. 91 (1H, m), 8. 03(1H, d, J = 2. 2Hz), 8. 12(1H, t, J = 1. 4Hz), 8. 15(1H, t, J= l. 9Hz), 8. 42( 1H, d, J=2. 2Hz) φ 2,2 -二曱基丙酸5 - (2_氰基_ 4_氟_ 6_甲基苯石黃醯基）-2 - (2, 2 -二曱基丙醯氧基）_ 3_硝基苯酯（化合物 14- 2) 依與實施例14相同方法，使用2 - (3, 4 -二經基-5 -硝基苯磺醯基）-5-氟-3-甲基苯曱腈（化合物丨-斗已）以代替3_氯-5-(3,4-二羥基-5-硝基苯磺醯基）苯曱腈，合成目標化合物。其結構式示於表23。 ]H- NMR(DMS〇- de) ά ppm : 1.30(9Η, s), 1. 32(9Η, s), 2. 58 (3Η, s), 7. 8K1H, dd5 J = 9. 5, 2. 6Hz), 8. 17(1H, dd5 J = 312XP/發明說明書(補件)/96-03/95143900 238 200800871 8·〇,2·6Ηζ)， 8· 45(1Η，d，J = 2. 1Hz)，8· 50(1Η，d，J = 2. 1Hz) (實施例15) 二乙基胺基曱酸5 - (2-氰基- 4-氟- 6 -曱基苯磺醯基）2 - —乙基胺曱酿氧基-3 -石肖基苯酯（化合物15 一 1) 在室溫攪拌下，將二乙基胺甲醯氯（〇· 〇6mL)加入至2 一 (3, 4-二經基- 5 -硝基苯磺醯基）-5-氟- 3 -甲基苯 ®曱腈（化合物1 - 45)(30mg)、吡啶（1· OmL)及四氫呋喃（lmL) 之混合物中，在60°C加熱攪拌18小時後，此反應混合物在減壓下進行濃縮。其殘留物以矽膠管柱色析法進行精製 (洗提液：己烷/醋酸乙酯= 98/2〜50/50)，得目標化合物 (46mg)。其結構式示於表23。 4 -丽R(DMS0 - de) ά ppm : 1. 06-1· 12(6H，m)，1· 15-1 μ (6H，m)，2· 59(3H，s)，3· 26-3· 32(4H，m)，3· 36-3· 41(4H，m)， φ 7. 81(1H, dd, J = 9· 2, 2· 9Hz)，8· 16(1H，dd， jThe substance was diluted with 酉a酉夂 vinegar, and washed according to "I 〇 heart B mGl / L hydrochloric acid and saline. The organic layer was dried over anhydrous magnesium sulfate and concentrated with diisopropyl ether. After the residue, ηΛ, ^ was injected into the 仃砰 and the target compound (90 mg) was obtained. The structural formula is shown in Table 23. Η - Li R (DMS0 - d6) 5 ppm :(2H,m),8·1〇—8.14(2H,m) I 41(9Η,s), 7. 85-7. 87 8· 64(lH, d, J=2· ΙΗζ), 11· 07 312ΧΡ/invention specification (supplement)/96·〇3/951439〇〇237 200800871 (lH'br) (Example 14) 2,2?methyldiacid 4_ (3_Chloro-5-cyanobenzenesulfonyl)-2-' 2-methylpropenyloxy)-6-nitrophenyl ester (Compound 14 - 1) will be known at 5 C 78 mg) is added to 3-chloro-5_(34-dihydroxy-5-nitrophenylsulfonyl)benzonitrile (, compound '} _ 24) (l 〇〇 mg), diethylamine (6 〇 mg) And a mixture of tetrahydrofuran (3) was stirred for 3 G minutes. This mixture was stirred overnight at room temperature. The reaction mixture was diluted with ga I 乙g, followed by lmQl/L citric acid and brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was pulverized with diisopropyl (tetra), and the title compound (117 mg) was obtained by filtration. The structural formula is shown in Table 23. _ _ 丽丽厅〇_ d6) 3 PPm : 1.37(9H,s), 1.39(9H,s), 7. 86-7. 91 (1H, m), 8. 03(1H, d, J = 2 2 Hz), 8. 12 (1H, t, J = 1. 4 Hz), 8. 15 (1H, t, J = 1. 9 Hz), 8. 42 ( 1H, d, J = 2. 2 Hz) φ 2 ,2-dimercaptopropionic acid 5-(2-cyano-4_fluoro-6-methylphenidinyl)-2 - (2,2-dimercaptopropoxy)_3_nitrobenzene Ester (Compound 14-2) In the same manner as in Example 14, 2-(3,4-di-diyl-5-nitrophenylsulfonyl)-5-fluoro-3-methylbenzonitrile (Compound)丨-斗已) In place of 3_chloro-5-(3,4-dihydroxy-5-nitrophenylsulfonyl)benzonitrile, the target compound was synthesized. The structural formula is shown in Table 23. ]H-NMR (DMS〇-de) ά ppm : 1.30(9Η, s), 1. 32(9Η, s), 2. 58 (3Η, s), 7. 8K1H, dd5 J = 9. 5, 2 6Hz), 8. 17(1H, dd5 J = 312XP/invention manual (supplement)/96-03/95143900 238 200800871 8·〇, 2·6Ηζ), 8·45 (1Η, d, J = 2. 1 Hz), 8·50 (1 Η, d, J = 2. 1 Hz) (Example 15) diethylamino phthalic acid 5-(2-cyano-4-fluoro-6-nonylbenzenesulfonyl) 2 - ethylamine oxime oxy-3 -shidocyl phenyl ester (Compound 15-1) Diethylamine formazan chloride (〇·〇6 mL) was added to 2 (3, 4) with stirring at room temperature a mixture of di-diyl-5-nitrophenylsulfonyl)-5-fluoro-3-methylbenzene®phthalonitrile (compound 1 - 45) (30 mg), pyridine (1.0 mL) and tetrahydrofuran (1 mL) After heating and stirring at 60 ° C for 18 hours, the reaction mixture was concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate = 98/2 to 50/50) to give the title compound (46 mg). The structural formula is shown in Table 23. 4 - Li R (DMS0 - de) ά ppm : 1. 06-1· 12(6H,m),1· 15-1 μ (6H,m),2· 59(3H,s),3· 26- 3· 32(4H,m),3· 36-3· 41(4H,m), φ 7. 81(1H, dd, J = 9· 2, 2· 9Hz), 8·16(1H,dd, j

8. 1, 2. 9Hz),8.37(lH,d, J = 2. 5Hz), 8. 48(1H5 d, J 2.5Hz) 312XP/發明說明書(補件)/96-03/95143900 239 200800871 [表 23]8. 1, 2. 9Hz), 8.37 (lH, d, J = 2. 5Hz), 8. 48 (1H5 d, J 2.5Hz) 312XP / invention manual (supplement) / 96-03/95143900 239 200800871 [ Table 23]

化合物 No, 構造式 ik合物 No. 構造式 5-1 。枚 11-2 °γ° 6-1 0H 1 11-3 OH 7-1 ΐχΛο OH Cl 11-4 OH 8-1 01^^ΧΧ.Ν OH Cl 11-5 OH 9-1 °^yVsV:yc1 HoV OH Cl 11-6 OH 10-1 OH 11 -7 °γ°" 11-1 Of HO^sOy〇H 11-8 OH 312XP/發明說明書(補件)/96-03/95143900 240 200800871 表23(續）Compound No, structural formula ik compound No. Structural formula 5-1. 11-2 °γ° 6-1 0H 1 11-3 OH 7-1 ΐχΛο OH Cl 11-4 OH 8-1 01^^ΧΧ.Ν OH Cl 11-5 OH 9-1 °^yVsV:yc1 HoV OH Cl 11-6 OH 10-1 OH 11 -7 °γ°" 11-1 Of HO^sOy〇H 11-8 OH 312XP/Invention Manual (supplement)/96-03/95143900 240 200800871 Table 23 ( Continued)

312XP/發明說明書(補件)/96-03/95143900 241 200800871 表23(續）312XP/Invention Manual (supplement)/96-03/95143900 241 200800871 Table 23 (continued)

化合物11 - 2〜化合物11 - 15及化合物12 - 2〜化合物 12 - 5之物性值係如下示。化合物11-2The physical property values of the compound 11 - 2 to the compound 11 - 15 and the compound 12 - 2 to the compound 12 - 5 are shown below. Compound 11-2

'H-NMRCDMSO-d ) 6 ppm:7e30 (1H, d, J=2.2Hz), 7.78 (1H, d, J=7.6Hz), 7.81 (1 6 H, d, J=2.2Hz), 7M (1H, dd, J=7.9, 7.6Hz), 8.00 (1H, d, J=7.9Hz), 11.18 (1H, br) 化合物11-3'H-NMRCDMSO-d ) 6 ppm: 7e30 (1H, d, J = 2.2 Hz), 7.78 (1H, d, J = 7.6 Hz), 7.81 (1 6 H, d, J = 2.2 Hz), 7M ( 1H, dd, J=7.9, 7.6Hz), 8.00 (1H, d, J=7.9Hz), 11.18 (1H, br) Compound 11-3

^-NMRiDMSO-d ) δ ppm:2.44 (3H, s), 2.62 (3H, s), 3〇38 (4H, dd, J=13.9, 6.9H 6 z), 3.43 (1H, brs), 7.39-7.47 (3H, m), 7.90 (1H, d, j=2.2Hz) 化合物11-4 'H-NMRCDMSO-d ) δ ppm:3.39 (3H, s), 4.89 (2H, s), 7〇29~7.32 (1H, m), 7.34 (1 6 ^ H, d, J=2.2Hz), 7.41-7.43 (1H, m), 7.84 (1H, d, J=2.2Hz), 1L08 (1H, br)^-NMRiDMSO-d ) δ ppm: 2.44 (3H, s), 2.62 (3H, s), 3〇38 (4H, dd, J=13.9, 6.9H 6 z), 3.43 (1H, brs), 7.39- 7.47 (3H, m), 7.90 (1H, d, j=2.2Hz) Compound 11-4 'H-NMRCDMSO-d ) δ ppm: 3.39 (3H, s), 4.89 (2H, s), 7〇29~ 7.32 (1H, m), 7.34 (1 6 ^ H, d, J=2.2Hz), 7.41-7.43 (1H, m), 7.84 (1H, d, J=2.2Hz), 1L08 (1H, br)

化合物11-5 ^-NMRCDMSO-d ) δ ppm:2.47 (3H, s), 4.45 (2H, s), 7.32 (1H, d, J=2.2Hz), 7.41 6 -7.43 (1H, m), 7.50-7.52 (2H, m), 7.83 (1H, d, J=2.2Hz) 化合物11 - 6 ^-NMRCDMSO-d ) δ ppm:"2.46 (3H, s), 3.89 (3H, s)5 7.46-7.53 (3H, m), 7.97 (1 6 H, d, J=2.2Hz), 1L20 (1H, br) 化合物11 - 7 242 312XP/發明說明書(補件)/96-03/95143900 200800871 ^-NMRiDMSO-d ) δ ppm:L95-2.03 (2H, m), 2.63 (2H, t, J=6e6Hz), 2.96 (2H, t, 6 J=5.8Hz), 7。48-7·54 (1H, m)，7.71-7.86 (3H, m), 8.26 (1H，d，J=7.9Hz) 化合物11 - 8 i-NMR(DMS〇-d ) δ ppm:2.50-2.60 (3H，m)，6.00-6„25 (1H，m)，7.31 -7.52 (3H 6 ,m), 7.75-7.85 (1H, m), 8.00-8.35 (1H, m), 11.15 (1H, br) 化合物11 - 9 1H-NMR(DMSO~d ) δ ppm:L92~le97 (2H, m), 2.70 (2H, t, J=7.2Hz), 3.97 (2H, t, 6Compound 11-5 ^-NMRCDMSO-d ) δ ppm: 2.47 (3H, s), 4.45 (2H, s), 7.32 (1H, d, J = 2.2 Hz), 7.41 6 -7.43 (1H, m), 7.50 -7.52 (2H, m), 7.83 (1H, d, J = 2.2 Hz) Compound 11 - 6 ^-NMRCDMSO-d ) δ ppm: "2.46 (3H, s), 3.89 (3H, s)5 7.46- 7.53 (3H, m), 7.97 (1 6 H, d, J=2.2Hz), 1L20 (1H, br) Compound 11 - 7 242 312XP / invention specification (supplement) /96-03/95143900 200800871 ^-NMRiDMSO -d ) δ ppm: L95-2.03 (2H, m), 2.63 (2H, t, J=6e6Hz), 2.96 (2H, t, 6 J=5.8Hz), 7.48-7·54 (1H, m ), 7.71-7.86 (3H, m), 8.26 (1H, d, J=7.9Hz) Compound 11 - 8 i-NMR (DMS〇-d ) δ ppm: 2.50-2.60 (3H, m), 6.00-6 „25 (1H, m), 7.31 -7.52 (3H 6 , m), 7.75-7.85 (1H, m), 8.00-8.35 (1H, m), 11.15 (1H, br) Compound 11 - 9 1H-NMR ( DMSO~d) δ ppm: L92~le97 (2H, m), 2.70 (2H, t, J=7.2Hz), 3.97 (2H, t, 6

J=6.3Hz), 7.13-7.29 (7H, m), 7.39 (1H, d, J=2.2Hz), 7.64-7.67 (1H, m), 7.91 (1H, d, J=2.2Hz), 8.00-8.02 (1H, m), 1L02 (1H, br) 化合物11_10 ^-NMRiDMSO-d ) δ ppm:3e90 (3H, s), 3.13 (3H, s), 7.29 (1H, d, J=2.2Hz), 7.66 6 -7.72 (2H, m), 7.81-7.84 (1H, m), 7.86 (1H, d, J=2.2Hz), 8.19-8.21 (1H, m), 10.95 (1H, br) 化合物11 -11 ^-NMRCDMSO-d ) δ ppm:6.79-6^81 (2H, m), 6.94-6.96 (1H, m), 7.15-7.18 (1H, 6 m), 7.34-7·42 (3H, m), 7·44 (1H, d，J=2.2Hz)，7.67-7.70 (1H, m)，7·83 (1H, d, J二2· 2Hz), 8.11-8.13 (IH, m), 11.03 (1H, br) 化合物11-12 … — - ------ — ^-NMRCDMSO-d ) δ ppm:7.48 (1H, d, J=2.5Hz), 7.60-7.70 (3H, m), 7.87-7.89 ( 6 3H, in), 8.04-8.07 (2H, m), 8.38-8.41 (1H, m), 8.46-8.49 (1H, m), 11.03 (1H, br) 化合物11-13 ^-NMRiDMSO-d ) δ ppm:7.39 (1H, d, J=2.2Hz), 7.48-7.52 (3H, m), 7.62-7.66 ( 6 3H, m), 7.67 (1H, d, J=2.2Hz), 7.79-7.85 (2H, m), 8.16-8.18 (1H, m), 10.98 (1H, b 243 312XP/發明說明書(補件)/96-03/95143900 200800871 化合物11-14 ^-NMRCDMSO-d ) δ ppm:4〇30 (2Η, s), 6.86-6.87 (2H, m), 7=09-7.28 (5H, m), 7. 6 56-7.68 (3H, m), 8.14-8.16 (1H5 m)s 10.97 (1H5 br) 化合物11-15 ^-NMRiDMSO-d ) 5 ppm:l.I5-L37 (7H, m), L64-L69 (3H, m), 3.24-3.30 (1H, 6 m), 7.30 (1H，d，J=2.2Hz)，7。47-7。57 (2H, m)，7.66-7.70 (1H, m)，7。81 (1H，d，J=2· 2Hz), 8.09-8.11 (1H, m), 11.07 (1H, br) 化合物12 - 2 # 'H-NMRCDMSO-d^ δ ppm:2.58 (3H, s), 7.47 (1H, d, j=2.2Hz), 7〇70 (1H, d, J=2.2J=6.3Hz), 7.13-7.29 (7H, m), 7.39 (1H, d, J=2.2Hz), 7.64-7.67 (1H, m), 7.91 (1H, d, J=2.2Hz), 8.00- 8.02 (1H, m), 1L02 (1H, br) Compound 11_10 ^-NMRiDMSO-d ) δ ppm:3e90 (3H, s), 3.13 (3H, s), 7.29 (1H, d, J=2.2Hz), 7.66 6 -7.72 (2H, m), 7.81-7.84 (1H, m), 7.86 (1H, d, J=2.2Hz), 8.19-8.21 (1H, m), 10.95 (1H, br) Compound 11 -11 ^-NMRCDMSO-d ) δ ppm: 6.79-6^81 (2H, m), 6.94-6.96 (1H, m), 7.15-7.18 (1H, 6 m), 7.34-7·42 (3H, m), 7·44 (1H, d, J=2.2Hz), 7.67-7.70 (1H, m), 7·83 (1H, d, J 2·2Hz), 8.11-8.13 (IH, m), 11.03 (1H , br) Compound 11-12 ... — - ------ — ^-NMRCDMSO-d ) δ ppm: 7.48 (1H, d, J=2.5Hz), 7.60-7.70 (3H, m), 7.87-7.89 (6 3H, in), 8.04-8.07 (2H, m), 8.38-8.41 (1H, m), 8.46-8.49 (1H, m), 11.03 (1H, br) Compound 11-13^-NMRiDMSO-d δ ppm: 7.39 (1H, d, J=2.2Hz), 7.48-7.52 (3H, m), 7.62-7.66 (6 3H, m), 7.67 (1H, d, J=2.2Hz), 7.79-7.85 ( 2H, m), 8.16-8.18 (1H, m), 10.98 (1H, b 243 312XP/invention specification (supplement)/96-03/95143900 200800871 compound 11-14 ^-NMRCDMSO-d ) δ Ppm: 4〇30 (2Η, s), 6.86-6.87 (2H, m), 7=09-7.28 (5H, m), 7. 6 56-7.68 (3H, m), 8.14-8.16 (1H5 m) s 10.97 (1H5 br) Compound 11-15 ^-NMRiDMSO-d ) 5 ppm: l.I5-L37 (7H, m), L64-L69 (3H, m), 3.24-3.30 (1H, 6 m), 7.30 (1H,d,J=2.2Hz), 7.47-7.57 (2H, m), 7.66-7.70 (1H, m), 7.81 (1H,d,J=2·2Hz), 8.09- 8.11 (1H, m), 11.07 (1H, br) Compound 12 - 2 # 'H-NMRCDMSO-d^ δ ppm: 2.58 (3H, s), 7.47 (1H, d, j=2.2Hz), 7〇70 (1H, d, J=2.2

Hz), 7.74-7.76 (1H, m), 8.08-8.10 (1H, m), 11.20-11.80 (2H, br) 化合物12-3 1H-NMR(DMS〇-d ) δ ppm:7.53 (1H, s), 7.70 (1H, s), 7.93 (2H, s), 1L18 (1H, br) 6 ，11.72 (1H，br) 化合物12 -4 MS ： 35KM-1) 0 (試驗例1) 人體COMT抑制活性Hz), 7.74-7.76 (1H, m), 8.08-8.10 (1H, m), 11.20-11.80 (2H, br) Compound 12-3 1H-NMR (DMS〇-d) δ ppm:7.53 (1H, s ), 7.70 (1H, s), 7.93 (2H, s), 1L18 (1H, br) 6 , 11.72 (1H, br) Compound 12 -4 MS : 35KM-1) 0 (Test Example 1) Human COMT inhibitory activity

1)調製人體C0MT之重組DNA1) Modulation of recombinant DNA of human C0MT

(1)調製人體兒茶酚-0 -轉曱基酶之重組DNA 依據以加入編號 BC01 1 935 在 NCBI (Nat ional Center of Biotechnology Inf ormat ion)上註冊之編碼出人體兒茶酚- 0 -轉甲基酶（以下簡稱C0MT)全長之DM序列，設計 2個寡核苷酸引子（〇1 igonucleotide primer)藉以放大編碼出序列編號1記載之人體C0MT之DM序列。5’引子序 312XP/發明說明書(補件)/96-03/95143900 244 200800871 列示於序列編號3，3’引子序列示於序列編號4。此等引子含有限制酶位點（5’側為BamH I、3’侧為EcoR I)，以使該PCR產物容易***至所需載體中。將序列編號3記載之5’引子及序列編號4記載之3，引子分別以TE緩衝液稀釋調製成15pmol / #溶液。將 H2〇(PCR 用、34· 8 /z L)、25niniol/LMgS〇4(2· 0 // L)、2niinol/L dNTPs(5· 0 // L)及濃縮10倍之ΜΑ聚合酶KOD plus缓衝液（5.0//L、東洋紡織製）予以混合，調製成PCR反應用混 ⑩合物。其次，將人體肝臟cDNA(5· 0// L、Clontech製）加入至上述PCR反應用混合物中，再加入各引子對（1 // L、 15pmol)，最後加入1 · 0/z L之KOD plus(東洋紡織製）。隨後進行PCR反應。PCR反應以94°C 2分鐘之處理後，以 94°C 15秒、59°C 30秒、68°C 1分鐘之循環共進行40循環。最後以68°C 5分鐘、4°C10分鐘處理以結束反應。將 PCR 產物用 QIAquick PCR Purification Kit (QIAGEN 鲁製）進行精製。所欲取得之嵌入DNA序列係以上述套件之 EB緩衝液（30 // L)溶出。 (2)人體C0MT嵌入重組DNA及pGEX- 2T載體之雙重消化將濃縮 10 倍之 EcoR I 緩衝液（3.0//L、New England Biolab 製）、Η2〇(11· 1 // L)、BamH 1(1· 5// L、15U、10U/ //L)及 EcoR K1.0//L、15U、10U///L)加入至人體 C0MT 嵌入重組DNA(1.5//g)進行混合。此混合溶液在37°C加熱 1· 5小時。其次，加入濃縮1〇倍之裝載（loading)缓衝液於該混合溶液。混合溶液以電泳進行分離，切取含有該消 312XP/發明說明書(補件)/96-03/95143900 245 200800871 化片段DNA之凝膠部份，用Min Elute Gel Extraction Kit(QIAGEN製）進行精製。至於pGEX- 2T載體DNA(1. 5 μ g、Amersham製）亦同樣進行雙重消化並精製。 (3) 連接（ligation)及大腸菌 JM109 之轉殖 (transformation) 將經雙重消化之pGEX - 2T載體DNA(2. 0 // L、50ng)及嵌入DNA(1.24/zL、33.4ng)加入至濃縮2倍之連接缓衝液（3· 24 // L、Promega製）中混合。其次，加入T4連接酶 _ (1 igase)(1 · 0 /z L、3U/ // L、Promega 製）於此混合溶液中，此混合物在25°C保溫1小時。其次，將大腸菌JM109(100 //L)於0°C下溶解，將以連接酶反應之上述混合溶液（5// L)加入至大腸菌JM109懸浮液中，緩緩混合後在0X：靜置 30分鐘。此混合物在不強烈振盪下以42它實施熱衝擊 (heat shock)40秒後在0〇C冷卻10分鐘。其次，力口入450 //L之S0C溶液於熱衝擊後之溶液中，在37°C振盪1小 •時。振盪後分別取50//L及200 //L混合溶液接種於LB-胺苄青黴素（Ampicillin)培養基平板上（直徑9cm、胺苄青黴素濃度100//g//zL)，在37°C靜置培養16小時。結 '果在平板上出現菌落。 (4) GST融合重組人體C0MT質體之JM109轉殖後之菌落選殖由上述靜置培養後之平板選擇適當數之菌落，以殺菌牙籤將此等接種於LB-胺苄青黴素液體培養基（各2mL、胺苄青黴素濃度100//g///L)，在37°C振盪培養16小時。 312XP/發明說明書(補件)/96-03/95143900 246 200800871 由各液體培養分別取2 〇〇从L放入1 · 5mL微量試管，以酚(1) Recombinant DNA for modulating human catechol-0-transferase. According to the number BC01 1 935, the coding of human catechol- 0-transcode is registered on NCBI (Nat ional Center of Biotechnology Inf ormat ion). A full-length DM sequence of methylase (hereinafter referred to as C0MT) was designed with two oligonucleotide primers (〇1 igonucleotide primer) to amplify the DM sequence encoding human C0MT of SEQ ID NO: 1. 5' primer sequence 312XP/invention specification (supplement)/96-03/95143900 244 200800871 is listed in SEQ ID NO: 3, 3' The primer sequence is shown in SEQ ID NO: 4. These primers contain a restriction enzyme site (BamH I on the 5' side and EcoR I on the 3' side) to allow the PCR product to be easily inserted into the desired vector. The 5' primer and the SEQ ID NO: 4 described in SEQ ID NO: 3 were used, and the primers were diluted with TE buffer to prepare a 15 pmol / # solution. H2〇 (for PCR, 34·8 /z L), 25niniol/LMgS〇4 (2·0 // L), 2niinol/L dNTPs (5·0 // L), and 10-fold concentration of ΜΑ polymerase KOD The plus buffer (5.0//L, manufactured by Toyobo Co., Ltd.) was mixed to prepare a mixed composition for the PCR reaction. Next, human liver cDNA (5·0//L, manufactured by Clontech) was added to the above mixture for PCR reaction, and each primer pair (1 // L, 15 pmol) was added, and finally KOD of 1 · 0/z L was added. Plus (Toyo Textile Co., Ltd.). The PCR reaction is then carried out. The PCR reaction was carried out at 94 ° C for 2 minutes, and then subjected to a cycle of 94 ° C for 15 seconds, 59 ° C for 30 seconds, and 68 ° C for 1 minute for a total of 40 cycles. Finally, the reaction was terminated by treatment at 68 ° C for 5 minutes and 4 ° C for 10 minutes. The PCR product was purified using QIAquick PCR Purification Kit (QIAGEN). The embedded DNA sequence to be obtained was eluted with EB buffer (30 // L) of the above kit. (2) Double digestion of human C0MT embedded recombinant DNA and pGEX-2T vector will concentrate 10 times of EcoR I buffer (3.0//L, New England Biolab), Η2〇 (11·1 // L), BamH 1 (1·5//L, 15U, 10U/ //L) and EcoR K1.0//L, 15U, 10U///L) were added to human C0MT embedded recombinant DNA (1.5//g) for mixing. This mixed solution was heated at 37 ° C for 1.5 hours. Next, a loading buffer concentrated 1 time was added to the mixed solution. The mixed solution was separated by electrophoresis, and the gel fraction containing the DNA of the fragment of the 312XP/invention specification (supplement)/96-03/95143900 245 200800871 was cut out and purified using a Min Elute Gel Extraction Kit (manufactured by QIAGEN). As for the pGEX-2T vector DNA (1.5 μg, manufactured by Amersham), double digestion and purification were also carried out. (3) Ligation and transformation of E. coli JM109 The double-digested pGEX - 2T vector DNA (2.0 k L, 50 ng) and the embedded DNA (1.24/zL, 33.4 ng) were added to the concentration. Mix 2 times the ligation buffer (3·24 // L, manufactured by Promega). Next, T4 ligase _ (1 igase) (1 · 0 /z L, 3U / //L, manufactured by Promega) was added to the mixed solution, and the mixture was incubated at 25 ° C for 1 hour. Next, the coliform JM109 (100 // L) was dissolved at 0 ° C, and the above mixed solution (5 / / L) of the ligase reaction was added to the suspension of Escherichia coli JM109, and slowly mixed at 0X: static 30 minutes. This mixture was cooled at 0 ° C for 10 minutes after being subjected to a heat shock for 40 seconds without vigorous shaking. Next, force the 450/L S0C solution into the solution after thermal shock and shake at 37 °C for 1 hour. After shaking, 50//L and 200 //L mixed solution were inoculated on LB-Ampicillin medium plate (diameter 9 cm, ampicillin concentration 100//g//zL), and static at 37 ° C. Incubate for 16 hours. The knot 'fruit appeared on the plate. (4) GST fusion recombinant human C0MT plastid JM109 colonization after colony selection The appropriate number of colonies were selected from the above-mentioned plate after static culture, and the LB-ampicillin liquid medium was inoculated with a sterilizing toothpick (each 2 mL, ampicillin concentration 100 / / g / / / L), shaking culture at 37 ° C for 16 hours. 312XP/Invention Manual (Supplement)/96-03/95143900 246 200800871 Take 2 〇 from each liquid culture 放入 Put 1 · 5mL micro-tube from L to phenol

消化之再確認。Re-confirmation of digestion.

μ L、15U/ // L)。乃1土囷洛之DNA溶液（各7//L)與濃縮衝液（〇· 9 // L、New England Biolab 製） mH K0.5//L、l〇U//zL)及 EcoR 1(0.5 此溶液在37¾加熱1小時後進行電泳。檢出位置β接近於約670bp之泳動帶判定為次級陽性菌落。 (5) 由大腸菌JM109萃取並精製GST融合重組人體c〇MT質體於上述（4)判定為次級陽性菌落之以GST融合重組人體 C0MT質體之JM109轉殖之培養液，係取其一部分（1〇〇// L)作為甘油貯存原種，其餘以12〇〇〇rpm離心1〇分鐘得大籲腸菌丸狀沈澱物（pellet)。使用QIAGENPlasmidmini kit (QIAGEN製）由此大腸菌丸狀沈澱物精製質體dna。以 OD260nm測定，其濃度為247ng///L。依常法確認其序列，結果序列編號2之DNA序列嵌入於所期望位置。 (6) GST融合重組人體C0MT質體DM之對大腸菌BL21 CODON PLUS(DE3)RP 的轉殖μ L, 15U/ // L). It is a DNA solution of 1 囷洛 (7/L) and concentrated rinsing (〇·9 // L, manufactured by New England Biolab) mH K0.5//L, l〇U//zL) and EcoR 1 ( 0.5 This solution was electrophoresed after heating for 1 hour at 373⁄4. The detection zone was determined to be a secondary positive colony with a distance of approximately 670 bp. (5) The GST fusion recombinant human c〇MT plastid was extracted and purified by Escherichia coli JM109. (4) JM109 transgenic culture medium with GST fusion recombinant human C0MT plastid was determined as a secondary positive colony, and a part (1〇〇//L) was taken as a glycerol storage stock, and the rest was 12 rpm. The pellet was pelleted by centrifugation for 1 minute. The plastid DNA was purified from the coliform pellet pellet using a QIAGEN Plasmidmini kit (manufactured by QIAGEN) at a concentration of 247 ng//L. The sequence was confirmed by the usual method, and the DNA sequence of SEQ ID NO: 2 was embedded in the desired position. (6) GST fusion recombinant human C0MT plastid DM for the transfection of coliform BL21 CODON PLUS (DE3) RP

將於上述（5)精製且確認序列之GST融合重組人體c〇MT 質體DNA(lng/ //L)加入至以〇C溶解之大腸菌BL21 C0D0N PLUS(DE3)RP細胞懸浮液（50//L)中，與上述（3)相同地進 312XP/發明說明書(補件)/96-03/95143900 247 200800871 行轉殖及平板培養。 (7) GST融合重組人體C0MT之表現由轉殖後之大腸菌BL21 CODON PLUS(DE3)RP平板上選取菌落，投入LB -胺苄青黴素液體培養基（5mL、胺苄青撤素ί辰度10 0 // g / # L )中，在3 7 °C振盈培養15小時。取培養液一部分（50/zL)作為甘油貯存原種，貯存於一 80 °C。使用時取此甘油貯存原種一部分接種於LB -胺苄青黴素液體培養基（15〇mL、胺苄青黴素濃度100 // g//z L) ⑩中，在37°C振盪培養16小時。此培養液各以500mL之7 瓶LB -胺苄青黴素液體培養基（胺苄青黴素濃度loo# g/ // L)稀釋，在20°C振盪培養4· 5小時。以600nm確認培養液之吸光度為0.44後，分別添加各50//L之異丙基-石-D_硫吡喃半乳糖苷（im〇i/L)，在20°C振盪培養18 小時。此培養液以9000rpm離心20分鐘回收得大腸菌丸狀沈澱物，以每支4g分成4支，冷凍貯存於一 80°C至使用為止。 (8) GST融合重組人體C0MT之凝血酶（thrombin)處理於上述（7)所得大腸菌丸狀沈殿物中添加BugBuster溶液（Novagen 製）40mL、Benzonase(Novagen 製）30//L 及 rLysozyme(Novagen製）1 // L，在室溫下缓缓攪拌處理15 分鐘。所得溶胞產物（lysate)以12000rpm、4°C離心20 分鐘，回收上清液。其次，加入預先以D - PBS (Du 1 be cco’ s Phosphate Buff ered Sal ine)均衡、並以 50%再懸浮於 D -PBS 之 20mL 穀胱甘肽（glutathione)4B Sepharose(樹脂 312XP/發明說明書(補件)/96-03/95143_ 248 200800871 床容量1 OmL)於上述上清液中，此混合物在4°C振盪1小時。振盪後之混合物以過濾器分成樹脂與濾液。所得樹脂以30mL D - PBS清洗5次，再以30mL凝血酶處理用緩衝液（150mmol/L NaCl、50mmol/L Tris - HC1、pH8.0、1〇% 甘油、2· 5mmol/L CaCh、0· 5%石-辛基- D -吼喃葡萄糖苷）清洗3次。其次，加凝jk酶處理用緩衝液於此樹脂使成30mL，加入凝血酶（Amersham Bioscienc製）30單位。此樹脂混合液在4°C緩緩攪拌15小時後過濾樹脂，以濾 ⑩液所得之重組人體C0MT溶液冷珠貯存於一8 0 °C至使用為止° 2)測定人體C0MT抑制作用人體C0MT抑制作用之測定係將Zurcher，G·等之方法 (J· Neurochem·，1982 年，38 卷，P.191-195)部份改變而實施。將於上述 1)所調製之重組人體 C0MT(約 lmg/mL)0· 25ml、鱗酸鉀缓衝液（50 Ommol/L、ρΗ7· 6)40 mL、 φ氣化鎂（l〇〇mmol/L) lOmL 、二硫蘇糖醇 (dithiothreitol 、 62.5mmol/L)10mL 、腺皆脫胺酶 (2550U/mL)(h 5mL與供試化合物之混合物在37°C預保溫5 分鐘。對照樣品亦以相同方法調製，但以二甲亞颯（5mL) 替代供試化合物。在添加[3H] - S -腺苷-L -曱硫胺酸 (12· 5mmol/L、1· 2Ci/mol、Amersham Bioscienc 製）20mL 後，加入兒茶紛基質（7mmol/L)25mL以開始反應。反應混合物（最終容量〇. 25mL)在37°C預保溫30分鐘。加入冰冷之含0· lg/L鄰甲氧基驗（guaiacol)之鹽酸（lmol/L、 312XP/發明說明書(補件)/%-〇3/95143900 249 200800871 〇· 25mL)以停止反應。加入閃爍液（scintillat()r、 Optif low(註冊商標）0、Packard公司製）2_ 5mL，強烈振盪1分鐘後，以Packard公司製之液體閃燦計數計 (Microscintilation counter、YRICARB 1 900CA)直接涓 ι| 定存定於有機液層之放射活性。空白試驗在兒茶酚基質不存在下進行保溫（反應停止後添加基質）。ICsg值表示抑制酵素活性50%所需要之濃度。比較例係使用多加邦 (Tolcapone)、安達加邦（Entacapone)及非專利文獻4記鲁載之5 -甲磺醯基—3 -硝苯基-1，2 -二醇（比較例1)進行相同試驗。此等結果示於表24。 [表 24] lb合物編氣 (n m ο 1 / L ) H；5〇(nmol/L)The GST fusion recombinant human c〇MT plastid DNA (lng/ //L) purified and confirmed in the above (5) was added to the E. coli BL21 C0D0N PLUS (DE3) RP cell suspension dissolved in 〇C (50// In L), the 312XP/invention specification (supplement)/96-03/95143900 247 200800871 is carried out in the same manner as in the above (3). (7) GST fusion recombinant human C0MT performance by colonization of coliform BL21 CODON PLUS (DE3) RP plate selected colonies, into LB-ampicillin liquid medium (5mL, benzyl chlorhexidine ί ί 10 10 10 / / g / # L ), incubated at 3 7 °C for 15 hours. A portion of the culture solution (50/zL) was taken as a glycerol stock and stored at 80 °C. A portion of this glycerol stock stock was inoculated into LB-ampicillin liquid medium (15 〇mL, ampicillin concentration 100 // g//z L) 10 during use, and cultured at 37 ° C for 16 hours with shaking. The culture solution was diluted with 7 mL of LB-ampicillin liquid medium (ampicillin concentration loo# g/ // L) in 500 mL, and shake cultured at 20 ° C for 4.5 hours. After confirming that the absorbance of the culture solution was 0.44 at 600 nm, 50/L of each of isopropyl-stone-D-thiogalactopyranoside (im〇i/L) was added thereto, and the mixture was cultured at 20 ° C for 18 hours with shaking. The culture solution was centrifuged at 9000 rpm for 20 minutes to recover a coliform pellet, which was divided into 4 pieces of 4 g each, and stored frozen at 80 ° C until use. (8) GST fusion recombinant human C0MT thrombin (thrombin) was added to the above-mentioned (7) coliform pellets to add BugBuster solution (Novagen) 40 mL, Benzonase (Novagen) 30 / / L and rLysozyme (Novagen) ) 1 // L, slowly agitate for 15 minutes at room temperature. The obtained lysate was centrifuged at 12,000 rpm and 4 ° C for 20 minutes, and the supernatant was collected. Next, 20 mL of glutathione 4B Sepharose (Resin 312XP/Invention Manual) which was previously equilibrated with D-PBS (Du 1 be cco's Phosphate Buffered Sal ine) and resuspended in D-PBS at 50% was added. (Supplement) / 96-03/95143_ 248 200800871 Bed capacity 1 OmL) In the above supernatant, the mixture was shaken at 4 ° C for 1 hour. The shaken mixture was separated into a resin and a filtrate by a filter. The obtained resin was washed 5 times with 30 mL of D-PBS, and then treated with 30 mL of thrombin-treated buffer (150 mmol/L NaCl, 50 mmol/L Tris-HCl, pH 8.0, 1% glycerol, 2.5 mmol/L CaCh, 0). · 5% stone-octyl-D-glucopyranoside) was washed 3 times. Next, a buffer solution for kj enzyme treatment was added to the resin to make 30 mL, and thrombin (manufactured by Amersham Bioscienc) was added in 30 units. The resin mixture was stirred slowly at 4 ° C for 15 hours, and then the resin was filtered. The recombinant human C0MT solution obtained by filtering 10 liquid was stored at 80 ° C until use. 2) Determination of human C0MT inhibition, human C0MT inhibition The measurement of the action was carried out by partially changing the method of Zurcher, G. et al. (J. Neurochem, 1982, Vol. 38, p. 191-195). Recombinant human C0MT (about 1 mg/mL) 0·25 ml, potassium citrate buffer (50 Ommol/L, ρΗ7·6) 40 mL, φ gasification magnesium (l〇〇mmol/L) prepared in the above 1) lOmL, dithiothreitol (62.5mmol / L) 10mL, gland deaminase (2550U / mL) (h 5mL and test compound mixture pre-incubated at 37 ° C for 5 minutes. Control sample also Prepared by the same method, but substituting dimethyl sulfoxide (5 mL) for the test compound. Add [3H] - S - adenosyl-L-indole thioacid (12·5 mmol/L, 1.2 Ci/mol, Amersham Bioscienc) After 20 mL, add 25 mL of catechin base (7 mmol/L) to start the reaction. The reaction mixture (final capacity 〇. 25 mL) was pre-incubated at 37 ° C for 30 minutes. Add ice-cold 0· lg/L o-methoxy Guacol hydrochloride (lmol / L, 312XP / invention instructions (supplement) /% - 〇 3 / 95143900 249 200800871 〇 · 25mL) to stop the reaction. Add scintillation fluid (scintillat () r, Optif low (registered 2) 5 mL, manufactured by Packard Co., Ltd., and shaken vigorously for 1 minute, using a liquid flash counter (Microscintilation counter, YRICARB 1 900CA) manufactured by Packard Co., Ltd.涓ι| The radioactivity of the organic layer is determined. The blank test is carried out in the absence of the catechol matrix (the matrix is added after the reaction is stopped). The ICsg value indicates the concentration required to inhibit the enzyme activity by 50%. The same test was carried out using Tolcapone, Entacapone, and 5-methylsulfonyl-3-nitrophenyl-1,2-diol (Comparative Example 1). These results are shown in Table 24. [Table 24] lb compound gas (nm ο 1 / L) H; 5 〇 (nmol / L)

(試驗例2) C0MT抑制劑抑制鼠腦及肝臟之⑶叽活性 1)投予及取樣將週齡（體重200g至250g)之雄性Sprague - Dawley 312_明說明書(補件)/___ 250 200800871 鼠（Charles River Japan公司）絕食16小時。所有供試化合物係在經口投予即刻前以2mg/mL濃度溶解於二曱亞颯/聚乙二醇400/0. lmol/L精胺酸水溶液=0. 5/20/79. 5 中。在化合物投予（10mg/kg)後1小時及5小時，將動物斷頭宰殺以摘取C0MT活性測定用之腦及肝臟。另由未處理動物摘取之臟器作為對照。所有臟器立即用液態氮進行冷凍。冷凍臟器用4倍量（w/v)之冰冷均質缓衝液（含 0.5mmol/L二硫蘇糖醇之Dulbecco’ s鱗酸緩衝食鹽液）馨進行均質化。均質物以900g、4°C離心10分鐘（使用久保田公司製、高容量冷束離心機8 8 0 0)。上清部分含有S -C0MT(可溶性C0MT)及MB-C0MT(膜結合型C0MT)之雙方 (即總C0MT部分），貯存於一80°C至供測定。各樣品之蛋白質濃度係依BCA蛋白質定量法（Pierce公司製）測定。 2)測定C0MT活性 C0MT之測定以部分改變Zurcher，G·等之方法（J. 鲁 Neurochem·，1982 年，38 卷，P.191-195)而實施。將均質樣品（樣品之蛋白質濃度係於腦及肝臟各約為15mg/mL及約35mg/mL)之一部分（腦及肝臟各約50mL及約3.5mL)與鱗酸鉀緩衝液（500mmol/L、pH7. 6)40mL、氯化鎮 (100mmol/L)10mL、二硫蘇糖醇（62.5mmol/L)10mL、腺苦脫胺酶（2550U/mL) (K5mL之混合物在37X：預保溫5分鐘。在添加[3H ] - S -腺普-L -曱硫胺酸（12. 5mmo 1 /L、 44-4GBq/mol、Amersham Bioscienc 製）20mL 後加入兒茶酚基質（7mmol/L)25mL以開始反應。反應混合物（最終容 312XP/發明說明書(補件)/96-03/95143900 251 200800871 量0· 25mL)在37°C預保溫90分鐘（腦）或30分鐘（肝臟）。此反應以加入冰冷之含〇· lg/L鄰甲氧基酚之lm〇1/L鹽酸 (0. 25mL)停止。加入閃爍液（sc^nti Hat〇r、i〇w(註冊商標）0'Packard公司製）2.5raL，強烈振盪1分鐘後，以Packard公司製液體閃爍計數計（TRICARB i9〇〇CA)直接測定存在於有機液層之放射活性。對照樣品則在兒茶酚基貝不存在下進行保溫（反應停止後添加基質）。C0MT活性％表示以空白當作1 〇〇%時之C〇MT活性比率。比較例使用多 •加邦（Tolcapone)、安達加邦（Entacap〇ne)及非專利文獻 4記載之5 -曱磺醯基-3 -硝苯基_ 1，2 -二醇（比較例 1)進行相同試驗。此等結果示如表25。 [表 25](Test Example 2) C0MT inhibitor inhibits (3) sputum activity in rat brain and liver 1) Administration and sampling Male Sprague-Dawley 312_ming instructions (supplement)/___ 250 200800871 rats of the age of the body (body weight 200 g to 250 g) (Charles River Japan) hunger strike for 16 hours.至中中中中中中中中中中中中中中中中中中中中中中中中中中中中中中中中中中中中中中中中中中中中中中中中中中中中中中中中中中中中中中中中中中中中中中中中中中中中中中中中中中中中中中中中中中中中中中中中中. One hour and five hours after the administration of the compound (10 mg/kg), the animals were decapitated and slaughtered to extract the brain and liver for C0MT activity measurement. The organs removed from the untreated animals were also used as controls. All organs were immediately frozen with liquid nitrogen. The frozen organ was homogenized with 4 times the amount (w/v) of ice-cold homogenization buffer (Dulbecco's squaric acid buffered saline containing 0.5 mmol/L dithiothreitol). The homogenate was centrifuged at 900 g for 10 minutes at 4 ° C (using a high-capacity cold-beam centrifuge 8008). The supernatant fraction contained both S-C0MT (soluble COMT) and MB-C0MT (membrane-bound COMT) (ie, the total C0MT fraction) and was stored at 80 ° C for measurement. The protein concentration of each sample was measured by a BCA protein quantification method (manufactured by Pierce). 2) Measurement of COMT activity The measurement of C0MT was carried out by partially changing the method of Zurcher, G. et al. (J. Lu Neurochem, 1982, Vol. 38, p. 191-195). A homogeneous sample (the protein concentration of the sample is about 15 mg/mL and about 35 mg/mL in each of the brain and liver) (about 50 mL and about 3.5 mL in the brain and liver) and potassium citrate buffer (500 mmol/L, pH7. 6) 40mL, chlorinated town (100mmol / L) 10mL, dithiothreitol (62.5mmol / L) 10mL, adenine deaminase (2550U / mL) (K5mL mixture at 37X: pre-insulation for 5 minutes Add catechol substrate (7mmol/L) 25mL after adding 20 mL of [3H]-S-adeno-L-oxime thiocyanate (12. 5mmo 1 /L, 44-4GBq/mol, Amersham Bioscienc) The reaction was started. The reaction mixture (final capacity 312XP / invention specification (supplement) / 96-03 / 95143900 251 200800871 volume 0 · 25mL) was pre-incubated at 37 ° C for 90 minutes (brain) or 30 minutes (liver). Add chilling 〇· lg/L o-methoxyphenol lm〇1/L hydrochloric acid (0.25 mL) to stop. Add scintillation fluid (sc^nti Hat〇r, i〇w (registered trademark) 0'Packard Company 2.5raL, after vigorously shaking for 1 minute, the radioactivity present in the organic layer was directly measured by a liquid scintillation counter (TRICARB i9〇〇CA) manufactured by Packard. The control sample was in catechol. The incubation was carried out in the absence of Kibe (the matrix was added after the reaction was stopped). The % activity of C0MT indicates the ratio of C〇MT activity when the blank was taken as 1%. The comparative example used Tolcapone, Andagabang ( The same test was carried out on 5-oxasulfonyl-3-nitrophenyl-1,2-diol (Comparative Example 1) described in Non-Patent Document 4. The results are shown in Table 25. [Table 25] ]

化合物一編號~_ 腦（C0MT 活性％) 肝臟（C U Μ ΐ活性％ ) 1 〇 A 1小時 5小時 1小時 b小時 1-24 4 7.3 94.5 1.5 ~071 ~ 1 - 4 5 3 4.1 9 3.7 2.3 ' Π-2 1 - 4 6 3 6.7 ~ΤΤΠ 1 . 6 7_ 5 1 - 97 6 5 . 0 94.8 4 . 6 ~2ΓΓ9~ 1-12 1 3 0.1 ~Τ2Τ1 ~ 1 . 7 19.3 1 - 12 5 5 3.9 86.7 6.5 ~~ΓΤ71 ~ 1-12 7 3 0.7 73.5 3.0 2 2-1 + I Γ 1 1 4 5.8 84.5 ΓΓο rrro~ 多加邦 9 . 9 57.9 2.5 ~3ΤΓ0~ 安達加邦 8 5.3 ~ITTTB~ 15,63 ~78T4~ 比較例1 9 2.7 9 4.2 86.9 10 6.2 312XP/發明說明書(補件)/96-03/95143900 252 200800871 驗Λ果’獲知相較於多加邦抑制腦及肝臟之 0ΜΤ活性，本發明之化合物在肝臟表現選：性。又，本發明之化合物在與多加邦、安化合物比較時，表現較持續性之肝c〇MT抑制7作用s :父例 (試驗例3 ) 對肝細胞之毒性將貯存於—150t：之鼠冷凍肝細胞3xl〇—6cells/vial加溫至，加人含㈣糖之解;東液（thawingmediumi〇mL) 中，以lOOOrpm離心！分鐘。去除上清液，使細胞沈澱懸浮於Williams E. medium(15mL)。供試化合物用二甲亞砜調製成45、15、4.5、1.5、〇.45mmol/L濃度後，將各供試化合物溶液及對照（二甲亞砜）各以2 〇从L注入至試管中，再將上述細胞懸浮液（330 //L)注入至各試管中進行混合。各懸浮液以100# L分注於96孔微量培養板後在 37 C之C〇2保溫相中保溫4小時。依Promega公司之Cel 1 _ Viability Assay法測定ATP活性。將對照之表現50%ATP 活性之派度當作E C5。值。此等結果示於如表2 6。 [表 26] 化合物編號 HCso C/zmol/L) 化合物編號 l：U5〇 C>mol/L) 1-6 >300 1-125 200 1-24 >300 1-127 >300 1-45 >300 4-2 >300 1 - 47 262 11-6 297 1-97 >300 多加邦 34·3 1-121 216 安達加邦 111 由此等試驗結果，獲知本發明之化合物僅表現極輕微之肝細胞毒性。 312XP/發明說明書(補件)/%-〇3/95143900 253 200800871 (試驗例4) 對單侧性6 -羥基多巴胺損傷之單侧巴金森症鼠之左多巴藥效增強作用 (1) 藥物使用下述各藥物： 6 -經基多巴胺鹽酸鹽（6 - 0HDA、Sigma製）； Desipramine hydrochloride(迪西普拉敏鹽酸鹽）（Desipramine(迪西普拉敏）、Sigma製）；L-抗壞血 _ 酸（Sigma 製）；戊巴比妥鈉（Pentobarbital sodium) (NembutaK寧必妥）注射劑、大日本住友製藥製）；鹽酸阿朴嗎啡1/2水合物（Apomorphine(阿朴嗎徘）、Sigma製）；二經基***酸（L - Dopa左多巴、Sigma製）；卡比多巴水合物（卡比多巴、Kenprotec製）；0· 5%甲基纖維素（和光純藥工業製）。 6- 0HDA係以2mg/mL濃度溶解於含0·2% L -抗壞血酸鲁之生理食鹽水中。迪西普拉敏用溫水浴以1 〇mg/mL濃度溶解於蒸餾水中。阿朴嗎啡以0.1mg/mL濃度溶解於生理食鹽水中。左多巴/卡比多巴懸浮於〇· 5%甲基纖維素水溶液中。供試化合物溶解於含二曱亞砜〇· 5%、聚乙二醇20% 及0· lmol/L精胺酸79. 5%之水溶液中。 (2) 製作6 - 0HDA損傷模式製作6 - 0HDA損傷模式係以部分改變非專利文獻5之方法而實施。將雄性Sprague - Daw ley品系鼠（6週齡、 Charles River Japan公司）用腹腔内注射戊巴比妥鈉 312XP/發明說明書(補件)/96-03/95143900 254 200800871 (45mg/kg)予以麻醉，固定於定位框（Narishige公司、東京、曰本）。為防止6 - 0HDA損傷去曱腎上腺素神經元 (noradrenaline neuron)，在 6 - 0ΗΜ 注射前 30 分鐘實施腹腔内迪西普拉敏注射（25mg/kg)。經切開頭頂部中央之鑑別前囟（Bregma)後，在6 - 0HDA注射部位用牙科用鑽孔器在頭蓋骨開孔。用微量注射器（Hami lton)連接注射用 Kanule套管（30gage針）將6 - 0ΗΜ(速度為每分鐘1 // L、 4//L中8/zg)注入至左侧之内侧前腦束以實施損傷（損傷 _部位座標：由前囟（Bregma)點及頭蓋骨表面，前後一 2· 5mm、左右一 1 · 8mm、深度一8· Omm)。將 Kanule 套管在損傷部位靜置5分鐘後小心由動物拔除。裝填牙科用水泥於頭蓋骨開孔，消毒後將頭皮之切開部位以外科方式縫合。由麻醉回復之動物以通常方法飼育至實驗曰。 (3)旋轉動作之評價經上述之損傷3週後，依據對皮下投予阿朴嗎啡鲁（O.lmg/kg)反應之對侧旋轉（一旋轉定義為360度之旋轉），測試鼠。於觀察動作時，將鼠放入半徑20公分之塑膠製圓筒中，以錄影機攝錄旋轉動作，再用鼠旋轉動作自動計測裝置R - RACS(Kissei Wei Icom製）定量化。將1小時旋轉100次以上之動物再使用於進一步之試驗。於實驗日，動物經16小時絕食後以3mg/kg用量經口投予供試化合物，並同時經口投予左多巴5mg/kg及卡比多巴 3Omg/kg。測定對侧旋轉次數作為藥效強度，以停止旋轉動作20分鐘以上為止之時間作為藥效持續時間。總旋轉 312XP/發明說明書(補件)/96-03/95143900 255 200800871 次數及藥效持續時間示於表27。以僅投予左多巴及卡比多巴之群作為對照組。 [表 27] lb合物編'^ #4- " ---- 持續時間（分-鐘）總旋轉次數 a c — Ύ487Τ-- 6 0 0.8 丄-4 b 1T3TT-— T754. 4 多巴組合使用時’較僅使用左多巴/卡比多巴之對照組有顯著之加強藥效。 (產業上之可利用性）由於本發明之化合物具有優異之c〇MT抑制作用，故可用於作為巴金森氏症、憂鬱症及高血壓症之治療或預防劑。尤其，藉由將本發明之化合物與左多巴組合使用，能夠增加左多巴之生體内利用率，並延長其作用時間，故適合於巴金森氏症之治療或預防。 φ〈序列表〉 <序列編號1 > 序列編號1為人體兒茶紛—〇 -轉曱基酶之重組DNA序列0 <序列編號2 > 序列編號2為使序列編號1之人體兒茶紛—〇 —轉甲基酶之重組DNA序列表現之以序列編號3及4之引子 (primer)放大之DNA序列。 <序列編號3 > 312XP/發明說明書(補件)/96-03/95143900 256 200800871 序列編號3為放大序列編號2之DNA所使用之5’引子序列。 <序列編號4 > 序列編號3為放大序列編號2之D N A所使用之3 ’引子序列。Compound No. ~_ Brain (C0MT activity %) Liver (CU Μ ΐ activity %) 1 〇A 1 hour 5 hours 1 hour b hour 1-24 4 7.3 94.5 1.5 ~071 ~ 1 - 4 5 3 4.1 9 3.7 2.3 ' Π-2 1 - 4 6 3 6.7 ~ΤΤΠ 1 . 6 7_ 5 1 - 97 6 5 . 0 94.8 4 . 6 ~2ΓΓ9~ 1-12 1 3 0.1 ~Τ2Τ1 ~ 1 . 7 19.3 1 - 12 5 5 3.9 86.7 6.5 ~~ΓΤ71 ~ 1-12 7 3 0.7 73.5 3.0 2 2-1 + I Γ 1 1 4 5.8 84.5 ΓΓο rrro~ Tokabang 9. 9 57.9 2.5 ~3ΤΓ0~ Andagabang 8 5.3 ~ITTTB~ 15,63 ~ 78T4~ Comparative Example 1 9 2.7 9 4.2 86.9 10 6.2 312XP/Invention Manual (Supplement)/96-03/95143900 252 200800871 Test Results 'Know the compound of the present invention compared to Doka's inhibition of brain and liver activity In the liver performance selection: sex. Further, the compound of the present invention exhibits a more persistent liver c〇MT inhibition when compared with the compound of Toga, and the effect of the s: s: the parent case (test example 3) toxicity to hepatocytes will be stored in -150t: rat Frozen hepatocytes 3xl〇-6cells/vial warmed up, plus human (4) sugar solution; Dongye (thawingmediumi〇mL), centrifuged at 1000 rpm! minute. The supernatant was removed and the cell pellet was suspended in Williams E. medium (15 mL). After the test compound was adjusted to a concentration of 45, 15, 4.5, 1.5, and 〇.45 mmol/L with dimethyl sulfoxide, each test compound solution and control (dimethyl sulfoxide) were each injected from L into a test tube at 2 Torr. Then, the above cell suspension (330 //L) was injected into each tube for mixing. Each suspension was dispensed at 100 #L in a 96-well microplate and incubated in a 37 C C〇2 incubation phase for 4 hours. ATP activity was determined according to Promega's Cel 1 _ Viability Assay method. The performance of the control showing 50% ATP activity was taken as E C5. value. These results are shown in Table 26. [Table 26] Compound No. HCso C/zmol/L) Compound No. 1: U5〇C>mol/L) 1-6 >300 1-125 200 1-24 >300 1-127 >300 1-45 >300 4-2 >300 1 - 47 262 11-6 297 1-97 >300 Dokabang 34·3 1-121 216 Andagabang 111 From the results of these tests, it is known that the compounds of the present invention are only extremely polar Mild hepatotoxicity. 312XP/Invention Manual (supplement)/%-〇3/95143900 253 200800871 (Test Example 4) Enhancement of left dopa efficacy in unilateral Parkinson's disease rats with unilateral 6-hydroxydopamine injury (1) The following drugs were used: 6 - via dopamine hydrochloride (6-0HDA, Sigma); Desipramine hydrochloride (Desipramine), Sigma; - Ascorbic acid _ acid (Sigma); Pentobarbital sodium (Nembuta K) injection, manufactured by Dainippon Sumitomo Pharmaceutical Co., Ltd.; Apomorphine hydrochloride 1/2 hydrate (Apomorphine)徘), Sigma); dipyridyl methacrylic acid (L-Dopa left dopa, Sigma); carbidopa hydrate (cabidopa, manufactured by Kenprotec); 0. 5% methylcellulose (and Pure chemical industry system). 6-HDA was dissolved in physiological saline containing 0.2% L-ascorbic acid at a concentration of 2 mg/mL. Desipramine was dissolved in distilled water at a concentration of 1 〇 mg/mL in a warm water bath. Apomorphine was dissolved in physiological saline at a concentration of 0.1 mg/mL. Levodopa/carbidopa is suspended in an aqueous solution of 5% methylcellulose. The test compound was dissolved in an aqueous solution containing bis(sulfoxide) 5%, polyethylene glycol 20%, and 0·lmol/L arginine 79.5%. (2) Production of 6 - 0 HDA damage mode The 6 - 0 HDA damage mode was produced by partially changing the method of Non-Patent Document 5. Male Sprague-Daw ley strains (6 weeks old, Charles River Japan) were anesthetized with intraperitoneal injection of sodium pentobarbital 312XP/invention manual (supplement)/96-03/95143900 254 200800871 (45 mg/kg) , fixed in the positioning frame (Narishige, Tokyo, Sakamoto). In order to prevent 6-0HDA injury to noradrenaline neuron, intraperitoneal diceipramin injection (25 mg/kg) was performed 30 minutes before the 6-0 injection. After cutting the front sputum (Bregma) at the top of the top, use a dental drill to open the skull at the 6-0HDA injection site. Use a micro syringe (Hami lton) to connect the injection Kanule cannula (30gage needle) to inject 6 - 0 ΗΜ (speed of 1 / 8 L per minute, 8 / zg in 4 / / L) into the medial forebrain bundle on the left side Implementation of the injury (injury _ site coordinates: from the front sputum (Bregma) point and the surface of the skull, before and after a 2. 5 mm, about 1 · 8 mm, a depth of 8 · Omm). The Kanule cannula was allowed to stand for 5 minutes at the injury site and carefully removed by the animal. The dental cement is filled in the cranial opening, and the incision of the scalp is surgically sutured after disinfection. Animals recovered from anesthesia were bred to the experimental sputum in the usual manner. (3) Evaluation of the rotational motion After 3 weeks of the above-mentioned injury, the rats were tested according to the contralateral rotation (one rotation was defined as a rotation of 360 degrees) for subcutaneous administration of apomorphine (O.lmg/kg). During the observation operation, the mouse was placed in a plastic cylinder having a radius of 20 cm, and the rotation was recorded by a video recorder, and then quantified by a rat rotation automatic measuring device R-RACS (manufactured by Kissei Wei Icom). Animals that were rotated more than 100 times in 1 hour were used for further testing. On the experiment day, the animals were orally administered with the test compound at a dose of 3 mg/kg after 16 hours of fasting, and simultaneously administered with 5 mg/kg of levodopa and 3 mg/kg of carbidopa. The number of contralateral rotations was measured as the pharmacodynamic intensity, and the time until the rotation was stopped for 20 minutes or more was used as the duration of the drug effect. Total rotation 312XP/Invention manual (supplement)/96-03/95143900 255 200800871 The number of times and duration of efficacy are shown in Table 27. A group of only left dopa and carbidopa was administered as a control group. [Table 27] lb compound '^ #4- " ---- Duration (minutes - clock) Total number of rotations ac — Ύ487Τ-- 6 0 0.8 丄-4 b 1T3TT-— T754. 4 Dopa combination When used, it was significantly more potent than the control group using only levobar/carbidopa. (Industrial Applicability) Since the compound of the present invention has excellent c〇MT inhibitory action, it can be used as a therapeutic or preventive agent for Parkinson's disease, depression and hypertension. In particular, by using the compound of the present invention in combination with levo-dopa, it is possible to increase the utilization rate of levodopa and prolong its action time, so it is suitable for the treatment or prevention of Parkinson's disease. φ <sequence list> <sequence number 1 > SEQ ID NO: 1 is a recombinant DNA sequence of human catechin-〇-transferase. 0 <SEQ ID NO: 2 > SEQ ID NO: 2 is a human body having SEQ ID NO: The recombinant DNA sequence of the tea-〇-transmethylase is represented by a primer amplified by the primers of SEQ ID NOs: 3 and 4. <SEQ ID NO: 3 > 312XP/Invention Manual (Supplement)/96-03/95143900 256 200800871 SEQ ID NO: 3 is a 5' primer sequence used to amplify the DNA of SEQ ID NO: 2. <SEQ ID NO: 4 > SEQ ID NO: 3 is a 3' primer sequence used for amplifying sequence number 2 of D N A .

312XP/發明說明書(補件)/96·03/95143900 257 200800871312XP/Invention Manual (supplement)/96·03/95143900 257 200800871

SEQUENCE LISTING <110> Kissei Pharmaceutical Co. t Ltd. 〈120〉 Novel catechol derivatives, pharmaceutical compositions containing the same, and their usesSEQUENCE LISTING <110> Kissei Pharmaceutical Co. t Ltd. <120> Novel catechol derivatives, pharmaceutical compositions containing the same, and their uses

<130> JP-A0559-TW <150〉 JP 2005/342987 <151〉 2005-11-29 <160〉 4<130> JP-A0559-TW <150> JP 2005/342987 <151> 2005-11-29 <160〉 4

<170> Patent In version 3.1<170> Patent In version 3.1

<210> 1 〈211〉 223 〈212〉 PRT 〈213>人•見代人 <400> 1 6ly Ser Met 6ly Asp Thr Lys GIu Gin Arg He Leo Asn His Val Leu 15 10 15<210> 1 <211> 223 <212> PRT <213> 人•代代 <400> 1 6ly Ser Met 6ly Asp Thr Lys GIu Gin Arg He Leo Asn His Val Leu 15 10 15

Gin His Ala GIu Pro 6Iy Asn Ala Gin Ser Val Leu 6lu Ala He Asp 20 25 30Gin His Ala GIu Pro 6Iy Asn Ala Gin Ser Val Leu 6lu Ala He Asp 20 25 30

Thr Tyr Cys Giu Gin Lys GIu Trp Ala Met Asn Val G!y Asp Lys Lys 35 40 45Thr Tyr Cys Giu Gin Lys GIu Trp Ala Met Asn Val G!y Asp Lys Lys 35 40 45

Gly Lys Me Val Asp Ala Val He 6ln Giu His Gin Pro Ser Val Leu 50 55 60Gly Lys Me Val Asp Ala Val He 6ln Giu His Gin Pro Ser Val Leu 50 55 60

Leu Giu Leu Gly Ala Tyr Cys Gly Tyr Ser Ala Val Arg Met Ala Arg 65 70 75 80Leu Giu Leu Gly Ala Tyr Cys Gly Tyr Ser Ala Val Arg Met Ala Arg 65 70 75 80

Leu Leu Ser Pro Gly Ala Arg Leu lie Thr lie Giu lie Asn Pro Asp 85 90 95Leu Leu Ser Pro Gly Ala Arg Leu lie Thr lie Giu lie Asn Pro Asp 85 90 95

Cys Ala Ala Me Thr Gin Arg Met Val Asp Phe Ala Giy Val Lys Asp 258 312XP/發明說明書(補件)/96-03/95143900 200800871 100 105 110Cys Ala Ala Me Thr Gin Arg Met Val Asp Phe Ala Giy Val Lys Asp 258 312XP/Invention Manual (supplement)/96-03/95143900 200800871 100 105 110

Lys Val Thr Leu Val Val Gly Ala Ser Gin Asp He lie Pro Gin Leu 115 120 125Lys Val Thr Leu Val Val Gly Ala Ser Gin Asp He lie Pro Gin Leu 115 120 125

Lys Lys Lys Tyr Asp Val Asp Thr Leu Asp Met Val Phe Leu Asp His 130 135 140Lys Lys Lys Tyr Asp Val Asp Thr Leu Asp Met Val Phe Leu Asp His 130 135 140

Trp Lys Asp Arg Tyr Leu Pro Asp Thr Leu Leu Leu Glu Glu Cys Gly 145 150 155 160Trp Lys Asp Arg Tyr Leu Pro Asp Thr Leu Leu Leu Glu Glu Cys Gly 145 150 155 160

Leu Leu Arg Lys Gly Thr Val Leu Leu Ala Asp Asn Val He Cys Pro 165 170 175 6!y Ala Pro Asp Phe Leu Ala His Va! Arg Gly Ser Ser Cys Phe Glu 180 185 190Leu Leu Arg Lys Gly Thr Val Leu Leu Ala Asp Asn Val He Cys Pro 165 170 175 6!y Ala Pro Asp Phe Leu Ala His Va! Arg Gly Ser Ser Cys Phe Glu 180 185 190

Cys Thr His Tyr Gin Ser Phe Leu Glu Tyr Arg 6lu Val Val Asp G!y 195 200 205Cys Thr His Tyr Gin Ser Phe Leu Glu Tyr Arg 6lu Val Val Asp G!y 195 200 205

Leu Glu Lys Ala lie Tyr Lys Gly Pro Gly Ser Glu Ala Gly Pro 210 215 220Leu Glu Lys Ala lie Tyr Lys Gly Pro Gly Ser Glu Ala Gly Pro 210 215 220

<210〉 2 <211〉 684 <212> DNA <213> Aii <220> 〈223>***騰， <400〉 2 60 120 180 tctggatcca tgggtgacac caaggagcag cgcatcctga accacgtgct gcagcatgcg gagcccggga acgcacagag cgtgctggag gccattgaca cctactgcga gcagaaggag tgggccatga acgtgggcga caagaaaggc aagatcgtgg acgccgtgat tcaggagcac cagccctccg tgctgGtgga gctgggggcc tactgtggct actcagctgt gcgcatggcc 259 312XP/發明說明書(補件)/96-03/95143900 240 200800871<210> 2 <211> 684 <212> DNA <213> Aii <220> <223> Insertion, <400> 2 60 120 180 tctggatcca tgggtgacac caaggagcag cgcatcctga accacgtgct gcagcatgcg gagcccggga acgcacagag cgtgctggag gccattgaca cctactgcga gcagaaggag Tgggccatga acgtgggcga caagaaaggc aagatcgtgg acgccgtgat tcaggagcac cagccctccg tgctgGtgga gctgggggcc tactgtggct actcagctgt gcgcatggcc 259 312XP/invention manual (supplement)/96-03/95143900 240 200800871

cgcctgctgt caccaggggc gaggctgatc accatcgaga tcaaccccga ctgtgccgcc 300 atcacccagc ggatggtgga tttcgctggc gtgaaggaca aggtcaccct tgtggttgga 360 gcgtcccagg acatcatccc ccagctgaag aagaagtatg atgtggacac actggacatg 420 gtcttcctcg accactggaa ggaccggtac ctgccggaca cgcttctctt ggaggaatgt 480 ggcctgctgc ggaaggggac agtgctactg gctgacaacg tgatctgccc aggtgcgcca 540 gacttcctag cacacgtgcg cgggagcagc tgctttgagt gcacacacta ccaatcgttc 600 ctggaataca gggaggtggt ggacggcctg gagaaggcca tctacaaggg cccaggcagc 660 gaagcagggc cctgagaatt ctct 684cgcctgctgt caccaggggc gaggctgatc accatcgaga tcaaccccga ctgtgccgcc 300 atcacccagc ggatggtgga tttcgctggc gtgaaggaca aggtcaccct tgtggttgga 360 gcgtcccagg acatcatccc ccagctgaag aagaagtatg atgtggacac actggacatg 420 gtcttcctcg accactggaa ggaccggtac ctgccggaca cgcttctctt ggaggaatgt 480 ggcctgctgc ggaaggggac agtgctactg gctgacaacg tgatctgccc aggtgcgcca 540 gacttcctag cacacgtgcg cgggagcagc tgctttgagt gcacacacta ccaatcgttc 600 ctggaataca gggaggtggt ggacggcctg gagaaggcca tctacaaggg cccaggcagc 660 gaagcagggc Cctgagaatt ctct 684

<210〉 3 <211> 27 <212〉 DNA <213〉Aifc <220〉 <223> 5,引子 <400> 3 tctggatcca tgggtgacac caaggag 27<210> 3 <211> 27 <212> DNA <213>Aifc <220> <223> 5, primer <400> 3 tctggatcca tgggtgacac caaggag 27

<210> 4 <211〉 28 〈212〉 DNA <213> Ait <220〉 <223〉3’ 引子 <400> 4 agagaattct cagggccctg cttcgctg 28 260 312XP/發明說明書(補件)/96-03/95143900<210> 4 <211> 28 <212> DNA <213> Ait <220><223> 3' primer <400> 4 agagaattct cagggccctg cttcgctg 28 260 312XP/invention specification (supplement)/96 -03/95143900

Claims

200800871 十、申請專利範固： 1 ·種化口物或其樂理學上容許之鹽，其特徵為以下列一般式（I)表示： [化1]200800871 X. Patent application: 1 · The chemical substance or the salt of the music theory is characterized by the following general formula (I): [Chemical 1]

•[式中： R及R分別獨立為氫原子、低級醯基、低級烷氧羰基、一 c(〇)NR R 2 ’ 或 Rl 及 R2 共同形成-c(o) - ； R3為硝基或氰基； R4及R5分別獨立為氫原子、鹵素原子、低級烷基、鹵化低級烷基、氰基、低級醯基； R6、R7、R8、R9及R1D分別獨立為以下之a)〜ah): φ a)氳原子， b )鹵素原子， c) 低級燒基， d) 鹵化低級烷基， e )低級稀基， f) 低級炔基， g) 環烷基， h) 環烷基低級烷基， i) 低級烧氧基， 312XP/發明說明書(補件)/96-03/95143900 261 200800871 j) 鹵化低級烷氧基， k) 經基， l) 經基低級烧基， m) 羧基， η)低級烷氧羰基，〇)環烧基氧幾基， Ρ)低級醯基， q)低級烷基磺醯基， • r)氰基， s) 确基’ t) - A1 - NRnR12， u) - C(0) - NRnR12， v) - S〇2 - NRnR12， w) - N(R13) C(0)R14， x) - N(R13) S〇2R15， # y)被逛自氰基、低級烷氧基、低級烷氧基羰基及_ c(0):NflR12/斤構成群中之基取代之低級烷基， Z)被m自氰基、低級烷氧基、低級烷氧基羰基及_ C(0)- NRnR12所構成群中之基取代之低級烷氧基， aa) 被選自氰基、低級烷氧基羰基及_ c(〇) _ nr11r12所構成群中之基取代之低級烯基， ab) 未被取代之芳基，或環被由鹵素原子、低級烷基、鹵化低級炫基、低級烧氧基、氰基、低級釀基及低級貌氧基羰基所構成群中獨立選擇之〗〜3個基所取代之芳基， 312XP/發明說明書(補件)/96·〇3/95ΐ43900 262 200800871 ac) 未被取代之芳烷基、或環被由鹵素原子、低級烷基、鹵化低級縣、低㈣氧基、氰基、低賴基及低級烧氧基戴基所構料+獨立選擇之丨〜3個基所取代之芳炫基，鹵素原子、低級烷基、、低級醯基及低級烷氧 / 3個基所取代之芳氧 ad) 未被取代之芳氧基，或環被由鹵化低級烧基、低級烧氧基、氰基基羰基所構成群中獨立選擇之1〜基，鲁ae)未被取代之芳烧氧基，或環被由鹵素原子、低級烧基、鹵化低級燒基、低級烧氧基、氰基、低級酿基及低級烧氧基幾基所構成群中獨立選擇之個基所取代之芳烷氧基， af)未被取代之芳醯基，或環被由鹵素原子、低級烷基、鹵化低級烷基及低級烷氧基所構成群中獨立選擇之丨〜3 個基所取代之芳醯基， • ag)未被取代之芳磺醯基，或環被由卣素原子、低級烷基、齒化低級烷基及低級烷氧基所構成群中獨立選擇之丄〜3個基所取代之芳磺醯基， ah)未被取代之雜芳基，或環被由鹵素原子、低級烷基、鹵化低級烧基及低級烧氧基所構成群中獨立選擇之1〜3 個基所取代之雜芳基，或於R6、R7、R8、R9及IT中之2個相鄰時，其等鍵結形成以-0(CH2)m0 -、-（CH2)n-、- c(0) - NH - C(0) -、一 CH=CH— CH=CH-或 _c(〇)— (CH2)p-表示之基； 312XP/發明說明書(補件)/96-03/95143900 263 200800871 R及R分別獨立為氳原子、低級烧基或芳烧基，或ril 及R12與其等所鍵結之氮原子共同形成環狀胺基； R13為氫原子、低級烧基； R14為氫原子、低級烷基、未被取代之芳基，或環被由鹵素原子、低級烷基、齒化低級烷基、低級烷氧基、氰基、低級酿基及低級烷氧基羰基中獨立選擇之1〜3個基所取代之芳基； R15為低級烷基、未被取代之芳基，或環被自鹵素原子、鲁低級烷基、i化低級烷基、低級烷氧基、氰基、低級醯基及低級烧氧基羰基獨立選擇之1〜3個基所取代之芳基； A1為鍵結或低級伸烷基； m為1或2 ; η為3或4 ; Ρ為2〜4之整數]。 2 _如申请專利範圍第1項之化合物或其藥理學上容許鲁之鹽，其中R3為硝基。 3·如申請專利範圍第2項之化合物或其藥理學上容許之鹽，其中R1及R2為氫原子。 4·如申請專利範圍第3項之化合物或其藥理學上容許之鹽，其中R4及R5為氫原子。 5·如申請專利範圍第4項之化合物或其藥理學上容許之鹽，其中，R6、R7、R8、R9& R1。分別獨立為以下之a) 〜h): a )氫原子， 31ZXP/發明說明書(補件)/96-03/95143900 264 200800871 b)鹵素原子， c )低級烧基， d )鹵化低級焼*基， e)低級烷氧基， f )低級烧氧基叛基， g) 低級醯基，或 h) 氰基。 6·如申請專利範圍第5項之化合物或其藥理學上容許鲁之鹽，其中， R為_素原子、低級烷基、鹵化低級烷基、低級烷氧基、低級烷氧基羰基、低級醯基或氰基； R7及R9為氫原子； R8及R1Q分別獨立為氫原子、鹵素原子、低級烷基、鹵化低級烷基、低級烷氧基、低級烷氧基羰基、低級醯基或氰基。 • 7·如申請專利範圍第5項之化合物或其藥理學上容許之鹽，其中， R6為氳原子、_素原子、低級烷基、鹵化低級烷基、低級烷氧基、低級烷氧基羰基、低級醯基或氰基； R及R分別獨立為齒素原子、低級烷基、鹵化低級烷基、低級烷氧基、低級烷氧基羰基、低級醯基或氰基； 1^及R1()為氫原子。 8·如申請專利範圍第5項之化合物或其藥理學上容許之鹽，其中， 312XP/發明說明書(補件)/96·〇3/95143900 265 200800871 R6為低級烷氧基羰基、低級醯基或氰基； R及R為氮原子； R及R分別獨立為鹵素原子或低級烧基。 9·如申請專利範圍第1項之化合物，其係選自以下所構成群中之化合物或其藥理學上容許之鹽： 5 - (2 -氟-6 -三氟曱基苯磺醯基）_ 3_硝基苯_ 1，2 - 二醇；• [wherein R and R are each independently a hydrogen atom, a lower fluorenyl group, a lower alkoxycarbonyl group, a c(〇)NR R 2 ' or R1 and R2 together form a -c(o) - ; R3 is a nitro group or Cyano; R4 and R5 are each independently a hydrogen atom, a halogen atom, a lower alkyl group, a halogenated lower alkyl group, a cyano group, a lower fluorenyl group; and R6, R7, R8, R9 and R1D are each independently a)~ah) : φ a) 氲 atom, b) halogen atom, c) lower alkyl group, d) halogenated lower alkyl group, e) lower dilute group, f) lower alkynyl group, g) cycloalkyl group, h) cycloalkyl lower alkane Base, i) lower alkoxy group, 312XP/invention specification (supplement)/96-03/95143900 261 200800871 j) halogenated lower alkoxy, k) mesogen, l) lower alkyl group, m) carboxyl group, η) lower alkoxycarbonyl, 〇)cycloalkyloxy group, Ρ) lower fluorenyl group, q) lower alkyl sulfonyl group, • r) cyano group, s) exact group 't) - A1 - NRnR12, u ) - C(0) - NRnR12, v) - S〇2 - NRnR12, w) - N(R13) C(0)R14, x) - N(R13) S〇2R15, # y) , lower alkoxy, lower alkoxycarbonyl and _ c(0): NflR12 a lower alkyl group substituted with a group in the group, Z) a lower alkoxy group substituted by a group of m from a group consisting of a cyano group, a lower alkoxy group, a lower alkoxycarbonyl group, and a _C(0)-NRnR12 group a group, aa) a lower alkenyl group substituted with a group selected from the group consisting of a cyano group, a lower alkoxycarbonyl group and a _c(〇)_nr11r12 group, ab) an unsubstituted aryl group, or a ring derived from a halogen atom , an alkyl group substituted by a lower alkyl group, a halogenated lower leukoyl group, a lower alkoxy group, a cyano group, a lower stage aryl group, and a lower oxycarbonyl group, which are independently selected by the group of ~3 groups, 312XP/Invention Manual ( Supplement) /96·〇3/95ΐ43900 262 200800871 ac) Unsubstituted aralkyl group, or ring is composed of halogen atom, lower alkyl group, halogenated lower stage, low (tetra)oxy group, cyano group, low lysyl group and lower level Alkoxy-based materials + independently selected aryl groups substituted by ~3 groups, halogen atom, lower alkyl group, lower sulfhydryl group and lower alkoxy / 3 group substituted aryl oxygen ad) An unsubstituted aryloxy group, or a ring independently of a group consisting of a halogenated lower alkyl group, a lower alkoxy group, and a cyanocarbonyl group Select 1~ base, Lu a) unsubstituted aryloxy group, or ring is composed of halogen atom, lower alkyl group, halogenated lower alkyl group, lower alkoxy group, cyano group, lower stage aryl group and lower alkoxy group An aralkoxy group substituted by an independently selected group of a group, af) an unsubstituted aryl group, or a ring consisting of a halogen atom, a lower alkyl group, a halogenated lower alkyl group, and a lower alkoxy group. An arylsulfonyl group substituted by 丨3 groups independently selected in the group, • ag) an unsubstituted arylsulfonyl group, or a ring consisting of a halogen atom, a lower alkyl group, a dentate lower alkyl group, and a lower alkane The arylsulfonyl group substituted by 丄~3 groups independently selected from the group consisting of oxy groups, ah) unsubstituted heteroaryl group, or the ring is halogenated, lower alkyl, halogenated lower alkyl and lower grade A heteroaryl group substituted by 1 to 3 groups independently selected from the group consisting of oxy groups, or when two of R6, R7, R8, R9 and IT are adjacent, the bond is formed to -0 (CH2) M0 -, -(CH2)n-, - c(0) - NH - C(0) -, a CH=CH-CH=CH- or _c(〇) - (CH2)p- represents a base; 312XP / invention said Book (Supplement)/96-03/95143900 263 200800871 R and R are each independently a helium atom, a lower alkyl group or an aryl group, or ril and R12 together with a nitrogen atom to which they are bonded form a cyclic amine group; R13 Is a hydrogen atom, a lower alkyl group; R14 is a hydrogen atom, a lower alkyl group, an unsubstituted aryl group, or a ring is composed of a halogen atom, a lower alkyl group, a dentate lower alkyl group, a lower alkoxy group, a cyano group, a lower stage An aryl group substituted independently of 1 to 3 groups in the alkoxy group and the lower alkoxycarbonyl group; R15 is a lower alkyl group, an unsubstituted aryl group, or a ring is derived from a halogen atom, a ru-low alkyl group, Lower alkyl, lower alkoxy, cyano, lower fluorenyl and lower alkoxycarbonyl independently selected from 1 to 3 aryl groups; A1 is a bonded or lower alkyl; m is 1 or 2 ; η is 3 or 4; Ρ is an integer of 2 to 4]. 2 _ A compound of claim 1 or a pharmacologically acceptable salt thereof, wherein R3 is a nitro group. 3. A compound as claimed in claim 2 or a pharmacologically acceptable salt thereof, wherein R1 and R2 are a hydrogen atom. 4. A compound of claim 3 or a pharmacologically acceptable salt thereof, wherein R4 and R5 are a hydrogen atom. 5. A compound of claim 4 or a pharmacologically acceptable salt thereof, wherein R6, R7, R8, R9 & R1. Separately the following a) ~h): a) hydrogen atom, 31ZXP/invention specification (supplement)/96-03/95143900 264 200800871 b) halogen atom, c) lower alkyl, d) halogenated lower 焼* group , e) lower alkoxy, f) lower alkoxylated, g) lower sulfhydryl, or h) cyano. 6. A compound according to claim 5 or a pharmacologically acceptable salt thereof, wherein R is a _ element atom, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group, and a lower stage Sulfhydryl or cyano; R7 and R9 are a hydrogen atom; R8 and R1Q are each independently a hydrogen atom, a halogen atom, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group, a lower fluorenyl group or a cyanogen group. base. 7. The compound of claim 5 or a pharmacologically acceptable salt thereof, wherein R6 is a halogen atom, a halogen atom, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group, a lower alkoxy group. a carbonyl group, a lower sulfhydryl group or a cyano group; R and R are each independently a dentate atom, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group, a lower fluorenyl group or a cyano group; () is a hydrogen atom. 8. The compound of claim 5 or a pharmacologically acceptable salt thereof, wherein 312XP/invention specification (supplement)/96·〇3/95143900 265 200800871 R6 is a lower alkoxycarbonyl group, a lower sulfhydryl group Or a cyano group; R and R are a nitrogen atom; and R and R are each independently a halogen atom or a lower alkyl group. 9. The compound of claim 1, wherein the compound is selected from the group consisting of the following or a pharmacologically acceptable salt thereof: 5 - (2-fluoro-6-trifluoromethylsulfonyl) _ 3_nitrobenzene_ 1,2-diol;

5~(4-氟-2 - 1，2 - 二醇；三氟甲基苯磺醯基 3 -硝基苯一5~(4-fluoro-2 - 1,2-diol; trifluoromethylbenzenesulfonyl 3-nitrobenzene

m石肖基苯伽基）苯甲猜 .，一孔氟求磺醯基）-硝基苯— ， 5 一氣一 3 - (3，4 -二魏其〜ς . + 土〜5 —硝基笨磺醯基）〜2 一甲基苯甲腈； τ 2 -（3, 4 基苯甲腈；羥基-5~硝基苯磺醯基）一 3 -氯-5 - (3, 4 -二基苯甲腈； 2 - (3, 4-二經基 - ί 甲腈； 5 -（2 -二氟甲基-4, 6 -二苯- 1，2 - 二醇； 5-氯 - 2 - (3, 4 -二羥基—5 — 苯甲腈；經基—5 —硝基苯磺醯基）-4 甲硝基苯磺醯基）-3,5-二氟苯氟苯磺醯基）-3 -確基硝基苯磺酿基）一 3 氟 312ΧΡ/發明說明書(補件)/96-03/95143900 266 200800871 醇； -(2 -氯-6 -甲基苯磺醯基）_ 3_硝基苯一 I? 2,4 -二氯-6 - (3,4_二羥基_ 5_硝基苯磺醯基）甲酸乙酯； 5 (3’5 —氯- 2-甲氧基苯石黃酿基）一 3一确基苯— 1，2 - 二醇；基；乙:::氯-HU-二經基-5-确基苯伽基)苯 2- (3,4_二羥基_5_硝基苯磺醯基）_3,5—二曱酸乙酯； 1- [2- (3’4-二羥基硝基苯磺醯基）_ 3-甲基苯基]乙酮；亂~ 2 -（3,4 -二羥基_ 5_硝基笨磺醯基）_ 曱酸甲酯；一氣本甲基-5 -（3, 4 - 一絲 f r 其贫田值· —匕基— I確基笨續酿 3 基）—4 一曱基笨甲腈； 2- (3,4_二羥基-5_硝基苯磺醯基）基苯甲酸甲|旨； 1 - [2 - (3, 4 -二氟笨基]乙酮；乂- [2_ (3’4_二羥基—5~硝基笨磺醯基）-3,5 -- 氣苯基]丙-1_S同；及 ’ — 3-氯-5-(3,4-二經基石肖基基苯甲腈。；4—甲 312XP/發明說明書(補件)/96-03/95143900 267 200800871 10. 一種醫藥組成物’其特徵為，含有中請專利範圍第 1至9項中任一項之化合物或其藥理學上容許之鹽古效成分。 ' 11.種兒余酚_ 〇 -轉甲基酶抑制劑，其特徵為，含申請專利範圍第丨至9項巾任—項之化合物或其藥容許之鹽作為有效成分。 + 12·種巴金森氏症或憂鬱症之治療或預防劑，其特徵m stone succinyl phenyl gamma) benzoquine., one hole of fluorosulfonyl)-nitrobenzene - , 5 gas - 3 - (3,4 - di Weiqi ~ ς. + soil ~ 5 - nitro stupid醯 base)~2 monomethylbenzonitrile; τ 2 -(3,4-based benzonitrile; hydroxy-5-nitrophenylsulfonyl)-3-chloro-5-(3,4-diylbenzene Benzonitrile; 2 - (3, 4-di-carbyl- phthalonitrile; 5-(2-difluoromethyl-4,6-diphenyl-1,2-diol); 5-chloro-2 - (3 , 4 -dihydroxy-5-benzonitrile; benzyl 5-nitrobenzenesulfonyl)-4 nitrophenylsulfonyl)-3,5-difluorophenylfluorobenzenesulfonyl)-3 - succinyl nitrobenzene sulfonate) 3 fluoro 312 ΧΡ / invention specification (supplement) / 96-03/95143900 266 200800871 alcohol; - (2 - chloro-6 -methyl benzene sulfonyl) _ 3 _ nitrate Ethylbenzene-I? 2,4-dichloro-6-(3,4-dihydroxy-5-nitrophenylsulfonyl) ethyl formate; 5 (3'5-chloro-2-methoxyphene) Yellow-based phenyl- 1,2-diol; base; B:::chloro-HU-diylidene-5-y-phenyl- phenyl gamma) benzene 2- (3,4-dihydroxyl _5_nitrophenylsulfonyl)_3,5-dioxalate ethyl ester; 1- [2- (3'4- Hydroxynitrobenzenesulfonyl) 3-methylphenyl]ethanone; chaotic ~ 2 -(3,4-dihydroxy-5-nitrososulfonyl)-methyl decanoate -5 -(3, 4 - a trace of fr, its poor field value - thiol - I is a base of stupid brewing 3 base) - 4 a sulfhydryl carbonitrile; 2- (3,4_ dihydroxy-5_ nitrate (1,2-[3,4-difluorophenyl]ethanone; 乂-[2_(3'4_dihydroxy-5~nitrostene sulfonate) Base-3,5-gas phenyl]propan-1_S; and '-3-chloro-5-(3,4-diyl succinyl benzyl carbonitrile; 4-A 312XP/invention specification ( </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; ' 11. Residual phenol _ 〇-transmethylase inhibitor, which is characterized by containing a compound of the ninth to nine items of the patent application or a salt thereof as an active ingredient. A therapeutic or prophylactic agent for Parkinson's disease or depression, characterized by

士 ’含有申請專利範圍第i至9項中任一項之化合物或其藥理學上容許之鹽作為有效成分。八 13. —種高血壓症之治療或預防劑，其特徵為，含有請專利範圍第項中任—項之化合物或其藥理學上容許之鹽作為有效成分。 14.-種醫藥’其特徵為，將中請專利範圍第i至9項中，一項之化合物或其藥理學上容許之鹽及選自左多巴與芳香族L-胺基酸脫羧酶抑制劑之至少丨種組合而成。一種申請專利範圍第i至9項中任一項之化合物或其藥理予上谷$之鹽的使用，係用於製造巴金森氏症或憂營症之治療或預防劑。 -種中請專利範圍第丨至9項中任—項之化合物或其樂理學上容許之鹽的使用，係用於製造高血壓症之治療或預防劑。 17·種H係巴金S氏症或憂鬱症之治療或預防方法’該方法之特徵為，包含投予有效量之中請專利範圍第 1至9射任一項之化合物或其藥理學上容許之鹽的步 312XP/發明說明書(補件)/96-03/95143900 268 200800871 驟。該方法 9項中 18. —種方法，係高血壓症之治療或預防方法之特徵為，包含投予有效量之申請專利範圍第1 任一項之化合物或其藥理學上容許之鹽的步驟。The compound containing any one of the items i to 9 of the patent application or a pharmacologically acceptable salt thereof is used as an active ingredient. 8. A therapeutic or prophylactic agent for hypertension, which comprises a compound of any one of the items of the patent scope or a pharmacologically acceptable salt thereof as an active ingredient. 14. A medicine characterized by a compound of the above-mentioned patent scopes i to 9 or a pharmacologically acceptable salt thereof and selected from the group consisting of levo-dopa and an aromatic L-amino acid decarboxylase At least one of the inhibitors is combined. The use of a compound of any one of claims i to 9 or a pharmacological agent thereof for the administration of a salt of Shanggu $ is for the manufacture of a therapeutic or prophylactic agent for Parkinson's disease or sorrow. - The use of a compound or any of its music-permitted salts in the scope of the patents in items 9 to 9 is used as a therapeutic or prophylactic agent for the manufacture of hypertension. 17. A method for treating or preventing H-type Bajin S's disease or depression. The method is characterized in that it comprises a compound of the patent range 1 to 9 or a pharmacologically acceptable one thereof. Step 312XP of the salt / invention manual (supplement) / 96-03/95143900 268 200800871. 18. The method of claim 9, wherein the method of treating or preventing hypertension is characterized by comprising the step of administering an effective amount of the compound of claim 1 or a pharmacologically acceptable salt thereof. .

312XP/發明說明書(補件)/96-03/95143900 269 200800871 七、指定代表圖： (一）本案指定代表圖為：無 (二) 本代表圖之元件符號簡單說明: 無312XP/Invention Manual (supplement)/96-03/95143900 269 200800871 VII. Designation of representative drawings: (1) The representative representative of the case is: None (2) Simple description of the symbol of the representative figure: None

八、本案若有化學式時，請揭示最能顯示發明特徵的化學式：8. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention:

312XP/發明說明書(補件)/96-03/95143900 5312XP / invention manual (supplement) / 96-03/95143900 5