TW200306817A

TW200306817A - Pharmaceutical composition for treating or preventing virus infectious diseases

Info

Publication number: TW200306817A
Application number: TW092107341A
Authority: TW
Inventors: Takayuki Inoue; Katsuyuki Maki; Kazuaki Hatakenaka; Yukiko Yamagisi
Original assignee: Fujisawa Pharmaceutical Co
Priority date: 2002-04-02
Filing date: 2003-04-01
Publication date: 2003-12-01
Also published as: WO2003082265A2

Abstract

This invention provides pharmaceutical compositions for treating or preventing virus infectious diseases, particularly caused by viruses belonging to Flaviviridae family.

Description

200306817 玖、發明說明 (發明說明應敘明：發明所屬之技術領域、先前技術、內容、實施方式及圖式簡單說明) (一）發明所屬之枝術領域本發明係關於治療或預防病毒感染性疾病之醫藥組成物，特別是治療或預防黃病毒科（Flaviviridae family)病毒所引起之病毒感染性疾病。 (二）先前技術技藝背景黃病毒科由肝炎病毒屬（Hepacivirus genus)，瘡病毒屬（pestivirus genus)，黃病毒屬及目前未指派專一屬別之其他數種病毒組成。屬於此科之病毒可於人類及動物引起顯著疾病。例如屬於肝炎病毒屬之C型肝炎病毒（HCV)爲引起全球性人類肝炎之一主因。已知大部分HCV感染者成爲終身帶原且約60%案例進展爲慢性肝病。慢性HCV 感染可進展爲肝硬化，肝細胞癌及肝衰竭。目前HCV感染的有效治療是投與干擾素（IFN)，雷巴威靈（ribavirin)或此二藥劑組合。然而，依據臨床硏究顯示上述HCV之治療效用是多變且治癒率低。馴養之家畜的瘟病毒感染造成全球顯著的經濟損失。瘟病毒造成一系列臨床表現，包括流產、畸形發生、呼吸道問題、慢性衰弱疾病、免疫系統失能、以及易遭第二種病毒及細菌感染。黃病毒屬是人類的重要病原且盛行於全世界。至少有 3 8種黃病毒與人類疾病具關聯性，包括登革熱病毒、黃 200306817 熱病病毒、以及日本腦炎病毒。黃病毒屬造成一系列急性發熱病態及出血性疾病。已知HCV具有正股RNA基因組含約9400核苷酸編碼3009-3030胺基酸之聚蛋白質，其組織類似黃病毒屬及瘟病毒屬。就病毒感染性疾病之預防及治療方法而論，常希望可鑑定病毒專一功能以利用於此等方法中。特別是已知之病毒編碼的RNA依存性RNA聚合酶（RdRp)，此蛋白質扮演許多RNA病毒生命週期之中心角色。RdRp在肝炎病毒屬及瘟病毒屬稱爲NS5B蛋白質，以及在黃病毒屬稱爲NS5。 RdRp爲病毒複製酶複合物之關鍵成分，能使病毒複製其 RNA基因組並產生病毒子代。已知某些化合物具有活性抑制RdRp，例如WO 00/ 1 3 70 8 之巴比妥酸衍生物，WOOO/ 1 823 1之苯并噻吩衍生物， WO00/ 1 057 3之吡咯啶衍生物，WO00/065 29之二酮酸衍生物，WO0 1 /47 8 8 3之稠環衍生物，以及WO0 1 /3 2 1 5 3之核苷衍生物。 (三）發明內窓發明之揭示本發明目的是提供一種醫藥組成物，含有選自式（la) 至（I e)所示化合物之稠合苯衍生物，其前藥或其醫藥可接受鹽，該化合物具有活性抑制RdRp，可作爲活性成分與醫藥可接受載劑混合。本發明另一目的是提供一種治療或預防病毒感染性疾 200306817 病之方法，其係經由投與有效量之該稠合苯衍生物，其前藥或其醫藥可接受鹽以抑制RdRp。本發明又一目的是提供一種稠合苯衍生物，其前藥或其醫藥可接受鹽於製備醫藥組成物之用途。包含於本發明醫藥組成物之稠合苯衍生物可以下列式 (la)、（lb)、（Ic)、（id)、及（ie)表示：式（la):200306817 发明 Description of the invention (The description of the invention should state: the technical field to which the invention belongs, the prior art, the content, the embodiments, and the drawings) (1) the field of the branch of the invention The invention relates to the treatment or prevention of viral infectivity Medical composition for diseases, especially for treating or preventing viral infectious diseases caused by viruses of the Flaviviridae family. (2) Prior art Technical background The Flaviviridae is composed of Hepacivirus genus, Pestivirus genus, Flaviviridae and several other viruses that have not been assigned a specific genus. Viruses belonging to this family can cause significant diseases in humans and animals. For example, hepatitis C virus (HCV), which belongs to the genus Hepatitis virus, is a major cause of global human hepatitis. Most people with HCV infection are known to become lifetime carriers and about 60% of cases progress to chronic liver disease. Chronic HCV infection can progress to cirrhosis, hepatocellular carcinoma, and liver failure. Currently effective treatments for HCV infection are administration of interferon (IFN), ribavirin or a combination of these two agents. However, clinical studies have shown that the therapeutic effect of HCV is variable and the cure rate is low. Pestivirus infections of domesticated livestock cause significant economic losses worldwide. Pestivirus causes a range of clinical manifestations, including miscarriage, malformations, respiratory problems, chronic debilitating diseases, disability of the immune system, and vulnerability to a second virus and bacterial infection. Flaviviruses are important human pathogens and are prevalent throughout the world. At least 38 flaviviruses are associated with human diseases, including dengue virus, flavi 2003200317 fever virus, and Japanese encephalitis virus. Flaviviruses cause a series of acute fever morbidity and bleeding disorders. HCV is known to have a positive-sense RNA genome containing about 9,400 nucleotides of a polyprotein encoding 3009-3030 amino acids, and its tissues are similar to those of the genus Flaviviridae and pestivirus. With regard to prevention and treatment of viral infectious diseases, it is often desirable to identify virus-specific functions for use in such methods. In particular, RNA-dependent RNA polymerase (RdRp), encoded by known viruses, plays a central role in the life cycle of many RNA viruses. RdRp is called the NS5B protein in the genus Hepatitis and Pestivirus, and NS5 in the flavivirus. RdRp is a key component of the virus replicase complex, enabling the virus to replicate its RNA genome and produce virus progeny. Certain compounds are known to have activity to inhibit RdRp, such as the barbituric acid derivative of WO 00/1 3 70 8, the benzothiophene derivative of WOOO / 18232, the pyrrolidine derivative of WO00 / 10571, WO00 / 065 29 diketo acid derivative, WO0 1/47 8 8 3 fused ring derivative, and WO0 1/3 2 1 5 3 nucleoside derivative. (3) Disclosure of the invention intrinsic invention The object of the present invention is to provide a medicinal composition containing a fused benzene derivative selected from the compounds represented by the formulae (la) to (I e), a prodrug thereof or a pharmaceutically acceptable salt thereof The compound has an activity to inhibit RdRp, and can be used as an active ingredient to be mixed with a pharmaceutically acceptable carrier. Another object of the present invention is to provide a method for treating or preventing a viral infectious disease 200306817 disease by inhibiting RdRp by administering an effective amount of the fused benzene derivative, a prodrug or a pharmaceutically acceptable salt thereof. Yet another object of the present invention is to provide a fused benzene derivative, a prodrug thereof or a pharmaceutically acceptable salt thereof for use in preparing a pharmaceutical composition. The fused benzene derivative contained in the pharmaceutical composition of the present invention can be represented by the following formulae (la), (lb), (Ic), (id), and (ie): Formula (la):

其中among them

Rla爲氫原子’或硝基或低級烷氧基，以及 R2a爲氯原子’或硝基，胺基，醯胺基或低級烷磺醯基，或Rla is a hydrogen atom 'or a nitro group or a lower alkoxy group, and R2a is a chlorine atom' or a nitro group, an amine group, an amidino group or a lower alkylsulfonyl group, or

Rla和R2a —起與其附著之鄰接碳原子形成芳基； R3a及R4a爲相同或不同之氫原子，或低級烷基，芳（低級）院基’芳基或式-CH = N_〇_# (低級）烷基之基，其中芳（低級Vk基及式m 0 -芳（低級）烷基可經一或多個取代基取代，或 R3a和R4a形成酮基； R5a及R6a爲相同或不同之氫原子或羥基，或 200306817 R5a和R6a形成酮基； R8a及R9a爲相同或不同之氫原子或羥基，或 R8a和R9a形成酮基；或0,其中爲氫原子，或殘基，低級院基，芳基，芳（低級）院基或芳（低級）院氧基，其中芳（低級）烷氧基可經一或多個取代基取代；另外和R“可一起與其附著之碳原子形成環院環或 = Ya-R⑴’其中CH或N，以及RUa爲羥基，芳基，芳胺基或低級烷氧基，其中芳基及芳胺說1 ^ ^ _ 〃 T/乂力收基可經一或多個取代基取代，或與尺“或R“—起與其附著之碳原子形成—鍵或環烷壞，式（lb):Rla and R2a together form an aryl group with the adjacent carbon atom to which they are attached; R3a and R4a are the same or different hydrogen atoms, or lower alkyl, aryl (lower) radical 'aryl or formula -CH = N_〇_ # (Lower) alkyl radicals, where aryl (lower Vk and m 0 -aryl (lower) alkyls may be substituted with one or more substituents, or R3a and R4a form a keto group; R5a and R6a are the same or different Hydrogen atom or hydroxyl group, or 200306817 R5a and R6a form a keto group; R8a and R9a are the same or different hydrogen atom or hydroxyl group, or R8a and R9a form a keto group; or 0, which is a hydrogen atom, or a residue, lower grade Group, aryl group, aryl (lower) compound or aryl (lower) compound, wherein the aryl (lower) alkoxy group may be substituted with one or more substituents; and R may form together with the carbon atom to which it is attached. Ring or ring = Ya-R⑴ 'where CH or N, and RUa is hydroxyl, aryl, arylamino or lower alkoxy, where aryl and arylamine say 1 ^^ ^ T / 乂Substituted by one or more substituents, or formed with a carbon atom to which "or R" is attached-a bond or a naphthenic group, of formula (lb) :

其中among them

Rlb爲氫或鹵素原子，或硝基，低級烷基，鹵（低級）烷基，低級烷氧基或鹵（低級）烷氧基； R2b及R3b爲相同或不同之氫原子，或低級烷基，芳基，方（低級）院基’雜環或醯基，其中低級烷基及芳（低級）烷 -10- 200306817 基可經一或多個取代基取代，或環烷環，可經取代 R2b和R3b一起與其附著之碳原子形成以鹵（低級）丨兀基之釀基取代， R4b及爲相同或不同之氫或 ^义圓累原子，或芳基或芳激）ί兀基，其中方（低級）燒基可砰〜〇兀土」蛀或多個鹵素原子取代，或 R4b和R5b形成酮基或可經一或兩· ^ ^兩個取代基取代之伸乙式（Ic): ’Rlb is hydrogen or halogen atom, or nitro, lower alkyl, halogen (lower) alkyl, lower alkoxy or halogen (lower) alkoxy; R2b and R3b are the same or different hydrogen atoms, or lower alkyl , Aryl, square (lower) courtyard group 'heterocyclic or fluorenyl, in which lower alkyl and aryl (lower) alk-10-200306817 group may be substituted with one or more substituents, or a cycloalkane ring may be substituted R2b and R3b together with the carbon atom to which they are attached are substituted with a halogen (lower) group, and R4b is the same or different hydrogen or a sense atom, or an aryl group or an aromatic group), where The square (lower) alkyl group may be substituted by ^ ^ ^ ^ 土土 or more halogen atoms, or R4b and R5b to form a keto group or can be substituted with one or two · ^ ^ two substituents of the formula (Ic): '

其中低級烷基，低 R 1 c爲氫或鹵素原子，或硝基低級烷硫基；以及 R2e爲氫或鹵素原子或低級烷氧基；或和—起與其附著之鄰接碳原子形成芳基； R3。爲氫或鹵素原子，或硝某，併姐^ /1Ί -义TO暴低礙烷基或鹵（低級）烷氧基；以及 Xe爲CH或N ; 式（Id): -11 - 200306817Wherein lower alkyl, lower R 1 c is hydrogen or halogen atom, or nitro lower alkylthio group; and R2e is hydrogen or halogen atom or lower alkoxy group; or together with the adjacent carbon atom to which it is attached to form an aryl group; R3. Is a hydrogen or halogen atom, or nitrate, and ^ / 1Ί-the meaning of TO is too low to hinder alkyl or halogen (lower) alkoxy; and Xe is CH or N; formula (Id): -11-200306817

RR

(Id) 其中(Id) where

Rld爲氫原子，或硝基，胺基或醯胺基；Rld is a hydrogen atom, or a nitro group, an amino group, or a fluorenyl group;

R2d爲選擇性經取代之芳基或芳（低級）烷基；以及 Xd爲CH或N;以及式（Ie):R2d is optionally substituted aryl or aryl (lower) alkyl; and Xd is CH or N; and formula (Ie):

其中among them

Rle爲氫原子或低級烷氧基； R2e爲氫原子；或Rle is a hydrogen atom or a lower alkoxy group; R2e is a hydrogen atom; or

Rle和R2e —起與其附著之鄰接碳原子形成芳基； R3e及R4e爲氫原子或形成酮基； -12- 200306817 p5eRle and R2e together form an aryl group with the adjacent carbon atom to which they are attached; R3e and R4e are hydrogen atoms or form a keto group; -12- 200306817 p5e

Xe 爲=〇，=ch2, =c=〇或=ccT 、6e OH —°、R8e 其中R、R“’r1 P爲相同或不同之氫原子，或經基，低級院基’低級垸氧基’芳基，醯氧基或碳環基，其中低級烷基，芳基及碳環基可經一或多個取代基取代；以及另外和可一起與其附著之碳原子形成經選擇性取代之不飽和雜環。式（la)至（Ie)中各種定義之適當實例及例證詳細說明如下。除非特別指示，否則“低級，，一詞意指丨至6碳原子。 “ 一或多個”一詞意指1至6，較佳爲1至3，以及更佳爲1或2。Xe is = 〇, = ch2, = c = 〇 or = ccT, 6e OH — °, R8e, where R, R "'r1 P is the same or different hydrogen atom, or via a radical, a lower academic radical' lower alkoxy 'Aryl, fluorenyl, or carbocyclyl, in which lower alkyl, aryl, and carbocyclyl may be substituted with one or more substituents; and in addition, may form a selectively substituted Saturated heterocycles. Suitable examples and illustrations of the various definitions in formulae (la) to (Ie) are detailed below. Unless specifically indicated otherwise, the term "lower," means 1-6 carbon atoms. The term "one or more" means 1 to 6, preferably 1 to 3, and more preferably 1 or 2.

Rh、、R7a、Rlb、R2b、R3b、RU、r3c、R5e、R6e、 R7e、及 R8e 之低級烷基；R3a、R4a、R7a、R2b、R3b、R4b、 R5b、及R2d芳（低級）烷基，Rlb及R3e鹵（低級）烷氧基，以及Rle低級烷硫基之低級烷基部分之適當實例爲直鏈或支鏈具有1至6碳原子者，例如甲基，乙基，正丙基，異丙基，正丁基，2-乙基丁基，異丁基，第三丁基，戊基以及正己基。 R2a低級烷磺醯基之適當實例爲甲烷磺醯基，乙烷磺醯基，丙烷磺醯基，丁烷磺醯基以及戊烷磺醯基。Lower alkyl of Rh, R7a, Rlb, R2b, R3b, RU, r3c, R5e, R6e, R7e, and R8e; R3a, R4a, R7a, R2b, R3b, R4b, R5b, and R2d aromatic (lower) alkyl , Rlb and R3e halo (lower) alkoxy, and suitable examples of the lower alkyl portion of the Rle lower alkylthio group are those having 1 to 6 carbon atoms in a straight or branched chain, such as methyl, ethyl, n-propyl , Isopropyl, n-butyl, 2-ethylbutyl, isobutyl, third butyl, pentyl and n-hexyl. Suitable examples of R2a lower alkylsulfonyl are methanesulfonyl, ethanesulfonyl, propanesulfonyl, butanesulfonyl and pentanesulfonyl.

Rla、R10a、Rlb、Ric、R2c、Rle、R5e、R6e、R7e、及 R8e -13- 200306817 之低級烷氧基；以及Rlb、R2b、及R3b鹵（低級）烷基，以及R7a芳（低級）烷氧基之低級烷氧基部分之適當實例爲甲氧基，乙氧基，丙氧基，丁氧基，戊氧基及己氧基。 111111413、尺515、1^、112。、及1^之_素原子；以及1^1)、 R2b、及R3b_ (低級）烷基，以及Rlb& R3。鹵（低級）烷氧基之鹵素部分之適當實例爲氟，氯，溴及碘。Lower alkoxy groups of Rla, R10a, Rlb, Ric, R2c, Rle, R5e, R6e, R7e, and R8e -13-200306817; and halogen (lower) alkyl groups of Rlb, R2b, and R3b, and aromatic (lower) groups of R7a Suitable examples of the lower alkoxy moiety of alkoxy are methoxy, ethoxy, propoxy, butoxy, pentoxy and hexyloxy. 111111413, ruler 515, 1 ^, 112. And a prime atom of 1 ^; and 1 ^ 1), R2b, and R3b_ (lower) alkyl, and Rlb & R3. Suitable examples of the halogen portion of the halogen (lower) alkoxy group are fluorine, chlorine, bromine and iodine.

Rla、R2a、R3a、R4a、R7a、R10a、R2b、R3b、R4b、R5b、 RlC、R2c、R2d、Rle、R2e、R5e、R6e、R7e、及 R8e 之芳基； R10a 芳胺基，R3a、R4a、R7a、R4b、R5b、及 R2d 芳（低級）烷基，以及R7a芳（低級）烷氧基之芳基部分之適當實例爲含有6至12碳原子之芳香烴殘基，例如苯基，甲苯基，二甲苯基，以及萘基。 R2b及R3b雜環基之適當實例爲含有1至4個雜原子選自氮、氧、及硫原子之飽和或不飽和單環或稠合雜環基。雜環基之較佳實例說明如下。 (1) 含有1至4個氮原子之不飽和3至7員，較佳爲5-或 6 -員雜單環基，例如吡咯基，吡咯啉基，咪唑基，吡唑基，吡啶基，四氫吡啶基，嘧啶基，四氫嘧啶基，吡畊基，嗒畊基，***基或四唑基； (2) 含有1至4個氮原子之飽和3至7員，較佳爲5-或6 -員雜單環基，例如吡咯啶基，咪唑啶基，六氫吡啶基，N -六氫吡啶基或六氫吡哄基； (3) 含有1至2個氧原子及1至3個氮原子之不飽和3 至7員，較佳爲5 -或6 -員雜單環基，例如噚唑基，異噂 -14- 200306817 唑基，或噚二唑基； (4) 含有1至2個氧原子及1至3個氮原子之飽和3 至7員，較佳爲5-或6-員雜單環基，例如嗎福啉基； (5) 含有1至2個硫原子及1至3個氮原子之不飽和3 至7員，較佳爲 5-或6-員雜單環基，例如噻唑基或噻二唑基； (6) 含有1至2個硫原子及1至3個氮原子之飽和3 至7員’較佳爲 5 -或6 -員雜單環基，例如噻嗎福啉基或噻唑啶基； (7) 含有1至2個氧原子之不飽和3至7員，較佳爲5-或6 -員雜單環基，例如呋喃基或哌喃基； (8) 含有1至2個氧原子之飽和3至7員，較佳爲5-或6 -員雜單環基，例如1,4 -二噚烷基； (9) 含有1至2個硫原子之不飽和3至7員，較佳爲5-或6 -員雜單環基，例如噻吩基； (10) 含有1至2個硫原子之飽和3至7員，較佳爲5-或6 -員雜單環基，例如四氫噻吩基； (1 1)含有丨至3個氮原子之不飽和稠合雜環基，例如苯并吡咯基，苯并咪唑基，苯并吡唑基，苯并***基，口奎啉基，異喹啉基，吲哚基或吲哚啉基； (12)3有1至2個氧原子之不飽和稠合雜環基，例如苯并咲喃基或苯并二氧雜環戊二烯基（benz〇di〇x〇lyl); (1 3) a有1至2個硫原子之不飽和稠合雜環基，例如本并[b ]曝吩基； -15 - 200306817 (14) 含有1至2個氧原子及1至3個氮原子之不飽和稠合雜環基，例如苯并噚唑基，苯并噚二唑基或啡噚哄基；以及 (15) 含有1至2個硫原子及1至3個氮原子之不飽和稠合雜環基，例如苯并噻唑基，苯并異噻唑基或啡噻畊基。 R6e及R7e不飽和雜環基環之適當實例爲含有1至4 個雜原子選自氮、氧、及硫原子之不飽和單環或稠合雜環基環，例如 (1) 含有1至4個氮原子之不飽和3至7員，較佳爲5-或6 -員雜單環，例如吡咯，二氫吡咯，吡咯啉，咪唑，吡唑，吡啶，四氫吡啶，嘧啶，四氫嘧啶，吡畊，嗒畊， ***或四唑； (2) 含有1至2個氧原子及1至3個氮原子之不飽和3 至7員，較佳爲5-或6-員雜單環，例如噚唑或異噚唑； (3) 含有1至2個硫原子及1至3個氮原子之不飽和3 至7員，較佳爲5 -或6 -員雜單環，例如噻唑或噻二唑； (4) 含有1至2個氧原子之不飽和3至7員，較佳爲5-或6 -員雜單環，例如呋喃，二氫呋喃或哌喃； (5) 含有1至2個硫原子之不飽和3至7員，較佳爲5-或6 -員雜單環，例如噻吩； (6) 含有1至3個氮原子之不飽和稠合雜環，例如苯并吡咯，苯并咪唑，苯并吡唑，苯并***，喹啉，異喹啉或吲哚； (7) 含有1至2個氧原子之不飽和稠合雜環，例如苯 200306817 并呋喃，二氫苯并呋喃或苯并二氧雜環戊二烯 (benzodioxole)； (8) 含有1至2個硫原子之不飽和稠合雜環，例如苯并[b]噻吩； (9) 含有1至2個氧原子及1至3個氮原子之不飽和稠合雜環，例如苯并噚唑，苯并噚二唑或啡噚哄；以及 (10) 含有1至2個硫原子及1至3個氮原子之不飽和稠合雜環，例如苯并噻唑，苯并異噻唑或啡噻哄。 R2b& R3b2 醯基；R2a& 111€1醯胺基，R5e、R6e、R7e、及R8e醯氧基之醯基部分之適當實例爲衍生自羧酸之脂肪族醯基、芳香族醯基及雜環醯基，以及衍生自胺基甲g变之低級烷基胺甲醯基以及芳基胺甲醯基。脂肪族醯基之實例爲 (1) 低級烷醯基（例如甲醯基，乙醯基，丙醯基，丁醯基，異丁醯基，戊醯基或己醯基）； (2) 環（低級）烷羰基（例如環丙羰基，環丁羰基，環戊鑛基或環己羰基）；以及 (3) 低級烯醯基（例如丙烯醯基，甲基丙烯醯基，巴豆 _基或3·甲基丁醯基）。芳香族醯基之實例爲可經硝基、胺基、噻吩甲_胺基等取代之芳醯基類（例如苄醯基及萘醯基）。雜環醯基之實例爲雜環羰基’例如呋喃甲醯基，噻吩甲醯基，菸鹼醯基等等。低級院基胺甲醯基之實例爲甲基胺甲醯基，乙基胺甲 -17- 200306817 醯基，丙基胺甲醯基等等。芳基胺甲醯基之實例爲苯基胺甲醯基以及萘基胺甲醯 R3a、R“、Rh、R6a、R2b、及R3b之環烷環之適當實例爲具有3至7碳原子之環烴，例如環丁烷，環戊烷，環己院以及環庚院。 R5e、R6e、R7e、及R8e之碳環基之適當實例爲具有3 至7碳原子之環烴殘基，例如環丁烯基，環戊基，環戊烯基，環己基以及茚基。Rla, R2a, R3a, R4a, R7a, R10a, R2b, R3b, R4b, R5b, RlC, R2c, R2d, Rle, R2e, R5e, R6e, R7e, and R8e aryl groups; R10a arylamino groups, R3a, R4a , R7a, R4b, R5b, and R2d aryl (lower) alkyl, and suitable examples of the aryl portion of the aryl (lower) alkoxy group are aromatic hydrocarbon residues containing 6 to 12 carbon atoms, such as phenyl, toluene , Xylyl, and naphthyl. Suitable examples of the R2b and R3b heterocyclic groups are saturated or unsaturated monocyclic or fused heterocyclic groups containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur atoms. Preferred examples of the heterocyclic group are described below. (1) Unsaturated 3 to 7 members, preferably 5- or 6-membered heterocyclic groups containing 1 to 4 nitrogen atoms, such as pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, Tetrahydropyridyl, pyrimidinyl, tetrahydropyrimidinyl, pyrhenyl, dahenyl, triazolyl or tetrazolyl; (2) 3 to 7 members saturated with 1 to 4 nitrogen atoms, preferably 5 -Or 6-membered heteromonocyclic groups, such as pyrrolidinyl, imidazolidinyl, hexahydropyridyl, N-hexahydropyridyl or hexahydropyridyl; (3) containing 1 to 2 oxygen atoms and 1 to Unsaturation of 3 to 7 members of 3 nitrogen atoms, preferably a 5- or 6-membered heteromonocyclic group, such as oxazolyl, isofluorene-14-200306817, or oxadiazolyl; (4) contains Saturated 3 to 7 members of 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, preferably 5- or 6-membered heteromonocyclic groups, such as morpholinyl; (5) containing 1 to 2 sulfur atoms And unsaturated 3 to 7 members of 1 to 3 nitrogen atoms, preferably 5- or 6-membered heteromonocyclic groups such as thiazolyl or thiadiazolyl; (6) containing 1 to 2 sulfur atoms and 1 Saturated 3 to 7 members of 3 to 3 nitrogen atoms are preferably 5-or 6-membered heteromonocyclic groups such as timorpholinyl or Thiazolidinyl; (7) Unsaturated 3 to 7 members containing 1 to 2 oxygen atoms, preferably 5- or 6-membered heteromonocyclic groups such as furyl or piperanyl; (8) containing 1 to Saturated 3 to 7 members of 2 oxygen atoms, preferably 5- or 6-membered heteromonocyclic groups, such as 1,4-dioxanyl; (9) Unsaturated 3 to 2 atoms containing 1 to 2 sulfur atoms 7 members, preferably 5- or 6-membered heteromonocyclic groups, such as thienyl; (10) 3 to 7 members, preferably 5- or 6-membered heteromonocyclic rings containing 1 to 2 sulfur atoms Group, such as tetrahydrothienyl; (1 1) unsaturated fused heterocyclic groups containing 1 to 3 nitrogen atoms, such as benzopyrrolyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl , Orthoquinolinyl, isoquinolinyl, indolyl or indolyl; (12) 3 unsaturated fused heterocyclic groups having 1 to 2 oxygen atoms, such as benzopyranyl or benzobis Oxadienyl (benz〇di〇x〇lyl); (1 3) a unsaturated fused heterocyclic group having 1 to 2 sulfur atoms, such as Benzo [b] exposed phenyl group; -15 -200306817 (14) Unsaturated fused heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as benzoxazolyl, benzo Oxadiazolyl or phenanthryl; and (15) unsaturated fused heterocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as benzothiazolyl, benzoisothiazolyl or phenothiazine Tillage. Suitable examples of R6e and R7e unsaturated heterocyclyl rings are unsaturated monocyclic or fused heterocyclyl rings containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur atoms, such as (1) containing 1 to 4 Unsaturated 3 to 7 members of each nitrogen atom, preferably 5- or 6-membered heterocyclic rings, such as pyrrole, dihydropyrrole, pyrroline, imidazole, pyrazole, pyridine, tetrahydropyridine, pyrimidine, tetrahydropyrimidine , Pyrene, Dagen, Triazole or Tetrazole; (2) Unsaturated 3 to 7 members, preferably 5 or 6-membered heterocyclic rings containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms , Such as oxazole or isoxazole; (3) Unsaturated 3 to 7 members containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, preferably 5-or 6-membered heteromonocyclic rings, such as thiazole or Thiadiazole; (4) Unsaturated 3 to 7 members, preferably 5- or 6-membered heterocyclic rings containing 1 to 2 oxygen atoms, such as furan, dihydrofuran or piperan; (5) containing 1 Unsaturated 3 to 7 members with 2 sulfur atoms, preferably 5- or 6-membered heteromonocyclic rings, such as thiophene; (6) Unsaturated fused heterocyclic rings containing 1 to 3 nitrogen atoms, such as benzo Pyrrole, benzimidazole, benzopyrazole, benzotriazole, quinoline, isoquine Or indole; (7) unsaturated fused heterocycles containing 1 to 2 oxygen atoms, such as benzene 200306817 benzofuran, dihydrobenzofuran or benzodioxole; (8) Unsaturated fused heterocyclic rings containing 1 to 2 sulfur atoms, such as benzo [b] thiophene; (9) Unsaturated fused heterocyclic rings containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as benzene Benzoxazole, benzoxadiazole or fluorene; and (10) unsaturated fused heterocycles containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as benzothiazole, benzoisothiazole, or Phanthi coaxed. R2b & R3b2 fluorenyl; R2a & 111 fluorenyl, suitable examples of fluorenyl moieties of R5e, R6e, R7e, and R8e fluorenyl are aliphatic fluorenyl, aromatic fluorenyl, and heterocyclic groups derived from carboxylic acids Cyclofluorenyl, and lower alkylaminoformamyl and arylaminoformamyl derived from aminoformyl. Examples of aliphatic fluorenyl groups are (1) lower alkyl fluorenyl (such as methyl fluorenyl, ethyl fluorenyl, propyl fluorenyl, butyl fluorenyl, isobutyl fluorenyl, pentyl fluorenyl, or hexamethylene); (2) cyclo (lower) alkane Carbonyl (such as cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentyl, or cyclohexylcarbonyl); and (3) lower alkenyl (such as propenyl, methacryl, crotonyl, or 3-methylbutyryl) ). Examples of the aromatic fluorenyl group are arylfluorenyl groups (e.g., benzylfluorenyl and naphthylfluorenyl) which may be substituted with nitro, amine, thienylamine and the like. Examples of heterocyclic fluorenyl are heterocyclic carbonyl 'such as furanomethylfluorenyl, thienylmethylfluorenyl, nicotinylfluorenyl and the like. Examples of lower nominylaminomethylamido are methylaminomethylamidino, ethylaminomethyl-17-200306817 methyl, propylaminomethylamidino, and the like. Examples of arylamine formamyl are phenylamine formamyl and naphthylamine formamidine R3a, R ", Rh, R6a, R2b, and R3b. Suitable examples are cycloalkane rings having 3 to 7 carbon atoms Hydrocarbons, such as cyclobutane, cyclopentane, cyclohexane, and cycloheptane. Suitable examples of carbocyclic groups of R5e, R6e, R7e, and R8e are cyclic hydrocarbon residues having 3 to 7 carbon atoms, such as cyclobutane Alkenyl, cyclopentyl, cyclopentenyl, cyclohexyl and indenyl.

Rlb、R2b、及R3b之鹵（低級）烷基，以及RU及r3。鹵（低級）烷氧基之鹵（低級）烷基部分之適當實例爲含有1至5 個鹵素原子（較佳爲1至3個，以氟、氯及/或溴爲佳）之Cm 烷基，較佳爲C i _ 2烷基。其較佳實例爲氯甲基，溴甲基，卜氟乙基，2-氟乙基，三氟甲基，三氯甲基，氯二氟甲基，二氯氟甲基，2,2-二氟乙基，2,2,2-三氟乙基，2,2,2-三氯乙基以及五氟乙基。 R3a、R“、R7a、R2b、R3b、R4b、R5b 及 R2d 之芳（低級）院基’以及R7 a芳（低級）院氧基之芳（低級）院基之適當實例爲苄基，苯乙基，苯丙基，苯丁基，苯戊基，苯己基，二苯甲基，三苯甲基，以及萘甲基。 R2b及R3b經鹵（低級）烷基取代之芳基之適當實例爲（氯甲基）苯基，（三氟甲基）苯基以及（2,2,2-H氯乙基）萘基。上述 R3a、R4a、R7a、R1()a、R2b、R3b、R4b、R5b、R2d、、R6e、R7e、及RSe各基經一或多個取代基取代時，該 -18- 200306817 取代基可爲羥基；胺基；羧基；氰基；硝基；胺申醯基；酮基；鹵素（例如氟，溴或氯）；經低級烷氧基（例如甲氧基）選擇性取代之低級烷基（例如甲基，乙基，異丙基或第三丁基）；經一或多個鹵素（例如氟，溴或氯）選擇性取代之芳基（例如苯基或萘基）；雜環基（例如吡啶基，嗎福啉基，吡咯啶基，六氫吡哄基或嘧啶基）；鹵（低級）烷基（例如三氟甲基）；芳（低級）烷基（例如苄基）；低級烷氧基（例如甲氧基，乙氧基，丁氧基或正-丙氧基）；芳氧基（例如本氧基），低級丨兀酸氧基（例如乙釀氧基）；低級院釀基（例如乙醯基或甲醯基）；芳醯基（例如苯甲醯基）；鹵（低級）烷醯基（例如三氟乙醯基）；雜環羰基（例如呋喃甲醯基或嗎福啉羰基）；低級烷氧羰基（例如甲氧羰基，乙氧羰基，第二丁氧類基或異丙氧鑛基）；芳（低級）院氧幾基（例如；氧羰基）；芳基胺甲醯基（例如苯基胺甲醯基）；芳（低級）烷基胺甲醯基（例如苄基胺甲醯基）；（低級）烷醯基胺基（例如乙醯基胺基）；經雜環羰胺基（例如噻吩甲醯胺基）選擇性取代之芳醯基胺基（例如苯甲醯基胺基）；雜環羰胺基（例如噻吩甲醯胺基）；（低級）烷硫基（例如甲硫基）等等。 (la)至（Ie)稠合苯衍生物之適當醫藥可接受鹽爲慣用且無毒性鹽類，例如有機酸加成鹽（例如甲酸鹽，醋酸鹽，三氟醋酸鹽，順-丁烯二酸酯，酒石酸鹽，草酸鹽，甲磺酸鹽，苯磺酸鹽或甲苯磺酸鹽），無機酸加成鹽（例如氯化氫，溴化氫，硫酸鹽或磷酸鹽），含胺基酸之鹽（例如精胺酸或麩胺酸）等等。 200306817 稠合苯衍生物可含有一或多個不對稱中心，故能以鏡像異構物或非鏡像異構物存在。稠合苯衍生物亦可以互變異構形式存在，因此本發明包括混合物及分開之個別互變異構物二者。稠合苯衍生物及其鹽可於溶劑合物形式，故亦包括於本發明範圍內。溶劑合物較佳包括水合物及乙醇酸鹽。稠合苯衍生物之放射線標記衍生物亦包括於本發明範圍內，可適用於生物學硏究。 “前藥”可爲稠合苯衍生物具有化學或代謝可分解基之衍生物，於生物轉形後變成醫藥活性物質。 os)實施方式某些稠合苯衍生物，其前藥或其鹽類爲市售商品。新穎稠合苯衍生物，其前藥或其鹽可以下列製法製備。其他稠合苯衍生物可由已知製法或其類似製法或類似下列實施例製備。 200306817Halo (lower) alkyl of Rlb, R2b, and R3b, and RU and r3. Suitable examples of the halogen (lower) alkyl portion of the halogen (lower) alkoxy group are Cm alkyl groups containing 1 to 5 halogen atoms (preferably 1 to 3, preferably fluorine, chlorine and / or bromine) Is preferably C i _ 2 alkyl. Preferred examples are chloromethyl, bromomethyl, fluoroethyl, 2-fluoroethyl, trifluoromethyl, trichloromethyl, chlorodifluoromethyl, dichlorofluoromethyl, 2,2- Difluoroethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl and pentafluoroethyl. Suitable examples of the aromatic (lower) radicals of R3a, R ", R7a, R2b, R3b, R4b, R5b, and R2d 'and the aromatic (lower) radicals of R7a (lower) radical are benzyl, phenethyl Phenyl, phenylpropyl, phenylbutyl, phenpentyl, phenylhexyl, diphenylmethyl, trityl, and naphthylmethyl. Suitable examples of aryl groups in which R2b and R3b are substituted with a halogen (lower) alkyl group are (Chloromethyl) phenyl, (trifluoromethyl) phenyl and (2,2,2-Hchloroethyl) naphthyl. R3a, R4a, R7a, R1 () a, R2b, R3b, R4b, When each of R5b, R2d, R6e, R7e, and RSe is substituted with one or more substituents, the -18-200306817 substituent may be hydroxyl; amine; carboxy; cyano; nitro; amine; keto ; Halogen (such as fluorine, bromine or chlorine); lower alkyl (such as methyl, ethyl, isopropyl or third butyl) optionally substituted with lower alkoxy (such as methoxy); Aryl (such as phenyl or naphthyl) optionally substituted with multiple halogens (such as fluorine, bromine or chlorine); heterocyclic (such as pyridyl, morpholinyl, pyrrolidinyl, hexahydropyridyl) Or pyrimidinyl); halogen (lower) alkyl (such as trifluoromethyl); aryl (lower) alkyl (such as benzyl); lower alkoxy (such as methoxy, ethoxy, butoxy, or n- -Propoxy); aryloxy (such as benzyl), lower oxy acid (such as ethyl alcohol); lower alkyl (such as ethyl or methyl); aryl (such as ethyl) Benzamidine); halo (lower) alkylfluorenyl (such as trifluoroethylfluorenyl); heterocyclic carbonyl (such as furanmethylfluorenyl or morpholine carbonyl); lower alkoxycarbonyl (such as methoxycarbonyl, ethoxy Carbonyl, second butoxy or isopropyloxy); aryl (lower) oxoyl (for example; oxycarbonyl); arylaminomethyl (such as phenylaminomethyl); aryl (lower) ) Alkylaminomethane (such as benzylaminomethane); (lower) alkylamidoamino (eg, ethylamino); selectivity via heterocyclic carbonylamino (eg, thienylmethylamino) Substituted arylfluorenylamino (such as benzamidoamino); heterocyclic carbonylamino (such as thienformamido); (lower) alkylthio (such as Methylthio), etc. Suitable medically acceptable salts of (la) to (Ie) fused benzene derivatives are customary and non-toxic salts, such as organic acid addition salts (e.g. formate, acetate, trifluoro Acetate, cis-butenedioate, tartrate, oxalate, mesylate, benzenesulfonate or tosylate), inorganic acid addition salts (such as hydrogen chloride, hydrogen bromide, sulfate or Phosphate), amino acid-containing salts (such as arginine or glutamic acid), etc. 200306817 Condensed benzene derivatives may contain one or more asymmetric centers, so they can be mirror-isomers or non-mirrors Condensed benzene derivatives can also exist in tautomeric forms, so the present invention includes both mixtures and separate individual tautomers. Condensed benzene derivatives and their salts can be in the form of solvates, so It is included in the scope of the present invention. Solvates preferably include hydrates and glycolates. Radiation-labeled derivatives of fused benzene derivatives are also included in the scope of the present invention and are applicable to biological research. A "prodrug" may be a derivative of a condensed benzene derivative having a chemically or metabolically degradable group, which becomes a pharmaceutically active substance after biological transformation. os) Embodiments Certain fused benzene derivatives whose prodrugs or salts thereof are commercially available products. The novel fused benzene derivative, its prodrug or its salt can be prepared by the following method. Other fused benzene derivatives can be prepared by a known method or a method similar thereto or similar to the following examples. 200306817

化合物(Ic)之製浩法3 〇Method for preparing compound (Ic) 3 〇

化合物（Ie)之製浩法5 ^c〇2ch3 HN 人 CH, 0Method for preparing compound (Ie) 5 ^ c〇2ch3 HN human CH, 0

OH (Ille)OH (Ille)

COoCH-, R2e H0 ^ 'CH3 (Ie-1) -21 - 200306817 其中 Rla、R2a、R3a、R4a、R7a、Rlb、R2b、R3b、R4b、R5b、 Rlc、R2c、R3e、Xc、Rld、R2d、Xd、Rle 及 R2e 各如上述定義，以及X爲脫離基。 X之適當脫離基可爲鹵素（例如氟，氯，溴或碘），芳香烴磺醯氧基（例如苯磺醯氧基或甲苯磺醯氧基），烷磺醯氧基（例如甲磺醯氧基或乙磺醯氧基）等等，其中較佳爲鹵素。製法1至5可根據以下實施例所述製法進行。爲舉例說明本發明醫藥組成物之有效性，稠合苯衍生物之藥理試驗說明如下。作爲HCV RNA- RNA依存性RNA聚合酶（RdRp)抑制劑之評估是使用C末端截頭重組體HCV#NS5B以及寡（G)12/ 聚C爲引子/模板來進行。活體外RdRp活性之測量是經由閃爍鄰近分析（Scintillation Proximity Assay，SPA)或排除管柱色層分析測定[H3] GMP倂入模板/引子之情形。 1.評估測試用截頭HCV RdRp之表現及純化缺少高疏水性C-末端21個胺基酸之HCV NS5B蛋白質可表現於細菌（E. Coli BL-21)，由於溶解度低，純化步驟期間全長HCV NS5B蛋白質常沉澱。再者，爲促進純化，截頭RdRp以N-末端融合GST及C-末端標籤His蛋白質表現之。HCV BK病毒株（基因型lb)之C末端截頭及C-末端標籤His之HCV NS5B蛋白質的cDNA編碼區域，在5’ 端導入 BamH I位置以及轉譯開始密碼（ATG)，以及在停止密碼下游導入S a 1 I位置。將c D N A編碼區域連接到榖 200306817 胱甘肽S-轉移酶（GST)表現載體（pGEX4T-2)之BamH I及Sal I位置。依據熱休克法以重組載體轉染細菌。以〇.4ιηΜ異丙基- A- D-Ctt喃半乳糖硫苷（iptg)加速截頭HCV RdRp的表現’以及經由S D S - P A G E分析偵測。於緩衝液A (含有}㈤Μ DTT及l%Tnton Χ-100之PBS)之經超音波震盪之細菌懸浮液如下處理以純化截頭RdRp。溶菌產物經調整至〇.3 3M NaCl並於DEAE瓊脂糖管柱。通過DEAE管柱之分層部分與經緩衝液A在4°C平衡1小時之DEAE榖胱甘肽瓊脂糖 SephairQse 4B小珠逐批培育。經淸洗之小珠及截頭RdRpCOoCH-, R2e H0 ^ 'CH3 (Ie-1) -21-200306817 where Rla, R2a, R3a, R4a, R7a, Rlb, R2b, R3b, R4b, R5b, Rlc, R2c, R3e, Xc, Rld, R2d, Xd, Rle and R2e are each as defined above, and X is a leaving group. Suitable leaving groups for X may be halogen (e.g. fluorine, chlorine, bromine or iodine), aromatic hydrocarbon sulfonyloxy (such as benzenesulfonyloxy or tosylsulfonyloxy), and alkanesulfonyloxy (eg methanesulfonyl Oxygen or ethanesulfonyloxy) and the like, and among them, halogen is preferred. Production methods 1 to 5 can be performed according to the production methods described in the following examples. To illustrate the effectiveness of the pharmaceutical composition of the present invention, the pharmacological test of the fused benzene derivative is explained as follows. Evaluation of HCV RNA-RNA dependent RNA polymerase (RdRp) inhibitors was performed using a C-terminal truncated recombinant HCV # NS5B and oligo (G) 12 / polyC as primers / templates. The measurement of RdRp activity in vitro is determined by scintillation proximity analysis (SPA) or column chromatography analysis [H3] GMP incorporation into the template / primer. 1. Evaluate the performance and purification of truncated HCV RdRp for testing. HCV NS5B protein lacking 21 amino acids at the highly hydrophobic C-terminal can be expressed in bacteria (E. Coli BL-21). Due to its low solubility, the full length during the purification step HCV NS5B protein often precipitates. Furthermore, to facilitate purification, truncated RdRp is expressed by an N-terminally fused GST and a C-terminal tag His protein. HCV BK virus strain (genotype lb) C-terminal truncation and C-terminal tag His HCV NS5B protein cDNA coding region, BamH I position and translation start code (ATG) introduced at the 5 'end, and downstream of the stop code Introduce the S a 1 I position. The c D N A coding region was linked to the BamH I and Sal I positions of the 榖 200306817 cystathione S-transferase (GST) expression vector (pGEX4T-2). Bacteria were transfected with recombinant vectors according to the heat shock method. The performance of the truncated HCV RdRp was accelerated with 0.4 μm isopropyl-A-D-Ctt galactopyranoside (iptg) and detected by SD DS-PAGE analysis. Ultrasonicated bacterial suspension in Buffer A (PBS containing ㈤Μ DTT and 1% Tnton X-100) was treated as follows to purify truncated RdRp. The lysate was adjusted to 0.3 3M NaCl and applied to a DEAE agarose column. The layered portion passed through the DEAE column was incubated with DEAE-cysteine agarose SephairQse 4B beads equilibrated with buffer A at 4 ° C for 1 hour. Washed beads and truncated RdRp

溶析於含 5 00mM NaCl 之緩衝液 B(50mM Tris-HCl(pH 8.0)， 10mM 穀胱甘肽，10mM DTT 及 l%Triton X-100)。溶析之懸浮液滲析於含1 5 0 m Μ N a C1之緩衝液b，然後載入經含 0.15M NaCl LG 緩衝液（20mM Tris-HCl(pH 7.5)，lmM £〇丁八，5111]\/[〇丁丁’20%甘油及0.5%丁出〇11又-100)平衡之肝素瓊脂糖C L - 6 B管柱。使用0 · 1 5至1 Μ N a C1梯度評估結合之蛋白質並分層於2ml。經SDS-PAGE確認含有截頭RdRp 之分層部分載入經含 0.15M NaCl LG緩衝液平衡之聚 (U)Sepharose 4B。小珠。亦使用0.15至1M NaCl梯度溶析結合之蛋白質並分層於2ml。收集含有截頭RdRp之分層部分並以甘油溶液貯存在-8 0 °C。最後匯集之截頭r d R p 經西方點墨法確認。 2 .截頭R d R p活體外分析本分析法是如下刊物所述方法之改良程序：B e h r e n s S E， Tomei L and De Francesco R, EMBO /., 1996，Jan 2, 15(1)， 200306817 12-22; Lohmann V，Korner F，Herian U and Bartenschlager R. /· 1 9 9 7，Nov，71(11)，84 1 6-28;以及 Yamashita 丁，Dissolve in 500 mM NaCl Buffer B (50 mM Tris-HCl (pH 8.0), 10 mM glutathione, 10 mM DTT and 1% Triton X-100). The lysed suspension was dialyzed against a buffer b containing 150 m MN Na C1, and then loaded with a LG buffer containing 0.15M NaCl (20mM Tris-HCl (pH 7.5), lmM £ 〇丁八, 5111) \ / [〇丁丁 '20% glycerol and 0.5% butyl out 〇011A-100) balanced heparin agarose CL-6 B column. The bound protein was assessed using a gradient of 0.15 to 1 M NaCl and stratified in 2ml. The layered portion containing truncated RdRp was confirmed by SDS-PAGE to be loaded with poly (U) Sepharose 4B equilibrated with LG buffer containing 0.15M NaCl. Beads. The bound protein was also eluted using a gradient of 0.15 to 1 M NaCl and layered into 2 ml. The fractions containing the truncated RdRp were collected and stored in a glycerol solution at -8 ° C. The truncated r d R p of the final collection was confirmed by the western dot method. 2. In vitro analysis of truncated Rd R p This assay is a modified procedure of the method described in the following publications: Behrens SE, Tomei L and De Francesco R, EMBO /., 1996, Jan 2, 15 (1), 200306817 12-22; Lohmann V, Korner F, Herian U and Bartenschlager R. / 1 9 9 7, Nov, 71 (11), 84 1 6-28; and Yamashita Ding,

Kaneko S, Shirota Y，Qin W，Nomura T，Kobay ashi K and Murakami S， J. Biol. Chem, 1 9 9 8， Jun 19， 27 3 (2 5 )， 1 547 9-86 ^ 於20//1之11〇11^緩衝液（2〇11114丁1七-1^1(?117.5)，111^ EDTA，5mM MgCl2, 25mM KC1 以及 ImM DTT)、0.01%BSA、 0.05mg/ml 放線菌素 D、1 · 5 U R N a s i η、0.0 7 5 mC i/m 1 [Η3 ]-GTP、4pmmol 生物素化寡（G)12、500ng 聚（C)、截頭 RdRp 最終分層部分進行RdRp反應。在22 °C培育2小時後，根據下列兩方法從無反應性中分出產生之放射性。於S P A 法’添加共轭鏈抗生物素蛋白（streptoavidin)之 SPA小珠及uM GTP至反應混合物。於閃爍計數器測量小珠捕捉之放射性。於排除管柱色層分析法，添加uM GTP至反應混合物然後載入快速旋轉管柱S e p h a d e X G - 5 0。管柱離心之後，於閃爍計數器測量溶析液之放射性。將對應於每一化合物增加劑量之放射性作圖，然後確定IC 5 Q値。 3 .結果表1測試化合物之活體外RdRp活性（IC5Q) 測試化合物 IC5〇( β Μ) N - (1, 3 - 一酬基-1，2,3,4 -四氨-6-異睦啉基）苯醯胺（實施例8) 2.290 (4E)-4-亞苄基-2-[(2,4-二氯苄基）氧基]-1，3(2H，4H)-異 U奎啉二酮 *** 200306817 9 -硝基吡啶并[2 ’，3 ’ ： 4，5 ]嘧啶并[1，2 - a ]吲哚_ 5,1 1-二酮（實施例 23) _ ______ 0.073 9 -(三氟甲氧基）吡啶并[2 ’，3 ’ ： 4，5 ]嘧啶并 [l，2-a]D弓丨哚-5，1 1-二酮 0.354 N-[4-({[4-(5-{[4-({4-[(2-噻吩基羰基）胺基]_ 苄醯基}胺基）苄醯基]胺基卜H-苯并咪唑- 2-基）苯基]胺基}羰基）苯基]-2-噻吩-甲醯胺 1.854 N-(4-{5-[(2-噻吩基羰基）胺基]-1H-苯并咪唑 -2-基丨苯基）-2-噻吩甲醯胺（實施例29) 4.274 5 -甲氧基-1，3 -二氫- 2H -茚-1，2,2,3-呋喃 1.992 2,2’-二羥基-lH,lH，-2,2，-聯茚 _ 1，1，，3,3’（211，21^)-四酮 2.639 1，3,4(2H)-異喹啉三酮（實施例42) 3.000 包含於本發明醫藥組成物之稠合苯衍生物具有如上所示活性抑制RdRp之功效。因此聯想到稠合苯衍生物可於 HCV感染疾病之治療具保護性效益。含有稠合苯衍生物、其前藥或其醫藥可接受鹽爲活性成分之組成物，可與適用於外用（局部）、腸道、靜脈內、肌肉內、非經腸機或無機載劑）或黏膜內應用之醫藥可接受載劑（例如有賦形劑混合於醫藥製備物中，例如於固體、半固體或液體形式。曰有稠合本仍生物、其前藥或其醫藥可接受鹽之組成物’例如可配方與用於軟膏、乳霜、貝占片、藥淀'小片、膠囊、栓劑、溶液如橄欖油）、氣溶_Kaneko S, Shirota Y, Qin W, Nomura T, Kobay ashi K and Murakami S, J. Biol. Chem, 1 9 9 8, Jun 19, 27 3 (2 5), 1 547 9-86 ^ at 20 // 1 of 11〇11 ^ buffer solution (2011114, 1 七 -1 ^ 1 (? 117.5), 111 ^ EDTA, 5mM MgCl2, 25mM KC1 and ImM DTT), 0.01% BSA, 0.05mg / ml actinomycin D , 1 · 5 URN asi η, 0.0 7 5 mC i / m 1 [Η3] -GTP, 4 pmmol biotinylated oligo (G) 12, 500ng poly (C), truncated RdRp The final layered part was subjected to RdRp reaction. After incubation at 22 ° C for 2 hours, the generated radioactivity was separated from the non-reactivity according to the following two methods. SPA beads and uM GTP of conjugated avidin (streptoavidin) were added to the SP A method to the reaction mixture. The radioactivity captured by the beads was measured in a scintillation counter. In the exclusion column chromatography method, uM GTP was added to the reaction mixture and loaded into a fast rotating column S p h a d e X G-50. After the column was centrifuged, the radioactivity of the eluate was measured in a scintillation counter. The radioactivity corresponding to the increasing dose of each compound was plotted and the IC 5 Q 値 was determined. 3. Results Table 1 In vitro RdRp activity of the test compound (IC5Q) Test compound IC50 (βM) N-(1, 3-monoalan-1, 2, 3, 4-tetraamino-6-isoxoline Group) benzamidine (Example 8) 2.290 (4E) -4-benzylidene-2-[(2,4-dichlorobenzyl) oxy] -1,3 (2H, 4H) -isoUrquine Porphyrindione *** 200306817 9 -Nitropyrido [2 ', 3': 4,5] pyrimido [1,2-a] indole-5,1 1-dione (Example 23) _ ______ 0.073 9 -(Trifluoromethoxy) pyrido [2 ', 3': 4,5] pyrimido [l, 2-a] D archindol-5,1 1-dione 0.354 N- [4-({ [4- (5-{[4-({4-[(2-thienylcarbonyl) amino] -benzylfluorenyl} amino) benzylfluorenyl] amino group H-benzimidazole-2-yl) Phenyl] amino} carbonyl) phenyl] -2-thiophene-formamidine 1.854 N- (4- {5-[(2-thienylcarbonyl) amino] -1H-benzimidazol-2-yl 丨Phenyl) -2-thiophenemethylamine (Example 29) 4.274 5-methoxy-1,3-dihydro-2H-indene-1,2,2,3-furan 1.992 2,2'-dihydroxy -lH, lH, -2,2, -biindene-1,1,3,3 '(211,21 ^)-tetraone 2.639 1,3,4 (2H) -isoquinoline trione (Example 42) 3.000 Included in this post The fused benzene derivative of the Ming pharmaceutical composition has the effect of inhibiting RdRp by the activity shown above. Therefore, it is thought that fused benzene derivatives can have protective benefits in the treatment of HCV infection. Composition containing fused benzene derivative, its prodrug or pharmaceutically acceptable salt as the active ingredient, and can be used with topical (topical), intestinal, intravenous, intramuscular, parenteral or inorganic carrier) Or a pharmaceutically acceptable carrier for intramucosal application (for example, excipients mixed with pharmaceutical preparations, such as in solid, semi-solid, or liquid form. There is a condensed organism, its prodrug, or its pharmaceutically acceptable salt The composition 'such as can be formulated and used in ointments, creams, shellac tablets, Yaodian' tablets, capsules, suppositories, solutions such as olive oil),

(例如生理食鹽水）、乳液、懸浮液（例、藥九、粉末、糖發、注射液、喉片、 -25- 200306817 泥罨劑、芳香水、外用藥水、頰式錠劑、舌下錠劑、鼻腔滴劑或任何其他適用形式之慣用無毒性醫藥可接受鹽載劑。可使用之載劑爲水、蠟、葡萄糖、乳糖、***膠樹、動物膠、甘露醇、澱粉貼片、三矽酸鎂、滑石、玉米澱粉、角素、石、膠狀矽石、馬鈴薯澱粉、尿素以及其他適用於製造各製備物之慣用載劑。除上述之外可選擇性使用輔助劑、穩定劑、增厚劑或著色劑以及香料。稠合苯衍生物、其前藥或其醫藥可接受鹽是包含於有效量之醫藥組成物中以治療或預防疾病。本發明提供一種醫藥組成物含有稠合苯衍生物、其前藥或其醫藥可接受鹽混合與醫藥可接受鹽載劑，用於治療或預防病毒感染以及黃病毒科病毒包括登革熱病毒、黃熱病病毒、以及日本腦炎病毒所引起之相關疾病：肝硬化、肝細胞癌、以及肝衰竭；流產、畸形發生、呼吸道問題、慢性衰弱疾病、免疫系統失能、以及易遭第二種病毒及細菌感染。可使用本發明醫藥組成物治療之哺乳動物包括家畜類哺乳動物，例如牛、馬等等，馴養的動物如狗、貓、老鼠等等以及人類，尤其爲人類。稠合苯衍生物之治療有效劑量視每一病人年齡及狀況而異’平均單劑約〇.〇lmg，〇.lmg，Img，1〇mg，50mg，lOOmg， 250mg’ 500mg，以及l〇〇〇mg之稠合苯衍生物可用於治療上述疾病。通常每日投與量界於〇.01mg/主體至約i，000mg/ 主體。 -26- 200306817 進行本發明之最佳熊樣下列製備例及實施例之目的是爲更詳細舉例說明本發明，但不因此推斷限制爲本發明範圍。製備例1(E.g. physiological saline), emulsions, suspensions (e.g., medicine nine, powder, sugar hair, injections, throat tablets, -25- 200306817 lozenge, aromatic water, topical medicine, buccal lozenge, sublingual Lozenges, nasal drops, or any other suitable form of conventional non-toxic pharmaceutically acceptable salt carrier. Water, wax, dextrose, lactose, gum arabic, animal gum, mannitol, starch patches, Magnesium trisilicate, talc, corn starch, keratin, stone, colloidal silica, potato starch, urea, and other conventional carriers suitable for the preparation of various preparations. In addition to the above, optional auxiliary agents, stabilizers , Thickener or colorant, and flavor. Fused benzene derivatives, prodrugs or pharmaceutically acceptable salts thereof are included in an effective amount of a pharmaceutical composition to treat or prevent a disease. The present invention provides a pharmaceutical composition containing a thickener Benzene derivatives, their prodrugs or their pharmaceutically acceptable salts, mixed with a pharmaceutically acceptable salt carrier for the treatment or prevention of viral infections and flaviviridae viruses including dengue virus, yellow fever virus, and Related diseases caused by the encephalitis virus: liver cirrhosis, hepatocellular carcinoma, and liver failure; abortion, malformations, respiratory problems, chronic debilitating diseases, immune system disability, and susceptibility to a second virus and bacterial infection. Mammals treated with the pharmaceutical composition of the present invention include livestock mammals, such as cattle, horses, etc., domestic animals such as dogs, cats, mice, etc., as well as humans, especially humans. A therapeutically effective dose of fused benzene derivatives Depending on the age and condition of each patient, an average single dose of about 0.01 mg, 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg, and 1000 mg of fused benzene derivatives are available For the treatment of the above-mentioned diseases. The daily dosage range is generally from 0.01 mg / subject to about 1,000 mg / subject. -26- 200306817 The best bear-like samples for carrying out the present invention The purpose of the following preparations and examples is to be more detailed The invention is exemplified, but is not limited to the scope of the invention.

2-溴-5-硝基苯甲酸（6.3 g)於丙二酸二甲酯（58.5ml)之溶液使充滿氮氣15分鐘。添加一份甲氧基鈉（3.3 2g)至該溶液，然後在室溫攪拌所得混合物1 5分鐘。添加一份溴化亞銅（3 67mg)至該溶液。在85 °C加熱混合物5小時並冷卻至室溫。添加水（100ml)至該混合物。以二乙基醚（100mlx3) 萃取水層，然後以2N-氫氯酸酸化。以乙酸乙酯萃取酸性水層。以鹽水淸洗合倂的有機層，經無水硫酸鎂乾燥，然後於真空中濃縮。以二乙基醚/正-己烷，然後異丙基醚淸洗所得固體得到灰白色固體2-[2-甲氧基-1-(甲氧基羰基）-2-酮基乙基]-5-硝基苯甲酸（4.3 g)。 mp.l 69- 1 70〇C NMR(DMS〇-d6， 5 ): 3.70(6H，s)， 5 · 8 7 (1 Η，s)， 7.6 6 (1 Η， d， J 二 8·5Ηζ)， 8·44(1Η， dd， J = 8.5, 2·5Ηζ)， 8·66(1Η， d, J = 2.5Hz)。質量：296(M-1) + 製備例2 添加11氫氧化鈉（20.21111)至2-[2-甲氧基-1-(甲氧基羰基卜2-酮基乙基]-5-硝基苯甲酸（2g)於甲醇（20ml)之溶液。在70°C攪拌反應混合物7小時並冷卻至室溫。真空中從混合物移除甲醇。在0°C以6N-氫氯酸酸化所得水性混 200306817A solution of 2-bromo-5-nitrobenzoic acid (6.3 g) in dimethyl malonate (58.5 ml) was filled with nitrogen for 15 minutes. A portion of sodium methoxide (3.3 2 g) was added to the solution, and the resulting mixture was stirred at room temperature for 15 minutes. Add a portion of cuprous bromide (3 67mg) to the solution. The mixture was heated at 85 ° C for 5 hours and cooled to room temperature. Water (100 ml) was added to the mixture. The aqueous layer was extracted with diethyl ether (100 ml x 3) and then acidified with 2N-hydrochloric acid. The acidic aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated in vacuo. The obtained solid was washed with diethyl ether / n-hexane and then isopropyl ether to obtain 2- [2-methoxy-1- (methoxycarbonyl) -2-ketoethyl] -5 as an off-white solid. -Nitrobenzoic acid (4.3 g). mp.l 69-1 70 ° C NMR (DMS 0-d6, 5): 3.70 (6H, s), 5.87 (1 Η, s), 7.6 6 (1 Η, d, J 2 8. 5Ηζ ), 8.44 (1Η, dd, J = 8.5, 2 · 5Ηζ), 8.66 (1Η, d, J = 2.5Hz). Mass: 296 (M-1) + Preparation Example 2 Add 11 sodium hydroxide (20.21111) to 2- [2-methoxy-1- (methoxycarbonyl-2-ketoethyl) -5-nitro A solution of benzoic acid (2g) in methanol (20ml). The reaction mixture was stirred at 70 ° C for 7 hours and cooled to room temperature. The methanol was removed from the mixture in vacuo. The resulting aqueous mixture was acidified with 6N-hydrochloric acid at 0 ° C. 200306817

合物。以乙酸乙酯萃取水溶液（兩次）。合倂之有機層經無水硫酸鎂乾燥’然後於真空中濃縮。以二氯甲烷淸洗所得固體得到淺黃色固體2_(羧甲基）_5_硝基苯甲酸（1.27g)。 m p . 1 8 2 - 1 8 4 °C NMR(DMS〇-d6，5 ): 4.11(2H,s), 7·67(1Η，d，J:8.5Hz)， 8·3 7 5 ( 1 Η，dd，卜 8.5, 2·5Ηζ)，8.62(1H，d, J = 2.5Hz)。質量：224(M-1) + 製備例3 2- (羧甲基）-5-硝基苯甲酸（l〇〇mg)，1,2-二氯乙烷（2ml) 以及乙酸酐（0.126ml)之混合物於氮氣氛下回流5小時，然後冷卻至室溫。真空濃縮反應混合物。以乙酸乙酯淸洗所得固體得到淺棕色固體7 -硝基-1 Η - 2 -苯并吡喃-1，3 (4 Η)-二酮（6 1 · 2mg)。组合。 The compound. The aqueous solution was extracted with ethyl acetate (twice). The combined organic layer was dried over anhydrous magnesium sulfate 'and then concentrated in vacuo. The obtained solid was washed with dichloromethane to give 2- (carboxymethyl) -5-nitrobenzoic acid (1.27 g) as a pale yellow solid. mp. 1 8 2-1 8 4 ° C NMR (DMS〇-d6,5): 4.11 (2H, s), 7.67 (1Η, d, J: 8.5Hz), 8.3 7 5 (1 Η , Dd, Bu 8.5, 2.5 Ηζ), 8.62 (1H, d, J = 2.5Hz). Mass: 224 (M-1) + Preparation Example 3 2- (carboxymethyl) -5-nitrobenzoic acid (100 mg), 1,2-dichloroethane (2 ml) and acetic anhydride (0.126 ml) The mixture was refluxed under a nitrogen atmosphere for 5 hours, and then cooled to room temperature. The reaction mixture was concentrated in vacuo. The obtained solid was washed with ethyl acetate to obtain 7-nitro-1 fluorene-2 -benzopyran-1,3 (4 fluorene) -dione (6 1.2 mg) as a light brown solid.

m p . 1 5 1 -1 5 3 °C NMR(DMS〇-d6，（5 ): 4.42(2H，s)， 7.74(1H， d， J = 8.5Hz)， 8.54(1H，d，J = 8.5)，8.68(lH，s)。質量：206(M-1) + 製備例4 3- 酮基丁醇酸乙酯（37.9mg) ’乙醇（100ml)，乙氧基鈉 (16.9g)，溴化亞銅（7.12g)以及2-氯-4-硝基苯甲酸（2〇g)之混合物於氮氣氛下加熱至90°C達5小時，然後冷卻至室溫。透過賽力特矽藻土墊（celite Pat)過濾混合物。真空濃縮濾液。殘留物溶解於2N-氫氯酸’然後以乙酸乙酯萃取酸性溶液。以鹽水淸洗有機層’經無水硫酸鎂乾燥’然後 -28- 200306817mp. 1 5 1 -1 5 3 ° C NMR (DMS 0-d6, (5): 4.42 (2H, s), 7.74 (1H, d, J = 8.5Hz), 8.54 (1H, d, J = 8.5 ), 8.68 (lH, s). Mass: 206 (M-1) + Preparation Example 4 3-Ethyl ketobutyrate (37.9 mg) 'Ethanol (100 ml), sodium ethoxylate (16.9 g), bromine A mixture of cuprous chloride (7.12g) and 2-chloro-4-nitrobenzoic acid (20g) was heated to 90 ° C for 5 hours under a nitrogen atmosphere, and then cooled to room temperature. Pass through Celite The mixture was filtered with a celite Pat. The filtrate was concentrated in vacuo. The residue was dissolved in 2N-hydrochloric acid 'and the acidic solution was extracted with ethyl acetate. The organic layer was washed with brine' dried over anhydrous magnesium sulfate 'and then -28- 200306817

於真空中蒸發。殘留物於矽膠以氯仿/甲醇（10 ·· 1)之混合物爲溶析液經快速管柱色層分析純化。以異丙基酸/正-己犬兀固化所得油狀產物得到灰白色固體2-(2-乙氧基嗣基乙基）-4 -硝基苯甲酸（5 · 〇 3 g)。 mp.140.5-141 °C NMR(DMS〇-d6, 5 ): 1 . 1 7 (3H, t, J = 7 · 0 Η z)， 4 · 0 7 (2 Η， q， J 二 7·0Ηζ), 4.l6(2H，s)，8.12(1H，d，J 二8·5Ηζ)，8·23(1Η，dd，Evaporate in vacuo. The residue was purified by flash column chromatography on silica gel using a mixture of chloroform / methanol (10 ·· 1) as the eluent. The resulting oily product was cured with isopropyl acid / n-hexane to give 2- (2-ethoxyfluorenylethyl) -4-nitrobenzoic acid (5.03 g) as an off-white solid. mp. 140.5-141 ° C NMR (DMS〇-d6, 5): 1.1 7 (3H, t, J = 7 · 0 Η z), 4 · 0 7 (2 Η, q, J 2 7 · 0Ηζ ), 4.16 (2H, s), 8.12 (1H, d, J 2: 8.5Ηζ), 8.23 (1Η, dd,

J = 8.5，2·0Ηζ)，8·30(1Η，d，J = 2.0Hz)。質量：25 2(M-1) + 製備例5J = 8.5, 2 · 0Ηζ), 8 · 30 (1Η, d, J = 2.0Hz). Mass: 25 2 (M-1) + Preparation Example 5

以類似製備4之方法得到2-(2-乙氧基-2-酮基乙基）_ 4-(甲基磺醯基）苯甲酸。 m p . 1 4 7 - 1 4 8 °C NMR(DMS〇-d6， (5 ): 1.18(3H， t， J = 7.0Hz)， 3.27(3H,s), 4.07(2H, q, J = 7.0Hz), 4.12(2H,s), 7.95(1H, d, J=8.5Hz),In a similar manner to Preparation 4, 2- (2-ethoxy-2-ketoethyl) -4- (methylsulfonyl) benzoic acid was obtained. mp. 1 4 7-1 4 8 ° C NMR (DMS〇-d6, (5): 1.18 (3H, t, J = 7.0Hz), 3.27 (3H, s), 4.07 (2H, q, J = 7.0 Hz), 4.12 (2H, s), 7.95 (1H, d, J = 8.5Hz),

7.97(lH，s)，8·12(1Η，d，J = 8.5Hz)，13.48(lH，brs)。質量：28 5 (M-1) + 製備例6 添加IN-氫氧化鈉（3.95ml)至2-(2-乙氧基-2-酮基乙基）-4-硝基苯甲酸（4〇〇mg)於1，4-二噚烷（8ml)之溶液。在室溫攪拌混合物2小時，然後以1 N -氫氯酸酸化。真空中蒸發有機溶劑，經由過濾收集所得沉澱物。以乙酸乙酯淸洗所得固體得到無色固體2 -(羧甲基）_ 4 -硝基苯甲酸 (2 8 4 · 9 m g) 〇 -29- 2003068177.97 (lH, s), 8.12 (1Η, d, J = 8.5Hz), 13.48 (lH, brs). Mass: 28 5 (M-1) + Preparation Example 6 Add IN-sodium hydroxide (3.95 ml) to 2- (2-ethoxy-2-ketoethyl) -4-nitrobenzoic acid (4〇 0 mg) in 1,4-dioxane (8 ml). The mixture was stirred at room temperature for 2 hours and then acidified with 1 N-hydrochloric acid. The organic solvent was evaporated in vacuo and the resulting precipitate was collected by filtration. The resulting solid was washed with ethyl acetate to give a colorless solid 2- (carboxymethyl) -4-nitrobenzoic acid (2 8 4 · 9 mg). -29-200306817

mp.192.5-193 °C NMR(DMSO-d6, o ): 4. 1 〇(2H,s), 8.09( 1 H, d, J = 8.5 Hz), 8.22(1H, dd，J=8.5，2.0Hz)，8 · 2 8 (1 H , d，J n 2 · OH z)。 - 質量：224(M-1) + 製備例7 以類似製備6之方法得到2 -(殘甲基）_ 4 -(甲基擴醯基）mp. 192.5-193 ° C NMR (DMSO-d6, o): 4. 1 〇 (2H, s), 8.09 (1 H, d, J = 8.5 Hz), 8.22 (1H, dd, J = 8.5, 2.0 Hz), 8 · 2 8 (1 H, d, J n 2 · OH z). -Mass: 224 (M-1) + Preparation Example 7 In a similar manner to Preparation 6, 2-(residual methyl) _ 4-(methyl fluorenyl)

苯甲酸。 mp.220-2 2 1 °C NMR(DMSO-d6，5 ): 3 · 2 7 (3 Η，s)， 4 · 0 6 (2 Η，s)， 7.9 3 (1 Η， d， J二8.5Hz)，7.94(lH，s)，8·09(1Η，d，J = 8.5Hz)。質量：25 7 (M-1) + 製備例8 2-(羧甲基）-4-硝基苯甲酸（2g)，甲苯（3〇1111)以及乙酸酐（1.68ml)之混合物於氮氣氛下回流5小時，然後冷卻至室溫。真空濃縮反應混合物。以乙酸乙酯淸洗所得固體得到淺頁色固體6_硝基苯并吡喃]，3(4Η)·二酮 φ (1.56g)。benzoic acid. mp.220-2 2 1 ° C NMR (DMSO-d6,5): 3 · 2 7 (3 Η, s), 4 · 0 6 (2 Η, s), 7.9 3 (1 Η, d, J 2 8.5 Hz), 7.94 (lH, s), 8.09 (1 mm, d, J = 8.5 Hz). Mass: 25 7 (M-1) + Preparation Example 8 A mixture of 2- (carboxymethyl) -4-nitrobenzoic acid (2g), toluene (301111) and acetic anhydride (1.68ml) under a nitrogen atmosphere Reflux for 5 hours and then cool to room temperature. The reaction mixture was concentrated in vacuo. The obtained solid was washed with ethyl acetate to obtain 6-nitrobenzopyran], 3 (4Η) · dione φ (1.56 g) as a light-pigmented solid.

mp.l 40- 1 43 〇C NMR(DMS〇-d6,5): 4.40(2H，S)，8 2 8 (2H，s)，8 3 5 ( 1 H，s)。質量：206(M-1) + 製備例9 以類似製備8之方法得到下列化合物（1)及（2)。mp. 1 40-1 43 ° C NMR (DMSO-d6,5): 4.40 (2H, S), 8 2 8 (2H, s), 8 3 5 (1 H, s). Mass: 206 (M-1) + Preparation Example 9 In a similar manner to Preparation 8, the following compounds (1) and (2) were obtained.

(1)6-(甲基磺醯基）-1Η-2-苯并吡喃二酮 mp.249-250〇C -30- 200306817 NMR(DMSO-d6, ο )： 3.32(3H,s), 4.38(2H，s), 8·03(1Η， d， J 二 8.0Hz), 8.05(lH，s)，8.28(1H, d, J = 8.0Hz)。質量：239(M-1) + (2)1H-萘并[2,3-c]吡喃 _i,3(4H)-二酮 mp.1 65 - 1 66.5 °C 製備例1 0(1) 6- (methylsulfonyl) -1′-2-benzopyranedione mp. 249-250 ° C -30- 200306817 NMR (DMSO-d6, ο): 3.32 (3H, s), 4.38 (2H, s), 8.03 (1Η, d, J = 8.0Hz), 8.05 (lH, s), 8.28 (1H, d, J = 8.0Hz). Mass: 239 (M-1) + (2) 1H-naphtho [2,3-c] pyran _i, 3 (4H) -dione mp.1 65-1 66.5 ° C Preparation Example 1 0

在〇°C氮氣氛下將萘并[2,3-c]吡喃-1,3-二酮（l〇g)於四氫呋喃（50 ml)及N，N-二甲基甲醯胺（50ml)之混合物逐滴添加至硼氫化鈉（1.91 g)於四氫呋喃（25ml)之懸浮液10分鐘。在室溫攪拌反應混合物45分鐘，然後在0°C以6N-氫氯酸酸化所得水性混合物。真空中濃縮混合物至體積約80ml。收集所得沉澱物，以水及二乙基醚淸洗得到無色固體萘并 [2,3-c]呋喃-1(3H)-酮（4.77g)。 mp.l 95 - 1 97 〇C NMR(DMS〇-d6，（5 ): 5.84(2H，s)， 7·65(1Η， t， J = 8.0Hz)， 7 · 7 3 (1 Η，t，J = 8.0 Η z)，8 · 1 0 (1 Η，d，J = 8.0 Η z)，8 . 1 6 (1 Η，s)， 8.22(1H，d，J = 8.0Hz)，8.60(lH，s)。質量：185(M+1) + 製備例1 1 萘并[2,3-c]呋喃-1(3H) -酮（8g)及細碎氰化鉀（9.33g)之混合物在2 0 0 °C加熱5小時，然後冷卻至室溫。添加水（8 〇 m}) 至混合物，然後濾除所得不溶解物質。以6 N -氫氯酸酸化濾液並以乙酸乙酯萃取（兩次）。以鹽水淸洗合倂之有機層，經硫酸鎂乾燥，然後於真空中蒸發。以二乙基醚淸洗 -31 - 200306817Naphthalo [2,3-c] pyran-1,3-dione (10 g) in tetrahydrofuran (50 ml) and N, N-dimethylformamidine (50 ml) under a nitrogen atmosphere at 0 ° C. The mixture) was added dropwise to a suspension of sodium borohydride (1.91 g) in tetrahydrofuran (25 ml) for 10 minutes. The reaction mixture was stirred at room temperature for 45 minutes, and then the resulting aqueous mixture was acidified with 6N-hydrochloric acid at 0 ° C. The mixture was concentrated in vacuo to a volume of about 80 ml. The resulting precipitate was collected and washed with water and diethyl ether to obtain a colorless solid naphtho [2,3-c] furan-1 (3H) -one (4.77 g). mp.l 95-1 97 ° C NMR (DMS 0-d6, (5): 5.84 (2H, s), 7.65 (1Η, t, J = 8.0Hz), 7 · 7 3 (11, t , J = 8.0 Η z), 8 · 1 0 (1 Η, d, J = 8.0 Η z), 8. 1 6 (1 Η, s), 8.22 (1H, d, J = 8.0 Hz), 8.60 ( lH, s). Mass: 185 (M + 1) + Preparation Example 1 1 A mixture of naphtho [2,3-c] furan-1 (3H) -one (8g) and finely divided potassium cyanide (9.33g) It was heated at 200 ° C for 5 hours, and then cooled to room temperature. Water (80 m) was added to the mixture, and the resulting insoluble matter was filtered off. The filtrate was acidified with 6 N-hydrochloric acid and extracted with ethyl acetate ( Twice). The combined organic layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. Washed with diethyl ether -31-200306817

殘留物，然後添加到氫氧化鉀（9.26g)於水（40ml)之溶液。回流混合物2小時，並冷卻至室溫。以6N-氫氯酸酸化混合物。以水及乙醇淸洗由過濾所收集之所得固體得到淺棕色固體3-(羧甲基）-2-萘甲酸（3.32g)。 mp.202-203 〇C NMR(DMSO-d6, 5 ): 4.08(2H,s), 7.57(1H, t, J = 8.〇Hz)， 7.64(1H, t, J = 8.0Hz), 7.83(lH,s), 7.9K1H, d, J^8.〇Hz), 8.07(1H, d, J 二 8.0Hz)，8.55(lH,s)。The residue was then added to a solution of potassium hydroxide (9.26 g) in water (40 ml). The mixture was refluxed for 2 hours and cooled to room temperature. The mixture was acidified with 6N-hydrochloric acid. The solid obtained by filtration was washed with water and ethanol to obtain 3- (carboxymethyl) -2-naphthoic acid (3.32 g) as a light brown solid. mp. 202-203 ° C NMR (DMSO-d6, 5): 4.08 (2H, s), 7.57 (1H, t, J = 8.〇Hz), 7.64 (1H, t, J = 8.0Hz), 7.83 (lH, s), 7.9K1H, d, J ^ 8.0 Hz), 8.07 (1H, d, J 8.0Hz), 8.55 (lH, s).

質量：229(M-1) + 製備例1 2Mass: 229 (M-1) + Preparation Example 1 2

以類似實施例1之方法得到2-(2-胺基-2-酮基乙基）_ 4-(甲基磺醯基）苯甲酸。 mp.209-2 1 2〇C NMR(DMS〇-d6, (5 )·· 3 · 2 4 (3 Η , s)， 3 · 8 7 (2 Η，s), 6 · 9 0 (1 Η，b i-s)， 7.79( lH,brs), 7.82(1H, d, J = 2.0Hz), 7.84( 1H, dd, J = 8.0,In a similar manner to Example 1, 2- (2-amino-2-ketoethyl) -4- (methylsulfonamido) benzoic acid was obtained. mp.209-2 1 2 ° C NMR (DMS〇-d6, (5) ·· 3 · 2 4 (3 Η, s), 3 · 8 7 (2 Η, s), 6 · 9 0 (1 Η , B is), 7.79 (lH, brs), 7.82 (1H, d, J = 2.0Hz), 7.84 (1H, dd, J = 8.0,

2.0Hz), 7.94(1H，d，J二8.0Hz)。實施例1 在0°C將氫氧化銨之28 %水溶液（8ml)逐滴添加到iH_ 異色烯·1，3(4Η)·二酮（10mg)於N，N-二甲基甲醯胺（2〇mi)之溶液。在0°C攪拌反應混合物1 5分鐘，然後於真空中濃縮。所得固體懸浮於二甲苯（l〇〇ml)，在150t攪拌懸浮液5.5 小時，然後冷卻至室溫。經由過濾所收集所得沉澱，以二甲苯、水及乙醇淸洗。殘留物於矽膠以氯仿/甲醇（1 〇 :丨）之混合物爲溶析液經快速管柱色層分析純化。以乙腈硏製所 -32- 2003068172.0Hz), 7.94 (1H, d, J = 8.0Hz). Example 1 A 28% aqueous solution (8 ml) of ammonium hydroxide was added dropwise to iH_isochromene · 1,3 (4Η) · dione (10mg) in N, N-dimethylformamide at 0 ° C ( 20 mi) solution. The reaction mixture was stirred at 0 ° C for 15 minutes and then concentrated in vacuo. The obtained solid was suspended in xylene (100 ml), the suspension was stirred at 150 t for 5.5 hours, and then cooled to room temperature. The resulting precipitate was collected by filtration and washed with xylene, water and ethanol. The residue was purified by flash column chromatography on silica gel using a chloroform / methanol (10: 丨) mixture as the eluent. Acetonitrile Plant -32- 200306817

得固體得到淺黃色固體1,3(2H，4H) -異喹啉二酮（4.01g)。 mp.241.5-242.5 〇C NMR(DMS〇-d6， ο ): 4.04(2H,s), 7.39(1Η? d, J = 8.0Hz)， Λ 7·46(1Η，t，J = 8.0Hz)，7·65(1Η，dt，J 二1.5, 8·0Ηζ)，8·01(1Η，dd， J = 8.0，1·5Ηζ)，1 1.31(lH，s)。實施例2 以類似實施例1之方法得到下列（1)至（3)化合物。 (1) 7-硝基-1,3(211，411)-異喹啉二酮 _ mp.202-203。。 NMR(DMS〇-d6， δ ): 4.19(2Hxl/2，s)， 5.8 4 (1 Η x 1/2 , s), 7.56(lHxl/2, d， J = 8.5Hz)， 7.68(lHxl/2, d， J = 8.5Hz), 8.21(lHxl/2，dd，J = 8.5，2.0Hz), 8.46(lHxl/2，dd，J = 8.5， 2.0Hz), 8.67(lHxl/2, d, J = 2.0Hz), 8.74(lHxl/2, d, J = 2.0Hz), 11.65(lHxl/2，s)，11.98(lHxl/2，s)。質量：205 (M-1) +Obtaining a solid gave 1,3 (2H, 4H) -isoquinolinedione (4.01 g) as a pale yellow solid. mp.241.5-242.5 〇C NMR (DMS〇-d6, ο): 4.04 (2H, s), 7.39 (1Η? d, J = 8.0Hz), Λ 7.46 (1Η, t, J = 8.0Hz) , 7.65 (1Η, dt, J = 1.5, 8 · 0Ηζ), 8.01 (1Η, dd, J = 8.0, 1.5 · ζ), 1 1.31 (lH, s). Example 2 In a similar manner to Example 1, the following compounds (1) to (3) were obtained. (1) 7-nitro-1,3 (211,411) -isoquinolinedione_ mp. 202-203. . NMR (DMS 0-d6, δ): 4.19 (2Hxl / 2, s), 5.8 4 (1 Η x 1/2, s), 7.56 (lHxl / 2, d, J = 8.5Hz), 7.68 (lHxl / 2, d, J = 8.5Hz), 8.21 (lHxl / 2, dd, J = 8.5, 2.0Hz), 8.46 (lHxl / 2, dd, J = 8.5, 2.0Hz), 8.67 (lHxl / 2, d, J = 2.0Hz), 8.74 (lHxl / 2, d, J = 2.0Hz), 11.65 (lHxl / 2, s), 11.98 (lHxl / 2, s). Mass: 205 (M-1) +

(2) 6-硝基-1，3(2H，4H)-異喹啉二酮 H mp.261-262 °C NMR(DMS〇-d6, 5 ): 4.17(2H，s)， 8.24(2H,s)， 8.30(lH,s)， 1 1.61(lH，s)。質量：205(M-1) +(2) 6-nitro-1,3 (2H, 4H) -isoquinolinedione H mp.261-262 ° C NMR (DMS〇-d6, 5): 4.17 (2H, s), 8.24 (2H , s), 8.30 (lH, s), 1 1.61 (lH, s). Mass: 205 (M-1) +

(3) 苯并[g]異喹啉-1，3(2H，4H)-二酮 mp.247-249〇C NMR(DMS〇-d6, 5 ): 4.20(2H,s), 7.58(1H, t， J = 8.0Hz), 7.67(1H，t，J二8.0Hz)，7.90(lH，s), 7.97(1H，d，；[二8.0Hz)， -33- 200306817 8.16(1H，d，J = 8.0Hz)，8.72(lH，s)，11.41(lH，s)° 實施例3 4 1H-異色烯-1，3(4H)-二酮（500mg)，2-氯苄基胺（〇.4〇9ml)(3) Benzo [g] isoquinoline-1,3 (2H, 4H) -dione mp.247-249 ° C NMR (DMS〇-d6, 5): 4.20 (2H, s), 7.58 (1H , t, J = 8.0Hz), 7.67 (1H, t, J = 8.0Hz), 7.90 (lH, s), 7.97 (1H, d ,; [two 8.0Hz), -33- 200306817 8.16 (1H, d , J = 8.0 Hz), 8.72 (lH, s), 11.41 (lH, s) ° Example 3 4 1H-isochromene-1,3 (4H) -dione (500mg), 2-chlorobenzylamine ( 0.04ml)

以及甲苯（4ml)之混合物於氮氣氛下回流8小時’然後冷卻至室溫。以氯仿稀釋混合物。以1N-氫氯酸、水、飽和碳酸氫鈉水溶液及鹽水淸洗該溶液，經硫酸鎂乾丨喿’然後於真空中蒸發。殘留物於矽膠以氯仿/甲醇（3〇:1)之混合物爲溶析液經快速管柱色層分析純化。以乙醇硏製所得1 111 _ 得到灰白色固體2-(2-氯苄基）-1，3(2Η，4Η)-異喹啉二_ (2 4 3 _ 6 m g) 〇 mp.l 3 6.5 - 1 3 7 〇C NMR(DMS〇-d6， 5 )·· 4.30(2H，s)， 5.09(2H，s)， 7·11(1Η， d， J=7.0Hz)，7.19-7.33(2H,s)，7.42-7.55(3H，m)，7·7 1(1Η，t， J = 7.0Hz), 8.06(1H, d, J = 7.5Hz)。質量：284(M-1) + 實施例4 以類似實施例3之方法得到下列（1)至（3)化合物。And a mixture of toluene (4 ml) was refluxed under a nitrogen atmosphere for 8 hours' and then cooled to room temperature. The mixture was diluted with chloroform. The solution was washed with 1N-hydrochloric acid, water, saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate, and then evaporated in vacuo. The residue was purified by flash column chromatography on silica gel using a chloroform / methanol (30: 1) mixture as the eluent. Obtaining 1 111 _ with ethanol to give off-white solid 2- (2-chlorobenzyl) -1,3 (2 Η, 4 喹) -isoquinoline di_ (2 4 3 _ 6 mg) 〇mp.l 3 6.5- 1 3 7 ° C NMR (DMS 0-d6, 5) ... 4.30 (2H, s), 5.09 (2H, s), 7.11 (1Η, d, J = 7.0Hz), 7.19-7.33 (2H, s), 7.42-7.55 (3H, m), 7.7.1 (1Η, t, J = 7.0Hz), 8.06 (1H, d, J = 7.5Hz). Mass: 284 (M-1) + Example 4 In a similar manner to Example 3, the following compounds (1) to (3) were obtained.

(1) 2-苯基-1，3(2H，4H)-異喹啉二酮 mp.l 94- 1 95 〇C NMR(DMSO-d6, (5 ): 4.28(2H,s), 7.26(2H, d, J = 8.0Hz), 7.38-7.55(5H，m)，7.72(1H，t，J = 8.0Hz), 8.06(1H, d，J = 8.0Hz)。質量：23 6(M-1) + (2) 2-(2-苯乙基）-1，3(2H,4H)-異喹啉二酮 mp.130-131.5 200306817 NMR(DMSO-d6, δ ): 2·81(2Η， t， J = 8 · 0 Η ζ)， 4.0 5 (2 Η， t， J = 8.0Hz)，4.15(2H，s)，7.18-7.34(5H，m)，7·40(1Η，d，J = 7.5Hz)， 7·48(1Η，t，J = 7.5Hz)，7.67(1H，t，J 二 7.5Hz)，8.05(1H，d， J = 7」Hz)。(1) 2-phenyl-1,3 (2H, 4H) -isoquinolinedione mp. 94-195 95 ° C NMR (DMSO-d6, (5): 4.28 (2H, s), 7.26 ( 2H, d, J = 8.0Hz), 7.38-7.55 (5H, m), 7.72 (1H, t, J = 8.0Hz), 8.06 (1H, d, J = 8.0Hz). Mass: 23 6 (M- 1) + (2) 2- (2-phenethyl) -1,3 (2H, 4H) -isoquinolinedione mp.130-131.5 200306817 NMR (DMSO-d6, δ): 2.81 (2Η , T, J = 8 · 0 Η ζ), 4.0 5 (2 Η, t, J = 8.0 Hz), 4.15 (2H, s), 7.18-7.34 (5H, m), 7.40 (1Η, d, J = 7.5Hz), 7.48 (1Η, t, J = 7.5Hz), 7.67 (1H, t, J = 7.5Hz), 8.05 (1H, d, J = 7 ″ Hz).

(3)2-(苄氧基）-1，3(2H,4H)-異喹啉二酮 mp.1 46- 1 46.5 °C(3) 2- (benzyloxy) -1,3 (2H, 4H) -isoquinolinedione mp.1 46- 1 46.5 ° C

NMR(DMSO-d6, (5 ): 4.30(2H,s), 5.04(2H,s), 7.3 6 - 7.4 6 (4 H, m), 7.5K1H, t, J-8.0Hz), 7.5 5 - 7.6 1 (2H , m), 7.70(1H, t, J = 8.0Hz), 8.07(1H，d, J = 8.0Hz)。質量：268 (M+1) + 實施例5NMR (DMSO-d6, (5): 4.30 (2H, s), 5.04 (2H, s), 7.3 6-7.4 6 (4 H, m), 7.5K1H, t, J-8.0Hz), 7.5 5- 7.6 1 (2H, m), 7.70 (1H, t, J = 8.0Hz), 8.07 (1H, d, J = 8.0Hz). Mass: 268 (M + 1) + Example 5

在氮氣氛下混合1,3(2H，4H)-異喹啉二酮（200mg)，碳酸鉀（18911^)及叱1二甲基甲醯胺（41111)並冷卻至0°(：。在0 °C添加4-溴-1-(溴甲基）-2-氟苯（3 32mg)至混合物。在室溫攪拌懸浮液2小時。在0°C添加水至混合物，然後於真空中過濾所得沉澱物。所得固體於矽膠以氯仿/甲醇（1 0 : 1)之混合物爲溶析液經快速管柱色層分析純化。以乙醇硏製所得固體得到無色固體4,4-貳（4-溴-2_氟苄基）-l，3(2H，4H)-異喹啉二酮（131.7mg)。 mp.203 -204〇C NMR(DMSO-d6, (5 ): 3 · 5 6 (2 Η， d， J 二 1 4 · 5 Η z)， 3 · 6 1 (2 Η， d， J 二 14·5Ηζ)，6·68(2Η，t，J = 8.0Hz), 7.16(2H，dd，J = 8.0, 2.0Hz)， 7.30(2H，dd，J二 10.0, 2.0Hz)，7.42(1H，t，J = 8.0Hz)，7.73(1H， t，J 二8.0Hz), 7.78(1H，d，J二 8.0Hz)，7.97(1H, d, J = 8.0Hz)， -35- 200306817 1 1.50(lH，s)。實施例6In a nitrogen atmosphere, 1,3 (2H, 4H) -isoquinolinedione (200 mg), potassium carbonate (18911 ^), and fluorene-1 dimethylformamide (41111) were mixed and cooled to 0 ° (: 4-Bromo-1- (bromomethyl) -2-fluorobenzene (3 32 mg) was added to the mixture at 0 ° C. The suspension was stirred at room temperature for 2 hours. Water was added to the mixture at 0 ° C and then filtered in vacuo The resulting precipitate. The obtained solid was purified on a silica gel using a chloroform / methanol (1 0: 1) mixture as an eluent and analyzed by flash column chromatography. The obtained solid was subjected to ethanol to obtain a colorless solid 4,4- 贰 (4- Bromo-2-fluorobenzyl) -1,3 (2H, 4H) -isoquinolinedione (131.7mg). Mp.203 -204 ° C NMR (DMSO-d6, (5): 3 · 5 6 ( 2 Η, d, J 2 1 4 · 5 Η z), 3 · 6 1 (2 Η, d, J 2 14 · 5 Η ζ), 6.68 (2Η, t, J = 8.0 Hz), 7.16 (2H, dd, J = 8.0, 2.0 Hz), 7.30 (2H, dd, J 2 10.0, 2.0 Hz), 7.42 (1H, t, J = 8.0 Hz), 7.73 (1H, t, J 2 8.0 Hz), 7.78 ( 1H, d, J (8.0 Hz), 7.97 (1H, d, J = 8.0 Hz), -35- 200306817 1 1.50 (lH, s). Example 6

以類似實施例5之方法得到 4,4-貳（2-硝基苄基）_ 1，3(2H，4H)-異喹啉二酮。 mp.246-247 °C NMR(DMS〇-d6，（5 ): 3 · 8 8 (2 Η , d， J = 1 4 · 0 Η z)， 4.0 1 (2 Η， d， J 二 14.0Hz), 6.82(2H, dd, J = 9.5, 2.0Hz), 7.3 0 - 7.4 4 (4 H ? m), 7.48( 1H, t, J = 7.5Hz), 7.65-7.74(3H,m), 7.76-7.86(2H,m), 1 1.44(lH，s)。實施例7In a similar manner to Example 5, 4,4-fluorene (2-nitrobenzyl) -1,3 (2H, 4H) -isoquinolinedione was obtained. mp.246-247 ° C NMR (DMS〇-d6, (5): 3 · 8 8 (2 Η, d, J = 1 4 · 0 Η z), 4.0 1 (2 Η, d, J 2 14.0 Hz ), 6.82 (2H, dd, J = 9.5, 2.0Hz), 7.3 0-7.4 4 (4 H? M), 7.48 (1H, t, J = 7.5Hz), 7.65-7.74 (3H, m), 7.76 -7.86 (2H, m), 1 1.44 (lH, s). Example 7

在周圍溫度3atm氫氣下攪拌6-硝基·1，3(2Η，4Η)-異睦啉二酮（3g)及 10%鈀/碳（291mg)於甲醇（30ml)及四氫呋喃 (60ml)之混合物2小時。透過賽力特砍藻土墊過濾反應混合物，然後在真空濃縮濾液。殘留物於矽膠以氯仿/甲醇 (1 0 : 1)之混合物爲溶析液經快速管柱色層分析純化。以乙醇硏製所得固體得到橘色固體6-胺基-1，3(2H,4H)-異喹啉二酮（72.0mg)。 mp.23 1 - 2 3 3 〇C NMR(DMSO-d6, 5 ): 3 · 8 3 (2 Η，s)， 6 .1 1 (2 Η，s)， 6.3 6 (1 Η， d， J=2.0Hz)，6·55(1Η，dd，J = 8.5，2·0Ηζ)，7·66(1Η，d，J = 8.5Hz), 10.77(lH，bi:s)。實施例8 氮氣氛下添加三乙基胺（0.079ml)及苯甲醯氯（0.127ml) 到6-胺基-1，3(2H,4H)-異喹啉二酮（80mg)於1,2-二氯乙烷 200306817A mixture of 6-nitro · 1,3 (2Η, 4Η) -isomurolindione (3g) and 10% palladium / carbon (291mg) in methanol (30ml) and tetrahydrofuran (60ml) was stirred at a surrounding temperature of 3atm hydrogen. 2 hours. The reaction mixture was filtered through a Celite celite pad, and the filtrate was concentrated in vacuo. The residue was purified by chromatography on a silica gel column using chloroform / methanol (10: 1) as the eluent. The obtained solid was mashed with ethanol to obtain 6-amino-1,3 (2H, 4H) -isoquinoline dione (72.0 mg) as an orange solid. mp. 23 1-2 3 3 OC NMR (DMSO-d6, 5): 3 · 8 3 (2 Η, s), 6.1 1 (2 Η, s), 6.3 6 (1 Η, d, J = 2.0Hz), 6.55 (1Η, dd, J = 8.5, 2.00Ηζ), 7.66 (1Η, d, J = 8.5Hz), 10.77 (lH, bi: s). Example 8 Add triethylamine (0.079ml) and benzamidine chloride (0.127ml) to 6-amino-1,3 (2H, 4H) -isoquinolinedione (80mg) in a nitrogen atmosphere at 1, 2-dichloroethane 200306817

(2ml)之混合物。回流反應混合物5小時’然後冷卻至室溫。經由過濾收集所得沉澱物並以乙醇淸洗得到淺黑黃色固體Ν·(1,3-二酮基-1,2,3,4 -四氫異喹啉基）苯醯胺 (3 7.6 m g ) 〇 m p . 2 8 8 - 2 9 0 °C NMR(DMSO-d6,5): 4.05(2H，s), 7.5 卜7.68(3H，m)，7.82(1H， dd，J = 8.5，2.0Hz)，7·91(1Η，d，J = 2.0Hz)，7.93-8.0〇(2H，m)， 8.00(1H，d，J = 8.5Hz)，10.60(lH，s)，11.21(lH，s)。實施例9(2ml). The reaction mixture was refluxed for 5 hours' and then cooled to room temperature. The resulting precipitate was collected by filtration and washed with ethanol to give a pale black-yellow solid N · (1,3-diketo-1,2,3,4-tetrahydroisoquinolinyl) benzidine (3 7.6 mg) 〇mp. 2 8 8-2 0 0 ° C NMR (DMSO-d6,5): 4.05 (2H, s), 7.5, 7.68 (3H, m), 7.82 (1H, dd, J = 8.5, 2.0Hz) , 7.91 (1Η, d, J = 2.0Hz), 7.93-8.00 (2H, m), 8.00 (1H, d, J = 8.5Hz), 10.60 (lH, s), 11.21 (lH, s) . Example 9

在150 °C攪拌2-(2-胺基-2-酮基乙基）-4-(甲基磺醯基）苯甲酸（3 4 5 m g)於卜甲基-2 -吡咯啶酮（4 m 1)之溶液3小時，然後冷卻至室溫。添加水到混合物並經由過濾收集沉澱物。固體於矽膠以氯仿/甲醇（1 〇 : 1)之混合物爲溶析液經快速管柱色層分析純化。以乙腈硏製所得固體得到灰白色固體6-(甲基磺醯基）-1，3(2Η,4Η)-異喹啉二酮（35.8mg)。 mp.293 -294 〇C NMR(DMS〇-d6，ά )·· 3.29(3H，s)， 4.15(2H，s)， 7.98(1Η， d， J 二8·0Ηζ)，7.99(lH，s)，8·24(1Η，d，J = 8.0Hz)，11.56(lH，brs)。質量：23 8(M-1) + 實施例1 0 在室溫氮氣氛下將硼氫化鈉（93.9mg)添加至 1，3(2H，4H)-異喹啉二酮（200mg)於甲醇（15ml)及二氯甲烷 (3 5 ml)之溶液。在室溫攪拌反應混合物18小時，然後在真空中濃縮。添加氯仿及1 N -氫氯酸至殘留物。以鹽水淸 -37- 200306817Stir 2- (2-amino-2-ketoethyl) -4- (methylsulfonyl) benzoic acid (3 4 5 mg) at 150 ° C at 150 ° C (4 m 1 ) Solution for 3 hours and then cooled to room temperature. Water was added to the mixture and the precipitate was collected via filtration. The solid in silica gel was purified by chromatographic analysis of a fast column using a mixture of chloroform / methanol (10: 1) as the eluent. The obtained solid was made by acetonitrile to obtain 6- (methylsulfonyl) -1,3 (2-1,4Η) -isoquinolinedione (35.8 mg) as an off-white solid. mp.293 -294 〇C NMR (DMS〇-d6,) · 3.29 (3H, s), 4.15 (2H, s), 7.98 (1Η, d, J 2 8. 0Ηζ), 7.99 (lH, s ), 8.24 (1Η, d, J = 8.0 Hz), 11.56 (lH, brs). Mass: 23 8 (M-1) + Example 10 0 Sodium borohydride (93.9 mg) was added to 1,3 (2H, 4H) -isoquinolinedione (200 mg) in methanol ( 15 ml) and dichloromethane (35 ml). The reaction mixture was stirred at room temperature for 18 hours and then concentrated in vacuo. Add chloroform and 1 N-hydrochloric acid to the residue. Take salt water -37- 200306817

洗分開之有機層，經硫酸鎂乾燥，然後於真空中蒸發。殘留物於矽膠以氯仿/甲醇（2 0 :1)之混合物爲溶析液經快速管柱色層分析純化。以二乙基醚硏製所得產物得到灰白色固體 1(2H)-異喹啉—丽（66.1mg)。 mp.210.5-211.5〇C NMR(DMSO-d6, ο )： 6·55(1Η， d， J 二 7 · 0 Η ζ)， 7 · 1 7 (1 Η， t， J=7.0Hz)，7.48(lH，t，J = 8.0Hz)，7.66(lH，t，J = 8.0Hz)，7.66-7.75(lH，m)，8.18(1Η，d，J = 8.0Hz)，11.25(lH，brs)。質量：146(M+1) + 實施例1 1The separated organic layer was washed, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by flash column chromatography on silica gel using a mixture of chloroform / methanol (20: 1) as the eluent. The obtained product was made by diethyl ether to obtain an off-white solid 1 (2H) -isoquinoline-reid (66.1 mg). mp. 210.5-211.5 ° C NMR (DMSO-d6, ο): 6.55 (1Η, d, J 2 7 · 0 Η ζ), 7 · 1 7 (1 Η, t, J = 7.0Hz), 7.48 (lH, t, J = 8.0Hz), 7.66 (lH, t, J = 8.0Hz), 7.66-7.75 (lH, m), 8.18 (1Η, d, J = 8.0Hz), 11.25 (lH, brs) . Mass: 146 (M + 1) + Example 1 1

在室溫氮氣氛下將硼氫化鈉（1 4 1 m g)添加至1，3 (2 H，4 H)-異喹啉二酮（3 00mg)於甲醇（20ml)及二氯甲烷（45ml)之溶液。在室溫攪拌反應混合物1 5小時，然後在真空中濃縮。添加氯仿及水至殘留物。以鹽水淸洗分開之有機層，經硫酸鎂乾燥’然後於真空中蒸發。殘留物於矽膠以氯仿/甲醇（1 0 :1)之混合物爲溶析液經快速管柱色層分析純化。以二乙基醚硏製所得產物得到淺黃色固體3 -羥基-3,4 -二氫-1(2H)-異喹啉二酮（30.3mg)。 mp.l 10-1 12°C NMR(DMSO-d6, ά ): 2.89(1Η, dd, J = 16.0, 2.5Hz), 3.16(1Η, dd, J 二 16.0， 4·0Ηζ)， 5.02-5.08(lH，m)， 5·80(1Η， d， J = 4.5Hz)， 7·30(1Η，d，J = 7.5Hz)，7.34(1H，t，J = 7.5Hz)，7.48(1H, dt， J 一 1.5，7.5Hz)，7.86(1H，dd，J = 7.5, 1.5Hz)，8.45(1H, d， J 二 3.5Hz)。 200306817 質量：164(M+1) + 眚施例1 2Add sodium borohydride (1 4 1 mg) to 1,3 (2 H, 4 H) -isoquinolinedione (300 mg) in methanol (20 ml) and dichloromethane (45 ml) under a nitrogen atmosphere at room temperature. Its solution. The reaction mixture was stirred at room temperature for 15 hours and then concentrated in vacuo. Add chloroform and water to the residue. The separated organic layer was washed with brine, dried over magnesium sulfate 'and evaporated in vacuo. The residue was purified by chromatography on a silica gel column using chloroform / methanol (1 0: 1) as the eluent. The obtained product was made with diethyl ether to obtain 3-hydroxy-3,4-dihydro-1 (2H) -isoquinolinedione (30.3 mg) as a pale yellow solid. mp.l 10-1 12 ° C NMR (DMSO-d6, ά): 2.89 (1Η, dd, J = 16.0, 2.5Hz), 3.16 (1Η, dd, J 2 16.0, 4 · 0Ηζ), 5.02-5.08 (lH, m), 5.80 (1Η, d, J = 4.5Hz), 7.30 (1Η, d, J = 7.5Hz), 7.34 (1H, t, J = 7.5Hz), 7.48 (1H, dt, J-1.5, 7.5 Hz), 7.86 (1H, dd, J = 7.5, 1.5Hz), 8.45 (1H, d, J 3.5Hz). 200306817 Quality: 164 (M + 1) + Example 1 2

在氮氣氛下將1，3(2H，4H) -異喹啉二酮（200mg)及碳酸鉀（3 5 2mg)懸浮於Ν,Ν·二甲基甲醯胺（4ml)並冷卻至（TC。在0°C將碘甲烷（0.155ml)添加至懸浮液，在室溫攪拌懸浮液3.5小時。在0t添加1N-氫氯酸至混合物，然後以乙酸乙酯萃取混合物（兩次）。以水及鹽水淸洗合倂之有機層，經硫酸鎂乾燥，然後於真空中蒸發。殘留物於矽膠以氯仿/甲醇（20 : 1)之混合物爲溶析液經快速管柱色層分析純化。以二乙基醚/異丙基醚之混合物硏製所得產物得到灰白色固體4,4-二甲基-1，3(2H，4H)-異喹啉二酮（76.8mg)。 mp.l 15.5-1 17°C NMR(DMSO-d6, 5 ): 1.53(6H，s)， 7 · 4 5 - 7 · 5 1 (1 Η，m), 7.68- 實施例1 3In a nitrogen atmosphere, 1,3 (2H, 4H) -isoquinolinedione (200 mg) and potassium carbonate (35 2 mg) were suspended in N, N · dimethylformamide (4 ml) and cooled to (TC Methyl iodide (0.155 ml) was added to the suspension at 0 ° C, and the suspension was stirred at room temperature for 3.5 hours. 1N-hydrochloric acid was added to the mixture at 0t, and then the mixture was extracted with ethyl acetate (twice). The combined organic layer was washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by flash column chromatography on silica gel using a chloroform / methanol (20: 1) mixture as the eluent. The obtained product was digested with a mixture of diethyl ether / isopropyl ether to obtain 4,4-dimethyl-1,3 (2H, 4H) -isoquinolinedione (76.8 mg) as an off-white solid. Mp.l 15.5 -1 17 ° C NMR (DMSO-d6, 5): 1.53 (6H, s), 7 · 4 5-7 · 5 1 (1 Η, m), 7.68- Example 1 3

將經基胺氯化氫（1.26g)於乙醇（2ini)及水（2mi)之溶液逐滴添加至1，3 - 一氫-2 Η -茚-2 -酮（2 g)於吡啶（6 m丨）之溶液。在室溫攪拌混合物3小時。添加水到混合物，經由過濾收集所得沉ί殿物得到灰白色固體1，3-二氫-2Η-茚-2-酮肟 (1.93g)。 mp.1 5 4 - 1 5 5.5 °C NMR(DMSO-d65(5): 3.69(4H, d, J^5.5Hz), 7 .1 7-7.25 (2H, m), 7.2 5 - 7. 3 5 (2H，m)，10.66(lH，s)。實施例1 4 -39- 200306817A solution of ammonium hydrogen chloride (1.26g) in ethanol (2ini) and water (2mi) was added dropwise to 1,3-monohydro-2 fluorene-indene-2-one (2 g) in pyridine (6 m 丨) Solution. The mixture was stirred at room temperature for 3 hours. Water was added to the mixture, and the obtained precipitate was collected by filtration to obtain 1,3-dihydro-2fluorene-indene-2-one oxime (1.93 g) as an off-white solid. mp.1 5 4-1 5 5.5 ° C NMR (DMSO-d65 (5): 3.69 (4H, d, J ^ 5.5Hz), 7.1 7-7.25 (2H, m), 7.2 5-7. 3 5 (2H, m), 10.66 (lH, s). Example 1 4 -39- 200306817

在- 30°C氮氣氛下將五氯化磷（2.23g)添加到1，3-二氫-2H-茚-2-酮肟（1.5g)於氯仿（45ml)之溶液。在-30°C攪拌混合物10分鐘，在室溫攪拌3小時，然後倒入冰水中。以鹽水淸洗分開之有機層，經硫酸鎂乾燥，然後於真空中蒸發。殘留物於矽膠以氯仿/甲醇（20 :1)之混合物爲溶析液經快速管柱色層分析純化。以二乙基醚/乙醇之混合物硏製所得產物得到灰白色固體 1，4 -二氫-3 (2 Η)-異喹_ _ (735_6mg) 〇Phosphorus pentachloride (2.23 g) was added to a solution of 1,3-dihydro-2H-indane-2-one oxime (1.5 g) in chloroform (45 ml) under a nitrogen atmosphere at -30 ° C. The mixture was stirred at -30 ° C for 10 minutes, then at room temperature for 3 hours, and then poured into ice water. The separated organic layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by chromatography on a silica gel column using chloroform / methanol (20: 1) as the eluent. The obtained product was prepared by diethyl ether / ethanol mixture to obtain 1,4-dihydro-3 (2 Η) -isoquine _ (735_6 mg) as an off-white solid.

m p . 1 5 4 - 1 5 5 °C NMR(DMS〇-d6，（5): 3.43(2H，s)，4.33(2H，s)，7·15-7·29(4Η，ιη)， 8.00(lH，brs)。質量：148(M+1) + 實施例 1 5mp. 1 5 4-1 5 5 ° C NMR (DMS 0-d6, (5): 3.43 (2H, s), 4.33 (2H, s), 7.15-7 · 29 (4Η, ιη), 8.00 (lH, brs). Mass: 148 (M + 1) + Example 1 5

在周圍溫度3atm氫氣下攪拌2-(;氧基異喹啉二酮（165 mg)及10 %鈀/碳（12.3 mg)於甲醇（5 ml)之混合物1 · 5小時。透過賽力特矽藻土墊過濾反應混合物，然後在真空濃縮濾液。以乙醇淸洗所得固體得到淺灰色固體 2-羥基-1，3(2H，4H)-異喹啉二酮（40.2mg)。 m p . 1 8 9 - 1 9 0 °C NMR(DMSO-d6, 5 ): 4.27(2H，s)， 7.39(1H， d, J:8.0Hz)， 7.48(1H，t, J = 8.0Hz)，7.66(1H，t，J = 8.0Hz), 8.03(1H，d， J = 8.0Hz)，1 1.40(lH，s)。質量：176(M-1) + 實施例1 6 -40- 200306817 热热訊下冷卻 5 -硝基- ΙΗ-卩彳丨卩朵-2,3*•二醒（300mg)於 N，N -二甲基甲醯胺（3ml)之溶液至0°C。在0°C逐滴添加氫化鈉（6 0 %礦物油懸浮液，7 4.9 m g)到該溶液，在室溫攪泮混合物1 5分鐘。然後在室溫添加（溴甲基）苯（〇 . 2 〇 4 m 1)到該溶液，在周圍溫度攪拌混合物4小時。添加水至混合物，並以乙酸乙酯萃取混合物。以飽和氯化銨水溶液、水（兩次）及鹽水淸洗分開之有機層，經硫酸鎂乾燥，然後於真空中蒸發。殘留物於矽膠以正-己烷/乙酸乙酯（3:1 —1:1)之爲溶析液經快速管柱色層分析純化。所得黃色非結晶形從二乙基醚結晶得到橘色固體1-苄基-5-硝基-1H-呵哚-2,3-二酮（3 08.3mg)。 mp· 1 7 5 - 1 7 6.5 t： NMR(DMS〇-d6,5)·· 5.00(2H，s), 7·14(1Η, d, J二8·5Ηζ), 7.25· 7.39(3H，m)，7·47(2Η, d，J = 7.0Hz)，8·27(1Η, d, J = 2.5Hz)， 8.45(1H, dd, J = 8.5, 2.5Hz)。實施例1 7 以類似實施例1 6之方法得到下列（1)至（丨3 )化合物。 (1) 5-硝基-1-(4-硝基苄基）-11^〇弓丨哚-2,3-二酮 mp.220.5 -222 t： NMR(DMSO-d6, 5 ): 5.17(2H,s), 7.13(1H, d， J = 8.5Hz)， 7.77(2H, d，J=9.0Hz)，8.22(2H，d，J = 9.0Hz), 8.3〇(ih，d， J = 2.5Hz)，8.45(1H，d d, J = 8.5，2.5 H z)。質量：3 26 (M-1) + (2) 5-硝基-1-(3-硝基苄基）-1 H-D弓丨哚-2,3-二酮 200306817Stir 2-(; oxyisoquinolinedione (165 mg) and 10% palladium / carbon (12.3 mg) in methanol (5 ml) for 1.5 hours at ambient temperature of 3 atm hydrogen. Pass through Celite Silicon The reaction mixture was filtered through a celite pad, and the filtrate was concentrated in vacuo. The resulting solid was washed with ethanol to give 2-hydroxy-1,3 (2H, 4H) -isoquinolinedione (40.2 mg) as a light gray solid. Mp. 1 8 9-190 ° C NMR (DMSO-d6, 5): 4.27 (2H, s), 7.39 (1H, d, J: 8.0Hz), 7.48 (1H, t, J = 8.0Hz), 7.66 (1H , T, J = 8.0 Hz), 8.03 (1H, d, J = 8.0 Hz), 1 1.40 (lH, s). Mass: 176 (M-1) + Example 1 6 -40- 200306817 Cool a solution of 5 -nitro- 1Η- 卩彳丨卩彳 -2,3 * • dioxine (300mg) in N, N-dimethylformamide (3ml) to 0 ° C. At 0 ° C Sodium hydride (60% mineral oil suspension, 7 4.9 mg) was added dropwise to the solution, and the mixture was stirred at room temperature for 15 minutes. Then (bromomethyl) benzene (0.24 m1) was added at room temperature. ) To this solution, stir the mixture at ambient temperature for 4 hours. Add water to the mixture, and extract the mixture with ethyl acetate. Saturate ammonium chloride water The separated organic layer was washed with solution, water (twice) and brine, dried over magnesium sulfate, and then evaporated in vacuo. The residue was subjected to silica gel with n-hexane / ethyl acetate (3: 1-1: 1). The eluate was purified by flash column chromatography. The obtained yellow amorphous was crystallized from diethyl ether to obtain an orange solid 1-benzyl-5-nitro-1H-oxolin-2,3-dione ( 3 08.3 mg). Mp · 1 7 5-1 7 6.5 t: NMR (DMS〇-d6,5) · 5.00 (2H, s), 7 · 14 (1, d, J 二 8 · 5Ηζ), 7.25 · 7.39 (3H, m), 7.47 (2Η, d, J = 7.0Hz), 8.27 (1Η, d, J = 2.5Hz), 8.45 (1H, dd, J = 8.5, 2.5Hz). Example 17 In a similar manner to Example 16, the following compounds (1) to (3) were obtained: (1) 5-nitro-1- (4-nitrobenzyl) -11 ^ 〇 2,3-dione mp.220.5 -222 t: NMR (DMSO-d6, 5): 5.17 (2H, s), 7.13 (1H, d, J = 8.5Hz), 7.77 (2H, d, J = 9.0 Hz), 8.22 (2H, d, J = 9.0 Hz), 8.3 (ih, d, J = 2.5 Hz), 8.45 (1H, dd, J = 8.5, 2.5 H z). Mass: 3 26 (M-1) + (2) 5-nitro-1- (3-nitrobenzyl) -1 H-D archindo-2,3-dione 200306817

m p . 1 5 4 - 1 5 5 . 5 °C NMR(DMSO-d6, 5 ): 5.17(2H，s), 7.19(1H， d, J = 8.5Hz)， 7.66(1H，t，J = 8.5Hz)，7.96(1H，d，J:8.5Hz)，8,16(1H，d， J = 8.5Hz)，8.29(1H，d，J = 2.5Hz)，8.41(lH，s)，8.45(1H，dd， J = 8.5, 2.5Hz)。 (3 ) 5 -硝基-1 - (3 -吡啶基甲基）-1 H - D弓丨哚-2,3 -二酮 NMR(DMSO-d6, 5 ): 5.05(2H，s), 7·24(1Η, d， J二9·0Ηζ),mp. 1 5 4-1 5 5 .5 ° C NMR (DMSO-d6, 5): 5.17 (2H, s), 7.19 (1H, d, J = 8.5Hz), 7.66 (1H, t, J = 8.5 Hz), 7.96 (1H, d, J: 8.5Hz), 8,16 (1H, d, J = 8.5Hz), 8.29 (1H, d, J = 2.5Hz), 8.41 (lH, s), 8.45 ( 1H, dd, J = 8.5, 2.5Hz). (3) 5-Nitro-1-(3-pyridylmethyl) -1 H-D archine indole-2,3-dione NMR (DMSO-d6, 5): 5.05 (2H, s), 7 · 24 (1Η, d, J 二 9 · 0Ηζ),

7.38(1H, dd, J-8.5, 5.0Hz), 7.88(1H? d, J = 8.0Hz)? 8.28(1H, d, J 二 2.0Hz)，8.47(1H，dd，J二9.0，2.0Hz)，8.51(1H，dd，J = 5.0, 2.0Hz)，8.72(1H, d，J = 2.0Hz)。7.38 (1H, dd, J-8.5, 5.0Hz), 7.88 (1H? D, J = 8.0Hz)? 8.28 (1H, d, J = 2.0Hz), 8.47 (1H, dd, J = 9.0, 2.0Hz) ), 8.51 (1H, dd, J = 5.0, 2.0Hz), 8.72 (1H, d, J = 2.0Hz).

(4) 1-(4-溴苄基）-5-硝基-1H-D弓丨哚-2,3-二酮 mp. 1 8 2- 1 8 3 〇C NMR(DMS〇-d6, (5 ): 4.98(2H，s), 7.13(1H, d, J = 9.0Hz)， 7.44(2H，d, J = 8.5Hz)，7.55(2H，d，J二8.5Hz)，8.27(1H，d, J 二 2.5Hz)，8.45(1H, dd，J 二 9.0, 2.5Hz)。(4) 1- (4-bromobenzyl) -5-nitro-1H-D archine indole-2,3-dione mp. 1 8 2- 1 8 3 〇C NMR (DMS〇-d6, ( 5): 4.98 (2H, s), 7.13 (1H, d, J = 9.0Hz), 7.44 (2H, d, J = 8.5Hz), 7.55 (2H, d, J = 8.5Hz), 8.27 (1H, d, J 2 2.5 Hz), 8.45 (1H, dd, J 2 9.0, 2.5 Hz).

(5) 1-(2-氟苄基）-5-硝基-1H-呵哚-2,3-二酮 m p . 1 6 4 - 1 6 5 °C NMR(DMS〇-d6，（5 ): 5.04(2H,s), 7. 16(1H, t, J = 7.5Hz), 7.22(1H, d，J二9.0Hz), 7.21-7.3 l(lH，m)，7.33-7.43(lH，m)， 7·52(1Η, dt，J 二1.5，7.5Hz)，8.28(1H，d，J = 2.5Hz)，8.49(1H, dd, J = 9.0, 2.5Hz) ° (6) 1-(4-溴-2-氟苄基）-5-硝基-1H-口弓丨哚-2,3-二酮 m ρ · 1 8 4 - 1 8 5 t NMR(DMSO-d6, 5 ): 5.00(2H，s), 7.23(1H, d, J = 8.5Hz), -42- 200306817 7.39(1H，dd，J = 8.0，2·0Ηζ)，7·51(1Η，t，J:8.0Hz), 7·62(1Η, dd，J = 9.5，2·0Ηζ), 8·28(1Η, d，J二2.5Hz)，8.48(1H，dd, J = 8.5, 2.5Hz”(5) 1- (2-fluorobenzyl) -5-nitro-1H-oxadole-2,3-dione mp. 1 6 4-16 5 ° C NMR (DMS〇-d6, (5) : 5.04 (2H, s), 7. 16 (1H, t, J = 7.5Hz), 7.22 (1H, d, J = 9.0Hz), 7.21-7.3 l (lH, m), 7.33-7.43 (lH, m), 7.52 (1Η, dt, J 1.5, 7.5Hz), 8.28 (1H, d, J = 2.5Hz), 8.49 (1H, dd, J = 9.0, 2.5Hz) ° (6) 1- (4-Bromo-2-fluorobenzyl) -5-nitro-1H-orthogonal indole-2,3-dione m ρ · 1 8 4-1 8 5 t NMR (DMSO-d6, 5): 5.00 (2H, s), 7.23 (1H, d, J = 8.5Hz), -42- 200306817 7.39 (1H, dd, J = 8.0, 2 · 0Ηζ), 7.51 (1Η, t, J: 8.0Hz ), 7.62 (1Η, dd, J = 9.5, 2.00 · ζ), 8.28 (1Η, d, J = 2.5Hz), 8.48 (1H, dd, J = 8.5, 2.5Hz "

(7) 5-硝基-1-(2-硝基苄基）-1H-吲哚-2,3-二酮 mp.199-200 °C NMR(DMS〇-d6,(5):5.36(2H，s)，7.22(lH，d，J = 8.5Hz)，7.54-7.71(2H，m)，7.75(1H，dd, J = 8.0Hz)， 8.23(1H，dd，J = 8.0, 1.5Hz), 8.32(1H，d，J = 2.5Hz)，8.44(1H, dd，J二8.5，2.5Hz)。質量：326(M-1) +(7) 5-nitro-1- (2-nitrobenzyl) -1H-indole-2,3-dione mp. 199-200 ° C NMR (DMS 0-d6, (5): 5.36 ( 2H, s), 7.22 (lH, d, J = 8.5Hz), 7.54-7.71 (2H, m), 7.75 (1H, dd, J = 8.0Hz), 8.23 (1H, dd, J = 8.0, 1.5Hz ), 8.32 (1H, d, J = 2.5Hz), 8.44 (1H, dd, J = 8.5, 2.5Hz). Mass: 326 (M-1) +

(8) 1-(2-甲基苄基）-5-硝基-1H-B弓丨哚-2,3-二酮 mp.l 82.5 - 1 8 3 〇C NMR(DMSO-d6, 5 ): 2 · 3 9 (3 H，s)， 4 · 9 5 (2 H，s)， 7.0 6 (1 H， d， J = 8.5Hz)， 7.10(1H， t, J = 7.5Hz)， 7·19(1Η， t， J = 7.5Hz)， 7.24(1H，d，J = 7.5Hz), 7.30(1H，d，J = 7.5Hz)，8.30(1H，d， J = 2.5Hz)，8.45(1H，dd，J = 8.5，2.5Hz)。(8) 1- (2-methylbenzyl) -5-nitro-1H-B, indole-2,3-dione mp. 1 82.5-1 8 3 〇C NMR (DMSO-d6, 5) : 2 · 3 9 (3 H, s), 4 · 9 5 (2 H, s), 7.0 6 (1 H, d, J = 8.5Hz), 7.10 (1H, t, J = 7.5Hz), 7 19 (1Η, t, J = 7.5Hz), 7.24 (1H, d, J = 7.5Hz), 7.30 (1H, d, J = 7.5Hz), 8.30 (1H, d, J = 2.5Hz), 8.45 (1H, dd, J = 8.5, 2.5Hz).

(9) 5-硝基-1-(4-吡啶基甲基）-1 H-呵哚-2,3-二酮 m p . 1 8 4 · 5 -1 8 5 . 5 °C NMR(DMS〇-d6, 5 ): 5.06(2H，s), 7.1 1(1H, d， J = 8.5Hz), 7.49(2H，d，J = 5.5Hz), 8·30(1Η，d，J = 2.0Hz), 8·45(1Η，dd， J = 8.5，2.0Hz)，8.53(2H，d，J = 5.5Hz)。質量：284(M+1)+ '(9) 5-nitro-1- (4-pyridylmethyl) -1 H-oxolin-2,3-dione mp. 1 8 4 · 5 -1 8 5 .5 ° C NMR (DMS. -d6, 5): 5.06 (2H, s), 7.1 1 (1H, d, J = 8.5Hz), 7.49 (2H, d, J = 5.5Hz), 8.30 (1Η, d, J = 2.0Hz ), 8.45 (1Η, dd, J = 8.5, 2.0Hz), 8.53 (2H, d, J = 5.5Hz). Quality: 284 (M + 1) + '

(10) 5 -硝基-1-(2-¾ Π定基甲基弓丨卩朵-2,3 -二醒 m p . 1 7 4 - 1 7 5 °C NMR(DMSO-d6, δ ): 5.10(2H,s), 7·22(1Η， d， J = 8.5Hz)， 200306817 7·32(1Η，dd, J = 7.5，4.5Hz)，7.54(1H，d，J:7.5Hz)，7·70(1Η， dt，J = 2.0，7·5Ηζ), 8.29(1H，d，J二2·5Ηζ)，8·48(1Η, dd，J = 8.5, 2·5Ηζ)，8·52(1Η，dd，J = 4.5，2.0Hz)。質量：2 84 (M+1) +(10) 5 -Nitro-1- (2-¾ hydradinylmethyl bow) 卩 -2,3-dioxine mp. 1 7 4-1 7 5 ° C NMR (DMSO-d6, δ): 5.10 (2H, s), 7.22 (1Η, d, J = 8.5Hz), 200306817 7 · 32 (1Η, dd, J = 7.5, 4.5Hz), 7.54 (1H, d, J: 7.5Hz), 7 · 70 (1Η, dt, J = 2.0, 7.5Ηζ), 8.29 (1H, d, J = 2.52ζ), 8.48 (1Η, dd, J = 8.5, 2.5, ζ), 8.52 ( 1Η, dd, J = 4.5, 2.0Hz). Mass: 2 84 (M + 1) +

(1 1)1-(4-硝基苄基）-5-(三氟甲基）-1 Η-呵哚-2,3-二酮 mp.265-266 °C NMR(DMSO-d6, (5 ): 5.49(2H，s), 7·05(1Η， d， J = 8.5Hz)，(1 1) 1- (4-nitrobenzyl) -5- (trifluoromethyl) -1 fluorene-oxindole-2,3-dione mp.265-266 ° C NMR (DMSO-d6, ( 5): 5.49 (2H, s), 7.05 (1Η, d, J = 8.5Hz),

7·75(2Η，d，J = 8.5Hz)，8·01(1Η, d，J = 2.0Hz)，8·22(1Η，dd, J = 8.5, 2.0Hz), 8.27(2H, d，J = 8.5Hz)。7.75 (2Η, d, J = 8.5Hz), 8.01 (1Η, d, J = 2.0Hz), 8.22 (1Η, dd, J = 8.5, 2.0Hz), 8.27 (2H, d, J = 8.5Hz).

(12) 1-(4-溴-2-氟苄基）-5-(三氟甲氧基）-lH-吲哚-2,3-二酮 mp.l 37.5 - 1 3 8 〇C NMR(DMSO-d6, 5 ): 4.93(2H，s), 7·09(1Η， d， J = 9.5Hz)， 7.38(lH,dd，J = 8.0，2.0Hz),7.49(lH，t，J = 8.0Hz)，7.57-7.68(3H，m)。(12) 1- (4-bromo-2-fluorobenzyl) -5- (trifluoromethoxy) -lH-indole-2,3-dione mp. L 37.5-1 3 8 ° C NMR ( DMSO-d6, 5): 4.93 (2H, s), 7.09 (1Η, d, J = 9.5Hz), 7.38 (lH, dd, J = 8.0, 2.0Hz), 7.49 (lH, t, J = 8.0 Hz), 7.57-7.68 (3H, m).

(13) 1-(4-硝基苄基）-5-(三氟甲氧基）-1Η-卩弓丨哚-2,3-二酮 mp.150-150.5 °C NMR(DMS〇-d6， 5 )·· 5.09(2H，s)， 7·01(1Η， d， J = 8.5Hz), 7.16(1H，d，J = 8.5Hz)，7.56(lH，s)，7·75(2Η，d，J = 9.0Hz)， 8.21(2H，d，J = 9.0Hz)。質量：3 65 (M-1) + 實施例1 8 氮氣氛下冷卻1H-吲哚-2,3-二酮（300mg)於N，N-二甲基甲醯胺（3 ml)之溶液至0°C。在逐滴添加氫化鈉（60% 礦物油懸浮液，81.6mg)到該溶液，在室溫攪拌混合物40 • 44- 200306817 分鐘。然後在室溫添加苯甲醯氯（0.23 7ml)到該溶液，在周圍溫度攪拌混合物3 0分鐘。添加冰水至混合物，經由過濾收集沉澱物。以水及乙醇淸洗固體得到黃色固體1 -苄基-111-口弓[口朵-2,3-二酮（394.61112)。 mp.203 -205 t： NMR(DMSO-d6, δ ): 7.39(1Η, t, J = 7.5Hz)， 7.52(2Η, t, J = 7.5Hz)，7·67(1Η，t, J = 7.5Hz)，7.79(1Η，d，J = 7.5Hz)， 7.80(1H，t，J = 7.5Hz)，7·89(2Η，d，J = 7.5Hz)，7·94(1Η，d， J = 7.5Hz)。竇施例1 9 在室溫氮氣氛下逐份添加（三苯基亞磷基）乙酸第三丁酯（4 3 7 mg)到1-(4-溴-2-氟苄基）-5-(三氟甲氧基）-1Η-吲哚-2,3-二酮（400mg)於四氫呋喃（8ml)之溶液。在60°C攪拌反(13) 1- (4-Nitrobenzyl) -5- (trifluoromethoxy) -1Η-pyrenoline indole-2,3-dione mp. 150-150.5 ° C NMR (DMS〇-d6 , 5) · 5.09 (2H, s), 7.01 (1Η, d, J = 8.5Hz), 7.16 (1H, d, J = 8.5Hz), 7.56 (lH, s), 7.75 (2Η , D, J = 9.0 Hz), 8.21 (2H, d, J = 9.0 Hz). Mass: 3 65 (M-1) + Example 1 8 A solution of 1H-indole-2,3-dione (300 mg) in N, N-dimethylformamide (3 ml) was cooled under a nitrogen atmosphere to 0 ° C. Add sodium hydride (60% mineral oil suspension, 81.6 mg) to the solution dropwise and stir the mixture at room temperature for 40 • 44-200306817 minutes. Then benzamidine chloride (0.23 7 ml) was added to the solution at room temperature, and the mixture was stirred at ambient temperature for 30 minutes. Ice water was added to the mixture, and the precipitate was collected by filtration. The solid was washed with water and ethanol to obtain 1-benzyl-111-portal bow [Kuduo-2,3-dione (394.61112) as a yellow solid. mp.203 -205 t: NMR (DMSO-d6, δ): 7.39 (1Η, t, J = 7.5Hz), 7.52 (2Η, t, J = 7.5Hz), 7.67 (1Η, t, J = 7.5Hz), 7.79 (1Η, d, J = 7.5Hz), 7.80 (1H, t, J = 7.5Hz), 7.89 (2Η, d, J = 7.5Hz), 7.94 (1Η, d, J = 7.5Hz). Dou Example 1 9 Add tributyl (triphenylphosphino) acetate (4 37 mg) to 1- (4-bromo-2-fluorobenzyl) -5- in portions under nitrogen at room temperature. (Trifluoromethoxy) -1H-indole-2,3-dione (400 mg) in tetrahydrofuran (8 ml). Stir at 60 ° C

應混合物2小時，然後在真空中濃縮。殘留物於矽膠以正 -己烷/乙酸乙酯（3:1)之混合物爲溶析液經快速管柱色層分析純化。以乙醇硏製所得產物得到黃色固體（2EM 1-(4-溴-2-氟苄基）-5-硝基-2-酮基-1，2 -二氫- 3H·亞吲哚啉-3-基]乙醇酸第三丁酯（294.1 mg)。 mp.150-151.5°C NMR(DMSO-d6, ό ): 1.58(9H，s)， 5.07(2H，s), 6.83(lH,s), 7.22(1H, d, J = 9.0Hz), 7.30(1H, t, J = 8.0Hz), 7.38(1H, dd, J = 8.0, 2.0Hz), 7.60(1H, dd, J=l〇.〇, 2.0Hz), 8.36(1H, dd, J = 9.0，2.5Hz)，9.22(1H，d, J二2.5Hz)。實施例2 0 -45- 200306817The mixture should be left for 2 hours and then concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using a mixture of n-hexane / ethyl acetate (3: 1) as the eluent. The obtained product was subjected to ethanol dehydration to obtain (2EM 1- (4-bromo-2-fluorobenzyl) -5-nitro-2-one-1,2-dihydro-3H · indoline-3. -Yl] Thirty-butyl glycolate (294.1 mg). Mp.150-151.5 ° C NMR (DMSO-d6,): 1.58 (9H, s), 5.07 (2H, s), 6.83 (lH, s) , 7.22 (1H, d, J = 9.0Hz), 7.30 (1H, t, J = 8.0Hz), 7.38 (1H, dd, J = 8.0, 2.0Hz), 7.60 (1H, dd, J = 10). 〇, 2.0Hz), 8.36 (1H, dd, J = 9.0, 2.5Hz), 9.22 (1H, d, J = 2.5Hz). Example 2 0 -45- 200306817

以類似實施例19之方法得到（2EM5-硝基-2-酮基-1,2-二氫-3 Η -亞呵哚啉-3 -基）乙醇酸第三丁酯。 m p . 1 6 1 -1 6 2 °C NMR(DMS〇-d6, 5 ): 1.57(9H,s), 6.68(lH,s), 7.07(1H, d, J-8.5Hz), 8.30(1H, dd, J = 8.5, 2.5Hz), 9.18(1H, d, J = 2.5Hz), 1 1 . 5 0 (1 H，b r s)。質量·· 28 9(M-1) + 實施例2 1In a similar manner to Example 19, (2EM5-nitro-2-keto-1,2-dihydro-3'-oxolinolin-3-yl) glycolic acid tert-butyl ester was obtained. mp. 1 6 1 -1 6 2 ° C NMR (DMS〇-d6, 5): 1.57 (9H, s), 6.68 (lH, s), 7.07 (1H, d, J-8.5Hz), 8.30 (1H , dd, J = 8.5, 2.5Hz), 9.18 (1H, d, J = 2.5Hz), 1 1. 5 0 (1 H, brs). Mass · 28 9 (M-1) + Example 2 1

在0°C添加三氟乙酸（lml)到（2E^[M4-溴-2-氟苄基）-5 -硝基-2 -酮基-1，2 -二氫-3 Η -亞吲哚啉-3 -基]乙醇酸第三丁酯（100mg)於二氯甲烷（〇·5 ml)之溶液。在室溫攪拌混合物 3 0分鐘，然後在真空中濃縮。以乙醇淸洗所得固體得到黃色固體（2E)-[ 1-(4-溴-2-氟苄基）-5-硝基-2-酮基-1，2-二氫 -3H-亞吲哚啉-3-基]乙醇酸（62.9mg)。 mp.214-214.5°CAdd trifluoroacetic acid (lml) to (2E ^ [M4-bromo-2-fluorobenzyl) -5 -nitro-2 -keto-1,2-dihydro-3 hydrazone -indole at 0 ° C Phenolin-3-yl] glycolic acid tert-butyl ester (100 mg) in dichloromethane (0.5 ml). The mixture was stirred at room temperature for 30 minutes and then concentrated in vacuo. The obtained solid was washed with ethanol to obtain (2E)-[1- (4-bromo-2-fluorobenzyl) -5-nitro-2-one-1,2-dihydro-3H-indole Phenolin-3-yl] glycolic acid (62.9 mg). mp.214-214.5 ° C

NMR(DMSO-d6, δ ): 5 · 0 7 (2 Η，s)， 6 · 9 1 (1 Η , s)， 7 · 2 2 (1 Η， d， J=9,0Hz)，7·30(1Η，t，J = 8.0Hz)，7·38(1Η，dd，J = 8.0, 2·0Ηζ)， 7·60(1Η，dd，J = 10.0，2·0Ηζ)，8·35(1Η, dd，J = 9.〇，2·5Ηζ)， 9.28(1H，d，J二2.5Hz)，13.84(lH,brs)。質量：419(M-1) + 實施例2 2 以類似實施例21之方法得到（2EM5-硝基-2-酮基-1，2-二氫-3 Η -亞吲哚啉-3 -基）乙醇酸。 NMR(DMSO-d6, <5 ): 6.77(lH，s)， 7.07(1H， d， J:9.0Hz)， -46- 200306817 8·30(1Η， dd， J = 9.0， 2.5Hz), 9·24(1Η, d， J:2.5Hz)， 1 1.49(lH，s), 13.70(lH，brs)。質量：23 3 (M-1) + 實施例2 3NMR (DMSO-d6, δ): 5 · 0 7 (2 Η, s), 6 · 9 1 (1 Η, s), 7 · 2 2 (1 Η, d, J = 9, 0Hz), 7 · 30 (1Η, t, J = 8.0Hz), 7.38 (1Η, dd, J = 8.0, 2.00Ηζ), 7.60 (1Η, dd, J = 10.0, 2.00Ηζ), 8.35 ( 1Η, dd, J = 9.0, 2.5Ηζ), 9.28 (1H, d, J = 2.5Hz), 13.84 (lH, brs). Mass: 419 (M-1) + Example 2 2 (2EM5-nitro-2-keto-1,2-dihydro-3 fluorene-indolinol-3-yl group was obtained in a similar manner to that in Example 21. ) Glycolic acid. NMR (DMSO-d6, < 5): 6.77 (lH, s), 7.07 (1H, d, J: 9.0Hz), -46- 200306817 8 · 30 (1Η, dd, J = 9.0, 2.5Hz), 9 · 24 (1Η, d, J: 2.5Hz), 1 1.49 (lH, s), 13.70 (lH, brs). Mass: 23 3 (M-1) + Example 2 3

在氮氣氛下混合2H-吡啶并[2,3-d][l，3]P§哄_2,4(1H)-二酮（8〇0mg)，5-硝基-1H-U弓ί 哚-2,3-二酮（93 7mg)，1，3-二異丙基碳二酿胺（0.7631111)，1-甲基六氫壯11定（1.931112)及口比啶（3.5ml)。在100°C攪拌下加熱混合物1.5小時，然後冷卻到室溫。添加甲醇（2 0 m 1)至混合物。經由過濾收集所得沉澱物，以甲醇淸洗得到棕色固體9-硝基吡啶幷[2，，3, ：4,5] 嘧啶并[l，2-a]吲哚-5,1卜二酮（515mg)。 m p . > 3 0 0 °C NMR(DMSO-d6,5): 7.71(lH,brs), 8.54-8.79(2H,m), 8.77(2H, d，J=8.0Hz)，9.12(1H, dd, J = 4.5, 2.0Hz)。質量：29 5 (M+1) + 實施例24Mixing 2H-pyrido [2,3-d] [l, 3] P in a nitrogen atmosphere Co_2,4 (1H) -dione (800 mg), 5-nitro-1H-U Indole-2,3-dione (93 7 mg), 1,3-diisopropylcarbodiamine (0.7631111), 1-methylhexahydrozine 11 (1.931112), and oripidine (3.5 ml). The mixture was heated with stirring at 100 ° C for 1.5 hours, and then cooled to room temperature. Methanol (20 ml) was added to the mixture. The resulting precipitate was collected by filtration and washed with methanol to give 9-nitropyridine [2,, 3,: 4,5] pyrimido [l, 2-a] indole-5,1budione as a brown solid ( 515 mg). mp. > 3 0 0 ° C NMR (DMSO-d6,5): 7.71 (lH, brs), 8.54-8.79 (2H, m), 8.77 (2H, d, J = 8.0Hz), 9.12 (1H, dd, J = 4.5, 2.0Hz). Mass: 29 5 (M + 1) + Example 24

加熱4-硝基-1，2-苯二胺（3g)及4-硝基苯甲酸（3.6g)於 ***（1 0 0 m 1)之溶液至回流2小時。冷卻混合物到室溫’倒至冰上並攪拌3 0分鐘。經由過濾收集所得固體，以飽和碳酸氣鈉水溶液、水及甲醇淸洗得到淺綠色固體5_ 硝基-2-(4-硝基苯基）-111-苯并咪唑（2.412)。 mp.>3 00°C NMR(DMS〇-d6,5): 7·84(1Η, d，J:8.5Hz)，8·18(1Η, dd，J二 8.5, 1.5Hz)，8.46(4H，s)，8·56(1Η，d, JUHz)。 200306817 質量：2 8 3 (M-1) + 實施例2 5 以類似實施例24之方法得到下列（1)及（2)化合物。A solution of 4-nitro-1,2-phenylenediamine (3 g) and 4-nitrobenzoic acid (3.6 g) in phosphorus oxychloride (100 m 1) was heated to reflux for 2 hours. The mixture was cooled to room temperature 'and poured onto ice and stirred for 30 minutes. The obtained solid was collected by filtration, and washed with a saturated aqueous solution of sodium carbonate, water and methanol to obtain 5-nitro-2- (4-nitrophenyl) -111-benzimidazole (2.412) as a pale green solid. mp. > 3 00 ° C NMR (DMS〇-d6,5): 7.84 (1Η, d, J: 8.5Hz), 8.18 (1Η, dd, J2 8.5, 1.5Hz), 8.46 ( 4H, s), 8.56 (1Η, d, JUHz). 200306817 Mass: 2 8 3 (M-1) + Example 25 In the same manner as in Example 24, the following compounds (1) and (2) were obtained.

(1) 5-硝基-2-(3-硝基苯基）-111-苯并咪0坐 m p . > 3 0 0 °C NMR(DMS〇-d6，5 ): 7.84(1H, d, J^8.5Hz), 7.91(1H, t, J-8.5Hz), 8.17(1H, dd, J = 8.5, 2.5Hz), 8.41(1H, dd? J = 8.5,(1) 5-nitro-2- (3-nitrophenyl) -111-benzimidol. &Gt; 3 0 0 ° C NMR (DMS〇-d6,5): 7.84 (1H, d , J ^ 8.5Hz), 7.91 (1H, t, J-8.5Hz), 8.17 (1H, dd, J = 8.5, 2.5Hz), 8.41 (1H, dd? J = 8.5,

2.5Hz)，8·54(1Η，d，J 二2.5Hz)，8·66(1Η, d，J 二8.5Hz)，9.05(1H， d，J=2.5Hz)，13.96(lH，brs)。質量：283(M-1) +2.5Hz), 8.54 (1Η, d, J 2.5Hz), 8.66 (1Η, d, J 8.5Hz), 9.05 (1H, d, J = 2.5Hz), 13.96 (lH, brs) . Mass: 283 (M-1) +

(2) 5-硝基-2-(4-硝基苄基）-1 H-苯并咪唑 mp.235 -23 6.5 °C NMR(DMSO-d6, 5 ): 4.45(2H，s)， 7·64(2Η， d， J = 9.0Hz)， 7.68(1H，d，J = 8.5Hz)，8.09(1H，dd，J = 8.5, 2.5Hz)，8.22(2H，d， J = 9.0Hz)，8.43(1H，d，J = 2.5Hz)，13.10(lH，s)。(2) 5-nitro-2- (4-nitrobenzyl) -1 H-benzimidazole mp.235 -23 6.5 ° C NMR (DMSO-d6, 5): 4.45 (2H, s), 7 64 (2Η, d, J = 9.0Hz), 7.68 (1H, d, J = 8.5Hz), 8.09 (1H, dd, J = 8.5, 2.5Hz), 8.22 (2H, d, J = 9.0Hz) , 8.43 (1H, d, J = 2.5Hz), 13.10 (lH, s).

質量：299(M+1) + 實施例2 6 將氯化錫（I I)二水合物（1 lg)添加到5-硝基- 2-(4-硝基苯基ΜΗ-苯并咪唑（2.3g)於濃鹽酸（25ml)之懸浮液。加熱混合物至回流4小時並冷卻到室溫。添加乙醇至溶液。真空中經由過濾收集所得沉澱物。將固體再次溶解於水中，經由添加氫氧化銨之2 8 %水溶液鹼化該溶液。經由過濾收集沉澱得到淺黑綠色固體2- (4 -胺基苯基）-1 Η -苯并咪唑-5 -胺（1.33g)。 -48- 200306817Mass: 299 (M + 1) + Example 2 6 Add tin (II) chloride dihydrate (1 lg) to 5-nitro-2- (4-nitrophenyl MΗ-benzimidazole (2.3 g) Suspension in concentrated hydrochloric acid (25ml). Heat the mixture to reflux for 4 hours and cool to room temperature. Add ethanol to the solution. Collect the resulting precipitate by filtration in vacuo. Dissolve the solid in water again and add ammonium hydroxide The solution was basified with a 28% aqueous solution. The precipitate was collected by filtration to give 2- (4-aminophenyl) -1 hydrazone-benzimidazole-5-amine (1.33 g) as a pale black green solid. -48- 200306817

mp.>300°C NMR(DMS〇-d6,5): 6.47(1H，dd，J 二8.5，2·5Ηζ), 6·63(2Η，d, J二 8·5Ηζ), 6·64(1Η， d， J=2.5Hz)， 7·17(1Η， d， J = 8.5Hz)， 7.73(2H，d，J 二8.5Hz)。質量：225 (M + 1) + 實施例27 以類似實施例26之方法得到下列（1)及（2)化合物。 (1) 2-(3-胺基苯基）-1Η-苯并咪唑-5-胺mp. > 300 ° C NMR (DMS〇-d6,5): 6.47 (1H, dd, J 8.5, 2.5 Ηζ), 6.63 (2 Η, d, J 8 8 · 5Ηζ), 6.64 (1Η, d, J = 2.5Hz), 7.17 (1Η, d, J = 8.5Hz), 7.73 (2H, d, J = 8.5Hz). Mass: 225 (M + 1) + Example 27 In a similar manner to Example 26, the following compounds (1) and (2) were obtained. (1) 2- (3-Aminophenyl) -1H-benzimidazole-5-amine

NMR(DMS〇-d6，5 ): 4.92(2H，s)， 5.21(2H,s)， 6.49(1H， dd， J二8.5，2.0Hz)，6·59(1Η，d，J二7·5Ηζ)，6·61(1Η，d，J = 2.0Hz)， 7.01-7.20(2H,m), 7.25(1H, d， J = 8.5Hz)， 7.3 1(lH，s)， 12.06(lH,s)。質量：225 (M+1) + (2) 2-(4-胺基苄基）-1Η-苯并咪唑-5-胺NMR (DMS 0-d6, 5): 4.92 (2H, s), 5.21 (2H, s), 6.49 (1H, dd, J2 8.5, 2.0Hz), 6.59 (1K, d, J 2 7 · 5Ηζ), 6.61 (1Η, d, J = 2.0Hz), 7.01-7.20 (2H, m), 7.25 (1H, d, J = 8.5Hz), 7.3 1 (lH, s), 12.06 (lH, s). Mass: 225 (M + 1) + (2) 2- (4-aminobenzyl) -1Η-benzimidazole-5-amine

NMR(DMSO-d6, 5 ): 4.91(2H,s), 6.40(1H, dd, J = 8.5, 2.0Hz)? 6.48(2H, d, J=8.5Hz), 6.52(1H, d, J = 2.0Hz), 6.92(2H, d, J二8.5Hz)，7.13(1H, d，J = 8.5Hz)，11.50(lH，s)。質量：23 9 (M+1) + 實施例2 8 在-78 °C氮氣氛下逐滴添加乙醯氯（〇.i66ml)到2-(4 -胺基苯基）-1Η-苯并咪卩坐-5-胺（209mg)及N，N -二異丙基乙基胺 (0.406ml)於四氫呋喃（4.5 ml)之溶液。在室溫攪拌混合物22 小時，並稀釋於乙酸乙酯。以水、飽和碳酸氫鈉水溶液及鹽水淸洗分開之有機溶液。所得固體自N，N -二甲基甲釀 -49- 200306817NMR (DMSO-d6, 5): 4.91 (2H, s), 6.40 (1H, dd, J = 8.5, 2.0Hz)? 6.48 (2H, d, J = 8.5Hz), 6.52 (1H, d, J = 2.0Hz), 6.92 (2H, d, J = 8.5Hz), 7.13 (1H, d, J = 8.5Hz), 11.50 (lH, s). Mass: 23 9 (M + 1) + Example 2 8 Ethyl chloride (0.16 ml) was added dropwise to 2- (4-aminophenyl) -1 fluorenyl-benzimid under a nitrogen atmosphere at -78 ° C. A solution of hydrazine-5-amine (209 mg) and N, N-diisopropylethylamine (0.406 ml) in tetrahydrofuran (4.5 ml). The mixture was stirred at room temperature for 22 hours and diluted in ethyl acetate. Rinse the separated organic solution with water, saturated aqueous sodium bicarbonate solution and brine. The solid obtained was from N, N-dimethylformamide -49- 200306817

胺/水再結晶得到淺棕色固體N-{ 4-[5-(乙醯胺基）-1H-苯并咪唑-2-基]苯基}乙醯胺（40.5mg)。 m p . > 3 0 0 °C NMR(DMS〇-d6, (5 ): 2.0 7 (3 Η，s)， 2 · 0 9 (3 Η，s)， 7 · 2 3 (1 Η， d d , J 二 8.5，1.0Hz)，7·49(1Η, d，J:8.5Hz)，7·74(2Η，d, J 二 8·5Ηζ)， 8.05(1H，d, J=8.5Hz)，8.07(1H，d，J:l.〇Hz)，9.98(lH，s)， 10.19(lH，s)，12.90(lH,brs)。Amine / water recrystallization gave N- {4- [5- (acetamido) -1H-benzimidazol-2-yl] phenyl} acetamidine (40.5 mg) as a light brown solid. mp. > 3 0 ° C NMR (DMS〇-d6, (5): 2.0 7 (3 Η, s), 2 · 0 9 (3 Η, s), 7 · 2 3 (1 Η, dd, J 2 8.5, 1.0 Hz), 7.49 (1Η, d, J: 8.5Hz), 7.74 (2Η, d, J 2 8.5Ηζ), 8.05 (1H, d, J = 8.5Hz), 8.07 (1H, d, J: 1.0 Hz), 9.98 (lH, s), 10.19 (lH, s), 12.90 (lH, brs).

質量：309(M+1) + 實施例2 9Mass: 309 (M + 1) + Example 2 9

在氮氣氛下逐滴添加 2-噻吩碳醯氯（0.267 ml)到2-(4-胺基苯基）_1H-苯并咪唑-5-胺（224mg)於吡啶（2ml)之溶液。在60 °C攪拌混合物6小時，並稀釋於氯仿。以1N-氫氯酸、水及鹽水淸洗分開之有機溶液，經硫酸鎂乾燥，然後於真空中蒸發。所得固體自 N，N-二甲基甲醯胺/水再結晶得到淺黑綠色固體N-(4-丨5-[(2-噻吩基羰基）胺基]-1Η-苯并咪唑 -2-基丨苯基）-2-噻吩甲醯胺（301.8mg)。 m p . > 3 0 0 °C NMR(DMS〇-d6，5 ): 7.21-7.30(2H，m)， 7.78(2H，s)， 7.87- 7.96(2H，m), 8.08(2H，d，J = 8.5Hz)，8.1 卜 8.17(2H，m)，8.24(2H, d, J 二8.5Hz)，8.37(lH，s), 10.58(lH,s)，l〇.71(lH,s)。質量：445 (M+1) + 實施例3 0 以類似實施例29之方法得到下列（1)至（3)化合物。 (1)Ν-[4-(3Η-咪唑[4,5-b]吡啶-2-基）苯基]噻吩甲醯胺 -50- 200306817Under a nitrogen atmosphere, a solution of 2-thiophenecarbamidine chloride (0.267 ml) to 2- (4-aminophenyl) _1H-benzimidazole-5-amine (224 mg) in pyridine (2 ml) was added dropwise. The mixture was stirred at 60 ° C for 6 hours and diluted in chloroform. The separated organic solution was washed with 1N-hydrochloric acid, water, and brine, dried over magnesium sulfate, and evaporated in the air. The obtained solid was recrystallized from N, N-dimethylformamide / water to obtain N- (4- 丨 5-[(2-thienylcarbonyl) amino] -1 羰 -benzimidazole-2- Phenyl) -2-thienformamide (301.8 mg). mp. > 300 ° C NMR (DMS〇-d6,5): 7.21-7.30 (2H, m), 7.78 (2H, s), 7.87- 7.96 (2H, m), 8.08 (2H, d, J = 8.5 Hz), 8.1, 8.17 (2H, m), 8.24 (2H, d, J 2 8.5Hz), 8.37 (lH, s), 10.58 (lH, s), 10.71 (lH, s) . Mass: 445 (M + 1) + Example 30 In the same manner as in Example 29, the following compounds (1) to (3) were obtained. (1) N- [4- (3Η-imidazole [4,5-b] pyridin-2-yl) phenyl] thienolamide -50- 200306817

m p . > 3 0 0 °C NMR(DMSO-d6, o ): 7 . 1 7 - 7.3 3 (2 H , m) ? 7.83-8. 13(3H,m)， 7.93(2H, d， J 二 7.5Hz), 8.23(2H, d, J=7.5Hz), 8.27- 8.42(lH,m)。質量：321(M+1) +mp. > 3 0 ° C NMR (DMSO-d6, o): 7. 1 7-7.3 3 (2 H, m)? 7.83-8. 13 (3H, m), 7.93 (2H, d, J Two 7.5Hz), 8.23 (2H, d, J = 7.5Hz), 8.27- 8.42 (lH, m). Quality: 321 (M + 1) +

(2)N-(3-{5-[(2-噻吩基羰基）胺基；I-1H-苯并咪唑-2-基卜苯基）-2 -噻吩甲醯胺 mp.l 7 5 - 1 8 5 〇C NMR(DMS〇-d6, (5 ): 7.2 1 -7.29 (2H ?m), 7.42-7.67 (3 Η , m), 7.80-7.94(4H,m), 8.03-8.17(3H，m)， 8.60(lH,s)， 10.24(lHxl/3，s)， 1 0.3 0 (1 H x 2 / 3 , s), 10.45(lH，s)， 12.90(lHx2/3，s)，12.94(lHxl/3，s)。質量：445 (M+1) + (3)N-[4-({5-[(2-噻吩基羰基）胺基]-1H-苯并咪唑-2-基卜甲基）苯基）-2-噻吩甲醯胺 mp.1 63 - 1 68。。 · NMR(DMSO-d6, (5 ): 4.14(2H,s), 7 . 1 8 - 7.2 5 (2 Η, m), 7.31(2Η, d, J = 8.5Hz)，7.3 2-7.5 5 (2H，m)，7.66(2H，d，J=8.5Hz),7.81-7.89(2H,m), 7.92-8.07(3H,m), 10.20(lH,brs), 10.22(lH,s), 1 2 · 2 4 (1 H，b r s)。質量：459(M+1) + 實施例3 1 在175°(：加熱2,3-吡啶二胺（12)，4-硝基苯甲酸（1.682) 及多磷酸（10ml)之混合物2小時。冷卻到Ot後，以固體 -51 - 200306817(2) N- (3- {5-[(2-thienylcarbonyl) amino group; I-1H-benzimidazol-2-ylbuphenyl) -2 -thienolamine mp.l 7 5- 1 8 5 ° C NMR (DMS 0-d6, (5): 7.2 1 -7.29 (2H? M), 7.42-7.67 (3 Η, m), 7.80-7.94 (4H, m), 8.03-8.17 (3H , M), 8.60 (lH, s), 10.24 (lHxl / 3, s), 1 0.3 0 (1 H x 2/3, s), 10.45 (lH, s), 12.90 (lHx2 / 3, s), 12.94 (lHxl / 3, s). Mass: 445 (M + 1) + (3) N- [4-({5-[(2-thienylcarbonyl) amino] -1H-benzimidazole-2- Methylmethyl) phenyl) -2-thienformamide mp. 1 63-1 68. . · NMR (DMSO-d6, (5): 4.14 (2H, s), 7. 1 8-7.2 5 (2 Η, m), 7.31 (2Η, d, J = 8.5Hz), 7.3 2-7.5 5 ( 2H, m), 7.66 (2H, d, J = 8.5Hz), 7.81-7.89 (2H, m), 7.92-8.07 (3H, m), 10.20 (lH, brs), 10.22 (lH, s), 1 2 · 2 4 (1 H, brs). Mass: 459 (M + 1) + Example 3 1 at 175 ° (: heating 2,3-pyridinediamine (12), 4-nitrobenzoic acid (1.682) And polyphosphoric acid (10ml) for 2 hours. After cooling to Ot, solid -51-200306817

碳酸鈉調整混合物至中性。經由過濾收集所得沉澱物，並以水淸洗。固體自 N , N -二甲基甲醯胺再結晶得到黃色固體2-(4-硝基苯基）-3H-咪唑[4,5-b]吡啶（2.20g)。 mp.>300°C NMR(DMS〇-d6,(5): 7·13(1Η，dd，J=8.0，5·0Ηζ)，8·11(1Η，dd， J = 8.0, Ι.ΟΗζ)，8·42(1Η，dd，J=5.0， 1.0Hz)，8·43(2Η，d， J=9.0Hz)，8.49(2H，d，J 二9.0Hz)。實施例3 2 將 S . Μ . I (1 g)於乙醇（1 5 m 1)添加到氯化銨（1 5 6 m g)於水 (1.5ml)之溶液。然後在室溫添加鐵（697mg)到該溶液，並回流混合物3小時。冷卻至室溫後，透過賽力特矽藻土墊過濾混合物。在真空濃縮濾液。以水及乙腈淸洗所得固體得到黑黃色固體 4-(3H -咪唑[4,5-b]吡啶-2 -基）苯基胺Sodium carbonate adjusts the mixture to neutral. The resulting precipitate was collected by filtration and washed with water. The solid was recrystallized from N, N-dimethylformamide to give 2- (4-nitrophenyl) -3H-imidazole [4,5-b] pyridine (2.20 g) as a yellow solid. mp. > 300 ° C NMR (DMS 0-d6, (5): 7.13 (1Η, dd, J = 8.0, 5.00Ηζ), 8.11 (1Η, dd, J = 8.0, Ι.ΟΗζ ), 8.42 (1Η, dd, J = 5.0, 1.0Hz), 8.43 (2Η, d, J = 9.0Hz), 8.49 (2H, d, J = 9.0Hz). Example 3 2 S Μ.I (1 g) in ethanol (15 m 1) was added to a solution of ammonium chloride (156 mg) in water (1.5 ml). Then iron (697 mg) was added to the solution at room temperature, and The mixture was refluxed for 3 hours. After cooling to room temperature, the mixture was filtered through a Celite pad. The filtrate was concentrated in vacuo. The resulting solid was washed with water and acetonitrile to give a black-yellow solid 4- (3H-imidazole [4,5- b] pyridin-2-yl) phenylamine

(207.5mg) 0 m p . > 3 0 0 °C(207.5mg) 0 m p. &Gt; 3 0 0 ° C

NMR(DMS〇-d6，5 ): 6.67(2H, d, J^7.5Hz), 7 .1 5 (1 H, b r s), 7.85(lH，brs)，7.90(2H，d，J:7.5Hz)，8.22(lH，brs)。質量：21 1(M+1) + 實施例3 3 過濾 2,2-二羥基-1H-茚-1，3(2H)-二酮（2g)於溫水（40ml) 之溶液以及（2E)-3-胺基-2-丁醇酸甲酯（1.29g)於溫水（26ml) 之溶液至同一燒瓶中。1 3小時後，經由過濾收集所得固體得到灰白色固體（3aS，8bS)-3a，8b-二羥基-2-甲基-4-酮基-1，3 a，4，8 b -四氫茚[1，2 - b ]吡咯-3 -殘酸甲酯（3 .1 g)。 -52- 200306817NMR (DMS〇-d6,5): 6.67 (2H, d, J ^ 7.5Hz), 7.15 (1H, brs), 7.85 (lH, brs), 7.90 (2H, d, J: 7.5Hz ), 8.22 (lH, brs). Mass: 21 1 (M + 1) + Example 3 3 Filtration of a solution of 2,2-dihydroxy-1H-indene-1,3 (2H) -dione (2g) in warm water (40ml) and (2E) A solution of methyl-3-amino-2-butanolate (1.29 g) in warm water (26 ml) was transferred to the same flask. After 13 hours, the resulting solid was collected by filtration to obtain (3aS, 8bS) -3a, 8b-dihydroxy-2-methyl-4-keto-1,3a, 4,8b-tetrahydroindene [ 1,2 -b] Pyrrole-3 -residue methyl ester (3.1 g). -52- 200306817

mp.203-203.5 °C NMR(DMS〇-d6, 5 ): 2.05(3H，s)， 3.51(3H，s)， 5.43(lH，s)， 6.38(lH，s)，7.51-7.56(lH，m)，7.66(1H，d，J-8·0Ηζ)，7·74- 7.82(2H，m)，8.83(1H，s)。質量：27 6(M+1) + 實施例3 4 以類似實施例33之方法得到下列（1)至（9)化合物。mp.203-203.5 ° C NMR (DMS 0-d6, 5): 2.05 (3H, s), 3.51 (3H, s), 5.43 (lH, s), 6.38 (lH, s), 7.51-7.56 (lH M), 7.66 (1H, d, J-8 · 0Ηζ), 7.74-7.82 (2H, m), 8.83 (1H, s). Mass: 27 6 (M + 1) + Example 3 4 In a similar manner to Example 33, the following compounds (1) to (9) were obtained.

(1) (3&3,85幻-33,81)-二羥基-2-甲基-4-酮基-4,81)-二氫-331^ 茚[1,2-b]呋喃-3-羧酸乙酯。(1) (3 & 3,85-33-81) -dihydroxy-2-methyl-4-keto-4,81) -dihydro-331 ^ indene [1,2-b] furan-3 -Ethyl carboxylate.

mp.101-104.5°C NMR(DMS〇-d6, ό ): 0.95(3Hxl/32, t, J二 7.0Hz)， 1.21(3Hx31/32, t, J 二7·0Ηζ), 2 . 1 3 (3 Η x 3 1 / 3 2 , s), 2.42(3Hxl/32,s), 4.0 0 - 4.1 4 (2 Η, m), 6.1 3 (1 Η, b r s), 7.61- 7.89(4H,m)，8.03(lHxl/32,s), 8.05(lHx31/32，s)。質量：2 8 9 (M-1) +mp.101-104.5 ° C NMR (DMS〇-d6, ό): 0.95 (3Hxl / 32, t, J = 7.0Hz), 1.21 (3Hx31 / 32, t, J = 7.0 · 0Ηζ), 2. 1 3 (3 Η x 3 1/3 2, s), 2.42 (3Hxl / 32, s), 4.0 0-4.1 4 (2 Η, m), 6.1 3 (1 Η, brs), 7.61- 7.89 (4H, m ), 8.03 (lHxl / 32, s), 8.05 (lHx31 / 32, s). Mass: 2 8 9 (M-1) +

(2) (3&3,8匕幻-3-乙醯基-3&，813-二羥基-2-甲基-3&，813-二氫-4H -茚[l，2-b]呋喃-4-酮。(2) (3 & 3,8 diphenoxy-3-ethylfluorenyl-3 &, 813-dihydroxy-2-methyl-3 &, 813-dihydro-4H-indene [l, 2-b] furan -4-one.

mp. 1 7 3 - 1 7 5 〇C NMR(DMS〇-d6，ά ): 2.12(3H，s)， 2.39(3H，s)， 6.52(lH，brs)， 7.63 - 8.02 (4H，m)，8.23(lH，brs)。質量：261(M+1) + (3) (3aS,8bS)-3a,8b -—'經基-2 -甲基-4 -酬基-1，3a,4,8b -四氣茚[1,2-b]吡咯-3-甲腈。mp. 1 7 3-1 7 5 〇C NMR (DMS〇-d6,): 2.12 (3H, s), 2.39 (3H, s), 6.52 (lH, brs), 7.63-8.02 (4H, m) , 8.23 (lH, brs). Mass: 261 (M + 1) + (3) (3aS, 8bS) -3a, 8b --- 'Cyclo-2 -methyl-4 -amyl-1,3a, 4,8b -tetrakiindene [1 , 2-b] pyrrole-3-carbonitrile.

mp.206 -207 〇C -53- 200306817 NMR(DMS〇-d6， ο ): 1.87(3H,s)， 6.10(lH，s)， 6.71(lH,s)， 7.59(1H，t，J = 7.5Hz)，7.74(1H，d, J 二 7.5Hz), 7.79(1H，d， J = 7.5Hz)，7.86(1H，t，J = 7.5Hz)，8.83(lH，s)。質量：243(M+1) +mp. 206 -207 ° C -53- 200306817 NMR (DMS 0-d6, ο): 1.87 (3H, s), 6.10 (lH, s), 6.71 (lH, s), 7.59 (1H, t, J = 7.5Hz), 7.74 (1H, d, J = 7.5Hz), 7.79 (1H, d, J = 7.5Hz), 7.86 (1H, t, J = 7.5Hz), 8.83 (lH, s). Mass: 243 (M + 1) +

(4)(3&3,86幻-33,813-二羥基-2-甲基-4-酮基-1^-苯基-4,81)-二氫-3aH-茚[1,2-b]呋喃-3-甲醯胺。 mp.215-215.5°C(4) (3 & 3,86-33,813-dihydroxy-2-methyl-4-keto-1 ^ -phenyl-4,81) -dihydro-3aH-indene [1,2-b] Furan-3-carboxamide. mp.215-215.5 ° C

N M R (D M S 〇-d 6，5 ): 2.3 4 (3 Η , s)，6.5 9 (1 Η，s)，6.6 7 - 6 · 7 3 (1 Η，m)， 7.24-7.3 l(2H,m), 7.38-7.48(4H,m)? 7.52-7.61 (2H,m), 7.74-7.77(lH，m)，12.84(lH，s)。質量：3 3 8 (M+1) +NMR (DMS 0-d 6,5): 2.3 4 (3 Η, s), 6.59 (1 Η, s), 6.6 7-6 · 7 3 (1 Η, m), 7.24-7.3 l (2H, m), 7.38-7.48 (4H, m)? 7.52-7.61 (2H, m), 7.74-7.77 (lH, m), 12.84 (lH, s). Mass: 3 3 8 (M + 1) +

(5)(3&3,8七1〇-3&，813-二羥基-4-酮基-2-苯基-4,8]3-二氫-33：9-茚[l，2-b]呋喃-3-羧酸乙酯。 mp. 1 14-1 15°C(5) (3 & 3,8seven10-3 &, 813-dihydroxy-4-keto-2-phenyl-4,8] 3-dihydro-33: 9-indene [l, 2- b] Ethyl furan-3-carboxylic acid. mp. 1 14-1 15 ° C

NMR(DMS〇-d6,5): l.〇5(3Hxl/2, t，J二7·0Ηζ)，1.09(3Hxl/2, t， J 二7.0Hz)， 3.96-4. ll(2H，m)， 5.2 5 (1 Η x 1/2 , s), 6.39(lHxl/2,brs), 7.0 8 (1 Η x 1 / 2 , s), 7.3 6 - 8.0 9 (9 H, m), 8.23(lHxl/2，s)。質量：3 5 3 (M+1) +NMR (DMS〇-d6,5): 1.05 (3Hxl / 2, t, J 2 7.0 Ηζ), 1.09 (3Hxl / 2, t, J 2 7.0Hz), 3.96-4. Ll (2H, m), 5.2 5 (1 Η x 1/2, s), 6.39 (lHxl / 2, brs), 7.0 8 (1 Η x 1/2, s), 7.3 6-8.0 9 (9 H, m), 8.23 (lHxl / 2, s). Mass: 3 5 3 (M + 1) +

(6)(333,81&)-3&,813-二羥基-2-甲基-4-酮基-4,8]3-二氫-3以-茚[1,2-b]呋喃-3-羧酸苄酯。 m p . 1 4 3 - 1 4 4 °C NMR(DMS〇-d6，（5 ): 2.14(3H，s)， 5.15(2H,s), 6.24(lH,s)， 7.29 - 7. 40(3H,m), 7.46(2H, d, J-7.5Hz), 7.6 2 - 7.8 8 (4 H, m), -54- 200306817 8.1 l(lH，s)。質量：3 5 3 (Μ + 1) + (7) (3&3,8乜幻-3&，81)-二羥基-2-甲基-4-酮基-4,813-二氫-3&11-茚[l，2-b]呋喃-3-羧酸甲酯。(6) (333,81 &)-3 &, 813-dihydroxy-2-methyl-4-keto-4,8] 3-dihydro-3 to -indene [1,2-b] furan- Benzyl 3-carboxylic acid. mp. 1 4 3-1 4 4 ° C NMR (DMS〇-d6, (5): 2.14 (3H, s), 5.15 (2H, s), 6.24 (lH, s), 7.29-7. 40 (3H , m), 7.46 (2H, d, J-7.5Hz), 7.6 2-7.8 8 (4 H, m), -54- 200306817 8.1 l (lH, s). Mass: 3 5 3 (Μ + 1) + (7) (3 & 3,8Magic-3 &, 81) -dihydroxy-2-methyl-4-keto-4,813-dihydro-3 & 11-indene [l, 2-b] furan -3-carboxylic acid methyl ester.

m p . 6 5 - 6 6 °C NMR(DMSO-d6, ο ): 2.14(3H,s)， 3.61(3H，s)， 6.20(lH，brs)， 7.61-7.89(4H，m)，8.07(lH，brs)。質量：277 (M + 1) +mp. 6 5-6 6 ° C NMR (DMSO-d6, ο): 2.14 (3H, s), 3.61 (3H, s), 6.20 (lH, brs), 7.61-7.89 (4H, m), 8.07 ( lH, brs). Mass: 277 (M + 1) +

(8) (3&3,85尺）-33,81二羥基-2-甲基-4-酮基-4,813-二氫-3311-茚[l，2-b]呋喃-3-羧酸異丙酯。(8) (3 & 3,85 feet) -33,81 dihydroxy-2-methyl-4-keto-4,813-dihydro-3311-indene [l, 2-b] furan-3-carboxylic acid iso Propyl ester.

mp.l 3 8 - 1 3 9 〇C NMR(DMSO-d6, 5 ): 1.2K6H, d， J-6.5Hz), 2.12(3H，s)， 4.89(lH，m), 6.04(lH，brs)，7.60-7.87 (4H，m)，8.02(lH，brs)。質量：3 05 (M+1) +mp.l 3 8-1 39 OC NMR (DMSO-d6, 5): 1.2K6H, d, J-6.5Hz), 2.12 (3H, s), 4.89 (lH, m), 6.04 (lH, brs ), 7.60-7.87 (4H, m), 8.02 (lH, brs). Mass: 3 05 (M + 1) +

(9) 2-(2-羥基-1，3-二酮基-2,3-二氫-1H-茚-2-基）-4,4-二甲基 -3-酮基戊醇酸乙酯。(9) 2- (2-hydroxy-1,3-diketo-2,3-dihydro-1H-inden-2-yl) -4,4-dimethyl-3-ketopentanoic acid ethyl ester.

mp.94-95 〇C NMR(DMSO-d6, (5 ): 0.98(3H,brs), 2.38-2.70(9H?m), 3.20- 3.50(lH，m)， 4 . 1 5 (1 H, b r s), 5.07(2H, q, J=6.0Hz)， 7.33- 7.78(4H，m)，。質量：3 3 3 (M+1) + 實施例3 5 過濾 2,2-二羥基-1H-茚-1，3(2H)-二酮（2g)於溫水（40ml) 之溶液以及3-酮基丁醇酸第三丁酯（1.78g)於溫水（3 0ml)之 -55- 200306817mp.94-95 ° C NMR (DMSO-d6, (5): 0.98 (3H, brs), 2.38-2.70 (9H? m), 3.20-3.50 (lH, m), 4. 1 5 (1 H, brs), 5.07 (2H, q, J = 6.0Hz), 7.33- 7.78 (4H, m) ,. Mass: 3 3 3 (M + 1) + Example 3 5 Filter 2,2-dihydroxy-1H- Solution of indene-1,3 (2H) -dione (2g) in warm water (40ml) and 3-ketobutyric acid tert-butyl ester (1.78g) in warm water (30ml) -55- 200306817

溶液至同一燒瓶中。1 5 . 5小時後，以乙酸乙酯萃取混合物。以水及鹽水淸洗有機層，經硫酸鎂乾燥，然後於真空中蒸發。殘留物於矽膠以氯仿/甲醇（2〇:1)之混合物爲溶析液經快速管柱色層分析純化。以正-己烷硏製所得產物得到無色固體（3aS，8bR)-3a，8b-二羥基-2 -甲基-4-酮基-4,8b-二氫-3&1茚[1，2-1)]呋喃-3-羧酸第三丁酯（1.73£)。 mp.l 17-120〇C NMR(DMS〇-d6， δ ): 1.07(9Hxl/8，s), 1.4 3 (9 Η χ 7 / 8 , s), 2.09(3Hx7/8,s), 2.4 3 (3 Η χ 1 / 8 ? s), 5.9 4 (1 Η , b r s), 7.62-8.06(5H，m)。質量：319(M+1) + 實施例3 6 以類似實施例35之方法得到下列（1)至（4)化合物。 (1) (3&8,8匕幻-2-乙基-3&，81)-二羥基-4-酮基-4,813_二氫-33}1-茚[l，2-b]呋喃-3-羧酸乙酯。Solution into the same flask. After 15.5 hours, the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by chromatography on a silica gel column using chloroform / methanol (20: 1) as the eluent. The resulting product was made by n-hexane to give (3aS, 8bR) -3a, 8b-dihydroxy-2 -methyl-4-keto-4,8b-dihydro-3 & 1 indene [1,2 -1)] tert-butyl furan-3-carboxylic acid (1.73 £). mp.l 17-120 ° C NMR (DMS〇-d6, δ): 1.07 (9Hxl / 8, s), 1.4 3 (9 Η χ 7/8, s), 2.09 (3Hx7 / 8, s), 2.4 3 (3 Η χ 1/8? S), 5.9 4 (1 Η, brs), 7.62-8.06 (5H, m). Mass: 319 (M + 1) + Example 3 6 The following compounds (1) to (4) were obtained in a similar manner to Example 35. (1) (3 & 8,8 di-2-ethyl-3 &, 81) -dihydroxy-4-keto-4,813_dihydro-33} 1-indene [l, 2-b] furan- 3-carboxylic acid ethyl ester.

mp.109.5-1 12°C NMR(DMS〇-d6，δ ): 0.94(3Η, t， J 二 7.5Hz)， 1·20(3Η， t, J 二 7·5Ηζ)，2.46-2.64(2H,m)，4.00-4.14(2H，m)’ 6.13(lH，brs), 7.60-7.89 (4H，m)，8.05(lH，brs)。質量：305 (M+1) + (2) (3aS，8bR)-3a，8b-二羥基-2-異丙基-4-酮基-4,8b-二氫-3aH-茚[l，2-b]呋喃-3-羧酸乙酯。mp.109.5-1 12 ° C NMR (DMS 0-d6, δ): 0.94 (3Η, t, J 2 7.5Hz), 1.20 (3Η, t, J 2 7.5Ηζ), 2.46-2.64 (2H m), 4.00-4.14 (2H, m) '6.13 (lH, brs), 7.60-7.89 (4H, m), 8.05 (lH, brs). Mass: 305 (M + 1) + (2) (3aS, 8bR) -3a, 8b-dihydroxy-2-isopropyl-4-keto-4,8b-dihydro-3aH-indene [1,2 -b] ethyl furan-3-carboxylic acid.

m p . 9 8 - 9 9 °C NMR(DMS〇-d6，（5 ): 0 · 7 5 (3 Η， d， J 二7 · 0 Η z), 1. 14(3H, d， -56- 200306817 J 二 7·0Ηζ)， 1 .20(3Η, t， J:7.0Hz)， 3.49(lH，m)， 3.99- 4.13(2H，m)，6.12(lH，brs)，7.60-7.88(4H，m)，8.05(lH，brs)。質量：319(M + 1) + (3) (3aS，8bR)-3a,8b-二羥基- 2-(2 -甲氧基乙基）-4-酮基- 4,8b-二氫-3aH-茚[l，2-b]呋喃-3-羧酸甲酯。mp. 9 8-9 9 ° C NMR (DMS〇-d6, (5): 0 · 7 5 (3 Η, d, J 2 7 · 0 Η z), 1. 14 (3H, d, -56- 200306817 J 27.0 0Ηζ), 1.20 (3Η, t, J: 7.0 Hz), 3.49 (lH, m), 3.99-4.13 (2H, m), 6.12 (lH, brs), 7.60-7.88 (4H , M), 8.05 (lH, brs). Mass: 319 (M + 1) + (3) (3aS, 8bR) -3a, 8b-dihydroxy-2- (2-methoxyethyl) -4- Keto-4,8b-dihydro-3aH-indene [l, 2-b] furan-3-carboxylic acid methyl ester.

m p . 1 2 0 - 1 2 2 °C NMR(DMSO-d6, (5 ): 2.7 7 - 2.9 3 (2 Η , m), 3.04(3H，s), 3.31-m p. 1 2 0-1 2 2 ° C NMR (DMSO-d6, (5): 2.7 7-2.9 3 (2 Η, m), 3.04 (3H, s), 3.31-

3.45(2H,m), 3.61 (3H,s), 6.2 4 (1 H, b r s), 7.6 1-7.8 9 (4H, m), 8.1 l(lH，brs)。質量：321(M+1) + (4) 1，1，1-三氟-3-(1，1，2-三羥基-3-酮基-2,3-二氫-111-茚-2-基）-2,4·戊烷二酮。3.45 (2H, m), 3.61 (3H, s), 6.2 4 (1 H, b r s), 7.6 1-7.8 9 (4H, m), 8.1 l (lH, brs). Mass: 321 (M + 1) + (4) 1,1,1-trifluoro-3- (1,1,2-trihydroxy-3-keto-2,3-dihydro-111-indene-2 -Yl) -2,4.pentanedione.

mp.136-136.5 °C NMR(DMSO-d6, δ ): 2.3 8 (3 Η x 2/3 , s), 2.4 3 (3 Η x 1 / 3 , s), 3.58(lHxl/3，s)， 3.7 2 (1 H x 2 / 3 , s), 6.79( lHx 1/3，s)，mp.136-136.5 ° C NMR (DMSO-d6, δ): 2.3 8 (3 Η x 2/3, s), 2.4 3 (3 Η x 1/3, s), 3.58 (lHxl / 3, s) , 3.7 2 (1 H x 2/3, s), 6.79 (lHx 1/3, s),

6.84(lHx2/3,s), 7.0 4 (1 H x 2 / 3 , s), 7.5 7 - 7.8 8 (4 H + (1 Η x 1 / 3 ), m), 7.89(lHxl/3，s), 7.96(lHx2/3，s)。質量：331(M-1) + 實施例3 7 將4,4,4-三氟-3-酮基丁醇酸乙酯（0.821ml)添加到2,2-二羥基-1H-茚-1，3(2H)-二酮（lg)於溫水（20ml)之溶液。在98 °C攪拌混合物2小時，然後冷卻到室溫。經由過濾收集所得沉澱物，並自二乙基醚/正-己烷結晶。固體自乙酸乙酯 /正-己院再結晶得到無色固體4，4,4 -三氟-3 -酮基-2 - (1，1，2 - -57- 200306817 三羥基-3-酮基-2,3 -二氫-1H-茚-2-基）丁醇酸乙酯 (8 9 8 · 1 m g) 〇 Γηρ·1 3 3 - 1 34·5π NMR(DMS〇-d6，（5): 1·15(3Ηχ5/7, t，J二7.0Hz)，1.24(3Hx2/7, t， J-7.0Hz), 3.41(lHx2/7,s), 3.5 5 (1 H x 5/7 , s), 4.06(2Hx5/7? q, J:7.0Hz)， 4.19(2Hx2/7, q, J-7.0Hz), 6.66(lHx5/7，s)， 6.70(lHx2/7,s)， 7.2 6 (1 H x 5/7 , s), 7.3 3 (1 H x 2/7, s), 7.57- 7.88(4H + (lHx5/7),m)，7.91(lHx2/7，s)。6.84 (lHx2 / 3, s), 7.0 4 (1 H x 2/3, s), 7.5 7-7.8 8 (4 H + (1 Η x 1/3), m), 7.89 (lHxl / 3, s ), 7.96 (lHx2 / 3, s). Mass: 331 (M-1) + Example 3 7 Add 4,4,4-trifluoro-3-ketobutanoic acid ethyl ester (0.821ml) to 2,2-dihydroxy-1H-indene-1 , 3 (2H) -dione (lg) in warm water (20ml). The mixture was stirred at 98 ° C for 2 hours and then cooled to room temperature. The resulting precipitate was collected by filtration and crystallized from diethyl ether / n-hexane. The solid was recrystallized from ethyl acetate / n-hexane to obtain a colorless solid 4,4,4-trifluoro-3 -keto-2-(1,1,2, -57- 200306817 trihydroxy-3-keto- Ethyl 2,3-dihydro-1H-inden-2-yl) butanoate (8 9 8 · 1 mg) 〇Γηρ · 1 3 3-1 34 · 5π NMR (DMS〇-d6, (5): 1 · 15 (3Ηχ5 / 7, t, J = 7.0Hz), 1.24 (3Hx2 / 7, t, J-7.0Hz), 3.41 (lHx2 / 7, s), 3.5 5 (1 H x 5/7, s ), 4.06 (2Hx5 / 7? Q, J: 7.0Hz), 4.19 (2Hx2 / 7, q, J-7.0Hz), 6.66 (lHx5 / 7, s), 6.70 (lHx2 / 7, s), 7.2 6 (1 H x 5/7, s), 7.3 3 (1 H x 2/7, s), 7.57- 7.88 (4H + (lHx5 / 7), m), 7.91 (lHx2 / 7, s).

質量：361(M-1) 實施例3 8 在〇°C氮氣氛下添加（三甲基矽烷基）重氮甲烷於正-己烷（0.517ml)之 2.0M 之溶液到（3aS，8bR)-3a，8b-二羥基-2-甲基-4-酮基-4,8b-二氫- 3aH-茚[l，2-b]呋喃-3-羧酸乙酯於二乙基醚（lml)及甲醇（0.5ml)溶液。在室溫攪拌混合物16小時，然後在真空中濃縮。所得殘留物於矽膠以正-己烷/乙酸乙酯（4 :1)之混合物爲溶析液經快速管柱色層分析純化得到黃色油狀（3aS，8bR)-3a-羥基-8b-甲氧基-2-甲基-4-酮基 -4,813-二氫-3&11-茚[1，2-13]呋喃-3-羧酸乙酯（33.11^)。 NMR(DMSO-d6, δ ): 1.23(3H， t, J=7.0Hz), 2.20(3H，s), 3.58(3H,s), 4.03-4.17(2H,m), 6.29( lH，s)， 7.70( 1H, t， J 二 7.0Hz)，7.78(1H，d，J=7.0Hz)，7.86(1H，t，J:7.0Hz)， 7.87(1H，d，J:7.0Hz)。質量：305 (M+1) + 實施例3 9 -58- 200306817 在〇°C氮氣氛下混合（3aS，8bR)-3a，8b-二羥基-2-甲基- 4-酮基-4,81)-二氫-331^茚[1,2-13]呋喃-3-羧酸乙酯（21〇1112)，二氯甲烷（10ml)，4-(二甲基胺基）吡啶（20mg)，吡啶（0.059ml) . 以及乙酸酐（0.14ml)。在室溫攪拌混合物6小時。混合物稀釋於氯仿，然後以飽和碳酸氫鈉水溶液、水及飽和氯化鈉水溶液淸洗，經無水硫酸鎂乾燥，然後於真空中濃縮。Mass: 361 (M-1) Example 3 8 Add a 2.0 M solution of (trimethylsilyl) diazomethane in n-hexane (0.517ml) to (3aS, 8bR) under a nitrogen atmosphere of 0 ° C. -3a, 8b-dihydroxy-2-methyl-4-keto-4,8b-dihydro-3aH-indene [l, 2-b] furan-3-carboxylic acid ethyl ester in diethyl ether (lml ) And methanol (0.5ml) solution. The mixture was stirred at room temperature for 16 hours and then concentrated in vacuo. The obtained residue was purified on a silica gel using a mixture of n-hexane / ethyl acetate (4: 1) as the eluent and analyzed by flash column chromatography to obtain (3aS, 8bR) -3a-hydroxy-8b-form as a yellow oil. Oxy-2-methyl-4-keto-4,813-dihydro-3 & 11-indene [1,2-13] furan-3-carboxylic acid ethyl ester (33.11 ^). NMR (DMSO-d6, δ): 1.23 (3H, t, J = 7.0Hz), 2.20 (3H, s), 3.58 (3H, s), 4.03-4.17 (2H, m), 6.29 (lH, s) , 7.70 (1H, t, J = 7.0Hz), 7.78 (1H, d, J = 7.0Hz), 7.86 (1H, t, J: 7.0Hz), 7.87 (1H, d, J: 7.0Hz). Mass: 305 (M + 1) + Example 3 9 -58- 200306817 Mix (3aS, 8bR) -3a, 8b-dihydroxy-2-methyl-4-keto-4, under 0 ° C nitrogen atmosphere, 81) -Dihydro-331 ^ indane [1,2-13] furan-3-carboxylic acid ethyl ester (21〇1112), dichloromethane (10 ml), 4- (dimethylamino) pyridine (20 mg) , Pyridine (0.059ml). And acetic anhydride (0.14ml). The mixture was stirred at room temperature for 6 hours. The mixture was diluted with chloroform, and then washed with a saturated aqueous sodium hydrogen carbonate solution, water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated in vacuo.

所得殘留物於矽膠以氯仿/乙酸乙酯（20 : 1)之混合物爲溶析液經快速管柱色層分析純化。以正-己烷硏製所得產物得 | 到無色固體（3aR，8bS)-3a，8b-貳（乙醯氧基）-2-甲基-4-酮基-4,81)-二氫-3311-茚[1，2-13]呋喃-3-羧酸乙酯（204.31112)。 m p . 1 5 0 -1 5 1 °C NMR(DMS〇-d6, 5 ): 1·25(3Η， t, J =7 · OH ζ)， 2 · 0 8 (3 Η，s)， 2.15(3H,s)，2.21(3H，s)，4·15(2Η，q，J=7.0Hz)，7·77(1Η, t， J 二 7.5Hz)，7.83(1H? d, J-7.5Hz), 7.94(1H, t, J=7.5Hz), 8.00(1H, d，J=7.5Hz)。質量：3 7 5 (M+1)+ φ 實施例4 0The resulting residue was purified by flash column chromatography on silica gel using a mixture of chloroform / ethyl acetate (20: 1) as the eluent. The resulting product was made by n-hexane extraction to obtain a colorless solid (3aR, 8bS) -3a, 8b-fluoren (ethoxy) -2-methyl-4-keto-4,81) -dihydro- 3311-Indene [1,2-2-13] furan-3-carboxylic acid ethyl ester (204.31112). mp. 15 0 -1 5 1 ° C NMR (DMS〇-d6, 5): 1.25 (3Η, t, J = 7 · OH ζ), 2 · 0 8 (3 Η, s), 2.15 ( 3H, s), 2.21 (3H, s), 4.15 (2Η, q, J = 7.0Hz), 7.77 (1Η, t, J 7.5Hz), 7.83 (1H? D, J-7.5Hz ), 7.94 (1H, t, J = 7.5Hz), 8.00 (1H, d, J = 7.5Hz). Mass: 3 7 5 (M + 1) + φ Example 4 0

將氫氯酸於乙酸乙酯（6ml)之 4N溶液添加到 (3以，851〇-3&，813-二羥基-2-甲基-4-酮基-4,81)-二氫-3211-茚 [1,2-b]呋喃-3-羧酸第三丁酯（6 17 mg)於乙酸乙酯（2ml)。在室溫攪拌混合物5 · 5小時，收集所得沉澱物得到無色固體 (338,8匕幻-33,813-二羥基-2-甲基-4-酮基-4,81^二氫-3&11-茚 [l，2-b]呋喃-3-羧酸（418.9mg) mp.l50.5-151〇C -59- 200306817 NMR(DMS〇-d6, 5 ): 2.1 1 (3H,s), 6 · 1 2 (1 H，b r s)， 7.59- 7.73(2H，m)，7.77 -7.87 (2H，m)，8.02(lH,s)，11.87(lH，brs)。質量：261(M-1) + 實施例4 1 以類似實施例40之方法得到（4bS,9bR)-4b-(乙醯氧基）-10-酮基-413，10-二氫-91311-苯并[13]茚[1，2-(1]呋喃-913-基乙酸酯以及2·[2-(乙醯氧基）-1,3-二酮基- 2,3-二氫·1Η-茚-2-基] 苯基乙酸酯。A solution of hydrochloric acid in ethyl acetate (6 ml) in 4N was added to (3, 8510-3 &, 813-dihydroxy-2-methyl-4-keto-4,81) -dihydro-3211 -Indene [1,2-b] furan-3-carboxylic acid tert-butyl ester (6 17 mg) in ethyl acetate (2 ml). The mixture was stirred at room temperature for 5.5 hours, and the resulting precipitate was collected to give a colorless solid (338,8 dagger-33,813-dihydroxy-2-methyl-4-keto-4,81 ^ dihydro-3 & 11- Indene [l, 2-b] furan-3-carboxylic acid (418.9 mg) mp. 150.5-151 ° C -59- 200306817 NMR (DMS ° -d6, 5): 2.1 1 (3H, s), 6 · 1 2 (1 H, brs), 7.59- 7.73 (2H, m), 7.77-7.87 (2H, m), 8.02 (lH, s), 11.87 (lH, brs). Mass: 261 (M-1) + Example 4 1 (4bS, 9bR) -4b- (acetamido) -10-keto-413,10-dihydro-91311-benzo [13] indene [1 , 2- (1) furan-913-ylacetate and 2. [2- (ethylacetoxy) -1,3-diketo-2,3-dihydro · 1fluorene-inden-2-yl] Phenyl acetate.

(朴3，外1〇-41^(乙醯氧基）-10-酮基-413，10-二氫-91)11-苯并[13] 茚[l，2-d]呋喃- 9b-基乙酸酯爲無色固體 mp.22 8 -229.5 °C NMR(DMS〇-d6， 5 ): 2.15(3H，s)， 2 · 1 7 (3 Η，s)， 6 · 8 7 (1 Η， d， J 二 7·5Ηζ)， 7·06(1Η， t， J=7.5Hz)， 7.36(1H， t， J=7.5Hz)， 7.60(1H, t, J-7.5Hz), 7.61(1H, d, J=7.5Hz), 7.80(1H, t,(Pak 3, outer 10-41 ^ (ethoxy) -10-keto-413, 10-dihydro-91) 11-benzo [13] indene [l, 2-d] furan-9b- Ethyl acetate is a colorless solid mp. 22 8 -229.5 ° C NMR (DMS 0-d6, 5): 2.15 (3H, s), 2 · 1 7 (3 Η, s), 6 · 8 7 (1 Η , D, J 2 7. 5Ηζ), 7.06 (1Η, t, J = 7.5Hz), 7.36 (1H, t, J = 7.5Hz), 7.60 (1H, t, J-7.5Hz), 7.61 ( 1H, d, J = 7.5Hz), 7.80 (1H, t,

J-7.5Hz), 7.84(1H, d, J-7.5Hz), 8 · 1 6 (1 H，d，J =7 · 5 H z)。 2-[2-(乙醯氧基）-1,3-二酮基-2,3-二氫-1H-茚-2-基]苯基乙酸酯爲無色固體 m p . 1 3 9 - 1 4 0 °C NMR(DMS〇-d6，5 ): 1.87(3H，s)， 2.22(3H，s), 7·08(1Η， dd， J 二 7.5，1.0Hz)，7·40(1Η, dt，J二1.0, 7·5Ηζ)，7·47(1Η, dt，J = 1.0, 7·5Ηζ)，7·77(1Η, dd，J 二7.5，1.0Hz)，8.04-8.14(4H,m)。實施例4 2 在室溫將1,3(2H，4H)-異喹啉二酮（500mg)於乙酸乙酯 (15ml)之懸浮液添加到氧化釕（IV)水合物（31 mg)及10%過 -60- 200306817 碘酸鈉（30mg)之混合物。在室溫強力攪拌反應混合物15 分鐘。分開各層後，以AcOEt萃取水層（3次）。合倂之有機溶液處以2-丙醇（2ml)2.5小時以分解氧化釕（VIII)，然後濾除黑色沉澱物（氧化釕（IV))。以水淸洗濾液，經硫酸鎂乾燥’然後於真空中蒸發。殘留物於矽膠以氯仿/甲醇 (1 0 : 1)之混合物爲溶析液經快速管柱色層分析純化。殘留固體自乙酸乙酯再結晶得到淺黃色固體i，3,4(2H)-異喹啉三酮（162.7mg)。J-7.5Hz), 7.84 (1H, d, J-7.5Hz), 8 · 1 6 (1 H, d, J = 7 · 5 H z). 2- [2- (Ethyloxy) -1,3-diketo-2,3-dihydro-1H-inden-2-yl] phenyl acetate is a colorless solid mp. 1 3 9-1 4 0 ° C NMR (DMS〇-d6,5): 1.87 (3H, s), 2.22 (3H, s), 7.08 (1Η, dd, J 7.5, 1.0Hz), 7.40 (1Η, dt, J 2 1.0, 7 · 5Ηζ), 7.47 (1Η, dt, J = 1.0, 7 · 5Ηζ), 7.77 (1Η, dd, J 2 7.5, 1.0 Hz), 8.04-8.14 (4H, m). Example 4 2 A suspension of 1,3 (2H, 4H) -isoquinolinedione (500 mg) in ethyl acetate (15 ml) was added to ruthenium (IV) oxide hydrate (31 mg) and 10 at room temperature. % Over -60- 200306817 A mixture of sodium iodate (30 mg). The reaction mixture was stirred vigorously at room temperature for 15 minutes. After the layers were separated, the aqueous layer was extracted with AcOEt (3 times). The organic solution was mixed with 2-propanol (2 ml) for 2.5 hours to decompose ruthenium (VIII) oxide, and then the black precipitate (ruthenium (IV) oxide) was filtered off. The filtrate was washed with water, dried over magnesium sulfate 'and evaporated in vacuo. The residue was purified by chromatography on a silica gel column using chloroform / methanol (10: 1) as the eluent. The residual solid was recrystallized from ethyl acetate to give i, 3,4 (2H) -isoquinoline trione (162.7 mg) as a pale yellow solid.

mp.230-23 1 °C NMR(DMS〇-d6，<n: 7·88(1Η，dt，J=2.0，7·5Ηζ)，7.93(1H，dt， J=2.0，7.5Hz)，8·05(1Η，dd，j:7.5，2.0Hz)，8·13(1Η，dd， J=7.5，2.0Hz)，1 1.97(lH,s)。 (五）圖式簡單說明：無 ~61.mp. 230-23 1 ° C NMR (DMS 0-d6, < n: 7.88 (1Η, dt, J = 2.0, 7.5Ηζ), 7.93 (1H, dt, J = 2.0, 7.5Hz), 8.05 (1Η, dd, j: 7.5, 2.0Hz), 8.13 (1Η, dd, J = 7.5, 2.0Hz), 1 1.97 (lH, s). (5) Simple illustration of the diagram: None ~ 61.

Claims

200306817 拾、申請專利範圍 1 ·一種含有式（la)化合物之醫藥組成物，200306817 Patent application scope 1 · A pharmaceutical composition containing a compound of formula (la),

(la)(la)

其中 R 1 3爲氫原子，或硝基或低級烷氧基，以及 R2a爲氫原子，或硝基，胺基，醯胺基或低級烷磺醯基，或 R1 a和R2a —起與其附著之鄰接碳原子形成芳基；Wherein R 1 3 is a hydrogen atom, or a nitro group or a lower alkoxy group, and R 2a is a hydrogen atom, or a nitro group, an amine group, a fluorenylamino group or a lower alkanesulfonyl group, or R1 a and R2a are attached to it Adjacent carbon atoms form an aryl group;

R3a及R4a爲相同或不同之氫原子，或低級烷基，芳（低級）烷基’芳基或式-CH = N-0-芳（低級）烷基之基，其中芳 (低級）烷基及式-C Η = N - 0 -芳（低級）烷基可經一或多個取代基取代，或 R3a和R4a形成酮基； 115&及1163爲相同或不同之氫原子或羥基，或 R5a和R6a形成酮基； 1183及R9爲相问或不同之氫原子或羥基，或 R8a和R9a形成酮基； Xa爲N-R7a或〇，其中爲氫原子，或羥基，低級烷 -62- b 1R Q- 200306817 基，芳基，芳（低級）烷基或芳（低級）烷氧基，其中芳（低級）烷氧基可經一或多個取代基取代；另外R3a和RU可一起與其附著之碳原子形成環烷環或其中Ya爲⑶或N，以及RlGa爲羥基，芳基，芳胺基或低級烷氧基，其中芳基及芳胺基可經一或多個取代基取代，或 R3a與R5a或R6a一起與其附著之碳原子形成一鍵或環焼環；其則樂或其醫藥可接受鹽混合醫藥可接受載劑。 2·—種含有式（Ib)化合物之醫藥組成R3a and R4a are the same or different hydrogen atoms, or lower alkyl, aryl (lower) alkyl'aryl or the formula -CH = N-0-aryl (lower) alkyl, of which aryl (lower) alkyl And the formula -C Η = N-0 -aryl (lower) alkyl may be substituted by one or more substituents, or R3a and R4a form a keto group; 115 & and 1163 are the same or different hydrogen atoms or hydroxyl groups, or R5a And R6a form a keto group; 1183 and R9 are interrelated or different hydrogen atoms or hydroxyl groups, or R8a and R9a form a keto group; Xa is N-R7a or 〇, which is a hydrogen atom, or a hydroxyl group, a lower alkane-62- b 1R Q- 200306817, aryl, aryl (lower) alkyl or aryl (lower) alkoxy, wherein aryl (lower) alkoxy may be substituted with one or more substituents; in addition, R3a and RU may be attached to it together A carbon atom of which forms a cycloalkane ring or wherein Ya is ⑶ or N, and R1Ga is a hydroxyl group, an aryl group, an arylamino group or a lower alkoxy group, wherein the aryl group and the arylamine group may be substituted with one or more substituents, or R3a and R5a or R6a together form a bond with the carbon atom to which they are attached; Acceptable carrier. 2 · —Medical composition containing compound of formula (Ib)

其中 R1 b爲氫或鹵素原子，或猫甘 ^ ^ _ $硝基，低級烷基，鹵（低級）烷基低級烷氧基或鹵（低級）烷氧基； R2b及R3b爲相同或不M〜— 4不间之氫原子，或低級烷基，芳基方（低級）院基，雜環球. # ^酿基，其中低級烷基及芳（低級' 基可經一或多個取代基取代，或尺21?和Rjb —'起與宜盼％、/、彳者之碳原子形成環院環，可經取以鹵（低級）院基之醯基取代，Where R1 b is hydrogen or a halogen atom, or cat ^ ^ _ $ nitro, lower alkyl, halo (lower) alkyl, lower alkoxy or halo (lower) alkoxy; R2b and R3b are the same or not M ~ —4 continuous hydrogen atoms, or lower alkyl, aryl (lower) courtyard, heterocyclic sphere. # ^ Brewing group, where lower alkyl and aryl (lower 'group can be substituted by one or more substituents , Or 21? And Rjb — from the formation of a ring with the carbon atom of Yipan%, /, 彳, can be replaced by a halogen group (lower) of the fluorenyl group,

-63- 200306817 1^41?及R5b爲相同或不同之氫或鹵素原子或芳基或芳（低級）烷基，其中芳（低級）烷基可經一或夕個_素原子取代，或 η 基； π形成酮基或可經一或兩個取代基取代之伸乙其前藥或其醫藥可接受鹽混合醫藥可接受載劑 3.—種含有式（Ic)化合物之醫藥組成物，-63- 200306817 1 ^ 41? And R5b are the same or different hydrogen or halogen atom or aryl group or aryl (lower) alkyl group, wherein the aryl (lower) alkyl group may be substituted by one or more prime atoms, or η Π forms a keto group or a prodrug or a pharmaceutically acceptable salt thereof which can be substituted by one or two substituents, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier 3. A pharmaceutical composition containing a compound of formula (Ic),

其中 Rle爲氫或鹵素原子，或硝基，低級院基，低級院氧基或低級烷硫基；以及 R2e爲氫或鹵素原子或低級烷氧基；或 Rle和R2e —起與其附著之鄰接碳原子形成芳基； R3 e爲氫或鹵素原子，或硝基，低級院基或鹵（低級）烷氧基；以及 Xc爲CH或N ; 其前藥或其醫藥可接受鹽混合醫藥可接受載劑。 4 · 一種含有式（I d)化合物之醫藥組成物， -64- 200306817 RWhere Rle is a hydrogen or halogen atom, or a nitro group, a lower compound, a lower compound or a lower alkylthio group; and R2e is a hydrogen or a halogen atom or a lower alkoxy group; or Rle and R2e are attached to the adjacent carbon Atoms form aryl groups; R3 e is a hydrogen or halogen atom, or a nitro group, a lower alkyl group or a halogen (lower) alkoxy group; and Xc is CH or N; its prodrug or its pharmaceutically acceptable salt Agent. 4. A pharmaceutical composition containing a compound of formula (I d), -64- 200306817 R

R2d (Id) 其中 R 1 d爲氫原子，或硝基，胺基或醯胺基；R2d (Id) wherein R 1 d is a hydrogen atom, or a nitro group, an amine group, or an amidino group;

R2d爲選擇性經取代之芳基或芳（低級）烷基；以及 Xd爲CH或N ; 其前藥或其醫藥可接受鹽混合醫藥可接受載劑。 5.—種含有式（Ie)化合物之醫藥組成物，R2d is optionally substituted aryl or aryl (lower) alkyl; and Xd is CH or N; its prodrug or pharmaceutically acceptable salt thereof is mixed with a pharmaceutically acceptable carrier. 5.—a pharmaceutical composition containing a compound of formula (Ie),

(Ie)(Ie)

其中 R1 e爲氫原子或低級烷氧基； R2e爲氫原子；或 Rle和R2e —起與其附著之鄰接碳原子形成芳基； R3e及&〃爲氫原子或形成酮基； -65- 200306817 Xe 爲=〇，=CH2, =〇〇或=c: 5e 6e 以及 Ye 爲 CH2，C=0，NH，rnC：；01"1 或 OHWhere R1 e is a hydrogen atom or a lower alkoxy group; R2e is a hydrogen atom; or Rle and R2e together form an aryl group with the adjacent carbon atom to which they are attached; R3e and & 〃 are hydrogen atoms or form a ketone group; -65- 200306817 Xe = 〇, = CH2, = 〇〇 or = c: 5e 6e and Ye is CH2, C = 0, NH, rnC :; 01 " 1 or OH

R7e R8e 其中R5e ’ R6e，R7e及爲相同或不同之氫原子，或羥基，低級烷基，低級烷氧基，芳基，醯氧基或碳環基，其中低級院基’芳基及碳環基可經一或多個取代基取代；以及另外R6e和R7e可一起與其附著之碳原子形成經選擇性取代之不飽和雜環；其前藥或其醫藥可接受鹽混合醫藥可接受載劑。 6 ·如申請專利範圍第丨至5項中任一項之醫藥組成物，其係用於治療或預防病毒感染性疾病。 7.如申請專利範圍第6項之醫藥組成物，其中病毒感染性疾病是由黃病毒科（Flaviviridae family)病毒之登革熱病毒、黃熱病病毒、以及日本腦炎病毒所引起之疾病：慢性肝病、肝硬化、肝細胞癌、以及肝衰竭；流產、畸形發生、呼吸道問題、慢性衰弱疾病、免疫系統失能、以及易遭第二種病毒及細菌感染。 8 · —種治療或預防病毒感染性疾病之方法，其係對有需要治療或預防之人類或動物投與含有式（la)至（Ie)化合物之申請專利範圍第1至5項中任一項之醫藥組成物。 9 .—種式（I a)至（I e)化合物於製備如申請專利範圍第1至5 項中任一項之醫藥組成物之使用。 -66- 200306817 -圖陸、（一）、本案指定代表圖爲：第_ (二）、本代表圖之元件代表符號簡單說明：無柴、本案若有化學式時，請揭示最能顯示發明特徵的化學式：式（la): R4a R、 R3^ R5a V-R6a p1a .Xa K R9a \8a (la) 式（lb):R7e R8e in which R5e 'R6e, R7e and the same or different hydrogen atoms, or hydroxyl, lower alkyl, lower alkoxy, aryl, fluorenyl or carbocyclic group, among which lower alkyl group' aryl and carbocyclic The group may be substituted with one or more substituents; and in addition, R6e and R7e together may form a selectively substituted unsaturated heterocyclic ring with the carbon atom to which it is attached; its prodrug or pharmaceutically acceptable salt thereof is mixed with a pharmaceutically acceptable carrier. 6. The pharmaceutical composition according to any one of claims 1-5, which is used for treating or preventing viral infectious diseases. 7. The pharmaceutical composition according to item 6 of the patent application, wherein the viral infectious disease is a disease caused by dengue virus of the Flaviviridae family virus, yellow fever virus, and Japanese encephalitis virus: chronic liver disease, Cirrhosis, hepatocellular carcinoma, and liver failure; miscarriages, malformations, respiratory problems, chronic debilitating diseases, disability of the immune system, and vulnerability to a second virus and bacterial infection. 8-A method for treating or preventing a viral infectious disease, which comprises administering to a human or animal in need of treatment or prevention any one of claims 1 to 5 containing a compound of formula (la) to (Ie) Item of pharmaceutical composition. 9. The use of the compounds of the formulae (I a) to (I e) in the preparation of a pharmaceutical composition according to any one of claims 1 to 5 of the scope of patent application. -66- 200306817-Figure Lu, (1), the designated representative of this case is: _ (二), the representative symbols of this representative are simply explained: no firewood, if there is a chemical formula in this case, please reveal the features that can best show the invention Chemical formula: Formula (la): R4a R, R3 ^ R5a V-R6a p1a .Xa K R9a \ 8a (la) Formula (lb):

0200306817 式（Ic):0200306817 Formula (Ic):

(Ic) 式（Id): 式（Ie):(Ic) Formula (Id): Formula (Ie):