TW201121944A - 5-fluorouracil compound having dutpase-inhibiting activity or salt thereof - Google Patents

5-fluorouracil compound having dutpase-inhibiting activity or salt thereof Download PDF

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TW201121944A
TW201121944A TW099141285A TW99141285A TW201121944A TW 201121944 A TW201121944 A TW 201121944A TW 099141285 A TW099141285 A TW 099141285A TW 99141285 A TW99141285 A TW 99141285A TW 201121944 A TW201121944 A TW 201121944A
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fluoro
compound
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Masayoshi Fukuoka
Tatsushi Yokogawa
Seiji Miyahara
Hitoshi Miyakoshi
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Taiho Pharmaceutical Co Ltd
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D239/00Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52Two oxygen atoms
    • C07D239/54Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C07D239/545Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/553Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms with halogen atoms or nitro radicals directly attached to ring carbon atoms, e.g. fluorouracil
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D403/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D405/00Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
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  • Engineering & Computer Science (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

A 5-fluorouracil compound represented by general formula (I) or a salt thereof, which has an excellent dUTPase-inhibiting activity and is useful as an efficacy potentiator for anti-tumor agents or the like. (In general formula (I), n represents a numeral value of 1 to 3; X represents a bond, an oxygen atom, a sulfur atom, an alkenylene having 2 to 6 carbon atoms, a bivalent aromatic hydrocarbon group which may have a substituent, or a bivalent saturated or unsaturated heterocyclic group which may have a substituent; Y represents a bond, or a linear or branched alkylene group having 1 to 8 carbon atoms; Z represents -SO2NR1R2, -NR3SO2-R4, or a group represented by formula (II) (a R5-substituted pyrrolidinylcarbonyl); R1 and R2 independently represent a hydrogen atom, or the like; R3 represents a hydrogen atom, or the like; R4 represents an aromatic hydrocarbon group which may have a substituent, or the like; and R5 represents a methyl group which may have a substituent.)

Description

201121944 六、發明說明: 【發明所屬之技術領域】 本發明係關於一種具有優異之人dUTP酶抑制活性,且 作為與dUTP酶相關之疾病、例如抗癌藥之效果增強劑等 較為有用的新穎5-氟尿嘧啶化合物或其鹽。 【先前技術】 脫氧尿苷三構酸酶(以下亦稱為dUTP酶(deoxyuridine triphosphatase)(EC3.6.1.23))為預防性 DNA(deoxyribonucleic acid,脫氧核糖核酸)修復酶。認為其係於天然型核酸三磷 酸體中僅特異性地識別脫氧尿苷三磷酸(以下稱為 dUTP(deoxyuridine triphosphate)),並分解成脫氧尿發單 墙酸(以下稱為 dUMP(deoxyuridine monophosphate))與焦鱗 酸之酶(非專利文獻1);擔負如下兩種反應:(1)藉由降低 細胞内之dUTP混合物(spool)之量,而避免尿鳴咬代替胸 腺嘧啶誤混入DNA中;(2)供給胸腺嘧啶核甘酸合成酶之 基質dUMP,該胸腺嘧啶核甘酸合成酶擔負用以向DNA中 供給胸腺嘧啶之重要de novo(重生)路徑(非專利文獻2)。 已知dUTP酶為原核生物、真核生物兩者之細胞生存所 必需者。因此,暗示本酶可成為抗癌藥(非專利文獻3),抗 瘧疾藥(專利文獻1及非專利文獻4),抗結核藥(非專利文獻 5),抗幽門螺桿菌藥(專利文獻2),錐體蟲或利什曼原蟲等 抗寄生蟲藥(非專利文獻6),及人疱疹單純型病毒、細胞巨 大病毒、Epstein-Barr(艾伯斯坦-巴爾)病毒之類的癌療病 毒(非專利文獻7)或牛痘病毒(非專利文獻8)等抗病毒藥之 152528.doc 201121944 靶標。 如以上所示,dUTP酶作為針對各種疾病之治療劑的乾 標而受到注目,亦對dUTP酶抑制劑進行廣泛之研究。 作為dUTP酶抑制劑,例如已知有擬三磷酸型低分子化 合物(例如專利文獻3、非專利文獻9等)、5’-0-取代苯基-脫氧尿苷化合物(非專利文獻10)。 [先前技術文獻] [專利文獻] [專利文獻1]國際公開第2005/065689號手冊 [專利文獻2]國際公開第2003/089461號手冊 [專利文獻3]國際公開第1995/15332號手冊 [非專利文獻] [非專利文獻 l]Structure,4, 1077-1092 (1996) [非專利文獻 2]Acta Biochim. Pol·,44, 159-171 (1997) [非專利文獻 3]Curr. Protein Pept. Sci.,2,361-370 (2001) [非專利文獻 4]Structure,13, 329-338 (2005) [非專利文獻 5]J. Mol. Biol.,341,503-517 (2004) [非專利文獻 6]Bioorg. Med. Chem. Lett., 16,3809-3812 (2006) [非專利文獻 7]Curr. Protein Pept. Sci.,2, 371-379 (2001) [非專利文獻 8]Acta Crystallogr. D. Biol. Crystallogr, 63, 571-580 (2007) [非專利文獻9]Mol. Pharmacol.,29, 288-292 (1986) [非專利文獻 1 〇]Nucleosides Nucleotides & Nucleic acids, £ 152528.doc 201121944 . 2〇, 1691-1704 (2001) 【發明内容】 [發明所欲解決之問題] 然而,該等對人dUTP酶之抑制活性均不充分,並非用 作醫藥品之化合物。 因此,本發明之課題在於提供一種具有優異之dUTp酶 抑制活性,且作為抗癌藥之效果增強劑等較為有用的化合 物或其鹽。 [解決問題之技術手段] 本發明者等人為解決上述課題而反覆進行努力研究,結 果發現5-氟尿嘴咳環N-1位具有續酿胺結構、或吼略咬·^ 基·羰基結構之5-氟尿嘧啶化合物或其鹽,具有優異之 UTP酶抑制活性,作為抗癌藥之效果增強劑等較為有 用;從而完成本發明。 P本發明提供一種5·氟尿嘴°定化合物或其鹽,其係由 下述式(I)表示: [化1][Technical Field] The present invention relates to a novel novel having excellent human dUTP enzyme inhibitory activity and useful as a disease-inducing agent for a dUTP enzyme, such as an anticancer drug. a fluorouracil compound or a salt thereof. [Prior Art] Deoxyuridine tri-acidase (hereinafter also referred to as doxylidine triphosphatase (EC 3.6.1.23)) is a prophylactic DNA (deoxyribonucleic acid) repair enzyme. It is considered that it only specifically recognizes deoxyuridine triphosphate (hereinafter referred to as dUTP (deoxyuridine triphosphate)) in natural nucleic acid triphosphate, and decomposes into deoxyuridine single wall acid (hereinafter referred to as dUMP (deoxyuridine monophosphate). An enzyme related to pyrophosphate (Non-Patent Document 1); the following two reactions are carried out: (1) by reducing the amount of dUTP in the cell, and avoiding urinary biting instead of thymine mis-mixing into the DNA; (2) A substrate dUMP for supplying thymidine synthase, which is an important de novo pathway for supplying thymine to DNA (Non-Patent Document 2). The dUTP enzyme is known to be essential for the survival of cells of both prokaryotes and eukaryotes. Therefore, it is suggested that the enzyme can be an anticancer drug (Non-Patent Document 3), an antimalarial drug (Patent Document 1 and Non-Patent Document 4), an antituberculosis drug (Non-Patent Document 5), and an anti-Helicobacter pylori drug (Patent Document 2) ), anti-parasitic drugs such as trypanosomes or Leishmania (Non-Patent Document 6), and cancer treatments such as human herpes simplex virus, cellular giant virus, Epstein-Barr (Eberstein-Barr) virus Antiviral drug 152528.doc 201121944 target such as virus (Non-Patent Document 7) or vaccinia virus (Non-Patent Document 8). As shown above, the dUTP enzyme has been attracting attention as a dry standard for therapeutic agents for various diseases, and extensive studies have been conducted on dUTP enzyme inhibitors. As the dUTP enzyme inhibitor, for example, a pseudotriphosphate type low molecular compound (for example, Patent Document 3, Non-Patent Document 9 and the like) and a 5'-0-substituted phenyl-deoxyuridine compound (Non-Patent Document 10) are known. [Prior Art Document] [Patent Document 1] [Patent Document 1] International Publication No. 2005/065689 Manual [Patent Document 2] International Publication No. 2003/089461 Handbook [Patent Document 3] International Publication No. 1995/15332 Manual [Non [Patent Document] [Non-Patent Document 1] Structure, 4, 1077-1092 (1996) [Non-Patent Document 2] Acta Biochim. Pol., 44, 159-171 (1997) [Non-Patent Document 3] Curr. Protein Pept. Sci., 2, 361-370 (2001) [Non-Patent Document 4] Structure, 13, 329-338 (2005) [Non-Patent Document 5] J. Mol. Biol., 341, 503-517 (2004) [Non Patent Document 6] Bioorg. Med. Chem. Lett., 16, 3809-3812 (2006) [Non-Patent Document 7] Curr. Protein Pept. Sci., 2, 371-379 (2001) [Non-Patent Document 8] Acta Crystallogr. D. Biol. Crystallogr, 63, 571-580 (2007) [Non-Patent Document 9] Mol. Pharmacol., 29, 288-292 (1986) [Non-Patent Document 1 N] Nucleosides Nucleotides & Nucleic Acids, £ 152528.doc 201121944 . 2〇, 1691-1704 (2001) [Summary of the Invention] [Problems to be Solved by the Invention] However, these inhibitory activities against human dUTP enzymes are insufficient, and are not used as pharmaceuticals. Compound. Therefore, an object of the present invention is to provide a compound or a salt thereof which is excellent in dUTp enzyme inhibitory activity and which is useful as an effect enhancer for an anticancer drug. [Means for Solving the Problem] The inventors of the present invention have repeatedly conducted an effort to solve the above problems, and as a result, have found that the N-1 position of the 5-fluorourine cough ring has a continuous amine structure or a slightly bite base group/carbonyl structure. The 5-fluorouracil compound or a salt thereof has excellent UTPase inhibitory activity and is useful as an effect enhancer for an anticancer drug, and the like. P The present invention provides a 5-fluorouridine compound or a salt thereof, which is represented by the following formula (I):

Γ通式⑴中’ η表示!〜3之數; (I) X表示鍵結、氧屌工 _ 于、硫原子、碳數2~6之伸稀基、可具有 取代基之2價芳香族 孩匕基、或者可具有取代基之2價飽和或 152528.doc 201121944 不餘和雜環基; y表示鍵結、或者碳數卜8之直鏈狀或支鏈狀伸院基; z表示-S〇2NRir2、_nr3s〇2_r4、或下述式: [化2] 人y R及R相同或不同’表不氫原子、碳數卜6之烷基或可具 有取代基之芳炫基,或者表示與鄰接之氮原子—併形成可 具有取代基之雜環基之基; R3表示氫原子或碳數1〜6之烷基; R表示可具有#代基之芳香族煙基或可具有取代基之不飽 和雜環基; R5表示可具有取代基之曱基]。 又,本發明提供一種醫藥組合物,其含有式⑴所示5-氟 尿嘧咬化合物或其鹽。 又,本發明提供一種dUTP酶抑制劑,其含有式⑴所示 5 -氟尿0^。定化合物或其鹽。 又,本發明提供一種式(I)所示5_氟尿嘧啶化合物或其 鹽,其係用以預防或治療dUTP酶參與之疾病。 又,本發明提供一種式(I)所示5-氟尿嘧啶化合物或其鹽 的用途,其係用以製造dUTP酶參與之疾病之預防藥或治 療藥。 進而,本發明提供一種dUTP酶參與之疾病的預防或治 152528.doc 201121944’ in the general formula (1) represents η! (I) X represents a bond, an oxygen enthalpy, a sulfur atom, a carbon number of 2 to 6, a divalent aromatic group having a substituent, or a substituent The valence of 2 is saturated or 152,528.doc 201121944 and the heterocyclic group; y represents a bond, or a linear or branched chain of carbon number 8; z represents -S〇2NRir2, _nr3s〇2_r4, or The following formula: [Chemical 2] Human y R and R are the same or different 'except hydrogen atom, carbon number 6 alkyl group or an aromatic group which may have a substituent, or may be formed with a neighboring nitrogen atom a group of a heterocyclic group having a substituent; R3 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms; and R represents an aromatic fluorenyl group which may have a substituent or an unsaturated heterocyclic group which may have a substituent; A thiol group which may have a substituent]. Further, the present invention provides a pharmaceutical composition comprising a 5-fluorouracil compound represented by formula (1) or a salt thereof. Further, the present invention provides a dUTP enzyme inhibitor comprising 5-fluorourine represented by the formula (1). A compound or a salt thereof. Further, the present invention provides a 5-fluorouracil compound of the formula (I) or a salt thereof for use in the prevention or treatment of a disease in which a dUTP enzyme is involved. Further, the present invention provides a use of a 5-fluorouracil compound of the formula (I) or a salt thereof for use as a prophylactic or therapeutic agent for a disease in which a dUTP enzyme is involved. Further, the present invention provides a disease prevention or treatment of dUTP enzyme involvement 152528.doc 201121944

療方法’其特徵在於:投予式(I 甘故 v)所不5_氟尿嘧啶化合物或 其鹽之有效量。 [發明之效果] 本發明之新穎5-氟尿嘧啶化合物The method of treatment is characterized in that an effective amount of the 5-fluorouracil compound or a salt thereof is not administered by the formula (I). [Effect of the Invention] Novel 5-fluorouracil compound of the present invention

〇物或其鹽具有優異之dUTP 酶抑制活性,作為dUTP酶參鱼之* — ,、之疾病、例如抗癌藥之效 果增強劑等較為有用。 【實施方式】 ,本發明之新穎5-氟尿嘴啶化合物之特徵在於:其係由上 述通式⑴表示’於5-銳尿嘧啶環N]位具有磺醯胺結構、 或。比咯啶-1-基-羰基結構。 於國際公開2005()65689號公報(專利文獻υ中揭示有具 有三苯甲*、三苯基残基等取代基(e(r6)(r7)(r8)基)作 為尿㈣環位取代基之末端的尿㈣化合物記載有 顯示出dUTP酶抑制活性’作為抗瘧疾藥較為有用。铁 而,並未揭示具有本發明之化合物所具有之續醯胺鍵的化 =物。又,如下述試驗例所示,具有三苯甲基作為尿㈣ 環N 1位取代基之末端的化合物幾乎未顯示出人扣丁? 制活性。 於日本專利特開2002·28娜號公報中揭示有經由經胺 酸殘基作為尿嘧啶環Ν]位取代基具有磺醯胺鍵之尿嘧啶 化合物。即於尿嘧啶環Ν]位上鍵結之伸烷基鏈上具有羥 胺酸基等作為取代基方面,與本發明之化合物不同。又, 载有“有MMP抑制作用,但完全未提及dUTp酶抑制活 性。 I52528.doc 201121944 本案說明書+ 女 之芳香族煙基,可二·;:族:基」,較佳為碳數6〜14 性方面’更佳為二本基、蔡基,一抑制活 個^二”飽和或不餘和雜環基」,較佳為具有1個或2 飽和或m y卞之任原子的早環性或二環性 哌畊其 雜裱基,例如可列舉:吡咯啶基、哌啶基、 \ : ”亞甲基亞胺基、嗎琳基、硫代嗎琳基、高派。定 四 =’坐基、噻吩基、呋喃基、吡咯基、呤唑基、異-号唑 、售唾基、異㈣基、対琳基、三峻基、四d坐基、。比 比井基、嘧啶基、嗒畊基、吲哚基、異吲哚基、吲 坐基、亞曱基二氧基苯基、伸乙基二氧基苯基、苯并咬。南 基一氫苯并呋喃基、苯并咪唑基、苯并嘮唑基、苯并噻 唑基、嘌呤基、喹啉基、異喹啉基、喹唑啉基、喹呵啉 基、四氫呋喃基、氫吡喃基等。其中,較佳為具有“固 氧原子或氮原子之任一者的5員〜7員飽和或不飽和雜環 基,於dUTP酶抑制活性方面,更佳為四氫呋喃基、 °比喃基、吡啶基。 又’作為「飽和雜環基」,較佳為具有1個或2個氧原 子、氮原子、硫原子之任一原子的單環性飽和雜環基,例 如可列舉:吡咯啶基、哌啶基、哌畊基、六亞甲基亞胺 基、嗎啉基、硫代嗎啉基、高哌啶基等。 作為「芳烧基」’可列舉經碳數6〜1 〇之芳香族烴基取代 之烧基’具體可列舉經苯基取代之碳數1〜6之烷基、經萘 基取代之碳數1〜6之烷基等。 152528.doc 201121944 作為上述芳㈣烴基、飽和或残和雜環基及芳燒基可 經取代之基(取代基),例如可列舉:齒素原子經基、氛 基、硝基、烷基、齒代烷基、環烷基環烷基·烷基、芳 烷基、婦基、燒氧基、齒代垸氧基、块基烧氧基、環院氧 基*炫基&氧基、芳燒氧基、烧硫基、環燒基·院硫 基、胺基、單或二貌基胺基、環焼基-貌基胺基、醯基、 酿氧基、側氧基、飽和或不飽和雜環基、芳香族煙基、飽 和雜環氧基等,於存在上述取代基之情形時,其個數通常 為1〜3個。 上述取代基中’作為鹵素原子,可列舉:氯原子、溴原 子、氟原子、蛾原子。 上述取代基中,作為烷基、鹵代烷基,較佳表示碳數 1〜6之直鏈狀或支鏈狀烷基或者該等烷基經上述鹵素原子 取代之基,可列舉:甲基、乙基、正丙基、異丙基、三氟 甲基等。 上述取代基中’作為環烷基’較佳為碳數3〜7之環烷 基,可列舉:環丙基、環丁基、環戊基 '環己基等。 上述取代基中,作為環烷基_烷基,較佳為經碳數3~7之 環烧基取代的碳數1〜6之烷基,可列舉:環丙基甲基、環 丙基乙基、環丁基甲基、環戊基甲基等。 上述取代基中’作為芳炫基,較佳為表示經碳數6〜丨4之 芳香族烴基取代的碳數之直鏈狀或支鏈狀烷基,可列 舉.苄基、苯基乙基、苯基丙基、萘基曱基、萘基乙基 等。 152528.doc 201121944 上述取代基中’作為烯基,表示含有碳_碳雙鍵之較佳 為碳數2〜6之烴基,可列舉:乙烯基、烯丙基、甲基乙烯 基、丙烯基、丁烯基、戊烯基、己烯基等。 上述取代基中,作為烷氧基、鹵代烷氧基、炔基烷氧 基,分別較佳為表示碳數卜6之直鏈狀或支鏈狀烷氧基、 該等烷氧基經上述鹵素原子取代之基、或該等烷氧基經碳 數2〜6之炔基取代之基,可列舉:曱氧基、乙氧基正丙 氧基、異丙氧基、1-曱基丙氧基、正丁氧基、第二丁氧 基、異丁氧基、2-曱基-丁氧基、新戊氧基、戊_2_基氧 基 '氟曱氧基、二氟甲氧基、三氟甲氧基、2_氟乙氧基、 1,1-二氣乙氧基、2,2-二氟乙氧基、2,2,2_三氟乙氧基、 1,1,2,2-四氟乙氧基、全氟乙氧基、3氟_2_(氣甲基丙氧 基、1,3-二氟丙-2·基氧基、2,2,3,3,3_五氟小丙氧基、丁· 3_炔-2-基氧基等。 上述取代基中,作為環烷氧基,較佳為碳數3〜7之環烷 氧基’可列舉:環㊉氧基、環丁氧基、環戊氧基、環己氧 基等》 上述取代基中,作為環烷基·烷氧基,較佳為經碳數3〜7 之環烷基取代的碳數卜6之烷氧基,可列舉:環丙基甲氧 基、環丙基乙氧基、環丁基甲氧基、環戊基甲氧基、⑴甲 基環丙基)甲氧基等。 上述取代基中,作為芳院氧基,較佳為表示具有上述芳 燒基之氧基’可列舉3氧基、苯基乙氧基、苯基丙氧 基、萘基甲氧基、萘基乙氧基等。The sputum or its salt has excellent dUTP enzyme inhibitory activity, and is useful as a disease of dUTP enzyme ginseng, and an effect agent such as an anticancer drug. [Embodiment] The novel 5-fluorouridine compound of the present invention is characterized in that it has a sulfonamide structure or a sulfonamide structure at the N-position of the 5-leuuracyclic ring from the above formula (1). Bilobidine-1-yl-carbonyl structure. A urethane (tetra) ring substituent is disclosed in Japanese Patent Laid-Open Publication No. 2005-65675 (Patent Document No.), which has a substituent such as a trityl* or a triphenyl residue (e(r6)(r7)(r8) group). The urinary (four) compound at the terminal is described as having an anti-malarial drug which exhibits dUTP-enzyme inhibitory activity. Iron does not disclose a hydrazine-containing bond having a compound of the present invention. Further, as the following test As shown in the examples, a compound having a trityl group as a terminal of the N 1 substituent of the urinary (tetra) ring hardly exhibits a human activity. It is disclosed in Japanese Patent Laid-Open Publication No. 2002-28 Na. The acid residue is a uracil compound having a sulfonamide bond as a urethane ring oxime substituent, that is, a hydroxyamino acid group or the like having a substituent on the alkyl chain bonded to the uracil ring oxime], The compound of the present invention is different. Further, it contains "the inhibition of MMP, but does not mention the activity of dUTp enzyme inhibition at all. I52528.doc 201121944 The present specification + the aromatic cigarette base of female, can be two;;: family: base", Preferably, the carbon number is 6 to 14, and the second aspect is better. a group, an inhibitory group of two or more saturated or heterocyclic groups, preferably an early or bicyclic group having one or two saturated or my hydrazine atoms, for example, For example, pyrrolidinyl, piperidinyl, \:"methyleneimido, morphinyl, thio- phenanthyl, gaoba. Dingsi = 'sityl, thienyl, furyl, pyrrolyl, Carbazolyl, iso-oxazole, salivation, iso-(tetra)yl, fluorene, trisyl, tetradyl, pyrene, pyrimidinyl, hydrazine, sulfhydryl, isodecyl , stilbene, fluorenyldioxyphenyl, ethylenedioxyphenyl, benzoated, succinyl, benzoxazolyl, benzoxazolyl, benzothiazole a group, a mercapto group, a quinolyl group, an isoquinolyl group, a quinazolinyl group, a quinoxalinyl group, a tetrahydrofuranyl group, a hydropyranyl group, etc. Among them, it is preferred to have either a "oxygen atom or a nitrogen atom" The 5- to 7-membered saturated or unsaturated heterocyclic group is more preferably a tetrahydrofuranyl group, a quaternary group or a pyridyl group in terms of dUTP enzyme inhibitory activity, and is also referred to as a "saturated heterocyclic group". Examples of the monocyclic saturated heterocyclic group having one or two oxygen atoms, nitrogen atoms, and sulfur atoms include pyrrolidinyl, piperidinyl, piperidinyl, and hexamethyleneimine. And a morpholinyl group, a thiomorpholinyl group, a homopiperidinyl group, etc. The "alkyl group" is exemplified by the alkyl group substituted with an aromatic hydrocarbon group having 6 to 1 carbon atoms. An alkyl group having 1 to 6 carbon atoms, an alkyl group having 1 to 6 carbon atoms substituted by a naphthyl group, etc. 152528.doc 201121944 A substitutable group as the above aromatic (tetra)hydrocarbyl group, a saturated or residual heterocyclic group, and an aryl group. (Substituent), for example, a dentate atom via a group, an aryl group, a nitro group, an alkyl group, a dentate alkyl group, a cycloalkylcycloalkyl group, an aralkyl group, a aryl group, an alkoxy group, Tooth oxime oxime, block alkoxy group, ring oxime oxyl group & oxy group, aryl alkoxy group, thiol group, cycloalkyl group, thiol group, amine group, mono or dimorphyl amine a sulfhydryl group, a fluorenyl group, a fluorenyl group, a fluorenyl group, a aryloxy group, a pendant oxy group, a saturated or unsaturated heterocyclic group, an aromatic fluorenyl group, a saturated heterocyclic oxy group, etc., in the presence of the above substituent When it is shaped, its number is usually 1 to 3. In the above substituent, 'the halogen atom' may, for example, be a chlorine atom, a bromine atom, a fluorine atom or a moth atom. In the above substituent, the alkyl group or the halogenated alkyl group preferably represents a linear or branched alkyl group having 1 to 6 carbon atoms or a group in which the alkyl group is substituted with the above halogen atom, and examples thereof include methyl group and ethyl group. Base, n-propyl, isopropyl, trifluoromethyl, and the like. In the above substituent, 'as a cycloalkyl group' is preferably a cycloalkyl group having 3 to 7 carbon atoms, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group and a cyclohexyl group. In the above substituent, the cycloalkyl-alkyl group is preferably an alkyl group having 1 to 6 carbon atoms which is substituted with a cycloalkyl group having 3 to 7 carbon atoms, and examples thereof include a cyclopropylmethyl group and a cyclopropyl group B. Base, cyclobutylmethyl, cyclopentylmethyl and the like. In the above substituent, 'as an aryl group, a linear or branched alkyl group having a carbon number substituted with an aromatic hydrocarbon group having 6 to 4 carbon atoms is preferable, and a benzyl group or a phenylethyl group is exemplified. , phenylpropyl, naphthylfluorenyl, naphthylethyl and the like. 152528.doc 201121944 In the above substituent, 'as an alkenyl group, a hydrocarbon group having a carbon-carbon double bond, preferably having a carbon number of 2 to 6, is exemplified by a vinyl group, an allyl group, a methylvinyl group, a propenyl group, and the like. Butenyl, pentenyl, hexenyl, and the like. In the above substituent, the alkoxy group, the halogenated alkoxy group, and the alkynyl alkoxy group are each preferably a linear or branched alkoxy group having a carbon number of 6, and the alkoxy group is bonded to the above halogen atom. The substituent group or the group in which the alkoxy group is substituted by the alkynyl group having 2 to 6 carbon atoms may, for example, be an anthracenyloxy group, an ethoxy-n-propoxy group, an isopropoxy group or a 1-mercaptopropoxy group. , n-butoxy, second butoxy, isobutoxy, 2-mercapto-butoxy, neopentyloxy, pent-2-yloxy 'fluorodecyloxy, difluoromethoxy, Trifluoromethoxy, 2-fluoroethoxy, 1,1-diethoxyethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 1,1,2 ,2-tetrafluoroethoxy, perfluoroethoxy, 3fluoro-2-((methylmethylpropoxy), 1,3-difluoropropan-2-yloxy, 2,2,3,3,3 _ pentafluoropropoxyl, butyl-3-alkyn-2-yloxy, etc. Among the above substituents, a cycloalkyloxy group is preferably a cycloalkyloxy group having 3 to 7 carbon atoms. Decano group, cyclobutoxy group, cyclopentyloxy group, cyclohexyloxy group and the like. Among the above substituents, a cycloalkyl·alkoxy group is preferably substituted with a cycloalkyl group having 3 to 7 carbon atoms. Bu 6 carbon atoms, alkoxy of include: cyclopropylmethoxy, cyclopropylethoxy, cyclobutylmethoxy, cyclopentyl methoxy, ⑴ methyl cyclopropyl) methoxy and the like. In the above substituent, the aryl group having the above-mentioned aryl group is preferably an oxy group, a phenylethoxy group, a phenylpropoxy group, a naphthylmethoxy group or a naphthyl group. Ethoxylate and the like.

S 152528.doc 201121944 上述取代基中,作為烷硫基’較佳為表示具有上述碳數 1〜6之烷基之硫基,可列舉:曱硫基、乙硫基、正丙硫基 等。 上述取代基中’作為環炫基-坑硫基’較佳為經碳數3〜7 之環烧基取代的碳數1〜6之烷硫基,可列舉:環丙基甲硫 基、環丙基乙硫基、環丁基甲硫基、環戊基甲硫基等。 上述取代基中,作為單或二烷基胺基,表示經上述烷基 單取代或二取代之胺基,可列舉:甲基胺基、二甲基胺 基、乙基胺基、二乙基胺基、甲基乙基胺基等。 上述取代基中,作為環烷基-烷基胺基,表示經上述環 烷基取代之烷基胺基,可列舉:環丙基甲基胺基、環丁基 曱基胺基、環戊基甲基胺基等。 上述取代基中,作為醯基’可列舉:甲醯基、乙醯基、 丙酿基、正丁酿基、異丁酿基、戊酿基、異戊酿基、特戍 醯基等具有直鏈或支鏈之碳數卜6之醯基、苯甲醯基等。 上述取代基中, 作為醯急其,άΓ抑组.,μ β -In the above substituent, the alkylthio group is preferably a thio group having an alkyl group having 1 to 6 carbon atoms, and examples thereof include a thiol group, an ethylthio group, a n-propylthio group and the like. In the above substituent, 'as cyclohexyl-p-thio group' is preferably an alkylthio group having 1 to 6 carbon atoms substituted by a cycloalkyl group having 3 to 7 carbon atoms, and examples thereof include a cyclopropylmethylthio group and a ring. Propylethylthio, cyclobutylmethylthio, cyclopentylmethylthio and the like. In the above substituent, the mono- or dialkylamino group means an amine group which is mono- or di-substituted with the above-mentioned alkyl group, and examples thereof include a methylamino group, a dimethylamino group, an ethylamino group, and a diethyl group. Amine group, methyl ethyl amine group and the like. In the above substituent, the cycloalkyl-alkylamino group represents an alkylamino group substituted by the above cycloalkyl group, and examples thereof include a cyclopropylmethylamino group, a cyclobutylguanidino group, and a cyclopentyl group. Methylamino group and the like. In the above substituent, examples of the fluorenyl group include a methyl group, an ethyl fluorenyl group, a propyl aryl group, a n-butyl aryl group, an isobutyl aryl group, a pentyl group, an isoprene group, and a thiol group. The carbon number of the chain or branch is a sulfhydryl group, a benzamidine group or the like. Among the above substituents, as an emergency, the depressing group, μ β -

苯甲醯氧基等。 上述取代基中,作為飽和或不飽和雜環基 較佳具有1個或2個氧原子、氮原子、Benzoyloxy and the like. Among the above substituents, the saturated or unsaturated heterocyclic group preferably has one or two oxygen atoms and a nitrogen atom.

嗎琳基 '高略咬基、 四氫呋喃基、 較佳為表示 氮原子、硫原子之任一原子的 飽和雜環基’例如可列舉··„比洛 亞甲基亞胺基、嗎你基、硫代 、四氫17比嗔基、咪D坐基、 I52528.doc •12· 201121944 噻吩基'呋喃基、吡咯基、嘮唑基、異崎唑基、噻唑基、 異噻唑基、吡唑啉基、三唑基、四唑基、吡啶基、吡畊 基、嘧啶基、嗒畊基、吲哚基、異吲哚基、吲唑基、亞甲 基二氧基苯基、伸乙基二氧基苯基、苯并呋喃基、二氫苯 并呋喃基、苯并咪唑基、苯并呤唑基、苯并噻唑基、嘌呤 基、喹啭基、異喹啉基、喹唑琳基、喹吟琳基等。 上述取代基中,作為芳香族烴基,較佳為表示碳數6〜14 之芳香族烴基’可列舉:苯基、萘基。 上述取代基中,作為飽和雜環氧基,表示具有上述飽和 雜環基之氧基,可列舉:四氫吱喃基氧基、四氫^南基氧 基0 於dUTP酶抑制活性 通式(I)中,作為n,表示1〜3之數 方面,較佳為1或3。 通式⑴中,X表示鍵結、氧原子、硫原子、碳數2〜6之 伸烯基、彳具有取代基之2價芳香族烴&、或纟可具有取 代基之2價飽和或不飽和雜環基。 X中,作為鍵結’較佳為單鍵。 X中,作為「碳數2〜6之伸烯基」,可例示上述伸烯基, 較佳為碳數2〜4之伸烯基,更佳為伸乙烯基。 土 作為X中之「可具有取代基之2價芳香族烴基、或者可具 有取代基之2價飽和或不飽和雜環基」之「料族煙基: 或者「飽和或不飽和雜環基」,可列舉與上述芳香族烴 基、及上述飽和或不飽和雜環基相同纟,尤佳為伸笨基、 或。比咬二基。 & 152528.doc £ 201121944 作為X ’於dUTP酶抑制活性方面,作為較佳之例示可列 舉:鍵結、氧原子、硫原子、伸乙烯基、伸苯基、吡啶二 基’尤佳為氧原子或伸乙稀基。 通式(I)中,Y表示鍵結、或者一個碳原子上可具有碳數 3〜6之環亞烷基結構的碳數丨〜8之直鏈狀或支鏈狀伸烷基, 較佳為鍵結、或者碳數卜8之直鏈狀或支鏈狀伸烷基。 此處’作為「直鏈狀或支鏈狀之碳數1〜8之伸烷基」,可 列舉.亞曱基、伸乙基、三亞甲基、四亞曱基、五亞曱 基、六亞甲基、伸丙基、伸丁基、二甲基三亞甲基、二甲 基四亞曱基、乙基三亞甲基、二乙基四亞曱基等。 又’通式(I)中’於X表示鍵結之情形時,(CH2)n_XY表 示碳數3〜6之伸烷基,較佳為三亞曱基或五亞甲基。 作為Y ’於dUTP酶抑制活性方面,作為較佳之例,可列 舉:鍵結、或者直鏈狀或支鏈狀之碳數卜8之伸烷基,尤 佳為伸乙基、二亞曱基(其中,於X表示鍵結之情形時, (CH2)n-X-Y表示三亞曱基或五亞曱基)。 通式⑴中’Z表示-SOzNRiR2或_nR3S02-R4、或者下述 式: [化3] R5 ζ中,R1及R2相同或不同,表示氫原子、碳數卜6之烷基 或可具有取代基之芳烷基,或者表示與鄰接之氮原子一併 152528.doc •14· 201121944 形成可具有取代基之飽和雜環基之基。 R1及R2中,作為「碳數1〜6之烷基」,表示碳數丨〜6之直 鏈狀或支鏈狀烷基’可列舉:甲基、乙基、正丙基、異丙 基、正丁基、第二丁基、第三丁基、正戊基、正己基等。 R及R2中,作為「可具有取代基之芳烷基」之「芳烷 基」,較佳為經碳數6〜14之可具有取代基之芳香族烴基取 代的碳數1〜6之直鏈狀或支鏈狀烷基,可列舉:苄基、苯 基乙基、苯基丙基、萘基曱基、萘基乙基等,較佳為苄 基。 ' 於構成上述「芳烷基」之經碳數6〜14之可具有取代基之 芳香奴經基取代的碳數1〜6之直鏈狀或支鏈狀烷基中,於 該烧基具有取代基之情形時,作為該取代基,可列舉:經 基,甲基、乙基、正丙基、異丙基、2_甲基丙基、正丁 基、正戊基等碳數1〜6之烷基;環丙基、環丁基、環戊 基、環己基等碳數3〜7之環烷基;甲硫基、乙硫基、正丙 硫基、異丙硫基等碳數1〜6之烷硫基;可具有鹵素原子、 甲氧基、乙氧基、異丁氧基、環丁氧基、環戊氧基'環丙 基甲氧基等取代基之芳香族烴基或噻吩基等不飽和雜環 基,可具有相同或不同之i〜2個取代基。又,於2個該取代 基為碳數1〜6之烷基之情形時,該烷基之碳原子彼此可形 成%亞炫《基結構。 又’構成上述「芳烷基」之經碳數6〜14之可具有取代基 之方香族烴基取代的碳數1〜6之直鏈狀或支鏈狀烷基中, 於"亥芳香族烴基具有取代基之情形時,作為該取代基可The hydrazinyl group is a succinyl group, a tetrahydrofuranyl group, and a saturated heterocyclic group which is preferably a nitrogen atom or a sulfur atom. Thio, tetrahydrogen 17 fluorenyl, imine D, I52528.doc •12· 201121944 thienyl 'furanyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazoline , triazolyl, tetrazolyl, pyridyl, pyridinyl, pyrimidinyl, hydrazine, decyl, isodecyl, carbazolyl, methylenedioxyphenyl, ethylidene Oxyphenyl, benzofuranyl, dihydrobenzofuranyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indolyl, quinacridyl, isoquinolinyl, quinazoline, In the above substituent, the aromatic hydrocarbon group preferably has an aromatic hydrocarbon group of 6 to 14 carbon atoms, and examples thereof include a phenyl group and a naphthyl group. Among the above substituents, a saturated heterocyclic oxy group is used. And an oxy group having the above saturated heterocyclic group, which may be exemplified by tetrahydrofuranyloxy group, tetrahydroanthranyloxy group 0, and dUTP enzyme inhibitory activity. In the formula (I), n is a number of 1 to 3, preferably 1 or 3. In the formula (1), X represents a bond, an oxygen atom, a sulfur atom, an alkenyl group having 2 to 6 carbon atoms, a divalent aromatic hydrocarbon having a substituent; or a divalent saturated or unsaturated heterocyclic group which may have a substituent. In X, a bond is preferably a single bond. In X, as a carbon number The alkenyl group of 2 to 6 may, for example, be an alkenyl group, preferably an alkenyl group having 2 to 4 carbon atoms, more preferably a vinyl group. The soil is referred to as "a divalent aromatic hydrocarbon group which may have a substituent or a divalent saturated or unsaturated heterocyclic group which may have a substituent" in X. "Organic group of smoke groups: or "saturated or unsaturated heterocyclic group" The above-mentioned aromatic hydrocarbon group and the above-mentioned saturated or unsaturated heterocyclic group may be the same, and particularly preferably a stabilizing group. Than two bases. & 152528.doc £ 201121944 As a preferred example of X' in the dUTP enzyme inhibitory activity, a bond, an oxygen atom, a sulfur atom, a vinyl group, a phenylene group, a pyridyl group, and an oxygen atom are preferred. Or stretch the base. In the formula (I), Y represents a bond, or a linear or branched alkyl group having a carbon number of 丨8 or more having a ring alkylene structure having a carbon number of 3 to 6 on one carbon atom, preferably It is a linear or branched alkyl group which is a bond or a carbon number of 8. Here, 'as a linear or branched alkyl group having 1 to 8 carbon atoms, an alkylene group, an exoethyl group, a trimethylene group, a tetradecylene group, a penta-indenyl group, and a sixth group are mentioned. Methylene, propyl, butyl, dimethyltrimethylene, dimethyltetralinylene, ethyltrimethylene, diethyltetradecyl, and the like. Further, in the case where "wherein" represents a bond in the formula (I), (CH2)n_XY represents an alkylene group having 3 to 6 carbon atoms, preferably a triindenylene group or a pentamethylene group. As a preferable example of Y' in the dUTP enzyme inhibitory activity, a bond or a linear or branched carbon number of the alkyl group is preferred, and an ethyl group and a diterpene group are particularly preferred. (Where, when X represents a bond, (CH2)nXY represents a tri-indenyl group or a penta-indenyl group). In the formula (1), 'Z represents -SOzNRiR2 or _nR3S02-R4, or the following formula: [Chem. 3] R5 In the oxime, R1 and R2 are the same or different and each represents a hydrogen atom, a carbon number of 6 or an alkyl group. An aralkyl group, or a unit of a saturated heterocyclic group which may have a substituent, 152528.doc •14·201121944. In R1 and R2, the "alkyl group having 1 to 6 carbon atoms" and the linear or branched alkyl group having a carbon number of 丨6 are exemplified by methyl, ethyl, n-propyl and isopropyl. , n-butyl, t-butyl, tert-butyl, n-pentyl, n-hexyl, and the like. In the case of R and R2, the "aralkyl group" which is a "aroyl group which may have a substituent" is preferably a carbon number of 1 to 6 which is substituted with an aromatic hydrocarbon group having a substituent of 6 to 14 carbon atoms. The chain or branched alkyl group may, for example, be a benzyl group, a phenylethyl group, a phenylpropyl group, a naphthylfluorenyl group or a naphthylethyl group, and is preferably a benzyl group. And a linear or branched alkyl group having 1 to 6 carbon atoms which is substituted with an aromatic aryl group which may have a substituent of 6 to 14 carbon atoms which constitutes the above-mentioned "aralkyl group", and has a linear or branched alkyl group having 1 to 6 carbon atoms; In the case of a substituent, examples of the substituent include a carbon number of a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a 2-methylpropyl group, a n-butyl group, a n-pentyl group, and the like. 6 alkyl; cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and other cycloalkyl groups having a carbon number of 3 to 7; methylthio, ethylthio, n-propylthio, isopropylthio and the like An alkylthio group of 1 to 6; an aromatic hydrocarbon group which may have a substituent such as a halogen atom, a methoxy group, an ethoxy group, an isobutoxy group, a cyclobutoxy group, a cyclopentyloxy 'cyclopropylmethoxy group or The unsaturated heterocyclic group such as a thienyl group may have the same or different i~2 substituents. Further, in the case where two of the substituents are an alkyl group having 1 to 6 carbon atoms, the carbon atoms of the alkyl group may form a % sub-glossy "base structure". Further, in the linear or branched alkyl group having 1 to 6 carbon atoms substituted by the aromatic hydrocarbon group having a carbon number of 6 to 14 and having a substituent of the above-mentioned "aralkyl group", When the group of a hydrocarbon group has a substituent, the substituent may be used.

S 152528.doc -15- 201121944 、破原子等鹵素原子;可S 152528.doc -15- 201121944, a halogen atom such as a broken atom;

基-烷硫基;可具有i〜2個該等取代基之任一 列舉_·氟原子、氯原子、溴原子 具有p至基、鹵素原子、乙炔基、 或支鍵狀之碳數1〜6之貌氧基;: 戊氧基、環己氧基等碳數3〜7之 通式(I)中,作為Ri、R2可與鄰接之氮原子一併形成之 「可具有取代基之飽和雜環基」之r飽和雜環基」,可列 舉上述飽和雜環基。 通式(I)中,作為R1、R2可與鄰接之氮原子一併形成之 「可具有取代基之飽和雜環基」之「取代基」,可列舉上 述取代基。 即,作為R1,於dUTP酶抑制活性方面,作為較佳之例 示’可列舉氫原子’作為R2,於dUTP酶抑制活性方面, 作為較佳之例示,可列舉可具有取代基之苄基[於該苄基 之亞曱基具有取代基之情形時’作為該取代基,可具有相 同或不同之卜2個羥基、碳數1〜6之烷基、碳數3〜7之環烧 基 '碳數1〜6之烷硫基、可具有取代基之芳香族烴基或不 飽和雜環基(於2個該取代基為碳數1〜6之烷基之情形時, 該烷基之碳原子彼此可形成環亞烷基結構),於該节美之 152528.doc -16 - 201121944 苯基具有取代基之情形時,作為該取代基,可具有卜2個 i素原子、可具有取代基之直鏈狀或支鏈狀之碳數卜6之 烷氧基、碳數3〜7之環烷氧基、碳數3〜7之環烷基烷氧 基、碳數3〜7之環烷基_烷硫基及飽和雜環氧基之任一 者]0 Z中,R3表示氫原子或碳數卜6之烷基,作為「碳數卜石 之烷基」’可列舉與!^及R2中之烷基相同之基。其中,於 dUTP酶抑制活性方面,較佳為氫原子。 中R表示可具有取代基之芳香族煙基或可具有取代 基之不飽和雜環基。 R中’作S「可具有取代基之芳香族煙基」之「芳香族 煙基」’可例示上述芳香族煙美# 4万戈撕/工丞,於duTP酶抑制活性方 面,較佳為苯基。 R4中’作為「可具有取代基之芳香族烴基」之「取代 基可列舉上述「取代基」’較佳為可經齒素取代之碳數 1〜6之烧氧基、碳數3〜7之我氧基、碳數3〜7之環烧基-烧 氧基’更佳為環丙基甲氧基、2,2_二氣乙氧基、 基。 R中’作為「可具有取代基之不飽和雜環基」之「不飽 和雜環基」,可例示上述不飽和雜環基。 R4中’作為「可具有取代基之不飽和雜環基」之「取代 基」,可例示上述取代基。 R5中 舉上述 作為「具有取代基之〒基」之「取代基」,可列 取代基」’較佳為芳香族烴基、經基,較佳為苯 £ 152528.doc -17· 201121944Any one of the substituents having i~2 such substituents may be a fluorine atom, a chlorine atom, a bromine atom having a p to a group, a halogen atom, an ethynyl group, or a bond-like carbon number of 1~ 6 oxy;; pentyloxy, cyclohexyloxy and the like in the general formula (I) having a carbon number of 3 to 7, as Ri and R2 may be formed together with an adjacent nitrogen atom, "may have a saturation of a substituent. The saturated heterocyclic group of the heterocyclic group "R saturated heterocyclic group" is exemplified. In the above formula (I), the "substituent" of the "saturated heterocyclic group which may have a substituent" which may be formed by a combination of a nitrogen atom and an adjacent nitrogen atom may be mentioned. In other words, R1 is a preferred example of the dUTP enzyme inhibitory activity, and a hydrogen atom is exemplified as R2. The dUTP enzyme inhibitory activity is preferably exemplified as a benzyl group which may have a substituent. When the sulfhydryl group has a substituent, 'as the substituent, it may have the same or different 2 hydroxyl groups, an alkyl group having 1 to 6 carbon atoms, and a cycloalkyl group having a carbon number of 3 to 7 carbon number 1 An alkylthio group of 1-6, an aromatic hydrocarbon group which may have a substituent or an unsaturated heterocyclic group (in the case where two substituents are an alkyl group having 1 to 6 carbon atoms, the carbon atoms of the alkyl group may form each other a cycloalkylene structure), in the case of a phenyl group having a substituent in the case of a phenyl group, 152528.doc -16 - 201121944, as the substituent, may have two im atoms and a linear chain which may have a substituent Or a branched alkoxy group of 6 carbon atoms, a cycloalkoxy group having 3 to 7 carbon atoms, a cycloalkylalkoxy group having 3 to 7 carbon atoms, a cycloalkyl group of a carbon number of 3 to 7 Any one of a group and a saturated heterocyclic oxy group], in the case of 0 Z, R3 represents a hydrogen atom or an alkyl group having a carbon number of 6 and can be listed as an "alkyl group of carbon number The same base as the alkyl group in !^ and R2. Among them, in terms of dUTP enzyme inhibitory activity, a hydrogen atom is preferred. Wherein R represents an aromatic fluorenyl group which may have a substituent or an unsaturated heterocyclic group which may have a substituent. The "aromatic smoke base" which is the "aromatic group which can have a substituent" in R can be exemplified by the above aromatic smoked product, and is preferably used in the case of the duTPase inhibitory activity. Phenyl. The "substituent of the "aromatic group which may have a substituent" in R4 is preferably an alkoxy group having 1 to 6 carbon atoms which may be substituted by dentate, and has a carbon number of 3 to 7. The cyclooxy-alkoxy group of the oxy group having a carbon number of 3 to 7 is more preferably a cyclopropylmethoxy group, a 2,2-dioxyethoxy group or a group. The "unsaturated heterocyclic group" which is "unsaturated heterocyclic group which may have a substituent" in R may, for example, be the above-mentioned unsaturated heterocyclic group. The "substituent" as the "unsaturated heterocyclic group which may have a substituent" in R4 may, for example, be the above substituent. R5 is a "substituent" as a "substituent group", and a substituent "" is preferably an aromatic hydrocarbon group or a mercapto group, preferably benzene. 152528.doc -17· 201121944

基、經基。該芳香族烴A 基了進而具有取代基,較佳為鹵素 原子’尤佳為氟原子。 乍為式(I)所7F化合物之藥學上所容許之鹽,可列舉:與 鹽酸、氫漠酸、氫硬酸、硫酸、硝酸、墻酸等無機酸,或Base, base. The aromatic hydrocarbon A group further has a substituent, and preferably a halogen atom ' is particularly preferably a fluorine atom. The pharmaceutically acceptable salt of the compound of the formula (I), which is a compound of the formula (I), may be exemplified by inorganic acids such as hydrochloric acid, hydrogen acid, hard acid, sulfuric acid, nitric acid, and wall acid, or

甲酸、乙酸、丙酸、苜缺 T 草敲、丙二酸、丁二酸、反丁烯二 酸、順丁烯項、乳酸、頻果酸、檸檬酸、酒石酸、碳 酸、、苦味酸、甲料、對甲苯韻、谷胺酸等有機酸之酸 加成鹽’納、卸、鎮、每、紹等無機驗,或甲基胺、乙基 胺葡甲胺乙醇胺等有機驗,或與甜菜驗、精胺酸、鳥 胺酸等驗性胺基酸之鹽或錄鹽。X,本發明之化合物中亦 含有光學異構物,亦含有水合物。 本發明之5_氟尿切化合物可依據下述反應步驟式而製 造: [化4]Formic acid, acetic acid, propionic acid, 苜T grass knock, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, frequency fruit acid, citric acid, tartaric acid, carbonic acid, picric acid, nail Ingredients, toluene rhyme, glutamic acid and other organic acid acid addition salts 'Na, unloading, town, each, Shao and other inorganic tests, or methylamine, ethylamine meglumine, ethanolamine and other organic tests, or with beets Test, arginine, ornithine and other salts of the test amine acid or recorded salt. X, the compound of the present invention also contains an optical isomer and also contains a hydrate. The 5-fluorourea compound of the present invention can be produced according to the following reaction step: [Chemical 4]

步驟AStep A

(1) 甲丄9 (2)或 Ra〇H(3> A-1(1) Hyperthyroidism 9 (2) or Ra〇H (3> A-1

[式中,Ra表示可具有取代基之直鏈狀或支鏈狀之碳數i〜6 之烷基、碳數3〜7之環烷基、碳數3〜7之環烷基_烷基、及 飽和雜環基之任一者,Lg表示齒素原子、曱基磺醯氧基、 對曱笨%醯氧基、三氟甲基續醯氧基等脫離基]。 [A-1] (a)本步驟中,可藉由於鹼存在下使可容易獲取之3氰基 i52528.doc •18- 201121944 苯紛(1)與通式所示烷基鹵化物' 烷基甲磺酸酯、烷基 甲苯確酸醋、或院基三氟甲磺酸酯等進行反應,而製造上 述通式(4)所示化合物。[wherein, Ra represents a linear or branched alkyl group having an alkyl number i to 6 which may have a substituent, a cycloalkyl group having 3 to 7 carbon atoms, or a cycloalkyl group having a carbon number of 3 to 7 And any of the saturated heterocyclic groups, Lg represents a dentate atom, a fluorenylsulfonyloxy group, a fluorenyloxy group, a trifluoromethyl fluorenyloxy group or the like. [A-1] (a) In this step, it can be easily obtained by the presence of a base. 3 Cyano i52528.doc • 18- 201121944 Benzene (1) and an alkyl halide of the formula 'Alkyl The compound represented by the above formula (4) is produced by reacting a mesylate, an alkyl toluene vinegar, or a hospital-based triflate.

作為所使用之反應溶劑,若為對反應不造成影響者,則 無特別限制,可例示:二乙醚、四氫呋喃(以下為 THF(tetrahydr〇fUran))、二噚烷、丙酮、二甲氧基乙烷、 乙腈、N,N-二曱基甲醯胺(以下為DMF(N,N-dimethylformamide))、N,N-二曱基乙醯胺(以下為 DMA(N,N-dimethylacetamide))、二甲基亞砜(以下為 DMSO (dimethyl sulfoxide))等,較佳為!;)]^。 作為所使用之驗,可例示:碳酸氫鈉、碳酸鈉、碳酸 钾、碳酸鉋、氫化鈉、氫化鉀等無機鹼或三甲基胺、三乙 基胺、三丙基胺、二異丙基乙基胺、N-甲基嗎啉、吡啶、 二曱基。比咬、三曱基》比啶等有機胺類,較佳為碳酸鉀。其 當量數為0.8〜10當量,較佳為1〇〜5 〇當量。 通式(2)之當量數為〇.8〜1〇當量,較佳為ι·〇〜5.0當量。反 應溫度為20〜150°C,較佳為50〜130°C。反應時間為0.5〜24 小時,較佳為1.0〜12小時。 (b)本步驟中,亦可藉由利用光延反應使可容易獲取之3_ 氰基苯酚(1)與通式(3)所示醇縮合,而製造通式(4)所示化 合物。 作為所使用之反應溶劑’若為對反應不造成影響者,則 無特別限制,可例示:二氯甲烷、12-二氣乙烷(以下為 DCE(l,2-dichloroethane))、苯、二曱苯、甲笨、乙酸乙 152528,doc 201121944 s旨、乙酸丙s旨、乙酸丁醋、二乙趟、THF、。号烷、兩 酮、二甲氧基乙烷、乙腈、DMF等,較佳為THF。 作為光延反應巾所制之觸,若為通常光延反應中可 使用之試劑則無特別限制,為偶氮二甲酸二乙酯(以下為 DEAD(diethyl azodicarboxylate))、偶氮二曱酸二異丙酯 (以下為 DIAD(diis〇propyl azodicarb〇xyiate))之類的偶氮二 甲酸二低級烷基酯,或1,1·-(偶氮二羰基)二哌啶之類的偶 氮二羰基等偶氮化合物與三苯基膦之類的三芳基膦或三· 正丁基膦之類的三低級烷基膦等的組合。較佳為DEAD、 三苯基膦之組合。 通式(3)、偶氮二甲酸二低級烷基酯或偶氮化合物、三 芳基膦或三低級烷基膦之當量數分別為〇 8〜5 〇當量,較佳 為1.0〜2.0當量。反應溫度為_2〇。〇〜12(TC ,較佳為 0〜60 C。反應時間為0.1〜24小時’較佳為〇·2〜6.0小時。 [A-2] 本步驟中’可藉由使通式(4)所示氰基化合物與通常眾 所周知之還原劑進行反應而製造通式(5)所示化合物。 作為所使用之反應溶劑’根據所使用之還原反應之種類 而有所不同,可例示:曱醇、乙醇、1-丙醇、2-丙醇、第 三丁醇、二甲氧基乙烷、二乙二醇二曱醚、二異丙醚、二 乙醚、THF、二呤烷等,較佳為THF。 作為所使用之還原劑,可例示使用氫化鋁鋰(以下為 LAH(lithium aluminium hydride))、氫化二乙氧基紹鐘、氮 化二乙氧基铭链、氫化三-第三丁氧基铭Μ、氫化叙鎂、 152528.doc -20- 201121944 氫化鋁氯化鎂、氫化鋁鈉、氫化三乙氧基鋁鈉、氫化雙(2_ 甲氧基乙氧基)鋁鈉、或鈀/碳、氫氧化鈀、鉑之類的觸媒 之接觸還原,較佳為LAH。其當量數為〇.5〜5.0當量,較佳 為0.8-2.0當量。反應溫度為〇〇c〜1〇〇〇c,較佳為2〇〜6(rc。 反應時間為0.1〜24小時’較佳為0.2〜6.0小時。 [化5]The reaction solvent to be used is not particularly limited as long as it does not affect the reaction, and examples thereof include diethyl ether and tetrahydrofuran (hereinafter, THF (tetrahydr〇fUran)), dioxane, acetone, and dimethoxy B. Alkane, acetonitrile, N,N-dimercaptocarboxamide (hereinafter, DMF (N, N-dimethylformamide)), N,N-dimercaptoacetamide (hereinafter, DMA (N, N-dimethylacetamide)), Dimethyl sulfoxide (hereinafter DMSO (dimethyl sulfoxide)), etc., preferably! ;)]^. As the test to be used, an inorganic base such as sodium hydrogencarbonate, sodium carbonate, potassium carbonate, carbonic acid planer, sodium hydride or potassium hydride or trimethylamine, triethylamine, tripropylamine or diisopropyl can be exemplified. Ethylamine, N-methylmorpholine, pyridine, dimercapto. An organic amine such as a bite or a triterpene group, preferably a potassium carbonate. The number of equivalents is from 0.8 to 10 equivalents, preferably from 1 to 5 equivalents. The equivalent number of the formula (2) is 〇.8 to 1 〇 equivalent, preferably ι·〇 to 5.0 equivalent. The reaction temperature is 20 to 150 ° C, preferably 50 to 130 ° C. The reaction time is from 0.5 to 24 hours, preferably from 1.0 to 12 hours. (b) In this step, the compound represented by the formula (4) can also be produced by condensing the easily obtainable 3-cyanophenol (1) with the alcohol represented by the formula (3) by a light-diffusing reaction. The reaction solvent to be used is not particularly limited as long as it does not affect the reaction, and examples thereof include dichloromethane, 12-dioxaethane (hereinafter, DCE (1,2-dichloroethane)), benzene, and Toluene, methyl stupid, ethyl acetate 152528, doc 201121944 s, acetic acid propyl, acetic acid butyl vinegar, diethyl hydrazine, THF. Alkane, diketone, dimethoxyethane, acetonitrile, DMF, etc., preferably THF. The touch made by the light-reacting reaction towel is not particularly limited as long as it is a reagent which can be used in a usual light-span reaction, and is diethyl azodicarboxylate (hereinafter, DEAD (diethyl azodicarboxylate)), diisopropyl azodicarboxylate An ester (hereinafter, DIAD (diis〇propyl azodicarb〇xyiate)), a diazoalkyl azodicarboxylate, or an azodicarbonyl group such as 1,1·-(azodicarbonyl)dipiperidine A combination of an azo compound and a triarylphosphine such as triphenylphosphine or a tri-lower alkylphosphine such as tri-n-butylphosphine. A combination of DEAD and triphenylphosphine is preferred. The equivalent number of the general formula (3), the di-lower alkyl azodicarboxylate or the azo compound, the triarylphosphine or the tri-lower alkylphosphine is 〇 8 to 5 〇 equivalents, preferably 1.0 to 2.0 equivalents. The reaction temperature was _2 Torr. 〇~12 (TC, preferably 0 to 60 C. The reaction time is 0.1 to 24 hours' is preferably 〇·2 to 6.0 hours. [A-2] In this step, 'the general formula (4) can be made The cyano compound shown is reacted with a generally known reducing agent to produce a compound of the formula (5). The reaction solvent used 'is different depending on the kind of the reduction reaction to be used, and examples thereof include decyl alcohol, Ethanol, 1-propanol, 2-propanol, tert-butanol, dimethoxyethane, diethylene glycol dioxime ether, diisopropyl ether, diethyl ether, THF, dioxane, etc., preferably As the reducing agent to be used, lithium aluminum hydride (hereinafter referred to as LAH (lithium aluminium hydride)), hydrogenated diethoxy oxime, nitrided diethoxy chain, hydrogenated tri-tertiary butoxide can be exemplified.基铭Μ, Hydrazine, 152528.doc -20- 201121944 Aluminum hydride magnesium chloride, sodium aluminum hydride, sodium triethoxyaluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride, or palladium/carbon, The contact reduction of a catalyst such as palladium hydroxide or platinum is preferably LAH, and the number of equivalents is 〇5 to 5.0 equivalents, preferably 0.8 to 2.0 equivalents. The reaction temperature is 〇〇c~1〇〇〇c, preferably 2〇~6 (RC. The reaction time is 0.1~24 hours' preferably 0.2~6.0 hours. [Formula 5]

步驟B ” Κ°〇Η(7)Step B ”°°〇Η(7)

[式中,Ra及Lg與上述含義相同,Rb表示氫原子或齒素原 子,RC、Rd分別獨立表示氫原子或可具有取代基的直鏈狀 或支鏈狀之碳數丨〜6之烷基,Hal表示鹵素原子]。 [B-1] 本步驟中,可利用通常眾所周知之方法,利用醇化合物 (7)使可容易獲取之化合物(6)之羧基酯化後,利用與[A i] 之步驟相同之方法,製造通式(8)所示化合物。 [B-2] 本步驟中,可藉由使通式(8)所示化合物與通常眾所周 头之還原劑進行反應而製造通式(9)所示化合物。 152528.doc • 21- 201121944 作為所使用之反應溶劑,若為不對反應造成影響者,則 無特別限制,可例示:二乙醚、二異丙醚、THF、二噚烷 等’較佳為THF。 作為所使用之還原劑,可例示:LAH、氫化二乙氧基鋁 鐘、氫化三乙氧基鋁鋰、氫化三-第三丁氧基鋁鋰、氫化 紹鎂、氫化鋁氯化鎂、氫化鋁鈉、氫化三乙氧基鋁鈉、氫 化雙(2-甲氧基乙氧基)鋁鈉、氫化二異丁基鋁(以下為 DIBAL(diis〇butyl aluminum hydride))、氫糊化鐘等,較佳 為氫侧化鋰。其當量數為0.8〜10當量,較佳為1.0〜5.0當 量。反應溫度為〜溶劑之沸點溫度,較佳為溶劑之沸點 溫度。反應時間為〇1〜24小時,較佳為2小時。 [B-3] 本步驟中,可藉由使通式(9)所示化合物與通常眾所周 知之氧化劑進行反應而製造通式(丨〇)所示醛化合物。 作為所使用之反應溶劑,若為對反應不造成影響者,則 無特別限制’可例示:二氯曱烷、氯仿、四氣化碳、 DCE、氣苯、甲苯、二曱苯等,較佳為二氯甲烷。 作為所使用之氧化劑,可例示:鉻酸酐、吡啶及乙酸肝 之複合試劑,吡啶氣鉻酸鹽、吡啶二鉻酸鹽等鉻系氧化 劑’ Dess-Martin(戴斯_馬丁)試劑等高原子價碘氧化劑、將 DMSO與乙酸酐、草醯氯、二環己基碳二醯亞胺(以下為 DCC(diCycl〇heXyl carb〇diimide))、•乙基 _3 (3 二曱基 胺基丙基)碳二醯亞胺鹽酸鹽(以下為ΕοοΗεΚί-ΜΐιγΜ- Ο dimethyl aminopr〇pyl)carbodiimide.HCl)) 組合 使用之 152528.doc -22· 201121944 DMSO系氧化劑,氧化猛(Iv)、2,2,6,6_四甲基裉唆小氧自 由基;較佳為氧化錳(IV)。其當量數為〇 8〜3〇,當量 ,較佳 為^〜2〇當量。反應溫度為-20〜15(TC,較佳為0〜100t。 反應時間為0.1〜24小時,較佳為0 5〜12小時。 又於R為氫原子之情形時,可將可容易獲取之3-經基 苯甲經作為起始原料,利用與[H]相同之方法而製造通 式(10)所不化合物H亦可藉由對通式⑷所示猜化合 物進行之通?ji眾所周知之還原反應、例如還原法, 而製造通式(10)所示化合物。 [B-4] 、本步驟中’可藉由使上述通式⑽)所示化合物與可容易 獲取之2·甲基·2·丙、酿胺於酸性條件下進行反應,而製造 上述通式(11)所示化合物。 作為所使用之反應溶劑,只要為不對反應造成影響者, 則無特別限制,可例示:二乙_ '二異丙醚、thf、二哼 燒一氣甲炫、氯仿、四氯化碳、曱苯、二曱苯等,較佳 為曱苯。 作為所使用之酸,可例示:鹽酸、硫酸鎂、對甲苯磺 酸、或四異丙醇鈦、四乙醇鈦等路易斯酸’較佳為四異丙 醇鈦。2-曱基-2-丙磺醯胺與四異丙醇鈦之當量數分別為 8 1〇备Ϊ,較佳為1.〇〜3 〇當量。反應溫度為2〇〜i5〇〇c, 較佳為50〜120 C反應時間為0.1〜24小時,較佳為〇.5〜6.0 小時。 [B-5] £ 152528.doc -23 201121944 本步驟中,可藉由.使通式(11)所示化合物與RdMgHal所 示Grignard試劑(12)或RdLi所示有機鋰試劑(13)進行反應, 而非對映選擇地製造通式(14)所示化合物。 作為所使用之反應溶劑,若為對反應不造成影響者,則 無特別限制,可例示:二乙醚、二異丙醚、第三丁基甲 醚、環戊基甲醚、THF、二甲氧基乙烷、二嘮烷、二氯甲 烧、氯仿、四氯化碳、甲苯、二甲苯等。Grignard試劑或 有機鋰試劑之當量為0.8〜20當量,較佳為1.0〜10當量。反 應溫度為_100°c〜100〇c,較佳為-78。〇〜50〇c。反應時間為 0.1〜24小時,較佳為〇.5~12小時。 [B-6] 本步驟中,可藉由利用酸對通式(14)所示化合物進行處 理’而製造通式(15)所示化合物。 作為所使用之溶劑,若為對反應未造成影響者,則無特 別限制’可例示:甲醇、乙醇、1 -丙醇、2-丙醇、1 _ 丁 醇、2-丁醇等醇類及二„号燒、乙酸乙酯等,較佳為曱醇。 作為所使用之酸’可例示:鹽酸、硫酸、構酸等,較佳 為鹽酸。其當量數為01〜10當量,較佳為1 〇〜2·0當量。反 應溫度為-2(TC〜10〇t,較佳為〇〜5〇。(:。反應時間為 〇.01〜24小時’較佳為0.1〜1.0小時。 又’於Rd為氫原子之情形時,亦可藉由利用通常眾所周 知之方法,使通式(9)所示化合物疊氮化後,利用通常眾所 周知之還原劑(例如LAH)進行處理,而製造通式(15)所示 化合物。進而,亦可藉由於以消旋體獲得通式(15)所示化 152528.doc •24· 201121944 合物之情形時’利用與步驟b.5相同之方法,將通式⑽所 不化合物轉換成醇化合物,利用通常眾所周知之方法疊氮 化後1用通常眾所周知之方法進行還原,而製造通式 (15)所不化合物: [化6][In the formula, Ra and Lg have the same meanings as above, Rb represents a hydrogen atom or a dentate atom, and RC and Rd each independently represent a hydrogen atom or a linear or branched carbon number of 丨~6 which may have a substituent. Base, Hal represents a halogen atom]. [B-1] In this step, the carboxyl group of the easily obtainable compound (6) can be esterified by the alcohol compound (7) by a commonly known method, and then produced by the same method as the step [A i]. A compound of the formula (8). [B-2] In the present step, a compound of the formula (9) can be produced by reacting a compound of the formula (8) with a usual reducing agent. 152528.doc • 21-201121944 The reaction solvent to be used is not particularly limited as long as it does not affect the reaction, and examples thereof include diethyl ether, diisopropyl ether, THF, and dioxane. As the reducing agent to be used, LAH, hydrogenated diethoxy aluminum clock, hydrogenated lithium triethoxyaluminum, hydrogenated tri-t-butoxide aluminum lithium, hydrogenated magnesium, aluminum aluminum hydride, sodium aluminum hydride can be exemplified. , hydrogenated sodium triethoxyaluminate, hydrogenated bis(2-methoxyethoxy)aluminum sodium, hydrogenated diisobutylaluminum (hereinafter, DIBAL (diis〇butyl aluminum hydride)), hydrogen gelatinization clock, etc. Jia is hydrogen hydrogenated. The number of equivalents is from 0.8 to 10 equivalents, preferably from 1.0 to 5.0 equivalents. The reaction temperature is - the boiling point of the solvent, preferably the boiling point of the solvent. The reaction time is 〇1 to 24 hours, preferably 2 hours. [B-3] In this step, an aldehyde compound represented by the formula (?) can be produced by reacting a compound of the formula (9) with a generally known oxidizing agent. The reaction solvent to be used is not particularly limited as long as it does not affect the reaction. Examples thereof include dichlorosilane, chloroform, tetra-carbonized carbon, DCE, gas benzene, toluene, and diphenylbenzene. It is dichloromethane. The oxidizing agent to be used may, for example, be a complex reagent such as chromic anhydride, pyridine or acetic acid, or a high valence such as a chromium-based oxidizing agent such as pyridine gas chromate or pyridine dichromate, and a Dess-Martin reagent. Iodine oxidizing agent, DMSO with acetic anhydride, oxalic acid chloride, dicyclohexylcarbodiimide (hereinafter DCC (diCycl〇heXyl carb〇diimide)), •ethyl_3 (3-didecylaminopropyl) Carbodiimide hydrochloride (hereinafter ΕοοΗεΚί-ΜΐιγΜ- Ο dimethyl aminopr〇pyl)carbodiimide.HCl)) 152528.doc -22· 201121944 DMSO oxidant, oxidized violent (Iv), 2, 2, 6,6_tetramethylhydrazine small oxygen radical; preferably manganese (IV) oxide. The number of equivalents is 〇 8 to 3 〇, equivalent, preferably ^ 2 〇 equivalent. The reaction temperature is -20 to 15 (TC, preferably 0 to 100 t. The reaction time is 0.1 to 24 hours, preferably 0 5 to 12 hours. Further, when R is a hydrogen atom, it can be easily obtained. 3-Phenylbenzene is used as a starting material, and the compound H of the formula (10) can be produced by the same method as [H], and it can also be known by the compound of the formula (4). A compound represented by the formula (10) can be produced by a reduction reaction, for example, a reduction method. [B-4] In this step, 'the compound represented by the above formula (10)) can be easily obtained by a 2·methyl group. 2. The reaction product of the above formula (11) is produced by reacting a propane and a brewing amine under acidic conditions. The reaction solvent to be used is not particularly limited as long as it does not affect the reaction, and examples thereof include diethyl _ 'diisopropyl ether, thf, diterpene, gas, chloroform, carbon tetrachloride, and benzene. And diterpene benzene, etc., preferably benzene. The acid to be used may, for example, be hydrochloric acid, magnesium sulfate, p-toluenesulfonic acid, or a Lewis acid such as titanium tetraisopropoxide or titanium tetraethoxide, which is preferably titanium tetraisopropoxide. The equivalent number of 2-mercapto-2-propanesulfonamide and titanium tetraisopropoxide is 8 1 Torr, preferably 1. 〇 3 〇 equivalent. The reaction temperature is 2 Torr to 5 cc, preferably 50 to 120 C, and the reaction time is 0.1 to 24 hours, preferably 5% to 6.0 hours. [B-5] £ 152528.doc -23 201121944 In this step, the compound represented by the formula (11) can be reacted with the Grignard reagent (12) represented by RdMgHal or the organolithium reagent (13) represented by RdLi. The compound of the formula (14) is selectively produced instead of the enantiomer. The reaction solvent to be used is not particularly limited as long as it does not affect the reaction, and examples thereof include diethyl ether, diisopropyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, THF, and dimethoxy B. Alkane, dioxane, methylene chloride, chloroform, carbon tetrachloride, toluene, xylene, and the like. The equivalent of the Grignard reagent or the organolithium reagent is from 0.8 to 20 equivalents, preferably from 1.0 to 10 equivalents. The reaction temperature is _100 ° c to 100 〇 c, preferably -78. 〇~50〇c. The reaction time is from 0.1 to 24 hours, preferably from 0.5 to 12 hours. [B-6] In this step, a compound of the formula (15) can be produced by subjecting a compound of the formula (14) to treatment with an acid. The solvent to be used is not particularly limited as long as it does not affect the reaction, and examples thereof include alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, and 2-butanol. The citron, ethyl acetate or the like is preferably decyl alcohol. The acid used may be exemplified by hydrochloric acid, sulfuric acid, acid, etc., preferably hydrochloric acid, and the equivalent number thereof is from 01 to 10 equivalents, preferably 1 〇~2·0 equivalent. The reaction temperature is -2 (TC~10〇t, preferably 〇~5〇. (: The reaction time is 〇.01~24 hours' is preferably 0.1~1.0 hours. In the case where Rd is a hydrogen atom, the compound represented by the formula (9) can be azide by a commonly known method, and then treated with a generally known reducing agent (for example, LAH) to produce a pass. The compound of the formula (15). Further, by the case of obtaining the 152528.doc •24·201121944 compound represented by the formula (15) as a racemate, the same method as in the step b. Conversion of a compound of the formula (10) to an alcohol compound, which is usually abbreviated by a commonly known method. The method of reduction, and producing the general formula (15) the compound is not: [Formula 6]

步驟CStep C

[式中R、R與上述含義相同,Rf相同或不同,表示 氫原子、可具有取代基的直鏈狀或支鏈狀之碳數1〜6之烷 基]。 [C-1] 本步驟中,可藉由使可容易獲取之化合物(16)與通式 (5)、(15)所示之任一胺,於鹼存在下進行反應,而製造通 式(7)所示化合物。作為所使用之反應溶劑,若為不對反 應也成影響者,則無特別限制’可例示:丙酮、THF、二 乙醚、二異丙醚、二,号烷、二氯甲烷、氯仿、四氣化碳、 DMF、DMA、乙腈等,較佳為二氯曱烷。 作為所使用之鹼,可例示:碳酸氫鈉、碳酸鈉、碳酸鉀[wherein R and R have the same meanings as defined above, and Rf is the same or different and represents a hydrogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms which may have a substituent]. [C-1] In this step, the compound (16) which can be easily obtained can be reacted with any of the amines represented by the general formulae (5) and (15) in the presence of a base to produce a general formula ( 7) The compound shown. The reaction solvent to be used is not particularly limited as long as it does not affect the reaction. Examples thereof include acetone, THF, diethyl ether, diisopropyl ether, dioxane, dichloromethane, chloroform, and tetra-gasification. Carbon, DMF, DMA, acetonitrile or the like is preferably dichlorodecane. As the base to be used, sodium hydrogencarbonate, sodium carbonate, and potassium carbonate can be exemplified.

S 152528.doc •25· 201121944 等無機鹼或二甲基胺、三乙基胺、三丙基胺、二異丙基乙 基胺、N-甲基嗎啉、吡啶、二曱基吡啶、三甲基吡啶等有 機胺類,較佳為二乙基胺《鹼及胺之當量數分別為〇5〜1〇 虽里,較佳為0.7〜5.0當量。反應溫度為_2〇。匸〜1〇〇〇c,較 佳為〇〜50C。反應時間為0.1〜24小時’較佳為〇2〜6〇小 時。 [C-2] 本步驟中,可利用通常眾所周知之方法,使通式(17)所 示氯化合物與乙酿氧基化試劑進行反應後,利用通常眾所 周知之脫乙醯化方法,而製造通式(18)所示醇化合物。 [C-3] 本步驟中’可藉由利用通常眾所周知之方法,使通式 (18) 所示化合物進行曱氧基曱基化(M〇M(meth〇xymethyl) 化),繼而進行路易斯酸處理後,於碘存在下,與市售之5_ 氟-2,4-雙(三甲基矽烷氧基)嘧啶進行反應,而製造通式 (19) 所示化合物。 作為路易斯酸處理中所使用之溶劑,若為不對反應造成 影響者,則無特別限制,可例示:二氯甲烷、氯仿、四氯 化碳、DCE、甲苯、二甲苯等,較佳為二氯甲烷。作為路 易斯酸,可例示:三氯化硼(以下為Bcl3)、三氟化硼、三 溴化硼等,較佳為BC13。其當量數為〇 〇1〜1〇當量較佳 為0.2〜0.5當量。反應溫度為_2〇〜1〇〇<)(:,較佳為〇〜5〇艽。 反應時間為0.1〜24小時,較佳為〇.5〜5·〇小時。 作為與5-氟-2,4-雙(三甲基矽烷氧基)嘧啶進行反應時所 152528.doc -26· 201121944 使用之溶劑,若為不對反應造成影響者,則無特別限制, 可例示:二氣曱烧、氯仿、四氯化碳、D C E、甲苯、二甲 苯等,較佳為DCE或曱苯。5-氟-2,4-雙(三甲基矽烷氧基) 嘧啶之當量數為〇.8~10當量,較佳為0.9〜5.0當量。碘之當 量數為0.001〜1.0當量,較佳為0.05〜0.5當量。反應溫度為 20〜150°C,較佳為50〜100°C。反應時間為0.1〜120小時, 較佳為0.5-100小時。 [化7]S 152528.doc •25· 201121944 Inorganic base or dimethylamine, triethylamine, tripropylamine, diisopropylethylamine, N-methylmorpholine, pyridine, dimercaptopyridine, three The organic amine such as methylpyridine is preferably diethylamine. The equivalent number of the base and the amine is 〇5 to 1 Torr, respectively, preferably 0.7 to 5.0 equivalent. The reaction temperature was _2 Torr.匸~1〇〇〇c, preferably 〇~50C. The reaction time is from 0.1 to 24 hours', preferably from 2 to 6 hours. [C-2] In this step, a chlorine compound represented by the formula (17) can be reacted with an ethyl ethoxylation reagent by a generally known method, and then a commonly known deacetylation method can be used to produce a pass. An alcohol compound represented by the formula (18). [C-3] In this step, 'the compound represented by the formula (18) can be subjected to oxime oximation by a method well known in the art, followed by Lewis acid After the treatment, a compound of the formula (19) is produced by reacting with commercially available 5-fluoro-2,4-bis(trimethyldecyloxy)pyrimidine in the presence of iodine. The solvent used in the Lewis acid treatment is not particularly limited as long as it does not affect the reaction, and examples thereof include dichloromethane, chloroform, carbon tetrachloride, DCE, toluene, xylene, etc., preferably dichloro. Methane. The Lewis acid may, for example, be boron trichloride (hereinafter referred to as Bcl3), boron trifluoride or boron tribromide, and is preferably BC13. The equivalent number is 〇 〜 1 〜 1 〇 equivalent is preferably 0.2 to 0.5 equivalent. The reaction temperature is _2〇~1〇〇<)(:, preferably 〇~5〇艽. The reaction time is 0.1 to 24 hours, preferably 〇5 to 5·〇 hours. As with 5-fluoro -2,4-bis(trimethyldecyloxy)pyrimidine 152528.doc -26· 201121944 The solvent used is not particularly limited if it does not affect the reaction, and it can be exemplified by: , chloroform, carbon tetrachloride, DCE, toluene, xylene, etc., preferably DCE or toluene. The equivalent number of 5-fluoro-2,4-bis(trimethyldecyloxy)pyrimidine is 〇.8~ 10 equivalents, preferably 0.9 to 5.0 equivalents, and the number of equivalents of iodine is 0.001 to 1.0 equivalents, preferably 0.05 to 0.5 equivalents, and the reaction temperature is 20 to 150 ° C, preferably 50 to 100 ° C. The reaction time is 0.1 to 120 hours, preferably 0.5 to 100 hours.

步驟DStep D

(27) [式中,Ra、Rb、Re、Rf與上述含義相同,Pg表示磺醯胺基 上氮原子之保護基,E表示鍵結或伸乙烯基(其中,於E表 示鍵結之情形時,CH2-E-(CH2)m表示正伸丙基或正伸戊 基),m表示1〜5之數,Bz表示苯甲醯基]。 S. 152528.doc -27- 201121944 [D-l] 本步驟中’可利用通常眾所周知之方法,將通式(17)所 示化合物之續酿胺基上氮原子,例如由甲氧基甲基、第三 丁氧基羰基等保護基加以保護後’利用與步轉[C-2]相同之 方法,製造通式(20)所示化合物。 [D-2] 本步驟中’可藉由利用與步驟[B-3]相同之方法獲得醛 化合物後’使通式(20)所不醇化合物與H〇rner-Wadsworth-Emmons試劑進行反應,而製造通式(22)所示化合物。 作為所使用之反應溶劑’若為不對反應造成影響者,則 無特別限制,可例示:苯、甲苯、二乙醚、二異丙醚' THF、二乙二醇二曱醚、二甲氧基乙烷、DMSO等’較佳 為 THF。(27) [wherein, Ra, Rb, Re, and Rf have the same meanings as defined above, Pg represents a protecting group of a nitrogen atom on a sulfonamide group, and E represents a bond or a vinyl group (wherein, the case where E represents a bond) In the case of CH2-E-(CH2)m, it is a propyl group or a pentylene group, and m represents a number of 1 to 5, and Bz represents a benzyl group. S. 152528.doc -27- 201121944 [Dl] In this step, the nitrogen atom on the amine group of the compound represented by the formula (17) can be obtained by a commonly known method, for example, from methoxymethyl, After protecting the protecting group such as tributyloxycarbonyl, the compound of the formula (20) is produced by the same method as the step [C-2]. [D-2] In this step, 'the aldehyde compound can be obtained by the same method as the step [B-3], and then the non-alcohol compound of the formula (20) can be reacted with the H〇rner-Wadsworth-Emmons reagent. The compound of the formula (22) is produced. The reaction solvent to be used is not particularly limited as long as it does not affect the reaction, and examples thereof include benzene, toluene, diethyl ether, diisopropyl ether 'THF, diethylene glycol dioxime ether, and dimethoxy B. Alkane, DMSO, etc. are preferably THF.

Horner-Wadsworth-Emmons試劑係例如利用氫化鈉、醯 胺納、二異丙基醯胺鋰、曱醇鈉等鹼對膦醯基乙酸三乙醋 (21)進行處理而製備。鹼之當量數為〇no當量,較佳為 0.8〜2_0當量。反應溫度為_2〇»c〜1〇〇〇c,較佳為〇〜7〇〇c。 反應時間為0.05-12小時,較佳為〇.ι~2.0小時。 Horner-Wadsworth-Emmons 試劑之當量數為 0.1 〜1〇 當 量’較佳為0.3〜5.0當量。反應溫度為0°C〜150°C,較佳為 l〇°C〜100°C。反應時間為0.0542小時,較佳為(Um o小 時。 [D-3] 本步驟中,可藉由對通式(22)所示化合物進行之通常眾 152528.doc -28 - 201121944 所周知之還原方法、較佳為DIBal還原法,而製造通式 (23)所示化合物。 [D-4] 本步驟中’可藉由對通式(23)所示化合物進行之通常眾 所周知之接觸還原法,而製造通式(2句所示化合物。 所使用之反應溶劑若為對反應不造成影響者,則無特別 限制,可例示:甲醇、乙醇、卜丙醇、2_丙醇、第三丁 醇、二曱氧基乙烷、二乙二醇二曱醚、二異丙醚、二乙 醚、THF、二噚烷 '乙酸乙酯、乙酸丁酯等,較佳為曱醇 或乙酸乙醋。 作為所使用之觸媒’可例示:5〜丨〇%鈀/碳、氫氧化鈀、 銘、雷氏鎳、氧化鉑、铑-氧化鋁,較佳為5〜1〇%鈀/碳。 其當量數為0.001〜10當量’較佳為〇〇1〜5.0當量》反應溫 度為0°C〜100°C ’較佳為20〜6(TC。反應時間為〇,1〜24小 時,較佳為0.2〜6.0小時。 Π>5] 本步驟中’可藉由使依據文獻(Bi〇org. Med. Chem. Lett·,12,1395-1397 (2002))中記載之方法獲得的3_苯甲醯 基-5-氟嘧啶-2,4(1H,3H)-二酮(25)與通式(20)、(23)、(24) 所示之任一醇化合物進行與步驟[A-l](b)相同的光延反 應,而製造通式(26)所示化合物。 [D-6] 本步驟中’可藉由利用通常眾所周知之脫保護方法,使 通式(26)所示化合物進行脫苯曱酿基化、脫pg化,而製造 £ 152528.doc -29- 201121944 通式(27)所示化合物: [化8]The Horner-Wadsworth-Emmons reagent is prepared, for example, by treating phosphinic acid triacetate (21) with a base such as sodium hydride, guanidine, lithium diisopropylamide or sodium decoxide. The number of equivalents of the base is 〇no equivalent, preferably 0.8 to 2_0 equivalent. The reaction temperature is _2〇»c~1〇〇〇c, preferably 〇~7〇〇c. The reaction time is from 0.05 to 12 hours, preferably from 0.1 to 2.0 hours. The number of equivalents of the Horner-Wadsworth-Emmons reagent is 0.1 to 1 Torr, and the amount ' is preferably 0.3 to 5.0 equivalents. The reaction temperature is from 0 ° C to 150 ° C, preferably from 1 ° C to 100 ° C. The reaction time is 0.0542 hours, preferably (Um o hour. [D-3] In this step, it can be reduced by the usual 152528.doc -28 - 201121944 of the compound of the formula (22). A method, preferably a DIBal reduction method, is used to produce a compound of the formula (23). [D-4] In the present step, a contact reduction method which is generally known by a compound represented by the formula (23) can be carried out. The compound of the formula (the compound of the two sentences is produced. The reaction solvent to be used is not particularly limited as long as it does not affect the reaction, and examples thereof include methanol, ethanol, propanol, 2-propanol, and tert-butanol. , dimethoxyethane, diethylene glycol dioxime ether, diisopropyl ether, diethyl ether, THF, dioxane 'ethyl acetate, butyl acetate, etc., preferably decyl alcohol or ethyl acetate. The catalyst used may be exemplified by 5 to 丨〇% palladium/carbon, palladium hydroxide, indium, nickels, platinum oxide, rhodium-alumina, preferably 5 to 1% palladium/carbon. The number is 0.001 to 10 equivalents, preferably 〇〇1 to 5.0 equivalents, and the reaction temperature is 0 ° C to 100 ° C. Preferably, it is 20 to 6 (TC. The reaction time is , 1 to 24 hours, preferably 0.2 to 6.0 hours. Π > 5] In this step ' can be made according to the literature (Bi〇org. Med. Chem. Lett., 12, 1395-1397 (2002)) 3-Benzylmercapto-5-fluoropyrimidine-2,4(1H,3H)-dione (25) obtained by the method described, and any one of the formulas (20), (23), (24) The alcohol compound is subjected to the same retardation reaction as in the step [Al] (b) to produce a compound of the formula (26). [D-6] In the present step, the formula can be obtained by using a generally known deprotection method. (26) The compound shown is subjected to dephenylation and de-pgification to produce a compound represented by the formula (27): [Chem. 8]

步驟EStep E

If ΟIf Ο

(29) (28) Ο(29) (28) Ο

(30) Ε·2 [式中,Hal、Ra、Rb、RlRf與上述含義相同,Ar表示2價 芳香族烴基或2價不飽和雜環基]。 [E-1] 本步驟中,可藉由利用與步驟[Cq]相同之方式,使通 式(28)所示化合物與通式(5)、〇5)所示之任一胺進行反 應’而製造通式(29)所示化合物。 [E-2] 本步驟中’可藉由於破存在下,使通式(29)所示化合物 與市售之5_氟_2,4·雙(三甲基矽烷氧基)嘧啶進行反應, 製造通式(30)所示化合物。 ’則無特 甲笨等, 作為所使用之溶劑,若為不對反應造成影響者 別限制’可例示:DCE、THF、二巧烷、乙睛、 較佳為DCE或曱笨。 5-氟·2’4-雙(三甲基矽烷氧基)嘧<之當量數為〇 杏 152528.doc -30· 201121944 碘之當量數分別為O.Oly.O當 量,較佳為1·0〜1.5當量 量,較佳為0.1〜0.5當量。 反應時間為 反應溫度為10〜l〇(TC,較佳為7〇〜95t 0.1〜120小時,較佳為0.5〜100小時。(30) Ε·2 [wherein, Hal, Ra, Rb, and RlRf have the same meanings as defined above, and Ar represents a divalent aromatic hydrocarbon group or a divalent unsaturated heterocyclic group]. [E-1] In this step, a compound represented by the formula (28) can be reacted with any of the amines represented by the formula (5) or hydrazine 5) by the same procedure as in the step [Cq]. The compound of the formula (29) is produced. [E-2] In this step, the compound represented by the formula (29) can be reacted with a commercially available 5-fluoro-2,4·bis(trimethyldecyloxy)pyrimidine by the presence of a cleavage. A compound of the formula (30) is produced. The solvent to be used is not limited as long as it does not affect the reaction. Illustrative: DCE, THF, dioxane, acetonitrile, preferably DCE or sputum. The equivalent number of 5-fluoro-2'4-bis(trimethyldecyloxy)pyrimidine is 〇545152.doc -30· 201121944 The equivalent number of iodine is O.Oly.O equivalent, preferably 1 0 to 1.5 equivalents, preferably 0.1 to 0.5 equivalents. The reaction time is a reaction temperature of 10 to 1 Torr (TC, preferably 7 Torr to 95 Torr, 0.1 to 120 hours, preferably 0.5 to 100 hours).

[化9] 步驟F[Chem. 9] Step F

[式中,Re、R/及m與上述含義相同。Rg& Rh相同或不同, 表示氫原子、齒素原子、苯甲醯氧基、可具有取代基的直 鏈狀或支鏈狀之碳數丨〜6之烷基、碳數3〜7之環烷基、可具 有取代基的直鏈狀或支鏈狀之碳數丨〜6之垸氧基、碳數3〜7 之環烷氧基、碳數3〜7之環烷基·烷氧基,Ar,表示芳香族烴 基或不飽和雜環基,Cbz表示苄氧基羰基,Μ〇Μ表示曱氧 基甲基]。 [F-1] 本步驟中’可藉由利用通常眾所周知之方法,使可容易 獲取之通式(31)所示胺基醇化合物之胺基cbz化後,利用 通常眾所周知之方法進行MOM化,而製造通式(32)所示化[wherein, Re, R/ and m have the same meanings as described above. Rg & Rh is the same or different, and represents a hydrogen atom, a dentate atom, a benzamethyleneoxy group, a linear or branched carbon group having a substituent of 丨~6, and a ring having a carbon number of 3 to 7. An alkyl group, a linear or branched carbon group having a carbon number of 丨6, a cycloalkyloxy group having 3 to 7 carbon atoms, a cycloalkyl group alkoxy group having 3 to 7 carbon atoms which may have a substituent. , Ar represents an aromatic hydrocarbon group or an unsaturated heterocyclic group, Cbz represents a benzyloxycarbonyl group, and Μ〇Μ represents a decyloxymethyl group]. [F-1] In the present step, the amine group of the amino alcohol compound represented by the formula (31) which can be easily obtained can be cbz-formed by a generally known method, and then MOM is carried out by a generally known method. And the production of the general formula (32)

S 152528.doc -31· 201121944 合物。 通式(31)所示胺基醇化合物,例如於m=2之情形時,可 藉由利用 LAH使利用 j. Med. Chem.,34, 633-642 (1991)中 記載之方法所獲得之3_胺基_3_甲基丁酸乙酯還原而製造; 又,於且Re及為甲基之情形時,可利用;Am.S 152528.doc -31· 201121944 Compound. The amino alcohol compound represented by the formula (31), for example, in the case of m = 2, can be obtained by the method described in J. Med. Chem., 34, 633-642 (1991) by using LAH. 3_Amino_3_methylbutyric acid ethyl ester is reduced to produce; in addition, when Re and is a methyl group, it can be utilized; Am.

Chem· S〇c.,77, ι〇79·1〇83 (1955)中記載之方法而製造。 [F-2] 本步驟中,可藉由利用通常眾所周知之方法,於氫氣環 境下,使通式(32)所示化合物與例如把·碳進行反應而脫 Cbz化後,於鹼性條件下,與可容易獲取之可具有取代基 之芳基磺醯氣(例如可依據j. Pesticide chem,13, 1〇7_ 5(1988)中§己載之方法而製造)進行反應,而製造通式 (33)所不化合物。 作為所使用之反應溶劑,若為不對反應造成影響者,則 無特別限制,可例示:二氣甲烷、DMF、乙酸乙酯、 THF、二噚烷、二乙醚、乙腈等,較佳為二氯甲烷。 可經取代之芳基磺醯氯的當量數為0_9〜5.0當量,較佳為 1·〇〜1·5當量。 作為所使用之驗,可例示:三甲基胺、三乙基胺、三丙 基胺、二異丙基乙基胺、Ν甲基嗎啉、吡啶、r甲基咣 唆、二甲基㈣、1,8·二氮雜雙環[5 4斗7十一稀(以下為 卿(UdiazabiWoMoh^e·))等有機胺類較 :為三乙基胺。當量數為〇 9〜1〇當量,較佳為i 〇〜3 〇當 152528.doc •32· 201121944 反應溫度為0〜60°C,較佳為〇〜30°C。反應時間為 0.1〜100小時,較佳為1.0〜72小時。 再者,於…或!^為苯曱醯氧基之情形時,可利用通常眾 所周知之方法轉換成各種官能基。 [F-3] 本步驟中,可藉由利用與[C-3]相同之方法使通式(33)所 示化合物進行反應’而製造通式(34)所示化合物: [化 10]Manufactured by the method described in Chem. S〇c., 77, ι〇79·1〇83 (1955). [F-2] In this step, the compound represented by the formula (32) can be subjected to Cbz reaction by reacting with, for example, carbon in a hydrogen atmosphere by a generally known method, under alkaline conditions. And reacting with an easily obtainable arylsulfonyl sulfonium having a substituent (for example, which can be produced according to the method described in j. Pesticide chem, 13, 1 〇 7_ 5 (1988)) (33) All compounds. The reaction solvent to be used is not particularly limited as long as it does not affect the reaction, and examples thereof include di-methane, DMF, ethyl acetate, THF, dioxane, diethyl ether, acetonitrile, etc., preferably dichloro Methane. The equivalent number of the arylsulfonyl chloride which may be substituted is from 0 to 9 to 5.0 equivalents, preferably from 1 to 1 to 1.5 equivalents. As the test to be used, trimethylamine, triethylamine, tripropylamine, diisopropylethylamine, hydrazine methylmorpholine, pyridine, rmethylhydrazine, dimethyl (tetra) can be exemplified. The organic amines such as 1,8·diazabicyclo[5 4 bucket 7 eleven (hereinafter, UdiazabiWoMoh^e·) are: triethylamine. The number of equivalents is 〇 9 to 1 〇 equivalent, preferably i 〇 〜3 〇 152528.doc • 32· 201121944 The reaction temperature is 0 to 60 ° C, preferably 〇 30 ° C. The reaction time is from 0.1 to 100 hours, preferably from 1.0 to 72 hours. Further, in the case where ... or ? is a benzoquinoneoxy group, it can be converted into various functional groups by a generally known method. [F-3] In this step, a compound of the formula (34) can be produced by reacting a compound of the formula (33) by the same method as [C-3]: [Chemical Formula 10]

步驟GStep G

[式中,Ar1、Re、Rf、Rg、Rh與上述含義相同]。 [G-l] 本步驟中’例如可藉由利用與[F-2]相同之方法,使可依 據 Tetrahedron Lett,,38,1241-1244 (1997)中記載之方法而 容易獲取之通式(35)所示化合物與可容易獲取之可具有取 代基之芳基磺醯氯(例如可依據j. Pesticide Chem.,13, 107-115 (198 8)中記載之方法而製造)進行反應,而製造通式 (36)所示化合物。 再者,於Rg或Rh為苯曱醯氧基之情形時,可利用通常眾 152528.doc -33-[wherein, Ar1, Re, Rf, Rg, and Rh have the same meanings as described above]. [Gl] In the present step, for example, the formula (35) which can be easily obtained according to the method described in Tetrahedron Lett, 38, 1241-1244 (1997) can be obtained by the same method as [F-2]. The compound shown is reacted with an easily obtainable arylsulfonyl chloride which may have a substituent (for example, which can be produced according to the method described in J. Pesticide Chem., 13, 107-115 (198 8)). A compound of the formula (36). Furthermore, in the case where Rg or Rh is a benzoquinoneoxy group, it is possible to use the usual 152528.doc -33-

I 201121944 所周知之方法而轉換成各種官能 [G-2] 本步驟巾,可藉由利用與[E_2]相同之方法使通式⑽ 所不化合物之甲基與通常眾所周知之溴化劑、例如溴酸鈉 及亞硫酸氫鈉、或N_溴代丁二醯亞胺及偶氮雙異丁腈 (AIBN(azobisisobutyr〇nhrile))進行反應而溴化後製造通 式(37)所示化合物。 [G-3] 本步驟中,可藉由利用通常眾所周知之方法,於利用日 本專利特開2006-508054號公報中記載之方法所獲得之6_ (羥基甲基)菸酸腈(38)之羥基中導入保護基、較佳為第三 丁基一曱基石夕院基(以下為 TBS(tert-butyldimethylsilyi^) 基’使所獲得之化合物與可由氯化鈽、甲基鐘製備之甲義 化劑進行反應後’利用與[F_2]相同之方法,與可容易獲取 之可經取代之芳基磺醯氯進行反應,而製造通式(39)所示 化合物。 作為甲基化中所使用之反應溶劑,可例示:THF、二气 燒、二乙醚等,較佳為THF、二乙醚。氯化鈽之當量數為 〜5.0當量,較佳為2.0〜4.0當量《曱基鋰之當量數為 1·〇〜5.0當量,較佳為2.〇〜4.0當量。 甲基化之反應溫度為-100〜40°C,較佳為-78~30。(:。反 應時間為0.5〜5_0小時,較佳為2.0〜3.0小時。 再者,於Rg*Rh為苯曱醯氧基之情形時,可利用通常眾 所周知之方法而轉換成官能基。 152528.doc -34- 201121944 [G-4] 本步驟中’將通式(39)所示化合物之TBS基除去,利用 通吊h所周知之方去’藉由例如三苯基膦及四溴化碳使所 生成之羥基溴化後,利用與[Ε·2]相同之方法,而製造通式 (40)所示化合物: [化 11] 步驟ΗI 201121944 Converted into various functionalities by the method known in the art [G-2] This step towel can be obtained by using the same method as [E_2] to form a methyl group of a compound of the formula (10) with a generally known brominating agent, for example. The compound of the formula (37) is produced by reacting bromate with sodium hydrogen sulfite, or N-bromosyl iminoimide and azobisisobutyronitrile (AIBN (azobisisobutyr〇nhrile)). [G-3] In the present step, the hydroxyl group of 6-(hydroxymethyl)nicotinic acid nitrile (38) obtained by the method described in JP-A-2006-508054 can be used by a method which is generally known. Introducing a protecting group, preferably a tert-butyl-fluorenyl group (hereinafter, TBS (tert-butyldimethylsilyi) group), the obtained compound and a sensitizer which can be prepared from cerium chloride or methyl quinone After the reaction, the compound represented by the formula (39) is produced by the same method as [F_2], and reacted with an easily obtainable substituted arylsulfonyl chloride. The reaction used in the methylation is used. The solvent may, for example, be THF, di-oxygen, diethyl ether or the like, preferably THF or diethyl ether. The equivalent number of cerium chloride is 〜5.0 equivalents, preferably 2.0 to 4.0 equivalents, and the equivalent number of fluorenyl lithium is 1 〇~5.0 equivalents, preferably 2. 〇~4.0 equivalents. The reaction temperature for methylation is -100 to 40 ° C, preferably -78 to 30. (: The reaction time is 0.5 to 5_0 hours, compared It is preferably 2.0 to 3.0 hours. In addition, when Rg*Rh is a benzoquinone group, it can be used in general. The method is converted into a functional group. 152528.doc -34- 201121944 [G-4] In this step, 'the TBS group of the compound represented by the general formula (39) is removed, and the well-known one is used to 'by For example, after triphenylphosphine and carbon tetrabromide bromine the resulting hydroxyl group, the compound of the formula (40) is produced by the same method as [Ε·2]: [Chemical Step 11]

[式中R、Rj、R相同或不同,表示氫原子、羥基、鹵素 原子、可具有取代基之芳香族烴基或可具有取代基之不飽 和雜環基]。 [H-1] 本步驟中’可藉由使利用文獻(Med chem. Res.,10, 3 90-403 (2001))中記載之方法所所獲得的4 (5氣4二氧 代3,4_一氫嘧啶-1(2H)-基)丁酸(41)與可容易獲取之吡咯 啶衍生物縮合,而製造通式(42)所示化合物。 作為所使用之反應溶劑,若為不對反應造成影響者,則 無特別限制,可例示:_、甲苯、二氯甲&、乙猜、 THF等’較佳為二氣曱&。作為所使用之縮合劑,作為 DCC、EDC.HC卜缩合助劑,可例示:卜輕基笨并三吐(以 152528.doc •35- 201121944 下為 HOBt(l-hydroxy benzotriazole))等,較佳為 EDC’HCl ' HOBt之組合。其當量數分別為〇 8〜5 〇當量, 較佳為分別為1.0〜3.0當量。胺化合物之當量數為〇8〜5 〇 當量,較佳為1.0〜3.0當量。反應溫度為〇〜1〇(rc,較佳為 10〜40°C。反應時間為0.U4小時,較佳為〇 5〜4 〇小時。 以上,以如上方式製造之本發明之化合物及合成中間體 可通常利用眾所周知之分離純化方法例如再結晶、晶化、 瘵餾、官柱層析法等而分離並純化。本發明之化合物及合 成中間體it常可利用眾所周知《方法形成其藥理學上所容 許之鹽,又可相互轉換。 如下述實施例所示’本發明之5_氟尿嘧啶化合物或其鹽 具有優異之dUTP酶抑制活性’因此作*dUTp酶參與之疾 病例如抗癌藥之效果增強劑所代表的醫藥品較為有用。 於醤藥”且口物中3有本發明之5 氟尿嘧咬化合物或其鹽 之It形時’可視而要與藥學載體調配,根據預防或治療目 的而採用各種投予形態,作為該形態,例如可列舉:經口 劑、注射劑、栓劑、軟膏劑、 等投予形態可利用對各業者而 而製造。 貼劑等,較佳為經口劑。該 吕眾所周知慣用之製劑方法 藥學載體可使用作為製劑素材而慣用之各種有機或無機 載體物質,係作為固形製劑中之職形劑、結合劑、崩解 劑、潤滑劑、著色劑;液狀製劑中 ^ μ T之,合劑、溶解助劑、懸 净劑、等張劑、緩衝劑、鎮痛劑 哥而調配。又,亦可視需 要使用防腐劑、抗氧化劑、著色劑、 匕削甜味劑、穩定劑等製 152528.doc •36· 201121944 劑添加物。 於製備經口用固形製劑之情形時,可於本發明之化合物 中添加賦形劑、視需要之結合劑、崩解劑、潤滑劑、著色 劑、矯味.矯臭劑等後,利用常規方法而製造錠劑、包覆 錠劑、顆粒劑、散劑、膠囊劑等。 作為賦形劑’可列舉:乳糖、白糖、D_甘露糖醇、葡萄 糖、澱粉、破酸辟、高嶺土、微晶纖維素、無水石夕酸等。 作為結合劑,可列舉:水、乙醇、L丙醇、2-丙醇、單 糖漿、葡萄糖液、CW殿粉液、明膠液、D•甘露糖醇、羧甲 基纖維素、羥丙基纖維素、羥丙基澱粉、曱基纖維素、乙 基纖維素、蟲膠、磷酸鈣、聚乙烯基吼咯啶酮等。 ,崩解劑’可列舉:乾燥澱粉”每藻酸鈉、壤脂末、 夂氫鈉碳I鈣、十二烷基硫酸鈉、硬脂酸單甘油酯、 乳糖等》 作為潤滑劑’可列舉:純化滑石、硬脂酸鹽納、硬脂酸 鎂、硼砂、聚乙二醇等。 作為著色劑,可列舉:氧化鈦、氧化鐵等。 :::橋味·矮臭劑,可列舉:白糖、撥皮、、酒 石酸等。 於製備經口用液體製劑之情形時,可於本發明之化人 =力I:味劑、緩衝劑、穩定劑 '橋臭劑等,常規 ζ服液劑、糖漿劑、驰劑等。作為該情形時之 …、、削,為上述所列舉者即可’作為緩衝劑,可列 j鷇鈉等,作為穩定劑,可 只耋膠、阿拉伯膠 152528.doc -37- 201121944 明勝等。亦可視需要,實施腸溶性包衣,或為了使效果持 續,而利用眾所周知之方法對經口製劑實施包衣。上述包 衣劑可列舉:經丙棊甲基纖维素、乙基纖維素、經甲基纖 維素、羥丙基纖維素、聚氧乙二醇、Tween8〇(註冊商標)等? =備注射劑之情形時,可於本發明之化合物中添加阳 2即劑、緩衝劑、敎劑、等張劑、局部麻醉劑等,利用 常規方法而製造皮下、肌肉内及靜脈内用注射劑。作為1 情形時之PH值調節劑及緩衝劑,可列舉··摔檬酸納、乙2 =、磷酸納等。作為穩定劑,可列舉:焦亞硫酸納、 TA(ethylene diamine 她咖以 acid,四乙酸乙二胺)、 ^代乙醇酸、疏代乳酸等。作為局部麻醉劑,可列舉:越 酸普魯卡因、鹽酸利多卡因等。作為等張劑,可列舉^ 化鈉、葡萄糖、D-甘露糖醇、甘油等。 、 眾:L備栓Γ之情形時,可於本發明之化合物中添加業界 眾所周知之製劑用載體、例如聚乙二醇、羊毛脂、可可油 月曰、脂肪酸二甘油妒楚 …之… 視需要之Tween80(註冊商 Μ之類的界面活性劑等後,利用常規方法而製造。 於製備軟膏劑之情形時,可於本發明之化合物中視需要 調配通常所#用夕I^ 土 J、穩定劑、濕潤劑、保存劑等,利 =方法加以混合,而製劑化。作為基劑,可列舉:液 L作二 林、白蜂蠛、辛基十二烧基醇、石蝶 甲酸乙:、存劑可列舉:對羥基苯甲酸曱酯、對羥基苯 甲酸乙醋、對經基苯曱酸丙醋等。 本 於製備貼劑之情报拉 _時’若利用常規方法於通常之支持體 152528.doc •38- 201121944 上塗布上述軟膏、霜劑、凝膠、糊劑等即可。作 體’較為合適的是含有棉、人造短纖維、化學纖維之織 布不織布或軟質氣乙稀、聚乙稀、聚胺基甲酸醋等薄膜 或發泡體片材。 、 上述各投予單位形態中可調配之本發明化合物的量係根 據可使用其之患者之症狀、或其劑形等而不固定,通常’ 每投予單位形態,經口劑約為〇 〇5〜1〇〇〇 ,注射劑約為 〇·01〜500 mg,栓劑約為1〜1000 mg左右。 又,具有上述投予形態之藥劑之每丨天的投予量係根據 患者之症狀、體重、年齡、性別等而有所不同,無法—概 決定,通常成人(體重5〇 kg)每1天約為〇.〇5〜5〇〇〇 mg& 右,較佳為0.1〜1000 mg,較佳為將該藥劑1天投予i次戈 者分成2〜3次左右投予。 作為可藉由投予含有本發明之化合物的藥劑而治療之疾 病,可列舉:惡性腫瘤、瘧疾、結核等,例如於惡性腫瘤 之情形時’可列舉:頭頸癌、食道癌、胃癌、結腸癌、直 腸癌、肝癌、膽囊·膽管癌、胰腺癌、肺癌、乳癌、卵巢 癌、子宮頸癌、子宮體癌、腎癌、膀胱癌、前列腺癌、筆 丸瘤、骨軟組織肉瘤、白血病、惡性淋巴瘤、多發性骨 趙瘤、皮膚癌、腦腫瘤等。又,亦可用作抗幽門螺桿菌 藥、抗寄生蟲藥、抗病毒藥。 [實施例] 以下’表示參考例、實施例、試驗例及製劑例,進而詳 細地說明本發明,但本發明並不限制於該等實施例。 152528.doc •39· 201121944 參考例1(3-(環丙基甲氧基)苯基)甲烷胺之合成 [化 12][wherein R, Rj and R are the same or different and each represents a hydrogen atom, a hydroxyl group, a halogen atom, an aromatic hydrocarbon group which may have a substituent or an unsaturated heterocyclic group which may have a substituent]. [H-1] This step can be obtained by using the method described in the literature (Med. Chem. Res., 10, 3 90-403 (2001)) 4 (5 gas 4 dioxo 3, The compound of the formula (42) is produced by condensing 4-i-hydropyrimidin-1(2H)-yl)butyric acid (41) with an easily obtainable pyrrolidine derivative. The reaction solvent to be used is not particularly limited as long as it does not affect the reaction, and examples thereof include _, toluene, methylene chloride & hexane, THF, etc., and preferably dioxin & As a condensing agent to be used, as a DCC, EDC.HC, and a condensation auxiliary agent, it can be exemplified as: a light-based base and a three-supplement (a 152528.doc • 35-201121944 is a HOBt (l-hydroxy benzotriazole)), etc. Jia is a combination of EDC 'HCl ' HOBt. The equivalent number thereof is 〇 8 to 5 〇 equivalents, preferably 1.0 to 3.0 equivalents, respectively. The equivalent number of the amine compound is 〇8 to 5 当量 equivalent, preferably 1.0 to 3.0 equivalents. The reaction temperature is 〇~1〇 (rc, preferably 10 to 40 ° C. The reaction time is 0. U 4 hours, preferably 〇 5 to 4 〇 hours. Above, the compound of the present invention and the synthesis thereof are produced as above. The intermediate can be usually isolated and purified by well-known separation and purification methods such as recrystallization, crystallization, hydrazine distillation, column chromatography, etc. The compound of the present invention and the synthetic intermediate it can often be formed by the well-known method to form its pharmacology. The salt which is allowed in the above can be mutually converted. As shown in the following examples, the 5-fluorouracil compound of the present invention or a salt thereof has excellent dUTP enzyme inhibitory activity, and thus the effect of a disease in which the *dUTp enzyme is involved, such as an anticancer drug. The pharmaceutical agent represented by the enhancer is more useful. The medicinal carrier can be formulated with the pharmaceutical carrier according to the purpose of prevention or treatment for the purpose of preventing or treating the fluorochemical. In the case of the above-mentioned form, for example, an oral preparation, an injection, a suppository, an ointment, or the like can be used in various forms. For example, a patch or the like is preferably used. Oral agent. It is well known that the pharmaceutical preparation method can use various organic or inorganic carrier materials which are conventionally used as a material for preparation, and is used as a shape agent, a binder, a disintegrator, a lubricant and a colorant in a solid preparation; In liquid preparations, it can be formulated with a mixture of ingredients, dissolution aids, suspensions, isotonic agents, buffers, and analgesics. Also, preservatives, antioxidants, colorants, and sweetening can be used as needed. Flavor, stabilizer, etc. 152528.doc • 36· 201121944 Additives. In the case of preparing an oral solid preparation, an excipient, an optional binder, a disintegrating agent may be added to the compound of the present invention. After the lubricant, the coloring agent, the flavoring, the flavoring agent, etc., the tablet, the lozenge, the granules, the powder, the capsule, etc. are produced by a conventional method. As the excipient, it may be mentioned: lactose, white sugar, D_ Mannitol, glucose, starch, acid-breaking, kaolin, microcrystalline cellulose, anhydrous oxalic acid, etc. As a binding agent, water, ethanol, L-propanol, 2-propanol, monosaccharide, glucose solution CW Temple powder, gelatin solution, D•mannitol, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropyl starch, thiol cellulose, ethyl cellulose, shellac, calcium phosphate, polyvinyl吼 啶 啶 等 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , Examples of the lubricant include purified talc, sodium stearate, magnesium stearate, borax, and polyethylene glycol. Examples of the coloring agent include titanium oxide and iron oxide. Examples of the odor agent include white sugar, scalp, tartaric acid, etc. In the case of preparing a liquid preparation for oral administration, it can be used in the present invention: force I: taste agent, buffer agent, stabilizer, bridge odor agent, etc. , conventional sputum liquid, syrup, granules and the like. In this case, the following items can be used as a buffering agent, and can be used as a buffering agent. As a stabilizer, only silicone rubber or gum arabic can be used. 152528.doc -37-201121944 Ming Sheng, etc. . The enteric coating may also be applied by a well-known method in order to carry out an enteric coating as needed or in order to maintain the effect. Examples of the above-mentioned coating agent include acetaminophen, ethylcellulose, methylcellulose, hydroxypropylcellulose, polyoxyethylene glycol, Tween8® (registered trademark), and the like. In the case of a preparation for injection, a hypoactive preparation, a buffer, an elixir, an isotonic agent, a local anesthetic or the like may be added to the compound of the present invention, and a subcutaneous, intramuscular, and intravenous injection may be produced by a conventional method. Examples of the pH adjusting agent and the buffering agent in the case of the case include sodium gluconate, sodium 2 =, sodium phosphate, and the like. Examples of the stabilizer include sodium metabisulfite, TA (ethylene diamine), acid glycol, ethylene glycolate, and lactic acid. As the local anesthetic, the more acidic procaine, lidocaine hydrochloride and the like can be mentioned. Examples of the isotonic agent include sodium, glucose, D-mannitol, and glycerin. In the case of L-supplement, a well-known carrier for preparation such as polyethylene glycol, lanolin, cocoa butter, and fatty acid diglycerin can be added to the compound of the present invention. Tween80 (registered as a surfactant or the like, and then manufactured by a conventional method. In the case of preparing an ointment, it can be formulated as needed in the compound of the present invention. , wetting agent, preservative, etc., and the method is mixed and formulated. As a base, the liquid L is used as the two forests, the white bee, the octyldodecanol, the stone butterfly B: The agent may be exemplified by decyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, p-propyl benzoate, etc. The information on the preparation of the patch is _ when using conventional methods in the usual support 152528. Doc •38- 201121944 Apply the above ointment, cream, gel, paste, etc. It is more suitable for fabrics containing cotton, staple fibers, chemical fibers, non-woven fabrics or soft ethylene, polyethylene. Thin, polyamino carboxylic acid, etc. The film or the foam sheet. The amount of the compound of the present invention which can be adjusted in each of the above-mentioned administration unit forms is not fixed depending on the symptoms of the patient to be used, or the dosage form thereof, and is usually 'per unit dosage form The oral preparation is about 〜5~1〇〇〇, the injection is about 〇·01~500 mg, and the suppository is about 1~1000 mg. Further, the administration of the above-mentioned administration form is administered every day. The amount varies according to the patient's symptoms, weight, age, sex, etc. It cannot be determined - usually adult (body weight 5 〇 kg) is about 〇.〇5~5〇〇〇mg& Preferably, it is 0.1 to 1000 mg, and it is preferred to administer the drug to the i-go group for about 2 to 3 times per day. As a disease which can be treated by administering a drug containing the compound of the present invention, it can be enumerated : malignant tumors, malaria, tuberculosis, etc., for example, in the case of malignant tumors' can be enumerated: head and neck cancer, esophageal cancer, stomach cancer, colon cancer, rectal cancer, liver cancer, gallbladder, cholangiocarcinoma, pancreatic cancer, lung cancer, breast cancer, ovarian cancer , cervical cancer, uterine body cancer, kidney cancer, bladder cancer Prostate cancer, pen tumor, bone soft tissue sarcoma, leukemia, malignant lymphoma, multiple bone tumor, skin cancer, brain tumor, etc. Also, it can also be used as anti-Helicobacter pylori, anti-parasitic, anti-viral drugs [Examples] Hereinafter, the present invention will be described in detail with reference to Examples, Examples, Test Examples, and Preparation Examples, but the present invention is not limited to the Examples. 152528.doc •39· 201121944 Reference Example 1 Synthesis of 3-(cyclopropylmethoxy)phenyl)methaneamine [Chemical 12]

使3-氰基苯酚(12.4 g)溶解於N,N-二甲基甲醯胺(以下為 DMF,100 mL)中,添加碳酸鉀(30.5 g)、蛾化鉀(1_74 g)、 (氯曱基)環丙烷(10.2 mL),於90°C下攪拌4小時。於反應 液中添加水(13 0 mL) ’利用曱苯(13 0 mL)進行萃取p利用 飽和食鹽水(100 mL)清洗有機層’利用無水硫酸鈉加以乾 燥後’進行減壓濃縮。使殘潰溶解於四氫Π夫D南(以下為 THF ’ 60 mL)中,於0°C下緩慢滴加氫化經銘(以下為lAH) 之THF溶液(2·4 Μ ’ 68 mL)後,於45°C下將反應液攪拌4小 時。於0°C下,向反應液中緩慢添加水(1 〇 mL)、氫氧化鈉 水溶液(1_0 Μ ’ 10 mL)、水(5‘0 mL)。將所生成之析出物 過渡除去’利用1 〇%曱醇/THF(400 mL)進行清洗後,將合 一之濾液減壓濃縮。於殘渣中添加水(50 mL),利用乙酸 乙酯(50 mLx3)進行萃取。利用飽和食鹽水(5〇 mL)清洗有 機層’利用無水硫酸鈉加以乾燥後’進行減壓濃縮,藉此 獲得作為粗產物之標記化合物(18.1 g)。 參考例2 (R)-1-(3-(環戊氧基)苯基)乙烷胺鹽酸鹽之合成 [化 13]3-cyanophenol (12.4 g) was dissolved in N,N-dimethylformamide (hereinafter DMF, 100 mL), potassium carbonate (30.5 g), potassium moth (1_74 g), (chlorine) was added. The fluorenyl)cyclopropane (10.2 mL) was stirred at 90 ° C for 4 hours. Water (13 mL) was added to the reaction mixture. The mixture was extracted with hydrazine (130 mL). The organic layer was washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate. The residue was dissolved in tetrahydrofurfuran D (hereinafter referred to as THF '60 mL), and slowly hydrotreated at 0 ° C under the THF solution (2·4 Μ '68 mL) of Ming (hereinafter referred to as lAH). The reaction solution was stirred at 45 ° C for 4 hours. Water (1 〇 mL), an aqueous sodium hydroxide solution (1_0 ’ '10 mL), and water (5 '0 mL) were slowly added to the reaction mixture at 0 °C. The resulting precipitate was removed by a transition and washed with 1% decyl alcohol/THF (400 mL), and the combined filtrate was concentrated under reduced pressure. Water (50 mL) was added to the residue and extracted with ethyl acetate (50 mL×3). The organic layer was washed with a saturated aqueous solution of sodium chloride (5 mL), and dried under reduced pressure, and concentrated under reduced pressure to give a crude compound (18.1 g). Reference Example 2 Synthesis of (R)-1-(3-(cyclopentyloxy)phenyl)ethaneamine hydrochloride [Chem. 13]

152528.doc • 40· 201121944 使3-羥基笨甲醛(12.2 g)溶解於DMF(120 mL)中,添加漠 環戊烷(32.8 mL)、碳酸鉀(27.6 g)、碘化鉀(1.66 g),於 120°C下攪拌3.5小時。將反應液放置冷卻後,添加水(12〇 mL) ’利用甲苯(12〇 mL)進行萃取。利用水(12〇 mL)、氫 氧化鈉水溶液(1_〇 M,120 mL)、飽和食鹽水(1〇〇 mL)清洗 有機層’利用無水硫酸鈉加以乾燥後,進行減壓濃縮。使 殘逢溶解於甲苯(250 mL)中,添加(SH_)_2_曱基_2_丙磺醯 胺(13.3 g)、四異丙醇欽(44.4 mL),於70 °C下授拌ό小時。 將反應液放置冷卻後’添加飽和碳酸氫鈉水溶液(13〇 mL)。將所生成之析出物過濾除去,利用乙酸乙酯(2〇〇 mLx4)進行清洗,將合一之濾液減壓濃縮。於殘渣中添加 飽和食鹽水(200 mL),利用乙酸乙酯(2〇〇 mL)進行萃取。 利用無水硫酸鎂乾燥有機層後,進行減壓濃縮。使殘渣 (29.3 g)中之一部分(1 47 g)溶解於THF(7 5 mL)中於 下滴加溴化曱基鎂之二乙醚溶液(3 〇 M,3 33 mL),於〇<>c 下授摔4小時。於0°C下,花費5分鐘於反應液中添加飽和 氯化銨水,谷液(6.〇 mL),利用乙酸乙酯(1〇 mL)進行萃取。 利用飽和食鹽水(6.〇 mL)M有機層,利用無水硫酸納加 以乾燥後’進行減壓濃縮。利用石夕膠層析法(4〇%乙酸乙醋/ 己烧)將殘1、純化。使所獲得之化合物G⑽3)溶解於甲醇 〇〇虹)中,添加鹽酸-二$燒溶液(4.0 M,1.1 mL),於室 ’皿下授拌30刀鐘。將反應液減壓濃縮後,利用甲苯(5 〇 .3)進行共沸,藉此獲得標記化合物(845 mg)。 參考例3 £ 152528.doc 201121944 (R)-l-(3-((R)-四氫呋喃-3-基氧基)苯基)乙烷胺鹽酸鹽之合成152528.doc • 40· 201121944 Dissolve 3-hydroxybenzaldehyde (12.2 g) in DMF (120 mL), add Cyclopentane (32.8 mL), Potassium Carbonate (27.6 g), Potassium Iodide (1.66 g), Stir at 120 ° C for 3.5 hours. After the reaction solution was allowed to stand for cooling, water (12 mL) was added and extracted with toluene (12 mL). The organic layer was washed with water (12 〇 mL), a sodium hydroxide aqueous solution (1 〇 M, 120 mL), and brine (1 〇〇 mL) and dried over anhydrous sodium sulfate. The residue was dissolved in toluene (250 mL), and (SH_)_2_mercapto-2-propanesulfonamide (13.3 g) and tetraisopropanol (44.4 mL) were added and the mixture was stirred at 70 °C. hour. After the reaction solution was left to cool, a saturated aqueous sodium hydrogencarbonate solution (13 mL) was added. The formed precipitate was removed by filtration, washed with ethyl acetate (2 mL mL 4), and the filtrate was concentrated under reduced pressure. Saturated brine (200 mL) was added to the residue and extracted with ethyl acetate (2 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. One part (1 47 g) of the residue (29.3 g) was dissolved in THF (75 mL), and a solution of bismuth bromide magnesium diethyl ether (3 〇M, 3 33 mL) was added dropwise to 〇 <>c gave a 4 hour drop. Saturated ammonium chloride water and glutamic acid (6. 〇 mL) were added to the reaction mixture at 0 ° C for 5 minutes, and extracted with ethyl acetate (1 mL). The organic layer was saturated with brine (6. 〇 mL) and dried over anhydrous sodium sulfate. Residue 1 was purified by Shixia gel chromatography (4% acetic acid ethyl acetate / hexane). The obtained compound G(10)3) was dissolved in methanol hydrazine, and a hydrochloric acid-two-burn solution (4.0 M, 1.1 mL) was added, and a mixture of 30 knives was placed under a chamber. The reaction liquid was concentrated under reduced pressure, and then azeotroped with toluene (5 〇.3) to obtain a labeled compound (845 mg). Reference Example 3 £ 152528.doc 201121944 Synthesis of (R)-l-(3-((R)-tetrahydrofuran-3-yloxy)phenyl)ethaneamine hydrochloride

[化 14] CIH · H2N 使3-羥基苯甲醛(1.3 g)、三苯基膦(3.6 g)、(S)-(+)-四氫-3-0夫喝甲醇(1.2 mL)溶解於THF(20 mL)中,於0°C下緩慢滴 加偶氮二甲酸二乙酯(以下為DEAD)之甲苯溶液(2.2 Μ, 6.2 mL)後’於室溫下攪拌2小時。將反應液減壓濃縮後, 添加乙酸乙酯(20 mL) ’利用氫氧化鈉水溶液(1.〇 μ,5.0 mL)清洗有機層,利用無水硫酸鈉加以乾燥後,進行減壓 濃縮。利用石夕膠層析法(50%乙酸乙酿/己燒)將殘渣純化。 使所獲得之化合物溶解於甲苯(6.5 mL)中,添加(S)-(-)-2-曱基-2-丙磺醯胺(33〇11^)、四異丙醇鈦(1.1111]^),於75。〇 下攪拌6小時。將反應液放置冷卻後,添加飽和碳酸氫鈉 水溶液(10 mL)。將所生成之析出物過濾除去,利用乙酸 乙醋(20 mLx4)進行清洗’將合一之濾液減壓濃縮。於殘 渣中添加飽和食鹽水(30 mL) ’利用乙酸乙酯進行萃取, 利用無水硫酸鎂乾燥有機層後,進行減壓濃縮。使殘渣溶 解於THF(7.5 mL)中,於(TC下滴加溴化甲基鎂之二乙醚溶 液(3_0 M,1.7 mL),於室溫下攪拌2小時。於〇β(:下花費1〇 分鐘於反應液中添加飽和氣化銨水溶液(1〇 mL),利用乙 酸乙酯(15 mL)進行萃取❶利用飽和食鹽水(1〇 mL)清洗有 機層’利用無水硫酸納加以乾燥後,進行減壓濃縮。利用 矽膠層析法(100%乙酸乙酯)將殘渣純化。使所獲得之化合 152528.doc -42· 201121944 物;谷解於甲醇(5.0 mL)_,添加鹽酸_二0号炫溶液(‘.ο %, 470 μί),於室溫下攪拌3〇分鐘。將反應液減壓濃縮後,利 用曱苯(4_0 mLx3)進行共沸,藉此獲得標記化合物(244 mgp 參考例4 (3-(環丙基曱氧基)_4·氟苯基)曱烧胺之合成 [化 15]CIH · H2N Dissolves 3-hydroxybenzaldehyde (1.3 g), triphenylphosphine (3.6 g), (S)-(+)-tetrahydro-3-0-drink methanol (1.2 mL) in In a THF (20 mL), a toluene solution of diethyl azodicarboxylate (hereinafter, DEAD) (2.2 Μ, 6.2 mL) was slowly added dropwise at 0 ° C, and then stirred at room temperature for 2 hours. After the reaction mixture was concentrated under reduced pressure, ethyl acetate (20 mL) was evaporated. The organic layer was washed with aqueous sodium hydroxide (1 〇μ, 5.0 mL) and dried over anhydrous sodium sulfate. The residue was purified by Shih Tzu chromatography (50% acetic acid / hexane). The obtained compound was dissolved in toluene (6.5 mL), and (S)-(-)-2-mercapto-2-propanesulfonamide (33〇11^), titanium tetraisopropoxide (1.1111)^ was added. ), at 75. Stir for 6 hours under the crucible. After the reaction solution was cooled, a saturated aqueous sodium hydrogen carbonate solution (10 mL) was added. The resulting precipitate was filtered off and washed with ethyl acetate (20 mL x 4). The combined filtrate was concentrated under reduced pressure. Saturated brine (30 mL) was added to the residue, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The residue was dissolved in THF (7.5 mL), and then diethyl ether (br. To the reaction mixture, a saturated aqueous solution of ammonium sulfate (1 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (15 mL). The organic layer was washed with saturated brine (1 mL) and dried over anhydrous sodium sulfate. Concentration under reduced pressure. The residue was purified by silica gel chromatography (100% ethyl acetate) to give the obtained compound 152528.doc -42 · 201121944; glutamic acid in methanol (5.0 mL) _, hydrochloric acid _2 No. Hyun solution ('.ο %, 470 μί), stirred at room temperature for 3 minutes. The reaction solution was concentrated under reduced pressure, and then azeotroped with terpene (4_0 mL×3) to obtain a labeled compound (244 mgp. Example 4 Synthesis of (3-(cyclopropyl decyloxy)_4·fluorophenyl) guanidine amine [Chemical 15]

H2N 使4-氟-3-羥基苯甲酸(15〇 g)溶解於dmf(200 mL)中, 添加(氯甲基)環丙烧(18.0 mL)、碳酸鉀(29.2 g)、破化卸 (1.6 g) ’於90°C下攪拌6小時。將反應液放置冷卻後,添 加水(120 mL),利用甲苯(12〇 mL)進行萃取。利用飽和食 鹽水(100 mL)清洗有機層,利用無水硫酸鈉加以乾燥後, 進行減壓濃縮。使殘渣溶解於曱苯(65 mL)中,於〇t»c下滴 加氫化二異丁基鋁(以下為DIBAL)之己烷溶液(1.0 M,130 mL) 後,於0°C下將反應液攪拌2小時。於反應液中緩慢添加水 (10 mL)、氫氧化鈉水溶液(丨〇 μ,1〇 mL)。將所生成之析 出物過濾除去,利用乙酸乙酯(1〇〇 mLx5)清洗後,將合一 之濾液減壓濃縮"於殘渣中添加水(1〇〇 mL),利用乙酸乙酯 (150 mL)進行萃取。利用飽和食鹽水(5〇 mL)清洗有機層,利用 無水硫酸鈉加以乾燥後,進行減壓濃縮。利用矽膠層析法 (40。/。乙酸乙酯/己烷)將殘渣純化。使所獲得之化合物溶解 於THF(75 mL)中,於室溫下滴加二苯基疊氮基磷酸酯 (12·9 mL)、1,8-二氮雜雙環[5 4.〇]_7-H--烯(以下為 DBU) 152528.doc -43- 201121944 (9.4 mL) ’於室溫下攪拌1小時。於反應液中添加飽和食鹽 水(100 mL),利用乙酸乙酯(1〇〇 mLx2)對水層進行萃取。利 用飽和食鹽水(100 mL)清洗有機層後,利用無水硫酸鈉加以 乾燥’並進行減壓濃縮。利用矽膠管柱層析法(2〇%乙酸己 酯/己烧)將殘渣純化。使所獲得之化合物溶解於THF(80 mL) 中,於〇°C下緩慢滴加LAH之THF溶液(2·4 Μ,40 mL),於 〇°C下攪拌1小時。於0°C下,於反應液中緩慢滴加水(5.〇 mL)、 氫氧化鈉水溶液(1.0 Μ,5 · 0 mL)。將析出物過濾除去,利 用10%曱醇/THF(200 mL)清洗後,將合一之渡液減壓濃 縮。於殘渣中添加飽和食鹽水(1 〇〇 mL),利用乙酸乙醋 (150 mL)進行萃取,利用無水硫酸鈉乾燥有機層,並進行 減壓濃縮,藉此獲得作為粗產物之標記化合物(丨〇 5 。 參考例5 (R)-1-(3-(環丙基曱氧基)_4-氟苯基)乙烷胺鹽酸鹽之合成 [化 16]H2N 4-Fluoro-3-hydroxybenzoic acid (15 〇g) was dissolved in dmf (200 mL), (chloromethyl)cyclopropane (18.0 mL), potassium carbonate (29.2 g), and decomposed ( 1.6 g) 'Stirring at 90 ° C for 6 hours. After the reaction solution was allowed to stand for cooling, water (120 mL) was added and extracted with toluene (12 mL). The organic layer was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate and evaporated. The residue was dissolved in toluene (65 mL), and a solution of hydrogenated diisobutylaluminum (hereinafter referred to as DIBAL) in hexane (1.0 M, 130 mL) was added under 〇t»c, and then at 0 ° C. The reaction solution was stirred for 2 hours. Water (10 mL) and an aqueous sodium hydroxide solution (丨〇 μ, 1 mL) were slowly added to the reaction mixture. The formed precipitate was removed by filtration, washed with ethyl acetate (1 mL mL 5), and then the filtrate was concentrated under reduced pressure. " Water (1 mL) was added to the residue. mL) for extraction. The organic layer was washed with brine (5 mL), dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel chromatography (40% ethyl acetate /hexane). The obtained compound was dissolved in THF (75 mL), and diphenyl azido phosphate (12·9 mL) and 1,8-diazabicyclo[5 4.〇]_7 were added dropwise at room temperature. -H--ene (hereinafter DBU) 152528.doc -43- 201121944 (9.4 mL) 'Stirring at room temperature for 1 hour. Saturated salt water (100 mL) was added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate (1 mL). The organic layer was washed with brine (100 mL) and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (2% hexyl acetate / hexane). The obtained compound was dissolved in THF (80 mL), and a THF solution (2·4 Μ, 40 mL) of LAH was slowly added dropwise at 〇 ° C, and stirred at 〇 ° C for 1 hour. Water (5. 〇 mL) and an aqueous sodium hydroxide solution (1.0 Μ, 5 · 0 mL) were slowly added dropwise to the reaction mixture at 0 °C. The precipitate was removed by filtration, washed with 10% decyl alcohol / THF (200 mL), and the mixture was concentrated under reduced pressure. Saturated brine (1 mL) was added to the residue, and the mixture was extracted with ethyl acetate (150 mL), and the organic layer was dried over anhydrous sodium sulfate. 〇5. Reference Example 5 Synthesis of (R)-1-(3-(cyclopropyldecyloxy)_4-fluorophenyl)ethaneamine hydrochloride [Chem. 16]

使4-氟-3-羥基苯曱酸(12·0 g)溶解於乙醇(2〇〇 mL)中, 添加硫酸(3.5 mL) ’於1 〇5°C下加熱回流4小時。將反應液 放置冷卻後,進行減壓濃縮《於殘渣中添加水(100 mL)、 碳酸鈉(18.0 g),利用乙酸乙酯(loo mLx2)萃取水層。利用 飽和食鹽水(100 mL)清洗混合之有機層,利用無水硫酸鈉 加以乾燥後’進行減壓濃縮。利用曱苯(丨5 mLx2)使殘渣 共沸後’溶解於DMF(100 mL)中,於90°C下添加(氣曱基) 152528.doc • 44. 201121944 環丙院(6·9 mL)、碳酸鉀(19.8 g)、碘化鉀(1.2 g),攪拌3.5 小時。將反應液放置冷卻後’添加水(200 mL),利用甲苯 (100 mLx2)進行萃取。利用飽和食鹽水(1〇〇 mL)清洗有機 層,利用無水硫酸鈉加以乾燥後,進行減壓濃縮。使殘渣 溶解於THF(75 mL)中,於室溫下滴加氫硼化鋰之THF溶液 (2.0 Μ ’ 54 mL) ’於80°C下加熱回流3 5小時。將反應液放 置冷卻後’於0 C下滴加水(200 mL),利用乙酸乙酯(1〇〇 mLx2)進行萃取。利用飽和食鹽水(1〇〇 mL)清洗有機層, 利用無水硫酸鈉加以乾燥後,進行減壓濃縮。使殘渣溶解 於二氯曱烷(250 mL)中,於室溫下添加二氧化錳(86 g), 於45 C下加熱回流6小時。將反應液放置冷卻後,將不溶 物過濾除去’利用氣仿(100 mLM)清洗後,將合一之濾液 濃縮,。使殘渣溶解於甲苯(150 mL)中,添加(s)-(-)-2-曱基-2-丙磺醯胺(8.5 g)、四異丙醇鈦(28·4 mL),於75°c下攪拌 6小時。將反應液放置冷卻後,添加飽和碳酸氫納水溶液 (150 mL)。將所生成之析出物過濾除去,利用乙酸乙酯 (200 mLx6)清洗,將合一之濾液減壓濃縮。於殘渣中添加 飽和食鹽水(150 mL),利用乙酸乙酯(2〇〇 mL)進行萃取。 利用無水硫酸鎮乾燥有機層後’進行減壓濃縮。使殘渣溶 解於THF(85 mL)中,於〇〇C下滴加溴化甲基鎂之二乙醚溶 液(3.0 Μ,42 mL),於室溫下攪拌2小時。於〇〇c下,花費 10分鐘於反應液中添加飽和氯化錄水溶液(丨〇〇 mL),利用 乙酸乙酯(100 mL><2)進行萃取。利用飽和食鹽水(1〇〇 mL) 清洗有機層’利用無水硫酸鈉加以乾燥後,進行減壓濃 152528.doc -45- 201121944 縮。利用矽膠層析法(5〇〇/0乙酸乙酯/己烷)將殘渣純化。使 所獲得之化合物溶解於甲醇(70 mL)中,添加鹽酸-二噚烷 溶液(4.0 Μ ’ 13 mL) ’於室溫下攪拌30分鐘。將反應液減 壓濃縮後’利用曱苯(4〇 mLx3)使殘渣共沸,藉此獲得標 記化合物(9.09 g)。 參考例6 (R)-1-(3-(環丙基曱氧基)_4_氟苯基)-2-甲基丙烧_1_胺鹽酸 鹽之合成 [化 17]4-Fluoro-3-hydroxybenzoic acid (12.0 g) was dissolved in ethanol (2 mL), and sulfuric acid (3.5 mL) was added and heated under reflux at 4 ° C for 4 hours. After the reaction mixture was allowed to cool, the mixture was concentrated under reduced pressure. Water (100 mL) and sodium carbonate (18.0 g) were added to the residue, and the aqueous layer was extracted with ethyl acetate (loo mLx2). The mixed organic layer was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate and then evaporated. The residue was azeotroped with hydrazine (丨 5 mL×2), dissolved in DMF (100 mL), and added at 90 ° C (gas sulfhydryl) 152528.doc • 44. 201121944 Cyclopropylamine (6·9 mL) Potassium carbonate (19.8 g) and potassium iodide (1.2 g) were stirred for 3.5 hours. After the reaction solution was left to cool, water (200 mL) was added and extracted with toluene (100 mL×2). The organic layer was washed with brine (1 mL), dried over anhydrous sodium sulfate and evaporated. The residue was dissolved in THF (75 mL), and then a THF solution of lithium borohydride (2.0 ’ ' 54 mL) was dropped at room temperature and refluxed at 80 ° C for 35 hours. After the reaction solution was allowed to stand for cooling, water (200 mL) was added dropwise at 0 C, and extracted with ethyl acetate (1 mL mL). The organic layer was washed with saturated brine (1 mL), dried over anhydrous sodium sulfate and evaporated. The residue was dissolved in dichloromethane (250 mL), and then, then, then,,,,,,,,,,,,,,,,,, After the reaction solution was allowed to stand for cooling, the insoluble matter was removed by filtration. After washing with a gas-like (100 mL), the combined filtrate was concentrated. The residue was dissolved in toluene (150 mL), and (s)-(-)-2-mercapto-2-propanesulfonamide (8.5 g) and titanium tetraisopropoxide (28·4 mL) were added at 75 Stir at °c for 6 hours. After the reaction solution was allowed to stand for cooling, a saturated aqueous solution of sodium hydrogencarbonate (150 mL) was added. The formed precipitate was removed by filtration, washed with ethyl acetate (200 mL×6), and the filtrate was concentrated under reduced pressure. Saturated brine (150 mL) was added to the residue, and ethyl acetate (2 mL) was applied. After drying the organic layer with anhydrous sulfuric acid, it was concentrated under reduced pressure. The residue was dissolved in THF (85 mL). EtOAc (EtOAc m. Under a vacuum of 10 minutes, a saturated aqueous solution of chlorinated chloride (? mL) was added to the reaction mixture, and ethyl acetate (100 mL <<2> The organic layer was washed with saturated brine (1 mL) and dried over anhydrous sodium sulfate, and then concentrated under reduced pressure 152528.doc -45 - 201121944. The residue was purified by silica gel chromatography (5 EtOAc/EtOAc). The obtained compound was dissolved in methanol (70 mL), and a hydrochloric acid-dioxane solution (4.0 ’ ' 13 mL) was added and stirred at room temperature for 30 minutes. After the reaction mixture was concentrated under reduced pressure, the residue was azeotroped with toluene (4 〇 mL x 3), whereby the title compound (9.09 g) was obtained. Reference Example 6 Synthesis of (R)-1-(3-(cyclopropyldecyloxy)-4-fluorophenyl)-2-methylpropan-1-amine hydrochloride [Chem. 17]

使4-氟-3-羥基苯甲酸(1.2 g)溶解於乙醇(2〇 mL)中,添 加硫酸(350 μί),於1〇5。(:下加熱回流4小時。將反應液放 置冷卻後’進行減壓濃縮。於殘潰中添加水(1 〇 mL) '碳 酸鈉(1.8 g),利用乙酸乙酯(2〇 mL><2)萃取水層。利用飽和 食鹽水(20 mL)清洗有機層,利用無水硫酸鈉加以乾燥 後,進行減壓濃縮。利用甲苯(4.0 mLx2)使殘渣共沸後, 溶解於DMF(50 mL)中,添加(氯甲基)環丙烷(762 、碳 酸鉀(2.1 g)、碘化鉀(133 mg),於90。(:下攪拌3.5小時。將 反應液放置冷卻後,添加水(2〇 mL),利用曱苯(20 mLx2) 進行萃取。利用飽和食鹽水(2〇 mL)清洗有機層,利用無 水硫酸鈉加以乾燥後,進行減壓濃縮。使殘渣溶解於 THF(8.0 mL)中’於室溫下滴加氫硼化鋰之THF溶液(2〇 152528.doc -46· 201121944 Μ ’ 7.5 mL) ’於75°C下加熱回流3.5小時。將反應液放置 冷卻後’於0°C下滴加水(20 mL),利用乙酸乙酯(20 mL><2) 萃取水層。利用飽和食鹽水(2〇 mL)清洗有機層,利用無 水硫酸鈉加以乾燥後,進行減壓濃縮。使殘渣溶解於二氣 甲烷(25 mL)中,於室溫下添加二氧化錳(8.6 g),於45。(:下 加熱回流6小時。將反應液放置冷卻後,將不溶物過濾除 去,利用氯仿(20 mLx4)進行清洗後,將合一之濾液濃 縮。使殘渣溶解於甲苯(17.5 mL)中,添加(R)-(+)-2-曱基-2_丙磺醯胺(985 mg)、四異丙醇鈇(3.3 mL),於75°C下攪 拌6小時。放置冷卻後’添加飽和碳酸氫鈉水溶液(i 5 mL)。將所生成之析出物過濾除去,利用乙酸乙酯(2〇 mLx6)清洗。利用飽和食鹽水(50 mL)清洗合一之濾液,利 用無水硫酸鎂加以乾燥後’進行減壓濃縮^使殘渣溶解於 THF(85 mL)中,於-78°C下滴加異丙基鋰之THF溶液(0.7 Μ, 12 mL),於_78°C下攪拌45分鐘。於-78。(:下,於反應液中添 加飽和氣化敍水溶液(10 mL),利用乙酸乙酯(20 mLx2)萃 取水層。利用飽和食鹽水(20 mL)清洗混合之有機層,利 用無水硫酸鈉加以乾燥後,進行減壓濃縮。利用矽膠層析 法(50%乙酸乙酯/己烷)將殘渣純化。使所獲得之化合物溶解 於曱醇(7·0 mL)中,添加鹽酸-二呤烷溶液(4.0 Μ,470 μί), 於室溫下攪拌30分鐘。將反應液減壓濃縮後,利用甲笨 (10 mLx3)使殘渣共沸,藉此獲得標記化合物(425 mg)。 以下之表所示胺係依據參考例2、3、5、6之任一方法而 合成。 152528.doc •47· 201121944 [表l] 參考例 原料 胺 製造方法 7 Η〇χαΓ \ CIH . 5 8 h\j°h CIH · H2N^^X^j^|^0^VV 2 9 Λχ CIH · 5 10 Λχη CIH 6 11 Λτ / CIH . H2N^^^j^〇、V 2 12 hVh CIH . H2N^^0^〇O 3 13 0 hA^^〇CF2CHF2 c旧· h2n、|0^OCF2CHF2 2 14 Η^α°Η CIH · H2N^v|j^|^〇^CF3 2 48- 152528.doc 201121944 [表2] 參考例 原料 胺 製造方法 15 ηΛΊ〇Τ〇η CIH . Η2Ν、|^^0丫 2 16 CIH · 2 17 η1〇Γ〇Η JL CIH · H2N^Y^j^ i 2 18 CIH · 3 19 ηΛ〇Γ〇η CIH . 2 20 Λχ CIH · H2N^|^j^〇^V% 3 21 H\yH CIH . H2N/'v'|^j^〇/V^ 3 22 ηΧ〇"η CIH · H2N^|^^0 34-Fluoro-3-hydroxybenzoic acid (1.2 g) was dissolved in ethanol (2 mL), and sulfuric acid (350 μί) was added at 1〇5. (: heating under reflux for 4 hours. After allowing the reaction solution to cool, 'concentrate under reduced pressure. Add water (1 〇 mL) 'sodium carbonate (1.8 g) to the residue, using ethyl acetate (2 mL) << 2) The aqueous layer was extracted, and the organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was azeotroped with toluene (4.0 mL×2) and dissolved in DMF (50 mL) In the middle, (chloromethyl)cyclopropane (762, potassium carbonate (2.1 g), potassium iodide (133 mg) was added, and the mixture was stirred at 90 ° for 3.5 hours. After the reaction solution was allowed to stand for cooling, water (2 mL) was added. The organic layer was washed with a saturated aqueous solution of sodium chloride (2 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was dissolved in THF (8.0 mL). The THF solution of lithium hydroboride (2〇152528.doc -46·201121944 Μ '7.5 mL) was heated under reflux for 3.5 hours at 75 ° C. The reaction solution was allowed to cool and then dropped at 0 ° C. Water (20 mL) was added, and the aqueous layer was extracted with ethyl acetate (20 mL <2). The organic layer was washed with anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was dissolved in di-methane (25 mL), and then, then, and then, at room temperature, manganese dioxide (8.6 g) was added at 45. The mixture was heated and refluxed for 6 hours. After the reaction mixture was allowed to stand for cooling, the insoluble material was filtered and removed, and washed with chloroform (20 mL×4), and then the filtrate was concentrated. The residue was dissolved in toluene (17.5 mL) and added (R) )-(+)-2-mercapto-2_propanesulfonamide (985 mg), tetraisopropanol oxime (3.3 mL), stirred at 75 ° C for 6 hours. After standing to cool, 'add saturated sodium bicarbonate Aqueous solution (i 5 mL). The resulting precipitate was removed by filtration and washed with ethyl acetate (2 mL mL). The combined filtrate was washed with saturated brine (50 mL) and dried over anhydrous magnesium sulfate. The residue was dissolved in EtOAc (EtOAc) (EtOAc) 78. (:: Add a saturated aqueous solution (10 mL) to the reaction solution, and extract the aqueous layer with ethyl acetate (20 mL×2). The combined organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate and evaporated. A solution of hydrochloric acid-dioxane (4.0 Μ, 470 μί) was added to decyl alcohol (7.0 mL), and the mixture was stirred at room temperature for 30 minutes. After the reaction mixture was concentrated under reduced pressure, the residue was azeotroped with <RTI ID=0.0>> The amines shown in the following table were synthesized according to any of Reference Examples 2, 3, 5 and 6. 152528.doc •47· 201121944 [Table l] Reference Example Raw Material Amine Manufacturing Method 7 Η〇χαΓ \ CIH . 5 8 h\j°h CIH · H2N^^X^j^|^0^VV 2 9 Λχ CIH · 5 10 Λχη CIH 6 11 Λτ / CIH . H2N^^^j^〇, V 2 12 hVh CIH . H2N^^0^〇O 3 13 0 hA^^〇CF2CHF2 c old · h2n, |0^OCF2CHF2 2 14 Η^α°Η CIH · H2N^v|j^|^〇^CF3 2 48- 152528.doc 201121944 [Table 2] Reference Example Raw Material Amine Manufacturing Method 15 ηΛΊ〇Τ〇η CIH . Η2Ν,|^^0丫2 16 CIH · 2 17 η1〇Γ〇Η JL CIH · H2N^Y^j^ i 2 18 CIH · 3 19 ηΛ〇Γ〇η CIH . 2 20 Λχ CIH · H2N^|^j^〇^V% 3 21 H\yH CIH . H2N/'v'|^j^〇/V^ 3 22 ηΧ〇"η CIH · H2N^|^^0 3

S 152528.doc •49- 201121944 [表3] 參考例 原料 胺 製造方法 23 CIH - 3 24 Λχ f 。人/ CIH ♦ H2N^|^^U 3 25 ηΧΧ70Η f 人八 CIH · 3 26 - * X A CIH · 3 27 C丨H · H2N^|^0八CF2CF3 2 28 aH,^Q^Q〇 3 29 CIH · H2N,^f^^〇>^) 3 30 η1〇γ〇η ! CIH · 3 參考例3 1 N-(3-(環丙基甲氧基)苄基)-3-(曱氧基曱氧基)丙烷-1-磺醯 胺之合成 [化 18] -50- 152528.doc 201121944S 152528.doc •49- 201121944 [Table 3] Reference Example Raw material Amine Manufacturing method 23 CIH - 3 24 Λχ f . Person / CIH ♦ H2N^|^^U 3 25 ηΧΧ70Η f 人八 CIH · 3 26 - * XA CIH · 3 27 C丨H · H2N^|^0八CF2CF3 2 28 aH,^Q^Q〇3 29 CIH · H2N, ^f^^〇>^) 3 30 η1〇γ〇η ! CIH · 3 Reference Example 3 1 N-(3-(Cyclopropylmethoxy)benzyl)-3-(decyloxy) Synthesis of decyloxy)propane-1-sulfonamide [Chem. 18] -50- 152528.doc 201121944

MOMOMOMO

使參考例1中獲得之(3-(環丙基甲氧基)苯基)甲烷胺(1〇.〇 g)溶解於二氣曱院(50 mL)中,於〇°c下添加三乙基胺(11.9 g)、3-氣丙磺醯氣(10.6 g),於室溫下攪拌12小時。於反應 液中添加水(100 mL),利用氯仿(5〇 mL)進行萃取。利用稀 鹽酸(1.0 Μ,100 mL)、飽和食鹽水(1〇〇 mL)清洗有機層, 利用無水硫酸鈉加以乾燥後,進行減壓濃縮。使殘渣溶解 於DMF(100 mL)中’添加乙酸鈉(1〇 2 g) '填化鈉(18 6 g),於80 C下攪拌8小時《將反應液放置冷卻後,添加水 (100 mL),利用乙酸乙酯(8〇 mLx2)進行萃取。利用飽和食 鹽水(100 mL)清洗有機層,利用無水硫酸鈉加以乾燥後, 進行減壓濃縮。利用矽膠管柱層析法(5〇%乙酸乙酯/己烷) 將殘渣純化。使所獲得之化合物溶解於5_丨〇%鹽酸/甲醇溶 液(100 mL)中,於8(rc下加熱回流丨小時。將反應液放置 冷卻後,進行減壓濃縮。利用矽膠管柱層析法(66%乙酸乙 酯/己烷)將殘渣純化。使所獲得之化合物溶解於二氣曱烷 (80 mL)中’添加N,N_二異丙基乙胺(141 mL)、氯甲基甲 醚(4.1 mL),於室溫下攪拌j小時◦於反應液中添加飽和氯 化銨水洛液(50 mL),利用氯仿(5〇 mL)進行萃取。利用飽 和食鹽水(30 mL)清洗有機層,利用無水硫酸鈉加以乾燥 後,進行減壓濃縮。利用矽膠管柱層析法(25%乙酸乙酯/ 己烷)將殘渣純化,藉此獲得標記化合物(115 g)。 以下之表所示化合物係使用參考例2〜3〇中獲得之任一 胺’依據參考例31之方法而合成。(3-(cyclopropylmethoxy)phenyl)methaneamine (1〇.〇g) obtained in Reference Example 1 was dissolved in Digastric Institute (50 mL), and triethyl bethane was added at 〇 °c. The amine (11.9 g), 3-acesulfamesulfonate (10.6 g) was stirred at room temperature for 12 hours. Water (100 mL) was added to the reaction mixture, and extracted with chloroform (5 mL). The organic layer was washed with diluted hydrochloric acid (1.0 mL, 100 mL) and brine (1 mL) and dried over anhydrous sodium sulfate. The residue was dissolved in DMF (100 mL). 'Add sodium acetate (1 〇 2 g) 'Sodium hydride (18 6 g) and stir at 80 C for 8 hours. After the reaction solution was allowed to cool, add water (100 mL). ), extraction was carried out using ethyl acetate (8 〇 mL x 2). The organic layer was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate and evaporated. The residue was purified by hydrazine column chromatography (5% EtOAc/hexane). The obtained compound was dissolved in a 5 丨〇% hydrochloric acid/methanol solution (100 mL), and heated under reflux for 8 hours at 8 rc. The reaction solution was allowed to stand for cooling, and then concentrated under reduced pressure. The residue was purified by the method (66% ethyl acetate / hexane). The obtained compound was dissolved in dioxane (80 mL). N,N-diisopropylethylamine (141 mL) Methyl ether (4.1 mL), stirring at room temperature for 1 hour, adding saturated ammonium chloride water solution (50 mL) to the reaction mixture, and extracting with chloroform (5 mL). Using saturated brine (30 mL) The organic layer was washed, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (25% ethyl acetate /hexane) to give the title compound (115 g). The compound shown in the table was synthesized according to the method of Reference Example 31 using any of the amines obtained in Reference Examples 2 to 3'.

S 152528.doc •51· 201121944 [表4] 參考例 胺參考例編號 目標物 32 2 33 3 MOMO "^^0^〇,、0〇 34 4 MOMO 〜 35 5 momo^^-^s-n^OCq^^ 36 6 37 7 MOMO^^S-N^OC〇/^^ 38 8 mom〇-^^s-n^〇L〇/^ 39 9 ΜΟΜΟ^'^^-ΒγΧΧο^Ο 40 10 momo^^|-R^〇C。^^ 152528.doc 52- 201121944 [表5] 目標物 胺參考例編號 目標物 41 11 42 12 λ/ιομο^^-H^OLo^^ 43 13 M〇M〇-^|-K^Xl〇CF2CHF2 44 14 M〇M〇 〜^|-i3y〇L〇ACF3 45 15 momo^^^s-n^〇L〇J^f 46 16 MOMO^^^S-N^XX〇^^ 47 17 momo-^^s-n^JOLq/s^^ 48 18 momo^^^s-n^〇L〇^^ 49 19 M〇M〇-^|-a^〇Lo^CHF2 50 20 MOM〇-^^|-Sy0L〇J^ £ 152528.doc 53- 201121944 [表6] 參考例 胺參考例編號 目標物 51 21 MOM〇/^|-Sy0l〇A% 52 22 ΜΟΜ〇·"^^8-Ν^ΧΧ〇/^Ρ 53 23 momo"^^s-n^J〇L〇A^ 54 24 55 25 56 26 mom〇-^^s-n^〇L〇A^. 57 27 酬。-^|-Ky〇L0ACF2CF3 58 28 M〇M〇^^s-N^x〇L〇X^J 59 29 mom〇-^^s-n^〇L〇>C/0 60 30 ΜΟΜ<Τ^^-ΗγΧΧ〇/\^ 參考例61 (R)-N-(卜(3-(環丙基曱氧基)-4-氟苯基)乙基)-3-羥基-N-(甲 氧基甲基)丙烷-1-磺醯胺之合成 [化 19] 152528.doc •54· 201121944S 152528.doc •51· 201121944 [Table 4] Reference Example Amine Reference Example No. Target 32 2 33 3 MOMO "^^0^〇,, 0〇34 4 MOMO ~ 35 5 momo^^-^sn^OCq ^^ 36 6 37 7 MOMO^^SN^OC〇/^^ 38 8 mom〇-^^sn^〇L〇/^ 39 9 ΜΟΜΟ^'^^-ΒγΧΧο^Ο 40 10 momo^^|-R^ 〇C. ^^ 152528.doc 52- 201121944 [Table 5] Target amine reference example number target 41 11 42 12 λ/ιομο^^-H^OLo^^ 43 13 M〇M〇-^|-K^Xl〇CF2CHF2 44 14 M〇M〇~^|-i3y〇L〇ACF3 45 15 momo^^^sn^〇L〇J^f 46 16 MOMO^^^SN^XX〇^^ 47 17 momo-^^sn^JOLq /s^^ 48 18 momo^^^sn^〇L〇^^ 49 19 M〇M〇-^|-a^〇Lo^CHF2 50 20 MOM〇-^^|-Sy0L〇J^ £ 152528.doc 53- 201121944 [Table 6] Reference Example Amine Reference Example No. Target 51 21 MOM〇/^|-Sy0l〇A% 52 22 ΜΟΜ〇·"^^8-Ν^ΧΧ〇/^Ρ 53 23 momo"^ ^sn^J〇L〇A^ 54 24 55 25 56 26 mom〇-^^sn^〇L〇A^. 57 27 Pay. -^|-Ky〇L0ACF2CF3 58 28 M〇M〇^^sN^x〇L〇X^J 59 29 mom〇-^^sn^〇L〇>C/0 60 30 ΜΟΜ<Τ^^-ΗγΧΧ 〇/\^ Reference Example 61 (R)-N-(Bu(3-(cyclopropyldecyloxy)-4-fluorophenyl)ethyl)-3-hydroxy-N-(methoxymethyl) Synthesis of propane-1-sulfonamide [Chem. 19] 152528.doc •54· 201121944

使參考例5中所獲得之(R)-l-(3-(環丙基甲氧基)-4-氟苯 基)乙烷胺鹽酸鹽(1.20 g)溶解於二氣曱烷(7·5 mL)中,於 〇°C下添加三乙基胺(1.6 mL)、3-氣丙磺醯氯(550 μΐ),於 室溫下攪拌2小時。於反應液中添加水(1〇 mL),利用氯仿 (30 mL)進行萃取。利用飽和食鹽水(15 mL)清洗有機層, 利用無水硫酸鈉加以乾燥後,減壓濃縮。利用矽膠管柱層 析法(4 0 °/〇乙酿乙醋/己烧)將殘潰純化。使所獲得之化合物 溶解於二氯曱烷(7.0 mL)中,添加N,N-二異丙基乙基胺 (5.0 mL)、氣甲基曱醚(1.5 mL),於40°C下攪拌6小時。於 反應液中添加飽和氯化錄水溶液(1 〇 mL),利用氣仿(20 mL)進行萃取。利用飽和食鹽水(10 mL)清洗有機層,利用 無水硫酸鈉加以乾燥後,進行減壓濃縮。利用石夕膠管柱層 析法(20%乙酸乙酯/己烧)將殘渣純化。使所獲得之化合物 溶解於DMF(8.0 mL)中’添加乙酸鈉(887 mg)、碘化鈉 (1.62 g),於80°C下攪拌8小時。將反應液放置冷卻後,添 加水(20 mL),利用乙酸乙酶(20 mLx2)進行萃取。利用飽 和食鹽水(20 mL)清洗有機層,利用無水硫酸鈉加以乾燥 後,並進行減壓濃縮。利用矽膠管柱層析法(5〇%乙酸乙酯/ 己炫>)將殘〉查純化。使所獲得之化合物溶解於曱基胺之曱 醇溶液(40%,7.0 mL)中’於室溫下攪拌i小時。將反應液 減壓濃縮後’利用石夕膠管柱層析法(66%乙酸乙|旨/己烧)進 行純化,藉此獲得標記化合物(932 mg)。 S' 152528.doc -55- 201121944 參考例62 (R,E)-N-(l-(3-(環丙基甲氧基)-4-氟苯基)乙基)-5-經基-N-(甲氧基甲基)戍-3-稀-1-確酿胺之合成 [化 20](R)-l-(3-(cyclopropylmethoxy)-4-fluorophenyl)ethaneamine hydrochloride (1.20 g) obtained in Reference Example 5 was dissolved in dioxane (7). In a solution of 5 mL), triethylamine (1.6 mL) and 3-air-propanesulfonium chloride (550 μM) were added at 〇 ° C, and stirred at room temperature for 2 hours. Water (1 〇 mL) was added to the reaction mixture, and the mixture was extracted with chloroform (30 mL). The organic layer was washed with brine (15 mL) and dried over anhydrous sodium sulfate. The residue was purified by a silica gel column chromatography (40 ° / 〇 乙 乙 乙 / / / / / / The obtained compound was dissolved in dichloromethane (7.0 mL), and N,N-diisopropylethylamine (5.0 mL) and methylene ether (1.5 mL) were added and stirred at 40 ° C 6 hours. A saturated aqueous solution of chlorinated chloride (1 〇 mL) was added to the reaction mixture, and the mixture was extracted with methylene chloride (20 mL). The organic layer was washed with brine (10 mL) and dried over anhydrous sodium sulfate. The residue was purified by a Shih-Hui-gel column chromatography (20% ethyl acetate / hexane). The obtained compound was dissolved in DMF (8.0 mL). sodium acetate (887 mg) and sodium iodide (1.62 g) were added, and the mixture was stirred at 80 ° C for 8 hours. After the reaction solution was allowed to stand for cooling, water (20 mL) was added and extracted with ethyl acetate (20 mL×2). The organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (5 〇% ethyl acetate / hex). The obtained compound was dissolved in a solution of mercaptoamine in decyl alcohol (40%, 7.0 mL) and stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (yield: 66% ethyl acetate) to afford the title compound (932 mg). S' 152528.doc -55- 201121944 Reference Example 62 (R,E)-N-(l-(3-(cyclopropylmethoxy)-4-fluorophenyl)ethyl)-5-carbyl- Synthesis of N-(methoxymethyl)indole-3-dilute-1-anthracene amine [Chem. 20]

使藉由參考例61獲得之(R)-N-(l-(3-(環丙基甲氧基)-4-氟 苯基)乙基)-3-羥基-N-(曱氧基甲基)丙烷-1-磺醯胺(844 mg) 溶解於二氯甲烷(1〇 mL)中,添加Dess-Martin試劑(1.4 g),於室溫下攪拌1.5小時。於反應液中添加飽和碳酸氫鈉 水溶液(20 mL)及飽和硫代硫酸鈉水溶液(20 mL),利用乙 酸乙酯(30 mLx2)萃取水層。利用飽和食鹽水(15 mL)清洗 有機層,利用無水硫酸鈉加以乾燥後,進行減壓濃縮。利 用甲苯(15 mLx2)使殘渣共沸後,溶解於thF(2.5 mL)中。 於〇°C下’於氫化鈉(55%,150 mg)之THF懸浮液(5.0 mL)中添加鱗酿基乙酸三乙醋(695 pL),於室溫下擾拌15 分鐘。於o°c下,於反應液中添加甲苯共沸之殘渣的THF 溶液’於70°C下攪拌1小時。將反應液放置冷卻,添加飽 和氣化銨水溶液(10 mL),利用乙酸乙酯(2〇 mLx2)進行萃 取。利用飽和食鹽水(10 mL)清洗有機層,利用無水硫酸 鈉加以乾燥後,進行減壓濃縮。利用矽膠管柱層析法(33〇/〇 乙酸乙酯/己烷)將殘渣純化。使所獲得之化合物溶解於 THF(8.0 mL)中,於-78°C 下添加 DIBAL 之 THF 溶液(1.〇 152528.doc -56· 201121944 Μ,4.0 mL),於-78°C下攪拌1小時。於反應液中添加水 (10 mL),利用乙酸乙酯(2〇 mLx3)進行萃取。利用飽和食 鹽水(10 mL)清洗有機層,利用無水硫酸鈉加以乾燥後, 進行減壓濃縮。利用矽膠管柱層析法(5〇%乙酸乙酯/己烷) 將殘渣純化’藉此獲得標記化合物(33〇 mg)。 參考例63 (R)-N-(l-(3-(環丙基甲氧基)·4_氟苯基)乙基)5•羥基_N_(曱 氧基曱基)戍烧-1 -續酿胺之合成 [化 21](R)-N-(l-(3-(cyclopropylmethoxy)-4-fluorophenyl)ethyl)-3-hydroxy-N-(decyloxymethyl) obtained by Reference Example 61 Propane-1-sulfonamide (844 mg) was dissolved in dichloromethane (1 mL), and then was added with a Dess-Martin reagent (1.4 g) and stirred at room temperature for 1.5 hours. A saturated aqueous solution of sodium hydrogencarbonate (20 mL) and a saturated aqueous solution of sodium thiosulfate (20 mL) was added to the mixture, and the aqueous layer was extracted with ethyl acetate (30 mL×2). The organic layer was washed with brine (15 mL) and dried over anhydrous sodium sulfate. The residue was azeotroped with toluene (15 mL x 2) and dissolved in thF (2.5 mL). To a suspension of sodium hydride (55%, 150 mg) in THF (5.0 mL) was added <RTI ID=0.0>> To the reaction mixture, a THF solution of a toluene-to-boiling residue was added to the reaction mixture, and the mixture was stirred at 70 ° C for 1 hour. The reaction solution was cooled, and a saturated aqueous solution of ammonium sulfate (10 mL) was added and extracted with ethyl acetate (2 〇 mL x 2). The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate and evaporated. The residue was purified by hydrazine column chromatography (33 EtOAc/hexanes). The obtained compound was dissolved in THF (8.0 mL), and a DIBAL THF solution (1. 〇 152528.doc - 56 · 201121944 Μ, 4.0 mL) was added at -78 ° C, and stirred at -78 ° C. hour. Water (10 mL) was added to the reaction mixture, and extracted with ethyl acetate (2 mL). The organic layer was washed with brine (10 mL) and dried over anhydrous sodium sulfate. The residue was purified by hydrazine column chromatography (5% ethyl acetate / hexane) to thereby afford the title compound (33 mg). Reference Example 63 (R)-N-(l-(3-(cyclopropylmethoxy).4_fluorophenyl)ethyl)5•hydroxy_N_(decyloxyfluorenyl) oxime-1 Synthesis of continuous amines [Chem. 21]

使參考例62中獲得之(R,E)_N_(1_(3_(環丙基曱氧基)_4•氟 苯基)乙基)-5-羥基(曱氧基曱基)戊_3_烯_丨_磺醯胺(296 mg)溶解於乙酸乙酯(5.〇 mL)中’添加10〇/〇鈀_碳(170 mg), 於氫氣環境下’於室溫下將反應液攪拌2小時。使用矽藻 土將不溶物過濾除去,利用乙酸乙酯(1〇〇 mL)清洗後,將 合一之慮液減壓浪縮,藉此獲得作為粗產物之標記化合物 (208 mg) ° 以下之表所示化合物係使用參考例1、2、8、11、19之 胺’依據參考例61〜63之任一方法而合成。 152528.doc •57- 201121944 [表7] 參考例 胺參考例編號 目標物 製造方法 64 1 MOM [\\ 62 65 1 63 66 2 /V. MOM \]\ ΓΛ H〇-^^s-NvAJiv0Ay 61 67 2 MOM \ |1 ΓΛ HO^^^S-Ny^X〇Xy 62 68 2 63 69 8 MOM \ |1 Λ Η0^ΥΝγ^α^Δ 61 70 8 MOM| (I 62 71 8 /v. ^N. MOMf |] H〇 s-Ny^Ao^ 63 72 11 61 73 19 H〇 rHY^〇^f 61 74 19 八^MOM广1 c H〇^^rr^〇JF 62 75 19 ho^^|_^〇l〇Jf 63 參考例76 (R)-4-(溴甲基)-Ν-(1-(3-(環丙基甲氧基)-4-氟苯基)乙基)苯 磺醯胺之合成 [化 22] 152528.doc • 58 - 201121944(R,E)_N_(1_(3_(cyclopropyldecyloxy)-4)fluorophenyl)ethyl)-5-hydroxy(nonyloxyindenyl)penta-3-ene obtained in Reference Example 62 _丨_sulfonamide (296 mg) was dissolved in ethyl acetate (5. 〇mL) 'add 10 〇 / 〇 palladium - carbon (170 mg), and stir the reaction solution at room temperature under hydrogen atmosphere 2 hour. The insoluble matter was removed by filtration using diatomaceous earth, and the mixture was washed with ethyl acetate (1 mL), and the combined solution was reduced in pressure to obtain a labeled compound (208 mg) as a crude product. The compounds shown in the table were synthesized according to any of Reference Examples 61 to 63 using the amines of Reference Examples 1, 2, 8, 11, and 19. 152528.doc •57- 201121944 [Table 7] Reference Example Amine Reference Example Number Target Manufacturing Method 64 1 MOM [\\ 62 65 1 63 66 2 /V. MOM \]\ ΓΛ H〇-^^s-NvAJiv0Ay 61 67 2 MOM \ |1 ΓΛ HO^^^S-Ny^X〇Xy 62 68 2 63 69 8 MOM \ |1 Λ Η0^ΥΝγ^α^Δ 61 70 8 MOM| (I 62 71 8 /v. ^ N. MOMf |] H〇s-Ny^Ao^ 63 72 11 61 73 19 H〇rHY^〇^f 61 74 19 八^MOM广1 c H〇^^rr^〇JF 62 75 19 ho^^| _^〇l〇Jf 63 Reference Example 76 (R)-4-(Bromomethyl)-indole-(1-(3-(cyclopropylmethoxy)-4-fluorophenyl)ethyl)benzenesulfonate Synthesis of guanamine [Chem. 22] 152528.doc • 58 - 201121944

使參考例5中獲知之(R)· 1-(3-(環丙基曱氧基)·4_氟苯基) 乙烧胺鹽酸鹽(393 mg)溶解於二氯曱燒(3〇 中,於 下添加三乙基胺(670 μΙ〇與4-(溴甲基)苯磺醯氯(45〇 mg), 授摔2小時。於反應液中添加水(!_〇 mL),利用氣仿(3 〇 mL) 進行萃取。利用飽和食鹽水(15 mL)清洗有機層,利用無 水硫酸鈉加以乾燥後,進行減壓濃縮。利用矽膠管柱層析 法(30%乙酸乙酯/己烧)將殘渣純化,藉此獲得標記化合物 (308 mg)。 以下之表所示化合物係使用參考例2、8、11、19之胺, 依據參考例76之方法而合成。 [表8] 參考例 胺參考例編號 目標物 77 2 78 8 79 11 Br喝而。, 80 19 參考例81 152528.doc -59- 201121944 5-(甲乳基甲氧基)-2 -曱基戊院-2-基胺基曱酸节g旨之合成 [化 23](R)· 1-(3-(cyclopropyl decyloxy)·4_fluorophenyl) ethionine hydrochloride (393 mg) known in Reference Example 5 was dissolved in dichlorohydrazine (3〇). In the above, triethylamine (670 μΙ〇 and 4-(bromomethyl)benzenesulfonium chloride (45 〇mg) were added and dropped for 2 hours. Water (!_〇mL) was added to the reaction solution to utilize The mixture was extracted with a methylene chloride (3 mL). The organic layer was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified to obtain a labeled compound (308 mg). The compound shown in the following table was synthesized according to the method of Reference Example 76 using the amines of Reference Examples 2, 8, 11, and 19. [Table 8] Example amine reference example number target 77 2 78 8 79 11 Br drink., 80 19 Reference example 81 152528.doc -59- 201121944 5-(methyllacylmethoxy)-2 -mercaptoin-2- Synthesis of alkaloid decanoic acid group g [Chem. 23]

使利用文獻(J. Am. Chem. Soc.,77,1079-1083 (1955))中 。己載之方法所獲付之4-胺基-4-甲基戍烧-1-醇(6·7 g)溶解於 二氯曱院(100 mL)中,添加N-苄氧羰基氧基丁二醯亞胺 (18 g),於室溫下攪拌22小時》將反應液減壓濃縮後,於 殘渣中添加水(200 mL),利用乙酸乙酯(200 mL)進行萃 取。利用飽和食鹽水(200 mL)清洗有機層,利用無水硫酸 鈉加以乾燥後’並進行減壓濃縮。利用矽膠管柱層析法 (40%乙酸乙醋/己院)將殘渣純化。使所獲得之無色油狀物 質(7.9 g)溶解於二氣甲烷(1〇〇 mL)中,添加N,N-二異丙基 乙基胺(19 mL)、氯曱基甲崎(6.0 mL),於室温下授拌3小 時。於反應液中添加飽和氣化銨水溶液(2〇〇 mL),利用乙 酸乙酯(300 mL)進行萃取。利用飽和氯化銨水溶液(15〇 mLx3)、飽和食鹽水(1〇〇 mL)清洗有機層,利用無水硫酸 鈉加以乾燥後,並進行減壓濃縮。利用矽膠管柱層析法 (20°/。乙酸乙酯/己烷)將殘渣純化,藉此獲得作為無色油狀 物質之標記化合物(7.8 g)。再者,节氧基羰基標記為 Cbz。 參考例82 3-(環丙基甲氧基)-N-(5-(曱氧基甲氧基)_2_甲基戊烷_2基) 苯磺醢胺之合成 152528.doc -60· 201121944 [化 24]It is used in the literature (J. Am. Chem. Soc., 77, 1079-1083 (1955)). The 4-amino-4-methylindole-1-ol (6·7 g) obtained by the method of the above method was dissolved in Dichlorohydrazine (100 mL), and N-benzyloxycarbonyloxylated was added. Diimine (18 g) was stirred at room temperature for 22 hours. The reaction mixture was evaporated. The organic layer was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and evaporated. The residue was purified by silica gel column chromatography (40% ethyl acetate / hexane). The obtained colorless oily substance (7.9 g) was dissolved in di-methane (1 mL), and N,N-diisopropylethylamine (19 mL) and chloromethylcarbazide (6.0 mL) were added. , and mix for 3 hours at room temperature. A saturated aqueous solution of ammonium sulfate (2 mL) was added to the reaction mixture, and ethyl acetate (300 mL) was applied. The organic layer was washed with a saturated aqueous solution of ammonium chloride (15 mL) and brine (1 mL) and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (yield: ethyl acetate/hexane) to give the title compound (7.8 g) as a colorless oil. Further, the oxycarbonyl group is labeled as Cbz. Reference Example 82 Synthesis of 3-(cyclopropylmethoxy)-N-(5-(decyloxymethoxy)_2-methylpentane-2-yl)benzenesulfonamide 152528.doc -60· 201121944 [Chem. 24]

o"s-=oo"s-=o

OMOM 使參考例81中獲得之5_(曱氧基甲氧基)_2_甲基戊烷_2_基 胺基曱酸苄酯(242 mg)溶解於曱醇(5.0 mL)中,添加10% 鈀-碳(250 mg),於氫氣環境下,於室溫下將反應液攪拌i 小時。使用矽藻土將不溶物過濾除去,利用甲醇(2〇 mL) 清洗後’將^ 之慮液濃縮。使殘潰溶解於二氣曱院(3.〇 mL)中’添加三乙基胺(170 μΙ〇、利用文獻(J_ PesticideOMOM The benzyl 5-(decyloxymethoxy)-2-methylpentane-2-ylamino decanoate (242 mg) obtained in Reference Example 81 was dissolved in decyl alcohol (5.0 mL), and 10% was added. Palladium-carbon (250 mg) was stirred at room temperature for 1 hour under a hydrogen atmosphere. The insoluble matter was removed by filtration using diatomaceous earth, and after washing with methanol (2 〇 mL), the solution was concentrated. Dissolve the residue in the Erqi brothel (3. 〇 mL) Add triethylamine (170 μΙ〇, use literature (J_ Pesticide)

Chem.,13,107-115 (1988))中記載之方法獲得之3-苯曱醯 氧基苯磺醯氣(297 mg),於室溫下攪拌2小時。於反應液 中添加水(7.0 mL),利用乙酸乙酯(1〇 mL)進行萃取。利用 飽和食鹽水(10 mL)清洗有機層,利用無水硫酸鈉加以乾 燥後,進行減壓濃縮。利用矽膠管柱層析法(3〇%乙酸乙酯/ 己烷)將殘渣純化。使所獲得之無色油狀物質(165 mg)溶解 於曱基胺之曱酵溶液(40%,3.0 mL)中,於室溫下授拌30 分鐘。將反應液濃縮後,使殘渣溶解於DMF(3.0 mL)中, 添加礙酸鉀(102 mg)、蛾化釺(6.0 mg)、(氣甲基)環丙烧 (3 4 μι) ’於90°C下攪拌14小時。將反應液放置冷卻後,添 加水(10 mL),利用乙酸乙酯(15 mL)進行萃取。利用水(1 〇 mL)、飽和食鹽水(1〇 mL)清洗有機層,利用無水硫酸鈉加 以乾燥後,並進行減壓濃縮。利用矽膠管柱層析法(30%乙 152528.doc •61 - 201121944 酸乙酯/己烷)將殘渣純化,藉此獲得作為無色油狀物質之 標記化合物(124 mg)。 參考例83 3-(2,2-二氟乙氧基)-Ν_(5·(甲氧基甲氧基)_2甲基戊烷_2 基)苯橫醯胺之合成 [化 25] ΓΛ3-Benzene oxybenzenesulfonate (297 mg) obtained by the method described in Chem., 13, 107-115 (1988)), was stirred at room temperature for 2 hours. Water (7.0 mL) was added to the reaction mixture, and extracted with ethyl acetate (1 mL). The organic layer was washed with brine (10 mL) and dried over anhydrous sodium sulfate. The residue was purified by hydrazine column chromatography (3% EtOAc/hexane). The obtained colorless oily substance (165 mg) was dissolved in a solution of decylamine (40%, 3.0 mL) and stirred at room temperature for 30 minutes. After concentrating the reaction solution, the residue was dissolved in DMF (3.0 mL), and potassium sulphate (102 mg), moth (6.0 mg), (gas methyl) cyproterone (3 4 μι) was added to 90 Stir at ° C for 14 hours. After the reaction mixture was cooled, water (10 mL) was evaporated and evaporated. The organic layer was washed with water (1 mL) and brine (1 mL), dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography (yield: 30%, EtOAc, EtOAc, EtOAc) Reference Example 83 Synthesis of 3-(2,2-difluoroethoxy)-indole_(5·(methoxymethoxy)_2methylpentane-2-yl)phthalic acid [Chem. 25] ΓΛ

由參考例81中獲得之5-(曱氧基甲氧基)_2_甲基戊烷_2_基 胺基曱酸苄酯(628 mg),依據參考例82之方法,獲得作為 淡黃色橡膠狀物質之標記化合物(367 mg)。 參考例84 3_(環戊氧基)-N-(5-(甲氧基甲氧基)_2_曱基戊烷_2_基)笨磺 醯胺之合成 [化 26]The benzyl 5-(decyloxymethoxy)-2-methylpentane-2-ylamino decanoate (628 mg) obtained in Reference Example 81 was obtained as a pale yellow rubber according to the method of Reference Example 82. Labeled compound (367 mg). Reference Example 84 Synthesis of 3_(cyclopentyloxy)-N-(5-(methoxymethoxy)_2-decylpentane-2-yl) oxasulfonyl decylamine [Chem. 26]

由參考例81中獲得之5·(甲氧基甲氧基)_2_甲基戊烷基 胺基曱酸苄酯(628 mg),依據參考例82之方法,獲得作為 淡黃色橡膠狀物質之標記化合物(379 mg)。 參考例85 152528.doc -62· 201121944 N-(2-(4-(漠曱基)苯基)丙院-2-基)-3-(環丙基甲氧基)苯確醢 胺之合成 [化 27]The benzyl (5-methoxymethoxy)-2-methylpentylamino decanoate (628 mg) obtained in Reference Example 81 was obtained as a pale yellow rubbery material according to the method of Reference Example 82. Labeled compound (379 mg). Reference Example 85 152528.doc -62·201121944 Synthesis of N-(2-(4-(indiyl)phenyl)propan-2-yl)-3-(cyclopropylmethoxy)benzamine [化27]

使利用文獻(Tetrahedron Lett.,38,1241-1244 (1997))中 記載之方法所獲得之2-對甲苯基丙烷-2-胺(298 mg)溶解於 二氣曱烷(5.0 mL)中’添加三乙基胺(420 pL)、利用文獻 (J. Pesticide Chem.,13,107-115 (1988))中記載之方法獲得 之3 -苯甲醯氧基苯續醯氯(445 mg),於室溫下攪拌16小 時。於反應液中添加水(15 mL),利用乙酸乙酯(20 mL)進 行萃取《利用飽和食鹽水(1〇 mL)清洗有機層,利用無水 硫酸鈉加以乾燥後,並進行減壓濃縮。利用矽膠管柱層析 法(20%乙酸乙酯/己烷)將殘渣純化。使所獲得之無色橡膠 狀物質(316 mg)溶解於甲基胺之甲醇溶液(4〇〇/0,4.0 mL) 中’於室溫下攪拌3 0分鐘。將反應液減壓濃縮後,利用甲 苯(5.0 mL)使殘渣共沸後,溶解於DMF(5.0 mL)中,添加 碳酸鉀(213 mg)、碘化鉀(13 mg)、(氣曱基)環丙烷(78 μΙ〇,於90°C下攪拌16小時。將反應液放置冷卻後,添加 水(15 mL) ’利用乙酸乙酯(2〇 mL)進行萃取。利用水(15 mL)、飽和食鹽水(1〇 mL)清洗有機層,利用無水硫酸鈉加 以乾燥後,並進行減壓濃縮。利用矽膠管柱層析法(20%乙 酸乙醋/己烷)將殘渣純化。使所獲得之無色固體(233 mg) 152528.doc -63- 201121944 溶解於四氣化碳(6.0 mL)中,添加N-溴代丁二醯亞胺(125 mg)、偶氮雙異丁腈(以下為AIBN,3.0 mg),於9(rc下加 熱回流2小時。將不溶物過濾除去’利用氣仿(3〇 mL)清洗 後,將合一之濾液濃縮。於殘渣中添加飽和食鹽水(1〇 mL) ’利用50%乙酸乙酯/己烷(10 mL)進行萃取。利用無水 硫酸鈉乾燥有機層後,並進行減壓濃縮,藉此獲得作為粗 產物之標記化合物(255 mg)。 參考例8 6 N-(2-(4-(漠甲基)苯基)丙烧_2_基)·3·(2,2·二氟乙氧基)苯續 醯胺之合成 [化 28]2-P-tolylpropan-2-amine (298 mg) obtained by the method described in the literature (Tetrahedron Lett., 38, 1241-1244 (1997)) was dissolved in dioxane (5.0 mL). Addition of triethylamine (420 pL), 3-benzoyloxybenzene chlorohydrazine (445 mg) obtained by the method described in the literature (J. Pesticide Chem., 13, 107-115 (1988)), Stir at room temperature for 16 hours. Water (15 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL). The organic layer was washed with saturated aqueous sodium chloride (1 mL) and dried over anhydrous sodium sulfate. The residue was purified by hydrazine column chromatography (20% ethyl acetate /hexane). The obtained colorless rubbery substance (316 mg) was dissolved in a methanol solution of methylamine (4 〇〇 / 0, 4.0 mL) and stirred at room temperature for 30 minutes. After the reaction mixture was concentrated under reduced pressure, the residue was azeotroped with toluene (5.0 mL), dissolved in DMF (5.0 mL), potassium carbonate (213 mg), potassium iodide (13 mg), (78 μΙ〇, stirred at 90 ° C for 16 hours. After the reaction solution was allowed to cool, water (15 mL) was added and extracted with ethyl acetate (2 mL). Water (15 mL), brine The organic layer was washed with (1 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20% ethyl acetate/hexane). (233 mg) 152528.doc -63- 201121944 Dissolved in four gasified carbon (6.0 mL) with N-bromosuccinimide (125 mg), azobisisobutyronitrile (hereinafter AIBN, 3.0) (mg), heating under reflux for 2 hours at 9 (rc. removal of insolubles by filtration) After washing with a gas imitation (3 mL), the filtrate was concentrated. Saturated brine (1 mL) was added to the residue. The extract was extracted with 50% ethyl acetate / hexane (10 mL). This gave the labeled compound (255 mg) as a crude product. Reference Example 8 6 N-(2-(4-(Methyl)phenyl)propan-2-yl)·3·(2,2·difluoro Synthesis of ethoxy) phenyl hydrazine

由利用文獻(Tetrahedron Lett.,38,1241-1244 (1997))中 記載之方法所獲得之2-對曱苯基丙烷·2·胺(414 mg),依據 參考例85之方法,獲得作為無色固體之標記化合物(54〇 mg)。 參考例87 N-(2-(4-(溴甲基)苯基)丙烷-2-基)_3·(環戊氧基)苯磺醯胺之 合成 [化 29] 152528.doc 2011219442-P-Phenylphenylpropane-2-amine (414 mg) obtained by the method described in the literature (Tetrahedron Lett., 38, 1241-1244 (1997)) was obtained as a colorless method according to the method of Reference Example 85. Solid labeled compound (54 mg). Reference Example 87 Synthesis of N-(2-(4-(bromomethyl)phenyl)propan-2-yl)_3·(cyclopentyloxy)benzenesulfonamide [Chem. 29] 152528.doc 201121944

由利用文獻(Tetrahedron Lett.,38,1241-1244 (1997))中 記載之方法所獲得之2-對甲苯基丙烷-2-胺(414 mg),依據 參考例85之方法,獲得作為無色固體之標記化合物(549 mg)。 參考例8 8 N-(2-(6-(漠甲基)吼。定_3_基)丙烧_2_基)_3_(環丙基曱氧基) 笨磺醯胺之合成 [化 30]2-P-tolylpropan-2-amine (414 mg) obtained by the method described in the literature (Tetrahedron Lett., 38, 1241-1244 (1997)) was obtained as a colorless solid according to the method of Reference Example 85. Labeled compound (549 mg). Reference Example 8 8 N-(2-(6-(Methyl-methyl) oxime. _3_))propanze-2-yl)_3_(cyclopropyldecyloxy) Synthesis of oxasulfonamide ]

使利用日本專利特開2006-508054號中記載之方法所獲 得之6·(羥基甲基)菸酸腈(1.59 g)溶解於DMF(30 mL)中, 添加咪°坐(2.丨g)、第三丁基二甲基矽烷基氣(2.33 g),於室 溫下攪拌1 ·5小時。於反應液中添加水(60 mL),利用50% 乙酸乙酯/己烷(60 mL)進行萃取。利用飽和食鹽水(3〇 mL) 清洗有機層,利用無水硫酸鈉加以乾燥後,進行減壓濃 縮。利用矽膠管柱層析法(5%乙酸乙酯/己烷)將殘造純 化。利用甲苯(10 mLx3)將所獲得之無色固體(199 g)共 ;弗0 S: 152528.doc 201121944 使氯化鈽(1.48 g)懸浮於THF(12 mL)中,於室溫下遽烈 授拌2小時。對反應液施加5分鐘超音波後,冷卻至 -78°C,緩慢滴加甲基鋰之二乙醚溶液q 〇9 μ,5.5 mL), 於-78°C下將反應液攪拌30分鐘。將甲苯共沸之無色固體 中之一部分(497 mg)溶解於THF(2.0 mL)中,於-78t下緩 慢添加至反應液中’於室溫下攪拌2小時。於反應液中添 加飽和氨水(5.0 mL),於室溫下遽烈攪拌30分鐘。使用矽 藻土將不溶物過濾除去,利用THF(l〇〇 mL)清洗後,將合 一之濾液濃縮。於殘渣中添加水(20 mL),利用氯仿(30 mL)進行萃取。利用飽和食鹽水(2〇 mL)清洗有機層,利用 無水硫酸鈉加以乾燥後,並進行減壓濃縮。使殘渣溶解於 二氯甲烷(6.0 mL)中,添加三乙基胺(420 μΙ〇、利用文獻 (J. Pesticide Chem.,13, 107-115 (1988))中記載之方法獲得 之3-苯甲醯氧基苯磺醯氣(593 mg),於室溫下攪拌3天。於 反應液中添加水(10 mL),利用乙酸乙酯(15 mL)進行萃 取。利用飽和食鹽水(10 mL)清洗有機層,利用無水硫酸 鈉加以乾燥後,並進行減壓濃縮。利用矽膠管柱層析法 (50%乙酸乙酯/己烷)將殘渣純化。使所獲得之淡橙色油狀 物質(700 mg)溶解於甲基胺之甲醇溶液(40%,3.0 mL)中, 於室溫下授拌20分鐘。將反應液減壓濃縮後,利用石夕膠管 柱層析法(60%乙酸乙酯/己烷)將殘渣純化。使所獲得之淡 黃色油狀物質(522 mg)溶解於DMF(12 mL)中,添加碳酸卸 (332 mg)、碘化鉀(20 mg)、(氯甲基)環丙烷(122 pL),於 90°C下攪拌18小時。將反應液放置冷卻後,添加水(2〇 152528.doc •66· 201121944 mL),利用乙酸乙醋(3〇 mL)進行萃取。利用水(25 mL)、 飽和食鹽水(20 mL)清洗有機層,利用無水硫酸納加以乾 燥後,進行減麗濃縮。利用石夕耀·管柱層析法(5 %曱醇./氯 仿)將殘;查純化,藉此獲得脫梦烧基體(254 mg)。使脫碎炫 基體(249 mg)溶解於THF(3.0 mL)中,添加三苯基膦(182 mg)、四溴化碳(23 0 mg),於室溫下攪拌】小時。將反應液 減壓濃縮後,利用矽膠管柱層析法(6〇%乙酸乙酯/己烷)將 殘渣純化,藉此獲得作為紫色橡膠狀物質之標記化合物 (226 mg)。 參考例89 Ν·(2-(6-(溴曱基)吼啶_3_基)丙烷_2_基)_3_(22二氟乙氧基) 苯磺醯胺之合成 [化 31]The 6(hydroxymethyl)nicotinic acid nitrile (1.59 g) obtained by the method described in JP-A-2006-508054 was dissolved in DMF (30 mL), and the mixture was added (2.丨g). Tributyl dimethyl decyl alkyl (2.33 g) was stirred at room temperature for 1.5 hours. Water (60 mL) was added to the reaction mixture, and then extracted with 50% ethyl acetate/hexane (60 mL). The organic layer was washed with saturated brine (3 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5% ethyl acetate / hexane). The obtained colorless solid (199 g) was obtained by using toluene (10 mL×3); s. 0 S: 152528.doc 201121944 The ruthenium chloride (1.48 g) was suspended in THF (12 mL) and incubated at room temperature. Mix for 2 hours. After the ultrasonic wave was applied to the reaction solution for 5 minutes, it was cooled to -78 ° C, and a solution of methyllithium in diethyl ether q 〇 9 μ, 5.5 mL) was slowly added dropwise, and the reaction mixture was stirred at -78 ° C for 30 minutes. One part (497 mg) of a toluene-azeotropic colorless solid was dissolved in THF (2.0 mL), and slowly added to the reaction mixture at -78t, and stirred at room temperature for 2 hours. Saturated aqueous ammonia (5.0 mL) was added to the mixture and stirred at room temperature for 30 min. The insoluble matter was removed by filtration using celite, washed with THF (1 mL), and the filtrate was concentrated. Water (20 mL) was added to the residue and extracted with chloroform (30 mL). The organic layer was washed with brine (2 mL), dried over anhydrous sodium sulfate and evaporated. The residue was dissolved in dichloromethane (6.0 mL), and triethylamine (420 μM, 3-benzene obtained by the method described in J. Pesticide Chem., 13, 107-115 (1988)) was added. Methoxy sulfonium sulfonate (593 mg) was stirred at room temperature for 3 days. Water (10 mL) was added to the mixture and extracted with ethyl acetate (15 mL). The organic layer was washed, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% ethyl acetate /hexane). 700 mg) dissolved in methanol solution of methylamine (40%, 3.0 mL), and stirred for 20 minutes at room temperature. The reaction solution was concentrated under reduced pressure and then chromatographed on silica gel column (60% acetic acid The residue was purified by ester (hexane / hexane). The obtained pale yellow oily material (522 mg) was dissolved in DMF (12 mL), hexane (332 mg), potassium iodide (20 mg), (chloromethyl) Cyclopropane (122 pL), stirred at 90 ° C for 18 hours. After the reaction solution was allowed to cool, add water (2〇152528.doc •66· 201121944 mL) The mixture was extracted with ethyl acetate (3 mL), and the organic layer was washed with water (25 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and then concentrated and concentrated. Chromatography (5 % sterol. / chloroform) was carried out; the residue was purified to obtain a depilation base (254 mg). The decomposed phantom (249 mg) was dissolved in THF (3.0 mL), and three were added. Phenylphosphine (182 mg) and carbon tetrabromide (23 0 mg) were stirred at room temperature for hr. The reaction mixture was concentrated under reduced pressure and then purified by EtOAc EtOAc The residue was purified to obtain a labeled compound (226 mg) as a purple rubbery substance. Reference Example 89 2-·(2-(6-(bromoindolyl)acridin-3-yl)propane_2-yl )_3_(22 difluoroethoxy) benzene sulfonamide synthesis [31]

由利用日本專利特開2006-508054號中記載之方法所獲 得之6·(羥基甲基)菸酸腈(372 mg),依據參考例之方 法,獲得作為紫色油狀物質之標記化合物(丨43瓜幻。 參考例90 N-(2-(6-(溴曱基)〇比咬_3_基)丙烷_2·基)_3_(環戊氧基)笨續 醯胺之合成 ” [化 32] S. 152528.doc -67- 201121944A 6-(hydroxymethyl)nicotinic acid nitrile (372 mg) obtained by the method described in JP-A-2006-508054 was used as a labeling compound as a purple oily substance according to the method of the reference example (丨43) Reference Example 90 Synthesis of N-(2-(6-(bromoindolyl)pyrene _3_yl)propane-2·yl)_3_(cyclopentyloxy)phenylidene amide ] S. 152528.doc -67- 201121944

由利用曰本專利特開2006-508054號中記載之方法所獲 付之6 (經基甲基)終酸腈(3 77 mg)’依據參考例88之方 法’獲得作為紫色泡狀物質之標記化合物(139 mg)。 實施例1 N-(3-(環丙基曱氧基)苄基)_3_((5_氟_2,4_二氧代_3,4·二氫 鳴咬-1(2H)_基)曱氧基)丙烷-1-磺醯胺之合成 [化 33] ΟThe label of the purple blister substance was obtained by the method of Reference Example 88, which was obtained by the method described in JP-A-2006-508054, by the method described in JP-A-2006-508054. Compound (139 mg). Example 1 N-(3-(cyclopropyl decyloxy)benzyl)_3_((5-fluoro-2,4-dioxo-3,4·dihydro-bite-1(2H)-yl) Synthesis of decyloxy)propane-1-sulfonamide [Chem. 33] Ο

使藉由參考例31所獲得之N-(3-(環丙基曱氧基)苄基)-3-(甲氧基甲氧基)丙烷_丨_磺醯胺(588 mg)溶解於二氯曱烷 (5.0 mL)中,於〇°c下添加三氯化硼(以下為bC13)之二氯曱 院溶液(1.0 Μ,561 μί),於室溫下攪拌1.5小時。將反應 液減壓濃縮,使殘渣溶解於1,2-二氯乙烷(以下為DCE,3.0 mL)中。 使市售之5-氟-2,4·雙(三曱基矽烷氧基)嘧啶(657 mg)溶 解於DCE(2.0 mL)中,添加殘渣之DCE(3.0 mL)溶液、及碘 (60 mg),於95°C下加熱回流3.5小時。將反應液放置冷卻 後’添加水(30 mL)、飽和硫代硫酸納水溶液(2.0 mL),利 152528.doc -68 - 201121944 用10°/〇曱醇/氣仿(20 mLx3)進行萃取。利用飽和食鹽水(15 mL)清洗混合之有機層,利用無水硫酸鈉加以乾燥後,進 行減壓濃縮。利用矽膠管柱層析法(90%乙酸乙酯/己烷)將 殘渣純化’藉此獲得作為無色泡狀物質之標記化合物(3〇5 mg,產率 41°/〇)。 !H-NMR (CDC13) δ (ppm): 0.32-0.39 (2H, m), 0.61-0.68 (2H, m), 1.20-1.31 (1H, m), 2.00-2.17 (2H, m), 3.02 (2H, t, J—7.0 Hz), 3.65 (2H, t, J=6.2 Hz), 3.81 (2H, d, J=7.〇 Hz), 4.26 (2H, d, J=5.7 Hz), 4.64 (1H, brs), 5.09 (2H, s), 6.83-6.89 (3H, m), 7.29-7.35 (2H, m) 實施例2〜實施例30 以下之化合物係由各個參考例32〜60中獲得之化合物, 依據實施例1之方法而合成。結果示於以下表。 實施例2 (R)-N-(l-(3-(環戊氧基)苯基)乙基氟_2,4_二氧代-3,4-二氫嘧啶-1(2Η)·基)甲氧基)丙烷―卜磺醯胺 實施例3 3-((5-氟-2,4-二氧代-3,4-二氫嘧啶-1(211)-基)甲氧基)->^ ((R)-l-(3-((R)-四氫呋喃_3_基氧基)苯基)乙基)丙烷·丨_磺 醯胺 實施例4 N-(3-(環丙基甲氧基)_4_氟苄基)_3_((5_氟-2,4·二氧代_ 3,4-二氫嘧啶-i(2H)-基)曱氧基)丙烷-卜磺醯胺 實施例5N-(3-(cyclopropyldecyloxy)benzyl)-3-(methoxymethoxy)propane-indolesulfonamide (588 mg) obtained in Reference Example 31 was dissolved in two In chlorodecane (5.0 mL), a solution of boron trichloride (hereinafter referred to as bC13) in dichloroindole (1.0 Μ, 561 μί) was added at 〇 ° C, and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in 1,2-dichloroethane (hereinafter DCE, 3.0 mL). Commercially available 5-fluoro-2,4·bis(tridecyldecyloxy)pyrimidine (657 mg) was dissolved in DCE (2.0 mL), DCE (3.0 mL) solution of residue was added, and iodine (60 mg) The mixture was heated to reflux at 95 ° C for 3.5 hours. After the reaction solution was left to cool, water (30 mL) and a saturated aqueous solution of sodium thiosulfate (2.0 mL) were added, and 152528.doc -68 - 201121944 was extracted with 10 ° / methanol / gas (20 mL x 3). The mixed organic layer was washed with brine (15 mL) and dried over anhydrous sodium sulfate. The residue was purified by hydrazine column chromatography (yield: 90% ethyl acetate/hexane) to thereby obtain a labeled compound (3 〇 5 mg, yield 41 ° / 〇) as a colorless blister. !H-NMR (CDC13) δ (ppm): 0.32-0.39 (2H, m), 0.61-0.68 (2H, m), 1.20-1.31 (1H, m), 2.00-2.17 (2H, m), 3.02 ( 2H, t, J—7.0 Hz), 3.65 (2H, t, J=6.2 Hz), 3.81 (2H, d, J=7.〇Hz), 4.26 (2H, d, J=5.7 Hz), 4.64 ( 1H, brs), 5.09 (2H, s), 6.83-6.89 (3H, m), 7.29-7.35 (2H, m) Example 2 to Example 30 The following compounds were obtained from each of Reference Examples 32 to 60. The compound was synthesized according to the method of Example 1. The results are shown in the table below. Example 2 (R)-N-(l-(3-(Cyclopentyloxy)phenyl)ethylfluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2Η)·yl Methoxy)propane-sulfonamide Example 3 3-((5-Fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(211)-yl)methoxy)- >^((R)-l-(3-((R)-tetrahydrofuran-3-yloxy)phenyl)ethyl)propane·丨_sulfonamide Example 4 N-(3-(cyclopropyl) Methoxy)_4_fluorobenzyl)_3_((5-fluoro-2,4·dioxo-3,4-dihydropyrimidine-i(2H)-yl)decyloxy)propane-sulfonate Amine Example 5

S 152528.doc 201121944 (R)-N-( 1-(3-(環丙基甲氧基)-4-氟笨基)乙基)-3-((5-氟- 2.4- 二氧代-3,4-二氫嘧啶-1(2H)-基)曱氧基)丙烷-1-磺醯胺 實施例6 (R)-N-(l-(3-(環丙基曱氧基)-4-氟苯基)-2-甲基丙基)-3-((5-氟-2,4-二氧代-3,4-二氫嘧啶-1(2H)-基)曱氧基)丙烷-1- 磺醯胺 實施例7 (R)-N-(l-(3-(環丙基甲氧基)-4-氟苯基)丙基)-3-((5-氟- 2.4- 二氧代-3,4-二氫嘧啶-1(211)-基)甲氧基)丙烷_1_磺醯胺 實施例8 (R)-N-(l-(3-(環丙基甲氧基)苯基)乙基)-3-((5-氟-2,4-二 氧代-3,4·二氫嘧啶-1(2H)-基)曱氧基)丙烷·ι·磺醯胺 實施例9 (R)-N-( 1 -(3-(環戊氧基)-4-氟笨基)乙基)-3-((5_ 氟 _2,4_二 氧代-3,4-二氫嘧啶-1(2H)-基)曱氧基)丙烷-1-磺醯胺 實施例10 N-( 1-(3-(環丙基曱氧基)-4-氟苯基)-2-曱基丙基)-3-((5-氟-2,4-二氧代-3,4-二氫嘧啶_1(211)-基)曱氧基)丙烷-1_ 磺醯胺 實施例11 (R)-N-(l-(3-(環丙基甲氧基)苯基)丙基)·3_((5_氟_24_二 氧代-3,4-二氫嘧啶-1(2Η)-基)甲氧基)丙烷_ι_磺醯胺 實施例12 (R)-N-〇-(3-(環戊基甲氧基)笨基)乙基)-3-((5-氟-2,4-二 152528.doc •70- 201121944 氧代-3,4、二氣喊 實施例13 °^_1(2Η)·基)甲氧基)丙烧_卜續酿胺 (R)-3-((5_ 氣 ,4_二氧代·3,4·二氫嘧啶-1(2H)-基)甲氧 _ A ' ,,2,2-四氟乙氧基)苯基)乙基)丙烷-1-磺醯胺 實施例14 )氟2,‘二氧代-3,4-二氫嘧啶_1(211)-基)曱氧基)-N-(l-(3-(2 2 ?-- ,,二氟乙氧基)苯基)乙基)丙烷_ι_磺醯胺 實施例15 ()(丨(^(丨’3-二氟丙院-2-基氧基)苯基)乙基)-3-((5_ 氟_2,4-二氧代_3,4_二氫嘧啶_1(2抝_基)甲氧基)丙烷_丨_磺 醯胺 實施例16 (R)-3-((5-氟-2,4-二氧代 _3,4_ 二氫喷 β定 _ι(2Η)_ 基)曱氧 基)-N-(l-(3-異丁氧基苯基)乙基)丙烷_丨_磺醯胺 實施例17 3-((5-氟-2,4-二氧代-3,4·二氫嘧啶·ι(2Η)-基)甲氧基)-N- ((R)-l-(3-((S)-2-甲基丁氧基)苯基)乙基)丙烷小磺醯胺 實施例18 (R)-3-((5-氟-2,4·二氧代·3,4-二氫嘧啶 _ι(2Η)_ 基)曱氧 基)-N-(l-(3-((卜甲基環丙基)甲氧基)苯基)乙基)丙烧·卜磺 酿胺 實施例19 (R)-N_(l-(3-(2,2-二氟乙氧基)苯基)乙基)_3_((5_ 氟-2,4· 二氧代-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷·卜磺醯胺 £ 152528.doc •71 · 201121944 實施例20 N-((R)-l-(3-((S)·丁 -3·炔 _2_基氧基)苯基)乙基)_3_((5_ 氟 _ 2.4- 二氧代-3,4-二氫嘧啶_1(211广基)曱氧基)丙烷·丨_磺醯胺 實施例21 N-((R)-l-(3-((R>丁 _3_炔_2·基氧基)苯基)乙基)_3_((5_氟_ 2.4- 二氧代-3,4-二氫嘧啶_1(211)_基)曱氧基)丙烷_丨_磺醯胺 實施例22 (R)-3-((5-氟-2,4-二氧代-3,4_ 二氫嘧啶 基)甲氧 基)-N-( 1-(3-(2-氟乙氧基)苯基)乙基)丙烷_丨磺醯胺 實施例23 义((1〇-1-(3-(11)-第二丁氧基苯基)乙基)_3_((5_氟-2,4_二 氧代-3,4-二氫嘧啶-1(2H)-基)曱氧基)丙烷-1-磺醯胺 實施例24 N-((R)-l-(3-(S)-第二 丁氧基苯基)乙基)·3-((5-氟-2,4-二 氧代-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-1-磺醯胺 實施例25 3-((5-氟-2,4-二氧代-3,4-二氫嘧啶·ι(2Η)-基)曱氧基)·Ν-((R)-l-(3-((S)-戊烷-2-基氧基)苯基)乙基)丙烷-1-磺醯胺 實施例26 3-((5-氟-2,4-二氧代-3,4-二氫嘧啶-i(2H)-基)甲氧基)-N-((R)-l-(3-((R)-戊烷-2-基氧基)苯基)乙基)丙烷-1-磺醯胺 實施例27 (R)-3-((5-氟-2,4-二氧代-3,4-二氫嘧啶-1(2H)-基)甲氧 基)-:^-(1_(3-(2,2,3,3,3-五氟丙氧基)笨基)乙基)丙烷-1_磺 152528.doc •72· 201121944 酿胺 實施例28 (R)-3-((5-氟-2,4-二氧代-3,4-二氫嘧啶·1(2Η)_基)甲氧 基)-N-(l-(3-(四氫-2Η-»比喃-4-基氧基)苯基)乙基)丙烷-l_磺 醯胺 實施例29 3-((5-氟-2,4-二氧代-3,4-二氫嘧啶-1(2Η)-基)甲氧基)-Ν-((R)-l-(3-((R)-四氫呋喃-3-基氧基)苯基)乙基)丙烷-ΐ_磺 醯胺 實施例30 (R)-N-( 1-(3-(2-環丙基乙氧基)苯基)乙基)_3_((5·氟·2,4-二氧代-3,4-二氫嘧啶-1(2Η)-基)甲氧基)丙烷磺醯胺 152528.doc •73· 201121944 [表9] 實施 例 參考例 編號 目標物 產 率 (%) ^-NMR δ (ppm) 形狀 2 32 0 m\F ^t〇^^|-NyCX〇X) 44 (CDCls) 1.53 (3H, d, J = 7.0 Hz), 1.62-1.65 (2H, m), 1.72-1.97 (8H, m), 2.70-2.88 (2H, m), 3.50-3.56 (2H, m), 4.56 (1H, quin, J = 6.8Hz), 4.74-4.78 (1H, m), 4.92 (1H, brs), 5.03 (2H, s), 6.78-6.88 (3H, m), 7.21-7.32 (2H, m), 9.08 (1H, brs) 泡狀物質 3 33 35 (CDC1S) 1.53 (3H, d, J = 7.0Hz), 1.85-1.95 (2H, m), 2. 06-2. 24 (2H, m), 2.68-2.88 (2H, m), 3.51-3.57 (2H, m), 3.89-4.06 (4H, m), 4.53-4.61 (1H, m), 4.70-4.74 (1H, m), 4.93-4.96 (1H, m), 5.03 (2H, s), 6.77 (1H, dd, J = 8. 1, 2.4 Hz), 6.82-6.84 (1H, m), 6.92 (1H, d, J = 7.3 Hz), 7.24-7.34 (2H, m), 8.76 (1H, brs) 泡狀物質 4 34 26 (CDCI3) 0. 33-0.39 (2H, m), 0.62-0. 69 (2H, m), 1.22-1.29 (1H, m), 1.99-2.08 (2H, m), 2.99 (2H, t, J = 7.6Hz), 3.65 (2H, t, J = 6.2Hz), 3.88 (2H, d, J = 7.0Hz), 4.22 (2H, d, j = 5.4 Hz), 4.78 (1H, brs), 5.08 (2H, s), 6.82-6.87 (1H, m), 6. 94-6. 98 (2H, m), 7. 34 (1H, d, J = 5. 4 Hz), 8.62 (1H, brs) 泡狀物質 74- 152528.doc 201121944 [表 ι〇] 實施 例 參考例 編號 目標物 產 率 (.%) frNMR δ (ppm) 形狀 - 5 35 16 (CDCI3) 0.33-0.39 (2H, m), 0.63-0.70 (2H, m), 1.23-1.31 (1H, m), 1.52 (3H, d, J=7.0 Hz), 1.83-1.98 (2H, m), 2.63-2.83 (2H, m), 3.55 (2H, t, J = 6.2Hz), 3.89 (2H, d, J = 7.0 Hz), 4.58 (1H, quin, J = 5. 9 Hz), 4. 78 (1H, d, J = 6. 2 Hz), 5.04 (2H, s), 6.84-6.96 (2H, m), 7.02-7.09 (1H, m), 7..33 (1H, d, J = 5.1 Hz), 8.76 (1H, brs) 泡狀物質 6 36 47 (CDC13) 0.32-0.39 (2H, m), 0.61-0.69 (2H, m), 0.80 (3H, d, J = 6.5Hz), 1.03 (3H, d, J = 6.8 Hz), 1.21-1.29 (1H, m), 1.70-2.00 (3H, m), 2.58-2.79 (2H, m), 3. 49 (2H, t, J = 5.9 Hz), 3. 89 (2H, d, J = 7.0 Hz), 4.05 (1H, t, J = 8.1 Hz), 4.91 (1H, d, J = 8.1Hz), 5.01 (2H, s), 6.76-6.81 (1H, m), 6,83-6.87 (1H, m), 7. 02-7. 09 (1H, in), 7. 32 (1H, d, J = 5. 2 Hz), 8.67 (1H, brs) 泡狀物質 7 37 40 (CDCI3) 0. 32-0. 38 (2H, m), 0.62-0. 69 (2H, m), 0.89 (3H, t, J = 7.0 Hz), 1.22-1.28 (1H, m), 1.72-1.94 (4H, m), 2.60-2.81 (2H, m), 3. 51 (2H, d, J = 5. 9 Hz), 3. 89 (2H, d, J = 7.3 Hz), 4.25 (1H, q, J = 7.6 Hz), 5.02 (2H, s), 5.10 (1H, d, J =7.0 Hz), 6.80-6.85 (1H, m), 6.88-6.92 (1H, m), 7.02-7.09 (1H, m), 7.34 (1H, d, J = 5.1 Hz), 9.20 (1H, brs) 泡狀物質 152528.doc -75- s·. •S& 201121944 [表 11] 實施 例 參考例 編號 目標物 產 率 (%) ^-NMR δ (ppm) 形狀 8 38 〇 hn\f 57 (CDCls) 0.32-0.38 (2H, m), 0.63-0.69 (2H, m), 1.23-1.31 (1H, m), 1.53 (3H, d, J = 6.8 Hz), 1.83-1.98 (2H, m), 2.70-2.90 (2H, m), 3.50-3.59 (2H, m), 3.81 (2H, d, J = 7. 0 Hz), 4. 55 (1H, quin, J = 5.1 Hz), 4.95 (1H, d, J = 7.0 Hz), 5.03 (2H, s), 6.80-6.84 (1H, m), 6.88-6.92 (2H, m), 7.22-7.33 (2H, m), 9.10 (1H, brs) 泡狀物質 9 39 61 (CDC13) 1.53 (3H, d, J = 6.8Hz), 1.61-1.70 (2H, m), 1.76-2.00 (8H, m), 2.68-2.83 (2H, m), 3.55 (2H, t, J = 5.9 Hz), 4.53-4.60 (2H, m), 4.81-4.85 (1H, m), 5.03 (2H, s), 6.81-6.87 (1H, m), 6.92-6.96 (1H, m), 7.00-7.08 (1H, m), 7.31 (1H, d, J = 5.1 Hz), 8.51 (1H, brs) 泡狀物質 10 40 52 (CDCI3) 0.32-0.39 (2H, m), 0.61-0.69 (2H, m), 0.80 (3H. d, J = 6. 5 Hz), 1.03 (3H, d, J = 6.5 Hz), 1.21-1.29 (1H, m), 1.70-2.00 (3H, m), 2.58-2.79 (2H, m), 3. 49 (2H, t, J = 5.9 Hz), 3. 89 (2H, d, J = 7.0Hz), 4.04(1H, t, J = 8.1Hz), 5.01 (2H, s), 5.16 (1H, brs), 6.76-6.81 (1H, m), 6,84-6.88 (1H, m), 7. 02-7. 09 (1H, m), 7. 33 (1H, d, J = 5. 4 Hz), 9.08 (1H, brs) 泡狀物質 ·76· 152528.doc 201121944 [表 12] 實施 iH 參考例 編號 目標物 產 率 (%) Ή-NMR δ (ppm) 形狀 11 41 〇 41 (CDC13) 0.34-0.38 (2H, m), 0.62-0.69 (2H, m), 0.90 (3H, t, J = 7.6 Hz), 1.22-1.28 (1H, m), 1.72-1.94 (4H, m), 2.60-2.83 (2H, m), 3.48-3.52 (2H, m), 3.81 (2H, d, J = 6.8 Hz), 4. 27 (1H, q, J = 7. 0 Hz), 4.74 (1H, brs), 5.01 (2H, s), 6.81-6.87 (3H, m), 7.22-7.31 (2H, m), 8.60 (1H, brs) 泡狀物質 12 42 43 (CDC13) 1.29-1.39 (2H, m), 1.53 (3H, d, J = 7.0 Hz), 1.54-1.78 (6H, m), 1.81-1.94 (2H, m), 2.32-2.38 (1H, m), 2.72-2.93 (2H, m), 3.50-3.55 (2H, m), 3.83 (2H, d, J = 7. 0 Hz), 4. 53-4. 61 (2H, m), 5. 03 (2H, s), 6.82-6.90 (3H, m), 7.26-7.30 (2H, m), 8.34 (1H, brs) 泡狀物質 13 43 48 (CDC13) 1.55 (3H, d, J = 6,8 Hz), 1.88-1.96 (2H, m), 2.69-2.88 (2H, m), 3.54 (2H, t, J = 6.2Hz), 4.62-4.70 (1H, m), 4.78 (1H, brs), 5.03 (2H, s), 5.94 (1H, tt, J = 52. 9, 2. 7 Hz,), 7.13-7. 29 (4H, m), 7.40 (1H, d, J = 8.1 Hz), 8.60 (1H, brs) 泡狀物質 152528.doc 77- £ 201121944 [表 13] 實施 例 參考例 編號 目標物 產 率 (%) ^-NMR δ (ppm) 形狀 14 44 46 (DMSO-i/^ 1.37 (3H, d, J = 7.0 Hz), 1.68-1.84 (2H, m), 2.60-2.71 (1H, n〇, 2.80-2.91 (1H, m), 3.36-3.47 (2H, m), 4.37-4.47 (1H, m), 4.68-4.80 (2H, m), 4.96 (2H, s), 6.89-6.95 (1H, m), 7.03-7.07 (2H, m), 7. 29 (1H, t, J = 8.1 Hz), 7. 74 (1H, d, J = 8.6 Hz), 8.07 (1H, d, J = 6. 8 Hz), 11.83 (1H, brs) 泡狀物質 15 45 0 36 (CDCI3) 1.53 (3H, d, J = 6.8 Hz), 1.87-1.94 (2H, m), 2.72-2.87 (2H, m), 3.49-3.57 (2H, m), 4. 59-4. 77 (7H, m), 5.03 (2H, s), 6.90-6.99 (3H, m), 7.27-7.34 (2H, m), 8.44 (1H, brs) 泡狀物質 16 46 47 (CDClj) 1.02 (6H, d, J = 6. 8 Hz), 1.53 (3H, d, J = 7.0 Hz), 1.82-1.96 (2H, m), 2.00-2.09 (1H, m), 2.65-2.90 (2H, m), 3. 50-3. 59 (2H, m), 3. 72 (2H, d, J = 6. 5 Hz), 4. 57 (1H, quin, J = 6. 8 Hz), 4.99 (1H, brs), 5.03 (2H, s), 6.80-6.91 (3H, m), 7.23-7.32 (2H, m), 9.20 (1H, brs) 泡狀物質 -78- 152528.doc 201121944 [表 14] 實施 例 參考例 編號 目標物 產 率 (%) 3H-NMR δ (ppm) 形狀 17 47 55 (CDClj) 0.95 (3H,t, J = 7.3 Hz), 1.02 (3H, d, J = 6.8Hz), 1.20-1.34 (1H, m), 1.53 (3H, d, J = 6.8Hz), 1.54-1.60 (1H, m), 1.80-1.95 (3H, m), 2.70-2.92 (2H, m), 3.50-3.56 (2H, m), 3.70-3.84 (2H, m), 4.56 (1H, quin, J = 6.8Hz), 4.76 (1H, brs), 5.03 (2H, s), 6.80-6.90 (3H, m), 7.23-7.31 (2H, m), 8.71 (lH, brs) 泡狀物質 18 48 hn\f °ν〇^1-Μ^Χλ0^ 35 (CDC13) 0. 41-0.46 (2H, a), 0.50-0.54 (2H, m), 1. 23 (3H, s), 1.53 (3H, d, J = 6.8 Hz), 1.80-1.98 (2H, m), 2.68-2.93 (2H, m), 3.51-3.56 (2H,m), 3.73 (2H, s), 4.54-4.62 (1H, m), 4.88-4.96 (1H, m), 5.03 (2H, s), 6.80-6.91 (3H, m), 7.22-7.32 (2H, m), 9.06 (1H, brs) 泡狀物質 19 49 18 (CDC13) 1.53 (3H, d, J = 7.0 Hz), 1.88-1.96 (2H, m), 2.71-2.84 (2H, m), 3.54 (2H, t, J=5.9Hz), 4.21 (2H, td, J = 13. 2, 4.1 Hz), 4. 60(1H, quin, J = 6.8 Hz), 5.03 (1H, brs), 5.04 (2H, s), 6.10 (1H, tt, J=54. 8, 3.8 Hz), 6.85 (1H, dd, J = 8.1, 1.6 Hz), 6.93 (1H, s), 6.93-7.00 (1H, m), 7.27-7.33 (2H, m), 9.05 (1H, brs) 泡狀物質 152528.doc 79- s: 201121944 [表 15] 實施 例 參考例 編號 目標物 產 率 (¾) iH-NMR δ (ppm) 形狀 20 50 12 (CDCl) 1. 53 (3H, d, J = 6. 8 Hz), 1. 67 (3H, d, J = 6.8 Hz), 1.84-1.96 (2H, m), 2.53-2.54 (1H, m), 2.75-2.92 (2H, m), 3.46-3.53 (2H, t, J = 5.9 Hz), 4.56-4.62 (1H, m), 4.80-4.92 (2H, m), 5.34 (2H, s), 6.92-6.97 (3H, m), 7.21-7.32 (2H, m), 8.55 (1H, brs) 泡狀物質 21 51 〇 21 (CDC13) 1. 53 (3H, d, J = 6.8 Hz), 1. 67 (3H, d, J = 6.8 Hz), 1.84-1.96 (2H, n〇, 2.53-2.54 (1H, m), 2.69-2.91 (2H, m), 3.48-3.53 (2H, m), 4.56-4. 62 (2H, m), 4.80-4.92 (1H, ra), 5.34 (2H, s), 6.93-6.97 (3H, m), 7.26-7.32 (2H, m), 8.53 (1H, brs) 泡狀物質 22 52 〇人 ΐΌν^·\^Ι』Υ〇·^\^ 32 (CDClj) 1.53 (3H, d, J = 6.8 Hz), 1.87-1.98 (2H, m), 2.71-2.86 (2H, m), 3.52 (2H, t, J = 5. 1 Hz), 4. 24 (2H, dt, J = 28. 6, 3.8 Hz), 4.56-4.67 (2H, m), 4.77 (2H, dt, J=47.0, 4.3 Hz), 5.03 (2H, s), 6.85-6.96 (3H, m), 7.26-7.33 (2H, m) 泡狀物質 80- 152528.doc 201121944 [表 16] 實施例 參考例 編號 目標物 產率 (¾) δ (ppm) 形狀 23 S3 35 (CDC13) 0.98 (3H,t, J = 7.3 Hz), 1.29 (3H,d J = 6. 2 Hz), 1. 54 (3H, d, J = 6. 8 Hz) 1.58-1.78 (2H, n〇, 1.86-1.95 (2H, m) 2.74-2.90 (2H, ra), 3.52-3.58 <2H, m) 4.28-4.36 (1H, m), 4.53-4.62 (1H, m) 4.69-4.72 (1H, m), 5.03 (2H, s) 6.81-6.89 (3H, m), 7.22-7.31 (2H, m) 8.63 (1H, brs) 泡狀物質 24 54 hn-Vf 23 (CDCls) 0.98 (3H, t, J=7.3Hz), 1.29 (3H, d J = 6. 2 Hz), 1. 54 (3H, d, J = 7. 0 Hz) 1.58-1.78 (2H, m), 1.86-1.95 (2H, m) 2.74-2.90 {2H, m), 3.52-3.58 (2H, m) 4.29-4.37 {1H, m), 4.53-4,62 (1H, m) 4.69-4,72 (IK, m), 5.03 (2H, s) 6.81-6.89 (3H, m), 7.22-7/31 (2H, m) 8.62 (1H, brs) 泡狀物質 25 55S 152528.doc 201121944 (R)-N-( 1-(3-(cyclopropylmethoxy)-4-fluorophenyl)ethyl)-3-((5-fluoro-2.4-dioxo- 3,4-Dihydropyrimidin-1(2H)-yl)decyloxy)propane-1-sulfonamide Example 6 (R)-N-(l-(3-(cyclopropyldecyloxy)- 4-fluorophenyl)-2-methylpropyl)-3-((5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)decyloxy) Propane-1-sulfonamide Example 7 (R)-N-(l-(3-(cyclopropylmethoxy)-4-fluorophenyl)propyl)-3-((5-fluoro-2.4) - Dioxo-3,4-dihydropyrimidin-1(211)-yl)methoxy)propane_1_sulfonamide Example 8 (R)-N-(l-(3-(cyclopropyl) Methoxy)phenyl)ethyl)-3-((5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)decyloxy)propane·ι· Sulfonamide Example 9 (R)-N-(1-(3-(cyclopentyloxy)-4-fluorophenyl)ethyl)-3-((5-fluoro-2,4-dioxo- 3,4-Dihydropyrimidin-1(2H)-yl)decyloxy)propane-1-sulfonamide Example 10 N-(1-(3-(cyclopropyldecyloxy)-4-fluorobenzene 2-mercaptopropyl)-3-((5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(211)-yl)decyloxy)propane-1_sulfonate Indoleamine Example 11 (R)-N-(l-(3-(cyclopropylmethoxy) Phenyl)propyl)·3_((5-fluoro-24-dioxo-3,4-dihydropyrimidin-1(2Η)-yl)methoxy)propane_methanesulfonamide Example 12 (R)-N-indole-(3-(cyclopentylmethoxy)phenyl)ethyl)-3-((5-fluoro-2,4-di 152528.doc •70-201121944 oxo-3 4, 2 gas shouting Example 13 ° ^ _1 (2 Η) · yl) methoxy) propane burning _ continuation of amine (R) -3- ((5_ gas, 4 dioxo 3, 4 · Dihydropyrimidin-1(2H)-yl)methoxy_A',,2,2-tetrafluoroethoxy)phenyl)ethyl)propane-1-sulfonamide Example 14) Fluorine 2, 'two Oxo-3,4-dihydropyrimidin-1(211)-yl)decyloxy)-N-(l-(3-(2 2 ?--, ,difluoroethoxy)phenyl)ethyl Propane_ι_sulfonamide Example 15 () (丨(^(丨'3-difluoropropyl-2-yloxy)phenyl)ethyl)-3-((5-fluoro-2,4) -dioxo-3,4-dihydropyrimidin-1(2拗-yl)methoxy)propane_丨_sulfonamide Example 16 (R)-3-((5-fluoro-2,4- Dioxo_3,4_Dihydropyrazine _ι(2Η)_yl) decyloxy)-N-(l-(3-isobutoxyphenyl)ethyl)propane 丨 sulfonamide Example 17 3-((5-Fluoro-2,4-dioxo-3,4-dihydropyrimidine·ι(2Η)-yl)methoxy)-N - ((R)-l-(3-((S)-2-methylbutoxy)phenyl)ethyl)propane sulfonamide Example 18 (R)-3-((5-Fluoro- 2,4·dioxo-3,4-dihydropyrimidine_ι(2Η)_yl)decyloxy)-N-(l-(3-((methylcyclopropyl)methoxy)phenyl)) Ethyl)propanesulfonate Example 19 (R)-N-(l-(3-(2,2-difluoroethoxy)phenyl)ethyl)_3_((5-fluoro-2,4 · Dioxo-3,4-dihydropyrimidin-1(2H)-yl)methoxy)propane·sulphonamide £152528.doc •71 · 201121944 Example 20 N-((R)-l- (3-((S)·丁-3·acetyl-2-yloxy)phenyl)ethyl)_3_((5-fluoro-2.4-dioxo-3,4-dihydropyrimidine_1 (211 Guang曱)oxy)propane·丨_sulfonamide Example 21 N-((R)-l-(3-((R> Buty_3_yn-2-yloxy)phenyl)ethyl) _3_((5_Fluoro-2.4-dioxo-3,4-dihydropyrimidin-1(211)-yl)decyloxy)propane_丨_sulfonamide Example 22 (R)-3-(( 5-fluoro-2,4-dioxo-3,4-dihydropyrimidinyl)methoxy)-N-(1-(3-(2-fluoroethoxy)phenyl)ethyl)propane 丨Sulfonamide Example 23 ((1〇-1-(3-(11)-Seconbutoxyphenyl)ethyl)_3_((5-fluoro-2,4-dioxo) -3,4-dihydropyrimidin-1(2H)-yl)decyloxy)propane-1-sulfonamide Example 24 N-((R)-l-(3-(S)-Second-butoxy Phenyl)ethyl)ethyl 3-((5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methoxy)propane-1-sulfonamide Example 25 3-((5-Fluoro-2,4-dioxo-3,4-dihydropyrimidine·ι(2Η)-yl)decyloxy)·Ν-((R)-l-(3 -((S)-pentan-2-yloxy)phenyl)ethyl)propane-1-sulfonamide Example 26 3-((5-Fluoro-2,4-dioxo-3,4 -dihydropyrimidine-i(2H)-yl)methoxy)-N-((R)-l-(3-((R)-pentan-2-yloxy)phenyl)ethyl)propane -1-sulfonamide Example 27 (R)-3-((5-Fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methoxy)-: ^-(1_(3-(2,2,3,3,3-pentafluoropropoxy)phenyl)ethyl)propane-1_sulfon 152528.doc •72· 201121944 Stearic amine example 28 (R) -3-((5-fluoro-2,4-dioxo-3,4-dihydropyrimidine·1(2Η)-yl)methoxy)-N-(l-(3-(tetrahydro-2Η) -»biam-4-yloxy)phenyl)ethyl)propane-l_sulfonamide Example 29 3-((5-Fluoro-2,4-dioxo-3,4-dihydropyrimidine) -1(2Η)-yl)methoxy)-indole-((R)-l-(3-((R)-tetrahydrofuran-3-yloxy) Phenyl)ethyl)propane-indolesulfonamide Example 30 (R)-N-(1-(3-(2-cyclopropylethoxy)phenyl)ethyl)_3_((5·Fluorine · 2,4-dioxo-3,4-dihydropyrimidin-1(2Η)-yl)methoxy)propanesulfonamide 152528.doc •73· 201121944 [Table 9] Example Reference Example No. Target Product Rate (%) ^-NMR δ (ppm) Shape 2 32 0 m\F ^t〇^^|-NyCX〇X) 44 (CDCls) 1.53 (3H, d, J = 7.0 Hz), 1.62-1.65 (2H , m), 1.72-1.97 (8H, m), 2.70-2.88 (2H, m), 3.50-3.56 (2H, m), 4.56 (1H, quin, J = 6.8Hz), 4.74-4.78 (1H, m ), 4.92 (1H, brs), 5.03 (2H, s), 6.78-6.88 (3H, m), 7.21-7.32 (2H, m), 9.08 (1H, brs) blister 3 33 35 (CDC1S) 1.53 (3H, d, J = 7.0Hz), 1.85-1.95 (2H, m), 2. 06-2. 24 (2H, m), 2.68-2.88 (2H, m), 3.51-3.57 (2H, m) , 3.89-4.06 (4H, m), 4.53-4.61 (1H, m), 4.70-4.74 (1H, m), 4.93-4.96 (1H, m), 5.03 (2H, s), 6.77 (1H, dd, J = 8. 1, 2.4 Hz), 6.82-6.84 (1H, m), 6.92 (1H, d, J = 7.3 Hz), 7.24-7.34 (2H, m), 8.76 (1H, brs) blister 4 34 26 (CDCI3) 0. 33-0.39 (2H, m), 0.62-0. 69 (2H, m), 1.22-1.29 (1H, m), 1.99-2.08 (2H, m), 2.99 (2H, t, J = 7.6Hz), 3.65 (2H, t, J = 6.2Hz), 3.88 (2H, d, J = 7.0Hz), 4.22 ( 2H, d, j = 5.4 Hz), 4.78 (1H, brs), 5.08 (2H, s), 6.82-6.87 (1H, m), 6. 94-6. 98 (2H, m), 7. 34 ( 1H, d, J = 5. 4 Hz), 8.62 (1H, brs) blister 74- 152528.doc 201121944 [Table ι] Example Reference Example Number Target Yield (.%) frNMR δ (ppm) Shape - 5 35 16 (CDCI3) 0.33-0.39 (2H, m), 0.63-0.70 (2H, m), 1.23-1.31 (1H, m), 1.52 (3H, d, J=7.0 Hz), 1.83-1.98 ( 2H, m), 2.63-2.83 (2H, m), 3.55 (2H, t, J = 6.2Hz), 3.89 (2H, d, J = 7.0 Hz), 4.58 (1H, quin, J = 5. 9 Hz ), 4. 78 (1H, d, J = 6. 2 Hz), 5.04 (2H, s), 6.84-6.96 (2H, m), 7.02-7.09 (1H, m), 7..33 (1H, d, J = 5.1 Hz), 8.76 (1H, brs) blister 6 36 47 (CDC13) 0.32-0.39 (2H, m), 0.61-0.69 (2H, m), 0.80 (3H, d, J = 6.5 Hz), 1.03 (3H, d, J = 6.8 Hz), 1.21-1.29 (1H, m), 1.70-2.00 (3H, m), 2.58-2.79 (2H, m), 3. 49 (2H, t, J = 5.9 Hz), 3. 89 (2H, d, J = 7.0 Hz), 4.05 (1H, t, J = 8.1 Hz), 4.91 (1H, d, J = 8.1Hz), 5.01 (2H, s) , 6.76-6.81 (1H, m), 6,83-6.87 (1H, m), 7. 02-7. 09 (1H, in), 7. 32 (1H, d, J = 5. 2 Hz), 8.67 (1H, brs) blister 7 37 40 (CDCI3) 0. 32-0. 38 (2H, m), 0.62-0. 69 (2H, m), 0.89 (3H, t, J = 7.0 Hz), 1.22-1.28 (1H, m), 1.72-1.94 (4H, m), 2.60-2.81 (2H, m), 3. 51 (2H, d, J = 5. 9 Hz), 3. 89 (2H, d , J = 7.3 Hz), 4.25 (1H, q, J = 7.6 Hz), 5.02 (2H, s), 5.10 (1H, d, J =7.0 Hz), 6.80-6.85 (1H, m), 6.88-6.92 (1H, m), 7.02-7.09 (1H, m), 7.34 (1H, d, J = 5.1 Hz), 9.20 (1H, brs) blister 152528.doc -75- s·. •S& 201121944 [ Table 11] Example Reference Example No. Target Yield (%) ^-NMR δ (ppm) Shape 8 38 〇hn\f 57 (CDCls) 0.32-0.38 (2H, m), 0.63-0.69 (2H, m), 1.23-1.31 (1H, m), 1.53 (3H, d, J = 6.8 Hz), 1.83-1.98 (2H, m), 2.70-2.90 (2H, m), 3.50-3.59 (2H, m), 3.81 ( 2H, d, J = 7. 0 Hz), 4. 55 (1H, quin, J = 5.1 Hz), 4.95 (1H, d, J = 7.0 Hz), 5.03 (2H, s), 6.80-6.84 (1H , m), 6.88-6.92 (2H, m), 7.22-7.33 (2H, m), 9.10 (1H, brs) blister 9 39 61 (CDC13) 1.53 (3H, d, J = 6 .8Hz), 1.61-1.70 (2H, m), 1.76-2.00 (8H, m), 2.68-2.83 (2H, m), 3.55 (2H, t, J = 5.9 Hz), 4.53-4.60 (2H, m ), 4.81-4.85 (1H, m), 5.03 (2H, s), 6.81-6.87 (1H, m), 6.92-6.96 (1H, m), 7.00-7.08 (1H, m), 7.31 (1H, d , J = 5.1 Hz), 8.51 (1H, brs) blister 10 40 52 (CDCI3) 0.32-0.39 (2H, m), 0.61-0.69 (2H, m), 0.80 (3H.d, J = 6. 5 Hz), 1.03 (3H, d, J = 6.5 Hz), 1.21-1.29 (1H, m), 1.70-2.00 (3H, m), 2.58-2.79 (2H, m), 3. 49 (2H, t , J = 5.9 Hz), 3. 89 (2H, d, J = 7.0Hz), 4.04(1H, t, J = 8.1Hz), 5.01 (2H, s), 5.16 (1H, brs), 6.76-6.81 (1H, m), 6,84-6.88 (1H, m), 7. 02-7. 09 (1H, m), 7. 33 (1H, d, J = 5. 4 Hz), 9.08 (1H, Brs) blister substance · 76· 152528.doc 201121944 [Table 12] Implementation iH Reference example No. Target yield (%) Ή-NMR δ (ppm) Shape 11 41 〇41 (CDC13) 0.34-0.38 (2H, m) , 0.62-0.69 (2H, m), 0.90 (3H, t, J = 7.6 Hz), 1.22-1.28 (1H, m), 1.72-1.94 (4H, m), 2.60-2.83 (2H, m), 3.48 -3.52 (2H, m), 3.81 (2H, d, J = 6.8 Hz), 4. 27 (1H, q, J = 7. 0 Hz), 4.74 (1H, brs), 5.01 (2H, s),6.81-6.87 (3H, m), 7.22-7.31 (2H, m), 8.60 (1H, brs) blister 12 42 43 (CDC13) 1.29-1.39 (2H, m), 1.53 (3H, d, J = 7.0 Hz), 1.54-1.78 (6H, m), 1.81-1.94 (2H, m), 2.32-2.38 (1H, m), 2.72-2.93 (2H, m), 3.50-3.55 (2H, m), 3.83 (2H, d, J = 7. 0 Hz), 4. 53-4. 61 (2H, m), 5. 03 (2H, s), 6.82-6.90 (3H, m), 7.26-7.30 (2H, m), 8.34 (1H, brs) blister 13 43 48 (CDC13) 1.55 (3H, d, J = 6,8 Hz), 1.88-1.96 (2H, m), 2.69-2.88 (2H, m), 3.54 (2H, t, J = 6.2Hz), 4.62-4.70 (1H, m), 4.78 (1H, brs), 5.03 (2H, s), 5.94 (1H, tt, J = 52. 9, 2. 7 Hz,), 7.13-7. 29 (4H, m), 7.40 (1H, d, J = 8.1 Hz), 8.60 (1H, brs) blister substance 152528.doc 77- £ 201121944 [Table 13] Example Reference Example No. Target Yield (%) ^-NMR δ (ppm) Shape 14 44 46 (DMSO-i/^ 1.37 (3H, d, J = 7.0 Hz), 1.68-1.84 (2H, m), 2.60-2.71 ( 1H, n〇, 2.80-2.91 (1H, m), 3.36-3.47 (2H, m), 4.37-4.47 (1H, m), 4.68-4.80 (2H, m), 4.96 (2H, s), 6.89- 6.95 (1H, m), 7.03-7.07 (2H, m), 7. 29 (1H, t, J = 8.1 Hz), 7. 74 (1H, d, J = 8.6 Hz ), 8.07 (1H, d, J = 6. 8 Hz), 11.83 (1H, brs) blister 15 45 0 36 (CDCI3) 1.53 (3H, d, J = 6.8 Hz), 1.87-1.94 (2H, m), 2.72-2.87 (2H, m), 3.49-3.57 (2H, m), 4. 59-4. 77 (7H, m), 5.03 (2H, s), 6.90-6.99 (3H, m), 7.27-7.34 (2H, m), 8.44 (1H, brs) blister 16 46 47 (CDClj) 1.02 (6H, d, J = 6. 8 Hz), 1.53 (3H, d, J = 7.0 Hz), 1.82-1.96 (2H, m), 2.00-2.09 (1H, m), 2.65-2.90 (2H, m), 3. 50-3. 59 (2H, m), 3. 72 (2H, d, J = 6. 5 Hz), 4. 57 (1H, quin, J = 6. 8 Hz), 4.99 (1H, brs), 5.03 (2H, s), 6.80-6.91 (3H, m), 7.23-7.32 (2H , m), 9.20 (1H, brs) blister substance -78-152528.doc 201121944 [Table 14] Example Reference Example No. Target Yield (%) 3H-NMR δ (ppm) Shape 17 47 55 (CDClj) 0.95 (3H,t, J = 7.3 Hz), 1.02 (3H, d, J = 6.8Hz), 1.20-1.34 (1H, m), 1.53 (3H, d, J = 6.8Hz), 1.54-1.60 (1H, m), 1.80-1.95 (3H, m), 2.70-2.92 (2H, m), 3.50-3.56 (2H, m), 3.70-3.84 (2H, m), 4.56 (1H, quin, J = 6.8Hz) , 4.76 (1H, brs), 5.03 (2H, s), 6.80-6.90 (3H, m), 7.23-7.31 (2H, m), 8.71 (lH, brs) Bubbly substance 18 48 hn\f °ν〇^1-Μ^Χλ0^ 35 (CDC13) 0. 41-0.46 (2H, a), 0.50-0.54 (2H, m), 1. 23 (3H, s) , 1.53 (3H, d, J = 6.8 Hz), 1.80-1.98 (2H, m), 2.68-2.93 (2H, m), 3.51-3.56 (2H, m), 3.73 (2H, s), 4.54-4.62 (1H, m), 4.88-4.96 (1H, m), 5.03 (2H, s), 6.80-6.91 (3H, m), 7.22-7.32 (2H, m), 9.06 (1H, brs) blister 19 49 18 (CDC13) 1.53 (3H, d, J = 7.0 Hz), 1.88-1.96 (2H, m), 2.71-2.84 (2H, m), 3.54 (2H, t, J=5.9Hz), 4.21 (2H , td, J = 13. 2, 4.1 Hz), 4. 60(1H, quin, J = 6.8 Hz), 5.03 (1H, brs), 5.04 (2H, s), 6.10 (1H, tt, J=54 8, 3.8 Hz), 6.85 (1H, dd, J = 8.1, 1.6 Hz), 6.93 (1H, s), 6.93-7.00 (1H, m), 7.27-7.33 (2H, m), 9.05 (1H, Brs) blister substance 152528.doc 79- s: 201121944 [Table 15] Example Reference Example No. Target Yield (3⁄4) iH-NMR δ (ppm) Shape 20 50 12 (CDCl) 1. 53 (3H, d, J = 6. 8 Hz), 1. 67 (3H, d, J = 6.8 Hz), 1.84-1.96 (2H, m), 2.53-2.54 (1H, m), 2.75-2.92 (2H, m), 3.46 -3.53 (2H, t, J = 5.9 Hz), 4.56-4.62 (1H, m), 4.80-4.92 (2H, m), 5.34 (2H, s), 6. 92-6.97 (3H, m), 7.21-7.32 (2H, m), 8.55 (1H, brs) Foaming substance 21 51 〇21 (CDC13) 1. 53 (3H, d, J = 6.8 Hz), 1. 67 (3H, d, J = 6.8 Hz), 1.84-1.96 (2H, n〇, 2.53-2.54 (1H, m), 2.69-2.91 (2H, m), 3.48-3.53 (2H, m), 4.56- 4. 62 (2H, m), 4.80-4.92 (1H, ra), 5.34 (2H, s), 6.93-6.97 (3H, m), 7.26-7.32 (2H, m), 8.53 (1H, brs) Shaped substance 22 52 〇人ΐΌν^·\^Ι』Υ〇·^\^ 32 (CDClj) 1.53 (3H, d, J = 6.8 Hz), 1.87-1.98 (2H, m), 2.71-2.86 (2H, m), 3.52 (2H, t, J = 5. 1 Hz), 4. 24 (2H, dt, J = 28. 6, 3.8 Hz), 4.56-4.67 (2H, m), 4.77 (2H, dt, J=47.0, 4.3 Hz), 5.03 (2H, s), 6.85-6.96 (3H, m), 7.26-7.33 (2H, m) Foaming substance 80-152528.doc 201121944 [Table 16] Example Reference Example No. Target yield (3⁄4) δ (ppm) Shape 23 S3 35 (CDC13) 0.98 (3H, t, J = 7.3 Hz), 1.29 (3H, d J = 6. 2 Hz), 1. 54 (3H, d, J = 6. 8 Hz) 1.58-1.78 (2H, n〇, 1.86-1.95 (2H, m) 2.74-2.90 (2H, ra), 3.52-3.58 <2H, m) 4.28-4.36 (1H, m) , 4.53-4.62 (1H, m) 4.69-4.72 (1H, m), 5.03 (2H, s) 6.81-6.89 (3H, m), 7. 22-7.31 (2H, m) 8.63 (1H, brs) blister 24 54 hn-Vf 23 (CDCls) 0.98 (3H, t, J=7.3Hz), 1.29 (3H, d J = 6. 2 Hz) , 1. 54 (3H, d, J = 7. 0 Hz) 1.58-1.78 (2H, m), 1.86-1.95 (2H, m) 2.74-2.90 {2H, m), 3.52-3.58 (2H, m) 4.29-4.37 {1H, m), 4.53-4,62 (1H, m) 4.69-4,72 (IK, m), 5.03 (2H, s) 6.81-6.89 (3H, m), 7.22-7/31 (2H, m) 8.62 (1H, brs) blister 25 55

34 (CDC13) 0.94 (3H, t, J = 7.3Hz), 1.29 (3H, d, J = 6.2 Hz), 1.38-1.64 (5H, m), 1.66-1.74 (2H, m), 1.84-1.99 (2H, m), 2.73-2.90 (2H, m), 3.50-3.58 (2H, m), 4.36-4.42 (1H, m), 4.52-4.62 (1H, m), 4.98 (1H. brs), 5.03 (2H, s), 6.80-6.89 (3H, m), 7.22-7.31 (2H, m), 8.60 (1H, brs) 泡狀物質 S- 152528.doc '81 · 201121944 表 實施例 參考 例 編號 目標物 產 率 (%) 1H-NMR 8 (ppm) 形狀 26 5634 (CDC13) 0.94 (3H, t, J = 7.3Hz), 1.29 (3H, d, J = 6.2 Hz), 1.38-1.64 (5H, m), 1.66-1.74 (2H, m), 1.84-1.99 ( 2H, m), 2.73-2.90 (2H, m), 3.50-3.58 (2H, m), 4.36-4.42 (1H, m), 4.52-4.62 (1H, m), 4.98 (1H. brs), 5.03 ( 2H, s), 6.80-6.89 (3H, m), 7.22-7.31 (2H, m), 8.60 (1H, brs) blister substance S- 152528.doc '81 · 201121944 Table example reference example number target yield (%) 1H-NMR 8 (ppm) Shape 26 56

35 (CDClj) 0. 94 (3H, t, J = 7. 0 Hz), 1. 29 (3H, d J = 6.2 Hz). 1.39-1.62 (5H, m) 1. 66-1. 73 (2H, m), 1. 85-1. 98 (2H, m) 2.73-2.90 (2H, m), 3.50-3.58 (2H, m) 4.36-4.42 (1H, m), 4.52-4.62 (lH, m) 4.73 (1H, brs), 5.03 (2H, s) 6.80-6.89 (3H, m), 7.22-7.31 (2H, m) 8.69 (1H, brs) 泡狀物質 27 57 47 (CDC13) 1.55 (3H, d, J = 6.8 Hz), 1.86-1.99 (2H, m), 2.70-2.90 (2H, m), 3.51-3.59 (2H, m), 4.45 (2H, t, J = 12.4 Hz), 4.61 <1H, quin, J = 6.8Hz), 4.93 (1H, brs), 5.04 (2H, s), 6.87 (1H, dd, J = 8.4, 2. 2 Hz), 6.95 (1H. s), 7.02 (1H, d, J = 7.6Hz), 7.29-7.35 (2H, m), 9.10 (1H, brs) 泡狀物質 5835 (CDClj) 0. 94 (3H, t, J = 7. 0 Hz), 1. 29 (3H, d J = 6.2 Hz). 1.39-1.62 (5H, m) 1. 66-1. 73 (2H (m), 1. 4.73 (1H, brs), 5.03 (2H, s) 6.80-6.89 (3H, m), 7.22-7.31 (2H, m) 8.69 (1H, brs) blister 27 57 47 (CDC13) 1.55 (3H, d , J = 6.8 Hz), 1.86-1.99 (2H, m), 2.70-2.90 (2H, m), 3.51-3.59 (2H, m), 4.45 (2H, t, J = 12.4 Hz), 4.61 <1H , quin, J = 6.8Hz), 4.93 (1H, brs), 5.04 (2H, s), 6.87 (1H, dd, J = 8.4, 2. 2 Hz), 6.95 (1H. s), 7.02 (1H, d, J = 7.6Hz), 7.29-7.35 (2H, m), 9.10 (1H, brs) blister 58

35 (CDC13) 1.53 (3H, d, J = 6.8 Hz), 1.73-2.10 (6H, m), 2.70-2.91 (2H, m), 3.51-3.66 (4H, in), 3.95-4.05 (2H, m), 4.48-4.62 (2H, m), 4.81 (1H, brs), 5.04 (2H, s), 6.83-6.93 (3H,m), 7.24-7.32 (2H, m), 8.83 (1H, brs) 泡狀物質 152528.doc 82- 201121944 [表 18] 實施例 參考例編號 目標物 產率 (%) 'H-NMR 5 (ppm) 形狀 〇 41 (cdci3) 1.53 (3H, d, J = 6.8 Hz), 1.85-1.95 (2H, m), 2.09-2.24 (2H, m), 2.68-2.88 (2H, m), 3. 51-3. 57 (2H, m), 3.90-4.06 (4H, m), 4.53-4.61 (1H, m), 4.70-4.74 (1H, m), 5.03 (2H, s), 5.06 (1H, brs), 6.77 (1H, dd, J = 7.8, 2.2 Hz), 6.82-6.84 (1H, m), 6.92 (1H, d, J = 7.6 Hz), 7. 24-7. 34 (2H, m), 8. 76 (1H, brs) 泡狀物質 Λ35 (CDC13) 1.53 (3H, d, J = 6.8 Hz), 1.73-2.10 (6H, m), 2.70-2.91 (2H, m), 3.51-3.66 (4H, in), 3.95-4.05 (2H, m ), 4.48-4.62 (2H, m), 4.81 (1H, brs), 5.04 (2H, s), 6.83-6.93 (3H, m), 7.24-7.32 (2H, m), 8.83 (1H, brs) Shape 152528.doc 82- 201121944 [Table 18] Example Reference Example No. Target Yield (%) 'H-NMR 5 (ppm) Shape 〇41 (cdci3) 1.53 (3H, d, J = 6.8 Hz), 1.85 -1.95 (2H, m), 2.09-2.24 (2H, m), 2.68-2.88 (2H, m), 3. 51-3. 57 (2H, m), 3.90-4.06 (4H, m), 4.53- 4.61 (1H, m), 4.70-4.74 (1H, m), 5.03 (2H, s), 5.06 (1H, brs), 6.77 (1H, dd, J = 7.8, 2.2 Hz), 6.82-6.84 (1H, m), 6.92 (1H, d, J = 7.6 Hz), 7. 24-7. 34 (2H, m), 8. 76 (1H, brs) blister substance Λ

49 (CDClj) 0. 11-0. 16 (2H, m), 0.45-0. 53 (2H, m), 0. 81-0. 89 (1H, m), 1. 53 (3H, d, J = 7. 0 Hz), 1.63-1.72 (2H, ra), 1.85-1.96 (2H, m), 2.69-2.90 (2H, m), 3.50-3.58 (2H, m), 4.04 (2H, t, J = 6. 8 Hz), 4.58 (1H, quin, J = 6.8Hz), 4.89 (1H, d, J = 6.8Hz), δ.03 (2H, s), 6.81-6.91 (3H, in), 7.23-7.31 (2H, m), 8.97 (1H, brs) 泡狀物質 實施例3 1 (R)-N-( 1-(3-(環丙基曱氧基)-4 -氟苯基)乙基)-3-(5 -氟-2,4-二氧代_3,4-二氫嘧啶-1(2H)-基)丙烷-1-磺醯胺之合成 [化 34] Ο49 (CDClj) 0. 11-0. 16 (2H, m), 0.45-0. 53 (2H, m), 0. 81-0. 89 (1H, m), 1. 53 (3H, d, J = 7. 0 Hz), 1.63-1.72 (2H, ra), 1.85-1.96 (2H, m), 2.69-2.90 (2H, m), 3.50-3.58 (2H, m), 4.04 (2H, t, J = 6. 8 Hz), 4.58 (1H, quin, J = 6.8Hz), 4.89 (1H, d, J = 6.8Hz), δ.03 (2H, s), 6.81-6.91 (3H, in), 7.23 -7.31 (2H, m), 8.97 (1H, brs) vesicular material Example 3 1 (R)-N-( 1-(3-(cyclopropyldecyloxy)-4-fluorophenyl)ethyl Synthesis of 3-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)propane-1-sulfonamide [Chem. 34] Ο

152528.doc -83- S, 201121944 使藉由參考例61所獲得之(R)-N-(l-(3-(環丙基曱氧基)-4-氟苯基)乙基)-3-羥基-N-(曱氧基曱基)丙烷-1_磺醯胺(230 mg)溶解於THF(4.5 mL)中,添加三苯基膦(189 mg)、依據 文獻(Bioorg· Med. Chem_ Lett·,12,1395-1397 (2002))中記 載之方法獲得之3 -苯曱醯基·5·氟嘧啶_2,4(1h,3H)-二酮 (162 mg),於室溫下攪拌5分鐘。於反應液中緩慢滴加 DEAD之曱苯溶液(2.2 Μ ’ 330 μί),於室溫下搜拌4小時。 將反應液減壓濃縮後,利用矽膠管柱層析法(7〇%乙酸乙酯/ 己烧)將殘渣純化。使所獲得之化合物溶解於甲基胺之曱 醇溶液(40%,4.0 mL)中,於室溫下攪拌3〇分鐘。將反應 液減壓濃縮後’利用矽膠管柱層析法(9〇%乙酸乙酯/己烷) 將殘、/查純化。使所獲得之化合物溶解於二哼烷(丨5 mL) 中,添加鹽酸-二噚烷溶液(4.0 Μ,500 μΙ〇,於室溫下攪 拌3小時。於0。(:下向反應液中添加飽和碳酸氫鈉水溶液 (4.0 mL)並中和後,利用乙酸乙酯(15 mLx2)、1〇%甲醇/氣 仿(15 mL><2)進行萃取。利用飽和食鹽水(1〇 mL)清洗有機 層,利用無水硫酸鈉加以乾燥後,並進行減壓濃縮。利用 矽膠管柱層析法(100%乙酸乙酯)將殘渣純化,藉此獲得標 記化合物(1 7 mg,產率6%)。 ]H-NMR (CDCI3) δ (ppm): 0.32-0.38 (2H, m), 0.60-0.67 (2H, m), 1.22-1.30 (1H, m)s 1.51 (3H5 d, J=6.8 Hz), 1.97-2.05 (2H, m), 2.63-2.75 (2H, m), 3.63-3.80 (2H, m), 3.88 (2H, d, J=7.0 Hz), 4.51-4.58 (1H, m), 5.54 (1H, brs), 6.86-7.09 (3H, m), 7.32 (1H, d, J=5.4 Hz) 152528.doc • 84 · 201121944 實施例32〜實施例45 以下之化合物係由各個參考例62〜75中獲得之化合物, 依據實施例3 1之方法而合成。結果示於以下表。 實施例32 (R,E)-N-(l-(3-(環丙基甲氧基)_4_氟苯基)乙基)·5-(5-氟- 2.4- 二氧代-3,4-二氬嘧啶_1(211)·基)戊_3_烯-1-磺醯胺 實施例33 (R)-N-(l-(3-(環丙基曱氧基)_4_氟苯基)乙基)-5-(5-氟- 2.4- 二氧代-3,4-二氫嘧啶_1(211)-基)戊烷-1-磺醯胺 實施例34 (E)-N-(3-(環丙基甲氧基)爷基)_5_(5_氣_2,4_二氧代-3,4_ 二氫嘧啶-1(2H)-基)戊_3_烯-1-磺醯胺 實施例35 N-(3-(環丙基甲氧基)苄基)_5_(5_氟_2,4_二氧代_3;4-二氫 嘧啶-1(2H)-基)戊烷小磺醯胺 實施例36 (R)-N-(l-(3-(環戊氧基)苯基)乙基)·3_(5_氟_2,4-二氧代_ 3.4- 二風鳴淀-1 (2 Η)-基)丙烧-1 -績酿胺 實施例37 (R,E)-N-(l-(3-(環戊氧基)苯基)乙基)·5_(5·氟-2,4-二氧 代-3,4-二氫嘧啶·1(2Η)-基)戊-3-烯-1-磺醯胺 實施例38 (R)-N-(l-(3-(環戊氧基)苯基)乙基)_5·(5·氟-2,4-二氧代_ 3.4- —氫喷咬-1(2Η)-基)戊烧-1-續酿胺152528.doc -83- S, 201121944 (R)-N-(l-(3-(cyclopropyldecyloxy)-4-fluorophenyl)ethyl)-3 obtained by reference Example 61 -Hydroxy-N-(decyloxymercapto)propane-1_sulfonamide (230 mg) was dissolved in THF (4.5 mL), triphenylphosphine (189 mg) was added, according to the literature (Bioorg· Med. Chem_) 3-Benzenyl-5-fluoropyrimidine-2,4(1h,3H)-dione (162 mg) obtained by the method described in Lett., 12, 1395-1397 (2002)), at room temperature Stir for 5 minutes. A solution of DEAD in benzene (2.2 ’ '330 μί) was slowly added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 4 hours. After the reaction mixture was concentrated under reduced pressure, the residue was purified using silica gel column chromatography (7% ethyl acetate / hexane). The obtained compound was dissolved in a methanol solution of methylamine (40%, 4.0 mL), and stirred at room temperature for 3 hr. The reaction solution was concentrated under reduced pressure and then purified by <RTI ID=0.0>> The obtained compound was dissolved in dioxane (丨5 mL), and a hydrochloric acid-dioxane solution (4.0 Μ, 500 μΙ〇) was added and stirred at room temperature for 3 hours at 0. (: in the lower reaction solution After adding a saturated aqueous solution of sodium hydrogencarbonate (4.0 mL) and neutralizing, extraction was carried out with ethyl acetate (15 mL×2), 1% methanol/methanol (15 mL >< 2). The organic layer was washed, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (100% ethyl acetate) to give the title compound (1 7 mg, yield 6 %). H-NMR (CDCI3) δ (ppm): 0.32-0.38 (2H, m), 0.60-0.67 (2H, m), 1.22-1.30 (1H, m)s 1.51 (3H5 d, J=6.8 Hz), 1.97-2.05 (2H, m), 2.63-2.75 (2H, m), 3.63-3.80 (2H, m), 3.88 (2H, d, J=7.0 Hz), 4.51-4.58 (1H, m) , 5.54 (1H, brs), 6.86-7.09 (3H, m), 7.32 (1H, d, J=5.4 Hz) 152528.doc • 84 · 201121944 Example 32 to Example 45 The following compounds are used in the respective reference examples. The compound obtained in 62 to 75 was synthesized according to the method of Example 31. The results are shown in the following table. Example 32 (R,E)-N-(l-(3-(cyclopropylmethoxy)-4-fluorophenyl)ethyl)·5-(5-fluoro-2.4-dioxo-3 4-Dihydropyrimidine-1(211).yl)penta-3-ene-1-sulfonamide Example 33 (R)-N-(l-(3-(cyclopropyldecyloxy)_4_ Fluorophenyl)ethyl)-5-(5-fluoro-2.4-dioxo-3,4-dihydropyrimidin-1(211)-yl)pentan-1-sulfonamide Example 34 (E) -N-(3-(cyclopropylmethoxy)-yl)_5_(5_gas_2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)pent-3-ene -1-sulfonamide Example 35 N-(3-(cyclopropylmethoxy)benzyl)-5-(5-fluoro-2,4-dioxo-3;4-dihydropyrimidin-1 (2H )-yl)pentane sulfonamide Example 36 (R)-N-(l-(3-(cyclopentyloxy)phenyl)ethyl)·3_(5-fluoro-2,4-dioxo代 _ 3.4- 二风鸣淀-1 (2 Η)-based) propyl- 1 - aryl amine Example 37 (R, E)-N-(l-(3-(cyclopentyloxy)phenyl Ethyl)·5_(5·fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2Η)-yl)pent-3-ene-1-sulfonamide Example 38 (R -N-(l-(3-(cyclopentyloxy)phenyl)ethyl)_5·(5·fluoro-2,4-dioxo- 3.4--hydrogen lanceolate-1(2Η)-yl ) pentane-1-continued amine

S 152528.doc -85- 201121944 實施例39 (R)-N-(l-(3-(環丙基甲氧基)苯基)乙基)_3-(5_氟_2,4_二氧 代-3,4-二氫嘧啶-1(2H)-基)丙烷-1·磺醯胺 實施例40 (R,E)-N-(l-(3-(環丙基曱氧基)苯基)乙基)_5_(5_氟_2,4_二 氧代-3,4-二氫嘧啶-1(2H)-基)戊-3-烯-1-磺醯胺 實施例41 (R)-N-(l-(3·(環丙基甲氧基)笨基)乙基)-5_(5_氟_24_二氧 代-3,4-二氫嘧啶-1(211)-基)戊烷-1-磺醯胺 實施例42 (R)-N-(l-(3-(環丙基甲氧基)苯基)丙基)_3_(5_氟-2,4_二氧 代-3,4-二氫嘧啶-l(2H)-基)丙烷-1-磺醯胺 實施例43 (R>N-(l-(3-(2,2-二氟乙氧基)苯基)乙基)_3_(5•氟 _2,4_二 氧代-3,4-二氫嘴咬_1(211)-基)丙炫<-1-績酿胺 實施例44 (R,E)-N-(l-(3-(2,2-二氟乙氧基)苯基)乙基)_5·(5_ 氟·24_ 二氧代-3,4-二氫嘧基)戊_3_稀·丨_磺醯胺 實施例45 (r)_N-(1-(3-(2,2-二氟乙氧基)苯基)乙基)-5_(5-氟_24·二 氧代-3,4-二氫嘧基)戊烷-1-磺醯胺 152528.doc * 86 - 201121944 [表 19] 實施例 參考 例 编號 目標物 產 率 (%) δ (ppm) 形狀 32S 152528.doc -85- 201121944 Example 39 (R)-N-(l-(3-(cyclopropylmethoxy)phenyl)ethyl)_3-(5-fluoro-2,4-dioxo Generation-3,4-dihydropyrimidin-1(2H)-yl)propane-1·sulfonamide Example 40 (R,E)-N-(l-(3-(cyclopropyldecyloxy)benzene Ethyl)ethyl)_5_(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)pent-3-ene-1-sulfonamide Example 41 (R )-N-(l-(3.(cyclopropylmethoxy)phenyl)ethyl)-5-(5-fluoro-24-dioxo-3,4-dihydropyrimidin-1 (211)- Pentyl-1-sulfonamide Example 42 (R)-N-(l-(3-(cyclopropylmethoxy)phenyl)propyl)_3_(5-fluoro-2,4_2 Oxo-3,4-dihydropyrimidin-l(2H)-yl)propane-1-sulfonamide Example 43 (R>N-(l-(3-(2,2-difluoroethoxy)) Phenyl)ethyl)_3_(5•fluoro-2,4-dioxo-3,4-dihydro-nose _1(211)-yl) propyl sulphate <-1-branched amine Example 44 ( R,E)-N-(l-(3-(2,2-difluoroethoxy)phenyl)ethyl)_5·(5_fluoro·24_dioxo-3,4-dihydrosulfanyl) __3_稀丨丨_sulfonamide Example 45 (r)_N-(1-(3-(2,2-difluoroethoxy)phenyl)ethyl)-5-(5-fluoro-24 Dioxo-3,4-dihydropyridyl)pentane-1-sulfonamide 152528.doc * 86 - 201121944 [Table 19] Example Reference Example No. Target Yield (%) δ (ppm) Shape 32

33 6333 63

12 (CDC13) 0.33-0.39 (2H, m), 0.62-0.70 (2H, ra), 1.25-1.32 (1H, m), 1.53 (3H, d, J = 6.8 Hz), 2.39-2.44 (2H, m), 2. 64-2. 84 (2H, m), 3. 89 (2H, d, J = 6.8 Hz), 4.23 (2H, d, J=6.2Hz), 4.58 (1H, quin, J = 6.8 Hz), 4.81 (1H, brs), 5.44-5.52 (1H, m), 5.59-5.67 (1H. m), 6. 85-7. 10 (3H, m), 7.25 (1H, d, J = 5.1 Hz), 8.75 (1H, brs) 泡狀物質 (CDC1S) 0.33-0.39 (2H, m), 0.62-0.69 (2H, m), 1.22-1.38 (3H, m), 1.53 (3H, d. J = 6.8 Hz), 1.54-1.73 (4H, m), 2. 62-2. 74 (1H, m), 3. 65 (2H, t, J = 6. 5 Hz), 3. 89 (2H, d, J = 7.0 Hz), 4. 57 (1H, quin, J = 6.8 Hz), 4.68 (1H, brs), 4.79 (1H, brs), 6.82-7.11 (3H, m), 7.20 (1H, d, J = 5.7 Hz), 8.60 (1H, brs) 34 6412 (CDC13) 0.33-0.39 (2H, m), 0.62-0.70 (2H, ra), 1.25-1.32 (1H, m), 1.53 (3H, d, J = 6.8 Hz), 2.39-2.44 (2H, m ), 2. 64-2. 84 (2H, m), 3. 89 (2H, d, J = 6.8 Hz), 4.23 (2H, d, J=6.2Hz), 4.58 (1H, quin, J = 6.8 Hz), 4.81 (1H, brs), 5.44-5.52 (1H, m), 5.59-5.67 (1H. m), 6. 85-7. 10 (3H, m), 7.25 (1H, d, J = 5.1 Hz), 8.75 (1H, brs) Foam (CDC1S) 0.33-0.39 (2H, m), 0.62-0.69 (2H, m), 1.22-1.38 (3H, m), 1.53 (3H, d. J = 6.8 Hz), 1.54-1.73 (4H, m), 2. 62-2. 74 (1H, m), 3. 65 (2H, t, J = 6. 5 Hz), 3. 89 (2H, d, J = 7.0 Hz), 4. 57 (1H, quin, J = 6.8 Hz), 4.68 (1H, brs), 4.79 (1H, brs), 6.82-7.11 (3H, m), 7.20 (1H, d, J = 5.7 Hz), 8.60 (1H, brs) 34 64

泡狀物質 (CDClj) 0.32-0. 37 (2H, m), 0.61-0.69 (2H, m), 1.23-1.29 (1H, m), 2.51-2.59 (2H, m), 3.00 (2H, t, J = 7.3Hz), 3.80 (2H, d, J = 7. 0 Hz), 4.23-4.29 (4H, a), 4.69-4.72 (1H, brs), 5.52-5.60 (1H, m), 5.67-5.75 (1H, m), 6.82-6.91 (3H, m), 7.23-7.29 (2H, m) 泡狀物質 152528.doc 87- 201121944 [表 20] 實 施 參考 例 目標物 產 率 lH~NMR 6 (ppm) - 例 編號 (%) 形狀 35 65 2 (CDClj) 0.33-0.37 (2H, a), 0.60-0.66 (2H, π), 1.22-1.30 (1¾ m), 1-39-1.44 (2H, m), 1.64-1.88 (4H, nO, 2.92 (2H, t, J = 7. 6 Hz), 3.67 (2H, t, J = 7. 0 Hz), 3.80 (2H, d, J = 7.0 Hz), 4.25 (2H, d, J = 6.2 Hz), 5.12 (1H, t, J = 6.2 Hz), 6.80-6.85 (1H, m), 6.89-6.92 (2H, m), 7.21-7.27 {2H, m), 9.38 (1H, brs) 泡狀物質 36 66 。^卿 14 (CDC13) 1.53 (3H, d, J = 6.8 Hz), 1.54- 2.10 (10H, m), 2.56-2.74 (2H, m), 3.54- 3,82 (2H, m), 4.54-4.59 (1H, m), 4.74-4.78 (1H, m), 5.22 (1H, brs),' 6.79-6.89 (3H, m), 7.22-7.28 (2H, m) 泡狀物質 37 67 13 (CDClj) 1.54 (3H, d, J = 6.8 Hz), 1.62-1.93 (8R m), 2.36-2.46 (2H, m), 2.64-2.84 (2H, m), 4.21-4.30 (2H, m), 4.54-4.59 (1H, m), 4.75-4.79 (1H, in), 4.99 (1H, d, J = 7.3 Hz), 5.38-5.49 (1H, m), 5.56-5.64 (1H, m), 6.79-6.94 (3H, m), 7.21-7.34 (2H, m), 9.21 (1H, brs) 泡狀物質 38 68 10 (CDClj) 1.26-1.38 (4H, m), 1.53 (3H, d, J = 7.0 Hz), 1.54-1.96 (10H, m), 2.59-2.80 (2H, m), 3.60-3.65 (2H, m), 4.52-4.58 (1H, m), 4.74-4.78 (1H, m), 5.20 (1H, d, J = 7.3 Hz), 6.77-6.90 (3H. m), 7.21-7.27 (2H, m), 9.51 (1H, brs) 泡狀物質 88- 152528.doc 201121944 [表 21] 實施例 參考 例 編號 目標物 產 率 (¾) 'HHNMR 8 (ppm) 形狀 39Foam (CDClj) 0.32-0. 37 (2H, m), 0.61-0.69 (2H, m), 1.23-1.29 (1H, m), 2.51-2.59 (2H, m), 3.00 (2H, t, J = 7.3 Hz), 3.80 (2H, d, J = 7. 0 Hz), 4.23-4.29 (4H, a), 4.69-4.72 (1H, brs), 5.52-5.60 (1H, m), 5.67-5.75 (1H, m), 6.82-6.91 (3H, m), 7.23-7.29 (2H, m) blister substance 152528.doc 87-201121944 [Table 20] Reference example target yield 1H~NMR 6 (ppm) - Example No. (%) Shape 35 65 2 (CDClj) 0.33-0.37 (2H, a), 0.60-0.66 (2H, π), 1.22-1.30 (13⁄4 m), 1-39-1.44 (2H, m), 1.64 -1.88 (4H, nO, 2.92 (2H, t, J = 7. 6 Hz), 3.67 (2H, t, J = 7. 0 Hz), 3.80 (2H, d, J = 7.0 Hz), 4.25 (2H , d, J = 6.2 Hz), 5.12 (1H, t, J = 6.2 Hz), 6.80-6.85 (1H, m), 6.89-6.92 (2H, m), 7.21-7.27 {2H, m), 9.38 ( 1H, brs) blistering material 36 66 . ^卿14 (CDC13) 1.53 (3H, d, J = 6.8 Hz), 1.54- 2.10 (10H, m), 2.56-2.74 (2H, m), 3.54- 3,82 (2H, m), 4.54-4.59 (1H, m), 4.74-4.78 (1H, m), 5.22 (1H, brs), ' 6.79-6.89 (3H, m), 7.22-7.28 (2H, m) blister 37 67 13 (CDClj) 1.54 (3H, d, J = 6.8 Hz), 1.62-1.93 (8R m), 2.36-2.46 (2H, m), 2.64-2.84 (2H, m), 4.21-4.30 (2H, m), 4.54-4.59 ( (1H, m) m), 7.21-7.34 (2H, m), 9.21 (1H, brs) blister 38 68 10 (CDClj) 1.26-1.38 (4H, m), 1.53 (3H, d, J = 7.0 Hz), 1.54- 1.96 (10H, m), 2.59-2.80 (2H, m), 3.60-3.65 (2H, m), 4.52-4.58 (1H, m), 4.74-4.78 (1H, m), 5.20 (1H, d, J = 7.3 Hz), 6.77-6.90 (3H.m), 7.21-7.27 (2H, m), 9.51 (1H, brs) Foaming material 88-152528.doc 201121944 [Table 21] Example Reference Example No. Target Yield (3⁄4) 'HHNMR 8 (ppm) Shape 39

(CDC13) 0.33-0.39 (2H, m), 0.62-0.70 (2H, b). 1.22-1.30 (1H, η), 1.53 (3H, d, J = 7.0 Hz), 1.95-2.05 (2H, m), 2.61-2.72 (2H, m), 3.61-3.70 (1H, m), 3.79-3.82 (3H, ta), 4.53-4.61 (1H, m), 5.01 (1H, brs), 6.81-5.90 (3H, m), 7.24-7.30 (2H, m), 8.91 (1H, brs) 泡狀物質(CDC13) 0.33-0.39 (2H, m), 0.62-0.70 (2H, b). 1.22-1.30 (1H, η), 1.53 (3H, d, J = 7.0 Hz), 1.95-2.05 (2H, m) , 2.61-2.72 (2H, m), 3.61-3.70 (1H, m), 3.79-3.82 (3H, ta), 4.53-4.61 (1H, m), 5.01 (1H, brs), 6.81-5.90 (3H, m), 7.24-7.30 (2H, m), 8.91 (1H, brs) blister

(CDC1,) 0.32-0.38 (2H, m), 0.62-0.69 (2H, m), 1.22-1.30 (1H, m), 1.54 (3H, d, J = 7.0 Hz), 2.37-2.43 (2H, m), 2.66-2.89 (2H, m), 3.80 (2H, d, J = 6. 8 Hz), 4. 22 (2H, d, J = 6. 2 Hz), 4.58 (1H, quin, J = 7. 0 Hz), 4.85 (1H, brs), 5,41-5.48 (lH, m), 5.56-5.66 (1H, m), 6.80-6.84 (1H, in), 6.88-6.92 (2H, m), 7.22-7.29 (2H, m), 8.89 (1H, brs) 泡狀物質 41 71(CDC1,) 0.32-0.38 (2H, m), 0.62-0.69 (2H, m), 1.22-1.30 (1H, m), 1.54 (3H, d, J = 7.0 Hz), 2.37-2.43 (2H, m ), 2.66-2.89 (2H, m), 3.80 (2H, d, J = 6. 8 Hz), 4. 22 (2H, d, J = 6. 2 Hz), 4.58 (1H, quin, J = 7 . 0 Hz), 4.85 (1H, brs), 5,41-5.48 (lH, m), 5.56-5.66 (1H, m), 6.80-6.84 (1H, in), 6.88-6.92 (2H, m), 7.22-7.29 (2H, m), 8.89 (1H, brs) blister 41 71

11 (CDC1S) 0.32-0.37 (2H, m), 0.62-0.68 (2H, m), 1.22-1.36 (3H. m), 1.53 (3H, d, J = 7.0 Hz), 1.54-1.78 (4H, m), 2.61-2.82 (2H, m), 3.60-3.66 (2H, m), 3.80 (2H, d, J = 7.0 Hz), 4.57 {1H, quin, J = 7.3Hz), 4.93 (1H, brs), 6.80-6.84 (1H, m>, 6.89-6.92 (2H, m), 7.19-7.28 (2H, m), 8.95 (1H, brs) 泡狀物質 s. 152528.doc 89. 201121944 [表 22] 152528.doc 實施例 42 72 目標物 產 率(%) δ (ppm) 形狀11 (CDC1S) 0.32-0.37 (2H, m), 0.62-0.68 (2H, m), 1.22-1.36 (3H. m), 1.53 (3H, d, J = 7.0 Hz), 1.54-1.78 (4H, m ), 2.61-2.82 (2H, m), 3.60-3.66 (2H, m), 3.80 (2H, d, J = 7.0 Hz), 4.57 {1H, quin, J = 7.3Hz), 4.93 (1H, brs) , 6.80-6.84 (1H, m>, 6.89-6.92 (2H, m), 7.19-7.28 (2H, m), 8.95 (1H, brs) blister substance s. 152528.doc 89. 201121944 [Table 22] 152528 .doc Example 42 72 Target Yield (%) δ (ppm) Shape

(CDC13) 0.32-0.39 (2H, m), 0.62-0.70 (2H, m), 0.90 (3H, t, J = 7.6 Hz), 1.22-1.32 (1H, m), 1.75-2.01 (2H, m), 2.57-2.68 (2H, m), 3.52-3.64 (1H, m), 3.70-3.79 (2H, m), 3.80 (2H, d, J = 7.0 Hz), 4.26-4.32 (2H, m), 5.08 (1H, brs), 6.80--6.88 (3H, m), 7.21-7.29 (2H, m), 8.98 <1H, brs) 泡狀物質 43 73(CDC13) 0.32-0.39 (2H, m), 0.62-0.70 (2H, m), 0.90 (3H, t, J = 7.6 Hz), 1.22-1.32 (1H, m), 1.75-2.01 (2H, m) , 2.57-2.68 (2H, m), 3.52-3.64 (1H, m), 3.70-3.79 (2H, m), 3.80 (2H, d, J = 7.0 Hz), 4.26-4.32 (2H, m), 5.08 (1H, brs), 6.80--6.88 (3H, m), 7.21-7.29 (2H, m), 8.98 <1H, brs) blister 43 73

(CDC13) 1.53 (3H, d, J = 7.0 Hz), 2.01-2.09 (2H, π), 2.67 {2H, t. J = 7. 3 Hz), 3.63-3.91 (2H, m), 4.21 (2H, td, J = 13.0 Hz, 4.1 Hz), 4.57-4.67 (1H, in), 5.08 (1H, brs), 6.10 (1H, tt, J = 55.1, 4.1 Hz), 6.83-6.99 (3H, m), 7.22-7. 33 (2H, m) 泡狀物質 44 74 17 (CDC13) 1.54 (3H, d, J = 7.0 Hz), 2.39-2.48 (2H, m). 2. 64-2. 88 (2H, m), 4.14-4. 26 (4H, m), 4.62 (1H, quin, J = 7.0 Hz), 4.78 (1H, brs), 5.42-5.50 (1H, m), 5.57-5.66 (1¾ m), 6.10 (1H, tt, J = 55.1, 3. 8 Hz), 6.85 (1H, dd, J = 8. 4, 2.4 Hz), 6.92-6.94 (1H, m), 6.98-7.01 (1H, m), 7.21-7.34 (2H, m), 8.63 (1H, brs) 泡狀物質 90- 201121944 [表 23] 實施例(CDC13) 1.53 (3H, d, J = 7.0 Hz), 2.01-2.09 (2H, π), 2.67 {2H, t. J = 7. 3 Hz), 3.63-3.91 (2H, m), 4.21 (2H , td, J = 13.0 Hz, 4.1 Hz), 4.57-4.67 (1H, in), 5.08 (1H, brs), 6.10 (1H, tt, J = 55.1, 4.1 Hz), 6.83-6.99 (3H, m) , 7.22-7. 33 (2H, m) blister 44 74 17 (CDC13) 1.54 (3H, d, J = 7.0 Hz), 2.39-2.48 (2H, m). 2. 64-2. 88 (2H , m), 4.14-4. 26 (4H, m), 4.62 (1H, quin, J = 7.0 Hz), 4.78 (1H, brs), 5.42-5.50 (1H, m), 5.57-5.66 (13⁄4 m) , 6.10 (1H, tt, J = 55.1, 3. 8 Hz), 6.85 (1H, dd, J = 8. 4, 2.4 Hz), 6.92-6.94 (1H, m), 6.98-7.01 (1H, m) , 7.21-7.34 (2H, m), 8.63 (1H, brs) blister substance 90-201121944 [Table 23] Example

45 7545 75

j-BsiXX^F 13 (CDC1S) 1. 39-1. 44 (2H, m), 1. 54 (3H, d, J = 7. 〇 Hz), 1.55-1.78 (4H, m), 2.66-2.78 (2H, n〇, 3.61-3.67 (2H, m), 4.20 (2H, td, J= 13· 2,4.1 Hz), 4.61 (1H, quin, j =7.0 Hz), 4.81 (1H, d, J = 6.5 Hz), 6.10 (1H, tt, J = 55.4, 4.1 Hz), 6.83-6.87 (1H, m), 6.93-6.95 (1H, m), 6.99 (1H, d, J = 7.6 Hz), 7.17-7.34 (2H, m), 8.62 (1H, brs) 泡狀物質 實施例46 (R)-N-(1_(3_(環丙基甲氧基)_4_氟苯基)乙基)_4_((5_氟_2,4_ 二氧代·3,4·二氫嘧啶-1(2H)-基)甲基)苯磺醯胺 [化 35] 〇j-BsiXX^F 13 (CDC1S) 1. 39-1. 44 (2H, m), 1. 54 (3H, d, J = 7. 〇Hz), 1.55-1.78 (4H, m), 2.66-2.78 (2H, n〇, 3.61-3.67 (2H, m), 4.20 (2H, td, J= 13· 2,4.1 Hz), 4.61 (1H, quin, j =7.0 Hz), 4.81 (1H, d, J = 6.5 Hz), 6.10 (1H, tt, J = 55.4, 4.1 Hz), 6.83-6.87 (1H, m), 6.93-6.95 (1H, m), 6.99 (1H, d, J = 7.6 Hz), 7.17 -7.34 (2H, m), 8.62 (1H, brs) vesicular material Example 46 (R)-N-(1_(3_(cyclopropylmethoxy)_4_fluorophenyl)ethyl)_4_(( 5_Fluoro-2,4_dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)benzenesulfonamide [Chem. 35] 〇

使藉由參考例76所獲得之((R)-4-(溴甲基)-Ν-(1-(3-(環丙 基甲氧基)-4-氟苯基)乙基)笨磺醯胺(12〇 mg)與市售之5_ 氟-2,4-雙(三甲基矽烷氧基)嘧啶(112 mg)溶解於dCE(1.5 mL)中’於室溫下添加碘(13 mg),於95 〇C下加熱回流4小 時。將反應液放置冷卻後’添加水(1() mL)、飽和硫代硫 £ •91 · 152528.doc 201121944 酸鈉水溶液(1.0 mL),利用ι〇%甲醇/氯仿(i〇 mLx3)進行萃 取。利用飽和食鹽水(10 mL)清洗有機層,利用無水硫酸 鈉加以乾燥後,並進行減壓濃縮。利用矽膠管柱層析法 (90%乙酸乙酯/己烷)將殘渣純化,藉此獲得作為泡狀物質 之標記化合物(44.2 mg,產率33°/〇)。 】H-NMR (DMSO-d6) δ (ppm): 0.32-0.36 (2H,m),0.59-0.62 (2H,m),1.14-1.38 (4H,m),3.76 (2H,d,J=7.0 Hz),4.33 (1H, quin, J=7.6 Hz), 4.86 (2H, s), 6.65 (1H, brs), 6.89. 6.96 (2H,m),7.38 (2H, d,J=8.3 Hz),7.62 (2H,d,J=8.3((R)-4-(Bromomethyl)-fluorene-(1-(3-(cyclopropylmethoxy)-4-fluorophenyl)ethyl)) sulfonate obtained by Reference Example 76 Indoleamine (12 mg) and commercially available 5_fluoro-2,4-bis(trimethyldecyloxy)pyrimidine (112 mg) were dissolved in dCE (1.5 mL). Add iodine (13 mg at room temperature) The mixture was heated to reflux for 4 hours at 95 ° C. After the reaction solution was allowed to stand for cooling, 'addition of water (1 () mL), saturated thiosulfuric sulphur sulphur sulphur sulphur sulphur sulphate (1.0 mL), using ι 〇% methanol/chloroform (i〇mLx3) was extracted, and the organic layer was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Ethyl acetate/hexane) The residue was purified, whereby a labeled compound (44.2 mg, yield 33 ° / 〇) was obtained as a blister material.] H-NMR (DMSO-d6) δ (ppm): 0.32-0.36 ( 2H,m),0.59-0.62 (2H,m),1.14-1.38 (4H,m), 3.76 (2H,d,J=7.0 Hz), 4.33 (1H, quin, J=7.6 Hz), 4.86 (2H , s), 6.65 (1H, brs), 6.89. 6.96 (2H, m), 7.38 (2H, d, J = 8.3 Hz), 7.62 (2H, d, J = 8.3

Hz), 8.14-8.20 (2H, m), 11.88 (1H, brs) 實施例47〜實施例5〇 以下之化合物係由各個參考例77〜8〇中獲得之化合物, 依據實施例46之方法而合成。結果示於以下表。 實施例47 (R)-N-(l-(3-(環戊氧基)苯基)乙基)_4_((5_氟_2,4二氧代_ 3,4-二氫嘧啶-1(211)_基)曱基)苯磺醯胺 實施例48 (R)_N-(1-(3-(環丙基甲氧基)苯基)乙基)-4-((5-氟-2,4-二 氧代-3,4-二氫嘧啶-U2H)-基)甲基)笨磺醯胺 實施例49 (R)-N_(1_(3·(環丙基甲氧基)苯基)丙基氟_2,4·二 氧代_3,4·二氫嘧啶_1(211)_基)甲基)苯磺醯胺 實施例5 0 (R) N (1 (3-(2,2-二氟乙氧基)笨基)乙基)_4_((5_氣·2木 152528.doc •92- 201121944二氧代-3,4-二氫嘧啶-1(2H)-基)曱基)笨磺醯胺 [表 24] 實施例 參考例編號 目標物 產率 (%) Ή-NMR δ (ppm) 形狀 47 77Hz), 8.14-8.20 (2H, m), 11.88 (1H, brs) The compounds of the following Examples 47 to 5 are the compounds obtained in each of Reference Examples 77 to 8, according to the method of Example 46. synthesis. The results are shown in the table below. Example 47 (R)-N-(l-(3-(Cyclopentyloxy)phenyl)ethyl)_4_((5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1 (211)-yl) mercapto) benzenesulfonamide Example 48 (R)_N-(1-(3-(cyclopropylmethoxy)phenyl)ethyl)-4-((5-fluoro- 2,4-dioxo-3,4-dihydropyrimidine-U2H)-yl)methyl) oxasulfonamide Example 49 (R)-N_(1_(3·(cyclopropylmethoxy)benzene) Phenylfluoro-2,4·dioxo-3,4-dihydropyrimidin-1(211)-yl)methyl)benzenesulfonamide Example 5 0 (R) N (1 (3-( 2,2-difluoroethoxy)phenyl)ethyl)_4_((5_气·2木152528.doc •92- 201121944 dioxo-3,4-dihydropyrimidin-1(2H)-yl曱 )) oxasulfonamide [Table 24] Example Reference Example No. Target Yield (%) Ή-NMR δ (ppm) Shape 47 77

ΐ^〇Ύ) (CDC1S) 1.45 (3H, d, J = 6.8 Hz), 1.53-1.64 (2H, m), 1.71-1.90 (6H, m), 4.49 (1H, quin, J = 6.9 Hz), 4.62-4.68 (1H, m), 4.75 (1H, d, J = 7.1Hz), 4.88 (2H, s), 6.57-6.66 (3H, m), 7.03 (1H, t, J = 8.1 Hz), 7.15 (1H, d, J = 5.4 Hz), 7. 25-7. 29 (2H, m), 7. 72 (2H, d, J = 8. 4 Hz). 8.29 (1H, brs) 泡狀物質 48 78 12ΐ^〇Ύ) (CDC1S) 1.45 (3H, d, J = 6.8 Hz), 1.53-1.64 (2H, m), 1.71-1.90 (6H, m), 4.49 (1H, quin, J = 6.9 Hz), 4.62-4.68 (1H, m), 4.75 (1H, d, J = 7.1Hz), 4.88 (2H, s), 6.57-6.66 (3H, m), 7.03 (1H, t, J = 8.1 Hz), 7.15 (1H, d, J = 5.4 Hz), 7. 25-7. 29 (2H, m), 7. 72 (2H, d, J = 8. 4 Hz). 8.29 (1H, brs) blister 48 78 12

(CDC13) 0.31-0.34 (2H, m), 0.60-0.67 (2H, m), 1.22-1.30 (1H, m), 1.43 (3H, d, J = 6.8 Hz), 3.69 (2H, d, J = 7.0Hz), 4.47 (1H, quin, J = 7. 0 Hz), 4. 89 (2H, s), 5.10 (1H, d, J = 7.3Hz), 6.51-6.59 (3H, m), 6.99-7.07 (1H, a), 7.16-7.27 (3H, in), 7. 69 (2H, d, J = 8. 4 Hz), 9. 05 (1H, brs) 泡狀物質 49 79 (CDC13) 0.29-0.34 (2H, m), 0.60-0.67 (2H, m), 0.82 (3H, t, J = 7.3 Hz), 1.18-1.28 (1H, m), 1.68-1.83 (2H, m), 3.66 (2H, d, J = 6.8 Hz), 4.20 (1H, q, J = 7. 3 Hz), 4.86 (2H, s), 5.07 (1H, d, J = 7.6 Hz), 6.50-6.65 (3H, m), 6.99 (1H, t, J = 7.8 Hz), 7.15-7.24 (3H. m), 7.63 (2H, d, J = 8.4Hz), 8.90 (1H, brs) 泡狀物質 s 152528.doc -93- 201121944 [表 25] 實施例 參考 例 編號 目標物 產率g *H-NMR δ (ppm)(CDC13) 0.31-0.34 (2H, m), 0.60-0.67 (2H, m), 1.22-1.30 (1H, m), 1.43 (3H, d, J = 6.8 Hz), 3.69 (2H, d, J = 7.0Hz), 4.47 (1H, quin, J = 7. 0 Hz), 4. 89 (2H, s), 5.10 (1H, d, J = 7.3Hz), 6.51-6.59 (3H, m), 6.99- 7.07 (1H, a), 7.16-7.27 (3H, in), 7. 69 (2H, d, J = 8. 4 Hz), 9. 05 (1H, brs) blister 49 79 (CDC13) 0.29- 0.34 (2H, m), 0.60-0.67 (2H, m), 0.82 (3H, t, J = 7.3 Hz), 1.18-1.28 (1H, m), 1.68-1.83 (2H, m), 3.66 (2H, d, J = 6.8 Hz), 4.20 (1H, q, J = 7. 3 Hz), 4.86 (2H, s), 5.07 (1H, d, J = 7.6 Hz), 6.50-6.65 (3H, m), 6.99 (1H, t, J = 7.8 Hz), 7.15-7.24 (3H.m), 7.63 (2H, d, J = 8.4Hz), 8.90 (1H, brs) blister substance 152528.doc -93- 201121944 [Table 25] Example Reference Example No. Target Yield g * H-NMR δ (ppm)

(CDCl,) 1.45 (3H, d, J = 6.9Hz), 4.05 (2H, td, 13.2, 4.5 Hz), 4.53 (iH, quin> J = 6·9ΗΖ), 4.80 (1H,brs>, 4 肋(2h 80 ^ίχΎ(CDCl,) 1.45 (3H, d, J = 6.9Hz), 4.05 (2H, td, 13.2, 4.5 Hz), 4.53 (iH, quin> J = 6·9ΗΖ), 4.80 (1H,brs>, 4 ribs (2h 80 ^ίχΎ

S), 6 05 (1H. U,J = SS.2, 4.lHz) 6·δ6 (1H, s), 6.67-6.77 (2H, lA (1H, t, J = 8.1 HZ), 7.17 (ih} d&gt; j 6.4 HZ), 7.25-7.28 (2H, m)&gt; 7[&amp;g {m 8-23JIH. brs) 泡狀物質 實施例51〜實施例53 以下之化合物係由各個參考例82〜84中獲得之化合物, 依據實施例1之方法而合成^結果示於以下表。 實施例5 1 3-(環丙基甲氧基)_Ν-(5-((5-氟·2,4-二氧代_3,4-二氫嘧 咬-1(2Η)-基)甲氧基)-2-曱基戊烷-2-基)苯磺醯胺 實施例52 3-(2,2-一氟乙氧基)_n-(5-((5 -氟二氧代-3,4-二氫0f 咬-1(2H)-基)甲氧基)-2-曱基戊烧-2-基)笨確酿胺 實施例53 3-(環戊氧基)-N-(5-((5-氟-2,4-二氧代_3,4-二氫嘴咬-1(2H)-基)甲氧基)-2-曱基戊烷-2-基)苯續酿胺 152528.doc •94· 201121944 [表 26] 實施例 參考例編號 目標物 產率 (%) Ή-NMR δ (pfMn) 形狀 51 82 。女丄W U°v^V^|~N-S—^ f! 49 (DMSO-dg) 0.30-0. 36 (2H, m), 0.53-0.60 (2H, η) 1.02 (6Η, s), 1.19-1.25〈1Η, m) 1.32-1.45 (4H, m), 3.27-3.33 (2H, m) 3.85 (2H, d, J = 6.9Hz), 4.97 (2H, s) 7.09-7.13 (1H, m), 7.30-7.45 (4H, m) 8.08 {1H, d, J = 6.4 Hz), 11.83 (1H brs) 泡狀物質 52 83 (DMS0-d6) 1.03 (BH, s). 1.33-1.51 (4H, m), 3.28-3.33 (2H, m), 4.39 (2H, td, J = 14.7, 3.5 Hz), 4.99 &lt;2H, s), 6.41 (1H, tt, J=54.4, 3.5 Hz), 7.21-7.25 (1H, m), 7.40-7.54 (4H, m), 8.09 (1H, d, J = 6.6 Hz), 11.82 (1H, brs) 無色橡膠狀物質 53 84S), 6 05 (1H. U, J = SS.2, 4.lHz) 6·δ6 (1H, s), 6.67-6.77 (2H, lA (1H, t, J = 8.1 HZ), 7.17 (ih } d&gt; j 6.4 HZ), 7.25-7.28 (2H, m)&gt;7[&amp;g {m 8-23JIH. brs) Foaming substance Examples 51 to 53 The following compounds are each of the reference examples 82. The compound obtained in ~84 was synthesized according to the method of Example 1. The results are shown in the following table. Example 5 1 3-(cyclopropylmethoxy)-indole-(5-((5-fluoro·2,4-dioxo-3,4-dihydropyrimidine-1(2Η)-yl)) Oxy)-2-decylpentan-2-yl)benzenesulfonamide Example 52 3-(2,2-Fluoroethoxy)_n-(5-((5-fluorodioxo-3) , 4-dihydro 0f ace-1 (2H)-yl) methoxy)-2-mercaptobutyl-2-yl) stilbene amine Example 53 3-(cyclopentyloxy)-N-( 5-((5-Fluoro-2,4-dioxo-3,4-dihydromouthbit-1(2H)-yl)methoxy)-2-decylpentan-2-yl)benzene continued Amine amine 152528.doc •94·201121944 [Table 26] Example Reference Example No. Target Yield (%) Ή-NMR δ (pfMn) Shape 51 82 .丄WU°v^V^|~NS—^ f! 49 (DMSO-dg) 0.30-0. 36 (2H, m), 0.53-0.60 (2H, η) 1.02 (6Η, s), 1.19-1.25 <1Η, m) 1.32-1.45 (4H, m), 3.27-3.33 (2H, m) 3.85 (2H, d, J = 6.9Hz), 4.97 (2H, s) 7.09-7.13 (1H, m), 7.30 -7.45 (4H, m) 8.08 {1H, d, J = 6.4 Hz), 11.83 (1H brs) blister 52 83 (DMS0-d6) 1.03 (BH, s). 1.33-1.51 (4H, m), 3.28-3.33 (2H, m), 4.39 (2H, td, J = 14.7, 3.5 Hz), 4.99 &lt;2H, s), 6.41 (1H, tt, J=54.4, 3.5 Hz), 7.21-7.25 (1H , m), 7.40-7.54 (4H, m), 8.09 (1H, d, J = 6.6 Hz), 11.82 (1H, brs) colorless rubbery substance 53 84

49 (DMSO-de) 1.03 (6H, s), 1.31-1.49 (4H, ro), 1,50-1.76 (6H, m), 1.83-2.02 (2H, m), 3.28-3.32 (2H, m), 4.82-4.86 (1H, m), 4.98 (2H, s), 7.07-7.11 (1H, m), 7. 29-7. 45 (4H, m), 8. 09 (1H, d. J = 6. 4 Hz), 11.84 (1H, brs) 泡狀物質 £ 152528.doc 95 · 201121944 實施例54〜實施例56 以下之化合物係由各個參考例8 5 s &gt;可例85〜87中獲得之化合物, 依據實施例46之方法而合成。結果示於以下表。 實施例54 3-(環丙基甲氧基)喜(2·(4_((5.氟_2,4_二氧代_3,4·二氣鳴 咬-1(2Η)-基)甲基)苯基)丙烷-2-基)苯績酿胺 實施例55 3-(2,2·二氟乙氧基)-Ν-(2-(4-((5-氟-2,4-二氧代 _3,4_二氫 嘴咬-1(2Η)-基)曱基)苯基)丙烧-2-基)笨績酿胺 實施例5 6 ,-(環戊氧基卜:^-^-^^^-氟-之一-二氧代^’心二氫喷唆-1(2Η)-基)曱基)苯基)丙烷-2-基)笨磺醯胺 152528.doc 96- 201121944 [表 27] 實 施 例 參考 例 編號 目標物 產 率 JH-NMR δ (ppra) (¾) 形狀 54 85 40 (DMSO-de) 0.30-0.36 (2H, m), 0.54-0.61 (2H, m), 1.16-1.27 (1H, m), 1.45 (6H, s), 3.78 (2H, d, J = 7. 1 Hz), 4.72 (2H, s), 6.96-7.00 (1H, m), 7.06-7.10 (4H, m), 7.21-7.28 (3H, m), 8.02 (1H, brs), 8.15 (1H, d( J = 6.8 Hz), 11.85 (1H, brs) 泡狀物質. 55 86 乂rF h9_y=^T 10 (DMS〇-d6) 1.47 (6H, s), 4.32 (2H, td, J = 14.7, 3.5 Hz), 4.73 (2H, s), 6.40 (1H, tt, J = 54.2, 3,5 Hz), 7.07-7.18 (5H, ra), 7.24-7.34 (3H, m), 8.06 (1H, brs), 8. 16 (1H, d, J = 6.8 Hz), 11.81 (1H, brs) 泡狀物質 56 87 。永 h-i-d ο 1~’ 31 (DMSO-de) 1.45 (6H, s), 1.51-1.72 (6H, n〇, 1.83-1.97 (2H, m), 4.72 (2H, s), 4.74-4.78 (1H, m), 6.92-6.96 (1H. m), 7.02-7.10 (4H, m), 7.19-7.28 (3H, m), 8.04 (1H, brs), 8. 15 (1H, d, J = 6.8 Hz), 11.85 (1H, brs) 泡狀物質 實施例57〜實施例59 以下之化合物係由各個參考例88〜90中獲得之化合物, 依據實施例46之方法而合成。結果示於以下表。 實施例57 3-(環丙基甲氧基)-&gt;^-(2-(6-((5-氟-2,4-二氧代-3,4-二氫嘧 -97- 152528.doc 201121944 啶-1(2H)-基)甲基)吼啶-3-基)丙烷-2·基)苯磺醯胺 實施例58 3-(2,2-二氟乙氧基)-义(2-(6-((5-氟_2,4·二氧代 _34_ 二氣 嘧啶-1(2Η)-基)曱基)吼啶-3-基)丙烷-2-基)苯磺醯胺 實施例59 3-(環戊氧基)-Ν-(2-(6·((5-氟-2,4-二氧代-3,4-二氫嘧啶-1(2Η)-基)甲基)《比唆-3-基)丙烧-2-基)笨續酿胺 152528.doc 98 - 201121944 8 2 表 實施例 參考例編號 目標物 產率 (%) HFNMR δ (ppra) 形狀 57 8849 (DMSO-de) 1.03 (6H, s), 1.31-1.49 (4H, ro), 1,50-1.76 (6H, m), 1.83-2.02 (2H, m), 3.28-3.32 (2H, m) , 4.82-4.86 (1H, m), 4.98 (2H, s), 7.07-7.11 (1H, m), 7. 29-7. 45 (4H, m), 8. 09 (1H, d. J = 6 4 Hz), 11.84 (1H, brs) Foaming substance £152528.doc 95 · 201121944 Examples 54 to 56 The following compounds are the compounds obtained in each of Reference Examples 8 5 s &gt; Examples 85 to 87. And synthesized according to the method of Example 46. The results are shown in the table below. Example 54 3-(cyclopropylmethoxy)H(2.(4.(5.Fluoro-2,4-dioxo-3,4·2 gas-bite-1(2Η)-yl)methyl) Phenyl)propan-2-yl)benzene-based amine example 55 3-(2,2·difluoroethoxy)-fluorene-(2-(4-((5-fluoro-2,4-) Oxo-3,4_dihydrobine bite-1(2Η)-yl)decyl)phenyl)propan-2-yl) stupid amine Example 5 6 -(cyclopentyloxybu:^ -^-^^^-Fluoro-mono-dioxo^'heart dihydro squirt-1(2Η)-yl)decyl)phenyl)propan-2-yl) oxasulfonamide 152528.doc 96 - 201121944 [Table 27] Example Reference Example No. Target Yield JH-NMR δ (ppra) (3⁄4) Shape 54 85 40 (DMSO-de) 0.30-0.36 (2H, m), 0.54-0.61 (2H, m) , 1.16-1.27 (1H, m), 1.45 (6H, s), 3.78 (2H, d, J = 7. 1 Hz), 4.72 (2H, s), 6.96-7.00 (1H, m), 7.06-7.10 (4H, m), 7.21-7.28 (3H, m), 8.02 (1H, brs), 8.15 (1H, d( J = 6.8 Hz), 11.85 (1H, brs) blister substance. 55 86 乂rF h9_y= ^T 10 (DMS〇-d6) 1.47 (6H, s), 4.32 (2H, td, J = 14.7, 3.5 Hz), 4.73 (2H, s), 6.40 (1H, tt, J = 54.2, 3,5 Hz), 7.07-7.18 (5H, ra), 7.24-7.34 (3H, m), 8.06 (1H, br s), 8. 16 (1H, d, J = 6.8 Hz), 11.81 (1H, brs) blistering material 56 87. 永hid ο 1~' 31 (DMSO-de) 1.45 (6H, s), 1.51- 1.72 (6H, n〇, 1.83-1.97 (2H, m), 4.72 (2H, s), 4.74-4.78 (1H, m), 6.92-6.96 (1H. m), 7.02-7.10 (4H, m), 7.19-7.28 (3H, m), 8.04 (1H, brs), 8. 15 (1H, d, J = 6.8 Hz), 11.85 (1H, brs) Foaming material Example 57 to Example 59 The following compounds are The compound obtained in each of Reference Examples 88 to 90 was synthesized according to the method of Example 46. The results are shown in the table below. Example 57 3-(cyclopropylmethoxy)-&gt;^-(2-(6-((5-fluoro-2,4-dioxo-3,4-dihydropyrimidine-97- 152528. Doc 201121944 pyridine-1(2H)-yl)methyl)acridin-3-yl)propan-2-yl)benzenesulfonamide Example 58 3-(2,2-difluoroethoxy)-yi 2-(6-((5-fluoro_2,4·dioxo-34-dioxapyrimidin-1(2Η)-yl)indolyl)acridin-3-yl)propan-2-yl)benzenesulfonate Amine Example 59 3-(Cyclopentyloxy)-indole-(2-(6.(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2Η)-yl) Methyl) "Compound-3-yl)propan-2-yl) Stupid amine 152528.doc 98 - 201121944 8 2 Table Examples Reference Example No. Target Yield (%) HFNMR δ (ppra) Shape 57 88

12 (CD3OD) 0.23-0.33 (2H, m), 0.50-0.57 (2H, m), 1.10- 1.21 (1H, m), 1.51 (6H, s), 3.71 (2H, d, J = 6.9 Hz), 4.88 (2H, s), 6.87-6.91 (1H, m)s 6.97-7.05 (3H, m), 7.11- 7.16 (1H, m), 7.60 (1H, dd, J = 2.5, 8. 2 Hz), 7.76 (lH, d, J=6.1Hz), 8.33 (1H, d, J = 2.3 Hz) 黃色橡膠狀物質 58 89 4.412 (CD3OD) 0.23-0.33 (2H, m), 0.50-0.57 (2H, m), 1.10- 1.21 (1H, m), 1.51 (6H, s), 3.71 (2H, d, J = 6.9 Hz), 4.88 (2H, s), 6.87-6.91 (1H, m)s 6.97-7.05 (3H, m), 7.11- 7.16 (1H, m), 7.60 (1H, dd, J = 2.5, 8. 2 Hz), 7.76 (lH, d, J=6.1Hz), 8.33 (1H, d, J = 2.3 Hz) Yellow rubbery material 58 89 4.4

(cd3〇d) 1.62 (6H, s), 4.23 (2H, td, J = 13.9, 3.9 Hz), 4.90 (2H, s), 6.33 (1H, tt, J = 54,9, 3.9 Hz), 7.05-7.08 (1H, m), 7. 10-7.13 (2H, m), 7.15-7.18 (1H, m), 7. 28 (1H, t, J = 8.1 Hz), 7. 69 (1H, dd, J = 2. 4, 8.1 Hz), 7. 84 (1H, d, J = 6. 3 Hz), 8.42 (1H, d, J = 2.0 Hz) 黃色橡膠狀物質 59 12 (CD,OD) 1.60 (6H, s), 1.63-1.67 (2H, m), 1.72-1.83 (4H, m), L 87-1. 99 (2H, m), 4.76-4.79 (1H, m), 4.90 (2H, s), 6.94-6.97 (1H, m), 7.04-7.15 (3H, m), 7.21 (1H, t, J = 8.1Hz), 7.71 (1H, dd, J = 2.4, 8.1 Hz), 7.84 (1H, d, J = 6.1 Hz), 8.44 (1H, d, J = 2.0 Hz) 黃色橡膠狀物質 實施例60(S)-5-氟-1-(4-(2-( 羥基 丁基)嘧啶-2,4(lH,3H)-[化 36] 苯基曱基比咯啶-1-基)-4_側氧基 酮 152528.doc -99- 201121944 ο(cd3〇d) 1.62 (6H, s), 4.23 (2H, td, J = 13.9, 3.9 Hz), 4.90 (2H, s), 6.33 (1H, tt, J = 54, 3.9 Hz), 7.05 -7.08 (1H, m), 7. 10-7.13 (2H, m), 7.15-7.18 (1H, m), 7. 28 (1H, t, J = 8.1 Hz), 7. 69 (1H, dd, J = 2. 4, 8.1 Hz), 7. 84 (1H, d, J = 6. 3 Hz), 8.42 (1H, d, J = 2.0 Hz) Yellow rubbery substance 59 12 (CD, OD) 1.60 ( 6H, s), 1.63-1.67 (2H, m), 1.72-1.83 (4H, m), L 87-1. 99 (2H, m), 4.76-4.79 (1H, m), 4.90 (2H, s) , 6.94-6.97 (1H, m), 7.04-7.15 (3H, m), 7.21 (1H, t, J = 8.1Hz), 7.71 (1H, dd, J = 2.4, 8.1 Hz), 7.84 (1H, d , J = 6.1 Hz), 8.44 (1H, d, J = 2.0 Hz) Yellow rubbery material Example 60(S)-5-fluoro-1-(4-(2-(hydroxybutyl)pyrimidine-2, 4(lH,3H)-[Chemical 36]phenylphenylpyrrolidin-1-yl)-4_sideoxy ketone 152528.doc -99- 201121944 ο

使利用文獻(Med. Chem. Res.,10,390-403 (2001))中記 載之方法所獲得之4-(5-氟-2,4-二氧代-3,4-二氫嘧啶-1(2H)-基)丁酸(25 mg)溶解於二氣曱烷(2.5 mL)中,添加1-乙基-3-(3-二甲基胺基丙基)碳二醯亞胺鹽酸鹽(以下為 EDC.HC1,34 mg)、1-羥基苯并三唑(以下為HOBt,23 mg)、及可容易獲取之(S)-二苯基(》比咯啶-2-基)甲醇(56 mg) ’於室溫下攪拌12小時。將反應液減壓濃縮後,利用 矽膠管柱層析法(90%乙酸乙酯/己烷)將殘渣純化,藉此獲 得作為泡狀物質之標記化合物(23 mg,產率46%)。 'H-NMR (CDC13) δ (ppm): 0.83-0.90 (1H, m), 1.55-1.70 (3H, m), 1.96-2.11 (2H, m), 2.44-2.48 (2H, m), 3.06-3.12 (1H, m), 3.33-3.42 (1H, m), 4.32-4.44 (2H, m), 5.21-5.25 (1H, m), 6.73 (1H, brs), 7.26-7.33 (9H, m), 7.40-7.43 (2H, m), 7.62 (1H, brs) 以下之化合物係依據實施例60之方法而合成9結果示於 以下表。 實施例61 (S)· 1-(4-(2-(雙(4-氟苯基)(羥基)曱基比咯啶-1-基)-4-側氧 152528.doc •100- 201121944 基丁基)-5-氟嘧啶-2,4(1Η,3Η)-:_ [表 29] 實 施 目標物 產 率 ^-NMR δ (pfHn) 例 (%) 形狀 61 〇λϊ^λνο 38 (CDC13) 0.85-0.90 (1H, m), 1.55-1.70 (3H, m), 1.87-1.95 (1H, m), 2.02-2.11 (1H, m), 2.44-2.48 (2H, m), 3.12-3.18 (1H, m), 3.42-3.45 (1H, m), 4.32-4.44 (2H, m), 5.13-5.18 (1H, m), 6.85 (1H, brs), 6.94-7.04 (4H, m), 7.27-7.40 (5H, ra), 7.64 (1H, brs) 泡狀物質 比較例1 卜((2-(三苯曱氧基)乙氧基)曱基)嘧啶-2,4-( 1H,3H)-二酮 [化 37] 〇4-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidine-obtained by the method described in the literature (Med. Chem. Res., 10, 390-403 (2001)) 1(2H)-yl)butyric acid (25 mg) was dissolved in dioxane (2.5 mL), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide salt was added. Acid salt (hereinafter EDC.HC1, 34 mg), 1-hydroxybenzotriazole (hereinafter referred to as HOBt, 23 mg), and readily available (S)-diphenyl ("pyrrolidin-2-yl) Methanol (56 mg) ' was stirred at room temperature for 12 hours. After the reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (yield: 90% ethyl acetate/hexane) to afford the title compound (23 mg, yield 46%). 'H-NMR (CDC13) δ (ppm): 0.83-0.90 (1H, m), 1.55-1.70 (3H, m), 1.96-2.11 (2H, m), 2.44-2.48 (2H, m), 3.06- 3.12 (1H, m), 3.33-3.42 (1H, m), 4.32-4.44 (2H, m), 5.21-5.25 (1H, m), 6.73 (1H, brs), 7.26-7.33 (9H, m), 7.40-7.43 (2H, m), 7.62 (1H, brs) The following compounds were synthesized according to the method of Example 60. The results are shown in the following table. Example 61 (S)· 1-(4-(2-(bis(4-fluorophenyl)(hydroxy)decylpyrrolidin-1-yl)-4-sideoxy 152528.doc •100- 201121944 Butyl)-5-fluoropyrimidine-2,4(1Η,3Η)-:_ [Table 29] Yield of target product ^-NMR δ (pfHn) Example (%) Shape 61 〇λϊ^λνο 38 (CDC13) 0.85 -0.90 (1H, m), 1.55-1.70 (3H, m), 1.87-1.95 (1H, m), 2.02-2.11 (1H, m), 2.44-2.48 (2H, m), 3.12-3.18 (1H, m), 3.42-3.45 (1H, m), 4.32-4.44 (2H, m), 5.13-5.18 (1H, m), 6.85 (1H, brs), 6.94-7.04 (4H, m), 7.27-7.40 ( 5H, ra), 7.64 (1H, brs) Foaming material Comparative Example 1 ((2-(triphenylphosphonium)ethoxy)indolyl)pyrimidine-2,4-(1H,3H)-dione [化37] 〇

利用國際公開W02005-065689號(專利文獻1)中記載之方 法合成。 比較例2 4-(2,4-二氧代-3,4-二氫嘧啶-1(211)-基)-:^-羥基-2-(!^-曱 基-4-苯氧基苯基磺醯胺)丁醯胺 [化 38] 152528.doc - 101 - 201121944It is synthesized by the method described in International Publication WO2005-065689 (Patent Document 1). Comparative Example 2 4-(2,4-dioxo-3,4-dihydropyrimidin-1(211)-yl)-:^-hydroxy-2-(!^-mercapto-4-phenoxybenzene Sulfolamine) butanamine [Chem. 38] 152528.doc - 101 - 201121944

利用日本專利特開2002-284686號公報中記載之方法合 成。 試驗例1人dUTP酶抑制作用 藉由利用下述方法測定來自[5-3H]脫氧尿苷三磷酸(以下 為[5-3H]dUTP)之[5-3H]脫氧尿苷單磷酸(以下為[5_ 3H]dUMP)的生成而求出本發明之化合物對於人dUTP酶之 抑制活性。 即,使 1 μΜ dUTP(含有 588 Bq/mL 之[5-3H]dUTP)0.02 mL、0,2 Μ三羥甲基胺基曱烷緩衝液(pH值為7.4)0.05 mL、16 mM氯化鎂 0.05 mL、20 mM 2-巯基乙醇0.02 mL、 1 %源自胎牛血清之白蛋白水溶液0.02 mL、各種濃度之受 檢化合物溶液或作為對照之純水0.02 mL及使用大腸菌而 表現並純化的人dUTP酶溶液0.02 mL總計0.2 mL反應於 37°C下15分鐘。反應後立即於100°C下加熱1分鐘,使反應 停止,以15000 rpm進行2分鐘之離心分離。離心分離後, 使用 Atlantis dC 1 8 管柱(Waters 公司製造,4.6x250 mm), 利用高速液相層析法(島津製作所製造,Prominence),對 所獲得之上清液之一部分(15 0 μ!〇進行分析。以流速0.8 mL/min自流動相A(10 mM填酸二氫錦(pH值6.7)、10 mM四 丁基銨、0.25%甲醇)與流動相B(50 mM磷酸二氫鉀(pH值 152528.doc -102- 201121944 6.7)、5·6 mM四丁基銨、30%甲醇)之4 : 6混合液向流動相 B流動30分鐘而形成濃度梯度,藉此進行溶離。於溶離液 中以1 : 2之比率混合閃爍體(帕金艾爾瑪公司製造, Ultima-Flo AP),測定利用 Radiomatic Flow Scintillation Analyzed帕金艾爾瑪公司製造,525TR)生成之[5-3H]dUMP(RT 10.2 min)之放射活性。 受檢化合物之抑制活性係利用下式求出,將抑制50%之 藉由人dUTP酶所生成之[5-3H]dUMP的量之受檢液之濃度 以Ι(:5()(μΜ)之形式示於表30 : [數1] 抑制率(%)= 1 受檢液存在下之[5-3H]dUMP量(dpm) 1一 ------- X100 對照之[5-3H]dUMP量(dpm) 以下之表中表示人dUTP酶抑制活性資料。 152528.doc 103- 201121944 [表 30] 實施例編號 Ι〇5〇 (μΜ) 實施例編號 ICS0 UM) 1 2.71 32 0.12 2 0. 50 33 0.18 3 4.14 34 1.30 4 1.96 35 2. 51 5 0. 28 36 5. 73 6 0.19 37 0. 36 7 0.16 38 0.46 8 0.57 40 0. 29 9 0.19 41 1. 15 10 0. 39 42 3. 90 11 0.31 43 8.99 12 7.83 44 0. 23 13 8.61 45 0.44 14 1.82 46 2.19 15 2.67 47 4. 52 16 1.70 48 6. 85 17 2.47 49 5.34 18 3. 56 50 6.10 19 1.08 51 0. 78 20 3.06 52 1.48 21 3· 98 53 0.90 22 2.08 54 0. 89 23 2,05 55 1.07 24 2.23 56 0.41 25 3. 93 57 0. 50 26 3.83 58 0. 78 27 6.11 59 0. 25 28 1.73 60 7.26 29 7. 62 61 8.39 30 2.61 比較例1 185 31 2.71 比較例2 97.2 152528.doc 104-It is synthesized by the method described in Japanese Laid-Open Patent Publication No. 2002-284686. Test Example 1 Human dUTP enzyme inhibition [5-3H] deoxyuridine monophosphate derived from [5-3H]deoxyuridine triphosphate (hereinafter referred to as [5-3H]dUTP) by the following method (hereinafter referred to as The inhibitory activity of the compound of the present invention on the human dUTP enzyme was determined by the formation of [5_3H]dUMP). That is, 1 μΜ dUTP ([5-3H]dUTP containing 588 Bq/mL) 0.02 mL, 0,2 Μ trishydroxymethylamino decane buffer (pH 7.4) 0.05 mL, 16 mM magnesium chloride 0.05 mL, 20 mM 2-mercaptoethanol 0.02 mL, 1% fetal bovine serum albumin solution 0.02 mL, various concentrations of test compound solution or 0.02 mL of pure water as a control, and human dUTP expressed and purified using Escherichia coli The enzyme solution 0.02 mL total 0.2 mL was reacted at 37 ° C for 15 minutes. Immediately after the reaction, the mixture was heated at 100 ° C for 1 minute to stop the reaction, and centrifuged at 15,000 rpm for 2 minutes. After centrifugation, an Atlantis dC 1 8 column (manufactured by Waters, 4.6 x 250 mm) was used, and high-performance liquid chromatography (manufactured by Shimadzu Corporation, Prominence) was used to obtain a fraction of the supernatant (15 0 μ! 〇Analysis was carried out at a flow rate of 0.8 mL/min from mobile phase A (10 mM acid dihydrogen (pH 6.7), 10 mM tetrabutylammonium, 0.25% methanol) and mobile phase B (50 mM potassium dihydrogen phosphate). (pH 152528.doc -102 - 201121944 6.7), 5·6 mM tetrabutylammonium, 30% methanol) The 4:6 mixture was flowed to the mobile phase B for 30 minutes to form a concentration gradient, thereby performing elution. The scintillant (Ultima-Flo AP, manufactured by Parkin Elmar) was mixed in a ratio of 1:2 in the eluent, and the [5-3H] was produced by the Radiomatic Flow Scintillation Analyzed, 525TR). Radioactivity of dUMP (RT 10.2 min). The inhibitory activity of the test compound is determined by the following formula, and the concentration of the test liquid which inhibits 50% of the amount of [5-3H]dUMP produced by the human dUTP enzyme is Ι(:5()(μΜ) The form is shown in Table 30: [Number 1] Inhibition rate (%) = 1 [5-3H]dUMP amount (dpm) in the presence of test liquid 1 -------- X100 Control [5-3H ]dUMP amount (dpm) The following table shows human dUTP enzyme inhibitory activity data. 152528.doc 103-201121944 [Table 30] Example No. Ι〇5〇 (μΜ) Example No. ICS0 UM) 1 2.71 32 0.12 2 0 50 33 0.18 3 4.14 34 1.30 4 1.96 35 2. 51 5 0. 28 36 5. 73 6 0.19 37 0. 36 7 0.16 38 0.46 8 0.57 40 0. 29 9 0.19 41 1. 15 10 0. 39 42 3 90 11 0.31 43 8.99 12 7.83 44 0. 23 13 8.61 45 0.44 14 1.82 46 2.19 15 2.67 47 4. 52 16 1.70 48 6. 85 17 2.47 49 5.34 18 3. 56 50 6.10 19 1.08 51 0. 78 20 3.06 52 1.48 21 3· 98 53 0.90 22 2.08 54 0. 89 23 2,05 55 1.07 24 2.23 56 0.41 25 3. 93 57 0. 50 26 3.83 58 0. 78 27 6.11 59 0. 25 28 1.73 60 7.26 29 7 62 61 8.39 30 2.61 Comparative Example 1 185 31 2.71 Comparative Example 2 97.2 15252 8.doc 104-

Claims (1)

201121944 七、申請專利範圍: 其係由通式(I)表示: 1. 一種5_氟尿嘧啶化合物或其鹽 [化1] 〇201121944 VII. Patent application scope: It is represented by the general formula (I): 1. A 5-fluorouracil compound or a salt thereof [Chemical Formula 1] 〇 (通式(I)中,n表示U之數; X表不鍵結、氧原子、硫原子、碳數2〜6之伸烯基、可具 有取代基之2{貝芳香族烴基、或者可具有取代基之2價飽 和或不飽和雜環基; Y表不鍵結、或者碳數丨〜8之直鏈狀或支鏈狀伸烷基; Z表示-S02NR1R2、_NR3s〇2_R4、或下述式· [化2] 0 ^n^r5 R及R2相同或不同,表示氫原子、碳數卜6之烷基或可 具有取代基之芳烷基,或者表示與鄰接之氮原子一併形 成可具有取代基之飽和雜環基之基; R3表示氫原子或碳數1〜6之烷基; R4表示可具有取代基之芳香族烴基或可具有取代基之不 飽和雜環基; R5表示可具有取代基之甲基)。 2.如請求項1之5-氟尿嘧啶化合物或其鹽,其中X表示鍵 152528.doc 201121944 結、氧原子、硫原子、伸乙稀基、伸苯基或β比咬二基, υ表示鍵結、或者直鏈狀或支鏈狀之碳數丨〜8之伸烷基。 3.如請求項1之5-氟尿嘧啶化合物或其鹽,其中ζ表示 -S〇2NR R2 ’ R1為氫原子,R2為可具有取代基之苄基(於 該苄基之亞甲基具有取代基之情形時,作為該取代基, 可具有相同或不同之1〜2個碳數1〜6之烷基(於2個該取代 基為峡數1〜6之烧基之情形時,該院基之碳原子彼此可 形成環亞烷基結構)’於該苄基之苯基具有取代基之情形 時,作為該取代基,可具有丨〜2個鹵素原子、可具有取 代基之直鏈狀或支鏈狀之碳數丨〜6之院氧基、碳數3〜7之 環烷氧基、碳數3〜7之環烷基-烷氧基及飽和雜環氧基之 任一者)。 如請求項1之5-氟尿嘧啶化合物或其鹽,其中n表示i或 3 ’ X表示鍵結、氧原子或伸乙烯基;γ表示鍵結、伸乙 基、或二亞甲基(其中,於χ表示鍵結之情形時,(CH2)n· X-Y表示二亞甲基或五亞曱基),Z為-s〇2nr丨R2 ’ r1為氫 原子’ R為可具有取代基之苄基(於該苄基之亞甲基具有 取代基之情形時,作為該取代基,可具有相同或不同之 1〜2個碳數1〜6之烷基(於2個該取代基為碳數1〜6之烷基 之情形時,該烷基之碳原子彼此可形成環亞烷基結構), 於該节基之苯基具有取代基之情形時,作為該取代基, 可具有1〜2個鹵素原子、可具有取代基之直鏈狀或支鏈 狀之碳數1〜6之烷氧基、碳數3〜7之環烷氧基、碳數3〜7 之核炫基-烧氧基及飽和雜環氧基之任一者)。 152528.doc • 2 201121944 5·如切求項1之5-氟尿嘧啶化合物或其鹽,其係選自下述之 群者: (R)-N-(1_(3_(環戊氧基)苯基)乙基)_3_((5•氟_24二氧 代-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷磺醯胺 (R)-N-( 1-(3-(環丙基甲氧基)·4_氟苯基)乙基)_3_((5氣_ 2.4- 二氧代_3,4-二氫嘧啶-1(2Η)-基)曱氧基)丙烷-丨-磺 醯胺 (R)-N-( 1-(3-(環丙基甲氧基)-4-氟苯基)-2-曱基丙基)-3_ ((5-氟-2,4-二氧代-3,4-二氫嘧啶_ι(2Η)·基)甲氧基)丙烷_ 1-續醯胺 (R)-N-( 1-(3-(環丙基甲氧基)-4-氟苯基)丙基)-3-((5-氟- 2.4- 二氧代-3,4-二氫嘧啶-1(2H)-基)曱氧基)丙烷-^磺 醯胺 (R)-N-〇(3-(環戊氧基)-4-氟苯基)乙基)-3-((5-氟-2,4-二氧代_3,4_二氫嘧β定基)曱氧基)丙烧-1-績酿胺 N-( 1-(3-(環丙基甲氧基)-4-氟苯基)-2-曱基丙基)-3-((5-氟-2,4-二氧代-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-i_磺 醯胺 (R)-N-〇-(3-(環丙基甲氧基)苯基)丙基)-3-((5-氟-2,4-二氧代-3,4-二氫嘧啶-1(2H)-基)甲氧基)丙烷-磺醯胺 (R,E)-N-(l-(3-(環丙基曱氧基)·4·氟苯基)乙基)_5-(5· 氟-2,4-二氧代-3,4-二氫嘧啶-1(2H)·基)戊-3-烯-1-磺醯胺 (R)-N-( 1-(3-(環丙基甲氧基)-4-氟苯基)乙基)-5-(5-氟- 2.4- 二氧代_3,4_二氫嘧啶-1(2H)-基)戊烷-1-磺醯胺 S 152528.doc 201121944 (R,E)-N-(1 -(3-(環戊氧基)苯基)乙基)_5_(5·氟_2,4-二氧 代-3,4-二&amp;嘧啶-1(2H)-基)戊-3-烯-1-磺醯胺 (11)-1^-(1-(3-(環戊氧基)笨基)乙基)_5_(5_氟-2,4-二氧 代-3,4-二氫嘧啶-i(2H)-基)戊烷-1-磺醯胺 (R,E)_N_(卜(3-(環丙基甲氧基)苯基)乙基)-5-(5-氟-2,4-二氧代_3,4-二氫嘧啶_1(211)_基)戊_3_烯_丨·磺醯胺 (R,E)-N-(1-(3-(2,2-二氟乙氧基)苯基)乙基)_5_(5-氟-2,4-二氧代-3,4-二氫嘧啶_1(211)_基)戊_3烯_丨_磺醯胺 (R)-N-(l-(3-(2,2-二氟乙氧基)苯基)乙基)_5_(5_氟_2,4- 二氧代-3,4·二氫嘧啶_1(2抝·基)戊烷小磺醯胺。 6· 一種醫藥組合物,豆人亡μ + = r ^ 明其含有如請求項1至5中任一項之5-氟 尿嘧啶化合物或其鹽。 7. 一種卿酶抑制劑’其含有如請求項1至5中任一項之5-氟尿嘧啶化合物或其鹽。 152528.doc -4- 201121944 四、 指定代表圖: (一) 本案指定代表圖為:(無) (二) 本代表圖之元件符號簡單說明: 五、 本案若有化學式時,請揭示最能顯示發明特徵的化學式: 0(In the formula (I), n represents the number of U; X represents a bond, an oxygen atom, a sulfur atom, an alkenyl group having 2 to 6 carbon atoms, a 2{beta aromatic hydrocarbon group which may have a substituent, or a divalent saturated or unsaturated heterocyclic group having a substituent; Y represents a bond or a linear or branched alkyl group having a carbon number of 丨8; Z represents -S02NR1R2, _NR3s〇2_R4, or the following Formula [Chemical Formula 2] 0 ^n^r5 R and R2 are the same or different and each represents a hydrogen atom, an alkyl group having a carbon number of 6 or an aralkyl group which may have a substituent, or may be formed together with an adjacent nitrogen atom. a group of a saturated heterocyclic group having a substituent; R3 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms; R4 represents an aromatic hydrocarbon group which may have a substituent or an unsaturated heterocyclic group which may have a substituent; a methyl group having a substituent). 2. The 5-fluorouracil compound of claim 1 or a salt thereof, wherein X represents a bond 152528.doc 201121944 a knot, an oxygen atom, a sulfur atom, a vinylidene group, a phenylene group or a beta group, and a bond represents a bond. Or a linear or branched carbon group having a carbon number of 丨8. 3. The 5-fluorouracil compound of claim 1 or a salt thereof, wherein ζ represents -S〇2NR R2 ' R1 is a hydrogen atom, and R 2 is a benzyl group which may have a substituent (the methylene group of the benzyl group has a substituent) In the case of the substituent, the substituent may have the same or different 1 to 2 alkyl groups having 1 to 6 carbon atoms (in the case where two of the substituents are a group of 1 to 6 gorges), the base is used. The carbon atoms may form a cycloalkylene structure with each other. When the phenyl group of the benzyl group has a substituent, the substituent may have a halogen atom of 2 to 2 halogen atoms, a linear group which may have a substituent or Any one of a branched carbon number of 66, a cycloalkyloxy group having 3 to 7 carbon atoms, a cycloalkyl-alkoxy group having 3 to 7 carbon atoms, and a saturated heterocyclic oxy group. The 5-fluorouracil compound of claim 1 or a salt thereof, wherein n represents i or 3 'X represents a bond, an oxygen atom or a vinyl group; γ represents a bond, an ethyl group, or a dimethylene group (wherein When χ represents a bond, (CH2)n· XY represents a dimethylene or penta-indenyl group, and Z is -s〇2nr丨R2 'r1 is a hydrogen atom' R is a benzyl group which may have a substituent ( When the methylene group of the benzyl group has a substituent, the substituent may have the same or different 1 to 2 alkyl groups having 1 to 6 carbon atoms (in the case of 2 substituents, the carbon number is 1 to 6). In the case of an alkyl group of 6 , the carbon atoms of the alkyl group may form a cycloalkylene structure with each other, and when the phenyl group of the nodal group has a substituent, as the substituent, it may have 1 to 2 halogens. Atom, a linear or branched alkoxy group having 1 to 6 carbon atoms, a cycloalkyloxy group having 3 to 7 carbon atoms, a nucleus group-alkoxy group having 3 to 7 carbon atoms; Any of saturated heterocyclic oxy groups). 152528.doc • 2 201121944 5. The 5-fluorouracil compound or a salt thereof according to Item 1, which is selected from the group consisting of: (R)-N-(1_(3_(cyclopentyloxy)phenyl) Ethyl)_3_((5•Fluoro-24 dioxo-3,4-dihydropyrimidin-1(2H)-yl)methoxy)propanesulfonamide (R)-N-( 1-(3) -(cyclopropylmethoxy)·4_fluorophenyl)ethyl)_3_((5 gas_2.4-dioxo-3,4-dihydropyrimidin-1(2Η)-yl)decyloxy) Propane-indole-sulfonamide (R)-N-(1-(3-(cyclopropylmethoxy)-4-fluorophenyl)-2-mercaptopropyl)-3_ ((5-fluoro-) 2,4-dioxo-3,4-dihydropyrimidine_ι(2Η)·yl)methoxy)propane _ 1-continuous guanamine (R)-N-( 1-(3-(cyclopropyl) Methoxy)-4-fluorophenyl)propyl)-3-((5-fluoro-2.4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)decyloxy)propane- ^sulfonamide (R)-N-indole (3-(cyclopentyloxy)-4-fluorophenyl)ethyl)-3-((5-fluoro-2,4-dioxo-3,4 _ dihydropyrimidine β-denyl) decyloxy) propyl ketone - 1 N-(1-(3-(cyclopropylmethoxy)-4-fluorophenyl)-2-mercaptopropyl) -3-((5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methoxy)propane-i_sulfonamide (R)-N-〇 -( 3-(cyclopropylmethoxy)phenyl)propyl)-3-((5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methoxy Propane-sulfonamide (R,E)-N-(l-(3-(cyclopropyldecyloxy).4.fluorophenyl)ethyl)_5-(5·fluoro-2,4- Dioxo-3,4-dihydropyrimidin-1(2H)-yl)pent-3-ene-1-sulfonamide (R)-N-( 1-(3-(cyclopropylmethoxy)) 4-fluorophenyl)ethyl)-5-(5-fluoro-2.4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)pentan-1-sulfonamide S 152528. Doc 201121944 (R,E)-N-(1 -(3-(cyclopentyloxy)phenyl)ethyl)_5_(5·fluoro-2,4-dioxo-3,4-di &amp;pyrimidine -1(2H)-yl)pent-3-ene-1-sulfonamide (11)-1^-(1-(3-(cyclopentyloxy)phenyl)ethyl)_5_(5_fluoro- 2,4-dioxo-3,4-dihydropyrimidine-i(2H)-yl)pentan-1-sulfonamide (R,E)_N_(Bu(3-(cyclopropylmethoxy)) Phenyl)ethyl)-5-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(211)-yl)penta-3-ene-2-indolesulfonamide ,E)-N-(1-(3-(2,2-difluoroethoxy)phenyl)ethyl)-5-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidine _1(211)-yl)penta-3-ene_丨_sulfonamide (R)-N-(l-(3-(2,2-difluoroethoxy)phenyl) ) _5_ (5_ _2,4- fluoro-3,4-dihydro-pyrimidin-dioxo _1 (Ao-2-yl) pentane sulfonamide Amides small. 6. A pharmaceutical composition, which comprises a 5-fluorouracil compound or a salt thereof according to any one of claims 1 to 5, which is a compound of any one of claims 1 to 5. A cleavage inhibitor of the present invention, which comprises the 5-fluorouracil compound or a salt thereof according to any one of claims 1 to 5. 152528.doc -4- 201121944 IV. Designated representative map: (1) The representative representative of the case is: (none) (2) The symbol of the symbol of the representative figure is simple: 5. If the case has a chemical formula, please reveal the best display. Chemical formula of the invention features: 0 S: 152528.docS: 152528.doc
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