TW201209056A

TW201209056A - Novel heterocyclic compound or salt thereof

Info

Publication number: TW201209056A
Application number: TW100118295A
Authority: TW
Inventors: Toshiya Noguchi; Fumihito Ushiyama; Hiromasa Horikiri; Keiko Yamamoto; Naoya Ono; Tetsuo Takayama; Tomoko Kamiyama
Original assignee: Taisho Pharmaceutical Co Ltd; Toyama Chemical Co Ltd
Priority date: 2010-05-25
Filing date: 2011-05-25
Publication date: 2012-03-01
Also published as: JP5685589B2; WO2011148962A1; JPWO2011148962A1

Abstract

Disclosed is a medicament having a strong antibacterial activity against Gram-positive bacteria, Gram-negative bacteria, and resistant bacteria. A compound represented by formula [I] or a salt thereof is useful as an antibacterial agent. In formula [I], a bond containing a dotted line and connecting X2 to Y1 represents a single bond or a double bond; Z1, Z2, Z3, Z4, Z5, and Z6 each represent a nitrogen atom, formula: CH, or the like; X1 represents a C1-4 alkylene group which may be substituted by an oxo group; X2 represents a bonding hand or formula: CH; Y1 represents a spirocyclic group selected from a group of formulae (II); X3 represents a C1-4 alkylene group, formula: NR10(CH2)m, formula: SOn, or a bonding hand; and R7 represents a C3-6 cycloalkyl group, a C3-6 cycloalkenyl group, an aryl group, a monocyclic heterocyclic group, a bicyclic heterocyclic group, or the like.

Description

201209056 六、發明說明：【發明所屬之技術領域】本發明係關於對於革氏陽性菌、革氏陰性菌及耐性菌具有強抗菌活性的新穎化合物或其鹽及含有此等之抗菌劑【先前技術】對於醫療現場，在感染症的治療上已使用種種抗生素或合成抗菌劑。然而，近年來亦出現抗藥性金黃色葡萄球菌（MRSA)、抗萬古黴素腸球菌（VRE)及耐青霉素肺炎鏈球菌（PRSP )等耐性菌。被如此耐性菌感染的患者之治療成爲重要課題。另外，亦出現對於複數藥劑具有耐性之多劑耐性菌。對於多劑耐性菌之感染症係爲難治性疾病成爲世界的大問題。對於這些耐性菌爲有效之抗生物質的登場成爲強烈期待，將來自細菌之酵素作爲標的之藥劑開發正進行者。例如，發現藉由阻礙作爲細菌在DNA複製的必須酵素而具有的Π型拓樸異構酶之topoisomerase IV及DNA gyrase的反應而顯示抗菌活性（非專利文獻1 )'國際公開第99/07682 號手冊（專利文獻1)中揭示對於MRS A爲有效之喹諾酮系 . 化合物。又，具有與既存的藥劑相異的作用機制之化合物 - 亦已多數被揭示（例如專利文獻2 - 7 )。且’亦揭示具有結構上具有特徵的螺環骨架之化合物（專利文獻8) ° 〔先行技術文獻〕 201209056 〔專利文獻〕〔專利文獻1〕國際公開第99/07682號手冊〔專利文獻2〕國際公開第20〇4/002490號手冊〔專利文獻3〕國際公開第2004/〇〇2992號手冊〔專利文獻4〕國際公開第2〇〇6/丨34 3 78號手冊〔專利文獻5〕國際公開第2006/ 1 3 7485號手冊〔專利文獻6〕國際公開第2〇〇7/138974號手冊〔專利文獻7〕國際公開第20〇8/〇〇970〇號手冊〔專利文獻8〕國際公開第20〇8/026 1 72號手冊〔非專利文獻〕〔非專利文獻 1〕Antimicrobial Agents and Chemotherapy、第 41卷、第 2362 〜2366 頁、1997 年【發明內容】發明所要解決之課題對於革氏陽性菌、革氏陰性菌及耐性菌具有強抗菌活性，且具有高安全性之藥劑的開發正被期待著。解決課題之手段如此狀況下’本發明者們進行詳細檢討結果，發現式 201209056201209056 VI. Description of the Invention: [Technical Field] The present invention relates to a novel compound having a strong antibacterial activity against a Gram-positive, Gram-negative, and resistant bacteria and a salt thereof and an antibacterial agent containing the same 】 For the medical field, various antibiotics or synthetic antibacterial agents have been used in the treatment of infectious diseases. However, resistant strains such as drug-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE), and penicillin-resistant Pneumococcal (PRSP) have also appeared in recent years. The treatment of patients infected with such resistant bacteria is an important issue. In addition, multiple dose-tolerant bacteria which are resistant to a plurality of agents have also appeared. The infection of multiple dose-tolerant bacteria is a refractory disease that has become a major problem in the world. The debut of these resistant bacteria as an effective anti-biomass has been strongly anticipated, and the development of pharmaceutical agents derived from bacteria as a target is underway. For example, it has been found that antibacterial activity is exhibited by the reaction of the topoisomerase IV and the DNA gyrase of the indole-type topoisomerase which is a necessary enzyme for bacterial DNA replication (Non-Patent Document 1)' International Publication No. 99/07682 A quinolone-based compound which is effective for MRS A is disclosed in the manual (Patent Document 1). Further, a compound having a mechanism of action different from the existing agent has also been disclosed (for example, Patent Documents 2 - 7). Further, 'a compound having a structurally characteristic spiro ring skeleton is also disclosed (Patent Document 8) ° [Prior Art Document] 201209056 [Patent Document] [Patent Document 1] International Publication No. 99/07682 (Patent Document 2) International Handbook No. 20〇4/002490 [Patent Document 3] International Publication No. 2004/〇〇2992 Handbook [Patent Document 4] International Publication No. 2〇〇6/丨34 3 78 Manual [Patent Document 5] International Publication Handbook No. 2006/1 3 7485 [Patent Document 6] International Publication No. 2/7, 974, 974 (Patent Document 7) International Publication No. 20〇8/〇〇970 No. [PTL 8] International Publication No. 20〇8/026 1 72 Handbook [Non-Patent Document] [Non-Patent Document 1] Antimicrobial Agents and Chemotherapy, Vol. 41, No. 2362 to 2366, 1997 [Invention] The problem to be solved by the invention is positive for Gee The development of agents with high antibacterial activity and high safety is expected. Means for Solving the Problem Under such circumstances, the inventors conducted detailed review and found the formula 201209056

X%1X%1

R7 Z5R7 Z5

[I] (式中，含有連結X2與Y1的點線之鍵結表示單鍵，或雙鍵， Z1表示氮原子或式CR1 ’ Z2表示氮原子或式CR2，Z3表示氮原子或式CR3’ Z4表示氮原子或式CR4, z5表示氮原子或式CR5，Ζό表示氮原子或式CR6， R1、R2、R3、R4、R5、及R6爲相同或相異，表示氫原子、Ci.6烷氧基、羥基、鹵素原子、Cl 6烷基、Ci 6鹵烷基、Cu鹵院氧基、C3_6環院基、氰基、硝基、c2_7院醇基、單環雜環基、式-NR8R9、式-C02R8，或式-CONR8R9， R8及R9爲相同或相異，表示氫原子，或Cl_6烷基， X1表示可由側氧基取代之Cm伸院基， X2中，含有連結X2與Y1的點線之鍵結爲單鍵時表示鍵結鍵，含有連結X2與Y1的點線之鍵結爲雙鍵時表示式CH > Y1可由選自羥基、鹵素原子、Ci .6烷基、Cu羥基烷基、C2-7院醇基、苯基、式-NR13r14、s_c〇2r13、及式_ C〇NR13R14所成群的1〜3個基所取代，表示選自以下式群〔II〕的螺環基’各螺環基中之氮原子亦可爲N-氧化物， R13、及R14爲相同或相異，表示氫原子，或Ci_6烷基 201209056 .〇[I] (wherein, a bond containing a dotted line connecting X2 and Y1 represents a single bond, or a double bond, Z1 represents a nitrogen atom or a formula CR1 'Z2 represents a nitrogen atom or a formula CR2, and Z3 represents a nitrogen atom or a formula CR3' Z4 represents a nitrogen atom or a formula CR4, z5 represents a nitrogen atom or a formula CR5, Ζό represents a nitrogen atom or a formula CR6, and R1, R2, R3, R4, R5, and R6 are the same or different, and represent a hydrogen atom, a Ci. 6 alkane. Oxyl group, hydroxyl group, halogen atom, Cl 6 alkyl group, Ci 6 haloalkyl group, Cu halogen oxy group, C3_6 ring-based group, cyano group, nitro group, c2_7-indolyl group, monocyclic heterocyclic group, formula -NR8R9 , -C02R8, or the formula -CONR8R9, R8 and R9 are the same or different, meaning a hydrogen atom, or a Cl_6 alkyl group, X1 represents a Cm-extension group which may be substituted by a pendant oxy group, and X2 contains a linkage of X2 and Y1. When the bond of the dotted line is a single bond, it represents a bond, and when the bond of the dotted line connecting X2 and Y1 is a double bond, the formula CH > Y1 may be selected from a hydroxyl group, a halogen atom, a Ci. The hydroxyalkyl group, the C2-7 alkoxy group, the phenyl group, the formula -NR13r14, s_c〇2r13, and the 1-3 C group of the formula _C〇NR13R14 are substituted, and are represented by the group of the following formula [II]. Spiral ring 'Each group of spiro ring nitrogen atom may also be a N- oxide, R13, and R14 are the same or different, represent a hydrogen atom, or Ci_6 alkyl 201209056 .〇

[Π][Π]

X3表示Ci-4伸烷基 '式NR1Q(CH2) m、式son，或鍵結鍵， R1Q爲相同或相異，表示氫原子，或c!.6烷基，m、及η 爲相同或相異，表示〇、1，或2， R7表示C3.6環烷基、C3.6環烯基、芳基、單環雜環基，或二環雜環基，其中，該C3.6環烷基、C3.6環烯基、芳基、單環雜環基、及二環雜環基可由選自C!.6烷氧基、羥基、鹵素原子、Cu烷基、Ci.6鹵烷基、h.6鹵烷氧基、C2-7烷醇基、單環雜環基、式-NRHR12、式-C02R11、及式-CONRuR12所成群的1〜5個取代基所取代， R11、及R12爲相同或相異，表示氫原子，或Ci-6烷基 -8- 201209056 )所示化合物或其鹽具有強抗菌活性，而完成本發明。發明的效果式〔〗〕的化合物或其鹽對於革氏陽性菌、革氏陰性菌及耐性菌具有強抗菌活性。實施發明之形態本發明中’所謂Cx-y表示碳數爲X至y的意思。所謂Ci-6烷氧基表示碳數1至6的直鏈狀或支鏈狀的烷氧基’例如可舉出甲氧基、乙氧基、丙氧基、異丙氧基、丁氧基、異丁氧基、sec-丁氧基、tert-丁氧基、戊氧基、異戊氧基、己氧基等。所謂鹵素原子爲氟原子、氯原子、溴原子、碘原子。所謂Ci.6烷基表示碳數1至6的直鏈狀或支鏈狀之烷基，例如可舉出甲基、乙基、丙基、異丙基、丁基、異丁基、sec-丁基、第三丁基、戊基、異戊基、己基等。所謂羥基烷基表示上述CU6烷基的任意1個氫原子由羥基取代的基，例如可舉出羥基甲基、羥基乙基、羥基丙基、羥基丁基、羥基戊基、羥基己基等。所謂Ci-6_院基表不上述Ci-6院基的任意氨原子由鹵素原子取代的基，例如可舉出氟甲基、二氟甲基、三氟甲基 '三氯甲基等。鹵素原子的取代數以1〜3爲佳。所謂CN6鹵烷氧基表示上述<^.6烷氧基的任意氫原子由鹵素原子之基*例如可舉出氟甲氧基、二氟甲氧基、三 -9- 201209056 氟甲氧基等。鹵素原子之取代數以1〜3爲佳。所謂C3_6環烷基爲環丙基、環丁基、環戊基，或環己基。所謂C3 _6環烯基爲環丙烯基、環丁烯基、環戊烯基，或環己烯基。所謂C2_7烷醇基表示碳數2至7的直鏈狀或支鏈狀之烷醇基，例如可舉出乙醯基、丙醯基、丁醯基、異戊醯基、三甲基乙醯基等。所謂c^4伸烷基表示碳數1至4的直鏈狀或支鏈狀之伸烷基，例如可舉出伸甲基、伸乙基、伸丙基、伸丁基等。所謂單環雜環基，例如可舉出呋喃基、噻嗯、2-吡咯基、咪唑基、3 -吡唑基、噻唑基、異噻唑基、噁唑基、異噁唑基、噻二唑基、咪唑基、吡啶基、嘧啶基、噠嗪基、吡啶基、吡咯烷基、哌嗪基、2-哌啶基、3-哌啶基、4-哌啶基、2-哌嗪基、2-嗎啉基、2-硫代嗎啉基、吡喃基、四氫吡喃基、四氫硫代吡喃基等。單環雜環基中作爲環構成原子，以含有選自氮原子、氧原子 '及硫原子的1至3個雜原子的5或6員者爲佳。所謂二環雜環基，例如可舉出苯並呋喃基、異苯並呋喃基、苯並噻嗯、吲哚基、異吲哚基、吲哚嗪基、苯並咪唑基、苯並噁唑基、苯並異噁唑基、苯並噻唑基、1 H-吲唑基、嘌呤基、香豆素基、色烯基、喹啉基、異喹啉基、酞嗪基、萘啶基、喹喔啉基、喹唑啉基、噌啉基、苯並二氫吡喃基、異苯並二氫吡喃基、奎寧環基、1 , 3 -苯並二噁 -10- 201209056 烷基、1，4-苯並二噁烷基、苯並嗎啉基、苯並嗎啉酮基、 2,3-二氫（1，4)二噁並（2,3-c)吡啶-7-基、3,4 -二氫- 2H-吡啶並（4,3-b) ( 1,4)噁嗪-7-基、3 -側氧- 3,4 -二氫- 2H- 吡啶並（3,2-b ) ( 1，4 )螺嗪-6-基、3-側氧- 3,4-二氫- 2H- 吡啶並（3,2-b) ( 1，4)噻嗪-6-基、3 -側氧- 3,4 -二氫- 2H- 苯並噻嗪-6-基、3,4-二氫-2H -吡喃並（2,3-c)吡啶-6-基、3,4 -二氫-2H-(1，4)二噁庚因並（2,3-c)吡啶-8-基、 (1，3 )二側氧（4,5-c )吡啶-6-基、6-氧化物-2,3-二氫（ 1，4)二噁並（2,3-c)吡啶-7-基、7-側氧-5,6,7,8 -四氫-1，8-萘啶-2-基、5,6,7,8 -四氫喹喔啉-2-基、1,4-苯並二噻烷基、噻吩並（3,2-b)噻吩-2-基、7-側氧- 7,8-二氫-6H-嘧啶並（5,4-b) (1，4)噁嗪-4-基等。所謂芳基，例如可舉出苯基、萘基、蒽基、菲基等。作爲式〔I〕的化合物之鹽，一般可舉出已知的胺基等鹼性基或酚性羥基或羧基等酸性基中之鹽。作爲鹼性基中之鹽，例如可舉出與鹽酸、溴化氫酸及硫酸等無機酸之鹽；與酒石酸、甲酸、乙酸、檸檬酸、三氯乙酸及三氟乙酸等有機羧酸之鹽；以及與甲磺酸、苯磺酸、p-甲苯磺酸、均三甲苯磺酸及萘磺酸等磺酸之鹽等》作爲酸性基中之鹽，例如可舉出與鈉及鉀等鹼金屬之鹽；與鈣及鎂等鹼土類金屬之鹽；錳鹽：以及與三甲基胺、三乙胺、三丁基胺、吡啶、N，N-二甲基苯胺、N-甲基哌啶、N-甲基嗎咐、二乙胺、二環己基胺、普羅卡因、二苯甲基胺、N-苯甲基-β-苯乙基胺及Ν,Ν’·二苯甲基伸乙基二 -11 - 201209056 胺等含氮有機鹼之鹽等。且，作爲上述鹽中式〔I〕的化合物之較佳鹽，可舉出藥理學上可被許可的鹽。又，本發明化合物或其鹽有時會形成水合物或溶劑合物，彼等亦包含於本發明中。對於本發明之式〔I〕的化合物，作爲較佳化合物可舉出以下化合物。 Z1爲式CR1之化合物爲佳，爲式CH之化合物爲較佳。 Z2爲氮原子或式CH之化合物爲佳。 Z3爲氮原子或式CH之化合物爲佳。 Z4爲式CR4之化合物爲佳，爲式CH之化合物爲較佳。 Z5爲式CR5之化合物爲隹’ ]^5爲（：1.6院氧基，或鹵素原子之化合物爲較佳。 Z6爲式CR6之化合物爲佳，爲式CH之化合物爲較佳。 X1爲可由側氧基所取代之C!.2伸烷基的化合物爲佳，由側氧基所取代之C , ·2伸烷基者爲較佳。 X2爲鍵結鍵（含有連結X2與Υ1的點線之鍵結爲單鍵）之化合物爲佳。 υ1可由選自羥基、鹵素原子、Cl_6烷基、Ci 6羥基烷基、c2_7烷醇基、苯基、式-NR13R“、式τοπΗ、及式. CONR^Ri4所成群的i〜3個基所取代，選自以下式群〔m 〕的螺環基之化合物爲佳，選自無取代之式群〔ΠΙ〕的螺環基之化合物爲較佳。 -12- 201209056X3 represents a Ci-4alkylene group of the formula NR1Q(CH2) m, a formula of a son, or a bond, and R1Q is the same or different, meaning a hydrogen atom, or a c..6 alkyl group, m, and η are the same or Different, meaning 〇, 1, or 2, R7 represents C3.6 cycloalkyl, C3.6 cycloalkenyl, aryl, monocyclic heterocyclic, or bicyclic heterocyclic, wherein the C3.6 ring The alkyl group, C3.6 cycloalkenyl group, aryl group, monocyclic heterocyclic group, and bicyclic heterocyclic group may be selected from a C..6 alkoxy group, a hydroxyl group, a halogen atom, a Cu alkyl group, and a Ci.6 halogen. Substituted with 1 to 5 substituents of the group of h.6 haloalkoxy, C2-7 alkanol, monocyclic heterocyclic, formula -NRHR12, formula -C02R11, and formula -CONRuR12, R11, And R12 is the same or different, and represents a hydrogen atom or a compound represented by Ci-6 alkyl-8-201209056) or a salt thereof having strong antibacterial activity, and the present invention has been completed. EFFECT OF THE INVENTION The compound of the formula [I] or its salt has strong antibacterial activity against Gram-positive bacteria, Gram-negative bacteria and resistant bacteria. MODE FOR CARRYING OUT THE INVENTION In the present invention, the term "Cx-y" means that the carbon number is X to y. The Ci-6 alkoxy group represents a linear or branched alkoxy group having 1 to 6 carbon atoms, and examples thereof include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, and a butoxy group. , isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, hexyloxy and the like. The halogen atom is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. The Ci.6 alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms, and examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, and a sec- group. Butyl, tert-butyl, pentyl, isopentyl, hexyl and the like. The hydroxyalkyl group is a group in which any one of the hydrogen atoms of the CU6 alkyl group is substituted by a hydroxyl group, and examples thereof include a hydroxymethyl group, a hydroxyethyl group, a hydroxypropyl group, a hydroxybutyl group, a hydroxypentyl group, and a hydroxyhexyl group. The Ci-6_hospital base table is not a group in which any of the amino atoms of the Ci-6 group is substituted with a halogen atom, and examples thereof include a fluoromethyl group, a difluoromethyl group, and a trifluoromethyl 'trichloromethyl group. The substitution number of the halogen atom is preferably from 1 to 3. The CN6 haloalkoxy group means that any hydrogen atom of the above-mentioned <6. alkoxy group is a group of a halogen atom *, for example, a fluoromethoxy group, a difluoromethoxy group, a tris-9-201209056 fluoromethoxy group Wait. The substitution number of the halogen atom is preferably from 1 to 3. The C3_6 cycloalkyl group is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group. The C3-6 cycloalkenyl group is a cyclopropenyl group, a cyclobutenyl group, a cyclopentenyl group, or a cyclohexenyl group. The C2-7 alkanol group represents a linear or branched alkanol group having 2 to 7 carbon atoms, and examples thereof include an ethyl fluorenyl group, a propyl fluorenyl group, a butyl group, an isoamyl group, a trimethyl acetyl group, and the like. . The alkyl group represented by C4 is a linear or branched alkyl group having 1 to 4 carbon atoms, and examples thereof include a methyl group, an ethyl group, a propyl group, and a butyl group. The monocyclic heterocyclic group may, for example, be a furyl group, a thiophene, a 2-pyrrolyl group, an imidazolyl group, a 3-pyrazolyl group, a thiazolyl group, an isothiazolyl group, an oxazolyl group, an isoxazolyl group or a thiadiazole. Base, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyridyl, pyrrolidinyl, piperazinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2-piperazinyl, 2-morpholinyl, 2-thiomorpholinyl, pyranyl, tetrahydropyranyl, tetrahydrothiopyranyl and the like. The monocyclic heterocyclic group is a ring-constituting atom, and preferably 5 or 6 members containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. The bicyclic heterocyclic group may, for example, be a benzofuranyl group, an isobenzofuranyl group, a benzothiophene group, a decyl group, an isodecyl group, a pyridazinyl group, a benzimidazolyl group or a benzoxazole. , benzoisoxazolyl, benzothiazolyl, 1 H-carbazolyl, fluorenyl, coumarinyl, chromenyl, quinolyl, isoquinolyl, pyridazinyl, naphthyridyl, Quinoxalinyl, quinazolinyl, porphyrinyl, chromanyl, isochroman, quinuclidinyl, 1,3-benzodioxin-10-201209056 alkyl , 1,4-benzodioxanyl, benzomorpholinyl, benzomorpholinone, 2,3-dihydro(1,4)dioxa(2,3-c)pyridine-7- , 3,4-dihydro-2H-pyrido(4,3-b) (1,4)oxazin-7-yl, 3-oxo-oxy-3,4-dihydro-2H-pyridyl (3 ,2-b ) ( 1,4 ) Spiro-6-yl, 3-oxo- 3,4-dihydro-2H-pyrido(3,2-b) ( 1,4)thiazine-6- 3-, 3-oxo- 3,4-dihydro-2H-benzothiazin-6-yl, 3,4-dihydro-2H-pyrano(2,3-c)pyridine-6-yl, 3,4-dihydro-2H-(1,4)dioxine (2,3-c)pyridine-8-yl, (1,3) di-oxo (4,5-c)pyridine-6 -based, 6-oxidation -2,3-dihydro(1,4)dioxa(2,3-c)pyridin-7-yl, 7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridine -2-yl, 5,6,7,8-tetrahydroquinoxalin-2-yl, 1,4-benzodithyl, thieno(3,2-b)thiophen-2-yl, 7 - Side oxygen - 7,8-dihydro-6H-pyrimido(5,4-b) (1,4)oxazin-4-yl and the like. Examples of the aryl group include a phenyl group, a naphthyl group, an anthracenyl group, and a phenanthryl group. The salt of the compound of the formula [I] is generally a basic group such as a known amino group or a salt of an acidic group such as a phenolic hydroxyl group or a carboxyl group. Examples of the salt in the basic group include salts with inorganic acids such as hydrochloric acid, hydrogen bromide, and sulfuric acid; and salts with organic carboxylic acids such as tartaric acid, formic acid, acetic acid, citric acid, trichloroacetic acid, and trifluoroacetic acid. And a salt of a sulfonic acid such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, orthotriphenylsulfonic acid or naphthalenesulfonic acid, etc. As a salt in the acidic group, for example, a base such as sodium or potassium is mentioned. a salt of a metal; a salt with an alkaline earth metal such as calcium or magnesium; a manganese salt: and a trimethylamine, triethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidin Pyridine, N-methyl hydrazine, diethylamine, dicyclohexylamine, procaine, benzhydrylamine, N-benzyl-β-phenethylamine and hydrazine, Ν'·diphenylmethyl Ethyl di-11 - 201209056 A salt such as a nitrogen-containing organic base such as an amine. Further, as a preferred salt of the compound of the formula [I] in the above salt, a pharmacologically acceptable salt can be mentioned. Further, the compound of the present invention or a salt thereof sometimes forms a hydrate or a solvate, and they are also included in the present invention. As the compound of the formula [I] of the present invention, the following compounds are exemplified as preferred compounds. Z1 is preferably a compound of the formula CR1, and a compound of the formula CH is preferred. Z2 is preferably a nitrogen atom or a compound of the formula CH. Z3 is preferably a nitrogen atom or a compound of the formula CH. Z4 is preferably a compound of the formula CR4, and a compound of the formula CH is preferred. The compound wherein Z5 is a compound of the formula CR5 is 隹']^5 is preferably a compound of the formula: wherein the compound is a compound of the formula CR6, and a compound of the formula CH6 is preferred. The compound having a C!.2 alkyl group substituted by a pendant oxy group is preferably a C, 2 alkyl group substituted by a pendant oxy group. X2 is a bonding bond (containing a point connecting X2 and Υ1). The compound in which the bond of the wire is a single bond is preferred. υ1 may be selected from the group consisting of a hydroxyl group, a halogen atom, a Cl-6 alkyl group, a Ci 6 hydroxyalkyl group, a c2-7 alkanol group, a phenyl group, a formula -NR13R", a formula τοπΗ, and a formula. a group of i to 3 groups in which CONR^Ri4 is substituted, preferably a compound selected from the group consisting of a spiro group of the following formula [m], and a compound selected from the group consisting of an unsubstituted group of spiro groups; Preferably -12- 201209056

pn]Pn]

及and

選自以下式群〔IV〕的螺環基之化合物爲更佳。A compound selected from the group consisting of a spiro group of the following formula [IV] is more preferred.

乂3爲C!·4伸烷基、式NR1Q、式s〇n，或鍵結鍵之化合物爲佳，爲鍵結鍵之化合物爲較佳。 R7爲芳基、單環雜環基，或二環雜環基，該芳基、單環雜環基、及二環雜環基可由選自C! -6烷氧基、羥基、鹵素原子、Ci.6院基、Ci.6齒院基、Ci-6齒院氧基、C2-7院醇基、單環雜環基、式-nrHr12、式-C02R"、及式-C ON RnR12所成群的1〜5個取代基所取代之化合物爲佳，可由選自鹵素原子、及Cm烷基的1〜3個取代基所取代之 -13- 201209056 芳基，或二環雜環基的化合物爲佳。將本發明之式〔1〕的化合物作爲醫藥使用時，可適宜地混合一般使用於製劑化的賦形劑、載體及稀釋劑等製劑輔助劑。這些依據常法’可藉由錠劑、膠囊劑、散劑、糖漿劑、顆粒劑、九劑、懸浮劑、乳劑、液劑、粉體製劑、塞劑、點眼劑、點鼻劑、點耳劑、貼劑、軟膏劑或注射劑等形態以經口或非經口方式投與。又投與方法、投與量及投與次數可配合患者年齡、體重及症狀做適宜選擇。一般對於成人，可藉由經口或非經口（例如注射、點滴及對直腸部位之投與等）投與，1天將〇.〇1〜lOOOmg/kg分1次至數次進行投與。本發明的式〔I〕之化合物對於含有多劑耐性金黃色葡萄球菌、多劑耐性肺炎球菌、萬古黴素耐性腸球菌等耐性菌之革氏陽性菌、革氏陰性菌、厭氣性菌或非定型抗酸菌等顯示優良抗菌力。其次，對於本發明化合物的製造法做說明。本發明的式〔I〕之化合物可藉由以下所示方法製造，但本發明化合物的製造方法並未限定於此等。The compound of 乂3 is a C!·4 alkyl group, a formula NR1Q, a formula s〇n, or a bond bond, and a compound which is a bond bond is preferred. R7 is an aryl group, a monocyclic heterocyclic group, or a bicyclic heterocyclic group, and the aryl group, monocyclic heterocyclic group, and bicyclic heterocyclic group may be selected from a C?-6 alkoxy group, a hydroxyl group, a halogen atom, Ci.6 yard base, Ci.6 tooth base, Ci-6 tooth base oxygen, C2-7 hospital alcohol base, monocyclic heterocyclic group, formula -nrHr12, formula -C02R", and formula -C ON RnR12 A compound substituted with 1 to 5 substituents in a group is preferably a-13-201209056 aryl group substituted with 1 to 3 substituents selected from a halogen atom and a Cm alkyl group, or a bicyclic heterocyclic group. The compound is preferred. When the compound of the formula [1] of the present invention is used as a medicine, a preparation auxiliary agent such as an excipient, a carrier and a diluent which are generally used for formulation can be suitably mixed. These can be used in the form of tablets, capsules, powders, syrups, granules, nine doses, suspensions, emulsions, liquids, powders, suppositories, eye drops, nose drops, and ear The form of the agent, the patch, the ointment or the injection is administered orally or parenterally. The method of administration, the amount of administration, and the number of administrations can be appropriately selected in accordance with the age, weight, and symptoms of the patient. Generally, for adults, it can be administered by oral or parenteral (for example, injection, drip, and administration to the rectal area, etc.), and 1 day to several times for 〇.〇1~lOOOOmg/kg. . The compound of the formula [I] of the present invention is a Gram-positive, Gram-negative, or anaerobic bacteria containing a multi-dose resistant Staphylococcus aureus, a multi-dose resistant pneumococci, a vancomycin-resistant enterococcus, or the like. Non-typed acid-fast bacteria and the like exhibit excellent antibacterial activity. Next, the production method of the compound of the present invention will be described. The compound of the formula [I] of the present invention can be produced by the method shown below, but the method for producing the compound of the present invention is not limited thereto.

-14- 201209056 式中，Z1-Z6、X3、及R7與前述同義。Xla表示c 烷基，Ylb表示於螺環內具有氮原子，鍵結於鄰接該子之氫原子上之螺環基。式〔la〕的化合物可依據國開第06/1 37485號手冊、及國際公開第07/1 3 8974號手所記載之方法或以此爲準的方法製造。式〔1〕的本發明化合物可在還原劑之存在下將 la〕的化合物與式〔lb〕的化合物進行反應而製造。應可由國際公開第06/465 52號手冊等所記載之方法或爲準的方法進行。該反應中，式〔lb〕之化合物及還之使用量僅對於式〔la〕之化合物爲1-20倍莫耳即可_ 卜3伸氮原際公冊等式〔該反以此原劑-14- 201209056 wherein Z1-Z6, X3, and R7 are synonymous with the foregoing. Xla represents a c-alkyl group, and Ylb represents a spiro group having a nitrogen atom in the spiro ring and bonded to a hydrogen atom adjacent to the sub-group. The compound of the formula [la] can be produced according to the method described in the Handbook No. 06/1 37485 and the method described in International Publication No. 07/1 3 8974 or the method therefor. The compound of the present invention of the formula [1] can be produced by reacting a compound of the formula [ll] with a compound of the formula [lb] in the presence of a reducing agent. It shall be carried out by the method described in International Manual No. 06/465, 52, or the like. In the reaction, the compound of the formula [lb] and the amount thereof are used in an amount of from 1 to 20 moles per mole of the compound of the formula [la], and that the original agent is the same.

式中，Ζ^Ζ6、X1、X3、Ylb、及R7與前述同義。示脫離基，作爲L1之例子’可舉出氯原子、溴原子、子、甲磺醯氧基、P -甲苯磺醯氧基、三氟甲磺醯氧基式〔2a〕的化合物可由國際公開第06/ 1 3 74 8 5號手冊國際公開第07/138974號手冊等所記載之方法或以此的方法製造。 L 1表碘原等。、及爲準 -15- 201209056 式〔2〕的本發明化合物可在鹼之存在下或非存在下 ’將式〔2a〕的化合物與式〔lb〕進行反應而製造。該反應可由美國專利第6603 005號說明書等所記載之方法或以此爲準的方法進行。該反應中，式〔lb〕的化合物及依據所需所使用的鹼之使用量對於式〔2a〕的化合物爲1-20倍莫耳即可。〔製造法3〕 0Wherein, Ζ^Ζ6, X1, X3, Ylb, and R7 are synonymous with the foregoing. The example of L1 is a compound of a chlorine atom, a bromine atom, a methane, a methanesulfonyloxy group, a P-toluenesulfonyloxy group, or a trifluoromethanesulfonyloxy group [2a]. The method described in the manual No. 07/13874, No. 07/138974, or the method described in the above. L 1 table iodine and so on. And -15-201209056 The compound of the present invention of the formula [2] can be produced by reacting a compound of the formula [2a] with the formula [lb] in the presence or absence of a base. This reaction can be carried out by the method described in the specification of U.S. Patent No. 6,603,005, or the like. In the reaction, the compound of the formula [lb] and the base to be used may be used in an amount of from 1 to 20 moles per mole of the compound of the formula [2a]. [Manufacturing Method 3] 0

[3aJ[3aJ

式中，Z^Z6、xla、X3、Ylb、及R7與前述同義。式〔3〕的本發明化合物可在鹼之存在下或非存在下 ’使用縮合劑將式〔3a〕的化合物與式〔lb〕的化合物進行反應而製造。該反應可由國際公開第03/0 1 0 1 3 8號手冊 '國際公開第03/0 8 7098號手冊及泉屋們之狀合成的基礎與實驗、第89- 1 42頁、1 9 8 5年、九善等所記載之法或以此爲準的方法進行》對於該反應，依據所需所使用的鹼、式〔lb〕的化合物、及縮合劑的使用量對於式〔3a〕的化合物而言爲1-20倍莫耳即可。 -16- 201209056Wherein Z^Z6, xla, X3, Ylb, and R7 are synonymous with the foregoing. The compound of the present invention of the formula [3] can be produced by reacting a compound of the formula [3a] with a compound of the formula [lb] using a condensing agent in the presence or absence of a base. The reaction can be based on the International Publication No. 03/0 1 0 1 3 8 'International Publication No. 03/0 8 7098 and the Spring and the Springs. The basis and experiment, pp. 89- 1 42, 1985 , the method described in Jiu Shan et al., or the method according to this. For the reaction, the amount of the base, the compound of the formula [lb], and the condensing agent used for the reaction is based on the compound of the formula [3a]. The words are 1-20 times Mo. -16- 201209056

[4a] [4b] [I] 式中’ Z^Z6、x\x3、Y1、R7、及L1與前述同義。式〔4a〕的化合物可由國際公開第06/ 1 3 7485號手冊、及國際公開第07/1 3 8974號手冊等所記載之方法或以此爲準的方法製造。式〔I〕的本發明化合物可在鹼之存在下或非存在下 ’將式〔4a〕的化合物與式〔4b〕的化合物進行反應而製造。對於該反應，依據所需所使用的鹼及式〔4b〕的化合物之使用量對於式〔4a〕的化合物爲1-2 0倍莫耳即可。[4a] [4b] [I] where 'Z^Z6, x\x3, Y1, R7, and L1 are synonymous with the foregoing. The compound of the formula [4a] can be produced by the method described in the International Publication No. 06/1 3 7485, and the method disclosed in the International Publication No. 07/1 8 8974, or the like. The compound of the present invention of the formula [I] can be produced by reacting a compound of the formula [4a] with a compound of the formula [4b] in the presence or absence of a base. For the reaction, the amount of the base to be used and the compound of the formula [4b] may be from 1 to 20 moles per mole of the compound of the formula [4a].

〔製造法5〕 X，）[Manufacturing Method 5] X,)

.0.0

.H y3b L1〆、R7 [5b] 式中，Ζ^Ζ6、X1、X2、示於螺環內具有氮原子，於鄰接該氮原子之氫原子所鍵結的螺環基，X3b表示（：,.4伸烷基。式〔5〕的本發明化合物可在鹼之存在下或非存在下 ’將式〔5a〕的化合物與式〔5b〕的化合物進行反應而製 -17- 201209056 造。該反應可由美國專利第6603 00 5號說明書等所記載之方法或以此爲準的方法進行。該反應中’式〔5b〕之化合物及依據所需所使用之鹼的使用量對於式〔5a〕的化合物爲卜20倍莫耳即可。.H y3b L1〆, R7 [5b] wherein Ζ^Ζ6, X1, X2 is a spiro group having a nitrogen atom in the spiro ring and bonded to a hydrogen atom adjacent to the nitrogen atom, and X3b represents (: The compound of the present invention of the formula [5] can be produced by reacting a compound of the formula [5a] with a compound of the formula [5b] in the presence or absence of a base to produce -17-201209056. The reaction can be carried out by the method described in the specification of the U.S. Patent No. 6,603,500, or the like, in which the compound of the formula [5b] and the amount of the base used as required are used for the formula [5a]. The compound is 20 times Mo.

[5a】 [6b] [6][5a] [6b] [6]

X1，X^-Y1a^S'X3c，，RX1, X^-Y1a^S'X3c,,R

式中，Z^z6、X1、χ2、R7、及Yla與前述同義。X3c表示C i . 3伸烷基^ 式〔6〕的本發明化合物可在還原劑之存在下，將式〔5a〕的化合物與式〔6b〕的化合物進行反應而製造。該反應可由國際公開第06/465 52號手冊等所記載之方法或以此爲準的方法進行。該反應中，式〔6b〕的化合物及還原劑之使用量對於式〔5a〕的化合物而言爲1-20倍莫耳即可〇若無特別記載時，作爲在各製造法之反應使用鹼時的鹼’例如可舉出碳酸鈉、碳酸鉀、碳酸絶、碳酸氫鈉、碳酸氫鉀、乙酸鈉、乙酸鉀、氫氧化鉀、氫氧化鈉、氫氧化鋰、鈉醯胺、甲氧化鈉、t e r t - 丁氧基紳、氣化鈉、氫化鋰、三乙胺、二異丙基乙胺、二甲基苯胺、二乙基苯胺、吡 -18- 201209056 啶、吡咯烷及N-甲基嗎啉等。作爲縮合劑，例如可舉出0-(7 -氮雜苯並三唑. )-^>^’，：^’-四甲基脲六氟磷酸鹽、1-(3_二甲基胺基）-3·乙基碳化二亞胺鹽酸鹽、二環己基碳化二亞胺基二咪唑、2 -氯-1 -甲基吡啶鑰碘化物鹽、4 - ( 4,6 -二基-1,3，5 -三嗪-2 -基）-4-甲基嗎琳氯化物鹽、〇-(7-苯並三唑-1-基）-N，N，N’，N’-四甲基脲六氟磷酸鹽及磷酸=(苯並三唑-1-氧基）三吡咯里嗪鐵等。作爲還原劑，例如可舉出氫化鋁鋰、氫化三乙酸鈉、氫化氰基硼鈉、氫化硼鈉、氫化硼鋰、氫化二異鋁等氫化錯化合物、硼烷類、鈉及鈉汞齊等。又，將鈾使用於陰極之電解還原；使用雷氏鎳、氧化鉑或鈀接觸還原以及使用「鋅-酸」之還原等。作爲溶劑，若爲該反應條件下爲穩定，且爲惰性會妨礙反應者即可，並無特別限制，例如可舉出甲醇醇、2-丙醇及2-甲基-2-丙醇等醇類；氯化伸甲基、氯二氯乙烷等鹵素化烴類；苯、甲苯及二甲苯等芳香族 ;二噁烷、四氫呋喃、苯甲醚、乙二醇二甲基醚、二醇二甲基醚、二乙二醇二乙基醚及乙二醇單甲基醚等 :二甲基亞颯等亞颯類；乙酸乙酯等酯類；N，N-二甲醯胺、N，N-二甲基乙醯胺及1-甲基-2-吡咯烷酮等醯胺及水等，可些亦可混合後使用。又反應爲選自-7 至使用於反應之溶劑沸點的範適當溫度，可在常壓下或加壓下以微波爐照射等實施 1-基基丙、羰甲氧氮雜六氟基硼丁基銅或黑的下不、乙仿及烴類乙二醚類基甲類以圍之 -19- 201209056 製造法1-6中，存在亞胺、胺基、羥基及羧基時，這些可適宜地保護，或亦可適宜地替代這些保護基而進行反應。製造法1-6中，將具有羰基之化合物使用於反應時，取代具有羰基之化合物可使用羰基經保護之化合物》【實施方式】實施例接著舉出本發明之參考例及實施例並做說明，但本發明並非受到這些限定者。且，溶離液中之混合比爲容量比。各參考例、實施例中之各簡稱爲以下意義。DM SO-d6 :重二甲基亞颯參考例1Wherein Z^z6, X1, χ2, R7, and Yla are synonymous with the foregoing. The compound of the present invention wherein X3c represents C i.3 alkylene group [6] can be produced by reacting a compound of the formula [5a] with a compound of the formula [6b] in the presence of a reducing agent. This reaction can be carried out by the method described in International Publication No. 06/465, 52, or the like. In the reaction, the compound of the formula [6b] and the reducing agent are used in an amount of from 1 to 20 moles per mole of the compound of the formula [5a], and if not specifically described, the base is used as a reaction in each production method. Examples of the base include sodium carbonate, potassium carbonate, carbonic acid, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium acetate, potassium acetate, potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium decylamine, and sodium methoxide. , tert-butoxy sulfonium, sodium hydride, lithium hydride, triethylamine, diisopropylethylamine, dimethylaniline, diethylaniline, pyro-18- 201209056 pyridine, pyrrolidine and N-methyl Morpholine and the like. The condensing agent may, for example, be 0-(7-azabenzotriazole.)-^>^', :^'-tetramethylurea hexafluorophosphate, 1-(3-dimethylamine) Base)-3·ethylcarbodiimide hydrochloride, dicyclohexylcarbodiimidediimidazole, 2-chloro-1-methylpyridinium iodide salt, 4-(4,6-diyl- 1,3,5-triazine-2-yl)-4-methylmorphine chloride salt, 〇-(7-benzotriazol-1-yl)-N,N,N',N'-four Methylurea hexafluorophosphate and phosphoric acid = (benzotriazol-1-oxy)tripyrrolidinium iron. Examples of the reducing agent include hydrogenated aluminum hydride, sodium hydrogenated triacetate, sodium cyanoborohydride, sodium borohydride, hydrogenated borohydride, hydrogenated dystrophic compounds such as hydrogenated diisoaluminum, boranes, sodium and sodium amalgam. . Further, uranium is used for electrolytic reduction of the cathode; contact reduction using Res made nickel, platinum oxide or palladium, and reduction using "zinc-acid". The solvent is not particularly limited as long as it is stable under the reaction conditions and is inert, and is not particularly limited, and examples thereof include alcohols such as methanol alcohol, 2-propanol and 2-methyl-2-propanol. Halogenated hydrocarbons such as methyl chloride and chlorodichloroethane; aromatics such as benzene, toluene and xylene; dioxane, tetrahydrofuran, anisole, ethylene glycol dimethyl ether, diol II Methyl ether, diethylene glycol diethyl ether and ethylene glycol monomethyl ether, etc.: anthraquinones such as dimethyl hydrazine; esters such as ethyl acetate; N,N-dimethylamine, N, Amidoxime such as N-dimethylacetamide or 1-methyl-2-pyrrolidone, water, etc. may be used in some cases. Further, the reaction is carried out at a suitable temperature selected from the group consisting of -7 to the boiling point of the solvent used for the reaction, and can be carried out under normal pressure or under pressure in a microwave oven or the like to carry out 1-based propyl, carbonyl methoxy oxa hexafluoroborolanium. Copper or black under-, non-, ethyl, and hydrocarbon-based Ethylene-based ketones are contained in the -19-201209056 manufacturing method 1-6. When imine, amine, hydroxyl, and carboxyl groups are present, these may be suitably protected. Alternatively, the reaction may be carried out by suitably replacing these protecting groups. In the production method 1-6, when a compound having a carbonyl group is used in the reaction, a compound having a carbonyl group may be used instead of the compound having a carbonyl group. [Embodiment] Examples Next, reference examples and examples of the present invention will be described and illustrated. However, the invention is not limited by these. Further, the mixing ratio in the eluent is a capacity ratio. Each of the reference examples and the examples is simply referred to as the following meaning. DM SO-d6 : heavy dimethyl hydrazine Reference example 1

將（7-氟-2-側氧- 2H-(1，5)-萘啶-1-基）乙醛500mg 溶解於甲醇5mL，加入氫化硼鈉164mg，在室溫進行6小時攪拌》將反應混合物在減壓下將溶劑餾去，將所得之殘餾物以矽膠管柱層析法〔矽膠；FUJI SILYSIA股份有限公司，Chromatorex-NH，溶離液：氯仿：甲醇=9: 1〕進行純化，得到無色固體狀的7-氟·1- ( 2-羥基乙基）-1H- ( 1，5 -20- 201209056 )萘啶-2-酮 282mg。 1H NMR ( CHLOROFORM-d ) δ 4.06 ( 2 H, t, J= 5.3 Hz) , 4.43 ( 2 H，t，J= 5.3 Hz)，6.90(1 H, d, J = 9.2Hz )，7.60 ( 1 H，dd, J=9.9，2.1 Hz)，7.94 ( 1 H，d, J=9.2500 mg of (7-fluoro-2-oxo-2H-(1,5)-naphthyridin-1-yl)acetaldehyde was dissolved in 5 mL of methanol, and 164 mg of sodium borohydride was added thereto, and the mixture was stirred at room temperature for 6 hours. The mixture was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (yield: FUJI SILYSIA Co., Ltd., Chromatorex-NH, eluent: chloroform:methanol = 9:1). 282 mg of 7-fluoro·1-(2-hydroxyethyl)-1H-( 1,5 -20- 201209056 )naphthyridin-2-one as a colorless solid was obtained. 1H NMR ( CHLOROFORM-d ) δ 4.06 ( 2 H, t, J = 5.3 Hz) , 4.43 ( 2 H, t, J = 5.3 Hz), 6.90 (1 H, d, J = 9.2 Hz ), 7.60 ( 1 H, dd, J = 9.9, 2.1 Hz), 7.94 ( 1 H, d, J = 9.2

Hz) , 8.44 ( 1 H, d, J=2.1 Hz)。參考例2Hz) , 8.44 ( 1 H, d, J = 2.1 Hz). Reference example 2

將7-氟-1-(2-羥基乙基）-111-(1,5)萘啶-2-酮1〇〇1^ 溶解於四氫呋喃10mL，冰冷下加入亞硫醯氯〇. imL。冰冷下進行1 · 5小時攪拌後，將反應混合物減壓下使溶劑餾去後得到黃色固體狀的1- ( 2-氯乙基）-7-氟-1H- ( 1，5 )萘陡-2-酮 1 OOmg。 1H NMR ( DMSO-d6) δ 3.85 - 3.94 ( 2 H, m) , 4.59 (2 H, t, J= 6.6 Hz) , 6.86 ( 1 H, d, J= 10.1 Hz) , 7.95 -8.02 ( 1 H, m) , 8.17 - 8.26 ( 1 H, m) , 8.55 - 8.61 C 1 H, m )。參考例37-Fluoro-1-(2-hydroxyethyl)-111-(1,5)naphthyridin-2-one 1〇〇1^ was dissolved in tetrahydrofuran (10 mL), and then sulphursulfonium chloride. After stirring for 1.5 hours under ice-cooling, the reaction mixture was evaporated under reduced pressure to give 1-(2-chloroethyl)-7-fluoro-1H- (1,5 2-ketone 1 OOmg. 1H NMR ( DMSO-d6) δ 3.85 - 3.94 ( 2 H, m) , 4.59 (2 H, t, J = 6.6 Hz) , 6.86 ( 1 H, d, J = 10.1 Hz) , 7.95 -8.02 ( 1 H , m) , 8.17 - 8.26 ( 1 H, m) , 8.55 - 8.61 C 1 H, m ). Reference example 3

將7-氟-1H-(1,5)-萘啶-2-酮528mg懸浮於N，N-二甲 201209056 基甲醯胺5mL，加入60%氫化鈉210mg，於80°C進行40分鐘攪拌。加入溴乙酸第三丁酯0.56mL，在80°C進行1小時攪拌。於反應混合物加入水20mL與氯仿100mL，分離並取出有機層。將有機層在飽和氯化鈉水溶液l〇mL中洗淨，以無水硫酸鎂乾燥，減壓下將溶劑餾去。將所得之殘餾物以矽膠管柱層析法〔矽膠；關東化學股份有限公司，矽膠 60N，溶離液；乙酸乙酯：己烷=1 : 1〕進行純化，得到 (7-氟-2-側氧-2H-(1，5)-萘啶-1-基）乙酸第三丁酯 6 4 0 m g ° 1H NMR ( CHLOROFORM-d ) δ ppm 1.48(9 H, s ), 4.91(2 H, s ) , 6.90(1 H, d，J=9.7 Hz)，7.12(1 H， dd，J = 9.9，2.2 Hz ) , 7.93 ( 1 H, d, J=9.7 Hz) , 8.43 ( 1 H, d, J = 2.2 Hz )。參考例4528 mg of 7-fluoro-1H-(1,5)-naphthyridin-2-one was suspended in 5 mL of N,N-dimethyl 201209056-based meglumine, and 60 mg of sodium hydride 60 mg was added thereto, and the mixture was stirred at 80 ° C for 40 minutes. . 0.56 mL of tributyl bromoacetate was added, and the mixture was stirred at 80 ° C for 1 hour. 20 mL of water and 100 mL of chloroform were added to the reaction mixture, and the organic layer was separated. The organic layer was washed with saturated aqueous sodium chloride (MgSO4), dried over anhydrous magnesium sulfate and evaporated. The obtained residue was purified by ruthenium column chromatography [矽胶; Kanto Chemical Co., Ltd., 矽60N, eluent; ethyl acetate:hexane = 1:1) to obtain (7-fluoro-2- Tributyl butyl-2H-(1,5)-naphthyridin-1-yl)acetate 6 4 0 mg ° 1H NMR (CHLOROFORM-d ) δ ppm 1.48 (9 H, s ), 4.91 (2 H, s ) , 6.90 (1 H, d, J = 9.7 Hz), 7.12 (1 H, dd, J = 9.9, 2.2 Hz), 7.93 ( 1 H, d, J = 9.7 Hz) , 8.43 ( 1 H, d , J = 2.2 Hz). Reference example 4

將（7-氟-2-側氧- 2H-(1，5)-萘啶-1-基）乙酸第三丁酯624mg溶解於1,4-二噁烷5mL，加入4 mol/L鹽酸之1,4 -二噁烷溶液l〇mL，在室溫進行30分鐘攪拌，再於60°C進行一晚攪拌。冷卻至室溫後，過濾取出析出物’並減壓下乾燥，得到（7-氟-2-側氧- 2H- ( 1，5 )-萘啶-1-基）乙酸的鹽酸鹽 86 5mg •22- 201209056 1H NMR ( METHANOL-d4 ) δ 5.09 ( 2 H, s ) , 6.91 ( 1 Η，d，J= 10.1 Hz)，7.82 ( 1 H, dd, J = 10.5, 1.4 Hz ), 8.03 ( 1 H, d, J= 10.1 Hz) , 8.51 ( 1 H，dd, J=2.3, 1.4 Hz )。參考例5624 mg of (3-fluoro-2-oxo-2H-(1,5)-naphthyridin-1-yl)acetic acid tert-butyl ester was dissolved in 5 mL of 1,4-dioxane, and 4 mol/L hydrochloric acid was added thereto. 1 ,4 -dioxane solution 10 mL, stirred at room temperature for 30 minutes, and stirred at 60 ° C overnight. After cooling to room temperature, the precipitate was taken out by filtration and dried under reduced pressure to give (5-fluoro-2-oxo-2H-(1,5)-naphthyridin-1-yl)acetic acid hydrochloride. • 22- 201209056 1H NMR ( METHANOL-d4 ) δ 5.09 ( 2 H, s ) , 6.91 ( 1 Η, d, J = 10.1 Hz), 7.82 ( 1 H, dd, J = 10.5, 1.4 Hz ), 8.03 ( 1 H, d, J = 10.1 Hz) , 8.51 ( 1 H, dd, J = 2.3, 1.4 Hz ). Reference example 5

使用7-甲氧基-1H-(1，5)-萘啶-2-酮5.00g進行與參考例3之同樣操作，得到黃色固體狀的（7-甲氧基-2-側氧-2H-(1,5) ·萘啶-1-基）乙酸第三丁酯2.26g。 1H NMR ( CHLOROFORM-d ) δ 1.46(9 H, s ) , 3.94 (3 Η, s ) , 4.95(2 Η, s ) , 6.78(1 Η, d, J = 9.6 Hz)， 6.80(1 Η, d, J = 2.3 Hz)，7.89(1 H, d, J = 9.6 Hz)， 8.29 ( 1 H, d, J = 2.8 Hz )。參考例6The same procedure as in Reference Example 3 was carried out using 7-methoxy-1H-(1,5)-naphthyridin-2-one 5.00 g to give (7-methoxy-2-oxo-2H) as a yellow solid. -(1,5) ·Naphthyridin-1-yl)acetic acid tert-butyl ester 2.26 g. 1H NMR (CHLOROFORM-d) δ 1.46 (9 H, s ) , 3.94 (3 Η, s ) , 4.95 (2 Η, s ) , 6.78 (1 Η, d, J = 9.6 Hz), 6.80 (1 Η, d, J = 2.3 Hz), 7.89 (1 H, d, J = 9.6 Hz), 8.29 ( 1 H, d, J = 2.8 Hz ). Reference example 6

使用（7-甲氧基-2-側氧-2H-(1，5)-萘啶-1-基）乙酸第三丁酯1 . 3 5 g進行與參考例4之同樣操作，得到淡黃色固 -23- 201209056 體狀的（7-甲氧基-2-側氧-2H-(1，5)-萘啶-1-基）乙酸的鹽酸鹽1.28g。 1 H NMR ( METHAN〇L-d4 ) δ 4.06 ( 3 H, s ) ,5.17(2 Η, s )，6.92(1 Η, d, J = 9.6 Hz)，7.66(1 H, d, J - 2.3 Hz)，8.00 - 8.04 ( 1 H，m)，8.46(1 H，d, J=2.3 Hz) o 參考例7The same operation as in Reference Example 4 was carried out using (7-methoxy-2-oxo-2H-(1,5)-naphthyridin-1-yl)acetic acid tert-butyl ester 1.35 g to give a pale yellow color.固-23- 201209056 The hydrochloride salt of (7-methoxy-2-oxo-2H-(1,5)-naphthyridin-1-yl)acetic acid was 1.28 g. 1 H NMR ( METHAN 〇 L-d4 ) δ 4.06 ( 3 H, s ) , 5.17 (2 Η, s ), 6.92 (1 Η, d, J = 9.6 Hz), 7.66 (1 H, d, J - 2.3 Hz), 8.00 - 8.04 ( 1 H, m), 8.46 (1 H, d, J = 2.3 Hz) o Reference example 7

將7-甲氧基-1H-喹啉-2-酮 290mg懸浮於N，N-二甲基甲醯胺5mL，加入60%氫化鈉213mg，在室溫進行30分鐘攪拌。加入溴乙酸乙酯〇.38mL，在90°C進行17小時攪拌。於反應混合物加入水20mL與乙酸乙酯lOOmL，分離並取出有機層。將有機層以飽和氯化鈉水溶液1 OmL洗淨，以無水硫酸鎂乾燥，減壓下將溶劑餾去。將所得之殘餾物以矽膠管柱層析法〔矽膠；關東化學股份有限公司，矽膠6 0，溶離液；乙酸乙酯〕進行純化，得到（7 ·甲氧基-2 -側氧-2 Η -喹啉-1-基）乙酸乙酯322mg。 1H NMR ( CHLOROFORM-d ) δ 1.26(3 Η, t, J = 7.1290 mg of 7-methoxy-1H-quinolin-2-one was suspended in 5 mL of N,N-dimethylformamide, and 213 mg of 60% sodium hydride was added thereto, and the mixture was stirred at room temperature for 30 minutes. 38 mL of ethyl bromoacetate was added, and the mixture was stirred at 90 ° C for 17 hours. 20 mL of water and 100 mL of ethyl acetate were added to the reaction mixture, and the organic layer was separated. The organic layer was washed with a saturated aqueous solution of sodium chloride (1 mL) and dried over anhydrous magnesium sulfate. The obtained residue was purified by silica gel column chromatography (Glue Gel; Kanto Chemical Co., Ltd., 矽60 0, a solution; ethyl acetate) to obtain (7. methoxy-2-sideoxy-2) Η-Quinolin-1-yl)acetate 322 mg. 1H NMR ( CHLOROFORM-d ) δ 1.26(3 Η, t, J = 7.1

Hz)，3_87(3H，s)，4.24(2H，q，J=7.1Hz) ,5.06(2 H, s ) , 6.55 ( 1 H, d, J = 1 .8 Hz)，6.57(1 H, d, J = 9.2 Hz) , 6.82 ( 1 H, dd, J= 8.7, 1.8 Hz) , 7.49 ( 1 H, d, J = 201209056Hz), 3_87(3H, s), 4.24 (2H, q, J=7.1Hz), 5.06(2 H, s ), 6.55 ( 1 H, d, J = 1. 8 Hz), 6.57 (1 H, d, J = 9.2 Hz), 6.82 ( 1 H, dd, J = 8.7, 1.8 Hz) , 7.49 ( 1 H, d, J = 201209056

將1H- ( 1，7 )-萘啶-2-酮 262mg懸浮於N，N-二甲基甲醯胺5mL，加入60%氫化鈉213mg，在室溫進行30分鐘攪拌。加入溴乙酸乙酯〇.4〇mL’在90°C進行17小時攪拌。於反應混合物加入水20mL與乙酸乙酯lOOmL，分離並取出有機層。將有機層以飽和氯化鈉水溶液1 〇mL洗淨，以無水硫酸鎂乾燥，減壓下將溶劑餾去。將所得之殘餾物以矽膠管柱層析法〔矽膠；關東化學股份有限公司，矽膠60，溶離液；乙酸乙酯〕進行純化，得到（2-側氧-2H- ( 1，7 )-萘啶-1-基）乙酸乙酯1 12mg。 1H NMR ( CHLOROFORM-d ) δ 1.30 ( 3 H, t, J= 7.1 Hz)，4.27 (2 H，q，J=7.1 Hz) , 5.13 (2 H，s) , 6.93 ( 1 H, d, J = 9.2 Hz ) , 7.45 ( 1 H, d, J= 5.0 Hz )，7.71 ( 1 H, d, J= 9.2 Hz ) ，8.48 ( 1 H, d, J= 5.0 Hz) ，8.59(1 H, s -25- 201209056262 mg of 1H-(1,7)-naphthyridin-2-one was suspended in 5 mL of N,N-dimethylformamide, and 213 mg of 60% sodium hydride was added thereto, and the mixture was stirred at room temperature for 30 minutes. Ethyl bromoacetate (4 〇 mL' was added and stirred at 90 ° C for 17 hours. 20 mL of water and 100 mL of ethyl acetate were added to the reaction mixture, and the organic layer was separated and taken out. The organic layer was washed with a saturated aqueous solution of sodium chloride (1 mL), dried over anhydrous magnesium sulfate and evaporated. The obtained residue was purified by silica gel column chromatography (Glue Gel; Kanto Chemical Co., Ltd., Silicone 60, Eluent; ethyl acetate) to obtain (2-oxo-2H-(1,7)- Naphthyridin-1-yl)acetate 1 12 mg. 1H NMR ( CHLOROFORM-d ) δ 1.30 ( 3 H, t, J = 7.1 Hz), 4.27 (2 H, q, J = 7.1 Hz) , 5.13 (2 H, s) , 6.93 ( 1 H, d, J = 9.2 Hz ) , 7.45 ( 1 H, d, J = 5.0 Hz ), 7.71 ( 1 H, d, J = 9.2 Hz ) , 8.48 ( 1 H, d, J = 5.0 Hz) , 8.59 (1 H, s -25- 201209056

使用7-甲氧基-1H- ( 1，5)-萘啶_2_酮3〇〇1^及3_溴丙酸乙基463mg’藉由與參考例7之同樣操作，得到無色油狀的3- ( 7-甲氧基-2-側氧-2H- ( 1，5)-萘啶-丨_基）丙酸乙基 2 0 7 m g ° 1H NMR ( CHLOROFORM-d) δ 1.18 - 1.29 ( 3 H m) ，2.77(2 Η，t，J=7.5 Hz)，3.99(3 Η, s)，4.15(2 Η， q，J=7.3 Hz) , 4.53 ( 2 H, t, J=7.5 Hz) ,6.75(1 H, d， J=9.7 Hz) , 7.29( 1 H, d, J=2.2 Hz) , 7.86(1 H, d, J ^9.7 Hz ) , 8.26 - 8.3 1 ( 1 H, m )。參考例1 0Using 7-methoxy-1H-(1,5)-naphthyridin-2-one 3?1? and 3-bromopropanoic acid ethyl 463 mg' obtained as a colorless oil. 3-( 7-Methoxy-2-oxo-2H-( 1,5)-naphthyridinium-yl)propionic acid ethyl 2 0 7 mg ° 1H NMR (CHLOROFORM-d) δ 1.18 - 1.29 ( 3 H m) , 2.77 (2 Η, t, J = 7.5 Hz), 3.99 (3 Η, s), 4.15 (2 Η, q, J = 7.3 Hz), 4.53 ( 2 H, t, J = 7.5 Hz), 6.75 (1 H, d, J = 9.7 Hz), 7.29 ( 1 H, d, J = 2.2 Hz), 7.86 (1 H, d, J ^ 9.7 Hz ) , 8.26 - 8.3 1 ( 1 H, m). Reference example 1 0

使用7-甲氧基-1H-喹喔啉-2-酮850mg及溴乙酸乙酯 1.06mL ’藉由與參考例7之同樣操作，得到黃色固體狀的 (7 -甲氧基-2-側氧- 2H-喹喔啉-1-基）乙酸乙酯288mg。 1H NMR ( CHLOROFORM-d) δ 1.28 ( 3 H, t, J = 7. 1 ^z) , 3.90 ( 3 H, s ) , 4.25 ( 2 H, q, J= 7.1 Hz) ,4.98(2 -26- 201209056 H, s) , 6.52 ( 1 Η, d, J=2.3 Hz) , 6.92 - 6.95 ( 1 H, m), 7.82 ( 1 H, d, J = 8.7 Hz ) , 8.18 ( 1 H, s )。參考例1 1Using 7-methoxy-1H-quinoxalin-2-one 850 mg and ethyl bromoacetate (1.06 mL) to give (7-methoxy-2- side as a yellow solid. Oxy- 2H-quinoxalin-1-yl)acetate 288 mg. 1H NMR (CHLOROFORM-d) δ 1.28 ( 3 H, t, J = 7. 1 ^z) , 3.90 ( 3 H, s ) , 4.25 ( 2 H, q, J = 7.1 Hz) , 4.98 (2 -26 - 201209056 H, s) , 6.52 ( 1 Η, d, J=2.3 Hz) , 6.92 - 6.95 ( 1 H, m), 7.82 ( 1 H, d, J = 8.7 Hz ) , 8.18 ( 1 H, s ) . Reference example 1 1

將2,3-二氫苯並（1，4 )戴奧辛-6-基胺l.〇〇g溶解於 N，N-二甲基甲醯胺10mL，加入氫化硼鈉346mg及溴乙腈 1.32mL，在室溫進行3小時攪拌。於反應混合物加入水 3 OmL >乙酸乙醋200mL及甲苯40mL，分離並取出有機層。將有機層以飽和氯化鈉水溶液20mL進行洗淨，以無水硫酸鎂乾燥，減壓下將溶劑餾去。將所得之殘餾物以矽膠管柱層析法〔矽膠；關東化學股份有限公司，矽膠60，溶離液；乙酸乙酯：己烷=1 : 1〕進行純化，得到（2，3 -二氫苯並（1，4)戴奧辛-6-基胺基）乙腈78 9mg。 1H NMR ( CHLOROFORM-d ) δ 3.67 ( 1 H, br. s.)， 4.03 ( 2 H, s) , 4.18 - 4.22 ( 2 H, m) , 4.23 - 4.27 ( 2 H, m)，6.25 ( 1 H，dd，J= 8.7，2.8 Hz) , 6.28 ( 1 H，d, J = 2.8 Hz ) , 6.78 ( 1 H, d, J= 8.7 Hz )。 -27- 201209056 參考例1 22,3-Dihydrobenzo(1,4)dioxin-6-ylamine l.〇〇g was dissolved in 10 mL of N,N-dimethylformamide, and 346 mg of sodium borohydride and 1.32 mL of bromoacetonitrile were added. Stirring was carried out for 3 hours at room temperature. Water (3 mL) > 200 mL of ethyl acetate and 40 mL of toluene were added to the reaction mixture, and the organic layer was separated and taken. The organic layer was washed with 20 mL of a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and evaporated. The obtained residue was purified by silica gel column chromatography (Glue Gel; Kanto Chemical Co., Ltd., Silicone 60, Eluent; ethyl acetate:hexane = 1 : 1) to obtain (2,3-dihydrogen). Benzo(1,4)dioxine-6-ylamino)acetonitrile 78 9 mg. 1H NMR ( CHLOROFORM-d ) δ 3.67 ( 1 H, br. s.), 4.03 ( 2 H, s) , 4.18 - 4.22 ( 2 H, m) , 4.23 - 4.27 ( 2 H, m), 6.25 ( 1 H, dd, J = 8.7, 2.8 Hz), 6.28 ( 1 H, d, J = 2.8 Hz ) , 6.78 ( 1 H, d, J = 8.7 Hz ). -27- 201209056 Reference example 1 2

於二異丙基乙胺1 72μί的四氫呋喃5.0mL溶液在冰冷下滴入η -丁基鋰（2.77mol/L η -己烷溶液）463μί並進行10分鐘。冷卻至-78°C，加入N-tert-丁氧基羰基哌啶_4_羧酸乙基30〇11^並進行1小時攪拌。加入（2,3-二氫苯並（1，4)戴奧辛-6-基胺基）乙.腈222mg的四氫呋喃5mL溶液，回復至室溫，進行18小時攪拌。於反應混合物加入水10mL及乙酸乙酯50m L ’分離並取出有機層。將有機層以飽和氯化鈉水溶液1 0 m L洗淨’以無水硫酸鎂乾燥，減壓下將溶劑餾去。將所得之殘餾物以矽膠管柱層析法〔矽膠；關東化學股份有限公司，砂膠60，溶離液；乙酸乙醋：己院=2: 3〕進行純化後得到黃色油狀的第三丁基=2- ( 2,3-二氣苯並（ 1，4)戴奧辛-6-基）-1-側氧-2,7-重氮螺（3_5)壬烷-7_羧酸醋65mg » 1H NMR ( CHLOROFORM-d ) δ 1.47 ( 9 H, s) , 1.74 1.83 (2 Η, m) , 1.96 - 2.03 ( 2 Η, m) , 3.37 - 3.44 ( 4 Η, m) , 3.73 - 3.80 ( 2 Η, m) , 4.21 - 4.26 (4 Η, m) , 6.80 -6.83(1 Η, m ) , 6.8 5 - 6.8 9 ( 2 Η, m )。 •28- 201209056To a solution of 1 72 μL of tetraisopropylfuran in 1.0 mL of diisopropylethylamine, 463 μί of η-butyllithium (2.77 mol/L η-hexane solution) was added dropwise under ice cooling for 10 minutes. After cooling to -78 ° C, N-tert-butoxycarbonylpiperidine-4-carboxylic acid ethyl group 30 〇 11 。 was added and stirred for 1 hour. A solution of 222 mg of (2,3-dihydrobenzo(1,4)dioxin-6-ylamino)acetonitrile was added in 5 mL of tetrahydrofuran, and the mixture was returned to room temperature and stirred for 18 hours. 10 mL of water and 50 ml of ethyl acetate were added to the reaction mixture, and the organic layer was taken out. The organic layer was washed with a saturated aqueous solution of sodium chloride (10 mL) and dried over anhydrous magnesium sulfate. The obtained residue was purified by silica gel column chromatography (矽胶; Kanto Chemical Co., Ltd., sand rubber 60, dissolving solution; acetic acid ethyl acetate: hexane=2:3) to obtain a yellow oil-like third. Butyl = 2-(2,3-dibenzobenzo (1,4) dioxin-6-yl)-1-oxo-2,7-diazospiro(3_5)decane-7_carboxylic acid vinegar 65mg » 1H NMR ( CHLOROFORM-d ) δ 1.47 ( 9 H, s) , 1.74 1.83 (2 Η, m) , 1.96 - 2.03 ( 2 Η, m) , 3.37 - 3.44 ( 4 Η, m) , 3.73 - 3.80 ( 2 Η, m) , 4.21 - 4.26 (4 Η, m) , 6.80 -6.83 (1 Η, m ) , 6.8 5 - 6.8 9 ( 2 Η, m ). •28- 201209056

HC^5； HCIHC^5; HCI

將第三丁基=2- (2,3-二氫苯並（1，4)戴奧辛-6-基 )側氧-2,7-重氮螺（3.5)壬烷-7-羧酸酯65mg溶解於氯仿l.OmL ’加入2 mol/L鹽酸的2-丙醇溶液3.0mL，在室溫進行1 5小時攪拌。將反應混合物在減壓下將溶劑餾去，得到淡黃色固體狀的2- (2,3-二氫苯並（I，4)戴奧辛-6-基 )-2,7-重氮螺（3.5)壬烷-1-酮的鹽酸鹽45mg。 1H NMR ( DEUTERIUM OXIDE) δ 2.13 - 2.27 ( 4 Η, m) , 3.28 (2 Η, br. s.) , 3.44 - 3.52 (2 Η, m) , 3,7 1 -3.75 ( 2 Η, m) , 4.28 - 4.3 6 ( 4 Η, m) , 6.90 - 6.94 ( 1 Η, m ) , 6.95 - 7.00 ( 2 Η, m)。參考例1 4The third butyl group = 2-(2,3-dihydrobenzo(1,4)dioxine-6-yl) side oxy-2,7-diazospiro(3.5)decane-7-carboxylate 65 mg Dissolved in 3.0 mL of 2-propanol solution of 2 mol/L hydrochloric acid dissolved in chloroform 1.0 mL, and stirred at room temperature for 15 hours. The solvent was distilled off under reduced pressure to give 2-(2,3-dihydrobenzo(I,4)dioxin-6-yl)-2,7-diazo snail (3.5) as a pale yellow solid. The hydrochloride salt of decane-1-one is 45 mg. 1H NMR ( DEUTERIUM OXIDE) δ 2.13 - 2.27 ( 4 Η, m) , 3.28 (2 Η, br. s.) , 3.44 - 3.52 (2 Η, m) , 3,7 1 -3.75 ( 2 Η, m) , 4.28 - 4.3 6 ( 4 Η, m) , 6.90 - 6.94 ( 1 Η, m ) , 6.95 - 7.00 ( 2 Η, m). Reference example 1 4

將6-碘-2,3-二氫苯並（1，4)戴奧辛34111^、第三丁基 =1-側氧-2,6-重氮螺（3.5)壬烷-6-羧酸酯300mg、碘化銅 25mg、磷酸鉀·η水合物6 6 0mg及（1R，2R) -N，N’-二甲基環 -29- 201209056 己烷-1，2·二胺41.1gL懸浮於N，N-二甲基甲醯胺l〇mL，在 1 l〇°C進行15.5小時攪拌。於反應混合物加入水30mL及乙酸乙酯lOOmL，分離並取出有機層。將有機層以飽和氯化鈉水溶液1 OmL洗淨，以無水硫酸鎂乾燥，減壓下將溶劑餾去。將所得之殘餾物以矽膠管柱層析法〔矽膠；關東化學股份有限公司，矽膠60，溶離液；乙酸乙酯：己烷=1: 1 〕進行純化，得到無色泡狀的第三丁基=2- ( 2,3-二氫苯並（1，4)戴奧辛-6-基）-1-側氧-2,6-重氮螺（3.5 )壬烷-6-羧酸酯442mg。 1H NMR ( CHLOROFORM-d ) δ 1.42 - 1.56 ( 1 0 H，m ),1.74 - 1.83 ( 1 H, m) , 1.89 - 2.01 (2 H, m) , 2.86 ( 1 H，br. s.)，3.23 ( 1 H, br_ s.)，3.33 ( 1 H，d，J=5.0 Hz) , 3.51 (1 H, br. s.) , 3.84 - 4.19(2 H, m) , 4.21 -4.27 ( 4 H, m) , 6.80 - 6.90 ( 3 H, m)。參考例1 56-iodo-2,3-dihydrobenzo(1,4)dioxine 34111^, tert-butyl=1-sideoxy-2,6-diazospiro(3.5)decane-6-carboxylate 300 mg, copper iodide 25 mg, potassium phosphate η hydrate 6 60 mg, and (1R, 2R) -N,N'-dimethylcyclo-29- 201209056 hexane-1,2.diamine 41.1 g L suspended in N N-dimethylformamide l〇mL was stirred at 1 l ° C for 15.5 hours. 30 mL of water and 100 mL of ethyl acetate were added to the reaction mixture, and the organic layer was separated and taken. The organic layer was washed with a saturated aqueous solution of sodium chloride (1 mL) and dried over anhydrous magnesium sulfate. The obtained residue was purified by silica gel column chromatography (Glue Gel; Kanto Chemical Co., Ltd., Silicone 60, Eluent; ethyl acetate:hexane = 1: 1) to obtain a third colorless bubble. Base = 2-(2,3-dihydrobenzo(1,4)dioxine-6-yl)-1-oxo-2,6-diazospiro(3.5)decane-6-carboxylate 442 mg. 1H NMR ( CHLOROFORM-d ) δ 1.42 - 1.56 ( 1 0 H,m ), 1.74 - 1.83 ( 1 H, m) , 1.89 - 2.01 (2 H, m) , 2.86 ( 1 H,br. s.), 3.23 ( 1 H, br_ s.), 3.33 ( 1 H, d, J = 5.0 Hz) , 3.51 (1 H, br. s.) , 3.84 - 4.19 (2 H, m) , 4.21 - 4.27 ( 4 H , m), 6.80 - 6.90 ( 3 H, m). Reference example 1 5

將第三丁基=2- (2,3-二氫苯並（1,4)戴奧辛-6-基 )-1-側氧-2,6-重氮螺（3.5)壬烷-6-羧酸酯440mg溶解於氯仿3mL，加入2 mol/L鹽酸之2 -丙醇溶液5mL，在室溫進行1 4.5小時攪拌。將反應混合物在減壓下將溶劑餾去，將所得之殘餾物以矽膠管柱層析法〔矽膠；FUJI SILYSIA股 -30- 201209056 份有限公司，Chromatorex-NH，溶離液；乙酸乙醋：己院 =4 : 1〕進行純化後得到淡黃色油狀的2- ( 2,3-二氫苯並 (1，4)戴奧辛-6-基）·2,6-重氮螺（3.5)壬烷-1-酮240mg 〇 1H NMR ( CHLOROFORM-d) δ 1.5 2 - 1.60 ( 1 H，m) ,1.79 - 1.90(2 H, m) , 1.98 - 2.05 ( 1 H, m) , 2.77 - 2.83 ( 1 H, m) , 2.84 - 2.90 ( 1 H, m) , 3.04 ( 1 H} d, J = 12.4 Hz) , 3.14 ( 1 H, d, J= 12.8 Hz)，3.3 7 ( 1 H，d，J = 5.5 Hz )，3.45 ( 1 H，d，J=5.5 Hz) , 4.21 - 4.27 ( 4 H, m ),6.79 - 6.84 ( 1 H, m) , 6.84 - 6.90 ( 2 H, m)。參考例1 6The third butyl group = 2-(2,3-dihydrobenzo(1,4)dioxine-6-yl)-1-oxo-2,6-diazospiro(3.5)decane-6-carboxylate 440 mg of the acid ester was dissolved in 3 mL of chloroform, and 5 mL of a 2 mol/L hydrochloric acid 2-propanol solution was added thereto, and the mixture was stirred at room temperature for 14.5 hours. The reaction mixture was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography [矽 ;; FUJI SILYSIA -30-201209056 parts, Chromatorex-NH, dissolving solution; ethyl acetate:己院=4 : 1] After purification, 2-( 2,3-dihydrobenzo(1,4)dioxin-6-yl)·2,6-diazosole (3.5)壬 was obtained as a pale yellow oil. Alkan-1-one 240 mg 〇1H NMR (CHLOROFORM-d) δ 1.5 2 - 1.60 ( 1 H, m) , 1.79 - 1.90 (2 H, m) , 1.98 - 2.05 ( 1 H, m) , 2.77 - 2.83 ( 1 H, m) , 2.84 - 2.90 ( 1 H, m) , 3.04 ( 1 H} d, J = 12.4 Hz) , 3.14 ( 1 H, d, J = 12.8 Hz), 3.3 7 ( 1 H,d, J = 5.5 Hz ), 3.45 ( 1 H, d, J = 5.5 Hz), 4.21 - 4.27 ( 4 H, m ), 6.79 - 6.84 ( 1 H, m) , 6.84 - 6.90 ( 2 H, m). Reference example 1 6

使用6-碘-2,3-二氫苯並（1，4)戴奧辛15711^及第三丁基=3-側氧-2,8-重氮螺（4.5)癸烷-8-羧酸酯152mg，藉由與參考例14之同樣操作，得到第三丁基=2- ( 2,3-二氫苯並（1，4)戴奧辛-6-基）-3-側氧-2,8-重氮螺（4.5)癸烷-8-羧酸酯279mg。 1H NMR ( CHLOROFORM-d) δ 1.46 ( 9 H, s ) , 1.62 -1.68(4 H, m) , 2.50(2 Η, s) , 3.27 - 3.35 (2 Η, m), -31 - 201209056 3.54 - 3.62 (4 H, m) , 4.22 - 4.28 (4 Η, m) , 6.85 ( 1 Η, d, J = 8.7 Hz ) , 7.02 ( 1 Η, dd, J = 8.7, 2.5 Hz ) ,7.12(1 Η, d, J=2.5 Hz) ο 參考例1 7Using 6-iodo-2,3-dihydrobenzo (1,4) dioxin 15511^ and tert-butyl = 3-oxo-2,8-diazospiro(4.5)decane-8-carboxylate 152 mg, by the same operation as in Reference Example 14 to give the titled butyl = 2-(2,3-dihydrobenzo (1,4) dioxin-6-yl)-3-oxo-2,8- Diazospiro (4.5) decane-8-carboxylate 279 mg. 1H NMR (CHLOROFORM-d) δ 1.46 ( 9 H, s ) , 1.62 -1.68 (4 H, m) , 2.50 (2 Η, s) , 3.27 - 3.35 (2 Η, m), -31 - 201209056 3.54 - 3.62 (4 H, m) , 4.22 - 4.28 (4 Η, m) , 6.85 ( 1 Η, d, J = 8.7 Hz ) , 7.02 ( 1 Η, dd, J = 8.7, 2.5 Hz ) , 7.12 (1 Η , d, J=2.5 Hz) ο Reference example 1 7

將第三丁基=2- (2,3-二氫苯並（1,4)戴奧辛-6-基 )-3-側氧-2,8-重氮螺（4.5)癸烷-8-羧酸酯248mg溶解於 1,4-二噁烷5mL，加入4 mol/L鹽酸之1,4-二噁烷溶液5mL，在50°C進行一晚攪拌。將反應混合物在減壓下使溶劑餾去，於所得之殘餾物中加入飽和碳酸氫鈉水溶液5mL及氯仿 2 0 mL，分離並取出有機層。將有機層以飽和氯化鈉水溶液 1 OmL洗淨，以無水硫酸鎂乾燥，減壓下將溶劑餾去，得到 2- (2,3-二氫苯並（1,4)戴奥辛-6-基）-3-側氧-2,8-重氮螺（4.5 )癸烷-3-酮 142mg。 1H NMR ( CHLOROFORM-d ) δ 1.66(4 H, t, J=5.5 Hz)，2.49(2 H，s) , 2.81 - 2.92(4 H，m)，3.58(2 H， s )，4.22 - 4.27 ( 4 H, m ) , 6.84 ( 1 H, d, J = 8.7 Hz)， 7.04 ( 1 H, dd, J=8.7, 2.3 Hz) , 7.13 ( 1 H, d, J=2.3 Hz -32- 201209056 參考例1 8The third butyl group = 2-(2,3-dihydrobenzo(1,4)dioxine-6-yl)-3-oxo-2,8-diazospiro(4.5)decane-8-carboxylate 248 mg of the acid ester was dissolved in 5 mL of 1,4-dioxane, and 5 mL of a 4 mol/L hydrochloric acid 1,4-dioxane solution was added thereto, and the mixture was stirred at 50 ° C overnight. The solvent was distilled off under reduced pressure, and the residue was evaporated and evaporated, and evaporated. The organic layer was washed with a saturated aqueous solution of sodium chloride (1 mL), dried over anhydrous magnesium sulfate, and then evaporated to the solvent to give 2-(2,3-dihydrobenzo (1,4) dioxin-6-yl. - -3-oxo-2,8-diazospiro(4.5)nonan-3-one 142 mg. 1H NMR (CHLOROFORM-d) δ 1.66 (4 H, t, J = 5.5 Hz), 2.49 (2 H, s), 2.81 - 2.92 (4 H, m), 3.58 (2 H, s ), 4.22 - 4.27 ( 4 H, m ) , 6.84 ( 1 H, d, J = 8.7 Hz), 7.04 ( 1 H, dd, J=8.7, 2.3 Hz) , 7.13 ( 1 H, d, J=2.3 Hz -32- 201209056 Reference example 1 8

使用6-碘-2,3-二氫苯並（1，4)戴奧辛293mg及第三丁基=1-側氧-2,9-重氮螺（5.5)十一烷-9-羧酸酯30〇1^，藉由與參考例14之同樣操作，得到黃色固體狀的第三丁基= 2- (2,3-二氫苯並（1，4)戴奧辛-6-基）-1-側氧-2,9-重氮螺（5.5) -j--院-9-翔酸醋 1 43mg。 1H NMR ( CHLOROFORM-d) δ 1.43 - 1.54 ( 2 H，m) ，1.46(9 Η，s)，1.88(2 H，d，J=4.6 Hz)，1.95(2 Η， br. s.) , 2.13 (2 H, ddd, J=13.6, 9.3, 4.1 Hz) , 3.29 (2 H, ddd, J = 13.3,' 9.2, 3.7 Hz) , 3.57 ( 2 H, t, J = 6.0 Hz ) ,3.75 - 3.8 1 ( 2 H, m )，4.24 ( 4 H，s)，6.6 6 ( 1 H，d d，J = 8.7, 2.3 Hz) , 6.71 ( 1 H, d, J=2.8 Hz) , 6.85 ( 1 H, d, J = 8.3 Hz )。參考例1 9Using 6-iodo-2,3-dihydrobenzo (1,4) dioxin 293 mg and tert-butyl = 1 - oxo-2,9-diazospiro (5.5) undecane-9-carboxylate 30 〇1^, by the same operation as in Reference Example 14 to give the title compound as the the the the the Lateral oxygen-2,9-diazo snail (5.5) -j--Yuan-9-xiang vinegar 1 43 mg. 1H NMR (CHLOROFORM-d) δ 1.43 - 1.54 ( 2 H,m) , 1.46 (9 Η, s), 1.88 (2 H, d, J = 4.6 Hz), 1.95 (2 Η, br. s.) , 2.13 (2 H, ddd, J = 13.6, 9.3, 4.1 Hz), 3.29 (2 H, ddd, J = 13.3, ' 9.2, 3.7 Hz), 3.57 ( 2 H, t, J = 6.0 Hz ) , 3.75 - 3.8 1 ( 2 H, m ), 4.24 ( 4 H, s), 6.6 6 ( 1 H, dd, J = 8.7, 2.3 Hz), 6.71 ( 1 H, d, J = 2.8 Hz) , 6.85 ( 1 H , d, J = 8.3 Hz ). Reference example 1 9

HC^V〇0HC^V〇0

HCI 使用第三丁基=2- (2,3-二氫苯並（1，4)戴奧辛-6-基 -33- 201209056 )-1-側氧-2,9-重氮螺（5·5)十一烷-9_羧酸酯M3mg，藉由與參考例14之同樣操作，得到無色粉末狀的2_ ( 2,3_二氫苯並（1，4 )戴奧辛_6_基）-丨_側氧-2,9_重氮螺（5 5 ) 十一烷-1-酮的鹽酸鹽1 12mg。HCI uses a third butyl group = 2-(2,3-dihydrobenzo (1,4) dioxin-6-yl-33-201209056)-1-side oxygen-2,9-diazo snail (5·5 Ethyl undecane-9-carboxylate M3 mg was obtained in the same manner as in Reference Example 14 to give 2-(2,3-dihydrobenzo(1,4)dioxin-6-yl)-oxime as a colorless powder. _ Side Oxygen-2,9-diazospiro (5 5 ) undecane-1-one hydrochloride 1 12 mg.

1H NMR(DMS0-d6) δ 1.63 - 1.69 (2 H, m) , 1.84 -1.88 (4 H，m)，2.14(2 H，ddd，J = 14.1，9.5，3.9 Hz)， 3.04 ( 2 H，ddd，J= 12.8, 9.4，3.4 Hz)，3.23 ( 2 H，ddd，J =12.6, 6.6, 4.1 Hz) , 3.48 - 3.5 3 ( 2 H, m) , 4.23 ( 4 H, s) , 6.64 - 6.68(1 H, m) , 6.74(1 H, d, J=2.3 Hz), 6.83(1 H, d, J = 8.7 Hz ) , 8.4 7 ( 1 H , b r. s .)。參考例2 01H NMR (DMS0-d6) δ 1.63 - 1.69 (2H, m), 1.84 -1.88 (4H, m), 2.14 (2H, ddd, J = 14.1, 9.5, 3.9 Hz), 3.04 ( 2 H, Ddd, J = 12.8, 9.4, 3.4 Hz), 3.23 ( 2 H, ddd, J = 12.6, 6.6, 4.1 Hz), 3.48 - 3.5 3 ( 2 H, m) , 4.23 ( 4 H, s) , 6.64 - 6.68 (1 H, m), 6.74 (1 H, d, J = 2.3 Hz), 6.83 (1 H, d, J = 8.7 Hz), 8.4 7 ( 1 H , b r. s .). Reference example 2 0

H〇^=oo — 將2-(1,4-二噁螺（4.5)癸烷-8-亞基）乙醇837mg溶解於氯仿20mL’加入三乙胺lmL’並使其冰冷下加入甲磺醯基氯化物0.5 3mL。在室溫進行1.5小時攪拌後，加入水 20mL，分離並取出有機層。將有機層以飽和氯化鈉水溶液 1 OmL洗淨，以無水硫酸鎂乾燥，減壓下將溶劑餾去，得到黃色油狀的8- (2-氯亞乙基）-1,4-二噁螺（4.5)癸烷 1.2 6 g ° 1H NMR ( CHLOROFORM-d) δ 1_66 - 1.77 ( 4 H，m) ，2.25 - 2.42 (4H，m)，3.95 - 4.00 (4 Η，m)，4.10 (2 H, d, J=8.0 Hz) , 5.47 ( 1 H, tt, J=8.0, 1.3 Hz)。 -34 - 201209056 參考例2 1H〇^=oo — 837 mg of 2-(1,4-dioxaspiro(4.5)decane-8-ylidene)ethanol was dissolved in chloroform 20 mL 'addition of triethylamine 1 mL' and added to the methanesulfonate under ice cooling Base chloride 0.5 3 mL. After stirring at room temperature for 1.5 hours, 20 mL of water was added, and the organic layer was separated and taken out. The organic layer was washed with aq. EtOAc (aq. Snail (4.5) decane 1.2 6 g ° 1H NMR (CHLOROFORM-d) δ 1_66 - 1.77 ( 4 H, m) , 2.25 - 2.42 (4H, m), 3.95 - 4.00 (4 Η, m), 4.10 (2 H, d, J = 8.0 Hz), 5.47 ( 1 H, tt, J = 8.0, 1.3 Hz). -34 - 201209056 Reference Example 2 1

將7 -氟-1H- ( 1，5)-萘啶-2 -酮392mg懸浮於N，N -二甲基甲醯胺l〇mL，加入60%氫化鈉116mg’並在室溫進行1.5 小時攪拌。加入2 - ( 1，4 -二噁螺（4 · 5 )癸烷-8 -基）乙基= 甲烷磺酸鹽631mg的Ν,Ν-二甲基甲醯胺5mL溶液’在室溫進行3天攪拌。於反應混合物加入水45mL '乙酸乙酯50mL 及甲苯lOmL，分離並取出有機層。將有機層以飽和氯化鈉水溶液l〇mL洗淨，以無水硫酸鎂乾燥，減壓下將溶劑餾去，將所得之殘餾物以矽膠管柱層析法〔矽膠；關東化學股份有限公司，矽膠60，溶離液；乙酸乙酯：甲醇=9: 1〕進行純化後得到淡黃色固體狀的1 - ( 2- ( 1，4-二噁螺（4 · 5 )癸院-8 -基）乙基）-7 -氟-1H-(1，5)萘 U定-2-酮 l〇8mg。 1H NMR ( CHLOROFORM-d) δ 1.3 6 - 1.4 3 ( 2 H，m) ,1.48 - 1.56(2 H, ra) , 1.57 - 1.67(3 H, m) , 1.79(2 H, dd, J=14.4, 2.1 Hz) , 1.85 - 1.90 (2 H, m) , 3.93 - 3.98 ( 4 H，m)，4_20 - 4.24 ( 2 H，m)，6.86 ( 1 H，d，J = 9.6 Hz) , 7.31 ( 1 H, dd, J= 10.1, 2.3 Hz) , 7.87 ( 1 H, d, J = 9.6 Hz ) , 8.42 ( 1 H, d, J = 2.3 Hz )。 -35- 201209056 參考例2 2392 mg of 7-fluoro-1H-(1,5)-naphthyridin-2-one was suspended in 100 mL of N,N-dimethylformamide, and added with 60% sodium hydride 116 mg' and allowed to stand at room temperature for 1.5 hours. Stir. Add 2-(1,4-dioxaspiro(4·5)decane-8-yl)ethyl = methanesulfonate 631 mg of hydrazine, hydrazine-dimethylformamide 5 mL solution 'at room temperature 3 Stir in the day. 45 mL of water, 50 mL of ethyl acetate and 10 mL of toluene were added to the reaction mixture, and the organic layer was separated and taken. The organic layer was washed with a saturated aqueous solution of sodium chloride (1 mL), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography [矽胶; 关东化工股份有限公司, phthalocyanine 60, eluent; ethyl acetate: methanol = 9: 1] After purification, 1 - (2-( 1,4-dioxanthene (4 · 5 ) 癸-8-yl) was obtained as a pale yellow solid. Ethyl)-7-fluoro-1H-(1,5)naphthalene U-di-2-one l〇8 mg. 1H NMR (CHLOROFORM-d) δ 1.3 6 - 1.4 3 ( 2 H,m) , 1.48 - 1.56(2 H, ra) , 1.57 - 1.67(3 H, m) , 1.79(2 H, dd, J=14.4 , 2.1 Hz) , 1.85 - 1.90 (2 H, m) , 3.93 - 3.98 ( 4 H,m), 4_20 - 4.24 ( 2 H,m), 6.86 ( 1 H,d,J = 9.6 Hz) , 7.31 ( 1 H, dd, J = 10.1, 2.3 Hz) , 7.87 ( 1 H, d, J = 9.6 Hz ) , 8.42 ( 1 H, d, J = 2.3 Hz ). -35- 201209056 Reference Example 2 2

將7-氟-1H- ( 1,5)-萘啶-2-酮350mg懸浮於N，N-二甲基甲醯胺l〇mL，冰冷下加入60%氫化鈉102mg，在室溫下進行2小時攪拌。加入8-(2-氯亞乙基）·1，4-二噁螺（4.5 )癸烷5 5 9mg的Ν，Ν-二甲基甲醯胺溶液3mL，在室溫進行3 天攪拌。於反應混合物加入水45mL、乙酸乙酯50m L及甲苯1 OmL，分離並取出有機層。將有機層以飽和氯化鈉水溶液1 OmL洗淨，以無水硫酸鎂乾燥，減壓下將溶劑餾去，將所得之殘餾物以矽膠管柱層析法〔矽膠；關東化學股份有限公司，矽膠60，溶離液：乙酸乙酯：甲醇=9: 1〕進行純化後得到淡黃色固體狀的1- ( 2- ( 1，4-二噁螺（4.5 )癸烷-8-亞基）乙基）-7-氟-1H-(1，5)萘啶-2-酮202mg。 1H NMR ( CHLOROFORM-d ) δ 1.67 - 1.73 ( 2 H, m ) ,1.79 - 1.84 ( 2 Η, m) , 2.27 ( 2 Η, t, J=6.4 Hz) , 2.54 -2.59 (2 Η，m)，3.95 - 4.02 (4 Η，m)，4.88 (2 Η, d, J = 6.4 Hz)，5.14 ( 1 H, t, J= 6.6 Hz) ， 6.88 ( 1 H, d, J = 10.1 Hz) , 7.30 ( 1 H, dd, J= 10.1, 2.3 Hz) , 7.85 - 7.90 (1 H, m ) , 8.4 1 ( 1 H, d, J = 2.3 Hz )。 -36- 201209056 參考例2 3350 mg of 7-fluoro-1H-(1,5)-naphthyridin-2-one was suspended in 100 mL of N,N-dimethylformamide, and 102 mg of sodium hydride 60% was added under ice cooling at room temperature. Stir for 2 hours. 8 mL of a solution of Ν, Ν-dimethylformamide in 8-(2-chloroethylidene)·1,4-dioxaspiro(4.5) decane was added, and the mixture was stirred at room temperature for 3 days. 45 mL of water, 50 ml of ethyl acetate and 10 mL of toluene were added to the reaction mixture, and the organic layer was separated. The organic layer was washed with a saturated aqueous solution of sodium chloride (1 mL), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (矽胶; Kanto Chemical Co., Ltd., Ethylene 60, Eluent: Ethyl acetate:methanol = 9:1] Purified to give 1-(2-(4-dioxaspiro(4.5)decane-8-ylidene) Base 7-fluoro-1H-(1,5)naphthyridin-2-one 202 mg. 1H NMR ( CHLOROFORM-d ) δ 1.67 - 1.73 ( 2 H, m ) , 1.79 - 1.84 ( 2 Η, m) , 2.27 ( 2 Η, t, J = 6.4 Hz) , 2.54 -2.59 (2 Η, m) , 3.95 - 4.02 (4 Η, m), 4.88 (2 Η, d, J = 6.4 Hz), 5.14 ( 1 H, t, J = 6.6 Hz) , 6.88 ( 1 H, d, J = 10.1 Hz) , 7.30 ( 1 H, dd, J = 10.1, 2.3 Hz), 7.85 - 7.90 (1 H, m ) , 8.4 1 ( 1 H, d, J = 2.3 Hz ). -36- 201209056 Reference Example 2 3

使用7-甲氧基-1H- ( 1，5)-萘啶-2-酮86 9mg及2- ( 1,4-二噁螺（4.5)癸烷-8-亞基）乙基=甲烷磺酸鹽1.43g，藉由與參考例2 1之同樣操作，得到淡黃色固體狀的1 - ( 2-( 1,4-二噁螺（4.5)癸烷-8-亞基）乙基）-7-甲氧基-1Η-( 1，5 )萘啶-2-酮 961mg。 1H NMR ( CHLOROFORM-d ) δ 1.75 ( 4 H, dt, J = 19.4, 6.8 Hz) , 2.21 - 2.32 ( 2 H, m ) , 2.52 - 2.62 ( 2 H, m) , 3.95(3 H, s) , 3.96 - 4.01 (4 H, m) , 4.92(2 H, d，J=6.2 Hz)，5.11 - 5.22 ( 1 H，m)，6.77 ( 1 H，d，J = 9.7 Hz)，7.02 ( 1 H，d, J=2.2 Hz)，7.81 - 7.88 ( 1 H，m ),8.27 ( 1 H，d，J = 2.2 Hz )。參考例24Using 9-methoxy-1H-(1,5)-naphthyridin-2-one 86 9 mg and 2-(1,4-dioxaspiro(4.5)decane-8-ylidene)ethyl = methanesulfonate 1.13 g of the acid salt (m.p. 7-Methoxy-1?-(1,5)naphthyridin-2-one 961 mg. 1H NMR ( CHLOROFORM-d ) δ 1.75 ( 4 H, dt, J = 19.4, 6.8 Hz) , 2.21 - 2.32 ( 2 H, m ) , 2.52 - 2.62 ( 2 H, m) , 3.95 (3 H, s) , 3.96 - 4.01 (4 H, m) , 4.92 (2 H, d, J = 6.2 Hz), 5.11 - 5.22 ( 1 H, m), 6.77 ( 1 H, d, J = 9.7 Hz), 7.02 ( 1 H, d, J = 2.2 Hz), 7.81 - 7.88 ( 1 H, m ), 8.27 ( 1 H, d, J = 2.2 Hz ). Reference example 24

將1-(2-(1，4-二噁螺（4.5)癸烷-8-基）乙基）-7-氟-1H-(1,5)萘啶-2-酮168mg溶解於丙酮6mL，力□入三氟 -37- 201209056 甲磺酸銦（III) 3mg’在室溫進行22小時攪拌，在50 °c進行48小時攪拌。將反應混合物在減壓下使溶劑餾去，將所得之殘餾物以砂膠管柱層析法〔矽膠；關東化學股份有限公司，矽膠60，溶離液；乙酸乙酯：己烷=95: 5〕進行純化後得到白色固體狀的7 -氣-1- ( 2_ ( 4 -側氧環己基）乙基）-1H-(1，5)蔡陡-2-嗣 95mg» 1H NMR ( CHLOROFORM-d ) δ 1.50 - 1.5 9 ( 2 H, m) ,1.71 - 1.76(2 Η, m) , 1.89 . 1.97( 1 Η, m) ; 2.19 - 2.25 ( 2 Η, m) , 2.3 5 - 2.46 ( 4 Η, m) , 4.27 - 4.30 ( 2 Η, m) , 6.88 ( 1 Η, d, J=9.6 Hz) , 7.32 ( 1 Η, dd, J = 10.1, 2.3 Hz)，7.89 . 7.91 ( 1 Η, m)，8 44 ( ) Η，d，J= 2 3 Ηζ )0 參考例2 5Dissolve 168 mg of 1-(2-(1,4-dioxaspiro(4.5)decane-8-yl)ethyl)-7-fluoro-1H-(1,5)naphthyridin-2-one in acetone 6 mL , force into trifluoro-37-201209056 indium (III) methanesulfonate 3mg' was stirred at room temperature for 22 hours, and stirred at 50 °c for 48 hours. The reaction mixture was distilled off under reduced pressure, and the obtained residue was subjected to grit column chromatography (gum.; Kanto Chemical Co., Ltd., Silicone 60, Eluent; ethyl acetate: hexane = 95: 5) Purified to give 7-gas-1-(2-(4-oxocyclohexyl)ethyl)-1H-(1,5) Chae-deep-2-嗣95 mg» 1H NMR (CHLOROFORM-d) as a white solid δ 1.50 - 1.5 9 ( 2 H, m) , 1.71 - 1.76(2 Η, m) , 1.89 . 1.97( 1 Η, m) ; 2.19 - 2.25 ( 2 Η, m) , 2.3 5 - 2.46 ( 4 Η , m) , 4.27 - 4.30 ( 2 Η, m) , 6.88 ( 1 Η, d, J = 9.6 Hz) , 7.32 ( 1 Η, dd, J = 10.1, 2.3 Hz), 7.89 . 7.91 ( 1 Η, m ),8 44 ( ) Η,d,J= 2 3 Ηζ )0 Reference Example 2 5

4.5 )癸烷-8-亞基）乙基〇mg’藉由與參考例24之使用 1- ( 2- ( 1,4-二噁螺（4·5) -7-氟-1H- ( 1，5 )萘啶-2-酮 2〇〇mg，同樣操作’得到白色固體狀的7-氟_1-(2-(4_側氧環亞己基）乙基）-1Η-(1，5)萘陡- 2-_95mg。 )2.4 1 - 2.46(2 Η, m ) Η，t，J=7.1 Hz)，2.82 1H NMR ( CHLOROFORM-d) δ 2.41 ,2.5 0 - 2.5 4 ( 2 H, m) , 2.56 ( 2 H t H，t，J = 7. 1 Hz )，4.92 ( H, d, J= 6.4 Hz) , 5.36 ( 201209056 1 H, td, J= 5.8, 1.1 Hz) , 6.89 ( 1 H, d, J = 10. 1 Hz ), 7.33 ( 1 H, dd, J=10.1, 1.8 Hz) , 7.86 - 7.94 ( 1 H, m), 8.44 ( 1 H, d, J= 1 .8 Hz )。參考例2 64.5) decane-8-ylidene)ethyl hydrazine mg' by the use of Reference Example 24 1-(2-(1,4-dioxaspiro(4·5)-7-fluoro-1H- (1 , 5) Naphthyridin-2-one 2 〇〇 mg, same operation 'to give 7-fluoro-1-(2-(4-oxo-oxocyclohexyl)ethyl)-1 Η-(1,5 as a white solid Naphthalene steepness - 2-_95 mg. ) 2.4 1 - 2.46 (2 Η, m ) Η, t, J = 7.1 Hz), 2.82 1H NMR (CHLOROFORM-d) δ 2.41 , 2.5 0 - 2.5 4 ( 2 H, m ), 2.56 ( 2 H t H,t,J = 7. 1 Hz ), 4.92 ( H, d, J= 6.4 Hz) , 5.36 ( 201209056 1 H, td, J= 5.8, 1.1 Hz) , 6.89 ( 1 H, d, J = 10. 1 Hz ), 7.33 ( 1 H, dd, J = 10.1, 1.8 Hz) , 7.86 - 7.94 ( 1 H, m), 8.44 ( 1 H, d, J = 1. 8 Hz ). Reference example 2 6

使用1-(2-( 1，4-二噁螺（4.5)癸烷-8-亞基）乙基 )-7-甲氧基-1H-(1,5)萘啶-2-酮950mg，藉由與參考例 24之同樣操作，得到黃白色固體狀的7-甲氧基-1-(2- (4-側氧環亞己基）乙基）-1H-(1，5)萘啶-2-酮280mg。 1H NMR ( CHLOROFORM-d ) δ 2.37 - 2.60 (6 H, m) ，2.77 - 2.8 8 ( 2 Η, m)，3.97 ( 3 Η, s)，4.94 ( 2 Η，d，J = 6.6 Hz) , 5.33 - 5.44 ( 1 H, m) , 6.77(1 H, d, J=9.7 Hz) , 7.03 ( 1 H, d, J = 2.2 Hz ) , 7.86 ( 1 H, d, J = 9.7 )， 8.30 ( 1 H, d, J = 2.2 Hz )。參考例2 71-(2-(1,4-dioxaspiro(4.5)decane-8-ylidene)ethyl)-7-methoxy-1H-(1,5)naphthyridin-2-one 950 mg, 7-Methoxy-1-(2-(4-oxocyclohexylidene)ethyl)-1H-(1,5)naphthyridine- 2-ketone 280 mg. 1H NMR ( CHLOROFORM-d ) δ 2.37 - 2.60 (6 H, m) , 2.77 - 2.8 8 ( 2 Η, m), 3.97 ( 3 Η, s), 4.94 ( 2 Η, d, J = 6.6 Hz), 5.33 - 5.44 ( 1 H, m) , 6.77 (1 H, d, J = 9.7 Hz) , 7.03 ( 1 H, d, J = 2.2 Hz ) , 7.86 ( 1 H, d, J = 9.7 ), 8.30 ( 1 H, d, J = 2.2 Hz ). Reference example 2 7

將7-氟-1- ( 2- ( 4-側氧環己基）乙基）-1 Η- ( 1,5 )萘 -39- 201209056 啶-2-酮94mg溶解於二甲基亞颯2mL，加入三甲基鎏碘化物 93mg、60%氫化鈉18mg，在50°C進行1小時攪拌。將反應混合物在冰冷下加入水20mL及二乙基醚20mL，分離取出有機層。將有機層以飽和氯化鈉水溶液1 OmL洗淨，以無水硫酸鎂乾燥，減壓下將溶劑餾去，得到白色固體狀的7-氟- 1- (2-(1-噁螺（2.5)辛-6 -基）乙基）-1H-(1，5)萘啶- 2- 酮 73mg。 1H NMR ( CHLOROFORM-d ) δ 0.82 - 0.91 ( 2 H, m) ，1.19 - 1.36 ( 4 H，m)，1.40 ( 1 H，dt，J = 13.2，2.6 Hz) ,1.5 5 - 1.63 ( 1 H, m) , 1.65 - 1.71 (2 H, m) , 1.85 -1.95 ( 2 H，m)，2.02 - 2.07 ( 1 H，m)，4.25 ( 2 H，dt，J = 12.2, 8.1 Hz) , 6.87 ( 1 H, d, J=9.6 Hz) , 7.30 - 7.33 (1 H, m) , 7.88 ( 1 H, dd, J=9.9, 1.6 Hz) , 8.43 ( 1 H, t, J= 2.3 Hz )。參考例2 8Dissolving 94 mg of 7-fluoro-1-(2-(4-oxocyclohexyl)ethyl)-1 Η-( 1,5 ) naphthalene-39- 201209056 pyridine-2-one in dimethyl hydrazine 2 mL, 93 mg of trimethylsulfonium iodide and 18 mg of 60% sodium hydride were added, and the mixture was stirred at 50 ° C for 1 hour. The reaction mixture was added with water (20 mL) and diethyl ether (20 mL) under ice cooling, and the organic layer was separated. The organic layer was washed with aq. EtOAc (aq. Oct-6-yl)ethyl)-1H-(1,5)naphthyridin-2-one ketone 73 mg. 1H NMR ( CHLOROFORM-d ) δ 0.82 - 0.91 ( 2 H, m) , 1.19 - 1.36 ( 4 H, m), 1.40 ( 1 H, dt, J = 13.2, 2.6 Hz) , 1.5 5 - 1.63 ( 1 H , m) , 1.65 - 1.71 (2 H, m) , 1.85 -1.95 ( 2 H,m), 2.02 - 2.07 ( 1 H,m), 4.25 ( 2 H,dt,J = 12.2, 8.1 Hz) , 6.87 ( 1 H, d, J = 9.6 Hz) , 7.30 - 7.33 (1 H, m) , 7.88 ( 1 H, dd, J = 9.9, 1.6 Hz) , 8.43 ( 1 H, t, J = 2.3 Hz ). Reference example 2 8

使用7-氟-1-(2-(4-側氧環亞己基）乙基）5 )萘啶-2-酮70mg，藉由與參考例27之同樣操作’得到淡黃色固體狀的7 -氟-1-( 2-(1-噁螺（2.5)辛-6*亞基）乙基）-1H-(1，5)萘啶-2-酮 51mg。 1H NMR ( CHLOROFORM-d) δ 1.52 - 1·57 ( 1 H，m) 201209056 ,1.64 - 1.69 ( 1 H, m) , 1.74 - 1.79 ( 1 Η, m) , 1.84 - 1.90 ( 1 Η, m) , 2.21 - 2.26 ( 1 Η, m) , 2.39 - 2.45 ( 1 Η, m) , 2.55 - 2.62 ( 1 Η, m) , 2.65 - 2.68 ( 1 Η, m) , 2.70 (1 Η, d, J=5.0 Hz) , 2.72 - 2.74 ( 1 Η, m) , 4.81 ( 1 Η, dd, J= 1 5.6, 6.0 Hz ) , 5.01 ( 1 Η, dd, J= 15.1, 6.9 Hz), 5.21 ( 1 H, t, J= 6.4 Hz) , 6.89 ( 1 H, d, J= 9.6 Hz), 7.33 ( 1 H, dd, J= 10.1, 1.8 Hz) , 7.87 - 7.91 ( 1 H, m), 8.42 ( 1 H, d, J = 1.8 Hz )。參考例2 97-fluoro-1-(2-(4-oxocyclohexylidene)ethyl)5)naphthyridin-2-one 70 mg was obtained by the same procedure as in Reference Example 27 to give a pale yellow solid. Fluor-1-(2-(1-oxaspiro(2.5) osin-6*ylidene)ethyl)-1H-(1,5)naphthyridin-2-one 51 mg. 1H NMR (CHLOROFORM-d) δ 1.52 - 1·57 ( 1 H,m) 201209056 ,1.64 - 1.69 ( 1 H, m) , 1.74 - 1.79 ( 1 Η, m) , 1.84 - 1.90 ( 1 Η, m) , 2.21 - 2.26 ( 1 Η, m) , 2.39 - 2.45 ( 1 Η, m) , 2.55 - 2.62 ( 1 Η, m) , 2.65 - 2.68 ( 1 Η, m) , 2.70 (1 Η, d, J= 5.0 Hz) , 2.72 - 2.74 ( 1 Η, m) , 4.81 ( 1 Η, dd, J = 1 5.6, 6.0 Hz ) , 5.01 ( 1 Η, dd, J= 15.1, 6.9 Hz), 5.21 ( 1 H, t, J = 6.4 Hz) , 6.89 ( 1 H, d, J = 9.6 Hz), 7.33 ( 1 H, dd, J = 10.1, 1.8 Hz) , 7.87 - 7.91 ( 1 H, m), 8.42 ( 1 H , d, J = 1.8 Hz ). Reference example 2 9

將 7-氟-1-( 2-(1-噁螺（2.5)辛-6-基）乙基）-1H-(1，5)萘啶-2-酮7〇11^及2,3-二氫苯並（1，4)戴奧辛-6-基胺35mg溶解於90%乙醇2mL，在85°C進行23小時攪拌。將反應混合物在減壓下使溶劑餾去，將所得之殘餾物以矽膠管柱層析法〔矽膠：FUJI SILYSIA股份有限公司， Chromatorex-NH，溶離液；乙酸乙酯：己烷=7: 3〕進行純化，得到1-(2- (4- ( (2,3 -二氫苯並（1，4)戴奧辛-6-基胺基）甲基）-4-羥基環己基）乙基）_7-氟- iH-C1，5) 萘啶-2-酮54mg (非對映異構物A : 24mg ’黃色固體狀物質，非對映異構物B: 3 0mg，黃色油狀物質）° 2012090567-Fluoro-1-(2-(1-oxaspiro(2.5) oct-6-yl)ethyl)-1H-(1,5)naphthyridin-2-one 7〇11^ and 2,3- 35 mg of dihydrobenzo(1,4)dioxin-6-ylamine was dissolved in 2 mL of 90% ethanol, and stirred at 85 ° C for 23 hours. The reaction mixture was subjected to distillation under reduced pressure, and the obtained residue was purified by silica gel column chromatography (solvent: FUJI SILYSIA Co., Ltd., Chromatorex-NH, eluent; ethyl acetate:hexane = 7: 3] Purification to obtain 1-(2-(4-((2,3-dihydrobenzo(1,4)dioxo-6-ylamino)methyl)-4-hydroxycyclohexyl)ethyl) _7-Fluoro-iH-C1,5) Naphthyridin-2-one 54 mg (diastereomer A: 24 mg 'yellow solid substance, diastereomer B: 30 mg, yellow oily substance) 201209056

非對映異構物A 1H NMR ( CHLOROFORM-d) δ 1.3 5 - 1.8 5 ( 1 1 H，m ),3.02 (2 H, s) , 4.14 - 4.31 (6 H, m) , 6.18 - 6.27 (2 H, m) , 6.65 - 6.75 ( 1 H, m) , 6.86 ( 1 H, d, J=9.7 Hz) ,7.33 ( 1 H, dd, J=9.4, 2.2 Hz) , 7.82 - 7.92 ( 1 H, m), 8.42 ( 1 H, d, J = 2.2 Hz )。Diastereomer A 1H NMR (CHLOROFORM-d) δ 1.3 5 - 1.8 5 ( 1 1 H,m ), 3.02 (2 H, s) , 4.14 - 4.31 (6 H, m) , 6.18 - 6.27 ( 2 H, m) , 6.65 - 6.75 ( 1 H, m) , 6.86 ( 1 H, d, J=9.7 Hz) , 7.33 ( 1 H, dd, J=9.4, 2.2 Hz) , 7.82 - 7.92 ( 1 H , m), 8.42 ( 1 H, d, J = 2.2 Hz ).

非對映異構物B 1H NMR ( CHLOROFORM-d ) δ 1.12 - 1.99 ( 11 H, m ),3.13 (2 H, s) , 4.15 - 4.27 (6 H, m) , 6.18 - 6.27 (2 H, m) , 6.66 - 6.74 ( 1 H, m) , 6.87 ( 1 H, d, J= 10.1 Hz ),7.31 ( 1 H, dd, J=9.9, 2.0 Hz) , 7.82 - 7.92 ( 1 H, m ),8.43 ( 1 H, d, J = 2.0 Hz )。參考例3 0Diastereomer B 1H NMR ( CHLOROFORM-d ) δ 1.12 - 1.99 ( 11 H, m ), 3.13 (2 H, s) , 4.15 - 4.27 (6 H, m) , 6.18 - 6.27 (2 H, m) , 6.66 - 6.74 ( 1 H, m) , 6.87 ( 1 H, d, J = 10.1 Hz ), 7.31 ( 1 H, dd, J = 9.9, 2.0 Hz) , 7.82 - 7.92 ( 1 H, m ) , 8.43 ( 1 H, d, J = 2.0 Hz ). Reference example 3 0

使用7-氟-1- ( 2- ( 1-噁螺（2.5 )辛-6-亞基）乙基）-1H-(1，5)萘啶-2-酮50mg及2,3-二氫苯並（1，4)戴奧辛-6_基胺28mg，藉由與參考例29之同樣操作，得到黃色油狀的1-(2-(4-( (2,3-二氫苯並（1，4)戴奧辛-6-基胺基）甲基）-4-羥基環亞己基）乙基）-7-氟-1H-(1,5)萘啶-2-酮 43mg。 -42- 201209056 1H NMR ( CHLOROFORM-d ) δ 1.47 - 1.62 ( 2 H, m) ,1.77 - 1.82 ( 1 H, m) , 1.90 - 1.95 ( 1 H, m) , 2.05 - 2.09 ( 1 H, m) , 2.42 - 2.51 ( 2 H, m) , 2.65 - 2.70 ( 1 H, m) , 3.08(2 H, d, J=2.8 Hz) , 4.18 - 4.20(2 H, m), 4.22 - 4.24 ( 2 H, m) , 4.74 - 4.79 ( 1 H, m) , 5.00 ( 1 H, dd, J=15.6, 6.4 Hz) , 5.13 ( 1 H, t, J=6.6 Hz) , 6.25 - 6.32 (2 H, m) , 6.72 ( 1 H, d, J=8.7 Hz) , 6.88 ( 1 H, d, J=9.6 Hz) , 7.32(1 H, dd, J=10.1, 2.3 Hz) , 7.88(1 H, d, J = 9.6 Hz ) , 8.42 ( 1 H, d, J= 2.3 Hz )。參考例3 1Using 7-fluoro-1-(2-(1-oxaspiro(2.5) osin-6-ylidene)ethyl)-1H-(1,5)naphthyridin-2-one 50 mg and 2,3-dihydrogen Benzo(1,4) dioxin-6-ylamine 28 mg was obtained in the same manner as in Reference Example 29 to give 1-(2-(4-(2,3-dihydrobenzo) as a yellow oil. 4) Dioxin-6-ylamino)methyl)-4-hydroxycyclohexylidene)ethyl)-7-fluoro-1H-(1,5)naphthyridin-2-one 43 mg. -42- 201209056 1H NMR ( CHLOROFORM-d ) δ 1.47 - 1.62 ( 2 H, m) , 1.77 - 1.82 ( 1 H, m) , 1.90 - 1.95 ( 1 H, m) , 2.05 - 2.09 ( 1 H, m ), 2.42 - 2.51 ( 2 H, m) , 2.65 - 2.70 ( 1 H, m) , 3.08 (2 H, d, J = 2.8 Hz) , 4.18 - 4.20(2 H, m), 4.22 - 4.24 ( 2 H, m), 4.74 - 4.79 ( 1 H, m) , 5.00 ( 1 H, dd, J = 15.6, 6.4 Hz), 5.13 ( 1 H, t, J = 6.6 Hz) , 6.25 - 6.32 (2 H, m) , 6.72 ( 1 H, d, J = 8.7 Hz) , 6.88 ( 1 H, d, J = 9.6 Hz) , 7.32 (1 H, dd, J = 10.1, 2.3 Hz), 7.88 (1 H, d , J = 9.6 Hz ) , 8.42 ( 1 H, d, J = 2.3 Hz ). Reference example 3 1

使用7-甲氧基-1- ( 2- ( 1-噁螺（2.5 )辛-6-亞基）乙_ 基）-1^(1，5)萘啶-2-酮11〇1^及2,3-二氫苯並（1，4)戴奧辛-6-基胺59mg，藉由與參考例30之同樣操作，得到黃色油狀的1-(2-(4-( (2,3-二氫苯並（1，4)戴奧辛-6-基胺基）甲基）-4-羥基環亞己基）乙基）-7-甲氧基-1H-( 1，5 )萘啶-2-酮 145mg。 1H NMR ( CHLOROFORM-d) δ 1.5 1 ( 1 H, td，J = 12.7, 4.4 Hz) , 1.59 ( 1 H, td, J= 12.7, 4.4 Hz) , 1.75 - 1.81 ( 1 H, m) , 1.8 9 - 1.95 ( 1 H, m) , 2.05 - 2.11 ( 1 H, m) , 2.40 - 2.50 ( 2 H, m) , 2.69 ( 1 H, dt, J= 13.5, 4.0Using 7-methoxy-1-(2-(1-oxaspiro(2.5) osin-6-ylidene)ethidyl)-1^(1,5)naphthyridin-2-one 11〇1^ and 2,3-Dihydrobenzo(1,4) dioxin-6-ylamine 59 mg was obtained in the same manner as in Reference Example 30 to give 1-(2-(4-((2,3-) Dihydrobenzo(1,4)dioxin-6-ylamino)methyl)-4-hydroxycyclohexylidene)ethyl)-7-methoxy-1H-(1,5)naphthyridin-2- Ketone 145 mg. 1H NMR (CHLOROFORM-d) δ 1.5 1 ( 1 H, td, J = 12.7, 4.4 Hz), 1.59 ( 1 H, td, J = 12.7, 4.4 Hz) , 1.75 - 1.81 ( 1 H, m) , 1.8 9 - 1.95 ( 1 H, m) , 2.05 - 2.11 ( 1 H, m) , 2.40 - 2.50 ( 2 H, m) , 2.69 ( 1 H, dt, J= 13.5, 4.0

Hz) , 3.02 - 3.09 (2 H, m) , 3.95 (3 H, s) , 4.18(2 H, -43- 201209056 td, J = 3.7, 1.8 Hz ) , 4.22(2 H, td, J = 3.8, 2.1 Hz ), 4.74 ( 1 H, dd, J = 15.4, 6.6 Hz ) , 5.09 ( 1 H, dd, J= 15.6, 6.0 Hz) , 5.14 - 5.18 ( 1 H, m) , 6.19 - 6.23 ( 1 H, m), 6.24 ( 1 H, s) , 6.70 ( 1 H, d, J= 8.7 Hz) , 6.76 ( 1 H, d, J= 9.6 Hz) , 7.04(1 H, d, J = 2.3 Hz) , 7.85(1 H, d, J =9.6 Hz ) , 8.27 ( 1 H, d, J = 2.3 Hz )。參考例3 2Hz) , 3.02 - 3.09 (2 H, m) , 3.95 (3 H, s) , 4.18 (2 H, -43- 201209056 td, J = 3.7, 1.8 Hz ) , 4.22 (2 H, td, J = 3.8 , 2.1 Hz ), 4.74 ( 1 H, dd, J = 15.4, 6.6 Hz ) , 5.09 ( 1 H, dd, J = 15.6, 6.0 Hz) , 5.14 - 5.18 ( 1 H, m) , 6.19 - 6.23 ( 1 H, m), 6.24 ( 1 H, s) , 6.70 ( 1 H, d, J = 8.7 Hz) , 6.76 ( 1 H, d, J = 9.6 Hz) , 7.04 (1 H, d, J = 2.3 Hz) ), 7.85 (1 H, d, J = 9.6 Hz), 8.27 ( 1 H, d, J = 2.3 Hz ). Reference example 3 2

使用7-氯-1-( 2-(1-頓螺（2.5)辛-6-亞基）乙基）-1H-(1，5)萘啶-2-酮 61mg 及 2,3-二氫-(1，4)二噁並（ 2.3- c)吡啶-7-基胺31 mg，藉由與參考例31之同樣操作，得到無色泡狀的1- ( 2- ( 4- (( 2,3-二氫-(1,4 )二噁並（ 2.3- c)吡啶-7-基胺基）甲基）-4-羥基環亞己基）乙基）-7-氟-1H- ( 1，5 )萘啶-2-酮 3mg。 1 H NMR ( CHLOROFORM-d) δ 1.37(1 H, td, J = 12.4, 4.6 Hz) , 1.47 ( 1 H, td, J= 12.5, 4.4 Hz) , 1.74 -1.81 ( 1 H, m) , 1.89 - 1.96 ( 1 H, m) , 2.04 ( 1 H, dt, J =13.4, 4.3 Hz) , 2.44 - 2.5 5 ( 2 H, m) , 2.5 9 - 2.66 ( 1 H, m) , 3.29 - 3.33 (2 H, m) , 4.17 - 4.21 (2 H, m), 4.27 - 4.31 ( 2 H, m) , 4.43 ( 1 H, br. s.) , 4.73 ( 1 H, dd, J = 15.1, 5.5 Hz) , 5.02 - 5.12 (2 H, m) , 5.99 ( 1 H, -44- 201209056 s ) , 6.88 ( 1 H, d, J = 1 0. 1 Hz) , 7.33 ( 1 H, dd, J = 10.1, 2.3 Hz) ， 7.64(1 H, s ) , 7.88 ( 1 H, d, J = 10.1 Hz), 8.4 1 ( 1 H, d, J = 2.3 Hz )。參考例3 3Using 7-chloro-1-(2-(1- snail (2.5) oct-6-ylidene)ethyl)-1H-(1,5)naphthyridin-2-one 61 mg and 2,3-dihydrogen - (1,4) dioxo(2.3-c)pyridin-7-ylamine 31 mg, which was obtained in the same manner as in Reference 31 to give 1-(2-(4-((), 3-Dihydro-(1,4)dioxin(2.3-c)pyridin-7-ylamino)methyl)-4-hydroxycyclohexylidene)ethyl)-7-fluoro-1H- (1 5) Naphthyridin-2-one 3 mg. 1 H NMR ( CHLOROFORM-d) δ 1.37 (1 H, td, J = 12.4, 4.6 Hz), 1.47 ( 1 H, td, J = 12.5, 4.4 Hz) , 1.74 -1.81 ( 1 H, m) , 1.89 - 1.96 ( 1 H, m) , 2.04 ( 1 H, dt, J = 13.4, 4.3 Hz) , 2.44 - 2.5 5 ( 2 H, m) , 2.5 9 - 2.66 ( 1 H, m) , 3.29 - 3.33 ( 2 H, m) , 4.17 - 4.21 (2 H, m), 4.27 - 4.31 ( 2 H, m) , 4.43 ( 1 H, br. s.) , 4.73 ( 1 H, dd, J = 15.1, 5.5 Hz ) , 5.02 - 5.12 (2 H, m) , 5.99 ( 1 H, -44- 201209056 s ) , 6.88 ( 1 H, d, J = 1 0. 1 Hz) , 7.33 ( 1 H, dd, J = 10.1 , 2.3 Hz) , 7.64(1 H, s ) , 7.88 ( 1 H, d, J = 10.1 Hz), 8.4 1 ( 1 H, d, J = 2.3 Hz ). Reference example 3 3

使用7-氟-1-(2-(1-噁螺（2.5)辛-6-亞基）乙基）-1H- ( 1,5)萘啶-2-酮200mg及6-胺基-4H-苯並（1，4)噁嗪-3-酮120mg，藉由與參考例29之同樣操作，得到淡黃色泡狀的6- ( ( 4- ( 2- ( 7-氟-2-側氧- 2H- ( 1，5 )萘啶-1-基 )亞乙基）-1-羥基環己基甲基）胺基）-4H-苯並（1,4 ) Π惡曝-3-酮30mg。 1H NMR ( CHLOROFORM-d ) δ 1.3 6 - 2.90 ( 8 H, m) ,3.07(2 H, s ) , 4.51 ( 2 H, s )，4 · 6 7 - 5 · 21 ( 3 Η，m )， 6.19 ( 1 H, s) , 6.29 ( 1 H, d, J=8.8 Hz) , 6.80 ( 1 H, d, J = 8.8 Hz )，6.89 ( 1 H，d，J=9.7 Hz) , 7.33 ( 1 H，dd，J = 10.3, 2.4 Hz) , 7.89( 1 H, d, J=9.7 Hz) , 8.43 ( 1 H, d, J = 2.4 Hz ) , 8.80 ( 1 H, s )。 -45- 201209056 參考例3 4Using 7-fluoro-1-(2-(1-oxaspiro(2.5) oct-6-ylidene)ethyl)-1H-(1,5)naphthyridin-2-one 200 mg and 6-amino-4H -Benzo(1,4)oxazin-3-one 120 mg, which was obtained in the same manner as in Reference Example 29 to give 6-((4-(2-(2-(4-)-2-oxoxy) - 2H-(1,5)naphthyridin-1-yl)ethylidene-1-hydroxycyclohexylmethyl)amino)-4H-benzo(1,4) apoxan-3-one 30 mg. 1H NMR ( CHLOROFORM-d ) δ 1.3 6 - 2.90 ( 8 H, m) , 3.07 ( 2 H, s ) , 4.51 ( 2 H, s ), 4 · 6 7 - 5 · 21 ( 3 Η, m ), 6.19 ( 1 H, s) , 6.29 ( 1 H, d, J = 8.8 Hz) , 6.80 ( 1 H, d, J = 8.8 Hz ), 6.89 ( 1 H, d, J = 9.7 Hz) , 7.33 ( 1 H, dd, J = 10.3, 2.4 Hz), 7.89 ( 1 H, d, J = 9.7 Hz), 8.43 ( 1 H, d, J = 2.4 Hz ) , 8.80 ( 1 H, s ). -45- 201209056 Reference Example 3 4

FF

txF 使用7-氟-1-(2-(1-噁螺（2.5)辛-6-亞基）乙 1H-(1，5)萘啶-2-酮194mg及3-氟-4-甲基苯胺99mg，與參考例29之同樣操作，得到淡黃色固體狀的7-氟 (4-( (3-氟-4-甲基苯基胺基）甲基）-4-羥基環3 )乙基）-1H-(1，5)萘啶-2-酮 132mg。 1 H NMR ( DMSO-d6 ) δ 1.40 ( 1 Η, td, J = 12.· Hz) , 1.47 ( 1 H, td, J= 12.6, 4.1 Hz) , 1.58 - 1.63 m)，1.71 - 1.76(1 H，m)，1.97(1 H，dt, J=13. Hz)，2.04 ( 3 H, s )，2.2 8 - 2.3 5 ( 2 H，m ) , 2.64 dt, J= 13.6, 4.2 Hz) , 2.95 ( 2 H, d, J = 6.0 Hz ) , 4. H, s) , 4.80 - 4.86 ( 1 H, m ) , 4.88 - 4.94 ( 1 H, 5.07(1 H, t, J = 6.6 Hz) , 5.42(1 H, t, J = 5.7 6.36 - 6.42 ( 2 H, m) , 6.84 ( 1 H, d, J=9.6 Hz) , 6 1 H, t, J = 8.9 Hz ) , 7.76(1 H, dd, J = 1 1 .0, 2.3 7.95 ( 1 H, d, J = 9.6 Hz ) , 8.57 ( 1 H, d, J = 2.3 Hz ) 基）-藉由 [-(2- ί己基 4, 4.6 (1 Η, 2, 4.2 (1 Η, 44 ( 1 m )， Hz), ι·89 ( Hz)， -46 - 201209056 參考例3 5txF 7-fluoro-1-(2-(1-oxaspiro(2.5) oct-6-ylidene)ethyl 1H-(1,5)naphthyridin-2-one 194 mg and 3-fluoro-4-methyl The aniline was obtained in the same manner as in the title compound (yield) to give 7-fluoro(4-((3-fluoro-4-methylphenylamino)methyl)-4-hydroxycyclo3)ethyl -1H-(1,5)naphthyridin-2-one 132 mg. 1 H NMR ( DMSO-d6 ) δ 1.40 ( 1 Η, td, J = 12.· Hz) , 1.47 ( 1 H, td, J = 12.6, 4.1 Hz) , 1.58 - 1.63 m), 1.71 - 1.76 (1 H, m), 1.97 (1 H, dt, J = 13. Hz), 2.04 ( 3 H, s ), 2.2 8 - 2.3 5 ( 2 H, m ) , 2.64 dt, J = 13.6, 4.2 Hz) , 2.95 ( 2 H, d, J = 6.0 Hz ) , 4. H, s) , 4.80 - 4.86 ( 1 H, m ) , 4.88 - 4.94 ( 1 H, 5.07 (1 H, t, J = 6.6 Hz) , 5.42(1 H, t, J = 5.7 6.36 - 6.42 ( 2 H, m) , 6.84 ( 1 H, d, J = 9.6 Hz) , 6 1 H, t, J = 8.9 Hz ) , 7.76 (1 H, Dd, J = 1 1 .0, 2.3 7.95 ( 1 H, d, J = 9.6 Hz ) , 8.57 ( 1 H, d, J = 2.3 Hz ) basis) - by [-(2- ί 己 4, 4.6 (1 Η, 2, 4.2 (1 Η, 44 ( 1 m ), Hz), ι·89 ( Hz), -46 - 201209056 Reference example 3 5

將（7-氟-2-側氧-2H-(1，5)萘啶-1-基）乙醛的鹽酸鹽280mg懸浮於氯仿lOmL，加入三乙胺3 22μί並使其溶解。在室溫進行1.5小時攪拌後，加入第三丁基=3,9-重氮螺 (5.5) "i 院-3·殘酸醋320mg的氯仿溶液5mL，進一步在室溫下進行16小時攪拌。將反應混合物冰冷下加入三乙酸基氫化硼鈉515mg，回復至室溫後進行3.5小時攪拌。於反應液中加入水5 mL，將反應混合物在減壓下使溶劑餾去，將所得之殘餾物以矽膠管柱層析法〔矽膠；關東化學股份有限公司，矽膠60，溶離液；乙酸乙酯〕進行純化後得到淡黃色油狀的第三丁基=9- ( 2- ( 7-氟-2-側氧-2H- ( 1，5 ) 萘啶-1-基）乙基）-3,9-重氮螺（5.5)十一烷-3-羧酸酯 4 6 8 m g 〇 1H NMR ( CHLOROFORM-d ) δ 1.3 8 - 1.48 ( 1 3 H, m )，1.49 - 1.55 (4 Η，m)，2.54(4 Η, t，J=5.5 Hz)， 2.61 - 2.68 ( 2 H, m) , 3.3 3 - 3.39 ( 4 H, m) , 4.32 ( 2 H, t, J=7.1 Hz) , 6.86(1 H, d, J=10.1 Hz) , 7.54(1 H, dd, J= 10.5, 2.3 Hz) , 7.86 - 7.90 ( 1 H, m) , 8.42 ( 1 H, d, J = 2.3 Hz )。 -47- 201209056 參考例3 6280 mg of (7-fluoro-2-oxo-2H-(1,5)naphthyridin-1-yl)acetaldehyde hydrochloride was suspended in 10 mL of chloroform, and triethylamine 3 22 μί was added and dissolved. After stirring at room temperature for 1.5 hours, 5 mL of a butyl chloride solution of tributyl = 3,9-diazosodium (5.5) "iyuan-3·residual acid vinegar was added, and further stirred at room temperature for 16 hours. . The reaction mixture was added to 515 mg of sodium triacetate triacetate under ice cooling, and the mixture was stirred at room temperature for 3.5 hours. 5 mL of water was added to the reaction solution, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [Glue; Kanto Chemical Co., Ltd., Silicone 60, Eluent; Acetic Acid The ethyl ester] was purified to give the third butyl = 9-(2-(7-fluoro-2-oxo-2H-(1,5)naphthyridin-1-yl)ethyl)- 3,9-diazospiro (5.5) undecane-3-carboxylate 4 6 8 mg 〇1H NMR (CHLOROFORM-d ) δ 1.3 8 - 1.48 ( 1 3 H, m ), 1.49 - 1.55 (4 Η , m), 2.54 (4 Η, t, J = 5.5 Hz), 2.61 - 2.68 ( 2 H, m) , 3.3 3 - 3.39 ( 4 H, m) , 4.32 ( 2 H, t, J = 7.1 Hz) , 6.86(1 H, d, J=10.1 Hz) , 7.54(1 H, dd, J= 10.5, 2.3 Hz) , 7.86 - 7.90 ( 1 H, m) , 8.42 ( 1 H, d, J = 2.3 Hz ). -47- 201209056 Reference Example 3 6

HCI 使用第三丁基=9-(2-(7-氟-2-側氧-211-(1，5)萘啶-1-基）乙基）-3,9-重氮螺（5.5)十一烷-3-羧酸酯 43 811^，藉由與參考例13之同樣操作，得到1-(2-(3,9-重氮螺（5.5)十一烷-3-基）乙基）-7-氟-1H-(1，5)萘啶-2-酮的鹽酸鹽318mg。 1H NMR(DMSO-d6) δ 1.5 0 - 1.5 8 ( 2 H, m) , 1.69 (2 Η, td, J = 13.9, 3.9 Hz) , 1.78 - 1.85 (2 H, m) , 1.90 (2 H, d, J = 15.6 Hz ) , 3.04 ( 2 H, d, J = 6.9 Hz ) ,3.10-3.20(2H,m) ,3.29-3.38(2H,m) ,3.49(2H,d,J = 11.9 Hz) , 4.47 - 4.84(2 H, m) , 6.88(1 H, d, J=9.2 Hz) , 8.00 ( 1 H, d, J = 9.2 Hz ) , 8.41 ( 1 H, dd, J = 1 1 .0, 1.8 Hz) , 8.62 ( 1 H, d, J=1.8 Hz) , 8.83 (2 H, br. s.) 參考例3 7HCI uses a third butyl group = 9-(2-(7-fluoro-2-oxo-211-(1,5)naphthyridin-1-yl)ethyl)-3,9-diazo snail (5.5) 11-(3-(3,9-diazospiro(5.5)undecyl-3-yl)ethyl ester was obtained by the same procedure as in Reference Example 13 The hydrochloride salt of 7-fluoro-1H-(1,5)naphthyridin-2-one was 318 mg. 1H NMR (DMSO-d6) δ 1.5 0 - 1.5 8 ( 2 H, m) , 1.69 (2 Η, td, J = 13.9, 3.9 Hz), 1.78 - 1.85 (2 H, m) , 1.90 (2 H, d, J = 15.6 Hz ) , 3.04 ( 2 H, d, J = 6.9 Hz ) , 3.10-3.20 (2H, m) , 3.29 - 3.38 (2H, m) , 3.49 (2H, d, J = 11.9 Hz) , 4.47 - 4.84(2 H, m) , 6.88(1 H, d, J=9.2 Hz) , 8.00 ( 1 H, d, J = 9.2 Hz ) , 8.41 ( 1 H, dd, J = 1 1 .0 , 1.8 Hz) , 8.62 ( 1 H, d, J = 1.8 Hz) , 8.83 (2 H, br. s.) Reference Example 3 7

-48- 201209056 使用（7-氟-2-側氧- 2Η· ( 1，5 )萘啶-1-基）乙醛的鹽酸鹽lOOmg及第三丁基=2,7-重氮螺（4.4)壬烷-2-羧酸酯 93 mg，藉由與參考例35之同樣操作，得到第三丁基=7-( 2- ( 7-氟-2-側氧-2H- ( 1，5 )萘啶-1-基）乙基）-2,7-重氮螺（4.4)壬烷-2-羧酸酯105mg。 1H NMR ( METHANOL-d4) δ 1.45 ( 9 H, s) , 1.75 -1.96 (4 Η, m) , 2.56 - 2.87 (4 Η, m) , 3.18 - 3.23 ( 1 Η, m) , 3.27 ( 1 Η, br. s.) , 3.3 3 - 3.3 6 ( 4 Η, m) , 4.39 -4.46 ( 2 Η, m) , 6.87 ( 1 Η, d, J=9.6 Hz) , 7.97 ( 2 Η, m )，8.49 ( 1 Η，d，J= 2.3 Hz )。參考例3 8-48- 201209056 Use of (7-fluoro-2-oxo- 2 Η·( 1,5 )-naphthyridin-1-yl)acetaldehyde hydrochloride 100 mg and tert-butyl = 2,7-diazo snail ( 4.4) decane-2-carboxylate 93 mg, which was obtained by the same procedure as that of Reference Example 35, to give a butyl s. Naphthyridin-1-yl)ethyl)-2,7-diazospiro(4.4)nonane-2-carboxylate 105 mg. 1H NMR ( METHANOL-d4) δ 1.45 ( 9 H, s) , 1.75 -1.96 (4 Η, m) , 2.56 - 2.87 (4 Η, m) , 3.18 - 3.23 ( 1 Η, m) , 3.27 ( 1 Η , br. s.) , 3.3 3 - 3.3 6 ( 4 Η, m) , 4.39 -4.46 ( 2 Η, m) , 6.87 ( 1 Η, d, J = 9.6 Hz) , 7.97 ( 2 Η, m ), 8.49 ( 1 Η, d, J = 2.3 Hz ). Reference example 3 8

使用第三丁基=7- (2-( 7-氟-2-側氧-2H- ( 1,5 )萘啶-1-基）乙基）-2,7-重氮螺（4.4)壬烷-2-羧酸酯10511^ ，藉由與參考例1 3之同樣操作，得到無色固體狀的1 - ( 2-(2,7-重氮螺（4.4)壬-2-基）乙基）-7-氟-1Η-( 1,5)-萘 0定-2-酮的鹽酸鹽92mg。 1H NMR ( DMSO-d6) δ 1.92 - 2.30 (4 H, m) , 3.18 -3.35 ( 6 H, m) , 3.45 ( 2 H，br. s.) ，3.68 - 3.86 ( 2 H, m -49- 201209056 )，4.52 - 4.63 (2 H，m)，6.88(1 H, d, J=9.6 Hz), 8.00 ( 1 H, d, J=9.6 Hz) , 8.29 - 8.3 8 ( 1 H, m) , 8.62 ( 1 H, d, J = 2.3 Hz )。參考例3 9Use of tert-butyl = 7-(2-( 7-fluoro-2-oxo-2H-( 1,5 )naphthyridin-1-yl)ethyl)-2,7-diazospiro (4.4)壬Alkyl-2-carboxylate 10511^, 1-(2-(2,7-diazospiro(4.4)indol-2-yl)ethyl as a colorless solid. The hydrochloride salt of 7-fluoro-1Η-( 1,5)-naphthalene 0-but-2-one was 92 mg. 1H NMR ( DMSO-d6) δ 1.92 - 2.30 (4 H, m) , 3.18 -3.35 ( 6 H, m) , 3.45 ( 2 H, br. s.) , 3.68 - 3.86 ( 2 H, m -49- 201209056 ), 4.52 - 4.63 (2 H,m), 6.88 (1 H, d, J=9.6 Hz), 8.00 ( 1 H, d, J=9.6 Hz) , 8.29 - 8.3 8 ( 1 H, m) , 8.62 ( 1 H, d, J = 2.3 Hz ). Reference example 3 9

將（7-氟-2-側氧-2H-( 1,5)萘啶-1-基）乙醛的鹽酸鹽200mg及第三丁基=1H-螺（異喹啉-4,4’-哌啶）-2 ( 3H )-羧酸酯279mg懸浮於氯仿5mL，加入三乙胺0.29mL並使其溶解。加入乙酸68 μί，在50°C進行6小時攪拌。將反應混合物在冰冷下加入三乙酸基氫化硼鈉3 68 mg，在室溫進行2 1小時攪拌。將反應混合物在減壓下使溶劑餾去，將所得之殘餾物以矽膠管柱層析法〔矽膠：FUJI SILYSIA股份有限公司，Chromatorex-NH，溶離液；乙酸乙醋：己院= 1 : 1〕進行純化後得到淡黃色油狀物。將此懸浮於2 -丙醇 50mL，力口入2 mol/L鹽酸之2-丙醇溶液10mL，在50°C進行 201209056 2 1小時攪拌。將反應混合物在減壓下溶劑餾去，得到白色固體狀的1-(2-(2,3-二氫-111-螺（異喹啉_4,4，_哌啶）_ 1’-基）乙基）-7-氟_(1，5) _萘啶_2(1H) _酮的鹽酸鹽 270mg ° 1H NMR ( DMSO-d6) δ 2.15 ( 2 H, d, J= 14.7 Hz), 2.52 - 2.59 ( 2 H, m) , 3.31 - 3.45 ( 4 H, m) , 3.5 8 - 3.69 (4 H, m) , 4.26 ( 2 H, t, J= 4.1 Hz) , 4.6 3 - 4.7 3 ( 2 H, m) , 6.90 ( 1 H, d, J=9.6 Hz) , 7.24 - 7.29 ( 1 H, m), 7.3 0 - 7.3 4 ( 1 h, m) , 7.43 ( 1 H, t, J = 7.3 H z ) # 7.5 6 ( 1 H, d, J= 7.8 Hz) , 8.01 ( 1 H, d, J= 9.6 Hz) , 8.4 1 ( 1 H, dd, J= ll.〇5 ! 8 Hz) 5 8 6 3 ( l h, d, J= 1.8 Hz), 1 1.63 ( 1 H, br. s.)。參考例4 0Hydrochloride of (7-fluoro-2-oxo-2H-(1,5)naphthyridin-1-yl)acetaldehyde 200 mg and tert-butyl=1H-spiro (isoquinoline-4,4' 279 mg of piperidine)-2(3H)-carboxylate was suspended in 5 mL of chloroform, and 0.29 mL of triethylamine was added and dissolved. 68 μί of acetic acid was added, and the mixture was stirred at 50 ° C for 6 hours. The reaction mixture was added to a solution of sodium triacetoxyborohydride (3, 68 mg) under ice cooling, and stirred at room temperature for 21 hours. The reaction mixture was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (tand: FUJI SILYSIA Co., Ltd., Chromatorex-NH, eluent; ethyl acetate: hexane = 1 : 1) Purification gave a pale yellow oil. This was suspended in 50 mL of 2-propanol, and 10 mL of a 2 mol/L hydrochloric acid solution of 2-propanol was added thereto, and the mixture was stirred at 50 ° C for 201209056 for 1 hour. The reaction mixture was evaporated under reduced pressure to give 1-(2-(2,3-dihydro-111-spiro(isoquinoline-4,4,-piperidine)-1'- group as a white solid. Ethyl)-7-fluoro-(1,5)-naphthyridinium-2(1H)-one hydrochloride hydrochloride 270 mg ° 1H NMR (DMSO-d6) δ 2.15 ( 2 H, d, J = 14.7 Hz) , 2.52 - 2.59 ( 2 H, m) , 3.31 - 3.45 ( 4 H, m) , 3.5 8 - 3.69 (4 H, m) , 4.26 ( 2 H, t, J = 4.1 Hz) , 4.6 3 - 4.7 3 ( 2 H, m) , 6.90 ( 1 H, d, J = 9.6 Hz) , 7.24 - 7.29 ( 1 H, m), 7.3 0 - 7.3 4 ( 1 h, m) , 7.43 ( 1 H, t, J = 7.3 H z ) # 7.5 6 ( 1 H, d, J= 7.8 Hz) , 8.01 ( 1 H, d, J= 9.6 Hz) , 8.4 1 ( 1 H, dd, J= ll.〇5 ! 8 Hz 5 8 6 3 ( lh, d, J = 1.8 Hz), 1 1.63 ( 1 H, br. s.). Reference example 4 0

將（7 -甲氧基-2-側氧-2H- ( 1，5 )萘啶-丨_基）乙醛 211mg及第三丁基= 2,8-重氮螺（4.5)癸烷-2-羧酸酯 279mg溶解於氯仿i〇mL及甲醇0.5mL，在室溫進行18小時攪拌。加入二乙酸基氫化硼鈉431mg，並進行2.5小時攪拌。於反應混合物加入飽和碳酸氫鈉水溶液10mL，分離並取出有機·層。將有機層在減壓下將溶劑餾去，將所得之殘餾 -51 - 201209056 物以矽膠管柱層析法〔矽膠：FUJI SILYSIA股份有限公司，Chromatorex-NH，溶離液；乙酸乙酿：己院=4: 1〕進行純化後得到無色油狀的第三丁基=8- ( 2- ( 7-甲氧基-2-側氧-2H- ( 1，5 )萘啶-1-基）乙基）-2,8-重氮螺（4·5 )癸烷-2-羧酸酯290mg。 lHNMR(CHLOROFORM-d)S1.46(9H，s)，1.55-1.64 ( 3 H, m) , 1.64 - 1.74 ( 4 H, m) , 2.49 ( 2 Η, br. s. ),2.59 - 2.69(3 Η, m) , 3.12(1 Η, s) , 3.20(1 Η, s ),3.35 ( 1 Η, t, J= 7.1 Hz ) , 3.40 ( 1 Η, t, J = 6.9 Hz )， 3.98 (3 H，s)，4.37 (2 H，br. s.)，6.75 ( 1 H，d，J=9.2 Hz)，7.21 ( 1 H，d，J = 1.8 Hz) , 7.84 ( 1 H，d，J=9.2 Hz )，8_28 ( 1 H，d，J= 1 .8 Hz )。211 mg of (7-methoxy-2-oxo-2H-(1,5)-naphthyridin-yl)acetaldehyde and a third butyl group = 2,8-diazospiro (4.5) decane-2 279 mg of a carboxylate was dissolved in chloroform i〇mL and methanol 0.5 mL, and stirred at room temperature for 18 hours. 431 mg of sodium diacetate diborohydride was added and stirred for 2.5 hours. To the reaction mixture was added 10 mL of a saturated aqueous sodium hydrogen carbonate solution, and the organic layer was separated. The organic layer was distilled off under reduced pressure, and the obtained residue -51 - 201209056 was subjected to silica gel column chromatography [矽胶:FUJI SILYSIA Co., Ltd., Chromatorex-NH, dissolving solution; acetic acid:院=4: 1] After purification, a third butyl group is obtained as a colorless oil = 8-(2-(7-methoxy-2-oxo-2H-(1,5)naphthyridin-1-yl) Ethyl)-2,8-diazospiro(4·5 )nonane-2-carboxylate 290 mg. lHNMR(CHLOROFORM-d)S1.46(9H,s), 1.55-1.64 ( 3 H, m) , 1.64 - 1.74 ( 4 H, m) , 2.49 ( 2 Η, br. s. ), 2.59 - 2.69 ( 3 Η, m) , 3.12(1 Η, s) , 3.20(1 Η, s ), 3.35 ( 1 Η, t, J = 7.1 Hz ) , 3.40 ( 1 Η, t, J = 6.9 Hz ), 3.98 ( 3 H, s), 4.37 (2 H, br. s.), 6.75 ( 1 H, d, J = 9.2 Hz), 7.21 ( 1 H, d, J = 1.8 Hz) , 7.84 ( 1 H, d, J = 9.2 Hz ), 8_28 ( 1 H, d, J = 1. 8 Hz ).

將第三丁基=8-(2-(7-甲氧基-2-側氧-21^-(1，5)萘啶-1-基）乙基）-2,8-重氮螺（4.5)癸烷-2-羧酸酯290mg 溶解於1，4-二噁烷5mL，加入4 mol/L鹽酸之1,4-二噁烷溶液5 mL·，在室溫進行4小時攪拌。將反應混合物在減壓下將溶劑餾去，得到黃白色固體狀的1- ( 2- ( 2,8-重氮螺（4.5 )癸烷-8-基）乙基）-7-甲氧基-1H-(1，5)萘啶-2-酮的鹽酸鹽4〇〇mg。 -52- 201209056 1H NMR ( DMSO-d6) δ 1.78 - 1.97 ( 6 H, m) , 2.99 (1 H, t, J=5.7 Hz) , 3.08 - 3.15 ( 1 H, m) , 3.18 ( 1 H, t, J=5.7 Hz) , 3.20 - 3.35 (5 H, m) , 3.58 - 3.63 (2 H, m) , 4.07 ( 3 H, s) , 4.69 - 4.73 ( 2 H, m ) , 6.71 ( 1 H, d, J=9.6 Hz) , 7.72 ( 1 H, d, J=2.3 Hz) , 7.94 ( 1 H, d, J=9.6 Hz) , 8.33 ( 1 H, d, J=2.3 Hz) 〇參考例42The third butyl group is 8-(2-(7-methoxy-2-oxooxy-21-(1,5)naphthyridin-1-yl)ethyl)-2,8-diazo snail ( 4.5) 290 mg of decane-2-carboxylate was dissolved in 5 mL of 1,4-dioxane, and 5 mL of a 1,4-dioxane solution of 4 mol/L hydrochloric acid was added thereto, and the mixture was stirred at room temperature for 4 hours. The solvent was evaporated under reduced pressure to give 1-(2-(2,8-diazaspiro(4.5)decane-8-yl)ethyl)-7-methoxy as a white solid. -1H-(1,5) naphthyridin-2-one hydrochloride 4 〇〇 mg. -52- 201209056 1H NMR ( DMSO-d6) δ 1.78 - 1.97 ( 6 H, m) , 2.99 (1 H, t, J = 5.7 Hz) , 3.08 - 3.15 ( 1 H, m) , 3.18 ( 1 H, t, J=5.7 Hz) , 3.20 - 3.35 (5 H, m) , 3.58 - 3.63 (2 H, m) , 4.07 ( 3 H, s) , 4.69 - 4.73 ( 2 H, m ) , 6.71 ( 1 H , d, J=9.6 Hz) , 7.72 ( 1 H, d, J=2.3 Hz) , 7.94 ( 1 H, d, J=9.6 Hz) , 8.33 ( 1 H, d, J=2.3 Hz) 〇 Reference example 42

將7-甲氧基-1H-(1,5)-萘啶-2-酮5.06g懸浮於N，N-二甲基甲醯胺50mL，加入60%氫化鈉2_51g，在氮環境下於 85 °C進行25分鐘攪拌。加入（3 -溴丙氧基）-第三丁基二甲基矽烷20.6mL之Ν,Ν-二甲基甲醯胺溶液30mL，在85°C進行 1 5小時攪拌。將反應混合物恢復至室溫後’加入水1 5 OmL 、乙酸乙酯70mL及甲苯30mL’分離並取出有機層。將有機層以飽和氯化鈉水溶液5 OmL進行洗淨’以無水硫酸鎂乾燥，減壓下將溶劑餾去，得到褐色油狀的卜（3 -(第三丁基二甲基矽烷氧基）丙基）-7-甲氧基-1H-(1，5)萘卩定-2-酮 4.0 8 g。 1H NMR ( CHLOROFORM-d ) δ 0.10(6 H, s ) , 0.94 (9 H, s) , 1.91- 1.98 (2 H, m) , 3.79 (2 H, t, J=5.5 -53- 2012090565.06g of 7-methoxy-1H-(1,5)-naphthyridin-2-one was suspended in 50 mL of N,N-dimethylformamide, and added to 60% sodium hydride 2_51 g under nitrogen atmosphere at 85 Stir at 25 °C for 25 minutes. 20.6 mL of (3-bromopropyloxy)-tert-butyldimethyl decane was added, and 30 mL of a hydrazine-dimethylformamide solution was stirred at 85 ° C for 15 hours. After the reaction mixture was returned to room temperature, water (10.5 mL, ethyl acetate 70 mL, and toluene 30 mL) was added and the organic layer was taken. The organic layer was washed with a saturated aqueous solution of sodium chloride (5 mL) and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give a brown oil (3 - (t-butyl dimethyl decyloxy) Propyl)-7-methoxy-1H-(1,5)naphthoquinone-2-one 4.0 8 g. 1H NMR ( CHLOROFORM-d ) δ 0.10(6 H, s ) , 0.94 (9 H, s) , 1.91- 1.98 (2 H, m) , 3.79 (2 H, t, J=5.5 -53- 201209056

Hz) , 3.96 ( 3 H, s ) , 4.3 1 - 4.38(2 H, m) , 6.76 ( 1 Η, d, J=7.8 Hz) , 7.28 ( 1 H, br. s.) , 7.88 ( 1 H, br. s.), 8.30 ( 1 H, br. s.)。參考例4 3Hz) , 3.96 ( 3 H, s ) , 4.3 1 - 4.38 (2 H, m) , 6.76 ( 1 Η, d, J = 7.8 Hz) , 7.28 ( 1 H, br. s.) , 7.88 ( 1 H , br. s.), 8.30 ( 1 H, br. s.). Reference example 4 3

將1-(3-(第三丁基二甲基矽烷氧基）丙基）-7-甲氧基-1H- ( 1,5)萘啶-2-酮3.989g溶解於四氫呋喃40mL，加入lmol/L的氟化四正丁基錳之四氫呋喃溶液22.9mL，在室溫進行1 4小時攪拌。將反應混合物在減壓下使溶劑餾去，將所得之殘餾物以矽膠管柱層析法〔矽膠；關東化學股份有限公司，矽膠60，溶離液；乙酸乙酯：甲醇=9: 1〕進行純化後得到白色固體狀的1- ( 3-羥基丙基）-7-甲氧基-1H- ( 1，5 )萘啶-2-酮 2.47g。 1H NMR ( CHLOROFORM-d ) δ 1.92 - 2.06 ( 2 H, m) ,3.49 - 3.63 (3 H, m) , 3.99(3 H, s) , 4.38 - 4.48 (2 H，m)，6.80( 1 H，d，J=9.7 Hz)，7.19( 1 H, d，J=2.2 Hz ) , 7.92 ( 1 H, d, J = 9.7 Hz ) , 8.33 ( 1 H, d, J = 2.2 Hz -54- 201209056 參考例4 43.89 g of 1-(3-(t-butyldimethylsilyloxy)propyl)-7-methoxy-1H-(1,5)naphthyridin-2-one was dissolved in 40 mL of tetrahydrofuran, and 1 mol was added. 22.9 mL of a tetrahydrofuran solution of tetra-n-butylmanganese fluoride was stirred at room temperature for 14 hours. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (gum, Gentung Chemical Co., Ltd., Silicone 60, eluent; ethyl acetate:methanol = 9:1) After purification, 1.47 g of 1-(3-hydroxypropyl)-7-methoxy-1H-(1,5)naphthyridin-2-one as a white solid was obtained. 1H NMR ( CHLOROFORM-d ) δ 1.92 - 2.06 ( 2 H, m) , 3.49 - 3.63 (3 H, m) , 3.99 (3 H, s) , 4.38 - 4.48 (2 H, m), 6.80 ( 1 H , d, J = 9.7 Hz), 7.19 ( 1 H, d, J = 2.2 Hz ) , 7.92 ( 1 H, d, J = 9.7 Hz ) , 8.33 ( 1 H, d, J = 2.2 Hz -54- 201209056 Reference example 4 4

將1-(3-羥基丙基）-7-甲氧基-111-(1，5)萘啶-2-酮 50 0mg溶解於氯仿30mL，加入1，1，1-三乙酸基-1,1-二氫-1，2-苯並碘氧雜戊環-3(111)-酮1.21§，在室溫進行6.5小時攪拌。將反應混合物在減壓下使溶劑餾去，將所得之殘餾物以矽膠管柱層析法〔矽膠；關東化學股份有限公司，矽膠60，溶離液；乙酸乙酯：甲醇=95 : 5〕進行純化，得到黃色油狀的3- ( 7-甲氧基-2-側氧-2H- ( 1，5 )萘陡基）丙醛562mg。 1H NMR ( CHLOROFORM-d ) δ 2.9 8 ( 2 H, td, J = 7 0 0.9Hz)，3.99(3H，s)，4.55(2H，t，J=6.8Hz)，6·75 (1 H，d, J = 10.1 Hz)，7.21 ( 1 H，d，J = 2.2 Hz)，7.83 · 7.91 ( 1 H，m)，8.29 ( 1 H，d，J=2.2 Hz)，9.87 - 9·”（ 1 H, m )。 -55- 201209056 參考例4550 mg of 1-(3-hydroxypropyl)-7-methoxy-111-(1,5)naphthyridin-2-one was dissolved in 30 mL of chloroform, and 1,1,1-triacetoxy-1 was added. 1-Dihydro-1,2-benzoindolooxalan-3(111)-one 1.21 §, stirred at room temperature for 6.5 hours. The reaction mixture was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (gum, Gentung Chemical Co., Ltd., Silicone 60, eluent; ethyl acetate: methanol = 95: 5) Purification was carried out to obtain 562 mg of 3-(7-methoxy-2-oxo-2H-(1,5)naphthalenyl)propanal as a yellow oil. 1H NMR ( CHLOROFORM-d ) δ 2.9 8 ( 2 H, td, J = 7 0 0.9 Hz), 3.99 (3H, s), 4.55 (2H, t, J = 6.8 Hz), 6·75 (1 H, d, J = 10.1 Hz), 7.21 ( 1 H, d, J = 2.2 Hz), 7.83 · 7.91 ( 1 H, m), 8.29 ( 1 H, d, J = 2.2 Hz), 9.87 - 9·” ( 1 H, m ). -55- 201209056 Reference Example 45

°Cr°°Cr°

HCI 將第三丁基=3-側氧-2,8-重氮螺（4.5)癸烷-8-羧酸酯75mg溶解於N，N-二甲基甲醯胺2mL ’加入60%氫化鈉 14mg。進一步加入7 -氯甲基-2,3-二氫-(1，4)二噁並（ 2,3-c)吡啶60mg之N，N-二甲基甲醯胺2mL-四氫呋喃2mL 溶液，在7〇°C進行1 5小時攪拌。將反應混合物恢復至室溫，加入水10mL、乙酸乙酯l〇mL，分離並取出有機層。將有機層以飽和氯化鈉水溶液1 0mL洗淨’以無水硫酸鎂乾燥，減壓下將溶劑餾去，得到褐色油狀的2 - ( 2，3 -二氫-( 1，4)二噁並（2,3-c)吡啶-7-基甲基）-3-側氧-2,8-重氮螺 (4.5)癸烷-8-羧酸酯108mg。將此溶解於乙酸乙酯2mL’ 加入4 mo丨/L鹽酸之乙酸乙酯溶液4mL，在室溫進行3小時攪拌。將反應混合物在減壓下將溶劑餾去’得到褐色固體狀的2-(2,3-二氫-(1，4)二噁並（2,3-c)吡啶-7-基甲基 -56- 201209056 )-2,8-重氮螺（4.5)癸烷-3-嗣的鹽酸鹽129 mg。 1H NMR ( DMSO-d6) δ 1.71 - 1.79 ( 4 H, m ) , 2.38 (2 Η，s) , 2.96 - 3.07 ( 4 Η, m) , 3.29 ( 2 Η, s) , 4.56 -4.62 (4 Η，m)，4.63 (2 Η，s)，7.33 ( 1 Η，s)，8.56 ( 1 Η，s)。參考例46HCI Dissolve 75 mg of tert-butyl = 3-oxo-2,8-diazospiro(4.5)decane-8-carboxylate in N,N-dimethylformamide 2 mL 'Add 60% sodium hydride 14mg. Further adding 7-chloromethyl-2,3-dihydro-(1,4) dioxin (2,3-c)pyridine 60 mg of N,N-dimethylformamide 2 mL-tetrahydrofuran 2 mL solution Stir for 15 hours at 7 °C. The reaction mixture was returned to room temperature, and water (10 mL) and ethyl acetate (1 mL) were added, and the organic layer was separated. The organic layer was washed with a saturated aqueous solution of sodium chloride (1 mL) and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 2-(2,3-dihydro-(1,4) dioxin as a brown oil. And (2,3-c)pyridin-7-ylmethyl)-3-oxo-2,8-diazospiro(4.5)decane-8-carboxylate 108 mg. This was dissolved in 2 mL of ethyl acetate. 4 mL of an ethyl acetate solution of 4 mol/L hydrochloric acid was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was evaporated under reduced pressure to give <"""""""""""" 56- 201209056 )-2,8- Diazospiro (4.5) decane-3-indole hydrochloride 129 mg. 1H NMR ( DMSO-d6) δ 1.71 - 1.79 ( 4 H, m ) , 2.38 (2 Η, s) , 2.96 - 3.07 ( 4 Η, m) , 3.29 ( 2 Η, s) , 4.56 -4.62 (4 Η , m), 4.63 (2 Η, s), 7.33 (1 Η, s), 8.56 (1 Η, s). Reference example 46

使用第三丁基=5’-側氧-8-氮雜螺（聯環（3.2.1 )辛烷-3,3’-吡咯烷）-8-羧酸酯177mg及6-碘-2,3-二氫苯並（ 1，4)戴奧辛165mg，藉由與參考例14之同樣操作，得到第三丁基=1’-(2,3-二氫苯並（b) (1,0戴奧辛-6-基）- 5，-側氧-8-氮雜螺（聯環（3.2.1)辛烷-3,3’-吡咯烷）_8_ 羧酸酯240mg。 1H NMR ( CHLOROFORM-d ) δ 1.46 ( 9 H, s ) , 1.72 -2.08 ( 8 H, m) , 2.73 - 2.80 ( 2 Η, m) , 3.3 4 - 3.5 7 ( 2 Η, m)，4.15 - 4.37(6 Η，m) , 6.83(1 Η，d，J=9.2 Ηζ)， 6.93 - 6.99 ( 1 Η, m) , 7.07 ( 1 Η, d, J = 2.3 Η ζ )。 -57- 201209056 參考例4 7Using butyl butyl = 5'-side oxygen-8-azaspiro(bicyclo(3.2.1)octane-3,3'-pyrrolidine)-8-carboxylate 177 mg and 6-iodo-2, 3-Dihydrobenzo(1,4) dioxin 165 mg, which was subjected to the same operation as in Reference Example 14 to give a tributyl-1'-(2,3-dihydrobenzo (b) (1,0 Dioxin) -6-yl)- 5,-sideoxy-8-azaspiro(bicyclo(3.2.1)octane-3,3'-pyrrolidine)_8_carboxylate 240 mg. 1H NMR (CHLOROFORM-d) δ 1.46 ( 9 H, s ) , 1.72 -2.08 ( 8 H, m) , 2.73 - 2.80 ( 2 Η, m) , 3.3 4 - 3.5 7 ( 2 Η, m), 4.15 - 4.37 (6 Η, m) , 6.83 (1 Η, d, J=9.2 Ηζ), 6.93 - 6.99 ( 1 Η, m) , 7.07 ( 1 Η, d, J = 2.3 Η ζ ). -57- 201209056 Reference Example 4 7

使用第三丁基=1’-(2，3-二氫苯並（b) (1，4)戴奧辛-6-基）-5’-側氧-8-氮雜螺（聯環（3.2.1)辛烷-3,3’-吡咯烷）-8-羧酸酯240mg，藉由與參考例15之同樣操作，得到1’-(2,3-二氫苯並（b) (1，4)戴奧辛-6-基）-8-氮雜螺（聯環（3.2.1)辛烷-3,3’-吡略烷）-5’-酮181mg。 1H NMR ( CHLOROFORM-d ) δ 1.77 - 1.91 ( 8 Η, m) ，2.72(2 Η，s)，3.47(2 Η，s) , 3.58 - 3.63 (2 Η, m)， 4.17 - 4.29 (4 Η, m) , 6.83 ( 1 Η, d, J=8.7 Hz) , 6.99 ( 1 Η, dd, J = 8.7, 2.3 Hz ) , 7.08 ( 1 H, d, J = 2.3 Hz )。參考例4 8Use of the third butyl = 1 '-(2,3-dihydrobenzo (b) (1,4) dioxin-6-yl)-5'-side oxo-8-aza snail (linked ring (3.2. 1) 240 mg of octane-3,3'-pyrrolidine)-8-carboxylate, which was obtained by the same procedure as in Reference 15 to give 1'-(2,3-dihydrobenzo (b) (1, 4) Dioxin-6-yl)-8-azaspiro(bicyclo(3.2.1)octane-3,3'-pyrrolidine)-5'-one 181 mg. 1H NMR ( CHLOROFORM-d ) δ 1.77 - 1.91 ( 8 Η, m) , 2.72 (2 Η, s), 3.47 (2 Η, s) , 3.58 - 3.63 (2 Η, m), 4.17 - 4.29 (4 Η , m) , 6.83 ( 1 Η, d, J = 8.7 Hz) , 6.99 ( 1 Η, dd, J = 8.7, 2.3 Hz ) , 7.08 ( 1 H, d, J = 2.3 Hz ). Reference example 4 8

使用苯甲基=1-噁-6-氮雜螺（2.5 )辛烷-6-羧酸酯 201209056 488mg 及 2,3 -二氫-(1，4)二噁並（2,3-c)吡啶-7 -基胺 2 0 Omg，藉由與參考例29之同樣操作，得到無色油狀的苯甲基=4-( (2,3·二氫-(1，4)二噁並（2,3-c)吡啶-7-基胺基）甲基）-4-羥基哌啶-1-羧酸酯51mg。 1H NMR ( CHLOROFORM-d) δ 1.42 ( 2 Η, br. s.)， 1.65 ( 2 Η, br. s.) , 3.28 ( 4 H, br. s.) , 3.88 - 4.02 ( 2 H, m) , 4.17 - 4.19(2 H, m) , 4.27 - 4.30 ( 2 H, m )， 4.43 - 4.51(1 H, m) , 5.13(2 H, s) , 5.99(1 H, s)， 7.29 - 7.38 ( 5 H, m) , 7.61 ( 1 H, s)。參考例49Use benzyl-1-oxa-6-azaspiro(2.5)octane-6-carboxylate 201209056 488mg and 2,3-dihydro-(1,4) dioxo(2,3-c) Phenyl-7-ylamine 20 mg, benzene = 4-((2,3·dihydro-(1,4) dioxo(2) was obtained as a colorless oil. , 3-c) Pyridin-7-ylamino)methyl)-4-hydroxypiperidine-1-carboxylate 51 mg. 1H NMR (CHLOROFORM-d) δ 1.42 ( 2 Η, br. s.), 1.65 ( 2 Η, br. s.) , 3.28 ( 4 H, br. s.) , 3.88 - 4.02 ( 2 H, m) , 4.17 - 4.19(2 H, m) , 4.27 - 4.30 ( 2 H, m ), 4.43 - 4.51(1 H, m) , 5.13(2 H, s) , 5.99(1 H, s), 7.29 - 7.38 ( 5 H, m) , 7.61 ( 1 H, s). Reference example 49

將苯甲基= 4-( (2,3-二氫-(1，4)二噁並Benzyl = 4-((2,3-dihydro-(1,4) dioxime

吡啶-7-基胺基）甲基）-4-羥基哌啶-1-羧酸酯51mg溶解於氯仿2mL，加入三乙胺〇.〇5mL及碳酸雙（三氯甲基）38mg ，氮環境下室溫中進行2小時攪拌。於反應混合物加入飽和碳酸氫鈉水溶液3mL及氯仿5mL，分離並取出有機層。將有機層以飽和氯化鈉水溶液2mL洗淨，以無水硫酸鎂乾燥，減壓下將溶劑餾去，得到黃色固體狀的苯甲基=3-( 2,3-二氫-(1，4)二噁並（2,3-c)吡啶-7-基）-2-側氧-1-嚼-3,8-重氮螺（4.5)癸烷-8-羧酸酯63mg。 1H NMR ( CHLOROFORM-d ) δ 1.78(2 H, br. s.), -59- 201209056 1.97 ( 2 H, br. s.) , 3.39 - 3.51 ( 2 H, m) , 3.88 - 3.99 ( 4 H, m) , 4.25 - 4.28 (2 H, m) , 4.32 - 4.35 (2 H, m), 5.15(2 H, s) , 7.31 - 7.39(5 H, m) , 7.75(1 H, s), 7.86 ( 1 H, s )。參考例5 051 mg of pyridyl-7-ylamino)methyl)-4-hydroxypiperidine-1-carboxylate was dissolved in 2 mL of chloroform, and added with 3 mL of triethylamine hydrazine, mL5 mL of bis(trichloromethyl) carbonate, and a nitrogen atmosphere. Stirring was carried out for 2 hours at room temperature. 3 mL of a saturated aqueous sodium hydrogencarbonate solution and 5 mL of chloroform were added to the mixture, and the organic layer was separated. The organic layer was washed with 2 mL of a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was evaporated to give benzene (yield: 3-(2,3-dihydro-(1,4) Dioxo(2,3-c)pyridin-7-yl)-2-oxo-1-cax-3,8-diazospiro(4.5)decane-8-carboxylate 63 mg. 1H NMR ( CHLOROFORM-d ) δ 1.78(2 H, br. s.), -59- 201209056 1.97 ( 2 H, br. s.) , 3.39 - 3.51 ( 2 H, m) , 3.88 - 3.99 ( 4 H , m) , 4.25 - 4.28 (2 H, m) , 4.32 - 4.35 (2 H, m), 5.15(2 H, s) , 7.31 - 7.39(5 H, m) , 7.75(1 H, s), 7.86 ( 1 H, s ). Reference example 5 0

將苯甲基=3-(2,3-二氫-(1，4)二噁並（2,3-〇)吡啶-7-基）-2-側氧-1-噁-3,8-重氮螺（4.5)癸烷-8-羧酸酯 63mg溶解於乙醇3mL，加入7.5%鈀碳22mg，在氫環境下 4〇t中進行6小時攪拌。過濾取出不溶物，將濾液在減壓下將溶劑餾去，得到白色固體狀的3-(2,3-二氫- (1,4) —·嚼並（2,3-。）卩比11定-7-基）-1-噪-3,8-重氮螺（4.5)癸院-2-酮 3 6mg。 1H NMR ( CHLOROFORM-d ) δ 2 · 1 2 ( 2 Η，d, J = 1 3 · 8Benzyl = 3-(2,3-dihydro-(1,4) dioxin(2,3-indolyl)pyridin-7-yl)-2-oxo-1-oxo-3,8- 63 mg of diazane snail (4.5) decane-8-carboxylate was dissolved in 3 mL of ethanol, and 22 mg of 7.5% palladium carbon was added thereto, and the mixture was stirred for 6 hours in a hydrogen atmosphere at 4 Torr. The insoluble material was taken out by filtration, and the solvent was distilled off under reduced pressure to give 3-(2,3-dihydro-(1,4)------ (2, 3-. D-7-yl)-1-noise-3,8-diazospiro (4.5) oxacin-2-one 3 6 mg. 1H NMR ( CHLOROFORM-d ) δ 2 · 1 2 ( 2 Η, d, J = 1 3 · 8

Hz) , 2.24 - 2.31 (2 H, m) , 3.27 - 3.33 (2 H, m) , 3.34 -3.40 (2 H, m) , 3.99 (2 H, s) , 4.25 - 4.28 (2 H, m), 4.33 - 4.35 ( 2 H, m) , 7.70 ( 1 H, s ) , 7.86 ( 1 H, s )。 -60- 201209056 參考例5 1Hz) , 2.24 - 2.31 (2 H, m) , 3.27 - 3.33 (2 H, m) , 3.34 - 3.40 (2 H, m) , 3.99 (2 H, s) , 4.25 - 4.28 (2 H, m) , 4.33 - 4.35 ( 2 H, m) , 7.70 ( 1 H, s ) , 7.86 ( 1 H, s ). -60- 201209056 Reference Example 5 1

使用7 -氟-1Η-(1，5)萘啶-2-酮5.06g，藉由與參考例 42之同樣操作’得到淡黃色固體狀的1- ( 3-(第三丁基二甲基砂院氧基）丙基）-7-氣-1H-(1，5)蔡陡-2-嗣1.23g。 1H NMR ( CHLOROFORM-d ) 6 0.11(6 H, s ) , 0.96 (9 H，s)，1.87 - 1.99 (2 H，m) , 3·70 - 3.77 (2 H, m)， 4.27 - 4.36 ( 2 H, m) , 6.86 ( 1 H, d, J= 10.1 Hz) , 7.68 -7.76 ( 1 H, m) , 7.85 - 7.92 ( 1 H, m) , 8.40 - 8.42 ( 1 H, m )。參考例5 2Using 1-fluoro-1-indole-(1,5)naphthyridin-2-one 5.06 g, the same procedure as in Reference 42 to give 1-(3-(t-butyldimethyl) as a pale yellow solid. Sandyard oxy)propyl)-7-gas-1H-(1,5) Tsai steep-2-嗣1.23g. 1H NMR ( CHLOROFORM-d ) 6 0.11 (6 H, s ) , 0.96 (9 H, s), 1.87 - 1.99 (2 H, m) , 3·70 - 3.77 (2 H, m), 4.27 - 4.36 ( 2 H, m) , 6.86 ( 1 H, d, J = 10.1 Hz) , 7.68 -7.76 ( 1 H, m) , 7.85 - 7.92 ( 1 H, m) , 8.40 - 8.42 ( 1 H, m ). Reference example 5 2

使用1-(3-(第三丁基二甲基矽烷氧基）丙基）-7_ 氟-1H-(1，5)萘啶-2-酮1.20g，藉由與參考例43之同樣操作，得到淡黃色固體狀的1- ( 3-羥基丙基）-7-氟-1H_ ( 1，5)萘啶-2-酮 0.70g。 2.03 ( 2 H, m) 1H NMR ( CHLOROFORM-d) δ 1.92 ，3.58 (2 H，br. s.)，4.40 (2 H，t，J=6.2 Hz)，6.92 -61 - 201209056 H, d, J= 9.6 Hz) , 7.51 ( 1 H, dd, J= 9.9, 2.3 Hz) , 7.95 (lH,d,J=9.6Hz) ,8.47(1 H,d,J=2.3Hz)。參考例5 31-(3-(t-butyldimethylsilyloxy)propyl)-7-fluoro-1H-(1,5)naphthyridin-2-one 1.20 g was used in the same manner as in Reference Example 43 There was obtained 0.70 g of 1-(3-hydroxypropyl)-7-fluoro-1H-(1,5)naphthyridin-2-one as a pale yellow solid. 2.03 ( 2 H, m) 1H NMR ( CHLOROFORM-d) δ 1.92 , 3.58 (2 H, br. s.), 4.40 (2 H, t, J = 6.2 Hz), 6.92 -61 - 201209056 H, d, J = 9.6 Hz), 7.51 ( 1 H, dd, J = 9.9, 2.3 Hz), 7.95 (lH, d, J = 9.6 Hz), 8.47 (1 H, d, J = 2.3 Hz). Reference example 5 3

使用1-( 3-羥基丙基）-7-氟-1Η-( 1,5)萘啶-2-酮 142mg’藉由與參考例44之同樣操作，得到無色固體狀的 3· ( 7 -氟-2-側氧- 2H- ( 1，5)萘啶-1-基）丙醛 158mg。 1H NMR ( CHLOROFORM-d ) δ 2 · 9 5 - 3.0 0 ( 2 Η，m ) ,4.5 1 ( 2 Η, t, J = 7. 1 Hz)，6.87(1 H, d, J = 9.6 Hz ), 7.50 ( 1 H, dd, J= 10.1, 2.3 Hz) , 7.90 - 7.93 ( 1 H, m ), 8.45 ( 1 H, d, J = 2.3 Hz )，9.88 ( 1 H，s)。參考例5 4Using 1-(3-hydroxypropyl)-7-fluoro-l-indole-(1,5)naphthyridin-2-one 142 mg'. Fluor-2-oxo- 2H-(1,5)naphthyridin-1-yl)propanal 158 mg. 1H NMR ( CHLOROFORM-d ) δ 2 · 9 5 - 3.0 0 ( 2 Η,m ) , 4.5 1 ( 2 Η, t, J = 7. 1 Hz), 6.87 (1 H, d, J = 9.6 Hz ) , 7.50 ( 1 H, dd, J = 10.1, 2.3 Hz) , 7.90 - 7.93 ( 1 H, m ), 8.45 ( 1 H, d, J = 2.3 Hz ), 9.88 ( 1 H, s). Reference example 5 4

將3 -甲氧基- 5Η-Π比陡並（2,3-b) D比曉-6-酮980mg懸浮於二甲基亞颯15mL，加入溴乙酸第三丁酯0 86mL及磷酸鉀1 .23g，在室溫進行一晚攪拌。於反應混合物加入水 lOOmL，並以乙酸乙酯lOOmL進行2次萃取。將有機層以飽 201209056 和食鹽水lOOmL洗淨，以無水硫酸鎂乾燥後，將溶劑減壓下餾去。將所得之殘餾物以矽膠管柱層析法〔矽膠；關東化學股份有限公司，矽膠60，溶離液；乙酸乙酯：甲醇= 1 : 1〕進行純化後得到淡黃色固體狀的第三丁基=(2-( 3-甲氧基-6-側氧-6H-吡啶並（2,3-b)吡嗪-5-基）乙酸酯 1 · 2 1 g。 1H NMR ( CHLOROFORM-d ) δ 1.49 ( 9 H, s)，4.02 (3 H，s)，5.08(2 H，s)，6.80( 1 H，d，J=10.1 Hz)， 7.89 ( 1 H, d, J= 10.1 Hz) , 8.12 ( 1 H, s) 〇參考例5 53-methoxy- 5Η-Π is steep and (2,3-b) D is suspended in dimethyl hydrazine 1500 mg in dimethyl hydrazine 15 mL, and butyl bromoacetate 0 86 mL and potassium phosphate 1 are added. .23g, stirred overnight at room temperature. 100 mL of water was added to the reaction mixture, and extraction was carried out twice with ethyl acetate (100 mL). The organic layer was washed with a saturated solution of 201209056 and brine, dried over anhydrous magnesium sulfate, and then evaporated. The obtained residue was purified by silica gel column chromatography (Glue Gel; Kanto Chemical Co., Ltd., Silicone 60, Eluent; ethyl acetate:methanol = 1:1) to obtain a third solid of pale yellow solid. Base = (2-(3-methoxy-6-oxo-6H-pyrido(2,3-b)pyrazin-5-yl)acetate 1 · 2 1 g. 1H NMR (CHLOROFORM-d δ 1.49 ( 9 H, s), 4.02 (3 H, s), 5.08 (2 H, s), 6.80 ( 1 H, d, J = 10.1 Hz), 7.89 ( 1 H, d, J = 10.1 Hz ) , 8.12 ( 1 H, s) 〇 Reference Example 5 5

將第三丁基=(2- ( 3-甲氧基-6_側氧-6H_吡啶並（ 2,3-b)吡嗪-5-基）乙酸酯980mg溶解於乙酸乙酯5mL，加入4mol/L鹽酸的乙酸乙酯溶液l〇mL，在室溫進行20小時攪拌。過濾並取出不溶物’以乙酸乙酯50mL洗淨並乾燥後得到無色固體狀的（2-(3-甲氧基-6-側氧_611-吡啶並（2,3邛 )吡嗪-5-基）乙酸的鹽酸鹽504mg。 1H NMR ( DMSO-d6) δ 3.99 ( 3 H，s)，5.00 ( 2 H，s )，6_77 ( 1 Η，d，J=9.7 Hz)，8.02 ( 1 Η，d，J=9.7 Hz) ,8.27 ( 1 H, s)。 -63- 201209056 參考例5 6980 mg of a third butyl group = (2-(3-methoxy-6-sideoxy-6H-pyrido(2,3-b)pyrazin-5-yl)acetate was dissolved in ethyl acetate 5 mL, After adding 4 mL of a solution of 4 mol/L hydrochloric acid in ethyl acetate, the mixture was stirred at room temperature for 20 hours, filtered, and the insoluble material was taken out and washed with ethyl acetate 50 mL and dried to give a colorless solid (2-(3-) Hydroxy-6-oxo-_611-pyrido(2,3邛)pyrazin-5-yl)acetic acid hydrochloride 504 mg. 1H NMR (DMSO-d6) δ 3.99 (3H, s), 5.00 ( 2 H, s ), 6_77 ( 1 Η, d, J = 9.7 Hz), 8.02 ( 1 Η, d, J = 9.7 Hz), 8.27 ( 1 H, s). -63- 201209056 Reference Example 5 6

使用第三丁基=1-噁-6-氮雜螺（2·5)辛烷羧酸酯 2 10mg 及 2,3-二氫-(Μ )二卩惡並（2,3-b )啦陡-6-胺 150mg，藉由與參考例29之同樣操作’得到褐色油狀的第三丁基=4_( ( (2,3-二氫-(1，4)二噁並（2,3-b)吡啶- 6-基）胺基）甲基）-4-經基峨陡-1·殘酸醋294mg° 1H NMR ( CHLOROFORM-d ) δ 1.49 ( 9 H, s) , 1.60 -1 67 (2 Η, m)，2·04 (2 Η，s)，3.20 (2 Η, d, J=5.0 Hz )3 29 - 3.34 (2 Η, m) , 4.13 - 4.18 (2 Η, m) , 4.34 - 439(2 Η，m)，4·4〇 _ 4.46(1 Η，ηι)，4.57(1 Η, s)， 602-609(1 H，m)，7.00-7.04(1 Η，m)。矣去伽5 7Use 3 butyl = 1 - oxa-6-azaspiro (2.5) octane carboxylate 2 10 mg and 2,3-dihydro-(Μ) dioxo and (2,3-b) Steep-6-amine 150 mg, by the same operation as in Reference Example 29, to give a tri-butyl = 4-(((2,3-dihydro-(1,4) dioxin and (2,3) -b) pyridine-6-yl)amino)methyl)-4-pyrimidin-1 -residual vinegar 294mg° 1H NMR (CHLOROFORM-d) δ 1.49 ( 9 H, s) , 1.60 -1 67 (2 Η, m), 2·04 (2 Η, s), 3.20 (2 Η, d, J=5.0 Hz) 3 29 - 3.34 (2 Η, m) , 4.13 - 4.18 (2 Η, m) , 4.34 - 439 (2 Η, m), 4·4 〇 _ 4.46 (1 Η, ηι), 4.57 (1 Η, s), 602-609 (1 H, m), 7.00-7.04 (1 Η, m) .矣去伽5 7

使用第三丁基= 4·( ( (2,3_二氫-(1，4)二噁並（ 289mg 2 3-b )吡啶-6_基）胺基）甲基）_4_經基哌啶-1-羧酸酯藉由與參考例4 9之同樣操作’得到無色油狀的第 -64 - 201209056 三丁基= 3-(2，3-二氫-(1，4)二噁並（2,3-b)吡啶-6-基 )-2_側氧-1-噁-3,8-重氮螺（4.5)癸烷-8-羧酸酯161111§。 1H NMR ( CHLOROFORM-d ) δ 1.49(9 H, s ) , 1.74 (2 Η, d, J=1.4 Hz) , 1.90 - 1.97 (2 H, m) , 3.38 (2 Η, br. s.) , 3.73 - 3.82 ( 2 H, m) , 3.94 ( 2 H, s ) , 4.21 - 4.25 ( 2 H, m) , 4.41 - 4.44 ( 2 H, m) , 7.23 - 7.26 ( 1 H, m) , 7.76 ( 1 H, d, J= 8.7 Hz)。參考例5 8Use of the third butyl group = 4 (((2,3-dihydro-(1,4) dioxin and (289mg 2 3-b)pyridine-6-yl)amino)methyl)_4 The pyridine-1-carboxylate was obtained by the same procedure as in Reference Example 49 to give the -64-201209056 tributyl- 3-(2,3-dihydro-(1,4) dioxane as a colorless oil. (2,3-b)pyridin-6-yl)-2_sideoxy-1-oxo-3,8-diazospiro(4.5)decane-8-carboxylate 161111§. 1H NMR (CHLOROFORM-d) δ 1.49(9 H, s ) , 1.74 (2 Η, d, J=1.4 Hz) , 1.90 - 1.97 (2 H, m) , 3.38 (2 Η, br. s.) , 3.73 - 3.82 ( 2 H, m) , 3.94 ( 2 H, s ) , 4.21 - 4.25 ( 2 H, m) , 4.41 - 4.44 ( 2 H, m) , 7.23 - 7.26 ( 1 H, m) , 7.76 ( 1 H, d, J = 8.7 Hz). Reference example 5 8

將第三丁基= 3-(2，3-二氫-(1，4)二噁並（2,3-b) 吡啶-6-基）-2-側氧-1-噁-3,8-重氮螺（4.5)癸烷-8-羧酸酯153mg溶解於氯仿2mL，加入三氟乙酸lmL，在室溫進行 1小時攪拌。於反應混合物加入飽和碳酸氫鈉水溶液使其成爲鹼性。將有機層以無水硫酸鎂乾燥，將溶劑減壓餾去後將所得之殘餾物以矽膠管柱層析法〔矽膠；FUJI SILYSIA股份有限公司，Chromatorex-NH，溶離液；氯仿 :甲醇=10 : 1〕進行純化，得到無色固體狀的3- ( 2,3-二氫-(1,4 )二噁並（2,3-b )吡啶-6-基）-1-噁-3,8-重氮螺 (4.5 )癸烷-2-酮 134mg。 1H NMR ( CHLOROFORM-d) δ 1.80 ( 2 Η, ddd, J = -65- 201209056 13.0，9.1，3.7 Hz)，1.91 - 1.98 (2 H，m)，2.84 - 2.91 ( 2 H，m)，3.03 - 3.14(2 H，m)，3.90 - 3.97 (2 H，m)， 4.17 - 4.26 (2 H, m) , 4.37 - 4.46 (2 H, m) , 7.20 - 7.28 (1 H, m ) , 7.77 ( 1 H, d, J= 8.7 Hz)。參考例5 9The third butyl group is 3-(2,3-dihydro-(1,4)dioxa-(2,3-b)pyridin-6-yl)-2-oxo-oxo-oxa-3,8 153 mg of diazospiro (4.5) decane-8-carboxylate was dissolved in 2 mL of chloroform, and 1 mL of trifluoroacetic acid was added thereto, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture to make it basic. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue obtained was purified by silica gel column chromatography (yield; FUJI SILYSIA Co., Ltd., Chromatorex-NH, eluent; chloroform:methanol = 10 : 1) Purification afforded 3-(2,3-dihydro-(1,4)dioxa-(2,3-b)pyridin-6-yl)-1-oxo-3,8 as a colorless solid - Diazospiro (4.5) decane-2-one 134 mg. 1H NMR (CHLOROFORM-d) δ 1.80 ( 2 Η, ddd, J = -65- 201209056 13.0, 9.1, 3.7 Hz), 1.91 - 1.98 (2 H, m), 2.84 - 2.91 ( 2 H, m), 3.03 - 3.14(2 H,m), 3.90 - 3.97 (2 H,m), 4.17 - 4.26 (2 H, m) , 4.37 - 4.46 (2 H, m) , 7.20 - 7.28 (1 H, m ) , 7.77 ( 1 H, d, J = 8.7 Hz). Reference example 5 9

將2-溴- 5H -吡啶並（3,2-d)嘧啶-6-酮200mg及碳酸氫鈉297mg懸浮於乙醇60mL與四氫呋喃60mL之混合溶劑’加入10%鈀碳20mg，氫環境下進行69小時攪拌。過濾除去不溶物，將濾液減壓下濃縮，得到淡褐色固體狀的5H-吡啶並（3,2-d)嘧啶-6-酮（粗純化物）220mg。使用此藉由與參考例54之同樣操作，得到淡灰色固體狀的第三丁基=2-(6-側氧-6H-吡啶並（3,2-d)嘧啶-5-基）乙酸酯89mg。 1H NMR ( CHLOROFORM-d ) δ 1.49(9 H, s ) , 4.98 (2 Η, s) , 7. 1 5 ( 1 Η, d, J = 1 0. 1 Hz ) , 7.90 ( 1 Η, d, J = 1 0· 1 Hz )，8.67 ( 1 Η，s )，9. 1 0 ( 1 Η，s )。參考例60200 mg of 2-bromo-5H-pyrido(3,2-d)pyrimidin-6-one and 297 mg of sodium hydrogencarbonate were suspended in a mixed solvent of 60 mL of ethanol and 60 mL of tetrahydrofuran, and 20 mg of 10% palladium carbon was added thereto, and 69 in a hydrogen atmosphere. Stir for hours. The insoluble material was removed by filtration, and the filtrate was evaporated to dryness crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Using the same procedure as in Reference Example 54 to give the title compound: Ester 89mg. 1H NMR ( CHLOROFORM-d ) δ 1.49(9 H, s ) , 4.98 (2 Η, s) , 7. 1 5 ( 1 Η, d, J = 1 0. 1 Hz ) , 7.90 ( 1 Η, d, J = 1 0· 1 Hz ), 8.67 ( 1 Η, s ), 9. 1 0 ( 1 Η, s ). Reference example 60

-66 - 201209056 使用第三丁基=2- ( 6-側氧-6Η-吡啶並（3,2-d )嘧啶-5-基）乙酸酯79mg，藉由與參考例55之同樣操作，得到淡褐色固體狀的2- ( 6-側氧- 6H-吡啶並（3,2-d )嘧啶- 5-基）乙酸的鹽酸鹽51mg。 1H NMR ( DMSO-d6) δ 5.07 ( 2 H, s) , 7.18 ( 1 Η, d, J=9.7 Hz)，8.02 ( 1 Η，d，J=9.7 Hz)，9.09 ( 1 Η，s)， 9.19 ( 1 H, s )。參考例6 1-66 - 201209056 79 mg of the third butyl group = 2-(6-oxo-6-pyrido(3,2-d)pyrimidin-5-yl)acetate was used, and the same operation as in Reference Example 55, 51 mg of 2-(6-oxo-6H-pyrido(3,2-d)pyrimidin-5-yl)acetic acid hydrochloride as a pale brown solid was obtained. 1H NMR ( DMSO-d6) δ 5.07 ( 2 H, s) , 7.18 ( 1 Η, d, J = 9.7 Hz), 8.02 (1 Η, d, J = 9.7 Hz), 9.09 (1 Η, s), 9.19 ( 1 H, s ). Reference example 6 1

使用苯甲基=1-噁-6-氮雜螺（2.5)辛烷-6-羧酸醋 318 mg及3-氟-4-甲基苯胺162mg，藉由與參考例29之同樣操作，得到淡褐色油狀的苯甲基=4- ((( 3-氟-4-甲基苯基）胺基）甲基）-4-羥基哌啶-1-羧酸酯301mg。 1H NMR ( CHLOROFORM-d ) δ 1.49 - 1.76 ( 4 Η, m) ,2.13(3 Η, s ) , 3.07(1 Η, br. s )，3.2 4 ( 2 Η，b r. s )， 3.80 - 4.03 ( 2 H，m)，5.06 - 5.17 ( 2 H，m)，6.31 · 6.38 (2 H，m)，6.86 - 6.99 ( 1 H, m)，7.2 8 - 7.40 ( 5 H，m) -67- 201209056The same procedure as in Reference Example 29 was carried out using benzyl benzyl-1-oxo-6-azaspiro(2.5) octane-6-carboxylic acid vinegar 318 mg and 3-fluoro-4-methylaniline 162 mg. Benzyl = 4-(((3-fluoro-4-methylphenyl)amino)methyl)-4-hydroxypiperidine-1-carboxylate 301 mg as a light brown oil. 1H NMR ( CHLOROFORM-d ) δ 1.49 - 1.76 ( 4 Η, m) , 2.13 (3 Η, s ) , 3.07 (1 Η, br. s ), 3.2 4 ( 2 Η, b r. s ), 3.80 - 4.03 ( 2 H,m), 5.06 - 5.17 ( 2 H,m), 6.31 · 6.38 (2 H,m), 6.86 - 6.99 ( 1 H, m), 7.2 8 - 7.40 ( 5 H,m) -67 - 201209056

使用苯甲基= 4-( ( (3-氟-4-甲基苯基）胺基）+甲基 )-4-羥基哌啶-1-羧酸酯287mg，藉由與參考例49之同樣操作，得到淡褐色油狀的苯甲基=3- (3_氟-4 -甲基苯基）-2-側氧-1-噁-3,8-重氮螺（4.5)癸烷-8-羧酸酯256mg。 1H NMR ( CHLOROFORM-d ) δ 1.17 - 1.27 ( 4 H, m) ，2.23 ( 3 Η，s)，3.34 - 3.43 ( 2 Η，m)，3.45 - 3.5 5 ( 2 Η，m)，3.70 (2 Η，s)，5.14 (2 Η，s)，7.09 - 7.12 ( 1 Η， m) , 7.13 - 7.17( 1 Η, m) , 7.29 - 7.41 (6 Η, m)。參考例6 3Benzyl = 4-((3-fluoro-4-methylphenyl)amino)+methyl)-4-hydroxypiperidine-1-carboxylate 287 mg was used as in Reference 49 Operation to give benzyl = 3-(3-fluoro-4-methylphenyl)-2-oxo-1-oxo-3,8-diazospiro(4.5)decane-8 as a light brown oil. - carboxylic acid ester 256 mg. 1H NMR ( CHLOROFORM-d ) δ 1.17 - 1.27 ( 4 H, m) , 2.23 ( 3 Η, s), 3.34 - 3.43 ( 2 Η, m), 3.45 - 3.5 5 ( 2 Η, m), 3.70 (2 Η, s), 5.14 (2 Η, s), 7.09 - 7.12 ( 1 Η, m) , 7.13 - 7.17 ( 1 Η, m) , 7.29 - 7.41 (6 Η, m). Reference example 6 3

Ο ΗΝ^ 使用苯甲基=3 - ( 3 -氟-4 -甲基苯基）-2 -側氧-1 -噁- 3,8-重氮螺（4.5)癸烷-8-羧酸酯250mg，藉由與參考例50 之同樣操作’得到無色固體狀的3 - ( 3 -氟-4-甲基苯基）- 1、噁-3,8-重氮螺（4.5)癸烷-2-酮6711^。 1H NMR(DMSO-d6) δ 2.01 - 2.14(4 H, m) , 2.19 (3 H，s)，3.08 - 3.15 (2 H，m)，3.17 - 3.24 (2 H，m)， -68- 201209056 3.93(2 H, s )，7.22(1 Η, dd，J= 8.3, 1.8 Hz ) , 7.27 -7.31 ( 1 H, m) , 7.40 - 7.45 ( 1 H, m) , 8.95 ( 1 H, br. s. 參考例64Ο ΗΝ^ Use benzyl = 3 - ( 3 -fluoro-4-methylphenyl) - 2 -oxy-1 -oxa-3,8-diazospiro (4.5) decane-8-carboxylate 250 mg of 3-(3-fluoro-4-methylphenyl)-1, cacao-3,8-diazaspiro(4.5)nonane-2 as a colorless solid. - Ketone 6711^. 1H NMR (DMSO-d6) δ 2.01 - 2.14(4 H, m) , 2.19 (3 H, s), 3.08 - 3.15 (2 H, m), 3.17 - 3.24 (2 H, m), -68- 201209056 3.93(2 H, s ), 7.22 (1 Η, dd, J= 8.3, 1.8 Hz ) , 7.27 -7.31 ( 1 H, m) , 7.40 - 7.45 ( 1 H, m) , 8.95 ( 1 H, br. s. Reference example 64

使用6 -溴-2,3 -二氫苯並（b) (1，4)二硫酮（ 0^1^1^)53〇1^及第三丁基=2-側氧-3,8-重氮螺（4.5) 癸烷-8-羧酸酯5 5 3 mg，藉由與參考例14之同樣操作，得到褐色油狀的第三丁基=3- (2,3-二氫苯並（b) (1，4)二硫酮（Dithiine) -6-基）-2-側氧-1-噁-3,8-重氮螺（4.5) 癸烷-8-羧酸酯76mg。 1H NMR ( CHLOROFORM-d ) δ 1.46 ( 9 H, s) , 1.71 -1.76 (2 H, m) , 1.94 - 1.96 (2 H, m) , 3.22 - 3.28 (4 Η, m) , 3.29 - 3.36(2 H, m) , 3.68(2 H, s) , 3.82 - 3.93 (2 H, m) , 7.14 ( 1 H, d, J=8.7 Hz) , 7.29 ( 1 H, dd, J =8.7, 2.5 Hz ) , 8.01 ( 1 H, s )。參考例6 5Using 6-bromo-2,3-dihydrobenzo (b) (1,4) dithione (0^1^1^) 53〇1^ and tert-butyl = 2-side oxygen-3,8 - diazonium sulphate (4.5) decane-8-carboxylate 5 5 3 mg, obtained in the same manner as in the title compound 14 And (b) (1,4) Dithiine-6-yl)-2-oxo-1-carbo-3,8-diazospiro (4.5) decane-8-carboxylate 76 mg. 1H NMR ( CHLOROFORM-d ) δ 1.46 ( 9 H, s) , 1.71 -1.76 (2 H, m) , 1.94 - 1.96 (2 H, m) , 3.22 - 3.28 (4 Η, m) , 3.29 - 3.36 ( 2 H, m) , 3.68(2 H, s) , 3.82 - 3.93 (2 H, m) , 7.14 ( 1 H, d, J=8.7 Hz) , 7.29 ( 1 H, dd, J =8.7, 2.5 Hz ) , 8.01 ( 1 H, s ). Reference example 6 5

-69- 201209056 使用第三丁基= 3-(2,3-二氫苯並（b) (1，4)二硫酮（Dithiine) -6-基）-2-側氧-1-噁-3,8-重氮螺（4.5)癸烷-8-羧酸酯33mg，藉由與參考例58之同樣操作，得到淡褐色固體狀的3-(2,3-二氫苯並（b) (1，0二硫酮（-69- 201209056 Use of tert-butyl = 3-(2,3-dihydrobenzo(b) (1,4) dithione (Dithiine)-6-yl)-2-sideoxy-1-oxo- 3,8-diazospiro (4.5) decane-8-carboxylate (33 mg, m.p. (1,0 dithione (

Dithiine) -6-基）-1-噁-3,8-重氮螺（4.5)癸烷-2-酮 I4mg 〇 , 1H NMR ( CHLOROFORM-d ) δ 1.77 - 1.81 ( 2 H, m) ,1.94 - 2.00 ( 2 Η, m) , 2.89 - 2.92 ( 2 Η, m ) , 3.09 -3.12(2 Η, m) , 3.23 - 3.29(4 Η, m) , 3.69(2 Η, s), 7.15 ( 1 Η，s)，7.28 ( 1 Η, d, J = 2.5 Hz)，7.32 ( 1 Η, dd, J = 8.7, 2.5 Hz )。參考例66 使用2-碘噻吩並（3,2-b)噻吩463mg及第三丁基= 2-側氧-3,8-重氮螺（4.5)癸烷-8-羧酸酯228mg，藉由與參考例14之同樣操作，得到淡褐色固體狀的第三丁基=2-側氧-3-(噻吩並（3,2-1?)噻吩-2-基）-1-噁-3,8-重氮螺（ 4.5 )癸烷-8-羧酸酯215mg。 1H NMR ( CHLOROFORM-d) 5 1.47 ( 9 H, s) , 1.76 -1.83 (2 Η, m) , 1.99 - 2.02 (2 Η, m) , 3.31 - 3.34 (2 Η, m)，3.77 (2 Η，s) ，3.86 - 3_95 (2 Η，m)，6.70( 1 Η, s -70- 201209056 )，7.18 ( 1 H，d，J=5.0 Hz)，7·23 - 7.26 ( 1 H，m)。參考例6 7Dithiine)-6-yl)-1-oxo-3,8-diazospiro(4.5)nonan-2-one I4mg 〇, 1H NMR (CHLOROFORM-d ) δ 1.77 - 1.81 ( 2 H, m) , 1.94 - 2.00 ( 2 Η, m) , 2.89 - 2.92 ( 2 Η, m ) , 3.09 -3.12(2 Η, m) , 3.23 - 3.29(4 Η, m) , 3.69(2 Η, s), 7.15 ( 1 Η, s), 7.28 (1 Η, d, J = 2.5 Hz), 7.32 (1 Η, dd, J = 8.7, 2.5 Hz). Reference Example 66 228 mg of 2-iodothieno(3,2-b)thiophene and 228 mg of a third butyl = 2-oxo-3,8-diazospiro(4.5)decane-8-carboxylate were used. The same procedure as in Reference Example 14 gave the butyl butyl = 2- s s s s s s s s s s s s s s s s s s , 8-diazospiro (4.5) decane-8-carboxylate 215 mg. 1H NMR (CHLOROFORM-d) 5 1.47 ( 9 H, s) , 1.76 -1.83 (2 Η, m) , 1.99 - 2.02 (2 Η, m) , 3.31 - 3.34 (2 Η, m), 3.77 (2 Η , s) , 3.86 - 3_95 (2 Η, m), 6.70 ( 1 Η, s -70- 201209056 ), 7.18 ( 1 H, d, J = 5.0 Hz), 7·23 - 7.26 ( 1 H, m) . Reference example 6 7

使用第三丁基=2-側氧- 3-(噻吩並（3,2-b)噻吩-2- / 基）-1-噁-3,8-重氮螺（4.5)癸烷-8-羧酸酯21〇11^，藉由與參考例5 8之同樣操作，得到褐色油狀的3 -(噻吩並（ 3,2-b)噻吩-2-基）-1-噁-3,8-重氮螺（4.5)癸烷-2-酮 1 3 1 m g。 1H NMR ( CHLOROFORM-d ) δ 1.74 - 1.81 ( 2 H, m) ,1.95 - 1.98 ( 2 Η, m) , 2.84 - 2.89 ( 2 Η, m) , 3.03 -3.10 (2 Η，m)，3.73 (2 Η，s)，6.65 ( 1 Η，s)，7.14 ( 1 Η, d, J=5.4 Hz) , 7.19 - 7.21 ( 1Η, m)。參考例6 8Use of tert-butyl = 2-oxo-3-(thieno(3,2-b)thiophen-2-yl)-1-oxo-3,8-diazospiro(4.5)decane-8- The carboxylic acid ester 21 〇 11 </ RTI> was obtained by the same procedure as that of the compound of Example 58 to give 3-(thieno(3,2-b)thiophen-2-yl)-1-oxo-3,8 as a brown oil. - Diazospiro (4.5) decane-2-one 1 3 1 mg. 1H NMR ( CHLOROFORM-d ) δ 1.74 - 1.81 ( 2 H, m) , 1.95 - 1.98 ( 2 Η, m) , 2.84 - 2.89 ( 2 Η, m) , 3.03 -3.10 (2 Η, m), 3.73 ( 2 Η, s), 6.65 ( 1 Η, s), 7.14 ( 1 Η, d, J = 5.4 Hz), 7.19 - 7.21 ( 1Η, m). Reference example 6 8

將第三丁基=6-胺基-2-氮雜螺（3.3)庚烷-2-羧酸酯 119mg 及 2,3 -二氫-(1,4)二噁並（2,3-c)吡啶-7 -羰醛 8 9mg溶解於氯仿5mL，加入乙酸46pL，在室溫進行3小時攪拌。加入三乙酸基氫化硼鈉250mg，在室溫進行2小時攪拌。於反應混合物加入水2mL，將溶劑減壓下餾去後，將 201209056 所得之殘餾物以矽膠管柱層析法〔矽膠；關東化學股份有限公司，矽膠60，溶離液；氯仿〕進行純化，得到淡黃色油狀的第三丁基=6- ( ( ( 2,3-二氫-(1，4 )二噁並（2,3-c)吡啶-7-基）甲基）胺基）-2-氮雜螺（3.3)庚烷-2-羧酸醋1 5 0 m g。 1H NMR ( CHLOROFORM-d ) δ 1.41 ( 9 H，br. s.)， 1.86 - 1.91 (2 H, m) , 2.39 - 2.42 (2 H, m) , 3.17 - 3.22 (1 H，m) , 3.66 ( 2 H, s ) , 3.82 ( 2 H, s ) , 3.89 ( 2 H, s ),4.25 - 4.28 ( 2 H, m) , 4.3 0 - 4.3 3 ( 2 H, m) , 6.78 ( 1 H， s) ， 8.09 ( 1 H， s)。參考例6 9138 mg of the third butyl group = 6-amino-2-azaspiro(3.3) heptane-2-carboxylate and 2,3-dihydro-(1,4) dioxo (2,3-c) 8 9 mg of pyridine-7-carbonylaldehyde was dissolved in 5 mL of chloroform, and 46 pL of acetic acid was added thereto, and the mixture was stirred at room temperature for 3 hours. 250 mg of sodium triacetate borohydride was added, and the mixture was stirred at room temperature for 2 hours. 2 mL of water was added to the reaction mixture, and the solvent was distilled off under reduced pressure. The residue obtained from 201209056 was purified by silica gel column chromatography (gum, Gentung Chemical Co., Ltd., silica gel 60, eluent; chloroform). Obtaining a third butyl = 6-(((2,3-dihydro-(1,4)dioxato(2,3-c)pyridin-7-yl)methyl)amino) as a pale yellow oil) 2-Azaspiro(3.3)heptane-2-carboxylic acid vinegar 1 50 mg. 1H NMR ( CHLOROFORM-d ) δ 1.41 ( 9 H,br. s.), 1.86 - 1.91 (2 H, m) , 2.39 - 2.42 (2 H, m) , 3.17 - 3.22 (1 H,m) , 3.66 ( 2 H, s ) , 3.82 ( 2 H, s ) , 3.89 ( 2 H, s ), 4.25 - 4.28 ( 2 H, m) , 4.3 0 - 4.3 3 ( 2 H, m) , 6.78 ( 1 H, s) , 8.09 ( 1 H, s). Reference example 6 9

使用第三丁基= 6-( ( (2，3 -二氫-(1，4)二囉並（ 2,3-c)吡啶-7-基）甲基）胺基）·2 -氮雜螺（3.3)庚院_ 2-羧酸酯130mg，藉由與參考例58之同樣操作’得到淡黃色油狀的N· ( ( 2,3-二氫-(1，4 )二嚼並（2,3-c )卩比D定- 7- 基）甲基）-2-氮雜螺（3.3)庚烷-6-胺88mg° 1H NMR ( CHLOROFORM-d) δ 1.80 - 1.85 ( 2 Η, m) ,2.42 - 2.45 (2 Η, m) , 3.15 - 3.17(1 Η, m) , 3.52(2 Η，s)，3.61 ( 2 Η，s)，3.66 ( 2 Η，s)，4.25 - 4.28 ( 2 Η， m)，4.29 - 4.33 ( 2 Η，m)，6.79 ( 1 Η，s) , 8.09 ( 1 Η，s -72- 201209056 參考例7 0Use of tert-butyl = 6-((2,3 -dihydro-(1,4)diindolo(2,3-c)pyridin-7-yl)methyl)amino)-2-aza Spirulina (3.3) Gengyuan _ 2-carboxylate 130 mg, obtained by the same procedure as in Reference Example 58 to give N (( 2,3-dihydro-(1,4)) 2,3-c ) 卩1 - 7-yl)methyl)-2-azaspiro(3.3)heptane-6-amine 88mg° 1H NMR (CHLOROFORM-d) δ 1.80 - 1.85 ( 2 Η, m) , 2.42 - 2.45 (2 Η, m) , 3.15 - 3.17(1 Η, m) , 3.52(2 Η, s), 3.61 ( 2 Η, s), 3.66 ( 2 Η, s), 4.25 - 4.28 ( 2 Η, m), 4.29 - 4.33 ( 2 Η, m), 6.79 ( 1 Η, s) , 8.09 ( 1 Η, s -72- 201209056 Reference example 7 0

使用（7-甲氧基-2-側氧-2Η- ( 1，5 )萘啶-1-基）乙醛的鹽酸鹽122mg及第三丁基=2,7-重氮螺（4.4)壬烷-2-羧酸酯123 mg，藉由與參考例35之同樣操作，得到褐色泡狀的第三丁基= 7-(2-(7-甲氧基-2-側氧- 2H-(1,5)萘啶-1-基）乙基）-2,7-重氮螺（4.4)壬烷-2-羧酸酯126mg。 1H NMR ( CHLOROFORM-d ) δ 1.45 ( 9 H, s) , 1.72 -1.90 (4 Η, m) , 2.68 - 2.82 (4 Η, m) , 3.15 - 3.29 (2 Η, m ) , 3.28 - 3.45 (4 Η, m) , 3.97 ( 3 Η, s ) , 4.35 ( 2 Η, t, J = 7.4 Hz ) , 6.74(1 Η, d, J = 9.5 Hz ) , 7.15 - 7.16(1 Η, m) , 7.83 ( 1 Η, d, J=9.5 Hz) , 8.27 ( 1 Η, d, J=1.7 Hz )。參考例7 1Using (7-methoxy-2-oxo-2-indole-(1,5)-naphthyridin-1-yl)acetaldehyde hydrochloride 122 mg and tert-butyl = 2,7-diazosole (4.4) The decane-2-carboxylate 123 mg was obtained by the same procedure as that of Reference Example 35 to give a brown ss. (1,5) Naphthyridin-1-yl)ethyl)-2,7-diazospiro(4.4)nonane-2-carboxylate 126 mg. 1H NMR ( CHLOROFORM-d ) δ 1.45 ( 9 H, s) , 1.72 -1.90 (4 Η, m) , 2.68 - 2.82 (4 Η, m) , 3.15 - 3.29 (2 Η, m ) , 3.28 - 3.45 ( 4 Η, m) , 3.97 ( 3 Η, s ) , 4.35 ( 2 Η, t, J = 7.4 Hz ) , 6.74 (1 Η, d, J = 9.5 Hz ) , 7.15 - 7.16(1 Η, m) , 7.83 ( 1 Η, d, J = 9.5 Hz) , 8.27 ( 1 Η, d, J = 1.7 Hz ). Reference example 7 1

-73- 201209056 使用第三丁基=7- ( 2- ( 7-甲氧基-2-側氧-2H- ( 1，5 ) 萘D定-1-基）乙基）-2,7 -重氮螺（4.4)壬院-2 -殘酸醋 105mg，藉由與參考例13之同樣操作，得到褐色固體狀的 1-(2-(2,7-重氮螺（4.4)壬-2-基）乙基）_7_甲氧基_1^[-(1,5)萘啶-2-酮的鹽酸鹽125mg。 1H NMR ( DMSO-d6) δ 1.84 - 2.17 ( 4 H, m) 3.16- 3.27 (4 Η, m) , 3.37 - 3.43 (2 Η, m) , 3.67 - 3.74 (2 Η, m) , 3.77 - 3.8 3 ( 2 Η, m) , 4.02 ( 3 Η, s) , 4.43 - 4.67 (2 Η, m) , 6.68 ( 1 Η, d, J = 9.5 Hz) , 7.62 - 7.69 ( 1 Η, m) , 7.89 (1 Η, d, J=9.5 Hz) , 8.29 ( 1 Η, d J = 2.1 Hz 實施例1、2-73- 201209056 Use of tert-butyl = 7-(2-( 7-methoxy-2-oxo-2H-( 1,5 ) naphthalene D-1,4-yl)ethyl)-2,7 - Diazo snail (4.4) brothel-2 - Residual vinegar 105 mg, by the same procedure as in Reference Example 13 to give 1-(2-(2,7-diaza snail (4.4) 壬-2 as a brown solid. -yl)ethyl)_7-methoxy_1^[-(1,5)naphthyridin-2-one hydrochloride salt 125 mg. 1H NMR ( DMSO-d6) δ 1.84 - 2.17 ( 4 H, m) 3.16- 3.27 (4 Η, m) , 3.37 - 3.43 (2 Η, m) , 3.67 - 3.74 (2 Η, m) , 3.77 - 3.8 3 ( 2 Η, m) , 4.02 ( 3 Η, s) , 4.43 - 4.67 (2 Η, m) , 6.68 ( 1 Η, d, J = 9.5 Hz) , 7.62 - 7.69 ( 1 Η, m) , 7.89 (1 Η, d, J=9.5 Hz) , 8.29 ( 1 Η, d J = 2.1 Hz Examples 1, 2

解於乙腈11^，加入3-(2,3-二氣苯並（1，4)戴奧辛_6_基 )-1-嚼-3,8-重氮螺（4.5)癸院-2-嗣9lmg及三乙胺〇〇511^ ，在50°C進行15小時攪拌。冷卻至室溫後，將反應混合物在減壓下將溶劑餾去，藉由矽膠管柱層桁法〔砂膠；關東化學股份有限公司，矽膠60，溶離液；氯仿：甲醇=丨〇 : -74- 201209056 1〕進行純化，得到1- ( 2- ( 3- ( 2,3-二氫苯並（1,4 )戴奧辛-6-基）-2-側氧-1-噁-3,8-重氮螺（4.5)癸烷-8-基）乙基）-7-氟-1H-(1，5)-萘啶-2-酮（實施例1) 14mg及1-( 2- ( 3- ( 2,3-二氫苯並（1,4 )戴奧辛-6-基）-2-側氧-1-噁-3,8-重氮螺（4.5)癸烷-8-氧化物-8-基）乙基）-7-氟-ΙΗ-(1，5 )-萘啶-2-酮（實施例2 ) 3.9mg。實施例1 1H NMR ( CHLOROFORM-d ) δ 1.80 - 1.8 6 ( 2 H, m) ,2.00 - 2.05 ( 2 H, m) , 2.70 - 2.76 ( 6 H, m) , 3.68 ( 2 H, s) , 4.23 - 4.27 (4 H, m) , 4.34 (2 H, t, J=7.1 Hz), 6.85 ( 1 H, d, J= 8.7 Hz) , 6.87(1 H, d, J=9.6 Hz), 6.99 ( 1 H，dd, J= 8.7，2.3 Hz)，7.07 ( 1 H，d，2.3 Hz ),7.47 ( 1 H, dd, J= 10.1, 2.3 Hz) , 7.88 - 7.91 ( 1 H, m ),8.43 ( 1 H, d, J= 2.3 Hz )。實施例2Solve in acetonitrile 11^, add 3-(2,3-dibenzobenzo (1,4) dioxin _6_yl)-1-che-3,8-diazo snail (4.5) brothel-2-嗣9 lmg and triethylamine 〇〇 511 ^ were stirred at 50 ° C for 15 hours. After cooling to room temperature, the reaction mixture was distilled off under reduced pressure, and the ruthenium tube was passed through a ruthenium column [sand gum; Kanto Chemical Co., Ltd., Silicone 60, dissolved solution; chloroform: methanol = 丨〇: - 74-201209056 1] Purification to obtain 1-(2-(3-(2,3-dihydrobenzo(1,4)dioxo-6-yl)-2-oxo-1-oxo-3,8 -diazospiro(4.5)decane-8-yl)ethyl)-7-fluoro-1H-(1,5)-naphthyridin-2-one (Example 1) 14 mg and 1-(2-(3) - ( 2,3-Dihydrobenzo(1,4 )dioxin-6-yl)-2-oxo-oxo-oxa-3,8-diazospiro(4.5)decane-8-oxide-8 -yl)ethyl)-7-fluoro-indole-(1,5)-naphthyridin-2-one (Example 2) 3.9 mg. Example 1 1H NMR (CHLOROFORM-d) δ 1.80 - 1.8 6 ( 2 H, m) , 2.00 - 2.05 ( 2 H, m) , 2.70 - 2.76 ( 6 H, m) , 3.68 ( 2 H, s) , 4.23 - 4.27 (4 H, m) , 4.34 (2 H, t, J = 7.1 Hz), 6.85 ( 1 H, d, J = 8.7 Hz) , 6.87 (1 H, d, J = 9.6 Hz), 6.99 ( 1 H, dd, J = 8.7, 2.3 Hz), 7.07 ( 1 H, d, 2.3 Hz ), 7.47 ( 1 H, dd, J = 10.1, 2.3 Hz) , 7.88 - 7.91 ( 1 H, m ), 8.43 ( 1 H, d, J = 2.3 Hz ). Example 2

1H NMR ( METHANOL-d3) δ 2.11 ( 2 H, d, J = 13.8 Hz) , 2.66 ( 2 H，td, J = 1 3.9，4.4 Hz ) , 3.26 - 3.3 7 ( 2 H, m) , 3.44 - 3.49 ( 2 H, m) , 3.68(2 H, dd, J=8.5, 6.6 Hz) , 3.72 - 3.80 ( 2 H, m ) , 3.92 ( 2 H, s) , 4.20 - 4.26 (4 H, m)，6.84 ( 1 H, d，J= 8.7 Hz)，6.90 ( 1 H, d，J = 9.6 Hz) , 6.97 ( 1 H, dd, J=8.7, 2.8 Hz) , 7.14 ( 1 H, d, J = 2.8 Hz ) , 8.02 ( 1 H, d, J= 9.6 Hz ) , 8.25 ( 1 H, dd, J -75- 201209056 =10.5, 2.3 Hz) , 8.52 ( 1 H, d, J=2.3 Hz)。實施例31H NMR ( METHANOL-d3) δ 2.11 ( 2 H, d, J = 13.8 Hz) , 2.66 ( 2 H, td, J = 1 3.9, 4.4 Hz ) , 3.26 - 3.3 7 ( 2 H, m) , 3.44 - 3.49 ( 2 H, m) , 3.68 (2 H, dd, J=8.5, 6.6 Hz), 3.72 - 3.80 ( 2 H, m ) , 3.92 ( 2 H, s) , 4.20 - 4.26 (4 H, m) , 6.84 ( 1 H, d, J = 8.7 Hz), 6.90 ( 1 H, d, J = 9.6 Hz) , 6.97 ( 1 H, dd, J=8.7, 2.8 Hz) , 7.14 ( 1 H, d, J = 2.8 Hz ) , 8.02 ( 1 H, d, J = 9.6 Hz ) , 8.25 ( 1 H, dd, J -75- 201209056 =10.5, 2.3 Hz) , 8.52 ( 1 H, d, J = 2.3 Hz). Example 3

將（7 -氟-2-側氧-2H-( 1,5)-萘啶-1-基）乙酸的鹽酸鹽8311^溶解於1^，1^-二甲基甲醯胺3111[，加入3-(2,3-二氫苯並（1,4)戴奧辛-6-基）-1-噁-3,8 -重氮螺（4.5)癸烷· 2 -酮78mg、六氟磷酸=(苯並三唑-1-氧基）三吡咯里嗪鐵210mg、及二異丙基乙胺69mg，在室溫進行27小時攪拌。於反應混合物加入乙酸乙酯1 5 mL、飽和碳酸氫鈉水溶液 15mL及水15mL，分離並取出有機層。將有機層以飽和氯化鈉水溶液1 OmL洗淨，以無水硫酸鎂乾燥，減壓下將溶劑餾去。將所得之殘餾物以矽膠管柱層析法〔矽膠；FUJI SILYSIA股份有限公司，Chromatorex-NH，溶離液；氯仿 :甲醇=98 : 2〕進行純化。進一步於純化物加入己烷 15mL及氯仿lmL，過濾取出析出物，得到白色固體狀的ΐ-ζ 2- ( 3- ( 2,3-二氫苯並（ 1，4) 戴奧辛 -6-基） -2-側氧 ·1-噁-3, 8 -重氮螺（4.5)癸烷-8-基）-2 -氧代乙基）-7 -氟-ΙΗ-(1，5 )-萘啶-2-酮 1 1 1 mg。 1H NMR ( CHLOROFORM-d ) δ 1.78 - 1.8 5 ( 1 H, m) ,1.98 - 2.10 (2 H, m) , 2.19 ( 1 H, dd, J = 14.2, 2.3 Hz) -76- 201209056 ,3.20 - 3.26 ( 1 H, m) , 3.74 ( 3 Η, d, J= 7.3 Hz ) , 3.98 -4.03 ( 1 H, m) , 4.23 - 4.29 ( 4 H, m) , 4.44 - 4.50 ( 1 H, m) , 4.72 ( 1 H, d, J= 16.5 Hz) , 5.42 ( 1 H, d, J = 16.5 Hz) , 6.87 ( 1 H, d, J=8.7 Hz) , 6.89 ( 1 H, d, J = 9.6 Hz) , 6.98 ( 1 H, dd, J= 8.7, 2.8 Hz ) , 7.08 ( 1 H, d, J=2.8 Hz) , 7.26 - 7.29 ( 1 H, m) , 7.94 - 7.98 ( 1 H, m ),8.44 ( 1 H, d, J= 2.3 Hz )。實施例4Dissolving (7-fluoro-2-oxo-2H-(1,5)-naphthyridin-1-yl)acetic acid hydrochloride 8311^ in 1^,1^-dimethylformamide 3111 [, 3-(2,3-Dihydrobenzo(1,4)dioxin-6-yl)-1-oxo-3,8-diazospiro(4.5)decane-2-one ketone 78 mg, hexafluorophosphoric acid = 210 mg of (benzotriazol-1-oxy)tripyrrolidinium iron and 69 mg of diisopropylethylamine were stirred at room temperature for 27 hours. Ethyl acetate (15 mL), saturated aqueous sodium hydrogencarbonate (15 mL) and water (15 mL) were added to the mixture, and the organic layer was separated. The organic layer was washed with 1 mL of a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The obtained residue was purified by silica gel column chromatography (gum, FUJI SILYSIA Co., Ltd., Chromatorex-NH, eluent; chloroform:methanol = 98:2). Further, 15 mL of hexane and 1 mL of chloroform were added to the purified product, and the precipitate was collected by filtration to obtain ΐ-ζ 2-(3-(2,3-dihydrobenzo (1,4) dioxin-6-yl) as a white solid. -2-Side oxygen·1-oxo-3,8-diazospiro(4.5)decane-8-yl)-2-oxoethyl)-7-fluoro-indole-(1,5)-naphthyridine -2-ketone 1 1 1 mg. 1H NMR ( CHLOROFORM-d ) δ 1.78 - 1.8 5 ( 1 H, m) , 1.98 - 2.10 (2 H, m) , 2.19 ( 1 H, dd, J = 14.2, 2.3 Hz) -76- 201209056 , 3.20 - 3.26 ( 1 H, m) , 3.74 ( 3 Η, d, J = 7.3 Hz ) , 3.98 -4.03 ( 1 H, m) , 4.23 - 4.29 ( 4 H, m) , 4.44 - 4.50 ( 1 H, m) , 4.72 ( 1 H, d, J = 16.5 Hz) , 5.42 ( 1 H, d, J = 16.5 Hz) , 6.87 ( 1 H, d, J = 8.7 Hz) , 6.89 ( 1 H, d, J = 9.6 Hz) , 6.98 ( 1 H, dd, J = 8.7, 2.8 Hz ) , 7.08 ( 1 H, d, J = 2.8 Hz) , 7.26 - 7.29 ( 1 H, m) , 7.94 - 7.98 ( 1 H, m ) , 8.44 ( 1 H, d, J = 2.3 Hz ). Example 4

鹽酸鹽1121^溶解於叱：^-二甲基甲醯胺4111[，加入3-(2,3-二氫苯並（1，4)戴奧辛-6-基）-1-噁-3,8 -重氮螺（4.5) 癸烷-2-酮lOlmg、六氟磷酸=(苯並三唑-1-氧基）三吡咯里嗪鱗269mg、及二異丙基乙胺0.12mL，在室溫進行15小時攪拌。於反應混合物加入乙酸乙酯20mL及飽和碳酸氫鈉水溶液l〇mL，分離並取出有機層。將有機層以飽和氯化鈉水溶液20mL洗淨，以無水硫酸鎂乾燥，減壓下將溶劑餾去。將所得之殘餾物以矽膠管柱層析法〔矽膠；FUJI SILYSIA股份有限公司，Chromatorex-NH，溶離液；乙酸乙酯：甲醇= 99: 1〕進行純化。進一步於純化物加入氯仿10mL及己烷150mL，過濾取出析出物，得到白色固體狀 -77- 201209056 的1-( 2- (3-( 2,3-二氫苯並（1,4)戴奧辛-6-基）-2-側氧-1-噁-3,8-重氮螺（4.5)癸烷-8-基）-2-氧代乙基）-7-甲氧基-1H-(1，5)-萘啶-2-酮 119mg。 1H NMR ( CHLOROFORM-d ) δ 1.75 - 1.81 ( 1 H, m) ,1.94 - 2.00 ( 1 Η, m) , 2.02 - 2.06 ( 1 Η, m) , 2.12 -2.16 ( 1 Η, m) , 3.18 - 3.25 ( 1 Η, m) , 3.67 - 3.74 (3 Η, m) , 3.96 ( 3 Η, s) , 4.03 - 4.0 8 ( 1 Η, m) , 4.23 - 4.28 (4 Η, m) , 4.44 - 4.48 ( 1 Η, m) , 4.73 ( 1 Η, d, J = 16.0The hydrochloride 1121 is dissolved in 叱:^-dimethylformamide 4111 [, 3-(2,3-dihydrobenzo(1,4)dioxin-6-yl)-1-oxo-3 is added. 8 - Diazo snail (4.5) decane-2-one lOlmg, hexafluorophosphoric acid = (benzotriazol-1-oxy)tripyrrolidine scale 269mg, and diisopropylethylamine 0.12mL, in the room Stir for 15 hours at room temperature. Ethyl acetate (20 mL) and a saturated aqueous solution of sodium hydrogencarbonate (1 mL) were added to the mixture, and the organic layer was separated. The organic layer was washed with 20 mL of a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The obtained residue was purified by silica gel column chromatography (gum, FUJI SILYSIA Co., Ltd., Chromatorex-NH, eluent; ethyl acetate:methanol = 99:1). Further, 10 mL of chloroform and 150 mL of hexane were added to the purified product, and the precipitate was collected by filtration to obtain 1-(2-(2,3-dihydrobenzo(1,4)dioxin-white-77-201209056- 6-yl)-2-oxo-1-oxo-3,8-diazospiro(4.5)decane-8-yl)-2-oxoethyl)-7-methoxy-1H-(1 , 5)-naphthyridin-2-one 119 mg. 1H NMR ( CHLOROFORM-d ) δ 1.75 - 1.81 ( 1 H, m) , 1.94 - 2.00 ( 1 Η, m) , 2.02 - 2.06 ( 1 Η, m) , 2.12 -2.16 ( 1 Η, m) , 3.18 - 3.25 ( 1 Η, m) , 3.67 - 3.74 (3 Η, m) , 3.96 ( 3 Η, s) , 4.03 - 4.0 8 ( 1 Η, m) , 4.23 - 4.28 (4 Η, m) , 4.44 - 4.48 ( 1 Η, m) , 4.73 ( 1 Η, d, J = 16.0

Hz ) ,5.46 (1 Η, d, J - 16.0 Hz )， 6.76 (】 H, d， J = 9.6 Hz ) ,6.87 (1 Η, d, J 8.7 Hz ) ，6_ 97 ( 1 H， dd, J = 8.7, 2.5 Hz), 7.07 (1 Η， J. J= 2.5 Hz ) ,7.08 ( 1 H， d, J - 2.3 Hz), 7.92 (1 Η, d, J= 9.6 Hz ) ,8.30 ( 1 H， d, J = 2.3 Hz )。實施例5Hz ) , 5.46 (1 Η, d, J - 16.0 Hz ), 6.76 () H, d, J = 9.6 Hz ) , 6.87 (1 Η, d, J 8.7 Hz ) , 6_ 97 ( 1 H, dd, J = 8.7, 2.5 Hz), 7.07 (1 Η, J. J= 2.5 Hz), 7.08 ( 1 H, d, J - 2.3 Hz), 7.92 (1 Η, d, J = 9.6 Hz ) , 8.30 ( 1 H , d, J = 2.3 Hz ). Example 5

第1步驟 -78 - 201209056 將（7-甲氧基-2-側氧-2H-喹啉-1-基）乙酸乙酯295mg 溶解於乙醇5mL-四氫呋喃5mL，加入氫氧化鈉187mg的水溶液（5mL)，在70°C進行1.5小時攪拌。冷卻至室溫後，以1 mol/L鹽酸成爲酸性，過濾取出析出物並乾燥後得到淡黃色固體狀的殘餾物147mg。第2步驟將在第1步驟所得之殘餾物140mg'及3- ( 2,3-二氫苯並 (1，4)戴奧辛-6-基）-1-噁-3,8-重氮螺（4.5)癸烷-2-酮 17 31^懸浮於氯仿1〇1111^，加入三乙胺0.421111^、1-乙基-3-( 3-二甲基胺基丙基）碳化二亞胺鹽酸鹽204mg及1-羥基苯並三唑1水合物35mg，在室溫進行3天攪拌。於反應液加入氯仿lOOmL及水20mL，分離並取出有機層。將有機層以飽和氯化鈉水溶液1 OmL洗淨，以無水硫酸鎂乾燥，減壓下將溶劑餾去。將所得之殘餾物以矽膠管柱層析法〔矽膠；關東化學股份有限公司，矽膠60，溶離液；氯仿：甲醇= 1〇〇 : 1〕進行純化，得到淡褐色泡狀的1- ( 2- ( 3- ( 2,3-二氫苯並（1，4 )戴奧辛-6-基）-2-側氧-1-噁- 3,8-重氮螺（ 4.5)癸烷-8-基）-2-氧代乙基）-7-甲氧基-1H-喹啉-2-酮 2 3 6 m g ° 1H NMR ( CHLOROFORM-d ) δ 1.78 ( 1 H, ddd, J = 13.5，12.4，4.4 Hz) , 1.90 - 1.96 ( 1 H，m)，2.02 ( 1 H， dd, J= 14.0，2.1 Hz)，2.11 ( 1 H, dd，J= 13.8，1.8 Hz)， 3.19 - 3.26 ( 1 H, m) , 3.64 - 3.73 ( 3 H, m ) , 3.89 ( 3 H, -79- 201209056 s) , 3.97 - 4.02 ( 1 H, m) , 4.23 - 4.2 8 ( 4 H, m) , 4.41 -4.47 ( 1 H, m) , 4.84 ( 1 H, d, J= 16.0 Hz) , 5.42 ( 1 H, d, J = 16.0 Hz)，6.55(1 H，d，J=9.2 Hz) , 6.75(1 H， d, J = 1.8 Hz) , 6.83 ( 1 H, dd, J=8.3,1.8 Hz) , 6.86 ( 1 H, d, J = 9.2 Hz ) , 6.95 - 6.98 ( 1 H, m) , 7.07 ( 1 H, d, J = 2.8 Hz ) , 7.49 ( 1 H, d, J = 8.3 Hz ) , 7.66( 1 H, d, J = 9.2 Hz )。Step 1 -78 - 201209056 295 mg of ethyl (7-methoxy-2-oxo-2H-quinolin-1-yl)acetate was dissolved in 5 mL of ethanol 5 mL-tetrahydrofuran, and an aqueous solution of 187 mg of sodium hydroxide (5 mL) was added. The mixture was stirred at 70 ° C for 1.5 hours. After cooling to room temperature, it was made acidic with 1 mol/L hydrochloric acid, and the precipitate was collected by filtration and dried to give 147 mg of a residue as a pale yellow solid. In the second step, the residue obtained in the first step is 140 mg' and 3-(2,3-dihydrobenzo(1,4)dioxin-6-yl)-1-oxo-3,8-diazo (4.5) decane-2-one 17 31^ was suspended in chloroform 1〇1111^, and triethylamine 0.421111^, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide salt was added. 204 mg of the acid salt and 35 mg of 1-hydroxybenzotriazole monohydrate were stirred at room temperature for 3 days. To the reaction liquid, 100 mL of chloroform and 20 mL of water were added, and the organic layer was separated and taken out. The organic layer was washed with 1 mL of a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The obtained residue was purified by silica gel column chromatography (Glue Gel; Kanto Chemical Co., Ltd., Silicone 60, Eluent; chloroform:methanol = 1 〇〇: 1) to obtain a light brown blister 1- ( 2-(3-(2,3-Dihydrobenzo(1,4)dioxine-6-yl)-2-oxo-1-carbo-3,8-diazospiro (4.5)decane-8- ))-2-oxoethyl)-7-methoxy-1H-quinolin-2-one 2 3 6 mg ° 1H NMR (CHLOROFORM-d) δ 1.78 ( 1 H, ddd, J = 13.5, 12.4 , 4.4 Hz), 1.90 - 1.96 ( 1 H, m), 2.02 ( 1 H, dd, J = 14.0, 2.1 Hz), 2.11 ( 1 H, dd, J = 13.8, 1.8 Hz), 3.19 - 3.26 ( 1 H, m) , 3.64 - 3.73 ( 3 H, m ) , 3.89 ( 3 H, -79- 201209056 s) , 3.97 - 4.02 ( 1 H, m) , 4.23 - 4.2 8 ( 4 H, m) , 4.41 - 4.47 ( 1 H, m) , 4.84 ( 1 H, d, J = 16.0 Hz) , 5.42 ( 1 H, d, J = 16.0 Hz), 6.55 (1 H, d, J = 9.2 Hz), 6.75 (1 H, d, J = 1.8 Hz) , 6.83 ( 1 H, dd, J = 8.3, 1.8 Hz) , 6.86 ( 1 H, d, J = 9.2 Hz ) , 6.95 - 6.98 ( 1 H, m) , 7.07 ( 1 H, d, J = 2.8 Hz ) , 7.49 ( 1 H, d, J = 8.3 Hz ) , 7.66 ( 1 H, d, J = 9.2 Hz ).

使用（2-側氧-2H- ( 1，7 ) ·萘啶-1-基）乙酸乙酯 105mg及 3-(2,3-二氫苯並（1，4)戴奧辛-6-基）-1-噁- 3,8-重氮螺（4.5)癸烷-2-酮124mg，藉由與實施例5之同樣操作，得到淡褐色泡狀的1- ( 2- ( 3- ( 2,3-二氫苯並（1，4 ) 戴奥辛-6-基）-2-側氧-1-噁-3,8-重氮螺（4.5)癸烷-8-基 )-2-氧代乙基）-1H-(1，7)-萘啶-2-酮 204mg。 1H NMR ( CHLOROFORM-d ) δ 1.82 ( 1 H, td, J = -80- 201209056 13.0，4·8 Hz)，2.01 ( 1 H，td，J= 13.0，4.4 Hz)，2.07 ( 1 H, dd, J= 14.0, 2.1 Hz) , 2.20 ( 1 H, dd, J= 13.8, 1.8 Hz ),3.21 - 3.27 ( 1 H, m) , 3.71 - 3.79 ( 3 H, m) , 3.95 -4.01 ( 1 H, m) , 4.24 - 4.28 ( 4 H, m) , 4.45 - 4.50 ( 1 H, m)，5_07 ( 1 H，d，J= 16.0 Hz)，5.35 ( 1 H，d，J= 16.0 Hz)，6.87 ( 1 H，d，J= 8.7 Hz)，6.92 ( 1 H，d，J= 9.6 Hz )，6.98 ( 1 H，dd，J=8.7，2.8 Hz)，7.09 ( 1 H，d，J=2.8 Hz) , 7.44 ( 1 H, d, J= 5.0 Hz) , 7.72 ( 1 H, d, J= 9.6 Hz )，8.46 ( 1 H，d，J=5.〇 Hz)，8.61 ( 1 H，s)。實施例7Using (2-oxo-2H-(1,7)-naphthyridin-1-yl)acetate 105 mg and 3-(2,3-dihydrobenzo(1,4)dioxin-6-yl)- 1-oxo-3,8-diazospiro(4.5)nonan-2-one 124 mg was obtained in the same manner as in Example 5 to give 1-(2-(3-(2,3) -Dihydrobenzo(1,4) dioxin-6-yl)-2-oxo-oxo-3,8-diazospiro(4.5)decane-8-yl)-2-oxoethyl -1H-(1,7)-naphthyridin-2-one 204 mg. 1H NMR ( CHLOROFORM-d ) δ 1.82 ( 1 H, td, J = -80- 201209056 13.0, 4·8 Hz), 2.01 ( 1 H, td, J = 13.0, 4.4 Hz), 2.07 ( 1 H, dd , J = 14.0, 2.1 Hz) , 2.20 ( 1 H, dd, J = 13.8, 1.8 Hz ), 3.21 - 3.27 ( 1 H, m) , 3.71 - 3.79 ( 3 H, m) , 3.95 -4.01 ( 1 H , m) , 4.24 - 4.28 ( 4 H, m) , 4.45 - 4.50 ( 1 H, m), 5_07 ( 1 H, d, J = 16.0 Hz), 5.35 ( 1 H, d, J = 16.0 Hz), 6.87 ( 1 H,d,J= 8.7 Hz), 6.92 ( 1 H,d,J= 9.6 Hz ), 6.98 ( 1 H,dd,J=8.7,2.8 Hz), 7.09 ( 1 H,d,J= 2.8 Hz), 7.44 ( 1 H, d, J = 5.0 Hz), 7.72 ( 1 H, d, J = 9.6 Hz ), 8.46 ( 1 H, d, J = 5. 〇 Hz), 8.61 ( 1 H, s). Example 7

將（7-甲氧基-2-側氧-2H- ( 1，5 )-萘啶-1·基）乙酸的鹽酸鹽14mg、2-(2,3-二氫苯並（1，4)戴奧辛-6-基）-1-側氧-2,7 -重氮螺（3.5)壬-1-酮16mg、二異丙基乙胺 44·8μί、1-乙基-3-(3-二甲基胺基丙基）碳化二亞胺鹽酸鹽15mg及1-羥基苯並三唑1水合物4mg懸浮於N，N-二甲基甲醯胺2mL，在室溫進行3.5小時攪拌。於反應混合物加入水 5 mL及乙酸乙酯50mL，分離並取出有機層。將有機層以飽和氯化鈉水溶液1 0 m L洗淨，以無水硫酸鎂乾燥，減壓下將溶劑餾去。將所得之殘餾物以矽膠管柱層析法[砂膠；關 -81 - 201209056 東化學股份有限公司，矽膠6 0，溶離液；氯仿：甲醇=9 :1〕進行純化，得到黃色油狀的1- ( 2- ( 2- ( 2,3-二氫苯並（1,4 )戴奧辛-6-基）-1-側氧- 2,7-重氮螺（3.5 )壬- 7-基）-2-氧代乙基）-7-甲氧基-1H-(1，5)萘啶-2-酮15mg。 1H NMR ( CHLOROFORM-d ) δ 1.82 - 1.91 ( 1 H, m) ,1.96 - 2.09 ( 2 Η, m) , 2.12 - 2.19(1 Η, m) , 3.38 -3.45 ( 2 Η，m)，3.73 ( 1 Η，ddd，J= 13.1，9.4, 3.2 Ηζ)， 3.78 - 3.8 4 ( 1 Η, m) , 3.91 - 3.98 ( 5 Η, m) , 4.22 - 4.27 (4 Η, m)，4.81 ( 1 Η，d，J= 16.0 Ηζ)，5.40 ( 1 Η，d，J =16.0 Ηζ) , 6.78 ( 1 Η, s) , 6.83 - 6.86 ( 2 Η, m) , 6.89 (1 Η, d, J=2.3 Hz) , 7.07 ( 1 Η, d, J=2.3 Hz) , 7.92 ( 1 H, d, J = 9.6 Hz ) , 8.29 ( 1 H, br. s.)。實施例8Hydrochloride salt of (7-methoxy-2-oxo-2H-(1,5)-naphthyridin-1-yl)acetate 14 mg, 2-(2,3-dihydrobenzo(1,4) Dioxin-6-yl)-1-sideoxy-2,7-diazospiro(3.5)nonan-1-one 16 mg, diisopropylethylamine 44·8 μί, 1-ethyl-3-(3- 15 mg of dimethylaminopropyl)carbodiimide hydrochloride and 4 mg of 1-hydroxybenzotriazole 1 hydrate were suspended in 2 mL of N,N-dimethylformamide, and stirred at room temperature for 3.5 hours. 5 mL of water and 50 mL of ethyl acetate were added to the reaction mixture, and the organic layer was separated and taken. The organic layer was washed with a saturated aqueous solution of sodium chloride (10 mL), dried over anhydrous magnesium sulfate and evaporated. The obtained residue was purified by silica gel column chromatography [sand gel; off-81 - 201209056 East Chemical Co., Ltd., 矽60 0, a solution; chloroform:methanol = 9:1) to obtain a yellow oil. 1-(2-(2-(2,3-dihydrobenzo(1,4)dioxo-6-yl)-1-oxo-2,7-diazospiro(3.5)壬-7-yl) 2-oxoethyl)-7-methoxy-1H-(1,5)naphthyridin-2-one 15 mg. 1H NMR ( CHLOROFORM-d ) δ 1.82 - 1.91 ( 1 H, m) , 1.96 - 2.09 ( 2 Η, m) , 2.12 - 2.19 (1 Η, m) , 3.38 - 3.45 ( 2 Η, m), 3.73 ( 1 Η,ddd,J= 13.1,9.4, 3.2 Ηζ), 3.78 - 3.8 4 ( 1 Η, m) , 3.91 - 3.98 ( 5 Η, m) , 4.22 - 4.27 (4 Η, m), 4.81 ( 1 Η ,d,J= 16.0 Ηζ), 5.40 ( 1 Η,d,J =16.0 Ηζ) , 6.78 ( 1 Η, s) , 6.83 - 6.86 ( 2 Η, m) , 6.89 (1 Η, d, J=2.3 Hz) , 7.07 ( 1 Η, d, J = 2.3 Hz) , 7.92 ( 1 H, d, J = 9.6 Hz ) , 8.29 ( 1 H, br. s.). Example 8

使用（7-甲氧基-2-側氧- 2H- ( 1,5 )-萘啶-1-基）乙酸的鹽酸鹽50mg及2-( (2,3)-二氫苯並（1，4)戴奧辛-6- 基）-2,6-重氮螺（3.5)-壬-1-酮6311^，藉由與實施例7之同樣操作，得到無色固體狀的1-(2- (2- (2,3-二氫苯並 (1,4 )戴奧辛-6-基）-1-側氧- 2,6-重氮螺（3.5 )壬-6-基 )-2-氧代乙基）-7-甲氧基-1H-(1，5)-萘啶-2-酮32mg。 201209056 1H NMR ( CHLOROFORM-d ) δ 1.31 - 1.62 ( 1 H, m) ,1.79 - 1.98 ( 2 H, m) , 1.99 - 2.18 ( 1 H, m) , 2.68 -2.79 ( 1 H, m) , 2.82 - 3.02 ( 1 H, m) , 3.11 - 3.21 ( 1 H, m) , 3.2 5 - 3.3 7 ( 1 H, m) , 3.52 - 3.74 ( 2 H, m) , 3.96 - 4.06 ( 3 H, m) , 4.19 - 4.29 (4 H, m) , 4.40 - 4.56 ( 1 H, m) , 4.60 - 4.77 ( 1 H, m) , 6.67 - 6.86 ( 4 H, m) , 7.39 - 7.47 ( 1 H, m) , 7.82 - 7.92 ( 1 H, m) , 8.26 - 8.3 2 ( 1 H, m )。實施例9Using (7-methoxy-2-oxo-2H-(1,5)-naphthyridin-1-yl)acetic acid hydrochloride 50 mg and 2-((2,3)-dihydrobenzo (1) , 4) Dioxin-6-yl)-2,6-diazospiro(3.5)-indol-1-one 6311^, obtained in the same manner as in Example 7 to give 1-(2-( 2-(2,3-Dihydrobenzo(1,4)dioxine-6-yl)-1-oxo- 2,6-diazospiro(3.5 )壬-6-yl)-2-oxo Base 7-methoxy-1H-(1,5)-naphthyridin-2-one 32 mg. 201209056 1H NMR ( CHLOROFORM-d ) δ 1.31 - 1.62 ( 1 H, m) , 1.79 - 1.98 ( 2 H, m) , 1.99 - 2.18 ( 1 H, m) , 2.68 -2.79 ( 1 H, m) , 2.82 - 3.02 ( 1 H, m) , 3.11 - 3.21 ( 1 H, m) , 3.2 5 - 3.3 7 ( 1 H, m) , 3.52 - 3.74 ( 2 H, m) , 3.96 - 4.06 ( 3 H, m) , 4.19 - 4.29 (4 H, m) , 4.40 - 4.56 ( 1 H, m) , 4.60 - 4.77 ( 1 H, m) , 6.67 - 6.86 ( 4 H, m) , 7.39 - 7.47 ( 1 H, m) , 7.82 - 7.92 ( 1 H, m) , 8.26 - 8.3 2 ( 1 H, m ). Example 9

將（7-甲氧基-2-側氧-2H-( 1,5)-萘啶-1-基）乙酸的鹽酸鹽42mg及2- (2,3-二氫苯並（1,4)戴奧辛-6-基）-3-側氧-2,8-重氮螺（4.5)癸烷-3-酮43mg懸浮於N，N-二甲基甲醯胺5mL，加入三乙胺0.09mL、1-乙基- 3-(3-二甲基胺基丙基）碳化二亞胺鹽酸鹽31.9mg及1-羥基苯並三唑1水合物25.9mg，於室溫進行1天，在60°C進行3小時攪拌。於反應混合物加入水10mL及氯仿50mL，分離並取出有機層。將有機層以飽和氯化鈉水溶液1 OmL洗淨，以無水硫酸鎂乾燥，減壓下將溶劑餾去。將所得之殘餾物以分取用矽膠薄層層法〔Merck株式会公司製PLC盤矽膠60F 2 5 4，展開 -83- 201209056 液；氯仿/甲醇=40/1 )〕進行純化，得到1- ( 2- ( 2-( 2,3-二氫苯並（1，4)戴奧辛-6-基）-3-側氧-2,8-重氮螺（ 4.5)癸烷-8-基）-2-氧代乙基）-7-甲氧基-1H-(1，5)-萘陡-2-酮 60mg。 1H NMR ( CHLOROFORM-d ) δ 1.64 - 1.7 5 ( 2 H, m) ,1.75 - 1.86(2 H, m) , 2.55(2 H, s) , 3.34 - 3.45 (1 H, m) , 3.54 - 3.60( 1 H, m) , 3.61(2 H, s) , 3.75 - 3.83(1 H, m) , 3.85 - 3.92 ( 1 H, m) , 3.96(3 H, s), 4.21 - 4.29 (4 H, m) , 4.98 ( 1 H, d, J=15.6 Hz) , 5.21 (1 H, d, J= 16.5 Hz) , 6.77 ( 1 H, d, J= 10.1 Hz) , 6.86 (1 H, d, J = 8.7 Hz )，7.01(1 H，dd，J = 8.7, 2.3 Hz), 7.10 ( 1 H, d, J=2.3 Hz) , 7.12 ( 1 H, br. s.) , 7.91 ( 1 H, d, J = 10.1 Hz) , 8.29 ( 1 H, d, J = 2.3 Hz )。實施例l 〇The hydrochloride salt of (7-methoxy-2-oxo-2H-(1,5)-naphthyridin-1-yl)acetic acid 42 mg and 2-(2,3-dihydrobenzo (1,4) Dioxin-6-yl)-3-oxo-2,8-diazospiro(4.5)nonan-3-one 43 mg was suspended in N,N-dimethylformamide 5 mL, and triethylamine 0.09 mL was added. 31.9 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 25.9 mg of 1-hydroxybenzotriazole 1 hydrate were allowed to stand at room temperature for 1 day. Stirring was carried out for 3 hours at 60 °C. 10 mL of water and 50 mL of chloroform were added to the reaction mixture, and the organic layer was separated and taken. The organic layer was washed with a saturated aqueous solution of sodium chloride (1 mL) and dried over anhydrous magnesium sulfate. The obtained residue was purified by a thin layer of tantalum (manufactured by Merck Co., Ltd., PLC 矽 60 60F 2 5 4 , developed -83-201209056 liquid; chloroform / methanol = 40/1 )) to obtain 1 - (2-(2-( 2,3-dihydrobenzo(1,4)dioxine-6-yl)-3-oxo-2,8-diazospiro (4.5)decane-8-yl) 2-Oxoethyl)-7-methoxy-1H-(1,5)-naphthalen-2-one 60 mg. 1H NMR ( CHLOROFORM-d ) δ 1.64 - 1.7 5 ( 2 H, m) , 1.75 - 1.86 (2 H, m) , 2.55 (2 H, s) , 3.34 - 3.45 (1 H, m) , 3.54 - 3.60 ( 1 H, m) , 3.61 (2 H, s) , 3.75 - 3.83 (1 H, m) , 3.85 - 3.92 ( 1 H, m) , 3.96 (3 H, s), 4.21 - 4.29 (4 H, m) , 4.98 ( 1 H, d, J = 15.6 Hz) , 5.21 (1 H, d, J = 16.5 Hz) , 6.77 ( 1 H, d, J = 10.1 Hz) , 6.86 (1 H, d, J = 8.7 Hz ), 7.01 (1 H, dd, J = 8.7, 2.3 Hz), 7.10 ( 1 H, d, J = 2.3 Hz) , 7.12 ( 1 H, br. s.) , 7.91 ( 1 H, d , J = 10.1 Hz) , 8.29 ( 1 H, d, J = 2.3 Hz ). Example l

-84- 201209056 第1步驟將3- ( 7-甲氧基-2-側氧-2H- ( 1,5 )-萘啶-1-基）丙酸乙基200mg溶解於甲醇3mL -水lmL，加入氫氧化鋰1水合物 4 6mg，在室溫進行19小時攪拌。於反應混合物中加入1 mol/L·鹽酸’並使其成爲酸性，減壓下將溶劑餾去後得到殘餾物1 〇 5 m g。第2步驟使用所得之殘餾物35mg (剩下的70mg在實施例丨丨使用）及2-(2,3-二氫苯並（1，4)戴奧辛-6-基）-3-側氧-2,8-重氮螺（4.5)癸烷-3-酮34mg，藉由與實施例5第2步驟之同樣操作，得到1 - ( 3 - ( 2 - ( 2，3 -二氫苯並（1，4 )戴奧辛-6-基）-3-側氧-2,8-重氮螺（4.5)癸烷-8-基）-3-側氧丙基）-7-甲氧基-1H-(1,5)-萘啶-2-酮21mg。 1H NMR ( CHLOROFORM-d ) δ 1.5 8 - 1.66 ( 2 H, m) ,2.47(2 Η, d, J=4.1 Hz) , 2.75 - 2.90(2 H, m) , 3.31 -3.40(2 H, m) , 3.50 - 3.58(4 H, m) , 3.81 - 3.89(1 H, m) 5 3.9 9 ( 3 H, s) , 4.21 - 4.27 ( 5 H, m ) , 4.50 - 4.63 ( 2 H, m.) , 6.75 ( 1 H, d, J= 10.1 Hz) , 6.85 ( 1 H, d, J=8.7 Hz) ,6.99(1 H, dd, J= 8.7, 2.3 Hz) , 7.10 ( 1 H, d, J=2.3 Hz) , 7.43 ( 1 H, d, J=2.3 Hz) , 7.88 ( 1 H, d, J= 10.1 Hz ) , 8.29 ( 1 H, d, J = 2.3 Hz ) 〇實施例1 1 -85- 201209056-84- 201209056 Step 1 Dissolve 200 mg of ethyl 3-( 7-methoxy-2-oxo-2H-( 1,5 )-naphthyridin-1-yl)propanoate in methanol 3 mL - 1 mL of water. 4 6 mg of lithium hydroxide monohydrate was added, and the mixture was stirred at room temperature for 19 hours. 1 mol/L·hydrochloric acid' was added to the reaction mixture to make it acidic, and the solvent was distilled off under reduced pressure to obtain a residue of 1 〇 5 m g. In the second step, 35 mg of the obtained residue (the remaining 70 mg used in the Example) and 2-(2,3-dihydrobenzo(1,4)dioxin-6-yl)-3-side oxygen were used. -2,8-diazospiro(4.5)nonan-3-one 34 mg, which was obtained in the same manner as in the second step of Example 5 to give 1-(3 -(2 -(2,3-dihydrobenzo) (1,4) Dioxin-6-yl)-3-oxo-2,8-diazospiro(4.5)decane-8-yl)-3-oxopropyl)-7-methoxy-1H -(1,5)-naphthyridin-2-one 21 mg. 1H NMR ( CHLOROFORM-d ) δ 1.5 8 - 1.66 ( 2 H, m) , 2.47 (2 Η, d, J = 4.1 Hz) , 2.75 - 2.90 (2 H, m) , 3.31 - 3.40 (2 H, m ), 3.50 - 3.58(4 H, m) , 3.81 - 3.89(1 H, m) 5 3.9 9 ( 3 H, s) , 4.21 - 4.27 ( 5 H, m ) , 4.50 - 4.63 ( 2 H, m. ), 6.75 ( 1 H, d, J = 10.1 Hz) , 6.85 ( 1 H, d, J = 8.7 Hz) , 6.99 (1 H, dd, J = 8.7, 2.3 Hz) , 7.10 ( 1 H, d, J = 2.3 Hz) , 7.43 ( 1 H, d, J = 2.3 Hz) , 7.88 ( 1 H, d, J = 10.1 Hz ) , 8.29 ( 1 H, d, J = 2.3 Hz ) 〇 Example 1 1 - 85- 201209056

使用在實施例10所得之殘餾物7〇mg及3- ( 2,3-二氫苯並（1,4)戴奧辛-6-基）-1-噁-3,8-重氮螺（4.5)癸烷-2-酮68mg，藉由與實施例5之第2步驟的同樣操作，得到白色固體狀的卜（3- ( 3- ( 2,3-二氫苯並（1，4)戴奧辛-6-基 )-2-側氧-1-噁-3,8-重氮螺（4.5)癸烷-8-基）-3-側氧丙基）-7-甲氧基-1H-(1,5)萘啶-2-酮67mg。 1H NMR ( CHLOROFORM-d ) δ 1.5 7 - 1.64 ( 2 H, m) ,2.00 ( 2 Η, d, J= 13.8 Hz) , 2.76 ( 1 H, ddd, J= 15.0, 8.8，6.0 Hz)，2.9 1 ( 1 H, ddd, J = 1 5.4, 8.5, 6.4 Hz ), 3.10-3.16(1 H,m) ,3.45-3.51(1 H,m) ,3.64(2H, d, J = 1.4 Hz )，3.77 ( 1 H, d，J = 14.2 Hz )，4.00 ( 3 H，s )，4.23 - 4.27 ( 4 H, m ) , 4.46 ( 1 H, d, J = 13.8 Hz ), 4.52 ( 1 H, ddd, J= 14.2, 8.5, 5.7 Hz ) , 4.5 9 - 4.6 5 ( 1 H, m) , 6.75 ( 1 H, d, J=9.6 Hz) , 6.85 ( 1 H, d, J=8.7 Hz ),6.93 - 6.96 ( 1 H, m ) , 7.05(1 H, d, J = 2.3 Hz ), -86- 201209056 7.41(1 H, d, J=2.3 Hz) , 7.88(1 H, d, J=9.6 Hz), 8.29 ( 1 H, d, J = 2.3 Hz )。實施例1 27 mg of the residue obtained in Example 10 and 3-( 2,3-dihydrobenzo(1,4)dioxin-6-yl)-1-oxo-3,8-diazo snail (4.5) were used. a decane-2-one 68 mg was obtained in the same manner as in the second step of Example 5 to give (3-(3-(2,3-dihydrobenzo (1,4) dioxin) as a white solid. -6-yl)-2-oxo-1-carbo-3,8-diazospiro(4.5)decane-8-yl)-3-oxopropyl)-7-methoxy-1H-( 1,5) naphthyridin-2-one 67 mg. 1H NMR ( CHLOROFORM-d ) δ 1.5 7 - 1.64 ( 2 H, m) , 2.00 ( 2 Η, d, J = 13.8 Hz) , 2.76 ( 1 H, ddd, J = 15.0, 8.8, 6.0 Hz), 2.9 1 ( 1 H, ddd, J = 1 5.4, 8.5, 6.4 Hz ), 3.10-3.16(1 H,m) , 3.45-3.51(1 H,m) , 3.64(2H, d, J = 1.4 Hz ), 3.77 ( 1 H, d, J = 14.2 Hz ), 4.00 ( 3 H, s ), 4.23 - 4.27 ( 4 H, m ) , 4.46 ( 1 H, d, J = 13.8 Hz ), 4.52 ( 1 H, ddd , J = 14.2, 8.5, 5.7 Hz ) , 4.5 9 - 4.6 5 ( 1 H, m) , 6.75 ( 1 H, d, J = 9.6 Hz) , 6.85 ( 1 H, d, J = 8.7 Hz ), 6.93 - 6.96 ( 1 H, m ) , 7.05 (1 H, d, J = 2.3 Hz ), -86- 201209056 7.41(1 H, d, J=2.3 Hz) , 7.88(1 H, d, J=9.6 Hz ), 8.29 ( 1 H, d, J = 2.3 Hz ). Example 1 2

將7-甲氧基-2-側氧-2H-(1，5)-萘啶-1-基）乙酸的鹽酸鹽40mg及2-(2,3 -二氫苯並（1,4)戴奧辛-6-基）-1-側氧-2,9-重氮螺（5.5 ) ~\--烷-1-酮的鹽酸鹽50mg懸浮於 Ν,Ν -二甲基甲醯胺5mL，加入二異丙基乙胺129μί並使其溶解。進一步加入1-乙基-3- (3-二甲基胺基丙基）碳化二亞胺鹽酸鹽52mg及1-羥基苯並三唑1水合物Umg，在室溫進行16.5小時攪拌。於反應混合物中加入水10mL及氯仿 5 OmL，分離並取出有機層。將有機層以飽和氯化鈉水溶液 1 OmL洗淨，以無水硫酸鎂乾燥，減壓下將溶劑餾去。將所得之殘餾物以分取用矽膠薄層層析法〔Merck株式会公司製PLC盤矽膠60F2 5 4、展開液；氯仿/甲醇=9/1 )〕進行純化，得到黃色油狀的1-(2-(2-(2，3-二氫苯並（1，4)戴奧辛-6-基）-1-側氧-2,9-重氮螺（5.5)十一烷-9-基）-2-氧代乙基）-7-甲氧基-1H-(1，5)萘啶-2-酮90mg。 1H NMR ( CHLOROFORM-d ) δ 1.4 8 - 1.5 8 ( 1 H, m ) ,1.59 - 1.66(1 Η, m) , 1.85 - 1.90(2 Η, m) , 1.92 - -87- 201209056 2.04 (2 H, m) , 2.10 - 2.17 ( 1 Η, m) , 2.20 - 2.27 ( 1 Η, m) , 3.55 - 3.63 (2 Η, m) , 3.64 - 3.71 ( 1 Η, m) , 3.73 - 3.79(1 Η, m) , 3.79 - 3.86( 1 Η, m) , 3.92(3 Η, s), 3.98 - 4.05 ( 1 Η, m) , 4.25 ( 4 Η, s) , 4.71 ( 1 Η, d, J = 16.0 Hz)，5.48(1 Η, d, J= 1 6.0 Hz ) , 6.66 ( 1 H，dd，J = 8.7，2.3 Hz)，6.71 ( 1 H，d，J=2.3 Hz)，6.76 ( 1 H，d， J = 9.6 Hz) , 6.88 ( 1 H, m) , 7.00 ( 1 H, d, J=2.3 Hz), 7.89 ( 1 H, d, J = 9.6 Hz ) , 8.26 ( 1 H, d, J - 2.3 Hz )。實施例1 3The hydrochloride salt of 7-methoxy-2-oxo-2H-(1,5)-naphthyridin-1-yl)acetic acid 40 mg and 2-(2,3-dihydrobenzo(1,4) 50 mg of the hydrochloride salt of dioxin-6-yl)-1-oxo-2,9-diazospiro(5.5)~\--alkan-1-one was suspended in Ν, Ν-dimethylformamide 5 mL, Diisopropylethylamine 129 μί was added and dissolved. Further, 52 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and Umg of 1-hydroxybenzotriazole monohydrate were added, and the mixture was stirred at room temperature for 16.5 hours. 10 mL of water and 50 mL of chloroform were added to the reaction mixture, and the organic layer was separated and taken. The organic layer was washed with a saturated aqueous solution of sodium chloride (1 mL) and dried over anhydrous magnesium sulfate. The obtained residue was purified by silica gel thin-layer chromatography (manufactured by Merck Co., Ltd., PLC 矽 60 60F2 5 4 , developing solution; chloroform/methanol = 9/1) to obtain a yellow oily product. -(2-(2-(2,3-dihydrobenzo(1,4)dioxin-6-yl)-1-oxo-2,9-diazospiro(5.5)undecane-9-yl) )-2-oxoethyl)-7-methoxy-1H-(1,5)naphthyridin-2-one 90 mg. 1H NMR ( CHLOROFORM-d ) δ 1.4 8 - 1.5 8 ( 1 H, m ) , 1.59 - 1.66 (1 Η, m) , 1.85 - 1.90 (2 Η, m) , 1.92 - -87- 201209056 2.04 (2 H , m) , 2.10 - 2.17 ( 1 Η, m) , 2.20 - 2.27 ( 1 Η, m) , 3.55 - 3.63 (2 Η, m) , 3.64 - 3.71 ( 1 Η, m) , 3.73 - 3.79 (1 Η , m), 3.79 - 3.86( 1 Η, m) , 3.92(3 Η, s), 3.98 - 4.05 ( 1 Η, m) , 4.25 ( 4 Η, s) , 4.71 ( 1 Η, d, J = 16.0 Hz), 5.48 (1 Η, d, J = 1 6.0 Hz), 6.66 ( 1 H, dd, J = 8.7, 2.3 Hz), 6.71 ( 1 H, d, J = 2.3 Hz), 6.76 ( 1 H, d, J = 9.6 Hz) , 6.88 ( 1 H, m) , 7.00 ( 1 H, d, J = 2.3 Hz), 7.89 ( 1 H, d, J = 9.6 Hz ) , 8.26 ( 1 H, d, J - 2.3 Hz). Example 1 3

第1步驟將（7-甲氧基-2-側氧-2H-喹喔啉-1-基）乙酸乙酯 280mg溶解於甲醇9mL，加入20%氫氧化鈉水溶液lmL，在室溫進行1.5小時攪拌。將反應混合物以3 mo 1/L鹽酸進行中和，減壓下使溶劑餾去後得到殘餾物46 1 mg。 -88- 201209056 第2步驟使用在第1步驟所得之殘餾物23 Omg (剩下在實施例1 4 使用）及3-(2,3-二氫苯並（1，4)戴奧辛-6-基）-1-噁-3,8-重氮螺（4.5)癸烷-2-酮154mg，藉由與實施例5之第2 步驟的同樣操作，得到無色粉末狀的1- ( 2- ( 3- ( 2,3-二羥基苯並（1，4)戴奧辛-6-基）-2-側氧-1-噁-3,8-重氮螺（ 4.5)癸烷-8-基）-2-氧代乙基）-7-甲氧基-1H-喹喔啉-2-酮 91 mg。 1H NMR ( CHLOROFORM-d ) δ 1.7 6 - 1.8 3 ( 1 H, m) ,1.95 ( 1 H, td, J= 12.8, 4.6 Hz) , 2.04 ( 1 H, dd, J = 14.0, 2.1 Hz) , 2.15 ( 1 H, dd, J= 13.8, 2.3 Hz) , 3.18 -3.27(1 H, m) , 3.65 - 3.75(3 H, m) , 3.90(3 H, s), 3.95(1 H, d, J= 13.8 Hz ) , 4.22 - 4.28 ( 4 H, m )，4.44 (1 H, d, J= 13.8 Hz)，4.79 ( 1 H，d, J= 16.0 Hz)，5.30 (1 H, d, J = 1 6.0 Hz )，6.64(1 H, d, J= 2.3 Hz) , 6.86 (1 H, d, J= 8.7 Hz) , 6.90 - 6.98 ( 2 H, m) , 7.07 ( 1 H, d，J=2.8 Hz) ，7.80(1 H，d，J=8.7 Hz) ，8.15 (1 H，s -89- 201209056 實施例1 4In the first step, 280 mg of ethyl (7-methoxy-2-oxo-2H-quinoxalin-1-yl)acetate was dissolved in 9 mL of methanol, and 1 mL of a 20% aqueous sodium hydroxide solution was added thereto, and the mixture was allowed to stand at room temperature for 1.5 hours. Stir. The reaction mixture was neutralized with 3 mol of 1/L hydrochloric acid, and the solvent was distilled off under reduced pressure to give a residue of 46 1 mg. -88- 201209056 The second step uses 23 Omg of the residue obtained in the first step (remaining used in Example 14) and 3-(2,3-dihydrobenzo(1,4)dioxine-6- 1-(2-(2-(2-(2-(2-(2-(2-(((((((((((((((((((( 3-( 2,3-Dihydroxybenzo(1,4)dioxine-6-yl)-2-oxooxy-1-oxo-3,8-diazospiro (4.5)decane-8-yl)- 2-oxoethyl)-7-methoxy-1H-quinoxalin-2-one 91 mg. 1H NMR ( CHLOROFORM-d ) δ 1.7 6 - 1.8 3 ( 1 H, m) , 1.95 ( 1 H, td, J = 12.8, 4.6 Hz) , 2.04 ( 1 H, dd, J = 14.0, 2.1 Hz), 2.15 ( 1 H, dd, J = 13.8, 2.3 Hz) , 3.18 -3.27(1 H, m) , 3.65 - 3.75(3 H, m) , 3.90(3 H, s), 3.95(1 H, d, J = 13.8 Hz ) , 4.22 - 4.28 ( 4 H, m ), 4.44 (1 H, d, J = 13.8 Hz), 4.79 ( 1 H, d, J = 16.0 Hz), 5.30 (1 H, d, J = 1 6.0 Hz ), 6.64 (1 H, d, J = 2.3 Hz), 6.86 (1 H, d, J = 8.7 Hz), 6.90 - 6.98 ( 2 H, m) , 7.07 ( 1 H, d, J =2.8 Hz), 7.80 (1 H, d, J = 8.7 Hz), 8.15 (1 H, s -89 - 201209056 Example 1 4

使用在實施例12之第1步驟所得之殘餾物2 3 0mg及2-( 2,3-二氫苯並（1,4 )戴奧辛-6-基）-3-側氧- 2,8-重氮螺（ 4.5)癸烷-3-酮154mg，藉由與實施例5第2步驟之同樣操作，得到無色粉末狀的1-(2-(2-(2，3-二氫苯並（1，4) 戴奧辛-6-基）-3-側氧-2,8-重氮螺（4.5)癸烷-8-基）-2- 氧代乙基）-7 -甲氧基-1H-喹喔啉-2-酮135mg。 1H NMR ( CHLOROFORM-d ) δ 1.7 1 ( 2 H, td, J = 9.4, 4.1 Hz) , 1.80 - 1.84 (2 H, m) , 2.55(2 H, s) , 3.38 - 3.44(1 H, m) , 3.52 - 3.58(1 H, m) , 3.62(2 H, s), 3.69 - 3.76 ( 1 H, m) , 3.85 - 3.92 ( 4 H, m) , 4.22 - 4.27 (4 H, m) , 4.92 - 4.98 ( 1 H, m) , 5.08 - 5.14 ( 1 H, m) ,6.63(1 H, d, J = 2.5 Hz)，6.85(1 H, d, J= 8.7 Hz)， 6.92 ( 1 H，dd，J= 8.7, 2.5 Hz)，7.01 ( 1 H, dd，J - 8.7, 2.3 Hz ) , 7.13(1 H, d, J=2.3 Hz) , 7.80 ( 1 H, d, J = -90- 201209056 8.7 Hz ) , 8.15 ( 1 H, s )。實施例1 5Using the residue obtained in the first step of Example 12, 2,300 mg and 2-(2,3-dihydrobenzo(1,4)dioxin-6-yl)-3-oxo- 2,8- The diazonium sulphate (4.5) decane-3-one 154 mg was obtained in the same manner as in the second step of Example 5 to give 1-(2-(2-(2,3-dihydrobenzo) as a colorless powder. 1,4) Dioxin-6-yl)-3-oxo-2,8-diazospiro(4.5)decane-8-yl)-2-oxoethyl)-7-methoxy-1H- Quinoxaline-2-one 135 mg. 1H NMR ( CHLOROFORM-d ) δ 1.7 1 ( 2 H, td, J = 9.4, 4.1 Hz) , 1.80 - 1.84 (2 H, m) , 2.55 (2 H, s) , 3.38 - 3.44 (1 H, m ), 3.52 - 3.58(1 H, m) , 3.62(2 H, s), 3.69 - 3.76 ( 1 H, m) , 3.85 - 3.92 ( 4 H, m) , 4.22 - 4.27 (4 H, m) , 4.92 - 4.98 ( 1 H, m) , 5.08 - 5.14 ( 1 H, m) , 6.63 (1 H, d, J = 2.5 Hz), 6.85 (1 H, d, J = 8.7 Hz), 6.92 ( 1 H , dd, J = 8.7, 2.5 Hz), 7.01 ( 1 H, dd, J - 8.7, 2.3 Hz ) , 7.13 (1 H, d, J = 2.3 Hz) , 7.80 ( 1 H, d, J = -90 - 201209056 8.7 Hz ) , 8.15 ( 1 H, s ). Example 1 5

FF

將1- ( 2- ( 4- ( ( 2,3-二氫苯並（1，4 )戴奧辛-6-基胺基）甲基）-4-羥基環己基）乙基）-7-氟·1Η-(1，5)萘啶-2-酮（參考例29:非對映異構物A) 21mg溶解於氯仿lmL ，加入三乙胺〇.〇2mL及碳酸雙（三氯甲基）14mg，在氮環境下於室溫中進行50分鐘攪拌。於反應混合物加入飽和碳酸氫鈉水溶液2mL及氯仿5mL，分離並取出有機層。將有機層以飽和氯化鈉水溶液2mL洗淨，以無水硫酸鎂乾燥，減壓下將溶劑餾去。將所得之殘餾物以分取用矽膠薄層層析法〔Merck株式会公司製PLC盤矽膠60F 2 5 4、展開液；乙酸乙酯）〕進行純化，得到白色固體狀的1 - ( 2_ ( 3 -( 2,3-二氫苯並（I，4)戴奧辛-6-基）-2-側氧-1-噁-3-氮雜螺 (4.5)癸烷-8-基）乙基）-7-氟-1H-(1，5)-萘啶-2-酮（非對映異構物A) 16mg。 1H NMR ( CHLOROFORM-d ) 5 1.50 - 1.58 ( 2 H, m) ,1.5 8 - 1.65 ( 3 H, m ) , 1.65 - 1.70 ( 2 Η, m) , 1-83 - 1.88(2 Η, m) , 2.09 - 2.13(2 Η, m) , 3.64(2 Η, s),1-(2-(4-((2,3-Dihydrobenzo(1,4)dioxoxin-6-ylamino)methyl)-4-hydroxycyclohexyl)ethyl)-7-fluoro· 1Η-(1,5)naphthyridin-2-one (Reference Example 29: diastereomer A) 21 mg was dissolved in 1 mL of chloroform, and triethylamine 〇.〇2 mL and bis(trichloromethyl)carbonate 14 mg were added. The mixture was stirred at room temperature for 50 minutes under a nitrogen atmosphere. 2 mL of a saturated aqueous sodium hydrogencarbonate solution and 5 mL of chloroform were added to the mixture, and the organic layer was separated. The organic layer was washed with 2 mL of a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and evaporated. The obtained residue was purified by silica gel thin-layer chromatography (manufactured by Merck Co., Ltd., PLC, silica gel 60F 2 5 4 , developing solution; ethyl acetate) to obtain 1 - (2_) as a white solid. (3-(2,3-Dihydrobenzo(I,4)dioxine-6-yl)-2-oxo-oxo-3-oxa-3-azaspiro(4.5)decane-8-yl)ethyl 7-fluoro-1H-(1,5)-naphthyridin-2-one (diastereomer A) 16 mg. 1H NMR ( CHLOROFORM-d ) 5 1.50 - 1.58 ( 2 H, m) , 1.5 8 - 1.65 ( 3 H, m ) , 1.65 - 1.70 ( 2 Η, m) , 1-83 - 1.88 (2 Η, m) , 2.09 - 2.13(2 Η, m) , 3.64(2 Η, s),

4.22 - 4.28 ( 6 Η, m) , 6.86 ( 2 Η, m) , 7.00 ( 1 Η, dd, J = 8.7, 2.8 Hz) , 7.0 7(1 Η, d, J=2.8 Hz) , 7.32(1 Η, -91 - 201209056 dd, J= 10.1, 1.8 Hz) , 7.87 - 7.90 ( 1 H, m) , 8.43 ( 1 H, d, J - 1.8 Hz )。實施例1 64.22 - 4.28 ( 6 Η, m) , 6.86 ( 2 Η, m) , 7.00 ( 1 Η, dd, J = 8.7, 2.8 Hz) , 7.0 7 (1 Η, d, J = 2.8 Hz) , 7.32 (1 Η, -91 - 201209056 dd, J= 10.1, 1.8 Hz) , 7.87 - 7.90 ( 1 H, m) , 8.43 ( 1 H, d, J - 1.8 Hz ). Example 1 6

使用1-(2-(4-( (2,3-二氫苯並（1,4)戴奧辛-6-基胺基）甲基）-4-羥基環己基）乙基）-7-氟-1Η-( 1,5)萘啶-2-酮（參考例29 :非對映異構物B ) 18mg，藉由與實施例1 5之同樣操作，得到無色泡狀的1 - ( 2 - ( 3 - ( 2，3 -二氫苯並（1，4 )戴奧辛-6-基）-2-側氧-1-噁-3-氮雜螺（4.5 ) 癸烷-8-基）乙基）-7-氟-1H-(1，5)-萘啶-2-酮（非對映異構物B) 15mg。 1H NMR ( CHLOROFORM-d ) δ 1.17 - 1.24 ( 2 H, m) ,1.58 - 1.64 ( 1 Η, m) , 1.64 - 1.69 (2 Η, m) , 1.86(2 Η, td, J= 12.8, 4.1 Hz) , 1.96 - 2.00 ( 2 Η, m) , 2.03 -2.08(2 Η, m) , 3.72(2 Η, s) , 4.21 - 4.27(6 Η, m), 6.85(1 Η, d, J=8.7 Hz) , 6.87(1 Η, d, J=9.6 Hz), 7.01 ( 1 H, dd, J=8.7, 2.8 Hz) , 7.10 ( 1 H, d, J=2.8 Hz ),7.3 1 ( 1 H, dd, J = 10.1, 2.3 Hz) , 7.89 ( 1 H, d, J = 9.6 Hz) , 8.44 ( 1 H, d5 J=2.3 Hz)。 -92- 201209056 實施例1 7 r〇1-(2-(4-((2,3-Dihydrobenzo(1,4)dioxoxin-6-ylamino)methyl)-4-hydroxycyclohexyl)ethyl)-7-fluoro- 1 Η-(1,5)naphthyridin-2-one (Reference Example 29: diastereomer B) 18 mg, which was obtained in the same manner as in Example 15. 3-(2,3-dihydrobenzo(1,4)dioxin-6-yl)-2-oxo-1-ox-3-azaspiro(4.5)decane-8-yl)ethyl) -7-Fluoro-1H-(1,5)-naphthyridin-2-one (diastereomer B) 15 mg. 1H NMR ( CHLOROFORM-d ) δ 1.17 - 1.24 ( 2 H, m) , 1.58 - 1.64 ( 1 Η, m) , 1.64 - 1.69 (2 Η, m) , 1.86 (2 Η, td, J= 12.8, 4.1 Hz) , 1.96 - 2.00 ( 2 Η, m) , 2.03 -2.08(2 Η, m) , 3.72(2 Η, s) , 4.21 - 4.27(6 Η, m), 6.85(1 Η, d, J= 8.7 Hz), 6.87 (1 Η, d, J=9.6 Hz), 7.01 ( 1 H, dd, J=8.7, 2.8 Hz), 7.10 ( 1 H, d, J=2.8 Hz ), 7.3 1 ( 1 H , dd, J = 10.1, 2.3 Hz), 7.89 ( 1 H, d, J = 9.6 Hz) , 8.44 ( 1 H, d5 J=2.3 Hz). -92- 201209056 Example 1 7 r〇

Ν^〇αΝ^〇α

使用卜（2-(4-( (2,3-二氫苯並（1，4)戴奧辛-6-基胺基）甲基）-4-羥基環亞己基）乙基）-7-氟-1H-(1，5) 萘啶-2-酮3 9mg，藉由與實施例15之同樣操作，得到無色泡狀的1-(2-(3-(2，3-二氫苯並（1,4)戴奧辛-6-基）-2-側氧-1-噁-3-氮雜螺（4.5)癸烷-8-亞基）乙基）-7-氟-1H-(1，5)-萘啶-2-酮 12mg。 1H NMR ( CHLOROFORM-d ) δ 1.70 ( 1 H, td, J = 12.6, 4.6 Hz) , 1.77 - 1.83 ( 1 H, m ) , 2.07 - 2.12 ( 1 H, m) , 2.13 - 2.18 ( 1 H, m) , 2.20 - 2.25 ( 1 H, m ) , 2.54 - 2.63 ( 2 H, m) , 2.73 - 2.7 8 ( 1 H, m ) , 3.65 - 3.72 ( 2 H, m) , 4.23 - 4.27 ( 4 H, m) , 4.63 - 4.68 ( 1 H, m) , 5.13 (1 H，dd，J=16_0，6.9 Hz)，5.21 ( 1 H，t，J=6.4 Hz)， 6.86(1 H, d, J = 8.7 Hz ) , 6.88(1 H, d, J = 9.6 Hz ), 7.00 ( 1 H, dd, J=8.7, 2.8 Hz) , 7.08 ( 1 H, d, J=2.8 Hz )，7.31 ( 1 H，dd，J= 10.1，2.3 Hz)，7.89 ( 1 H，d，J = 9.6 Hz) , 8.43 ( 1 H, d, J = 2.3 Hz )。 -93- 201209056 實施例1 8Use of (2-(4-((2,3-dihydrobenzo(1,4)dioxoxin-6-ylamino)methyl)-4-hydroxycyclohexylene)ethyl)-7-fluoro- 1H-(1,5)naphthyridin-2-one 3 9 mg was obtained in the same manner as in Example 15 to give 1-(2-(3-(2,3-dihydrobenzo) (1). , 4) Dioxin-6-yl)-2-oxo-oxo-3-oxa-3-azaspiro(4.5)decane-8-ylidene)ethyl)-7-fluoro-1H-(1,5) -Naphthyridin-2-one 12 mg. 1H NMR ( CHLOROFORM-d ) δ 1.70 ( 1 H, td, J = 12.6, 4.6 Hz) , 1.77 - 1.83 ( 1 H, m ) , 2.07 - 2.12 ( 1 H, m) , 2.13 - 2.18 ( 1 H, m) , 2.20 - 2.25 ( 1 H, m ) , 2.54 - 2.63 ( 2 H, m) , 2.73 - 2.7 8 ( 1 H, m ) , 3.65 - 3.72 ( 2 H, m) , 4.23 - 4.27 ( 4 H , m) , 4.63 - 4.68 ( 1 H, m) , 5.13 (1 H, dd, J=16_0, 6.9 Hz), 5.21 ( 1 H, t, J = 6.4 Hz), 6.86 (1 H, d, J = 8.7 Hz ) , 6.88 (1 H, d, J = 9.6 Hz ), 7.00 ( 1 H, dd, J=8.7, 2.8 Hz) , 7.08 ( 1 H, d, J=2.8 Hz ), 7.31 ( 1 H , dd, J = 10.1, 2.3 Hz), 7.89 ( 1 H, d, J = 9.6 Hz), 8.43 ( 1 H, d, J = 2.3 Hz ). -93- 201209056 Example 1 8

使用1-(2-(4-( (2,3-二氫苯並（1,4)戴奧辛-6-基胺基）甲基）-4-羥基環亞己基）乙基）-7-甲氧基-1Η-( 1,5 )萘啶-2-酮140mg，藉由與實施例15之同樣操作，得到無色泡狀的1- ( 2- ( 3- ( 2,3-二氫苯並（1,4)戴奧辛- 6-基）-2-側氧-1-噁-3-氮雜螺（4.5)癸烷-8-亞基）乙基）-7-甲氧基-1H- ( 1，5)-萘啶-2-酮 107mg。 1H NMR ( CHLOROFORM-d ) δ 1.67 - 1.74 ( 1 H, m) ,1.77 - 1.84 ( 1 Η, m) , 2.07 - 2.12 ( 1 Η, m) , 2.16 ( 1 Η, dt, J = 13.8, 4.4 Hz) , 2.22 ( 1 Η, ddt, J=9.1, 6.8, 4.4, 4.4 Hz) , 2.5 2 - 2.62 ( 2 H, m) , 2.78 ( 1 Η, dt, J= 13.8, 4.4 Hz) , 3.65 - 3.72 ( 2 H, m) , 3.97 ( 3 Η, s) , 4.22 - 4.27 (4 Η, m) , 4.57 ( 1 Η, dd, J = 14.9, 5.7 Hz) , 5.21 - 5.30 ( 2 Η, m) , 6.76 ( 1 Η, d, J=9.6 Hz) , 6.85 ( 1 Η, d, J = 8.7 Hz ) , 6.99 ( 1 H, dd, J = 8.7, 2.3 Hz ) , 7.03 ( 1 H, d，J=2.3 Hz)，7.08 ( 1 H，d，J=2.8 Hz)，7.86( 1 H, m ),8.29 ( 1 H, d, J = 2.8 Hz )。 -94- 201209056 實施例1 91-(2-(4-((2,3-Dihydrobenzo(1,4)dioxoxin-6-ylamino)methyl)-4-hydroxycyclohexylene)ethyl)-7-A ethoxy-1Η-(1,5)naphthyridin-2-one 140 mg was obtained in the same manner as in Example 15 to give 1-(2-(3-(2,3-dihydrobenzo) as a colorless foam. (1,4) Dioxin-6-yl)-2-oxo-1-oxo-3-azaspiro(4.5)decane-8-ylidene)ethyl)-7-methoxy-1H- ( 1,5)-naphthyridin-2-one 107 mg. 1H NMR ( CHLOROFORM-d ) δ 1.67 - 1.74 ( 1 H, m) , 1.77 - 1.84 ( 1 Η, m) , 2.07 - 2.12 ( 1 Η, m) , 2.16 ( 1 Η, dt, J = 13.8, 4.4 Hz) , 2.22 ( 1 Η, ddt, J=9.1, 6.8, 4.4, 4.4 Hz) , 2.5 2 - 2.62 ( 2 H, m) , 2.78 ( 1 Η, dt, J= 13.8, 4.4 Hz) , 3.65 - 3.72 ( 2 H, m) , 3.97 ( 3 Η, s) , 4.22 - 4.27 (4 Η, m) , 4.57 ( 1 Η, dd, J = 14.9, 5.7 Hz) , 5.21 - 5.30 ( 2 Η, m) , 6.76 ( 1 Η, d, J = 9.6 Hz) , 6.85 ( 1 Η, d, J = 8.7 Hz ) , 6.99 ( 1 H, dd, J = 8.7, 2.3 Hz ) , 7.03 ( 1 H, d, J =2.3 Hz), 7.08 ( 1 H, d, J = 2.8 Hz), 7.86 ( 1 H, m ), 8.29 ( 1 H, d, J = 2.8 Hz ). -94- 201209056 Example 1 9

使用 1-(2-(4-( (2,3-二氫-(1，4)二噁並（2,3-c) 吡啶-7-基胺基）甲基）-4-羥基環亞己基）乙基）·7-氟-1Η- ( 1，5 )萘啶-2-酮3mg，藉由與實施例15之同樣操作，得到無色泡狀的1- ( 2- ( 3- ( 2,3-二氫-(1，4 )二噁並（ 2,3-c)耻啶-7-基）-2-側氧-1-噁-3-氮雜螺（4.5)癸烷-8-亞基）乙基）-7-氟-1H-(1，5)萘啶-2-酮3mg。 1H NMR ( CHLOROFORM-d ) δ 1.69 - 1.77 ( 1 H, m) ,1.83 ( 1 Η, ddd, J= 13.6, 11.1, 4.6 Hz) , 2.02 - 2.09 ( 1 H, m) , 2.12 - 2.22(2 H, m) , 2.48 - 2.58 (1 H, m), 2.59 - 2.66 ( 1 H, m) , 2.67 - 2.74 ( 1 H, m) , 3.95 ( 2 Η, q, J= 10.1 Hz) , 4.24 - 4.29 ( 2 H, m) , 4.32 - 4.3 6 ( 2 H, m) , 4.72 ( 1 H, dd, J= 15.6, 6.0 Hz) , 5.06 ( 1 H, dd, J = 15.6, 6.4 Hz) , 5.21 ( 1 H, t, J=6.4 Hz) , 6.88 ( 1 H, d, J = 9.6 Hz ) , 7.31 ( 1 H, dd, J= 10.1, 2.3 Hz) , 7.78 ( 1 H, s ) , 7.87 ( 1 H, s ) , 7.89 ( 1 H, d, J = 9.6 Hz ) , 8.43 (1 H, d, J= 2.3 Hz )。 -95- 201209056 實施例2 01-(2-(4-((2,3-Dihydro-(1,4) dioxin(2,3-c)pyridin-7-ylamino)methyl)-4-hydroxycyclo) Benzyl)ethyl)·7-fluoro-1 fluorene-(1,5)naphthyridin-2-one 3 mg was obtained in the same manner as in Example 15 to give 1-(2-(3-(2-) ,3-dihydro-(1,4)dioxa(2,3-c)pteridine-7-yl)-2-oxo-oxo-3-azaspiro(4.5)decane-8 -ylidene)ethyl)-7-fluoro-1H-(1,5)naphthyridin-2-one 3 mg. 1H NMR ( CHLOROFORM-d ) δ 1.69 - 1.77 ( 1 H, m) , 1.83 ( 1 Η, ddd, J = 13.6, 11.1, 4.6 Hz) , 2.02 - 2.09 ( 1 H, m) , 2.12 - 2.22 (2 H, m) , 2.48 - 2.58 (1 H, m), 2.59 - 2.66 ( 1 H, m) , 2.67 - 2.74 ( 1 H, m) , 3.95 ( 2 Η, q, J = 10.1 Hz) , 4.24 - 4.29 ( 2 H, m) , 4.32 - 4.3 6 ( 2 H, m) , 4.72 ( 1 H, dd, J = 15.6, 6.0 Hz) , 5.06 ( 1 H, dd, J = 15.6, 6.4 Hz) , 5.21 ( 1 H, t, J = 6.4 Hz) , 6.88 ( 1 H, d, J = 9.6 Hz ) , 7.31 ( 1 H, dd, J = 10.1, 2.3 Hz) , 7.78 ( 1 H, s ) , 7.87 ( 1 H, s ) , 7.89 ( 1 H, d, J = 9.6 Hz ) , 8.43 (1 H, d, J = 2.3 Hz ). -95- 201209056 Example 2 0

使用 6- ( ( 4- ( 2- ( 7-氟-2-側氧- 2Η- ( 1，5 )萘啶-1- 基）亞乙基）-1-羥基環己基甲基）胺基）-4H-苯並（1，4 )噁嗪-3-酮3 Omg，藉由與實施例15之同樣操作，得到無色粉狀的6- ( 8- ( 2- ( 7-氟-2-側氧-2H- ( 1，5 )萘啶-卜基 )亞乙基）-2-側氧-1-噁-3-氮雜螺（4.5)癸烷-3-基）· 4 Η -苯並（1，4 )噁嗪-3 -酮 1 5 m g。 1H NMR(DMS0-d6) δ 1.73 - 1.80 ( 1 H, m) , 1.82 -1.91 (2 Η, m) , 1.97 - 2.03 ( 1 Η, m) , 2.13 - 2.20 ( 1 Η, m) , 2.25 - 2.3 2 ( 1 Η, m) , 2.60 - 2.67 ( 2 Η, m) , 3.79 - 3.88(2 Η, m )，4.54(2 Η, s )，4.85 ( 1 Η, dd, J = 15.6, 6.4 Hz) , 4.93 - 5.00 ( 1 Η, m) , 5.21 ( 1 Η, t, J=6.9 Hz ),6.86(1 Η, d, J=9.2 Hz) , 6.90 - 6.93 ( 1 H, m), 6.95 - 6.97 ( 1 H, m) , 7.39 ( 1 H, d, J=2.8 Hz) , 7.85 ( 1 H, dd, J=11.0, 2.3 Hz) , 7.96(1 H, d, J=9.2 Hz), 8.58 ( 1 H, d, J= 2.3 Hz ) , 10.74( 1 H, s )。Using 6-((4-(2-(7-fluoro-2-oxo- 2Η-(1,5)-naphthyridin-1-yl)ethylidene)-1-hydroxycyclohexylmethyl)amine) -4H-benzo(1,4)oxazin-3-one 3 Omg, 6-(4-(2-(7-fluoro-2-) side as a colorless powder. Oxy-2H-(1,5)naphthyridinyl-ethyl)-2-oxo-oxo-3-oxa-3-azaspiro(4.5)decane-3-yl)· 4 Η-benzo (1,4) Oxazine-3-one 1 5 mg. 1H NMR (DMS0-d6) δ 1.73 - 1.80 ( 1 H, m) , 1.82 -1.91 (2 Η, m) , 1.97 - 2.03 ( 1 Η, m) , 2.13 - 2.20 ( 1 Η, m) , 2.25 - 2.3 2 ( 1 Η, m) , 2.60 - 2.67 ( 2 Η, m) , 3.79 - 3.88 (2 Η, m ), 4.54 (2 Η, s ), 4.85 ( 1 Η, dd, J = 15.6, 6.4 Hz ) , 4.93 - 5.00 ( 1 Η, m) , 5.21 ( 1 Η, t, J = 6.9 Hz ), 6.86 (1 Η, d, J = 9.2 Hz) , 6.90 - 6.93 ( 1 H, m), 6.95 - 6.97 ( 1 H, m) , 7.39 ( 1 H, d, J = 2.8 Hz) , 7.85 ( 1 H, dd, J = 11.0, 2.3 Hz) , 7.96 (1 H, d, J = 9.2 Hz), 8.58 ( 1 H, d, J = 2.3 Hz ) , 10.74 ( 1 H, s ).

實施例2 1 ,ο OCs -96- 201209056 使用7 -氣-1-( 2- (4-( (3 -氣-4 -甲基苯基胺基）甲基 )-4-羥基環亞己基）乙基）-1H- ( 1，5 )萘啶-2-酮80mg，藉由與實施例15之同樣操作，得到白色固體狀的7-氟-1-( 2- ( 3- ( 3-氟-4-甲基苯基）-2-側氧-1-噁-3-氮雜螺（4.5 ) 癸烷-8-亞基）乙基）-1H-(1，5)萘啶-2-酮82mg。Example 2 1 , ο OCs -96- 201209056 7-Gas-1-(2-(4-((3-)-methyl-4-methylphenylamino)methyl)-4-hydroxycyclohexylene) Ethyl)-1H-(1,5)-naphthyridin-2-one (80 mg, mp. -4-methylphenyl)-2-oxooxy-1-oxo-3-azaspiro(4.5)decane-8-ylidene)ethyl)-1H-(1,5)naphthyridin-2- Ketone 82 mg.

1H NMR ( CHLOROFORM-d ) δ 1.7 1 ( 1 H, td, J = 12.6, 4.6 Hz) , 1.7 8 - 1.84 ( 1 H, m) , 2.10 ( 1 H, dtd, J =13.5, 4.4, 4.4, 2.5 Hz) , 2.14 - 2.19 ( 1 H, m ) , 2.20 - 2.23 ( 1 H, m) , 2.24 ( 3 H, d, J= 1.4 Hz) , 2.5 3 - 2.63 ( 2 H, m) , 2.76 ( 1 H, dt, J= 14.1, 4.4 Hz) , 3.67 - 3.71 ( 1 H, m) , 3.72 - 3.75 ( 1 H, m) , 4.65 ( 1 H, dd, J= 15.6, 5.5 Hz) , 5.12 ( 1 H, dd, J= 15.6, 6.9 Hz) , 5.22 ( 1 H, t, J=6.4 Hz) , 6.87(1 H, d, 9.6 Hz) , 7.10 - 7.13(1 H, m) , 7.13 - 7.17(1 H, m) , 7.31(1 H, dd, J=10.15 2.3 Hz) , 7.36 ( 1 H, dd, J = 11.7, 2.1 Hz ) , 7.89 ( 1 H, d, J = 9.6 Hz ) , 8.43 ( 1 H, d, J = 2.3 Hz )。實施例2 21H NMR ( CHLOROFORM-d ) δ 1.7 1 ( 1 H, td, J = 12.6, 4.6 Hz) , 1.7 8 - 1.84 ( 1 H, m) , 2.10 ( 1 H, dtd, J = 13.5, 4.4, 4.4, 2.5 Hz) , 2.14 - 2.19 ( 1 H, m ) , 2.20 - 2.23 ( 1 H, m) , 2.24 ( 3 H, d, J = 1.4 Hz) , 2.5 3 - 2.63 ( 2 H, m) , 2.76 ( 1 H, dt, J = 14.1, 4.4 Hz) , 3.67 - 3.71 ( 1 H, m) , 3.72 - 3.75 ( 1 H, m) , 4.65 ( 1 H, dd, J = 15.6, 5.5 Hz) , 5.12 ( 1 H, dd, J = 15.6, 6.9 Hz) , 5.22 ( 1 H, t, J = 6.4 Hz) , 6.87 (1 H, d, 9.6 Hz) , 7.10 - 7.13(1 H, m) , 7.13 - 7.17 (1 H, m) , 7.31 (1 H, dd, J = 10.15 2.3 Hz), 7.36 ( 1 H, dd, J = 11.7, 2.1 Hz ) , 7.89 ( 1 H, d, J = 9.6 Hz ) , 8.43 ( 1 H, d, J = 2.3 Hz ). Example 2 2

將1- ( 2- ( 3,9-重氮螺（5.5 )十一烷-3-基）乙基）-7-氟-1H-(1,5)萘啶-2-酮的鹽酸鹽20mg及7-氯甲基-2,3- -97- 201209056 二氫-(1,4)二噁並（2,3-c)吡啶的鹽酸鹽13mg懸浮於四氫呋喃2mL-N，N·二甲基甲醯胺2mL，加入碳酸鉀33mg，在 8 Ot進行18小時攪拌。於反應混合物加入水5mL、乙酸乙酯50mL及甲苯10mL，分離並取出有機層。將有機層以飽和氯化鈉水溶液5mL洗淨，以無水硫酸鎂乾燥，減壓下將溶劑餾去。將所得之殘餾物以矽膠管柱層析法〔矽膠； FUJI SILYSIA股份有限公司，Chromatorex-NH，溶離液；氯仿：甲醇=9 : 1〕進行純化，得到1- ( 2- ( 9- ( 2,3-二氫-(1，4)二噁並（2,3-(〇吡啶-7-基甲基）-3,9-重氮螺（ 5.5)十一烷-3-基）乙基）-7-氟-1H-(1，5)萘啶-2-酮 1 7 m g 〇 1H NMR ( CHLOROFORM-d ) δ 1.47 - 1.57 ( 8 H, m ) ，2.39 - 2.58 ( 8 Η，m)，2.61 - 2.67(2 Η，m)，3.52(2 Η, s ) , 4.2 5 - 4.3 6 ( 6 Η, m )，6.86 ( 1 Η，d，J=9.6 Hz)， 6.90 ( 1 H, s ) ,7.56(1 Η，d d，J = 1 0 · I，2 · 3 Hz )，7.88 ( 1 H, d, J = 9.6 Hz )，8. 1 1 ( 1 H，s )，8.4 1 ( 1 H, d，J = 2.3 Hz )。實施例2 3Hydrochloride of 1-(2-(3,9-diazospiro(5.5)undecano-3-yl)ethyl)-7-fluoro-1H-(1,5)naphthyridin-2-one 20 mg and 7-chloromethyl-2,3- -97- 201209056 Dihydro-(1,4)dioxin (2,3-c)pyridine hydrochloride 13 mg suspended in tetrahydrofuran 2 mL-N, N·2 2 mL of methylmethionamine was added to 33 mg of potassium carbonate, and the mixture was stirred at 8 Ot for 18 hours. 5 mL of water, 50 mL of ethyl acetate and 10 mL of toluene were added to the reaction mixture, and the organic layer was separated and taken. The organic layer was washed with 5 mL of a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated. The obtained residue was purified by silica gel column chromatography (矽; FUJI SILYSIA Co., Ltd., Chromatorex-NH, eluent; chloroform:methanol = 9:1) to obtain 1-(2-(9-( 2,3-Dihydro-(1,4)dioxin(2,3-(indolylpyridin-7-ylmethyl)-3,9-diazospiro(5.5)undecyl-3-yl)B 7-fluoro-1H-(1,5)naphthyridin-2-one 1 7 mg 〇1H NMR (CHLOROFORM-d ) δ 1.47 - 1.57 ( 8 H, m ) , 2.39 - 2.58 ( 8 Η,m ), 2.61 - 2.67 (2 Η, m), 3.52 (2 Η, s ) , 4.2 5 - 4.3 6 ( 6 Η, m ), 6.86 ( 1 Η, d, J = 9.6 Hz), 6.90 ( 1 H, s ) , 7.56 (1 Η, dd, J = 1 0 · I, 2 · 3 Hz ), 7.88 ( 1 H, d, J = 9.6 Hz ), 8. 1 1 ( 1 H, s ), 8.4 1 ( 1 H, d, J = 2.3 Hz ). Example 2 3

將1-(2-(2,7-重氮螺（4.4)壬-2-基）乙基）-7-氟- 1H- ( 1,5 )-萘啶-2-酮的鹽酸鹽30mg懸浮於氯仿3mL，加 -98- 201209056 入三乙胺33kL並使其溶解。加入2,3-二氫-(1，4)二噁並 (2,3-c)吡啶-7-羰醛13mg之氯仿溶液2mL，在55°C進行3 小時攪拌。將反應混合物在冰冷下’加入三乙酸基氫化硼鈉53mg，在室溫進行3小時攪拌。將反應混合物在減壓下使溶劑餾去，將所得之殘餾物以矽膠管柱層析法〔矽膠； FUJI SILYSIA股份有限公司，Chromatorex-NH，溶離液；氯仿：甲醇=96 : 4〕進行純化後得到黃色油狀的1- ( 2-( 7-(2,3-二氫-(1，4)二噁並（2,3-(〇吡啶-7-基甲基）-2,7-重氮螺（4.4)壬-2-基）乙基）-7-氟-111-(1，5)萘啶-2 -酮 1 8 m g。 1H NMR ( CHLOROFORM-d ) δ 1.76 - 1.94 ( 4 H, m) ,2.50 ( 1 Η，d，J=9.2 Hz)，2.56 - 2.81 (9 Η，m)，3.60 -3.69 ( 2 H, m) , 4.25 - 4.36 ( 6 H, m ) , 6.86 ( 1 H, d, J =9.6 Hz)，6.91(1 H, s )，7.56(1 H, dd, J= 10.3, 2.1 Hz)，7.88 ( 1 H，d, 9.6 Hz ) , 8.09 ( 1 H, s ) ,8.40(1 H, d, J= 2.1 Hz )。實施例243-(2-(2,7-diazospiro(4.4)indol-2-yl)ethyl)-7-fluoro-1H-(1,5)-naphthyridin-2-one hydrochloride 30 mg It was suspended in 3 mL of chloroform, and -98-201209056 was added to 33 kL of triethylamine and dissolved. 2 mL of a chloroform solution of 2,3-dihydro-(1,4)dioxin (2,3-c)pyridine-7-carbonylaldehyde (13 mg) was added, and the mixture was stirred at 55 ° C for 3 hours. The reaction mixture was added to 53 mg of sodium triacetate hydride under ice cooling, and stirred at room temperature for 3 hours. The reaction mixture was subjected to distillation under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (purine; FUJI SILYSIA Co., Ltd., Chromatorex-NH, eluent; chloroform:methanol = 96:4). After purification, 1-(2-(7-(2,3-dihydro-(1,4)dioxin(2,3-(indolyl)-7-ylmethyl)-2,7) was obtained as a yellow oil. -diazospiro (4.4) fluoren-2-yl)ethyl)-7-fluoro-111-(1,5)naphthyridin-2-one 1 8 mg. 1H NMR (CHLOROFORM-d) δ 1.76 - 1.94 ( 4 H, m) , 2.50 ( 1 Η, d, J = 9.2 Hz), 2.56 - 2.81 (9 Η, m), 3.60 - 3.69 ( 2 H, m) , 4.25 - 4.36 ( 6 H, m ) , 6.86 ( 1 H, d, J = 9.6 Hz), 6.91 (1 H, s ), 7.56 (1 H, dd, J = 10.3, 2.1 Hz), 7.88 ( 1 H,d, 9.6 Hz ) , 8.09 ( 1 H , s ) , 8.40 (1 H, d, J = 2.1 Hz ). Example 24

使用1-( 2-( 2,3-二氫-1 H-螺（異喹啉-4,4’-哌啶）- -99- 201209056 1’-基）乙基）-7-氟-(1，5)-萘啶-2(1H)-酮的鹽酸鹽 100mg及 2,3 -二氫-(1，4)二 D惡並（2,3-c)啦卩定-7 -羰醒 3 9mg，藉由與實施例23之同樣操作，得到淡黃色油狀的1-(2- ( 2- ( ( 2,3-二氫-(1，4 )二噁並（2,3-c )吡啶-7-基 )甲基）-2,3-二氫-1H-螺（異喹啉-4,4’-哌啶）-1’-基）乙基）-7-氟-(1，5)-萘啶- 2(1H)-酮 73mg。 1H NMR ( CHLOROFORM-d) δ 1.81 - 1.89 ( 2 H，m) ,2.01 - 2.12 ( 2 H, m) , 2.20 ( 2 H, t, J = 11.5 Hz) , 2.63 (2 H, t, J = 6.9 Hz ) , 2.70(2 H, s ) , 2.79 - 2.8 8 ( 2 H, m )，3.68 (2 H，s)，3.71 (2 H，s) , 4.2 7 - 4.3 0 ( 2 H, m ),4.31 - 4.38(4 H, m) , 6.87(1 H, d, J-9.6 Hz), 6.97 - 7.02 ( 2 H, m) , 7.09 - 7.15 ( 1 H, m) , 7.21 ( 1 H, t, J = 7.8 Hz) , 7.40 ( 1 H, d, J = 7.8 Hz) , 7.62 ( 1 H, d, J = 9.2 Hz )，7.90(1 H, d, J = 9.6 Hz )，8.11(1 H, s )， 8.44 ( 1 H, d, J = 2.3 Hz )。實施例2 51-(2-(2,3-Dihydro-1 H-spiro(isoquinolin-4,4'-piperidine)- -99- 201209056 1'-yl)ethyl)-7-fluoro-( 1,5)-naphthyridin-2(1H)-one hydrochloride hydrochloride 100 mg and 2,3-dihydro-(1,4)di-D-(2,3-c)ladenidine-7-carbonyl After waking up to 39 mg, 1-(2-(2-((2,3-dihydro-(1,4)) dioxin (2,3-) was obtained as a pale yellow oil. c) Pyridin-7-yl)methyl)-2,3-dihydro-1H-spiro(isoquinolin-4,4'-piperidine)-1'-yl)ethyl)-7-fluoro-( 1,5)-naphthyridine-2(1H)-one 73 mg. 1H NMR (CHLOROFORM-d) δ 1.81 - 1.89 ( 2 H,m) , 2.01 - 2.12 ( 2 H, m) , 2.20 ( 2 H, t, J = 11.5 Hz) , 2.63 (2 H, t, J = 6.9 Hz ) , 2.70(2 H, s ) , 2.79 - 2.8 8 ( 2 H, m ), 3.68 (2 H, s), 3.71 (2 H, s) , 4.2 7 - 4.3 0 ( 2 H, m ) , 4.31 - 4.38(4 H, m) , 6.87(1 H, d, J-9.6 Hz), 6.97 - 7.02 ( 2 H, m) , 7.09 - 7.15 ( 1 H, m) , 7.21 ( 1 H, t , J = 7.8 Hz) , 7.40 ( 1 H, d, J = 7.8 Hz) , 7.62 ( 1 H, d, J = 9.2 Hz ), 7.90 (1 H, d, J = 9.6 Hz ), 8.11 (1 H , s ), 8.44 ( 1 H, d, J = 2.3 Hz ). Example 2 5

〇、 %Ό〇將1-(2- (2,8-重氮螺（4.5)癸烷-8-基）乙基）-7-甲氧基_1只-(1，5)萘啶-2-酮的鹽酸鹽9111^、6-溴-2,3-二氫苯並（1，4)戴奧辛43mg、tert-丁氧基鉀90mg、乙酸鈀 -100- 201209056 0.2mg、及2-(二環己基膦基）聯苯基0.7mg懸浮於三氟甲基苯4mL，在微波爐中進行150°C之20分鐘攪拌。將反應混合物在減壓下將溶劑餾去，將所得之殘餾物以矽膠管柱層析法〔矽膠；FUJI SILYSIA股份有限公司，Chromatorex-NH，溶離液；乙酸乙酯：己烷=4: 1〕及分取用矽膠薄層層析法NH型〔FUJI SILYSIA株式会公司製PLC盤NH、展開液；乙酸乙酯）〕進行純化，得到黃色油狀的1-(2- (2-(2,3-二氫苯並（1，4)戴奧辛_6-基）-2,8-重氮螺（ 4.5)癸烷-8-基）乙基）-7 -甲氧基-1H-(1，5)萘卩定-2-酮 1 2 m g。 1H NMR ( CHLOROFORM-d ) δ 1.60 - 1.69 ( 4 H, m) ,1.84(2 Η, t, 3= 6.9 Hz) , 2.51 (2 Η, br. s.) , 2.62 -2.69 ( 4 Η, m) , 3.07 ( 2 Η, s) , 3.27 ( 2 Η, t, J= 6.9 Hz )，3.98 ( 3 Η，s)，4.17 - 4.20 ( 2 Η，m)，4.23 - 4.25 ( 2 Η, m) , 4.38 (2 Η, t, J=7.3 Hz) , 6.06 - 6.09 (2 H, m) ，6.74 6.77 (2 H，m)，7.21 ( 1 H，d，J=2.3 Hz)，7.85 (1 H，d，J=9.6 Hz)，8.28 ( 1 H, d，J=2.3 Hz)。實施例2 6 HQ>。〇, %Ό〇 1-(2-(2,8-diazospiro(4.5)decane-8-yl)ethyl)-7-methoxy-1-(-1,5)naphthyridine- 2-ketone hydrochloride 9111^, 6-bromo-2,3-dihydrobenzo (1,4) dioxin 43 mg, tert-butoxy potassium 90 mg, palladium acetate-100-201209056 0.2 mg, and 2- 0.7 mg of (dicyclohexylphosphino)biphenyl was suspended in 4 mL of trifluoromethylbenzene, and stirred in a microwave oven at 150 ° C for 20 minutes. The reaction mixture was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (yield; FUJI SILYSIA Co., Ltd., Chromatorex-NH, eluent; ethyl acetate:hexane = 4: 1] and the fractionation was carried out by silica gel thin layer chromatography NH (FUJI SILYSIA Co., Ltd. PLC disk NH, developing solution; ethyl acetate)] and purified to obtain 1-(2-(2-(2-(2-) 2,3-Dihydrobenzo(1,4)dioxine_6-yl)-2,8-diazospiro (4.5)decane-8-yl)ethyl)-7-methoxy-1H-( 1,5) naphthoquinone-2-one 1 2 mg. 1H NMR ( CHLOROFORM-d ) δ 1.60 - 1.69 ( 4 H, m) , 1.84 (2 Η, t, 3 = 6.9 Hz) , 2.51 (2 Η, br. s.) , 2.62 -2.69 ( 4 Η, m ), 3.07 ( 2 Η, s) , 3.27 ( 2 Η, t, J = 6.9 Hz ), 3.98 ( 3 Η, s), 4.17 - 4.20 ( 2 Η, m), 4.23 - 4.25 ( 2 Η, m) , 4.38 (2 Η, t, J=7.3 Hz) , 6.06 - 6.09 (2 H, m) , 6.74 6.77 (2 H,m), 7.21 ( 1 H,d,J=2.3 Hz), 7.85 (1 H , d, J = 9.6 Hz), 8.28 ( 1 H, d, J = 2.3 Hz). Example 2 6 HQ>.

-101 201209056 將7 -甲氧基-2 -側氧-2H- ( 1,5 )萘啶-1-基）乙醛 188mg溶解於氯仿12mL，加入3-(2,3 -二氫苯並（1，4)戴奧辛-6-基）-1-噁-3,8-重氮螺（4.5)癸烷-2-酮275 mg及甲醇0.5mL，在室溫進行5小時攪拌。加入乙酸50μί及三乙酸基氫化硼鈉3 84mg，在室溫進行2.5小時攪拌。於反應混合物中加入飽和碳酸氫鈉水溶液15mL，分離並取出有機層。將有機層以飽和氯化鈉水溶液5mL洗淨，以無水硫酸鎂乾燥，減壓下將溶劑餾去。將所得之殘餾物以矽膠管柱層析法〔矽膠；FUJI SILYSIA 股份有限公司，Chromatorex-NH ，溶離液；乙酸乙酯：己烷=98 : 2〕進行純化後得到白色泡狀的1· ( 2- ( 3- ( 2,3 -二氫苯並（1，4)戴奧辛-6 -基 )-2 -側氧-1-噁-3,8 -重氮螺（4.5)癸烷-8-基）乙基）-7-甲氧基-1H-(1，5)萘啶-2-酮3 3 0mg。 1H NMR ( CHLOROFORM-d) δ 1.83 - 1.8 9 ( 2 H，m) ,2.01 - 2.05 (2 H, m) , 2.70 - 2.78 (6 H, m) , 3.68 (2 H，s)，3.99 (3 H，s) , 4.23 - 4.27 ( 4 H, m)，4.39 (2 H， t, J = 7. 1 Hz) ,6.75(1 H, d, J = 9.6 Hz ) ,6.85(1 H，d， J=8.7 Hz)，6.99 ( 1 H，dd，J=8_7，2.8 Hz)，7.07 ( 1 H， d，J=2.8 Hz)，7.15 ( 1 H，br_ s.) , 7.85 ( 1 H，d, J=9.6 Hz ) , 8.29 ( 1 H, d, J = 2.8 Hz )。 -102- 201209056 實施例27-101 201209056 188 mg of 7-methoxy-2-oxo-oxy-2H-(1,5)naphthyridin-1-yl)acetaldehyde was dissolved in 12 mL of chloroform, and 3-(2,3-dihydrobenzoyl ( 1,4) Dioxin-6-yl)-1-oxo-3,8-diazospiro(4.5)nonan-2-one 275 mg and methanol 0.5 mL were stirred at room temperature for 5 hours. 50 μg of acetic acid and 3 84 mg of sodium triacetate triacetate were added, and the mixture was stirred at room temperature for 2.5 hours. To the reaction mixture was added 15 mL of a saturated aqueous sodium hydrogencarbonate solution, and the organic layer was separated. The organic layer was washed with 5 mL of saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The obtained residue was purified by silica gel column chromatography (矽胶; FUJI SILYSIA Co., Ltd., Chromatorex-NH, eluent; ethyl acetate:hexane = 98: 2) to obtain a white blister. (2-(3-(2,3-dihydrobenzo(1,4)dioxo-6-yl)-2-oxo-1-oxo-3,8-diazospiro(4.5)decane-8 -yl)ethyl)-7-methoxy-1H-(1,5)naphthyridin-2-one 3 30 mg. 1H NMR (CHLOROFORM-d) δ 1.83 - 1.8 9 ( 2 H,m) , 2.01 - 2.05 (2 H, m) , 2.70 - 2.78 (6 H, m) , 3.68 (2 H, s), 3.99 (3 H, s) , 4.23 - 4.27 ( 4 H, m), 4.39 (2 H, t, J = 7. 1 Hz) , 6.75 (1 H, d, J = 9.6 Hz ) , 6.85 (1 H, d, J=8.7 Hz), 6.99 ( 1 H, dd, J=8_7, 2.8 Hz), 7.07 ( 1 H, d, J=2.8 Hz), 7.15 ( 1 H, br s.) , 7.85 ( 1 H, d , J = 9.6 Hz ) , 8.29 ( 1 H, d, J = 2.8 Hz ). -102- 201209056 Example 27

使用3-(7-甲氧基-2-側氧- 2H-(1，5)萘啶-1-基）丙醛86mg及3-(2,3-二氫苯並（1，4)戴奧辛-6-基）-1-噁-3,8-重氮螺（4.5)癸烷-2_酮118mg，藉由與實施例26之同樣操作，得到無色油狀的1- ( 3- ( 3- ( 2,3-二氫苯並（1，4 )戴奧辛-6-基）-2-側氧-1-噁-3,8-重氮螺（4.5)癸烷-8-基）丙基）-7-甲氧基-1H-(1，5)萘啶-2-酮82mg。 1H NMR ( CHLOROFORM-d ) δ 1.87 ( 2 H, dt，J = 13.4, 6.8 Hz )，1.93 (2 H，quin, J=7.0 Hz)，2.01 - 2.06 (2 H，m)，2.52 (2 H，t, J=6.6 Hz)，2.61 (4 H，br. s. ),3.68(2 H, s) , 3.99(3 H, s ) , 4.2 3 - 4.2 7 ( 4 H, m ),4-30 ( 2 H, t, J= 7.3 Hz ) , 6.76 ( 1 H, d, J = 9.6 Hz )， 6.85 ( 1 H, d, J=9.2 Hz)，6.98 - 7.01 ( 1 H，m)，7.07 ( 1 H, d, J= 2.8 Hz)，7.24( 1 H，d，J=2.3 Hz)，7.85 ( 1 H, d, J = 9.6 Hz ) , 8.29 ( 1 H, d, J = 2.3 Hz )。 -103- 201209056 實施例2 83-(7-Methoxy-2-oxo-2H-(1,5)naphthyridin-1-yl)propanal 86 mg and 3-(2,3-dihydrobenzo(1,4)dioxin -6-yl)-1-oxo-3,8-diazospiro(4.5)decane-2-one ketone 118 mg was obtained in the same manner as in Example 26 to give 1-(3-(3) as colorless oil. - (2,3-Dihydrobenzo(1,4)dioxin-6-yl)-2-oxo-1-oxo-3,8-diazospiro(4.5)decane-8-yl)propyl ) 7-Methoxy-1H-(1,5)naphthyridin-2-one 82 mg. 1H NMR ( CHLOROFORM-d ) δ 1.87 ( 2 H, dt, J = 13.4, 6.8 Hz ), 1.93 (2 H, quin, J = 7.0 Hz), 2.01 - 2.06 (2 H, m), 2.52 (2 H ,t, J=6.6 Hz), 2.61 (4 H, br. s. ), 3.68 (2 H, s) , 3.99 (3 H, s ) , 4.2 3 - 4.2 7 ( 4 H, m ), 4- 30 ( 2 H, t, J = 7.3 Hz ) , 6.76 ( 1 H, d, J = 9.6 Hz ), 6.85 ( 1 H, d, J = 9.2 Hz), 6.98 - 7.01 ( 1 H, m), 7.07 ( 1 H, d, J = 2.8 Hz), 7.24 ( 1 H, d, J = 2.3 Hz), 7.85 ( 1 H, d, J = 9.6 Hz ) , 8.29 ( 1 H, d, J = 2.3 Hz ) . -103- 201209056 Example 2 8

使用（2-側氧- 2H- ( 1,7 )萘啶-1-基）乙醛90mg及3-(2,3-二氫苯並（1，4)戴奧辛-6-基）-1-噁-3,8-重氮螺（ 4.5 )癸烷-2-酮153mg，藉由與實施例26之同樣操作，得到淡橙色固體狀的1-(2-(3-(2,3-二氫苯並（1,4)戴奧辛-6-基）-2·側氧-1-噁-3,8-重氮螺（4.5)癸烷-8-基）乙基）-1H-(1，7)萘啶-2-酮 100mg。 1H NMR ( CHLOROFORM-d ) δ 1.84 ( 2 H, dt, J = 13.5, 7.0 Hz ) , 2.02 ( 2 H, d, J = 1 3 .3 Hz ) , 2.72 - 2.81 ( 6 H, m) , 3.67 (2 H, s) , 4.23 - 4.27 (4 H, m) , 4.49 (2 H, t, J = 7.1 Hz) , 6.85 ( 1 H, d, J= 8.7 Hz ) , 6.90 ( 1 H, d, J = 9.2 Hz ) , 6.99 ( 1 H, dd, J = 8.7, 2.8 Hz ) , 7.07(1 H, d, J = 2.3 Hz ) , 7.43 ( 1 H, d, J= 5.0 Hz ) , 7.66 ( 1 H, d, J= 9.2 Hz) , 8.46(1 H, d, J= 5.0 Hz) ，8.90 ( 1 H, s -104- 201209056 實施例2 9Using (2-oxo-2H-(1,7)-naphthyridin-1-yl)acetaldehyde 90 mg and 3-(2,3-dihydrobenzo(1,4)dioxin-6-yl)-1- Ethylene-3,8-diazospiro(4.5)nonan-2-one 153 mg was obtained in the same manner as in Example 26 to give 1-(2-(3-(2, 3-) Hydrogen benzo (1,4) dioxin-6-yl)-2. sideoxy-1-oxo-3,8-diazospiro (4.5)decane-8-yl)ethyl)-1H-(1, 7) Naphthyridin-2-one 100 mg. 1H NMR ( CHLOROFORM-d ) δ 1.84 ( 2 H, dt, J = 13.5, 7.0 Hz ) , 2.02 ( 2 H, d, J = 1 3 .3 Hz ) , 2.72 - 2.81 ( 6 H, m) , 3.67 (2 H, s) , 4.23 - 4.27 (4 H, m) , 4.49 (2 H, t, J = 7.1 Hz) , 6.85 ( 1 H, d, J = 8.7 Hz ) , 6.90 ( 1 H, d, J = 9.2 Hz ) , 6.99 ( 1 H, dd, J = 8.7, 2.8 Hz ) , 7.07 (1 H, d, J = 2.3 Hz ) , 7.43 ( 1 H, d, J = 5.0 Hz ) , 7.66 ( 1 H, d, J = 9.2 Hz) , 8.46 (1 H, d, J = 5.0 Hz), 8.90 ( 1 H, s -104 - 201209056 Example 2 9

將2-(2,3-二氫苯並（1，4)戴奧辛-6-基）-1-側氧-2,7-重氮螺（3.5)壬-1-酮的鹽酸鹽30mg懸浮於氯仿1.5mL ’加入三乙胺67 μΐ^並使其溶解。加入3- ( 7-甲氧基-2-側氧-2Η-(1，5)萘啶-1-基）丙醛21mg及乙酸22μί，在室溫進行1 · 5小時攪拌。將反應混合物冰冷下加入三乙酸基氫化硼鈉43mg，恢復至室溫後進行3小時攪拌。將反應混合物在減壓下使溶劑餾去，將所得之殘餾物以矽膠管柱層析法〔矽膠；關東化學股份有限公司，矽膠60，溶離液；乙酸乙酯〕進行純化，得到黃色固體狀的1-(2-(2-(2,3-二氫苯並（1，4)戴奧辛-6-基）-1-側氧-2,7-重氮螺（3_5 )壬-7-基）乙基）-7-甲氧基-1H-(1，5)萘啶-2-酮32mg。 1H NMR ( CHLOROFORM-d ) δ 1.86 - 1.93 ( 2 H, m ) ,2.10 ( 2 Η, ddd, J= 13.2, 9.1, 3.4 Hz) , 2.52 ( 2 H, br. s.) , 2.73 (2 H, t, J=7.3 Hz) , 2.98 - 3.03 (2 H, m), 3.40(2 H, s) , 4.00(3 H, s) , 4.21 - 4.26(4 H, m ), 4.41 (2 H, t, J=7.3 Hz) , 6.75 (1 H, d, J=9.6 Hz), 6.80 - 6.83 ( 1 H, m) , 6.84 - 6.87 ( 1 H, m) , 6.88 ( 1 H, d, J = 2.3 Hz ) , 7.26 ( 1 H, d, J= 2.3 Hz) ,7.86(1 H, ds -105- 201209056 J = 9.6 Hz ) , 8.29 ( 1 H, d, J = 2.3 Hz )。實施例3 0Suspension of 2-(2,3-dihydrobenzo(1,4)dioxine-6-yl)-1-oxo-2,7-diazospiro(3.5)nonan-1-one hydrochloride 30 mg Add 3.5 μM of triethylamine to chloroform and dissolve it. 21 mg of 3-(7-methoxy-2-oxo-2-indole-(1,5)naphthyridin-1-yl)propanal and 22 μg of acetic acid were added, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was added to sodium triacetate sodium hydride 43 mg under ice cooling, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was subjected to distillation under reduced pressure, and the obtained residue was purified by silica gel column chromatography, EtOAc, EtOAc, EtOAc, EtOAc (EtOAc) 1-(2-(2-(2,3-dihydrobenzo(1,4)dioxo-6-yl)-1-oxo-2,7-diazospiro(3_5 )壬-7- Ethyl)-7-methoxy-1H-(1,5)naphthyridin-2-one 32 mg. 1H NMR ( CHLOROFORM-d ) δ 1.86 - 1.93 ( 2 H, m ) , 2.10 ( 2 Η, ddd, J = 13.2, 9.1, 3.4 Hz) , 2.52 ( 2 H, br. s.) , 2.73 (2 H , t, J=7.3 Hz) , 2.98 - 3.03 (2 H, m), 3.40(2 H, s) , 4.00(3 H, s) , 4.21 - 4.26(4 H, m ), 4.41 (2 H, t, J=7.3 Hz) , 6.75 (1 H, d, J=9.6 Hz), 6.80 - 6.83 ( 1 H, m) , 6.84 - 6.87 ( 1 H, m) , 6.88 ( 1 H, d, J = 2.3 Hz ) , 7.26 ( 1 H, d, J = 2.3 Hz) , 7.86 (1 H, ds -105 - 201209056 J = 9.6 Hz ) , 8.29 ( 1 H, d, J = 2.3 Hz ). Example 3 0

使用3- ( 7-甲氧基-2-側氧- 2H- ( 1，5 )萘啶-1-基）乙醛29.911^及2-(2,3-二氫苯並（1，4)戴奧辛-6-基）-3-側氧-2,8-重氮螺（4.5)癸烷-3-酮38.4mg，藉由與實施例26 之同樣操作，得到1- ( 2· ( 2- ( 2,3-二氫苯並（1，4 )戴奧辛-6-基）-3-側氧-2,8-重氮螺（4.5)癸烷-8-基）乙基）-7-甲氧基-1H- ( 1，5)-萘啶-2-酮 45mg。 1H NMR ( CHLOROFORM-d ) δ 1.73(4 H, t, J = 5.53-(7-Methoxy-2-oxo-2H-(1,5)naphthyridin-1-yl)acetaldehyde 29.911^ and 2-(2,3-dihydrobenzo(1,4) Dioxin-6-yl)-3-oxo-2,8-diazospiro(4.5)nonan-3-one 38.4 mg was obtained by the same procedure as in Example 26 to give 1-(2·(2- (2,3-Dihydrobenzo(1,4)dioxine-6-yl)-3-oxo-oxy-2,8-diazos(4.5)decane-8-yl)ethyl)-7- Oxy-1H-(1,5)-naphthyridin-2-one 45 mg. 1H NMR ( CHLOROFORM-d ) δ 1.73(4 H, t, J = 5.5

Hz) , 2.47(2 H, s) , 2.50 - 2.59 (2 H, m) , 2.59 - 2.72 (4 H, m )，3.57 ( 2 H, s )，3.98(3 H, s ) , 4.20 - 4.28 (4 H, m)，4.37 (2 H，t，J=7.3 Hz) , 6.75 ( 1 H, d, J = 9.6 Hz) , 6.84 ( 1 H, d, J = 9.2 Hz )，7.03(1 H, dd, J = 8.7, 2.8 Hz) , 7.12 ( 1 H, s) , 7.17 ( 1 H, d, J-2.3 Hz), 7.85 ( 1 H, d, J = 9.6 Hz ) , 8.29 ( 1 H, d, J - 2.8 Hz )。 -106- 201209056 實施例3 1Hz) , 2.47(2 H, s) , 2.50 - 2.59 (2 H, m) , 2.59 - 2.72 (4 H, m ), 3.57 ( 2 H, s ), 3.98 (3 H, s ) , 4.20 - 4.28 (4 H, m), 4.37 (2 H, t, J = 7.3 Hz), 6.75 ( 1 H, d, J = 9.6 Hz) , 6.84 ( 1 H, d, J = 9.2 Hz ), 7.03 (1 H , dd, J = 8.7, 2.8 Hz), 7.12 ( 1 H, s) , 7.17 ( 1 H, d, J-2.3 Hz), 7.85 ( 1 H, d, J = 9.6 Hz ) , 8.29 ( 1 H, d, J - 2.8 Hz). -106- 201209056 Example 3 1

使用3-( 醛 35mg及 2-( 2,8 -重氮螺（樣操作，得到基）-3-側氧基-1H- ( 1，5 ) 1H NMR Hz ) , 1.92(： ),3.56 ( 2 1 ),4.27 - 4. 6.85 ( 1 H, d, ),7.13 ( 1 ： 7-甲氧基-2-側氧-2H- ( 1,5 )萘啶-1-基）丙 2,3-二氫苯並（1,4 )戴奧辛-6-基）-3-側氧-4.5)癸烷-3-酮41mg，藉由與實施例26之同 1-(3-(2-(2，3-二氫苯並（1，4)戴奧辛- 6-!，8-重氮螺（4.5)癸烷-8-基）丙基）-7-甲氧萘啶-2-酮56mg。 (CHLOROFORM-d ) δ 1.73 ( 4 H，t，J = 5.5 :H, quin, J= 6.9 Hz) , 2.34 - 2.5 7 ( 8 H，m [，s ) ， 3.99(3 H, s ) , 4.21 - 4.27 ( 4 H, m 32(2 H, m ) , 6.75(1 H, d, J = 9.6 Hz ), J= 8.7 Hz) , 7.04 ( 1 H, dd, J- 8.7, 2.3 Hz i, d, J = 2.3 Hz) , 7.20 - 7.25 ( 1 H, m ), 7.84 ( 1 H, d, J = 9.6 Hz ) ，8.2 8 ( 1 H, d，J = 2 · 3 H z )。 201209056 實施例3 2Using 3-(aldehyde 35 mg and 2-(2,8-diazospiro), 1-oxo-1H-(1,5) 1H NMR Hz), 1.92 (: ), 3.56 ( 2 1 ), 4.27 - 4. 6.85 ( 1 H, d, ), 7.13 ( 1 : 7-methoxy-2-oxo-2H-( 1,5 )naphthyridin-1-yl)propane 2,3 -Dihydrobenzo(1,4)dioxin-6-yl)-3-oxo-4.5)nonan-3-one 41 mg by the same as Example 26 1-(3-(2-(2) , 3-dihydrobenzo (1,4) dioxin-6-!, 8-diazospiro(4.5)decane-8-yl)propyl)-7-methoxynaphthyridin-2-one 56 mg. CHLOROFORM-d ) δ 1.73 ( 4 H,t,J = 5.5 :H, quin, J= 6.9 Hz) , 2.34 - 2.5 7 ( 8 H,m [,s ) , 3.99(3 H, s ) , 4.21 - 4.27 ( 4 H, m 32(2 H, m ) , 6.75(1 H, d, J = 9.6 Hz ), J= 8.7 Hz) , 7.04 ( 1 H, dd, J- 8.7, 2.3 Hz i, d, J = 2.3 Hz) , 7.20 - 7.25 ( 1 H, m ), 7.84 ( 1 H, d, J = 9.6 Hz ) , 8.2 8 ( 1 H, d, J = 2 · 3 H z ). 201209056 Example 3 2

使用7 -甲氧基-2-側氧-2H- ( 1，5 )萘啶-1-基）乙醛 58mg及 2- ( 2,3-二氫-(1，4 )二噁並（2,3-c )吡啶-7-基甲基）-2,8-重氮螺（4.5)癸烷-3-酮的鹽酸鹽118mg，藉由與實施例29之同樣操作，得到白色泡狀的1 - ( 2- ( 2-( 2,3-二氫·（ 1,4 )二噁並（2,3-c )吡啶-7-基甲基）-3-側氧-2,8-重氮螺（4.5)癸烷-8-基）乙基）-7-甲氧基-1Η-( 1，5 )萘啶-2-酮 50mg。 1 H NMR ( CHLOROFORM-d ) δ 1.64(4 H, br. s.)， 2.32(2 H, s) , 2.52(4 H, br. s.) , 2.61 - 2.65 (2 H, m ),3.18(2 H, s) , 3.72 (2 H, q, J=7.2 Hz) , 3.97(3 H, s) , 4.27 - 4.30 (2 H, m) , 4.32 ( 2 H, td, J=3.8, 2.1Using 7-methoxy-2-oxo-2H-(1,5)naphthyridin-1-yl)acetaldehyde 58 mg and 2-( 2,3-dihydro-(1,4 ) dioxo (2) , 3-c)pyridin-7-ylmethyl)-2,8-diazospiro(4.5)nonan-3-one hydrochloride (118 mg, m. 1-(2-(2-( 2,3-Dihydro·(1,4) dioxa-(2,3-c)pyridin-7-ylmethyl)-3-oxo-2,8- Diazospiro(4.5)decane-8-yl)ethyl)-7-methoxy-1Η-(1,5)naphthyridin-2-one 50 mg. 1 H NMR ( CHLOROFORM-d ) δ 1.64(4 H, br. s.), 2.32(2 H, s) , 2.52(4 H, br. s.) , 2.61 - 2.65 (2 H, m ), 3.18 (2 H, s) , 3.72 (2 H, q, J=7.2 Hz) , 3.97(3 H, s) , 4.27 - 4.30 (2 H, m) , 4.32 ( 2 H, td, J=3.8, 2.1

Hz) , 4.44 ( 2 H, s ) , 6.74 ( 1 H, d, J = 9.6 Hz ) , 6.76 ( 1 H, s) , 7.16(1 H, d, J=2.3 Hz) , 7.84(1 H, d, J=9.6Hz) , 4.44 ( 2 H, s ) , 6.74 ( 1 H, d, J = 9.6 Hz ) , 6.76 ( 1 H, s) , 7.16 (1 H, d, J = 2.3 Hz) , 7.84 (1 H, d, J=9.6

Hz) , 8.08 ( 1 H, s) , 8.28 ( 1 H, d, J=2.3 Hz)。 -108- 201209056 實施例3 3Hz) , 8.08 ( 1 H, s) , 8.28 ( 1 H, d, J = 2.3 Hz). -108- 201209056 Example 3 3

使用（7-甲氧基-2-側氧-2H-喹啉-1-基）乙醛98mg及 2- (2,3-二氫苯並（1，4)戴奧辛-6-基）-3-側氧-2,8-重氮螺（4.5 )癸烷-3-酮4 1 mg，藉由與實施例26之同樣操作，得到無色泡狀的1- ( 2- ( 2- ( 2,3-二氫苯並（1,4 )戴奧辛-6-基）-3-側氧-2,8-重氮螺（4.5)癸烷-8-基）乙基）-7-甲氧基-1H-唾啉-2-酮98mg。 1 H NMR ( CHLOROFORM-d ) δ 1 · 76 ( 4 Η，br · s ·)， 2.47(2 H, s ) , 2.5 0 - 2.75 ( 6 H, m ) , 3.57(2 H, s ), 3.92 ( 3 H, s) , 4.19 - 4.27 (4 H, m) , 4.41 (2 H, t, J = 7.6 Hz ) , 6.52 ( 1 H, d, J = 9.2 Hz ) , 6.79 - 6.86 ( 2 H, m )，6.90 ( 1 H，s) , 7.03 ( 1 H, dd, J= 8.3, 2.3 Hz ) ,7.13 (1 H, d, J = 2.8 Hz ) , 7.47 ( 1 H, d, J = 8.3 Hz ) , 7.59 ( 1 H, d, J - 9.2 Hz )。 -109- 201209056 實施例3 4Using (7-methoxy-2-oxo-2H-quinolin-1-yl)acetaldehyde 98 mg and 2-(2,3-dihydrobenzo(1,4)dioxin-6-yl)-3 - side oxy-2,8-diazospiro(4.5)nonan-3-one 4 1 mg, which was obtained in the same manner as in Example 26 to give 1-(2-(2-(2). 3-Dihydrobenzo(1,4)dioxin-6-yl)-3-oxo-2,8-diazospiro(4.5)decane-8-yl)ethyl)-7-methoxy- 1H-Sialolin-2-one 98 mg. 1 H NMR ( CHLOROFORM-d ) δ 1 · 76 ( 4 Η, br · s ·), 2.47(2 H, s ) , 2.5 0 - 2.75 ( 6 H, m ) , 3.57(2 H, s ), 3.92 ( 3 H, s) , 4.19 - 4.27 (4 H, m) , 4.41 (2 H, t, J = 7.6 Hz ) , 6.52 ( 1 H, d, J = 9.2 Hz ) , 6.79 - 6.86 ( 2 H, m ), 6.90 ( 1 H, s) , 7.03 ( 1 H, dd, J = 8.3, 2.3 Hz ) , 7.13 (1 H, d, J = 2.8 Hz ) , 7.47 ( 1 H, d, J = 8.3 Hz ), 7.59 ( 1 H, d, J - 9.2 Hz ). -109- 201209056 Example 3 4

使用7 -甲氧基-2-側氧-2.H- ( 1，5 )萘啶-1-基）乙醛 7〇11^及2-(2,3-二氫苯並（1，4)戴奧辛-6-基）-2,6-重氮螺（3.5)-壬烷-1-酮83mg，藉由與實施例26之同樣操作，得到無色泡狀的1-(2-(2-(2，3-二氫苯並（1，4)戴奧辛-6-基）-1-側氧-2,6-重氮螺（3.5)壬-6-基）乙基）-7-甲氧基-1H- ( 1，5 )萘啶-2-酮 84mg。 1H NMR ( CHLOROFORM-d ) δ 1.8 0 - 1.8 5 ( 2 H, m) ,1.8 6 - 1.93 ( 2 H, m) , 2.08 - 2.14 ( 1 H, m) , 2.44 -2.55 ( 3 H, m) , 2.74 - 2.80 ( 1 H, m) , 2.85 - 2.91 ( 1 Η, m)，3.39 ( 1 H，d，J=6.0 Hz)，3.51 ( 1 H，d, J=5.5 Hz ),3.94 (3 H, s) , 4.19 - 4.27 (5 H, m) , 4.31 - 4.38 ( 1 H, m) , 6.74 ( 1 H, d, J=9.6 Hz) , 6.80 - 6.83 ( 1 H, m) ,6.85 - 6.90 ( 2 H, m) , 7.19( 1 H, d, J=2.3 Hz) , 7.84 (1 H, d, J = 9.6 Hz ) ，8.28 ( 1 H, d，J=2.3 Hz)。 -110 - 201209056 實施例3 5Using 7-methoxy-2-oxo-2.H-(1,5)naphthyridin-1-yl)acetaldehyde 7〇11^ and 2-(2,3-dihydrobenzo (1,4) Dioxin-6-yl)-2,6-diazospiro(3.5)-nonane-1-one 83 mg was obtained in the same manner as in Example 26 to give 1-(2-(2-). (2,3-Dihydrobenzo(1,4)dioxine-6-yl)-1-sideoxy-2,6-diazospiro(3.5)壬-6-yl)ethyl)-7-methoxy Base-1H-(1,5)naphthyridin-2-one 84 mg. 1H NMR ( CHLOROFORM-d ) δ 1.8 0 - 1.8 5 ( 2 H, m) , 1.8 6 - 1.93 ( 2 H, m) , 2.08 - 2.14 ( 1 H, m) , 2.44 -2.55 ( 3 H, m) , 2.74 - 2.80 ( 1 H, m) , 2.85 - 2.91 ( 1 Η, m), 3.39 ( 1 H,d,J=6.0 Hz), 3.51 ( 1 H,d, J=5.5 Hz ), 3.94 (3 H, s), 4.19 - 4.27 (5 H, m) , 4.31 - 4.38 ( 1 H, m) , 6.74 ( 1 H, d, J = 9.6 Hz) , 6.80 - 6.83 ( 1 H, m) , 6.85 - 6.90 ( 2 H, m) , 7.19 ( 1 H, d, J = 2.3 Hz) , 7.84 (1 H, d, J = 9.6 Hz ) , 8.28 ( 1 H, d, J = 2.3 Hz). -110 - 201209056 Example 3 5

使用（7-甲氧基-2-側氧-2H-喹啉-1-基）乙醛57mg及 3-(2,3-二氫苯並（1，4)戴奧辛-6-基）1-噁-3,8-重氮螺（ 4.5 )癸烷-2-酮76mg，藉由與實施例26之同樣操作，得到白色固體狀的1-(2-(3-(2，3-二氫苯並（1,4)戴奧辛- 6-基）-2-側氧-1-噁-3,8-重氮螺（4.5)癸烷-8-基）乙基）-7-甲氧基-1H-喹啉-2-酮49mg。 1H NMR ( CHLOROFORM-d) δ 1.85 - 1.91 ( 2 H，m) ,2.02 - 2.07 ( 2 H, m) , 2.75 ( 6 Η, m, J= 15.8, 8.0 Hz), 3.69(2 H, s ) , 3.92(3 H, s ) , 4.23 - 4.27 ( 4 H, m ), 4.39 - 4.43 ( 2 H, m) , 6.53 ( 1 H, d, J=9.6 Hz) , 6.83 ( 1 H, dd, J= 8.3, 2.1 Hz) , 6.85(1 H, d, J= 8.7 Hz), 6.87(1 H, d, J = 2. 1 Hz) , 6.99 ( 1 H, dd, J = 8.7, 2.8 Hz ),7.08 ( 1 H, d, J = 2.8 Hz )，7.47 ( 1 H, d, J=8.3 Hz) ,7.59 ( 1 H, d, J = 9.6 Hz )。 -111 - 201209056 實施例3 6Using (7-methoxy-2-oxo-2H-quinolin-1-yl)acetaldehyde 57 mg and 3-(2,3-dihydrobenzo(1,4)dioxin-6-yl)1- Ethylene-3,8-diazospiro(4.5)nonan-2-one 76 mg was obtained in the same manner as in Example 26 to give 1-(2-(3-(2,3-dihydro) as a white solid. Benzo(1,4)dioxin-6-yl)-2-oxo-oxo-3,8-diazospiro(4.5)decane-8-yl)ethyl)-7-methoxy- 1H-quinolin-2-one 49 mg. 1H NMR (CHLOROFORM-d) δ 1.85 - 1.91 ( 2 H,m) , 2.02 - 2.07 ( 2 H, m) , 2.75 ( 6 Η, m, J= 15.8, 8.0 Hz), 3.69(2 H, s ) , 3.92(3 H, s ) , 4.23 - 4.27 ( 4 H, m ), 4.39 - 4.43 ( 2 H, m) , 6.53 ( 1 H, d, J=9.6 Hz) , 6.83 ( 1 H, dd, J = 8.3, 2.1 Hz), 6.85 (1 H, d, J = 8.7 Hz), 6.87 (1 H, d, J = 2. 1 Hz), 6.99 ( 1 H, dd, J = 8.7, 2.8 Hz ), 7.08 ( 1 H, d, J = 2.8 Hz ), 7.47 ( 1 H, d, J = 8.3 Hz) , 7.59 ( 1 H, d, J = 9.6 Hz ). -111 - 201209056 Example 3 6

使用（7-甲氧基-2-側氧- 2H-(1，5)萘啶-1-基）乙醛 39mg及2-(2,3-二氫苯並（1，4)戴奧辛-6-基）-1-側氧-2,9-重氮螺（5.5)十一烷-1-酮的鹽酸鹽60mg，藉由與實施例29之同樣操作，得到淡黃色泡狀的1- ( 2- ( 2- ( 2,3-二氫苯並（1，4)戴奧辛-6-基）-1-側氧-2,9-重氮螺（5.5 )十一烷-9-基）乙基）-7-甲氧基-1Η-( 1,5)萘啶-2-酮 9 5 m g。 1H NMR ( DMSO-d6 ) δ 1.48(2 H, d, J = 11.0 Hz)， 1.82 (4 H, br. s.) , 1.94 - 2.03 (2 H, m) , 2.20 - 2.29 ( 2 H, m) , 2.53 - 2.59 (2 H, m) , 2.79(2 H, d, J=10.1 Hz)，3.49 ( 2 H，br. s. ) , 3 .99 ( 3 H, s )，4.23 ( 4 H，s) ，4.34 · 4.40 ( 2 H，m)，6_61 - 6.72 ( 3 H, m) , 6.81 ( 1 H, d, J = 8.7 Hz ) , 7.46 ( 1 H, d, J = 1.8 Hz) ,7.87(1 H, d, J = 9.6 Hz ) , 8.28 ( 1 H, br. s.)。 -112- 201209056 實施例3 7Using (7-methoxy-2-oxo-2H-(1,5)naphthyridin-1-yl)acetaldehyde 39 mg and 2-(2,3-dihydrobenzo(1,4)dioxin-6 -K-l-oxo-2,9-diazospiro(5.5) undecane-1-one hydrochloride 60 mg, obtained in the same manner as in Example 29 (2-(2-(2,3-dihydrobenzo(1,4)dioxo-6-yl)-1-oxo-2,9-diazospiro(5.5)undec-9-yl) Ethyl)-7-methoxy-1Η-(1,5)naphthyridin-2-one 9 5 mg. 1H NMR ( DMSO-d6 ) δ 1.48 (2 H, d, J = 11.0 Hz), 1.82 (4 H, br. s.) , 1.94 - 2.03 (2 H, m) , 2.20 - 2.29 ( 2 H, m ) , 2.53 - 2.59 (2 H, m) , 2.79 (2 H, d, J = 10.1 Hz), 3.49 ( 2 H, br. s. ) , 3 .99 ( 3 H, s ), 4.23 ( 4 H , s) , 4.34 · 4.40 ( 2 H, m), 6_61 - 6.72 ( 3 H, m) , 6.81 ( 1 H, d, J = 8.7 Hz ) , 7.46 ( 1 H, d, J = 1.8 Hz) , 7.87 (1 H, d, J = 9.6 Hz), 8.28 ( 1 H, br. s.). -112- 201209056 Example 3 7

使用 (7-年 i氧基-2- 側氧-2H- ( 1，5 ) -萘啶_ 1-基）乙酸 3 1 mg 及 1 ’ -(2, 3 -二氫苯並 (b ) ( 1,4 ) 戴奧辛 -6 -基 )- 8- 氮雜螺（聯環 (3.2.1 ) 辛 ¥烷-3,3’-吡咯烷）-5, -酮 37] mg > 藉由與實施例5 的第2步驟之同樣操作，得到白色固體狀的 1， -( 2,3- 二氫苯並（b ) ( 1，4)戴奧辛- 6-基）- 8-(2- •( 7- 甲氧基-2 -側氧_ -(1,5) 萘啶-1 ( 2H )-基）乙醯基） 8- 氮雜螺 (聯環（3 • 2.1 )辛烷 -3,3’-吡咯烷） -5，-酮: 5 4 m g 〇 1H NMR ( CHLOROFORM-d ) δ 1.83 丨-1.93 (2 Η, m ) 5 1.98(1 H, d, J= 3.7 Hz ) , 1.99 - 2.09 ( 4 H: ,m ), 2. 11 - 2.22 ( 1 H, m ),2.81 ( 2 H, d，J = 5.0 Hz), 3.45 ( 2 Η, d, J : =1.8 Hz ) ,3.96 ( 3 H，s)，4· 1 9 -4.29 ( 4 Η, m ), 4. 54 -4.6 丨1 ( 1 H, m ), 4. 69 - 4.74 ( 1 H, m ), 4.77 ( 1 Η, d， J : =16. 0 Hz ) ,5.27 ( 1 Η, d, J= 16.0 Hz), 6.76 ( 1 Η, d, J =9.6 Hz ) ,6.83 ( 1 Η, d, J= 8.7 Hz), 6.94 ( 1 Η, -113- 201209056 dd, J= 8.7, 2.3 Hz) , 7.07(1 H, d, J = 2.3 Hz) ,7.22(1 H, d, J = 2.3 Hz ) , 7.91 ( 1 H, d, J = 9.6 Hz ) , 8.29 ( 1 H, d, J= 2.3 Hz )。實施例3 8Use (7-year ioxy-2-oxo-2H-(1,5)-naphthyridin-1-yl)acetic acid 3 1 mg and 1 '-(2,3-dihydrobenzo(b) ( 1,4) Dioxin-6-yl)- 8-azaspiro (bicyclo(3.2.1) octane-3,3'-pyrrolidine)-5, -ketone 37] mg > The same procedure as in the second step of Example 5 gave 1-(2,3-dihydrobenzo(b)(1,4)dioxin-6-yl)- 8-(2- •(7) as a white solid. - methoxy-2-oxo-oxy-(1,5)naphthyridin-1(2H)-yl)ethenyl) 8-azaspiro(bicyclo(3 • 2.1)octane-3,3' -pyrrolidine) -5,-one: 5 4 mg 〇1H NMR (CHLOROFORM-d ) δ 1.83 丨-1.93 (2 Η, m ) 5 1.98 (1 H, d, J= 3.7 Hz ) , 1.99 - 2.09 ( 4 H: , m ), 2. 11 - 2.22 ( 1 H, m ), 2.81 ( 2 H, d, J = 5.0 Hz), 3.45 ( 2 Η, d, J : =1.8 Hz ) , 3.96 ( 3 H ,s),4·1 9 -4.29 ( 4 Η, m ), 4. 54 -4.6 丨1 ( 1 H, m ), 4. 69 - 4.74 ( 1 H, m ), 4.77 ( 1 Η, d, J : =16. 0 Hz ) , 5.27 ( 1 Η, d, J = 16.0 Hz), 6.76 ( 1 Η, d, J = 9.6 Hz ) , 6.83 ( 1 Η, d, J = 8.7 Hz), 6.94 ( 1 Η, -113- 201209056 Dd, J= 8.7, 2.3 Hz), 7.07 (1 H, d, J = 2.3 Hz), 7.22 (1 H, d, J = 2.3 Hz), 7.91 ( 1 H, d, J = 9.6 Hz ) , 8.29 ( 1 H, d, J = 2.3 Hz ). Example 3 8

使用（7-甲氧基-2-側氧- 2H- ( 1，5 )萘啶-1-基）乙醛 36mg及 l’-(2,3-二氫苯並（b) (1，4)戴奧辛-6-基）-8- 氮雜螺（聯環（3.2.1 )辛烷-3,3’-吡咯烷）-5’-酮52mg，藉由與實施例26之同樣操作，得到泡狀的1 ’-( 2,3-二氫苯並（b) (1，4)戴奧辛-6-基）-8-(2-(7-甲氧基-2-側氧- (l,5)-萘啶-l(2H)-基）乙基）-8-氮雜螺（聯環（ 3.2.1)辛烷·3,3’_吡咯烷）-5’-酮 60mg。 1H NMR ( CHLOROFORM-d ) δ 1.69 - 1.81 ( 4 H, m) ,1.89 ( 2 Η, dd, J = 13.8, 3.2 Hz) , 1.92 - 2.03 ( 2 H, m) ,2.62 - 2.74 (4 H, m) , 3.36 (2 H, br. s.) , 3.45 (2 H, s -114- 201209056 )，3.98 ( 3 H，s)，4·20 - 4.27 ( 4 H，m)，4.34 ( 2 H，t， J= 7.3 Hz)，6.75 ( l h，d，J= 9.6 Hz)，6.83 ( 1 H，d，J =8.7 Hz)，6.97 ( 1 H，dd，J= 8.7，2.3 Hz)，7.08 ( 1 H， d，J=2.3 Hz)，7.25 ( 1 H，d，J=2.3 Hz)，7.85 ( 1 H，d， J=9.6 Hz)，8.28 ( 1 H，d，J=2.3 Hz)。實施例3 9 HQ>。Using (7-methoxy-2-oxo-2H-(1,5)-naphthyridin-1-yl)acetaldehyde 36 mg and l'-(2,3-dihydrobenzo(b) (1,4) Dioxin-6-yl)-8-azaspiro(bicyclo(3.2.1)octane-3,3'-pyrrolidine)-5'-one 52 mg, obtained by the same operation as in Example 26 Bubbly 1 '-( 2,3-dihydrobenzo (b) (1,4) dioxin-6-yl)-8-(2-(7-methoxy-2-sideoxy-(l, 5)-Naphthyridine-l(2H)-yl)ethyl)-8-azaspiro(bicyclo(3.2.1)octane·3,3'-pyrrolidine)-5'-one 60 mg. 1H NMR ( CHLOROFORM-d ) δ 1.69 - 1.81 ( 4 H, m) , 1.89 ( 2 Η, dd, J = 13.8, 3.2 Hz) , 1.92 - 2.03 ( 2 H, m) , 2.62 - 2.74 (4 H, m) , 3.36 (2 H, br. s.) , 3.45 (2 H, s -114- 201209056 ), 3.98 ( 3 H,s), 4·20 - 4.27 ( 4 H,m), 4.34 ( 2 H , t, J = 7.3 Hz), 6.75 ( lh, d, J = 9.6 Hz), 6.83 ( 1 H, d, J = 8.7 Hz), 6.97 ( 1 H, dd, J = 8.7, 2.3 Hz), 7.08 ( 1 H, d, J = 2.3 Hz), 7.25 ( 1 H, d, J = 2.3 Hz), 7.85 ( 1 H, d, J = 9.6 Hz), 8.28 ( 1 H, d, J = 2.3 Hz) . Example 3 9 HQ>.

將（7-氟-2-側氧- 2H- ( 1，5 )萘啶-1-基）乙醛26mg懸浮於氯仿2mL’加入三乙胺〇.01mL，在室溫進行35分鐘攪拌。加入3-(2,3-二氫_( ι，4)二噁並（2,3-c)吡啶-7-基 )-1-噁-3,8-重氮螺（4.5)癸烷-2-酮31mg之氯仿溶液lmL 。在室溫進行16小時攪拌後，加入三乙酸基氫化硼鈉48mg ，進行2.5小時攪拌。加入飽和碳酸氫鈉水溶液3mL及氯仿 5mL，分離並取出有機層。將有機層以飽和氯化鈉水溶液 5 mL洗淨，以無水硫酸鎂乾燥，減壓下將溶劑餾去。將所得之殘餾物以分取用矽膠薄層層析法NH型〔FUJI SILYSIA株式会公司製PLC盤NH、展開液；乙酸乙酯）〕進行純化，得到白色固體狀的1- ( 2- ( 3- ( 2,3-二氫-(1，4 -115- 201209056 )B惡並（2,3-c)卩比陡-7-基）-2-側氧-1-D惡- 3,8-重氛螺（ 4.5)癸烷-8-基）乙基）-7-氟-1H-(1，5)萘啶-2·酮 21mg 〇 1H NMR ( CHLOROFORM-d ) δ 1.82 - 1.8 8 ( 2 H, m) ,2.01 ( 2 Η, dt, J = 13.4, 3.6 Hz) , 2.69 - 2.78 ( 6 H, m) ,3.93 ( 2 H, s) , 4.25 - 4.28 ( 2 H, m) , 4.33 ( 4 H, dt, J = 3.8, 2.0 Hz) , 6.87 ( 1 H, d, J-9.6 Hz) , 7.48 ( 1 H, dd, J = 10.1, 1 .8 Hz)，7.76(1 H, s ) , 7.86(1 H, s ), 7.89 ( 1 H, d, J = 9.6 Hz ) , 8.43 ( 1 H, d, J = 1.8 Hz)。實施例4 026 mg of (7-fluoro-2-oxo-2H-(1,5)-naphthyridin-1-yl)acetaldehyde was suspended in 2 mL of chloroform to add triethylamine oxime. 01 mL, and stirred at room temperature for 35 minutes. Add 3-(2,3-dihydro-((,4)dioxin(2,3-c)pyridin-7-yl)-1-oxo-3,8-diazaspiro(4.5)decane- 2-ketone 31 mg of chloroform solution 1 mL. After stirring at room temperature for 16 hours, 48 mg of sodium triacetate triborohydride was added, and the mixture was stirred for 2.5 hours. 3 mL of a saturated aqueous sodium hydrogencarbonate solution and 5 mL of chloroform were added, and the organic layer was separated and taken. The organic layer was washed with 5 mL of saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The obtained residue was purified by silica gel thin-layer chromatography NH ([PLC, NH, developed from FUJI SILYSIA Co., Ltd., developing solution; ethyl acetate) to obtain 1-(2- ( 3- ( 2,3-dihydro-(1,4 -115- 201209056 ) B oxo (2,3-c) oxime ratio steep-7-yl)-2-side oxy-1-D oxa-3 ,8-heavy snail (4.5)decane-8-yl)ethyl)-7-fluoro-1H-(1,5)naphthyridin-2-one ketone 21 mg 〇1H NMR (CHLOROFORM-d ) δ 1.82 - 1.8 8 ( 2 H, m) , 2.01 ( 2 Η, dt, J = 13.4, 3.6 Hz) , 2.69 - 2.78 ( 6 H, m) , 3.93 ( 2 H, s) , 4.25 - 4.28 ( 2 H, m) , 4.33 ( 4 H, dt, J = 3.8, 2.0 Hz) , 6.87 ( 1 H, d, J-9.6 Hz) , 7.48 ( 1 H, dd, J = 10.1, 1. 8 Hz), 7.76 (1 H , s ) , 7.86(1 H, s ), 7.89 ( 1 H, d, J = 9.6 Hz ) , 8.43 ( 1 H, d, J = 1.8 Hz). Example 4 0

使用（7-氟-2-側氧- 2H- ( 1,5 )萘啶-1-基）乙酸的鹽酸鹽36mg及2-(2,3-二氫-苯並（1，4)戴奧辛-6-基）-3-側氧-2,8-重氮螺（4.5)癸烷-3-酮33mg，藉由與實施例3之同樣操作，得到無色粉末狀的1- ( 2- ( 2- ( 2,3-二氫苯並 (b ) ( 1,4)戴奧辛-6-基）-3-側氧-2,8-重氮螺（4_5)癸烷-8-基）-2-氧代乙基）-7-氟-1H- ( 1，5 )萘啶-2-酮 2 5.2 m g ° 1H NMR ( CHLOROFORM-d) δ 1.72 - 1.77 ( 2 Η, m ) ,1.84 - 1.89(2 Η，m)，2.58(2 Η，s)，3.40 - 3.45 (1 -116- 201209056 H, m) , 3.57 - 3.62( 1 Η, m) , 3.65(2 Η, s) , 3.76 -3.81 ( 1 Η, m) , 3.8 8 - 3.94 ( 1 Η, m) , 4.24 - 4.28 ( 4 Η, in) , 4.96 ( 1 Η, d, J= 16.0 Hz) , 5.16 ( 1 Η, d, J= 16.5Using (7-fluoro-2-oxo-2H-(1,5)-naphthyridin-1-yl)acetic acid hydrochloride 36 mg and 2-(2,3-dihydro-benzo(1,4) dioxin -6-yl)-3-oxo-2,8-diazospiro(4.5)nonan-3-one 33 mg was obtained in the same manner as in Example 3 to give 1- (2-) 2-( 2,3-Dihydrobenzo(b ) ( 1,4) Dioxin-6-yl)-3-oxo-2,8-diazospiro(4_5)decane-8-yl)-2 -oxoethyl)-7-fluoro-1H-(1,5)naphthyridin-2-one 2 5.2 mg ° 1H NMR (CHLOROFORM-d) δ 1.72 - 1.77 ( 2 Η, m ) , 1.84 - 1.89 ( 2 Η,m), 2.58(2 Η,s), 3.40 - 3.45 (1 -116- 201209056 H, m) , 3.57 - 3.62( 1 Η, m) , 3.65(2 Η, s) , 3.76 -3.81 ( 1 Η, m) , 3.8 8 - 3.94 ( 1 Η, m) , 4.24 - 4.28 ( 4 Η, in) , 4.96 ( 1 Η, d, J = 16.0 Hz) , 5.16 ( 1 Η, d, J= 16.5

Hz) , 6.86 - 6.89 ( 2 H, m ) , 7.02 ( 1 H, dd, J= 8.7, 2.8Hz) , 6.86 - 6.89 ( 2 H, m ) , 7.02 ( 1 H, dd, J= 8.7, 2.8

Hz) , 7.13(1 H, d, J= 2.8 Hz)，7.24 ( 1 H, dd, J= 9.9, 2.1 Hz) , 7.95(1 H, d, J= 9.6 Hz ) ， 8.43 ( 1 H, d, J = 2.1 Hz )。實施例4 1Hz) , 7.13 (1 H, d, J = 2.8 Hz), 7.24 ( 1 H, dd, J = 9.9, 2.1 Hz) , 7.95 (1 H, d, J = 9.6 Hz ) , 8.43 ( 1 H, d , J = 2.1 Hz). Example 4 1

使用（7-氟-2-側氧- 2H- ( 1,5 )萘啶-1-基）乙醛的鹽酸鹽37mg及2-(2,3-二氫-苯並（1，4)戴奧辛-6-基）-3-側氧-2,8-重氮螺（4.5)癸烷-3-酮44mg，藉由與實施例39之同樣操作，得到無色粉末狀的1- ( 2- ( 2- ( 2,3-二氫苯並 (1,4)戴奧辛-6-基）-3-側氧-2,8-重氮螺（4.5)癸烷- 8-基）乙基）-7-氟-1H-(1，5)萘啶-2-酮 31.4mg。 1H NMR ( CHLOROFORM-d ) δ 1.71 ( 4 H, t, J= 5.3 Hz) , 2.46(2 H, s ) , 2.50 - 2.55 (2 H, m) , 2.59 - 2.62 (2 H, m) , 3.56(2 H, s) , 4.22 - 4.26(4 H, m) , 4.32 -117 - 201209056 (2 H, t，J=6.9 Hz)，6.82 - 6·87 (2 H, m)，7.02 ( 1 H， dd, J = 8.7, 2.8 Hz )，7.12(1 H, d, J = 2.8 Hz ) , 7.49 ( 1 H, d, J= 10.1 Hz) , 7.88 ( 1 H, d, J= 10.1 Hz) , 8.42 ( 1 H, d, J = 2.3 Hz )。實施例4 2Using (7-fluoro-2-oxo-2H-(1,5)-naphthyridin-1-yl)acetaldehyde hydrochloride 37 mg and 2-(2,3-dihydro-benzo(1,4) Dioxin-6-yl)-3-oxo-2,8-diazospiro(4.5)nonan-3-one 44 mg was obtained in the same manner as in Example 39 to give 1-(2- (2-( 2,3-Dihydrobenzo(1,4)dioxin-6-yl)-3-oxo-2,8-diazospiro(4.5)decane-8-yl)ethyl)- 7-Fluoro-1H-(1,5)naphthyridin-2-one 31.4 mg. 1H NMR ( CHLOROFORM-d ) δ 1.71 ( 4 H, t, J = 5.3 Hz) , 2.46 (2 H, s ) , 2.50 - 2.55 (2 H, m) , 2.59 - 2.62 (2 H, m) , 3.56 (2 H, s) , 4.22 - 4.26(4 H, m) , 4.32 -117 - 201209056 (2 H, t, J=6.9 Hz), 6.82 - 6·87 (2 H, m), 7.02 ( 1 H , dd, J = 8.7, 2.8 Hz ), 7.12 (1 H, d, J = 2.8 Hz ) , 7.49 ( 1 H, d, J = 10.1 Hz) , 7.88 ( 1 H, d, J = 10.1 Hz) , 8.42 ( 1 H, d, J = 2.3 Hz ). Example 4 2

使用3- ( 7-氟-2-側氧-2H- ( 1,5 )萘啶-1-基）丙醛 150mg 及 3-(2,3-二氫苯並（1，4)戴奧辛-6-基）-1-噁-3,8-重氮螺（4.5)癸烷-2-酮186mg，藉由與實施例26之同樣操作，得到無色固體狀的1- ( 3- ( 3- ( 2,3-二氫苯並（1，4 )戴奧辛-6-基）-2-側氧-1-噁-3,8-重氮螺（4.5)癸烷-8-基）丙基）-7-氟-1H-(1，5)萘啶-2-酮 42mg。 1H NMR ( CHLOROFORM-d ) δ 1.60(2 Η, br. s.), 1.91 - 2.00 (4 Η, m) , 2.10 - 2.12 (2 Η, m) , 2.49 - 2.51 (2 Η, m) , 2.65(4 Η, br. s.) , 3.75(2 Η, s) , 4.27 - 4.34(4 Η, m) , 6.90(2 Η, t, J=8.9 Hz) , 7.04(1 Η, dd, J=8.9, 2.5 Hz) , 7.12 ( 1 H, d, J=2.8 Hz) , 7.83 ( 1 H, d, J=10.5 Hz) , 7.93(1 H, d, J=9.6 Hz) , 8.46 (1 H, d, J = 2.3 Hz )。 -118- 201209056 實施例43Using 3-( 7-fluoro-2-oxo-2H-( 1,5 )naphthyridin-1-yl)propanal 150 mg and 3-(2,3-dihydrobenzo(1,4)dioxin-6 1-(3-(3-)(3-(3-(3-(3-(3-(((((((((((((((((((((((((((((( 2,3-Dihydrobenzo(1,4)dioxin-6-yl)-2-oxo-oxo-oxa-3,8-diazospiro(4.5)decane-8-yl)propyl)- 7-Fluoro-1H-(1,5)naphthyridin-2-one 42 mg. 1H NMR ( CHLOROFORM-d ) δ 1.60(2 Η, br. s.), 1.91 - 2.00 (4 Η, m) , 2.10 - 2.12 (2 Η, m) , 2.49 - 2.51 (2 Η, m) , 2.65 (4 Η, br. s.) , 3.75(2 Η, s) , 4.27 - 4.34(4 Η, m) , 6.90(2 Η, t, J=8.9 Hz) , 7.04(1 Η, dd, J= 8.9, 2.5 Hz), 7.12 ( 1 H, d, J = 2.8 Hz), 7.83 ( 1 H, d, J = 10.5 Hz), 7.93 (1 H, d, J = 9.6 Hz), 8.46 (1 H, d, J = 2.3 Hz). -118- 201209056 Example 43

使用（2- ( 3-甲氧基-6-側氧- 6H-吡啶並（2,3-b )吡嗪-5-基）乙酸的鹽酸鹽11 6mg及3- (2,3-二氫苯並（1，4) 戴奧辛-6-基）-1-噁-3,8-重氮螺（4.5)癸烷-2-酮11611^，藉由與實施例3之同樣操作，得到無色粉末狀的3- ( 2,3-二氫苯並（b) (1,4)戴奧辛-6-基）-8-(2-(3-甲氧基- 6- 側氧-6H-吡啶並（2,3-b)吡嗪_5_基）乙醯基）-1-噁-3,8-重氮螺（4.5)癸院-2-酮183mg。 1H NMR ( CHLOROFORM-d ) δ 1.79 - 1.8 6 ( 2 H, m) ,2.00 - 2.07(2 Η, m) , 2.14 - 2.19(1 Η, m) , 3.21 -3.25 ( 1 Η，m)，3.70 - 3.77 ( 3 Η，m)，4.00 ( 3 Η, s)， 4.22 - 4.28 ( 4 Η, m) , 4.42 - 4.44 ( 1 Η, m) , 5.25 - 5.31 (2 Η, m )，6.78 ( 1 Η，d，J=9.6 Hz) ,6.86(1 Η，d，J = 8.7 Hz ) , 6.97 ( 1 H, dd, J= 8.9, 2.5 Hz) , 7.07 ( 1 H, d, J = 2.8 Hz ) , 7.91 ( 1 H, d, J= 9.6 Hz ) , 8. 1 1 ( 1 H, s )。 -119- 201209056 實施例44Using (2-(3-methoxy-6-oxo-6H-pyrido(2,3-b)pyrazine-5-yl)acetic acid hydrochloride, 11 6 mg and 3- (2, 3-) Hydrogen benzo (1,4) dioxin-6-yl)-1-oxo-3,8-diazospiro(4.5)nonan-2-one 11611^, obtained by the same procedure as in Example 3 Powdered 3-(2,3-dihydrobenzo(b)(1,4)dioxin-6-yl)-8-(2-(3-methoxy-6-oxo-6H-pyridine) (2,3-b)pyrazine-5-yl)ethenyl)-1-oxo-3,8-diazospiro (4.5) oxacin-2-one 183 mg. 1H NMR (CHLOROFORM-d) δ 1.79 - 1.8 6 ( 2 H, m) , 2.00 - 2.07(2 Η, m) , 2.14 - 2.19(1 Η, m) , 3.21 -3.25 ( 1 Η,m), 3.70 - 3.77 ( 3 Η,m), 4.00 ( 3 Η, s), 4.22 - 4.28 ( 4 Η, m) , 4.42 - 4.44 ( 1 Η, m) , 5.25 - 5.31 (2 Η, m ), 6.78 ( 1 Η, d, J = 9.6 Hz) , 6.86 (1 Η, d, J = 8.7 Hz), 6.97 ( 1 H, dd, J = 8.9, 2.5 Hz) , 7.07 ( 1 H, d, J = 2.8 Hz ) , 7.91 ( 1 H, d, J = 9.6 Hz ) , 8. 1 1 ( 1 H, s ). -119- 201209056 Example 44

使用2- ( 7-甲氧基-2-側氧- 2H- ( 1，5 )萘啶-1-基）乙醛 46mg及 3-(2,3-二氫-(1，4)二噁並（2,3-b)吡啶-6-基 )-1-噁-3,8-重氮螺（4.5)癸烷-2-酮61mg，藉由與實施例 26之同樣操作，得到無色泡狀的3- ( 2,3-二氫-(1，4 )二噁並（2,3 · b )吡啶-6 -基）-8 - ( 2 - ( 7 -甲氧基-2 -側氧-2 Η -(1，5)萘啶-1-基）乙基）-1-噁-3,8-重氮螺（4_5)癸烷-2 -酮 6 0 m g。 1H NMR ( CHLOROFORM-d) δ 1.8 3 - 1.8 8 ( 2 H，m) ,1.98 - 2.04 (2 H, m) , 2.69 - 2.78 ( 6 H, m) , 3.94(2 H, s) , 3.98 ( 3 H, s) , 4.22 - 4.2 5 ( 2 H, m) , 4.36 - 4.38 ( 2 H, m) , 4.42 - 4.43 ( 2 H, m) , 6.74 ( 1 H, d, J = 9.6 Hz) , 7.16 ( 1 H, d, J= 1.8 Hz) , 7.2 3 - 7.26 ( 1 H, m ),7.76 ( 1 H, d, J= 8.7 Hz ) , 7.84 ( 1 H, d, J = 9.6 Hz ) ,8.28 ( 1 H, d, J - 2.3 Hz )。 -120- 201209056 實施例45Using 2-( 7-methoxy-2-oxo- 2H-( 1,5 )naphthyridin-1-yl)acetaldehyde 46 mg and 3-(2,3-dihydro-(1,4) dioxins (2,3-b)pyridin-6-yl)-1-oxo-3,8-diazaspiro(4.5)nonan-2-one 61 mg, obtained by the same procedure as in Example 26 3-(2,3-Dihydro-(1,4)dioxin and (2,3 · b)pyridin-6-yl)-8 - ( 2 - ( 7 -methoxy-2- - side oxygen) -2 Η -(1,5)Naphthyridin-1-yl)ethyl)-1-oxo-3,8-diazospiro(4-5)nonane-2-one 6 0 mg. 1H NMR (CHLOROFORM-d) δ 1.8 3 - 1.8 8 ( 2 H,m) , 1.98 - 2.04 (2 H, m) , 2.69 - 2.78 ( 6 H, m) , 3.94 (2 H, s) , 3.98 ( 3 H, s) , 4.22 - 4.2 5 ( 2 H, m) , 4.36 - 4.38 ( 2 H, m) , 4.42 - 4.43 ( 2 H, m) , 6.74 ( 1 H, d, J = 9.6 Hz) , 7.16 ( 1 H, d, J = 1.8 Hz) , 7.2 3 - 7.26 ( 1 H, m ), 7.76 ( 1 H, d, J = 8.7 Hz ) , 7.84 ( 1 H, d, J = 9.6 Hz ), 8.28 ( 1 H, d, J - 2.3 Hz ). -120- 201209056 Example 45

使用（7-甲氧基-2-側氧-2H- ( 1,5 )萘啶-1-基）乙酸的鹽酸鹽5 7mg及3-(2,3-二氫-(1,4)二噁並（2,3-b)吡啶-6-基）-1-噁-3,8-重氮螺（4.5)癸烷-2-酮61mg，藉由與實施例3之同樣操作，得到淡黃色粉末狀的3- ( 2,3-二氫- (1，4)二噁並（2,3-b)吡啶-6-基）-8-(2-(7-甲氧基-2-側氧-2H- ( 1，5 )萘啶-1-基）乙醯基）-1-噁- 3,8-重氮螺（4.5 )癸烷-2-酮 59mg。 1H NMR ( DMSO-d6 ) 5 1.77 - 1.8 7 ( 2 H, m) , 2.01 -2.05 ( 2 H, m) , 3.21 - 3.22 ( 1 H, m) , 3.5 9 - 3.64 ( 1 Η, m) , 3.82 - 3.8 5 ( 3 H, m) , 3.90 - 3.92 ( 1 H, m) , 3.92 (3 H, s)，4.19 - 4.22 (2 Η，m)，4.36 - 4.39 (2 H, m)， 5.15 - 5.21 ( 1 H, m) , 5.25 - 5.31 ( 1 H, m) , 6.66 ( 1 Η, d，J=9_6 Hz)，7.20 ( 1 H，d，J = 1.8 Hz)，7_36 ( 1 H，d， J=8.7 Hz) , 7.57 ( 1 H, d, J=8.7 Hz) , 7.89 ( 1 H, d, J = 9.6 Hz) , 8.27 ( 1 H, d, J = 1.8 Hz)。 201209056 實施例4 6Using (7-methoxy-2-oxo-2H-(1,5)-naphthyridin-1-yl)acetic acid hydrochloride 5 7 mg and 3-(2,3-dihydro-(1,4) Dioxo(2,3-b)pyridin-6-yl)-1-oxo-3,8-diazospiro(4.5)nonan-2-one 61 mg was obtained by the same operation as in Example 3. 3-(2,3-Dihydro-(1,4)dioxin(2,3-b)pyridine-6-yl)-8-(2-(7-methoxy-2) as a pale yellow powder - Side oxy-2H-(1,5)naphthyridin-1-yl)ethenyl)-1-oxo-3,8-diazospiro(4.5)nonan-2-one 59 mg. 1H NMR ( DMSO-d6 ) 5 1.77 - 1.8 7 ( 2 H, m) , 2.01 -2.05 ( 2 H, m) , 3.21 - 3.22 ( 1 H, m) , 3.5 9 - 3.64 ( 1 Η, m) , 3.82 - 3.8 5 ( 3 H, m) , 3.90 - 3.92 ( 1 H, m) , 3.92 (3 H, s), 4.19 - 4.22 (2 Η, m), 4.36 - 4.39 (2 H, m), 5.15 - 5.21 ( 1 H, m) , 5.25 - 5.31 ( 1 H, m) , 6.66 ( 1 Η, d, J=9_6 Hz), 7.20 ( 1 H,d,J = 1.8 Hz), 7_36 ( 1 H, d, J = 8.7 Hz), 7.57 ( 1 H, d, J = 8.7 Hz), 7.89 ( 1 H, d, J = 9.6 Hz) , 8.27 ( 1 H, d, J = 1.8 Hz). 201209056 Example 4 6

使用2- ( 6-側氧- 6H-吡啶並（3,2-d )嘧啶-5-基）乙酸的鹽酸鹽10211^及3-(2,3-二氫苯並（1，4)戴奧辛-6-基）-1-噁-3,8-重氮螺（4.5)癸烷-2-酮135mg，藉由與實施例3 之同樣操作，得到淡黃色粉末狀的3_ (2,3 -二氫苯並（b) (1，4 )戴奧辛-6 -基）-8 - ( 2 - ( 6 -側氧-6 Η -吡啶並（3，2 - d )嘧啶-5-基）乙醯基）-1-噁-3,8-重氮螺（4.5)癸烷-2-酮 1 5 8 m g 〇 lHNMR(DMSO-d6)S 1.75 - 1.83 (lH，m)，1.84-1.90 ( 1 H, m) , 2.02 - 2.06 ( 2 H, m) , 3.5 9 - 3.65 ( 1 Η, m) , 3.78 - 3.82 ( 3 H, m) , 3.83 - 3.88 ( 2 H, m) , 4.19 - 4.22 ( 4 H, m) , 5.21 - 5.34 ( 2 H, m) , 6.85 ( 1 H, d, J = 8.7 Hz) , 6.98 ( 1 H, dd, J=8.7, 2.3 Hz) , 7.09 - 7.15 ( 2 H, m ) , 7.98 ( 1 H, d, J = 9.6 Hz ) , 9.03 ( 1 H, s )，9.05 (1 H, s)。 -122 - 201209056 實施例47Using 2-(6-oxo-6H-pyrido(3,2-d)pyrimidin-5-yl)acetic acid hydrochloride 10211^ and 3-(2,3-dihydrobenzo(1,4) Dioxin-6-yl)-1-oxo-3,8-diazaspiro(4.5)nonan-2-one 135 mg was obtained in the same manner as in Example 3 to give 3 (2,3) as pale yellow powder. -Dihydrobenzo (b) (1,4) Dioxin-6-yl)-8 - ( 2 - ( 6 - side oxo-6 Η -pyrido(3,2 - d )pyrimidin-5-yl) Mercapto)-1-oxo-3,8-diazospiro(4.5)decane-2-one 1 5 8 mg 〇lHNMR(DMSO-d6)S 1.75 - 1.83 (lH,m),1.84-1.90 ( 1 H, m) , 2.02 - 2.06 ( 2 H, m) , 3.5 9 - 3.65 ( 1 Η, m) , 3.78 - 3.82 ( 3 H, m) , 3.83 - 3.88 ( 2 H, m) , 4.19 - 4.22 ( 4 H, m) , 5.21 - 5.34 ( 2 H, m) , 6.85 ( 1 H, d, J = 8.7 Hz) , 6.98 ( 1 H, dd, J=8.7, 2.3 Hz) , 7.09 - 7.15 ( 2 H , m ) , 7.98 ( 1 H, d, J = 9.6 Hz ) , 9.03 ( 1 H, s ), 9.05 (1 H, s). -122 - 201209056 Example 47

將（7 -甲氧基-2-側氧-2H- ( 1，5 )萘啶-1-基）乙酸 22mg及3-(3-氟-4-甲基苯基）-1-噁-3,8-重氮螺（4.5)癸烷-2-酮2 6mg懸浮於氯仿10mL，加入三乙胺65μί、1-乙基-3-(3-二甲基胺基丙基）碳化二亞胺鹽酸鹽2 8mg及1-羥基苯並三唑1水合物4mg，在室溫進行1 8小時攪拌。將反應混合物以乙酸乙酯lOOmL稀釋，以水10mL、飽和食鹽水 1 OmL之順序洗淨，以無水硫酸鎂乾燥，減壓下將溶劑餾去。將所得之殘餾物以矽膠管柱層析法〔矽膠；FUJI SILYSIA股份有限公司，Chromatorex-NH，溶離液：氯仿〕進行純化。進一步於純化物加入氯仿10mL及己烷15 OmL ，過濾取出析出物並乾燥後得到白色固體狀的3- ( 3 _氟-4-甲基苯基）-8-(2-(7-甲氧基-2-側氧-2H-(1，5)萘啶-1-基）乙酿基）-1-卩惡-3,8 -重氮螺（4.5)癸院-2-嗣22mg。 1H NMR ( CHLOROFORM-d ) δ 1.70 - 1.74 ( 1 H, m ) ,1.77 - 1.79 ( 1 Η, m) , 1.95 - 2.05 (2 Η, m) , 2.21 (3 Η, s) , 3.17 - 3.27 (4 Η, m) , 3.66 - 3.76(2 Η, m), 3.95 ( 3 Η, s) , 4.72 ( 1 Η, d, J= 16.1 Hz) , 5.45 ( 1 Η, d，J=16.1 Hz )，6.75 ( 1 H, d, J=9.9 Hz) , 7.07 ( 1 H, d, J = 1.7 Hz ) , 7.08 ( 1 H, d, J = 2.1 Hz ) , 7.14 - 7.18 ( 1(7-Methoxy-2-oxo-2H-(1,5)naphthyridin-1-yl)acetic acid 22 mg and 3-(3-fluoro-4-methylphenyl)-1-oxo-3 , 8-diazospiro (4.5) decane-2-one 2 6 mg suspended in 10 mL of chloroform, added with triethylamine 65 μί, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide 2 mg of the hydrochloride salt and 4 mg of 1-hydroxybenzotriazole monohydrate were stirred at room temperature for 18 hours. The reaction mixture was diluted with 100 mL of ethyl acetate, washed with water (10 mL) and brine (1 mL), dried over anhydrous magnesium sulfate and evaporated. The obtained residue was purified by silica gel column chromatography (gum, FUJI SILYSIA Co., Ltd., Chromatorex-NH, eluent: chloroform). Further, 10 mL of chloroform and 15 mL of hexane were added to the purified product, and the precipitate was filtered and dried to give 3-(3-fluoro-4-methylphenyl)-8-(2-(7-methoxy) as a white solid. Keto-2-oxo-2H-(1,5)naphthyridin-1-yl)ethidyl)-1-oxo-3,8-diazospiro (4.5) brothel-2-嗣22 mg. 1H NMR ( CHLOROFORM-d ) δ 1.70 - 1.74 ( 1 H, m ) , 1.77 - 1.79 ( 1 Η, m) , 1.95 - 2.05 (2 Η, m) , 2.21 (3 Η, s) , 3.17 - 3.27 ( 4 Η, m) , 3.66 - 3.76(2 Η, m), 3.95 ( 3 Η, s) , 4.72 ( 1 Η, d, J = 16.1 Hz) , 5.45 ( 1 Η, d, J = 16.1 Hz ), 6.75 ( 1 H, d, J = 9.9 Hz) , 7.07 ( 1 H, d, J = 1.7 Hz ) , 7.08 ( 1 H, d, J = 2.1 Hz ) , 7.14 - 7.18 ( 1

H, m) , 7.35 ( 1 H, dd, J= 11.6, 2.1 Hz) , 7.91 ( 1 H, d, J -123- 201209056 = 9.9 Hz ) , 8.28 ( 1 H, d, J=2.5 Hz)。實施例4 8H, m), 7.35 ( 1 H, dd, J = 11.6, 2.1 Hz), 7.91 ( 1 H, d, J -123- 201209056 = 9.9 Hz ) , 8.28 ( 1 H, d, J = 2.5 Hz). Example 4 8

使用2- ( 7-甲氧基-2-側氧-2H- ( 1，5 )萘啶-1-基）乙醛 62mg 及 3-(2,3-二氫-(1，4)二噁並（2,3-c)吡啶-7-基 )-1-噁-3,8-重氮螺（4.5)癸烷-2-酮85mg，藉由與實施例 26之同樣操作，得到無色固體狀的3- ( 2,3-二氫-(1，4 ) —B惡並（2,3-c) titfcD定-7-基）-8- ( 2- ( 7 -甲氧基-2-側氧_ 2H- ( 1，5 )萘啶-1-基）乙基）-1-噁- 3,8-重氮螺（4.5 )癸院-2-酮 9 5mg。 1H NMR ( CHLOROFORM-d ) δ 1.8 2 - 1.8 8 ( 2 H, m) ,1.98 - 2.03 (2 H, m) , 2.69 - 2.78 (6 H, m) , 3.93 (2 H, s) , 3.97(3 H, s) , 4.24 - 4.27 ( 2 H, m) , 4.31 - 4.34 (2 H, m) , 4.37 (2 H, t, J=7.0 Hz) , 6.74 ( 1 H, d, J = 9.5 Hz)，7.15(1 H，d，J = 2. 1 Hz)，7.75(1 H, s )， 7.82 - 7.87 ( 2 H, m) , 8.28 ( 1 H, d, J=2.5 Hz)。 -124- 201209056 實施例4 9Using 2-( 7-methoxy-2-oxo-2H-( 1,5 )naphthyridin-1-yl)acetaldehyde 62 mg and 3-(2,3-dihydro-(1,4) dioxins And (2,3-c)pyridin-7-yl)-1-oxo-3,8-diazaspiro(4.5)nonan-2-one 85 mg, obtained as a colorless solid. 3-(2,3-Dihydro-(1,4)-Boxo(2,3-c) titfcD-dec-7-yl)-8-(2-(7-methoxy-2-) Side Oxygen_2H-(1,5)Naphthyridin-1-yl)ethyl)-1-oxo-3,8-diazospiro (4.5) oxacin-2-one 9 5 mg. 1H NMR ( CHLOROFORM-d ) δ 1.8 2 - 1.8 8 ( 2 H, m) , 1.98 - 2.03 (2 H, m) , 2.69 - 2.78 (6 H, m) , 3.93 (2 H, s) , 3.97 ( 3 H, s) , 4.24 - 4.27 ( 2 H, m) , 4.31 - 4.34 (2 H, m) , 4.37 (2 H, t, J=7.0 Hz) , 6.74 ( 1 H, d, J = 9.5 Hz ), 7.15 (1 H, d, J = 2. 1 Hz), 7.75 (1 H, s ), 7.82 - 7.87 ( 2 H, m) , 8.28 ( 1 H, d, J = 2.5 Hz). -124- 201209056 Example 4 9

使用（7-甲氧基-2-側氧- 2H-( 1,5)萘啶-1-基）乙酸 77mg及 3- ( 2,3-二氫-(1，4 )二噁並（2,3-c )吡啶-7-基 )-1-噁-3,8-重氮螺（4.5)癸烷-2-酮95mg，藉由與實施例 47之同樣操作，得到無色固體狀的3- ( 2,3-二氫-〇,4 ) 二噁並（2,3-c )吡啶-7-基）-8- ( 2- ( 7 -甲氧基-2-側氧-2H- ( 1,5 )萘啶-1-基）乙醯基-1-噁- 3,8-重氮螺（4.5 )癸院-2-酮 1 1 1 mg。 1H NMR ( CHLOROFORM-d ) δ 1.70 - 1.79 ( 1 H, m) 5 1.8 6 - 1.9 3 ( 1 H, m) , 1.97 - 1.99 ( 1 H, m ) , 2.05 -2.10 ( 1 H, m) , 3.21 - 3.28 ( 1 H, m) , 3.64 - 3.70 (3 H, m) , 3.90 - 3.9 7 ( 2 H, m) , 3.92 ( 3 H, s ) , 4.21 - 4.24 (2 H, m) , 4.29 - 4.31 (2 H, m) , 4.78 ( 1 H, d, J=16.1Using (7-methoxy-2-oxo-2H-(1,5)naphthyridin-1-yl)acetate 77 mg and 3-(2,3-dihydro-(1,4)dioxo(2) , 3-c)pyridin-7-yl)-1-oxo-3,8-diazospiro(4.5)nonan-2-one 95 mg, obtained in the same manner as in Example 47 - ( 2,3-dihydro-indole, 4 ) dioxo(2,3-c )pyridin-7-yl)-8- ( 2-( 7 -methoxy-2-oxo-2H- ( 1,5)Naphthyridin-1-yl)ethenyl-1-oxo-3,8-diazosodium (4.5) oxazol-2-one 1 1 mg. 1H NMR (CHLOROFORM-d) δ 1.70 - 1.79 ( 1 H, m) 5 1.8 6 - 1.9 3 ( 1 H, m) , 1.97 - 1.99 ( 1 H, m ) , 2.05 -2.10 ( 1 H, m) , 3.21 - 3.28 ( 1 H, m) , 3.64 - 3.70 (3 H, m) , 3.90 - 3.9 7 ( 2 H, m) , 3.92 ( 3 H, s ) , 4.21 - 4.24 (2 H, m) , 4.29 - 4.31 (2 H, m) , 4.78 ( 1 H, d, J=16.1

Hz)，5.34(1 H，d，J=16.1 Hz)，6.73(1 H，d，J=9.9 Hz) , 7.04 ( 1 H, d, J= 2.1 Hz ) , 7.70 ( 1 H, s ) , 7.83 ( 1 H，s )，7.87 ( 1 H, d, J= 9.9 Hz)，8.25 ( 1 H，d，J = 2.1Hz), 5.34 (1 H, d, J = 16.1 Hz), 6.73 (1 H, d, J = 9.9 Hz), 7.04 ( 1 H, d, J = 2.1 Hz ) , 7.70 ( 1 H, s ), 7.83 ( 1 H,s ), 7.87 ( 1 H, d, J= 9.9 Hz), 8.25 ( 1 H,d,J = 2.1

Hz )。 -125 - 201209056 實施例5 0Hz). -125 - 201209056 Example 5 0

使用（7-甲氧基-2-側氧- 2Η- ( 1，5 )萘啶-1-基）乙酸 18mg 及 3-(2,3-二氫苯並（b) (1，4)二硫酮（0丨11^1^ )-6-基）-1-噁-3,8-重氮螺（4.5)癸烷-2-酮26mg，藉由與實施例47之同樣操作，得到無色固體狀的3- ( 2,3-二氫苯並（b) (1，4)二硫酮（Dithiine) -6-基）-8-(2-(7- 甲氧基-2-側氧- 2H- ( 1,5 )萘啶-1-基）乙醯基）-1-噁- 3,8-重氮螺（4.5 )癸烷-2-酮27mg。 1H NMR ( CHLOROFORM-d ) δ 1.73 - 1.7 8 ( 1 H, m) ,1.91 - 2.02(2 H, m) , 2.08 - 2.12(1 H, m) , 3.20 -3.26(4 H, m) , 3.66 - 3.72 (4 H, m) , 3.93(3 H, s), 4.01 - 4.03 ( 1 H, m) , 4.41 - 4.43 ( 1 H, m) , 4.71 ( 1 Η, d，J= 16.1 Hz) , 5.42 ( 1 H, d, J= 1 6. 1 Hz) , 6.73 ( 1 H， d, J = 9.5 Hz ) ,7.05(1 H, d, J = 2. 1 Hz) , 7.12 ( 1 H，d，Using (7-methoxy-2-oxo-2 Η-( 1,5 )naphthyridin-1-yl)acetic acid 18 mg and 3-(2,3-dihydrobenzo(b) (1,4) Thiophenone (0丨11^1^)-6-yl)-1-oxo-3,8-diazospiro(4.5)nonan-2-one 26 mg, obtained by the same procedure as in Example 47 Solid 3-(2,3-dihydrobenzo(b)(1,4)dithione (Dithiine-6-yl)-8-(2-(7-methoxy-2-sideoxy) - 2H-(1,5)naphthyridin-1-yl)ethenyl)-1-oxo-3,8-diazospiro(4.5)nonan-2-one 27 mg. 1H NMR ( CHLOROFORM-d ) δ 1.73 - 1.7 8 ( 1 H, m) , 1.91 - 2.02 (2 H, m) , 2.08 - 2.12 (1 H, m) , 3.20 -3.26(4 H, m) , 3.66 - 3.72 (4 H, m) , 3.93 (3 H, s), 4.01 - 4.03 ( 1 H, m) , 4.41 - 4.43 ( 1 H, m) , 4.71 ( 1 Η, d, J = 16.1 Hz) , 5.42 ( 1 H, d, J = 1 6. 1 Hz) , 6.73 ( 1 H, d, J = 9.5 Hz ) , 7.05 (1 H, d, J = 2. 1 Hz) , 7.12 ( 1 H,d ,

J= 8.7 Hz)，7.24 ( 1 H, d, J = 2.5 Hz)，7.25 ( 1 H, d，J = 2.1 Hz) , 7.89 ( 1 H, d, J = 9.5 Hz )，8.27 ( 1 H，d，J = 2.1 Hz )。 -126- 201209056 實施例5 1J = 8.7 Hz), 7.24 ( 1 H, d, J = 2.5 Hz), 7.25 ( 1 H, d, J = 2.1 Hz), 7.89 ( 1 H, d, J = 9.5 Hz ), 8.27 ( 1 H, d, J = 2.1 Hz). -126- 201209056 Example 5 1

使用（7-甲氧基·2-側氧-2H- ( 1，5 )萘啶-1-基）乙酸 32mg及3-(噻吩並（3,2-b)噻吩-2-基）-1-噁- 3,8 -重氮螺 (4.5 )癸烷-2-酮43mg，藉由與實施例47之同樣操作，得到淡褐色固體狀的8- ( 2- ( 7-甲氧基-2-側氧-2H- ( 1，5 )萘啶-1-基）乙醯基）-3-(噻吩並（3,2-b)噻吩-2-基）-1-嚼-3,8-重氮螺（4.5)癸院-2-酮45111£。 1H NMR ( CHLOROFORM-d ) δ 1.79 - 1.86 ( 1 H, m) ,2.00 - 2.08 ( 2 H, m) , 2.12 - 2.19(1 H, m) , 3.18 -3.22 ( 1 H, m) , 3.67 - 3.71 ( 1 H, m) , 3.76 - 3.82 (2 H, m) , 3.95 ( 3 H, s) , 4.07'- 4.09 ( 1 H, m) , 4.46 - 4.49 (1 H, m) , 4.72 ( 1 H, d, J=16.1 Hz) , 5.45 ( 1 H, d, J = 16.1 Hz)，6.70(1 H，s)，6.75(1 H，d，J=9.5 Hz)， 7.08 ( 1 H，s) ，7.18 ( 1 H，d, J=5.0 Hz) ，7.25 - 7.26 ( 1 H, m) , 7.91 ( 1 H, d, J=9.5 Hz) , 8.29 ( 1 H, d, J=2.1 Hz )。 -127- 201209056 實施例5 2Using (7-methoxy-2-sideoxy-2H-(1,5)naphthyridin-1-yl)acetic acid 32 mg and 3-(thieno(3,2-b)thiophen-2-yl)-1 - oxa- 3,8-diazospiro(4.5)nonan-2-one 43 mg, obtained in the same manner as in Example 47 to give 8-(2-(7-methoxy-2) as pale brown solid. -Sideoxy-2H-(1,5)naphthyridin-1-yl)ethenyl)-3-(thieno(3,2-b)thiophen-2-yl)-1-che-3,8- Diazo snail (4.5) sputum-2-ketone 45111 £. 1H NMR ( CHLOROFORM-d ) δ 1.79 - 1.86 ( 1 H, m) , 2.00 - 2.08 ( 2 H, m) , 2.12 - 2.19 (1 H, m) , 3.18 -3.22 ( 1 H, m) , 3.67 - 3.71 ( 1 H, m) , 3.76 - 3.82 (2 H, m) , 3.95 ( 3 H, s) , 4.07'- 4.09 ( 1 H, m) , 4.46 - 4.49 (1 H, m) , 4.72 ( 1 H, d, J = 16.1 Hz), 5.45 ( 1 H, d, J = 16.1 Hz), 6.70 (1 H, s), 6.75 (1 H, d, J = 9.5 Hz), 7.08 ( 1 H, s ), 7.18 ( 1 H, d, J = 5.0 Hz) , 7.25 - 7.26 ( 1 H, m) , 7.91 ( 1 H, d, J = 9.5 Hz) , 8.29 ( 1 H, d, J = 2.1 Hz ) . -127- 201209056 Example 5 2

使用（7-甲氧基-2-側氧- 2H- ( 1，5 )萘啶-1-基）乙醛的鹽酸鹽611^及1((2,3-二氫-(1,4)二噁並（2,3-(：) 吡啶-7-基）甲基）-2-氮雜螺（3.3)庚烷-6-胺80mg，藉由與實施例3 9之同樣操作，得到淡褐色固體狀的1 - ( 2 -( 6 - ( ( ( 2，3 -二氫-(1，4 )二噁並（2，3 - c )吡啶-7 -基）甲基）胺基）-2-氮雜螺（3.3)庚烷-2-基）乙基）-7-甲氧基-1H- ( 1，5 )萘啶-2-酮 33mg。 1H NMR ( CHLOROFORM-d ) δ 1.8 2 - 1.8 5 ( 2 H, m), 2.35 -2.38 (2 H, m) , 2.71 (2 H, t, J=7.2 Hz) , 3.16 -3.19(1 H, m ) , 3.22 (2 H，s) , 3.28 ( 2 H, s ) , 3.65 ( 2 H, s )，3.95 (3 H，s) , 4.17 ( 2 H, t, J = 7.2 Hz ) , 4.25 -4.27 (2 H，m)，4.29 - 4.33 ( 2 H, m) , 6.72 ( 1 H，d，J = 9.9 Hz) , 6.77(1 H, s ) , 7.18(1 H，d，J = 1 · 7 H z ), 7.82 ( 1 H, d, J = 9.9 Hz )，8.0 8 ( 1 H，s )，8.2 5 ( 1 H，d, J = 2.5 Hz )。 -128- 201209056 實施例5 3Using (7-methoxy-2-oxo-2H-(1,5)-naphthyridin-1-yl)acetaldehyde hydrochloride 611^ and 1 ((2,3-dihydro-(1,4) Dioxo(2,3-(:)pyridin-7-yl)methyl)-2-azaspiro(3.3)heptane-6-amine 80 mg, obtained by the same procedure as in Example 39 1 - ( 2 -( 6 - ( ( 2,3 -Dihydro-(1,4 ) dioxato(2,3 - c )pyridin-7-yl)methyl)amino) as a pale brown solid 2-Azaspiro(3.3)heptan-2-yl)ethyl)-7-methoxy-1H-(1,5)naphthyridin-2-one 33 mg. 1H NMR (CHLOROFORM-d) δ 1.8 2 - 1.8 5 ( 2 H, m), 2.35 -2.38 (2 H, m) , 2.71 (2 H, t, J = 7.2 Hz) , 3.16 -3.19(1 H, m ) , 3.22 (2 H,s ), 3.28 ( 2 H, s ) , 3.65 ( 2 H, s ), 3.95 (3 H, s) , 4.17 ( 2 H, t, J = 7.2 Hz ) , 4.25 -4.27 (2 H, m), 4.29 - 4.33 ( 2 H, m) , 6.72 ( 1 H,d,J = 9.9 Hz) , 6.77(1 H, s ) , 7.18(1 H,d,J = 1 · 7 H z ), 7.82 ( 1 H , d, J = 9.9 Hz ), 8.0 8 ( 1 H, s ), 8.2 5 ( 1 H, d, J = 2.5 Hz ) -128 - 201209056 Example 5 3

使用1-(2- (2,7-重氮螺（4.4)壬-2-基）乙基）-7-甲氧基-1H-(1,5)萘啶-2_酮的鹽酸鹽19mg及7-側氧-( 7,8)二氫-6H-嘧啶並（5,4-b) (1，4)噁嗪-2-羰醛 10mg，藉由與實施例23之同樣操作，得到淡褐色固體狀的2-(( 7-(2-(7-甲氧基-2-側氧- 2H-(1,5)萘啶-1-基）乙基）-2,7-重氮螺（4.4)壬-2-基）甲基）-811-嘧啶並（5,4-15) (1,4) H惡曉-7-酮 10.5mg。 1H NMR ( CHLOROFORM-d ) δ 1.7 8 - 1.95 ( 4 H, m ) ,2.52 -2.54 ( 2 Η, m) , 2.61 - 2.67 ( 2 Η, m ) , 2.68 -2.78 ( 6 Η, m) , 2.81 - 2.91 ( 2 Η, m) , 3.95 ( 3 Η, s), 4.16 -4.21 ( 1 Η, m) , 4.53 - 4.59 ( 1 Η, m) , 4.70 (2 Η, s) , 6.87(1 Η, d, J=9.5 Hz) , 7.15(1 Η, d, J=2.1 Hz )，7.84 ( 1 H, d, J = 9.5 Hz)，8.20(1 H, s ) , 8.27 ( 1 H，d, J= 2.1 Hz)。實施例54The hydrochloride salt of 1-(2-(2,7-diazospiro(4.4)indol-2-yl)ethyl)-7-methoxy-1H-(1,5)naphthyridin-2-one was used. 19 mg and 7-side oxygen-(7,8)dihydro-6H-pyrimido(5,4-b)(1,4)oxazine-2-carboxaldehyde 10 mg, by the same operation as in Example 23, 2-((7-(2-(7-Methoxy-2-oxo- 2H-(1,5)-naphthyridin-1-yl)ethyl)-2,7-heavy as a pale brown solid Nitrogen snail (4.4) 壬-2-yl)methyl)-811-pyrimido(5,4-15) (1,4) H dioxin-7-one 10.5 mg. 1H NMR ( CHLOROFORM-d ) δ 1.7 8 - 1.95 ( 4 H, m ) , 2.52 -2.54 ( 2 Η, m) , 2.61 - 2.67 ( 2 Η, m ) , 2.68 -2.78 ( 6 Η, m) , 2.81 - 2.91 ( 2 Η, m) , 3.95 ( 3 Η, s), 4.16 -4.21 ( 1 Η, m) , 4.53 - 4.59 ( 1 Η, m) , 4.70 (2 Η, s) , 6.87 (1 Η, d, J=9.5 Hz) , 7.15(1 Η, d, J=2.1 Hz ), 7.84 ( 1 H, d, J = 9.5 Hz), 8.20 (1 H, s ) , 8.27 ( 1 H,d, J = 2.1 Hz). Example 54

-129- 201209056 使用1-(2-(2,7-重氮螺（4.4)壬-2-基）乙基）-7-甲氧基-1Η-( 1,5)萘啶-2-酮的鹽酸鹽12.Omg及環己烷羰醛12.4mg，藉由與實施例23之同樣操作，得到淡褐色固體狀的1-(2- (7-環己基甲基-2,7-重氮螺（4.4)壬-2-基）乙基）-7-甲氧基-111-(1，5)萘啶-2-酮10.3111§。 1H NMR ( CHLOROFORM-d ) δ 0.82 - 0.91 ( 4 H, m) ,1.09 - 1.27(6 H, m) , 1.63 - 1.73 (4 H, m) , 1.74 -1.92 ( 6 H, m) , 2.49 - 2.60 ( 3 H, m) , 2.67 - 2.80 ( 4 Η, m)，3.98(3 H，s)，4.36(2 H，t，J=7.4 Hz)，6.74 (1 H, d, J = 9.5 Hz ) , 7.23 ( 1 H, d, J=2.1 Hz)，7.84 ( 1 H， d, J= 9.5 Hz ) ，8.28 ( 1 H，d，J=2.1 Hz)。實施例5 5-129- 201209056 Using 1-(2-(2,7-diazospiro(4.4)indol-2-yl)ethyl)-7-methoxy-1Η-( 1,5)naphthyridin-2-one 1-(2-(7-cyclohexylmethyl-2,7-heavy) was obtained as a pale brown solid, m. Azaindole (4.4) fluoren-2-yl)ethyl)-7-methoxy-111-(1,5)naphthyridin-2-one 10.3111 §. 1H NMR ( CHLOROFORM-d ) δ 0.82 - 0.91 ( 4 H, m) , 1.09 - 1.27 (6 H, m) , 1.63 - 1.73 (4 H, m) , 1.74 -1.92 ( 6 H, m) , 2.49 - 2.60 ( 3 H, m) , 2.67 - 2.80 ( 4 Η, m), 3.98 (3 H, s), 4.36 (2 H, t, J = 7.4 Hz), 6.74 (1 H, d, J = 9.5 Hz ), 7.23 ( 1 H, d, J = 2.1 Hz), 7.84 ( 1 H, d, J = 9.5 Hz ) , 8.28 ( 1 H, d, J = 2.1 Hz). Example 5 5

使用1-(2-(2,7-重氮螺（4.4)壬-2-基）乙基）-7-甲氧基-1H-(1，5)萘啶-2-酮的鹽酸鹽ll_4mg及3-環己烯-1-羰醛9.6mg，藉由與實施例23之同樣操作，得到淡褐色固體狀的1-(2-(7-(3-環己烯-1-基甲基）-2,7-重氮螺（ 4.4)壬-2-基）乙基）-7 -甲氧基-1Η-( 1,5)萘啶-2-酮 9.9 m g。 -130- 201209056 1H NMR ( CHLOROFORM-d) δ 1.17 - 1.33 ( 2 H，m) ,1.61 - 1.92 ( 10 H, m) , 1.94 - 2.18 ( 4 H, m) , 2.25 -2.45 ( 2 H, m) , 2.49 - 2.64 ( 3 H, m) , 2.67 - 2.80 ( 2 H, m ) , 3.97(3 H, s) , 4.36(2 H, t, J=7.4 Hz) 5 5.62 -5.71 (2 H，m)，6.75 ( 1 H，d，J=9.5 Hz)，7.23 ( 1 H，d， J = 1.7 Hz)，7.84 (1 H, d，J=9.5 Hz)，8.28(1 H，d，J =1.7 Hz)。實施例5 6The hydrochloride salt of 1-(2-(2,7-diazospiro(4.4)indol-2-yl)ethyl)-7-methoxy-1H-(1,5)naphthyridin-2-one was used. Ll_4 mg and 3-cyclohexene-1-carboxaldehyde 9.6 mg were obtained in the same manner as in Example 23 to give 1-(2-(7-(3-cyclohexene-1-yl) as a pale brown solid. 2,7-diazospiro(4.4)non-2-yl)ethyl)-7-methoxy-1Η-(1,5)naphthyridin-2-one 9.9 mg. -130- 201209056 1H NMR (CHLOROFORM-d) δ 1.17 - 1.33 ( 2 H,m) , 1.61 - 1.92 ( 10 H, m) , 1.94 - 2.18 ( 4 H, m) , 2.25 -2.45 ( 2 H, m ) , 2.49 - 2.64 ( 3 H, m) , 2.67 - 2.80 ( 2 H, m ) , 3.97(3 H, s) , 4.36(2 H, t, J=7.4 Hz) 5 5.62 -5.71 (2 H, m), 6.75 ( 1 H, d, J = 9.5 Hz), 7.23 ( 1 H, d, J = 1.7 Hz), 7.84 (1 H, d, J = 9.5 Hz), 8.28 (1 H, d, J =1.7 Hz). Example 5 6

使用1-(2-(2,7-重氮螺（4.4)壬-2-基）乙基）-7-甲氧基-1H-(1，5)萘啶-2-酮的鹽酸鹽7.3mg及四氫-2H-噻喃-4-羰醛10.1 mg，藉由與實施例23之同樣操作，得到淡褐色固體狀的7-甲氧基-1-( 2-(7-((四氫- 2H-噻喃-4-基 )甲基）-2,7-重氮螺（4.4)壬-2-基）乙基）-111-(1，5) 萘啶-2-酮5.8mg。 1H NMR ( CHLOROFORM-d) δ 1.18 - 1.55 ( 2 H, m) ,1.60 - 1.91 (4 H, m) , 2.02 - 2.17(2 Η, m) , 2.25 (2 Η, br. s.) , 2.43 - 2.52 ( 2 Η, m) , 2.54 - 2.71 ( 5 Η, m) ,2.74 - 2.84 ( 6 Η, m) , 3.46 - 3.50 ( 2 Η, m) , 3.98 ( 3 H，.s) , 4.37(2 Η，br. s.)，6.74(1 Η，d，J=9.5 Ηζ)， -131 - 201209056 7.24(1 H，br. s.)，7.85(1 H, d，J=9.5 Hz)，8.28(1 H, d, J=2.1 Hz)。且本發明之式〔1〕的化合物之有用性可由以下試驗例做說明。試驗例1感受性測定試驗1 將被驗物質溶解於二甲基亞颯中，藉由以CLSI( Clinical and Laboratory Standards Institute)的標準法爲準之微量液體稀釋法測定抗菌活性（MIC )。被驗菌株使用金黃色葡萄球菌（Staphylococcus aureus: MSSA，MRSA)。於心浸出物寒天培養基平板上’ 將在35 °C培養一夜之菌體懸浮於米樂海頓培養基至相當於 0.5McFarland。將該懸浮液稀釋至1〇倍稀，作爲接種菌液。將接種菌液約〇.〇〇5mL接種於含有被驗物質之陽離子調整米樂海頓培養基（100pL/well)，在35°C進行一夜培養。將肉眼無法確認的菌發育之最低被驗物質濃度作爲MIC (pg/mL)。結果如表1所示。無數値記載的部分表示未進行試驗。 -132- 201209056 【表1 — 1】實施例號碼 S.aureus Smith 4 (MSSA) S. aureus ATCC29213 (MSSA) S. aureus ATCC BAA-8 11 (MRSA) S.aureus 4050 (MRSA) 1 0. 03 0. 03 2 4 3 0. 12 0.125 0. 25 4 0.03 0. 12 5 0.06 0. 12 6 0.25 1 7 0.25 0. 5 8 2 8 9 0. 12 0. 5 10 16 16 11 0. 5 1 12 64 >64 13 0.03 0.06 14 0. 12 0.25 15 0. 5 16 0.12 0. 125 0. 5 17 0.03 0.06 18 0. 06 0. 06 19 0.25 1 20 0.016 0.016 21 0.5 1 22 16 23 4 24 128 25 4 4 26 0. 016 0. 03 27 0. 03 0.06 28 0.03 0. 12 29 0.03 0. 06 30 0.015 0.06 -133- 201209056 【表1 - 2】 31 2 4 32 16 32 33 0. 06 0.25 34 2 2 35 0. 03 0. 12 36 16 16 37 16 32 38 0. 12 0. 25 39 0. 5 40 0. 5 4 41 0. 12 1 42 0.25 0. 5 43 0.03 0. 06 44 0.03 0. 25 45 0. 12 0. 5 46 0.25 1 47 0. 06 0. 12 48 0. 06 0. 12 49 0.25 0. 5 50 0. 06 0. 12 51 0. 03 0. 03 52 4 8 53 4 2 54 55 56 試驗例2 Staphylococcus aureus老鼠全身感染試驗 (1 )接種菌液之調製將金黃色葡萄球菌（Staphylococcus aureus Smith 4) 懸浮於5%黏蛋白-生理食鹽液至約2xl08 CFU/mL’將此作 -134- 201209056 爲接種菌液。 (2)感染將接種菌液〇.5mL接種於雄性ICR系老鼠（4週齡之日本SLC)腹腔內（8〜lOxlO7 CFU/老鼠），使其引起感染 (3 )治療將在實施例4所製造之化合物溶解於10%羥基丙基化β 環糊精水溶液，於菌接種1小時後進行lmg/kg皮下投與。以一群8隻進行實施。 (4 )效果之判定感染治療效果係以菌接種7天後之生存數作爲指標。非治療群至菌接種1天後雖全例子皆死亡，但實施例4中菌接種7天後，8例中確認7例之生存，顯示in vivo之抗菌活性》試驗例3對於來自金黃色葡萄球菌之拓樸異構酶IV的阻礙活性之測定測定使用 S. aureus Topoisomerase IV Decatenation Kit ( Inspiralis公司）。於 Eppendorf 試管中添加 5xAssay Buffer 198μΙ>、0.1pg/pL kinetoplast DNA 溶液 66μί 及滅菌超純水462 μι，調製出反應基礎溶液A。於PCR試管添加反 201209056 應基礎溶液Α 22μί及調製成10倍濃度之實施例26的化合物或 Ciprofloxacin ( CPFX ) 3 pL。進一步添加使用 Dilution Buffer稀釋至0· 16U~L的拓樸異構酶IV溶液5hL。將全量在3 7°C進行30分鐘恆溫培養。反應後，添加反應停止液（含有0.1% BPB之0.5M EDTA ) 5μί，將20μί在1 %瓊脂膠體電泳中進行電泳。電泳後將瓊脂膠體電泳以2Mg/mL溴化乙錠溶液中進行染色，讀取影像求得各DNA量。即，未含有實施例26之化合物或CPFX的酵素未添加群及酵素添加群之單股且環狀DN A片段量各作爲0%及100 %，算出反應產物成爲50%時的藥物濃度之1C 5〇 (解開連接活性的IC5Q)。實施例26的化合物及CPFX之IC5G各爲lpg/mL以下。試驗例4對於來自金黃色葡萄球菌之DNA旋轉酶的阻礙活性之測定測定使用 S. aureus DNA Gyrase Supercoiling AssayThe hydrochloride salt of 1-(2-(2,7-diazospiro(4.4)indol-2-yl)ethyl)-7-methoxy-1H-(1,5)naphthyridin-2-one was used. 7.3 mg and tetrahydro-2H-thiopyran-4-carboxaldehyde 10.1 mg were obtained in the same manner as in Example 23 to give 7-methoxy-1-(2-(7-(() Tetrahydro-2H-thiopyran-4-yl)methyl)-2,7-diazospiro (4.4)indol-2-yl)ethyl)-111-(1,5) naphthyridin-2-one 5.8 Mg. 1H NMR (CHLOROFORM-d) δ 1.18 - 1.55 ( 2 H, m) , 1.60 - 1.91 (4 H, m) , 2.02 - 2.17 (2 Η, m) , 2.25 (2 Η, br. s.) , 2.43 - 2.52 ( 2 Η, m) , 2.54 - 2.71 ( 5 Η, m) , 2.74 - 2.84 ( 6 Η, m) , 3.46 - 3.50 ( 2 Η, m) , 3.98 ( 3 H,.s) , 4.37 ( 2 Η, br. s.), 6.74 (1 Η, d, J = 9.5 Ηζ), -131 - 201209056 7.24 (1 H, br. s.), 7.85 (1 H, d, J = 9.5 Hz), 8.28 (1 H, d, J = 2.1 Hz). Further, the usefulness of the compound of the formula [1] of the present invention can be illustrated by the following test examples. Test Example 1 Sensitivity Test Test 1 The test substance was dissolved in dimethyl hydrazine, and the antibacterial activity (MIC) was measured by a micro liquid dilution method which was determined by the standard method of CLSI (Clinical and Laboratory Standards Institute). The test strain used Staphylococcus aureus (MSSA, MRSA). On the heart extract medium cold medium plate, the cells cultured at 35 ° C overnight were suspended in Miller Hayden medium to the equivalent of 0.5 McFarland. The suspension was diluted to 1 Torr as a inoculum. 5 mL of the inoculum was inoculated into a cation-conditioned Miller-Hyton medium (100 pL/well) containing the test substance, and cultured overnight at 35 °C. The concentration of the lowest test substance for the development of bacteria that could not be confirmed by the naked eye was taken as the MIC (pg/mL). The results are shown in Table 1. The countless parts indicate that no tests have been carried out. -132- 201209056 [Table 1 - 1] Example No. S. aureus Smith 4 (MSSA) S. aureus ATCC29213 (MSSA) S. aureus ATCC BAA-8 11 (MRSA) S.aureus 4050 (MRSA) 1 0. 03 0. 03 2 4 3 0. 12 0.125 0. 25 4 0.03 0. 12 5 0.06 0. 12 6 0.25 1 7 0.25 0. 5 8 2 8 9 0. 12 0. 5 10 16 16 11 0. 5 1 12 64 >64 13 0.03 0.06 14 0. 12 0.25 15 0. 5 16 0.12 0. 125 0. 5 17 0.03 0.06 18 0. 06 0. 06 19 0.25 1 20 0.016 0.016 21 0.5 1 22 16 23 4 24 128 25 4 4 26 0. 016 0. 03 27 0. 03 0.06 28 0.03 0. 12 29 0.03 0. 06 30 0.015 0.06 -133- 201209056 [Table 1 - 2] 31 2 4 32 16 32 33 0. 06 0.25 34 2 2 35 0. 03 0. 12 36 16 16 37 16 32 38 0. 12 0. 25 39 0. 5 40 0. 5 4 41 0. 12 1 42 0.25 0. 5 43 0.03 0. 06 44 0.03 0. 25 45 0. 12 0. 5 46 0.25 1 47 0. 06 0. 12 48 0. 06 0. 12 49 0.25 0. 5 50 0. 06 0. 12 51 0. 03 0. 03 52 4 8 53 4 2 54 55 56 Test Example 2 Staph Systemic infection test of ylococcus aureus mice (1) preparation of inoculating bacteria solution Staphylococcus aureus Smith 4 was suspended in 5% mucin-physiological saline solution to about 2xl08 CFU/mL 'this was made -134-201209056 Inoculate the bacterial solution. (2) Infection The inoculated bacterial solution 〇5 mL was inoculated into the male ICR mice (4 weeks old Japanese SLC) intraperitoneally (8~lOxlO7 CFU/mouse) to cause infection (3) treatment will be in Example 4 The produced compound was dissolved in a 10% aqueous solution of hydroxypropylated β-cyclodextrin, and subcutaneously administered at 1 mg/kg after inoculation for 1 hour. Implemented in groups of eight. (4) Determination of effect The effect of infection treatment was based on the number of survivals after 7 days of inoculation. After 1 day of inoculation of the non-treated group to the bacteria, all the cases died, but after 7 days of inoculation in the case 4, 7 cases were confirmed to survive in 8 cases, showing in vivo antibacterial activity. Test Example 3 for from golden yellow grapes The inhibition activity of the topoisomerase IV of cocci was determined using S. aureus Topoisomerase IV Decatenation Kit (Inspiralis). The reaction base solution A was prepared by adding 5xAssay Buffer 198μΙ>, 0.1 pg/pL kinetoplast DNA solution 66 μί and sterilized ultrapure water 462 μm to an Eppendorf tube. The compound of Example 26 or Ciprofloxacin (CPFX) 3 pL was added to the PCR tube by adding the anti-201209056 base solution Α 22 μί and to a 10-fold concentration. Further, add a topoisomerase IV solution diluted to 0·16 U~L with Dilution Buffer for 5 h. The whole amount was incubated at 37 ° C for 30 minutes at a constant temperature. After the reaction, a reaction stop solution (0.5 M EDTA containing 0.1% BPB) was added to 5 μί, and 20 μί was electrophoresed on a 1% agar colloid electrophoresis. After electrophoresis, the agar colloid was electrophoresed and stained in a 2 Mg/mL ethidium bromide solution, and the amount of DNA was determined by reading an image. In other words, the single-stranded and unreacted DN A fragment of the enzyme-free group and the enzyme-added group, which did not contain the compound of Example 26 or CPFX, were each 0% and 100%, and the drug concentration at the time when the reaction product became 50% was calculated as 1C. 5〇 (Unlock the active IC5Q). The compound of Example 26 and IC5G of CPFX were each lpg/mL or less. Test Example 4 Determination of the inhibitory activity against DNA rotase from S. aureus S. aureus DNA Gyrase Supercoiling Assay

Kit ( Inspiralis公司）。於 Eppendorf 試管中添加 5xAssay Buffer 210pL、1 \igl\aL relaxed pBR3 22 DNA 溶液 17·5μί 及滅菌超純水5 42.5 μί，調製出反應基礎溶液B。於PCR試管中添加反應基礎溶液Β 22μί及調製成10倍濃度之實施例26 的化合物或CPFX 3pL。進一步添加使用Dilution Buffer稀釋至0.25U~L的DNA旋轉酶溶液5pL。將全量在37°C進行 30分鐘恆溫培養。 -136- 201209056 反應後，添加反應停止液5μί，將20μί在1%瓊脂膠體電泳中進行電泳。泳動後將瓊脂膠體電泳以2 pg/mL溴化乙錠溶液中進行染色，讀取影像後求得各DN A量。即，未含有實施例26之化合物或CPFX的酵素未添加群及酵素添加群之超螺旋狀的DNA片段量各作爲0%及100 %，算出反應產物成爲50%時的藥物濃度之IC5G(超螺旋活性的IC5Q)。實施例26的化合物之IC5〇爲lpg/mL以下。另一方面 CPFX之 IC50爲 12pg/mL。由試驗例3及4得知，實施例26的化合物對於雙方酵素具有強阻礙活性。產業上上可利用性本發明的雜環化合物或其鹽因具有強抗菌活性與高安全性，故可作爲有用的優良抗菌劑。 -137-Kit (Inspiralis). Add 5xAssay Buffer 210pL, 1 \igl\aL relaxed pBR3 22 DNA solution 17·5μί and sterilized ultrapure water 5 42.5 μί to Eppendorf tube to prepare reaction base solution B. A reaction base solution Β 22 μί was added to the PCR tube and the compound of Example 26 or CPFX 3pL was prepared at a 10-fold concentration. Further, 5 pL of a DNA rotase solution diluted to 0.25 U to L using a Dilution Buffer was added. The whole amount was incubated at 37 ° C for 30 minutes at a constant temperature. -136-201209056 After the reaction, 5 μί of the reaction stop solution was added, and 20 μί was electrophoresed on a 1% agar colloidal electrophoresis. After the migration, the agar colloid was electrophoresed and stained in a 2 pg/mL ethidium bromide solution, and the amount of each DN A was determined after reading the image. In other words, the amount of the supercoiled DNA fragment containing no enzyme of the compound of Example 26 or CPFX and the supercoiled DNA fragment of the enzyme-added group was 0% and 100%, and the IC5G of the drug concentration when the reaction product became 50% was calculated. Spiral-active IC5Q). The compound of Example 26 had an IC5 lp of lpg/mL or less. On the other hand, CPFX has an IC50 of 12pg/mL. It is known from Test Examples 3 and 4 that the compound of Example 26 has a strong inhibitory activity against both enzymes. Industrial Applicability The heterocyclic compound of the present invention or a salt thereof has excellent antibacterial activity and high safety, and thus can be used as a useful excellent antibacterial agent. -137-

Claims

201209056 VII. Patent application scope: 1. A compound or a salt thereof,

It is represented by the formula [I] (wherein, the bond containing the dotted line connecting χ2 and γ1 represents a single bond, or a double bond, Ζ1 represents a nitrogen atom or sCRl, Ζ2 represents a nitrogen atom or a formula CR2, and the furnace represents nitrogen Atom or formula CR3' Z4 represents a nitrogen atom or a formula cR4, z5 represents a nitrogen atom or a formula CR5 'Z6 represents a nitrogen atom or a formula cr6, R1 'R2 'R3' R4, R5, and R6 are the same or different and represent a hydrogen atom , Cm, alkoxy, thiol, halogen atom, Ci.6 alkyl, Ci6 haloalkyl, C|·6 halogen oxy, C:3·6 ring, cyano, nitro, c2_7 A monocyclic heterocyclic group, a formula -NR8R9, a formula -C〇2R8, or a formula -CONR8R9, R8, and R9 are the same or different and each represents a hydrogen atom, or a C!-6 alkyl group, and X1 represents a pendant oxy group. Substituting 2 (^-4 alkylene group, X2 contains a bond connecting the dotted line of X2 and Y1 as a single bond, and represents a bond bond, and the bond containing the dotted line connecting X2 and Y1 is a double bond, and represents a formula CH Y1 represents a group which may be grouped from a group selected from a hydroxyl group, a halogen atom, a C, -6 alkyl group, a Cu hydroxyalkyl group, a c2-7 alkanol group, a phenyl 'form-nri 3r14, a formula -C02R13, and a formula - CONR13R14 ~3 bases replaced Selected from the following group of the formula [II] spiro cycloalkyl group, each group of spiro ring nitrogen atom may be a N- oxide 'R13, and R14 are the same or different, represent a hydrogen atom, an alkyl group or Ch6 -138-201209056

X3 represents a Ci-4 alkyl group, a formula NR1Q(CH2)m, a formula SOn, or a bond bond, and R1() is the same or different, meaning a hydrogen atom, or an alkyl group, and m, and η are the same or different , represents 〇, 1, or 2, R7 represents 〇3_6 cycloalkyl, C3.6 cycloalkenyl, aryl, monocyclic heterocyclic, or bicyclic heterocyclic, wherein the C3_6 cycloalkyl, C3_6 ring The alkenyl group, the aryl group, the monocyclic heterocyclic group, and the bicyclic heterocyclic group may be selected from the group consisting of C alkoxy group, hydroxyl group, halogen atom, 1-6 yard base, 匸1.6 halogen compound base, and ^! The oxy, fluorene 2-7 alkoxy group, monocyclic heterocyclic group, the formula -NR1 iRU, the formula -COzR11, and the formula -CONR1 iR12 are substituted by 1 to 5 substituents, and R11 and R12 are the same. Or different, meaning a hydrogen atom, or h. 6 alkyl-139-201209056 2. The compound of the first aspect of the patent application or a salt thereof, wherein the compound may be selected from a hydroxyl group, a halogen atom, and a C1-6 alkyl group. a group consisting of Ci-6 hydroxyalkyl, C 2-7 alkanol, phenyl, formula -NR13R14, formula -C02R1,3, and 1-3 groups of formula -CONR13R 14 substituted with the group of the following formula a spiro group of [111], wherein the nitrogen atom in each spiro group may be N- The oxides, R13, and R14 are the same or different and represent a hydrogen atom, or a Ci-6 alkyl group.

X3 represents a Cm alkyl group, a formula NR1〇, a formula s〇n, or a bond, R 1 (5 is the same or different, represents a hydrogen atom, or a Cm alkyl group, „为〇, 1, or 2, R An aryl group, a monocyclic heterocyclic group or a bicyclic heterocyclic group, wherein the aryl group, the monocyclic heterocyclic group, and the bicyclic heterocyclic group may be selected from a Cm alkoxy group, a hydroxyl group, a halogen atom, and C. |·6 alkyl, Ci 6 haloalkyl, C丨.6 haloalkoxy, C2-7 alkanol, monocyclic heterocyclic, formula _nr11r12, -140- 201209056 Formula - C〇2R", and Formula - CONR] 1 to 5 pieces of the 1R12 group Μ Π: the group is substituted, R11, and R12 are the same or different 'representing a hydrogen atom, or 4 L 1.7 alkyl 3 · as claimed The compound of the first or second aspect, or a compound thereof, wherein Z1 is a formula CR1, Z4 is a formula CR4, and Z6 is a formula CR6. 4. A compound according to claim 3 or a salt thereof, wherein R1, R4, And R6 are all a hydrogen atom. 5. A compound or a salt thereof according to any one of claims 1 to 4, wherein Z2 is a nitrogen atom or a formula CH. 6. The scope of claim 1 to a compound of any of the five or And a compound or a salt thereof, wherein Z5 is a formula CR5. 8. A compound according to claim 7 of the patent application, wherein Z3 is a nitrogen atom or a formula CH. 7. The compound of any one of clauses 1 to 6 or a salt thereof. Or a salt thereof, wherein R1_Ci-6 alkoxy' or a halogen atom. 9. A compound according to any one of the items of the present invention, or a salt thereof, wherein X1 is a Cl 2 which may be substituted by a pendant oxy group The compound or a salt thereof according to any one of claims 1 to 8, wherein X1 is a group which may be substituted by a pendant oxy group. The compound of any one of clauses 1 to 0 or a salt thereof, wherein Y1 is an unsubstituted spiro group selected from the group (III). 1 2 · as claimed in the first to the first Or a salt thereof, wherein γ ΐ is a spiro group selected from the group [IV] below; -141 - 201209056

〇

And -n〇^n- 1 3 . As claimed in claim 1 or its salt, wherein X3 is a bonding bond. An antibacterial agent, which is a compound I according to any one of the above items (1) to (1), or a salt thereof. . -142- 201209056 Four designated representatives: (1) The representative representative of the case is: None (2) The symbol of the representative figure is simple: No 201209056 5. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention. :Form (I)