TW299332B

TW299332B -

Info

Publication number: TW299332B
Application number: TW82108669A
Authority: TW
Original assignee: Upjohn Co
Priority date: 1992-12-08
Filing date: 1993-10-19
Publication date: 1997-03-01
Also published as: IL107663A; IL107663A0; CN1092413A; MX9307705A; MY117563A; CN1044473C; PH31085A

Description

A7 B7 五、發明説明（/ ) 發明瞄· 本發明係有翮用為抗细菌劑之新穎之環庚三烯酮取代之苯基啤唑啶謂化合物。發职背兽嗶唑啶嗣為口服具活性之合成抗细菌劑之一類·且在此技藝中許多參考揭示各種啤唑啶醑衍生物。例如，有許多參考掲示在苯基環上具一、二或三個取代基之3-苯基-2-噚唑啶釅化合物。揭示於苯基環軍一取代之參考包括美國專利 4,948,801; 4,461,773; 4,340,606; 4,476.136; 4,250,318; 4,128,654及 Re 29,607 。對 3-[(單取代）苯基]-2-嗶唑啶酮之另外之參考可發規於》洲専利公告 0 132 000, Gregory等人· J. Med. Che·· 32 ： 1673 (1989) , Gregory 等人，J. Med. Che·· 33-2569 (1990) , Dark 等人，J. Med. Che屋.35 : 1 156 (1992)及 Wang等人，Tetrahedron 45: 1323 (1989)。此類型之化合物亦包括抗细菌劑DuP 721 。 3-[(二-，三-¾稠合環取代）苯基]-2-啤唑啶萌報告於美國専利 4,977,173、4,921,869 及 4,801,600;歐洲専利公告 0 316 594 、 0 184 170 及 0 127 902;及PCT 申請案 PCT/US89/03548 ' PCT/US90/06220 ' PCT/US92/08267及美國申講案編號第07/880,492 (1992年5月8日提出申請） Ο 吾等已發現有效為抗细菌繭之3-[(單一、二-及三-取代 - 3 - 木紙張又度適用中國國家標準（CNS)A4規格（210 X297公釐） 83.3.10,000 -----------厂裝---------訂-------丨丨線 (請先閲讀背面之注意事項再塡寫本頁) A7 B7 S99332 五、發明説明（夕） )笨基]-2-啤唑啶嗣。本發明化合物以在苯基環之對位上具有環庚三烯釅或取代之環庚三烯嗣環，及視情況於苯基環之間位上有各種基之額外之取代之3 -苯基-2 -嗶唑啶酮為特徵。畜料堪沄囟茲下面之參考掲示在笨基環上具單一取代之3 -苯基-2 -吗唑啶酮，美國専利4,948,801掲示具抗细菌活性之3-[(芳基輿雜芳基）笨基]-2-嗶唑啶醑。美画專利4,476,136揭示具抗细菌活性之3-[(對芳烷基，芳烯基及芳炔系取代）苯基]-5-(胺甲基）-2-鸣唑啶酮。美圔專利4,461,773揭示具抗细菌活性之經取代3-苯基 -5-(羥甲基）-2-嗶唑啶萌。美國専利4,340,606掲示於哺乳類具抗细菌活性之經取代3-[(對烷磺醣基）苯基]-5-(羥甲基）-或（醢氧甲基）-2-嗶唑啶嗣。 —-—. 美B專利4,250,318掲示具抗抑鬱用途之經取代3-苯基 -5-(羥甲基）-2-嗶唑啶釅。美_専利4,128,654掲示用於控制植物之徽菌與细菌病之經取代3 -苯基- 5- (由甲基）-2 -噚唑啶酮。美釀再發行専利29,60 7掲示具抗抑鬱、安神及縝靜用途之經取代3-苯基-5-(羥甲基）-2·•噚唑啶嗣。比利時専利892,270掲示相當於上列美國專利本紙張又度通用中國國家標準（CNS)A4规格（210 X 297公if ) 83.3.10,000 -----------ί >裝---------訂-------Γ線 (請先閱讀背面之注意事項再塡寫本頁) 五、發明説明（3) A7 B7 部 :Tt. % % !， 1 Ps 4,476,136之3-[(芳烷基，芳烯基或芳炔基取代）苯基 ]-5-(胺甲基）-2-啤唑啶醑。歐洲專利公告0 352 781掲示相當於上列美國專利 4,948,801之芳基及雜芳基取代之3-苯基-2-〇f唑啶鼷。歐洲專利公告 0 312 000 如於 Derwent 89-116142/16 中報告，揭示笨甲基及吡啶甲基取代之3-苯基-2-噚唑啶酮。· C, -H. Park 等人，J. Med. Chen. 35:1156 (1992), tf.A. Gregory等人，J. Med. Che·. 33:2569 (1990)及 J. Med. Che·. 32 : 1673 (1989); C. J. Wang 等人. Tetrahedron 45:1323 (1989);及 A. M. Slee 等人•抗微生物劑及化學療法，31:1791 (1987)及D.C. Eustice 等人，抗撤生物劑及化學療法，32:1218 (1988)為掲示 3-[(單取代）苯基]-2-啤唑啶酮之另外之近來之參考。下面參考掲示3-[(二取代）苯基]-，3-[(三取代）笨基] -或3-[(稠合環取代）苯基]-2-啤唑啶嗣；美國專利4,977,173揭示在苯基環之對位具内釀胺及在間位具氟之3-苯基-2-嗶唑啶嗣（式XIII)。美國專利4,921,869及4,801,600揭示6’-吲哚啉基-或烷酮嗶唑啶嗣（其中吲哚啉基氮對啤唑啶麵氮為間位）。美國專利4,705,799掲示具抗细菌活性之取代之胺甲基酮基嗶唑啶基苯衍生物包括硫化物、亞礪、瞋及磺鼸胺。 C. -H. P.9rk 等人，J. Med. Chen. 35:1 156 為掲示 3-[(二取代）苯基]-及3-[(三取代）苯基]-2唑啶踴之另 I n I n II ϋ I n ϋ ^ n 1 (請先閲讀背面之注意事項再填寫本頁)A7 B7 V. Description of the invention (/) Invention aim · The present invention is a novel compound of phenylpyrazolidine substituted by cycloheptatrione which is used as an antibacterial agent. The beast is a class of synthetic antibacterial agents that are active orally. And many references in this art disclose various derivatives of pyrazolidine. For example, there are many references to 3-phenyl-2-oxazolidine pyridine compounds having one, two, or three substituents on the phenyl ring. References disclosed in the first substitution of phenyl ring army include US patents 4,948,801; 4,461,773; 4,340,606; 4,476.136; 4,250,318; 4,128,654 and Re 29,607. Additional references to 3-[(monosubstituted) phenyl] -2-pyrazolidinone can be published in "Zhouzhanli Bulletin 0 132 000, Gregory et al. J. Med. Che · 32: 1673 (1989 ), Gregory et al., J. Med. Che. 33-2569 (1990), Dark et al., J. Med. Che Wu. 35: 1 156 (1992) and Wang et al., Tetrahedron 45: 1323 (1989) . Compounds of this type also include the antibacterial agent DuP 721. 3-[(di-, tri-¾ fused ring substituted) phenyl] -2-pyrazolidine was reported in U.S. Kazakhstan 4,977,173, 4,921,869 and 4,801,600; European Kazakhstan announcement 0 316 594, 0 184 170 and 0 127 902; And PCT application PCT / US89 / 03548 'PCT / US90 / 06220' PCT / US92 / 08267 and US application number 07 / 880,492 (application on May 8, 1992) Ο We have found to be effective as antibacterial Cocoon 3-[(single, two- and three-replacement- 3-wood paper is again applicable to the Chinese National Standard (CNS) A4 specification (210 X297 mm) 83.3.10,000 ----------- Factory Outfit --------- Order ------- 丨 Line (please read the precautions on the back before writing this page) A7 B7 S99332 5. Description of the invention (Xi)) Benji] -2-Pyrazolidine. The compound of the present invention uses 3-heptene having a cycloheptatriene or substituted cycloheptatriene ring in the para position of the phenyl ring, and optionally an additional substituted 3-benzene having various groups between the phenyl ring It is characterized by 2-pyridazolone. Livestock feeds refer to the following references: 3-phenyl-2-morphazolidone with a single substitution on the stupid ring, U.S. Patent 4,948,801, 3-[(aryl and heteroaryl) ) Benzy] -2-pyrazolidine. US Patent 4,476,136 discloses 3-[(p-aralkyl, arylalkenyl and arylalkynyl substituted) phenyl] -5- (aminomethyl) -2-oxazolidinone with antibacterial activity. U.S. Patent 4,461,773 discloses substituted 3-phenyl-5- (hydroxymethyl) -2-pyrazolidine with antibacterial activity. U.S. Patent No. 4,340,606 shows that 3-[(p-alkylsulfonyl) phenyl] -5- (hydroxymethyl)-or (acetoxymethyl) -2-pyrazolidine has antibacterial activity in mammals. —-—. US Patent 4,250,318 shows substituted 3-phenyl-5- (hydroxymethyl) -2-pyrazolidine with antidepressant use. U.S.A. 4,128,654 shows the substitution of 3-phenyl-5- (by methyl) -2-oxazolidinone for the control of plant emblem bacteria and bacterial diseases. Fine Brew reissued Zuri 29,60 7 to show the substituted 3-phenyl-5- (hydroxymethyl) -2 · • zodimidin with antidepressant, soothing and calming uses. Belgium 892,270 shows that it is equivalent to the above-mentioned U.S. patented paper and the general Chinese National Standard (CNS) A4 specification (210 X 297 public if) 83.3.10,000 ----------- ί > installed- ------- Subscribe ------- Γ line (please read the precautions on the back before writing this page) 5. Description of the invention (3) Part A7 B7: Tt.%% !, 1 Ps 4,476,136 of 3-[(aralkyl, arylalkenyl or arylalkynyl substituted) phenyl] -5- (aminomethyl) -2-pyrazolidine. European Patent Announcement 0 352 781 shows the aryl and heteroaryl substituted 3-phenyl-2-〇f oxazolidines equivalent to the above-mentioned US Patent 4,948,801. European Patent Announcement 0 312 000 As reported in Derwent 89-116142 / 16, discloses 3-phenyl-2-oxazolidinone substituted with stupylmethyl and pyridylmethyl. · C, -H. Park et al., J. Med. Chen. 35: 1156 (1992), tf.A. Gregory et al., J. Med. Che .. 33: 2569 (1990) and J. Med. Che 32. 1673 (1989); CJ Wang et al. Tetrahedron 45: 1323 (1989); and AM Slee et al. • Antimicrobial Agents and Chemotherapy, 31: 1791 (1987) and DC Eustice et al. Agents and Chemotherapy, 32: 1218 (1988) is another recent reference to 3-[(monosubstituted) phenyl] -2-pyrazolidone. The following references refer to 3-[(disubstituted) phenyl]-, 3-[(trisubstituted) benzyl]-or 3-[(fused ring substituted) phenyl] -2-pyrazolidine; US Patent 4,977,173 The amine in the para position of the phenyl ring and the 3-phenyl-2-pyrazolidine with fluorine in the meta position (formula XIII) are revealed. U.S. Patent Nos. 4,921,869 and 4,801,600 disclose 6'-indolinyl- or alkanone pyrazolidine (in which the indolinyl nitrogen is meta to the nitrogen of the pazolidinium). U.S. Patent No. 4,705,799 shows that substituted amine methyl ketopyridazolidinyl benzene derivatives with antibacterial activity include sulfide, sulfonamide, pyridine and sulfonamide. C. -HP9rk et al., J. Med. Chen. 35: 1 156 is another example of 3-[(disubstituted) phenyl]-and 3-[(trisubstituted) phenyl] -2 oxazolidine. n I n II ϋ I n ϋ ^ n 1 (Please read the notes on the back before filling this page)

、SJ 線衣紙張又度適用中國國家標準（CNS)A4規格（210 X 297公釐） 83.3.10,000 A7 B7 五、發明説明外之近來之參考。歐洲專利公告0 316 594揭示相當於上列之美國専利 4,977,173之取代之3-(苯乙烯基）-2-嗶唑啶醑。歎洲専利公告0 184 170及0127 902相當於上述美國專利 4,705,799 。 PCT/US89/035 48及PCT/US90/06220掲示用為抗细菌劑之 3-[(稠合環取代）苯基]-2-噚唑啶醑。 PCT/US92/08267掲示用為抗细菌劑之取代之芳基-及雜芳基-笨基吗唑啶嗣。美國専利申請案钃虢第07/880,492 (1992年5月8日提出申請）揭示含取代之二哄部分之苯基啤唑啶_。上面列舉之參考揭示本發明之環庚三烯围取代之笨基吗唑啶酮。雄明《诚一種具式I化合物及其藥用蘧輿水合物 (請先閲讀背面之注意事/在填寫本頁) 經濟部令央榀準局员工消費合作社印奴 R2, SJ thread clothing paper is again applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 83.3.10,000 A7 B7 V. References outside the description of the invention. European Patent Announcement 0 316 594 discloses a substituted 3- (styryl) -2-pyrazolidine equivalent to the above-mentioned U.S. Patent 4,977,173. The announcements of Tanzhouli 0 184 170 and 0127 902 are equivalent to the above-mentioned US patents 4,705,799. PCT / US89 / 035 48 and PCT / US90 / 06220 show 3-[(fused ring substituted) phenyl] -2-pyrazolidine as an antibacterial agent. PCT / US92 / 08267 shows substituted aryl- and heteroaryl-benzyl morphazolidines used as antibacterial agents. The US application No. 07 / 880,492 (filed on May 8, 1992) reveals the phenylpyrazolidine containing the substituted bis part. The above-cited references reveal the cyclopentapene-substituted benzyl morphazolidinone of the present invention. Xiongming "Sincerity A compound of formula I and its medicinal hydrates (please read the precautions on the back first / fill in this page) Ministry of Economy ordered the Central Bureau of Industry and Commerce Employee Consumer Cooperative Inno R2

0 人 N1C0R1 本紙張又度適用中國國家標準（CNS)A4规格（210 X 297公釐） 83.3.10,000 如 9332 A7 B7五、發明説明（）式中R1為 (a) 氫 (b) (Ct-Ce)烷基視須要以下列之一或多個取代·· F、C1、羥基、烷氧基、醢氧基； (c) (C3-Ce)環烷基 (d) 胺基， (e) (Ci-Ce)烷胺基， (f ) (Ci-Ce)二烷胺基， (g) (Ci-C*»)烷氧基 / 式中R2與R 3為相同或不同且僅選自下列之基： U)氩 (b) 氟基 (c) 氛基 (d) (“-Ce)烷基， (e) 三氟甲基 (f) 羥基 (g) (Ca-Ce)烷氣基， (h) 硝基 (i) 胺基其限制條件為當R2與R3皆為氫Μ外時，則R2與R3相同；式中R4僅選自 (請先閲讀背面之注意事項再填寫本頁) -裝 •J :6 線本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 83.3.10,000 A7 B7 五、發明説明（）何ί50 people N1C0R1 This paper is again applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 83.3.10,000 As 9332 A7 B7 V. Description of invention () where R1 is (a) hydrogen (b) (Ct- Ce) The alkyl group may be substituted with one or more of the following if necessary. F, C1, hydroxy, alkoxy, acetoxy; (c) (C3-Ce) cycloalkyl (d) amino, (e) (Ci-Ce) alkylamine group, (f) (Ci-Ce) dialkylamine group, (g) (Ci-C * ») alkoxy group / where R2 and R 3 are the same or different and are only selected from The following groups: U) Argon (b) Fluorine (c) Amino group (d) (“-Ce) alkyl, (e) Trifluoromethyl (f) Hydroxy (g) (Ca-Ce) alkane , (H) The nitro (i) amine group is restricted when R2 and R3 are both hydrogen M, then R2 and R3 are the same; where R4 is only selected (please read the precautions on the back before filling this page ) -Installation • J: 6 The size of the paper in line is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 83.3.10,000 A7 B7 5. Description of the invention () He ί5

(b) R5'(b) R5 '

(Ο 〇.(Ο 〇.

(d) 〇(d) 〇

----------」-裝---- (請先閱讀背面之注意事項再塡寫本頁) 式中R與R·為相同或不同，且僅選自（Cx-Ce)烷基（視須要Μ氯基、氟基、羥基、（Ci-Ce)烷氧基、胺基、訂 (C^-Ce)烷胺基·（“-(：β)二烷胺基取代）；其中Rs僅選自氫、0Re、SRe、HHR7，---------- "-install ---- (please read the precautions on the back before writing this page) where R and R · are the same or different and are only selected from (Cx-Ce ) Alkyl (M chloride, fluoro, hydroxy, (Ci-Ce) alkoxy, amine, (C ^ -Ce) alkylamino · (“-(: β) dialkylamino substitution ); Where Rs is only selected from hydrogen, 0Re, SRe, HHR7,

Ν αι 線 %Ν αι line%

Sw t I R-Sw t I R-

N— K一 o /~\ 5 W——v_y 本紙張又度適用中國國家標準（CNS)A4規格（210 X 297公嫠） 83.3.10,000 五、發明説明 A7 B7 ·.% r I1- 及 NR7R12 ; 其中ReS U)氫 (b) (Ca-Ce)烷基，梘須要Μ —或多個鹵素取代 (c) (“-(；8)烷基，視須要Μ胺基、（h-Cs)烷胺基、 (Ca-Cs)二烷胺基取代 (d) (Ci-Cs)烷基，視須要Μ —或多個羥基及以胺基、烷胺基、二烷胺基取代 (e) (“-(：8)烷基，視須要Μ —或多個（Ci-Ce)烷氧基取代 (f) (C2-Ce)烯基（“-“）烷基，視須要Μ胺基、 (h-Ce)烷胺基、（Ci-Ce)二烷胺基取代 (g) (C2-C8)炔基（Ca-Ce)烷基*視須要Μ胺基、 (h-CO烷胺基、（Ci-Ce)二烷胺基取代 (h) (C2-C8)醢基，視須要以羥基、胺基、（“-(：8)烷胺基、（“-Cd二烷胺基取代 (i) 苯基（Ci-Cs)烷基，視須要於苯基上Μ胺基、 (“-(：8)烷胺基、（“-(：β)二烷胺基取代 (j) 吡啶基（C^-Ce)烷基*視須要於吡啶基上Μ胺基、（“-(：8)烷胺基、（Ci-Ce)二烷胺基取代 (k) 胺基，視須要以一或二涸（Ci-Ce)烷基取代其中R7為 (a) 氫 (b) (Ci-C*)烷基，視須要由一或多涸氣基、氟基、 (請先閱讀背面之注意事項再塡寫本頁) 裝訂線本紙張尺度適用中國國家標準（CNS)A4規格（210 X 29?公釐） 83.3.10,000N— K 一 o / ~ \ 5 W——v_y This paper is again applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 public daughter) 83.3.10,000 V. Description of the invention A7 B7 ·.% R I1- and NR7R12 ; Among them, ReS U) hydrogen (b) (Ca-Ce) alkyl, and M should be replaced by M—or more halogens (c) (“-(; 8) alkyl, as required, M amino, (h-Cs) Alkylamine group, (Ca-Cs) dialkylamine group substituted (d) (Ci-Cs) alkyl group, if necessary, M—or multiple hydroxyl groups and substituted with amine group, alkylamine group, dialkylamine group (e) (“-(: 8) alkyl, as required, M—or multiple (Ci-Ce) alkoxy substituted (f) (C2-Ce) alkenyl (“-“) alkyl, as required, amine, (h-Ce) alkylamine group, (Ci-Ce) dialkylamine group substitution (g) (C2-C8) alkynyl group (Ca-Ce) alkyl group * M amino group, (h-CO alkylamino group if necessary) , (Ci-Ce) dialkylamine substituted (h) (C2-C8) acetyl group, if necessary, substituted with hydroxyl, amine, (“-(: 8) alkylamine, (“ -Cd dialkylamine (i) Phenyl (Ci-Cs) alkyl, optionally substituted with (M) amino group on the phenyl group, (“-(: 8) alkylamino group, (“-(: β) dialkylamino group (j) pyridine Group (C ^ -Ce) alkyl * M-amino group, ("-( ： 8) Alkylamino group, (Ci-Ce) dialkylamino group substituted (k) amine group, if necessary, substituted with one or two (Ci-Ce) alkyl group where R7 is (a) hydrogen (b) (Ci -C *) alkyl group, if necessary, one or more gas-based, fluorine-based, (please read the precautions on the back before writing this page) binding line paper size is applicable to China National Standard (CNS) A4 specifications (210 X 29? Mm) 83.3.10,000

I 五、發明説明（ A7 B7 部 1% 'p % Ϊ， ± (c) (d) (e) (f ) (g ) (h) (i) (j) 其中Re& (a) (b) (c) (d) (e) (f ) 其中『與 (a) (b) 羥基、胺基、（“-“）烷胺基、（“-Ce)二烷胺基、苯基、吡啶基、（Ci-Ce)烷氧基、（Cx-Ce) 烷氣羰基部分取代 (C3-Ce)環烷基，視須要以胺基、（Ci-C8)烷胺基或（Ci-Ce)二烷胺基取代胺基 (“-Ce)烷胺基 (Ci-Ce)二烷胺基羥基 (Ci-Ce)烷氧基 (c2-c8)烯基（Ci-Cio)烷基*視須要Μ胺基、 (Ci-C*)烷胺基、（“-“）二烷胺基取代 (C2-Ce)炔基（Ci-Cio)烷基，視須要Μ胺基、 (“-D烷胺基、（Ci-C*)二烷胺基取代氳 (Ci-Ce)烷基 —·»-. (Ca-Ce)環院基 (Ci-Ce)醢基 (Ci-Ce)烷氧羰基 (Cx-Ce)烷磺釀基 R10可為相同或不同且為氰 (Ci-Ce)烷基 10 本紙張尺度適用中國國家標準（CNS)A4规格（210 X 297公釐） 83.3.10,000 (請先閱讀背面之注意事項再塡寫本頁) 裝 -J 、言線五、發明説明 A7 B7 濟郎 t ψ § 员I. Description of the invention (A7 B7 part 1% 'p% Ϊ, ± (c) (d) (e) (f) (g) (h) (i) (j) where Re & (a) (b) (c) (d) (e) (f) where 『(a) (b) hydroxyl, amine, (“-“) alkylamino, (“ -Ce) dialkylamino, phenyl, pyridyl , (Ci-Ce) alkoxy, (Cx-Ce) alkane carbonyl partly substituted (C3-Ce) cycloalkyl, optionally with amine, (Ci-C8) alkylamine or (Ci-Ce) Alkylamino substituted amine ("-Ce) alkylamino (Ci-Ce) dialkylamino hydroxy (Ci-Ce) alkoxy (c2-c8) alkenyl (Ci-Cio) alkyl * as required Amino group, (Ci-C *) alkylamino group, (“-“) dialkylamino group substituted (C2-Ce) alkynyl (Ci-Cio) alkyl group, if necessary, M amino group, (“-D alkylamine Group, (Ci-C *) dialkylamine substituted 氲 (Ci-Ce) alkyl— · »-. (Ca-Ce) cyclohomoyl group (Ci-Ce) alkyl group (Ci-Ce) alkoxycarbonyl group ( Cx-Ce) alkanesulfonyl R10 can be the same or different and be cyano (Ci-Ce) alkyl 10 This paper scale is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 83.3.10,000 (please first Read the precautions on the back and then write this page) 装 -J 、言线五、 Invention A7 B7 济郎 t ψ § member

寅， fi -P U 其中R11為 (a) 氫 (b) 羥基 (C) (Ci_Ca)院氧基 (d) 胺基 (e) 烷胺基 (f ) (Cn-Ce)二烷胺基 (g) (C/C8)烷基，視須要Μ胺基、（Ci-CO烷胺基及 (U-CJ二烷胺基取代；其中R12為（Ci-C8)烷基。環庚三烯嗣取代之苯基啤唑啶嗣la、lb、Ic與Id含至少一個對掌性中心。對精於此道者為顯然的*當一個對掌性中心存在時*化合物可以兩種可能之光學異構物[(R)_與 (S)-對掌異構物]中之一·或兩者之外消旋混合物存在。兩者之各別（R)-與（S)-對掌異構物及其混合物在本發明之環庚三烯酮取代之苯基啤唑啶嗣範園内。於另外之對掌性中心存在之情形，所得之非對掌異構物（M外消旋及富有一 ·-- 對掌異構型式）亦在本發明提出申請専利範画之抗细菌劑 la、lb、Ic與Id之範画内。本發明之嗶唑啶嗣之較佳絕對姐態如由一般结構Ia-Id 所表示。Μ絕對組態在Cahn-Ingold-P.relog命名糸統下稱為（S)。以（S)-對掌異構物為具抗细菌活性之光學異構物。外消旋混.合物與肫的（S)-對掌異構物同樣地有用且供同一目的使用*差異在於外消旋物質必須用兩倍之多來產生 11 (請先閲讀背面之注意事項再塡窝本頁) -裝Yin, fi-PU where R11 is (a) hydrogen (b) hydroxy (C) (Ci_Ca) oxy (d) amino (e) alkylamino (f) (Cn-Ce) dialkylamino (g ) (C / C8) alkyl, optionally substituted with Μamino group, (Ci-CO alkylamino group and (U-CJ dialkylamino group; R12 is (Ci-C8) alkyl group. Cycloheptatriene substitution The phenylpyrazolidines la, lb, Ic and Id contain at least one para palmate center. It is obvious to those who are proficient in this way * When a para palmate center exists * the compound can be in two possible optical isomers One of the compounds [(R) _ and (S) -para-isomers] · or a racemic mixture of both. The difference between the two (R)-and (S) -p-isomers And their mixtures are within the cyclopentaquinone substituted phenylpyrazolidine model garden of the present invention. In the presence of other palmitic centers, the resulting non-palmitomeric isomers (M racemic and rich one ·-The palmo-isomeric type) is also within the scope of the antibacterial agents la, lb, Ic and Id in the application of the present invention. The preferred absolute form of the pyrazolidine of the present invention is of general structure Ia-Id. Μ absolute configuration is called under the Cahn-Ingold-P.relog naming system It is (S). The (S) -para- palmisomer is an optical isomer with antibacterial activity. The racemic mixture is the same useful and The use of the same purpose * The difference is that the racemic substance must be produced twice as much (please read the precautions on the back before reading this page)-install

*SJ 線本紙張又度適用中國國家標準（CNS)A4規格（210 X 297公釐） 83.3.10,000 五、發明説明 A7 B7 ί|5 % •Γ 如同（S)-對掌異構物之抗细菌作用。本發明之較佳具«實施例為由通式la與lb表示之啤哇啶酮0 更佳之化合物為la與lb中R2為氫及R3為氫或氟基之化合物。最佳化合物為la為lb中R2與R3皆為氟基及R1為甲基之化合物。琎明夕註Μ銳明各種含烴部分之联原子含量由表示此部分中之最低與最高碳原子數之宇首指示；字首（Ci-Ce)指示包含整數”i” 至整數” j ”碳原子之部分。因此，（G-Ce)烷基係指包含 1至4個碳原子之烷基，或甲基、乙基、丙基、丁基、戊基、己基、庚基、辛基及異構型式。用詞（Ci-Ce)烷胺基意即含1個具1至8涸碳原子之烷基部分之胺基部分。用詞（Ci-Ce)二烷胺基意即含2個具1 至8個碳原子之烷基部分之胺基部分。分別例如丙胺基及二丙胺基。用詞視須要ϋ意即此部分可K 1至4個列舉之取代基取代。例如·（“-(：««)烷基視須要Μ氯基、氟基、羥基、 (CfCis)烷氣基、胺基、（“-Ce)烷胺基、（Cx-C*)二烷胺基取代包括1-氮丙基、1-氟丙基、3-氛丙基、3-氟丙基、1-羥丁基、2-羥丁基、1-甲氧丙基、1-辛氧丙基、卜胺丙基、1-胺辛基、卜丁胺丙基、1-二丁胺丙基之類。 12 本紙張尺·度適用中國國家標準（CNS)A4规格（210 X 297公釐） 83.3.10,000 (請先閲讀背面之注意事項再填寫本頁) 1 A7 B7 五、發明説明式T a h会物夕聰儋製備本發明化合物之代表性製程概要於卜7圈中。1-4 圓描述富有對掌異構之環庚三烯酮取代之啤唑啶酮之製備 * 5-7圔顯示至外消旋中間物及類似物之途徑。顯然於精於此道者的是這些只是代表性製程•將允許將提供之合成計畫窨做稍微修飾，製備環庚三烯酮取代之苯基嗶唑啶飼之另外實例。 -----------1 -^---- (請先閲讀背面之注意事項再塡寫本頁) J Μ0 線祁 $ 13 83.3.10,000 本紙張又度適用中國國家標準（CNS )八4规格（210 X四7公釐） A6Ββ* SJ line paper is again applicable to the Chinese National Standard (CNS) A4 specifications (210 X 297 mm) 83.3.10,000 V. Description of the invention A7 B7 ί | 5% • Γ is like (S)-resistance to palm isomers Bacterial effect. The preferred embodiment of the present invention is a pravalidone represented by the general formulas la and lb. The more preferred compounds are the compounds in which la and lb have R2 as hydrogen and R3 as hydrogen or fluorine. The most preferable compound is a compound in which la is lb and R2 and R3 are both fluorine groups and R1 is methyl group.鐎明夕注 M Ruiming The content of the linked atoms of various hydrocarbon-containing parts is indicated by the Yushou, which represents the lowest and highest number of carbon atoms in this part; the prefix (Ci-Ce) indicates that the integer contains "i" to integer "j" The carbon atom. Therefore, (G-Ce) alkyl refers to an alkyl group containing 1 to 4 carbon atoms, or methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and isomeric forms. The term (Ci-Ce) alkylamino means an amine moiety containing an alkyl moiety having 1 to 8 carbon atoms. The term (Ci-Ce) dialkylamino means an amine moiety containing 2 alkyl moieties with 1 to 8 carbon atoms. Examples are propylamino and dipropylamino. The wording needs to mean that this part can be replaced by K 1 to 4 listed substituents. For example, (“-(:« «) alkyl requires chloro, fluoro, hydroxy, (CfCis) alkane, amine, (“ -Ce) alkylamine, (Cx-C *) dioxane Amino substitutions include 1-azapropyl, 1-fluoropropyl, 3-aminopropyl, 3-fluoropropyl, 1-hydroxybutyl, 2-hydroxybutyl, 1-methoxypropyl, 1-octyl Oxypropyl, propylamine, 1-aminooctyl, butylaminepropyl, 1-dibutylaminepropyl, etc. 12 The paper size and degree are applicable to China National Standard (CNS) A4 specification (210 X 297 Mm) 83.3.10,000 (please read the precautions on the back before filling in this page) 1 A7 B7 5. Description of the invention The representative process for preparing the compounds of the present invention is summarized in circle 7 of Bu. 1 -4 circle describes the preparation of palmitoxenone-substituted pyrazolidinone, which is rich in para-isomerism. * 5-7 shows the route to racemic intermediates and the like. Obviously those who are skilled in this These are only representative processes. • The synthetic plans provided will be allowed to be modified slightly to prepare another example of cycloheptrienone-substituted phenylpyrazolidine feed. ----------- 1- ^ ---- (Please read the notes on the back before writing this page) J Μ0 line Qi $ 13 83.3.10,000 This paper is again applicable to the Chinese National Standard (CNS) 8.4 specifications (210 X 4.7 mm) A6Ββ

{CSs) ι X 'J'J： r.r,·) A7 B7 五、發明説明（）如_1所示•將中間物6 (如圔3與4中所示製備）與新穎 (請先閲讀背面之注意事項再填寫本頁) 環庚三烯_7 (自已知之溴基環庚三烯嗣8製備， B a n w e 1 1 等人，0 r g · P r e p . P r 〇 c . (19 8 8) 3 9 3 ;{CSs) ι X 'J'J: rr, ·) A7 B7 5. Description of the invention () As shown in _1 • Intermediate 6 (prepared as shown in 圔 3 and 4) and novel (please read the back first Please fill in this page again) cycloheptatriene_7 (prepared from the known bromocycloheptatriene 8, Banwe 1 1 et al. 0 rg · P rep. P r 〇c. (19 8 8) 3 9 3;

Banvell 等人，Tetrahedron Lett. (1985). 26, 4543，如鼷1之底所示）於竈宜之鈀觸媒如氣化肆（三笨基膦）鈀或雙（三苯基膦）鈀存在下、於逋宜溶蜊如H,N-二甲基甲醢胺（DMF)或1,4-二嗶烷中*於*宜湛度（典型地 70-lOOt!)下反應，供給偶聯之產物9 。化合物9為结構 la之環庚三烯嗣取代之苯基啤唑啶酮之實例、且若須要可藏由將9與缠宜親核性物如胺於遽宜溶劑***如甲苯或四氫呋喃水/水中，於»宜溫度（周園至迴流溫度）下反應進一步處理*得另外之la實例。化合物9之甲氧基亦可Μ 替代之烷氣基殘基代替·鞴由將9與所須之酵（通常以過量），於催化量之«[例如氢化钠存在下反應•得欏的之加成物（參見-實例之實驗節）。將顧然於精於此道者為所須之R1基可在鈀媒介之偁聯步骤以前•已存在於瑁庚三烯嗣7上。亦將顧然於精於此道者為改變所用之溴基環庚三嫌酮（上面之參考，Takaya等人，J. Ae. Che·. Soc. ( 1978) , 100, 1778等）及各種中間物之取代基·容許製佾為本發明禰羅之其他富有對掌異構之式Ia-d之瑁庚三烯醑取代之苯基噚唑啶嗣。 -15 - 本紙張尺度適用中國國家標準（CNS)A4规格（21〇 X 2耵公釐） 83.3_10,000Banvell et al., Tetrahedron Lett. (1985). 26, 4543, as shown at the bottom of Na 1) Yu Zaoyi ’s palladium catalysts such as gasification (tribenzylphosphine) palladium or bis (triphenylphosphine) palladium In the presence of, it should be dissolved in a suitable clam such as H, N-dimethylformamide (DMF) or 1,4-dipyrane * to be reacted under the optimum concentration (typically 70-lOOt!).联的产品 9. Compound 9 is an example of a phenylpyrazolidone substituted with cycloheptatriene of structure la, and if necessary, it can be stored by combining 9 with a nucleophilic substance such as an amine in a suitable solvent system such as toluene or tetrahydrofuran water / In water, the reaction is further processed at the appropriate temperature (Zhouyuan to reflux temperature) * to obtain another example of la. The methoxy group of compound 9 can also be replaced by an alkyl group residue substituted by M. The reaction of 9 with the required enzyme (usually in excess) in a catalytic amount of «[eg in the presence of sodium hydride Adducts (see-Experimental Section of Examples). The R1 group required for Gu Ranyu to be skilled in this way can exist on the heptatriene heir 7 before the palladium-medium coupling step. Gu Ranyu will also use the bromocycloheptanone which is used by those who are proficient in this method (reference above, Takaya et al., J. Ae. Che ·. Soc. (1978), 100, 1778, etc.) and various Substituents of intermediates are allowed to be prepared by other phenylpyrazolidines of the present invention, which are rich in para-isomers of formula Ia-d. -15-This paper scale applies the Chinese National Standard (CNS) A4 specification (21〇 X 2 mm) 83.3_10,000

Λ 6 BG 五、發明説明（14 I2Λ 6 BG 5. Description of the invention (14 I2

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iieO R2iieO R2

Pd m媒Pd m media

<功先閲:5背0&之;±5事項再培寫衣頁)< Prior reading: 5 back 0 &; ± 5 matters before writing the page)

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0., f ι50., f ι5

Λ yicoi1 la 16 (CNS) >P t twjr>(210 X 297 A7 B7 五、發明説明（）圖2中顯示另外之合成替代法，其中中間物6 (如圔3與 4中之指示製備）之澳或磺進行鹵素-金靥交換反應，得金臞化之衍生物10(M = Me3Sn或ZnX) ·其再與溴基環庚三稀鼷8於逋宜鈀觸媒如氣化肆（三苯基膦）鈀或雙（三苯基膦）鈀存在下，於適宜溶劑如Ν,Ν-二甲基甲醢胺（DMF)或 1,4-二嗶烷中，於遒宜溫度（典型地70-1001C)下進行偁聯反應，完成偁聪之產物9 ，若須要，再將化合物9進 —步如上述處理。 (請先閲讀背面之注意事項再塡寫本頁) 裝訂 < 線 f !* 17 83.3.10,000 本紙張又度適用中國國家標準（CNS)A4规格（210 X 297公釐） A6 B6 五、發明説明（Μ ) mΛ yicoi1 la 16 (CNS) > P t twjr > (210 X 297 A7 B7) 5. Description of the invention () FIG. 2 shows another synthetic alternative method, in which intermediate 6 (prepared as indicated in 圔 3 and 4) O- or sulfone undergoes a halogen-golden exchange reaction to obtain a gold-bearing derivative 10 (M = Me3Sn or ZnX). It is then combined with a bromocycloheptatrile 8 in a palladium catalyst such as a gasification plant ( In the presence of triphenylphosphine) palladium or bis (triphenylphosphine) palladium, in a suitable solvent such as N, N-dimethylformamide (DMF) or 1,4-dibenzane, at an appropriate temperature ( Typically 70-1001C) under the sieve reaction to complete the product of chong Cong 9, if necessary, then compound 9 is further processed as described above. (Please read the precautions on the back before writing this page) Binding < Line f! * 17 83.3.10,000 This paper is again applicable to the Chinese National Standard (CNS) A4 specifications (210 X 297 mm) A6 B6 V. Invention description (Μ) m

22twenty two

(I = I) «： Ύ MM vf* ^C\S) (Jiu X 1-J： ) s^9332 A7 B7五、發明説明（）圖3概要富有對掌異構之结構6中間物之製備。结構6 (見上）為製備本發明檷題之旋光性環庚三烯嗣取代之苯基啤唑啶嗣la之製備（參見圖1與2)所須。於此製程中之鼷鍵之第一步驟包括視須要取代之異氰酸苯酯（11)與商業上可得之（-)-(R)-丁酸縮水甘油酯 > 使用首先由Herweh等人於Tetrahedron Lett. (1971), 809所用之條件反應，得苯基嗶唑啶鬭中間物12。使用丁酸縮水甘油酯於此種反應製備噚唑啶萌中間物揭示於美國專利4,705,799 。於公開文獻中之刊物亦已出現*例如Gregory等人，J. Med Chen. (1989), 32, 1673 。丁醣基再藉由與酵鹽（較好為甲酵納）於甲酵中反應除去，完成酵13(R = H)。再將化合物13藉由甲磺醢氛/吡啶或甲磺雄氨/三乙胺/二氛甲烷或對甲苯磺醢氛/吡啶之作用•轉化成對應之甲基磺酸酯 (R = S〇2CH3)或芳基磺酸酯（R = S〇2Ar)衍生物（較好是甲磺酸酯或甲苯磺酸釀）。所得磺酸酷再輿叠氮化物如叠氬化納或鉀於非質子溶爾如DMF或1-甲基-2-吡咯烷酮中，視須要於觴媒如18-冠-6存在下•於50°至90 t：之溫度下作用一--. 提供叠氮化物14。叠氮化物14再»由Pd/C或鉑觸媒於«當溶劑如乙酸乙酷或甲酵中氫化堪原。替代地，此叠氮化物可»由从三價磷化合物如三笨基膦於水存在下，並於班宜溶劑如四氫呋喃（THF)中處理堪原。再將藉由通原叠氮化物14所得之胺甲基化合物藉精於此道者已知之反應酿基化 •得结構15 >中間物。例如•可將此胺與鼸氛或酸鼾於鐮性溶劑如吡啶中，於範麵由-30°至50 之灌度下反應· -19 - 本紙張又度適用中國國家標準（CNS )A4規格（210 X 2町公釐） 83.3.10,000 (請先閲讀背面之注意事項再填寫本頁) f 裝(I = I) «: Ύ MM vf * ^ C \ S) (Jiu X 1-J:) s ^ 9332 A7 B7 V. Description of the invention () Figure 3 outlines the preparation of the intermediate 6 with a heterogeneous structure . Structure 6 (see above) is required for the preparation of the optically active cycloheptatriene substituted phenylpyrazolidine la of the present invention (see FIGS. 1 and 2). The first step of the bond in this process includes optionally substituted phenyl isocyanate (11) and commercially available (-)-(R) -glycidyl butyrate > used first by Herweh, etc. People reacted under the conditions used in Tetrahedron Lett. (1971), 809 to obtain phenylpyrazolidine intermediate 12. The use of glycidyl butyrate in this reaction to prepare oxazolidine intermediates is disclosed in U.S. Patent 4,705,799. Publications in public literature have also appeared * such as Gregory et al., J. Med Chen. (1989), 32, 1673. The butanose group is then removed by reacting with fermented salt (preferably formazan) in formazan to complete the fermentation 13 (R = H). The compound 13 is then converted into the corresponding methanesulfonate by the action of mesylate / pyridine or mesylate / triethylamine / dichloromethane or p-toluenesulfonate / pyridine (R = S〇 2CH3) or aryl sulfonate (R = S〇2Ar) derivatives (preferably mesylate or toluenesulfonate). The resulting sulfonic acid azide such as sodium azide or potassium in an aprotic solvent such as DMF or 1-methyl-2-pyrrolidone, if necessary in the presence of a medium such as 18-crown-6 ° to 90 t: a role under the temperature --- Provide azide 14. The azide 14 is then hydrogenated by Pd / C or platinum catalyst in «as solvent such as ethyl acetate or formazan. Alternatively, the azide can be treated from a trivalent phosphorus compound such as tribenzylphosphine in the presence of water and treated in a Banyi solvent such as tetrahydrofuran (THF). The amine methyl compound obtained from the original azide 14 is then basified by reactions known to those skilled in the art. • Structure 15 > intermediate is obtained. For example, this amine can be reacted with a snorkel or acid snoring in a sickle solvent such as pyridine, at a range of -30 ° to 50 degrees. -19-This paper is also applicable to the Chinese National Standard (CNS) A4 Specifications (210 X 2 mm) 83.3.10,000 (Please read the precautions on the back before filling out this page) f

，5J 線 A7 B7 五、發明説明（）提供醢基化之中間物15其中Rh視須要取代之烷基。將顯然於精於此道者為本發明之其他》基可«由精於此道者已知之檷準豳基化技術，容易地附加於胺甲基中間物。將中間物15M氛化碘於乙酸/三氟乙酸中於0°至70t：之溫度下，或Μ碘及三氟乙酸銀碘化*得富有對掌異構之碘笨基嗶唑啶醑中間物6(Χ=Ι)。替代地，可將15ΚΝ-溴基琥珀醮亞胺澳化得澳化之同類物6(X = Br)。 (請先閲讀背面之注意事項再塡寫本頁) 裝線 -20 - 83.3.10,000 本紙張又度適用中國國家標準（CNS)A4规格（210 X 29*7公釐）五、發明説明（19 ) A6 B6 m一一j, 5J line A7 B7 V. Description of the invention () Provide an alkylated intermediate 15 where Rh is optionally substituted alkyl. It is obvious that those skilled in the art are the others of the present invention. The quasi-quasi-ylation technology known by those skilled in the art can easily be attached to the amine methyl intermediate. Intermediate 15M iodized iodine in acetic acid / trifluoroacetic acid at a temperature of 0 ° to 70t: or iodine and silver trifluoroacetate iodide物 6 (Χ = Ι). Alternatively, 15KN-bromosuccinimide imine can be oxalized to obtain the oxalized analog 6 (X = Br). (Please read the precautions on the back before writing this page) Binding Line -20-83.3.10,000 This paper is again applicable to the Chinese National Standard (CNS) A4 specification (210 X 29 * 7 mm) V. Description of the invention (19 ) A6 B6 m one one j

6 (¾先閱讀戈忐之注意事項再項寫本頁) 丨裝· 訂. 線‘ 21 A7 B7 五、發明説明（）圈4描述匾3中所述之合成計畫軎之變化法*其中结構 6之碘或溴部分（X)已存在於用於次序之第一步»中之異氰酸芳基海16中。用圃3中所述反應（見上），將異氰酸芳基酯16首先轉化成噚唑啶嗣17，且随後成衍生物18與19。再將叠氮化物19藉由將其與三價磷化合物如三苯基膦、於水存在下、於適宜溶劑如THF中反應堪原。所得胺甲基中間物之醢化則提供富有對掌異構之化合物6 。 (請先閲讀背面之注意事項再填寫本頁) 裝6 (¾ Read Gor's precautions first and then write this page) 丨 Package · Order. Thread '21 A7 B7 V. Description of Invention () Circle 4 Describe the change method of the synthetic plan described in the plaque 3 * Among them The iodine or bromine portion (X) of structure 6 is already present in the aryl sea 16 of isocyanate used in the first step of the sequence ». Using the reaction described in Garden 3 (see above), the aryl isocyanate 16 is first converted to oxazolidine 17 and then to derivatives 18 and 19. The azide 19 can then be reacted by reacting it with a trivalent phosphorus compound such as triphenylphosphine in the presence of water in a suitable solvent such as THF. The resulting amine methyl intermediates provide compounds rich in para-isomers 6. (Please read the precautions on the back before filling out this page)

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05 13 (A = H) 18 (A = Br. Γ) 23 ·· ·?； (cns) r -I κ\:> (-ίο x ：,ij： ^ A7 B7 五、發明説明（）圃4a描述富有對掌異構之结構13(見圓3)及18(見圖4)之中間物之替代製備法。於此次序中，將缠當之Cbz保護之苯胺（易於藉由標_史庫添-雎曼（Schotten-Baumann)條件或已知於精於此道者之其他變化法製備）Μ正丁基鋰於適宜溶劑如四氬呋喃中及於適宜溫度如-78至-68 t：下脫去質子。加商業上可得之（-)-(R) -丁酸縮水甘油_ *接著湛至周溫，則直接提供羥甲基取代之苯基啤唑啶蘭中間物 13(A = H)及18(A = Br, I)。化合物13與18用1-4黼中概要之方法可容易地轉化成富有對掌異檐之式la至Id之環庚三烯酮取代之苯基嗶唑啶_。 (請先閲讀背面之注意事項再填寫本頁) 裝線 -24 - 本纸張尺度適用中國國家標準（CNS)A4規格（2丨〇 X 297公釐） 83.3.10,000 A6 B6 五、發明説明（23 )05 13 (A = H) 18 (A = Br. Γ) 23 ····; (cns) r -I κ \: > (-ίο x ：, ij: ^ A7 B7 V. Invention description () nursery 4a describes an alternative preparation method for intermediates rich in para-isomerized structures 13 (see circle 3) and 18 (see FIG. 4). In this sequence, the aniline protected by Cbz (which is easy to pass Kutin-Baumann conditions or other known methods known to those skilled in the art) M n-butyl lithium in a suitable solvent such as tetrahydrofuran and at a suitable temperature such as -78 to -68 t : Deprotonation. Add commercially available (-)-(R) -butyric acid glycidyl _ * Then Zhan to the ambient temperature, then directly provide hydroxymethyl substituted phenyl pyrazolidine intermediate 13 ( A = H) and 18 (A = Br, I). Compounds 13 and 18 can be easily converted to cycloheptatrione substituted by the formula la to Id, which is rich in palmate eaves by the method outlined in 1-4. Phenylpyridine_. (Please read the precautions on the back before filling out this page) Binding -24-This paper size is applicable to China National Standard (CNS) A4 specifications (2 丨〇X 297mm) 83.3.10,000 A6 B6 5. Description of the invention (23)

五、發明説明（） A7 B7 圖5描述至外消旋環庚三烯嗣取代之啤哇啶_抗细菌劑之途徑。於代表性實例中•將自4 -溴苯胺於檷準史庫添-跑曼條件下製備之Cbz衍生物20(X = Br)，M2當量正丁基鋰於THF中。-78°至-40 t：下處理，再以氣化三丁基鍚中止反應，得鍚衍生物21 (R =正丁基）。再將化合物21與澳基環庚三烯鼷8 ，於逋宜鈀觸媒如氛化肆（三苯基膦）鈀或雙（三苯基膦）鈀存在下，於適宜溶劑如Ν,Ν -二甲基甲醢胺（DMF)或1,4-二啤烷中，於適宜溫度（典型地 70-100 =)下反應，完成偶脚產物22。22之烯丙基化係箱由Κ逋宜之《{如氫化納，於缠宜溶劑如THF中脫去質子，再將反應混合物以烯丙基澳，視須要於催化性碘化物源如碘化四丁基銨存在下，於周溫至渔流溫度下處理來完成提供23，使中間物23受到卡迪羅-歃諾（Cardillo-Ohno)環胺基甲酸酯化反應，包括將23M碘於逋宜溶劑如氣仿中及於缠宜溫度（典型地為周溫）下處理*提供碘甲基嗶唑啶酮 2 4 , C a r d i 1 I 〇等人，T e t r a h e d r ο η (1 9 8 7 )，4 3，2 5 0 5， 0 h η o 等人，T e t r* a h e d r ο n L e 11. (1 9 8 7 ) , 2 8 , 3 1 2 3。可再將化合物24藉由三種反應之次序較化成25(為结構la之類似物實例）。這些反應包括叠氮化物置換。缠原成對應之胺甲基啤唑啶嗣及釀化反應，所有反應皆如上述进行。將顯然於精於此道者為合理的變化各種殘基之取代基•容許製備為本發明禰題之其他外消旋之式la州之環庚三烯醑取代之苯基噚啤啶醑。 -26 - 衣紙張尺度適用中國國家標準（CNS)A4規格（2!〇 X 297公釐） 83.3.10,000 (請先閲讀背面之注意事項再填寫本頁) 裝 J *言線 ΑΰV. Description of the invention () A7 B7 Figure 5 describes the route to the racemic cyproterone substituted antipyrudin_antibacterial agent. In a representative example, Cbz derivative 20 (X = Br), M2 equivalent of n-butyl lithium prepared from 4-bromoaniline under the conditions of quasi-Skutin-Runman, M2 equivalent of n-butyl lithium in THF. -78 ° to -40 t: under treatment, and then the reaction is terminated with gasified tributyl thorium to obtain thorium derivative 21 (R = n-butyl). Then, compound 21 and o-cycloheptatrienol 8 are used in the presence of a suitable palladium catalyst such as palladium (triphenylphosphine) palladium or bis (triphenylphosphine) palladium in a suitable solvent such as Ν, Ν -In dimethylformamide (DMF) or 1,4-dibrane, react at a suitable temperature (typically 70-100 =) to complete the production of the foot product 22. The allylation system of 22 is composed of Κ Yi Yizhi "{such as sodium hydride, deprotonated in a suitable solvent such as THF, and then the reaction mixture to allyl o, if necessary in the presence of a catalytic iodide source such as tetrabutylammonium iodide, in the week The treatment is carried out under the temperature of the fishing stream to complete the provision of 23, and the intermediate 23 is subjected to Cardillo-Ohno cyclic carbamate esterification reaction, including 23M iodine in a suitable solvent such as aerobic and Treatment at an appropriate temperature (typically a weekly temperature) * Provides iodomethylpyridazolone 2 4, C ardi 1 I 〇 et al., T etrahedr ο η (1 9 8 7), 4 3, 2 5 0 5, 0 h η o et al., T etr * ahedr ο n L e 11. (1 9 8 7), 2 8, 3 1 2 3 Compound 24 can be compared to 25 by the order of the three reactions (an example of the analog of structure la). These reactions include azide substitution. The entangled raw materials form the corresponding amine methyl pyrazolidine and brewing reactions, and all reactions proceed as described above. It will be apparent to those skilled in the art that it is reasonable to change the substituents of various residues. • It is possible to prepare phenyl-pyridinium substituted for the other racemic formula la state cycloheptatriene which is the subject of the present invention. -26-The size of clothing paper is in accordance with Chinese National Standard (CNS) A4 specification (2! 〇 X 297mm) 83.3.10,000 (please read the precautions on the back before filling in this page) Install J * 言线 Υ

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! 1 4Ί I i !1 I , _ _ n 丨丨 I —Λ^〆 I — I I ί _.τ丨丨! I 約9332 A7 B7 五、發明説明（）圖6概要了至外消旋之结_Ia之嗶唑啶酮之另外之合成處理方法•其可視為圃1、2與5之混合體。將自對應之苯胺經由檷準之史庫添-跑跑曼條件製得之Cbz衍生物26, 首先藉由K癰宜之«[如氫化納於適宜溶劑如THF中脫去質子*再將反應混‘合物以烯丙基溴，視須要於催化性碘化物源如碘化四丁基铵存在下.，於周溫至迺流溫度下烯丙基化提供27。將中間物27受卡迪羅-歐諾環胺甲酸_化反應，包括將27以碘於適宜溶劑如氫仿中及於缠宜溫度（典型地為周溫）下處理•提供碘甲基噚唑啶酮28。再將磺化物 28與叠氮化物源如叠氮化納或鉀，於非質子溶劑如DMF或 1-甲基-2-吡咯烷嗣中，視須要於觸媒如18-冠-6存在下，於50°至90¾之溫度下反應，提供叠氮化物29。再將叠氮化物箱由K Pd/C或鉑觸媒於適當溶劑如乙酸乙酷或甲酵中氫化而堪原。替代地，可將叠氮化物«由Μ三價磷化合物如三苯基膦於水存在下，於通宜溶繭如四氫呋哺（THF)中處理而«原。再將自叠氮化物29所得之胺甲基化合物《由巳知於精於此藏f之反應醣基化，得中間物结構30。30之苯基環用上述製備視情況為活性之中間物6之條件溴化或碘化，則提供外消旋化合物31。结構31之中間物可再處理成外消旋之式la之環庚三烯願取代之苯基嗶唑啶醣•«由用來轉化富有對掌異構之结構6中間物成la之技術（見圈 1與2)為之。將顧然於精於此道者的是合理的變化各種殘基之取代基/容許製備為本發明檷®之其他外消旋之式 la-d之環庚三烯醑取代之苯基嗶唑啶醑。 -28 - 本紙張疋度適用中國國家標準（CNS)A4規格UlO X297公釐） 83.3.10,000 (請先閲讀背面之注意事項再填寫本頁) 裝訂線! 1 4Ί I i! 1 I, _ _ n 丨丨 I —Λ ^ 〆I — II ί _.τ 丨丨 !! I about 9332 A7 B7 V. Description of the invention () Figure 6 summarizes the knot to race _Ia's other synthetic treatment method of oxazolidone • It can be regarded as a mixture of garden 1, 2 and 5. The Cbz derivative 26 prepared from the corresponding aniline through the standard Shikutian-Runman conditions is first deprotoned by K 爈宜的 «[such as hydrogenation in a suitable solvent such as THF * and then the reaction The mixture is allyl bromide, optionally in the presence of a catalytic iodide source such as tetrabutylammonium iodide. Allylation at ambient temperature to bleed temperature provides 27. Intermediate 27 is subjected to Cardio-onoframic acid formic acid reaction, including treatment of 27 with iodine in a suitable solvent, such as hydroform, and at a suitable temperature (typically ambient temperature) Azolidinone 28. The sulfonate 28 and azide source, such as sodium or potassium azide, in an aprotic solvent such as DMF or 1-methyl-2-pyrrolidine, if necessary in the presence of a catalyst such as 18-crown-6 , At a temperature of 50 ° to 90¾ to provide azide 29. The azide tank is then hydrogenated by K Pd / C or platinum catalyst in an appropriate solvent such as ethyl acetate or formazan. Alternatively, the azide can be treated «from a M trivalent phosphorus compound such as triphenylphosphine in the presence of water in a Tongyi soluble cocoon such as tetrahydrofurfur (THF). Then, the amine methyl compound obtained from the azide 29 is glycosylated by the reaction known to be skilled at the reservoir f to obtain the intermediate structure 30. The phenyl ring of 30 is prepared as described above and is optionally an active intermediate 6 The conditions of bromination or iodination provide racemic compound 31. The intermediate of structure 31 can be reprocessed into the racemic formula la phenylpyrazolidine sugar substituted by cycloheptatriene. «From the technique used to convert the intermediate 6 rich in para-isomers into la ( See circles 1 and 2) for this. It is reasonable to be skilled in this field to reasonably change the substituents of various residues / allow the preparation of phenylpyrazole substituted with cycloheptatriene bispyridine of the other racemic formula la-d of the Pentium® of the present invention Pyridine. -28-This paper is suitable for China National Standard (CNS) A4 specification UlO X297 mm) 83.3.10,000 (please read the precautions on the back before filling this page) Binding line

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ncoi1 1 29 ^ (CNS) 1 ^J.> (210 X ：,!J7 ) 五、發明説明（圖7 溴或碘烯丙基之碘基叠氮化價磷化中反應化合物之稍微例〇用於地藉先本發括其蕖 Η3?Ολ 及有櫬來酸、製造之 R1為羥離子但離子如本發種活性 0 . 1至 A7 B7 描述示於圖6中之概要圖之變化法，其中结構31之原子已存在於Cbz -取代之起始物質32。32如上述之化提供加成物33。33於通常之卡迪羅-歐諾條件下環胺基甲酸酷化則完成碘甲基吗唑啶酮中間物34。物置換提供叠氮甲基嗶唑啶嗣35*其藉由將其K三合物如三苯基膦·於水存在下及於逋宜溶劑如THF 而理原。所得之胺甲基中間物之醢化則提供外消旋 31，其可容易地轉化成外消旋之la。此實驗計畫窖修飾將容許精於此道者製備嗶唑啶酮la-d之另外實 1至7圖之方法中之起始物質皆為商業可得或可容易前技蕤中已知之方法製造。明當式I化合物中有驗性基如胺基殘基存在時，包用酸加成鹽。尤佳者為自礦酸（HC1 、HBr 、 1!23〇4等）、有機磺酸（甲磺酸、對甲苯磺酸等）羧酸（乙酸、琥珀酸、酒石酸、擰攆酸、乳酸、馬草酸等；肢基酸；糖酸如蔔糖酸及半乳糖醛酸等） —* ·. 那些鹽。當式I化合物有酸性基存在如羧酸或當基時*亦包括其第用嫌加成蘧。此等蘧包括下列陽不限於埴些：«Ϊ金觴離子如鉀、納、鋰土金牖鎂或鈣；銨離子如銨、四丁基銨及吡錠。明化合物可口服、局部或腸外給藥。一般而言•此組份·之抗细菌上有效劑量將在每公斤《盪每天約 100 (較好約3至約50)奄克之範麵，依患者之«簠 30 本紙張又度適用中國國家標準（CNS)A4規格（210 X 297公釐） 83.3.10,000 (請先閱讀背面之注意事項再塡寫本頁) 裝訂線 A7 B7 五、發明説明（）、年龄及情況而定。此劑量較佳地可κ分開之劑董投予且每天投予2-4次。較佳之投予途徑及對於患者或口服途徑之特別劑fi依情況之特別實情包括感染之性質（涉及之特別微生物、其毒性、感染之程度）及患者之年龄、®簠、性別與一般身體情況而定。缠宜腸外給藥（溶液、油中懸浮液）及口服（錠劑、膠囊劑、糖漿劑、懸浮液等）之一般轚藥劑型為精於此道者所知，且有W使用式I之瑁庚三烯嗣取代之苯基啤唑啶酮之劑型並無不尋常之處。本發明各種化合物抗金黄色葡萄球菌之活《外抗细菌活性係藉由技藝中已知之方法测定並示於表1中。埴些為用於處理哺乳類（人與動物如牛、馬、羊、狗、貓等）由革 «氏限性及厭氧性生物所引起之感染之抗细菌劑。式I之環庚三烯嗣取代之笨基嗶唑啶嗣亦用於處理被一種或多種分枝桿菌菌種感染之患者。特別重要的*本發明之la-Id 化合物用於處理被结核分枝桿菌及烏分枝桿菌感染之患者〇式I之環庚Ξ择酮取代之苯基噚唑啶酮可覃用或與其化已知於精於此道者之抗细菌或非抗细菌_併用。斛備1 三正丁基[4-(苄氧羰胺基）苯基]» 將1<-(^2-4-溴基苯胺（3.08克，11.2奄其耳）溶於50奄升無水THF並將溶液經由乾冰/丙嗣浴冷卻至- 78t!。其次 •於5分内加正丁基鋰溶液（1.6M (於己烷中）， -31 - 83.3.10,000 (請先閱讀背面之注意事項再塡寫本頁) 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 2们公釐）五、發明説明（）ncoi1 1 29 ^ (CNS) 1 ^ J. > (210 X:,! J7) V. Description of the invention (Figure 7 A few examples of reaction compounds in the iodide azide phosphating of bromine or iodoallyl. It is used for the first time, including the original Η3? Ολ and citric acid, R1 is made of hydroxyl ions but the ions are as active as the present species 0.1 to A7 B7 describes the method of change shown in the schematic diagram in Figure 6 , Where the atoms of structure 31 already exist in the Cbz-substituted starting material 32. 32 as described above provides the adduct 33. 33 under normal Kadiro-Uno conditions cyclic carbamic acid is quenched to complete iodine Methylmazolidinone intermediate 34. Substitution provides azidomethylpyrazolidine 35 * by combining its K trimer such as triphenylphosphine in the presence of water and in a suitable solvent such as THF. The rationale. The resulting amine methyl intermediate provides the racemate 31, which can be easily converted into the racemic la. This experimental plan cellar modification will allow those who are skilled in this process to prepare azolidinone The starting materials in the methods of Figures 1 to 7 for la-d are all commercially available or can be easily prepared by known methods in the prior art. When an authentic group such as an amine residue is present, an acid addition salt is used. The preferred ones are self-mineral acids (HC1, HBr, 1,23〇4, etc.), organic sulfonic acids (methanesulfonic acid, p-toluenesulfonic acid Etc.) Carboxylic acids (acetic acid, succinic acid, tartaric acid, fumaric acid, lactic acid, horse oxalic acid, etc .; alkaloid acids; sugar acids such as glucuronic acid and galacturonic acid, etc.)-* · those salts. When the compound of formula I The presence of acidic groups such as carboxylic acid or radicals * also includes the first additions. These include the following ions, but not limited to: «Ϊgold ions such as potassium, sodium, lithium earth, magnesium or calcium ; Ammonium ions such as ammonium, tetrabutylammonium, and pyridium. Ming compounds can be administered orally, topically, or parenterally. Generally speaking, the effective dose of this component for anti-bacteria will be about 100 Preferably about 3 to about 50) 圄克的面面, according to the patient's «簠 30 This paper is again applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 83.3.10,000 (please read the notes on the back first Re-write this page) Binding line A7 B7 V. Description of the invention (), age and circumstances. This dose is preferably administered by a separate agent that can be separated by κ It is administered 2-4 times a day. The preferred route of administration and the special agent fi for patients or oral routes, depending on the circumstances, include the nature of the infection (special microorganisms involved, their toxicity, degree of infection) and the age of the patient , ® 簠, gender and general physical conditions. The general dosage forms for parenteral administration (solution, suspension in oil) and oral administration (lozenges, capsules, syrups, suspensions, etc.) are good at As is known to this expert, it is not unusual to have a dosage form of phenylpyrazolidinone substituted with pentapentarin of formula I. The activity of various compounds of the invention against Staphylococcus aureus The activity was measured by a method known in the art and shown in Table 1. These are antibacterial agents used to treat infections caused by leather-bound and anaerobic organisms in mammals (humans and animals such as cattle, horses, sheep, dogs, cats, etc.). The stupylpyridazolium substituted by cycloheptatriene of formula I is also used to treat patients infected with one or more mycobacterial strains. Particularly important * The la-Id compound of the present invention is used to treat patients infected with Mycobacterium tuberculosis and Mycobacterium tuberculosis. Phenazolidinone substituted with cycloheptazone of formula I can be used or converted Anti-bacterial or non-antibacterial known to those skilled in this are used together.斛备 1 Tri-n-butyl [4- (benzyloxycarbonylamino) phenyl] »dissolve 1 <-(^ 2-4-bromoaniline (3.08 g, 11.2 mols) in 50 liters of anhydrous THF And cool the solution to -78t by dry ice / propylene bath. Secondly, add n-butyl lithium solution (1.6M (in hexane), -31-83.3.10,000 within 5 minutes (please read the notes on the back Matters will be written on this page) This paper scale is applicable to the Chinese National Standard (CNS) A4 specification (210 X 2 mm) V. Description of invention ()

Aldrich, 23.52毫莫耳）。溶液變成深黄色。攢拌溶液 10分並以氯化三正丁基鍚（3.83充，11.76¾其耳）中止反應。黃色之漿變成無色溶液。攪拌30分並溫至-2〇υ後· Μ胞和NIUC1水溶液（50奄升）中止反應。將反應混合物與 250毫升醚及100 «升水一起倒入分液漏斗中。振搖混合物並分離有櫬相再於無水Ha2S〇4上乾煉、通»並濃鑲得油，將其藉曆析法於矽膠上（K20:l己烷/醚溶離）純化。單雛2. 99克禰囲化合物為無色油。 MS(EL):m/z 相對強度：460 (25), 404 (5), 227,91 (100). NMR CDC 13 ： δ 7.48-7.31 (·, 9Η) , 5.19 (s, 2Η), 1.55-1.47 (β. 6Η), 1.38-1.26 (， 6Η), 1.03 (t, 6Η, J=8.33 Hz), 0.877 (t, 9Η, J=7.26 Hz). 製備2 N-(苄氧羰基）-4-(4-甲氧基-5-醑基-1 · 3,6-環庚三烯-1-基）苯胺將三正丁基[4-(苄氧羰胺基）苯基]鍚（726奄克，1.4毫莫耳）溶於10春身1,4-二啤烷中並加5-澳-2-甲氧基環庚 -2,4,6-三烯•卜_ (215奄克，1.0毫莫耳），所得之漿藉抽空脫氣並Μ N2沖洗（3次）。加觴媒氱化雙（三苯基膦）鈀 (II)，混合物於卩2下加熱至埋流。藉由TLC監测進展。2 小時後反應顧示完全。冷卻反應物至周画灌度並於滅®下濃縮。殘留物於75毫升CH2CU中成漿狀，並與jfi和KF水溶液(75奄升.·）攫拌15分。分雕有機相並K水（50毫升）及蘧水（50毫升）洗。有機相於無水Na2S(U上乾嫌、過濉並 -32 - 83.3.10,000 (請先閱讀背面之注意事項再填寫本頁) 本紙張又度適用中國國家標準（CNS)A4规格（210 X W7公釐） 899352 A7 B7 五、發明説明（）濃縮，得黃色固«，將其藉徑向層析法（Μΐ:ι CHCG/EtOAc (具U MeOH)溶離）純化。此得361奄克禰題化合物為黃色固(溶點）： 193-195¾ 。 HRMS(EI):[M] + , C22HieN204 之計算值：361.1314;實测值：361 . 1311。 ^ NHR (CDCla) ： 5 7.54-7.23 (η, 6Η), 6.84 (d, 2H), 5.23 (s, 1H), 3.98 (s, 3H). 1{備3 N-(2-丙烯基）-H-(苄氧羰基）-4-(4-甲氣基-5- 酮基-1,3,6-環庚三烯-卜基）苯胺將N-(苄氣羰基）-4-(4-甲氣基-5-醑基-1,3,6-瓖庚三嫌 -1-基）笨胺（195¾克* 0.54奄莫耳）於5奄升無水THF中成漿狀，並加HaH之50*!油懸浮液。観察到氣體放出。令混合物於周溫下攪拌20分並加烯丙基溴及碘化四正丁基銨。令混物於周溫“下攢拌。3.5小時後TLC顧示6已耗盡。_由加pH 7磷酸鹽缓衝液（25奄升）耗盡遇量之NaH 。混合物與25毫升水一起倒入分液漏斗中，水相MCH2C12 (2x25奄升）抽。合併之有懺相於無水Ka2S〇4上乾嫌。濃縮有機相後所得之油《徑向曆析法（MIX MeOH/CHCU (300毫升}及2!1{ MeOH/CHCl3 {100毫升}溶離）純化。此得198奄克禰埋化合物為油，其經放置固化。 HRMS(EI):[M] + , C2BH23N(U之計算值：401.1627 ;實測值 :401 . 1630 .,。 JH NMR (CDCla) ： 5 7.52 (dd, 1H, J = 12.6 Hz), -33 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 83.3.10,000 (請先閲讀背面之注意事項再塡寫本頁) A7 B7 五、發明説明（） 7.46-7.42 (π, 2Η), 7.34-7.33 (m. 8H), 7.26 (dd, 1H, J=10.6 Hz), 6.845 (d, 1H, J=10.6 Hz), 5.93 (m, 1H), % 20-5.18 (bs, 3H), 5.15-5.14 (m, 1H), 4.32 (d, 2H, J+5.6 Hz), 3.99 (s, 3H). 脚備4 (± )-5-(碘甲基）-3-[4-甲氧基-5-酮基 -1 , 3,6-瓖庚三烯-1-基）苯基]-2-啤唑啶萌將N-(2-丙烯基）-N-(苄氧羰基）-4-(4-甲氣基-5-嗣基 -1,3,6-環庚三烯-1-基）苯胺（180奄克，0.449毫莫耳）溶於8 «升氣仿中，加12 (285毫克，1 . 12«其耳）。混合物變成葡萄紫色並於周溫《2下攪拌。20小時之反應時間後，TLC顯示7已耗盡並形成新的較低L產物。反應混合物與50奄升CHC13 —起倒入分液獮計，溶液Μ疏代碕酸納之 20 X水溶液（25奄升）洗。分雛有機相*於無水Ha 2S04上乾嫌·通濾並濃縮得檷題化合物為澄色固II，其》徑向靥析法（M 200 毫升之 IX MeOH/CHCU 再 M 200 « 升之 2X MeOH/CHCl3溶離）纯化。單離139奄克摞理化合物為淡黄色固體。 MP ： 194-196 ¾ 分析值：C18HieN〇4I 之計算值：C, 49.45; H, 3.69; 3.20 。實测值：C, 49.03; H, 3.62; N, 3.00。 HRMS:CieHieIN(U之計算值：437.0126 。實測值：437.01 10 1n HHR (CDC13) ί 5 7. 65 (d, 2H, J = 8.8 Hz), 7.55 -3 4 - 83.3.10,000 (請先閲讀背面之注意事項再塡寫本頁) 衣紙張又度適用中國國家標準（CNS)A4规格（21〇 X 2们公發） A7 B7 五、發明説明（） (dd, 1H ,J = ll. 5, 12.6 Hz), 7 .52 (d, 2Η , J = 8.8 Hz), 7. 34 (d, 1Η, J=10.4 Η ζ). 7.28 (d, 1H, J = ll.5 Hz), 6 . 88 (d, 1Η, J=10.6 Η z ) .4.79 ( d, 1H, 4.24 (t, 1H, J = 8 . 9 Hz) . 4.00 (s 1 3H) , 3 . 855 (dd ,1H,. J=9.2 H z), 3.505 (dd, 1H , J = 14.5 Hz) ,3.395 (dd, 1H, J=10.4 Hz) * 鄣備ϋ (± ) -5 - (叠氮甲基 )- 3- [4- (4- 甲氧基 -5-酮基 -1,3,6- 環庚三烯-1 -基）苯基- 2- 嗶唑啶酮將（士 )-5 -(供甲基）-3- [4-甲氧基-5-鼷基-1 · 3,6-環庚三稀-1 ** 基）苯基 -2- 啤唑啶酮 (125毫克* 0.286«莫耳）溶於6毫升無水DMF中並加叠氮化納 (93¾ 克， 1.43毫莫耳）與 18 -冠 6 -(10毫克）《 >混合物於 n2 下加热至 Q0V * 並藉TLC 監測進展。2小時後* TLC顯示 8巳耗盡。將反應物冷卻至周溫並在減壓下除去DMF 。將留下之殘留物於 CHCla (75毫升 )中成漿狀，並藉由水洗 (2x30奄升）除去鹽。分離有機相並Μ鹽夺 (30毫升）洗，有機相於無水 NaSO 4上乾煉並過漶、濃縮得 105 邂克檷題化合物為黄色固體。此物質足夠純來攆續無須進一步純化〇 ΜΡ： 170 -171¾ 分析值： C 1 β Η 1 〇 N 4 0 4 之計算值； C ,61.36; Η, 4. 58; N , 15.90° 實澜值： C, 61.08； Η 9 4.52； Η. 15.75 〇 HRMS ： Ci β Η ^, 〇 Ν 4 0 4之計算值：352 .1171。實拥值： 352.1169° (請先閱讀背面之注意事項再塡寫本頁) 裝 J *言線 -35 - 83.3.10,000 本紙張尺·度適用令國國家標準（CNS>A4規格（210 X 297公釐）五、發明説明（） A7 B7 XH HMR (CDCla) ： 5 7.645 (.d, 2H, J = 8.8 Hz), 7.545 (dd. 1H, J=16, 12.5 Hz), 7.515 (d, 2H, J=8.8 Hz), 7.34 (d, 1H, J=12.5 Hz), 7.285 (dd, 1H, J=10.6 Hz), 6.88 (d, 1H, J=10.6 Hz), 4,84-4.85 (b, 1H), 4.16 (t, 1H, J=8.9 Hz), 4.00 (s, 3H), 3.91 (dd, 1H, J=8.9 Hz), 3.755 (dd, 1H, J=13.2 Hz), 3.625 (dd, 1H, J=13.2 Hz). ：r< i|5 MJO. 三甲基（4-甲氧基-5-嗣基-1,3,6-環庚三烯 -1-基）錫將六甲基二鍚（305毫克，0.930 «莫耳）溶於5奄升 1,4-二嗶烷，並將溶液_抽空脫氣再MN2沖洗（3次）。加澳基環庚三烯酮8 (200«克· 0.930 «莫耳）及觸媒氣化雙（三苯基膦）鈀（IIM16.3奄克，2.5莫耳X)。混合物最後脫氣並於N2下加热至堰流。反應藉TLC監测。反應混合物經加溫顔色變黑。1.5小時後，TLC顬示3已耗盡。反應混合物冷卻至周溫並於減壓下濃嫌。此得黑色油•將其藉 -. 層析法於矽膠上（Ml:l EtOA/CHCU(具Ιίί MeOH)溶離）純化。此得禰題化合物（239毫克）為油，經放於冰箱中固化。 MP :60-61^ HRMSKnHieOsiSn之計算值：300.0170。實测值：300.0159 ^ HMR (CDC13) ： 5 7. 36 (d, 1H. J = 11.8 Hz), 7.23 36 本紙張又度適用中國國家標準（CNS)A4規格（210 X 297公釐） 83.3.10,000 (請先閲讀背面之注意事項再塡寫本頁) 裝Aldrich, 23.52 millimoles). The solution turned dark yellow. Save the mixed solution for 10 minutes and stop the reaction with tri-n-butyl chloride (3.83 charge, 11.76¾ ears). The yellow slurry becomes a colorless solution. After stirring for 30 minutes and warming to -200 ° C, the reaction between the M cells and the NIUC1 aqueous solution (50 μL) was stopped. The reaction mixture was poured into a separatory funnel with 250 ml of ether and 100 «L of water. Shake the mixture and separate the decanted phase, then dry dry on anhydrous Ha2S〇4, pass through and concentrate to obtain oil, and purify it by silica gel (K20: 1 hexane / ether dissolution) by calendar analysis. Single young 2.99 grams of 团囲 compound is a colorless oil. MS (EL): m / z relative intensity: 460 (25), 404 (5), 227,91 (100). NMR CDC 13: δ 7.48-7.31 (·, 9Η), 5.19 (s, 2Η), 1.55 -1.47 (β. 6Η), 1.38-1.26 (, 6Η), 1.03 (t, 6Η, J = 8.33 Hz), 0.877 (t, 9Η, J = 7.26 Hz). Preparation of 2 N- (benzyloxycarbonyl)- 4- (4-Methoxy-5-vinyl-1 · 3,6-cycloheptatrien-1-yl) aniline will tri-n-butyl [4- (benzyloxycarbonylamino) phenyl] thion ( 726 ng grams, 1.4 millimoles) dissolved in 10 Chunshen 1,4-dibrane and added 5-Ao-2-methoxycyclohepta-2,4,6-triene • Bu_ (215 奄Grams, 1.0 millimoles), the resulting slurry was degassed by evacuation and rinsed with MN2 (3 times). Add bismuth (triphenylphosphine) palladium (II), and the mixture is heated to buried flow under 2. Monitor progress by TLC. After 2 hours, the reaction was complete. Cool the reaction to the weekly draw and concentrate under ME®. The residue was slurried in 75 ml of CH2CU and stirred with jfi and KF aqueous solution (75 l ..) for 15 minutes. Separate the organic phase and wash with K water (50 ml) and water (50 ml). The organic phase is anhydrous Na2S (U on the suspected, susceptible -32-83.3.10,000 (please read the precautions on the back before filling in this page) This paper is also applicable to the Chinese National Standard (CNS) A4 specification (210 X W7 Mm) 899352 A7 B7 V. Description of the invention () Concentrate to obtain a yellow solid «, and purify it by radial chromatography (Ml: ι CHCG / EtOAc (with U MeOH) dissociation). This is the 361-gram problem The compound is a yellow solid (melting point): 193-195¾. HRMS (EI): [M] +, Calculated value of C22HieN204: 361.1314; Found value: 361.1313. ^ NHR (CDCla): 5 7.54-7.23 (η , 6Η), 6.84 (d, 2H), 5.23 (s, 1H), 3.98 (s, 3H). 1 {备 3 N- (2-propenyl) -H- (benzyloxycarbonyl) -4- (4 -Methyl-5-keto-1,3,6-cycloheptatriene-butyl) aniline will be N- (benzylcarbonyl) -4- (4-methan-5-pyridyl-1, 3,6-Wengheptan-1-yl) stupid amine (195¾ g * 0.54 mol) was slurried in 5 liter of anhydrous THF and added 50 * of HaH! Oil suspension. Gas evolution was observed The mixture was stirred at ambient temperature for 20 minutes and allyl bromide and tetra-n-butylammonium iodide were added. The mixture was allowed to mix at ambient temperature. After 3.5 hours, TLC 6 has been depleted._ Deplete the amount of NaH by adding pH 7 phosphate buffer (25 liters). The mixture is poured into a separatory funnel with 25 ml of water, and the aqueous phase MCH2C12 (2x25 liters) is pumped. Combine There is a possibility that the phase will dry on anhydrous Ka2SO4. The oil obtained after concentrating the organic phase is purified by "radial calorimetry (MIX MeOH / CHCU (300 ml) and 2. 1 {MeOH / CHCl3 {100 ml} dissolution) . This gives 198 奄祢 embed compound as an oil, which solidified after being placed. HRMS (EI): [M] +, C2BH23N (calculated value of U: 401.1627; found value: 401.1630., JH NMR (CDCla) : 5 7.52 (dd, 1H, J = 12.6 Hz), -33-This paper scale is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 83.3.10,000 (please read the notes on the back before writing This page) A7 B7 5. Description of the invention () 7.46-7.42 (π, 2Η), 7.34-7.33 (m. 8H), 7.26 (dd, 1H, J = 10.6 Hz), 6.845 (d, 1H, J = 10.6 Hz), 5.93 (m, 1H),% 20-5.18 (bs, 3H), 5.15-5.14 (m, 1H), 4.32 (d, 2H, J + 5.6 Hz), 3.99 (s, 3H). 4 (±) -5- (iodomethyl) -3- [4-methoxy-5-keto-1, 3,6-oxohtrien-1-yl) phenyl] -2-pyrazole Nimidine will N -(2-propenyl) -N- (benzyloxycarbonyl) -4- (4-methoxy-5--5-yl-1,3,6-cycloheptatrien-1-yl) aniline (180 g , 0.449 millimoles) was dissolved in 8 «lift gas imitation, add 12 (285 mg, 1.12« its ears). The mixture turns into grape purple and stirs at 2 times at a weekly temperature. After a reaction time of 20 hours, TLC showed that 7 had been consumed and a new lower L product was formed. The reaction mixture was poured into a liquid separation meter together with 50 μl of CHC13, and the solution M was washed with 20 X aqueous solution (25 μl) of sodium benzoate. Separate the organic phase * on anhydrous Ha 2S04, dry, filter and concentrate to obtain the title compound as a clear solid II, its "radial analysis" method (M 200 ml of IX MeOH / CHCU and then M 200 «liter of 2X MeOH / CHCl3 dissociation) purification. The 139-gram monolithic compound alone is a pale yellow solid. MP: 194-196 ¾ Analysis value: Calculated value of C18HieN〇4I: C, 49.45; H, 3.69; 3.20. Found: C, 49.03; H, 3.62; N, 3.00. HRMS: CieHieIN (Calculated value of U: 437.0126. Measured value: 437.01 10 1n HHR (CDC13) ί 5 7. 65 (d, 2H, J = 8.8 Hz), 7.55 -3 4-83.3.10,000 (please read the back first The matters needing attention will be written on this page) The clothing paper is again applicable to the Chinese National Standard (CNS) A4 specifications (21〇X 2 are issued by the public) A7 B7 V. Invention description () (dd, 1H, J = ll. 5, 12.6 Hz), 7.52 (d, 2Η, J = 8.8 Hz), 7. 34 (d, 1Η, J = 10.4 Η ζ). 7.28 (d, 1H, J = ll.5 Hz), 6.88 (d, 1Η, J = 10.6 Η z) .4.79 (d, 1H, 4.24 (t, 1H, J = 8.9 Hz). 4.00 (s 1 3H), 3.855 (dd, 1H ,. J = 9.2 H z), 3.505 (dd, 1H, J = 14.5 Hz), 3.395 (dd, 1H, J = 10.4 Hz) * 鄣备 ϋ (±) -5-(azidomethyl)-3- (4- (4-Methoxy-5-keto-1,3,6-cycloheptatrien-1-yl) phenyl-2-pyridazolidone will (±) -5-(for methyl) -3 -[4-Methoxy-5-brenyl-1 · 3,6-cycloheptatrile-1 ** yl) phenyl-2-pyrazolidone (125 mg * 0.286 «mole) dissolved in 6 Ml of anhydrous DMF and add sodium azide (93¾ g, 1.43 mmol) and 18-crown 6- (10 mg) "> mixture in n2 Heat to Q0V * and monitor progress by TLC. After 2 hours * TLC showed 8% depletion. Cool the reaction to ambient temperature and remove DMF under reduced pressure. Place the remaining residue in CHCla (75 mL) Form a slurry and remove the salt by washing with water (2x30 liters). Separate the organic phase and wash with M salt (30 ml). The organic phase is dried on anhydrous NaSO 4 and dried, and concentrated to obtain 105% of the title compound. It is a yellow solid. This material is pure enough to continue without further purification. 〇MP: 170-1712. Analytical value: calculated value of C 1 β Η 1 〇N 4 0 4; C, 61.36; Η, 4. 58; N, 15.90 ° Actual value: C, 61.08; Η 9 4.52; Η 15.75 〇HRMS: Ci β Η ^, 〇Ν 4 0 4 calculated value: 352.1171. Actual value: 352.1169 ° (please read the precautions on the back before writing this page) Install J * 言线 -35-83.3.10,000 The paper size and degree are applicable to the national standard (CNS> A4 specifications (210 X 297 Mm) 5. Description of invention () A7 B7 XH HMR (CDCla): 5 7.645 (.d, 2H, J = 8.8 Hz), 7.545 (dd. 1H, J = 16, 12.5 Hz), 7.515 (d, 2H , J = 8.8 Hz), 7.34 (d, 1H, J = 12.5 Hz), 7.285 (dd, 1H, J = 10.6 Hz), 6.88 (d, 1H, J = 10.6 Hz), 4,84-4.85 (b , 1H), 4.16 (t, 1H, J = 8.9 Hz), 4.00 (s, 3H), 3.91 (dd, 1H, J = 8.9 Hz), 3.755 (dd, 1H, J = 13.2 Hz), 3.625 (dd , 1H, J = 13.2 Hz) .: r < i | 5 MJO. Trimethyl (4-methoxy-5-inyl-1,3,6-cycloheptatrien-1-yl) tin will six Methyldithione (305 mg, 0.930 mol) was dissolved in 5 liters of 1,4-dipyridane, and the solution was evacuated and degassed and then flushed with MN2 (3 times). Add Cyclotrienone 8 (200 «g · 0.930« mol) and catalyst gasified bis (triphenylphosphine) palladium (IIM 16.3 ng, 2.5 mol X). The mixture was finally degassed and heated to weir flow under N2. Reaction Monitored by TLC. The reaction mixture turned black after heating. 1.5 hours After time, TLC showed that 3 had been exhausted. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The black oil was obtained. • Borrow-. Chromatography on silica gel (Ml: l EtOA / CHCU (with Ιίί MeOH) Dissociation) Purification. The title compound (239 mg) was obtained as an oil and solidified in a refrigerator. MP: 60-61 ^ HRMSKnHieOsiSn calculated value: 300.0170. Found: 300.0159 ^ HMR (CDC13): 5 7. 36 (d, 1H. J = 11.8 Hz), 7.23 36 This paper is again applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 83.3.10,000 (please read the precautions on the back before reading Write this page)

，§J 線 i*- A7 B7 五、發明説明（） (d, 1H, J+9.6, Hz), 7.15 (d, 1H, J=11.8 Hz). (請先閱讀背面之注意事項再填寫本頁) 6.725 (d, 1H, J=9.6 Hz). 3.94 (s, 3H). 0.32 (s, 9H. lieSn J=129.3 Hz,…Sn J=55.2 Hz, llsSn J = 5 2.9 Hz). 脚備7 (R)-丁酸[3-(3-氟苯基）-2-嗣基-5-嗶唑啶基] 甲釀將澳化鋰（0.181克》2.08«莫耳）、氧化三正丁基膦 (0.45 4克，2.08«克耳）及無水鄰二甲笨（10毫升）之混合物共沸乾煉1小時。於迴流點以下冷卻後，於10分内將 (R)-丁酸縮水甘油賄（5.000克，34.68毫其耳）及異氰酸 3-氣苯鹿（4.755克或3.96毫升，34.68毫莫耳）於無水鄰二甲苯（10奄升）中之溶液加至热溶液（於添加時觀察到一些娌流）。當完成添加時，將溶液加热至迴流2小時再令冷卻至室溫。真空除去溶劑並於矽膠上將殘留物靥析* K 己烷/乙酸乙酯（6:1，4:1·再2:1)溶«，提供8.758克 (90¾)檷題化合物為具下列特激之無色糖漿狀物。 —·., §J line i *-A7 B7 5. Description of invention () (d, 1H, J + 9.6, Hz), 7.15 (d, 1H, J = 11.8 Hz). (Please read the notes on the back before filling in this Page) 6.725 (d, 1H, J = 9.6 Hz). 3.94 (s, 3H). 0.32 (s, 9H. LieSn J = 129.3 Hz,… Sn J = 55.2 Hz, llsSn J = 5 2.9 Hz). 7 (R) -butyric acid [3- (3-fluorophenyl) -2-pyridyl-5-pyridazolyl] methyl alcohol lithium (0.181 g》 2.08 «mol), tri-n-butyl oxide The mixture of phosphine (0.45 4 g, 2.08 kg) and anhydrous o-dimethyl stupid (10 ml) was azeotropically dried for 1 hour. After cooling below the reflux point, (R) -butyric acid glycidol (5.000 g, 34.68 mmol) and 3-cyanopyridine isocyanate (4.755 g or 3.96 mL, 34.68 mmol) ) The solution in anhydrous o-xylene (10 liters) was added to the hot solution (some flow was observed during the addition). When the addition is complete, the solution is heated to reflux for 2 hours and allowed to cool to room temperature. Remove the solvent in vacuo and dissolve the residue on silica gel * K Hexane / ethyl acetate (6: 1, 4: 1, then 2: 1) dissolved «, provide 8.758 g (90¾) of the title compound with the following characteristics Exciting colorless syrup. — ·.

[α ]2Β〇 -46.7° (c 1.0, CHCla) IR (摻雜確油）1758, 1615, 1591, 1498, 1229, 1 197, 1169 cm-1 。 lH-HMR (CDCla, 300 HHz)57.44 ("dt", J=11.2, 2.3 Hz. 1H). 7.34 ("dt”， J=8.3, 6.5 Hz, 1H). 7.23 (ddd, J = 8..3, 2.1, 0.9 Hz, 1H), 6.86 (dddd, J = 8.2, 8.2, 2.5, 0.9 Hz, 1H), 4.88 (η. 1H), 4.39 (dd, -37 - 本紙張&度適用中國國家標準（CNS)A4規格（210 X 297公釐） 83.3.10,000 A7 B7 五、發明説明（） J=12,3, 3.8 Hz, 1H). 4.32 (dd, J=12.3, 4.7 Hz, (請先閲讀背面之注意事項再填寫本頁) 1H), 4.13 (”t, J=9.0 Hz, 1H), 3.82 (dd, J=9.0 6,1 Hz, 1H), 2.33 (t,J=7.3 Hz, 2H), 1.63 (b, 2H), 0.92 (t, J = 7.4 Hz, 3H). MS m/z (相對強度）281 (33.1, M，），193 (9.9), 180 (3.3), 150 (28.7), 148 (68.6), 137 (59.3), 123 (41.7), 95 (38.3), 43 (100)。 HRMS m/z 281.1068 (C14HieFN〇4之計算值：281.1063)。分析值：C14HiePN〇4之計算值：C. 59.78; Η, 5.73; Η, 4.98,實測值：C, 59.98 ; Η, 5.72; H, 4.88. 剪備8 (R)-3-(3-氟苯基）-5-(羥甲基）-2-醑基吗唑啶將（R) 丁酸[3-(3-氟苯基）-2-醑基-5-啤唑啶基]甲_ (2.789克，9.91«莫耳）於甲酵（10毫升）中之溶液· Μ 2 5¾重量比之甲酵納於甲酵（57撤升，0.99«莫耳）中周溫下處理。45分後，TLC (5X MeOH/CHCU)顯示起始物質耗盡。反應混合物小心地藉由加1 NHC1 (0.99毫升* 0.99毫莫）中止反應再真空瀠縮。粗產物於矽膠上曆析首 Ml:l己烷/乙酸乙_再以乙酸乙_溶離，提供1.903克 (9U)禰題化合物為具下列特徵之白色固體： mp 106.5-107.5 Ό [a ]2BD-66 . 8° (c 1.1. CHaCH). IR (摻雜確油）3520, 1724, 16 12, 1590，1496, 1428, 1420, 1232, 1199 c·-1 ° -38 - 本紙張又度適用中國國家標準（CNS)A4规格（210 X 297公釐） 83.3.10,000 五、發明説明（ A7 B7 ^-NMR (CDCU, 300 ΜΗζ)δ7.44 ("dt", J = 11.3, 2.3 Hz, 1H), 7.32 ("dt", J=8.3, 6.5 Hz, 1H), 7.23 (ddd, J=8.3, 2.1, 1.0 Hz, 1H), 6.84 (dddd, J=8.2, 8.2, 2.5, 1.0 Hz, 1H), 4.77 (m, 1H), 4.07-3.96 (a. 3H), 3.76 (dd, J=12.7, 3.9 Hz, 1H), 2.44(br, s, 1H). MS b/z (相對強度）211 (100, M + ), 180 (6.8), 136 (34.3), 124 (84.7), 95 (71.6)。 HRHS b/z 211.0641 (C1〇H1〇FN032計算值： 21 1.0645)。分析值：C1〇H1〇FH03之計算值：C. 56.87; Η, 4.77; N, 6.63,實澜值：C, 56.85 ; Η, 4.94; H· 6.56. 嗶唑啶嗣酵之對掌異構之遇量，藉由將其與（R)-( + )- ct -甲氧基-α-(三氟甲基）苯基乙酸（DCC, DMAP, CH2CU· 室溫）反應並審査所得之其欧爾Mosher)酯之1H-NMR光譜而测定。％比評估為2 95¾ 。 (請先閱讀背面之注意事項再填寫本頁) 裝[α] 2B〇 -46.7 ° (c 1.0, CHCla) IR (doped oil) 1758, 1615, 1591, 1498, 1229, 1 197, 1169 cm-1. lH-HMR (CDCla, 300 HHz) 57.44 (" dt ", J = 11.2, 2.3 Hz. 1H). 7.34 (" dt ”, J = 8.3, 6.5 Hz, 1H). 7.23 (ddd, J = 8 ..3, 2.1, 0.9 Hz, 1H), 6.86 (dddd, J = 8.2, 8.2, 2.5, 0.9 Hz, 1H), 4.88 (η. 1H), 4.39 (dd, -37-this paper & degree applies China National Standard (CNS) A4 specification (210 X 297 mm) 83.3.10,000 A7 B7 V. Description of invention () J = 12,3, 3.8 Hz, 1H). 4.32 (dd, J = 12.3, 4.7 Hz, ( Please read the notes on the back before filling this page) 1H), 4.13 (”t, J = 9.0 Hz, 1H), 3.82 (dd, J = 9.0 6,1 Hz, 1H), 2.33 (t, J = 7.3 Hz, 2H), 1.63 (b, 2H), 0.92 (t, J = 7.4 Hz, 3H). MS m / z (relative intensity) 281 (33.1, M,), 193 (9.9), 180 (3.3), 150 (28.7), 148 (68.6), 137 (59.3), 123 (41.7), 95 (38.3), 43 (100). HRMS m / z 281.1068 (calculated value for C14HieFN04: 281.1063). Analysis value: Calculated value of C14HiePN〇4: C. 59.78; Η, 5.73; Η, 4.98, found value: C, 59.98; Η, 5.72; H, 4.88. Scissor 8 (R) -3- (3-fluoro Phenyl) -5- (hydroxymethyl) -2-pyridylmorphazolidine (R) butyric acid [3- (3-fluorophenyl) -2-pyridyl-5-pyrazolidine] methyl_ (2.789 g, 9.91 «mol) solution in formazan (10 ml) · M 2 5¾ weight ratio of formazan was treated with formazan (57 withdrawal, 0.99« mol) at mid-week temperature. After 45 minutes, TLC (5X MeOH / CHCU) showed that the starting material was exhausted. The reaction mixture was carefully stopped by adding 1 NHC1 (0.99 ml * 0.99 mmol) and then condensed in vacuo. The crude product was analyzed on silica gel with the first Ml: l hexane / ethyl acetate_ and then dissolved with ethyl acetate_ to provide 1.903 g (9U) of the title compound as a white solid with the following characteristics: mp 106.5-107.5 Ό [a] 2BD -66. 8 ° (c 1.1. CHaCH). IR (doped oil) 3520, 1724, 16 12, 1590, 1496, 1428, 1420, 1232, 1199 c · -1 ° -38-This paper is suitable again China National Standard (CNS) A4 specification (210 X 297 mm) 83.3.10,000 V. Description of invention (A7 B7 ^ -NMR (CDCU, 300 ΜΗζ) δ7.44 (" dt ", J = 11.3, 2.3 Hz, 1H), 7.32 (" dt ", J = 8.3, 6.5 Hz, 1H), 7.23 (ddd, J = 8.3, 2.1, 1.0 Hz, 1H), 6.84 (dddd, J = 8.2, 8.2, 2.5, 1.0 Hz , 1H), 4.77 (m, 1H), 4.07-3.96 (a. 3H), 3.76 (dd, J = 12.7, 3.9 Hz, 1H), 2.44 (br, s, 1H). MS b / z (relative intensity ) 211 (100, M +), 180 (6.8), 136 (34.3), 124 (84.7), 95 (71.6). HRHS b / z 211.0641 (C1〇H1〇FN032 calculated value: 21 1.0645). Analysis value: Calculated value of C1〇H1〇FH03: C. 56.87; Η, 4.77; N, 6.63, actual value: C, 56.85; Η, 4.94; H. , By comparing it with (R)- (+)-ct -Methoxy-α- (trifluoromethyl) phenylacetic acid (DCC, DMAP, CH2CU · room temperature) reacted and examined the 1H-NMR spectrum of the obtained Eul-Mosher ester to determine. The% ratio is estimated to be 2 95¾. (Please read the precautions on the back before filling out this page)

、-SJ 4丨5 * ·/? % t 脚備9 (R ) U3 -氟笨基）-5-(羥甲基）-2 -嗣基嗶唑啶將N-(苄氧羰基）-3-氟笨胺（1.000克，4.08毫莫耳）於無水四氫呋喃（10毫升）中之溶液Μ乾冰/丙嗣浴冷卻至約 -78t：，再加正丁基鋰（1.87毫升之1.6Μ己烷溶液，2.91« 莫耳）。再經由注射器加（R)-丁酸缩水甘油酯（0.420克或 0.413奄升· 2.91奄其耳）·令冷卻浴過夜消敗•而反應混.合物達周.画溫度。反應混合物鞴小心加鉋和NiUCl水溶液中止反應•全部混合物Μ二氛甲烷洙移至分液獮斗•混 39 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 83.3.10,000 線 A7 B7五、發明説明（）經濟部中央G局31"-費^";1"8 合物以二氛甲烷抽。合併之有機抽提物於Na2S〇4上乾煉、過濾並真空潇縮得油•其藉層析法於矽膠上以10¾乙腩/ 氮仿（含U甲酵）溶離纯化，提供0.555克（90¾，基於丁酸縮水甘油醮）禰題化合物為白色固«，其所有方面皆與如前面實驗方法中所述所得基準樣品相同。 m m\0 (R)-4-甲基苯磺酸[3-(3-氟苯基）-2-酮基-5- 鸣唑啶基]甲酯將（R)-3-(3-氟苯基）-5-(羥甲基）-2-_基嗶唑啶 (1.800克，8.52«莫耳）於無水吡啶（10奄升）中之溶液冷卻至約5C ，再Μ對甲苯磺酸氣（1.706克，8.95«其耳）處理。令溶液放於此溫下過夜。TLC (5¾甲酵/氯仿或 1:1己烷/乙酸乙_)指示起始物質已耗盡。將反應混合物倒入冰水（30毫升）中· «真空通濾通遇中等孔隙率燒结玻璃漏斗收集所得沈澱。收集之固»檄底Μ冷水洗、真空乾烽並自乙酸乙_ /己烷中雇结晶得2.7 43克 (88J!)摞題化合物為白色固髓具下列持徽： mp 114-115¾ [a ]2bd-62.6° (c 1.0, CHaCN) IR (摻雜礦油）1751，1617，1591, 1499，1415, 1362, 1227, 1202, 1191， 1172, 1093, 967 cn-1 ^-HMR (CDCU, 300 MHz) 5 7.78 ("d", J = 8.4, 2H), 7.38 ("dt", J=11.2, 2.3 Hz, 1H), 7.36 ("d". J=7.8 Hz, 2H), 7.33 ("dt" . J = 8.3, 6.6 Hz, 1H), 7.16 -4 0 - 衣紙張次度適用中囤國家標準（CNS)A4规格（210 X 2町公釐） 83.3.10,000 (請先閲讀背面之注意事項再塡寫本頁) 裝, -SJ 4 丨 5 * · /?% T Pin 9 (R) U3 -fluorobenzyl) -5- (hydroxymethyl) -2 -benzylpyrazolidine N- (benzyloxycarbonyl) -3 -A solution of fluorobenzylamine (1.000 g, 4.08 mmol) in anhydrous tetrahydrofuran (10 mL) Μ dry ice / propylene bath cooled to about -78t :, then add n-butyl lithium (1.87 mL of 1.6M hexane) Solution, 2.91 «mol). Then add (R) -glycidyl butyrate (0.420 g or 0.413 liters · 2.91 liters) via the syringe · Let the cooling bath disappear overnight · and the reaction mixture reaches the temperature. The reaction mixture was carefully planed and the NiUCl aqueous solution was used to terminate the reaction. • The entire mixture M dichloromethane sucrose was transferred to the liquid separation bucket. Mix 39. The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 83.3.10,000 Line A7 B7 V. Description of the invention () 31 " -fee ^ "; 1 " 8 of the Central Bureau of Economic Affairs of the Ministry of Economic Affairs. The combined organic extracts were dried on Na2SO4, filtered, and vacuum-shrunk to obtain an oil. It was purified by chromatography on silica gel with 10¾ ethyl ketone / nitroform (containing U formazan) to provide 0.555 g ( 90¾, based on glycidyl butyrate) The title compound is white solid, all aspects of which are the same as the reference sample obtained as described in the previous experimental method. mm \ 0 (R) -4-methylbenzenesulfonic acid [3- (3-fluorophenyl) -2-keto-5-oxazolidinyl] methyl ester (R) -3- (3-fluoro Phenyl) -5- (hydroxymethyl) -2-ylpyridazolidine (1.800 g, 8.52 mol) in anhydrous pyridine (10 l) was cooled to about 5C, and then p-toluenesulfonic acid Gas (1.706g, 8.95 «its ears) treatment. Leave the solution at this temperature overnight. TLC (5¾ formazan / chloroform or 1: 1 hexane / ethyl acetate) indicates that the starting material has been consumed. Pour the reaction mixture into ice water (30 ml). «Vacuum filtration is carried out with a medium porosity sintered glass funnel to collect the resulting precipitate. The collected solids were washed with cold water, dried in vacuum, and crystallized from ethyl acetate / hexane to obtain 2.7 43 g (88J!). The title compound was white solid marrow with the following emblem: mp 114-115¾ [a ] 2bd-62.6 ° (c 1.0, CHaCN) IR (doped mineral oil) 1751, 1617, 1591, 1499, 1415, 1362, 1227, 1202, 1191, 1172, 1093, 967 cn-1 ^ -HMR (CDCU, 300 MHz) 5 7.78 (" d ", J = 8.4, 2H), 7.38 (" dt ", J = 11.2, 2.3 Hz, 1H), 7.36 (" d ". J = 7.8 Hz, 2H), 7.33 (" dt ". J = 8.3, 6.6 Hz, 1H), 7.16 -4 0-The paper grades are applicable to China National Standard (CNS) A4 specification (210 X 2 mm) 83.3.10,000 (please first Read the notes on the back and write this page)

Me 線五、發明説明 A7 B7 (ddd, J=8.3, 2.2, 1.0 Hz, 1H), 6.86 (dddd, J=8.2, 8.2, 2.5, 1.0 Hz, 1H), 4.84 (m, 1H), 4.29 (dd, J=ll.l, 4.1 Hz, 1H), 4.24 (dd, J=ll.l 4.6 Hz, 1H), 4.10 ("t", J=9.1 Hz, 1H), 3.88 (dd, J=9.2, 6.0 Hz, 1H) , 2.46 (s, 3H). MS m/z (相對強度）365 (70.6, M*), 149 (100), 122 (32 . 8) , 91 (52.8). HRHS m/z 365.0738 (C17HieFH〇5S之計算值：365.0733)。分析值：C17HieFN〇eS 之計算值：C. 55.88; H, 4.41; N, 3.83,實测值：C, 55.96 ; Η, 4.38; N, 3.80. 骢備 (R) -[3-(3-氟苯基）-2-酮基-5-嗶唑啶基]甲基叠氮將（R)-[3-(3-氟苯基）-2-嗣基_ 基苯磺酸酷（2.340克· 6.40«莫耳之溶液Μ固β «_择化納（3.331克· 處理。所得之漿溫至65Ό歷4.5小置遇夜。反應混合物再以乙酸乙酿斗*並以乙酸乙_抽。合併之乙酸，再乾嫌（Na2S〇4)。通滹並真空濃色固《•其實質上為純的。顯示下 ΜΡ. 81-82Ό [α ]2Β〇 -136.5° (c 0.9, CHCla) 5-噚唑啶基]甲基-4-甲 )於無水DMF(60奄升）中 51 /23«莫耳）於周溫下時•再冷卻至周溫並放及水稀釋•移至分泌獮乙酯抽提物Μ水徹底洗縮，得禰鼸化合物為白列特撤：裝！1訂！！線 (請先閲讀背面之注意事項再塡寫本頁) 41 本紙張&度適用中國國家標準（CNS)A4規格（210 X 297公釐） 83.3.10,000 A7 B7 五、發明説明（ IR (確油摻雜）21 15, 1736, 1614，1591, 1586, 1497, 1422, 1233, 1199, 1081, 1049 ci»-1 〇 ^-HMR (CDCla, 300 MHz) δ 7.45 ("dt", J=11.2, 2.3 Hz, 1H), 7.34 ("dt”， J=8.3, 6.4 Hz, 1H). 7.23 (ddd, J=8.1, 2.1, 1.0 Hz, 1H), 6.86 (dddd, J=8.2, 8.2, 2.5, 1.0 Hz, 1H), 4.81 (ih, 1H), 4.09 ("t", J=8.9 Hz, 1H), 3.86 (dd, J=9.0, 6.2 Hz, 1H), 3.72 (dd, J=13.2, 4.5 Hz, 1H), 3.60 (dd, J=13.2, 4.4 Hz, 1H)。 MS m/z (相對強度）236 (59.0, JT), 179 (94.9), 136 (59.5), 122 (62.4), 109 (71.8), 95 (100), 75 (40.7)° HRMS n/z 236.0708 (“oHeFJUOsi之計算值：236.0709)。分析值：C1〇HeFIU〇2之計算值：C. 50.85; Η, 3.84; H, 23.72,實测值：C, 50.74; Η, 3.76; H, 23.71。製備12 (S)-N-[[3-(3-氟苯基）-2-醑基-5-嗶唑啶基] —-.. 甲基]乙鼸胺將（R)-[3-(3-氟苯基）-2-嗣基-5-0?唑啶基]甲基叠氮 (8.200克· 34.71奄其耳）於乙酸乙ft (100¾升）中之溶液Ml OX Pd/C (0.8 20克）於氮下處理。再經由蕹複抽空及充填，Μ氳（球形瓶）代替大氣。於fi下攢拌17小時後，TLC (5X曱酵/氯仿）顯示叠氮化物已耗盡。以氮氣代替大氣•再將吡啶（6毫升）及乙酸酐（4.1奄升· 43.40奄莫 83.3.10,000 (請先閲讀背面之注意事項再塡寫本頁) 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 2幻公釐）五、發明説明（ A7 B7 耳）加至反應混合物。反應混合物於周溫下攪拌1小時再通遇寅式鹽（Cal ite)過濾，Μ乙酸乙酯洗滹垫。真空濃縮璩液，殘留物溶於二氣甲烷。加***提供沈載。於冰箱放置過夜後，藉真空過濾收集固想· Κ冷己烷洗並真空乾嫌 •完成4.2 70克禰題化合物為白色固《。自母液得另外 3. 700克，總產量為91J；。於另外之外理中*粗產物》靥析法於矽膠上纯化，K5S!甲酵/氣仿溶離。顧示下列特微 mp 140.0-140.5¾ [α ]28〇 -6.6° (c 1.0, CHCla) 製備13 (S) -H- [ [3- (3-氟-4-磺苯基）-2-嗣基-5-聘唑啶 (請先閲讀背面之注意事項再填寫本頁) f 裝 ]甲基]乙酺胺將（S) -N- [[3- (3-氣苯基）-2-酮基-5-啤唑啶基線 f 醢胺（0.280克，酸（5奄升）之混莫耳）於周溫T 拌。逐漸形成橙稀釋，並藉由真固體，以£1^0洗溶）•移至分液硫酸納水溶液及真空灞縮·.提供示下列特徵： 1. 11毫莫耳）溶合液，再Μ —氛處理。將暗紅棕色沈澱。約2 4小空通濾通逢中等。將粗固《I溶於漏斗者並以飽和鹽水洗。有櫬相 0.295克（70!«)禰於乙酸（20奄升）化碘[2. 343克，色混合物於室溫時後，反應混合孔隙率磨砂玻璃热氱仿中（加少 NaHC03A 溶液、於Na2S04上乾嫌鼸化合物為白色 ]甲基]乙與三氟乙 14.43 毫、氮下攪物K*** 濾器收集許甲酵肋 2 0X疏代，逢濾並固《Γ。顧 43 83.3.10,000 本紙張又度適用中國國家標準（CNS)A4规格（210 X 297公釐） ^^9332 A7 B7 五、發明説明（） mp 185.5-186.5 t： [a ]zbd -37.6° (c 1.0. DMF) 拟備1 4 (土）-5-乙醣胺甲基-3-(4三甲基三笨基）啤唑唾-2 -銅將六甲基二鍚（1.772克，5.41«莫耳）及（±)-5-乙醸胺甲基-3-U’-碘笨基）嗶唑啶-2-酮（ 1.840克，5.11奄萁耳 )於23«升二嗶烷中之溶液，交替地抽空並以氮充填3次。然後加氣化雙（三苯基膦）鈀（11)(0.155克* 0.22毫莫耳 )，並將糸統再度抽空並以氮充填3次，並於96 〇下通液加热此糸统。蒸發溶劑，粗物質於中壓二氧化矽管柱（40 X 63 2.5厘米X 25厘米，MIX甲酵/氛仿填塞， Μ二氯甲烷垓充•並Μ甲酵/氛仿梯度溶劑）得1.148克 (56 . 5 5Κ)所須物質•為白色固艚· mp 130-132Ό,與 0.537克（26.5X)之稍微不純之物質一起。 HMR (CDCla, 300 MHz) δ ： 7.48 (s, 4Η), 6.71 (bt, J = 6.0 Η6..1Η), 4.77 (ddd, J = 13.2 Hz, J，=8.7 Hz, J''=4.5 Hz, 1H), 4.05 (t, J=9.0 Hz, 1H), 3.80 (dd. J=9.0 Hz, J'=6.6 Hz. 1H), 3.63 (dd, J=6.0 Hz, J'=4.5 Hz, 2H), 2.01 (s, 3H), 0.28 (t, J=27.0 Hz . 9H) 〇 IR (礦油摻雜，cm·1): 3356(m), 1746(s), 1665(s). 質(相對含量）：398 (8.8 M*), 383 (100), 382 (36.9), 381 (75.3), 380 (29.0), 379 (42.7), 43 -44 - 83.3.10,000 (請先閲讀背面之注意事項再塡寫本頁) 表紙張疋度適用中國國家標準（CNS)A4規格（210 X 297公釐） A7 B7 五、發明説明（） (23.1 ), 29 (27.5); ClsH22N2〇3Sn 之計算真正質 S : 398.0650，實测值：398.662 。分析值：ClsH22N2〇3Sn 之計算值：C, 45.37, H, 5.58; N. 7.06。實測值：C, 45.28; H, 5.51; 6.87。 TLC: 5X 甲酵 / 氛仿：Rf = 0.34。剪備15 (R) - [3-(3,5-二氟苯基）-2-萌基-5-啤唑啶基] 甲酵。將N-苄氣羰基-3,5-二氟苯胺（10.9克，30.01毫莫耳）於無水THF (250奄升）中之溶液冷卻至-78t：，再於15分内滴加正-BuLi (19.7毫升，31.51毫其耳）處理。令反應物於-78¾攪拌1小時*再於10分期間内滴加 (1〇-(-)-丁酸縮水甘油_(4.67亳升，33.01毫莫耳）處理。將反應物再於-78 携拌2小時，再令遇液（17小時）慢慢溫至室溫。於此點，反應物ME t0 Ac (300«升）稀釋再以 NfU Cl (30 0毫升）及S水（300奄升）洗。有機Jf於無水Na2S0 4上乾嫌、過濾再減壓澹縮得金黄色油。將此油於矽膠上曆析（250克SG，K 0-3S5 MeOH (於10¾ CH3CN/CHCU中）梯度溶離）得6.82克（99S；)禰鼸化合物為蠟狀白色固髓，具mp 84-85t!且對C1〇HeN03F2計算之 HRMS (Μ” 為 229.0550,實測值為 229.0552。製備邝 (R)-[[3-(3,5-二氟苯基）-2-嗣基-5-Df唑啶基 ]甲基]對甲苯磺酸酷 -45 - 本紙張又度適用中國國家標準（CNS)A4规格（210 X W7公釐} 83.3.10,000 -----------{ 裝-- n I aa— ϋ n n n {請先閱讀背面之注意事項再填寫本頁) A7 B7 五、發明説明（將（R)-[3-(3,5-二氟苯基）-2-醑基-5-噚唑啶基]甲酵 (4. 68克，20.42毫冥耳）溶於吡啶（35毫升）再冷卻至Ot) (冰浴）。其次將***液Μ對甲苯磺醢氯（4.67克，24.50毫莫耳）處理。令反應物於冷房中携拌過夜（17小時）°次晨，藉由以冰水（1〇〇毫升）中止反應使產物沈澱。經由抽吸過滤單離物質，再於高真空下乾煉過液（20小時）°此反應得7.46克（95¾)標題化合物為白色粉末狀固體•具ηρ 110.5-111.5亡及對（：171113川《^23計算之111^5(忖*)為 383.0639，實测值為 383.0639。剪備1 7 (R)-[[3 -(3,5-二氟苯基）-2-酮基-5-吗唑啶基 (請先閱讀背面之注意事項再填寫本頁) 装 Λ t ]甲基]叠氮將（R)-[[3-(3,5-二氟苯基）-2-_基-5-噚唑啶基]甲基 ]對甲苯磺酸_(7.34克*19.15奄莫耳）溶於無水0»^(50 奄升），再Μ固體NaH3 (3.73克，57.44毫其耳）處理。將反應物加热至60C歷2.5小時再令過夜（17小時）冷卻至室溫。於此時I.薄由TLC (65K CH3CN/CHC13, UV短波）發現反應已完全。真空澹縮反應物得非純白色固*。粗產物溶於乙酸乙酯（1升）再Μ水（400奪升）洗。水性部分再以 EtOAc(5 X 100奄升）反抽。合併之有機抽提物再Κ水 (40 0奄升）洗，並Μ鹽水（400¾升）洗一次。其次將有櫬部分於無水Na2S04上乾煉、通濾再減壓濃雄，得4.45克 (qiX)禰鼴化合物為非純白色结晶性固Hup 96.5-98C 且對（：1〇11«^4(^2計算之111?»<5(»<*)為 254.0615,實测值為 46 本紙張又度適用中國國家標準（CNS)A4規格（210 X 297公f ) 83.3.10,000 訂線五、發明説明（ 254.0609 ° A7 B7 (S)-N-[[3-(3,5-二氣笨基）-2-嗣基-5-啤唑啶 η ¥ t 基]甲基]乙醢胺將U)-[[3-(3,5-二氟苯基）-2-酮基-5-啤唑啶基]甲基 ]*氮（6.8克，26.75奄莫耳）溶於無水1'[^(50毫升），再 Μ於30分期間内分成部分地添加三苯基膦（10.52克， 40.13奄莫耳）。2小時後，藉由1^(：(10!|{»(6〇11/(^(：13, UV短波）發現反應巳完全。其次•加水（11.57«升| 642 奄其耳），並維持反應物於50C歷4小時。經冷卻藉由 TLC (10Χ HeOH/CHCU, UV短波）發現反應不完全，所Μ再加水（2.9«升）。加热（50Ό)另4小時後•反應經测定為完全。反應物再KCHCU (300奄升）稀釋並將產物抽入 2Ν HC1 (3 X 150毫升）中。酸性曆藉由小心添加50Χ重量比之HaOH，小心地中和至pH 14 。驗化之水相再以 CH2C12 (3 X 150毫升）抽。合併之有《相於無水Na2S〇4 上乾嫌、遇濾再-減壓澹繽•得4.53克（74X)白色结晶性固 »。將粗胺（4.53克）溶於（：112(：12(100亳升）及啦啶（10« 升）。將溶液冷卻至ου (冰浴）再經由添加钃斗滴加乙酸酐（5.05毫升，53.5毫莫耳）。令反應物於室溫、^下遇液（20小時）攢拌。次展•藉由TLC (5Χ MeOH/CHCU· UV短波）發現反縻已完全。反應混合物以EtOAc (200¾升 ).稀釋並M‘2H HC 1 (200毫升）。飽和NaHC〇3 (200奄升 )及鹽水（200奄升）洗。有櫬暦於無水Na2S04上乾嫌、過 47 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 83.3.10,000 -----------.Γ裝---------訂---------線 (請先閱讀背面之注意事項再填寫本頁) 五、發明説明（） A7 B7 灌再滅壓濃縮，得4.61克（鐮共64J!)檷題化合物為白色固趙•熔點 145-148C，且對 C1〇H12H2〇3F2 計算之 HRMS (Μ* )為 270 . 08 16，實测值為 270 . 08 1 5。製備19 (3)-1<-[[3-(4-碘基-3,5-二氟苯基）-2-醑基 -5-嗶唑啶基]-甲基]乙豳胺將（S)-N-[[3-(3,5-二氟笨基）-2-酮基-5-嗶唑啶基]_ 甲基]乙醣胺（1.25克，4.64奄莫耳）溶於冰乙酸（12奄升）及三氟乙酸（3奄升），再以固»12 (4.52克，27.8 4奄莫耳）處理。令所得深紫色溶液於室溫攪拌通夜（20小時）。橙色固《幾乎立刻開始自溶液迅速產生。次展，反應物 Μ醚（100奄升）稀釋再通通多孔玻璃通濾。橙色固_再Μ 醚（3 X 50毫升）洗，並再溶於溫的10Χ MeOH/CHCU中。 MeOH/CHCU 溶液 M20X Na2S203 (100 奄升）、飽和 HaHC〇3 (100奄升）及凿水（100奄升）洙。有機部分於無水 Na2S0«上乾嫌、過濾再減壓濃缩，得1.31克（71X)檷囲化合物為非純白色.固體，具192-193¾之溶點且對 (：121111}<2〇3「21計算之[11?1^(»< + )為 395.9784，資測值為 395.9779. ° 製備20 苄氧羰基-3,5-二氟苯胺將3,5-二氟硝基苯胺（10克，77.45«莫耳）慢慢加至 Na.HC03 (13.01克，154.9毫莫耳）於無水THF (200奄升 )中之漿。將此溶液冷卻至Ot：(冰浴）再Μ氯甲酸苄_ 4 8 - 衣紙張疋度適用中國國家標準（CNS)A4規格（210 X 2W公f ) 83.3.10,000 (請先閲讀背面之注意事項再填寫本頁) 裝、-=" 線五、發明説明（） A7 B7 (22.11奄升，154.9奄莫耳）滴加處理。經完成添加後，除去冰浴，令反應物於N2下搅拌4小時。於此時間後，箱 TLC (15¾ EtOAc/己烷，UV短波）測定反應已完全。反應物Μ飽和HaHC〇3 (300奄升）中止反應並抽提於CH2CU (3 X 200奄升）內。合併之有櫬抽提物再Μ水（400毫升）及鹽水（400毫升）洗。其次將有櫬層於無水HaS04上乾嫌、過濾並滅壓濃縮，得覆蓋有琥珀色油之结晶性物質。將此物質於矽膠（312克SG)上層析，M5及10« EtOAc/己烷溶離，得20.6克（100S!)摞題化合物為白色固體，bp 86-87¾ 且對C^HuFzNOz計算之MS (M*)為263 ，»測值為263 餺備21 N-烯丙基-N-苄氧羰基-3,5-二氟苯胺將H-苄氧羰基-3,5-二氟苯胺（10克溶於最小量之 1'11「，37.99奄莫耳）滴加至預先冷卻（0<〇*冰浴）之》1311 (於油中60X, 2.28克，56.99毫莫耳）於無水THF (150奄升）中之漿。經完成添加後，令混合物於〇〇、下携拌 ——-. 30分。於此時加觸媒、（正Bu)4 HI (1.0克，10X重量比 )及烯丙基溴（4.93¾升，56.99毫莫耳）。令反應物慢慢之溫至室溫，於N2下攪拌通夜（17小時）。次展· » TLC (15X EtOAc/己烷，UV短波）發現反應巳完全。反應混合物Μ水（150毫升）中止反應再抽提於EtOAc (3 X 150 « 升）内。合.併之有櫬抽提物再Μ鹽水（400 «升）洗並於無水Na2S0 «上乾嫌。乾煉後•將溶液通濾並減懕濃嫌得黄色 -49 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 2们公釐} 83.3.10,000 (請先閱讀背面之注意事項再填寫本頁) 裝訂線 B7 五、發明説明（）油。將此油於矽膠（250克）上層析、Μ 5及10X EtOAc/己烷溶離得10.58克（92X)標題化合物為澄清、無色油，對 C17H15F2N02 計算之 MS (M*)為 303 * 實測值為 303 。剪備22 (± ) - [3-(3,5-二氟苯基）-2-嗣基-5-〇f哇啶基 ]碘甲烷將N-烯丙基-N-苄氧羰基-3,5-二氟苯胺（11.5克，38.9 奄莫耳）溶於（：11(：13(100奄升）再以固«12(19.37克， 76. 19«莫耳）處理。令所得溶液於室溫、N2下祝拌過液 (20小時）。次展•箱TLC (15XEtOAc/己烷，Μ短波）發現反應已完全。反應混合物KCHCU (200奄升）稀釋，再Μ 20S! Na2S203 (250毫升）及鹽水（250奄升）洙。其次將有櫬曆於無水Na2S04上乾煉、過滹並濃嫌，得金黄色油。將此油於矽膠（300克）上層析•以15及50¾ EtOAc/己烷溶離，得12.67克（98¾)禰趄化合物為淡黃色固體，對 (：1〇1^?21川2計算之111^5(}^)為 338.9570，實测值為 338.9572° 製備23 (± )-[3-(3,5 -二氟笨基）-2 -萌基-5-鸣唑啶基 ]甲基]叠氮將（土）-[3-(3,5-二氟苯基）-2-嗣基-5-啤唑啶基]碘甲烷（12.64克· 37.3«莫耳）溶於DMF (100奄升）•再K固 «NaN3 (7.28克，111.9奄莫耳）處理。所得溶液於（<2下加热至60 υ歷2.5小時，再令回至室溫•攪拌逢夜（16小 -5 0 - 83.3.10,000 (請先閲讀背面之注意事項再塡寫本頁) 衣紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） A7 B7 五、發明説明（）時）。次晨，藉TLC (6X CH3CN/CHC13, UV短波）發現反應已完全。反應混合物Μ水（1〇〇〇奄升）中止反應·再抽提於EtOAc (3 X 150毫升）内。合併之有機抽提物再Μ水 (40 0毫升）洗並以鹽水（40 0毫升）再洗1次。其次，有機層於無水Na2S〇4上乾堍。過滤並減壓濃縮，得9.41克 (99¾)標題化合物為淡黃色固艚，mp 72-73t：對 (：1<^81?2^4〇2計算之111^5(1^)為 254.0615，實测殖為 254.0617 〇 ISL 備 24 (士）-N-[[3-(3,5-二氟苯基）-2-醑基-5-嗶唑唾基]甲基]乙醢胺將（± )-[[3-(3·5-二氟苯基）-2-酮基-5-啤唑啶基]甲基 ]叠氮（2.36克，9.30奄莫耳）溶於5)1!»(6011/£1:(^<:(200奄升）得涅淸黄色溶夜。此溶液KH2脫氣3次再M10X Pd-C (460毫克，20X重董比）處理。將溶液再脫氣（3X)，並經由球形瓶Μ 代替大氣壓。反應物於室溫攪拌20小時。於此時間後，薄TLC (30X EtOAc/己烷，UV短波）测定反應已 —---. 完全。反應混合物通過寅式鹽過濾，Μ過量CH2CU洗寅式鹽漶餅。濾液真空濃嫌得澄清、無色油。將此油再溶於 CH2CU (20毫升）及吡啶（10毫升）·再Μ乙酸酐（1.76 奄升，18.60奄莫耳）處理。令反應物於室溫|<2下攪拌過夜（17小時）。次展*反應物以EtOAc (100奄升）稀釋並以 2NHC1 (2 X. 100奄升）、飽和HaHC03 (100奄升）及鹽水 (100奄升）洗。有櫬曆於無水Na2S04上乾嫌、過濾並減懕 -51 - 83.3.10,000 (請先閱讀背面之注意事項再塡寫本頁) 本紙張又度適用中國國家標準（CNS)A4規格（210 X 297公釐） A7 B7 五、發明説明（）濃縮得白色固《。將此固體於矽膠（175克）上層析.K 0.5-2¾ MeOH (於 10¾ CH3CN/CHCU 中）梯度溶離，得 1;07克（42¾)標囲化合物為白色固體，mp 131.5-132.5 =，對（：12{112卩2^203 之計算之[11^5(讨*)為 270.0816，實測值為270.0810 。剪備25 (±)1-[[3-(4-碘基-3,5-二氟苯基）-2-嗣基-5-嗶唑啶基]-甲基]***胺將（土）-H-[ [3-(3,5-二氣苯基）-2-酮基-5-嗶唑啶基]-甲基]乙醢胺（500奄克*1.85毫萁耳）溶於乙酸（5奄升），再以1C 1(1. 8克，11.1奄冥耳）處理。令所得紅棕色溶液於室溫攪拌過夜（17小時）。次展，反應物以_(5 0毫升）稀釋再通過多孔波璃過濾。殘留之橙色固《再Μ醚（3 X 30 毫升）洗*再溶於溫的10»!Me0H/CHCl3 (100¾升）。此溶液以 20!K Na2S2〇3 (100毫升）、飽和 NaHC〇3 (100奄升）及鹽水（100毫升）洗。於無水Ha2S04上乾嫌後，過濾有櫬層再減壓濃縮，得387毫克檷題化合物為白色固體。2小時 -- - _ 後，更多產物自濾液中迅速產生。傾倒溶液*留下之固體 Μ醚洗。其次，亦將言些固體溶於热10X MeOH/CHCU (50奄升）中，再K20X Na2S2〇3 (50¾升）洗，K飽和 NaHC〇3 (50奄升）及鹽水（50奄升）洗。此有機曆亦於無水 Na2S04上乾煉，過濉並減壓濃縮·得另外142 «克禰題化合物為非婢.白色固«。單離雄共529 «克（72*)之所須化合物為白色固β，bp 191-1921C，對C^HuFssIHssOa計算 -52 - 本紙張X-度適用中國國家標準（CNS)A4規格（210 X 297公釐） 83.3.10,000 (請先閱讀背面之注意事項再填寫本頁) 裝訂線 ^99332 A7 B7 五、發明説明（之111{1^-(>4*)為 395.9784，實測值為 395.9774。脚備26 (± )-N-[ [3-[4-(三甲基鍚烷基）-3, 5-二氟苯基]-2-嗣基-5-嗶唑啶基]甲基]乙豳胺將（土）-料-[[3-(4-碘基-3,5-二氟苯基）-2-酮基-5-啤唑啶基]甲基]乙醢胺（1〇〇奄克，0.25毫冥耳）溶於1,4 -二噚烷（15奄升）中，再以六甲基二鍚（165, 0.50毫其耳）處理。反應混合物Μ N2脫氣3次後’加氯化雙（三苯基膦）鈀（II) (9毫克，0.0125毫其耳）。溶液再度脫氣（3X)並加熱至埋流（ll〇t!)歷5小時。此時間後，箱TLC (10J! MeOH/CHCl3, UV短波）測定反應已完全。真空除去溶劑，所得之油於矽除（75克）上曆析，以0.5-5» MeOH/CHCl3 梯度溶雕*得105毫克（97JO標題化合物為起泡沫之淡黄色固體，對（：115112<^203卩2511計算之111^$(材*)為 434.0461, 實测值為434.0457 。窗例 (±)-乙醢胺，N-[[3-[4-(4-甲氧基嗣基 (請先閲讀背面之注意事項再填寫本頁) 裝Me line V. Description of invention A7 B7 (ddd, J = 8.3, 2.2, 1.0 Hz, 1H), 6.86 (dddd, J = 8.2, 8.2, 2.5, 1.0 Hz, 1H), 4.84 (m, 1H), 4.29 ( dd, J = ll.l, 4.1 Hz, 1H), 4.24 (dd, J = ll.l 4.6 Hz, 1H), 4.10 (" t ", J = 9.1 Hz, 1H), 3.88 (dd, J = 9.2, 6.0 Hz, 1H), 2.46 (s, 3H). MS m / z (relative intensity) 365 (70.6, M *), 149 (100), 122 (32.8), 91 (52.8). HRHS m / z 365.0738 (calculated for C17HieFH〇5S: 365.0733). Analysis value: Calculated value of C17HieFN〇eS: C. 55.88; H, 4.41; N, 3.83, measured value: C, 55.96; Η, 4.38; N, 3.80. 骢备 (R)-[3- (3- Fluorophenyl) -2-keto-5-pyridazolyl] methyl azide (R)-[3- (3-fluorophenyl) -2-yl-ylbenzenesulfonic acid (2.340 g · 6.40 «Mohr's solution M solid β« _ selective chemical sodium (3.331 g · treated. The resulting slurry was heated to 65 ° C and 4.5 hours at night. The reaction mixture was then brewed with ethyl acetate * and pumped with ethyl acetate. Combined acetic acid, then dry (Na2S〇4). Pass and condense in vacuo to solidify it. • It is essentially pure. It is shown below MP. 81-82Ό [α] 2Β〇-136.5 ° (c 0.9, CHCla) 5-oxazolidinyl] methyl-4-methyl) in anhydrous DMF (60 mL) 51/23 «mole) at ambient temperature • Cool again to ambient temperature and release and dilute with water • Move to secretion The ethyl ester extract M was thoroughly shrunk in water, and the compound was obtained as Brexit: Pack! 1 order! ! Line (please read the precautions on the back before writing this page) 41 This paper & degree is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 83.3.10,000 A7 B7 V. Description of invention (IR Oil doped) 21 15, 1736, 1614, 1591, 1586, 1497, 1422, 1233, 1199, 1081, 1049 ci »-1 ^^-HMR (CDCla, 300 MHz) δ 7.45 (" dt ", J = 11.2, 2.3 Hz, 1H), 7.34 (" dt ”, J = 8.3, 6.4 Hz, 1H). 7.23 (ddd, J = 8.1, 2.1, 1.0 Hz, 1H), 6.86 (dddd, J = 8.2, 8.2 , 2.5, 1.0 Hz, 1H), 4.81 (ih, 1H), 4.09 (" t ", J = 8.9 Hz, 1H), 3.86 (dd, J = 9.0, 6.2 Hz, 1H), 3.72 (dd, J = 13.2, 4.5 Hz, 1H), 3.60 (dd, J = 13.2, 4.4 Hz, 1H). MS m / z (relative intensity) 236 (59.0, JT), 179 (94.9), 136 (59.5), 122 ( 62.4), 109 (71.8), 95 (100), 75 (40.7) ° HRMS n / z 236.0708 (“oHeFJUOsi calculated value: 236.0709). Analysis value: C10〇HeFIU〇2 calculation value: C. 50.85; Η , 3.84; H, 23.72, found: C, 50.74; Η, 3.76; H, 23.71. Preparation 12 (S) -N-[[3- (3-fluorophenyl) -2-pyridyl-5- Pyrazolidinyl] —- .. methyl] ethylamine (R)-[3- (3-fluorophenyl)- 2-Phenyl-5-0? Azolidinyl] methyl azide (8.200 g · 34.71 mol) in ethyl acetate ft (100¾ liter) solution Ml OX Pd / C (0.8 20 g) under nitrogen Treatment. After evacuation and filling, the Mg (spherical bottle) replaced the atmosphere. After 17 hours of storage under fi, TLC (5X fermentation / chloroform) showed that the azide was exhausted. The atmosphere was replaced with nitrogen. Pyridine (6 ml) and acetic anhydride (4.1 μL · 43.40 μM 83.3.10,000 (please read the precautions on the back before writing this page) This paper size applies to China National Standard (CNS) A4 (210 X 2 (Magic mm) 5. The description of the invention (A7 B7 ear) is added to the reaction mixture. The reaction mixture was stirred at ambient temperature for 1 hour and then filtered through a calcium salt, and the pad was washed with ethyl acetate. The liquid was concentrated in vacuo, and the residue was dissolved in methane. Add ether to provide sinking. After leaving in the refrigerator overnight, collect Guxiang by vacuum filtration. K cold hexane was washed and dried in vacuum. • Complete 4.2 70 grams of the title compound as white solid. An additional 3.700 grams was obtained from the mother liquor, with a total output of 91J ;. In addition to the above, the "crude product" is purified on silica gel by Kanalysis, K5S! Consider the following special micro mp 140.0-140.5¾ [α] 28〇-6.6 ° (c 1.0, CHCla) Preparation 13 (S) -H- [[3- (3-fluoro-4-sulfophenyl) -2-劣基 -5- 擊 zodidine (Please read the precautions on the back before filling in this page) f Pack] Methyl] Ethylamine (S) -N- [[3- (3-Gasophenyl) -2 -Keto-5-pyrazolidine baseline f acetamide (0.280 g, acid (5 mol) mixed mole) was mixed at ambient temperature T. Gradual formation of orange dilution, and dissolve with a true solid, £ 1 ^ 0) • Move to a liquid sodium sulfate solution and vacuum shrinkage. Provide the following characteristics: 1. 11 millimoles) solution, and then M -Atmospheric treatment. Precipitate dark reddish brown. About 2 4 small air-pass filter every medium. Dissolve the crude solid "I in the funnel and wash with saturated saline. There are 0.295 g (70! «) Of the phase of acetic acid (20 liters) in acetic acid (2. 343 g). After the color mixture is at room temperature, the reaction mixes the porosity of the frosted glass in the hot simulating (add less NaHC03A solution, On Na2S04, the suspected eel compound is white] methyl] ethyl and trifluoro ethyl 14.43 milliliter, nitrogen agitator K ether filter to collect Xujia ribs 2 0X sparse, filter and solidify "Γ. Gu 43 83.3.10,000 This paper is again applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) ^^ 9332 A7 B7 V. Description of invention () mp 185.5-186.5 t: [a] zbd -37.6 ° (c 1.0. DMF) Preparation of 1 4 (earth) -5-ethylsaminomethyl-3- (4trimethyltribenzyl) -pyrazole saliva-2-copper-hexamethyldithione (1.772g, 5.41 «mole) and (±) -5-acetamidomethyl-3-U'-iodobenzyl) pyrazolidin-2-one (1.840 g, 5.11 ammonium) in 23 «l dipyridane, alternately Pump down and fill with nitrogen 3 times. Then, gasified bis (triphenylphosphine) palladium (11) (0.155 g * 0.22 mmol) was evacuated and the system was evacuated again and filled with nitrogen 3 times, and the system was heated at a temperature of 96 °. After evaporating the solvent, the crude material was packed in a medium pressure silica column (40 X 63 2.5 cm X 25 cm, MIX formazan / aero-filled, Μmethylene chloride filled with M-methanase / atmosphere gradient solvent) to obtain 1.148 Gram (56. 5 5K) required material is white solid mp130-132Ό, together with 0.537 g (26.5X) of slightly impure material. HMR (CDCla, 300 MHz) δ: 7.48 (s, 4Η), 6.71 (bt, J = 6.0 Η6..1Η), 4.77 (ddd, J = 13.2 Hz, J, = 8.7 Hz, J '' = 4.5 Hz , 1H), 4.05 (t, J = 9.0 Hz, 1H), 3.80 (dd. J = 9.0 Hz, J '= 6.6 Hz. 1H), 3.63 (dd, J = 6.0 Hz, J' = 4.5 Hz, 2H ), 2.01 (s, 3H), 0.28 (t, J = 27.0 Hz. 9H) 〇IR (doped with mineral oil, cm · 1): 3356 (m), 1746 (s), 1665 (s). Quality ( Relative content): 398 (8.8 M *), 383 (100), 382 (36.9), 381 (75.3), 380 (29.0), 379 (42.7), 43 -44-83.3.10,000 (please read the notes on the back first Please write this page on the matter.) The table paper degree is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) A7 B7 5. Description of invention () (23.1), 29 (27.5); The calculation of ClsH22N2〇3Sn is true Quality S: 398.0650, measured value: 398.662. Analysis value: Calculated value of ClsH22N203Sn: C, 45.37, H, 5.58; N. 7.06. Found: C, 45.28; H, 5.51; 6.87. TLC: 5X formazan / aerial imitation: Rf = 0.34. Scissor preparation 15 (R)-[3- (3,5-difluorophenyl) -2-Mengyl-5-Pyrazolidinyl] formazan. Cool a solution of N-benzylcarbonyl-3,5-difluoroaniline (10.9 g, 30.01 mmol) in anhydrous THF (250 l) to -78 t :, then add n-BuLi dropwise within 15 minutes (19.7 ml, 31.51 milliliter) treatment. Stir the reaction at -78¾ for 1 hour * and then add (10-(-)-butyric acid glycidol_ (4.67ml, 33.01 millimoles) dropwise over 10 minutes. Treat the reaction again at -78 Stir for 2 hours and let the solution (17 hours) slowly warm to room temperature. At this point, dilute the reaction product ME t0 Ac (300 «L) and then use NfU Cl (30 mL) and S water (300 μL) L) Wash. Organic Jf is dried on anhydrous Na2S0 4, filtered and then decompressed to obtain a golden yellow oil. This oil is analyzed on silicone rubber (250 g SG, K 0-3S5 MeOH (in 10¾ CH3CN / CHCU ) Gradient dissociation) yielded 6.82 g (99S;) The anthrax compound was a waxy white solid marrow with mp 84-85t! And the calculated HRMS (Μ ”for C10〇HeN03F2 was 229.0550, the measured value was 229.0552. Preparation of Kwong (R )-[[3- (3,5-Difluorophenyl) -2-pyridin-5-Dfazolidinyl] methyl] p-toluenesulfonic acid Ku-45-This paper is again applicable to the Chinese National Standard (CNS ) A4 specification (210 X W7 mm) 83.3.10,000 ----------- {装-n I aa— ϋ nnn {Please read the precautions on the back before filling this page) A7 B7 5 3. Description of the invention ((R)-[3- (3,5-difluorophenyl) -2-pyridyl-5-oxazolidinyl] Fermented yeast (4.68 g, 20.42 mmol) was dissolved in pyridine (35 ml) and cooled to Ot (ice bath). Secondly, the cold solution M-toluenesulfonyl chloride (4.67 g, 24.50 mmol) was treated. The reaction was allowed to stir overnight (17 hours) in the cold room. The next morning, the product was precipitated by stopping the reaction with ice water (100 mL). The isolated material was filtered by suction and dried under high vacuum Liquid (20 hours) ° This reaction yielded 7.46 g (95¾) of the title compound as a white powdery solid • with ηρ 110.5-111.5 death and pair (: 171113 Sichuan "^ 23 calculated 111 ^ 5 (忖 *) is 383.0639, the actual The measured value is 383.0639. Cut 1 7 (R)-[[3-(3,5-difluorophenyl) -2-keto-5-morphazolidinyl (please read the precautions on the back before filling in this Page) Install Λ t] methyl] azide (R)-[[3- (3,5-difluorophenyl) -2-_yl-5-oxazolidinyl] methyl] p-toluenesulfonic acid _ (7.34 g * 19.15 mol) was dissolved in anhydrous 0 »^ (50 mol), and then treated with solid NaH3 (3.73 g, 57.44 mmol). The reaction was heated to 60C for 2.5 hours and allowed to stand overnight ( 17 hours) Cool to room temperature. At this time I. Thin by TLC (65K CH3CN / CHC1 3. UV short wave) found that the reaction was complete. The reaction product is condensed in vacuum to obtain a non-pure white solid *. The crude product was dissolved in ethyl acetate (1 liter) and washed with M water (400 liters). The aqueous portion was back pumped with EtOAc (5 X 100 mL). The combined organic extracts were washed again with K water (40 mL) and once with M brine (400 L). Secondly, the dried part was dried on anhydrous Na2S04, filtered and concentrated under reduced pressure, to obtain 4.45 g (qiX) of 祢缹 compound is non-pure white crystalline solid Hup 96.5-98C and right (: 1〇11 «^ 4 (^ 2 calculated 111? »&Lt; 5 (» < *) is 254.0615, the measured value is 46. This paper is again applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 public f) 83.3.10,000 V. Description of the invention (254.0609 ° A7 B7 (S) -N-[[3- (3,5-Difluorobenzyl) -2-pyridyl-5-pyrazolidine η ¥ t yl] methyl] acetate Amine dissolves U)-[[3- (3,5-difluorophenyl) -2-keto-5-pyrazolidinyl] methyl] * nitrogen (6.8 g, 26.75 mmol) in anhydrous 1 '[^ (50 ml), and then add triphenylphosphine (10.52 g, 40.13 μmol) in portions over 30 minutes. After 2 hours, by 1 ^ (:( 10! | {»( 6〇11 / (^ (: 13, UV short wave) found that the reaction was complete. Secondly • add water (11.57 «L | 642 ears), and maintain the reaction at 50C for 4 hours. After cooling by TLC (10Χ HeOH / CHCU, UV short wave) It was found that the reaction was incomplete, so add water (2.9 «L). After heating (50Ό) for another 4 hours, the reaction was determined to be complete. The product was diluted with KCHCU (300 μL) and the product was pumped into 2Ν HC1 (3 X 150 ml). The acidity was carefully neutralized to pH 14 by carefully adding 50 OH by weight of HaOH. The aqueous phase of the test was then Pumped with CH2C12 (3 X 150 ml). Combined with "Dried on anhydrous Na2S〇4, and then filtered-under reduced pressure to get Bin • get 4.53 g (74X) white crystalline solid». The crude amine (4.53 G) dissolved in (: 112 (: 12 (100 ml) and ralidine (10 «l). The solution was cooled to ου (ice bath) and then acetic anhydride (5.05 ml, 53.5 mmol) was added dropwise through the addition of a scoop ). Keep the reaction mixture at room temperature under ^ (20 hours) and mix. Second exhibition • Through TLC (5Χ MeOH / CHCU · UV short wave), it was found that the reaction was complete. The reaction mixture was EtOAc (200¾ liter). Dilute and wash with M'2H HC 1 (200 ml). Wash with saturated NaHC〇3 (200 liters) and brine (200 liters). It may be dried on anhydrous Na2S04, and it may exceed 47. CNS) A4 specification (210 X 297 mm) 83.3.10,000 -----------. Γ installed --------- ordered --------- line (please (Read the notes on the back before filling out this page) 5 Description of the invention () A7 B7 After refilling and condensing the pressure, 4.61 g (64J in total of Si!) Is obtained. The title compound is white solid Zhao. Melting point 145-148C, and the calculated HRMS (Μ *) for C1〇H12H2〇3F2 is 270 . 08 16, the measured value is 270. 08 1 5. Preparation 19 (3) -1 <-[[3- (4-iodo-3,5-difluorophenyl) -2-pyridin-5-pyridazolyl] -methyl] acetamide will ( S) -N-[[3- (3,5-Difluorobenzyl) -2-keto-5-pyridazolyl] _methyl] ethylamine (1.25 g, 4.64 mol) Glacial acetic acid (12 liters) and trifluoroacetic acid (3 liters) were treated with solid »12 (4.52 grams, 27.8 4 mols). The resulting dark purple solution was stirred at room temperature overnight (20 hours). The orange solid starts to produce rapidly from the solution almost immediately. In the second exhibition, the reactant was diluted with Μ ether (100 μL) and then filtered through porous glass. The orange solid _ ether M (3 X 50 ml) was washed and redissolved in warm 10X MeOH / CHCU. MeOH / CHCU solution M20X Na2S203 (100 liters), saturated HaHC〇3 (100 liters) and chiseled water (100 liters). The organic portion was dried on anhydrous Na2S0 «, filtered, and concentrated under reduced pressure to obtain 1.31 g (71X) of the bicarbonate compound as a non-pure white. Solid, with a melting point of 192-193¾ 3 "21 calculated [11? 1 ^ (» < +) is 395.9784, the estimated value is 395.9779. ° Preparation of 20 benzyloxycarbonyl-3,5-difluoroaniline 3,5-difluoronitroaniline ( 10g, 77.45 «mole) was slowly added to the slurry of Na.HC03 (13.01g, 154.9 millimoles) in anhydrous THF (200 liters). This solution was cooled to Ot: (ice bath) and then chlorine Benzyl formate _ 4 8-Applicable to China National Standard (CNS) A4 specification (210 X 2W male f) 83.3.10,000 (Please read the precautions on the back before filling out this page) Packing,-= " Line 5 3. Description of the invention () A7 B7 (22.11 liters, 154.9 mols) dropwise. After the addition was completed, the ice bath was removed and the reaction was stirred under N2 for 4 hours. After this time, the box was TLC (15¾ EtOAc / Hexane, UV short wave) The reaction was determined to be complete. The reactant M was saturated with HaHC〇3 (300 liters) to stop the reaction and extracted into CH2CU (3 X 200 liters). The combined extracts were mixed with water. (40 0 ml) and brine (400 ml). Secondly, dry the layer over anhydrous HaS04, filter and concentrate under pressure to obtain a crystalline substance covered with amber oil. Apply this substance to silica gel (312 g SG) Chromatography, M5 and 10 «EtOAc / hexane dissociated, to obtain 20.6 g (100S!) Of the title compound as a white solid, bp 86-87¾ and the MS (M *) calculated for C ^ HuFzNOz is 263,» measured value Prepare 21 N-allyl-N-benzyloxycarbonyl-3,5-difluoroaniline for 263 E. Dissolve H-benzyloxycarbonyl-3,5-difluoroaniline (10g in a minimum amount of 1'11 " , 37.99 mol) dropwise added to a slurry of pre-cooled (0 < 〇 * ice bath) 1311 (60X in oil, 2.28 g, 56.99 mmol) in anhydrous THF (150 mol). After the addition, the mixture was stirred at 〇〇, under-30 minutes. At this time, add catalyst, (normal Bu) 4 HI (1.0 g, 10X weight ratio) and allyl bromide (4.93 ¾ liters, 56.99 millimoles). The reaction was slowly warmed to room temperature and stirred overnight under N2 (17 hours). Second exhibition »TLC (15X EtOAc / hexane, UV short wave) found the reaction was complete. The reaction mixture M Water (150 ml) aborted Then extracted in EtOAc (3 X 150 «l) inner. Co., And then extract it with a coffin Μ brine (400« L) and washed in the water-free dry too Na2S0 «. After dry refining • The solution is filtered and reduced to a thick yellow color -49-This paper scale is applicable to the Chinese National Standard (CNS) A4 specification (210 X 2 mm) 83.3.10,000 (please read the precautions on the back first (Fill in this page) Binding line B7 V. Invention description () Oil. Chromatograph this oil on silica gel (250g), dissolve Μ 5 and 10X EtOAc / hexane to obtain 10.58g (92X) of the title compound as a clear, colorless oil , The calculated MS (M *) for C17H15F2N02 is 303 * the measured value is 303. Scissor 22 (±)-[3- (3,5-difluorophenyl) -2-oxi-5-〇f Group] methyl iodide Dissolve N-allyl-N-benzyloxycarbonyl-3,5-difluoroaniline (11.5 g, 38.9 mol) in (: 11 (: 13 (100 liter)) and then solidify « 12 (19.37g, 76.19 «mole) treatment. The resulting solution was mixed at room temperature under N2 (20 hours). Sub-exhibition • Box TLC (15X EtOAc / hexane, M short wave) found the reaction was complete The reaction mixture is diluted with KCHCU (200 μL), then soaked in M 20S! Na2S203 (250 mL) and brine (250 μL). Secondly, it will be dried on the anhydrous Na2S04, dried and concentrated, and get golden yellow Oil. Chromatography on silica gel (300 g) • Dissolve with 15 and 50¾ EtOAc / hexane to obtain 12.67 g (98¾) of the compound as a pale yellow solid, calculated as 111 ^ 5 for (: 1〇1 ^? 21 Sichuan 2 (} ^) Is 338.9570, the measured value is 338.9572 ° Preparation 23 (±)-[3- (3,5 -difluorobenzyl) -2 -meng-5-oxazolidinyl] methyl] azide Dissolve (earth)-[3- (3,5-difluorophenyl) -2-oxi-5-pyrazolidinyl] iodomethane (12.64 g · 37.3 «mole) in DMF (100 liters) • Treated with Ksolid «NaN3 (7.28 g, 111.9 mol). The resulting solution was heated to 60 ° C for 2.5 hours under <2, and then returned to room temperature. • Stirred every night (16 hours-5 0- 83.3.10,000 (Please read the precautions on the back before writing this page) The size of the clothing paper is in accordance with the Chinese National Standard (CNS) A4 specification (210 X 297 mm) A7 B7 5. Invention description () time. The next morning, The reaction was found to be complete by TLC (6X CH3CN / CHC13, UV short wave). The reaction mixture was quenched with water (100 mL). It was extracted in EtOAc (3 X 150 mL). The combined organic extracts Wash again with M water (40 mL) and wash again with brine (40 mL) Next, the organic layer was dried over anhydrous Na2S〇4 Tu. Filtration and concentration under reduced pressure gave 9.41 g (99¾) of the title compound as a pale yellow solid scorpion, mp 72-73t: 111 ^ 5 (1 ^) calculated as (: 1 < ^ 81? 2 ^ 4〇2 was 254.0615, The measured colonization is 254.0617. ISL prepared 24 (±) -N-[[3- (3,5-difluorophenyl) -2-pyridyl-5-pyrazolyl] methyl] acetamide will ( ±)-[[3- (3 · 5-Difluorophenyl) -2-keto-5-pyrazolidinyl] methyl] azide (2.36 g, 9.30 mmol) dissolved in 5) 1! »(6011 / £ 1: (^ < :( 200 ul)) Nirvana yellow dissolve night. This solution KH2 degassed 3 times and then treated with M10X Pd-C (460 mg, 20X heavy Dong ratio). Degas (3X) and replace atmospheric pressure via spherical flask M. The reaction was stirred at room temperature for 20 hours. After this time, thin TLC (30X EtOAc / hexane, UV short wave) determined that the reaction was complete. The reaction mixture was filtered through sodium salt, and the excess salt was washed with CH2CU. The filtrate was concentrated in vacuo to be a clear, colorless oil. This oil was redissolved in CH2CU (20 mL) and pyridine (10 mL). (1.76 liters, 18.60 mols) treatment. Allow the reaction to stir overnight (17 hours) at room temperature | <2. The solution was diluted with EtOAc (100 liters) and washed with 2NHC1 (2 X. 100 liters), saturated HaHC03 (100 liters) and brine (100 liters). There was a dry salt on anhydrous Na2S04, filtered and懕懕 -51-83.3.10,000 (Please read the precautions on the back before writing this page) This paper is again applicable to the Chinese National Standard (CNS) A4 specifications (210 X 297 mm) A7 B7 V. Description of invention () Concentrate to obtain a white solid. This solid was chromatographed on silica gel (175 g). K 0.5-2¾ MeOH (in 10¾ CH3CN / CHCU) was dissolved in a gradient to obtain 1.07 g (42¾) of the standard compound as a white solid. mp 131.5-132.5 =, for the calculation of (: 12 {112 2 2 203 [11 ^ 5 (discussion *) is 270.0816, the actual value is 270.0810. Shearing 25 (±) 1-[[3- (4- Iodo-3,5-difluorophenyl) -2-oxi-5-pyridazolyl] -methyl] ether amine will (earth) -H- [[3- (3,5-difluorobenzene Group) -2-keto-5-pyridazolyl] -methyl] acetamide (500 μg * 1.85 mmol) was dissolved in acetic acid (5 μL), and then 1C 1 (1.8 g , 11.1 Ammonium) treatment. The resulting red-brown solution was stirred overnight (17 hours) at room temperature. 0 ml) diluted and filtered through porous glass. The remaining orange solid was washed with M ether (3 X 30 mL) * and then dissolved in warm 10 »! Me0H / CHCl3 (100¾ L). This solution was washed with 20! K Na2S2〇3 (100 ml), saturated NaHC03 (100 l) and brine (100 ml). After drying on anhydrous Ha2S04, the layer was filtered and concentrated under reduced pressure to obtain 387 mg of the title compound as a white solid. After 2 hours --- _, more product was rapidly produced from the filtrate. Pour the solution * and wash with the solid M ether left. Secondly, some solids were also dissolved in hot 10X MeOH / CHCU (50 liters), and then washed with K20X Na2S2〇3 (50 ¾ liters), K saturated NaHC〇3 (50 liters) and brine (50 liters). . This organic calendar was also dried on anhydrous Na2S04, then concentrated and concentrated under reduced pressure. Another 142 «Ke title compounds are non-maid. White solid«. A total of 529 gram (72 *) required compounds are white solid β, bp 191-1921C, calculated for C ^ HuFssIHssOa -52-The X-degree of this paper is applicable to China National Standard (CNS) A4 specification (210 X 297mm) 83.3.10,000 (Please read the precautions on the back before filling in this page) Binding line ^ 99332 A7 B7 V. Description of the invention (The number of 111 {1 ^-(> 4 *) is 395.9784, the measured value is 395.9774 . Foot preparation 26 (±) -N- [[3- [4- (trimethylthyrinyl) -3, 5-difluorophenyl] -2-yl--5-pyridazolyl] methyl ] Acetoamine will be (earth) -material-[[3- (4-iodo-3,5-difluorophenyl) -2-keto-5-pyrazolidinyl] methyl] acetamide ( 100 mg, 0.25 mC) dissolved in 1,4-dioxane (15 mL), and then treated with hexamethyldithione (165, 0.50 m). The reaction mixture was degassed M 2 After 3 times, add bis (triphenylphosphine) chloride palladium (II) (9 mg, 0.0125 milliliter). The solution is degassed again (3X) and heated to buried flow (ll〇t!) For 5 hours. After this time, the box TLC (10J! MeOH / CHCl3, UV short wave) determined that the reaction was complete. The solvent was removed in vacuo and the resulting oil was analyzed by silica gel removal (75 g) Using 0.5-5 »MeOH / CHCl3 gradient dissolution engraving * to obtain 105 mg (97JO title compound is foaming light yellow solid, 111 ^ $ (material *) calculated for (： 115112 < ^ 203 卩 2511 is 434.0461, measured The value is 434.0457. Window example (±)-acetaminophen, N-[[3- [4- (4- methoxy phenyl) (please read the precautions on the back before filling in this page)

IJ 部：Λ I? 土 -1,3,6-環庚三烯-卜基）苯基]-2-嗣基-5-噚唑啶基]甲基 ] 將（士）-5-(叠氮甲基）-3-[4-(4_甲氧基-5-_基 -1,3,6-環庚三烯-卜基）苯基-2-嗶唑啶酮（1〇〇奄克， 0.286奄奄莫耳）溶於10«升EtOAc及4奄升MeOH之混合 $並藉助於超音波振暹及溫和的加溫。在K2氣流下加觸媒 (10X Pd/C, 50 «克）。將燒瓶抽空並以Ιί2沖洗（3次）箱線 53 83.3.10,000 本紙張义度通用中國國家標準（CNS)A4规格（210 X 297公釐）五、發明説明（ A7 B7 著經由球形瓶引入H2。混合物於（12下於大氣壓下自攢拌，並藉TLC監测進展。3小時後，TLC顯示9已耗盡。反應混合物通過寅式鹽填塞物過濾，漶液減壓濃縮。將所得油溶於10毫升CH2C12中並加1毫升吡啶與乙酸酐（500微升）。10分後，將反應混合物濃縮成淡黃色固《•其藉徑哼層析法纯化（ JWCHCU/MeOH混合物，：U-5X ，各100毫升溶離）。此得78奄克檷題化合物為淡黃色固體。 MP：231 -232 t? HRMS: C2〇H2〇N2〇S之計算值：368.1372 ，實測值 :368.1364 ° NMR： (CDCU) ： 5 7.61 (d. 2H, J = 8.8 Hz), 7.53-7.51 (m, 1H), 7.515 (d, 2H, J=8.8 Hz), 7.34 (d, 1H, J=11.7 Hz), 7.31-7.28 (n, 1H), 6.97 (bt, 1H), 6.89 (d, 1H, J = 11.7 Hz), 4.82 (通，1H), 4.12 (t, 1H, J=9.1 Hz), 4.00 (s, 3H), 3.85 (dd, 1H, J+9.2 Hz), 3.67-3.65 (Μ, 2H), 2.03 (s, 3H). 管俐2 (±)-乙随胺，N-[[3-[4-[(4-甲氧基-5-網基 -1,3,6-環庚三烯-1-基）苯基]-2-蹰基-5-嗶唑啶基]甲基 ] 將三甲基（4-甲氧基-5-_基-1,3,6-環庚三烯-1-基）鍚 (50奄克，0.167奄莫耳）溶於5毫升1,4-二啤烷中並加芳棊磺（50毫克，0.139毫其耳）。混合物W抽空脫氣並以 N2沖洗（3次）。其次*加觸媒氱化雙（三苯基膦）鈀（10 54 农紙張尺·度適用中國國家標準（CNS)A4規格（210 X 297公釐） 83.3.1〇,〇〇〇 ------------f-裝---------訂---------線 (請先閱讀背面之注意事項再塡寫本頁) A7 B7 五、發明説明（）奄克），最後將混合物脫氣。混合物於下加热至迴流，並藉TLC監测進展。混合物經加热變成均態。5小時後， TLC顯示起始物質已耗盡。反應混合物冷卻至周溫接著通過寅式鹽之填塞物遇漶混合物，自混合物除去鈀黑。濃縮母液得固體殘留物，其賴徑向層析法純化。二氧化矽以 CHCl3/MeOH混合物（U至5»)分成100毫升之部份溶離。藉由TLC收集對應於10之基準樣品之溶離份並濃嫌得黄色泡沫。將泡沫溶於最小量CH2CU中並藉加醚沈澱固體。過濾固體，以醚洗並真空乾煉，得37奄克禰題化合物。此物霣藉由TLC, 1 MNR及mp之比較在所有方面皆與基準樣品相同。 3013 (± )-乙醢胺，N-[ [3-[3-氣-4-(4-甲氧基-5-嗣基-1,3,6-環庚三烯-1-基）苯基]-2-酮基-5-啤唑啶基]甲基] 將芳基碘19 (50毫克，0.132 «其耳）溶於4毫升 1,4-二啤烷中」__並加環庚三烯基鍚烷u (43.5奄克，’ 0.146奄莫耳），混合物藉抽空脫氣並以K2沖洗（3次）苒加觭媒Pd (Ph3P)2CL2(9.3毫克），最後脫氣接著加熱至迴流，藉TLC監测進展。8小時後，TLC顯示19實霣上已耗盡。湄縮成棕色固體，將其溶於10¾ MeOH / C H C 1 3中並通遇小的矽膠填塞管過濾。濃縮成固體，箱徑向廢析法纯化 MCHCl3/MeOH混合物（U MeOH移至6J!(於75«升«積中）溶離。單離40奄克之檷题化合物20為非禰準白色固Μ。 _ 5 5 - 表紙張又度適用中國國家標準（CNS)A4規格（210 X 297公釐） 83.3.10,000 (請先閲讀背面之注意事項再塡寫本頁) 裝線 A7 B7五、發明説明（） MP ： 200-201 1：分析值：C2〇HieFN2〇Bt計算值：C, 62,17; H, 4.96; N， 7.25,實測值：C, 60.62; Η, 4.99; N, 6.98 HRMS: C2〇HieFN2〇5 之計算值：.388 . 1278;實测值 386.1271 ^ NMR (CDCU) ： 5 7.55 (d, 1H), 7.42-7.31 (m, 4H), 7.205 (d, 1H. J=10.5 Hz), 6.82 (d, 1H, J=10.5 Hz), 6.10 (bt, 1H), 4.82 (m, 1H), 4.09 (t, 1H, J=9.00 Hz), 4.00 (s, 3H), 3.85 (·, 1H). 3.70 (m, .2H), 2.04 (s, 3H). 下面為式Ia-c之經甲氧基取代之實例之胺置換反應之代表性方法。奮例4 (± )-乙醢胺，N-[ [2-酮基-3-[4-[5-嗣基 -4-[(苯甲基）胺基]-1,3,6-瓌庚三烯-1-基）笨基]-5-啤唑啶基]甲基（4a) 將（±)-乙醢胺，^-[[3-[4[(4-甲«基-5-醑基-1,3,6- 一. 環庚三烯-1-基）苯基]-2-嗣基-5-啤唑啶基]甲基（25«克 ,0.07奄莫耳）於1.5奄升苄胺及5毫升無水甲苯之混合液中使成漿狀。混合物於N2下加热至溫和埋流。16小時後，藉TLC顯示混合物已耗盡。將混合物冷卻至周溫並Μ 15«升醚稀揮。ift濉沈赧並Μ醚洗。真空乾嫌亮黄色固體。此得32鼇標鼸化合物。 HP :239-240 ^ -56 - 本紙張尺度適用中國國家標準（CNS)A4规格（210 X 2幻公釐） 83.3.10,000 (請先閲讀背面之注意事項再填寫本頁) 裝 ij 線五、發明説明（ A7 B7 i|S M. •7? % 分析值：C2aH25N3〇4之計算值：C, 70.41; Η, 5.68; N, 9.47，實測值：C, 70.06; Η, 5.67; N, 9.41 HRMS:C2eH25N3(U 之計算值：443.1845:實測值 443.1859. NMR (CDCU) ： δ 7.66-7.54 (m, 3H), 7.465 (d, 1H), 7.48-7.32 (m, 7H), 7.27 (d, 1H, J=11.5 Hz), 6.70 (d, 1H, J=11.5 Hz), 4.80 (m, 1H), 4.63 (s, 2H), 4.12 (T. 1H, J = 9.1 Hz), 3.85-3.80 (m, 1H), 3.65-3.59 (m, 2H), 2.02 (s, 3H). 用類似實例4中所用之方法，但以適當之胺代替苄胺，得下列化合物： (± )-乙雔胺，N-[[2-嗣基- 3- [4-[5 -酮基-4-[(二乙基 )胺基]-1,3,6-環庚三烯-2-基]苯基]-5-晖唑啶基]甲基 (4b) MP ： 164-165¾ C23H27N3〇4之計算值：409.2001;實測值：409.1994。 XH NMR (CDC 1 3) ： δ 7.57-7.46 (m, 3H), 7.37-7.24 ( m, 3H), 6.97 (d, 1H, J=12.2 Hz), 6.655 (d, 1H, J=11.2 Hz), 4.82 (m, 1H), 4.12 (t, 1H, J=9.0 Hz), 3.88-3.83 (m, 1H) (±) -乙睡胺，N-[[2-萌基- 3- [4-[5 -酮基- 4- [(2-經乙基）胺基]-1,3,6-環庚三烯-1-基]苯基]-5-嗶唑啶基]甲基 ](4c) Μ P ： 2 1 2 - 2 1 3 Ό HRMS: C21H23N3〇s 之計算值：+1Κ: 398.1716 ;實测值： 57 本紙張&度適用中國國家標準（CNS)八4規格（2丨0 X 2W公釐） 83.3.10,000 (請先閱讀背面之注意事項再塡寫本頁) 裝訂線 A7 B7 五、發明說明（ 398.1735 NMR (CDCla)： δ 7.56-7.43 (m, 6H), 7.20 (d, 1H, J=11.5 Hz), 4.78-4.87 (m, 1H), 4.10 (t, 1H, J=9.0 Hz), 3.94 (bt, 2H), 3.86-3.84 (m, 1H), 3.66 (bt, 2H), 3.53 (bt, 2H), 2.03 (s, 3H). (± )-乙豳胺，N-[[2-萌基- 3-[4-[5-嗣基- (4-嗎啉基 )-1,3,6-環庚三烯-1-基]苯基]-5-噚唑啶基]甲基](4d) MP :231 -232 ¾ HRMS: C23H25N3〇5 之計算值：423.1794;實测值： 423.1785 aH NMR (CDCla) ： δ 7. 585 (d, 2Η, J = 8.8 Hz), 7.485 (d, 2H, J=8.8 Hz), 7.38 (dd, 1H, J=12.5 Hz). 7.225 (dd, 1H, J=10.7 Hz), 7.12 (d, 1H, J=12.5 Hz), 6.775 (d, 1H, J=10.7 Hz), 6.11 (bt, 1H), 4.81 (m, 1H), 4.10 (t, 1H, J=9.1 Hz).3.90 (bt, 4H, J=4.6 Hz), 3.835 (dd, 1H, J=9.1 Hz), 3.70-3.67 (nu.._2H), 3.39 (bt, 4H, J = 4.6 Hz), 2.04 (s, 3H). (± )-乙醢胺，M-[[2-國基-3-[4-[5-Sl基- 4-[(環丙胺基]-1,3,6-環庚三烯-1-基]苯基]-5-啤唑啶基]甲基] (4 e) MP :233-234^ MS(EI): n/z (相對強度）393 [Μ*] (68), 337 (31, 222(30), 181 (34), 42 (100)。 58 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 83.3.10,000 (請先閱讀背面之注意事項再塡寫本頁) 裝訂線五、發明説明（ A7 B7 ^ NMR (CDC13)： 5 7.88-7.48 (m, 6H), 7.195 (d, 1H, J=12.1 Hz), 7.125 (d, 1H, J=10.8 Hz). 4.81 (m, 1H), 4.10 (t, 1H, J=9.0 Hz), 3.875 (dd, 1H, J=9.0 Hz), 3.64 (bt, 2H, J=5.5 Hz), 2.65-2.62 (m, 1H), 2.01 (s, 3H), 1.01-0.95 (m, 2H), 0.73-0.68 (m, 2H). (± )-乙豳胺，N-[[2 -酮基- 3- [4-[5 -酮基- 4- [(4 -後醒 )六氫吡畊基]-1,3,6-環庚三烯-卜基]苯基]-5-晖唑啶基 ]甲基](4f) MP :255-257¾ MS(EI): m/z (相對強度）450 [Μ*] (5), 406 (86), 56(100)。 NMR (CDCU) ： δ 7.61-7.57 (m, 2H), 7.51-7.42 (m, 3H), 7.28-7.23 (m, 1H), 7.18 (d, 1H, J=12.5 Hz), 6.82 (d, 1H. J=10.7 Hz), 6.73 (bt, 1H), 4.80 (m, 1H), 4.11 (t, 1H, J=9.0 Hz), 3.84-3.78 (m, 2H), 3.70-3.60 (m,...4H), 3.40 (bt, 3H), 3.32 (bt, 1H), 3.09 (bt, 1H), 2.03 (s, 3H). (土）-乙豳胺，N-[ [2-_ 基-3-[4-[5-嗣基-4-[ (2-丙稀基）胺基]-1,3, 6-環庚三烯-卜基]-5-嗶唑啶基]甲基] (4g) MP :213-215¾ ”》^:(：22汗23»<3〇4之計算值：393.1688;實测值： 393.1673° 59 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 83.3.10,000 (請先閱讀背面之注意事項再塡寫本頁) 裝IJ Department: Λ I? Tu-1,3,6-cycloheptatriene-butyl) phenyl] -2-oxi-5--5-oxazolidinyl] methyl] will (Shi) -5- (stack Nitromethyl) -3- [4- (4-methoxy-4-yl-1,3,6-cycloheptatriene-butyl) phenyl-2-pyridazolidone (100 ℃ Grams, 0.286 mols) dissolved in a mixture of 10 liters of EtOAc and 4 liters of MeOH and warmed with ultrasonic vibration. Add catalyst under K2 flow (10X Pd / C, 50 «g). The flask was evacuated and rinsed with Ιί2 (3 times). Box line 53 83.3.10,000 This paper is compliant with the Chinese National Standard (CNS) A4 specification (210 X 297 mm) V. Description of the invention (A7 B7 Introduce H2 via spherical bottle The mixture was self-mixed at (at 12 under atmospheric pressure, and progress was monitored by TLC. After 3 hours, TLC showed that 9 was exhausted. The reaction mixture was filtered through a pad of ethyl salt, and the eluent was concentrated under reduced pressure. The resulting oil Dissolve in 10 ml of CH2C12 and add 1 ml of pyridine and acetic anhydride (500 μl). After 10 minutes, concentrate the reaction mixture to a pale yellow solid. • Purify by the method of chromatographic chromatography (JWCHCU / MeOH mixture, U -5X, 100 ml each dissociated). This yielded 78 mg of the title compound as a pale yellow solid. MP: 231 -232 t? HRMS: Calculated value for C2〇H2〇N2〇S: 368.1372, found value: 368.1364 ° NMR : (CDCU): 5 7.61 (d. 2H, J = 8.8 Hz), 7.53-7.51 (m, 1H), 7.515 (d, 2H, J = 8.8 Hz), 7.34 (d, 1H, J = 11.7 Hz) , 7.31-7.28 (n, 1H), 6.97 (bt, 1H), 6.89 (d, 1H, J = 11.7 Hz), 4.82 (pass, 1H), 4.12 (t, 1H, J = 9.1 Hz), 4.00 ( s, 3H), 3.85 (dd, 1H, J + 9.2 H z), 3.67-3.65 (Μ, 2H), 2.03 (s, 3H). Guan Li 2 (±) -Ethylamine, N-[[3- [4-[(4-methoxy-5-net Yl-1,3,6-cycloheptatrien-1-yl) phenyl] -2-hexyl-5-pyridazolyl] methyl] will trimethyl (4-methoxy-5-_ Yl-1,3,6-cycloheptatrien-1-yl) thorium (50 ng, 0.167 mol) dissolved in 5 ml of 1,4-dibrane and added sulfonamide (50 mg, 0.139 Milligrams). The mixture W was evacuated and degassed and rinsed with N2 (3 times). Secondly, the catalyst was added with bis (triphenylphosphine) palladium (10 54 agricultural paper ruler). The Chinese National Standard (CNS) A4 was applied Specifications (210 X 297 mm) 83.3.1〇, 〇〇〇 ------------ f-installed --------- ordered --------- Line (please read the precautions on the back before writing this page) A7 B7 V. Description of the invention () 奄克), and finally degas the mixture. The mixture is heated to reflux under, and the progress is monitored by TLC. The mixture is heated It became homogeneous. After 5 hours, TLC showed that the starting material had been consumed. The reaction mixture was cooled to ambient temperature and then the mixture was shaken through a pad of indium salt, and palladium black was removed from the mixture. The mother liquor was concentrated to obtain a solid residue, which was purified by radial chromatography. The silicon dioxide was dissolved in a 100 ml portion with a CHCl3 / MeOH mixture (U to 5 »). The dissolved fraction corresponding to the reference sample of 10 was collected by TLC and concentrated as yellow foam. Dissolve the foam in the minimum amount of CH2CU and precipitate the solid by adding ether. The solid was filtered, washed with ether and dried in vacuo to obtain 37 mg of the title compound. This object is the same as the reference sample in all respects by comparison of TLC, 1 MNR and mp. 3013 (±) -acetamidoamine, N- [[3- [3-gas-4- (4-methoxy-5-hexyl-1,3,6-cycloheptatrien-1-yl) benzene Group] -2-keto-5-pyrazolidinyl] methyl] Dissolve aryl iodide 19 (50 mg, 0.132 «Ear) in 4 ml of 1,4-dibromoane" __ and add ring Heptatrienyltinane u (43.5 μg, 0.146 μmol), the mixture was degassed by evacuation and rinsed with K2 (3 times) with the Pd (Ph3P) 2CL2 (9.3 mg) and finally degassed followed by Heat to reflux and monitor progress by TLC. After 8 hours, TLC showed that 19 of them were exhausted. Mae shrinks into a brown solid, dissolves it in 10¾ MeOH / CHC13 and filters through a small silicone plugged tube. Concentrate to a solid and purify the MCHCl3 / MeOH mixture (U MeOH to 6J! (In the 75 «L« volume) by radial waste analysis in a box. Dissolve away. 40 ng of the title compound 20 is a non-quasi-white solid M. _ 5 5-The table paper is again applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 83.3.10,000 (please read the precautions on the back before writing this page) Thread A7 B7 V. Invention description ( ) MP: 200-201 1: Analysis value: C2〇HieFN2〇Bt calculated value: C, 62,17; H, 4.96; N, 7.25, found value: C, 60.62; Η, 4.99; N, 6.98 HRMS: C2 Calculated value of HieFN2〇5: .388.1278; found value 386.1271 ^ NMR (CDCU): 5 7.55 (d, 1H), 7.42-7.31 (m, 4H), 7.205 (d, 1H. J = 10.5 Hz ), 6.82 (d, 1H, J = 10.5 Hz), 6.10 (bt, 1H), 4.82 (m, 1H), 4.09 (t, 1H, J = 9.00 Hz), 4.00 (s, 3H), 3.85 ( , 1H). 3.70 (m, .2H), 2.04 (s, 3H). The following is a representative method for the amine replacement reaction of the methoxy substituted example of formula Ia-c. Example 4 (±) -B Acetylamine, N- [[2-keto-3- [4- [5-benzyl-4-[(benzyl) amino] -1,3,6-pyridin-1-yl) Benzy] -5-Pyrazolidinyl] methyl (4a ) The (±) -acetamide, ^-[[3- [4 [(4-methyl «yl-5-pyryl-1,3,6-a. Cycloheptatrien-1-yl) phenyl ] -2-Butyl-5-pyrazolidinyl] methyl (25 «g, 0.07 mol) was slurried in a mixture of 1.5 liter benzylamine and 5 ml of anhydrous toluene. The mixture was heated to a gentle buried flow under N2. After 16 hours, the mixture was exhausted by TLC. The mixture was cooled to ambient temperature and diluted with 15 liters of ether. Ift sinks and rinses with M ether. Vacuum dry a bright yellow solid. This gave 32 鳌 standard compound. HP: 239-240 ^ -56-The paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 2 mm) 83.3.10,000 (please read the precautions on the back before filling out this page). Description of the invention (A7 B7 i | S M. • 7?% Analysis value: Calculated value of C2aH25N3〇4: C, 70.41; Η, 5.68; N, 9.47, found value: C, 70.06; Η, 5.67; N, 9.41 HRMS: C2eH25N3 (Calculated value of U: 443.1845: Found value 443.1859. NMR (CDCU): δ 7.66-7.54 (m, 3H), 7.465 (d, 1H), 7.48-7.32 (m, 7H), 7.27 (d, 1H, J = 11.5 Hz), 6.70 (d, 1H, J = 11.5 Hz), 4.80 (m, 1H), 4.63 (s, 2H), 4.12 (T. 1H, J = 9.1 Hz), 3.85-3.80 ( m, 1H), 3.65-3.59 (m, 2H), 2.02 (s, 3H). Using a method similar to that used in Example 4 but substituting the appropriate amine for benzylamine, the following compounds were obtained: (±) -ethylcarboxamide , N-[[2-Butyl-3- [4- [5-keto-4-[(diethyl) amino] -1,3,6-cycloheptatrien-2-yl] phenyl ] -5-Hizazolidinyl] methyl (4b) MP: 164-165¾ Calculated value of C23H27N3〇4: 409.2001; Found value: 409.1994. XH NMR (CDC 1 3): δ 7.57-7.46 (m, 3H) , 7.37-7.24 (m, 3H), 6.97 (d, 1H, J = 12.2 Hz), 6.655 (d, 1H, J = 11.2 Hz), 4.82 (m, 1H), 4.12 (t, 1H, J = 9.0 Hz), 3.88-3.83 (m, 1H) (±) -ethylpyramine, N- [ [2-Meng-3-[4- [5-keto-4-([2-diethyl) amino] -1,3,6-cycloheptatrien-1-yl] phenyl]- 5-pyridazolyl] methyl] (4c) Μ P ： 2 1 2-2 1 3 Ό HRMS: Calculated value of C21H23N3〇s: + 1Κ: 398.1716; measured value: 57 This paper & degree is suitable for China National Standard (CNS) 8.4 specifications (2 丨 0 X 2W mm) 83.3.10,000 (please read the precautions on the back before writing this page) Binding line A7 B7 5. Description of the invention (398.1735 NMR (CDCla): δ 7.56-7.43 (m, 6H), 7.20 (d, 1H, J = 11.5 Hz), 4.78-4.87 (m, 1H), 4.10 (t, 1H, J = 9.0 Hz), 3.94 (bt, 2H), 3.86 -3.84 (m, 1H), 3.66 (bt, 2H), 3.53 (bt, 2H), 2.03 (s, 3H). (±) -acetate, N-[[2- 萌萌-3- [4 -[5-Butyl- (4-morpholinyl) -1,3,6-cycloheptatrien-1-yl] phenyl] -5-oxazolidinyl] methyl] (4d) MP: 231 -232 ¾ HRMS: calculated value of C23H25N3〇5: 423.1794; measured value: 423.1785 aH NMR (CDCla): δ 7. 585 (d, 2Η, J = 8.8 Hz), 7.485 (d, 2H, J = 8.8 Hz ), 7.38 (dd, 1H, J = 12.5 Hz). 7.22 5 (dd, 1H, J = 10.7 Hz), 7.12 (d, 1H, J = 12.5 Hz), 6.775 (d, 1H, J = 10.7 Hz), 6.11 (bt, 1H), 4.81 (m, 1H), 4.10 (t, 1H, J = 9.1 Hz) 3.90 (bt, 4H, J = 4.6 Hz), 3.835 (dd, 1H, J = 9.1 Hz), 3.70-3.67 (nu .._ 2H), 3.39 (bt, 4H, J = 4.6 Hz), 2.04 (s, 3H). (±) -acetanilide, M-[[2-Guo-3- [4- [5-Slyl- 4-[(cyclopropylamino ] -1,3,6-cycloheptatrien-1-yl] phenyl] -5-pyrazolidinyl] methyl] (4 e) MP: 233-234 ^ MS (EI): n / z ( Relative intensity) 393 [Μ *] (68), 337 (31, 222 (30), 181 (34), 42 (100). 58 The size of this paper is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) 83.3.10,000 (please read the precautions on the back before writing this page). Binding line 5. Invention description (A7 B7 ^ NMR (CDC13 ): 5 7.88-7.48 (m, 6H), 7.195 (d, 1H, J = 12.1 Hz), 7.125 (d, 1H, J = 10.8 Hz). 4.81 (m, 1H), 4.10 (t, 1H, J = 9.0 Hz), 3.875 (dd, 1H, J = 9.0 Hz), 3.64 (bt, 2H, J = 5.5 Hz), 2.65-2.62 (m, 1H), 2.01 (s, 3H), 1.01-0.95 (m , 2H), 0.73-0.68 (m, 2H). (±) -acetamidoamine, N-[[2-keto-3-] [4- [5-keto-4-[(4-wake up) Hexahydropyridyl] -1,3,6-cycloheptatriene-p-yl] phenyl] -5-huiazolidinyl] methyl] (4f) MP: 255-257¾ MS (EI): m / z (relative intensity) 450 [Μ *] (5), 406 (86), 56 (100). NMR (CDCU): δ 7.61-7.57 (m, 2H), 7.51-7.42 (m, 3H), 7.28- 7.23 (m, 1H), 7.18 (d, 1H, J = 12.5 Hz), 6.82 (d, 1H. J = 10.7 Hz), 6.73 (bt, 1H), 4.80 (m, 1H), 4.11 (t, 1H , J = 9.0 Hz), 3.84-3.78 (m, 2H), 3.70-3.60 (m, ... 4H), 3.40 (bt, 3H), 3.32 (bt, 1H), 3.09 (bt, 1H), 2.03 (s, 3H). (earth) -acetaminophen, N- [[2-_yl-3- [4- [5-benzyl-4- [(2-propenyl Amine] -1,3, 6-cycloheptatriene-bromo] -5-pyridazolyl] methyl] (4g) MP: 213-215¾》》 ^ :(: 22Khan23 »< 3 Calculated value of 〇4: 393.1688; measured value: 393.1673 ° 59 The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 83.3.10,000 (Please read the precautions on the back before writing this page ) Pack

MC 線 A7 B7 ^99332 五、發明説明（） XH NMR (CDC13) ： δ 7.62-7.43 (m , 6Η), 7.255 (d, 1Η, J=12.1 Hz), 6.645 (d, 1H, J=11.0 Hz), 6.00-6.63 (m, 1H), 5.29-5.26 (m, 1H), 4.81 (m, 1H), 4.11 (t, 1H, J=9.0 Hz), 4.06 (m, 2H), 3.87-3.81 (m, 1H), 3.68-3.66 (m, 2H), 2.03 (s, 3H). (±)-乙醢胺，N-[[2-酮基-3-[4-[5-醑基-4-[吡咯烷 -卜基]-1,3,6-環庚三烯-卜基]苯基]-5-啤唑啶基]甲基] (4h) MP ： 230-231 Ό HRMS: C23H25N3〇4 之計算值：407.1845;實测值： 407.1859 ΧΗ NMR (CDCla)： δ 7.555 (d, 2H, J=8.9 Hz), 7.455 (d, 2H, J=8.9 Hz), 7.345 (dd, 1H, J=10.1 Hz), 7.26 (dd, 1H, J=11.3 Hz), 6.98 (d, 1H, J=12.1MC line A7 B7 ^ 99332 V. Description of the invention () XH NMR (CDC13): δ 7.62-7.43 (m, 6Η), 7.255 (d, 1Η, J = 12.1 Hz), 6.645 (d, 1H, J = 11.0 Hz ), 6.00-6.63 (m, 1H), 5.29-5.26 (m, 1H), 4.81 (m, 1H), 4.11 (t, 1H, J = 9.0 Hz), 4.06 (m, 2H), 3.87-3.81 ( m, 1H), 3.68-3.66 (m, 2H), 2.03 (s, 3H). (±) -Ethylamine, N-[[2-keto-3- [4- [5-acetin-4 -[Pyrrolidine-bromo] -1,3,6-cycloheptatriene-bromo] phenyl] -5-pyrazolidinyl] methyl] (4h) MP: 230-231 Ό HRMS: C23H25N3. Calculated value of 4: 407.1845; measured value: 407.1859 ΧΗ NMR (CDCla): δ 7.555 (d, 2H, J = 8.9 Hz), 7.455 (d, 2H, J = 8.9 Hz), 7.345 (dd, 1H, J = 10.1 Hz), 7.26 (dd, 1H, J = 11.3 Hz), 6.98 (d, 1H, J = 12.1

Hz), 6.78 (bt, 1H), 6.445 (d, 1H, J=11.2 Hz), 4.79 (m, 1H), 4.10 (t, 1H, J=9.0 Hz), 3.825 (dd, 1H, J=9.0 Hz), 3.69 (bs, 6H). 2.03 (s, 3H), 1.98 (bs, 4H). (土）-乙睡胺，N-[[2 -酮基- 3- [4-[5_酮基-4-(4-甲基六氫吡畊-1-基）-1,3,6-環庚三烯-卜基]苯基]-5-噚唑啶基 ]甲基](4 i ) MP :204-206¾ HRMS:C24H2eN4〇4之計算值：436.21 10;實測值：436.21 17 (請先閱讀背面之注意事項再塡寫本頁) I !|S 4 % C.Hz), 6.78 (bt, 1H), 6.445 (d, 1H, J = 11.2 Hz), 4.79 (m, 1H), 4.10 (t, 1H, J = 9.0 Hz), 3.825 (dd, 1H, J = 9.0 Hz), 3.69 (bs, 6H). 2.03 (s, 3H), 1.98 (bs, 4H). (Earth) -acetolamine, N-[[2-keto-3-[4- [5-_one 4- (4-methylhexahydropyridin-1-yl) -1,3,6-cycloheptatrien-butyl] phenyl] -5-oxazolidinyl] methyl] (4 i ) MP: 204-206¾ HRMS: Calculated value of C24H2eN4〇4: 436.21 10; Measured value: 436.21 17 (Please read the notes on the back before writing this page) I! | S 4% C.

L 60 83.3.10,000 本紙張&度適用中國國家標準（CNS)A4規格（2丨0 X 297公釐） A7 B7 五、發明説明（） XH NMR (CDCU) ： δ 7. 575 (d, 2H, J = 8.8 Hz), 7.475 (d, 2H, J=8.8 Hz), 7.375 (dd, 1H, J=12.5 Hz). 7.255 (dd, 1H, J=10.7 Hz), 7.10 (d, 1H, J=12.5L 60 83.3.10,000 This paper & degree is applicable to the Chinese National Standard (CNS) A4 specification (2 丨 0 X 297 mm) A7 B7 V. Invention description () XH NMR (CDCU): δ 7. 575 (d, 2H , J = 8.8 Hz), 7.475 (d, 2H, J = 8.8 Hz), 7.375 (dd, 1H, J = 12.5 Hz). 7.255 (dd, 1H, J = 10.7 Hz), 7.10 (d, 1H, J = 12.5

Hz), 6.80 (d, 1H J=10.7 Hz), 6.17 (bt, 1H), 4.81 (m, 1H), 4.10 (t, 1H, J=9.0 Hz), 3.835 (dd, 1H, J=9.0 Hz), 3.72-3.61 (m, 2H), 3.43 (bt, 4H, J=4.80 Hz), 2.62 (bt, 4H, J=4.80 Hz), 2.36 (s, 3H), 2.04 (s, 3H). · (±)-***胺，N-[[2-嗣基-3-[4-[5-酮基-4-(環戊基）胺基]-1,3,6-環庚三烯-1-基]苯基]-5-嗶唑啶基]甲基] (4j) MP ： 208-210¾ HRMS:C24H27N3〇4之計算值：421.2001;實測值：421.1987 Ο XH NMR (CDC 13) ： δ 7.61-7.44 (m , 6H), 7.20 (d, 1H, J=12.0 Hz), 6.71 (d, 1H, J=11.2 Hz), 4.81 (m, 1H), 4.10 (t, 1H, J=9.0 Hz), 4.00 (η, 1H, 3.865 ---- (dd, 1H, J=10.0 Hz), 3.68-3,66 (m, 2H). 2.20-2.10 (m, 2H), 2.04 (s, 3H). 1.81-1.68 (m, 6H). (士）-乙醢胺，N-[[2 -酮基- 3- [4-[5 -萌基- 4- (六氫吡畊 -1-基]-1,3,6-環庚三烯-卜基]苯基]-5-啤唑啶基]甲基] (4k) Μ P ： > 3 0 0 υ HRMS: C23H2efU〇4 之計算值：422.1954;實測值： 422.1965. - 61 - 木紙張又度適用中國國家標準（CNS)A4規格（210 X 2Q7公釐） 83.3.10,000 (請先閱讀背面之注意事項再塡寫本頁) 裝線五、發明説明（ A7 B7 Γ § XH NMR (CDC13) ： δ 7.585 (d, 2H, J = 8.8 Hz), 7.485 (d, 2H, J=8.8 Hz), 7.395 (dd, 1H, J=12.5 Hz), 7.255 (dd, 1H, J=10.8 Hz), 7.12 (d, 1H, J=12.5 Hz), 6.815 (d, 1H, J=10.8 Hz), 6.70 (bt. 1H), 4.81 (m, 1H), 4.11 (t, 1H, J=9.0 Hz), 3.854 (dd, 1H, J=8.8 Hz), 3.68 (m, 2H), 3.38 (bt, 4H, J=4.8 Hz), 3.08 (bt, 4H, J=4.8 Hz), 2.03 (s, 3H). (±)_乙醢胺，N-[[2-醑基-3-[4-[5-酮基-4-(正丁基）胺基]-1,3, 6-環庚三烯-卜基]苯基]-5-嗶唑啶基]甲基] (41) MP :197-198 ¾ HRMS:C23H2efU〇4 之計算值：422.1954;實測值：422.1964 Ο aH NMR (CDC13)：5 7.58-7.45 (m, 6H), 7.22 (d, 1H, J=12.0 Hz), 6.66 (d, 1H, J=11.0 Hz), 4.80 (m, 1H), 4.11 (t, 1H, J=9.0 Hz), 3.835 (dd, 1H, J=9.1 Hz), 3.68 (m, 2H), 3.36 (t, 2H, J=7.2 Hz), 2.03 (s, 3H), 1.78-1.74 (m, 2H), 1.53-1.45 (m, 2H), 1.00 (t, 3H, J = 7.2 Hz). (土）-***胺，N-[[2-酮基-3-[4-[5-嗣基-4-(順式 -3.5-二甲基六氳吡畊-1-基）-1,3,6-環庚三烯-1-基]-2-_基-5-啤〇$啶基]甲基](4n) MP : 142-144Ό 62 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公藿） 83.3.10,000 -----------•一 -裝---------訂---------線 (請先閲讀背面之注意事項再塡窝本頁) i 經濟部t央榀準局工消費合作社印¾ A7 B7 五、發明説明（） MS(EI): m/z (相對強度）450 [M*] (45), 380 (54), 366 (43)， 367 (53), 84 (100)。 aH NMR (CDC13) ： 5 7. 585 (d, 2H, J = 8.8 Hz), 7.475 (d, 2H, J=8.8 Hz), 7.355 (dd, 1H, J=12.5 Hz), 7.215 (dd, 1H, J=10.8 Hz), 7.10 (d, 1H, J=12.5Hz), 6.80 (d, 1H J = 10.7 Hz), 6.17 (bt, 1H), 4.81 (m, 1H), 4.10 (t, 1H, J = 9.0 Hz), 3.835 (dd, 1H, J = 9.0 Hz ), 3.72-3.61 (m, 2H), 3.43 (bt, 4H, J = 4.80 Hz), 2.62 (bt, 4H, J = 4.80 Hz), 2.36 (s, 3H), 2.04 (s, 3H). (±) -diethyl etheramine, N-[[2-Butyl-3- [4- [5-keto-4- (cyclopentyl) amino] -1,3,6-cycloheptatriene-1 -Yl] phenyl] -5-pyridazolyl] methyl] (4j) MP: 208-210¾ HRMS: Calculated value for C24H27N3〇4: 421.2001; Found value: 421.1987 Ο XH NMR (CDC 13): δ 7.61 -7.44 (m, 6H), 7.20 (d, 1H, J = 12.0 Hz), 6.71 (d, 1H, J = 11.2 Hz), 4.81 (m, 1H), 4.10 (t, 1H, J = 9.0 Hz) , 4.00 (η, 1H, 3.865 ---- (dd, 1H, J = 10.0 Hz), 3.68-3,66 (m, 2H). 2.20-2.10 (m, 2H), 2.04 (s, 3H). 1.81-1.68 (m, 6H). (±) -Acetylamine, N-[[2-keto-3-[4- [5-meng-4- (hexahydropyridin-1-yl)- 1,3,6-cycloheptatriene-butyl] phenyl] -5-pyrazolidinyl] methyl] (4k) M P: > 3 0 0 υ HRMS: Calculated value for C23H2efU〇4: 422.1954 ; Measured value: 422.1965.-61-Wood paper is again applicable to China National Standard (CNS) A4 specification (210 X 2Q7 mm) 83.3.10,000 (please Read the precautions on the back and write this page again. Fifth, the description of the invention (A7 B7 Γ § XH NMR (CDC13): δ 7.585 (d, 2H, J = 8.8 Hz), 7.485 (d, 2H, J = 8.8 Hz), 7.395 (dd, 1H, J = 12.5 Hz), 7.255 (dd, 1H, J = 10.8 Hz), 7.12 (d, 1H, J = 12.5 Hz), 6.815 (d, 1H, J = 10.8 Hz) , 6.70 (bt. 1H), 4.81 (m, 1H), 4.11 (t, 1H, J = 9.0 Hz), 3.854 (dd, 1H, J = 8.8 Hz), 3.68 (m, 2H), 3.38 (bt, 4H, J = 4.8 Hz), 3.08 (bt, 4H, J = 4.8 Hz), 2.03 (s, 3H). (±) _Ethylamine, N-[[2-Diethyl-3- [4- [ 5-keto-4- (n-butyl) amino] -1,3, 6-cycloheptatriene-butyl] phenyl] -5-pyridazolyl] methyl] (41) MP: 197 -198 ¾ HRMS: calculated value of C23H2efU〇4: 422.1954; found value: 422.1964 Ο aH NMR (CDC13): 5 7.58-7.45 (m, 6H), 7.22 (d, 1H, J = 12.0 Hz), 6.66 (d , 1H, J = 11.0 Hz), 4.80 (m, 1H), 4.11 (t, 1H, J = 9.0 Hz), 3.835 (dd, 1H, J = 9.1 Hz), 3.68 (m, 2H), 3.36 (t , 2H, J = 7.2 Hz), 2.03 (s, 3H), 1.78-1.74 (m, 2H), 1.53-1.45 (m, 2H), 1.00 (t, 3H, J = 7.2 Hz). (Soil)- Diethyl etheramine, N-[[2-keto-3- [4- [5-benzyl-4- (cis-3.5-dimethylhexahydropyrrol-1-yl) -1, 3,6-cycloheptatrien-1-yl] -2-_yl-5-berryl [pyridyl] methyl] (4n) MP: 142-144Ό 62 This paper scale is applicable to China National Standard (CNS) A4 Specification (210 X 297 common patchouli) 83.3.10,000 ----------- • one-pack --------- order --------- line (please read first Note on the back of this page) i Printed by the Ministry of Economic Affairs, Central Bureau of Industry and Consumer Cooperatives A7 B7 V. Description of invention () MS (EI): m / z (relative intensity) 450 [M *] (45 ), 380 (54), 366 (43), 367 (53), 84 (100). aH NMR (CDC13): 5 7. 585 (d, 2H, J = 8.8 Hz), 7.475 (d, 2H, J = 8.8 Hz), 7.355 (dd, 1H, J = 12.5 Hz), 7.215 (dd, 1H , J = 10.8 Hz), 7.10 (d, 1H, J = 12.5

Hz), 6.79 (d, 1H, J=10.8 Hz), 6.12 (bt, 1H), 4.80 (m, 1H), 4.11 (t, 1H, J = 9.0 Hz), 3.89-3.81 (m, 3H), 3.49-3.47 (η, 2H), 3.16 (m, 2H), 2.45 (bt, 2H, J=112.4 Hz). 2.04 (s, 3H), 1.18 (d, 6H, J = 6.30 Hz). (±)-乙豳胺，N-[[2-酮基-3-[4-[5-酮基-4-(六氫吡啶 -卜基]-1,3,6-環庚三烯-1-基]苯基]-5-啤唑啶基]甲基] (4n) MP :211-212¾ HRMS:C24H27N3〇4之計算值：42 1.2001;實测值：421.2007 Ο aH NMR (CDCU) ： δ 7. 565 (d, 2Η, J = 8.8 Hz). 7.465 (d, 2H, J=8.8. Hz), 7.33 (dd, 1H, J=12.4 Hz), 7.195 (dd, 1H, J=10.8 Hz), 7.07 (d, 1H, J=12.4 Hz), 6.80 (d, 1H, J=10.8 Hz), 6.25 (bt, 1H), 4.81 (b, 1H), 4.10 (t, 1H, J=9.0 Hz), 3.835 (dd, 1H, J=9.0 Hz), 3.73-3.61 (m, 2H), 3.41-3.39 (m, 4H), 2.04 (s,· 3H), 1.74-1.72 (m. 6H). (士）-乙醢胺，1[[2-_基-3-[-[5-酮基-4-(3-甲基六 - 63 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 83.3.10,000 -----------^1—裝---------訂-------I線 (請先閲讀背面之注意事項再填寫本頁) 五、發明説明（ A7 B7 氫吡哄-1-基]-1,3,6 -環庚三烯-1-基]苯基]-5-啤唑啶基 ]甲基](4〇) MP ： 189-1911： HRMS:C24H28N4〇4之計算值：436.21 10;實測值：436.21 10 Ο NMR (CDCU) ： δ 7. 575 (d, 2H, J = 8.8 Hz), 7.485 (d, 2H, J=8.8 Hz), 7.395 (d, 1H, J=12.5 Hz), 7.255 (dd, 1H, J=10.7 Hz), 7.255 (dd, 1H, J=10.7 Hz), 7.12 (d, 1H, J=12.4 Hz), 6.82 (d, 1H, J=10.7 Hz), 4.81 (m, 1H), 4.11 (t, 1H, J=9.0 Hz), 3.86-3.83 (m, 3H), 3.67-3.63 (η, 2H), 2.87 (m, 1H), 2.50 (bt, 1H, J=10.4 Hz), 2.03 (s, 3H), 1.14 (d , 3H , J = 6.3 Hz). (±)_乙醢胺，N-[ [2-嗣基-3-[4-[5-國基-4-(3-羥基吡咯烷-1-基）-1 ,3,6-環庚三烯-1-基]苯基]-5-嗶唑啶基 ]甲基](4p) MP :223-224¾ HRMSiCzaHzBHaOs + fUi計算值：424. 1872;實测值： 424. 1900 "H NMR (CDC13) ： 5 7.495 (d, 2H, J = 8.8 Hz), 7.395 (d. 2H, J=8.8 Hz), 7.32 (d, 1H, J=12.2 Hz). 7.23 (d, 1H, J=11.2 Hz), 6.95 (d, 1H, J=12.2 Hz), 6.465 (d, 1H, J=11.2 Hz), 4.81 (b, 1H), 4.56 (a, 1H), 4.09 (t, 1H, J=9.0 Hz), 3.99-3.95 (bd, 1H), (請先閲讀背面之注意事項再塡寫本頁) 裝 •ΤΓ 線本紙張义度適用中國國家標準（CNS)A4規格（210 X 297公釐） 83.3.10,000 ^9332 A7 B7 五、發明説明（ 3.85-3.77 (m, 3H), 3.67-3.66 (·, 2H), 2.93-2.88 (m, 1H), 2.07 (bs, 2H), 2.03 (s, 3H). 奮俐 5 (±)-N-[[3-[4-(4-乙氧基 _5-_基-1,3,6-環庚三烯-卜基]苯基]-2-萌基-5-嗶唑啶基]甲基]乙醢胺將（±)-忖-[[3-[4-(4-甲氧基-5-醑基-1,3,6-環庚三烯 -1-基]苯基]-2-醑基-5-噚唑啶基]甲基]乙醣胺（0.100克 • 0.27«莫耳）於無水乙酵（10奄升）中之漿Μ催化量之氫化納（5毫克之60S!分散液（於礦油中））處理。混合物於 Ν2下加熱至迴流，於其時，混合物變成均態溶液。迴流 15分後，將溶液冷卻至周溫並顧示固體沈澱。反應混合物 Μ***稀釋並藉過濾收集固體。真空乾嫌後•得0.08 8克 (85Χ)檷題化合物為淡黃色固«具下列特激： up 228-229Ό XH NMR (CDCla, 300 ΗΗζ)：δ7.60 (d, J=8.7 Hz, 2H), 7.52-7.47 (m. 1H), 7.48 (d, J=8.5 Hz, 2H), 7.33-7.26 (·, 1H), 7.24 (d, J=10.5 Hz, 1H), 6.87 (d, J=10.6 Hz, 1H), 6.80 (bt, 1H). 4.82 (b, 1H), 4.19 (q, J = 6.9 Hz, 2H), 4.11 (" t", J = 8.9 Hz, 1H), 3.86 (dd, J=9.0, 6.8 Hz, 1H), 3.75-3.60 (m, 2H), 2.03 (s, 3H), 1.56 (t, J = 6.9 Hz, 3H).’ MS m/z (相對強度）382 (36.5, M+), 338 (55.0), 310 (26.3), 254 (26.8), 226 (100.0) HRMS m/z 382.1536 (C21H22N2〇B 之計算值：382.1529) (請先閲讀背面之注意事項再填寫本頁) 、11 綿Hz), 6.79 (d, 1H, J = 10.8 Hz), 6.12 (bt, 1H), 4.80 (m, 1H), 4.11 (t, 1H, J = 9.0 Hz), 3.89-3.81 (m, 3H), 3.49-3.47 (η, 2H), 3.16 (m, 2H), 2.45 (bt, 2H, J = 112.4 Hz). 2.04 (s, 3H), 1.18 (d, 6H, J = 6.30 Hz). (±) -Acetylamine, N-[[2-keto-3- [4- [5-keto-4- (hexahydropyridinyl-l-yl) -1,3,6-cycloheptatrien-1-yl ] Phenyl] -5-pyrazolidinyl] methyl] (4n) MP: 211-212¾ HRMS: C24H27N304 calculated value: 42 1.2001; measured value: 421.2007 Ο aH NMR (CDCU): δ 7. 565 (d, 2Η, J = 8.8 Hz). 7.465 (d, 2H, J = 8.8. Hz), 7.33 (dd, 1H, J = 12.4 Hz), 7.195 (dd, 1H, J = 10.8 Hz), 7.07 (d, 1H, J = 12.4 Hz), 6.80 (d, 1H, J = 10.8 Hz), 6.25 (bt, 1H), 4.81 (b, 1H), 4.10 (t, 1H, J = 9.0 Hz), 3.835 (dd, 1H, J = 9.0 Hz), 3.73-3.61 (m, 2H), 3.41-3.39 (m, 4H), 2.04 (s, · 3H), 1.74-1.72 (m. 6H). (士)- Acetylamine, 1 [[2-_yl-3-[-[5-keto-4- (3-methylhexa-63-This paper scale is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 %) 83.3.10,000 ----------- ^ 1—installed --------- ordered ------- I line (please read the precautions on the back before filling in this Page) 5 Description of the invention (A7 B7 Hydropyridin-1-yl] -1,3,6-cycloheptatrien-1-yl] phenyl] -5-pyrazolidinyl] methyl] (4〇) MP: 189 -1911: HRMS: calculated value of C24H28N4〇4: 436.21 10; found value: 436.21 10 NMR (CDCU): δ 7. 575 (d, 2H, J = 8.8 Hz), 7.485 (d, 2H, J = 8.8 Hz), 7.395 (d, 1H, J = 12.5 Hz), 7.255 (dd, 1H, J = 10.7 Hz), 7.255 (dd, 1H, J = 10.7 Hz), 7.12 (d, 1H, J = 12.4 Hz) , 6.82 (d, 1H, J = 10.7 Hz), 4.81 (m, 1H), 4.11 (t, 1H, J = 9.0 Hz), 3.86-3.83 (m, 3H), 3.67-3.63 (η, 2H), 2.87 (m, 1H), 2.50 (bt, 1H, J = 10.4 Hz), 2.03 (s, 3H), 1.14 (d, 3H, J = 6.3 Hz). (±) _acetamide, N- [[ 2-Butyl-3- [4- [5-Guo-4- (3-hydroxypyrrolidin-1-yl) -1,3,6-cycloheptatrien-1-yl] phenyl] -5 -Pyridazolyl] methyl] (4p) MP: 223-224¾ HRMSiCzaHzBHaOs + fUi calculated value: 424.1872; measured value: 424.1900 " H NMR (CDC13): 5 7.495 (d, 2H, J = 8.8 Hz), 7.395 (d. 2H, J = 8.8 Hz), 7.32 (d, 1H, J = 12.2 Hz). 7.23 (d, 1H, J = 11.2 Hz), 6.95 (d, 1H, J = 12.2 Hz), 6.465 (d, 1H, J = 11.2 Hz), 4.81 (b, 1H), 4.56 (a, 1H), 4.09 (t, 1H, J = 9.0 Hz), 3.99-3.95 (bd, 1H), (please read the precautions on the back before writing this page) Installation • ΓΓ line paper is applicable to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 83.3.10,000 ^ 9332 A7 B7 5. Description of the invention (3.85-3.77 (m, 3H), 3.67-3.66 (·, 2H), 2.93-2.88 (m, 1H), 2.07 (bs, 2H), 2.03 (s, 3H). Fenli 5 (±) -N-[[3- [4- (4-ethoxy_5-_yl-1,3,6-cycloheptatriene-heptyl] phenyl] -2-menyl -5-pyridazolyl] methyl] acetaminophen (±)-忖-[[3- [4- (4-methoxy-5-pyridyl-1,3,6-cycloheptatriene -1-yl] phenyl] -2-pyridyl-5-oxazolidinyl] methyl] ethylamine (0.100 g • 0.27 mol) in a slurry of anhydrous ethyl yeast (10 l) The amount of hydrogenated sodium (5 mg of 60S! Dispersion (in mineral oil)) treatment. The mixture was heated to reflux under N2, at which time the mixture became a homogeneous solution. After refluxing for 15 minutes, the solution was cooled to ambient temperature and the solid precipitated. The reaction mixture was diluted with diethyl ether and the solid was collected by filtration. After vacuum drying, 0.08 8g (85Χ) of the title compound was obtained as a pale yellow solid with the following special excitation: up 228-229Ό XH NMR (CDCla, 300 ΗΗζ): δ7.60 (d, J = 8.7 Hz, 2H ), 7.52-7.47 (m. 1H), 7.48 (d, J = 8.5 Hz, 2H), 7.33-7.26 (·, 1H), 7.24 (d, J = 10.5 Hz, 1H), 6.87 (d, J = 10.6 Hz, 1H), 6.80 (bt, 1H). 4.82 (b, 1H), 4.19 (q, J = 6.9 Hz, 2H), 4.11 (" t ", J = 8.9 Hz, 1H), 3.86 (dd , J = 9.0, 6.8 Hz, 1H), 3.75-3.60 (m, 2H), 2.03 (s, 3H), 1.56 (t, J = 6.9 Hz, 3H). 'MS m / z (relative intensity) 382 ( 36.5, M +), 338 (55.0), 310 (26.3), 254 (26.8), 226 (100.0) HRMS m / z 382.1536 (Calculated value of C21H22N2〇B: 382.1529) (Please read the precautions on the back before filling in this Page), 11 cotton

Sw L· 本紙張尺度適用中國國家標準（CNS)A4规格（210 X 297公釐） 83.3.10,000 A7 B7 五、發明説明（）〇竇例6 (S)-N-[ [3-[3-氟-4-(4-甲氧基-5-酮基 -1,3,6-環庚三烯-1-基]苯基]-2-嗣基-5-嗶唑啶基]甲基 ]乙釀胺將上述之（S)-N-[[3-[3-氟-4-碘苯基）-2-酮基-5-啤唑啶基]甲基]乙醢胺（4.200克，11.11毫莫耳）及三甲基 (4-甲氧基-5-酮基-1,3,6-環庚三烯-卜基）鍚（4.150克· 13.88«莫.耳）於1,4-二嗶烷（50毫升）中之漿藉璽複之抽空脫氣再K氮充填。加氛化雙（三苯基膦）鈀（II) (0.545克， 0.78毫莫耳），再將反應物脫氣，然後於氮下使混合物至邇流。3小時後，TLC顥示一些碘化物仍存在。加另外之鍚試劑（0.400克，1.34奄莫耳）及鈀觸媒（0.100克，0.14 奄莫耳）並將混合物迴流4小時•冷卻反應混合物至周溫並減至濃縮。殘留物溶於20¾甲酵/氛仿·通過寅式鹽通濾並真空濃縮。將粗固體與二氣甲烷/***研磨，過滹固體，K***洗並真空乾煉得4.200克（98ίί)摞題化合物。一 ·- 顧示下列特徵： mp 227-228Ό [a ]2B〇 +39.5° (c 0.9, DMF) 替代地，可將上述之啤唑啶嗣化碘轉化成 (S)-N-[[3-[3-氟- 4-(三甲級烷基）笨基]-2-嗣基-5-啤唑啶基]甲基].乙醢胺，使用對對應之外消旋物質揭示於TR 72 46-92-050之條件。將此鍚取代之中間物（0.180克，本紙張尺度通用中國國家標準（CNS)A4規格（210 X 297公釐） 83.3.10,000 -------------裝---------訂---------線 (請先閲讀背面之注意事項再填寫本頁) Α7 Β7 五、發明説明（） 0.43毫莫耳）及5-溴-2-甲氧基環庚-2,4,6-三烯-卜酮 (0.103克· 0.48奄莫耳）溶於無水DMF (3毫升）中，所得溶液藉反覆抽空脫氣及Μ氮充填。加氛化雙（三苯基膦）祀 (11)(0.015克，0.02奄莫耳）·再將反應物脫氣，混合物加热至80 C歷2小時。TLC顧示一些起始物質仍然存在，所Μ加另外之鈀觸媒（0.0 15克）· 混合物再加熱5小時。反應混合物真空下濃縮，殘留物於矽膠上層析* Μ甲酵/ 氯仿梯度溶離，得0.096克（57!K)標題化合物，與經由上面之實驗計畫窨製備之物質•於所有方面皆相同。實蓋7 (±)-«-[[3-[4-(4-甲氧基-3-酮基-1,4,6-環庚三烯-卜基]笨基]-2-醑基-5-噚唑啶基]甲基]乙醯胺將（± )-5-乙醢胺甲基- 3-(4·-三甲錫苯基）晖唑啶-2-酮 (1.172克，2.95毫莫耳）及6-溴-2-甲氧基瑁庚-2,4,6-三烯-1-嗣（0,677克，3.13毫莫耳）之二〇?烷（50毫升）溶液，交替地抽空並Μ氮充填3次。再加«化雙（三苯基膦）鈀（1 1)(0.200克，0.28奄莫耳）。再將此糸统抽空並Μ氮充填3次，並於90t：下加熱過夜。反應並不完全；因此加 0.103克（0.15奄莫耳）鈀觸媒，將此***交替地抽空及以氮充填4次。酒潦2小時後，通逋矽藻土填塞管通濾•將其小心地Μ二氛甲烷及甲酵洗。蒸發溶劑得粗物質，將其於中®二氣化矽管柱（40 X 63 w, 2.5厘米X 26厘米，以U甲酵/..纽仿裝垓，以氯仿充填，並以甲酵/氮仿梯度溶離）上純化，得0.889克（82«產量）所須物質為白色固本紙張&度適用中囤國家標準（CNS}A4规格（210 X 297公釐） 83.3.10,000 -------------裝---------訂---------線 (請先閲讀背面之注意事項再塡寫本頁) A7 B7 五、發明説明（體。此物質再自丙酮中重结晶得0.557克（51.2¾)白色固體，mp 213-214 =供分析。 "H NMR (CDCU, 300 ΜΗζ)δ ： 7.63 (d, J = 9.0 Hz, 2H), 7.60 (d, J=9.0 Hz, 2H), 7.45 (s, 1H), 7.10 (m, 2H), 6.73 (d, J=8.7 Hz, 1H), 6.02 (bt, J=6.0 H z , 1 H ) , 4 . 8 1 (m , 8 線，1 H ) , 4 . 1 2 (t , J = 9.0 H z , 1H), 3.98 (s, 3H), 3.78 (dd, J=9.0 Hz, J''=6.9 Hz, 1H), 3.74 (ddd, J=14.7 Hz, J'=6.0 Hz, J''=3.3 Hz, 1H), 3.64 (dt, J=14.7 Hz, J'=6.0 11111H), 2.04 (s, 3H). 13C NMR (75.47 MHz, CDC13)； 23.11, 41.93, 47.46, 56.34, 72.00, 111.63, 118.25, 128.62, 129.52, 132.17, 135.72, 137.97. 138.75, 148.91, 154.38, 165.16, 170.63, 179.38. IR (礦油摻雜，cm-1): 3307(m), 1739(s), 16 49 U), 1592(s), 1575(s), 1561(s). 質譜：m/e (相對含量）：368 (9.8, M*), 340 (32.3), 296 (24.1), 240 (26.5), 237 (20.5), 212 (100), t η ¥ 199 (34.3), 85 (37.6), 56 (28.2), 43 (29.5), 29 (34.1); C2〇H2〇N20b之真正計算值量：368.1372,實測值：368.1385. 分析值 C2〇H2〇N20e 之計算值：C, 65.21; H, 5.47; N, 7.60;實测值：C, 64.79; H, 5.28; N, 7.60. TLC:51« 甲酵 / 氣仿：Rr = 0.21 · L· -68 - 83.3.10,000 (請先閱讀背面之注意事項再塡寫本頁) 本紙張尺度適用中®國家標準（CNS>A4規格（210 X 297公釐） A7 B7Sw L · The size of this paper is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) 83.3.10,000 A7 B7 5. Description of invention () 〇Sinus 6 (S) -N- [[3- [3- Fluoro-4- (4-methoxy-5-keto-1,3,6-cycloheptatrien-1-yl] phenyl] -2-oxyl-5-pyridazolyl] methyl] Ethylamine will the above (S) -N-[[3- [3-fluoro-4-iodophenyl) -2-keto-5-pyrazolidinyl] methyl] acetamide (4.200 g, 11.11 millimoles) and trimethyl (4-methoxy-5-keto-1,3,6-cycloheptatriene-butyl) thorium (4.150 g · 13.88 «Mo. ear) at 1,4 -The slurry in the two benzanes (50 ml) is degassed by Xifu and then filled with K nitrogen. Aerated bis (triphenylphosphine) palladium (II) (0.545 g, 0.78 mmol) was added, the reaction was degassed, and the mixture was allowed to flow under nitrogen. After 3 hours, TLC indicated that some iodide was still present. Additional thionium reagent (0.400 g, 1.34 mol) and palladium catalyst (0.100 g, 0.14 mol) were added and the mixture was refluxed for 4 hours. • Cool the reaction mixture to ambient temperature and reduce to concentration. The residue is dissolved in 20¾ formazan / ammonia, filtered through sodium salt and concentrated in vacuo. The crude solid was triturated with dichloromethane / ether, washed with solid, washed with K ether and dried under vacuum to obtain 4.200 g (98L) of the title compound. 1.- Consider the following characteristics: mp 227-228Ό [a] 2B〇 + 39.5 ° (c 0.9, DMF) Alternatively, the above-mentioned pyrazolidine iodide can be converted into (S) -N-[[3 -[3-Fluoro-4- (trimethylalkyl) benzyl] -2-yl--5-pyrazolidinyl] methyl]. Ethylamine, the use of the corresponding racemic substance is revealed in TR 72 Conditions of 46-92-050. Intermediate (0.180g, this paper replaces this Chinese standard (CNS) A4 specification (210 X 297mm) 83.3.10,000 ----------------- ------ Subscribe --------- Line (please read the precautions on the back before filling in this page) Α7 Β7 5. Description of the invention () 0.43 millimoles) and 5-bromo-2- Methoxycycloheptan-2,4,6-triene-propanone (0.103 g · 0.48 mol) was dissolved in anhydrous DMF (3 ml), and the resulting solution was repeatedly degassed and filled with nitrogen. Add bis (triphenylphosphine) target (11) (0.015 g, 0.02 mol). Then degas the reaction and heat the mixture to 80 C for 2 hours. TLC indicated that some of the starting material was still present, so additional palladium catalyst (0.015 g) was added to the mixture and the mixture was heated for another 5 hours. The reaction mixture was concentrated in vacuo, and the residue was chromatographed on silica gel * ΜFormaldehyde / chloroform gradient to give 0.096 g (57! K) of the title compound, which is the same as the material prepared by the above experimental plan . Real cover 7 (±)-«-[[3- [4- (4-Methoxy-3-keto-1,4,6-cycloheptatriene-butyl] benzyl] -2-vinyl -5-oxazolidinyl] methyl] acetamide will (±) -5-acetacetamide methyl-3- (4 · -trimethyltinphenyl) huizolin-2-one (1.172 g, 2.95 Millimoles) and 6-bromo-2-methoxyxanthene-2,4,6-triene-1-zinc (0,677 grams, 3.13 millimoles) in dioxane (50 ml), alternating Evacuate the ground and fill it with nitrogen 3 times. Add bis (triphenylphosphine) palladium (11) (0.200 g, 0.28 mol). Then evacuate this system and fill it with nitrogen 3 times, and add 90t: Heating overnight. The reaction is not complete; therefore add 0.103 g (0.15 mol) of palladium catalyst, alternately evacuate the system and fill it with nitrogen 4 times. After 2 hours of wine, diatomite filling Tube-pass filtration • Wash it carefully with methane dichloride and formazan. Evaporate the solvent to obtain the crude material, and place it in a Zhong ® digasification silicon column (40 X 63 w, 2.5 cm X 26 cm, with U formazan / .. New Zealand imitation, filled with chloroform, and purified by formazan / nitroform gradient dissolution) to obtain 0.889g (82 «yield) of the required material is white solid paper & degree applicable National standard (CNS) A4 specification (210 X 297 mm) 83.3.10,000 ------------- installed --------- order -------- -Line (please read the precautions on the back before writing this page) A7 B7 5. Description of the invention (body. This material is then recrystallized from acetone to give 0.557g (51.2¾) white solid, mp 213-214 = for analysis &Quot; H NMR (CDCU, 300 ΜΗζ) δ: 7.63 (d, J = 9.0 Hz, 2H), 7.60 (d, J = 9.0 Hz, 2H), 7.45 (s, 1H), 7.10 (m, 2H) , 6.73 (d, J = 8.7 Hz, 1H), 6.02 (bt, J = 6.0 H z, 1 H), 4.8 1 (m, 8 wire, 1 H), 4. 1 2 (t, J = 9.0 H z, 1H), 3.98 (s, 3H), 3.78 (dd, J = 9.0 Hz, J '' = 6.9 Hz, 1H), 3.74 (ddd, J = 14.7 Hz, J '= 6.0 Hz, J' '= 3.3 Hz, 1H), 3.64 (dt, J = 14.7 Hz, J' = 6.0 11111H), 2.04 (s, 3H). 13C NMR (75.47 MHz, CDC13); 23.11, 41.93, 47.46, 56.34, 72.00, 111.63, 118.25, 128.62, 129.52, 132.17, 135.72, 137.97. 138.75, 148.91, 154.38, 165.16, 170.63, 179.38. IR (doped with mineral oil, cm-1): 3307 (m), 1739 (s), 16 49 U), 1592 (s), 1575 (s), 1561 (s). Mass spectrum: m / e (relative content): 368 (9.8, M *), 340 (32.3), 296 (24.1), 240 (26.5) , 237 (20.5), 212 (100), t η ¥ 199 (34.3), 85 (37.6), 56 (28.2), 43 (29.5), 29 (34.1); the actual calculated value of C2〇H2〇N20b: 368.1372 , Measured value: 368.1385. Calculated value of analysis value C2〇H2〇N20e: C, 65.21; H, 5.47; N, 7.60; measured value: C, 64.79; H, 5.28; N, 7.60. TLC: 51 «A Fermentation / gas imitation: Rr = 0.21 · L · -68-83.3.10,000 (please read the precautions on the back before writing this page) This paper scale is applicable to the China® National Standard (CNS> A4 specification (210 X 297 mm ) A7 B7

Hz, Hz, 1H) 1H) 1H) (s , 五、發明説明（ S Μ-.δ- (±)-1^-[[3-[4-(6-甲氧基_-5-酮基-1，3,6-環庚三烯_卜基]苯基]-2-酮基-5-噚唑啶基]甲基]乙藤胺，Ic 將（± )-5-乙酿胺甲基- 3-(4·-三甲鍚苯基）啤唑唾-2__ (0.352克，0.89奄莫耳）及4-溴-2-甲氧基環庚-2,4,6-三烯-卜酮（0.200克，0.93奄莫耳）之乙臃（2 5奄升）溶液交替地抽空並以氮充填3次。再加氛化雙（三苯基膦）鈀 ( 1 1 )(0.076克，0.11毫莫耳），再將此糸統抽空並以氮充填3次。混合物迴流過液，再通過矽藻土之垓塞管通濾，並小心將其以二氣甲烷洗。蒸發溶劑得粗物質，將其於中壓二氧化矽管柱（40 X 63 « ，2.5厘米X 27厘米，Μ U甲酵/氛仿装填，Κ氣仿充填；Μ甲酵/氛仿梯度溶齄 )上純化，得0.277克（8 5Χ)所須物質為黃色固《。此物質自丙嗣中重结晶，得0.123克（38!〇黃色固艚* up 107-110 t ° NMR (CDCU, 300 MHz) δ ： 7.63 (d, J = 9.0 Hz, 2H). 7.56 (d, J=9.0 Hz, 2H), 7.31 (m， 1H), 7.20 —· (dd, J=12.0 Hz, J'=0.9 Hz. 1H), 7.02 (dd, J=7.5 J，=0.9 Hz, 1H), 6.94 (s. 1H)， 6.07 (t, J=6.0 1H), 4.83(·, 9線，1H), 4.13 (t, J=9.0 Hz, 3.99 (s, 3H), 3.87 (dd. J=9.〇 Hz, J'=6.9 Hz, 3.74 (ddd, J=14.7 Hz. J'=6.3 Hz. J*'=3.6 Hz, 3.66 (dt, J=14.7 Hz, J'=6.0 Hz. 1H), 2.04 3H). 衣紙張尺度適用中國國家標準（CNS) A4規格（210 X 297公釐） 83.3.10,000 -------------裝---------訂---------線 (請先閲讀背面之注意事項再塡寫本頁) A7 B7 五、發明説明（ 13C HMR (75.47 MHz, CDCU)： 23.12, 41.96, 47.55, 56.37, 72.09, 114.39, 118.55, 126.87, 128.39, 135.41, 136.52, 138.13, 139.06, 145.78, 154.22, 164.53, 171 . 09, 179.84. IR (礦油摻雜，cm-1): 3469 (br), 3288 (br), 1745 (s), 1662 (m). 質譜：ra/e (相對含量）：368 (72.4, M*), 296 (33.3), 237 (35.9), 236 (34.3), 212 (100), 199 (56.8) 85 (53.8), 56 (49.8), 44 (30.3), 43 (50.1); C2〇H2〇N2〇e之真正計算質量：368.1.372,實測值 :368.1384. 分析值：C2〇H2〇N2〇B 之計算值：C, 65.21; Η, 5.47; 7.60;實测值：C, 62.05; Η, 5.74; N, 7.09. TLC :5ϋί甲酵 / 氛仿：(U=0.17 窨例9 (± )-N-[ [3-[4-[4-(2-丙烯基）胺基-3-酮基 -1,4,6-瑪庚三烯-1-基]苯基]-2-嗣基-5-酮基-5-噚唑啶基]甲基]乙醢胺· I b 將甲氧基環庚三烯鹂-取代之噚唑啶酮（0.077克， 0.21奄莫耳）及烯丙基胺（3.5奄升，46.6毫莫耳）於氮大氣下埋流過液。再興空濃縮反應混合物•得粗物質，其經於1000 //製備用TLC板上（M3X甲酵/二氯甲烷溶離3次 )纯化，以.定量性產率得所須化合物為黄色固»。此物質再於另外之製備用TLC板（250 /x，M75X丙酮/二氯甲烷 70 本紙張又度通用中國國家標準（CNS)A4規格（210 X 2耵公釐） 83.3.10,000 -------------裝---------訂---------線 (請先閲讀背面之注意事項再填寫本頁) A7 B7 t 五、發明説明（溶離3次）上純化，得0.033克（40S!)標题化合物為黃色固體，mp 169-171t：及0.026克（32Χ)稍撤不純之物質。 HMR (CDCla, 300 MHz) δ ： 7.59 (bs, 4H), 7.47 (bt, J=6.0 Hz, 1H), 7.40 (d, J=1.8 Hz, 1H), 7.25 (t, J=10.5, 1H), 6.88 (dd, J=10.5 Hz, J'=1.8 Hz, 1H), 6.51 (d, J=10.5 Hz, 1H), 6.13 (bt, J=6.0 Hz, 1 H ) , 5 . 9 4 (in, 1 0 媒，1 H) , 5.2 9 (m，2 H ) , 4 · 81 (n , 9 線，1H), 4.12 (t, J=9.0 Hz, 1H), 4.03 (t, J=5.7 Hz, 2H), 3.84 (dd, J=9.3 Hz, J'=6.9 Hz, 1H), 3.73 (ddd, J=14.7 Hz, J'=6.0 Hz, J''=3.3 Hz,, 1H), 3.64 (dt, J=14.7 Hz. J'=B.O Hz, 1H), 2.04 (s, 3H). 1SC HMR (75.47 MHz, CDCla)： 0.01, 23.13, 41.88, 45.15, 47.53, 71.95, 108.21, 117.57, 118.23, 123.59, 128.78, 132.05, 135.46, 137.81, 139.38, 149.38, 154.06, 155.16, 170.63, 175.16. IR (礦油摻雜，cm-1): 3343 (b), 3293 (η), 17·45 (s) , 1662 (s) , 1589 (s). «譜：n/e (相對含量）：393 (100, Ml. 394 (24.7), 265 (18.7), 152 (11.0), 56 (33.0), 44 (14.6), 43 (22.9), 29 (31.3); C22H23N3(U 之真正計算之霣量： 393.1688·..實测值：393.1685 分析值，C22H23N3〇4 之計算值：C, 67.16; H, 5.89; -71 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 83.3.10,000 -----------^ -裝---------訂---------線 (請先閲讀背面之注意事項再填寫本頁) A7 B7 •λ i|S y. *-r 五、發明説明 10.68;實測值：C, 64.74; Η, 5·74; N, 9.83. TLC:2.5!K 甲醇 / 氯仿 χ 2 : Rf = 0.36。奮例 1 0 ( ± )-N-[ [3-[4-[4-(4-嗎啉基）-3-麵基 -1,4,6-環庚三烯-1-基]苯基]-2-酮基-5-噚唑啶基]甲基 ]乙釀胺（lb) 將甲氧基環庚三烯酮取代之嗶唑啶嗣（0.078克，0.21毫其耳）及嗎啉（0.3毫升，3.43毫莫耳）於3.5笔升甲苯中之溶液迴流過夜。蒸發溶劑，粗物質於^備用TLC板 (1000 M 3¾甲醇/二氛甲烷溶離ί；次）上純化，得定量性產率之所須物質為黃色固體，其再於另外之製備用 TLC板（250 w，M 75¾丙嗣/二氛甲烷溶離3次）純化，得0.050克（56¾)檷題化合物為黃色固體*mp. 143-144"C 及0.016克（18¾)給不純之物質。 XH NHR (CDCU, 300 ΜΗζ)δ ： 7.60 (d, J = 9.0 Hz, 2f；), 7.58 (d, J = 9.0 Hz, 2H), 7.21 (d, J = 1.8 Hz, 1H), 7.08 (t, J=10.8 Hz, 1H). 6.93 (dd, J=10.8Hz, Hz, 1H) 1H) 1H) (s, V. Description of the invention (S Μ-.δ- (±) -1 ^-[[3- [4- (6-methoxy_-5-keto -1,3,6-cycloheptatriene_pyl] phenyl] -2-keto-5-oxazolidinyl] methyl] acetamide, Ic will (±) -5-ethylamine Yl-3- (4 · -trimethylthyrylphenyl) -pyrazole salazine-2__ (0.352 g, 0.89 mol) and 4-bromo-2-methoxycyclohepta-2,4,6-triene-bu The solution of ketone (0.200 g, 0.93 mol) in acetophenone (25 5 liter) was alternately evacuated and filled with nitrogen 3 times. Then, ambiance bis (triphenylphosphine) palladium (1 1) (0.076 g, 0.11 millimoles), then evacuate the system and fill it with nitrogen three times. The mixture was refluxed, filtered through a diatomaceous earth plug tube, and carefully washed with dichloromethane. The crude solvent was evaporated The material was purified on a medium-pressure silica column (40 X 63 «, 2.5 cm X 27 cm, MU formazan / atmosphere filling, Κgasimum for filling; Μ formazan / atmosphere gradient solution) , 0.277 g (85X) of the required substance is yellow solid. This substance is recrystallized from Bing Si to obtain 0.123g (38! 〇 yellow solid stern * up 107-110 t ° NMR (CDCU, 300 MHz) δ : 7.63 (d, J = 9.0 Hz, 2H). 7.56 (d, J = 9.0 Hz, 2H), 7.31 (m, 1H), 7.20 — (dd, J = 12.0 Hz, J '= 0.9 Hz. 1H), 7.02 (dd, J = 7.5 J, = 0.9 Hz, 1H), 6.94 (s. 1H), 6.07 (t, J = 6.0 1H), 4.83 (·, 9-wire, 1H), 4.13 (t, J = 9.0 Hz, 3.99 (s, 3H), 3.87 (dd. J = 9.〇Hz, J '= 6.9 Hz, 3.74 (ddd, J = 14.7 Hz. J' = 6.3 Hz. J * '= 3.6 Hz, 3.66 (dt, J = 14.7 Hz , J '= 6.0 Hz. 1H), 2.04 3H). Applicable to China National Standard (CNS) A4 (210 X 297 mm) for garment paper size 83.3.10,000 ------------- --------- order --------- line (please read the notes on the back before writing this page) A7 B7 5. Description of the invention (13C HMR (75.47 MHz, CDCU): 23.12, 41.96, 47.55, 56.37, 72.09, 114.39, 118.55, 126.87, 128.39, 135.41, 136.52, 138.13, 139.06, 145.78, 154.22, 164.53, 171.09, 179.84. IR (mineral oil doped, cm-1): 3469 (br), 3288 (br), 1745 (s), 1662 (m). Mass spectrum: ra / e (relative content): 368 (72.4, M *), 296 (33.3), 237 (35.9), 236 ( 34.3), 212 (100), 199 (56.8) 85 (53.8), 56 (49.8), 44 (30.3), 43 (50.1); the real calculated quality of C2〇H2〇N2〇e: 368.1.372, measured value: 368.1384. Analysis value: Calculated value of C2〇H2〇N2〇B: C, 65.21; Η, 5.47; 7.60; found value: C, 62.05; Η, 5.74; N, 7.09. TLC: 5ϋίFormula / atmosphere Imitation: (U = 0.17 Example 9 (±) -N- [[3- [4- [4- (2-propenyl) amino-3-keto-1,4,6-maheptatriene- 1-yl] phenyl] -2-pyridin-5-keto-5-pyridazolidinyl] methyl] acetamide · Ib oxazolidinone substituted by methoxycycloheptatrile (0.077 g, 0.21 mol) and allylamine (3.5 liter, 46.6 mmol) were passed through the liquid under nitrogen atmosphere. The reaction mixture was concentrated again in Xingkong to obtain the crude material, which was purified on a 1000 // preparation TLC plate (M3X formazan / dichloromethane was dissolved three times) to obtain the desired compound as a yellow solid in a quantitative yield ». This material is used in another preparation TLC board (250 / x, M75X acetone / dichloromethane 70. This paper is again in accordance with the Chinese National Standard (CNS) A4 specification (210 X 2 mm) 83.3.10,000 ---- --------- installed --------- order --------- line (please read the precautions on the back before filling in this page) A7 B7 t 5. Description of the invention (Dissolve 3 times) purification to obtain 0.033 g (40S!) Of the title compound as a yellow solid, mp 169-171t: and 0.026 g (32X) slightly withdrawn impure material. HMR (CDCla, 300 MHz) δ: 7.59 (bs , 4H), 7.47 (bt, J = 6.0 Hz, 1H), 7.40 (d, J = 1.8 Hz, 1H), 7.25 (t, J = 10.5, 1H), 6.88 (dd, J = 10.5 Hz, J ' = 1.8 Hz, 1H), 6.51 (d, J = 10.5 Hz, 1H), 6.13 (bt, J = 6.0 Hz, 1 H), 5. 9 4 (in, 1 0 medium, 1 H), 5.2 9 ( m, 2 H), 4 · 81 (n, 9-wire, 1H), 4.12 (t, J = 9.0 Hz, 1H), 4.03 (t, J = 5.7 Hz, 2H), 3.84 (dd, J = 9.3 Hz , J '= 6.9 Hz, 1H), 3.73 (ddd, J = 14.7 Hz, J' = 6.0 Hz, J '' = 3.3 Hz ,, 1H), 3.64 (dt, J = 14.7 Hz. J '= BO Hz , 1H), 2.04 (s, 3H). 1SC HMR (75.47 MHz, CDCla): 0.01, 23.13, 41.88, 45.15, 47.53, 71.95, 108.21, 117.57, 118.23, 123.59, 128.78 , 132.05, 135.46, 137.81, 139.38, 149.38, 154.06, 155.16, 170.63, 175.16. IR (mineral oil doped, cm-1): 3343 (b), 3293 (η), 17.45 (s), 1662 ( s), 1589 (s). «Spectrum: n / e (relative content): 393 (100, Ml. 394 (24.7), 265 (18.7), 152 (11.0), 56 (33.0), 44 (14.6), 43 (22.9), 29 (31.3); C22H23N3 (U's actual calculated volume: 393.1688 .. measured value: 393.1685 analytical value, C22H23N3〇4 calculated value: C, 67.16; H, 5.89; -71- The paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 83.3.10,000 ----------- ^ -installed --------- order ---- ----- Line (please read the precautions on the back before filling in this page) A7 B7 • λ i | S y. * -R V. Description of invention 10.68; measured value: C, 64.74; Η, 5.74; N, 9.83. TLC: 2.5! K methanol / chloroform χ 2: Rf = 0.36. Example 1 0 (±) -N- [[3- [4- [4- (4-morpholinyl) -3-hexyl-1,4,6-cycloheptatrien-1-yl] phenyl ] -2-Keto-5-oxazolidinyl] methyl] acetylamine (lb) pyrazolidine (0.078 g, 0.21 mmol) and morpholine substituted by methoxycycloheptatrienone (0.3 ml, 3.43 mmol) The solution in 3.5 litres of toluene was refluxed overnight. The solvent was evaporated and the crude material was purified on a spare TLC plate (1000 M 3¾ methanol / dichloromethane dissociation; second time) to obtain a quantitative yield of the required material as a yellow solid, which was then prepared on another TLC plate ( 250 w, M 75¾ propylene / dichloromethane dissolution 3 times) purification, to obtain 0.050 g (56¾) of the title compound as a yellow solid * mp. 143-144 " C and 0.016 g (18¾) for impure material. XH NHR (CDCU, 300 ΜΗζ) δ: 7.60 (d, J = 9.0 Hz, 2f;), 7.58 (d, J = 9.0 Hz, 2H), 7.21 (d, J = 1.8 Hz, 1H), 7.08 (t , J = 10.8 Hz, 1H). 6.93 (dd, J = 10.8

Hz, J'=1.8 Hz, 1H), 6.66 (d, J=9.9 Hz, 1H), 6.30 ---_ (bt, J=6.3 Hz， 1H), 4.80 (m, 10線，1H), 4.11 (t, J=9.0 Hz, 1H), 3.90 (t, J=4.8 Hz, 4H), 3.84 (dd, J=9.3 Hz, J'=6.9 Hz, 1H), 3.70 (ddd, J=14.7 Hz, J'=6.0 Hz, J''=3.3 Hz, 1H), 3.64 (dt, J=14.7 Hz, J'=6.0 Hz, 1H), 3.37 (t, J=4.8 Hz. 4H), 2.03 (s, 3H). 13C NHR (75.47 MHz, CDCU)： 0.01, 23.13, 41.98, -72 本紙張又度適用中國國家標準（CNS)A4規格（210 X 297公釐） 83.3.10,000 --------------裝---------訂---------線 (請先閲讀背面之注意事項再塡寫本頁) A7 B7 五、發明説明（ 47.50, 49.09, 66.71, 72.01, 117.43, 118.26, 127.85, 128.59, 132.92, 134.45, 138.34, 147.58, 154.32, 159.57, 171.11, 181.55. IR (礦油摻雜，cm-1 ): 3307 (m), 1731 (s), 1658 (m), 1563 (s). 質譜：m/e (相對含最）：423 (100, ίΤ), 424 (27.0), 380 (17.9), 379 (23.9). 364 (23.8), 280 (28.5), 152 (18.8), 86 (34.7), 56 (23.8), 29 (23.3); C23H2SN3〇5之與正計算質量：423.1794,實測值： 423.1814. 分析值，C23H2sN3〇e 之計算值：C, 65.23; H, 5.95; N, 9.92,實測值：C, 63..83; H, 5.90; 9.66 TLC:5%甲酵 / 氣仿：Rf = 〇.29 實—例11 (5)-卜[[3-[4-(4-甲氣基-5-嗣基-1,3,6-環庚三烯-卜基]-3,5-二氟苯基]-2-_基-5-嗶唑啶基]甲基] 乙醢胺將叁（二亞苄基丙醑）二鈀（0)-氣仿加成物（45 0毫克， 0.492奄莫耳）及三呋哺基膦（460奄克· 1.969«莫耳）於 1,4-二噚烷（25¾升）中一起攢拌5分*接著加 (S)-N-[[3-(4-碘-3,5-二氟苯基）-2-酮基-5-11?唑啶基]甲基]乙醢胺（1.3克· 3.28毫其耳 >。脫氣後，以H2洗溶液 3次，加三甲基（4-甲氣基-5-鬭基-1,3,6 -環庚三嫌-1-基. )»(1.47克，4.92毫其耳）。溶液再脫氣（3乂），再於》12 -73 - 衣紙張疋度適用中國國家標準（CNS)A4規格（210 X 2刃公釐） 83.3.10,000 -------------裝---------訂---------線 (請先閱讀背面之注意事項再塡寫本頁) A7 B7 五、發明説明（）下加熱溶液至迴滾（110 〇)歷12小時。經冷卻’藉TLC (10¾ MeOH/CHCU, UV短波）测定反應已完全。減壓下湄缩反應物再溶於CH2CU (100毫升）中，此溶液於KF水溶液（100奄升）上攪拌45分再分離。有機部分以鹽水（100毫升）洗再於無水Na2S〇4上乾燥。乾煉後*將其過漶並減壓濃縮得棕色固髖。粗產物放矽膠上層析（175克矽膠M10« CH3CH/CHC13 装填，M1-55K MeOH (於 10¾ CH3CN/CHC13 中 )梯度溶雄得淡黃色固體。此固體藉溶於CH2Cl2/MeOH中重结晶•並以醚研磨得907毫克（68X)檷題化合物為非纯白色固體，bp 129C (分解）並對算之 HRMS (M + )為 404.1184,實测值為 404.1183。實例 12 (土）-1<-[[3-[4-(4-甲氧基-5-醑基-1，3,6-琢庚三烯-1-基]3,5-二氟苯基]-2-萌基-5-噚唑啶基]甲基] 乙醣胺將（±)-N-[ [3-[4-(三甲鍚烷基）-3,5-二氟苯基]-2-酮基-5-啤唑啶基]甲基]乙醮胺（80奄克，0.185奄莫耳）溶一 ·- 經濟部中央標準局0QT工消費合作社印^ (請先閲讀背面之注意事項再塡寫本頁) 於1,4-二噚烷（5毫升）再M5-澳-2-甲氣基環庚三烯酚酮 (49.5奄克，230奄莫耳）處理。脫氣後，以1<2沖洗溶液3 次*加氛化雙（三苯基膦）鈀（11)(28¾克，0.040«莫耳 )。再將溶液脫氣（3X)，其後，將反應物加热至邇流 (1101)5小時。於此時•反應並不完全；再加觸媒（28« 克，0.0_0毫其耳），脫無（3Χ)後*溶液再加热至迴流5 小時。於此時•反應仍完全。再以新的觸媒（28毫克）簠複 -7 4 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 83.3.10,000 A7 B7 五、發明説明（）上面方法3次。最後•真空下除去溶劑*殘留之油溶於 CH2CU (50毫升）中。Ha2S〇4溶液JWKF水溶液（75奄升）及鹽水（50奄升）洗。於無水Na2S04上乾埭後，過滹有機層並減壓濃縮得起泡之固體。此固體首先藉製備用TLC (5% MeOH/CHCU)純化，再藉徑向層析法（M0-5« MeOH (於 10X CH3CN/CHC13)溶離）得7奄克（9S!)標題化合物為固體，對 C2〇HieF2N2〇5 計算之 HRMS ((T)為 404.1184,實測值為 404. 1 183 ° 將（±)-»-[[3-(4-碘-3,5-二氟苯基）-2-嗣基-5-〇?唑啶基]甲基]乙醢胺（250奄克，0.631毫莫耳）溶於1,4-二嗶烷（15毫升），再K錫烷基環庚三烯酮（226毫克，0.757奄莫耳）處理。脫氣後，溶液K 沖洗3次，加氣化雙（三笨基膦）鈀（II) (70毫克，0.10毫莫耳）。溶液再脫氣 (3Χ)再將其加熱至迴流（110Ό) 7小時。於此時，反應並不完全；加新的觸媒（70毫克，0.10毫莫耳），於再脫氣 (3Χ)後，溶硖再加熱至迴流7小時。於此時。真空除去溶劑*殘留之油濟於CH2CU(50毫升）。CH2CU溶液以KF水溶液（40奄升）及鹽水（40毫升）洗。於無水Na2S〇4上乾燥後，通濾有機層並減壓濃縮得起泡之棕色固想。此固髑於矽膠 (100克）上曆析，M0-10S! MeOH (於 10« CH3CN/CHC13 中 )梯度溶離）得不純產物。此產物》製備用TLC (5JK MeOH/CHCU)純化，得72毫克（28X)檷趙化合物為非純白 fe固鱧.·Ρ 218 *0.(分解）且所有方面與如上述製得之物質相同。 -7 5 - 本紙張尺度適用中國國家標準（CNS)A4規格（21〇 X 297公釐） 83.3.10,000 -----------·!裝---------訂---------線 (請先閲讀背面之注意事項再填寫衣頁) A7 B7 五、發明説明（化合物名路夕索引魷磕 1. (± )-N-[ [3-[4-(4-甲氧基-5-酮基-1 , 3, 6-環庚三輝 -基]苯基]-2-啤唑啶基]甲基醢胺， 2. (土）-N-[[3-[4-(4-二乙胺基-5-嗣基-1,3,6-環庚三烯-卜基]苯基]-2-嗣基-5-啤唑啶基]甲基酿胺， 3. (±)_ 乙釀胺，N-[[2-酮基-3-(4-[5-酮基-4-[(苯.甲基）胺基]-1 , 3,6 -環庚三烯-：L -基]苯基]-5 -啤唑啶基 ]甲基， 4. (± )-N-[[3-[4-[4-[(2-羥乙基）胺基]-5-酮基 -1,3,6-環庚三烯-1-基]苯基]-2-嗣基-5-噚唑啶基] 甲基乙豳胺， 5. (±)-«-[[3-[4-[4-(4-嗎啉基）-5-醑基-1,3,6-環庚三烯-1-基]苯基]-2-醑基-5-嗶唑啶基]甲基]-乙醯胺 9 6. (土）-卜[[3-[4-(4-環丙胺基-5-酮基-1,3,6-環庚三烯-卜基]苯基]-2-酮基-5-嗶唑啶基]甲基]-乙醢胺 (請先閱讀背面之注意事項再塡寫本頁) 裝、tr ：w. •Γ ?- %Hz, J '= 1.8 Hz, 1H), 6.66 (d, J = 9.9 Hz, 1H), 6.30 ---_ (bt, J = 6.3 Hz, 1H), 4.80 (m, 10-wire, 1H), 4.11 (t, J = 9.0 Hz, 1H), 3.90 (t, J = 4.8 Hz, 4H), 3.84 (dd, J = 9.3 Hz, J '= 6.9 Hz, 1H), 3.70 (ddd, J = 14.7 Hz, J '= 6.0 Hz, J' '= 3.3 Hz, 1H), 3.64 (dt, J = 14.7 Hz, J' = 6.0 Hz, 1H), 3.37 (t, J = 4.8 Hz. 4H), 2.03 (s, 3H). 13C NHR (75.47 MHz, CDCU): 0.01, 23.13, 41.98, -72 This paper is again applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 83.3.10,000 ------- ------- installed --------- order --------- line (please read the precautions on the back before writing this page) A7 B7 V. Invention description (47.50 , 49.09, 66.71, 72.01, 117.43, 118.26, 127.85, 128.59, 132.92, 134.45, 138.34, 147.58, 154.32, 159.57, 171.11, 181.55. IR (mineral oil doped, cm-1): 3307 (m), 1731 ( s), 1658 (m), 1563 (s). Mass spectrum: m / e (relatively included): 423 (100, ίΤ), 424 (27.0), 380 (17.9), 379 (23.9). 364 (23.8) , 280 (28.5), 152 (18.8), 86 (34.7), 56 (23.8), 29 (23.3); C23H2SN3〇5 and the positive calculated quality: 423.1794, measured value: 423.1814. Analysis value, C23H2s Calculated value of N3〇e: C, 65.23; H, 5.95; N, 9.92, measured value: C, 63..83; H, 5.90; 9.66 TLC: 5% formazan / gas imitation: Rf = 〇.29 actual —Example 11 (5) -Bu [[3- [4- (4-Methyl-5-phenyl) -1,3,6-cycloheptatriene-Buyl] -3,5-difluorophenyl ] -2-_yl-5-pyrazolidinyl] methyl] acetophenone tris (dibenzylidenepropionylidene) dipalladium (0) -gas imitation adduct (45 mg, 0.492 mmol) ) And trifurophosphine (460 ng · 1.969 «mole) in 1,4-dioxane (25¾ liter) and save together for 5 minutes * and then add (S) -N-[[3- (4 -Iodo-3,5-difluorophenyl) -2-keto-5-11? Azolidinyl] methyl] acetamide (1.3 g. 3.28 mmol). After degassing, the solution was washed 3 times with H2, and trimethyl (4-methylpyrrolid-5-yl-1,3,6-cycloheptathiol-1-yl.) »(1.47 g, 4.92 mmol) Its ears). The solution is degassed again (3 乂), and then "12 -73-Applicable to China National Standard (CNS) A4 specification (210 X 2 blade mm) 83.10,000 ---------- --- installed --------- order --------- line (please read the precautions on the back before writing this page) A7 B7 5. Description of the invention () Heat the solution to Rollback (110 〇) lasted 12 hours. After cooling, the reaction was determined to be complete by TLC (10¾ MeOH / CHCU, UV short wave). The reduced reaction product was redissolved in CH2CU (100 ml) under reduced pressure, and the solution was stirred in KF aqueous solution (100 μL) for 45 minutes and then separated. The organic portion was washed with brine (100 mL) and dried over anhydrous Na 2 SO 4. After refining *, it will be overwhelmed and concentrated under reduced pressure to obtain a brown solid hip. The crude product was chromatographed on silica gel (175 grams of silica gel M10 «CH3CH / CHC13 loaded, M1-55K MeOH (in 10¾ CH3CN / CHC13) gradient dissolved to give a pale yellow solid. This solid was recrystallized by dissolving in CH2Cl2 / MeOH • It was triturated with ether to obtain 907 mg (68X) of the title compound as a non-pure white solid, bp 129C (decomposition), and the calculated HRMS (M +) was 404.1184, the measured value was 404.1183. Example 12 (soil) -1 < -[[3- [4- (4-methoxy-5-vinyl-1,3,6-cutheptatrien-1-yl] 3,5-difluorophenyl] -2-menyl- 5-oxazolidinyl] methyl] glycosaminoglycan (±) -N- [[3- [4- (trimethylthyrinyl) -3,5-difluorophenyl] -2-keto-5 -Pyrazolidinyl] methyl] acetamide (80 ng, 0.185 mol) dissolved in one--Printed by the Central Bureau of Standards of the Ministry of Economic Affairs 0QT Industrial and Consumer Cooperatives ^ (Please read the notes on the back before writing this page ) Treated with 1,4-dioxane (5 ml) and then treated with M5-Ao-2-methylcycloheptanol (49.5 μg, 230 μmol). After degassing, rinse with 1 < 2 Solution 3 times * Aerated bis (triphenylphosphine) palladium (11) (28¾ g, 0.040 «mol) is added. The solution is then degassed (3X), after which the reaction is heated to (1101) 5 hours. At this time • The reaction is not complete; add catalyst (28 «g, 0.0_0 milliseconds), after removing (3Χ) * the solution is heated to reflux for 5 hours again. At this time • The reaction is still complete. Then use the new catalyst (28 mg) 簠复 -7 4-This paper scale is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 83.3.10,000 A7 B7 V. Description of invention () Repeat the above method 3 times. Finally • Remove the solvent under vacuum * The remaining oil is dissolved in CH2CU (50 ml). The Ha2S〇4 solution JWKF aqueous solution (75 μL) and brine (50 μL) are washed. Dry on anhydrous Na2S04 After that, the organic layer was decanted and concentrated under reduced pressure to obtain a foamy solid. This solid was first purified by preparative TLC (5% MeOH / CHCU), and then by radial chromatography (M0-5 «MeOH (at 10X CH3CN / CHC13) dissociated) to obtain 7 mg (9S!) Of the title compound as a solid, the calculated HRMS ((T) for C2〇HieF2N2〇5 ((T) is 404.1184, the measured value is 404.1 183 ° will (±)-»-[[ 3- (4-iodo-3,5-difluorophenyl) -2-oxi-5-o? Azolidinyl] methyl] acetamide (250 mg, 0.631 mmol) dissolved in 1, 4-Dipyridane (15 ml), then K tin Tropone-yl (226 mg, 0.757 mole castrate) process. After degassing, solution K was rinsed 3 times, and gasified bis (tribenzylphosphine) palladium (II) (70 mg, 0.10 mmol) was added. The solution was degassed (3X) and heated to reflux (110Ό) for 7 hours. At this time, the reaction was not complete; new catalyst (70 mg, 0.10 mmol) was added, and after degassing (3Χ), the solution was heated to reflux for 7 hours. At this time. The solvent was removed in vacuo * residual oil was added to CH2CU (50 ml). The CH2CU solution was washed with KF aqueous solution (40 mL) and brine (40 mL). After drying over anhydrous Na 2 SO 4, the organic layer was filtered through and concentrated under reduced pressure to give a foamy brown solid. This solid was analyzed on silica gel (100g) and M0-10S! MeOH (gradiently dissociated in 10 «CH3CN / CHC13) gave an impure product. This product was prepared by TLC (5JK MeOH / CHCU) and purified to obtain 72 mg (28X) of P. azulium compound is a non-pure white feguchi. · P 218 * 0. (Decomposition) and all aspects are the same as those prepared as above . -7 5-This paper scale is applicable to China National Standard (CNS) A4 specification (21〇X 297 mm) 83.3.10,000 ----------- !! ------------ Order --------- line (please read the precautions on the back before filling in the clothes page) A7 B7 V. Description of the invention (Compound name Lu Xi index squid 1. (±) -N- [[3- [4- (4-methoxy-5-keto-1, 3, 6-cycloheptatrisyl-yl] phenyl] -2-pyrazolidinyl] methylacetamide, 2. (soil)- N-[[3- [4- (4-Diethylamino-5-pyridyl-1,3,6-cycloheptatriene-butyl) phenyl] -2-pyridyl-5-pyrazolidine Base] Methylamine, 3. (±) _ Ethylamine, N-[[2-keto-3- (4- [5-keto-4-[(phenyl.methyl) amine]- 1, 3,6 -cycloheptatriene-: L -yl] phenyl] -5 -pyrazolidinyl] methyl, 4. (±) -N-[[3- [4- [4-[( 2-hydroxyethyl) amino] -5-keto-1,3,6-cycloheptatrien-1-yl] phenyl] -2-oxoyl-5-oxazolidinyl] methylacetate Amine, 5. (±)-«-[[3- [4- [4- (4-morpholinyl) -5-pyridyl-1,3,6-cycloheptatrien-1-yl] phenyl ] -2-Acetyl-5-pyridazolyl] methyl] -acetamide 9 6. (Earth) -Bu [[3- [4- (4-Cyclopropylamino-5-keto-1, 3,6-cycloheptatriene-butyl] phenyl] -2-keto-5-pyridazolyl] methyl] -acetamide ( Matters to read the back of the note and then Chen wrote on this page) equipment, tr: w • Γ -%.?

土 P 7. (士）-N-[[3-[4-(4-甲豳基-卜六氬吡畊基）-5-嗣基 -1,3,6-環庚三烯-卜基]苯基]-2-酮基-5-噚唑啶基] 甲基]-乙豳胺， 8. (±)-^-[[3-[4-[4-(2-丙稀胺基）-5-萌基-1,3,6-環庚三烯-卜基]苯基]-2-萌基-5-啤唑啶基]甲基]-乙醢胺， 9. (土）-N-[ [3-[4-[4-U-吡咯烷基）-5-酮基-1 , 3,6-環線 76 83.3.10,000 衣紙張又度適用中國國家標準（CNS)A4規格（2i0 X 2Q7公釐） A7 B7 五、發明説明（）庚三烯-1-基]苯基]-2-萌基-5-嗶唑啶基]甲基]-乙酿胺， 10. (±)-N-[[3-[4-[4-(4 -甲基-1-六氫吡哄基）-5 -酮基 -1,3,6-環庚三烯-卜基]苯基]-2-酮基-5-噚唑啶基 ]甲基]-乙豳胺， 11. (±)-卜[[3-[4-(4-環戊胺基-5-酮基-1,3,6-環庚三烯-卜基）苯基]-2-醑基-5-喟唑啶基]甲基]-乙釀胺 12. (± )-Ν-[[3-[4-[4-(1-六氫吡畊基）-5 -嗣基-1,3,6-環庚三烯-1-基]苯基]-2-酮基-5-噚唑啶基]甲基]-乙醢胺， 13. (±)-N-[[3-[4-(4-丁胺基-5-酮基-1,3,6-環庚三烯 -1-基）苯基]-2-酮基-5-吗哇啶基]甲基]-乙醢胺 14. ( 土）-N-[[3-[4-[4-(順式-3,5-二甲基-1-六氫吡哄基 )-5-萌基 -1,3,6-環庚三烯-1-基）苯基]-2-萌基- 5-噚唑啶基]甲基]-乙醢胺， 15. (± )-N-[[3-[4-[4-(卜六氫吡啶基）-5-酮基 -1,3,6-環_軎三稀-：1-基]苯基]-2-嗣基-5-噚唑咱基] 甲基]-乙醜胺， 16. (±)-1[[3-[3-氟-4-(4-甲氧基-5-嗣基-1,3,6-環庚三烯-卜基]苯基]-2-嗣基-5-嗶唑啶基]甲基]-乙醢胺， 17. (± )-N-[[3-[4-[4-(3-甲基-卜六氫吡畊基）-5-嗣基 -1,3,6-環庚三烯-1-基]苯基]-2-酮基-5-啤唑啶基] 甲基]-***胺· -77 - 本紙張又度適用中國國家標準（CNS)A4規格（210 X 29*7公釐） 83.3.10,000 -------------裝---------訂---------線 (請先閱讀背面之注意事項再塡寫本頁) 299332 A7 B7 五、發明説明 18. ( 土）-N-[[3-[4-[4-(3-羥基-卜吡咯烷基）-5-酮基 -1,3,6-環庚三烯-卜基]苯基]-2-酮基-5-噚唑啶基] 19 甲基]-乙酿胺， (5)-«-[[3-氟-4-(4-甲氧基-5-酮基-1,3,6-環庚三稀 ± (t .¾ S. 土 -1-基]苯基]-2-酮基-5-啤唑啶基]甲基]-乙醢胺， 20. ( 士）-N-[[3-[4-[4-甲氧基-3-嗣基-1,4,6-環庚三稀 -卜基]苯基]-2-萌基-5-嗶唑啶基]甲基]-乙醢胺， 21. (±)-^-[[3-[4-[6-甲氧基-5-酮基-1,3,6-環庚三稀 -1-基]苯基]-2-萌基-5-噚唑啶基]甲基]-乙醢胺， 22. (±)叫-[[3-[4-[4-乙氧基-5-萌基-1,3,6-環庚三稀 -1-基]苯基]-2-醑基-5-啤唑啶基]甲基]-乙醢胺， 23. (± )-M-[[3-[4-[4-(3-胺基-1-吡咯烷基）-5-酮基 -1,3,6-環庚三烯-1-基]苯基]-2-醑基-5-噚唑啶基] 甲基]-乙醣胺， 24. (± )-N-[[3-[4-[4-U-甲基乙氧基）-5-嗣基-1,3,6-瓌庚三烯-卜基]苯基]-2-嗣基-5-噚唑啶基]甲基]-乙醢胺， 25. (5)1-[[3-[4-[4-(4-嗎啉基）-5-嗣基-1,3,6-環庚三烯-1-基]苯基]-2-醑基-5-嗶唑啶基]甲基]-乙醢胺， 26. (±)-N-[[3-[4- [4-(2-丙稀胺基）-3-酮基-1;4,6-環庚三烯-1-基]苯基]-2-萌基-5-噚唑啶基]甲基]-乙釀胺， 27. (土）-.[1-[[3-[4-[4-(4-嗎啉基）-3-酮基-1,4,6-環庚三烯-卜基]苯基]-2-酮基-5-啤唑啶基]甲基]-乙醢胺 78 本紙張又度適用中國國家標準（CNS)A4規格（210 X 297公釐） 83.3.10,000 (請先閱讀背面之注意事項再塡寫本頁) A7 B7 五、發明説明（) ，及 28. (5)4-[[3-[4-甲氧基-5-嗣基-1,3,6-環庚三烯基]苯基]-2-嗣基-5-噚唑啶基]甲基]-乙豳胺· 29. (±)-^-[[3-[4-[4-(2-丙块胺基）-3-酮基-1，4,6-環庚三烯-1-基]苯基]-2-酮基-5-噚唑啶基]甲基]-乙醢胺， 30. ( 土）-N-[[3-[4-[ -[[(甲氧羰基）甲基]胺基]-5-酮基 -1,3,6-環庚三烯-1-基]苯基]-2-嗣基-5-噚唑啶基] 甲基]-乙醢胺， 31. (±)-卜[[3-[4-(4-甲胺基-5-萌基-1,3,6-環庚三烯 -卜基）苯基]-2-酮基-5-嗶唑啶基]甲基]-乙醢胺， 3 2 . ( ± ) - N - [ [ 3 - [ 4 - [ 4 - (2，5 -二氫-1 Η -吡咯-：1 -基）-5 -醑基-1,3,6-環庚三烯-1-基]苯基]-2-醑基-5-啤唑啶基 ]甲基]-乙醢胺， 33. (±)-Ν-[[3-[4-[4-(2-丙烯氧基）-5-酮基-1,3,6-環庚三烯-1-基]苯基]-2-嗣基-5-噚唑啶基]甲基]-乙醢胺， --- 34. (S)-H-[[3-[3 -氟- 4- [(2 -丙块胺基）-5-萌基 -1,3,6-環庚三烯-1-基]苯基]-2-酮基-5-啤唑啶基] 甲基]-乙醢胺， 35. (± )-N-[[3-[4-[4-(2-甲氧基乙氧基）-5-酮基 -1,3,6-環庚三烯-卜基]苯基]-2-_基-5-嗶唑啶基] 甲基卜乙醢胺， 36. (5)1-[[3-[3-氟-4-[(4-嗎咐基）-5-嗣基-1，3,6-環 -79 - 本紙張义度適用中國國家標準（CNS)A4规格（2!0 X 297公釐） 83.3.10,000 -----------ί _裝-- n n I n n n n _^i I n n 1 (請先閲讀背面之注意事項再塡寫衣頁) 五、發明説明（）烯三 - 庚胺基苯 U 基 A7 B7 醢乙 I TIJ 基甲 U 基啶唑哼 I 5- 基 0 (請先閱讀背面之注意ί、再塡寫本頁) 訂線經濟部_央標準局3工消f合作社印製本紙張尺度適用中國國家標準（CNS)A4規格（210 X 2W公釐） 83.3.10,000 五、發明説明（79 ) A6 B6 活體外最小抑制濃度（Μ微克/毫升表示） {諳先閲讀背面之注意事項再填寫衣頁) 經濟邾中央標準局貝工消費合作钍印5* 金黃色葡萄釀膿鏈球菌化会物塭號技 Μ II「. (Rl Q 2 1 3 II C 0¾ 1 R ?. 化合物 1 2 0.25 化合物 2 4 · 1 化合物 3 >64 4 化合物 4 4 0.5 化合物 5 2 0.5 化合物 6 2 0.5 化合物 7 4 0.5 化合物 8 2 0.5 化合物 9 4 1 化合物 10 一 - 2 0.12 化合物 11 4 1 化合物 12 8 0.25 化合物 13 2 0.5 化合物 14 8 0 . 5 -81 - •M氏張尺度通用taa家律爭（CNS) f 4規烙（210 X 297公货） -裝. •1T. .線. 五、發明説明（80 ) A6 Ββ 經濟部中央橒準局®工消脅合作钍印¾ 化合物1 5 2 1 化合物16 1 0 .25 化合物1 7 8 0 .25 化合物1 3 4 1 化合物1 9 1 0.25 化合物20 4 0.5 化合物21 64 8 化合物2 2 4 . 0 . 5 .化合物2 3 ισ 0.25 化合物24 4 1 化合物2 5 2 0 · 5 化合物26 2 1 化合物27 4 1 化合物2 8 1 化合物29 2 0.5 化合物3 0 4 . 1 化合物3 1 ~ _ 2 0.25 化合物3 2 32 4 化合物3 3 4 1 化合物3 4 1 0 .25 化合物3 5 4 1 化合物3 6 2 • 0.5 -82 - 本呔張尺戊通用taaa?戊革（cns)甲<規烙（210 X 297公坌） -裝------II------^ {請先S讀背面之注意事項再填寫本1)Soil P 7. (Shi) -N-[[3- [4- (4-methylbenzoyl-hexahydropyridyl) -5-pyridyl-1,3,6-cycloheptatriene-butyl ] Phenyl] -2-keto-5-oxazolidinyl] methyl] -acetamide, 8. (±)-^-[[3- [4- [4- (2-propenylamino ) -5-Meng-1,1,3,6-cycloheptatriene-butyl] phenyl] -2-Mengyl-5-pyrazolidinyl] methyl] -acetamide, 9. (soil) -N- [[3- [4- [4-U-pyrrolidinyl) -5-keto-1, 3,6-ring 76 83.3.10,000 clothing and paper are again applicable to China National Standard (CNS) A4 specifications ( 2i0 X 2Q7mm) A7 B7 V. Description of the invention () Heptatrien-1-yl] phenyl] -2-Mengyl-5-pyridazolyl] methyl] -ethylamine, 10. (± ) -N-[[3- [4- [4- (4-methyl-1-hexahydropyridinyl) -5-keto-1,3,6-cycloheptatriene-phenyl] phenyl ] -2-keto-5-oxazolidinyl] methyl] -acetamide, 11. (±) -Bu [[3- [4- (4-cyclopentylamino-5-keto-1 , 3,6-cycloheptatriene-butyl) phenyl] -2-vinyl-5-azazolidinyl] methyl] -ethylamine 12. (±) -Ν-[[3- [4 -[4- (1-hexahydropyridinyl) -5-pyridyl-1,3,6-cycloheptatrien-1-yl] phenyl] -2-keto-5-pyridazolyl] Methyl] -acetamide, 13. (±) -N-[[3- [4- (4-Butylamino-5-keto-1,3,6-cycloheptatriene- 1-yl) phenyl] -2-keto-5-morpholinyl] methyl] -acetamide 14. (T) -N-[[3- [4- [4- (cis-3 , 5-dimethyl-1-hexahydropyridinyl) -5-mengyl-1,3,6-cycloheptatrien-1-yl) phenyl] -2-mengyl-5-pyrazolidine Group] Methyl] -acetamide, 15. (±) -N-[[3- [4- [4- (Buhexahydropyridyl) -5-keto-1,3,6-cyclo_ 軎Tris-: 1-yl] phenyl] -2-oxyl-5-oxazolazyl] methyl] -ethiamine, 16. (±) -1 [[3- [3-fluoro-4- (4-methoxy-5-pyridyl-1,3,6-cycloheptatriene-p-yl) phenyl] -2-pyridyl-5-pyrazolidinyl] methyl] -acetamide, 17. (±) -N-[[3- [4- [4- (3-Methyl-hexahydropyridyl) -5-pyridyl-1,3,6-cycloheptatriene-1- Group] Phenyl] -2-keto-5-pyrazolidinyl] methyl] -diethyl etheramine · -77-This paper is again applicable to the Chinese National Standard (CNS) A4 specification (210 X 29 * 7 mm) 83.3.10,000 ------------- installed --------- order --------- line (please read the precautions on the back before writing this page ) 299332 A7 B7 V. Description of the invention 18. (土) -N-[[3- [4- [4- (3-hydroxy-pyrrolidinyl) -5-keto-1,3,6-cycloheptane Triene-Buyl] phenyl] -2-keto-5-oxazolidinyl] 19 methyl] -ethylamine, (5)-«-[[3- -4- (4-Methoxy-5-keto-1,3,6-cycloheptatriene ± (t .¾ S. tur-1-yl) phenyl) -2-keto-5-berro Oxazolidinyl] methyl] -acetamide, 20. (±) -N-[[3- [4- [4-methoxy-3-indol-1,4,6-cycloheptanyl- Butyl] phenyl] -2-menyl-5-pyridazolyl] methyl] -acetamide, 21. (±)-^-[[3- [4- [6-methoxy-5 -Keto-1,3,6-cycloheptatrien-1-yl] phenyl] -2-menyl-5-oxazolidinyl] methyl] -acetamide, 22. (±) is called- [[3- [4- [4-ethoxy-5-menyl-1,3,6-cycloheptatrien-1-yl] phenyl] -2-vinyl-5-pyrazolidinyl] Methyl] -acetamide, 23. (±) -M-[[3- [4- [4- (3-amino-1-pyrrolidinyl) -5-keto-1,3,6- Cycloheptatrien-1-yl] phenyl] -2-vinyl-5-oxazolidinyl] methyl] -glycosamine, 24. (±) -N-[[3- [4- [4 -U-methylethoxy) -5-pyridyl-1,3,6-cycloheptatriene-butyl] phenyl] -2-pyridyl-5-oxazolidinyl] methyl] -ethyl Acetamide, 25. (5) 1-[[3- [4- [4- (4-morpholinyl) -5-pyridyl-1,3,6-cycloheptatrien-1-yl] phenyl ] -2-acetoxy-5-pyridazolyl] methyl] -acetamide, 26. (±) -N-[[3- [4- [4- (2-propenylamino) -3 -Keto-1; 4,6-cycloheptatrien-1-yl] phenyl] -2-Mengyl-5-oxazolidinyl] methyl] -B Amine, 27. (earth)-. [1-[[3- [4- [4- (4-morpholinyl) -3-keto-1,4,6-cycloheptatriene-brenyl] benzene Radical] -2-keto-5-pyrazolidinyl] methyl] -acetamide 78 This paper is again applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 83.3.10,000 (please read first (Notes on the back and then write this page) A7 B7 5. Description of the invention (), and 28. (5) 4-[[3- [4-methoxy-5-hexyl-1,3,6-ring Heptatrienyl] phenyl] -2-oxi-5--5-oxazolidinyl] methyl] -acetamide · 29. (±)-^-[[3- [4- [4- (2- Propylamino) -3-keto-1,4,6-cycloheptatrien-1-yl] phenyl] -2-keto-5-oxazolidinyl] methyl] -acetamide, 30. (Soil) -N-[[3- [4-[-[[(methoxycarbonyl) methyl] amino] -5-keto-1,3,6-cycloheptatrien-1-yl ] Phenyl] -2-oxo-5-pyridazolyl] methyl] -acetamide, 31. (±) -Bu [[3- [4- (4-methylamino-5-Mengyl -1,3,6-cycloheptatriene-butyl) phenyl] -2-keto-5-pyridazolyl] methyl] -acetamide, 3 2. (±)-N-[[ 3-[4-[4-(2,5-dihydro-1 Η -pyrrole-: 1-yl) -5 -benzyl-1,3,6-cycloheptatrien-1-yl] phenyl] -2-acetoxy-5-pyrazolidinyl] methyl] -acetamide, 33. (±) -Ν-[[3- [4- [4- (2-propenyloxy) -5-keto-1,3,6-cycloheptatrien-1-yl] phenyl] -2- Phenyl-5-oxazolidinyl] methyl] -acetamide, --- 34. (S) -H-[[3- [3 -Fluoro-4-[(2-propanylamino)- 5-Meng-1,3,6-cycloheptatrien-1-yl] phenyl] -2-keto-5-pyrazolidinyl] methyl] -acetamide, 35. (±)- N-[[3- [4- [4- (2-Methoxyethoxy) -5-keto-1,3,6-cycloheptatriene-butyl] phenyl] -2-yl -5-pyridazolyl] methyl ethyl acetamide, 36. (5) 1-[[3- [3-fluoro-4-[(4-morphoyl) -5--5-yl-1,3 , 6-Ring-79-This paper is applicable to Chinese National Standard (CNS) A4 specification (2! 0 X 297 mm) 83.3.10,000 ----------- ί _ 装-nn I nnnn _ ^ i I nn 1 (please read the precautions on the back before writing the clothing page) V. Description of the invention () enetri-heptylaminobenzene U-based A7 B7 醢乙 I TIJ 基甲 U 基基基兹 ZOhum I 5- Base 0 (please read the note on the back first, and then write this page). Ministry of Economics_Central Standards Bureau 3 Gongxiao F Cooperative. This paper is printed in accordance with the Chinese National Standard (CNS) A4 (210 X 2W Mm) 83.3.10,000 V. Description of the invention (79) A6 B6 in vitro Small inhibitory concentration (expressed in mcg / ml) {Read the precautions on the back before filling in the clothes page) Economic and Central Bureau of Standards and Technology Consumption Cooperation Thorium Seal 5 * Golden Yellow Grape Streptomyces Spp. II ". (Rl Q 2 1 3 II C 0¾ 1 R?. Compound 1 2 0.25 Compound 2 4 · 1 Compound 3 > 64 4 Compound 4 4 0.5 Compound 5 2 0.5 Compound 6 2 0.5 Compound 7 4 0.5 Compound 8 2 0.5 Compound 9 4 1 Compound 10 1-2 0.12 Compound 11 4 1 Compound 12 8 0.25 Compound 13 2 0.5 Compound 14 8 0. 5 -81-• M's Zhang scale universal taa family law (CNS) f 4 regulation ( 210 X 297 public goods)-installed. • 1T. Line. Fifth, the description of the invention (80) A6 Ββ Ministry of Economic Affairs Central Bureau of Industry and Commerce Threat Cooperative Thorium Seal ¾ Compound 1 5 2 1 Compound 16 1 0 .25 Compound 1 7 8 0 .25 Compound 1 3 4 1 Compound 1 9 1 0.25 Compound 20 4 0.5 Compound 21 64 8 Compound 2 2 4 .0 .5 .Compound 2 3 ισ 0.25 Compound 24 4 1 Compound 2 5 2 0 · 5 Compound 26 2 1 Compound 27 4 1 Compound 2 8 1 Compound 29 2 0.5 Compound 3 0 4. 1 Compound 3 1 ~ _ 2 0.25 Compound 3 2 32 4 Compound 3 3 4 1 Compound 3 4 1 0 .25 Compound 3 5 4 1 Compound 3 6 2 • 0.5- 82-This 呔弔弔 general purpose taaa? Cn leather (cns) A < gauge branding (210 X 297 gong)-installed ------ II ------ ^ {please read the back first Matters needing attention and fill in this 1)

Claims

A8 B8 C8 D8 經濟部中央標準局員工消费合作杜印製申請專利範圍 L 一種具式I化合物*及其藥用鹽與水合物 R2 R.A8 B8 C8 D8 Du Printing Co., Ltd. Employee Consumption Cooperation of the Central Bureau of Standards of the Ministry of Economic Affairs Application for patent scope L A compound of formula I * and its pharmaceutically acceptable salts and hydrates R2 R.

HBCOR1 式中R 1為 (a) 氫 (b) (“-Ca)烷基；式中R2與R3為相同或不同，且自下列之基選出 (a) 氫 (b) 氟基 (c) 氛基式中R4自下列之基選出： CO (0 (HBCOR1 where R 1 is (a) hydrogen (b) (“-Ca) alkyl; where R 2 and R 3 are the same or different, and (a) hydrogen (b) fluoro (c) atmosphere is selected from the following groups R4 in the basic formula is selected from the following bases: CO (0 (

其中Rs自下列之基理出：氫、ORe、NHRt -83 - 本紙張尺度適用中國國家標準（CNS)A4规格（210 X 297公釐） -----------f —裝---------訂-------？線 (請先閱讀背面之注意事項再塡寫本頁) (b) RAmong them, Rs is derived from the following principles: hydrogen, ORe, NHRt -83-This paper scale is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) ----------- f-installed --------- Order -------? Line (please read the notes on the back before writing this page) (b) R

經濟部中央標準局貝工消費合作杜印製 2923^0 A8 C8 D8 六、申請專利範圍Du Printed by Beigong Consumer Cooperation, Central Bureau of Standards, Ministry of Economic Affairs 2923 ^ 0 A8 C8 D8 VI. Scope of patent application

〇- Cx_ y - 及 P7R12; 其中Reg (a) 氫 (b) 視情況為（Ci-Ca)烷氧基、乙烯基或苯基所取代之（Ci-Ce)烷基一 . 其中R7為 U)氫 (b) (Ci-Ce)烷基視須要以一或多個、羥基、苯基、 (Ca-Ce)烷氧基、（“-Ce)烷氧羰基部分取代 (c) (C3-C8)環烷基 (d) (C2-Ce)炔基（Ci-“。）烷基其中”為 -8 4 - 本紙張尺度適用中國國家標準（CNS)A4规格（210 X297公釐） -----------f -裝---------訂-------{ 線 (請先閲讀背面之注意事項再塡寫本頁) 經濟部中央標準局貝工消费合作社印製 A8 B8 C8 D8 六、申請專利範圍 (a) 氫 (b) (Ca-Ce)烷基 (c) 醛基其中1^與1?1<5可為相同或不同，且為 U)氫 (b) (Ci-Cs)烷基其中R11為 (a) & (b) 羥基 (c) 胺基其中R12為（Ci-Ca)烷基。 2. 根據申讅專利範圃第1項之化合物·具下式la〇- Cx_ y-and P7R12; where Reg (a) hydrogen (b) optionally (Ci-Ca) alkoxy, vinyl or phenyl substituted (Ci-Ce) alkyl one. Where R7 is U ) Hydrogen (b) (Ci-Ce) alkyl is optionally substituted with one or more, hydroxyl, phenyl, (Ca-Ce) alkoxy, (“-Ce) alkoxycarbonyl (c) (C3- C8) Cycloalkyl (d) (C2-Ce) alkynyl (Ci- ".) Alkyl where" is -8 4-This paper scale is applicable to China National Standard (CNS) A4 specifications (210 X297 mm)- --------- f -installed --------- order ------- {line (please read the notes on the back before writing this page) Central Bureau of Standards, Ministry of Economic Affairs Printed by Beigong Consumer Cooperative A8 B8 C8 D8 6. Scope of patent application (a) Hydrogen (b) (Ca-Ce) alkyl (c) Aldehyde group where 1 ^ and 1? 1 <5 may be the same or different, and Is U) hydrogen (b) (Ci-Cs) alkyl where R11 is (a) & (b) hydroxy (c) amine group where R12 is (Ci-Ca) alkyl. 2. According to the patent application The compound of item 1 has the formula la

la 式中R1、R2、卩3與！^如申請專利範園第1項所定義。 a 根據申請專利範面第2項之化合物*係由下列遘出 (± )-N-[[3-[4-(4-甲氧基-5-酮基-1,3,6-環庚三烯基]苯*]-2_啤唑啶基]甲基-乙醸胺， (土）1-[[3-[4-(4-二乙胺基-5-嗣基-1,3,6-環庚三 -85 - 本紙張尺度適用中·國國家標準（CNS)A4规格（210 X 297公釐） ---------------------f -裝一I -----丨丨訂-------{ —線 (請先閱讀背面之注意事項再塡寫本頁) 六、申請專利範圍 '88 818 A B c D 經濟部中央標準局S工消费合作社印製烯-1-基]笨基]-2-酮基-5-晖唑啶基]甲基]-乙酿胺， (±)-N-[[2-酮基-3-(4-[5-酮基-4-[(苯甲基）胺基 ]-1，3，6 -環庚三烯-：1 -基]苯基]-5 -噚唑啶基]甲基-乙醢胺， (土）-H-[[3-[4-[4-[(2-經乙基）胺基]-5 -嗣基 -1,3,6-環庚三烯-1-基]苯基]-2-酮基-5-噚唑啶基]甲基-乙醯胺， (± )-N-[[3-[4-[4-(4-嗎琳基）-5 -酮基-1，3,6-環庚三烯-卜基]苯基]-2-酮基-5-嗶唑啶基]甲基]-乙醢胺 » (± )-N-[[3-[4-(4 -環丙胺基-5-嗣基-1,3,6-環庚三烯-1-基]苯基]-2-酮基-5-嗶唑啶基]甲基]-乙醢胺， (土）-N-[[3-[4-[4-(4-甲醯基-1-六氣啦哄基）-5 -萌基-1,3,6 -環庚三烯-1-基]苯基]-2 -嗣基-5-啤唑啶基] 甲基]-乙醢胺， (± )-N-[[3-[4-[4-(2-丙稀胺基）-5-嗣基 _ 1,3,6 -環庚三烯-1-—基]苯基]-2 -酮基-5-嗶唑啶基]甲基]-乙醢胺， (± )-N-[[3-[4-[4-(l-ltt 略燒基）-5 -嗣基-1,3,6-環庚三烯-1-基]苯基]-2-酮基-5-嗶唑啶基]甲基]-乙醢胺 > (± )-N-[[3-[4-[4-(4 -甲基-1-六氫阳：哄基）-5 -嗣基 -1,3,6-環庚三烯-1-基]苯基]-2-嗣基-5-噚唑啶基] 甲基]-乙醢胺* (請先閱讀背面之注意事項再塡寫本頁) -裝---------訂—------K線 -8 6 - 本紙張又度適用中國國家標準（CNS)A4規格（210 X 297公釐）經濟部中央標準局貝工消费合作社印製 A8 B8 C8 D8 六、申請專利範圍 (± )-N-[[3-[4-(4-環戊胺基-5-酮基-1,3,6-環庚三烯-1-基）苯基]-2-酮基-5-嗶唑啶基]甲基]-乙醢胺 (±)-Ν-[[3-[4-[4-(1-六氫吡畊基）-5-嗣基-1,3,6-環庚三烯-1-基]苯基]-2-嗣基-5-噚唑陡基]甲基]-乙豳胺， (±)-1[[3-[4-(4-丁胺基-5-酮基-1,3,6-環庚三烯 -1-基）苯基]-2-酮基-5-嗶唑啶基]甲基]-乙醣胺， (± )-N-[[3-[4-[4-(順式-3,5-二甲基-；1-六氫吡畊基 0_5-嗣基 -1,3,6-環庚三稀-1-基）苯基]-2 -酮基-5-曙唑啶基]甲基]-乙醢胺， (± )_N_[[3_[4_[4_(1_六运阳；症基）_5_爾基 -1,3,6-環庚三烯-1-基]苯基]-2-嗣基-5-晖唑啶基]甲基]-乙醢胺， (±)4-[[3-[3-氣-4-(4-甲氧基-5-酮基-1,3.6-環庚三烯-1-基]苯基]-2-嗣基-5-噚唑啶基]甲基]-乙醢胺 9 (± )-N-[[3-[4-[4-(3-甲基-1-六氫吡畊基）-5-_基 -1,3,6-環庚三烯-卜基]苯基]-2-酮基-5-嗶唑啶基]甲基]-乙豳胺， (土）-N-[[3-[4-[4-(3 -殘基-1-阳：略燒基）-5 -酮基 -1,3,6-環庚三烯-卜基]苯基]-2-酮基-5-啤唑啶基]甲基]-乙酿胺， (5)-»1-[[3-氟-4-(4-甲氧基-5-嗣基-1,3,6-環庚三烯-1-基]苯基]-2-嗣基-5-嗶唑啶基]甲基]-乙醢胺， -87 - 本紙張尺度適用中國國家標準（CNS)A4规格（210 X 2叼公釐） -----------f '裝---------訂-------線 (請先閱讀背面之注意事項再塡寫本頁) 經濟部中央標準局0¾工消费合作社印製 299332 S D8 六、申請專利範圍 (±)-1[[3-[4-[4-乙氧基-5-酮基-1,3,6-環庚三烯 -卜基]苯基]-2-嗣基-5-吗唑啶基]甲基]-乙醢胺* (土）-K-[[3-[4-[4-[3-胺基-1-吡咯烷基）-5-酮基 -1,3,6-環庚三烯-卜基]苯基]-2-酮基-5-嗶唑啶基]甲基]-乙藤胺， (土）-Ν-[[3-[4-[4-(1-甲基乙氧基）-5-酮基-1,3,6-環庚三烯-1-基]苯基]-2-酮基-5-嗶唑啶基]甲基]-乙醢胺， (5)1-[[3-[4-[4-(4-嗎啉基）-5-嗣基-1,3,6-環庚三烯-1-基]苯基]-2-嗣基-5-嗶唑啶基]申基]-乙醢胺* (5)1-[[3-[4-甲氧基-5-嗣基-1,3,6-環庚三烯基]苯基]-2-嗣基-5-嗶唑啶基]甲基]-乙醢胺， (±)-1<-[[3-[4-[4-丙氧基-5-嗣基-1,3,6-環庚三烯 -卜基]苯基]-2-嗣基-5-嗶唑啶基]甲基]-乙醢胺· (±)-N-[[3-[4-[ -[[(甲氧羰基）甲基]胺基]-5-酮基 -1,3,6-環庚三烯-卜基]苯基]-2-酮基-5-嗶唑啶基] 甲基]-乙醢联， (±)-1^-[[3-[4-(4-甲胺基）-5-酮基-1,3,6-環庚三烯 -卜基]苯基]-2-嗣基-5-曙唑啶基]甲基]-乙醢胺， (±)-衫-[[3-[4-[4-(2,5-二氣-111-阳；略-1-基）-5-麵基-1,3,6-環庚兰烯-1-基]苯基]-2-酮基-5-嗶唑啶基] 甲基]-乙醢胺， (± )-N-[[3-[4-[4-(2-丙稀氧基）-5- _ 基-1,3,6-瑁庚三烯-1-基]苯基]-2-酮基-5-噚唑啶基]甲基]-乙醢胺 -8 8 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） (請先閲讀背面之注意事項再塡寫本頁) -裝------- 訂丨 A8 B8 C8 D8六、申請專利範圍經濟部中央標準局貝工消費合作社印製 (S)-N-[[3-[3-氟- 4-[(2-丙炔氧基）-5-酮基 -1,3,6-環庚三烯-卜基]苯基]-2-嗣基-5-嗶唑啶基]甲基]-乙醢胺， (士）-H-[[3-[4-[4-(3,6-二氫-1(2H)_吡啶基）-5-嗣基-1,3,6-環庚三烯-卜基]-2-酮基-5-鸣唑啶基]甲基 ]-乙豳胺* (I)-N-[[3-[4-[4-(2-甲氧基乙氧基）-5-銅基 -1,3, 6-環庚三烯-卜基]苯基]-2-願基-5-噚唑啶基]甲基]-乙醸胺， (5)1-[[3-[3-氟-4-[(4-嗎啉基）-5-萌基-1,3,6-環庚三烯-1-基]苯基]-2-酮基-5-鸣唑啶基]甲基]-乙醢胺 . (土）-H-[[3-[3,5-二氟-4-[4-甲氧基-5-醑基 -1,3,6-環庚三烯-卜基]苯基]-2-酮基-5-噚唑啶基 ]甲基]-乙醢胺， (S)-N-[[3-[4-(4-甲胺-5-_ 基- l,3,6-環庚三烯-l-基]苯基]-2-酮基-5-啤唑啶基]甲基]-乙醢胺， (S)-N-f[ 3-氟- 4-(4-甲胺基-5-酮基-1,3,6-環庚三烯 -1-基）笨基]-2-酮基-5-啤唑啶基]甲基]-乙醣胺· (5)-1[[3-(4-(4-環丙基）胺基-5-酮基-1,3,6-環庚三烯-卜基）-3-氟苯基]-2-酮基-5-嗶唑啶基]甲基]-乙醢胺， (S)-H-[[3-[4-[4-(2-羥乙基）胺基]-5-酮基-1,3,6-瓖庚三烯-1-基）笨基]-2-醑基-5-啤唑啶基]甲基]-乙醢 -89 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 1装 —訂丨^ ~線 (請先閱讀背面之注意事項再塡寫本頁) 經濟部中央標準局貝工消费合作社印製 299332 ^ C8 D8 六、申請專利範圍胺，及 (S)-N-[[2-酮基- 3-[3-氟- 4-[5-酮基-4-(苯基甲氧基 )-1,3,6-環庚三烯-1-基）苯基]-5-嗶唑啶基]甲基]-乙醢胺。 4. 根據申請專利範圍第2項之化合物，其中R2與R3係自氫與氟基選出。 5. 根據申請專利範圍第4項之化合物，係自下列選出 (±)-^-[[3-3-氟-[4-(4-甲氧基-5-覼基-1,3,6-環庚三烯-卜基）苯基]-2-酮基-5-噚唑啶基]甲基-乙醢胺 * (S)-N-[[3-[3 -氣- 4- (4-甲氧基 _5 -酮基 _1，3,6 -環庚三烯-卜基）苯基]-2-嗣基-5-啤唑啶基]甲基]-乙醯胺， (S)-H-[[3-[3-氟-4-[(2-丙炔胺基）-5-萌基 -1,3,6-環庚三烯-1-基]苯基]-2-嗣基-5-噚唑啶基]甲基]-乙醢胺， (5)1-[[3-[3-氣-4-[(4-嗎琳基）-5-飼基-1,3,6-環庚三烯-卜基]苯基]-2-酮基-5-鸣唑啶基]甲基]-乙醢胺， (±)-N-[[3-[3,5-二氟-4-[4-甲氧基-5- _ 基 -1,3,6-環庚三烯-1-基]苯基]-2-嗣基-5-啤唑啶基]甲基]-乙釀胺， (5)-1<-[[3-氣-4-(4-甲胺基-5-醣基-1，3,6-環庚三摊 -1-基）苯基]-2-酮基-5-噚唑啶基]甲基]-乙醢胺*及 -90 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） II--------{-裝---------訂-------ί •線 (請先閱讀背面之注意事項再塡寫本頁) 六、申請專利範圍 (S)-N-[[2-嗣基-3-[3-氟-4-[5-_基-4-(苯甲氧基） 1,3,6-環庚三烯-卜基）苯基-5-噚唑啶基]甲基]-乙醢胺 Ο a 根據申請專利範圍第5項之化合物，其為 (土）-1<-[[3-[3-氟-4-(4-甲氧基）-5-嗣基-1,3,6-環庚三烯-1-基]苯基]-2-嗣基-5-嗶唑啶基]甲基]-乙醢胺 Ο 7. 根據申請專利範画第5項之化合物，其為 (5)-[<-[[3-[3-氣-4-(4-甲氧基-5-萌基-1,3,6-環庚三烯-1-基）苯基]-2 -嗣基-5-噚唑啶基]甲基]-乙醸胺〇 a 根據申謫專利範園第5項之化合物，其為 (5)咄-[[3-[3-氣-4-[(2-丙炔胺基）-5-嗣基 -1,3,6-環庚三烯-卜基]苯基]-2-酮基-5-嗶唑啶基]甲基]-乙醢胺。 a 根據申請專利範圍第5項之化合物*其為 (5)-1<-[[3-[3-氟-4-[(4-嗎啉基）-5-嗣基-1,3,6-環庚三烯-1-基]苯基]-2-酮基-5-嗶唑啶基]甲基]-乙醢胺經濟部中央標準局員工消費合作社印製 (請先閱讀背面之注意事項再塡寫本頁) Ο ία 根據申請專利範围第5項之化合物，其為 (±)-Ν-[[3-[3,5-二氟-4-[4-甲氧基-5-萌基 -1,3 ,6-環庚三烯-1-基]苯基]-5-嗶唑啶基]甲基]-乙醢胺。 11 根據申請専利範_第5項之化合物，其為 -91 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐）申請專利範圍 12. ia 14. 15. A8 B8 C8 D8 (5)-1[[3-氟-4-(4-甲胺基-5-酮基-1,3,6-環庚三烯 -1-基）苯基]-2 -萌基-5-嗶唑啶基]甲基]-乙醢胺。根據申請專利範圍第5項之化合物，其為 (S)_N_[[2 -嗣基_3-[3_氣_4_[5_飼基_4_(苯甲氧基） 1,3,6-環庚三烯-1-基）苯基]-5-嗶唑啶基]甲基]-乙醢胺。根據申請專利範圍第5項之化合物，其為 (5)4-[[3-[4-(4-甲氧基-5-酮基-1,3,6-環庚三烯 -1-基]-3 ,5-二氟笨基]-2-酮基-5-啤唑啶基]甲基]-乙醢胺。根據申請專利範圔第5項之化合物，其為 (5)-1-[[3-[4-(4-甲氧基-5-酮基-1,3,6-環庚三烯 -卜基]-3,5-二氟苯基]-2-萌基-5-嗶唑啶基]甲基]-乙醢胺。根據申請專利範園第1項之化合物，，具下式lb (請先閱讀背面之注意事項再塡寫本頁) 經濟部中央標準局貝工消费合作社印製In formula la, R1, R2, 卩 3 and! ^ As defined in item 1 of the patent application park. a The compound according to item 2 of the patent application profile is derived from the following (±) -N-[[3- [4- (4-methoxy-5-keto-1,3,6-cycloheptane Trienyl] benzene *]-2_pyrazolidinyl] methyl-ethylammonium amine, (soil) 1-[[3- [4- (4-diethylamino-5-pyridyl-1,3 , 6-Cyclohengsan-85-This paper scale is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) -------------------- -f-装一 I ----- 丨丨 Subscribe ------- {-line (please read the precautions on the back before writing this page) 六、 Apply for patent scope '88 818 AB c D Economy Printed by the Central Standards Bureau of the Ministry of Industry and Consumer Cooperatives of ene-1-yl] benzyl] -2-keto-5-hyzazolidinyl] methyl] -ethylamine, (±) -N-[[2- Keto-3- (4- [5-keto-4-[(benzyl) amino] -1,3,6-cycloheptatriene-: 1-yl] phenyl] -5-pyrazole Pyridyl] methyl-acetamide, (earth) -H-[[3- [4- [4-[(2-ethyl) amino] -5-yl-1,3,6-ring Heptatrien-1-yl] phenyl] -2-keto-5-oxazolidinyl] methyl-acetamide, (±) -N-[[3- [4- [4- (4- Morpholinyl) -5 -keto-1,3,6-cycloheptatriene-diphenyl] phenyl] -2-keto-5-pyridazolyl] methyl] -acetamide »(± ) -N-[[3- [4- (4- Alanyl-5-pyridyl-1,3,6-cycloheptatrien-1-yl] phenyl] -2-keto-5-pyridazolyl] methyl] -acetamide, (soil) -N-[[3- [4- [4- (4-Methanoyl-1-hexafluoropyridinyl) -5 -mengyl-1,3,6-cycloheptatrien-1-yl] benzene Group] -2 -pyridin-5-pyrazolidinyl] methyl] -acetamide, (±) -N-[[3- [4- [4- (2-propenylamino) -5- Benzyl_1,3,6-cycloheptatrien-1-yl] phenyl] -2-keto-5-pyridazolyl] methyl] -acetamide, (±) -N- [ [3- [4- [4- (l-ltt slightly burned group) -5 -indolyl-1,3,6-cycloheptatrien-1-yl] phenyl] -2-keto-5-beep Oxazolidinyl] methyl] -acetaminophen > (±) -N-[[3- [4- [4- (4-methyl-1-hexahydroamin: carbamoyl) -5 -yl- 1,3,6-cycloheptatrien-1-yl] phenyl] -2-oxi-5--5-oxazolidinyl] methyl] -acetamide * (Please read the precautions on the back before writing This page) -Installed --------- Ordered ------- K line-8 6-This paper is again applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) Ministry of Economic Affairs A8 B8 C8 D8 printed by Beigong Consumer Cooperative of Central Bureau of Standards 6. Scope of patent application (±) -N-[[3- [4- (4-cyclopentylamino-5-keto-1,3,6- Cycloheptatrien-1-yl) phenyl] -2-keto-5- Oxazolidinyl] methyl] -acetamide (±) -Ν-[[3- [4- [4- (1-hexahydropyridyl) -5-pyridyl-1,3,6-cycloheptan Trien-1-yl] phenyl] -2-oxyl-5-oxazolidyl] methyl] -acetamide, (±) -1 [[3- [4- (4-butylamino- 5-keto-1,3,6-cycloheptatrien-1-yl) phenyl] -2-keto-5-pyridazolyl] methyl] -glycosamine, (±) -N- [[3- [4- [4- (cis-3,5-dimethyl-; 1-hexahydropyridinyl 0_5-hexyl-1,3,6-cycloheptan-1-yl) Phenyl] -2-keto-5-oxazolidinyl] methyl] -acetamide, (±) _N _ [[3_ [4_ [4_ (1_Liuyunyang; Zhengji) _5_ 尔基- 1,3,6-cycloheptatrien-1-yl] phenyl] -2-oxi-5-pyridazolyl] methyl] -acetamide, (±) 4-[[3- [3 -Gas-4- (4-methoxy-5-keto-1,3.6-cycloheptatrien-1-yl] phenyl] -2-oxyl-5-oxazolidinyl] methyl]- Acetamide 9 (±) -N-[[3- [4- [4- (3-methyl-1-hexahydropyridinyl) -5-_yl-1,3,6-cycloheptatriene -Bulkyl] phenyl] -2-keto-5-pyridazolyl] methyl] -acetamide, (soil) -N-[[3- [4- [4- (3-residue- 1-Yang: Slightly burned group) -5-keto-1,3,6-cycloheptatriene-butyl] phenyl] -2-keto-5-pyrazolidinyl] methyl] -ethyl alcohol Amine, (5)-»1-[[3-fluoro-4- (4-methoxy-5 -Penyl-1,3,6-cycloheptatrien-1-yl] phenyl] -2-oxenyl-5-pyridazolyl] methyl] -ethylacetamide, -87-This paper size is applicable China National Standard (CNS) A4 specification (210 X 2 mm) ----------- f 'installed --------- ordered ------- line (please Read the precautions on the back before writing this page) Central Bureau of Standards of the Ministry of Economic Affairs Printed 299332 S D8 by the Industrial and Consumer Cooperatives VI. Patent application scope (±) -1 [[3- [4- [4-ethoxy- 5-keto-1,3,6-cycloheptatriene-diphenyl] phenyl] -2-oxo-5-morphazolidinyl] methyl] -acetamide * (soil) -K- [ [3- [4- [4- [3-Amino-1-pyrrolidinyl] -5-keto-1,3,6-cycloheptatriene-blanyl] phenyl] -2-keto- 5-pyridazolyl] methyl] -acetamide, (soil) -Ν-[[3- [4- [4- (1-methylethoxy) -5-keto-1,3, 6-cycloheptatrien-1-yl] phenyl] -2-keto-5-pyridazolyl] methyl] -acetamide, (5) 1-[[3- [4- [4- (4-morpholinyl) -5-pyridyl-1,3,6-cycloheptatrien-1-yl] phenyl] -2-pyridyl-5-pyridazolyl] shenyl] -ethylpyridine Amine * (5) 1-[[3- [4-Methoxy-5-phenyl-1,3,6-cycloheptatrienyl] phenyl] -2-yl-5-pyridazolyl ] Methyl] -acetamide, (±) -1 <-[[3- [4- [4-propoxy-5 -Butyl-1,3,6-cycloheptatriene-pyl] phenyl] -2-oxyl-5-pyrazolidinyl] methyl] -acetamide · (±) -N-[[ 3- [4- [-[[(Methoxycarbonyl) methyl] amino] -5-keto-1,3,6-cycloheptatriene-butyl] phenyl] -2-keto-5 -Pyrazolidinyl] methyl] -acetanilide, (±) -1 ^-[[3- [4- (4-methylamino) -5-keto-1,3,6-cycloheptan Alkenyl-phenyl] phenyl] -2-yl-5--5-oxazolidinyl] methyl] -acetamide, (±) -shirt-[[3- [4- [4- (2,5- Diqi-111-yang; abbreviated-1-yl) -5-facet-1,3,6-cycloheptanen-1-yl] phenyl] -2-keto-5-pyridazolyl] Methyl] -acetamide, (±) -N-[[3- [4- [4- (2-propenyloxy) -5- yl-1,3,6-heptatriene-1 -Yl] phenyl] -2-keto-5-oxazolidinyl] methyl] -acetamide-8 8-This paper scale is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) ( (Please read the precautions on the back before writing this page) -Installed ------- Ordered 丨 A8 B8 C8 D8 六、 Apply for Patent Scope Printed by Beigong Consumer Cooperative of the Central Standards Bureau of the Ministry of Economy [[3- [3-Fluoro-4-[(2-propynyloxy) -5-keto-1,3,6-cycloheptatriene-butyl] phenyl] -2-yl] -5 -Pyridazolyl] methyl] -acetamide, (± ) -H-[[3- [4- [4- (3,6-dihydro-1 (2H) _pyridyl) -5-pyridyl-1,3,6-cycloheptatriene-butyl] -2-keto-5-oxazolidinyl] methyl] -acetamide * (I) -N-[[3- [4- [4- (2-methoxyethoxy) -5- Copper-based-1,3, 6-cycloheptatriene-butyl] phenyl] -2-yl-5--5-oxazolidinyl] methyl] -ethylamide, (5) 1-[[3- [3-fluoro-4-[(4-morpholinyl) -5-menyl-1,3,6-cycloheptatrien-1-yl] phenyl] -2-keto-5-oxazolidine Yl] methyl] -acetamide. (Earth) -H-[[3- [3,5-difluoro-4- [4-methoxy-5-vinyl-1,3,6-cycloheptane Triene-pyl] phenyl] -2-keto-5-oxazolidinyl] methyl] -acetamide, (S) -N-[[3- [4- (4-methylamine-5 -_Yl-1,3,6-cycloheptatrien-1-yl] phenyl] -2-keto-5-pyrazolidinyl] methyl] -acetamide, (S) -Nf [3 -Fluoro- 4- (4-methylamino-5-keto-1,3,6-cycloheptatrien-1-yl) benzyl] -2-keto-5-pyrazolidinyl] methyl ] -Glycosamine · (5) -1 [[3- (4- (4-Cyclopropyl) amino-5-keto-1,3,6-cycloheptatriene-butyl) -3- Fluorophenyl] -2-keto-5-pyridazolyl] methyl] -acetamide, (S) -H-[[3- [4- [4- (2-hydroxyethyl) amino ] -5-Keto-1,3,6- 瓖 heptatrien-1-yl) benzyl] -2-vinyl-5-pyrazolidinyl] methyl] -acetin-8 9-The size of this paper is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) 1 Binding—Binding 丨 ^ ~ Line (please read the precautions on the back before writing this page) Bei Gong Printed by Consumer Cooperative 299332 ^ C8 D8 VI. Patent application scope of amine, and (S) -N-[[2-keto-3- [3-fluoro-4- [5-keto-4- (phenylmethyl Oxy) -1,3,6-cycloheptatrien-1-yl) phenyl] -5-pyridazolyl] methyl] -acetamide. 4. The compound according to item 2 of the patent application scope, wherein R2 and R3 are selected from hydrogen and fluorine groups. 5. The compound according to item 4 of the patent application is selected from the following (±)-^-[[3-3-fluoro- [4- (4-methoxy-5- 覼 yl-1,3,6 -Cycloheptatriene-butyl) phenyl] -2-keto-5-oxazolidinyl] methyl-acetamide * (S) -N-[[3- [3-gas- 4- ( 4-methoxy_5 -keto_1,3,6 -cycloheptatriene-butyl) phenyl] -2-oxi-5-pyrazolidinyl] methyl] -acetamide, ( S) -H-[[3- [3-fluoro-4-[(2-propynylamino) -5-menyl-1,3,6-cycloheptatrien-1-yl] phenyl]- 2-Butyl-5-oxazolidinyl] methyl] -acetamide, (5) 1-[[3- [3-gas-4-[(4-morpholinyl) -5-feeder- 1,3,6-cycloheptatriene-butyl] phenyl] -2-keto-5-oxazolidinyl] methyl] -acetamide, (±) -N-[[3- [3 , 5-difluoro-4- [4-methoxy-5-_yl-1,3,6-cycloheptatrien-1-yl] phenyl] -2-yl--5-pyrazolidinyl ] Methyl] -ethylamine, (5) -1 <-[[3-gas-4- (4-methylamino-5-glycosyl-1,3,6-cycloheptan-1-yl ) Phenyl] -2-keto-5-oxazolidinyl] methyl] -acetamide * and -90-This paper scale is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) II- ------- {-装 --------- 定 ------- ί • Line (please read the notes on the back first (Write this page) 6. Scope of patent application (S) -N-[[2-Butyl-3- [3-fluoro-4- [5-_yl-4- (benzyloxy) 1,3, 6-cycloheptatriene-butyl) phenyl-5-oxazolidinyl] methyl] -acetamide amine a Compound according to item 5 of the patent application scope, which is (土) -1 <-[[ 3- [3-fluoro-4- (4-methoxy) -5-pyridyl-1,3,6-cycloheptatrien-1-yl] phenyl] -2-pyridyl-5-pyrazole Pyridyl] methyl] -acetamidoamine 7. The compound according to item 5 of the patent application, which is (5)-[<-[[3- [3-gas-4- (4-methoxy Yl-5-mengyl-1,3,6-cycloheptatrien-1-yl) phenyl] -2 -indolyl-5-oxazolidinyl] methyl] -ethylammonium 〇a according to Shen The compound of the 5th item of the patent garden, which is (5) -Blank-[[3- [3-Ga-4-[(2-propynylamino) -5-pyridin-1,3,6-cycloheptane Triene-pyl] phenyl] -2-keto-5-pyridazolyl] methyl] -acetamide. a The compound according to item 5 of the patent application scope * is (5) -1 <-[[3- [3-fluoro-4-[(4-morpholinyl) -5-pyridin-1,3,6 -Cycloheptatrien-1-yl] phenyl] -2-keto-5-pyrazolidinyl] methyl] -ethylacetamide Printed by the Employee Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the notes on the back first Matters, please write this page) Ο ία The compound according to item 5 of the patent application scope is (±) -Ν-[[3- [3,5-difluoro-4- [4-methoxy-5 -Meng-1,3,6-cycloheptatrien-1-yl] phenyl] -5-pyridazolyl] methyl] -acetamide. 11 According to the application of the compound _ Item 5 which is -91-This paper scale is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). Scope of patent application 12. ia 14. 15. A8 B8 C8 D8 (5) -1 [[3-fluoro-4- (4-methylamino-5-keto-1,3,6-cycloheptatrien-1-yl) phenyl] -2 -meng-5 -Pyridazolyl] methyl] -acetamide. The compound according to item 5 of the patent application scope is (S) _N _ [[2-嗣基 _3- [3_ 气 _4_ [5_feeder_4_ (benzyloxy) 1,3,6- Cycloheptatrien-1-yl) phenyl] -5-pyridazolyl] methyl] -acetamide. The compound according to item 5 of the patent application scope is (5) 4-[[3- [4- (4-methoxy-5-keto-1,3,6-cycloheptatrien-1-yl ] -3,5-Difluorobenzyl] -2-keto-5-pyrazolidinyl] methyl] -acetamide. The compound according to item 5 of the patent application, which is (5) -1 -[[3- [4- (4-Methoxy-5-keto-1,3,6-cycloheptatriene-butyl) -3,5-difluorophenyl] -2-Meng- 5-pyrazolidinyl] methyl] -acetamide. The compound according to item 1 of the patent application park has the following formula lb (please read the notes on the back before writing this page) Central Bureau of Standards Printed by Beigong Consumer Cooperative

0 人 HCOE 式中R1、R2、R3與RB如申謫專利範圃第1項。 1& 根據申請專利範園第5項之化合物·係由下列埋出 92 - 本紙張尺度適用中國國家標準（CNS)A4规格（210 X 297公釐）丨裝-----II--訂------—線經濟部中央標準局貝工消费合作社印製 A8 B8 C8 D8 六、申請專利範圍 (土）-N-[[3-[4-(4-甲氧基-3-嗣基-1,4·6-環庚三烯 -1-基]苯基]-2-酮基-5-啤唑啶基]甲基]-乙醢胺· (± )-Ν-[[3-[4-([ 2-丙烯基）胺基-3-萌基-1,4,6-環庚三烯-卜基]苯基]-2-_基-5-嗣基-5-聘唑啶基]甲基]-乙醢胺* (±)-^1-[[3-[4-[4-(4-嗎啉基）-3-酮基-1,4,6-環庚三烯-卜基]苯基]-2-酮基-5-酮基-5-噚唑啶基]甲基]-乙豳胺，及 (± )-Ν-[ [3-[4-[4-(2-丙炔胺基）-3-嗣基-1 , 4, 6-環庚三烯-1-基]苯基]-2-萌基-5-嗶唑睡基]甲基]-乙醢胺 Ο 17.'根據申請專利範圍第16項之化合物’其為 (± )-Ν-[[3-[4-(4-甲氧基-3-嗣基-1,4,6-環庚三烯 -卜基]苯基]-2-酮基-5-晖唑啶基]甲基]-乙釀胺。 la 根據申請專利範圃第16項之化合物’其為 (± )-N-[[3-[4-[4-(2-丙烯胺基）-3-酮基-1,4,6-環庚三烯-卜基]苯基]-2-酮基-5-嗶唑啶基]甲基]-乙醢胺 —-Ο ia 根據申讅專利範圍第16項之化合物’係自下列選出 (土）-N-[[3-[4-[4-(4-嗎琳基）-3-酮基-1,4,6-環庚三烯-卜基]苯基]-2-酮基-5-嗶唑啶基]甲基]-乙醣胺* 及 (± )-H-[[3-[4-[4-(2-丙炔胺基）-3-酮基-1,4,6-瑁庚三烯-卜基]苯基]-2-酮基-5-嗶唑啶基]甲基]-乙醢胺 -93 - 本紙張尺度適用中國國家標準（CNS)A4规格（210 X 297公釐） ------------f装---------訂--------(線 (請先閒讀背面之注意事項再塡寫本頁) 299332 A8 B8 C8 D8 〒、申請專利範圍 2Q 根據申請專利範圍第1項之化合物，具下式I I5 20 people HCOE In the formula, R1, R2, R3 and RB are as the first item of the application for patent patent. 1 & The compound according to item 5 of the patent application park is buried in the following 92-This paper scale is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) ------- Printed by the Beigong Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs A8 B8 C8 D8 VI. Scope of patent application (soil) -N-[[3- [4- (4-methoxy-3- Phenyl-1,4 · 6-cycloheptatrien-1-yl] phenyl] -2-keto-5-pyrazolidinyl] methyl] -acetamide · (±) -Ν-[[ 3- [4-([2-propenyl) amino-3-menyl-1,4,6-cycloheptatriene-butyl] phenyl] -2-_yl-5-pyryl-5- Oxazolidinyl] methyl] -acetamide * (±)-^ 1-[[3- [4- [4- (4-morpholinyl) -3-keto-1,4,6-ring Heptatriene-butyl] phenyl] -2-keto-5-keto-5-oxazolidinyl] methyl] -acetamide, and (±) -Ν- [[3- [4- [4- (2-propynylamino) -3-pyridyl-1, 4, 6-cycloheptatrien-1-yl] phenyl] -2-meng-5-pyridazolyl] methyl ] -Acetylamine Ο 17. 'The compound according to item 16 of the patent application' which is (±) -Ν-[[3- [4- (4-methoxy-3-inyl-1,4, 6-cycloheptatriene-butyl] phenyl] -2-keto-5-hyzazolidinyl] methyl] -ethylamine. La According to the application The compound 16 in Fanpu's is (±) -N-[[3- [4- [4- (2-propenylamino) -3-keto-1,4,6-cycloheptatriene- BU] Phenyl] -2-keto-5-pyrazolidinyl] methyl] -acetamide--0 ia The compound according to item 16 of the patent scope of the application is selected from the following (soil) -N -[[3- [4- [4- (4-Molininyl) -3-keto-1,4,6-cycloheptatriene-butyl] phenyl] -2-keto-5-beep Oxazolidinyl] methyl] -glycosamine * and (±) -H-[[3- [4- [4- (2-propynylamino) -3-keto-1,4,6- 瑁Heptatriene-butyl] phenyl] -2-keto-5-pyrazolidinyl] methyl] -acetamide-93-This paper scale is applicable to China National Standard (CNS) A4 specification (210 X 297 Ali) ------------ f outfit --------- order -------- (line (please read the precautions on the back first before writing this page ) 299332 A8 B8 C8 D8 〒Applicable patent scope 2Q The compound according to item 1 of the patent application scope has the following formula I I5 2

0 Λ〇Η: ..1 1 KB COX 式中R1、R2、R3與RB如申請專利範困第1項。 2L 根據申請專利範園第20項之化合物，其為 (±)-只-[[3-[4-(6-甲氧基-5-酮基-1，3,6-環庚三稀 -1-基]苯基]-2-醑基-5-啤唑啶基]甲基]-乙醢胺。 22 根據申請專利範圃第1項之化合物，具下式Id (請先閲讀背面之注意事項再塡寫本頁) 經濟部中央標準局員工消費合作社印製0 Λ〇Η: ..1 1 KB COX In the formula, R1, R2, R3 and RB are the first item of patent application. 2L The compound according to item 20 of the patent application garden, which is (±)-only-[[3- [4- (6-methoxy-5-keto-1,3,6-cycloheptanyl- 1-yl] phenyl] -2-pyridin-5-pyrazolidinyl] methyl] -acetamide. 22 The compound according to item 1 of the patent application garden has the following formula Id (please read the back side first Matters needing attention will be written on this page) Printed by the Employee Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

R3與R«如申請專利範園第1項。 -94 - 本紙張尺度適用中國國家標準（CNS)A4规格（210 X 297公釐）R3 and R «if applying for patent patent garden item 1. -94-This paper scale applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm)