TW470741B

TW470741B - Benzocycloalkylazolethione derivatives, a process making the same, and a pharmaceutical composition containing said derivatives

Info

Publication number: TW470741B
Application number: TW84104052A
Authority: TW
Inventors: Gregory Ricardo Martinez; David Bruce Repke; Philip Jay Teitelbaum; Keith Adrian Murray Walker; Owen Will Gooding
Original assignee: Syntex Inc
Priority date: 1995-04-25
Filing date: 1995-04-25
Publication date: 2002-01-01

Abstract

The present invention relates to novel benzocycloalkylazolethione compounds which are dopamine β-hydroxylase inhibitors in which the benzocycloalkyl portion of the compound is selected from indanyl, 1,2,3,4-tetrahydronaphthalenyl and 6,7,8,9-tetrahydro-5H-benzocycloheptenyl (in which the benzo is optionally substituted with one to three substituents) and the azolethione portion of the compound is selected from 2-thioxo-2,3-dihydro-1H-imidazol-3-y1, 5-thioxo-4,5-dihydro-1H-[1,2,4]triazol-4-y1 and 5-thioxo-4,5-dihydro-1H-[1,2,4]triazol-1-y1 (each optionally substituted with one to three substituents); and the prodrugs, pharmaceutically acceptable salts, individual isomers and mixtures of isomers and the methods of using and preparing such benzocycloalkylazolethione compounds.

Description

470741 經濟部中央標隼局員工消費合作社印製 A7 B7五、發明説明（）發明領域本發明係關於一種新穎的苯並環烷基唑硫網度巴明 (dopamine)/8 —羥基酶抑制劑K及使用及製備此類抑制劑的方法。領域敘述度巴明為與特定抗度巴明受體係最主要在中樞神經系統發現的兒茶酚胺（catechol amine)神經傳送子。正腎上腺素（norepinephrine}為一循環的兒茶酚胺，其作用於末稍糸統内不連鏞的腎上腺皮質素受髑。度巴明/3 —羥基酶 (DBH)催化度巴明轉化成正贤上腺素的作用，同時在中樞和末稍交感神經單位被發琨。度巴明一羥基酶之抑制因阻斷其代謝而提高度巴明水平》並同時阻斷其合成而降低正腎上腺素水平。因此，抑制度巴明/8 -羥基酶的藥物可用於治療與降低度巴明水平有關聯的疾病（例如帕金森病），並治療與提高正腎上腺素水平有關聯的疾病（例如高血壓，充血性心臟病等）。富沙酸（fusai'ic acid)是一種度巴明/β -羥基酶抑制劑，其可減少震顗和其它與帕金森病有關聯的異常琨象。富沙酸也能降低高血膣患的血颳；然而，也観察到從腎上腺釋出正腎上腺素Μ及所造成的心搏過速。其它更具選擇性的度巴明；8 —羥基酶抑制规為此技人士所熟知，但是通常會帶來副作用。發明概要本發明係關於一種式I化合物 (請先閱讀背面之注意事項再填寫本頁) 訂本紙張尺度適用中國國家標準（CNS ) Α4規格（210X297公釐） 470741 A7 B7 經濟部中央標準局員工消費合作社印製五、發明説明（）470741 A7 B7 printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of the invention () Field of the invention The present invention relates to a novel dopamine / 8-hydroxylase inhibitor. K and methods of using and preparing such inhibitors. Field description Dubamine is a catechol amine neurotransmitter most commonly found in the central nervous system with specific resistance bammin receptor systems. Norepinephrine is a cyclic catecholamine that acts on uncorrupted adrenocortical hormones in the terminal nervous system. Dubamine / 3 —hydroxylase (DBH) catalyzes the conversion of dubamine to the adrenal gland The effect of serotonin is cyanotic in both central and terminal sympathetic units. The inhibition of dubamine-hydroxylase increases the dubamine level by blocking its metabolism, and at the same time blocks its synthesis and reduces the level of adrenaline. Therefore, drugs that inhibit dubamin / 8-hydroxylase can be used to treat diseases that are associated with lowering dobamin levels (such as Parkinson's disease) and to treat diseases that are associated with increasing epinephrine levels (such as hypertension, Congestive heart disease, etc.). Fusai'ic acid is a dubamine / β-hydroxylase inhibitor that reduces tremors and other abnormal signs associated with Parkinson's disease. Fusolic acid Can also reduce the blood scraping of hypertensive patients; however, it is also observed that the release of adrenaline M from the adrenal glands and the resulting tachycardia. Other more selective dobamin; 8-hydroxylase inhibitory regulation is The person skilled in the art is familiar with However, it usually brings side effects. Summary of the Invention The present invention relates to a compound of formula I (please read the precautions on the back before filling out this page) The size of the paper is applicable to the Chinese National Standard (CNS) A4 (210X297 mm) 470741 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs

其中： η為0，1或2 ; t 為 0 · 1 · 2 或 3 ; R1個自獨立為鹵素，羥基或（Ci — C4 )烷基氧基；和 R2被接於α，/9或7位置，且為選自式（a)， (b )和（c )之基團：Where: η is 0, 1 or 2; t is 0 · 1 · 2 or 3; R1 is independently halogen, hydroxyl or (Ci — C4) alkyloxy; and R2 is connected to α, / 9 or 7 And is a group selected from the group consisting of formulae (a), (b) and (c):

(b) (Ο 其中： R4為氫· R3為氫或一(CH2 ) qR9 {其中q為 0， 1*2，3或4，R9為羧基，（C!-C4)烷基氧基羰基，氨基甲醸或選自芳基和雑芳基者（該基團選擇性再被一到二個獨立選自羥基，（Ct—Ci)烷基氧基，氰基，1H —四唑一 5 —基，羧基和（Ci -C4)烷基氧基羰基之取代基所取代）} ，Rs為氫或—NHR1 c {其中R1 0為氫· （C! -C4 )烷醯基，三氟（C! 一 C4 )垸醢基，氨基甲醜，（Ct —C4 )烷基氧基羰本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） (請先閱讀背面之注意事項再填寫本頁) 470741 A7 B7 五、發明説明（）基，（Ci-Ci)烷基氨基甲醢，二（Cl 一c4)烷基氨基甲醯，胺基（Ci —C4 )烷醢基* (Ci — C4 )烷基胺基（Ci _C4 )烷酿基*二（Ci -C4 )烷基胺基（Ci -C4 )烷醯基•選自芳醢基和雜芳醢基者 (該芳醸基和雜芳豳基選擇性再被一到二個獨立選自羥基，（Ci — C4 )烷基氧基，氰基，1H —四唑一 5 —基，羧基和（Ci -C4 )烷基氧基羰基的取代基所取代）或一C (NR1 i) NHR12 (其中 R1 1 和 R12 個自獨立為氫，乙醯基或三級一丁氧基羰基））；或114和 R5均為氫，R3為一 NHR1 0 (其中R1 0定義同上 );或R5為氫，R3為氫或一（CH2)q R 9 (其中 <1和R9定義同上），R4為（Ci —C4 )烷基，二（(b) (0 where: R4 is hydrogen, R3 is hydrogen or mono (CH2) qR9 {wherein q is 0, 1 * 2, 3 or 4, R9 is carboxyl, (C! -C4) alkyloxycarbonyl, Carbamate or those selected from aryl and fluorenyl groups (the group is optionally one or two independently selected from hydroxyl, (Ct-Ci) alkyloxy, cyano, 1H-tetrazole-5) Group, substituted with carboxyl and (Ci -C4) alkyloxycarbonyl)}, Rs is hydrogen or —NHR1 c {wherein R1 0 is hydrogen · (C! -C4) alkylfluorenyl, trifluoro (C -A C4) fluorenyl, carbamate, (Ct —C4) alkyloxycarbonyl paper size applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling in this Page) 470741 A7 B7 V. Description of the invention () group, (Ci-Ci) alkylcarbamidine, bis (Cl-c4) alkylcarbamidine, amine (Ci — C4) alkylamino group * (Ci — C4) Alkylamino (Ci_C4) Alkyl * Di (Ci-C4) Alkylamino (Ci-C4) Alkyl Heteroarylfluorenyl is optionally selected from one to two independently selected from hydroxy, (Ci — C4) alkyloxy , Cyano, 1H —tetrazol — 5 —yl, substituted with carboxyl and (Ci -C4) alkyloxycarbonyl substituents or C (NR1 i) NHR12 (where R1 1 and R12 are independently Hydrogen, ethynyl or tertiary monobutoxycarbonyl)); or 114 and R5 are both hydrogen, R3 is an NHR1 0 (where R1 0 is the same as defined above); or R5 is hydrogen and R3 is hydrogen or one (CH2) q R 9 (wherein < 1 and R9 have the same meanings as above), R4 is (Ci-C4) alkyl, and di (

Ci ~C4 )烷基胺基甲基，锨啶一1—基甲基，嗎啉一 4 一基甲基，甲_基，1 一羥基（Ci — C4 )烷基胺基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填寫本頁) 或—CHzNHR1] {其中 RiS 為氫，（Ci 一 C4 >烷基，（Ci -C4 )烷醯基，三氟（Ci — C4 )烷醢基，氨基甲醯，（Ct-Ci)烷基氧基羰基，（Ct —C4 )烷基氨基甲醯，二（Ci 一〇4 )烷基氨基甲騸，胺基（Ci —C4 )烷酿基，（Ci -C4 )烷基胺基 (Ci —C4 )烷醸基*二（Ci -C4 )烷基胺基（Ci -c4 )烷醯基，羧基（Ci - c4 )烷基，（Cjl - C4 ) 烷基氧基羰基（Ci -c4 )烷基•氨基甲醢（Ci —c4 ) 烷基•選自Μ下的基團：芳醮基，雑芳醢基，芳基（Ci -6- 本紙張尺度適用中國國家標準（CNS ) A4規格（210 X 297公釐） 470741 A7 B7 五、發明説明（）經濟部中央標準局員工消費合作社印製一 C 4 ) 烧基和雜芳基 ( C 1 — C 4 ) 烧基 ( 該芳醯基和雜芳醯基 1 芳基和雜芳基選擇性再被一到二個獨立選白羥基 9 ( C ί — C 4 ) 院基氧基 9 鎮基 $ 1 Η — 四唑 — 5 — 基 » 狻基和 ( C 1 一 C 4 ) 烧基氧基羰基的取代基所取代 ) 或 — C ( Ν R 1 1 ) N Η R 1 2 ( 其中 R 1 1 和 R 1 2 定義同上 ) } > R 3 為氫或 — ( C Η Ζ ) q R 9 (其中Q 和 R 9 定義同上 ) 參 R 4 為氫 * ( C 1 — C 4 ) 烷基或 — C ( 0 ) R 1 4 ( 其中 R 1 4 為胺基 > » 羥基 ( C 1 — C 4 ) 焼基氧基 > 2 一 ( 二甲基胺基 ) 乙基胺基 4 —. 甲基哌嗪 — 1 — 基 t 2 一 ( 二甲基胺基 ) 乙基氯硫 » 4 一 ( 甲基磺醯胺基 ) 笨胺基或 1 Η — 四唑 — 5 — 基胺基 ) 1 R 5 為氰基 * 羥基甲基 f 1 Η — 四唑 — 5 — 基 4 » 5 一二氫眯唑 — 2 — 基 * 砒咯烷 — 1 — 基甲基 » # 啶 — 1 一基甲基 > 嗎啉 — 4 — 基甲基 » 哌嗪 — 1 — 基甲基 » 4 — ( C 1 一 C 4 ) 燒基顿嗪 — 1 一基甲基， — C ( 0 ) R ί 4 ( 其中 R 1 4 定義同上 ) » — C ( Ν Η ) Ν R 1 R 1 6 ( 其中 R 1 5 和 R 1 6 個白獨立為氫 » ( C 1 — C 斗 ) 烷基或三氟 ( C 1 — C 4 ) 燒基 ) 或 — C Η 2 Ν R 1 〇 R 1 7 ( 其中 R 1 0 定義同上 9 R X 7 為氫或 ( C 1 — C 4 ) 烷基 ) • 或 R 3 為氫或 — ( C Η Ζ ) q R 9 (其中Q和] R 9 定義同上 ) R 4 和 R 個白獨立為二 ( C 1 一 C 4 ) 烷基胺基甲基 * 呢啶一 1 一基甲基 t 嗎啉 4 一基甲基或羥基甲就 ♦ 密 , (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 470741 A7 _B7___ 五、發明説明（） R6為氫* 2 —羧基乙基，2 —氨基甲醯乙基或2 — (Ci)烷基氣基羰基乙基； R7為氫，吡咯烷一 1 一基甲基，哌啶一 1 —基甲基，嗎啉一 4-基甲基，呢嗪一 1_基甲基，4 - (Ci — C4 )烷基哌嗪一 1—基甲基或一 CH2 NR1 ° R1 7 (其中R10和R1 7定義同上）；和 R8為氫，2 —羧基乙基· 2 —氨基甲醢乙基，2 — (C»— C4)烷基氧基羰基乙基或一 NHR10 (其中 R1 〇定義同上）•，和槩學上可接受鹽’個別異構物和其異構物混合物。本發明另一內容是一藥學組成物，其包括有效治療數董的式I化合物或個別異構物*異構物混合物或其槩學上可接受鹽，Μ及一或多個藥學上可接受賦形劑。本發明的另一内容是一種治療能夠賴由抑制爾治療動物的度巴明卢羥基酶而獲得改菩的疾病的方法，其包括對此動物投與有效治療數量的式I化合物，或個別異構物，異構物混合物，或藥學上可接受鼸或其鹽。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填寫本頁) 本發明另一內容為製備式I化合物的方法，將在"_ 明詳述〃中說明。本發明另一內容係關於式I I化合物：本紙張尺度適用中國國家標準（CNS ) Α4規格（2!ΟΧ297公釐） 470741 A7 B7五、發明説明（其中： η為0 * 1或2 ; t 為 Ο，1 ，2 或 3 ; R1個自獨立為鹵素，羥基或（Ct -C4 )烷基氧基；和 R1 8被接於《 * /3或7位置，且為選自式（d)， (e )和（f )之基團：Ci ~ C4) alkylaminomethyl, pyridin-1-ylmethyl, morpholine 4-ylmethyl, methyl, 1-hydroxy (Ci-C4) alkylamino Printed by the employee consumer cooperative (please read the notes on the back before filling this page) or—CHzNHR1] {where RiS is hydrogen, (Ci-C4 > alkyl, (Ci -C4) alkylfluorenyl, trifluoro (Ci — C4) alkylamino, carbamate, (Ct-Ci) alkyloxycarbonyl, (Ct —C4) alkylcarbamomethane, bis (Ci 104) alkylcarbamomidine, amine (Ci —C4) Alkyl, (Ci -C4) Alkylamino (Ci -C4) Alkyl * Di (Ci -C4) Alkylamino (Ci -c4) Alkyl, Carboxy (Ci-c4) Alkyl, (Cjl-C4) alkyloxycarbonyl (Ci -c4) alkyl • carbamidine (Ci — c4) alkyl • Group selected from M: arylfluorenyl, fluorenylaryl, aryl (Ci -6- This paper size applies to Chinese National Standard (CNS) A4 specifications (210 X 297 mm) 470741 A7 B7 V. Description of the invention () Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 1 C 4)) And heteroaryl (C 1-C 4) alkyl (The arylfluorenyl and heteroarylfluorenyl 1 aryl and heteroaryl are selectively selected by one or two white hydroxyl 9 (C ί — C 4) alkyloxy 9 sulphuryl radicals $ 1 Η — tetrazole — 5 — group »substituted with fluorenyl and (C 1 -C 4) alkenyloxycarbonyl) or — C (NR 1 1) N Η R 1 2 (where R 1 1 and R 1 2 are defined Same as above)} > R 3 is hydrogen or — (C Η AZ) q R 9 (where Q and R 9 have the same definitions as above) R 4 is hydrogen * (C 1 — C 4) alkyl or — C (0) R 1 4 (where R 1 4 is an amine group) »hydroxy (C 1 — C 4) fluorenyloxy group> 2 mono (dimethylamino) ethylamine 4 —. Methylpiperazine — 1 — T 2 mono (dimethylamino) ethyl chlorosulfide »4 mono (methylsulfonamido) benzylamino or 1 Η —tetrazole — 5 —ylamino) 1 R 5 is cyano * hydroxyl Methyl f 1 hydrazone — tetrazol — 5 — radical 4 »5 monodihydrooxazole — 2 — radical * pyrrolidine — 1 — methylmethyl» # pyridine — 1 mono &Gt; morpholine — 4 —methylmethyl »piperazine — 1 — methylmethyl» 4 — (C 1 -C 4) alkynyl — 1 monomethyl, — C (0) R ί 4 ( Where R 1 4 has the same definition as above) — — C (Ν Η) NR R 1 R 1 6 (where R 1 5 and R 1 6 are independently hydrogen) (C 1 — C bucket) alkyl or trifluoro (C 1 — C 4) alkyl) or — C Η 2 NR 1 〇R 1 7 (where R 1 0 has the same definition as above 9 RX 7 is hydrogen or (C 1 — C 4) alkyl) • or R 3 is hydrogen or — (C Η ZO) q R 9 (where Q and R 9 are as defined above) R 4 and R are independently di (C 1 -C 4) alkylaminomethyl * The morpholine 4 monomethyl or hydroxymethyl is dense, (Please read the notes on the back before filling this page) This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) 470741 A7 _B7___ V. Invention Explanation () R6 is hydrogen * 2 -carboxyethyl, 2-carbamoylethyl or 2- (Ci) alkylaminocarbonylethyl; R7 is hydrogen, pyrrolidine-1 Monomethyl, piperidine-l-ylmethyl, morpholine-4-ylmethyl, morphazine-l-ylmethyl, 4- (Ci-C4) alkylpiperazine-l-ylmethyl or 1 CH2 NR1 ° R1 7 (where R10 and R1 7 have the same definitions as above); and R8 is hydrogen, 2-carboxyethyl · 2-carbamoylethyl, 2- (C »—C4) alkyloxycarbonylethyl Or an NHR10 (wherein R10 is the same as defined above), and scientifically acceptable salts' individual isomers and mixtures of isomers thereof. Another aspect of the present invention is a pharmaceutical composition comprising a compound of formula I or an individual isomer * isomer mixture or a pharmaceutically acceptable salt thereof, which is effective for treating several groups, M and one or more pharmaceutically acceptable excipient. Another aspect of the present invention is a method for treating a disease that can be modified by inhibiting the treatment of dobaminlu hydroxylase in an animal, which comprises administering to the animal a therapeutically effective amount of a compound of formula I, or an individual Structure, isomer mixture, or pharmaceutically acceptable hydrazone or a salt thereof. Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the notes on the back before filling this page). Another aspect of the present invention is a method for preparing a compound of formula I, which will be described in " Another aspect of the present invention is related to the compound of formula II: The paper size is applicable to the Chinese National Standard (CNS) A4 specification (2.0 × 297 mm) 470741 A7 B7 V. Description of the invention (where: η is 0 * 1 or 2; t is 〇, 1,2, or 3; R1 is independently halogen, hydroxyl or (Ct-C4) alkyloxy; and R1 is connected to the "* / 3 or 7 position, and is selected from formula (d), (e) and (f) groups:

〔d〕 (e) 〔f〕 (請先閱讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製其中： R2 0為氫，R1 9為氫或一(CH2 ) qR {其中q 為 0，1*2，3或4，119為羧基，（Ct—CU)烷基氧基羰基*氨基甲_或選自芳基和雜芳基之基團（該基團選擇性再被一到二個獨立選自羥基，（Cv-CU)烷基氧基，氰基，1— Η —四唑-5_基，羧基和（Ci -C4 )烷基氧基羰基之取代基所取代）），R2 1為一 N R 2 R 2 6 (其中R25為氫或（Cx—CU)烷基，R 2 6為L—丙氨醯，L 一精氨酿，L 一門冬醢，L 一 α-門冬氨醢，L — /3 —門冬氨醢，L 一半胱氨醯，L 一谷醸氨基，L — α —谷醯基，L — 7 —谷瞳基，Ν - (Ci - -9- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 470741 A7 B7 五、發明説明（） C4 )烷醣基一 L — α_谷醢基，N - （Ci 一04 )烷酿基一 L — 7 -谷醢基，甘氛酸基，L 一組氨醢· L 一異白氨醢，L —白氨醢· L 一賴氨醢，L 一蛋氨醢，L 一鳥氨酸基，L —苯基丙氨醢，L 一脯氨醣，L 一絲氨醢，L —蘇氨醢，L —色氨醢，L 一胳氨醢，L-纈氨醢，1 — 胺基一環丙基羰基，1 一胺基環己基羰基）；或只2<)和 R2 1 均為氫，R1 9 為一 NR2 5 R2 6 (其中 R2 5 和R26定義同上）：或R2 1為氫，R19為氫或一（ C Η 2 ) qR 9 (其中Q和R9定義同上），R20為 -CHz NR2 5 R2 6 (其中R2 5和R2 6定義同上 );或尺19為氫或一（0^12)91^9 (其中q和R9定義同上）· R2 0為氫，（Ci —C4 )烷基或一 C (0 )R 1 4 (其中R14為胺基，羥基（Ci _C4 )烷基氧基，2 — （二甲基胺基）乙基胺基，4 一甲基锨嗪一1 一基·2_ (二甲基胺基）乙基氫硫，4 —(甲基磺醢胺基）笨胺基或1 Η —四唑一 5 —基胺基）和R2 1為 -CHz NR2 5 R2 6 (其中R2 S和R2 6定義同上經濟部中央標準局員工消費合作社印製 (請先閲讀背面之注意事項再填寫本頁) );R2 2為氫· 2 —羧基乙基，2 —氨基甲醢乙基或2 -(Ci -C4 )烷基氧基羰基乙基；〔D〕 (e) 〔f〕 (Please read the notes on the back before filling out this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs: R2 0 is hydrogen, R1 9 is hydrogen or one (CH2) qR { Where q is 0,1 * 2,3 or 4,119 is carboxyl group, (Ct-CU) alkyloxycarbonyl * carbamoyl group or group selected from aryl and heteroaryl group (the group is Substituted by one or two substituents independently selected from hydroxy, (Cv-CU) alkyloxy, cyano, 1-fluoren-tetrazol-5-yl, carboxyl and (Ci-C4) alkyloxycarbonyl (Replacement)), R2 1 is a NR 2 R 2 6 (where R25 is hydrogen or (Cx-CU) alkyl, R 2 6 is L-alanine, L-arginine, L-asparagus, L- α-Aspartate, L — / 3 —Aspartate, L Cysteine, L-Glutamine, L — α —Glutyl, L — 7 —Glutyl, N-(Ci--9 -This paper size is in accordance with Chinese National Standard (CNS) A4 (210X297 mm) 470741 A7 B7 V. Description of the invention () C4) Alkanyl — L — α_glutaryl, N — (Ci — 04) Alkanyl — L — 7 -glutamyl, glycine, L a group of aminoamidine · L a Leucine, L-Leucine · L-Lysine, L-Methionine, L-Ornithine, L-Phenylalanine, L-Proline, L-Serine, L- Threonine, L-tryptamine, L-aminopyridine, L-valinine, 1-amino-cyclopropylcarbonyl, 1-aminocyclohexylcarbonyl); or only 2 <) and R2 1 are both Hydrogen, R1 9 is NR2 5 R2 6 (where R2 5 and R26 are the same as defined above): or R2 1 is hydrogen, R19 is hydrogen or one (C Η 2) qR 9 (where Q and R9 are defined as above), and R20 is- CHz NR2 5 R2 6 (where R2 5 and R2 6 are defined as above); or rule 19 is hydrogen or one (0 ^ 12) 91 ^ 9 (where q and R9 are defined as above) · R2 0 is hydrogen, (Ci —C4) Alkyl or mono-C (0) R 1 4 (where R14 is amine, hydroxy (Ci_C4) alkyloxy, 2- (dimethylamino) ethylamino, 4-methylpyrazine-1 1- (2-dimethylamino) ethylhydrosulfide, 4- (methylsulfonamido) benzylamino or 1 (-tetrazol-5-ylamino) and R2 1-CHz NR2 5 R2 6 (where R2 S and R2 6 have the same definitions as above printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the notes on the back first) Then fill page)); R2 2 is hydrogen · 2 - carboxyethyl, 2 - carbamoyl Dukes ethyl or 2 - (Ci -C4) alkyloxycarbonyl group;

Rz 3 為一 CHz R2 5 R2 6 (其中 Rz s 和只2 6定義同上）；和 R24 為一NR2 5 R2 6 (其中 R2 5 e 定義同上）；和藥學上可接受鹽，個別異構物和其異構物混 -10- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 470741 A7 ___B7___五、發明説明（）合物。本發明另一内容是一藥學組成物，其包括有效治療數量的式I I化合物或個別異構物，異構物琨合物或其藥學上可接受鹽，Μ及一或多個藥學上可接受賦形劑。本發明的另一內容是一種治療能夠藉由抑制餺要治療的動物的度巴明；8羥基酶而獲得改善的疾病的方法，其包括對此動物投與有效治療數躉的式I I化合物，或個別異構物，異構物混合物·或藥學上可接受鹽或其鹽。本發明另一内容為製備式I I化合物的方法*將在〃發明詳述"中說明。本發明係關於一種式III化合物 (請先閱讀背面之注意事項再填寫本頁) .桨.Rz 3 is a CHz R2 5 R2 6 (where Rz s and only 2 6 are as defined above); and R24 is a NR2 5 R2 6 (where R2 5 e is as defined above); and pharmaceutically acceptable salts, individual isomers and Its isomers are mixed -10- This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) 470741 A7 ___B7___ V. Description of the invention () Compound. Another aspect of the present invention is a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula II or an individual isomer, an isomer complex or a pharmaceutically acceptable salt thereof, M and one or more pharmaceutically acceptable excipient. Another aspect of the present invention is a method for treating a disease that can be improved by inhibiting tobamin; 8-hydroxylase in an animal to be treated, which comprises administering to the animal a compound of formula II that is effective in treating several tadpoles, Or individual isomers, isomer mixtures, or pharmaceutically acceptable salts or salts thereof. Another aspect of the present invention is a method for preparing a compound of formula II, which will be described in 〃 Detailed Description of the Invention ". This invention relates to a compound of formula III (please read the notes on the back before filling this page).

,1T, 1T

經濟部中央標準局員工消費合作社印製其中： η為Ο，1或2 ; t 為 Ο · 1 ，2 或 3 ; R1個自獨立為鹵素，羥基或（C^ _C4 )烷基氧基；和 R2 7被接於α，/8或7位置，且為選自式（g)， (h )和（i )之基囿： -11- 本紙張^度適用中國國家標準（〇呢）厶4規格（210父297公釐） 470741 A7 B7 五、發明説明（）Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs where: η is 0, 1 or 2; t is 0 · 1, 2, or 3; R1 is independently halogen, hydroxy, or (C ^ _C4) alkyloxy; and R2 7 is connected to the α, / 8 or 7 position and is a base selected from the formulas (g), (h) and (i): -11- This paper is compliant with the Chinese National Standard (〇呢) 厶 4 Specifications (210 father 297 mm) 470741 A7 B7 V. Description of the invention ()

經濟部中央標準局員工消費合作社印製 (g) U) ( ：i) 其中 : R 4 為氳 t R 5 為氫或 — Ν Η R 1 0 { 其中 R 1 0 為 m » ( C 1 一 C 4 ) 焼醒基 % 三氣 ( C 1 — C 4 ) 烷醯基 9 氨基甲醒 » ( C X — C 4 ) 烷基氧基撕欺基 > ( C i — C 4 ) 焼基氨基甲豳 » 二 ( C Ϊ — C 4 ) 烷基氨基甲趣 f 胺基 ( C 1 — C 4 ) 烷醯基 t ( C 1 — C 4 ) 焼基胺基 ( C 1 一 C 4 ) 烷醯基 • 二 ( C 1 — C 4 ) 烷基胺基 ( C 1 — C 4 ) 焼醢基 9 選白芳醱基和雜芳醢基 ( 該芳釅基和雜芳豳基選擇性再被 -~- 到二個獨立選 i 羥基 > ( C 1 — C 4 ) 焼基氧基 $ 氰基 % 1 Η — 四唑 — 5 — 基 » 羧基和 ( C 1 — C 4 ) 燒基氧基羰基的取代基所取代 ) 或 — C ( N R 1 1 ) N Η R 1 2 ( 其中 R 1 1 和 R 1 Z 個白獨立為氫 * 乙醢基或三級 — 丁氧基羰基 ) } 或 R 5 為 t=t 置 R 4 為 ( C 1 — C 4 ) 烷基 > 二 ( C 1 — C 4 ) 烷基胺基乙基 » 呢啶 — 1 — 基甲基 » 嗎啉 — 4 一基甲基 % 1 — 羥基 ( C 1 — C 4 ) 烷基或 — C Η 2 N Η R 1 3 { 其中 R 1 3 為氩 9 ( C 1 一 C 4 ) 燒基 t ( C 1 — C 4 ) 焼醯基 t 三鼠 ( C — C 4 ) 烷騙基 $ 氨基甲醢 9 ( C X — C 4 ) 焼基氧基羰基 t ( C 1 — C 4 ) 烧基氨基甲 ahet 酾 » 二 ( C 1 — C 4 ) 烷基氨基甲釅 9 胺基 ( C 1 — C 4 ) 烷醯基 » ( C 1 一 C 4 ) 焼基胺基 ( C 1 一 C 4 ) 燒醒基，二 ( C 1 — C 4 ) 燒 -12- (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 470741 經濟'部中央標準局員工消費合作社印製 A7 B7五、發明説明（）基胺基（Ci —c4 )烷豳基•羧基（Cx —c4 )烷基，（Ci -c4 )烷基氧基羰基（Ci _C4 )烷基，氨基甲醯（Ci _C4 )烷基*選自Μ下的基围：芳醢基，雜芳酿基，芳基（C^ 一〇4 )烷基和雑芳基（Ci 一 c4 )烷基（該芳醃基和雜芳醢基，芳基和雜芳基選擇性再被一到二個獨立選自羥基· （Ci — C4 )烷基氧基，氰基，1H -四唑一 5_基，羧基和（Ci _C4 )烷基氧基羰基取代基的取代基所取代）或一C (NR11) N H R 1 2 (其中R1 1和R12定義同上）};或尺4為氫，（Ci-Ci)烷基或一C(0)R14 (其中 R1 4為胺基，羥基（Ci _C4 )烷基氧基，2 —(二甲基胺基）乙基胺基，4 一甲基顿啶一1 一基，2 — （二甲基胺基）乙基氫硫，4一（甲基磺醯胺基）笨胺基或1H — 四唑一 5 —基胺基），R5為羥基甲基，1H —四唑一5 一基，4，5 —二氫眯唑一 2 —基*吡咯烷一 1 一基甲基，哌啶一1 -基甲基，嗎啉一4 —基甲基，呢嗓-1 -基甲基，4 一（Ci 一04)烷基哌嗪一1—基甲基， -C ( 0 ) R 1 4 (其中 R14 定義同上），一 C (NH )N R 1 5 R 1 6 (其中R1 5和R1 6個自獨立為氫， (Ci 一 C4 )烷基或三氟（Ct —CU )烷基）或 -CH2NR10R17 (其中 R1 0 定義同上，R1 7 為氫或（Ci -C4 )烷基）；或114和Rs個自獨立為二（Ci 一〇4 )烷基胺基甲基*哌啶一 1 一基甲基，嗎 -13- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） (請先閱讀背面之注意事項再填寫本頁) 470741 Α7 Β7 經濟部中央標準局員工消費合作社印製五、發明説明（）啉一4一基甲基或羥基甲基； R6為氬，2 —羧基乙基，2 —氨基甲醸乙基或2 — (Ci — C4 )烷基氧基羰基乙基； R7為Μ，毗咯烷一 1 一基甲基，呢啶一1一基甲基，嗎啉一 4_基甲基，顿嗓一 1 一基甲基*4 - (Ct-C4 )烷基锨嗪一 1-基甲基或一 CH2 NR10 R1 7 (其中R10和R1 7定義同上），•和 R2 8為（C2 _C6 )烷基{該烷基再被一到二個獨立選自—N (R29)2 ，— C (0) 〇R3〇，一 p 0 ( 0 R 3 0 ) 2 « - S 0 a R 3 0 · - S 0 2 N H R 3 0和一 OR3 〇 (其中每個R2 9獨立為氫，乙醣基或三氟乙豳基，每個R3 0嫌立為氫或（Ci —Cs )烷基）的取代基所取代};和藥學上可接受鹽，個別異構物和其異構物混合物。本發明另一內容是一藥學組成物•其包括有效治療數量的式III化合物或個別異構物•異構物混合物或其蕖學上可接受盥，Μ及一或多個藥學上可接受賦形劑。本發明的另一內容是一種治療能夠改良動物度巴明/3 羥基酶受抑制情況的方法*其包括對此動物投與有效治療數量的式I I I化合物，或個別異構物•異構物混合物，或藥學上可接受鹽或其鹽。本發明另一內容為製備式III化合物的方法*將在〃發明詳述〃中說明。 -14- .111 I ! n Ί I I (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標率（CNS ) A4規格（210X297公釐〉 470741 A7 B7 經濟部中央標準局員工消費合作社印製五、發明説明（）本發明另一內容是下式化合物：Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (g) U) (: i) where: R 4 is 氲 t R 5 is hydrogen or — Ν Η R 1 0 {where R 1 0 is m »(C 1-C 4) Alkyl% tris (C 1 —C 4) Alkyl 9 carbamate »(CX — C 4) Alkyloxytyl > (C i — C 4) Alkyl carbamate »Di (C Ϊ — C 4) Alkylcarbamate f Amino (C 1 — C 4) Alkyl t (C 1 — C 4) Alkylamino (C 1-C 4) Alkyl Di (C 1 —C 4) alkylamino (C 1 —C 4) fluorenyl 9 is selected from white arylfluorenyl and heteroarylfluorenyl (the arylfluorenyl and heteroarylfluorenyl groups are selectively To two independently selected hydroxyl groups (C 1 — C 4) fluorenyloxy $ cyano% 1 fluorenyl — tetrazol — 5 —yl »substitution of carboxyl and (C 1 — C 4) alkyloxycarbonyl Substituted) or — C (NR 1 1) N Η R 1 2 (where R 1 1 and R 1 Z are independently hydrogen —Butoxycarbonyl)} or R 5 is t = t and R 4 is (C 1 —C 4) alkyl > bis (C 1 —C 4) alkylaminoethyl »morphine — 1 — Methyl »morpholine — 4-monomethyl% 1 — hydroxy (C 1 — C 4) alkyl or — C Η 2 N Η R 1 3 {where R 1 3 is argon 9 (C 1-C 4) T (C 1 — C 4) fluorenyl t tris (C — C 4) alkyl carbamoyl 9 (CX — C 4) fluorenyloxycarbonyl t (C 1 — C 4) alkyl Carbamate 酾 »Di (C 1 — C 4) Alkyl Carbamate 9 Amine (C 1 — C 4) Alkyl» »(C 1-C 4) Alkamino (C 1-C 4) Burning base, two (C 1 — C 4) burning -12- (Please read the precautions on the back before filling this page) This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) 470741 Ministry of Economy Printed by the Consumer Standards Cooperative of the Central Bureau of Standards A7 B7 V. Description of the invention ) Alkyl, carbamate (Ci_C4) alkyl * selected from the group consisting of: arylfluorenyl, heteroaryl, aryl (C ^ 104) alkyl, and fluorenyl (Ci_c4) Alkyl (the aryl pickling and heteroarylfluorenyl, aryl and heteroaryl are optionally selected from one to two independently selected from hydroxyl · (Ci — C4) alkyloxy, cyano, 1H-tetrazole 5-yl, carboxyl and (Ci_C4) alkyloxycarbonyl substituents) or a C (NR11) NHR 1 2 (where R1 1 and R12 have the same meanings as above)}; or Chi 4 is hydrogen, ( Ci-Ci) alkyl or mono-C (0) R14 (where R1 4 is amine, hydroxy (Ci_C4) alkyloxy, 2- (dimethylamino) ethylamino, 4-methylton) Pyridine-1, 2- (dimethylamino) ethylhydrosulfide, 4-((methylsulfonamido) benzylamino or 1H-tetrazol-5-ylamino), R5 is hydroxymethyl 1H-tetrazol-5-yl, 4,5-dihydroxazol-2-yl * pyrrolidine-1 1-ylmethyl, piperidine 1-ylmethyl, morpholine 4-4-methyl -1, 2-methyl, 4- (Ci-04) alkylpiperazine-1-methyl, -C (0) R 1 4 (where R14 is Synonymous with the above), a C (NH) NR 1 5 R 1 6 (wherein R1 5 and R1 6 are independently hydrogen, (Ci-C4) alkyl or trifluoro (Ct-CU) alkyl) or -CH2NR10R17 ( Where R1 0 is the same as defined above, and R1 7 is hydrogen or (Ci -C4) alkyl); or 114 and Rs are independently bis (Ci-10) alkylaminomethyl * piperidine-1 1-methyl -13? This paper size is in accordance with Chinese National Standard (CNS) A4 (210X297 mm) (Please read the notes on the back before filling out this page) 470741 Α7 Β7 Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Description of the invention () Phenyl-4-methyl or hydroxymethyl; R6 is argon, 2-carboxyethyl, 2-carbamoylethyl or 2- (Ci-C4) alkyloxycarbonylethyl; R7 Is M, pyrrolidine- 1-ylmethyl, oxidine- 1-ylmethyl, morpholine- 4-ylmethyl, oxo- 1-ylmethyl * 4-(Ct-C4) alkyl 锨Azine 1-ylmethyl or CH2 NR10 R1 7 (where R10 and R1 7 have the same definitions as above), and R2 8 are (C2_C6) alkyl {The alkyl group is independently selected from one or two -N ( R29) 2, — C (0) 〇 R3〇, a p 0 (0 R 3 0) 2 «-S 0 a R 3 0 ·-S 0 2 NHR 3 0 and one OR3 〇 (where each R2 9 is independently hydrogen, ethylglycosyl or trifluoroacetamidine, each R3 0 It is substituted with a substituent of hydrogen or (Ci-Cs) alkyl); and pharmaceutically acceptable salts, individual isomers and mixtures of isomers thereof. Another aspect of the present invention is a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula III or an individual isomer Shape agent. Another aspect of the present invention is a method for improving the inhibition of dobamin / 3 hydroxylase in an animal *, which comprises administering to the animal an effective therapeutic amount of a compound of formula III, or an individual isomer / isomer mixture , Or a pharmaceutically acceptable salt or a salt thereof. Another aspect of the present invention is a method for preparing a compound of formula III * which will be described in "Detailed Description of the Invention". -14- .111 I! N Ί II (Please read the notes on the back before filling in this page) This paper size applies to China National Standards (CNS) A4 specifications (210X297 mm) 470741 A7 B7 Employees of the Central Standards Bureau of the Ministry of Economic Affairs Printed by a consumer cooperative V. Description of the invention () Another aspect of the present invention is a compound of the following formula:

也就是（S) -5 * 7-二氣一 1 ，2，3，4 一四氩一萘一 2 —基胺。本發明的另一内容是製備（S) -5，7-二氟一 1 ，2，3，4 一四氫一萘一 2 —基胺的方法，將在"發明詳述"中說明。發明詳述定義此處所用者：〃烷基〃意指直鏈或支鏈飽和烴基•其含1到設定的碳原子數（例如（Ci -C4 )烷基，包括甲基*乙基，丙一 1—基，丙—2 —基，丁 —. 1—基，丁一 2 —基，2 一甲基丙基和1，1 一二甲基乙基）。 Λ三氟烷基#意指上述定義烷基含一到設定碳原子數者，其中含有三氟甲基（例如三氟（Ci _C4 )烷基包括三氟甲基，2，2，2 —三氟乙基，3，3，3 —三氟丙基一 1—基，1 ，1 ，1 一三氟两一 2 —基等）0 #烷基氧基〃意味一 OR，其中R為含一到設定碳原子數目的烷基（例如（Ci -C4 )烷基氧基包括甲氧基 -15- (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 470741 經濟部中央標準局員工消費合作社印製 A7 B7五、發明説明（），乙氧基，丙一 1一基氧基，丙一 2 —基氧基，丁一 1 — 基氧基，丁一 2 —基氧基，2 —甲基丙一 1 一基氣基和2 一甲基丙一2—基氧基）。〃芳基"，如同在芳基或芳基（Ci 一 C4 )烷基中者，意味衍生自含6到1 4個碳原子的芳番糸烴有機基，包括單環或稠合碳環芳番環（例如苯基，萘基，想基•菲憩基等），遘擇性再被一到二個獨立的鹵素和氣基所取代〇 ''芳醢基〃意指一 C (0) R，其中R為如上所述的芳基（例如苯釀基等）。 "雜芳基〃如同在雜芳基或雜芳基（Ci _C4 )烷基中，意指衍生自含5到1 4個原子芳白烴的有機基，其中1到5個為選自N，0或S的雜原子，包括單環，稠合雑環和稠合碳環和雜瓌芳番環（例如噻嗯基，呋喃基，吡咯基，哦啶基，異噁唑基，噁唑基，吲哚基，笨並[b〕噻嗯基，異笨並呋喃基，嘌呤基，異喹咐基，蝶啶基，白啶基，咪唑基，吡啶基，吡唑基，吡嗪基等），選擇性再被一到二個獨立選自齒素和氰基取代基所取代。 "雜芳醯基〃意味一C (0) R，其中R為同上定義的雜芳基（例如菸醢胺*2 —呋喃醯基，皮考豳基等）。〃氨基甲醯"在氨基甲釀，（Ci — C4 )烷基氨基甲醢，二（Ci -C4 )烷基氨基甲醣或氨基甲酿（Ct 一C4)烷基意指肢基羰基。 -16- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） (請先閲讀背面之注意事項再填寫本頁) 470741 Α7 Β7 經濟部中央標隼局員工消費合作社印製五、發明説明（） "烷醯基"意指含一到設定碳原子數的一c (0> R (例如甲醢基，乙醯基，丙豳基，丁醢基等）。〃鹵素〃意指氟，氣或澳。〃離去基〃係與傳統合成有機化學有闞聯，也就是在烷基化條件下可被置換的原子或基團，包括鹵素和鰱烷磺醢氧基或砷磺醢氧基•例如甲磺醃氧基，乙烷磺醯氧基，笨磺醢氧基，三氟甲烷磺豳氧基和甲笨磺醢氧基和類似物 0 〃動物〃包括人類*非人類哺乳動物，例如狗，貓* 兔，牛，馬，羊，豬和鹿和非哺乳動物，例如鳥和類似者 0 w疾病〃特定包括動物或其任何部位的任何不健康狀況，K及由對動物所進行發療或動物治療所造成或者間接造成不健康狀況，例如此類治療造成的副作用。〃藥學上可接受〃意指可用於製備大致上安全、無骞性且無生物學上或其它不欲的效應的藥學組成物，包括可被動物學上Μ及人類藥學用途接受者。 "藥學上可接受鹽〃意指藥學上可接受（如Μ上所述 )且具備所要的蘖理活性者。此鹽類包括與無機酸形成的酸加成鹽，無機酸例如氫氯酸*氫溴酸，硫酸，硝酸，磷酸和類似物；或者與有機酸所形成者，有機酸例如甲酸，乙酸，丙酸，己酸，庚酸，環戊烷丙酸，乙酵酸，丙_酸，乳酸，丙二酸，琥珀酸，蘋果酸，順丁烯二酸，反丁烯 -17- 1¾本 I I 訂 n n'" (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐〉 470741 經濟部中央標準局員工消費合作社印製 A7 B7五、發明説明（）二酸，酒石酸*擰檬酸，苯甲酸，鄰一（4一羥基苯甲醸基）苯甲酸，肉桂酸，苯乙醇酸，甲烷磺酸*乙烷磺酸， 1，2 -乙烷磺酸，2 —羥基乙烷磺酸•苯磺酸，對一氯苯磺酸，2 —萘磺酸，甲苯磺酸，樟腦磺酸* 4 一甲基二環〔2 · 2 . 2〕辛一 2 —烯_1 一羧酸，葡庚耱酸，4 •4' 一甲撐雙（3 —羥基_2 —烯~1—羧酸）*3 — 苯基丙酸，三甲基乙酸*三級丁基乙酸，月桂硫酸，葡萄酸，谷氨酸，羥基萘酸·水楊酸*硬脂酸，黏庚酸和類似物。藥學上可接受強也包括鹼加成鼸*其係形成於酸性質子能夠與無機或有機鹸反應者。可接受的無機鹼包括氬氧化納，碳酸納，氫氧化鉀，氫氧化鋁和氫氧化鈣。可接受的有機鹼包括乙酵胺，二乙醇胺，三乙醇胺，卓甲胺，N —甲基葡萄胺和類似物。〃治療有效數董#意指投與動物治療疾病的數量足Μ 得到此類治療疾病的效果者。 "治療〃意指任何治療哺乳動物疾病者•包括 (1)預防疾病•亦即使疾病臨床症狀不再發展下去； (2>抑制疾病·亦即控制臨床症狀的發展；和/或 (3)減輕病情，亦即減輕臨床症狀。式I化合物中R3 ，RS或R8為胺基或其中R4 ， R5或R7為胺基甲基者可與胺基酸反應而得到式I I化合物。合適的胺基酸包括L 一丙氨酸，L 一精氨酸* L- -18- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） (請先閱讀背面之注意事項再填寫本頁) 470741 A7 B7 經濟部中央標準局員工消費合作社印製五、發明説明（）門冬酸，L-門冬氨酸，L 一半眯氨酸，L —谷醢第酸* 甘氨酸，L 一姐氨酸，L 一異白氨酸，L 一白氨擊，L — 賴氨酸，L 一蛋氨酸· L_鳥氨酸· L 一苯基丙氨酸* L 一脯氨酸，L —絲氨酸，L 一蘇氨酸，L —色氨酸· L 一酪氨酸或L 一纈氛酸，非對掌中心環胺基酸例如為1 一胺基一 1 一環丙基羧酸，1—胺基一1環丁烷羧酸· 1 一胺基一 1 一環戊烷羧酸（環白氨酸）或1 一胺基_1 一瑭己烷羧酸。胺基酸基賦予分子親水性性質•親水性促進分子的水溶解度。醣胺鍵結接蕃在活體内的蛋白質分子作用中被切斷。因此，式II化合物為式I中R3 ，RS或R8 為胺基或其中R4 ，R5或R7為胺基甲基者的水溶性前藥劑。式I化合物中，R6或R8為氫者可與獨立選自下列一到二取代基所取代的烷基反應而形成二硫鍵结： -N ( R 2 9 ) 2 · - C (0) 0 R 3 〇 . - P 〇 ( 0 R 3 〇 ) 2 * - S 0 3 R 3 ° ，一 S02NHR3O 和一0R3 0 ，其中每個R2 9獨立為氫，乙醢基或三氣乙醸基•每個 R3 °獨立為氫或<C, _Cs )烷基。被取代的烷基賦予分子親水性性質，親水性促進分子的水溶解度。二硫鍵结接著在活體內的化學，酵素或代謝酯形成作用中被切斷。因此•式I I I化合物為式I化合物中R3 ，R5或 Rv為氫者的水溶性前劑。式I ，I I和I I I化合物為笨並環烷基唑硫酮衍生 -19- (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS〉A4规格（210X29?公釐〉 470741 A7 B7 五、發明説明（）物，其中分子的笨並環烷基部份為下式That is (S) -5 * 7-digas-1,2,3,4-tetra-argon-naphthalene-2-ylamine. Another aspect of the present invention is a method for preparing (S) -5,7-difluoro-1,2,3,4-tetrahydro-naphthalene- 2-ylamine, which will be described in " Detailed Invention " . Detailed description of the invention Definitions As used herein: "Alkyl" means a straight or branched chain saturated hydrocarbon group containing 1 to a specified number of carbon atoms (eg, (Ci -C4) alkyl, including methyl * ethyl, propyl 1-yl, propan-2-yl, butyl-. 1-yl, butan-2-yl, 2-methylpropyl and 1,1-dimethylethyl). ΛTrifluoroalkyl # means the above definition of alkyl groups containing one to a set number of carbon atoms, which contains trifluoromethyl (for example, trifluoro (Ci_C4) alkyl includes trifluoromethyl, 2,2,2-tri Fluoroethyl, 3,3,3-trifluoropropyl-1-yl, 1,1,1, trifluorotwo-one 2-yl, etc.) 0 # alkyloxy〃 means an OR, where R is a To set the number of carbon atoms alkyl (such as (Ci -C4) alkyloxy including methoxy-15- (Please read the precautions on the back before filling this page) This paper size applies Chinese National Standard (CNS) A4 Specifications (210X297 mm) 470741 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (), ethoxy, propanyl 1-yloxy, propanyl 2 —yloxy, butan 1 — Alkoxy, butan-2-yloxy, 2-methylpropanyl-l-yloxy and 2-methylpropan-2-yloxy). 〃Aryl ", as in aryl or aryl (Ci-C4) alkyl, means derived from an aromatic arylene hydrocarbon group containing 6 to 14 carbon atoms, including monocyclic or fused carbocyclic Aromatic rings (such as phenyl, naphthyl, phenanthrene, phenanthrene, etc.) are optionally substituted with one or two independent halogen and alkyl groups. `` Arylpyridyl '' means a C (0) R, where R is an aryl group as described above (for example, benzoyl, etc.). " Heteroaryl, as in heteroaryl or heteroaryl (Ci_C4) alkyl, means an organic group derived from an aromatic white hydrocarbon containing 5 to 14 atoms, of which 1 to 5 are selected from N , 0 or S heteroatoms, including monocyclic, fused fluorene and fused carbocyclic and heterofluorene aromatic rings (such as thienyl, furyl, pyrrolyl, oxidyl, isoxazolyl, oxazole , Indolyl, benzo [b] thienyl, isobenzofuranyl, purinyl, isoquinyl, pteridinyl, white pyridyl, imidazolyl, pyridyl, pyrazolyl, pyrazinyl, etc.) The selectivity is further substituted by one or two substituents independently selected from the group consisting of halide and cyano. " Heteroarylfluorenyl group means a C (0) R, where R is a heteroaryl group as defined above (e.g. nicotinamide * 2-furylfluorenyl, picolinyl, etc.). "Carbamate" In Carbamate, (Ci-C4) alkylaminoformamidine, di (Ci-C4) alkylcarbamose or carbamate (Ct-C4) alkyl means limb carbonyl. -16- This paper size is in accordance with Chinese National Standard (CNS) A4 (210X297 mm) (Please read the notes on the back before filling this page) 470741 Α7 Β7 Printed by the Consumers' Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs Explanation () " Alkyl group " means a c (0 > R (e.g. methyl, ethyl, propyl, propyl, butyl, etc.) containing one to a set number of carbon atoms. "Halogen" means fluorine气 Leaving group is linked to traditional synthetic organic chemistry, that is, atoms or groups that can be replaced under alkylation conditions, including halogen and sulfanylsulfonyloxy or arsenylsulfonium Oxygen • For example, mesylate, ethanesulfonyloxy, benzylsulfonyloxy, trifluoromethanesulfonyloxy and methylbenzylsulfonyloxy and the like. 0 Animals include humans * non-human mammals Animals, such as dogs, cats * rabbits, cows, horses, sheep, pigs and deer and non-mammals, such as birds and the like 0 Diseases specifically include any unhealthy condition of the animal or any part of it, K and Unhealthy condition caused by hair or animal treatment Such as side effects caused by such treatments. "Pharmaceutically acceptable" means a pharmaceutical composition that can be used to prepare a drug that is generally safe, non-toxic, and free of biological or other undesired effects. Accepters of human pharmaceutical use. &Quot; Pharmaceutically acceptable salts " means those that are pharmaceutically acceptable (as described above) and have the desired physiological activity. Such salts include acid addition salts with inorganic acids, Inorganic acids such as hydrochloric acid * hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or those formed with organic acids such as formic acid, acetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, Acetic acid, propionic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumarate-17- 1¾ this II order n n '" (Please read the precautions on the back before (Fill in this page) This paper size applies Chinese National Standard (CNS) A4 specifications (210X297 mm> 470741 Printed by A7 B7, Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention () Diacid, tartaric acid * citric acid, benzene Formic acid, o- (4-hydroxybenzene Formamyl) benzoic acid, cinnamic acid, phenylglycolic acid, methanesulfonic acid * ethanesulfonic acid, 1,2-ethanesulfonic acid, 2-hydroxyethanesulfonic acid • benzenesulfonic acid, p-chlorobenzenesulfonic acid , 2-naphthalenesulfonic acid, toluenesulfonic acid, camphorsulfonic acid * 4 monomethylbicyclo [2 · 2. 2] octan-2-ene-1 monocarboxylic acid, glucoheptanoic acid, 4 • 4 'monomethyl Bis (3-hydroxy_2-ene ~ 1-carboxylic acid) * 3-Phenylpropionic acid, trimethylacetic acid * tertiary butylacetic acid, lauric acid, grape acid, glutamic acid, hydroxynaphthoic acid · water Salicylic acid * stearic acid, mucoheptanoic acid, and the like. Pharmaceutically acceptable strong also includes base addition hydrazones * which are formed in acidic protons capable of reacting with inorganic or organic hydrazones. Acceptable inorganic bases include sodium argon oxide, sodium carbonate, potassium hydroxide, aluminum hydroxide, and calcium hydroxide. Acceptable organic bases include acetaminol, diethanolamine, triethanolamine, tromethamine, N-methylglutamine, and the like. 〃Treatment Effective Number Dong # means that the number of animals treated with the disease is sufficient to obtain the effect of treating such diseases. " Treatment means any person who treats mammalian disease, including (1) preventing disease, even if the clinical symptoms of the disease no longer develop; (2 > suppressing the disease, that is, controlling the development of clinical symptoms; and / or (3) Relieve the disease, that is, reduce the clinical symptoms. Compounds of formula I where R3, RS or R8 are amine groups or where R4, R5 or R7 are aminomethyl groups can be reacted with amino acids to obtain compounds of formula II. Suitable amino groups Acids include L-alanine, L-arginine * L- -18- This paper size applies Chinese National Standard (CNS) A4 (210X297 mm) (Please read the precautions on the back before filling this page) 470741 A7 B7 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs. 5. Description of the invention () Aspartic acid, L-aspartic acid, L-haloperine, L-glutamic acid * glycine, L-alanine, L-isoleucine, L-white ammonia, L-lysine, L-methionine · L_ ornithine · L-phenylalanine * L-proline, L-serine, L-threonine L-tryptophan · L-tyrosine or L-valeric acid, non-palladium cyclic amino acids such as 1- Amino-1 Cyclopropylcarboxylic acid, 1-Amino-1 Cyclobutanecarboxylic acid · 1Amino-1 Cyclopentanecarboxylic acid (cycloleucine) or 1Amine_1-Heptane Carboxylic acid. Amino acid group imparts hydrophilic properties to the molecule. • Hydrophilicity promotes the water solubility of the molecule. The glycosylamine bond is cut off by the action of protein molecules in the living body. Therefore, the compound of formula II is R3 in formula I. RS or R8 is an amine group or a water-soluble prodrug in which R4, R5 or R7 is an aminomethyl group. In the compound of formula I, R6 or R8 is hydrogen and may be substituted with independently selected Alkyl groups react to form disulfide bonds: -N (R 2 9) 2 ·-C (0) 0 R 3 〇.-P 〇 (0 R 3 〇) 2 *-S 0 3 R 3 °, -S02NHR3O And a 0R3 0, where each R2 9 is independently hydrogen, ethenyl or tris (2,3) ethionyl. Each R3 ° is independently hydrogen or < C, _Cs) alkyl. The substituted alkyl group imparts hydrophilic properties to the molecule, and the hydrophilicity promotes the water solubility of the molecule. The disulfide bond is then cut off by chemical, enzyme or metabolic ester formation in the body. Therefore, the compound of formula I I I is a water-soluble prodrug of the compounds of formula I in which R3, R5 or Rv is hydrogen. Compounds of formula I, II and III are derived from benzocycloalkylazolidinone -19- (Please read the precautions on the back before filling this page) This paper size applies to Chinese national standard (CNS> A4 specification (210X29? 〉 470741 A7 B7 V. Description of the invention (), in which the benzocycloalkyl part of the molecule is the following formula

更特定的界定如下： (1) 一基團中η為0且單價碳位於1 一或2 —位置 (也就是α —或；8 —位置），其具備下式A more specific definition is as follows: (1) η in a group is 0 and the monovalent carbon is located at the 1 or 2 -position (that is, α -or; 8 -position), which has the following formula

VV

其係分別為選擇性被取代的茚滿- 1 一基或茚滿-2 -基 I (2) —基團中η為1且單價碳位於1_或2 —位置 (也就是cx —或/9 —位置），其具備下式經濟部中央標準局負工消費合作社印製 (請先閲讀背面之注意事項再填寫本頁) 其係分別為選擇性被取代的1 ，2，3 * 4 —四氫萘一 1 一基或1 ，2，3，4 一四氳萘一 2 —基； (3) —基團中η為2且單價碳位於5 —，6 —或7 -位置*其具備下式 -20- 本紙張尺度適用中國國家標準（CNS ) Α4規格（210Χ297公釐） 470741 A7 B7 五、發明説明（）It is an optionally substituted indane-1 or indane-2 -yl I (2) — group in which η is 1 and the monovalent carbon is located at 1 — or 2 — position (that is, cx — or / 9 —Position), which is printed by the Consumers ’Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page). These are 1, 2, 3 * 4 — Tetrahydronaphthalene-1 group or 1,2,3,4 tetranaphthalene-2 group; (3) —group η is 2 and the monovalent carbon is located at 5 —, 6 — or 7 — position * It has The following formula -20- This paper size applies to Chinese National Standard (CNS) A4 specification (210 × 297 mm) 470741 A7 B7 V. Description of the invention ()

經濟部中央標準局員工消費合作社印製其係分別為選擇性被取代的6，7，8 * 9 —四鏟一 5H 一苯並環庚烯一 5 —基，6，7，8 · 9 —四氫一 5H-苯並環庚烯—6 —基或6，7，8，9 —四氫一 5H —笨並環庚烯一7-基。苯並環烷基的單價碳可為對掌中心。因此*式I化合物和某些用於其合成的化合物可為一對不同對掌中心的對映異構物或此對映異構物的混合物。式I I和I I I的化合物個別含一或二個對掌中心。含二個對掌中心的式II 和III有二對對映異構物（也就是四個非對映異構物），可為任何一個對映異構物或其混合物。對映異構物的特徽為其對掌中心的絕對組態，M Cahn, Ingold and Prelog 的R —和S -纊列規則加以敘述。當有二個對掌中心時· 每個對掌中心的組態適當的被命名為R或S。傳統的立體化學命名，決定立體化學的方法Μ及立髏異構物的分雔方法係為習知技藝（例如參考"Advanced Organic Chemistry", 3rd edition, March, Jerry, John Wiley & Sons, New York, 1 985 )。除非另外說明，舉凡說明中關於式 I ’ I I · III ，1一6，8 — 32，44 一 46 和4 8或申謫専利範圍中的特別對掌化合物的說明*敘述或命名意欲包括兩個個別對映異構物和其混合物，消旋物或其它。 -21- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） I I n I 11 I n n I- . I n n I (請先閱讀背面之注意事項再填寫本頁) 470741 A7 B7 五、發明説明（分子的唑硫酮部份（也就是分別為式I ，I I和I I I的RZ · R1 8和R2 7 )為眯唑硫酮或***硫酮基。例如，R2特定地被界定為 (1 )式（a )的基團·· R: (a) 當形成母糸命名時為1 ，3 —二氩咪唑一 2 —硫酮，或者形成母糸命名的字頭時為2 —硫酮一 2，3 —二氫—1 Η 一眯唑； (2 )式（b )的基團 (請先閱讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 (b) 當形成母糸命名時為2，4 一二氫〔1 ，2，4〕*** 3 —硫酮*或者形成母糸命名的字頭時為5 —硫酮一 4 5- 二氫一 1H - 〔1 ，2，4〕***基； (3 )式（c )的基團Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs, which are selectively substituted 6,7,8 * 9 —four shovel — 5H —benzocycloheptene — 5-based, 6, 7, 8 · 9 — Tetrahydro-5H-benzocycloheptene-6-yl or 6,7,8,9-tetrahydro-5H-benzylcycloheptene-7-yl. The monovalent carbon of the benzocycloalkyl group may be the palm center. The compound of formula I and some of the compounds used in its synthesis may therefore be a pair of enantiomers of different palm centers or a mixture of such enantiomers. The compounds of the formulae I I and I I I each contain one or two palm centers. Formulae II and III with two palm centers have two enantiomers (ie, four diastereomers), which can be either one of the enantiomers or a mixture thereof. The special feature of the enantiomer is its absolute configuration of the center of the palm, described by the R — and S — queue rules of McCahn, Ingold and Prelog. When there are two palm centers · The configuration of each palm center is appropriately named R or S. Conventional stereochemistry nomenclature, the method of determining stereochemistry M and the method of tiller isomerization are known techniques (for example, reference " Advanced Organic Chemistry ", 3rd edition, March, Jerry, John Wiley & Sons, New York, 1 985). Unless stated otherwise, the descriptions of formulae I'II.III, 1-6, 8-32, 44-46, and 48 or specific compounds in the range of Shenli are stated. The description or name is intended to include two Individual enantiomers and mixtures thereof, racemates or others. -21- This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) II n I 11 I nn I-. I nn I (Please read the notes on the back before filling this page) 470741 A7 B7 V. DESCRIPTION OF THE INVENTION (The azolidinone portion of the molecule (ie, RZ · R1 8 and R2 7 of formulas I, II, and III, respectively) is an oxazolidinone or a triazolithone group. For example, R2 is specifically defined as (1) Groups of formula (a) · R: (a) When forming the parent pyrene name, it is 1, 3 -diamidazole-2-thione, or when forming the prefix of the parent pyrene name, it is 2-sulfur Keto-2,3-dihydro-1 oxanimidazole; (2) groups of formula (b) (please read the notes on the back before filling this page) printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (b ) 2,4-dihydro [1,2,4] triazole 3-thione * when forming the parent name, or 5--thione-4 5-dihydro-1H when forming the prefix of the parent name -[1,2,4] triazolyl; (3) a group of formula (c)

(C) -22 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 470741 A7 —_____B7 五、發明説明（） (請先閱讀背面之注意事項再填寫本頁) 當形成母系命名時為2，4 一二氫〔1 ，2，4〕三睡一 3 —硫麵，或者形成母系命名的字頭時為5 —硫酮一 4， 5 -二氫一 1H — 〔1，2，4〕***基；某些R2和R1 8基在硫_互變異構物和氫硫互變異構（例如式（a)基囫中R3為氫）之間圼互變異構平衡。含有K互變異構物形式存在的式1或丨〗化合物在此申請案中係K硫酮或硫代取代衍生物被命名，說明或作其它敘述。然而，應該理解的是氫硫互變異構物亦包括於此種命名，說明及敘述中。式 I * ϊ I 和 I I I 的化合物係 KAUTONOM Version 1.0 by Beilstein-Institut a n d Springer-Verlag Berlin Heidelberg加K命名，該系統為一完全電腦化的命名ΙϋΡAC命名系統，可Μ直接從有機化合物的結構圃加以命名。例如，式I化合物中η為1 ，t為0且R2接於冷位置而為式（a)基圄者，也就是(C) -22 This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 470741 A7 —_____ B7 V. Description of invention () (Please read the notes on the back before filling this page) When forming the matrilineal nomenclature It is 2,4-dihydro [1,2,4] three sleeps and one 3-sulfur surface, or when forming the prefix of the matrilineal name, it is 5-thioketone-4, 5-dihydro-1H— [1,2, 4] Triazolyl; Some R2 and R18 groups are tautomerically balanced between sulfur-tautomers and hydrogen-sulfur tautomers (eg, R3 is hydrogen in the formula (a)). Compounds of formula 1 or 丨 containing K tautomers are named, described or otherwise described in this application as K-thioketones or thio-substituted derivatives. It should be understood, however, that hydrogen-sulfur tautomers are also included in such nomenclature, descriptions, and narratives. The compounds of the formula I * ϊ I and III are KAUTONOM Version 1.0 by Beilstein-Institut and Springer-Verlag Berlin Heidelberg plus K designation. This system is a fully computerized naming system. The IPAC nomenclature system can be applied directly from the structure of organic compounds. name. For example, in the compound of formula I, η is 1, t is 0, and R2 is connected to the cold position to be a group of formula (a), that is,

經濟部中央標準局員工消費合作社印製當115為胺基甲基時•被命名為5 —胺基甲基一1 一（1 ，2，3，4 一四氫萘一 2-基）一 1 · 3 —二氫咪唑一 2-硫酮，當尺5為羧基時，被命名為3— （1 ，2，3 ，4 —四氫萘—2-基）—2 —硫嗣一 2，3 —二氫—1 -23- 本紙張尺度適用中國國家標準（CNS ) A4規格（2l〇X297公釐） 470741 A7 B7五、發明説明（） Η-脒唑一4一羧酸。式I化合物中η為1 ，t為0且R2接於々位置*為式（b)基團者，當R6為胺基甲基時，被命名為5 —胺基甲基一 4_ (1 ，2，3，4 -四氫萘一2 —基）~*2 ,4 一二氲〔1 ，2，4〕***—3 —硫酮。式I化合物中η為1 ，t為0且R2接於点位置，為式（c)基團者，當R7為胺基時，被命名為4 —胺基一 2 - (1 ，2，3，4 -四氫萘-2 —基）一 2，4 一二氮〔1 ，2 , 4〕三唾—3—硫銅，當R7為乙釀胺基時 *被命名為N — 〔1 一（1 ，2，3 ，4 一四氬萘一 2 — 基）—5 —硫酮一4 ’ 5 —二氫〔1 ’ 2 ’ 4〕二睡一 4 —基〕乙豳胺。式I I化合物中η為1 ，t為0且R1 8接於Θ位置，為式（d)基團者，其中R2 1為L — α —門冬氨醢胺基甲基時，也就是下式、11麟 (請先閱讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 ΗPrinted by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs when 115 is an aminomethyl group • It is named 5-aminomethyl-1 1- (1,2,3,4-tetrahydronaphthalene-2-yl) -1 · 3-Dihydroimidazol-2-thione, when the rule 5 is a carboxyl group, it is named 3- (1,2,3,4-tetrahydronaphthalene-2-yl) -2-thithio-2,3 —Dihydro—1 -23- This paper size is applicable to Chinese National Standard (CNS) A4 specification (210 × 297 mm) 470741 A7 B7 V. Description of the invention () Η-oxazole-4-monocarboxylic acid. In the compound of the formula I, η is 1, t is 0, and R2 is connected to the 々 position * is a group of formula (b), when R6 is an aminomethyl group, it is named 5-aminomethyl-4_ (1, 2,3,4-tetrahydronaphthalene-2-yl) ~ * 2,4 dioxin [1,2,4] triazol-3-thione. In the compound of formula I, η is 1, t is 0, and R2 is connected to the point position, which is a group of formula (c). When R7 is an amine group, it is named 4-amino group 2-(1, 2, 3 , 4 -tetrahydronaphthalene-2 -yl) -2,4 -diazine [1,2,4] trisaloxan-3-sulfocopper, when R7 is ethylamine amino group * is named N-[1- (1,2,3,4-tetrahydronaphthalene- 2-yl) -5 -thione-4 '5-dihydro [1' 2 '4] dipyridine 4-yl] acetamidamine. In the compound of formula II, η is 1, t is 0, and R1 8 is connected to Θ, and is a group of formula (d), where R2 1 is L — α —aspartyl aminomethyl, which is the following formula 11 Lin (Please read the precautions on the back before filling out this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic AffairsΗ

被命名為3S —胺基一 Ν- 〔3— （1 ，2·3，4 一四氫萘一 2 —基）一 2_硫酮一 2，3 —二氫_1 Η —眯哩 —4 一基甲基〕琥珀酿胺酸。 -24- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 470741 A7 B7 經濟部中央標準局員工消費合作社印製五、發明説明（）式I I I化合物中η為1 * t為0且R2 7接於/3位置，為式（g)基團者，其中Rs為胺基甲基* R2 8為 2 —胺基一 2 —羧基乙基，也就是下式 s^^GOOH xsIt is named as 3S-amino-N- [3- (1,2,3,4-tetrahydronaphthalene- 2-yl)-2_thioketone-2,3-dihydro_1 Η —Ηmile — 4 Monomethyl] succinic acid. -24- This paper size applies to Chinese National Standard (CNS) A4 (210X297mm) 470741 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention () η is 1 * t in the compound of formula III And R2 7 is connected to the / 3 position, and is a group of formula (g), where Rs is an aminomethyl group * R2 8 is a 2-amino group-2 carboxyethyl group, which is the following formula s ^^ GOOH xs

被命名為2 —胺基一 3 — 〔5 —胺基甲基一1 一（1 ，2 ，3，4 一四氳萘一 2-基）一 1 Η —咪唑一2 —基二硫酸酐基〕丙酸。較佳具體實施例本發明所欲涵蓋的化合物範圍雖然在發明概要中已提出，其中又Μ某些式I * I I和I I I化合物較佳。較佳的式I化合物中R2為式（a)，K式I (a)化合物命名之。較佳的式I (a)化合物為其中R2接於分子/3位置的苯並環烷基部份*較佳為其中η為0或1 ，R5為二 (Ci -C4 )烷基胺基甲基，吡咯烷一 1一基甲基，呢啶一 1 —基甲基，嗎啉一4 —基甲基，锨嗪一 1 —基甲基，4 — (Ci — C4)烷基哌嗪一 1 一基甲基或- CH2 N H R 1 0 。最佳的式I (a)化合物為其中R2接於/3 位置，η為1 ，t為2，每個R1為氟，較佳在5 -和7 -25- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） (請先閱讀背面之注意事項再填寫本頁) 470741 Μ Β7 經濟部中央標準局員工消費合作社印製五、發明説明（ ) 1 1 1 一位 BEI 置 ,R 為 — C Η 2 N Η R 1 0 > 其中 R 1 〇為氫 9 1 1 I 氨基甲醢或 ( C 1 C 4 ) 烷醒基 t 較佳為釅基，待別 /—•ν 1 | 請 I 是其 S -對映異稱物 0 先間諸 1 1 式 I化合物中 R Ζ 為式 ( b ) 者被命名為式 I ( b ) 背 1 I 之 1 化合物 0較佳的式 I ( b ) 化合物為其中 R Ζ 接於分子 β 注意 1 I 位置較佳為其中 η 為 0 或 1 » R 7 為二 ( C 1 — C 4 ) 項再 1 1 烷基胺基甲基吡咯燒 — 1 一基甲基哌啶一 1 — 基甲基 4 寫本 1 % * 嗎啉一 4 — 基甲基锨嗪 — 1 — 基甲基 » 4 — ( C 1 —* 頁 'S-^ 1 1 C 4 ) 烷基哌嗪 — 1 — 基甲基或 — C Η Ζ N Η R 1 〇 0 最 1 I 佳的式 I ( b ) 化合物為其中 R Z 接於 β 位置 • η 為 1 * 1 1 I t 為 2 ，每個 R 1 為氟 $ 較佳在 5 — 和 7 一位置 R 6 為 1 訂二 ( C 1 — C 4 ) 烷基胺基甲基吡咯焼 — 1 — 基甲基 » 1 1 锨啶 — 1 - 基甲基 9 嗎啉一 4 — 基甲基哌嗪 — 1 — 基甲 1 I 基 4 -( C X — C 4 ) 燒基哌嗪 — 1 一基甲基或 1 1 I *— C Η 2 Ν Η R 1 0 » 特別是其是其 S 對映舆構物 0 1 綠式 I化合物中 R Ζ 為式 ( C ) 者被命名為式 I ( C ) 1 1 化合物。較佳的式 I ( C ) 化合物為其中 R Ζ 接於分子 β 1 I 位置 9 較佳為其中 η 為 0 或 1 R 8 為 — N Η Ζ 〇最佳的 1 1 I 式 I ( C ) 化合物為其中 R Ζ 接於 β 位置 f η 為 1 » t 為 1 1 2 1 每個R 1 為氟較佳在 5 — 和 7 — 位置 9 R 8 一 N Η 2 1 1 t 特別其是其 S — 對映異構物〇 1 | 較佳式 I I 化合物中 R 1 8 為式 ( d ) 且接於 β 位置 1 I 9 較佳為其中 η 為 0 或 1 » R Z X 為一 C Η Ζ Ν Η R Z 6 1 1 I ·2ί 卜 1 1 本紙張尺度適用中國國家標準（CNS ) Α4規格（210 X 297公釐） 1 4 7 ο 7 4 A7 B7 經濟部中央標準局員工消費合作社印製五、發明説明（）。最佳的式I I 位置，η為0或和7 —位置，R 為精氨醢基》α 基或鳥氨醯基。較佳的式I 置的化合物，較 C 4 )烷基胺基基甲基，嗎啉一 C i - C 4 )烷 Q 。最佳的式I 位置的化合物* 佳在5 —和7 — 甲基，吡咯烷一 4 —基甲基·呢基顿嗪—1 —基自乙基，1 ，1 自羧基，甲氧基取代基所取代） _甲氧基羰基乙 (R ) - 2 -三一胺基乙基，（甲基乙基或3 _ 化合物為其中 R 1 8 1 9 t 為 2 ，每個 R 2 1 為 — C Η 2 N Η — 門冬氨釅基 » β — I I 中 R Ζ 7 為式 ( 佳為其中 η 為 0 或 1 甲基 » 吡咯烷 — 1 — 4 — 基甲基 » 哌嗪 — 基锨嗪 — 1 — 基甲基 I I 為其中 R Ζ 7 為 η 為 0 或 1 9 t 為 2 位置 » R 5 為二 ( C 1 一基甲基 9 锨啶 — 嗪 — 1 — 基甲基 9 4 甲基或 — C Η 2 Ν Η — 二甲基乙基和丙基羰基 » 胺基和三氟乙較佳者 R 2 8 為 ( 基 9 ( R ) — 2 — 胺氣乙 m 基胺基 — 2 — S ) — 2 — 胺基 — 2 胺基 — 3 *«-· 羧基丙一 -27- 為式（d )且接於/3 1為氟，較佳在5 — 2 6 ，較佳為R 2 6 門冬氨醢基，組氨醢 g)並接於分子/3位，R 5 為二（C i 一基甲基，#啶一 1一 1—基甲基*4 —( 或- CHz NHR1 式（g )基且接於/3 ，每個R 1為氟，較 i — C 4 )烷基胺基 1 —基甲基》嗎咐一 -(C i - C 4 )烷 R 1 0 ，R 2 8 為選 (該基團再被獨立選醯基胺基的一到二個 R) — 2 — 胺基一 2 基—2 —羧基乙基，甲氧基羰基乙基* 2 一羧基一 1 ，1 一二 1 -基。 (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 470741 經濟部中央標準局員工消費合作社印製 A7 B7 五、發明説明（）藥理學和應用本發明的化合物為度巴明/9羥基酶。據上所述•本發明的化合物可用於治療能夠抑制度巴明yS羥基酶而獲得改菩的疾病。例如，本發明化合物姐斷正S上腺素之生物合成，可用治療由交感神經過度反應造成或使惡化的疾病。特別是因為本發明化合物為末稍血管擴張劑，該化合物可在為治療充血性心臓病的減少後負荷試劑。再者，因為本發明化合物降低正腎上腺素水平，而可以減輕因交感神經過度作用所產生充血性疾病而對心肌所造成的傷害。因此，本發明化合物特別有用於治療充血性心臟病*因為藉著減少後負荷而得到心臟輸出的初步改善K及減少心肌組織之正腎上腺素水平而維持心臟功能。测試化合物的度E明/8 —羥基酶抑制性質可經由此技藝所諶定的活體外評鑑方法加Μ決定，該評鑑方法係依氫基對乙酚對八巴明之度巴明/8 —羥基酶催化轉Μ及測試化合物的效果而定，在實例6 3有詳细記載。測試化合物的度巴明/9 一羥基酶抑制劑性質也可經由此技藝所認定的活體內評鑑方法加Κ決定，該評鑑方法係依度巴明和正聚上腺素組織濃度，Κ及測試化合物的效果而定（例如Β.Α. Berkowitz et a 1 . , 1988，J . Pharm· Exp Ther. 245, 8 5 0-8 5 7所述），在實例64中有詳细記載。测試化合物之降血壓性霣可由活體内評鑑方法進行►其係使用患自發性高血壓的大鼠為對象，如實例65所記載。 -2 8 - 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） ----------辦本------tr------# (請先閱讀背面之注意事項再填寫本頁) 470741 經濟部中央標隼局員工消費合作杜印製 A7 B7五、發明説明（）投與和藥學組成物一般而言·本發明化合物經由任何此技藝中習知的有用和可接受模式投與有效治療數量，可軍獮使用或與本發明另外的化合物或與其它治療劑一起使用。有效治療數量依疾病，年紀和對象相對健康狀況，使用化合物的藥效和其它因素而定，故範圍變化大。有效洎療數最約從0 · 1 毫克/公斤（奄克/公斤）體重/天到30奄克/公斤體重/天。因此，對體重70公斤的人而言*有效治療數量範圍為7·0到2100毫克/天，較佳70到700毫克/天。治療此疾病的習知技藝人士可確漯本發明化合物用於治療某疾病的有效治療數量而不需要過當的實驗，憑賴個人知識Κ及本發明所掲示即可。一般而言，本發明的化合物係Μ藥學組成物形式採下列一種方式加Μ投與：口服· 条統（例如穿皮，ft內或栓劑）或非經腸（例如肌內*靜脈或皮上注射）。組成物的形式為錠劑，藥九，膠嚢，半固體，粉末•維持釋出配方*溶液，懸浮物，酏劑，噴劑 *或者任何其它合適的組成物* 一般包括本發明的化合物與至少一藥學上可接受賦形劑。可接受的賦形劑為非毒性 •輔肋投與，不會對式I化合物的治療產生副作用。此類賦形劑可為任何的固體，液體，半固體•或者為噴劑組成物，一般對習知此藝人士可取得的氣態賦形劑。固體藥學賦形劑包括溅粉，纖維素，滑石粉·葡萄糖 -29* n·.^ I n n n I n 綠 (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標隼（CNS ) Μ規格（210X297公釐） 470741 經濟部中央標隼局員工消費合作社印製 A7 B7五、發明説明（），乳糖，蔗糖，凝膠，麥芽•米，麵粉，白堃，砂膠，硬脂酸鎂，硬脂酸納，甘油單硬脂酸酯，氯化納，乾燥脫脂牛奶和類似物。液體和半固體賦形劑可選自水，乙醇，甘油，丙二醇和各種油，包括石油，動物，植物油或合成源 (例如花生油，大豆油*確物油•芝麻油等）。較佳的液體載體*特別是供可注射溶液使用者，包括水，鹽水，水性葡萄糖和甘油。壓縮氣體可被用於將本發明化合物分散成噴劑形式。適合此目的的惰性氣體為氮氣，二氧化碳，氧化氮等。其它合適的藥學載體和其配方被記載於A.R. Alfonso Remington's Pharmaceutical Sciences 1 985 , 1 7 th ed. Easton, Pa. :Mack Publishing Company 〇組成物中的本發明化合物數量依配方型態•單劑劑量大小，賦形劑種類和其它藥學科學人士習知的其它因素之不同而變化很大。一般而言•最終組成物將包括1 0%到 9 0%重量的化合物，較佳2 5%到7 5%重量，其它含量為一或多個賦形劑。較佳的藥學組成物係K單一單位劑形式進行持續治療 •或者特定需要解除症狀時Μ單一單位劑量形式而劑量不拘方式進行。含式I化合物的代表性藥學配方如實例6 7 所記載。化學方面：式I ( a )化合物： -30- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） (請先閲讀背面之注意事項再填寫本頁) 470741 A7 B7 五、發明説明（）一種製備式I (a)中R3 ，R4和r5各為氫的化合物的方法由以下反應圖I所表示：It is named 2-amino- 3-[5-aminomethyl-1 1- (1,2,3,4-tetramethylnaphthalene- 2-yl)-1 fluorene-imidazol-2-yl disulfonic anhydride group 〕 Propionic acid. Preferred Specific Examples Although the range of compounds to be covered by the present invention has been set forth in the Summary of the Invention, certain compounds of the formula I * I I and I I I are preferred. Among the preferred compounds of formula I, R2 is the formula (a), and K is the compound of formula I (a). Preferred compounds of formula I (a) are benzocycloalkyl moieties where R2 is attached to the molecular / 3 position * preferably where η is 0 or 1 and R5 is bis (Ci-C4) alkylaminomethyl Methyl, pyrrolidine-l-ylmethyl, oxidine-l-ylmethyl, morpholine-l-ylmethyl, pyrazine-l-ylmethyl, 4- (Ci-C4) alkylpiperazine-l 1 monomethyl or -CH2 NHR 1 0. The best compound of formula I (a) is in which R2 is connected to the / 3 position, η is 1 and t is 2, each R1 is fluorine, preferably between 5-and 7 -25-This paper scale applies Chinese national standards ( CNS) A4 specification (210X297 mm) (Please read the notes on the back before filling this page) 470741 Μ B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention () 1 1 1 One BEI set, R Is — C Η 2 N Η R 1 0 > wherein R 1 〇 is hydrogen 9 1 1 I carbamate or (C 1 C 4) alkyl group t is preferably a fluorenyl group. Let I be its S-enantiomeric synonym 0 1st 1 1 1 of the compounds of formula I where R Z is of formula (b) is named as formula I (b) followed by 1 I of 1 compound 0 preferred formula I ( b) The compound is where R Z is attached to the molecule β Note that the position of I is preferably where η is 0 or 1 »R 7 is a term of (C 1-C 4) and 1 1 alkylaminomethylpyrrole-1 Monomethylpiperidine-1 —Methylmethyl 4 1% * Morpholine-4 —Methylmethylpyrazine — 1 —Methylmethyl »4 — (C 1 — * Page 'S- ^ 1 1 C 4) Alkylpiperazine — 1 — Methyl or — C Η Z N Η R 1 〇0 The best 1 I compounds of formula I (b) are those where RZ is at the β position • η is 1 * 1 1 I t is 2 and each R 1 is fluorine It is preferred that R 6 is 1 at the 5-and 7 positions. Bis (C 1-C 4) alkylaminomethylpyrrolidin — 1 —ylmethyl »1 1 pyridine — 1 -ylmethyl 9 morpholine Mono 4-methylmethylpiperazine — 1 —methylmethyl 1 I group 4-(CX — C 4) alkenylpiperazine — 1 monomethyl or 1 1 I * — C Η 2 Ν Η R 1 0 »Special Yes, it is the S enantiomer 0 1 of the green formula I, and R Z is a compound of formula (C), which is named a compound of formula I (C) 1 1. Preferred compounds of formula I (C) are those in which R Z is attached to the β 1 I position 9 preferably of which η is 0 or 1 R 8 is-N Η ZO. The best 1 1 I compounds of formula I (C) Where R R is connected to β position f η is 1 »t is 1 1 2 1 Each R 1 is fluorine preferably at 5 — and 7 — position 9 R 8 -N Η 2 1 1 t especially its S — Enantiomers 〇1 | Preferred compounds of formula II in which R 1 8 is of formula (d) and is attached to the β position 1 I 9 is preferably where η is 0 or 1 »RZX is a C Z Ν Η RZ 6 1 1 I · 2ί Bu 1 1 This paper size applies to the Chinese National Standard (CNS) Α4 specification (210 X 297 mm) 1 4 7 ο 7 4 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs ). The most preferred position of the formula I I, n is 0 or and 7-position, and R is arginino "α group or ornithino group. Preferred compounds of formula I are more preferred than C 4) alkylaminomethyl, morpholine-C i -C 4) alkane Q. The most preferred compound at position I of formula * is preferably 5- and 7-methyl, pyrrolidine-4-ylmethyl · denyltonazine-1-yl from ethyl, 1, 1 from carboxyl, methoxy substituted Substituted by __methoxycarbonylethyl (R)-2 -triamidoethyl, (methyl ethyl or 3 _ compounds where R 1 8 1 9 t is 2 and each R 2 1 is- C Η 2 N Η — aspartame »β — II R R 7 is of the formula (preferably where η is 0 or 1 methyl» pyrrolidine — 1 — 4 —ylmethyl »piperazine — methylpyrazine — 1 —ylmethyl II is where R Z 7 is η is 0 or 1 9 t is 2 position »R 5 is bis (C 1 monomethyl 9 pyridin — azine — 1 — yl methyl 9 4 methyl Or — C Η 2 Ν Η — dimethylethyl and propylcarbonyl »amino and trifluoroethyl are preferred R 2 8 is (group 9 (R) — 2 — amine ethyl amine — 2 — S) — 2 — amine — 2 amine — 3 * «-· carboxypropyl-1-27- is of formula (d) and is connected to / 3 1 is fluorine, preferably 5-2 6, more It is preferably R 2 6 aspartyl group, histamine group g) and is connected to the molecule / 3 position, and R 5 is di (C i monomethyl group, #pyridine 1-1 1-methyl group * 4 — ( Or-CHz NHR1 group of formula (g) and connected to / 3, each R 1 is fluorine, which is more than i — C 4) alkylamino 1 — methylmethyl — mono- (C i-C 4) alkane R 1 0 and R 2 8 are selected (the group is independently selected by one to two R of fluorenylamino) — 2 —amino — 2 — 2 —carboxyethyl, methoxycarbonylethyl * 2 Carboxyl-1, 1-12-base. (Please read the notes on the back before filling this page) This paper size applies to China National Standard (CNS) A4 (210X297 mm) 470741 Employees of the Central Standards Bureau of the Ministry of Economic Affairs Printed by Consumer Cooperative A7 B7 V. Description of the invention () Pharmacology and application The compound of the present invention is dubamine / 9-hydroxylase. According to the above, the compound of the present invention can be used for the treatment of dubmin yS Obtaining a disease that has been modified. For example, the compound of the present invention, which corrects the biosynthesis of S-adrenaline, can be used to treat diseases caused by or exacerbated by sympathetic overreaction. Especially since the compound of the present invention is a terminal vasodilator, the compound can be used as a post-reduction agent for the treatment of congestive palpitations. Furthermore, because the compounds of the present invention reduce the level of norepinephrine, it can reduce the damage to the heart muscle caused by congestive diseases caused by the excessive action of sympathetic nerves. Therefore, the compounds of the present invention are particularly useful in the treatment of congestive heart disease * because of the initial improvement in cardiac output by reducing afterload K and the reduction of ortho adrenaline levels in myocardial tissue to maintain cardiac function. The degree of test compound Emin / 8-hydroxylase inhibitory properties can be determined by the in vitro evaluation method determined by this technique plus M, the evaluation method is based on the hydrocarbyl p-ethylphenol to octabamine-dubamin / 8-hydroxylase catalyzes the transduction of M and the effect of the test compound, which is described in detail in Example 63. The properties of the test compound dubamin / 9-hydroxylase inhibitor can also be determined by the in-vivo evaluation method identified by this technique plus κ, which is based on the tissue concentration of edubamin and positive polyadrenaline, κ and The effect of the test compound (for example, described in B.A. Berkowitz et al., 1988, J. Pharm. Exp Ther. 245, 8 0 5-8 5 7) is described in detail in Example 64. The antihypertensive properties of the test compound can be evaluated in vivo by using a rat with spontaneous hypertension as described in Example 65. -2 8-This paper size is applicable to Chinese National Standard (CNS) A4 (210X297 mm) ---------- Do this ------ tr ------ # (please first (Please read the notes on the back and fill in this page) 470741 Consumption cooperation by employees of the Central Bureau of Standards, Ministry of Economic Affairs, printed A7 B7 V. Description of the invention () Administration and pharmaceutical composition Known useful and acceptable modes for administering effective therapeutic amounts can be used either with other compounds of the invention or with other therapeutic agents. The number of effective treatments varies widely depending on the disease, age, and relative health of the subject, the efficacy of the compound used, and other factors. The number of effective treatments ranges from about 0.1 mg / kg (kg / kg) body weight / day to 30 mg / kg body weight / day. Therefore, for a person weighing 70 kg * the effective treatment amount ranges from 7.0 to 2100 mg / day, preferably 70 to 700 mg / day. Those skilled in the art of treating this disease can ascertain the effective therapeutic amount of the compound of the present invention for the treatment of a certain disease without undue experimentation, it is only necessary to rely on the knowledge of the person and the present invention. Generally speaking, the compounds of the present invention are administered in the form of M pharmaceutical composition in one of the following ways: oral or systemic (such as transdermal, intraft or suppository) or parenteral (such as intramuscular * vein or subcutaneous) injection). The composition is in the form of lozenges, medicines, capsules, semi-solids, powders. • Maintaining release formulations * solutions, suspensions, tinctures, sprays * or any other suitable composition * generally includes the compounds of the invention and At least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic • Co-costal administration does not cause side effects on the treatment of compounds of formula I. Such excipients can be any solid, liquid, semi-solid • or spray composition, and are generally gaseous excipients available to those skilled in the art. Solid pharmaceutical excipients include splash powder, cellulose, talc · glucose-29 * n ·. ^ I nnn I n green (please read the precautions on the back before filling this page) This paper size is applicable to Chinese national standard ( CNS) M specifications (210X297 mm) 470741 A7 B7 printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of the invention (), lactose, sucrose, gel, malt • rice, flour, white lotus root, mortar, Magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dry skim milk and the like. Liquid and semi-solid excipients can be selected from water, ethanol, glycerin, propylene glycol, and various oils, including petroleum, animal, vegetable, or synthetic sources (such as peanut oil, soybean oil * real oil, sesame oil, etc.). Preferred liquid carriers * are especially intended for users of injectable solutions, including water, saline, aqueous glucose and glycerol. Compressed gas can be used to disperse the compounds of the invention into the form of a spray. Suitable inert gases for this purpose are nitrogen, carbon dioxide, nitrogen oxide, and the like. Other suitable pharmaceutical carriers and their formulations are described in AR Alfonso Remington's Pharmaceutical Sciences 1 985, 17 th ed. Easton, Pa .: Mack Publishing Company 〇 The amount of the compound of the present invention in the composition depends on the formulation type · single dose size The types of excipients and other factors known to those skilled in the pharmaceutical sciences vary widely. In general • The final composition will include 10% to 90% by weight of the compound, preferably 25% to 75% by weight, and the other content will be one or more excipients. The preferred pharmaceutical composition is K single unit dosage form for continuous treatment. Or, in the case of specific need to relieve symptoms, M single unit dosage form is used in an arbitrary manner. A representative pharmaceutical formulation containing a compound of formula I is described in Example 67. Chemical aspects: Compounds of formula I (a): -30- This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) (Please read the notes on the back before filling this page) 470741 A7 B7 V. Description of the invention () A method for preparing a compound in which each of R3, R4 and r5 in formula I (a) is hydrogen is represented by the following reaction scheme I:

(請先閱讀背面之注意事項再填寫本頁)(Please read the notes on the back before filling this page)

經濟部中央標準局員工消費合作社印製其中L為一離去基，R3 1為烷基，較佳為甲基或乙基* 每個η，t和R1定義同發明概要中的式I 。式I (a)中R3 ，R4和rs各為氪的化合物（式 1)係製備於式2化合物與硫氰酸在一合適的溶劑中的反應，典型溶劑為醇類（例如甲醇，乙醇，任何合適醇類的合適混合物等），Μ甲酵較佳。反應係在酸水溶液（例如 -31-Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economics where L is a leaving group and R3 1 is an alkyl group, preferably methyl or ethyl. Compounds of formula I (a) where R3, R4 and rs are each fluorene (Formula 1) are prepared by reacting a compound of Formula 2 with thiocyanic acid in a suitable solvent. Typical solvents are alcohols (such as methanol, ethanol, Any suitable mixture of suitable alcohols, etc.), M formase is preferred. The reaction is based on aqueous acid (eg -31-

本紙張尺度適用中國國家標準（CNS ) Α4規格（210Χ297公釐） 470741 A7 B7 經濟部中央標準局員工消費合作社印製五、發明説明（）稀氫氯酸，磷酸或硫酸等水溶液）存在下與硫氰酸納於 50*0到1 00·0，典型在70¾到90t!，較佳約在 8 0 t：反應1到5小時。式2化合物係製備於二烷基氧基乙醛，較佳二甲氧基乙醛或二乙氧基乙醛與式3化合物的遒原胺化反應。堪原胺化反應係在化學遒原劑（例如氣棚氫化納，鏟硼化納等 )或觸媒性氫化反應（例如氫，庚上鈀，氫，Raney®鎳等 )存在下於一合適溶劑（例如甲酵，乙醇*醋酸乙酯•任何合適的合適溶劑混合物等）中進行。可以選擇性地K標準方法（例如用乾燥劑如分子篩或共沸）除去水份。有瞄此處及前段的進一步詳细反應步驟在Μ下的實例9有記載。或者，式2化合物可藉式7化合物This paper size applies to Chinese National Standard (CNS) A4 specifications (210 × 297 mm) 470741 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention Sodium thiocyanate is 50 * 0 to 100 · 0, typically 70¾ to 90t !, preferably about 80t: reaction for 1 to 5 hours. The compound of formula 2 is prepared from a dialkyloxyacetaldehyde, preferably dimethoxyacetaldehyde or diethoxyacetaldehyde, and reacted with a compound of formula 3 by a primogen amination. The kannogenization reaction is carried out in the presence of a chemical rhenium agent (such as hood sodium hydride, sodium borohydride, etc.) or a catalytic hydrogenation reaction (such as hydrogen, palladium on hydrogen, hydrogen, Raney® nickel, etc.) In a solvent (e.g. formazan, ethanol * ethyl acetate • any suitable suitable solvent mixture, etc.). Water can be selectively removed by K-standard methods (e.g. with a desiccant such as molecular sieve or azeotropic). Further detailed reaction steps here and in the previous paragraph are described in Example 9 under M. Alternatively, the compound of formula 2 may be a compound of formula 7

與2 · 2 —二烷基氧基乙基胺，較佳2，2 —二甲氧基乙基胺或2，2 —二乙氧基乙基胺進行遢原胺化反應而加以製備（進一步的詳情參考Κ下的實例12)。式3化合物可購得或者可以使式5化合物與一合適的盤氮鹽（例如疊氮納*蠱氮鋰等）在一合適的溶劑（例如二甲基亞硼（DMSO) ，Ν，Ν -二甲基甲醢胺（DM F)等）中反應，先製得式4叠氮，然後遨原之而製得式 -3 2 - 本紙張尺度適用中國國家標準（CNS ) Μ规格（210Χ297公釐） (請先聞讀背面之注意事項再填寫本頁) 470741 經濟部中央標準局員工消費合作杜印製 A7 B7五、發明説明（） 3化合物。與叠氮鹽的反應係在50¾到90Ό，典型在 5 0 °C到6 0 "G，較佳在約5 0 t進行1 2到1 8小時。式4化合物的堪原可藉著在一合適的溶劑（例如醋酸乙酯，乙酵等）中的觸媒性氩化反應（例如，氫，10%庚上鈀；或氫，炭上鉑等）而進行。此段所提到的反應步驟之進一步詳情可參考K下的實例8。式5化合物的製備係以一合適的試劑處理式6化合物而製造離去基L。例如，式5中L為甲磺醯氧基的化合物可製備於式6化合物與甲烷磺豳氯化物在一合適溶劑（例如二乙基醚，四氫呋喃（THF)，甲撐氯化物*任何合適溶劑的混合物等）中的反應。該反應係在三乙基胺存在下於一 20¾到5¾ ·典型在一 1 5¾到一5t!，較佳在約一 1〇υ進行3到15小時（進一步的詳情參考Μ下的實例7 )。另一種製備式I (a)中R3 ，R4和R5各為氫的化合物的替代方法記載於Μ下反應圖I I : 反應圖I I (yth (B310)2CHCE2HH2 i —.— — — I— I I I In i I I— n (請先聞讀背面之注意事項再填寫本頁)It is prepared by performing a hydrazone amination reaction with 2 · 2-dialkyloxyethylamine, preferably 2,2-dimethoxyethylamine or 2,2-diethoxyethylamine (further For details, refer to Example 12) under K. The compound of formula 3 is commercially available or the compound of formula 5 can be obtained with a suitable plate nitrogen salt (such as sodium azide * lithium azide, etc.) in a suitable solvent (such as dimethyl boron (DMSO), N, N- Dimethylformamide (DM F), etc.), first formula 4 azide, and then the original formula -3 2-This paper size applies to China National Standard (CNS) M specifications (210 × 297) (%) (Please read the precautions on the reverse side before filling out this page) 470741 Consumption Cooperation by Staff of the Central Bureau of Standards, Ministry of Economic Affairs, Printed A7 B7 V. Invention Description (3) Compound. The reaction with the azide salt is carried out at 50¾ to 90Ό, typically at 50 ° C to 60 °, and preferably at about 50 ° T for 12 to 18 hours. The compounds of formula 4 can be prepared by a catalytic argonization reaction (for example, hydrogen, 10% heptane on palladium; or hydrogen, platinum on carbon, etc.) in a suitable solvent (for example, ethyl acetate, ethyl acetate, etc.) ). Further details of the reaction steps mentioned in this paragraph can be found in Example 8 under K. The compound of formula 5 is prepared by treating the compound of formula 6 with a suitable reagent to produce a leaving group L. For example, a compound of formula 5 where L is methanesulfonyloxy can be prepared from a compound of formula 6 and methanesulfonyl chloride in a suitable solvent (eg, diethyl ether, tetrahydrofuran (THF), methylene chloride * any suitable solvent). Mixture, etc.). The reaction is carried out in the presence of triethylamine at a temperature of 20¾ to 5¾. It is typically performed at a temperature of 1525 to 5t !, preferably at about 10 ° for 3 to 15 hours (for further details, please refer to Example 7 under M) . Another alternative method for preparing compounds where each of R3, R4 and R5 in formula I (a) is hydrogen is described in Scheme II below: Scheme II (yth (B310) 2CHCE2HH2 i —. — — — I — III In i II— n (Please read the notes on the back before filling in this page)

HCSHCS

8 %! N -33- __1_ 本紙張尺度適用中國國家標準（CNS ) A4規格（210 X 297公釐）8%! N -33- __1_ This paper size applies to China National Standard (CNS) A4 (210 X 297 mm)

470741 經濟部中央標準局員工消費合作社印製 A7 B7 五、發明説明（）其中R3 1為烷基，較佳為甲基或乙基，每個η * t和 R1定義同發明概要中的式I。式I (a)中R3 ，R4和R5各為氫的化合物可製備於式9化合物與2，2 —二烷基氧基乙基胺，較佳2， 2_二甲氧基乙基胺成2，2 —二乙氧基乙基肢在一合適的溶劑（二甲基甲醯，二甲基亞楓，1 ，3 —二甲基一3 ，4，5 * 6 —四氫一 2 (1H) - 嘧啶画（DMPU) 等）的反應，先得到式8化合物，然後用酸（例如氫氯酸 )處理式8化合物而進行閉環作用。與胺的反應係於2 0 t!到90*0，典型為70t!到90¾ *較佳約85t!進行 1到2 . 5小時。用酸處理Μ及最終的閉瑁作用是在2 Ot：到9 5 Ό，典型7 0 t到8 5 C，較佳約8 0 °C進行3到 7 2小時。有闞此段的進一步反應步驟詳情記載於以下的實例1 1。式化合物可製備於式3化合物與1 * 1' 一硫代羰基二眯唑在一合適的溶劑（醋酸乙酯，乙腈，丙酮，甲撐氯化物，任何合適溶劑的混合物等）。反應係於0 °C到5 0 Ό ，典型為1 ου到30t!，較佳約20Ϊ：進行3到1 85 -34- 本紙張尺度適用中國國家標準（CNS ) Α4規格（210Χ297公釐） 111 1111 n 11 I I (請先閱讀背面之注意事項再填寫本頁) 470741 A7 B7470741 Printed by A7 B7, Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention () where R3 1 is alkyl, preferably methyl or ethyl, and each η * t and R1 are defined as Formula I in the summary of the invention . Compounds in which each of R3, R4 and R5 in formula I (a) is hydrogen can be prepared from a compound of formula 9 and 2,2-dialkyloxyethylamine, preferably 2,2-dimethoxyethylamine 2,2-diethoxyethyl limb in a suitable solvent (dimethylformamidine, dimethylmethylene maple, 1,3-dimethyl-3,4,5 * 6-tetrahydro-1 ( 1H)-reaction of pyrimidine (DMPU), etc., to obtain a compound of formula 8 first, and then treating the compound of formula 8 with an acid (such as hydrochloric acid) to perform ring closure. The reaction with the amine ranges from 20 t! To 90 * 0, typically 70 t! To 90¾ *, preferably about 85 t !, and is carried out for 1 to 2.5 hours. The treatment of M with acid and the final occlusion effect is performed at 2 Ot: to 9 5 Ό, typically 70 t to 8 5 C, preferably about 80 ° C for 3 to 72 hours. The details of the further reaction steps in this paragraph are described in Example 11 below. The compound of formula can be prepared from a compound of formula 3 with 1 * 1 'monothiocarbonyldioxazole in a suitable solvent (ethyl acetate, acetonitrile, acetone, methyl chloride, any suitable solvent mixture, etc.). The reaction range is from 0 ° C to 5 0 Ό, typically 1 ου to 30 t !, preferably about 20 Ϊ: carried out 3 to 1 85 -34- This paper size applies the Chinese National Standard (CNS) A4 specification (210 × 297 mm) 111 1111 n 11 II (Please read the notes on the back before filling this page) 470741 A7 B7

五、發明説明（）小時（進一步詳情參考Μ下的實例1) ° 一種製備式I (a)中R3為一（CHz ) qR9的化合物的方法記載於Μ下的反應圖I I I : 反應圃I I IV. Description of the invention () hours (for further details, please refer to Example 1 under M) ° A method for preparing a compound of formula I (a) where R3 is one (CHz) qR9 is described in the reaction diagram under M I I I: Reaction Garden I I I

R4 L-CCH2) Η9R4 L-CCH2) Η9

(請先閲讀背面之注意事項再填寫本頁)(Please read the notes on the back before filling this page)

經濟部中央標準局員工消費合作衽印製其中L為一離去基，每個η · t · R1 ，R4 ，Rs和 R9定義同發明概要中的式I 。式I (a)中R3為一（ch2 ) qR9的化合物（式 10)的製備可K式L 一（CH2 ) qR9的烷化劑來烷化式1 1的化合物，得到相對應的蹄銼鹽，然後進行硫化而完成。烷化作用是在一合適溶劑（例如乙腈，二甲基甲豳胺，四氫呋喃，任何合適溶劑的混合物），較佳乙腈或二甲基甲醯胺，在0¾到1 6〇υ，典型2 回流1到 16小時。硫化反應係與蟲漆硫在一合適溫合鹼（例如三乙基胺*吡啶*任何適合的溫和鐮混合物等•較佳為三乙基胺和吡啶的混合物）中，於50°C到125Ό，典型 8〇υ到1 〇〇〇，較佳在約90t!進行1到8小時。在 -35- 本紙張尺度適用中國國家標準（CNS ) A4規格（21〇Χ297公釐） 470741 經濟部中央標準局員工消費合作社印製 A7 B7五、發明説明（）一類似方式中*式I (a)中R3為胺基的化合物可製備於式1 1化合物與肢基芳基成烷基磺酸鹽（例如鄰* 3，5 —三甲基笨磺醢一羥基胺，鄰甲烷磺醢羥基胺或鄰 —羥基胺磺酸）反應，得到相對應3 —胺基眯锉鹽•然後進行硫化而完成。與磺酸鹽的反應係在一合適溶劑（例如乙臈，甲撐氯化物，四氫呋喃•任何合適溶劑的混合物等，較佳為乙睛）中’於到4〇υ’典塱10¾到30¾ ，較佳在約20¾進行0 · 5到18小時。有闞此段的進 —步反應步驟詳情記載於K下的實例1 5 ° 式1 1化合物可製備於相對應式5化合物與一合通取代眯唑在一合適溶劑（二甲基甲醢胺•二甲基亞礪，乙腈等）中的反應。反應係在50C到100¾*較佳約85 °C進行8到24小時（進一步的詳情參考Μ下的實例13 )。一類似方式中，式11中η為1而分子的眯唑部份接於位置的化合物的製備•可使合適取代的2 —溴一 1 · 2 · 3，4 -四氦萘一1 -酮與一合適取代眯唑反應，然後予Μ堪原而完成。堪原反應係在一合遘酸性溶劑（例如硫酸•醋酸，任何酸的合適混合物等）中於15到100 ps i ，典型40到60ps i *較佳約50ps i進行觸媒氫化1到2 4小時。或者•式1 1化合物可製備於用Raney®鎳處理相對應式I。用Raney®鎳處理係在一合遒溶劑（例如乙醇，甲醇 •醋酸，水，合適溶劑的適當混合物等，較佳為乙醇）中 -36- (請先閲讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家擦準（CNS ) A4規格（210X297公釐） 470741 A7 B7 五、發明説明（），於ΟΌ到1 ΟΟΠ，典型25Ό到8 ου，較佳約8〇υ 進行0 ♦ 2 5到4小時（進一步的詳情參考Μ下的實例 14) ° 式I (a)中RS和R4為氫，rs為二（Ci 一 c 4)垸基胺基甲基，哌啶一1_基甲基或嗎啉一4一基甲基的化合物的製備，可K適當N，N —二取代甲撐銨鹽（例如N，N —二（Ci -C4 )烷基甲撐銨鹽如N · N_ 二甲基甲撐銨氯化物· N，N —二乙基甲撐銨氯化物和類似物，1 一甲撐哌錠氯化物，4 一甲撐嗎啉氯化物等）對式1 1中R4和R5均為氳的化合物進行烷化反應，然後予Μ硫化而製得。烷化反應係於一合適的溶劑（二甲基甲醯胺，DMPU，乙腈，合適溶劑的適當混合物等，較佳為二甲基甲酿胺）中於5〇π到ιοου，典型8〇υ到 1 0 0 °C ·較佳約9 5 t：進行4到1 8小時。式I (a)中R3為氫的化合物可製備於式1 1化合物與一強鹼（例如正丁基鋰•二異丙基醢胺鋰（L D A ) 經濟部中央標準局員工消費合作社印製 (請先間讀背面之注意事項再填寫本頁) 等）在一合適溶劑（例如1 ，2 —二甲氧基乙烷·四氫呋喃，2 —甲氧基乙基醚等）中的反應，得到相對應2 —眯唑烷，然後予以硫化而製得。與鹼的反應係將式1 2化合物的溶液冷卻到0¾到一 78¾之間，典型為一 50¾到 —78Ό之間，較佳約一 78¾，添加鹼，然後進行反應0 . 2 5到3小時。硫化反應係在〇 I到一 7 8 Ό，典型一50Ό到一 78Ό，較佳約一 78¾進行2到1 8小 -37- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 470741 A7 B7 五、發明説明（Printed by the staff of the Central Bureau of Standards of the Ministry of Economic Affairs for consumer cooperation, where L is a leaving group, and each η · t · R1, R4, Rs and R9 is defined as the formula I in the summary of the invention. The compound of formula I (a) in which R3 is mono (ch2) qR9 (formula 10) can be prepared by alkylating an alkylating agent of formula L- (CH2) qR9 to obtain the corresponding compound file salt. , And then vulcanization to complete. The alkylation is carried out in a suitable solvent (e.g. acetonitrile, dimethylformamide, tetrahydrofuran, a mixture of any suitable solvents), preferably acetonitrile or dimethylformamide, at a temperature of 0¾ to 160, typically 2 reflux. 1 to 16 hours. Vulcanization reaction with shellac sulfur in a suitable mild base (such as triethylamine * pyridine * any suitable mild sickle mixture, etc. • preferably a mixture of triethylamine and pyridine) at 50 ° C to 125Ό It is typically from 80 to 100, preferably at about 90 t! For 1 to 8 hours. In -35- This paper size applies the Chinese National Standard (CNS) A4 specification (21 × 297 mm) 470741 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 5. Description of the invention () A similar method in the formula I ( a) Compounds in which R3 is an amine group can be prepared in a compound of formula 11 and an alkyl aryl group is formed into an alkyl sulfonate (for example, o- * 3,5-trimethylbenzylsulfonium monohydroxyamine, o-methanesulfonylhydroxyamine) Or o-hydroxyamine sulfonic acid) reaction to obtain the corresponding 3-amino sulfamate salt, and then vulcanization to complete. The reaction with the sulfonate is in a suitable solvent (e.g., ethyl acetate, methylene chloride, tetrahydrofuran, a mixture of any suitable solvents, etc., preferably acetonitrile). It is preferably carried out at about 20¾ to 0.5 to 18 hours. There are further steps in this paragraph. The details of the reaction steps are described in Example 15. 5 ° The compound of formula 1 can be prepared from the corresponding compound of formula 5 and a substituted substituted oxazole in a suitable solvent (dimethylformamide • Dimethyl sulfite, acetonitrile, etc.). The reaction is performed at 50C to 100¾ *, preferably about 85 ° C, for 8 to 24 hours (for further details, refer to Example 13 under M). In a similar manner, the preparation of a compound in which η is 1 in formula 11 and the oxazole moiety of the molecule is attached to the position • Suitable substituted 2-bromo-1, 2 · 3,4-tetrahelonaphthyl-1-one Reaction with a suitable substituted oxazole is then completed by Mkanogen. The kangen reaction is a catalyst hydrogenation at 15 to 100 ps i, typically 40 to 60 ps i * preferably about 50 ps i in a mixed acidic solvent (such as sulfuric acid, acetic acid, any suitable mixture of acids, etc.) 1 to 2 4 hour. Or • A compound of formula 1 can be prepared by treating the corresponding formula I with Raney® nickel. Raney® nickel treatment is in a compound solvent (such as ethanol, methanol • acetic acid, water, suitable mixture of suitable solvents, etc., preferably ethanol) -36- (Please read the precautions on the back before filling this page) This paper size is applicable to China National Standard for Scrubbing (CNS) A4 (210X297 mm) 470741 A7 B7 V. Description of the invention (), from 0Ό to 1 〇ΟΠ, typically 25Ό to 8 ου, preferably about 8 〇 υ 2 0 2 5 to 4 hours (for further details see Example 14 under M) ° RS and R4 in formula I (a) are hydrogen, rs is bis (Ci-c 4) fluorenylaminomethyl, piperidine-l-yl The preparation of a methyl or morpholine-4-ylmethyl compound can be performed using an appropriate N, N-disubstituted methylammonium salt (eg, N, N-di (Ci-C4) alkylmethylammonium salt such as N · N_ Dimethylmethylene chloride · N, N-Diethylmethylene chloride and the like, 1-methylene piperidine chloride, 4-methylenemorpholine chloride, etc.) Compounds in which R4 and R5 are fluorene are alkylated and then vulcanized to obtain M. The alkylation reaction is carried out in a suitable solvent (dimethylformamide, DMPU, acetonitrile, a suitable mixture of suitable solvents, etc., preferably dimethylformamide) at 50 π to ιοου, typically 80. To 100 ° C · preferably about 9 5 t: for 4 to 18 hours. Compounds of formula I (a) where R3 is hydrogen can be prepared from compounds of formula 11 and a strong base (for example, n-butyllithium lithium diisopropylamidamine (LDA) printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs ( Please read the notes on the back before filling in this page) etc.) The reaction in a suitable solvent (such as 1,2-dimethoxyethane · tetrahydrofuran, 2-methoxyethyl ether, etc.), the phase Corresponding to 2-oxazolidine, and then vulcanized to obtain. The reaction with the base is to cool the solution of the compound of Formula 12 to between 0¾ and -78¾, typically between 50¾ and -78Ό, preferably about 78¾, adding the base, and then carrying out the reaction for 0.25 to 3 hours. . The curing reaction ranges from 0 to 7 8 到, typically from 50 一 to 78 Ό, preferably from about 78 进行 to 2 to 1 8 hrs. -37- This paper size applies Chinese National Standard (CNS) A4 specifications (210X297 mm) 470741 A7 B7 V. Description of the invention (

時。有關此段的進一步反應步嫌詳情記載於Μ下的實例 1 6 〇一種製備式I (a)中R3和R4為氫的化合物的方法由Μ下反應圖IV所表示：反應圖I VTime. Details of further reaction steps in this paragraph are described in Example 16 under M. A method for preparing compounds in which R3 and R4 are hydrogen in formula I (a) is shown in Reaction Diagram IV below M

經濟部中夬標準局員工消費合作社印製其中每個η · t 式 I ( a ) (式1 2 )的製理式1 3化合物在0 C到4 0 C 行0 . 1到2小式1 3的化化物在一合適溶二甲基甲醯胺或到1 Ο Ο Ό，典 1 2到2 4小時以下的實例1 7 一種製備式和R1定義同發明概要中的式I。中R3和R4為氫，R5為胺基的化合物備可用鹼（例如氫氧化鉀或氬氧化納）處，進行簠排。用鍮處理Μ及伴随的重排係，典型1 0¾到30°C，較佳約20t!進時。合物可製備於式9化合物與胺基乙腈氫氯劑（例如三乙基胺，乙腈中的三乙基胺’ 二甲基亞確I)中進行反應。反應係在2〇υ 型1 0¾到30C，較佳約20¾進行。有關此段的進一步反應步驟詳情記載於〇 I (a)中R3為氬，R4為氳，（Cji ----------f------IT------.if (請先閲讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標隼（CNS〉A4規格（210X297公釐〉 1 4 7 ο 7 4 A7 B7 五、發明説明（The China National Standards Bureau Employees' Cooperative of the Ministry of Economic Affairs printed each of these η · t formula I (a) (formula 1 2). Formula 1 3 compounds in 0 C to 4 0 C rows 0.1 to 2 small formula 1 The compound of 3 is dissolved in dimethylformamide or to 100 μΌ, and is shown in Example 1 within 2 to 24 hours. 7 A preparation formula and R1 are defined as Formula I in the summary of the invention. Where R3 and R4 are hydrogen, and R5 is an amine compound. The depletion can be performed with a base (such as potassium hydroxide or sodium argon). The treatment of M and the accompanying rearrangement system with plutonium is typically 10 to 30 ° C, preferably about 20t! The compound can be prepared by reacting a compound of formula 9 with an amine acetonitrile hydrochloride agent (e.g., triethylamine, triethylamine ' dimethylacetone I in acetonitrile). The reaction is carried out at 200 ° C to 30 ° C, preferably about 20 °. Details of the further reaction steps in this paragraph are described in 〇 (a) where R3 is argon and R4 is krypton, (Cji ---------- f ------ IT ------ .if (Please read the precautions on the back before filling this page) This paper size applies to Chinese national standard (CNS> A4 size (210X297mm> 1 4 7 ο 7 4 A7 B7) 5. Description of the invention (

一 C4 )烷基或（Ct 一04 )烷基氧基羰基，R5為氰基或（Ci 一 C4 )烷基氧基羰基的化合物的方法如Μ下反應圖V所載：反應圖VA method for a compound of C4) alkyl or (Ct04) alkyloxycarbonyl, and R5 is cyano or (Ci-C4) alkyloxycarbonyl is as shown in Reaction Scheme V: Reaction Scheme V

肛-BuOCHO orAnal-BuOCHO or

CH.C(0)CHO L-CC〇)R3/CH.C (0) CHO L-CC〇) R3 /

CHOCHO

3SCK3SCK

其中L為一離去基（例如鹵素*烷基氧基*醯氧基，芳氧基等），R3 2為氰基或（Cx —C4 )烷基氧基羰基），R33為氩，（〇1一（：4)烷基或（〇1—(：4)烷基氧基羰基*每個η，t和R1定義同發明概要中的式I 經濟部中央標準局員工消費合作社印製式I(a)中R3為氫，R4為氫，（Ci-Ci) 烷基或（Ci -C4 )烷基氧基羰基和R5為氰基或（Ci 一 C4 )烷基氧基羰基（式14)的化合物係製備於反應式16化合物與式R3 3 c (0) L化合物，得到式15 化合物，然後使式1 5化合物與硫氰酸反應而製得。與式 -39- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 470741 A7 B7 經濟部中央標準局員工消費合作社印製五、發明説明（） R3 3 C (0) L的反應係於鹼（例如三鈒丁氧化鉀， LDA等）存在下及在一合適溶劑（例如四氫肤喃，1 · 2 _二乙氧基乙烷，二乙基醚，任何合適溶劑的適當混合物等）中進行。例如，式1 5中R4為氫的化合物可製備於式1 6化合物與烷基或甲酸芳酯（例如甲酸乙酯，甲酸苯_等）於三級丁氧化鉀存在下的反應。與甲酸酯的反應係在一 4 0¾ 到65C，典型一 30t!到0°C，較佳在約一 1 5¾反應 3到24小時（進一步的詳情參考Μ下的實例24)。式 15中R4為（Ct -C4 )烷基的化合物可製備於式 1 6化合物與（C2 — C5 )烷酸氯化物或酸酐（例如乙醸基氯化物，丙醢基氯化物*醋酸酐等）在LDA存在下的反應。與酸氯化物或酸酐的反應係在一 781C到_ 1 ，典型—50Ό到一 78¾，較佳約一 78¾進行1到 24小時（進一步的詳情參考Μ下的實例25)。與硫氰酸的反應係與硫氣酸鉀在酸水溶液（例如水性氫氯酸I水性硫酸，水性磷酸等水溶液）存在下於5 0¾到1 〇〇〇，典型7 5 t：到9 5 t：，較佳約8 5 t：進行1到5小時。式1 6化合物的製備可將式1 7化合物在甲酸正丁酯中，於7〇υ到105t：·較佳約105t!加熱3到24 小時。或者，式1 6化合物可製備於式1 7化合物與醋酸甲酸酐在一合適溶劑（例如甲撐氯化物，二氯甲烷，四氫呋喃等）中的反應。與醋酸甲酸酐的反應係於一iSt!到 -40- (請先閱讀背面之注意事項再填寫本頁) 裝· --11 絲本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 470741Where L is a leaving group (for example, halogen * alkyloxy * fluorenyloxy, aryloxy, etc.), R3 2 is cyano or (Cx -C4) alkyloxycarbonyl), R33 is argon, ( 1 a (: 4) alkyl or (〇1 -—: 4) alkyloxycarbonyl group * each η, t and R1 are defined as in formula I in the summary of the invention. (a) in which R3 is hydrogen, R4 is hydrogen, (Ci-Ci) alkyl or (Ci-C4) alkyloxycarbonyl and R5 is cyano or (Ci-C4) alkyloxycarbonyl (Formula 14) The compound is prepared by reacting a compound of formula 16 and a compound of formula R3 3 c (0) L to obtain a compound of formula 15 and then reacting a compound of formula 15 with thiocyanic acid. With formula -39- This paper is applicable to China National Standard (CNS) A4 specification (210X297 mm) 470741 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention () The reaction of R3 3 C (0) L is based on alkali (such as potassium trioxobutoxide , LDA, etc.) and in a suitable solvent (such as tetrahydrofuran, 1.2-diethoxyethane, diethyl ether, any suitable mixture of suitable solvents, etc.) For example, a compound in which R4 is hydrogen in Formula 15 can be prepared by reacting a compound of Formula 16 with an alkyl or aryl formate (such as ethyl formate, benzene formate, etc.) in the presence of tertiary potassium butoxide. The reaction of the acid ester is at a temperature of 4 0¾ to 65C, typically a 30t! To 0 ° C, and preferably at a temperature of about 1 5¾ to 3 to 24 hours (for further details, refer to Example 24 under M). R4 in Formula 15 is (Ct -C4) alkyl compounds can be prepared from compounds of formula 16 and (C2-C5) alkanoic acid chlorides or anhydrides (such as ethenyl chloride, propionyl chloride * acetic anhydride, etc.) in the presence of LDA The reaction with acid chlorides or anhydrides is carried out at 781C to -1, typically -50 ° to -78¾, preferably about -78¾ for 1 to 24 hours (for further details, see Example 25 under M). With sulfur The reaction system of cyanic acid and potassium thiosulfate in the presence of an aqueous acid solution (such as aqueous hydrochloric acid I aqueous sulfuric acid, aqueous phosphoric acid and other aqueous solutions) from 50 to 100, typically 7 5 t: to 9 5 t :, Preferably about 8 5 t: for 1 to 5 hours. Preparation of the compound of formula 16 The compound of formula 17 can be prepared in n-butyl formate From 70 to 105 t: preferably about 105 t! Heating for 3 to 24 hours. Alternatively, a compound of formula 16 can be prepared from a compound of formula 17 and acetic acid formic anhydride in a suitable solvent (eg, methylene chloride, methylene chloride , Tetrahydrofuran, etc.). The reaction with acetic acid formic anhydride is from iSt! To -40- (Please read the precautions on the back before filling out this page.) Packing --11 Silk paper size applies Chinese national standards ( CNS) A4 size (210X297 mm) 470741

A7 B7五、發明説明（） 2 5 t：，較佳約Ο Ό進行0 · 5到3小時。式1 7中R3 2為乙氧基羧基的化合物可製備於乙基 (glycoxalte)與式3化合物的堪原胺化反應。遨原胺化反應係在化學遨原劑（例如氰硼氫化納，氫硼化納等）或觸媒性氫化反應（例如氫·炭上鈀，氫，鎳等）存在下於一合適溶劑（例如甲醇*乙醇，醋酸乙酯，任何合適溶劑的適當混合物等）中進行。可Μ壤擇性地K標準方法（例如用乾燥劑如分子篩或共沸）除去水份。有關此處及前段的進一步詳细反應步驟在以下的實例2 3有記載。式1 7中R3 2為氰基的化合物可製備於式3化合物與甲醛亞硫酸氫納錯合物和氰化鉀在一合適溶劑（水，水性乙酵等）中的反應。反應係在50¾到80 °C，典型 5 0 °C到6 0 ，較佳約5 0 t!進行0 . 5到2小時（進一步的詳情參考以下的實例19)。一種製備式I (a)中R3和R5為氫，為甲醯基的化合物的方法，如Μ下反應圃V I所載：反應圖VI (請先閲讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製A7 B7 V. Description of the invention (2) 2 5 t: It is preferably about 0 to 5 hours for 0.5 to 3 hours. The compound in which R3 2 is an ethoxycarboxyl group in Formula 17 can be prepared in the kangen amination reaction of ethyl compound (glycoxalte) with the compound of Formula 3. The rhenium amination reaction is in the presence of a chemical rhenium agent (such as sodium cyanoborohydride, sodium borohydride, etc.) or a catalytic hydrogenation reaction (such as palladium, hydrogen, nickel, etc. on hydrogen and carbon) in a suitable solvent ( Such as methanol * ethanol, ethyl acetate, any suitable mixture of suitable solvents, etc.). Water can be selectively removed by standard methods (e.g., using a desiccant such as molecular sieve or azeotropic). Further detailed reaction steps here and in the previous paragraph are described in Example 23 below. A compound in which R3 2 is a cyano group in Formula 17 can be prepared by reacting a compound of Formula 3 with a formaldehyde sodium bisulfite complex and potassium cyanide in a suitable solvent (water, ethyl acetate, etc.). The reaction is carried out at 50¾ to 80 ° C, typically 50 ° C to 60 °, preferably about 50 t! For 0.5 to 2 hours (for further details, refer to Example 19 below). A method for preparing compounds wherein R3 and R5 in formula I (a) are hydrogen and formyl groups, as shown in Reaction Garden VI under M: Reaction Diagram VI (Please read the notes on the back before filling this page) Ministry of Economic Affairs Printed by the Consumer Standards Cooperative of the Central Bureau of Standards

-41- 本紙張尺度適用中國國家標準（CNS ) Α4規格（210Χ297公釐）經濟部中央標準局員工消費合作社印製 470741 A7 _B7_____ 五、發明説明（）其中每個η，t和R1定義同發明概要中的式I ° 式I (a)中R3和R5為氫· R4為甲醣基的化合物（式18)係製備於氧化式19化合物。氧化作用係採用一合適的氧化劑（例如四醋酸鉛，高碘酸等）於一合癯溶劑（例如醋酸笨，醋酸甲笨，醋酸，任何合適溶劑的適當混合物）中，在到8〇υ，典型20t：到40Ό’ 較佳約2 5 t：進行0 ‘ 2 5到4小時。式19化合物係製備於式19化合物與D— （+)葡萄胺的反應。該反應係在一合適溶劑*典型為酵類（例如乙醇，甲醇•任何醇的適當混合物等），較佳為乙酵，在 5〇υ到80C，典型70Ό到80¾，較佳約80Ό進行1到2小時。有瞄此段的進一步反應步驟詳情記載於K 下的實例2 2。式I中R3和R4為氫，R5為羥基甲基的化合物可製備於式3化合物或其酸加成鹽與硫氰酸和二羥基丙_在一合適溶劑（例如醋酸乙酯*四氫呋喃•二噁烷，任何合適溶劑的適當混合物等，較佳為醋酸乙酯）中的反應•然後選擇性地用硫酸（用硫酸處理K提高純度）處理反應混合物。反應係與硫氰酸鉀在酸存在下（冰醋酸，丙酸等，較佳為冰醋酸），於氮氣中及20¾到5 Ot：進行0 . 5 到3小時（進一步的詳情參考以下的實例丨8)。式I ( b )化合物一種製備式I (b)中R7為氫，胺基甲基，（Ct -42- 本紙張尺度適用中國國家標準（CNS ) A4規格（2丨0X297公釐） ----------，裝------，灯------Μ (請先閱讀背面之注意事項异填寫本頁)-41- This paper size applies to Chinese National Standard (CNS) A4 specification (210 × 297 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 470741 A7 _B7_____ V. Description of the invention () where each η, t, and R1 have the same definition as the invention In the general formula I ° A compound (Formula 18) in which R3 and R5 are hydrogen and R4 is a methylose group in formula I (a) is prepared by oxidizing the compound of formula 19. Oxidation is carried out using a suitable oxidant (such as lead tetraacetate, periodic acid, etc.) in a synthetic solvent (such as benzyl acetate, methylbenzyl acetate, acetic acid, any suitable mixture of suitable solvents). 20t: to 40Ό ', preferably about 2 5t: 0'2 to 5 to 4 hours. The compound of formula 19 is prepared by reacting the compound of formula 19 with D-(+) glucosamine. The reaction is carried out in a suitable solvent * typically fermentation (e.g. ethanol, methanol, any suitable mixture of alcohols, etc.), preferably acetogenic fermentation, at 50o to 80C, typically 70Ό to 80¾, preferably about 80Ό. 1 To 2 hours. Further reaction steps for this paragraph are detailed in Example 22 under K. Compounds of formula I in which R3 and R4 are hydrogen and R5 is hydroxymethyl can be prepared from a compound of formula 3 or an acid addition salt thereof with thiocyanate and dihydroxypropane in a suitable solvent such as ethyl acetate * tetrahydrofuran · di Oxane, a suitable mixture of any suitable solvent, etc., preferably ethyl acetate) • The reaction mixture is then optionally treated with sulfuric acid (treatment of K with sulfuric acid to increase purity). Reaction with potassium thiocyanate in the presence of an acid (glacial acetic acid, propionic acid, etc., preferably glacial acetic acid), under nitrogen at 20¾ to 5 Ot: for 0.5 to 3 hours (for further details, refer to the following examples)丨 8). A compound of formula I (b) is prepared in formula I (b) where R7 is hydrogen, aminomethyl, (Ct -42- this paper size applies Chinese National Standard (CNS) A4 specification (2 丨 0X297 mm) --- -------, install ------, lamp ------ Μ (please read the notes on the back first and fill in this page)

470741 A7 _____B7 _ 五、發明説明（）一 c4 )烷基甲基，二（Ci -c4 )烷基胺基甲基，吡咯烷一1 一基甲基，锨啶一 1 一基甲基，嗎啉一 4 —基甲基•哌嗪-1 一基甲基，4 — (Ct — C4 )烷基哌嗪一 1 一基甲基的化合物的方法由K下反應圖V I I所表示：470741 A7 _____B7 _ 5. Explanation of the invention () a c4) alkylmethyl, di (Ci-c4) alkylaminomethyl, pyrrolidine 1 1 methyl, pyrimidine 1 1 methyl, The method of the phosphino-4-methylmethylpiperazine-1 monomethyl, 4- (Ct-C4) alkylpiperazine-1 monomethyl group is shown in the reaction diagram VII under K:

反應圖V I IReaction diagram V I I

其中R3 4為氫，胺基甲基，（Ci -C4 )烷基甲基，二（Ci -C4 )烷基胺基甲基·#!；咯烷一1 一基甲基，呢啶—1 —基甲基，嗎啉_4-基甲基，呢嗪一1 —基甲基，4 - (Ci —C4)烷基锨嗪一 1 一基甲基，或其保護衍生物•每涸n，t和R1定義同發明概要中的式I。式I (b)中R?為氳，胺基甲基* ( C i ~ C 4 ) 烷基甲基，二（Ct -C4 )烷基胺基甲基，吡咯烷一 1 —基甲基，呢啶一 1 —基甲基，嗎啉一4 —基甲基，顿嚷一 1-基甲基，4 - (Ci -C4 )烷基哌嗓一1—基甲基（式2 0)的化合物可製備於式2 1化合物或其保護衍生物與一_ (例如乙氧化納，三級丁氧化鉀等）及在一合適溶劑，典型為酵（例如乙醇，三级丁醇，異丙酵，任何合適醇的適當混合物），較佳在乙醇中進行閉環反應，然 -43- 本紙張尺度適用中國國家標準（CNS ) A4規格（210 X 297公釐） ----------并衣------1T------線 (請先閱讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 470741 經濟部中央標準局員工消費合作社印製 A7 B7五、發明説明（）後除去任何保護基。與鹼的反應及最終的閉環反應係在 0 t：到7 5 υ，較佳約2 Ο 進行1到2 4小時。去保護作用可在一合適溶劑（例如15%無水氯化氫（醋酸乙酯中），三氟醋酸（甲撐氯化物中）等）中用酸予Κ處理。式2 1化合物係製備於式9化合物與式Hz NHNC (0) R3 4醯肼或其保護衍生物在一合適溶劑（例如二甲基甲醯胺，醋酸乙酯，任何合適溶劑的適當混合物等）中的反應。反應係在5〇t：到1 οου，典型7〇υ到 9 0 °C，較佳約8 0 D進行1到4小時。式H2 NHNC (0) R3 4醢肼可製備於相對應胺基醋酸甲酯，或其保護衍生物與醯胼在一合適溶劑（例如甲醇，乙酵，二甲基甲醯胺，任何合適溶劑的適當混合物等）中的反應。反應係在2〇υ到80Ό，典型50t!到 70t：，較佳約65Ό進行48到96小時。合適的胺基醋酸甲酯可購得，或者可Μ藉有機合成簡單地加以製備。例如，被保護的胺基醋酸甲酿的衍生物可製侮於Ν-(三級丁氧基羰基）甘氨酸的酯化反應。其它胺基醋酸酯可製備於相對應氯醋酸甲酯與式NHR3 6 R3 7胺（其中 R3 6和R3 7個自獨立為（Ci 一 C4 )烷基或一起為 —(C Η 2 ) 4 — 1 — ( C Η 2 ) 5 —，— ( C Η 2 ) 2 0 (CH2) 2 -或-(CH2) 2 NR3 8 ( C Η 2 ) 2 - ，其中R3 8為氫或（Ci 一 c4 )烷基）於一合適溶劑 (乙腈，乙醇，二甲基甲醃胺，任何合適溶劑的適當混合 -44- (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) A4規格（210 X 297公釐） 470741 Α7 Β7 五、發明説明（）物等）中的反應。反應係在0¾到loot;，典型65¾ 到9 5 *0，較佳約8 Ο Ό進行1到4 8小時。有關此段的進一步反應步驟詳情記載於Μ下的實例2 6。一種製備式I (c)中R7為氫的化合物的方法由从下反應画VIII所表示：Where R3 4 is hydrogen, aminomethyl, (Ci -C4) alkylmethyl, bis (Ci -C4) alkylaminomethyl · # !; pyridine-1 monomethyl, and morphidine-1 —Ylmethyl, morpholine 4-ylmethyl, morphazine 1-ylmethyl, 4- (Ci —C4) alkylpyrazine-1 1-methyl, or its protected derivative • per n , T and R1 are as defined in Formula I in the Summary of the Invention. In Formula I (b), R? Is fluorene, aminomethyl * (Ci ~ C4) alkylmethyl, bis (Ct-C4) alkylaminomethyl, pyrrolidine-1-ylmethyl, 1-methylmethyl, 1-ylmethyl, morpholine, 4-ylmethyl, 1-ylmethyl, 4- (Ci-C4) alkylpiperazine, 1-methylmethyl (Formula 2) The compound can be prepared from a compound of formula 21 or a protected derivative thereof with mono- (such as sodium ethoxylate, tertiary potassium butoxide, etc.) and in a suitable solvent, typically a leaven (such as ethanol, tertiary butanol, isopropylase , Any suitable mixture of suitable alcohols), preferably closed-loop reaction in ethanol, but -43- This paper size is applicable to China National Standard (CNS) A4 specifications (210 X 297 mm) --------- -Combination ------ 1T ------ line (please read the notes on the back before filling out this page) Printed by the Employees' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 470741 Preparation of A7 B7 V. Description of the invention () After removing any protecting groups. The reaction with the base and the final ring-closing reaction are performed at 0 t: to 7 5 υ, preferably about 20 for 1 to 24 hours. Deprotection can be treated with acid pre-K in a suitable solvent (e.g. 15% anhydrous hydrogen chloride (in ethyl acetate), trifluoroacetic acid (in methylene chloride), etc.). The compound of formula 21 is prepared from a compound of formula 9 and a compound of formula NHNC (0) R3 4 hydrazine or a protected derivative thereof in a suitable solvent (for example, dimethylformamide, ethyl acetate, a suitable mixture of any suitable solvent, etc. ). The reaction is carried out at 50 ° to 1 °, typically 70 ° to 90 ° C, and preferably about 80 ° D for 1 to 4 hours. The formula H2 NHNC (0) R3 4 hydrazine can be prepared from the corresponding amino methyl acetate, or its protected derivative and hydrazone in a suitable solvent (such as methanol, ethyl acetate, dimethylformamide, any suitable solvent). Appropriate mixture, etc.). The reaction is carried out at 20 to 80 Ό, typically 50 to 70 ：:, preferably about 65 Ό for 48 to 96 hours. Suitable amino methyl acetate is commercially available or can be prepared simply by organic synthesis. For example, protected derivatives of aminoacetic acid methyl esters can react with the esterification of N- (tertiary butoxycarbonyl) glycine. Other amino acetates can be prepared from the corresponding methyl chloroacetate and amines of the formula NHR3 6 R3 7 (wherein R3 6 and R3 7 are independently (Ci-C4) alkyl or together are-(C Η 2) 4- 1 — (C Η 2) 5 —, — (C Η 2) 2 0 (CH2) 2 -or-(CH2) 2 NR3 8 (C Η 2) 2-, where R3 8 is hydrogen or (Ci -c4) Alkyl) in a suitable solvent (acetonitrile, ethanol, dimethyl methylamine, any suitable solvent -44- (Please read the precautions on the back before filling this page) This paper size applies to Chinese national standards (CNS ) A4 size (210 X 297 mm) 470741 A7 B7 V. Reaction in the description of the invention (). The reaction is carried out at 0¾ to 10 minutes, typically 65¾ to 9 5 * 0, preferably about 80 Ό for 1 to 48 hours. Details of further reaction steps in this paragraph are described in Example 26 under M. A method for preparing a compound in which R7 is hydrogen in formula I (c) is represented by the following reaction scheme VIII:

反應圖V I I IReaction diagram V I I I

(ctt2>3aiscK —^1 n n 1 H I n n in n I I : I (請先閱讀背面之注意事項再填寫本頁)(ctt2 > 3aiscK — ^ 1 n n 1 H I n n in n I I: I (Please read the precautions on the back before filling this page)

nh2 Η〆 I Ε CEOnh2 Η〆 I Ε CEO

,CH0, CH0

經濟部中央標準局員工消費合作社印製於丁在行備級係進製三應 P 。可，反 ο I 物鉀環 7 式合化朗約的化氧的佳中的氫終較要 >%最，概 2 ο 及 P 明 2 1 應 ο 發式如反 9 同 ί 例的到義氯 < 餓 Ρ 定為鹼與 ο - 7 適 05 RR合應，和中一反 Ρ t } 與的 ο 。 , C 物中 ο 時 n{ 合 } 1 小個 I 化等到 4 每式 3 鉀 P 2 中 2 化 ο 到其式氧 2 1Printed by Yu Ding's Reserve Department of the Central Standards Bureau's Consumer Cooperative Department of the Ministry of Economic Affairs. However, the reaction of the compound I, potassium ring 7 and the chemical formula of the long-term oxygen of hydrogen is more important than%, most probably 2 ο, and P 2 21 should be issued. Isochloride is defined as the combination of alkali and ο-7 05 RR, and 中 of the secondary one. , In C, n {combined} 1 small I is equal to 4 per 3 potassium in formula P 2 is ο to its oxygen 2 1

-45- 本紙張尺度適财_家標準（CNS)从麟_ ( 2獻297公酱〉 470741 Α7 Β7 五、發明説明（）式2 3化合物係製備於式24化合物與異硫氰酸鹽（例如三甲基甲矽烷基異硫氟酸鹽等）在一合適溶劑（例如甲笨，1 ，2 —二甲氧基乙烷*任何合適溶劑的適當混合物等）中的反應。反應係在20t：到100Ό，典型到9 0 t，較佳約7 0 °C進行1 8到2 4小時。式2 4化合物係製備於式7化合物與甲酸胼在一合適溶劑（例如乙醇，異丙醇等）中的反應，然後遯原。與肼的反應係在一酸存在下（例如氫氯酸，對-甲笨磺酸，硼酸，三氟醋酸等）於2 0 C到1 0 0 C，典型6 0 Ό到9 0 ，較佳約 7 5¾進行1到5小時。堪原反應可採用一化學堪原劑 (例如氫硼化鋰，氫硼化納*氫氰硼化納等）於一合適溶劑，典型為醇（例如乙醇，任何合適醇的適當混合物），較佳為乙酵中於2 01到8 0°C進行8到24小時。有關此段的進一步反應步驟詳情記載於Μ下的實例2 7。式I (c)中R7為胺基的化合物可製備於式5化合物與1 ，2，4 一***一 4 一基胺基的反應，得到相對應 4_胺基三锉鹽，然後予Μ硫化。與4 —胺基〔1 * 2，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填寫本頁) 4〕***的反應係在50Ό到1 00Ό，典型80Ό到9 0Ό，較佳約9〇υ進行1到8小時。硫化反應係與蟲漆硫在溫和鹼（例如三乙基胺等）存在下，於50¾到125Ό ，典型8 0 °C到1 0 0 t，較佳約9 0 Ό進行1到8小時 (進一步的詳情參考Μ下的實例28)。製備式I化合物的另外方法 -46- 本紙張尺度適用中國國家標準（CNS ) Α4規格（210Χ297公釐） 470741 經濟部中央標準局員工消費合作社印製 A7 B7五、發明説明（）式I中R5為1 Η —四唑一 5 —基的化合物可製備於式I中R5為氰基的化合物與蠱氮酸衍生物（例如三丁基錫叠氮，三苯基甲矽烷基叠氮，三級丁基二苯基甲矽烷基叠氮等）的反應。反應係在1〇〇υ到150Ό，典型 1 2 0 t：到1 4 0 t： *較佳約1 3 Ο 進行2到1 8小時 (進一步的詳情參考以下的實例21)。式I中R5為氨基甲醢的化合物可製備於水解式I中 Rs為氰基的化合物。水解反應係與氫氯酸水溶液在 1 00¾到140¾，典型1 25Ϊ!到1 35¾，較佳約 1 3 0 t進行2到1 8小時。如K上所述進行，得到5， 6_二氟茚滿一 2 —基一 2 —硫賙一 2，3 —二氫一 1 Η 一咪唑一 4-基一羧醢胺，熔點高於280¾。式I中R5為一 C (NH) NR1 s R1 6的化合物可製備於式I中R5為氣基的化合物與式（CHs ) 2 A 1 NR1 5 R1 6試劑在一合適溶劑（例如甲苯•苯，甲撐氯化物，四氯乙烷，任何合適溶劑的適當混合物等）中的反應。反應係在20°C到1 3〇υ，典型60t!到1 00Ό ，較佳約8 0 進行1到1 8小時。式（C Η 3 ) 2 A 1 NR1 5 R1 6試劑係製備於式NHR1 5 R1 6胺與三甲基鋁的反應。如Μ上所述進行，得到5 —(胺基亞胺基甲基）一1- (5 *6 -二氟茚一 2 -基 > -1 ，3 -二氫咪唑一2—硫酮和1一（5，6-二氟茚滿一2-基） -5 〔亞胺基一(2，2，2 —三氟乙基胺基）甲基〕_ -47- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐） n-11 11 n n n n 11 ^ n 11111 ,Μ. (請先閱讀背面之注意事項再填寫本頁) 470741 經濟部中央標準局員工消費合作社印製 A7 B7 五、發明説明（） 1 ·3 —二氫脒唑—2 —硫酮，熔點199υ到20〇υ 〇式I中Rs為4，5 —二氣咪唑~2 —基的化合物可製備於式I中R5為氰基的化合物與乙烯二胺的反應。反懕係在對一甲笨磺酸存在下將試劑在1 0 0¾到2 5 Ot! ，典型1 8 0 到2 2 Ό，較佳約2 0 0 t!進行1到3小時。如Μ上所述進行，製得1 ，2，3，4 —四氫萘一2 一基一 5 — （4，5 — 二氫畔哩一 2_ 基）1 ，3 -二氫咪唑一 2 —硫酮，熔點1 30t!到145t：。式I中R3和R4為氫，R5為胺基乙基的化合物可製備於遨原式I中R5為氣基的化合物。遨原反應可採用一化學遢原劑（例如氫鋁化鋰，硼烷（四氫呋喃中），氫化鋁等）在一合適溶劑（例如四氲肤喃，1 ，2 —二甲氧基乙烷，2，2 —二甲氧基乙基醚，任何合通溶劑的適當混合物等），在0°C到65t!，典型〇Ό到20t!，較佳約0 °C進行1到5小時（進一步的詳情參考Μ下的實例 2 0) 〇一種製備式I中R3和R4為氩，Rs為胺基甲基的化合物的方法，由以下反應圖I X所表示：-45- The paper size is suitable for household use (CNS) from Lin_ (2 297 male sauces) 470741 Α7 Β7 V. Description of the invention () The compound of formula 2 3 is prepared from the compound of formula 24 and isothiocyanate ( For example, the reaction of trimethylsilyl isothiofluorate, etc.) in a suitable solvent (eg methylbenzyl, 1,2-dimethoxyethane * any suitable mixture of suitable solvents, etc.). The reaction system is at 20t. : To 100 Ό, typically to 90 t, preferably about 70 ° C for 18 to 24 hours. The compound of formula 24 is prepared from the compound of formula 7 and formic acid in a suitable solvent (such as ethanol, isopropanol, etc.) ), Followed by Korihara. The reaction with hydrazine is in the presence of an acid (such as hydrochloric acid, p-toluenesulfonic acid, boric acid, trifluoroacetic acid, etc.) at 20 C to 100 C, typically 60 to 90, preferably about 7 to 5¾, for 1 to 5 hours. The kangen reaction can use a chemical kanogen (such as lithium borohydride, sodium borohydride * sodium cyanoborohydride, etc.) in a suitable The solvent is typically an alcohol (e.g. ethanol, any suitable mixture of suitable alcohols), preferably in acetic acid for 8 to 24 hours at 21 to 80 ° C. Related The details of the further reaction steps in this paragraph are described in Example 27 under M. Compounds in which R7 is an amine group in formula I (c) can be prepared from compounds of formula 5 and 1,2,4-triazole-4 4-aminoamine The reaction yields the corresponding 4-amine-based trifile salt, which is then vulcanized. It is printed with 4-amine-based [1 * 2, printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page 4) The reaction system of triazole is 50 在 to 100Ό, typically 80Ό to 90Ό, preferably about 90 约 for 1 to 8 hours. The sulfurization reaction system and shellac sulfur are in a mild base (such as triethylamine, etc.) In the presence of 50 to 125 Ό, typically 80 ° C to 100 t, preferably about 90 Ό for 1 to 8 hours (for further details, see Example 28 under M). Another method for preparing compounds of formula I- 46- This paper size applies Chinese National Standard (CNS) A4 specification (210 × 297 mm) 470741 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs A7 B7 V. Description of the invention () R5 in Formula I is 1 Η -tetrazole-5 -Based compounds can be prepared from compounds of formula I where R5 is cyano and hydrazone derivatives (such as tributyl Tin azide, triphenylsilyl azide, tert-butyldiphenylsilyl azide, etc.). The reaction range is 100 to 150 Ό, typically 12 0 t: to 1 4 0 t: * preferably about 1 3 0 for 2 to 18 hours (for further details, refer to Example 21 below). Compounds of formula I where R5 is carbamate can be prepared by hydrolysis of compounds of formula I where Rs is cyano The hydrolysis reaction is carried out with an aqueous hydrochloric acid solution at a temperature of from 100 ¾ to 140 ¾, typically 1 25 Ϊ! To 1 35 ¾, preferably about 1 30 t for 2 to 18 hours. As described in K, 5, 6-difluoroindan- 2-yl-2 -thithio-2,3-dihydro-1 1 -imidazole -4-yl-carboxamidine is obtained with a melting point higher than 280¾ . A compound in which R5 is a C (NH) NR1 s R1 6 in formula I can be prepared from a compound in which R5 is a gas group in formula I and a formula (CHs) 2 A 1 NR1 5 R1 6 reagent in a suitable solvent (such as toluene · benzene , Methylene chloride, tetrachloroethane, any suitable mixture of suitable solvents, etc.). The reaction is carried out at 20 ° C to 130 ° C, typically 60t! To 100 ° C, preferably about 80 for 1 to 18 hours. The formula (C Η 3) 2 A 1 NR1 5 R1 6 reagent is prepared by the reaction of the formula NHR1 5 R1 6 amine with trimethylaluminum. Performing as described above, 5- (aminoiminomethyl) -1- (5 * 6-difluoroinden-2-yl) is obtained, and -1,3-dihydroimidazol-2-thione and 1- (5,6-difluoroindan-2-yl) -5 [Imine ((2,2,2-trifluoroethylamino) methyl]]--47- This paper is applicable to China Standard (CNS) A4 specification (210X 297 mm) n-11 11 nnnn 11 ^ n 11111, M. (Please read the precautions on the back before filling out this page) 470741 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (1) 3-dihydrooxazole-2-thione, melting point 199υ to 20〇υ 〇 Compounds in formula I where Rs is 4,5-diimidazol ~ 2- can be prepared in formula I In the reaction of R5 is a cyano compound and ethylenediamine. The reaction system is in the presence of p-toluenesulfonic acid, and the reagent is 10 0¾ to 2 5 Ot !, typically 180 to 2 2 Ό, preferably about 2 0 0 t! For 1 to 3 hours. 1,2,3,4-tetrahydronaphthalene-2 2-yl-5— (4,5—dihydro-2-yl) ) 1,3-dihydroimidazole- 2-thione, melting point 1 30t! To 145t :. Compounds where R3 and R4 are hydrogen and R5 is amine ethyl in I can be prepared from compounds where R5 is gaseous in formula I. The rheogen reaction can use a chemical rhenium agent (such as lithium aluminum hydride, borane) (In tetrahydrofuran), aluminum hydride, etc.) in a suitable solvent (e.g. tetrahydrofuran, 1,2-dimethoxyethane, 2,2-dimethoxyethyl ether, any suitable mixture of solvents) Etc.), at 0 ° C to 65t !, typically 0 ° to 20t !, preferably about 0 ° C for 1 to 5 hours (for further details, refer to Example 2 under M) 0) R3 and A method in which R4 is argon and Rs is an aminomethyl compound is shown in the following reaction diagram IX:

反應圖I X -48- 本紙張尺度適用中國國家標準（CNS ) Α4規格（210Χ297公釐） I I 11 ^4· n τ 口 IΜ (請先閱讀背面之注意事項再填寫本頁) 470741 A7 B7 五、發明説明（Reaction Chart IX -48- This paper size is in accordance with Chinese National Standard (CNS) A4 specification (210 × 297 mm) II 11 ^ 4 · n τ mouth IM (Please read the precautions on the back before filling this page) 470741 A7 B7 V. Invention Description (

OHOH

(請先閱讀背面之注意事項再填寫本頁) 其中R3 5為氫* (C^ - C4 )烷基或三氟（Ci — CU ) 烷基，每個η，t和R1定義同發明概要中的式I。式I 中R3和R4均為氫，R5為胺基甲基化合物（式25) 經濟部中央標準局員工消費合作社印製的酸加成鹽可製備於式I中1?5為甲醢胺基甲基，（C農一 C4 )烷基羰基胺基甲基或三氟（Ci —C4 )烷基羰基一胺基甲基（式26)相對應化合物的酸觸媒水解。水解係在一合適溶劑*典型為酵（例如異丙醇，乙醇•甲酵，任何合適醇的適當混合物等）*較佳為在異丙醇中，於氮氣及65¾到82Ό，較佳在回流下進行0 . 5到4小時。式I中R3和R4均為氫* R5為胺基甲基的化合物的藥學上可接受酸加成鹽可製備於藥學上可接受酸（例如 2到8當量濃氫氯酸，較佳約5當最）的水解反應。或者，式2 5化合物的任何酸加成鹽形式可被轉換成相對應的自由態鹼形式，其係與可接受無機或有機敝反應*然後藉 -49-本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 470741 A7 B7 五、發明説明（）著與一合適藥學上可接受酸反應而將其轉換成蕖學上可接受酸加成盥。有關此段及前段的進一步反應步驟詳情記載於K下的實例3 1。式I中R5為甲醢胺基甲基* (Ci-C*)烷基羰基胺基甲基或三氟（Ci -C4 )烷基羰基胺基甲基的化合物可製備於式I中Rs為羥基甲基的相對應化合物與式 Hz NC (0) R3 s的一級醢胺（例如甲醮胺，乙醮胺，三氟乙醢胺等）反應。反應係將式27化合物添加到豳胺，然後在通人氮氣時將混合物在1 50Ό到1 90¾加熱0 · 5到2小時。較佳者•醢胺為甲醢胺·反應在17 0°C到1 751加熱約1小時。以類似方法進行，唯一不同的是用尿素取代一級豳胺，可製得式I中Rs為腺基甲基的化合物。有關此段的進一步反應步驟詳情記載於Μ下的實例2 9。一製備式2 6化合物的較佳方法包括式2 7化合物與式NH4 + -OC (0) R3 5 (例如甲酸銨，醋酸銨，經濟部中央標準局員工消費合作社印製 (請先閲讀背面之注意事項再填寫本頁) 三氟醋酸銨等，Κ甲酸銨較佳）反應。例如，式27化合物可與甲酸銨反應，製得式24中R3 5為氫的化合物。反應係在有或無甲醯胺情況下進行*較佳在1 0 0¾到 1 8 0 C，較佳在1 2 0 Ό到1 5 0 t!進行1到2小時 (進一步的詳情參考K下的實例30)。式I中R3和R4為氫，Rs為氫，胺基甲基，（Ct 一 C4 )烷基甲基，二（C^ 一（：4 )烷基胺基甲基，毗 -50- 本紙張尺度適用中國國家標準（CNS ) A4規格（210 X 297公釐） 470741 Α7 Β7 五、發明説明（）咯烷一 1 —基甲基，锨啶一 1 —基甲基，嗎啉一 4 一基甲基，哌嗪一1 一基甲基，4 一（C^ — C4)烷基呢嗪— 1 _基甲基的化合物係的製備係將式I中R5為羥基甲基的化合物轉換成式26化合物(Please read the notes on the back before filling this page) where R3 5 is hydrogen * (C ^-C4) alkyl or trifluoro (Ci — CU) alkyl, each η, t and R1 are defined in the summary of the invention Formula I. In formula I, R3 and R4 are both hydrogen and R5 is an amino methyl compound (formula 25). The acid addition salt printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs can be prepared in formula I. 1 to 5 are formamidine Corresponding compounds of methyl, (Con-C4) alkylcarbonylaminomethyl or trifluoro (Ci-C4) alkylcarbonylmonoaminomethyl (Formula 26) are hydrolyzed by an acid catalyst. The hydrolysis is in a suitable solvent * typically fermentation (such as isopropanol, ethanol, formazan, any suitable mixture of suitable alcohols, etc.) * Preferably in isopropanol under nitrogen and 65¾ to 82Ό, preferably under reflux It is carried out for 0.5 to 4 hours. R3 and R4 in formula I are both hydrogen * R5 is an aminomethyl compound. A pharmaceutically acceptable acid addition salt of a compound can be prepared from a pharmaceutically acceptable acid (for example, 2 to 8 equivalents of concentrated hydrochloric acid, preferably about 5 When most) hydrolysis reaction. Alternatively, any acid addition salt form of the compound of Formula 25 can be converted to the corresponding free-state base form, which reacts with an acceptable inorganic or organic hydrazone * and then borrows -49- This paper applies the Chinese National Standard (CNS ) A4 size (210X297 mm) 470741 A7 B7 5. Description of the invention () Reacting with a suitable pharmaceutically acceptable acid to convert it into a pharmaceutically acceptable acid addition toilet. Details of further reaction steps in this and the previous paragraph are described in Example 31 under K. Compounds in which R5 is methylamidomethyl * (Ci-C *) alkylcarbonylaminomethyl or trifluoro (Ci-C4) alkylcarbonylaminomethyl can be prepared in formula I where Rs is The corresponding compound of hydroxymethyl is reacted with primary ammonium amine (such as formamidine, acetamide, trifluoroacetamide, etc.) of the formula Hz NC (0) R3 s. In the reaction system, a compound of formula 27 is added to ammonium amine, and the mixture is heated at a temperature of 150 to 190 ¾ under a nitrogen atmosphere for 0.5 to 2 hours. Preferred: Formamide is formamide. The reaction is heated at 170 ° C to 1 751 for about 1 hour. In a similar manner, the only difference is that the primary amidine is replaced with urea, and compounds of formula I in which Rs is adenylmethyl are obtained. Details of further reaction steps in this paragraph are described in Example 29 under M. A preferred method for preparing compounds of formula 26 includes compounds of formula 27 and formula NH4 + -OC (0) R3 5 (for example, ammonium formate, ammonium acetate, printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the Note: Please fill in this page again) Ammonium trifluoroacetate, etc., K ammonium formate is preferred). For example, a compound of formula 27 can be reacted with ammonium formate to produce a compound of formula 24 where R3 5 is hydrogen. The reaction is carried out in the presence or absence of formamidine * preferably at 1 0 0¾ to 1 8 0 C, preferably at 1 2 0 Ό to 15 0 t! For 1 to 2 hours (for further details see under K Example 30). In formula I, R3 and R4 are hydrogen, Rs is hydrogen, aminomethyl, (Ct-C4) alkylmethyl, bis (C ^-(: 4) alkylaminomethyl, -50- Standards are applicable to Chinese National Standard (CNS) A4 specifications (210 X 297 mm) 470741 A7 B7 V. Description of the invention () Pyridine-1 -ylmethyl, pyridine-1 -ylmethyl, morpholine-4 1yl Methyl, piperazine- 1-methyl-, 4- (C ^ -C4) alkylmorphazine- 1-ylmethyl compounds are prepared by converting the compound of formula I in which R5 is a hydroxymethyl group into the formula 26 compounds

(請先閱讀背面之注意事項再填寫本頁) 裝. 經濟部中央標準局員工消費合作社印製其中L為一離去基，每個η，t和R1定義闻發明概要中的式I 。使式28化合物與式HNR3 6 R3 7胺反應，其中R3 6和R3 7個自獨立為（Ci -C4 >烷基或一起為一（CHz) 4·— ，一 ( C Η 2 ) 5 — ，一 ( C Η 2)2〇(CH2)2 -或-(CH2)2NR38 ( c H2) 2 — （其中R3 8為氫或（Ci —C4)烷基）。轉換成式2 8化合物係採用一合適試劑Μ形成一合適的離去基（例如甲烷磺酿氯化物，亞硫基氛化物，五氯化磷》氧氛化磷等），其係於一合適溶劑（例如甲撐氯化物，氣仿*四氫呋喃*任何合適溶劑的適當混合物等）中進行。係與胺的反應係在一合適溶劑（例如四氫呋喃，1 · 2 — 二甲氧基乙烷*乙腈，任何合適溶劑的適當混合物等）中在一 ίου到2〇υ進行1到4小時（進一步的詳情參考 "51- 訂鍵本纸張尺度適用中國國家標準（CNS ) Α4規格（210X297公釐） 1J 4 7 ο 7 4 經濟部中央標準局員工消費合作社印製 A7 _ B7五、發明説明（） Μ下的實例3 2 )。式I中R4為胺基甲基的化合物可製備於式I中R4 為甲醢基的相對應化合物與羥基胺氫氯化物的反應*得到的相對懕肟，然後堪原之。與羥基胺氫氯化物的反應係在一合適鹼（例如氫氧化納，醋酸納等）及一合適溶劑，典型為醇（例如乙醇，甲醇•任何合適醇的適當混合物等）或醇和水混合物（例如乙酵/水（1 : 1)等）中*在 2〇υ到 loot!，典型50Ό到70"C，較佳約60t! 進行1到8小時。肟的遢原可與一化學堪原劑（例如氫化鋁鋰等）在一合適溶劑（例如四氫呋喃*任何合適溶劑的適當混合物等）及一 5〇υ到50*0，典型一 2〇υ到 2 0 *較佳約0°C進行。有關此段的進一步反應步驟詳情記載於K下的實例4 7。式I中R4為一CHzNHR10 ，其中R10定義同發明概要中式I的化合物•可製備於式I中R4為甲醢基的化合物與式NH2 R1 〇胺（例如甘氨酸，三級丁基酯氫氯化物，甘氨醯胺氫氯化物，苯乙胺，4 一（2 -胺基乙基）苯甲酸甲酯等）的遯原胺化反應。堪原胺化反應係在化學堪原劑（例如氰硼氫化納*氫硼化納等）或觸媒性氫化反應（例如氫，炭上鈀，氫，Raney®鎳等）存在下於一合適溶劑（例如甲酵，乙醇，醋酸乙酯，任何合適溶劑的適當混合物等）中於20^到1 0 0¾，較佳約5〇υ 進行1到8小時（進一步的詳情參考Μ下的實例48)。 -52- 本紙張尺度適用中國國家揲準（CNS ) Α4規格（210Χ297公釐） H-— —I! I n I、\'云 :ί II 錄 (請先閱讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 470741 A7 B7 五、發明説明（）式I中R4為1 一羥基（Ci -C4 )烷基的化合物可製備於式I中R4為甲醢基的相對應化合物與一合適烷基化試劑（例如甲基氯化鎂*乙基氯化鎂，正丙基氯化鎂等）的反應。烷基化反應係在一 20¾到60 °C，典型 ου到25t：，較佳約0¾進行（進一步的詳情參考以下的實例4 0 )。(Please read the notes on the back before filling out this page.) Pack. Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economics, where L is a leaving base, and each η, t, and R1 are defined by Formula I in the summary of the invention. A compound of formula 28 is reacted with an amine of formula HNR3 6 R3 7, wherein R3 6 and R3 7 are independently (Ci -C4 > alkyl or together are one (CHz) 4 · —, one (C Η 2) 5 — , (C Η 2) 2〇 (CH2) 2-or-(CH2) 2NR38 (c H2) 2 — (wherein R3 8 is hydrogen or (Ci —C4) alkyl). Conversion to a compound of formula 28 uses A suitable reagent M forms a suitable leaving group (e.g. methanesulfonate chloride, thionyl chloride, phosphorus pentachloride, phosphorus oxychloride, etc.), which is in a suitable solvent (such as methyl chloride, Gas imitation * tetrahydrofuran * a suitable mixture of any suitable solvent, etc.) The reaction with the amine is performed in a suitable solvent (e.g. tetrahydrofuran, 1 · 2-dimethoxyethane * acetonitrile, a suitable mixture of any suitable solvent, etc.) ) For 1 to 4 hours at 1 οο 2〇υ (For further details, please refer to "51- Bookmarking. The paper size is applicable to the Chinese National Standard (CNS) Α4 specification (210X297 mm) 1J 4 7 ο 7 4 Economy Printed by A7 _ B7 of the Consumer Cooperatives of the Ministry of Standards and Standards of the People's Republic of China. 5. Description of the Invention () Example 3 under M) 2) In the formula I, R4 is an amine. A methyl group compound can be prepared by reacting a corresponding compound in which R4 is methylamidyl in formula I with a hydroxylamine hydrochloride *, and then obtaining the relative hydrazine, and then the original one. The reaction with the hydroxylamine hydrochloride is in A suitable base (e.g. sodium hydroxide, sodium acetate, etc.) and a suitable solvent, typically an alcohol (e.g. ethanol, methanol • any suitable alcohol, suitable mixture, etc.) or an alcohol and water mixture (e.g. acetic acid / water (1: 1) Etc.) * In 2〇υ to loot !, typically 50Ό to 70 " C, preferably about 60t! For 1 to 8 hours. The oxime of the oxime can be combined with a chemical activator (such as lithium aluminum hydride, etc.) in a Appropriate solvents (such as tetrahydrofuran * suitable mixture of any suitable solvents, etc.) and 50 ° to 50 * 0, typically 20 ° to 20 *, preferably about 0 ° C. Details of further reaction steps in this paragraph are recorded Example 4 under K. R4 in formula I is CHzNHR10, where R10 is defined as the compound of formula I in the summary of the invention. Compounds of formula I in which R4 is a methyl group and an amine of formula NH2 and R10 (eg glycine, Tertiary butyl ester hydrochloride, glycinamide hydrochloride, Ethylamine, 4-mono (2-aminoethyl) benzoic acid methyl ester, etc.) Kryogen amination reaction. Kangen amination reaction is based on chemical kangen agent (such as sodium cyanoborohydride * sodium borohydride, etc.) Or a catalytic hydrogenation reaction (such as hydrogen, palladium on carbon, hydrogen, Raney® nickel, etc.) in a suitable solvent (such as formazan, ethanol, ethyl acetate, any suitable mixture of suitable solvents, etc.) at 20 ^ It takes from 1 to 0 0¾, preferably about 50 ° for 1 to 8 hours (for further details refer to Example 48 under M). -52- This paper size applies to China National Standards (CNS) Α4 size (210 × 297 mm) H-— —I! I n I, \ 'Cloud: ί II Records (Please read the precautions on the back before filling this page ) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 470741 A7 B7 V. Description of the invention () Compounds in which R4 is 1-hydroxy (Ci-C4) alkyl in formula I can be prepared in the phase where R4 is formamyl The corresponding compound is reacted with a suitable alkylating agent (eg, methyl magnesium chloride * ethyl magnesium chloride, n-propyl magnesium chloride, etc.). The alkylation reaction is carried out at 20¾ to 60 ° C, typically ου to 25t :, preferably about 0¾ (for further details, please refer to Example 40 below).

式 I 中 R3 ，R5 或 R8 為一 NHC (NR1 N HR1 2的化合物或式I中R4 ，R5或R7為一 cH2 NHC (NR1 M NHR12 (其中R11為氫，乙醢基或三级丁氧基羰基，R 1 2為乙醢基或三級丁氧基羰基 )的化合物可製備於式I中R3 . R 4 , R 5 ，R7或 R8為胺基或胺基甲基的化合物與一合適取代脒（例如 N1 — （三級丁氧基羰基）甲基硫胖，N1 ，N2 —二（三級丁氧基羰基）甲基硫脒，N1 ，N2 —二（乙豳基）硫脒等）的反應。反應係在一合適溶劑（例如四氫呋喃*甲酵，乙酵，二甲基甲醯胺，水，任何合適溶劑的適當混合物等，較佳為四氫呋喃）•在ου到回流溫度•典型20¾到回流溫度，較佳約在5〇t!，以及在惰性大氣中進行1到24小時（進一步的詳情參考K下的實例49 )〇 -53- (請先閲讀背面之注意事項再填寫本頁) .装.R3, R5 or R8 in formula I is a compound of NHC (NR1 N HR1 2 or R4 in formula I, R5 or R7 is a cH2 NHC (NR1 M NHR12 (wherein R11 is hydrogen, ethenyl or tertiary butoxy Carbonyl, R 1 2 is ethenyl or tertiary butoxycarbonyl) compounds can be prepared in formula I R 3. R 4, R 5, R 7 or R 8 are amino or amino methyl compounds with a suitable substitution Samarium (such as N1- (tertiary butoxycarbonyl) methylsulfanium, N1, N2-bis (tertiary-butoxycarbonyl) methylsulfanium, N1, N2-bis (ethylfluorenyl) sulfanium, etc.) The reaction is in a suitable solvent (such as tetrahydrofuran * formazan, acetonitrile, dimethylformamide, water, suitable mixture of any suitable solvent, etc., preferably tetrahydrofuran) • at ο to reflux temperature • typical 20¾ To reflux temperature, preferably at about 50t !, and in an inert atmosphere for 1 to 24 hours (for further details, refer to Example 49 under K) 〇-53- (Please read the precautions on the back before filling this page ) .Install.

、1T 製備式I中R3 ，R5或R8為一NHC (NR11 )NHR12 或式 I 中 R4 ，R5 或 R7 為-CHzNH C(nR1i)NHR12 (其中 R11 和 R12 為氫）, 1T to prepare R3 in formula I, R5 or R8 is an NHC (NR11) NHR12 or R4 in formula I, R5 or R7 is -CHzNH C (nR1i) NHR12 (where R11 and R12 are hydrogen)

經濟部中央標準局員工消費合作社印製 470741 A7 __B7_ 五、發明説明（）的化合物，可採用一合適的酸（例如三氟醋酸（TFA) ，氫氯酸·氫溴酸，硫酸等，MTFA較佳）和壤擇性的一合適共溶劑（例如乙醇）處理式I中R1 1和/或R* 2為乙醯基或三級丁氧基羰基的化合物而完成。酸處理反應係在ΟΌ到1 20Ό，典塱0¾到80°C，較佳約25C 進行0 · 5到1 2小時（進一步的詳情參考Κ下的實例 5 0)。製備式I中R3和RS為氫，R4為二— C4 )烷基胺基甲基，哌啶—1—基甲基或嗎啉一 4_基甲基的化合物可用一合適的N·N-二取代甲撐銨鹽烷基化式 I中R3 ，R4和R5為氫的化合物。烷基化係在一合適溶劑（例如二甲基甲醯胺*乙腈*任何合適溶劑的適當混合物等，較佳為二甲基甲醢胺）中，在50¾到130Ό ，典型8 0 C到1 1 0 t!，較佳約9 5 t：進行1到2 4小時。製備式I中R4為氫，R5為二（Ci - C4 )烷基胺基甲基，哌啶一 1 一基甲基或嗎啉—4 一基甲基，R3 不為氫的化合物*可用約1奠耳當量的合適的N，N —二取代甲撐銨鹽烷基化式I中R5為氫的相對應化合物。烷基化係在一合適溶劑（例如二甲基甲釀胺* DMPU，乙睛，任何合適溶劑的適當混合物等，較佳為二甲基甲醯胺 )中，在OC到回流溫度，典型20t!到100Ό，較佳約8 01進行1到24小時（進一步的詳情參考Μ下的實 -54- 本紙張尺度適用中國國家標準（CNS ) Α4規格（210Χ297公釐〉 ----------参------ΐτ------if (請先閲讀背面之注意事項再填寫本頁) 470741 A7 B7 五、發明説明（）例 3 5 )。製備式I中R3和R4為氫，R5為二（Ci -C4 )烷基胺基甲基，哌啶_ 1 一基甲基或嗎啉一 4 —基甲基的化合物，可用約1炱耳當量合瓛的N · N —二取代甲撐銨鹽烷基化式I中R5為氫的相對應化合物的硫保護衍生物（例如其3 —(咪唑一 2 —基硫基）丙酸鹽衍生物），並進行去保護。烷基化係在一合適溶麵（例如二甲基甲豳胺，DMPU，乙腈，任何合適溶劑的適當混合物等，較佳為二甲基甲醯胺）中*在50¾到130¾，較佳80t! 到1 0 0 °C進行1到2 4小時*去保護作用可用一合適鹼 (例如烷氧化納如乙氧化納和類Μ物，氫氧化納，氫氧化鉀等，較佳為乙氧化納）在ου到50¾*較佳在約25υ 進行。一合適的硫保護衍生物可製備於式I中R3為氫的化合物與丙烯酸乙酯的反應而得到3 - （咪唑一 2 —基硫基 )丙烯酸酿衍生物。保護步驟是在酸（例如無水籯氣酸）經濟部中央標準局員工消費合作社印製 (請先間讀背面之注意事項再填寫本頁) 中及一合適溶劑（典型為醇（例如甲酵，乙醇*任何合適醇的適當混合物等））*較佳在乙醇中*於ου到回流溫度，典型為50¾到回流溫度，較佳在約80Ό進行。製備式I中R3為氫，R4和RS各為二（Ci_ C4)烷基胺基甲基，哌啶一1一基甲基或嗎啉一4_基甲基的化合物*可用約2到1 5莫耳當量的合適N * N-二取代甲撐銨鹽，典型為5到1 0莫耳當董·較佳約7莫 -5 5 - 本紙浪尺度適用中國國家標準（CNS ) A4規格（210X297公釐） ~~~ 1 4 7 ο 7 4 經濟部中央標準局員工消費合作社印製 A7 B7五、發明説明（）耳當量*對式I中R4和R5為氫的相對應化合物的保護衍生物進行烷基化，然後去保護。烷基化係在一合適溶劑 (例如二甲基甲醢胺·DMPU·乙腈•任何合適溶劑的適當混合物等，較佳為二甲基甲醢胺）中，在5〇t：到 130Ό，典型9〇υ到1 ίου，較佳約lOOt：進行 1到24小時（進一步的詳情參考Μ下的實例36)。式I中R4和/或R5為羥基甲基的化合物可製備於堪原式I中R4和/或R5為乙氧基羰基的化合物。遒原反應係用一化學遨原劑（例如氫化硼納，氫化硼鈣*氫化硼鋰，氫化鋁鋰等*較佳為氬化硼納及氯化鈣存在下）於一合適溶劑（例如四氫呋喃，二乙二醇二甲醚，二噁烷，任何合適溶劑的適當混合物等，較佳為四氫呋喃）•於 —2 0 °C到回流溫度，典型為0 t!到8 0 t：，較佳約5 0 t! ，進行1到72小時（進一步的詳情參考K下的實例33 )〇製備式I中R3 ，R4 ，R5 ，R7或Re為選自芳醯基，雜芳醣基，芳基（Ct -C4 )垸基（其芳酿基，雜芳豳基，芳基和雜芳基再被1 Η —四唑—基取代基取代）的化合物，可Κ式I中芳醢基，雜芳醢基，芳基和雜芳基取代基再被取代的化合物與叠氮酸衍生物（例如三丁基錫叠氮）。反應係在有或無合適溶劑（例如二甲苯甲苯，笨，任何合適溶劑的適當混合物等，較佳為二甲苯）及8〇υ到15〇υ，典型8〇υ到13〇υ，較 -56- 本紙張尺度適用中國國家標準（CNS ) Α4規格（210Χ297公釐） (請先閱讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 470741 A7 B7 _ 五、發明説明（）佳在回流溫度進行4到2 4小時（進一步的詳情參考K下的實例3 9 )。式I中R5或R4和R5同為1H —四唑一 5 —基一胺基氨基甲醯，2 — （二甲基胺基）乙基氨基甲醢，4 一甲基哌嗪一 1 一基羰基，甲基磺豳基苯胺羰基或2-(二甲基胺基）乙基氫硫羰基的化合物的製備，可反應式I中 Rs或1^4和R5同為羧基的化合物，或其酸衍生物，與一合適的胺或硫赶（也就是5 -胺基一 1 Η —四唑，2 — (二甲基胺基）乙基胺，4 一甲基哌嗦，4_甲基磺醢基胺基苯胺或2-二甲基胺基乙烷硫赶氫氯化物）反應。例如，式I中Rs為1 Η —四唑一 5 —基氨基甲繭的化合物的製備，可將相對應羧酸轉換成酸鹵化物，然後使酸鹵化物與5 —胺基一 1 Η —四唑反應。與5 —胺基一 1 Η —四唑的反應係在一合適溶劑（例如吡啶*二甲基甲醢胺，任何合適溶劑的適當谠合物等），在0*0到40t：，典型2 Ο Ό到2$ Ο υ，較佳約2 5 t)進行1到2 4小時（進一步的詳情參考K下的實例41)。製備式I中R5爲2 — （二甲基胺基）乙基氨基甲醯，4 一甲基哌嗪一 1_基羰基或2 — （二甲基胺基）乙基氫硫羰基的化合物，可用一偶合劑（例如1 , 1' 一羰基二咪唑，二環己基碳二豳亞胺，苯並***_ 1 —基氧三吡咯垸_六氟磷酸鹽（ByBOP)等）處理相對應羧酸，其係在一合適溶劑（例如四氫呋哺，甲撐氯化物，二甲基 -57- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐〉 —.— — — II 抑本 I 訂— I I I I 絲 (請先閱讀背面之注意事項再填寫本頁) 470741 經濟部中央標隼局員工消費合作社印製 A7 B7 五、發明説明（）甲酶胺，任何合適溶劑的適當混合物等）中進行，然後與合適的胺或硫赶反應。與胺或硫赶的反應係在OC到8 Ot) ，典型2 0 °C到3 Ο υ，較佳約2 5 Ό進行1到2 4小時 (進一步的詳情參考Κ下的實例4 2 )。式I中R3 ，R6或R8為2 — （Ci— C4)烷基氧基羰基乙基的化合物可製備於反應式I中R3 ，RS或 R8分別為氫的化合物與（Ci 一04 )烷基丙烯酸酿 (例如丙烯酸甲酯，丙烯酸乙酯等）反應。反應係在鹼 (例如乙氧化納，苄基二甲基氫氧化銨，氫化納等）及一合適溶劑（例如乙醇，N，N-二甲基甲醢胺，N，N — 二甲基乙醯胺，乙腈等）存在下，於50°C到100C，較佳約8 0 °C進行1到6小時（進一步的詳情參考Μ下的實例3 4 )。製備式I中R3 ，R4 ，RS ，R6 ，R7或R8取代基為羧基或再被羧基取代基取代者的化合物，可水解式 I 中 R3 ，R4 ，R5 ，R6 ，R7 或 R8 取代基為（c ^ -C4 )烷基氧基羰基或再被（Ci —CU )烷基氧基羰基取代基取代者的相對應化合物而製成。該水解反應可與一鹸水溶液（例如氫氧化鉀，氫氧化納，氫氧化鋰等水溶液）於一合適溶劑，典型為酵（例如乙醇，甲酵，異丙醇或任何合適醇的適當混合物）*較佳為乙酵中進行*或者與酸水溶液（例如氫氯酸*氫溴酸等水溶液）*於一合適溶劑（例如甲撐氯化物，醋酸乙酿，二噁烷，二甲基甲 -58- 本紙張尺度適用中國國家標準（CNS ) A4規格（2丨0XW7公釐） ----------装、11·" (請先閱讀背面之注意事項再填寫本頁) 470741 經濟部中央標準局員工消費合作社印製 A7 B7五、發明説明（）醯胺，四氫肤喃等），在20°C到120¾，典型90Ό 到1 1 0 t!，較佳約1 0 0 t：進行4到2 4小時（進一步的詳情參考Μ下的實例37)。式I中R3 , R 4 , R 5 , R 6 或R8為氨基甲豳或另外被氨基甲醢取代基取代的基團的化合物可製備於胺化式I中R3 ，R 4 , R 5 , R 6 ，R7或R8為羧基或另外被羧基取代基取代的基围的相對應化合物而製成。胺化反應可將狻酸轉換成為相對應的酸氯化物，然後使酸氯化物與氫氧化絞水溶液反應。將酸轉換成酸氯化物係與一合適氯化劑（例如亞硫基氣化物，草趣基氣化物*五氯化磷等）及一合適溶劑（例如二甲基甲醢胺，甲撐氯化物，二氯乙烷，任何合適溶劑的適當混合物等，較佳為二甲基甲醯胺），在10Ό到40t!，典型15°C到30Ό ，較佳約2 Ο υ進行2到1 8小時。酸氯化物與氫氧化銨水溶液的反應係在0¾到50°C，典型20Ό到30¾，較佳約25C進行0 · 5到24小時（有闞此段的進一步反應步驟詳情記載於以下的實例38)。式 I 中 R3 , R 4 , R 5 . R 6 ，117或1^8為（（3 1 一 C4 )烷基氧基羰基或另外被（Ci —C4 )烷氧氧基羰基取代基取代的基團的化合物可製備於式I中R3 ， R 4 ，R5 » R 6 ，R7或R8為羧基或另外被羧基取代的基團的式I化合物與（Ci _C4 ) _的反應。反應係在2 0 *0到1 1 0 t；，較佳約8 5 t：進行8到7 2小時。-59- ^紙張尺度適用中國國家標举（CNS ) A4規格（210X297公i ) (請先閱讀背面之注意事項再填寫本頁) 470741 A7 B7 五、發明説明（）式I中R10為（Ci — C4 )烷醃基，三氟（Ci 一 C4 )烷醢基，氨基甲醜，—C4 )烷基氧基羰基，（Ci 一 C4 )烷基羰基，二（Ci - C4 )烷基氨基甲醯*胺基（Ci-CA)烷醢基，（Ci-CU)烷基胺基（Ct -c4 )烷醸基，二（C^ — C4 )烷基胺基（Ci -C4 )烷醢基，芳醣基或雜芳醢基的化合物可製備於式I中R3 ，R4 ，R5 ，R7或R8為胺基或胺基甲基的相對應化合物與一合適醢化劑（例如醢基鹵化物，例如二甲基氨基甲醢氯化物，笨甲醢氮化物，菸醢氣化物和類似物*酸酐如醋酸酐和類似物，活化酯如氮甲酸甲酯和類似物等）或其保護衍生物反應。反應係於一合遒溶劑）（例如甲撐氯化物，四氳呋喃，毗啶水，任何合適溶劑的適當混合物等，較佳為吡啶），於一lot：到40t! ，典型1 5 C到3 5 C，較佳約2 5 t!進行0 . 5到8小時（進一步的詳情參考K下的實例44)。經濟部中央標準局員工消費合作社印製 (請先閲讀背面之注意事項再填寫本頁) 或者，式I中R1 °為氨基甲醢，（Cl —c4 )烷基氧基羰基，（〇1-（：4)烷基羰基，二（（：1一（：4 )烷基氨基甲醯，胺基（Ci-CU)烷醜基，（Ci-C4 )烷基胺基（Ci ~C4 )烷醢基，二（Ci -C4 )烷基胺基（Ci 一04 )烷豳基，芳醯基或雜芳酿基的化合物可製備於式I中R3 ，R4 ，RS ，R7或 R8為胺基或胺基甲基的相對應化合物與一合適酸（例如皮可林酸和類似酸）或其保護衍生物（例如N — （三级丁 -60- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）經濟部中央標準局員工消費合作社印製 470741 A7 B7 五、發明説明（）氧基羰基）甘氨酸和類似物）的反應。反應係於一非親核性鹼（例如N , N —二異丙基乙基胺（DI EA) · N， N —二環己基甲基胺等，較佳為D I EA>和一合適偶合劑（例如PyBOP，1 * 1' _羰基二眯唑，二環己基碳二醢亞胺等，較佳為ByBOP)，於一合適溶劑（例如二甲基甲醯胺，DMPU，乙腈，四氫肤喃，甲撐氣化物，四氫呋喃•任何合適溶劑的適當混合物等，較佳為二甲基甲醢胺），於一20°C到8〇υ·典型ου到30t：，較佳約25¾(進一步的詳情參考Μ下的實例45)。或者，式I中R3 ，115或118為一肘^11^1<)或式 I 中 R4 ，R5 或 R7 為一 CH2NHR10 ，R10 為 (Ci — C4 )烷基氨基甲醢的化合物可製備於式I中 R 3 ，R4 ，RS ，R6 ，R7或R8為胺基或胺基甲基的相對應化合物與（Ci _C4 )烷基異氰酸酯的反應。反應係選擇性在一鐮（例如三乙基胺，吡啶等）及一合適溶劑（例如四氫呋喃，苯，甲撐氛化物•任何合適溶劑的適當混合物等，較佳為四氫呋喃）在ου到回流溫度，典型2 5 υ到8 0 t：，較佳約5 0 °C反應（進一步的詳情參考Μ下的實例46)。式I中R1為羥基和/或R3 * R 4 ，RS ，R6 ， R7或R8為選自芳醢基和雜芳酿基，芳基（Ci — C4 )和雜芳基（Ci _C4 )烷基（該芳醢基*雜芳醣基，芳基和雑芳基再被一到二涸羥基取代基取代）可製備於式 -6 1 ~ 本紙張尺度逋用中國國家標準（CNS ) A4規格（210 X 297公釐） 1-^1 m n n I I n I n i I n 嗜 I I n 1.1.. I (請先閱讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 470741 A7 ___B7 五、發明説明（） I中R1為甲氧基和/或其中式I中R3 , R 4 , R 5 , R 6 ，R7或R8為選自芳醢基和雜芳醢基，芳基（C: —C4 )和雜芳基— C4 )烷基（該芳醯基，雜芳醢基，芳基和雜芳基苒被一到二個羥基取代基取代）的脫甲基反應。脫甲氧反應係與三溴化硼在一合適溶® (例如甲撐氮化物·1·2—二氯乙烷*硝甲烷，任何合適溶劑的適當混合物等，較佳為甲撐氯化物）於在- 1 ου到 2〇υ，典型一 5υ到5Ό，較佳約0¾進行〇 . 5到4 小時（進一步的詳情參考Μ下的實例4 3> 。式I化合物可製備成為個別立體異構物，其係使其消旋混合物與一選擇性的活性分離劑反應而形成一對非對映異構物*分雠非對異映構物和回收純光學活性對映異構物。雖然分離對映異構物可使用式I的共價非對映異構衍生物進行，Μ可解雔的錯合物較佳（例如结晶性非對映異構鹽）。含鹼性胺基（例如結晶性非對異構鹽）的式I化合物的製備可使用合適的光學活性酸作為分離劑（例如酒石酸，扁桃酸，蘋果酸，2_芳基丙酸，一般為樟腦磺酸等 )。非對映異構物具備不同的物理性質（例如熔點*沸點，溶解度*反應性等），可Μ很快藉由Μ上不同的物理性質加Κ分離。非對映異構物可藉層析或較佳由Μ不同溶解度為基礎的分離/解析技術加Κ完成。然後藉由不會造成旋光作用的實用方法回收光學純對映異構物Κ及解析劑。 -62- 本紙張尺度適用中國國家標準（CNS ) Α4規格（210Χ297公釐） ! I I I— n 訂 I 線 (請先閱讀背面之注意事項再填寫本頁) 470741 A7 B7 五、發明説明（）可用於解析旋光混合物與立體異構物化合物的更詳细技術可參考 J e a n j a c q u e 8，A n d r e C ο 11 e t，S s m u e 1 H . W i 1 e η， Enantiomers, Racemates and Resolutions, John Wiley & Sons, Inc. (1981)。總括而言，本發明係闞於一種製備式I化合物的方法 (請先閱讀背面之注意事項再填寫本頁)Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 470741 A7 __B7_ V. The compound of the invention () can use a suitable acid (such as trifluoroacetic acid (TFA), hydrochloric acid · bromic acid, sulfuric acid, etc. A suitable co-solvent (e.g., ethanol) and optionally a suitable co-solvent (e.g., ethanol) is used to treat compounds of formula I in which R1 1 and / or R * 2 are ethenyl or tertiary butoxycarbonyl. The acid treatment is performed at 0 ° to 120 ° C, 0 ° to 80 ° C, and preferably about 25 ° C for 0.5 to 12 hours (for further details, refer to Example 50 under K). In the formula I, compounds in which R3 and RS are hydrogen, R4 is di-C4) alkylaminomethyl, piperidin-1-ylmethyl or morpholine 4-ylmethyl can be prepared with a suitable N · N- The disubstituted methylammonium salt alkylates compounds of Formula I in which R3, R4 and R5 are hydrogen. The alkylation is in a suitable solvent (such as dimethylformamide * acetonitrile * suitable mixture of any suitable solvents, etc., preferably dimethylformamide), at 50¾ to 130Ό, typically 80C to 1 10 t !, preferably about 9 5 t: for 1 to 24 hours. In the formula I, R4 is hydrogen, R5 is di (Ci-C4) alkylaminomethyl, piperidine-1ylmethyl or morpholine-4monomethyl, and R3 is not hydrogen. 1 Molar equivalent of a suitable N, N-disubstituted methylene ammonium salt alkylates the corresponding compound of formula I where R5 is hydrogen. The alkylation is in a suitable solvent (eg dimethylformamide * DMPU, acetonitrile, any suitable mixture of suitable solvents, etc., preferably dimethylformamide), at OC to reflux temperature, typically 20t ! To 100Ό, preferably about 8 01 for 1 to 24 hours (for further details, refer to the real -54 under M-This paper size applies to Chinese National Standard (CNS) A4 specifications (210 × 297 mm> ------- --- see ------ ΐτ ------ if (Please read the notes on the back before filling out this page) 470741 A7 B7 V. Description of the invention () Example 3 5). R3 in Formula I And R4 is hydrogen, R5 is bis (Ci-C4) alkylaminomethyl, piperidin-1 monomethyl or morpholine 4-ylmethyl compound, about 1 炱 equivalent of N · N-disubstituted methylammonium salt is alkylated with a sulfur-protected derivative of the corresponding compound of formula I in which R5 is hydrogen (for example, its 3- (imidazol-2-ylthio) propionate derivative), and Deprotection. Alkylation is in a suitable solvent (such as dimethylformamide, DMPU, acetonitrile, any suitable mixture of suitable solvents, etc., preferably dimethylformamide) * at 50 ¾ to 130¾, preferably 80t! To 100 ° C for 1 to 24 hours * Deprotection can be performed with a suitable base (for example, sodium alkoxide such as sodium ethoxide and M-like substances, sodium hydroxide, potassium hydroxide, etc. (Preferably sodium ethoxylate) is performed at ου to 50¾ *, preferably at about 25υ. A suitable sulfur-protected derivative can be prepared by reacting a compound in which R3 is hydrogen in formula I with ethyl acrylate to give 3-(imidazole A 2-base thio) acrylic acid derivative. The protection step is printed in the acid (such as anhydrous tritium acid) printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) and A suitable solvent (typically an alcohol (e.g. formazan, ethanol * any suitable mixture of suitable alcohols, etc.)) * Is preferably in ethanol * at a temperature of from 0 ° to reflux, typically from 50 ° to reflux, preferably at about 80 ° C. Preparation of compounds in which R3 is hydrogen, R4 and RS are each a di (Ci_C4) alkylaminomethyl, piperidine-1ylmethyl or morpholine-4-ylmethyl compound * about 2 to 1 are available 5 mol equivalent of a suitable N * N-disubstituted methylene ammonium salt, typically 5 to 10 mol, preferably about 7 mol -5 5-The paper scale is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) ~~~ 1 4 7 ο 7 4 Printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 5. Description of the invention () Ear equivalent * Alkylation of protected derivatives of the corresponding compounds where R4 and R5 are hydrogen in Formula I, and then deprotection. Alkylation is performed in a suitable solvent (eg dimethylformamide · DMPU · acetonitrile · any suitable A suitable mixture of solvents, etc., preferably dimethylformamide, at 50t: to 130Ό, typically 909 to 1 ο, preferably about 100t: for 1 to 24 hours (for further details refer to Μ Example 36 below). Compounds in which R4 and / or R5 are hydroxymethyl in formula I can be prepared from compounds in which R4 and / or R5 are ethoxycarbonyl groups in formula I. Kryogen reaction uses a chemical rhenium agent (such as borohydride, calcium borohydride * lithium borohydride, lithium aluminum hydride, etc. * preferably in the presence of sodium borohydride and calcium chloride) in a suitable solvent (such as tetrahydrofuran) , Diethylene glycol dimethyl ether, dioxane, suitable mixture of any suitable solvent, etc., preferably tetrahydrofuran) • at -20 ° C to reflux temperature, typically 0 t! To 80 t :, preferably About 50 t! For 1 to 72 hours (for further details refer to Example 33 under K). Preparation of R3, R4, R5, R7 or Re in formula I is selected from arylfluorenyl, heteroarylglycosyl, aryl (Ct -C4) fluorenyl (the aromatic group, heteroarylfluorenyl, aryl and heteroaryl are further substituted with 1 Η -tetrazole -yl substituents) compounds, can be aryl fluorenyl, hetero Compounds with arylfluorenyl, aryl and heteroaryl substituents and azide derivatives (such as tributyltin azide). The reaction is carried out in the presence or absence of a suitable solvent (such as xylene, toluene, benzene, any suitable mixture of suitable solvents, etc., preferably xylene) and 80-150 to 150, typically 80-130, and more- 56- This paper size is in accordance with Chinese National Standard (CNS) A4 specification (210 × 297 mm) (Please read the notes on the back before filling this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 470741 A7 B7 _ V. Description of the invention () It is best to perform at reflux temperature for 4 to 24 hours (for further details, refer to Example 3 9 under K). In formula I, R5 or R4 and R5 are both 1H-tetrazol-5-yl-aminocarbamidine, 2- (dimethylamino) ethylcarbamidine, 4-methylpiperazine-1 Carbonyl, methylsulfonylaniline carbonyl or 2- (dimethylamino) ethylhydrosulfide carbonyl can be prepared by reacting the compound of formula I in which Rs or 1 ^ 4 and R5 are both carboxyl groups, or an acid thereof Derivatives, with a suitable amine or sulfur (ie 5-amino-1, 1 Η-tetrazole, 2- (dimethylamino) ethylamine, 4-methyl piperidine, 4-methylsulfone Fluorenylaminoaniline or 2-dimethylaminoethanethiosulfide hydrochloride). For example, in formula I, the compound in which Rs is 1 Η -tetrazole-5 -ylcarbamoyl cocoon can be prepared by converting the corresponding carboxylic acid into an acid halide, and then making the acid halide and 5 -amino-1 Η- Tetrazole reaction. The reaction with 5-amino-1,1,4-tetrazole is in a suitable solvent (such as pyridine * dimethylformamide, any appropriate solvent of a suitable solvent, etc.), at 0 * 0 to 40t :, typical 2 Ο Ό to 2 $ Ο υ, preferably about 2 5 t) for 1 to 24 hours (for further details, refer to Example 41 under K). Preparing a compound of formula I in which R5 is 2- (dimethylamino) ethylcarbamidine, 4-methylpiperazine-1-ylcarbonyl or 2- (dimethylamino) ethylhydrothiocarbonyl, The corresponding carboxyl can be treated with a coupling agent (such as 1, 1'-carbonyldiimidazole, dicyclohexylcarbodiimide, benzotriazole_1-yloxytripyrrole, hexafluorophosphate (ByBOP), etc.) Acid, which is in a suitable solvent (such as tetrahydrofuran, methylene chloride, dimethyl-57-) This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm> — — — — — — — II Order I—IIII silk (please read the notes on the back before filling this page) 470741 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs A7 B7 V. Description of the invention () Methanamine, a suitable mixture of any suitable solvents, etc. ) And then react with a suitable amine or sulfur. The reaction with amine or sulfur is between OC and 8 Ot), typically 20 ° C to 3 0 υ, preferably about 2 5 Ό 1 to 2 4 Hours (for further details refer to Example 4 2 under K). A compound in which R3, R6 or R8 is 2- (Ci-C4) alkyloxycarbonylethyl in formula I can be prepared in a compound of formula I in which R3, RS or R8 are hydrogen and (Ci-04) alkyl Acrylic acid (such as methyl acrylate, ethyl acrylate, etc.) reaction. The reaction is based on a base (e.g. sodium ethoxide, benzyldimethylammonium hydroxide, sodium hydride, etc.) and a suitable solvent (e.g. ethanol, N, N-dimethylformamide, N, N-dimethylethyl In the presence of hydrazine, acetonitrile, etc.), it is performed at 50 ° C to 100C, preferably about 80 ° C, for 1 to 6 hours (for further details, refer to Example 3 4 under M). Compounds of formula I in which R3, R4, RS, R6, R7 or R8 are carboxyl groups or substituted with carboxyl substituents can be hydrolyzed. R3, R4, R5, R6, R7 or R8 substituents in formula I are ( c ^ -C4) alkyloxycarbonyl or a corresponding compound substituted with (Ci-CU) alkyloxycarbonyl substituent. The hydrolysis reaction can be carried out with an aqueous solution (such as potassium hydroxide, sodium hydroxide, lithium hydroxide, etc.) in a suitable solvent, typically a fermentation (such as ethanol, formazan, isopropanol or any suitable mixture of suitable alcohols) * Preferably performed in acetic acid fermentation * or with acid aqueous solution (such as hydrochloric acid * hydrobromic acid and other aqueous solutions) * in a suitable solvent (such as methyl chloride, ethyl acetate, dioxane, dimethyl methyl- 58- This paper size applies to Chinese National Standard (CNS) A4 (2 丨 0XW7mm) ---------- Package, 11 · " (Please read the precautions on the back before filling this page) 470741 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention () Amidoamine, tetrahydrofuran, etc.), at 20 ° C to 120¾, typically 90Ό to 1 10 t !, preferably about 10 0 t: 4 to 24 hours (for further details refer to Example 37 under M). Compounds of formula I in which R3, R4, R5, R6 or R8 are carbamate or groups substituted by carbamate substituents can be prepared by amination of R3, R4, R5, R in formula I 6, R7 or R8 is a corresponding compound of a carboxyl group or a group substituted with a carboxyl substituent. The amination reaction converts osmic acid to the corresponding acid chloride, and then reacts the acid chloride with a hydrogen hydroxide solution. The acid is converted into an acid chloride system with a suitable chlorinating agent (such as a sulfinyl gaseous agent, grass grass gasification * phosphorus pentachloride, etc.) and a suitable solvent (such as dimethylformamide, methyl chloride Compounds, dichloroethane, any suitable mixture of suitable solvents, etc., preferably dimethylformamide), at 10Ό to 40t !, typically 15 ° C to 30Ό, preferably about 2 0 υ 2 to 1 8 hour. The reaction of acid chloride and ammonium hydroxide solution is at 0¾ to 50 ° C, typically 20 ， to 30¾, and preferably about 25C for 0 · 5 to 24 hours. (The details of the further reaction steps in this paragraph are described in Example 38 below. ). In formula I, R3, R4, R5. R6, 117 or 1 ^ 8 is ((3 1 -C4) alkyloxycarbonyl group or another group substituted by (Ci -C4) alkoxyoxycarbonyl substituent group Compounds of formula I can be prepared by reacting a compound of formula I with (Ci_C4) _ in the formula I where R3, R4, R5 »R6, R7 or R8 is a carboxyl group or another group substituted by a carboxyl group. The reaction system is at 20 * 0 to 1 1 0 t ;, preferably about 8 5 t: 8 to 7 2 hours. -59- ^ Paper size applies to China National Standards (CNS) A4 specifications (210X297 male i) (Please read the back Please note this page, please fill in this page) 470741 A7 B7 V. Description of the invention () In formula I, R10 is (Ci — C4) alkyl salt, trifluoro (Ci — C4) alkyl group, carbamate, —C4) alkyl group Oxycarbonyl, (Ci-C4) alkylcarbonyl, bis (Ci-C4) alkylcarbamidine * amino (Ci-CA) alkylfluorenyl, (Ci-CU) alkylamino (Ct-c4) Alkyl, di (C ^ -C4) alkylamino (Ci-C4) alkyl, aryl, or heteroaryl groups can be prepared in formula I where R3, R4, R5, R7 or R8 are Corresponding compound of amino group or aminomethyl group and a suitable amylating agent (eg Fluorenyl halides, such as dimethylcarbamidine chloride, benzamidine nitride, soot gas and the like * anhydrides such as acetic anhydride and the like, activated esters such as methyl carbamate and the like) or Its protective derivative reacts. The reaction is based on a single solvent (such as methylene chloride, tetramethylenefuran, pyridine water, a suitable mixture of any suitable solvent, etc., preferably pyridine), in a lot: to 40t !, typically 1 5 C to 3 5 C, preferably about 2 5 t! For 0.5 to 8 hours (for further details refer to Example 44 under K). Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) or, in formula I, R1 ° is carbamate, (Cl —c4) alkyloxycarbonyl, (〇1- (: 4) alkylcarbonyl, bis ((: 1-mono (: 4) alkylcarbamidine, amine (Ci-CU) alkyl group, (Ci-C4) alkylamino group (Ci ~ C4) alkane Amidino, bis (Ci-C4) alkylamino (Ci-04) alkylfluorenyl, arylfluorenyl or heteroaryl groups can be prepared in formula I where R3, R4, RS, R7 or R8 are amine groups The corresponding compound of amino or methyl group and a suitable acid (such as picolinic acid and similar acids) or its protected derivative (such as N — (tertiary butan-60-) This paper applies Chinese National Standard (CNS) A4 Specifications (210X297 mm) Printed 470741 A7 B7 by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the Invention () Oxycarbonyl) glycine and the like) The reaction is based on a non-nucleophilic base (such as N, N-diisopropylethylamine (DI EA) · N, N-dicyclohexylmethylamine, etc., preferably DI EA > and a suitable coupling agent such as PyB OP, 1 * 1'-carbonyldioxazole, dicyclohexylcarbodiimide, etc., preferably ByBOP), in a suitable solvent (such as dimethylformamide, DMPU, acetonitrile, tetrahydrofuran, Methane gaseous compounds, tetrahydrofuran • A suitable mixture of any suitable solvents, etc., preferably dimethylformamide), at a temperature of 20 ° C to 80 ° C, typically ου to 30t:, preferably about 25¾ (further details Refer to Example 45) under M. Alternatively, R3, 115 or 118 in Formula I is one elbow ^ 11 ^ 1 <) or R4, R5 or R7 in Formula I is CH2NHR10, and R10 is (Ci-C4) alkylamino The formazan compounds can be prepared in the reaction of the corresponding compounds in formula I in which R 3, R 4, RS, R 6, R 7 or R 8 are amine or amino methyl groups with (Ci _C4) alkyl isocyanate. The selectivity of the reaction system is A sickle (for example, triethylamine, pyridine, etc.) and a suitable solvent (for example, tetrahydrofuran, benzene, methylidene) • an appropriate mixture of any suitable solvent, etc., preferably tetrahydrofuran, at ου to reflux temperature, typically 2 5 υ To 80 t :, preferably about 50 ° C reaction (for further details refer to Example 46 under M). R1 in formula I is Hydroxyl and / or R3 * R4, RS, R6, R7 or R8 are selected from the group consisting of arylfluorenyl and heteroaromatic, aryl (Ci-C4) and heteroaryl (Ci_C4) alkyl (the arylfluorenyl * Heteroaryl sugar group, aryl group and aryl group are substituted by one to two hydroxy substituents) can be prepared in formula-6 1 ~ This paper size adopts Chinese National Standard (CNS) A4 specification (210 X 297 mm) ) 1- ^ 1 mnn II n I ni I n II II 1.1 .. I (Please read the notes on the back before filling out this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 470741 A7 ___B7 V. Description of the invention ( R1 in I is methoxy and / or R3, R4, R5, R6, R7 or R8 in formula I is selected from arylfluorenyl and heteroarylfluorenyl, aryl (C: -C4) and Demethylation of heteroaryl—C4) alkyl (the arylfluorenyl, heteroarylfluorenyl, aryl and heteroarylfluorene are substituted with one or two hydroxyl substituents). The demethoxy reaction system is in a suitable solution with boron tribromide (for example, methylene nitride · 1.2-dichloroethane * nitromethane, any suitable mixture of suitable solvents, etc., preferably methylene chloride) From-1 ο to 2 〇υ, typically a 5 υ to 5 Ό, preferably about 0 ¾ for 0.5 to 4 hours (for further details refer to Example 4 3 under M). Compounds of formula I can be prepared as individual stereoisomers It is the reaction of its racemic mixture with a selective active separating agent to form a pair of diastereomers * Tillering diastereomers and recovering purely optically active enantiomers. Although separated Enantiomers can be carried out using covalent diastereomeric derivatives of formula I. M-solvable complexes are preferred (such as crystalline diastereomeric salts). Basic amino groups (such as A crystalline non-isomeric salt) can be prepared using a suitable optically active acid as a separating agent (eg, tartaric acid, mandelic acid, malic acid, 2-arylpropionic acid, generally camphorsulfonic acid, etc.). Enantiomers have different physical properties (such as melting point * boiling point, solubility * reactivity Etc.), M can be separated by adding different K physical properties quickly. Diastereomers can be completed by chromatography or preferably by separation / analysis techniques based on different solubility of M plus K. Then by A practical method that does not cause optical rotation to recover optically pure enantiomers K and resolving agents. -62- This paper size applies to China National Standard (CNS) A4 specifications (210 × 297 mm)! III—n Order I line (please (Please read the notes on the back before filling this page) 470741 A7 B7 V. Description of the invention () For more detailed techniques that can be used to resolve optically active mixtures and stereoisomer compounds, please refer to Jeanjacque 8, Andre C ο 11 et, S smue 1 H. W i 1 e η, Enantiomers, Racemates and Resolutions, John Wiley & Sons, Inc. (1981). In summary, the present invention relates to a method for preparing compounds of formula I (please read the back (Please fill in this page again)

經濟部中央標準局員工消費合作社印製其中： η 為 0 » 1 或 2 ·· t 為 0，1 ，2 或 3 ; R1個自獨立為鹵素，羥基或（Ci -C4 )烷基氧基；和 R2被接於或位置*且為選自式（a)， (b )和（c )之基團：Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs where: η is 0 »1 or 2 ·· t is 0, 1, 2 or 3; R1 is independently halogen, hydroxyl or (Ci -C4) alkyloxy; And R2 are attached to or at position * and are a group selected from formulas (a), (b) and (c):

U〕（c〕其中： R4為氫，R3為氮或一（CH2 ) qR9 (其中q為〇，1，2，3或4，119為羧基，（CV—C4)烷基氧基羰基•氨基甲醯或選自芳基和雜芳基者（該基團選擇 -63- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 470741 A7 B7 經濟部中央標準局員工消費合作社印製五、發明説明（) 性再被一到二個獨立選自羥基，（Ci—C*)烷基氧基，氰基，1H -四唑一5 —基，羧基和（C! — C4)烷基氧基羰基之取代基所取代）} ，Rs為氫或—NHR1 0 {其中R1 0為氫，（Ci 一〇4 )烷醯基，三氟（Ct 一 C4 )烷醢基*氨基甲醜，（Ci — C4 )烷基氧基羰基，（Ci 一（：4 )烷基氨基甲醸，二（C! — C4 )烷基氨基甲豳，胺基（Ci — C4 )烷醯基，（Ci 一（：4 )烷基胺基（Ci _C4 )烷醯基，二（Ct — C4 )烷基胺基（Ci _C4 )烷醯基，選自芳醯基和雜芳醯基者 (該芳醃基和雜芳醢基選擇性再被一到二個獨立選自羥基，（C! - C4 )烷基氧基，氰基* 1H-四唑一 5 —基 *羧基和（C1 _C4 )烷基氧基羰基的取代基所取代）或一 C (NR1 i) NHR12 (其中 R1 1 和 R12 個自獨立為氫，乙醯基或三級一丁氧基羰基）};或R4和 R5均為氫，R3為- NHR1 0 (其中R1 0定義同上 );或只5為氫*1?3為氫或一（0：^12)9 R 9 (其中 <j和R9定義同上），R4為（Ci -C4)烷基，二（ Ct — C4 )烷基胺基甲基，呢啶一1—基甲基，嗎啉一 4_基甲基，甲醯基* 1 一羥基（C! — C4 )烷基胺基或一CH2NHR13 {其中 R43 為氫，（Ci-CU )烷基，（C! — C4 )烷醯基*三氟（Ci 一〇4 )烷豳基，氨基甲醢，（Ci_C4)烷基氧基羰基，（Ct —C4 )烷基氨基甲醯，二（C! -C4 )烷基氨基甲醯 -64- (請先閲讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) A4规格（210X297公釐） 470741 A7 B7 經濟部中央標準局員工消費合作社印製五、發明説明（），胺基（Ci — C4 )烷醯基* (Ci _C4 )烷基 (Ci -C4 )烷醯基，二（Ci -C4 )烷基胺基（Ci —C4 )烷醯基，羧基（Ci -C4 )烷基，(C ! - C 4 ) 烷基氧基羰基（Ci -C4 )烷基，氨基甲醢（Ci — C4 ) 烷基*選自K下的基團：芳醯基，雑芳醢基，芳基（Ci —C4 )烷基和雜芳基（Ct — CU )烷基（該芳醯基和雜芳醯基*芳基和雜芳基選擇性再被一到二個獨立選自羥基，（C! -C4 )烷基氧基，氟基，1H —四唑一 5 -基，羧基和（Ci 一 C4 )烷基氧基羰基的取代基所取代 )或一C (NR1 i) NHR1^ (其中 R1 1 和 Riz 定義同上>};或R3為氫或一（CH2)q R 9 (其中 q和R9定義同上），R4為氫，（0^—〇4)烷基或 -C (0) R 1 4 (其中R14為胺基，，羥基（Ci — C4 )烷基氧基，2 —(二甲基胺基）乙基胺基·4_甲基呢嚷一 1—基，2 - （二甲基胺基）乙基氫硫，4一（甲基磺醯胺基）笨胺基或1Η~四唑一5—基胺基）， Rs為氰基，羥基甲基，1Η —四唑一 5 —基，4，5 — 二氫咪唑一2 —基，吡咯烷一 1 _基甲基，咪啶一1 —基甲基，嗎啉一 4~基甲基，哌嗪一1 一基甲基，4 一（C i-C4)烷基呢嗪一 1—基甲基，一C(0)R14 ( 其中 R14 定義同上），一 C(NH)NR1SR16 ( 其中R1 5和R1 6個自獨立為氫* (Ci 一〇4 )烷基或三氟（Ci -C4 )烷基）或一 CHz NR1 0 R1 7 -65- (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標隼（CNS〉A4規格（210X297公釐〉 470741 A7 B7 經濟部中央標準局員工消費合作社印製五、發明説明（） (其中Rio定義同上* R1 7為氫或（Ci -C4 )烷基）；或R3為氫或一（CH2)q R 9 (其中<1和R9 定義同上），R4和R5個自獨立為二（Ci _C4 )烷基胺基甲基，哌啶一 1 一基甲基，嗎啉一4 一基甲基或羥基甲基； R6為氫· 2 —羧基乙基，2 —氨基甲豳乙基或2 — (Ci —C4 )烷基氧基羰基乙基； R7為氫，吡咯烷一 1 一基甲基*哌啶—1 —基甲基，嗎啉一4 一基甲基，咪嗪一1_基甲基，4 一 ( C 1 -C4 )烷基顿嗪—1-基甲基或- CHz NR1 ° R1 7 (其中R10和R1 7定義同上）；和 R8為氫，2 —羧基乙基，2 —氨基甲醸乙基，2 — — C4 )烷基氧基羰基乙基或—NHR1 ° (其中 R1Q定義同上）；和藥學上可接受鹽*個別異構物和其異構物混合物；該方法包括： (a)使下式3化合物U] (c) where: R4 is hydrogen, R3 is nitrogen or mono (CH2) qR9 (where q is 0,1,2,3 or 4,119 is carboxyl group, (CV-C4) alkyloxycarbonylamino group Formamidine or those selected from aryl and heteroaryl (the group chooses -63-) This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) 470741 A7 B7 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs V. Description of the invention The () property is further selected from one to two independently selected from hydroxyl, (Ci-C *) alkyloxy, cyano, 1H-tetrazol-5-yl, carboxyl and (C! -C4) alkane Substituted by a substituent of an carbonyloxy group)}, Rs is hydrogen or -NHR1 0 {wherein R1 0 is hydrogen, (Ci-10) alkylfluorenyl, trifluoro (Ct-C4) alkylfluorenyl * carbamoyl , (Ci-C4) alkyloxycarbonyl, (Ci- (4) alkylcarbamidine, bis (C! -C4) alkylcarbamidine, amine (Ci-C4) alkylfluorenyl, ( Ci mono (: 4) alkylamino (Ci_C4) alkylfluorenyl, di (Ct-C4) alkylamino (Ci_C4) alkylfluorenyl, selected from the group consisting of arylfluorenyl and heteroarylfluorenyl (the aromatic Pickles and heteroaryl groups are optionally one or two more Independently selected from hydroxy, (C! -C4) alkyloxy, cyano * 1H-tetrazol-5-yl * carboxyl and (C1-C4) alkyloxycarbonyl substituted with a substituent) or C (NR1 i) NHR12 (wherein R1 1 and R12 are independently hydrogen, ethenyl or tertiary monobutoxycarbonyl)}; or R4 and R5 are both hydrogen, and R3 is -NHR1 0 (where R1 0 is the same as defined above); Or only 5 is hydrogen * 1? 3 is hydrogen or one (0: ^ 12) 9 R 9 (wherein < j and R9 have the same meanings as above), R4 is (Ci -C4) alkyl, and di (Ct-C4) alkane Aminoaminomethyl, iridinyl-1-ylmethyl, morpholine-4-ylmethyl, methylamino * 1 monohydroxy (C! — C4) alkylamino or CH2NHR13 {wherein R43 is hydrogen, (Ci-CU) alkyl, (C! -C4) alkylfluorenyl * trifluoro (Ci_4) alkylfluorenyl, carbamate, (Ci_C4) alkyloxycarbonyl, (Ct-C4) alkyl Carbamate, bis (C! -C4) alkylcarbamidine-64- (Please read the precautions on the back before filling out this page) This paper size applies to China National Standard (CNS) A4 (210X297 mm) 470741 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs ), Amine (Ci — C4) alkyl group * (Ci — C4) alkyl (Ci-C4) alkyl group, bis (Ci-C4) alkylamino group (Ci — C4) alkyl group, carboxyl group (Ci -C4) alkyl, (C! -C4) alkyloxycarbonyl (Ci-C4) alkyl, carbamate (Ci-C4) alkyl * selected from the group of K: arylfluorenyl, fluorene Aryl, aryl (Ci — C4) alkyl and heteroaryl (Ct — CU) alkyl (the aryl amidino and heteroaryl amidino * aryl and heteroaryl are optionally one to two separate Selected from the group consisting of hydroxy, (C! -C4) alkyloxy, fluoro, 1H-tetrazol-5-yl, substituted with carboxyl and (Ci-C4) alkyloxycarbonyl) or C (NR1 i) NHR1 ^ (where R1 1 and Riz are as defined above); or R3 is hydrogen or mono (CH2) q R 9 (where q and R9 are defined as above), R4 is hydrogen, and (0 ^ -0) alkyl Or -C (0) R 1 4 (where R14 is an amine group, a hydroxy (Ci — C4) alkyloxy group, a 2- (dimethylamino) ethylamino group, 4-methyl fluorene-1 —-, 2- (dimethylamino) ethylhydrosulfide, 4-((methylsulfonamido) benzylamino or 1Η ~ tetrazol-5-ylamino), Rs is cyano, and hydroxyl , 1′-tetrazol-5-yl, 4,5-dihydroimidazol-2-yl, pyrrolidin-1-ylmethyl, imididin-1-ylmethyl, morpholine-4-yl, Piperazine- 1-methylmethyl, 4- (C i-C4) alkylmorphazine-1-ylmethyl, -C (0) R14 (where R14 has the same definition as above), -C (NH) NR1SR16 (where R1 5 and R1 6 are independently hydrogen * (Ci_04) alkyl or trifluoro (Ci-C4) alkyl) or a CHz NR1 0 R1 7 -65- (Please read the notes on the back before filling in this Page) This paper size applies to Chinese national standard (CNS> A4 specification (210X297mm> 470741 A7 B7) Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention () (Ci -C4) alkyl); or R3 is hydrogen or mono (CH2) q R 9 (wherein < 1 and R9 have the same definitions as above), R4 and R5 are independently di (Ci_C4) alkylaminomethyl , Piperidine-1 methyl group, morpholine-4 methyl group or hydroxymethyl group; R6 is hydrogen · 2-carboxyethyl group, 2-carbamoylethyl group or 2- (Ci-C4) alkyl group Oxycarbonylethyl; R7 is hydrogen, pyrrolidine-1 Monomethyl * piperidine-1-ylmethyl, morpholine-4 monoylmethyl, imidazine-1-ylmethyl, 4-mono (C 1 -C4) alkyltonazine-1-ylmethyl Or-CHz NR1 ° R1 7 (where R10 and R1 7 have the same definitions as above); and R8 is hydrogen, 2-carboxyethyl, 2-carbamoylethyl, 2-C4) alkyloxycarbonylethyl or- NHR1 ° (wherein R1Q is as defined above); and pharmaceutically acceptable salts * individual isomers and mixtures of isomers thereof; the method includes: (a) using a compound of formula 3 below

其中每個η，t和R1定義同K上的式I ·與二烷基氧基乙醛在一化學遨原劑存在下或觸媒氫化中反應，然後用硫 -6 6 ~ 本紙張尺度適用中國國家標準（CNS〉A4規格（210X297公釐） (請先閱讀背面之注意事項再填寫本頁) 470741 A7 B7 經濟部中央標準局員工消費合作社印製五、發明説明（）氰酸處理，製得式I中R2為式（a)基中R3 * R4和 R5均為氫的化合物；或 (b)使式3化合物或其酸加成鹽（其中每個η，t和R 1定義同K上的式I )與硫氰酸和二羥基丙_反應，接蕃選擇性用硫酸處理反應混合物，製得式I中R3和R4為氫* R5為羥基甲基的化合物；或 (c )使式5化合物Each of these η, t and R1 has the same definition as Formula I on K · Reacts with dialkyloxyacetaldehyde in the presence of a chemical rhenium agent or catalyst hydrogenation, and then uses sulfur-6 6 ~ This paper is applicable Chinese National Standard (CNS> A4 Specification (210X297mm) (Please read the notes on the back before filling out this page) 470741 A7 B7 Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs It is obtained that R2 in formula I is a compound in which R3 * R4 and R5 in the group of formula (a) are both hydrogen; or (b) a compound of formula 3 or an acid addition salt thereof (wherein each of η, t and R 1 has the same definition as K The above formula I) is reacted with thiocyanate and dihydroxypropane, and then the reaction mixture is selectively treated with sulfuric acid to obtain a compound of formula I in which R3 and R4 are hydrogen * R5 is hydroxymethyl; or (c) Compound of formula 5

其中每個η，t和R1定義同Μ上的式I ，與1 ，2，4 —***_4 一基胺基反應•然後硫化而製得式I中R2為式（c)(其中R8為胺基）的化合物；或 (d )使式7化合物Where each η, t and R1 are defined as the formula I on M, and reacted with 1,2,4-triazole-4 monoamine group • and then vulcanized to obtain formula I in which R2 is formula (c) (where R8 A amine group); or (d) a compound of formula 7

其中每個η，t和R1定義同Μ上的式I ，與2，2，一二烷基氧基乙基胺在一化學遨原劑化中或者觸媒氫化中反應，然後用硫氟酸處理，製得式I中R2為式（a)(其中R3 ，R4和R5為氫）的化合物；或 -67- 本紙張尺度適用中國國家摞準（CNS ) A4規格（210X2SI7公釐） (請先閱讀背面之注意事項再填寫本頁) 470741 A7 B7 五、發明説明（） (e )使式9化合物Wherein each η, t and R1 are defined as the formula I in M, and reacted with 2,2, -dialkyloxyethylamine in a chemical priming or catalytic hydrogenation, and then with thiofluoric acid Processing to obtain compounds in formula I where R2 is formula (a) (wherein R3, R4 and R5 are hydrogen); or -67- This paper size applies to China National Standard (CNS) A4 (210X2SI7 mm) (please (Please read the notes on the back before filling this page) 470741 A7 B7 V. Description of the invention () (e) Make the compound of formula 9

經濟部中央標準局負工消費合作社印製其中每個η，t和R1定義同Μ上的式I ，與2，2 —二烷基氧基乙基胺反應，然後用酸處理，製得式I中R2為式（a)(其中R3，R4和R5為氫）的化合物；或 (f) 使式9與胺基乙腈氫氯化物反應，然後用鹼處理* 製得式I中R2為式（a)(其中R3和R4為氫，R5 為胺基）的化合物：或 (g) 使式9化合物與D_ (+) —葡萄胺反應•然後氧化，製得式I中R2為式（a)中R3和rs為氫，為甲醯基的化合物；或 (h) 使式9化合物與式H2NHNC (0) R 3 4 (其中R3 4為氫，胺基甲基，（Ct -C4 )垸基甲基，二 (Ci 一04 )烷基胺基甲基，吡咯垸一1—基甲基，呢啶一 1 一基甲基，嗎啉一4 —基甲基，哌嗪一1 —基甲基，4 一（Ci 一〇4 )烷基#嗪—1 一基甲基）的化合物或其保護衍生物反應，然後用鹼處理，視需要去保護，製得式I中R2為式（b)(其中Rs為氫，R7為氮，胺基甲基，（C! _C4 )烷基甲基，二（C! 一〇4 )燒基胺基甲基，吡咯烷一 1 —基甲基，呢啶一 1 —基甲基， -6 8 - 本紙張尺度適用中國國家標準（CNS ) A4規格（210 X 297公釐） (請先閱讀背面之注意事項再填寫本頁) 470741 A7 B7五、發明説明（）嗎啉_4 一基甲基，哌嗪一 1—基甲基，4 一 (Ci ~ C 4 ) 烷基#嗪一1~基甲基的化合物；或 (i)使式11的化合物The Central Standard Bureau of the Ministry of Economic Affairs, the Consumer Cooperatives printed each of which η, t, and R1 are defined as the formula I on M, reacted with 2,2-dialkyloxyethylamine, and then treated with acid to obtain the formula R2 in I is a compound of formula (a) (wherein R3, R4 and R5 are hydrogen); or (f) reacting formula 9 with aminoacetonitrile hydrochloride and then treating with base * to obtain R2 in formula I (A) (wherein R3 and R4 are hydrogen and R5 is an amine group): or (g) reacting a compound of formula 9 with D _ (+)-glucosamine and then oxidizing to obtain R2 in formula I as formula (a ) In which R3 and rs are hydrogen and are methylformyl; or (h) a compound of formula 9 and formula H2NHNC (0) R 3 4 (where R3 4 is hydrogen, aminomethyl, (Ct -C4)) Methyl, bis (Ci_04) alkylaminomethyl, pyrrolidine-1,1-methyl, morpholin-1, 1-methyl, morpholine 4-4-methyl, piperazine 1-yl A methyl, 4- (Ci_04) alkyl # azin-1-ylmethyl) compound or a protected derivative thereof is reacted, and then treated with a base, and deprotected if necessary, to obtain R2 in formula I as ( b) (where Rs is hydrogen, R7 is nitrogen, aminomethyl, (C! _ C4) Alkylmethyl, bis (C! 104) alkylaminomethyl, pyrrolidine-1-ylmethyl, oxidine-1-1-ylmethyl, -6 8-This paper is for Chinese country Standard (CNS) A4 specification (210 X 297 mm) (Please read the precautions on the back before filling out this page) 470741 A7 B7 V. Description of the invention () Morpholine_4 monomethyl, piperazine 1-yl Methyl, 4-mono (Ci ~ C 4) alkyl # azine-1-methyl compounds; or (i) a compound of formula 11

經濟部中央標準局員工消費合作社印製其中每個η，t和R1 ，R4和R5定義同Μ上的式I ，與一強鹸反應，然後硫化，製得式I中R3為氫的化合物 ;或 (j) 使式1 1中每個η，t ，R1 ，R4和Rs定義冏 Μ上的式I與式L—(CH2)qR9 (其中L為一離去基，每個q和R9定義同式I)反應，然後硫化’製得式I 中R2為式（a)(其中R3為一（CH2)qR9)的化合物；或 (k) 使式1 1中R4和R5為氫，每個η，t和R1定義同K上的式I的化合物與胺基芳基磺酸鹽或烷基磺酸鹽反應，製得式I中R2為式（a)(其中R3為胺基）的化合物；或 (1 )用適當的N * N-二取代甲撐銨鹽烷基化式1 1中 R4和R5為氫，每個η，t和R1定義間Μ上的式I的化合物，然後硫化·製得式I中R2為式（a)(其中R -69- 本紙張尺度適用中國國家標準（CNS ) A4規格（210 X 297公釐） (請先閱讀背面之注意事項再填寫本頁) 470741 Α7 Β7 五、發明説明（） S為二（Ci -C4 )烷基胺基甲基，哌啶一1一基甲基或嗎啉-4一基甲基的化合物；或 (m)使式1 6化合物 CR/；)The Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs printed each of these η, t and R1, R4 and R5 are defined with the formula I on M, reacted with a strong hydrazone, and then vulcanized to obtain a compound of formula I where R3 is hydrogen; Or (j) Let each η, t, R1, R4, and Rs in Formula 11 define Formula I and Formula L— (CH2) qR9 (where L is a leaving group, and each q and R9 is defined React with formula I) and then vulcanize to obtain a compound of formula I in which R2 is formula (a) (wherein R3 is one (CH2) qR9); or (k) such that R4 and R5 in formula 1 are hydrogen, each The definitions of η, t and R1 are the same as those of the compound of formula I on K reacted with amine aryl sulfonate or alkyl sulfonate to obtain a compound of formula I in which R2 is formula (a) (wherein R3 is amine group) Or (1) alkylate an appropriate N * N-disubstituted methylammonium salt in Formula 1 where R4 and R5 are hydrogen, and each η, t, and R1 define a compound of formula I on m and then vulcanize · In the formula I, R2 is formula (a) (where R -69- this paper size is applicable to Chinese National Standard (CNS) A4 specification (210 X 297 mm) (Please read the precautions on the back before filling in this page) 470741 Α7 Β7 V. Description of the invention () S is di (Ci-C4) alkane Compounds of aminoaminomethyl, piperidine-l-ylmethyl or morpholine-4-ylmethyl; or (m) a compound of formula 16 CR /;)

其中R3 2為氰基或（Cn —C4 )烷基氧基羰基，每個 η，t和R1定義同Μ上的式I *與式R3 3 c ( 0 ) L 化合物反應，然後用硫氰酸處理*製得式I中R2為式（ a )(其中R3為氫，R5為氰基或（c：1 —C4 )烷基氧基羰基，R4為氫，（Ci —C4 )烷基氧基羰基或（ Ci _C4 )烷基的化合物；或 (η)使式24化合物Wherein R3 2 is cyano or (Cn —C4) alkyloxycarbonyl, each η, t and R1 are defined as the same as those of formula I * on M and reacted with the compound of formula R3 3 c (0) L, and then use thiocyanate Treatment * yields formula I where R2 is formula (a) (where R3 is hydrogen, R5 is cyano or (c: 1-C4) alkyloxycarbonyl, R4 is hydrogen, and (Ci-C4) alkyloxy A carbonyl or (Ci_C4) alkyl compound; or (η) a compound of formula 24

.CEO 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填寫本頁) η，t和R1定義同Μ上的式I ，與異硫氰酸鹽反應，然後用鹼處理，製得式I中R2為式（c)(其中R8為氪 )的化合物；或 (〇)使式I中R5為羥基甲基的化合物與式Η2 Ν (0 .7 Π 本紙張尺度適用中國國家標準（CNS ) Α4規格（210X297公釐） 470741 經濟部中央標準局員工消費合作杜印製 A7 B7五、發明説明（） )R3 1的化合物或式NH4 +-OC (0) R3 1 (其中R3i為氫，（Ci-CU)烷基或三氟 )烷基）的銨鹽反應*製得式I中Rs為甲豳胺基甲基， (Ci -C4 )烷基羰基胺基甲基或三氟（Ci— C4 ) 烷基羰基肢基甲基的化合物，該化合物可另外埋擇性地被水解成式I中R3和R4為氫，Rs為胺基甲基的酸加成遡；或 (P)使式I中R5為羥基甲基的化合物與尿素反應，製得式I中R5為脲基甲基的化合物；或 (q) 使式I中R5為氰基的化合物與叠氮酸反應，製得式I中R5為1H —四唑一 5 —基的化合物；或 (r) 遨原式I中RS為氰基的化合物·製得式I中rs 為胺基甲基的化合物； (s) 水解式I中RS為氰基的化合物，製得式I中r5 為氨基甲醯的化合物；或 (t) 使式I中RS為氰基的化合物與乙烯二胺反應，製得式I中R5為4，5 —二氫眯唑一 2 —基的化合物；或 (u) 使式I中RS為氰基的化合物與式（CHs ) 2 A 1 RN1 5 R1 6的化合物反應，製得式I中RS為一 c (NH) NR1 5 R1 6的化合物；或 (v) 堪原式I中R5或R4和rs同為乙氧基羰基的化合物，製得式I中RS或R4和RS同為羥基甲基的化合物；或 *71- 本紙張尺度適用中國國家標準（CNS〉A4規格（210X297公釐） 470741 A7 B7 經濟部中央標準局員工消費合作社印製五、發明説明（）(w)將式I中R5為羥基甲基的化合物轉換成式28的化合物.CEO Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the notes on the back before filling this page) η, t and R1 have the same definition as Formula I on M, react with isothiocyanate, and then treat with alkali , To obtain a compound of formula I in which R2 is formula (c) (wherein R8 is 氪); or (〇) a compound in which R5 in formula I is a hydroxymethyl group and formula Η2 Ν (0.7 Π This paper standard applies to China National Standard (CNS) A4 Specification (210X297 mm) 470741 Employees' cooperation cooperation with Central Standards Bureau of the Ministry of Economic Affairs Du printed A7 B7 V. Description of Invention ()) Compounds of formula R3 1 or formula NH4 + -OC (0) R3 1 (of which R3i is hydrogen and (Ci-CU) alkyl or trifluoro) alkyl) ammonium salt is reacted * to obtain Rs in formula I is methylamidomethyl, (Ci -C4) alkylcarbonylaminomethyl or A trifluoro (Ci—C4) alkylcarbonylalkylmethyl compound, which can additionally be selectively hydrolyzed to an acid addition hydrazone of formula I in which R3 and R4 are hydrogen and Rs is an aminomethyl group; or (P) reacting a compound in which R5 is hydroxymethyl in formula I with urea to produce a compound in which R5 is ureidomethyl in formula I; or (q) making a compound in which R5 is cyano in formula I and azide Reaction to obtain a compound in which R5 is 1H-tetrazol-5-yl in formula I; or (r) a compound in which RS is cyano in formula I · a compound in which rs is aminomethyl in formula I; (s) Hydrolysing a compound of which RS is a cyano group in formula I to obtain a compound in which r5 is a carbamate in formula I; or (t) reacting a compound of which RS is a cyano group in formula I with ethylenediamine to obtain a formula A compound in which R5 is a 4,5-dihydrooxazole-2-yl group in I; or (u) a compound in which RS in formula I is a cyano group is reacted with a compound of formula (CHs) 2 A 1 RN1 5 R1 6 to produce A compound in which RS in Formula I is c (NH) NR1 5 R1 6 is obtained; or (v) a compound in which R5 or R4 and rs are both ethoxycarbonyl groups in Formula I, and RS or R4 and RS is also a hydroxymethyl compound; or * 71- This paper size applies to Chinese national standards (CNS> A4 specification (210X297 mm) 470741 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. w) converting a compound in which R5 is hydroxymethyl in formula I to a compound of formula 28

其中 L 為離去基 9 η 9 t 和 R 1 定義同 K 上發明概要的式 I 使式 2 8 的化合物與式 Η N R 3 6 R 3 7 ( 其中 R 3 6 和 R 3 7 個白獨立為 ( C 1 — C 4 ) 烷基或 —1 起為 — ( C Η Ζ ) 4 — 9 — ( C Η Ζ ) S — t — ( C Η Ζ ) ζ 0 ( C Η 2 ) 2 — 或 — ( C Η Ζ ) 2 N R 3 8 ( C Η 2 ) 2 — 9 其中 R 3 8 為氫或 ( C 1 — C 4 ) 院基 ) 的胺反應 » 製得式 I 中 R Β 為胺基甲基 t ( C 1 — C 4 ) 烷基胺基甲基 > 二 ( C 1 — C 4 ) 烷基胺基甲基吡咯燒 — 1 — 基甲基 9 锨啶 — 1 — 基甲基 9 嗎啉 — 4 — 基甲基 * 哌嗪一 1 — 基甲基 » 4 — ( C X — C 4 ) 烷基锨嗪 — 1 — 基甲基的化合物或 ( X ) 使式 I 中 R 4 為甲藤基的化合物與羥基胺氫氯化物反應 > 然後 m 原製得式 I 中 R 4 為胺基甲基的化合物 9 或 ( y ) 使式 I 中 R 4 為甲醯基的化合物與式 N Η 2 R 1 0 的胺在一化學遛原劑存在下或在觸媒氫化中 9 製得式 I 中 R 4 為一 C Η 2 Ν Η R 1 0 ( 其中 R 1 0 定義同上述式 I )的化合物；或 ~ 7 2 - 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） I ~訂备， (請先閱讀背面之注意事項再填寫本頁) 470741 A7 B7 五、發明説明（）經濟部中央標準局員工消費合作社印製 ( ζ ) 烷基化式 I 中 R 4 為甲醒基的化合物 $ 製得式 I 中 R 4 為 1 — 羥基 ( C 1 — C 4 ) 燒基的化合物 > 或 ( a a ) 使式 I 中 R 3 f R 5 或 R 6 為胺基或 R 4 9 R S 或 R 8 為胺基甲基的化合物與一適當取代胖反應製得式 I 中 R 3 • R S 或 R 6 為 — N Η C ( Ν R 1 1 ) N Η R 1 2 或 R 4 » R 5 或 R 8 為 — C Η ζ Ν Η C ( N R 1 1 ) Ν Η R 1 2 ( 其中 R 1 1 為氫 9 乙醯基或三級丁氧基羰基 > R 1 2 為乙豳基或三级丁氧基羰基 ) 的相對應化合物反應 ί 或 ( b b ) 用酸處理式 I 中 R 3 > R 5 或 R 6 為 —* N Η C ( N R 1 1 ) N Η R 1 2 或 R 4 • R 5 或 R 8 為 — C Η ζ Ν Η C ( N R 1 1 ) Ν Η R 1 2 ( 其中 R 1 1 為氫乙醯基或三級丁氧基羰基 R X 2 為乙醯基或三鈒丁氧基羰基 ) 的化合物反應 » 製得式 I 中 R 3 » R 5 或 R 6 為 — Ν Η C ( N Η ) N Η Ζ 或 R 4 ， R S 或 R 8 為 — C Η ζ N Η C ( N H ) N Η 2 的化合物 » 或 ( c c ) 用 -- 合適的醢化劑或其保護衍生物醢 FBta 化式 I 中 R 3 * R 5 或 R 6 為胺基或 R 4 $ R 或 R 8 為胺基甲基的化合物 » > 然後視需要去保護 » 製得式 I 中 R 3 * R 5 或 R 6 為一 Ν Η R 1 0 或 R 4 9 R 5 或 R 8 為 — C Η 2 Ν Η R i 0 的相對應化合物 » 其中 R X 0 為 ( C 1 — C 4 ) 燒醯基 -- 氟 ( C 1 '— C 4 ) 焼胞基 t 氨基甲醯 9 ( C 1 — C 4 ) 烷基氧基羰基 t ( C 1 — C 4 ) 燒基氨基甲醢 9 -73- (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家擦準（CNS ) A4規格（210 X 297公釐） 470741 A7 B7 經濟部中央標準局—工消費合作社印製五、發明説明（) 二（Cl -C4 )烷基氛基甲醢•胺基（Ci _c4 )烷釀基· （C^ —C4 )烷基胺基（Cl —c4 )烷醢基，二（Ci — C4 )烷基胺基（Ci -C4 )烷醚基，或遵自芳醢基和雜芳醯基者（該芳醢基和雜芳醢基選擇性再被一到二個獨立選自羥基，（Ci _c4 )烷基氧基，氰基，：LH —四唑一5 -基，羧基和（Ci -c4 )烷基氧基羰基的取代基所取代）；或 (dd)式I中R3 ，RS或R6為胺基或R4 ，rs或 R8為胺基甲基的化合物與（Ct — C4 >烷基異氰酸鹽反應，製得式I中R3 ，R5或R6為一 NHR1 0或胺基或 R4 ，RS 或 R8 為一 CH2NHRio (其中 R1 °為（Ci _C4 )烷基氨基甲醢）的化合物； (e e)用一合適的N，N —二取代甲撐銨鹽烷基化式I 中R3 ，R4和R5為氫的化合物•製得式I中和r 5為氫，R4為二（Ci -C4 )烷基胺基甲基，吡咯烷 -1 -基甲基或嗎啉一4-基甲基的化合物；或 (f f)用一合適的N，N —二取代甲撐銨鹽烷基化式I 中R4為氫，R3不為氫的化合物，製得式I中RS為二 (Ci 一（：4 )烷基胺基甲基，吡咯烷一 1—基甲基或嗎啉一 4~基甲基的相對應化合物；或 (gg)用硫赶保護基保護式I中R3為氫的化合物，用一合適的N，N—二取代甲撐銨鹽烷基化，然後去保護，製得式I中R3和R4為氫，RS為二（Ci -c4 >烷 -74- (請先閱讀背面之注意事項再填寫本頁)Where L is a leaving group 9 η 9 t and R 1 are defined as the formula I of the invention summary on K. The compound of formula 2 8 and formula Η NR 3 6 R 3 7 (wherein R 3 6 and R 3 7 are (C 1 — C 4) alkyl or —1 from — (C Η Η) 4 — 9 — (C Η Η) S — t — (C Η Ζ) ζ 0 (C Η 2) 2 — or — ( C Η) 2 NR 3 8 (C Η 2) 2 — 9 where R 3 8 is hydrogen or (C 1 — C 4) (radical)) amine reaction »The formula I in which R B is aminomethyl t (C 1-C 4) alkylaminomethyl > bis (C 1 -C 4) alkylaminomethylpyrrole — 1 —ylmethyl 9 pyridine — 1 —ylmethyl 9 morpholine — 4-methylmethyl * piperazine-1-methylmethyl »4- (CX-C4) alkylpyrazine-1-ylmethyl compound or (X) a compound in which R4 in formula I is methenyl Reaction with Hydroxylamine Hydrochloride > Then m is prepared in the formula I in which R 4 is an amino methyl group 9 or (y ) The compound of formula I in which R 4 is a methyl group and the amine of formula N Η 2 R 1 0 is prepared in the presence of a chemical phosphonium agent or in a catalyst hydrogenation 9 to obtain R 4 in formula I as C Η 2 Ν Η R 1 0 (where R 1 0 is defined as the compound of the above formula I); or ~ 7 2-This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) I ~ Order, (Please read first Note on the back, please fill in this page again) 470741 A7 B7 V. Description of the invention () Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (ζ) Alkylated compound of formula I in which R 4 is a methyl group. Where R 4 is a 1-hydroxyl (C 1-C 4) alkyl group or or (aa) such that R 3 f R 5 or R 6 in formula I is an amine group or R 4 9 RS or R 8 is an amine group A methyl compound is reacted with an appropriately substituted fat to obtain R 3 in formula I: • RS or R 6 is — N Η C (NR 1 1) N Η R 1 2 or R 4 »R 5 or R 8 is — C Ζ ζ Ν Η C (NR 1 1) Ν Η R 1 2 (where R 1 1 is hydrogen 9 ethyl) Or tertiary butoxycarbonyl > R 1 2 is ethenyl or tertiary butoxycarbonyl) corresponding compound; or (bb) R 3 > R 5 or R 6 in formula I is treated with acid — * N Η C (NR 1 1) N Η R 1 2 or R 4 • R 5 or R 8 is — C Η ζ Ν Η C (NR 1 1) Η Η R 1 2 (where R 1 1 is hydrogen ethyl Fluorenyl or tertiary butoxycarbonyl RX 2 is ethenyl or trifluorenylbutoxycarbonyl) and react the compound »to obtain R 3 in formula I» R 5 or R 6 is — Ν Η C (N Η) N Η Z or R 4, RS or R 8 is-C Η ζ N Η C (NH) N Η 2 compound »or (cc)-with a suitable halogenating agent or a protected derivative thereof FBta Formula I R 3 * R 5 or R 6 is an amine group or R 4 $ R or R 8 is an amino methyl compound »> then deprotect if necessary» to obtain R 3 * R 5 or R 6 in formula I Ν Η R 1 0 or R 4 9 R 5 or R 8 is the relative of — C Η 2 Ν Η R i 0 Compounds »where RX 0 is (C 1 — C 4) alkyl (fluoro) (C 1 '—C 4) carbamoyl t carbamate 9 (C 1 — C 4) alkyloxycarbonyl t ( C 1 — C 4) Carbamate 9 -73- (Please read the notes on the back before filling this page) This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) 470741 A7 B7 Printed by the Central Standards Bureau of the Ministry of Economic Affairs—Industrial and Consumer Cooperatives 5. Description of the invention () Di (Cl -C4) alkylaminomethylamino group (Ci_c4) Alkyl group (C ^ —C4) alkylamine (Cl —c4) alkylfluorenyl, bis (Ci — C4) alkylamino (Ci -C4) alkylether, or those derived from arylfluorenyl and heteroarylfluorenyl (the arylfluorenyl and heteroarylfluorenyl) The group is optionally substituted with one or two independently selected from hydroxyl, (Ci_c4) alkyloxy, cyano: LH-tetrazol-5-yl, carboxyl and (Ci-c4) alkyloxycarbonyl Or (dd) a compound of formula I in which R3, RS or R6 is an amine group or R4, and rs or R8 is an aminomethyl group is reacted with (Ct — C4 > alkyl isocyanate) to obtain R3, R5 or R6 in formula I Is a compound of NHR10 or amine or R4, RS or R8 is a CH2NHRio (where R1 ° is (Ci_C4) alkylcarbamidine); (ee) a suitable N, N-disubstituted methylammonium Salts alkylate compounds of formula I in which R3, R4 and R5 are hydrogen. • A compound of formula I is neutralized with r5 being hydrogen, R4 is di (Ci-C4) alkylaminomethyl, and pyrrolidine-1 -ylmethyl. Or a morpholine 4-ylmethyl compound; or (ff) alkylating a compound of formula I in which R4 is hydrogen and R3 is not hydrogen with an appropriate N, N-disubstituted methylammonium salt In formula I, RS is a corresponding compound of bis (Ci- (4) alkylaminomethyl, pyrrolidine-1-ylmethyl or morpholine-4 ~ ylmethyl; or (gg) protected with sulfur. The compounds of formula I in which R3 is hydrogen are alkylated with a suitable N, N-disubstituted methylammonium salt, and then deprotected to obtain R3 and R4 in formula I as hydrogen and RS as di (Ci- c4 > alkane-74- (Please read the precautions on the back before filling this page)

、1T 線本紙張尺度適用中國國家標準（CNS ) Α4規格（210Χ297公釐）經濟部中央標準局員工消費合作社印製 470741 A7 B7 五、發明説明（）基胺基甲基，吡咯烷一 1 一基甲基或嗎啉—4 一基甲基的相對應或其中R3為，R4和RS為二（Cl __C4 )烷基胺基甲基，吡咯烷—1 一基甲基或嗎啉_4 一基甲基的化合物；或 (hh)使式；[中RS或R4和RS為羧基或其酸衍生物與一合適的胺或硫赶反應，製備式I中RS或R4和RS 為1H —四唑一 5 —基氨基甲醢，2 — （二甲基胺基）乙基氨基甲醜，4 一甲基哌嗪一1 ~基羰基或2 —(二甲基胺基）乙基氫硫；或 (i i)使式I中R3 ，R6或R8為氫的化合物與（C 1 一〇4 )烷基丙烯酸酯反應，製得式I中R3 ，R6或 R8為2 - (Ct _C4)烷基氧基羰基乙基的化合物；或1. The paper size of the 1T line is applicable to the Chinese National Standard (CNS) A4 specification (210 × 297 mm) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 470741 A7 B7 V. Description of the invention Corresponds to methyl or morpholine-4 monomethyl or R3 is, R4 and RS are bis (Cl__C4) alkylaminomethyl, pyrrolidine-1 monomethyl or morpholine-4 Methyl compounds; or (hh) make the formula; [wherein RS or R4 and RS are carboxyl groups or their acid derivatives react with a suitable amine or sulfur to prepare RS or R4 and RS in formula I as 1H—four Azole-1 5-ylcarbamidine, 2- (dimethylamino) ethylcarbamate, 4-methylpiperazine-1 ~ ylcarbonyl or 2- (dimethylamino) ethylhydrosulfide; Or (ii) reacting a compound in which R3, R6 or R8 in formula I is hydrogen with (C 1-10) alkyl acrylate to obtain R3, R6 or R8 in formula I as 2- (Ct_C4) alkyl Oxycarbonylethyl compounds; or

(j·))水解式 I 中 R3 » R 4 » R 5 . R 6 *R7 或 R 8為（Ci -C4 )烷基氧基羰基或另外被（Ci _C4 )烷基氧基羰基取代基取代的基團的化合物，製得式I中 R3 , R 4 , R 5 , R 6 ，R7或R8為羧基或另外被羧基取代基取代的基團的化合物； (kk)胺化式 I 中 R3 , R 4 , R S , R 6 ，R7 或 R8為羧基或另外被羧基取代基取代的基團的化合物•製得式I中R3 · R 4 ，RS * R 6 ，R7或R8為氨基甲醯或或另外被氨基甲醢取代基取代的基團的化合物；或 (11)使式 I 中 R3 ，R4 ，R5 , R 6 ，R7 或 R8 -75- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐）(j ·)) hydrolyzed R3 »R 4» R 5. R 6 * R7 or R 8 is (Ci -C4) alkyloxycarbonyl or is substituted with (Ci —C4) alkyloxycarbonyl substituent A compound of the formula I to obtain a compound of the formula I in which R3, R4, R5, R6, R7 or R8 is a carboxyl group or another group substituted with a carboxyl substituent; (kk) amination of R3 in formula I, Compounds in which R 4, RS, R 6, R 7 or R 8 are a carboxyl group or another group substituted with a carboxyl substituent • A compound of formula I in which R3 · R 4, RS * R 6, R7 or R8 are carbamate or Compounds that are further substituted by a carbamate substituent; or (11) R3, R4, R5, R6, R7 or R8 in the formula I-75- This paper size applies the Chinese National Standard (CNS) A4 specification ( 210X 297 mm)

Hi I n I n n I I n I ^ n I (請先閱讀背面之注意事項再填寫本頁) 470741 A7 B7 經濟部中央標準局員工消費合作社印製五、發明説明（）為羧基或另外被羧基取代基取代的基團的化合物與（Ci 一 C4)酵反應，製得式I中R3 * R 4 ，RS · R 6 ， R7或R8為（Ci 一 C4 )烷基氧基羰基或另外被（C i _C4 )烷基氧基氨基甲醢取代基取代的基團的化合物 ;或 (mm)對式I中R1為甲氧基和/或其中式I中R3 ， R4 .R5 ，R6 ，R7或R8為選自芳醢基和雜芳醢基 •芳基（Ci 一〇4 )烷基和雜芳基（C^ -C4 )烷基者（該芳醸基，雜芳醢基，芳基和雜芳基另外被一到二個甲氧基取代基所取代）進行脫甲基反應’製得式I中R1 為羥基和/或R3 ，R4 ，R5 ，RS ，R7或R8為選自芳醢基和雜芳醢基*芳基（Ci _C4 )烷基和雜芳基 (Ci 一〇4 )烷基者（該芳醢基，雑芳醢基*芳基和雑芳基另外被一到二個羥基取代基所取代）；或 (nn)使式 I 中 R3 ，R5 或 R8 為一 NHR1 〇或其中R4 *R5或R7為一CHzNHR1。的化合物（其中R1 °為選自芳醢基和雜芳醢基，芳基（Ct — C4 )烷基和雜芳基（Ci _C4 )烷基者（該芳醢基，雑芳醢基，芳基和雜芳基另外被一個氰基取代基所取代） )與叠氮酸衍生物反應，製得式I中R1 0為選自芳醢基和雑芳醢基*芳基（Ct -C4 )烷基和雜芳基（Ci — C4 )烷基者（該芳醢基•雜芳醢基•芳基和雜芳基另外被一個1H~四唑一 5_基取代基所取代）的化合物；或 -76- (請先閱讀背面之注意事項再填寫本頁) -裝. -9- 線本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 470741 A7 B7 經濟部中央標準局員工消費合作社印製Hi I n I nn II n I ^ n I (Please read the precautions on the back before filling out this page) 470741 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention () is a carboxyl group or is replaced by a carboxyl group A compound of a substituted group is reacted with (Ci-C4) to obtain R3 * R 4, RS · R 6, R7 or R8 in formula I is (Ci-C4) alkyloxycarbonyl or is further i_C4) a compound substituted with an alkyloxycarbamidine substituent; or (mm) for R1 in formula I is methoxy and / or wherein R3, R4, R5, R6, R7 or R8 in formula I Is selected from the group consisting of arylfluorenyl and heteroarylfluorenyl • aryl (Ci-10) alkyl and heteroaryl (C ^ -C4) alkyl (the arylfluorenyl, heteroarylfluorenyl, aryl and heteroaryl The aryl group is additionally substituted with one or two methoxy substituents) and subjected to a demethylation reaction to obtain a formula I in which R1 is a hydroxyl group and / or R3, R4, R5, RS, R7 or R8 is selected from arylfluorenyl groups And heteroarylfluorenyl * aryl (Ci_C4) alkyl and heteroaryl (Ci_4) alkyl (the arylfluorenyl, fluorenylfluorenyl * aryl and fluorenylaryl are additionally one to two Hydroxy substituent); or (nn) In formula I, R3, R5 or R8 is an NHR1 0 or R4 * R5 or R7 is a CHzNHR1. Compounds (where R1 ° is selected from the group consisting of arylfluorenyl and heteroarylfluorenyl, aryl (Ct-C4) alkyl and heteroaryl (Ci_C4) alkyl (the arylfluorenyl, fluorenylaryl, aryl And heteroaryl are further substituted with a cyano substituent))) and azide derivative to obtain R1 0 in the formula I is selected from the group consisting of arylfluorenyl and ararylfluorenyl * aryl (Ct -C4) Compounds of alkyl and heteroaryl (Ci-C4) alkyl (the arylfluorenyl, heteroarylfluorenyl, aryl and heteroaryl are additionally substituted with a 1H ~ tetrazole-5 radical.) OR -76- (Please read the notes on the back before filling this page) -Packing. -9- The size of thread paper is applicable to China National Standard (CNS) A4 specification (210X297mm) 470741 A7 B7 Employees of Central Bureau of Standards, Ministry of Economic Affairs Printed by Consumer Cooperatives

五、發明説明（） (〇〇)使式I化合物相對應非鹽形態與一藥學上可接受無機或有機酸或鹼反應，製得藥學上可接受鹽或 (p P)使式I化合物相對應酸加成鹽或鹼加成鹽分別與一合適鹼或酸反應，製得自由態酸或鹼；或 (CIQ)分離式I化合物的立體異構物混合物，得到單一立體異構物。式3化合物一種製備式3中η為1而胺連接於；8位置的個別（S )-對映異構物的較佳方法如Μ下反應圖X所示：反應圖XV. Description of the invention () (00) Reacting the corresponding non-salt form of the compound of formula I with a pharmaceutically acceptable inorganic or organic acid or base to prepare a pharmaceutically acceptable salt or (p P) The corresponding acid addition salt or base addition salt is reacted with a suitable base or acid, respectively, to prepare a free acid or base; or (CIQ) the mixture of stereoisomers of the compound of formula I is obtained to obtain a single stereoisomer. A compound of formula 3 A preferred method for preparing the individual (S) -enantiomer at position 8 in which η is 1 and the amine is attached to the compound is shown in Reaction Scheme X at M: Reaction Scheme X

3232

JTHCC〇)Cr, 30JTHCC〇) Cr, 30

3Ca〕 (請先閲讀背面之注意事項再填寫本頁) [Η]3Ca] (Please read the notes on the back before filling this page) [Η]

3131

[Η][Η]

NHC(0)CF. 29NHC (0) CF. 29

-77 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 470741 Α7 Β7 五、發明説明（）經濟部中央標準局員工消費合作社印製其中t和R1定義同K上的發明概要的式I。式3中η為1且胺連接於/8位置的化合物可製備如（ S )—對映異構物（式3 (a))，其係水解式29化合物而製成。水解可與鹼水溶液（例如氫氧化鋰單水合物，氫氧化納，氩氧化鉀，碳酸鉀等，較佳為氫氧化鉀單水合物）於一合適溶劑*典型為酵（例如甲醇，乙酵，異丙醇 )•較佳在甲醇中於25t：到100Ό*較佳在回流溫度進行0 . 5到5小時。式2 9化合物可製備於水解式3 0化合物。水解反應可採用二道步驟方法加Μ完成，包括（i)水解式30化合物，直到完成轉換成相對應1一萘酚，和（i i)添加硫酸，持纊氫化而製成式29的化合物。氫化式30化合物成為1 —萘酚係在一合適觸媒（例如Pearluian觸媒，庚上鈀等，較佳為Pearlman觸媒）中於醋酸或三氟醋酸（T f a)，較佳醋酸中在i3〇ps ί s和ίου到3〇υ 進行0 · 5到4小時。1 —萘酚的氫化是在添加1到1 〇當量*較佳4到6當量的硫酸或過氯酸並在相同條件下持續氫化3到1 2 0小時而進行的。或者，氫解係由一單一步驟方法進行的，該方法包括在一合適觸媒Μ及磙酸或過氯酸存在下氫化式3 0化合物 -78- 本纸張尺度適用中國國家標準（CNS ) Α4規格（210Χ297公釐） ~ II I I 訂 II I 务 (請先閱讀背面之注意事項再填寫本頁) 470741 Α7 Β7 經濟部中央標準局員工消費合作社印製五、發明説明（）式3 0化合物係K分子内Friedel-Crafts反應製備於式31化合物。該反應係將式31化合物轉換成為相對應的酸氯化物，然後用一合適的路易酸（例如氛化鋁*氟化氫等•較佳為氯化鋁）處理酸氯化物*製得式30化合物。轉換成酸氛化物可採用一合適氯化劑（例如五氯化磷* 亞硫基氯化物，草醯基氯化物等•較佳為五氣化磷）於甲撐氯化物中於0¾到1 0¾，典型5¾到1 Ot：進行0 * 5到2小時。Μ路易酸處理及最終的閉環係在0 C到1 〇 °C，較佳在5 Ό到1 0 進行1到3小時。較佳者，從甲醇/水或異丙酵/水混合物结晶而分離粗產物，然後視需要從甲笨/庚烷混合物中再结晶。式3 1化合物係製備於式3 2化合物的氫解。氫解係在一合適觸媒（例如2 0%炭上氫氧化鈀（Pearlman觸媒，炭上鈀等，較佳為Pearl man觸媒），1到5當量•較佳1 • 5到2當量硫酸及冰醋酸中，及1到60ps i g » 5 X)到3 0 ΐ!進行氫化2到4 8小時。式3 2化合物係Ν由 Friedel-Crafts烷基化選擇性取代的苯基和N— （三氟乙醢基）一L一門冬親酸酐而製成。烷基化係在一路易酸（例如氣化鋁*氯化錫，氟化氫等，較佳為氯化鋁）於一合適溶劑（例如甲撐氯化物等· 較佳為甲撐氮化物）於2到401，較佳在回流溫度進行2到5小時。 Ν- （三氟乙醯基）一L—門冬氛酸酐係製備於L一 -79- (請先閱讀背面之注意事項再填寫本頁) -裝. 、vs 銶本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）經濟部中央標準局員工消費合作社印製 470741 A7 B7 五、發明説明（）-77 This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 470741 A7 B7 V. Description of invention () Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs where the definitions of t and R1 are the same as those of the invention summary on K Formula I. A compound in which n is 1 in formula 3 and an amine is attached to the / 8 position can be prepared as (S) -enantiomer (formula 3 (a)), which is prepared by hydrolyzing the compound of formula 29. It can be hydrolyzed with alkaline aqueous solution (such as lithium hydroxide monohydrate, sodium hydroxide, potassium argon oxide, potassium carbonate, etc., preferably potassium hydroxide monohydrate) in a suitable solvent. , Isopropanol) • preferably in methanol at 25t: to 100Ό * preferably at reflux temperature for 0.5 to 5 hours. Compounds of formula 29 can be prepared by hydrolysis of compounds of formula 30. The hydrolysis reaction can be completed by adding M in a two-step process, including (i) hydrolyzing the compound of formula 30, until the conversion into the corresponding 1-naphthol, and (i i) adding sulfuric acid, and then hydrogenating to form a compound of formula 29. The hydrogenated compound of formula 30 becomes 1-naphthol based on a suitable catalyst (such as Pearluian catalyst, palladium on heptane, etc., preferably Pearlman catalyst) in acetic acid or trifluoroacetic acid (T fa), preferably in acetic acid. i3〇ps ί s and ίου to 3〇υ for 0 · 5 to 4 hours. The hydrogenation of 1-naphthol is performed by adding 1 to 10 equivalents * preferably 4 to 6 equivalents of sulfuric acid or perchloric acid and continuously hydrogenating under the same conditions for 3 to 120 hours. Alternatively, the hydrogenolysis is performed by a single-step method, which includes hydrogenating a compound of formula 30 in the presence of a suitable catalyst M and gallic acid or perchloric acid-78- This paper applies Chinese national standards (CNS) Α4 Specification (210 × 297 mm) ~ II II Order II I Service (Please read the precautions on the back before filling this page) 470741 Α7 Β7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of Invention () Compound of Formula 30 The Friedel-Crafts reaction in the K molecule was prepared from a compound of formula 31. This reaction is to convert the compound of formula 31 into the corresponding acid chloride, and then treat the acid chloride * with a suitable Lewis acid (such as aluminized aluminum * hydrogen fluoride, etc., preferably aluminum chloride) to obtain a compound of formula 30. Conversion to acidic odorants can be achieved using a suitable chlorinating agent (eg, phosphorus pentachloride * thionyl chloride, chlorosulfenyl chloride, etc. • preferably phosphorus pentachloride) in methylene chloride at 0¾ to 1 0¾, typical 5¾ to 1 Ot: 0 * 5 to 2 hours. The MW acid treatment and the final closed-loop system are performed at 0 ° C to 10 ° C, preferably 5 ° to 10 ° C, for 1 to 3 hours. Preferably, the crude product is isolated by crystallizing from a methanol / water or isopropion / water mixture, and then recrystallized from a methylbenzyl / heptane mixture if necessary. The compound of formula 31 is prepared by the hydrogenolysis of the compound of formula 32. Hydrogenolysis is in a suitable catalyst (for example, 20% palladium hydroxide on carbon (Pearlman catalyst, palladium on carbon, etc., preferably Pearl man catalyst), 1 to 5 equivalents • preferably 1 • 5 to 2 equivalents Sulfuric acid and glacial acetic acid, and 1 to 60 ps ig »5 X) to 30 ΐ! Hydrogenation for 2 to 48 hours. Compound 32 of formula 32 is prepared by Friedel-Crafts alkylation of a substituted phenyl group and N- (trifluoroethylfluorenyl) -L-aspartic anhydride. Alkylation is carried out in a convenient acid (for example, gasified aluminum * tin chloride, hydrogen fluoride, etc., preferably aluminum chloride) in a suitable solvent (for example, methyl chloride, etc., preferably methyl nitride) at 2 To 401, preferably at reflux temperature for 2 to 5 hours. Ν- (trifluoroacetamido) -L-aspartic anhydride is prepared on L-79- (Please read the precautions on the back before filling out this page) -pack., Vs. 銶 This paper size is applicable to Chinese national standards (CNS) A4 specification (210X297 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 470741 A7 B7 V. Description of the invention ()

門冬氨酸與三氟醋酸酐（TFAA)的反應。該反應係為高度放熱反應•當使用1 〇〇克Μ上的反應物時，必須在能夠控制放熱條件下進行。例如，一種進行該反應的方便方法是加熱2到4當量，較佳2 ♦ 3到2 * 5當量的 TFAA到30t!和40t!9之間*較佳加熱到回流溫度 *然後K能夠進行反應而能藉回流散掉反應所產生熱董的方式添加1當量的L-門冬氨酸。較佳者是將L一門冬氨酸在TFA中的溶液形式在30到60分鐘內加入TFAA Ο 依反應圖XI I I所述進行反應*但是MD —門冬氨酸取代L 一門冬氨酸，Μ製備式3 (a)的（R)對映異構物。有關反應圖XII反步步驟詳情記載於實例6中。式6化合物式6化合物可製備於堪原式7的相對應化合物。堪原反應係與一化學遒原劑如氫硼化納於一合適溶劑*典型為酵（例如乙醇，甲酵，異丙醇，任何合適酵的缠當混合物等）或氫化鋁鋰（LAH)於一合適溶劑（例如二乙基醚，四氫呋喃，1，2—二甲氧基乙烷，任何合適溶劑的適當混合物等）在0 Ό到8 0 ΐ：反應1到2小時（進一步的詳情參考Κ下的實例1)。另一種製備式6中η為0或1，羥基連接於办位置的化合物的方法係如Κ下反應圖X I所述反應圖X I -80- 本紙張尺度適用中國國家標準（CNS ) Α4規格（210Χ297公釐） I I n i I m.訂 n I 絲 (請先閲讀背面之注意事項再填寫本頁)Reaction of aspartic acid with trifluoroacetic anhydride (TFAA). This reaction is a highly exothermic reaction. When using 100 g of reactants on M, it must be carried out under controlled exothermic conditions. For example, a convenient way to carry out the reaction is to heat 2 to 4 equivalents, preferably 2 ♦ 3 to 2 * 5 equivalents of TFAA to between 30t! And 40t! 9 * preferably to reflux temperature * then K can proceed with the reaction By adding reflux, one equivalent of L-aspartic acid can be added to dissipate the heat generated by the reaction. Preferably, TFAA is added as a solution of L-aspartic acid in TFA within 30 to 60 minutes. 0 The reaction is performed as described in Reaction Diagram XI II. * However, MD-aspartic acid replaces L-aspartic acid, M Prepare the (R) enantiomer of Formula 3 (a). Details of the reverse steps of reaction diagram XII are described in Example 6. Compounds of formula 6 Compounds of formula 6 can be prepared from the corresponding compounds of formula 7. The kangen reaction is reacted with a chemical ammonium agent such as sodium borohydride in a suitable solvent. Typically it is a leaven (such as ethanol, formazan, isopropanol, any suitable leaven mixture, etc.) or lithium aluminum hydride (LAH) In a suitable solvent (eg diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, any suitable mixture of suitable solvents, etc.) at 0 Ό to 8 0 ΐ: reaction for 1 to 2 hours (for further details refer to Example 1) under K. Another method for preparing a compound in which η is 0 or 1 in formula 6 and the hydroxyl group is connected to the office is as shown in the reaction chart XI below KK. Mm) II ni I m. Order n I wire (Please read the precautions on the back before filling this page)

470741 A7 B7 五、發明説明（470741 A7 B7 V. Description of the invention (

其中每個η為0或1 * t和R1定義同發明概要的式I ° 式6中η為0或1且羥基連接於jS位置化合物（式6 (b))的方法係製備於式34與3_氯遇氧笨酸（m_ CPBA)的反應，製得式33的瓌氧化物，然後堪原環氧化物而得到相對應的/S醇。與m — C P BA的反應係在一合適溶劑（例如苯，甲撐氯化物*氣仿·任何合適溶劑的適當混合物等）於ΟΌ到20¾，較佳約ου進行〇 · 5 到5小時。與環氧化物的遨原反應可賴觸媒氫化（例如Η2 * 10%炭上鈀等）於一合適溶劑（例如醋酸乙酷，乙酵，異丙醇，任何合適溶劑的適當混合物等）中進行。式34化合物的製備可使式6 (a)的α醇與對一甲苯磺酸於一合適溶劑（例如苯，甲苯，二氯乙烷，甲撐氯化物等）中在20t!到11 01*典型60¾到10〇t! -81- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） ^1- n n n Ϊ I I n I I (請先閱讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 470741 A7 B7 經濟部中央標準局員工消費合作社印製五、發明説明（），較佳約801^進行1到5小時。有關此段及先前的進一步反應步驟詳情記載於以上的實例2。式I化合物可從起始物質的個別立體異構物製成個別立體異構物。起始物質可由任何上述解析技術或任何热知此技人士習知方法被製成個別的立體異構物。例如，式6 化合物可由動力酵素解析與一合適酵素（例如豬胰脂肪酵素，變白菌靥（Candida cylindracea)，胰酶等）製備成個別的立體異構物。或者，在製備式I化合物的某些起始物質可藉旋光合成製備成個別立體異構物。例如，式6化合物可旋光堪原相對應的式7化合物而製成個別的立體異構物。式6化合物，其中羥基連接於α位置者•可在（S) — 1 —氮雜_ 2 —硼一 3 —噁一 4，4 —二苯基〔3 . 3 . 0〕二環辛烷（四氫肤喃中）用氫化硼將相對應的式7化合物适原而製備。類似地，（S) —對映異構物可製備於在（R) — 1 一氮雜一 2 —硼一3-噁一 4，4-二苯基〔3 . 3 . 0〕二環辛烷存在下堪原式7化合物。式6化合物，其中羥基連接於；S位置，可被製備成（ R)對映異構物，其係用氫化鋁鋰在（1R，2S) — Ν 一甲基非啶（methylephedrine)和2 -乙基胺基毗啶中堪原相對應的式7化合物。反應係在二乙基醚中於一 7 8t!到一 6 5 t!，較佳約_ 7 8 °C進行2到3小時（進一步的詳情參考實例3)。相似地，（S)—對映異構物的製備係 -8 2 _ 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） (請先閱讀背面之注意事項再填寫本頁) 470741Wherein each η is 0 or 1 * t and R1 are defined as in the general formula of the invention I ° Formula 6 wherein η is 0 or 1 and the hydroxyl group is attached to the jS position compound (formula 6 (b)) is prepared in formula 34 and The reaction of 3-chloro with oxypeptone (m_CPBA) yields a sulfonium oxide of formula 33, which is then converted to an epoxide to give the corresponding / S alcohol. The reaction with m-C P BA is carried out in a suitable solvent (e.g., benzene, methylene chloride * aerosol, suitable mixture of any suitable solvent, etc.) at 0Ό to 20¾, preferably about 0 to 5 to 5 hours. The reaction of lutetium with epoxide depends on the hydrogenation of the catalyst (such as Η2 * 10% palladium on carbon, etc.) in a suitable solvent (such as ethyl acetate, acetic acid, isopropanol, any suitable mixture of suitable solvents, etc.) get on. The preparation of the compound of formula 34 allows the alpha alcohol of formula 6 (a) and p-toluenesulfonic acid in a suitable solvent (eg, benzene, toluene, dichloroethane, methylene chloride, etc.) at 20t! To 11 01 * Typical 60¾ to 10〇t! -81- This paper size is applicable to Chinese National Standard (CNS) A4 (210X297 mm) ^ 1- nnn Ϊ II n II (Please read the precautions on the back before filling this page) Ministry of Economy Printed by the Consumer Standards Cooperative of the Central Bureau of Standards 470741 A7 B7 Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of Invention (), preferably about 801 ^ for 1 to 5 hours. Details about this paragraph and previous further reaction steps are described in Example 2 above. Compounds of formula I can be prepared from individual stereoisomers of the starting material. The starting materials can be made into individual stereoisomers by any of the analytical techniques described above or by any method known to those skilled in the art. For example, the compound of formula 6 can be prepared as a separate stereoisomer by kinetic enzyme analysis and a suitable enzyme (such as porcine pancreatic fat enzyme, Candida cylindracea, pancreatin, etc.). Alternatively, certain starting materials in the preparation of compounds of formula I may be prepared as individual stereoisomers by optical synthesis. For example, a compound of formula 6 can be optically converted to a corresponding compound of formula 7 to make individual stereoisomers. A compound of formula 6 in which the hydroxyl group is attached to the alpha position. In tetrahydrofuran), the corresponding compound of formula 7 is prepared by boron hydride. Similarly, (S) -enantiomers can be prepared in (R) -1-aza-2-boron 3-oxo-4,4-diphenyl [3.3.0] bicyclooctyl A compound of formula 7 in the presence of alkane. A compound of formula 6, in which the hydroxyl group is attached to the S position, can be prepared as the (R) enantiomer, which uses lithium aluminum hydride at (1R, 2S) —N-methylephedrine and 2- The corresponding compound of formula 7 in ethylaminopyridine. The reaction is carried out in diethyl ether at a temperature of from 78 t! To 6 65 t !, preferably about -78 ° C for 2 to 3 hours (for further details, refer to Example 3). Similarly, (S) —the preparation of enantiomers -8 2 _ This paper size applies to China National Standard (CNS) A4 (210X297 mm) (Please read the precautions on the back before filling out this page) 470741

COOH 36 A7 B7 五、發明説明（）於（IS，2R) — N —甲基非啶和2 —乙基胺基吡啶存在下遒原式7化合物而成。式7化合物式7化合物可自市面購得*或者可K很快的由習知此技人士製成。例如，合適的式7化合物可製備於氧化可取得的式6化合物。式6化合物的氧化反應可與一合適的氧化劑（例如Dess-Martin試劑）於一合適溶劑（例如四氫呋喃 *甲撐氯化物等）中於20Ό到50¾進行。式7中η為0或1且氧基連接於α位置的化合物見於 Μ下反應圖X I I : 免冬勸χΐΙCOOH 36 A7 B7 V. Description of the invention () The (IS, 2R) -N-methyl non-pyridine and 2-ethylaminopyridine exist in the original compound of formula 7 below. Compounds of formula 7 Compounds of formula 7 are commercially available * or can be made quickly by those skilled in the art. For example, suitable compounds of formula 7 can be prepared from compounds of formula 6 which are obtainable by oxidation. The oxidation reaction of the compound of formula 6 can be carried out with a suitable oxidizing agent (e.g. Dess-Martin reagent) in a suitable solvent (e.g. tetrahydrofuran * methylene chloride, etc.) at 20 ° to 50 °. Compounds in which η is 0 or 1 and the oxy group is attached to the α position in Formula 7 are shown in the reaction diagram X I I: 冬冬催 χΐΙ

其中η為0或1 * t和R1定義同Μ上發明概要的式1 -83* 本紙張尺度適用中國國家橾準（CNS ) Α4規格（210Χ297公釐） I n 11 11 111i I I— I I口 111111 (請先閲讀背面之注意事項再填寫本頁) 經濟、邵中央標準局員工消費合作杜印製 470741 Α7 Β7 五、發明説明（）式7中η為0或1且氧基連接於α位置）的化合物 (式7 (a)的製備*可用一路易酸（例如氯化鋁，溴化鋁•三氟化硼，氟化氫等）在一合適溶劑（例如甲撐氣化物*二硫化碳，硝基苯•任何合適溶劑的適當混合物等）中與式3 5化合物反應。反應係在二硫化碳存在下於2 0Ό 到4 5 t：，典型3 0 t：到4 5 "Ό，較佳約4 5 t：進行1到 8小時。式3 5化合物可製備於式3 6化合物與一氯化劑（例如草醢氯化物，亞硫基氯化物，五氯化磷等，較佳為草醢氯化物）於一合適溶劑（例如甲撐氯化物，二氯乙烷*任何合適溶劑的適當混合物等）中*在20¾到40Ό ·典型1 0 〇到3 0 Ό，較佳約2 0 進行2到1 8小時（有關此段和先前的進一步反應步驟詳情記載於實例1)。經濟部中央標準局—工消費合作社印製 (請先閲讀背面之注意事項再填寫本頁) 式3 6中η為0的化合物可製備於選擇性取代的溴苯或碘笨和丙烯酸乙酯在一合適溶劑（二甲基甲醢胺，二甲基乙酿胺，DMPU，任何合適溶劑的適當混合物等）中反應，進行堪原，然後水解。與丙烯酸乙酿的反應係在一合適鈀觸媒（例如雙（三笨基磷鈀（I I)氛化物）中於 7〇t：到 1 lot：，典型 80¾ 到 100¾，較佳約 90t：進行4到7 2小時。邐原反應係在標準條件下Μ觸媒氫化進行、水解可與鹼或酸水溶液在一合適溶劑（例如乙酵中的水性氫氧化鈉，二噁烷中的水性硫酸等）中進行。相似地，式36中η為1的化合物可製備於選擇性取 -84- 本紙張尺度適用中國國家標準（CNS ) Α4規格（210X297公釐）與3 —丁 470741 A7 B7 五、發明説明（代的溴笨或碘苯和3 -丁一 1—醇在一合適溶劑（二甲基甲醯胺和三乙基胺等）中的反應*進行遯原和氧化反應。醇的反應係在一合適鈀觸媒（例如雙（苯基磷鈀（I I)氯化物）中於801^到90Ό，較佳約 8 5Ό進行4到24小時。後嫌的遒原反應係Μ觸媒氫化進行，氧化反應可與一合適的氧化劑（例如二鉻酸鉀（V I)，高錳酸鉀等）進行。一種製備式7中η為1且氧基係連接於Θ位置的化合物的方法係依照Κ下反應圖XI I I所示：Where η is 0 or 1 * t and R1 are defined as the formula 1-83 * of the summary of the invention above. This paper size is applicable to China National Standard (CNS) A4 specification (210 × 297 mm). (Please read the precautions on the back before filling this page) Economic and Shao Central Bureau of Staff Consumer Cooperation Du printed 470741 Α7 Β7 V. Description of the invention () In Formula 7, η is 0 or 1 and the oxygen group is connected to α position) Preparation of the compound (Formula 7 (a)) * A monoacid (for example, aluminum chloride, aluminum bromide, boron trifluoride, hydrogen fluoride, etc.) can be used in a suitable solvent (for example, methane gaseous compound * carbon disulfide, nitrobenzene • Any suitable mixture of suitable solvents, etc.) is reacted with a compound of Formula 35 in the presence of carbon disulfide at 20Ό to 4 5 t :, typically 30 0: to 4 5 " Ό, preferably about 4 5 t: It is carried out for 1 to 8 hours. A compound of formula 3 can be prepared from a compound of formula 36 and a chlorinating agent (such as chloracetin, thionyl chloride, phosphorus pentachloride, etc., preferably chloracetin) in A suitable solvent (e.g. methylene chloride, dichloroethane * any suitable mixture of suitable solvents Etc.) * In 20¾ to 40Ό · Typical 100 ~ 30 0, preferably about 20 for 2 to 18 hours (Details of this paragraph and previous further reaction steps are described in Example 1). Central Standards of the Ministry of Economic Affairs Printed by the Bureau-Industrial and Consumer Cooperative (please read the precautions on the back before filling out this page) The compound with η of 0 in formula 3 6 can be prepared from selectively substituted bromobenzene or iodobenzyl and ethyl acrylate in a suitable solvent ( Dimethylformamide, dimethyl ethyl amine, DMPU, any suitable solvent, suitable mixture, etc.), kangen, and then hydrolyzed. The reaction with ethyl acrylate is a suitable palladium catalyst (such as (Tribenzylphosphine palladium (II) atmosphere) in 70 to: 1 lot :, typically 80¾ to 100¾, preferably about 90t: for 4 to 7 2 hours. Kryogen reaction is performed under standard conditions. Hydrogenation and hydrolysis can be carried out with an alkali or acid solution in a suitable solvent (such as aqueous sodium hydroxide in acetic acid, aqueous sulfuric acid in dioxane, etc.) Similarly, a compound with η of 1 in Formula 36 can be Manufactured on a selective basis -84- This paper size applies to China Standard (CNS) A4 specification (210X297 mm) and 3-butane 470741 A7 B7 V. Description of the invention (Substituted bromobenzene or iodobenzene and 3-butane-1-ol in a suitable solvent (dimethylformamide and The reaction in triethylamine, etc.) is to carry out the rhenium and oxidation reactions. The reaction of the alcohol is in a suitable palladium catalyst (such as bis (phenylphosphonium palladium (II) chloride) at 801 ^ to 90Ό, preferably The reaction is carried out for about 4 to 24 hours at about 85 ° C. The subsequent reaction of the lutetium is carried out by M catalyst hydrogenation, and the oxidation reaction can be performed with a suitable oxidant (such as potassium dichromate (VI), potassium permanganate, etc.). A method for preparing a compound in which η is 1 and the oxy group is connected to the Θ position in Formula 7 is shown in the reaction diagram XI I I under K:

XIII (請先閲讀背面之注意事項再填寫本頁)XIII (Please read the notes on the back before filling this page)

GOOE 38GOOE 38

ClCCQ)CC〇)ClClCCQ) CC〇) Cl

C(0)C1 3V A1C1C (0) C1 3V A1C1

經濟部中央標準局員工消費合作社印製Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs

7(b) 每個t和R1定義同K上發明槪要的式I。式7中η為1且氧碁連接於石位置的化合物（式7 ( b))的製備*可將式38化合物轉換成相對應的酸氮化 -8 5 - 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 470741 A7 _____B7_ 五、發明説明（） (請先閲讀背面之注意事項再填寫本頁) 物（式37)，然後酸氯化物和乙烯在路易酸（例如氯化鋁*三氟化硼，溴化鋁等）中反應。轉換成酸氯化物係在一合適氯化劑（例如亞硫氯化物，草醯氯化物，五氯化磷等）於一合適溶劑（例如甲撐氣化物，二氯乙烷，任何合適溶劑的適當混合物等）中，於2〇υ到40D，典型 2 0 t：到3 0 t：，較佳約2 0 t進行2到1 8小時。與乙烯的反應係在一合適溶劑（例如甲撐氯化物，二硫化碳，任何合適溶劑的適當混合物等）中，藉著添加酸氯化物到路易酸使反應混合物維持在一 4 ΟΌΜ下，較佳在—6 0 °CM下，然後在一 78°C到一 40°C，典型在_60t!到一 78¾，較佳約一 78¾用乙烯氧基吹入混合物中達 0 · 1到0 · 5小時。有關此段的進一步反應步驟詳情記載於實例3。一種製備式7中η為2且氧基係連接於/3位置的化合物的方法係依照以下反應圖X I V所示：7 (b) Each t and R1 have the same definition as in formula I above. Preparation of the compound in which η is 1 in formula 7 and the oxyfluorene is connected to the stone position (formula 7 (b)) * The compound of formula 38 can be converted into the corresponding acid nitride-8 5-This paper size applies Chinese national standards ( CNS) A4 specification (210X297 mm) 470741 A7 _____B7_ 5. Description of the invention () (Please read the notes on the back before filling out this page) (Formula 37), then acid chloride and ethylene in the Lewis acid (such as chlorinated Aluminum * boron trifluoride, aluminum bromide, etc.). The conversion to acid chloride is based on a suitable chlorinating agent (such as thionyl chloride, grasshopper chloride, phosphorus pentachloride, etc.) in a suitable solvent (such as methane vapor, dichloroethane, any suitable solvent). A suitable mixture, etc.) is performed at 20 to 40D, typically 20 t: to 30 t :, preferably about 20 t for 2 to 18 hours. The reaction with ethylene is in a suitable solvent (such as methylene chloride, carbon disulfide, any suitable solvent, etc.), and the reaction mixture is maintained at 400 μM by adding acid chloride to the Lewis acid, preferably at —6 0 ° CM, then at a temperature of 78 ° C to 40 ° C, typically at _60t! To -78¾, preferably about 78¾ with vinyl oxygen blowing into the mixture for 0. 1 to 0. 5 hours . Details of further reaction steps in this paragraph are described in Example 3. A method for preparing a compound in which η is 2 in Formula 7 and the oxygen group is linked to the / 3 position is shown in the following reaction diagram X IV:

反應圖X I V 經濟部中央標準局員工消費合作社印製Response diagram X I V Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs

7(C] 407 (C) 40

-86- 本紙張尺度適用中國國家標準（CNS ) Α4規格（210Χ297公釐） 470741 A7 B7五、發明説明（）經濟部中央標準局員工消費合作社印製15 每個t和R1定義同K上發明概要的式I。式7中η為2且氧基連接於/9位置的化合物（式7 ( d))的製備，可將式39化合物與硝酸納在一合適溶劑 (醋酸一水，三氟醋酸一水，醋酸一乙醇等）中反應。該反應係在—i5°c到2〇υ，典型_ι〇υ到0¾，較佳約0°C進行1到18小時（進一步的詳情參考Μ下的實例 )° 式39化合物係製備於式7 (c)化合物與三甲基甲矽烷氰化物（TMSCN)和氯化鋅反應或者在一合適溶劑（例如甲撐氮化物，任何合適溶劑的適當混合物等）中反應，得到式40化合物，然後遢原。與TMSCN的反應係在0 °C到2 0 °C *典型1 0 °C到2 Ο Ό ·較佳約2 0 °C 進行1到1 8小時。堪原反應係與一化學堪原劑在一合適溶劑中進行。有關此段的進一步反應步驟詳情記載於實例 4 ° 一種製備式7中η為2且氧基係連接於7位置的化合物的方法係依照Μ下反應圖XV所示： I I .^111 n 11 n I I (請先閱讀背面之注意事項再填寫本頁) -8 7 - 本紙張尺度適用中國國家標準（CNS ) Α4規格（210Χ297公釐） 470741 Α7 Β7 五、發明説明（-86- This paper size applies Chinese National Standard (CNS) A4 specification (210 × 297 mm) 470741 A7 B7 V. Description of the invention () Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 15 Each t and R1 definition is the same as the invention on K Schematic formula I. The compound of formula 7 in which η is 2 and the oxy group is connected to the / 9 position (formula 7 (d)) can be prepared by combining the compound of formula 39 with sodium nitrate in a suitable solvent (acetic acid monowater, trifluoroacetic acid monowater, acetic acid -Ethanol, etc.). The reaction is performed at -i5 ° c to 2〇υ, typically _ι〇υ to 0¾, preferably about 0 ° C for 1 to 18 hours (for further details, refer to the example under M) ° The compound of formula 39 is prepared in formula 7 (c) Compounds are reacted with trimethylsilyl cyanide (TMSCN) and zinc chloride or in a suitable solvent (eg, methylene nitride, any suitable mixture of suitable solvents, etc.) to obtain a compound of formula 40, and then Sugawara. The reaction with TMSCN is at 0 ° C to 20 ° C * Typical 10 ° C to 2 0 Ό · It is preferably about 20 ° C for 1 to 18 hours. The kangen reaction is performed with a chemical kanogen in a suitable solvent. The details of the further reaction steps in this paragraph are described in Example 4 ° A method for preparing a compound in which η is 2 in formula 7 and the oxy group is attached to the 7 position is shown in the reaction diagram XV under M: II. ^ 111 n 11 n II (Please read the precautions on the back before filling out this page) -8 7-This paper size applies to Chinese National Standard (CNS) Α4 specification (210 × 297 mm) 470741 Α7 Β7 V. Description of the invention (

COOEt COOSt 43 [a]COOEt COOSt 43 [a]

NaOEt (b 之〕tNaOEt (b of) t

42 COOEt COOEt42 COOEt COOEt

COOEt (〇tCOOEt (〇t

7(e) (請先閱讀背面之注意事項再填寫本頁) 每個t和R1定義同M上發明概要的式I。式7中n為2且氧基連接於7位置的化合物（式7 ( 經濟部中央標準局員工消費合作社印製 e))的製備，可K乙氧化納處理式42化合物，進行閉環，製得式4 1化合物，水解式4 1化合物，製得相對應酸，然後進行酸的脫羧基反應。與乙氧化鈉和最終閉環反應係在一合適溶劑（例如甲苯，乙醇，任何合適溶劑的適當混合物等）中，於8 0 υ到1 1 0 Ό，典塱9 0 Ό到 1 1 0 °C *較佳約1 0 0 C進行3到1 8小時。水解作用可在一鹼或酸水溶液中加熱。脫羧基反應可在8 Ot：到 1251，典型90Ό到1 ΙΟΌ*較佳約100¾進行 4到8小時。式4 2化合物可製備於還原式4 3化合物。遨原可藉觸媒氫化（例如H2 · 10%炭上鈀等）進行。式4 3中η為0的化合物可製備於選擇性取代的溴笨或碘笨和丙烯酸乙酿的反應。與丙烯酸乙酯的反應係在一合適鈀觸媒（例如雙（三苯基磷鈀（I I)氯化物）中於7 (e) (Please read the notes on the back before filling out this page) Each t and R1 is defined as Formula I in the summary of the invention above M. The compound in formula 7 in which n is 2 and the oxy group is connected to the 7 position (formula 7 (printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs, printed by e)) can be treated by sodium ethoxylate and closed loop to obtain The compound of formula 41 is hydrolyzed to obtain a corresponding acid, and then the acid is decarboxylated. The reaction with sodium ethoxide and the final ring closure is in a suitable solvent (such as toluene, ethanol, any suitable mixture of suitable solvents, etc.) at 80 0 to 1 1 0 Ό, code 塱 9 0 Ό to 1 1 0 ° C * Preferably at about 100 ° C for 3 to 18 hours. Hydrolysis can be heated in an alkaline or acid aqueous solution. The decarboxylation reaction can be carried out at 8 Ot: to 1251, typically 90 ° to 1 10 ° *, preferably about 100 ° for 4 to 8 hours. Compounds of formula 42 can be prepared from compounds of formula 43. Kashihara can be carried out by catalytic hydrogenation (such as H2 · 10% palladium on carbon, etc.). The compound in which n is 0 in Formula 43 can be prepared by the reaction of selectively substituted bromobenzyl or iodobenzyl and ethyl acrylate. The reaction with ethyl acrylate is in a suitable palladium catalyst (such as bis (triphenylphosphine-palladium (II) chloride)).

-R R 本紙張尺度適用中國國家標準（CNS ) Α4規格（210X297公釐） 470741 A7 B7 五、發明説明（） 75C到1 3〇υ，典型85¾到1 〇5ΐ!，較佳約95 υ進行72到1 68小時。有瞄此段的進一步反應步驟詳情記載於實例5。式I I化合物的製備一種製備式II中R18為式（d)，其中R21為一 CH3 NR2 5 R2 6的化合物的方法，如Μ下反應圃 X V I所述：-RR This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 470741 A7 B7 V. Description of the invention () 75C to 1 3〇υ, typical 85¾ to 1 0ΐ !, preferably about 95 υ to 72 To 1 68 hours. Further reaction steps for this paragraph are detailed in Example 5. Preparation of a compound of formula I I A method for preparing a compound of formula II in which R18 is formula (d), wherein R21 is a CH3 NR2 5 R2 6 is as described in reaction garden X VI under M:

反應圖X V I (請先聞讀背面之注意事項再填寫本頁)Reaction diagram X V I (Please read the notes on the back before filling in this page)

·- .·-.

jfR2SR26 經濟部中央標準局員工消費合作社印製每個n，t，Ri ，R2s和R26定義闻以上發明概要的式I I 。製備式II中為式（d)(其中為一 CHz NR2 5 R2 6 )(式44)的化合物可Μ在一合適溶劑（例如二甲基甲醯胺，甲撐氯化物，四氫呋喃，任何合適溶劑的適當混合物等）中反應式I (a)中115 為一 CHz NHR2 5 (式45)化合物與L —胺基酸保護衍生物，然後除去所有存在的保護基。與L -胺基酸的反應係在非親核鹼（例如D I EA，N，N—二環己基甲 -89- .. 本紙張適财賴家標準（⑽〉A4規格（2iQx297公襲） 470741 A7 B7 ___ 五、發明説明（）基胺等）存在下Μ及肽偶合劑（例如PyBOP *苯並三唑一 1 一基氧參（二甲基胺基）鱗六氟磷酸鹽，N · N — 二環己基碳二醯亞胺•溴參（吡咯烷一 1 一基）辚六氟磷酸鹽等）中在 20¾到80t：，較佳約20t：進行8到 24小時（進一步的詳情參考Μ下的實例51)。被保護的L —胺基酸係製備於一合適L 一胺基酸與一合適保護劑（例如二一三級丁基二碳酸鹽，9 一笏基甲基琥珀基碳酸鹽等）的反應。例如，被保護的L —賴氨酸衍生物係製備於L 一賴氨酸與二一三級一丁基二碳酸鹽在一合適溶劑（例如四氫呋喃，二甲基甲醢胺，任何合適溶劑的適當混合物等）中反應。反應係在Ot：到20¾，較佳約20t!進行8到48小時。除去保護基可藉酸解（例如 15%氯化氫）在一合適溶劑（例如醋酸乙酿，1 ，2 — 二甲氧基乙烷，任何合適溶劑的適當混合物等）中進行。 9 一芴基甲氧基羰基保護基可在二甲基甲醢胺中Μ哌啶將之除去。碳苄基氧基保護基可用炭上鈀氫化而除去。經濟部中夬標準局員工消費合作社印製 (請先聞讀背面之注意事項再填寫本頁) Μ類似方法進行*式I I中R1 8為式（d)(其中 R2 0為—CHz NR2 5 R2 6 )的化合物係從式I ( a)中R4為一CH2 NHR2 5的化合物加以製備。式 II 中 R18 為式（d)(其中 R2 1 為一NR2s R26) 的化合物係製備於式I (a)(其中Rs為一 NHR2S )的化合物。式I I中R1 8為式（e)(其中R23為 _CH2 NR2 s R2 6 )的化合物係製備於式1 (]b) -90- ^紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 470741 經濟部中央標準局員工消費合作社印製 A7 B7 五、發明説明（） (其中R7為一 CH2 NHR2 5 )的化合物。。式I I 中 R1 8 為式（d)(其中 R1 9 為一 NR2 5 R2 6 ) 的化合物係製備於式I (&)(其中R3為一 NHR25 )的化合物。式I I中R1 8為式（f)(其中S為一 NR2 s R2 6 )的化合物係製備於式I (C)(其中 R8為—NHR2 5 )的化合物。式I I I化合物的製備一種製備式I I I中R2 7為式（g)化合物的方法，如Μ下反應圖XV I I所述：jfR2SR26 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Each n, t, Ri, R2s, and R26 define the formula I I described in the summary of the invention above. The compound of formula (d) (wherein a CHz NR2 5 R2 6) (formula 44) can be prepared in a suitable solvent (eg, dimethylformamide, methylene chloride, tetrahydrofuran, any suitable solvent) Suitable mixture, etc.) in reaction formula I (a) 115 is a CHz NHR2 5 (formula 45) compound and an L-amino acid protected derivative, and then all the protecting groups present are removed. The reaction with L-amino acid is based on non-nucleophilic bases (such as DI EA, N, N-dicyclohexyl methyl-89- .. This paper is suitable for household use (⑽> A4 size (2iQx297 public attack) 470741 A7 B7 ___ V. Description of the invention (Methylamine, etc.) in the presence of M and peptide coupling agent (such as PyBOP * benzotriazole-1 1-oxyl (dimethylamino) scale hexafluorophosphate, N · N — Dicyclohexylcarbodiimide • bromide (pyrrolidine-1 1-yl), hexafluorophosphate, etc.) at 20¾ to 80t :, preferably about 20t: for 8 to 24 hours (for further details see M The following example 51). The protected L-amino acid is prepared from a suitable L-amino acid and a suitable protecting agent (such as di-tertiary butyl dicarbonate, 9-methyl succinic carbonic acid). Salt, etc.). For example, protected L-lysine derivatives are prepared from L-lysine and 213-butyl dicarbonate in a suitable solvent (eg, tetrahydrofuran, dimethylformamidine). Amine, any suitable mixture of suitable solvents, etc.) The reaction is carried out at Ot: to 20¾, preferably about 20t! For 8 to 48 hours. Deprotection can be carried out by acid hydrolysis (eg 15% hydrogen chloride) in a suitable solvent (eg ethyl acetate, 1,2-dimethoxyethane, any suitable mixture of suitable solvents, etc.). The oxycarbonyl protecting group can be removed by piperidine in dimethylformamide. The carbon benzyloxy protecting group can be removed by hydrogenation of palladium on carbon. Printed by the Consumer Cooperative of the China Standards Bureau of the Ministry of Economic Affairs (please first Please read the notes on the back of the page and fill in this page again.) Μ Performed in a similar way. * In formula II, R1 8 is formula (d) (where R2 0 is -CHz NR2 5 R2 6). From formula I (a), R4 is A compound of CH2 NHR2 5 is prepared. A compound of formula R18 in formula II (where R2 1 is a NR2s R26) is prepared from a compound of formula I (a) (where Rs is a NHR2S). R1 8 is a compound of formula (e) (where R23 is _CH2 NR2 s R2 6). It is prepared in formula 1 () b) -90- ^ Paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 470741 Printed by the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs A7 B7 V. Description of invention () (where R7 is a CH2 NHR2 5) A compound in which R1 8 in formula II is formula (d) (where R1 9 is -NR2 5 R2 6) is a compound prepared from formula I (&) (where R3 is -NHR25). R1 8 in formula II is Compounds of formula (f) (wherein S is -NR2 s R2 6) are prepared from compounds of formula I (C) (wherein R8 is -NHR2 5). Preparation of a compound of formula I I I A method for preparing R 2 7 in formula I I I is a compound of formula (g), as described in the reaction diagram XV I I below:

反應圖X V I I 5Β28Reaction Diagram X V I I 5Β28

每個η ’ t，R1和R2 8定義同以上發明概要的式I I Ϊ 〇式I I I中R2 7為式（g)(式46)的化合物係製備於式I (a)(其中R3為氫）（式48)的化合物與式147化合物或其保護衍生物在一合適溶劑（例如醋酸乙酯，乙烯二氮化物，四氫呋喃•任何合適溶劑的適當混合物等）的反應，然後除去所有存在的保護基。與式47 -91- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） ----------褽------訂------銶 (請先閱讀背面之注意事項再填寫本頁)Each η 't, R1 and R2 8 are defined as Formula II in the summary of the invention above. In Formula III, R2 7 is Formula (g) (Formula 46). The compound is prepared from Formula I (a) (where R3 is hydrogen). The compound of formula (48) is reacted with a compound of formula 147 or a protected derivative thereof in a suitable solvent (for example, ethyl acetate, ethylene dinitride, tetrahydrofuran, a suitable mixture of any suitable solvent, etc.), and then all the protecting groups present are removed .和式 47 -91- This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) ---------- 褽 ------ Order ------ 銶 (Please (Read the notes on the back before filling out this page)

470741 經濟部中央標準局員工消費合作社印製 Α7 Β7 五、發明説明（）化合物的反應係在20t：到1 1 Ot：，較佳約80¾進行 1到4小時。式47化合物可製備於式X — SR2 8 (其中X為卤素）或其保護衍生物與酞醢亞胺鉀在一合適溶劑（例如乙烯二氯化物，四氯化碳，1 ，1 ，1 ，2 —四氳乙烷等）中的反應。反應係在一 3〇υ到20¾，較佳約一20Ό 進行1到3小時。式X — SR2 8化合物可Μ很快的由習知此技人士加以製備。例如，式X-SR28 (其中X為溴·ϋ2 8為2 -三級一丁氧基羰基—2 — （三級丁基氧基羰基胺基）乙基的化合物可製備於Ν - （三級丁氧基羰基）胱氨酸與溴在一合適溶劑（例如二氯乙烷等）中反應。反應係在一 40t：到20¾，較佳約一 23¾進行1到 3小時。有關此段的進一步反應步驟詳情記載於Μ下的實例5 2。 Μ類似的方法進行，式I I I中R2 7為式（h)化合物可製備於式I (b)化合物。式I I I中R2 7為式 (i)的化合物可製備於式I (c)中R8為氫的化合物〇實例1 5，6 —二氟-1 一羥基茚滿 K下係製備式6中η為0，t為2，位於5 —和6 — 位置的R1為氟置的化合物。 3 - (3，4 一二氟苯基）丙酸（80 . 0 克，0 ·43 -92- 本紙張尺度適用中國國家標隼（CNS ) Μ规格（210X297公釐） ! I I n n 訂 ~~ n I'if (請先閱讀背面之注意事項再填寫本頁) 470741 經濟部中央標準局員工消費合作杜印製 A7 B7 五、發明説明（）莫耳）溶於3滴二甲基甲醢胺和350毫升甲撐氯化物中。加入草豳氯化物（75奄升，〇 · 860莫耳），在室溫下通入氮氣時搅拌混合物約3小時。藉蒸發除去過量的草醢氯化物，殘留物與20 〇奄升四氯化碳共蒸發兩次，製得95.0克的殘留物（油）。氯化鋁（200克）懸浮於800毫升二硫化碳，將懸浮物冷卻到〇t)。殘留物在3 0 0毫升二硫化碳中所形成的溶液在2 0分鐘内被加入懸浮物•混合物在回流溫度下搅拌4小時。將混合物倒入2公斤的碎冰•用醋酸乙酯 (3x300毫升）萃取水層。二硫化碳層和醋酸乙酯萃取物均被硫酸鎂乾燥，過濾，然後予Κ混合。藉蒸發除去溶劑，殘留物在異丙醚中結晶，製得54 · 3克固體的5 ，6 —二氟茚滿—1 一嗣。母液於矽膠上被管柱層析純化 (沖提液：10%醋酸乙酿/己烷），製得額外的5. 2 克5，6 —二氟茚滿一 1 一酮。 5，6 -二氟茚滿-1-酮（59 . 3 克，0 . 35 3其耳）溶於1升乙醇中，加入氫硼化納（6 · 68克* 〇· 176其耳）。搜拌混合物48小時，減壓蒸發除去 2*醇°殘留物在二***和水之間分層，混合物被1 N氫氯酸酸化。混合物在硫酸鎂乾燥，過溏之。蒸發溶劑，製得 5 ’6 -二氟-i 一羥基茚滿（59. 8克）（油）。如實例1進行，但是用不同的起始物質取代3 — （3 ’ 4_二氟笨基）丙酸，Μ下的式6化合物為： -93- 本氏張尺度適用中國國家標準（CNS〉Α4規格（2l〇X297公釐） -----------裝------1T------'線 (請先閱讀背面之注意事項再填寫本頁) 470741 Α7 Β7 經濟部中央標準局員工消費合作社印製五、發明説明（）用3 — (3，5 -二氟笨基）丙酸取代，製得5，7 —二氟_1 一羥基一茚滿，熔點03Ό; 用4 一（2 *4 —二氟笨基）丁酸取代，製得5 · 7 一二氟一 1 ，2，3，4 一四氫一 1—羥基萘（油）；用4 一（3，4 —二氟苯基）丁酸取代，製得6 * 7 一二氟一 1 ，2，3，4 一四氫—1—羥基萘（油）；用4— (4一氟苯基）丁酸取代，製得7—氟一1· 2，3*4 —四氫一 1—羥基萘（油）；用4 — (3 —氣苯基）丁酸取代，製得6 —氟一 1 * 2，3，4 —四氫一 1—羥基萘（油）；用4 一（3，5 -二氟苯基）丁酸取代•製得6 · 8 —二氟一 1 ，2，3，4 一四氫一 1 一羥基萘（油）*熔點 ι〇2υ-ι〇3υ; 實例2 5，6_二氟一2—羥基茚滿 Μ下係製備式6中η為0，t為2，位於5 —和6 -位置的R1為氟的化合物。如實例1所製備的5，6_二氟一 1 一羥基茚滿（5 9 · 8克，356毫奠耳）溶於600毫升笨，加入對一甲笨磺酸單水合物（3 ♦ 36克，1 7 ♦ 66奄莫耳）。加熱混合物到1 ，蒸緬約2小時，然後予Μ冷卻。加入飽和碳酸氫納溶液，苯層被硫酸鎂乾燥。然後過濾苯 -94- 本紙張尺度適用中國國家標準（CNS ) Α4規格（210Χ297公釐） (請先閱讀背面之注意事項再填寫本頁) 470741 經濟部中央標準局員工消費合作社印製 A7 __B7__五、發明説明（）層，用二乙醇沖洗濾紙殘留物。將笨/二***混合物冷卻到ot!，15分鐘內加入m 一 CPBA (75. 5克，0.35莫耳）。在室溫攪拌混合物5小時。K旋轉蒸發器除去二****加入4 0 0毫升甲撐氯化物，攪拌混合物2小時。另外加入m_CPB A (30 . 0克，0 ♦ 14莫耳）•播拌混合物2小時。冷卻混合物到0¾ *加入硤化鉀（45克）（於1 50水中）•約攪拌混合物15分鐘，然後加入硫代硫酸納（ 4 0克）（於1 5 0毫升水中）。經過Kugelrohr蒸餾（沸點 60- 90 Π [0.1毫米汞柱])製得3 0克不純的1，2 — 環氧基一二氟茚滿（油）。不純的1 ，2 —環氧基—5，6 —二氟茚滿（4 · 5 克）溶於100毫升乙醇，在10%炭上鈀（450毫克 )氫化1 5小時。過濾混合物，蒸發之，得到5，6 —二氟一 2 —羥基茚滿（2 . 72克，15 . 9奄莫耳），熔點 57 °C - 58¾。如實例2進行，但是用不闻的起始物質取代5，6 — 二氟一 1 一羥基茚滿，Μ下的式6化合物為：用5，7 —二氣一1，2，3，4 —四氫一1-羥基萘取代，製得5，7—二氟一 1 ，2，3，4一四氫一 2 —羥基茚滿•熔點9 3 °C到9 4 Ό ; 用4 * 6 —二氟_1 一羥基萘•製得4，6 -二氟一 2 -羥基茚滿取代，熔點52¾到56t：; -95- (請先閲讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 470741 A7 B7 五、發明説明（) 用6 * 7 —二氟一 1 ，2，3，4 一四氫—2 —羥基萘取代，製得6，7 -二氟一 1 ，2，3 * 4 —四氫一 2 一羥基茚滿（油）υ ;和用6 * 8 —二氟—1，2 * 3，四氫—1—羥基萘取代，製得6，8 —二氟—1 ，2，3，4 一四氬—2 一羥基茚滿。實例3 (R ) 一 5，7 -二氟—1 ，2 * 3，4 —四氫一 2 -羥基萘 Μ下係製備式6中t為2，位於5_和7 —位置的 R 1為氟的化合物。 3 * 5 -二氟苯基醋酸（100克，0 · 58奠耳）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填寫本頁) 和亞硫基氯化物（13 · 7M，100毫升，1 · 37莫耳）的混合物在室溫攪拌1 5小時，蒸發之後得到油狀殘留物的3，5 —二氟笨基乙醯氯化物。氯化鋁（154克，1·16莫耳）在1升甲撐氯化物中所形成的攪拌懸浮物被冷卻到一65 °C，滴加該酸氯化物（在200奄升甲撐氯化物中），使得反應溫度不超過—601。在—65Ϊ! 快速將乙烯氣體吹人懸浮物中。在2小時中將反應溫度回溫到0 °C，然後再冷卻到一 1 0 t：，Μ 5 0 0毫升水處理之。分離有機層，用1 00毫升氯化納水溶液洗滌•然後 Κ硫酸鎂乾燥之。過濾混合物，在減壓下濃縮濾液。在真空中（沸點90—1 IOC 〔1 · 0到0 · 7毫米汞柱〕一 9 6 - 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 470741 Α7 Β7 經濟部中央標隼局員工消費合作社印製五、發明説明（） )蒸豳殘留物，得到澄清濾液。再蒸餾（沸點100 — 105Ό〔0·3毫米汞柱〕），得到白色固體的5，7 一二氟一1 ，2，3，4 —四氩萘—2-酮（73 . 56 克，0·342其耳），熔點46*0。 45分鐘内將（1R，2S) -Ν —甲基非啶（81 · 3 克· 〇 · 454萁耳）在1 ，2升無水二***中所形成的溶液被加入氫化鋁鋰（在二***中圼1 · ΟΜ，4 1 6毫升，0 · 4 1 6莫耳），在回流溫度下加熱混合物1小時，然後使其冷卻到室溫。在45分鐘内加人2—乙基胺基吡啶（1 10 · 7克，0 . 907莫耳）在100奄升無水二***中所形成的溶液。在回流溫度下加热混合物，然後冷卻到_65Ό。滴加5，7_二氟一 1 ，2 · 3，4 一四氫萘一 2 —酮（23 . 0克，0 · 1 07莫耳）在 1 0 0毫升二***中所形成的溶液，使反應溫度不超過 —6〇υ。在一到一 68Ό携拌混合物3小時，然後加入甲醇，使反應溫度不超過一 6 Ot：。在一 6 5¾到一 68¾攪拌混合物，然後使其回溫到一 20¾，加入 3 · 0升的3N氫氯酸，使反應溫度不超過35¾。分離二***層，M2 0 0毫升飽和氯化納洗滌，以硫酸鎂乾燥之。過濾混合物*在減壓下濃縮滹液。在20毫升二*** 和200毫升己烷中结晶，在真空中乾煉，製得（R) — 5，7 —二氟一 1 ，2，3，4-四氫—2_羥基萘（ 10. 87 克，0.05 莫耳），熔點 85t：。〔α〕25 -97" (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) Α4規格（210Χ297公釐） 470741 經濟部中央標準局員工消費合作社印製 A7 B7五、發明説明（） =+36.03° (〇=1.59，氯仿）。如實例3進行*但是用不_的起始物質取代3，5 一二氟笨基醋酸，Μ下的式6化合物為：用3 —氟苯基醋酸取代，製得（R) — 7 —氟—1 * 2，3，4 一四氫一2 -羥基萘，熔點〔α〕25=+48.8° (c=2.0，氯仿）；用4 一氟苯基醋酸取代，製得（R) — 6 —氟一 1 ， 2，3，4 一四氫一 2 -羥基蔡，[a = + 49.2° (c=l*84，氯仿）；用苯基醋酸取代，製得（R) _1 * 2，3 ·4 —四氫一 2 -羥基萘（油），〔α〕$ =+62.2° (c =1 · 6，氯仿）；和用3，4 一二氟笨基醋酸取代，製得（R) — 6，7 一氟一 1 ，2，3，4 —四氫—2 —羥基萘，熔點88Ό -92¾，〔a〕25 = + 39·0° (c = 2.2* 氯仿）。如實例3進行，但是用（1R，2S) —N—甲基吡啶取代（IS，2R) — N —甲基锨啶，製得（S) -5 ，7 —二氟一 1 ，2，3，4 一四氫一2 —羥基萘，熔點 8 4 - 8 5 t： * i a f = + 37.48° (c = 2 * 6，氯仿）。如實例3進行，但是用不同的起始物質取代3，5 一二氟笨基醋酸，在沒有（1R，2S) — N —甲基哌啶 -9 8 _ 本紙張尺度適用中國國家標準（CMS〉A4規格（210X297公釐）訂 . 線 (請先閱讀背面之注意事項再填寫本頁) 470741 經濟、那中央標準局員工消費合作杜印製 A7 B7五、發明説明（）或2 -乙基胺基吡啶存在下，製得Μ下的式6化合物為：用4 一溴苯基醋酸取代，製得6 —溴一 1 ，2，3 · 4 一四氫—2 —羥基萘（油）；用4 —氯苯基醋酸取代，製得6 —氯一 1 · 2，3， 4 一四氫一 2 —羥基萘（油）；用3 —氯苯基醋酸取代，製得7 —溴一1 ，2，3， 4 —四氫一 2—羥基萘，熔點7 9°C— 8 1 Ό ; 用3，5 —二氯笨基醋酸取代，製得5，7 —二氯一 1 ，2，3，4 -四氫一 2 —羥基萘，熔點84¾ — 86 °C ；用3，5 —二氟笨基醋酸取代，製得5，7 —二氟一 1，2，3，4一四氫一2—羥基萘；用3，4 一二氟笨基醋酸取代，製得6，7 —二氟_ 1 ，2，3，4一四氫一2 —羥基萘；用3，4 —二氯苯基醋酸取代，製得6，7 —二氯_ 1 ，2，3，4 —四氳一 2 —羥基萘，熔點1 03Ό — 1 0 5 t);和用4 一氟笨基醋酸取代，製得6 —二氟一 1 ，2，3 ，4 —四氫一 2 —羥基萘。實例4 1 ，3 —二氟一 6，7，8，9 一四氫一6 —羥基—5Η _笨並環庚烯 -99- 本紙張尺度適用中國國家標準（CNS〉Α4规格（210Χ297公釐） ----------淋衣------1Τ------^ (請先閱讀背面之注意事項再填寫本頁) 470741 A7 B7 經濟部中央標準局員工消費合作社印製五、發明説明（ ) 1 1 I Μ 下係製備式 6 中 t 為 2 R 1 為 jgg· m 且位於 1 — 和 3 1 1 1 —- 位置的化合物 0 /—^ 1 I 請 1 1 5 9 7 — ___. 氟 — 1 $ 2 > 3 9 4 — 四氫萘 — 1 一麵 ( 先閱 1 | 4 0 克 9 2 2 • 0 奄莫耳 ) 9 蝌化辛 ( 2 2 • 0 奄克，讀背 1 面 | 6 8 • 9 奄莫耳 ) 和三甲基甲矽烷基氰化物 ( 3 • 2 3 毫之注意 1 升 2 4 • 2 毫奠耳 ) 的混合物在室溫下及氱氣中攪拌 1 事項 1 I 再 1 1 8 小時 0 在真空中蒸發三甲基甲矽燒基氰化物 » 將殘留物寫本 1 裝 I ( 6 1 3 克 ) 溶於 4 5 毫升 m 水二乙醚 0 氫化鋁鋰 ( 頁 1 I 1 0 Μ 1 2 4 2 毫升 2 4 2 毫莫耳 ) 於二乙醚中 1 1 1 被加入溶液 » 其加入速率得 Μ 維持溫和的回流〇在室溫下 1 1 授拌混合物 1 小時然後依序加入 0 8 4 毫升水 0 • I 訂 8 4 奄升的 1 5 % 氫氧化納和 1 6 3 毫升額外的水〇攪 1 I 拌水層 1 0 分鐘過 m Μ 二乙 m 萃取〇 >λ 硫酸鎂乾燥混 1 1 1 合萃取物濃縮得到 4 2 1 克殘留物 0 >λ 急驟曆析術 ( 1 1 沖提液為 1 0 % 甲醇 / 甲撐氯化物 ) 純化殘留物得到 1 1 線 — 胺基甲基 — 5 $ 7 一二氟 — 1 一羥基 — 1 f 2 » 3 » 4 1 I — 四氫 m ( 3 • 6 7 克 t 1 7 2 毫莫耳 ) 〇 1 1 I 1 一胺基一 5 t 7 一二氟 — 1 一羥基一 1 2 t 3 t 1 1 4 — 四氫萘 ( 3 ♦ 5 8 克 » 1 6 • 8 奄其耳 ) 和亞硝酸納 1 1 ( 2 • 3 2 克 * 3 3 • 6 奄莫耳 ) 的混合物在 8 毫升酿酸 1 I 和 2 0 毫升水及 — 5 V 中加熱参然後使其回溫到室溫 » 攪 1 | 拌 1 8 小時 0 蒸發除去溶劑 » Μ 急驟層析術 (沖提液為 1 1 5 0 % 己烷 / 甲撐氯化物 ) 純化 3 • 1 4 克的殘留物 $ 製 1 1 100- 1 1 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 470741 經濟部中央標準局員工消費合作社印製 A7 B7五、發明説明（）得1 · 8克殘留物。純化的殘留物和氫化鋁鋰（9 · 2毫升，9 · 2毫奠耳）的混合物在四氫呋喃中於〇υ攪拌 1 8小時，然後依序加入0 · 64毫升水，0 · 64毫升 1 5%氫氧化納和1 · 3毫升額外的水。以硫酸鎂乾煉四氫呋喃層，濃縮得到1 · 8克的殘留物。以急驟曆析術（沖提液為甲撐氯化物）純化，製得1 ，3 —二氟一 6，7 ，8，9 —四氫一 6 -羥基一 5Η —苯並環庚烯（1 . 4 克，7 · 0 6毫奠耳）。實例5 1 ，3-二氟-6，7，8，9 —四氫一7 — 羥基一 5Η -苯並環庚烯 Κ下係製備式6中t為2，R1為氟且位於1 一和3 -位置的化合物。 1 ，2 — 二溴一 3，5 —二氟苯（24 . 7 克，91 . 6 毫莫耳），雙（三笨基膦）鈀（I I)氯化物（2 · 57 克，3 · 66毫莫耳）和三乙胺（51 · 0毫升，366 毫莫耳）混合物在300毫升二甲基甲醯胺中•於氧氣及 851C約被攪拌15分鐘。加入肼水合物（366微升， 7· 54毫莫耳），另外攪拌混合物10分鐘。加入丙烯酸乙酯（39 · 7毫升，366毫莫耳）*混合物在氩氣中及約8 5 "C下被攬拌約1 4 4小時。減壓蒸發而除去溶劑*殘留物溶於1升醋酸乙酯*用水洗滌醋酸乙酯溶液三 -101- 本紙張尺度適用中國國家標準（CNS ) Α4規格（210Χ297公釐） (請先閎讀背面之注意事項再填寫本頁) 470741 A7 B7 經濟部中央標準局員工消費合作社印製五、發明説明 K ) 1 1 I 次 Μ 硫酸鎂乾燥之 0 蒸發溶劑 » 得到粗製的 3 — { 3 > 1 1 1 5 — 二唐一 2 — { 2 — ( 乙氧基羰基 ) 乙烯基 ) 笨基 } 丙 /—V 1 1 請 1 j 烯酸酯 ( 3 6 克 ) 0 先閲 1 | 3 — { 3 5 — 二氟 — 2 一 C 2 一 ( 乙氧基羰基 ) 乙讀背面 1 I 烯基 ] 苯基 } 丙烯酸乙酯 ( 5 • 7 克 9 1 8 ♦ 4 奄其耳 ) 1 I 意 I 在 2 5 0 毫升醋酸乙酯中於 6 0 P S * 及在 1 0 % 炭上事項 1 I 再 1 I 鈀 ( 0 5 7 克 ) 氫化 4 小時 i 然後 Μ Ce lite 過 m 〇蒸發填寫本 1 裝溶劑得到無色油狀的 3 一 { 3 5 — 二氟 — 2 一 [ 2 一頁 1 I ( 乙氧基羰基 ) 乙基 3 苯基 } 丙酸乙酯 ( 5 • 7 3 克 1 1 1 2 2 4 毫奠耳 ) 〇 1 1 三級丁氧化鉀 ( 1 6 7 毫升 0 1 6 7 奄莫耳 ) 於 1 訂 1 I 二甲基醢胺中被加入 4 0 0 毫升甲苯蒸發除去二甲基甲 16*$ m 胺〇加入 3 — { 3 5 — 二氟一 2 — C 2 一 ( 乙氧基羰 1 1 I 基 ) 乙基苯基 } 丙酸乙酯 ( 5 6 5 克 • 1 8 0 毫莫 1 1 耳 ) 在氣氣及 1 0 0 V 攪拌混合物 8 小時 0 冷卻混合物 1 、绩到 0 V ， Μ 1 1 5 毫升醋酸酸化 Μ 水洗滌三次硫 1 I 酸鎂乾燥之〇蒸發溶劑 * 得到 1 3 — 二氟一 6 7 ί 8 1 1 $ 9 — 四氫一 7 一氧一 5 Η — 笨並環庚烯 — 6 — 羧酸乙酯 1 1 和 1 % 3 一二氟一 6 7 8 » 9 — 四氫一 7 — 氧 — 5 Η 1 1 一笨並環庚烯一 8 — 羧酸乙酯的混合物 ( 4 « 3 克 ) 0 1 I 羧酸酯異士旗稱物 (4 • 2 克 ) 溶於 2 0 奄升醋酸和 1 0 1 1 I 毫升 9 N 氫氯酸 f 回流溶液 1 0 小時 0 冷卻混合物到室溫 1 1 1 * Μ 二乙醚萃取 ( 1 X 2 0 0 奄升 f 然後 1 X 5 0 毫升 ) 1 1 -102- 1 1 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）經濟部中央標準局員工消費合作社印製 470741 A7 B7 _ 五、發明説明（) 。混合物萃取物，並與1 20奄升1 0%碳酸納水溶液混合。Μ硫酸鎂乾燥有機層，然後蒸發除去溶劑。Μ急驟層析術（沖提液為 50%己烷/甲撐氯化物）純化殘留物，製得 1 ，3 — 二氟一 6，7，8，9 一四氫一 5Η —苯並環庚一 7 —酮（1 . 5克，7 . 6毫冥耳）。 1，3 —二氟—6，7，8，9 一四氣一 5Η—笨並環庚一 7__ (1 . 5克，7 . 6毫莫耳）溶於30毫升無水四氫呋嘲中，在氩氣中將溶液冷卻到〇·Ό，2分鐘内加入1Μ氫化鋁鋰（7 · 5毫升，7 * 5奄莫耳）（於四氫呋喃中）。在ου攪拌混合物1小時·然後依序加入 0 · 28毫升水* 0 · 28毫升1 5%氫氧化納水溶液和 0 · 9毫升水。攪拌混合物5分鐘，過濾* Μ醋酸乙酷洗滌，硫酸鎂乾燥。蒸發溶劑，得到1 ，3 —二氟一 6，7 ，8，9一四氫-7-羥基-5Η —苯並環庚烯（1 . 55 克，7 · 8毫莫耳）的油。實例6 (S ) — 5，7 —二氣—1 ，2，3，4一四氫萘—2 — 基胺氫氯化物以下係製備式3中η為1 * t為2，5 —和7 —位置的R1為氟的化合物。 (a>三氟醋酸酐（7 · 7公斤· 5 ♦ 3升，37 ♦ 5莫耳）被加熱到回流，在30分鐘內將L 一門冬氨酸（2 · -103- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） ----------装------tr------.# (請先閱讀背面之注意事項再填寫本頁) 470741 A7 B7 經濟部中央梯準局員工消費合作社印製. 五、發明説明（） 0公斤，15·0莫耳）在9升三氟醋酸中所形成的溶液 (逐漸加熱到6 5 °C，攪拌3小時而製成）加入回流中的三氟醋酸酐。然後蒸餾混合物，除去9升的三氟醋酸。在通入氮氣下將殘留的混合物加入8升的冷己烷。在冰浴中攪拌己烷混合物3小時，製得結晶性物質。過濾並分離該物質· Μ約25升己烷洗滌濾過的殘留物，在50 °C及通入氮氣的真空烘箱中乾燥到恆重，得到N— （三氟乙醢基 )—L 一門冬氨酸酐（2 . 9公斤，13 . 7莫耳），熔點 140Ό-14ΐυ。〔α〕0 -27.4ο (c = 3 · 2 8，四氫呋喃）。 (b ) 1 ，3-二氟笨（2 · 3公斤，20 . 0莫耳）在 5升甲撐氯化物中所形成的溶液加入在2 5升甲撐氯化物中的N —(三氟乙醯基）一L 一門冬氨酸酐（4 . 2公斤，20 · 0莫耳）和氯化鋁（7 .4公斤，55 . 5莫耳 )混合物。反應混合物的溫度在1 . 5小畤内逐漸增加* 另外保持在回流溫度達3小時。然後冷卻混合物，在良好攪拌下加入1 0升的水和20升的6N氳氯酸。分離甲撐氯化物曆，先後用水和盥水洗滌，在大氣懕下蒸發Μ除去揮發物。將殘留物溶於4 0升甲苯，在真空中蒸發混合物Κ除去揮發物，將溶液加熱到5 ΟΌ，加入8升的己烷。將混合物冷卻到30Ό，加入90升的己烷。然後在25C搅捽混合物3小時，得到結晶性物質。過濾並分離該物質， -104- (請先閱讀背面之注意事項再填寫本頁) 裝.470741 Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs Α7 Β7 V. Description of the invention () The reaction of the compound is from 20t: to 1 1 Ot :, preferably about 80¾ for 1 to 4 hours. Compounds of formula 47 can be prepared from formula X-SR2 8 (wherein X is halogen) or a protected derivative thereof with potassium phthalimide imide in a suitable solvent (eg ethylene dichloride, carbon tetrachloride, 1, 1, 1, 1, 2-tetramethane, etc.). The reaction is carried out at a range of 30 to 20¾, preferably about 20 °, for 1 to 3 hours. Compounds of formula X-SR2 8 can be prepared quickly by those skilled in the art. For example, a compound of formula X-SR28 (where X is bromo · ϋ2 8 is 2-tertiary monobutoxycarbonyl-2- (tertiary butyloxycarbonylamino) ethyl can be prepared in N-(tertiary Butoxycarbonyl) cystine is reacted with bromine in a suitable solvent (such as dichloroethane, etc.). The reaction is carried out at a temperature of 40t: to 20¾, preferably about 23¾, for 1 to 3 hours. Further on this paragraph The details of the reaction steps are described in Example 5 2 under M. A similar method is carried out. R 2 7 in formula III is a compound of formula (h). Compounds of formula I (b) can be prepared. R 2 7 in formula III is of formula (i). Compounds can be prepared in compounds of formula I (c) where R8 is hydrogen. Example 1 Preparation of 5,6-difluoro-1 monohydroxyindane K In formula 6, η is 0, t is 2, located at 5-and 6 — Position R1 is a fluoro compound. 3-(3,4-difluorophenyl) propionic acid (80. 0 g, 0.43 -92- This paper size applies to China National Standard (CNS) M specifications ( 210X297 mm)! II nn Order ~~ n I'if (Please read the precautions on the back before filling out this page) 470741 Employees' cooperation with the Central Bureau of Standards, Ministry of Economic Affairs, printed A7 B7 Note () Moore) is dissolved in 3 drops of dimethylformamide and 350 ml of methylene chloride. Add grass grass chloride (75 奄, 0.860 mol), and pass nitrogen at room temperature. The mixture was stirred for about 3 hours. The excess grasshopper chloride was removed by evaporation, and the residue was co-evaporated twice with 200 liters of carbon tetrachloride to obtain 95.0 g of a residue (oil). Aluminum chloride (200 g) Suspend in 800 ml of carbon disulfide and cool the suspension to 0t). A solution of the residue in 300 ml of carbon disulfide was added to the suspension in 20 minutes. The mixture was stirred at reflux temperature for 4 hours. Pour the mixture into 2 kg of crushed ice • Extract the aqueous layer with ethyl acetate (3x300 ml). Both the carbon disulfide layer and the ethyl acetate extract were dried over magnesium sulfate, filtered, and then mixed with K. The solvent was removed by evaporation, and the residue was crystallized from isopropyl ether to obtain 54.3 g of 5,6-difluoroindane-1 as a solid. The mother liquor was purified by column chromatography on silica gel (eluent: 10% ethyl acetate / hexane) to obtain an additional 5.2 g of 5,6-difluoroindane-1 1-one. 5,6-difluoroindan-1-one (59.3 g, 0.335 acetone) was dissolved in 1 liter of ethanol, and sodium borohydride (6.68 g * 176 acetic acid) was added. The mixture was searched and stirred for 48 hours, and the 2 * alcohol was removed by evaporation under reduced pressure. The residue was partitioned between diethyl ether and water, and the mixture was acidified with 1 N hydrochloric acid. The mixture was dried over magnesium sulfate and dried. The solvent was evaporated to obtain 5'6-difluoro-i-hydroxyindane (59.8 g) (oil). As in Example 1, but replacing 3- (3'4-difluorobenzyl) propionic acid with a different starting material, the compound of formula 6 under M is: -93- This scale is applicable to Chinese national standards (CNS> Α4 specification (2l0 × 297mm) ----------- install ------ 1T ------ 'line (Please read the precautions on the back before filling this page) 470741 Α7 Β7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention () Substituted with 3-(3,5-difluorobenzyl) propionic acid to obtain 5,7-difluoro_1-hydroxyl-indane , Melting point: 03Ό; Substituted with 4- (2 * 4-difluorobenzyl) butyric acid to obtain 5 · 7-difluoro-1,2,3,4-tetrahydro-1-hydroxynaphthalene (oil); use 4- (3,4-difluorophenyl) butyric acid was substituted to obtain 6 * 7-difluoro-1,2,3,4-tetrahydro-1-hydroxynaphthalene (oil); 4- (4-a Substituted by fluorophenyl) butyric acid to obtain 7-fluoro-1,2,3 * 4-tetrahydro-1-hydroxynaphthalene (oil); substituted with 4- (3-aminophenyl) butyric acid to obtain 6 —Fluoro-1 * 2,3,4—Tetrahydro-1—hydroxynaphthalene (oil); Use 4-mono (3,5-difluorophenyl) Substitution of butyric acid to obtain 6. 8-difluoro-1, 2, 3, 4 tetrahydro-1 1-hydroxynaphthalene (oil) * melting point ι〇2υ-ι〇3υ; Example 2 5,6_difluoro-1 The 2-hydroxyindane M is used to prepare a compound in which η is 0, t is 2, and R1 at the 5- and 6-positions is fluorine. The 5,6-difluoro-1 monohydroxy group prepared as in Example 1. Indane (59. 8 grams, 356 millimoles) was dissolved in 600 ml benzine, and p-toluenesulfonic acid monohydrate (3 ♦ 36 g, 17 ♦ 66 mol) was added. Heat the mixture to 1, Steam for about 2 hours, then cool down. Add a saturated sodium bicarbonate solution, and the benzene layer is dried over magnesium sulfate. Then filter benzene-94- This paper is in accordance with the Chinese National Standard (CNS) A4 specification (210 × 297 mm) (please (Please read the notes on the back before filling this page) 470741 Printed by A7 __B7__ of the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of the invention () layer, rinse the filter paper residue with diethanol. Add m-CPBA (75.5 grams, 0.35 moles) over 15 minutes. Stir the mixture at room temperature for 5 hours. Remove on K rotary evaporator Diethyl ether * was added 400 ml of methylene chloride, and the mixture was stirred for 2 hours. M_CPB A (30.0 g, 0 ♦ 14 moles) was added, and the mixture was sown for 2 hours. Cool the mixture to 0¾ * Add potassium tritide ( 45 g) (in 150 water) • Stir the mixture for about 15 minutes, then add sodium thiosulfate (40 g) (in 150 ml water). After Kugelrohr distillation (boiling point 60-90 Π [0.1 mm Hg]), 30 g of impure 1,2-epoxy-difluoroindane (oil) were obtained. Impure 1,2-epoxy-5,6-difluoroindane (4.5 g) was dissolved in 100 ml of ethanol and palladium (450 mg) was hydrogenated on 10% carbon for 15 hours. The mixture was filtered and evaporated to give 5,6-difluoro-2-hydroxyindane (2.72 g, 15.9 mol), melting point 57 ° C-58¾. As in Example 2, but replacing 5,6-difluoro-1,1-hydroxyindane with an obscure starting material, the compound of formula 6 under M is: with 5,7-digas-1,2,3,4 —Substituted by tetrahydro 1-hydroxynaphthalene to obtain 5,7-difluoro-1,2,3,4-tetrahydro-2 2-hydroxyindane • Melting point 9 3 ° C to 9 4 Ό; 4 * 6 —Difluoro_1 monohydroxynaphthalene • 4,6 -difluoro-2 -hydroxyindane substituted, melting point 52¾ to 56t :; -95- (Please read the precautions on the back before filling this page) This paper size Applicable to China National Standard (CNS) A4 specification (210X297 mm) 470741 A7 B7 V. Description of the invention () Substituted by 6 * 7-difluoro-1, 2, 3, 4 tetrahydro-2-hydroxynaphthalene 6,7-difluoro-1,2,3 * 4-tetrahydro-2-hydroxyindane (oil) υ; and 6 * 8-difluoro-1,2 * 3, tetrahydro-1-hydroxynaphthalene Substitute to obtain 6,8-difluoro-1,2,3,4-tetraargon-2-hydroxyindane. Example 3 (R)-5,7-difluoro-1, 2 * 3,4-tetrahydro- 2-hydroxynaphthalene M is prepared in the formula 6 where t is 2 and R 1 at the 5 and 7 positions is Fluorine compounds. 3 * 5-Difluorophenylacetic acid (100 g, 0.58 Moore) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) and thionyl chloride (13 • 7M, 100 ml, 1.37 mol) of the mixture was stirred at room temperature for 15 hours. After evaporation, 3,5-difluorobenzylacetamidine chloride was obtained as an oily residue. A stirred suspension of aluminum chloride (154 g, 1.16 mol) in 1 liter of methylene chloride was cooled to a temperature of 65 ° C, and the acid chloride (at 200 奄 methylene chloride) was added dropwise. Middle) so that the reaction temperature does not exceed -601. At -65Ϊ! Quickly blow ethylene gas into the suspension. The reaction temperature was warmed to 0 ° C in 2 hours, and then cooled to a temperature of 100 t :, treated with 500 ml of water. The organic layer was separated, washed with 100 ml of an aqueous sodium chloride solution, and then dried over MgSO4. The mixture was filtered, and the filtrate was concentrated under reduced pressure. In a vacuum (boiling point 90-1 IOC [1 · 0 to 0 · 7 mm Hg]-9 6-This paper size applies to Chinese National Standard (CNS) A4 size (210X297 mm) 470741 Α7 Β7 Central Standard of the Ministry of Economic Affairs Printed by the Bureau's Consumer Cooperatives V. Description of the Invention ()) The residue was steamed to obtain a clear filtrate. Distillation again (boiling point 100 — 105Ό [0.3 mm Hg]) to obtain 5,7-difluoro-1,2,3,4-tetrahydronaphthalene-2-one (73.56 g, 0 · 342 its ears), melting point 46 * 0. A solution of (1R, 2S) -N-methyl non-pyridine (81 · 3 g ··· 454 萁) in 1.2 liters of anhydrous diethyl ether was added to lithium aluminum hydride (in diethyl ether) over 45 minutes. Medium (1. 0M, 4 16 ml, 0.41 16 mol), the mixture was heated at reflux temperature for 1 hour, and then allowed to cool to room temperature. A solution of 2-ethylaminopyridine (1 10.7 g, 0.907 mol) in 100 l of anhydrous diethyl ether was added over 45 minutes. The mixture was heated at reflux temperature and then cooled to -65 ° F. A solution of 5,7_difluoro-1,2,3,4-tetrahydronaphthalene-2-one (23.0 g, 0.107 mol) in 100 ml of diethyl ether was added dropwise, The reaction temperature is not allowed to exceed -6〇υ. The mixture was stirred at 1 to 68 ° C for 3 hours, and then methanol was added so that the reaction temperature did not exceed 1 6 Ot :. The mixture was stirred at a temperature between 65 and 68 ¾, and then allowed to warm to a temperature of 20 ¾, and 3.0 L of 3N hydrochloric acid was added so that the reaction temperature did not exceed 35 ¾. The diethyl ether layer was separated, washed with 200 ml of saturated sodium chloride and dried over magnesium sulfate. The mixture was filtered * and the mash was concentrated under reduced pressure. Crystallized in 20 ml of diethyl ether and 200 ml of hexane, and dried in vacuum to obtain (R) — 5,7 —difluoro-1,2,3,4-tetrahydro-2 —hydroxynaphthalene (10. 87 grams, 0.05 mole), melting point 85t :. 〔Α〕 25 -97 " (Please read the notes on the back before filling this page) This paper size applies to China National Standard (CNS) Α4 size (210 × 297 mm) 470741 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention () = + 36.03 ° (〇 = 1.59, chloroform). Performed as in Example 3 but replacing 3,5 difluorobenzylacetic acid with a non-starting material, the compound of formula 6 under M is: Substituting with 3-fluorophenylacetic acid to obtain (R) -7-fluoro —1 * 2,3,4 Tetrahydro-2 hydroxynaphthalene, melting point [α] 25 = + 48.8 ° (c = 2.0, chloroform); Substituted with 4 monofluorophenylacetic acid to obtain (R) — 6 —Fluoro-1,2,3,4-tetrahydro-2-hydroxycai, [a = + 49.2 ° (c = 1 * 84, chloroform); Substituted with phenylacetic acid to obtain (R) _1 * 2, 3 · 4 —tetrahydro-2 -hydroxynaphthalene (oil), [α] $ = + 62.2 ° (c = 1.6, chloroform); and substitution with 3,4 difluorobenzylacetic acid to obtain (R ) — 6,7 monofluoro-1,2,3,4 —tetrahydro-2 —hydroxynaphthalene, melting point 88Ό -92¾, [a] 25 = + 39 · 0 ° (c = 2.2 * chloroform). It was carried out as in Example 3, but (S, 2R) -N-methylpyridine was substituted with (1R, 2S) -N-methylpyridine to obtain (S) -5,7-difluoro-1,2,3 , 4-tetrahydro-2-hydroxynaphthalene, melting point 8 4-8 5 t: * iaf = + 37.48 ° (c = 2 * 6, chloroform). As in Example 3, but replacing 3,5 difluorobenzylacetic acid with a different starting material, in the absence of (1R, 2S) — N —methylpiperidine-9 8 _ This paper applies the Chinese National Standard (CMS) 〉 A4 specification (210X297mm) Order. Thread (please read the precautions on the back before filling this page) 470741 Economy, the Central Bureau of Standards and Consumers ’cooperation, printed A7, B7, 5. Description of invention () or 2-ethyl In the presence of aminopyridine, the compound of formula 6 under M is obtained by substitution with 4-bromophenylacetic acid to obtain 6-bromo-1,2,3,4-tetrahydro-2-hydroxynaphthalene (oil); Substituted with 4-chlorophenylacetic acid to obtain 6-chloro-1,2,3,4-tetrahydro-2-hydroxynaphthalene (oil); substituted with 3-chlorophenylacetic acid to obtain 7-bromo-1 2,3,4-tetrahydro-2-hydroxynaphthalene, melting point 7 9 ° C-8 1 Ό; Substituted with 3,5-dichlorobenzylacetic acid to obtain 5,7-dichloro-1,2, 3,4-tetrahydro-2-hydroxynaphthalene, melting point 84¾-86 ° C; Substituted with 3,5-difluorobenzylacetic acid to obtain 5,7-difluoro-1,2,3,4-tetrahydro One 2-hydroxynaphthalene Substitution with 3,4-difluorobenzylacetic acid to obtain 6,7-difluoro-1,2,3,4-tetrahydro-2-hydroxynaphthalene; substitution with 3,4-dichlorophenylacetic acid to produce To obtain 6,7-dichloro_1,2,3,4-tetramethylene-1,2-hydroxynaphthalene, melting point 1 03Ό — 1 0 5 t); and substitution with 4 monofluorobenzylacetic acid to obtain 6-difluoro -1,2,3,4-tetrahydro-2-hydroxynaphthalene. Example 4 1, 3-Difluoro-6,7,8,9 Tetrahydro-6-Hydroxy-5Η _Benzocycloheptene-99- The paper size applies to Chinese national standard (CNS> A4 specification (210 × 297 mm) ) ---------- Linyi ------ 1T ------ ^ (Please read the notes on the back before filling out this page) 470741 A7 B7 Staff Consumption of Central Standards Bureau, Ministry of Economic Affairs Printed by the cooperative V. Description of the invention () 1 1 I Μ Preparation of compound 6 in which t is 2 R 1 is jgg · m and is located at 1 — and 3 1 1 1 —- position 0 / — ^ 1 I Please 1 1 5 9 7 — ___. Fluorine — 1 $ 2 > 3 9 4 — Tetrahydronaphthalene — 1 side (read first | 4 0 g 9 2 2 • 0 奄 mole) 9 hydrazone (2 2 • 0 奄 g, read 1 side | 6 8 • 9 奄 moles) and trimethylsilyl cyanide (3 • 2 3 millinotes 1 liter 2 4 • 2 millimoles) at room temperature And stirring in the radon gas 1 item 1 I 1 1 8 hours 0 Evaporation of trimethylsilyl cyanide in vacuum »Residues 1 in Pack 1 (6 1 3 g) dissolved in 4 5 ml m water diethyl ether 0 lithium aluminum hydride (Page 1 I 1 0 Μ 1 2 4 2 Ml 2 4 2 mmol) in diethyl ether 1 1 1 was added to the solution »its addition rate was maintained at a gentle reflux 0 at room temperature 1 1 the mixture was stirred for 1 hour and then 0 8 4 ml of water was added sequentially • I order 8 4 liters of 15% sodium hydroxide and 163 milliliters of additional water. Stir 1 I mix with water for 10 minutes. Extraction through m Μ diethyl m 0 > λ magnesium sulfate dry mix 1 1 1 The combined extract was concentrated to give 4 2 1 g of residue 0 > λ flash calorimetry (1 1 extract was 10% methanol / methylene chloride), and the residue was purified to obtain 1 1 line — aminomethyl — 5 $ 7 monodifluoro— 1 monohydroxy — 1 f 2 »3» 4 1 I — tetrahydrom (3 • 67 grams g 1 7 2 mmol) 〇1 1 I 1 monoamine 5 5 7 One difluoro — 1 one hydroxy — 1 2 t 3 t 1 1 4 — tetrahydronaphthalene (3 ♦ 5 8 g »1 6 • 8 piercing ears) and sodium nitrite 1 1 (2 • 3 2 g * 3 3 • 6 mol) in a mixture of 8 ml of brewing acid 1 I, 20 ml of water and — 5 V, then heat the ginseng to room temperature »Stir 1 | Stir 1 8 hours 0 Evaporate to remove the solvent» Μ 急Chromatography (eluent is 1 150% hexane / methylene chloride) Purified 3 • 1 4 g of residue $ 1 1 100- 1 1 This paper size applies to China National Standard (CNS) A4 specifications (210X297 mm) 470741 A7 B7 printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of the invention () There were 1.8 grams of residue. A mixture of the purified residue and lithium aluminum hydride (9.2 ml, 9.2 millimoles) was stirred in tetrahydrofuran at 0 ° for 18 hours, and then 0. 64 ml of water was added, followed by 0. 64 ml of 15 % Sodium hydroxide and 1.3 ml of additional water. The tetrahydrofuran layer was dried over magnesium sulfate and concentrated to give 1.8 g of a residue. Purified by flash calorimetry (eluent is methylene chloride) to obtain 1,3-difluoro-6,7,8,9-tetrahydro-6-hydroxy-5pyridine-benzocycloheptene (1 4 grams, 7.06 millimoles). Example 5 1, 3-Difluoro-6,7,8,9 —Tetrahydro-7—Hydroxy-5′-benzocycloheptene K Preparation of formula 6 where t is 2, R1 is fluorine and is located at 1- 3-position compound. 1,2,2-dibromo-3,5-difluorobenzene (24.7 g, 91.6 mmol), bis (tribenzylphosphine) palladium (II) chloride (2.57 g, 3.66 Mmol) and triethylamine (51.0 ml, 366 mmol) in 300 ml of dimethylformamide • Stirred in oxygen and 851C for about 15 minutes. Add hydrazine hydrate (366 μl, 7.54 mmol) and stir the mixture for another 10 minutes. Ethyl acrylate (39.7 ml, 366 mmol) was added. * The mixture was stirred under argon at about 8 5 " C for about 1 4 4 hours. Evaporate under reduced pressure to remove the solvent * The residue is dissolved in 1 liter of ethyl acetate * Wash the ethyl acetate solution with water III-101- This paper size applies to Chinese National Standard (CNS) Α4 size (210 × 297 mm) (Please read the back first Please pay attention to this page and fill in this page again) 470741 A7 B7 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention K) 1 1 I Μ Magnesium sulfate dried 0 Evaporated solvent 1 1 5 — Ertang 1 2 — {2 — (ethoxycarbonyl) vinyl) benzyl} Propane / —V 1 1 Please 1 j enoate (3 6 g) 0 Read 1 | 3 — {3 5 — difluoro — 2 —C 2 — (ethoxycarbonyl) Ethyl Acetate 1 I Alkenyl] Phenyl} Ethyl Acrylate (5 • 7 g 9 1 8 ♦ 4 Achilles) 1 I means I in 2 50 ml of ethyl acetate at 60 PS * and 10% charcoal matters 1 I then 1 I Palladium (0 57 g) hydrogenated for 4 hours i then Μ Ce lite over m 〇 Evaporate and fill in this 1 solvent to obtain 3 1 {3 5 — difluoro — 2 1 [2 page 1 I (ethoxycarbonyl) ethyl 3 phenyl} ethyl propionate (5 • 7 3 g 1 1 1 2 2 4 mil) 〇1 1 tertiary potassium butoxide (167 ml 0 1 6 7 mol) was added to 1 order 1 I dimethylammonium amine 4 0 ml of toluene was evaporated to remove the dimethylmethyl 16 * $ m amine. 3 — {3 5 — Difluoro-1 2 — C 2 mono (ethoxycarbonyl 1 1 I group) ethylphenyl} ethyl propionate Ester (5 65 g • 1 80 mmol 1 1 ear) Stir the mixture for 8 hours under gas and 100 V 0 Cool the mixture 1 to 0 V, Μ 1 1 5 ml acetic acid Μ water wash three times sulfur 1 I Magnesium acid is dried and the solvent is evaporated * to give 1 3 —difluoro-6 7 ί 8 1 1 $ 9 —tetrahydro-1 7 monooxy-5 Η —benzylcycloheptene — 6 — ethyl carboxylate 1 1 And 1% 3 6 7 8 »9 — Tetrahydro-7 — Oxygen — 5 Η 1 1 Mixture of 1-benzylcycloheptene- 8-carboxylic acid ethyl ester (4« 3 g) 0 1 I Carboxylic acid isotaxel ( 4 • 2 g) dissolved in 20 ml of acetic acid and 1 0 1 1 1 ml of 9 N hydrochloric acid f refluxing solution for 10 hours 0 cool the mixture to room temperature 1 1 1 * Μ diethyl ether extraction (1 X 2 0 0 Ff then 1 X 50 ml) 1 1 -102- 1 1 This paper size is applicable to China National Standard (CNS) A4 (210X297 mm) Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economy 470741 A7 B7 _ V. Invention Description (). The mixture was extracted and mixed with 120 ml of a 10% aqueous sodium carbonate solution. The organic layer was dried over MgSO4, and the solvent was removed by evaporation. Purification of the residue by MX flash chromatography (50% hexane / methylene chloride extract) to obtain 1,3-difluoro-6,7,8,9-tetrahydro-5 氢 -benzocycloheptan One 7-keto (1.5 grams, 7.6 millineurs). 1,3 -difluoro-6,7,8,9 a tetrakis and a 5Η-benzylcycloheptan-7__ (1.5 g, 7.6 mmol) dissolved in 30 ml of anhydrous tetrahydrofuran, The solution was cooled to 0 · Ό under argon, and 1M lithium aluminum hydride (7.5 ml, 7 * 5 奄 Mol) was added over 2 minutes (in tetrahydrofuran). The mixture was stirred for 1 hour. Then 0. 28 ml of water * 0. 28 ml of a 1% aqueous sodium hydroxide solution and 0. 9 ml of water were added sequentially. The mixture was stirred for 5 minutes, filtered and washed with ethyl acetate and dried over magnesium sulfate. The solvent was evaporated to give 1,3-difluoro-6,7,8,9-tetrahydro-7-hydroxy-5'-benzocycloheptene (1.55 g, 7.8 mmol) as an oil. Example 6 (S) —5,7—Digas—1,2,3,4-tetrahydronaphthalene-2 —ylamine hydrochloride The following system is used to prepare Formula 3 where η is 1 * t is 2,5 — and 7 The compound at position R1 is fluorine. (a > Trifluoroacetic anhydride (7 · 7 kg · 5 ♦ 3 liters, 37 ♦ 5 mol) is heated to reflux, and L-aspartic acid (2 · -103- This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) ---------- install ------ tr ------. # (Please read the precautions on the back before filling this page ) 470741 A7 B7 Printed by the Consumer Cooperative of the Central Government Bureau of the Ministry of Economic Affairs. V. Description of the invention () 0 kg, 15.0 mol) in 9 liters of trifluoroacetic acid (gradually heated to 6 5 ° C , Made by stirring for 3 hours) added trifluoroacetic anhydride under reflux. Then the mixture was distilled to remove 9 liters of trifluoroacetic acid. The remaining mixture was added to 8 liters of cold hexane under nitrogen. In an ice bath The hexane mixture was stirred for 3 hours to prepare a crystalline substance. The substance was filtered and separated. The filtered residue was washed with about 25 liters of hexane, and dried to a constant weight in a vacuum oven at 50 ° C and nitrogen, to obtain N. — (Trifluoroacetamido) —L-aspartic anhydride (2.9 kg, 13.7 moles), melting point 140Ό-14ΐυ. [Α] 0 -27.4ο (c = 3 · 2 8 , (Tetrahydrofuran). (B) A solution of 1,3-difluorobenzyl (2.3 kg, 20.0 mol) in 5 liters of methyl chloride was added to N in 2.5 liters of methyl chloride. — A mixture of (trifluoroacetamyl) -L-aspartic anhydride (4.2 kg, 20.0 mol) and aluminum chloride (7.4 kg, 55.5 mol). The temperature of the reaction mixture was at 1 Gradually increase within 5 mashes * Also keep at reflux temperature for 3 hours. Then cool the mixture, add 10 liters of water and 20 liters of 6N chlorochloric acid with good stirring. Separate the methylene chloride calendar, then use water and Wash with water and evaporate the volatiles under atmospheric pressure to remove the volatiles. Dissolve the residue in 40 liters of toluene, evaporate the mixture in a vacuum to remove the volatiles, heat the solution to 50 ℃, and add 8 liters of hexane. Mix the mixture Cool to 30Ό, add 90 liters of hexane. Then stir the mixture at 25C for 3 hours to obtain a crystalline substance. Filter and separate the substance, -104- (Please read the precautions on the back before filling this page).

、1T 絲_ 本紙張尺度適用中國國家標準（CNS〉Α4規格（210X297公釐） 470741 A7 B7__ 五、發明説明（) K3 X 1 0升己烷洗滌滤過的殘留物，在室溫及通入氮氣的真空烘箱中乾燥到恆重，得到（s ) — 2 一〔（三氟乙醯基）胺基〕—4 — (2，4_二氟苯基）一 4 一氧丁酸（5，2公斤，16，0莫耳），熔點82. 4-84 •ΟΌ。〔α〕《 +15.2° (c=0.956，甲醇 )0 (c ) (S) — 2 — 〔（三氟乙豳基）胺基〕一 4 - (2 ，4 一二氟苯基）一 4 一氧丁酸（4 . 8公斤，14 · 7 奠耳）和活性碳（Darco® (0*4公斤）混合物在 5升醋酸中於室溫下搜拌1小時。混合物被過漶到 Pearlman觸媒（0 . 5公斤* 50%濕重），K1 5升冰醋酸予Μ洗滌。1升冰醋酸中的硫酸（1 · 2升，2 1 ，8奠耳）被過濾到混合物中，Κ2 · 8升泳醋酸洗滌。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填寫本頁) 反應容器在氮氣三次然後通入氮氣氣六次以抽真空’使壓力到1 Op s i g。在通入氫氣的大氣壓力及室溫下激烈攪拌混合物達24小時。然後將氮氣通入反應容器，過瀘混合物到4 · 6公斤的醋酸納三水合物。用1 〇升冰醋酸洗滌滹紙*在真空中蒸餾除去冰醋酸。殘留物在20升甲撐氯化物和40升水中分層*水曆被1 0升甲撐氯化物萃取，混合的甲撐氯化物被1 0升水洗滌，然後甲撐氯化物在硫酸納（10公斤）乾燥*過瀘。在真空中除去溶劑*殘留物溶於5升的甲撐氮化物中。在通入氮氣中將溶液加入1 5升的己烷，其加入速率使己 -105- 本紙張尺度適用中國國家標準（CNS ) Α·4規格（210X297公釐）經濟部中央標準局員工消費合作社印製 470741 A7 B7 五、發明説明（）烷混合物的溫度維持在ot：和5T：之間。使混合物靜置1 小時，得到结晶性物質。過滤並分離該物質· Ml 0升己烷洗滌濾過的殘留物，在2 5¾及通入氮氣的真空烘箱中乾煉到恆重，得到（S) — 2 — 〔（三氟乙豳基）胺基〕一 4 一（2，4 一二氟苯基）丁酸（3 · 3 公斤，10 · 4莫耳），熔點62 — 83· 5Ό。分析上純樣品的熔點為 +6.8° (c=0.9 9 5 ，甲醇）。 (d)五氯化磷在12升甲撐氯化物中所形成的懸浮物冷卻到5t：，在20分鐘内加入（S) — 4 — （2，4 —二氟笨基）一 2 — 〔（三氟乙醢社）胺基〕丁酸（3 · 1公斤，9 · 9莫耳）（12升甲撐氯化物中）。薄層層析（甲醇驟冷整份）證實丁酸已轉換成相對應的酸氯化物。攪拌混合物30分鐘，然後被加入氯化鋁（4 · 3公斤）在38 · 8升甲撐氯化物中所形成的泥狀物，添加速率使泥狀物溫度維持在1 Ό和5 Ό之間。攢拌反應混合物 1小時*然後被加入28公斤的冰和5 · 3公斤濃氫氣酸中。搜拌混合物1小時，使溫度回升到2 ο υ。分離水相*Μ甲撐氯化物萃取（2x1 5升），用水洗漉甲撐氯化物層，與甲撐氣化物萃取物混合。然後用水洗猫混合的甲撐氯化物。添加碳酸氫納水溶液Κ調整水相的ρ Η。再分別用水和鹽水洗滌甲撐氯化物曆。Κ硫酸納乾燥甲撐氯化物。在大氣壓下蒸發濃縮混合物，殘留物溶 -1 0 6 - 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） ----------f------IT------,# (請先閱讀背面之注意事項再填寫本頁) 470741 A7 B7 經濟部中央標準局員Η消費合作杜印製五、發明説明（ ) 1 1 | 於 1 5 升甲醇中〇蒸餾甲醇溶液 Μ餘去殘留的甲撐氯化物 1 1 1 9 然後加入 9 • 9 升水〇使混合物回溫到 5 6 V t 使其冷 1 I 請 1 I 卻到室溫 9 然後約攪 1 2 小時 0 過澳分離而製得結晶性閱 1 I 物質 0 用 1 5 升水洗猫 m 紙殘留物在真空中及室溫下通讀背 1 1 面 I 入氮氮以乾燥分離的物質到圼恆重為止 0 之注 1 I 意 1 在 9 0 將該物質溶於 5 升甲苯中在 8 0 V 與 1 0 事項 1 I 再 1 I 升的庚烷混合 0 混合物的溫度在 1 5 小時內逐漸降低，填 1 裝然後在寫本 5 攪拌混合物約 1 2 小時 t 得到結晶性物質〇過页 1 I m 分雛該物質用 1 5 升庚烷洗滌漶紙殘留物 t 在真空及 1 1 室溫下通入氮氣使乾燥分離的物質到呈恆重為止製得 ( 1 1 S ) — 5 7 — 二氟 — 2 — C ( 三氟乙醢基 ) 胺基一 3 1 訂 1 I 9 4 一二氫 — ( 2 Η ) 一蔡一 1 — 酮 ( 2 0 公斤 6 • 8 莫耳 ) 熔點 1 4 2 4 — 1 4 4 6 "C 〇 C α 1 1 I — 5 9 4 0 ( C = 0 9 9 4 甲酵 ) 〇 1 1 ( e ) 含 ( S ) 一 5 7 一二氟 — 2 — C ( 氟乙醢基 ) 1 锊胺基 ] — 3 4 — 二氫一 ( 2 Η ) 一萘一 1 — 調 ( 1 • 1 I 1 公斤 » 3 8 莫耳 ) 和在 1 1 升 = 氟醋酸中的 Pear 1 man 1 1 1 觭媒 ( 0 • 5 5 公斤 f 5 0 % 濕重 ) 的混合物在反應容 1 1 器中 » 容器被通入風氣八次 > 然後通入 Most 凰氣氣八次 Η 抽真 1 1 空 9 使膣力到 1 1 P S i g 0 在通入氫氣的及室溫下激烈 1 I 报拌混合物達 2 4 小時〇薄層層析術證實 m — 1 酮轉換 1 1 成 ( S ) 一 1 一羥基 — 5 * 7 一二氟 — 2 — C ( 氟乙釅 1 1 基 ) 胺基 — 3 4 一二氫一 ( 2 Η ) — 蔡 0 1 1 - 107- 1 1 很尺度適用中國國家操準（CNS ) A4規格（210X297公釐） 470741 經濟部中失標準局員工消費合作社印製 A7 _B7_五、發明説明（） (f) 然後加入硫酸（1·1升，19·4莫耳）（在1 升三氟醋酸中），在室溫下通入氫氣（125ps i g) 又攪拌混合物24小時。然後將氮氣通入反應容器 Celite過濾混合物，Ml 1升三氟醋酸洗滌。濾液與2 . 8 公斤醋酸納三水合物和80升水混合，混合物冷卻到1 〇〇 7，得到結晶性物質。過濾分雛該物質，用1 0升冰水洗滁漶紙殘留物，乾燥製得（S) — 5，7 —二氟一〔 (三氟乙醯基）胺基〕一1 ，2，3，四氫萘（〇 . 8 公斤，2. 9 莫耳），熔點 159. 9— 160.9¾。 C α -56·0° (c = l，01，甲醇）。 (g) 氫氧化鋰軍水合物（7 · 8克，Ο · 2莫耳）加入 (S) -5，7 -二氟一 2 -〔（三氟乙醯基）胺基〕一 1 ，2，3，4 —四氫萘（20 . 8克，74 . 5毫莫耳 )在187毫升甲醇和21奄升水中所形成的溶液中。在回流下攪拌混合物30分鐘，Μ200毫升甲酵稀釋之。然後將稀釋後的混合物與60毫升水，24 ♦ 8毫升濃氫氯酸和4 · 2克活性碳Darco®混合。攪拌混合物30分鐘，然後K 〇61“6過滤。蒸餾漶液直到頭溫度達75<〇°使殘留的混合物冷卻，並靜置約6 0小時。然後使混合物在冰浴中冷卻，得到結晶性物質。過濾分離該物質*用水洗滌濾紙殘留物，在真空及室溫下通入氮氣K乾燥分離的物質到圼恆重為止，製得（S) — 5，7 —二氟一1 ，2， 3，4 —四氫萘—2 —基胺氫氯化物（14 . 8克，67 ‘ 6 -1 0 8 - 本紙張尺度適用中國國家標隼（CNS〉A4規格（210X297公釐} ----------t------、玎------絲 (請先閱讀背面之注意事項再填寫本頁} 470741 經濟部中央標準局員工消費合作社印製 A7 B7 五、發明説明（）、 1T silk _ This paper size applies to Chinese national standards (CNS> A4 size (210X297 mm) 470741 A7 B7__ V. Description of the invention () K3 X 10 liters of filtered residue washed with hexane, at room temperature and through Dry to constant weight in a vacuum oven of nitrogen to obtain (s) — 2-[(trifluoroethylammonium) amino] -4 — (2,4-difluorophenyl) -4 monooxybutyric acid (5, 2 kg, 16,0 mol), melting point 82.4-84 • 0Ό. 〔Α〕《+ 15.2 ° (c = 0.956, methanol) 0 (c) (S) — 2 — [(trifluoroacetamido ) Amine]-4-(2,4 difluorophenyl)-4 monooxobutyric acid (4.8 kg, 14.7 Moore) and activated carbon (Darco® (0 * 4 kg) in a mixture of 5 Search and stir for 1 hour at room temperature in liter of acetic acid. The mixture was washed with Pearlman catalyst (0.5 kg * 50% wet weight), K1 5 liter of glacial acetic acid was washed with M. 1 liter of sulfuric acid in glacial acetic acid (1 · 2 liters, 21, 8 mols) are filtered into the mixture, and K 2 · 8 liters are washed with acetic acid. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page). Reaction vessel in Three times and then pass nitrogen gas six times to evacuate to make the pressure reach 1 Op sig. Stir the mixture vigorously for 24 hours under the atmospheric pressure of hydrogen gas and room temperature. Then pass nitrogen into the reaction vessel and pass the mixture to 4 · 6 kg of sodium acetate trihydrate. Wash the paper with 10 liters of glacial acetic acid * Distill off the glacial acetic acid in vacuo. The residue is separated in 20 liters of methyl chloride and 40 liters of water. L of methylene chloride is extracted, the mixed methylene chloride is washed with 10 liters of water, and then the methylene chloride is dried in sodium sulfate (10 kg) * over 泸. The solvent is removed in a vacuum. The residue is dissolved in 5 liters of methyl chloride. Nitrogen is added to the solution. Nitrogen is added to the solution to add 15 liters of hexane, and the rate of addition is such that hex-105- This paper size applies to Chinese National Standard (CNS) A · 4 (210X297 mm) Central Ministry of Economic Affairs Printed by the Consumer Cooperatives of the Standards Bureau 470741 A7 B7 V. Description of the invention () The temperature of the alkane mixture is maintained between ot: and 5T :. The mixture is allowed to stand for 1 hour to obtain a crystalline substance. The substance is filtered and separated. Ml 0 Liters of hexane was washed and filtered The residue was dried to constant weight in a vacuum oven with a nitrogen gas of 2 5¾ and nitrogen to obtain (S) — 2 — [(trifluoroethylfluorenyl) amino] —4— (2,4—difluorophenyl) ) Butyric acid (3.3 kg, 10 · 4 mol), melting point 62—83 · 5Ό. The melting point of the analytically pure sample is + 6.8 ° (c = 0.9 95, methanol). (d) The suspension of phosphorus pentachloride in 12 liters of methylene chloride is cooled to 5t: (S) — 4 — (2,4 —difluorobenzyl) — 2 — [ (Trifluoroacetamide) Amino] butyric acid (3.1 kg, 9.9 moles) (12 liters of methylene chloride). Thin layer chromatography (quenching the entire portion with methanol) confirmed that butyric acid had been converted to the corresponding acid chloride. The mixture was stirred for 30 minutes, and then a slurry of aluminum chloride (4.3 kg) in 38.8 liters of methylene chloride was added at a rate to maintain the temperature of the slurry between 1 5 and 5 Ό . The reaction mixture was stirred for 1 hour * and then added to 28 kg of ice and 5.3 kg of concentrated hydrogen acid. Search the mixture for 1 hour and allow the temperature to rise back to 2 ο υ. The aqueous phase was separated and extracted with methylene chloride (2 x 15 liters). The methylene chloride layer was washed with water and mixed with the methane gaseous extract. The cat mixed methyl chloride was then washed with water. Aqueous sodium bicarbonate was added to adjust the pH of the aqueous phase. The methylene chloride calendar was washed with water and brine, respectively. K Sodium Sulfate Dry methylene chloride. Concentrate the mixture by evaporation under atmospheric pressure, and the residue dissolves -1 0 6-This paper size applies to China National Standard (CNS) A4 (210X297 mm) ---------- f ------ IT ------, # (Please read the precautions on the back before filling this page) 470741 A7 B7 Member of the Central Standards Bureau of the Ministry of Economic Affairs, Consumption Cooperation, Du V. Description of the invention () 1 1 | In 15 liters of methanol 〇 Distill the methanol solution to remove the remaining methylene chloride 1 1 1 9 and then add 9 • 9 liters of water. 回 Allow the mixture to warm to 5 6 V t to cool 1 I, please 1 I to room temperature 9 and stir about 1 2 hours 0 Separation through Australia to obtain crystallinity 1 I Substance 0 Wash the cat m paper residue with 15 liters of water. Read through the back 1 1 side under vacuum and room temperature. Nitrogen and nitrogen are added to dry the separated substance to constant temperature. Note 1 up to 0 I means 1 at 9 0 This substance is dissolved in 5 liters of toluene at 8 0 V and 1 0. Matter 1 I Then 1 I liter of heptane is mixed. The temperature of the mixture is gradually reduced within 15 hours. Fill with 1 and then stir the mixture for about 1 2 hours in the writing book. T Get a crystalline substance. 5 liters of heptane washes the paper residue t under vacuum and 1 1 at room temperature under nitrogen to dry the separated materials until constant weight is obtained (1 1 S) — 5 7 — difluoro — 2 — C (three Fluoroethenyl) Amine 1 3 1 Order 1 I 9 4 1 Dihydro — (2 Η) 1 Tsai 1 — 1 (one 2 kg 6 • 8 mol) Melting point 1 4 2 4 — 1 4 4 6 " C 〇C α 1 1 I — 5 9 4 0 (C = 0 9 9 4 formazan) 〇1 1 (e) containing (S) 5 7 1 difluoro-2 — C (fluoroethenyl) 1 Amido] — 3 4 — dihydromono (2 Η) mononaphthalene-1 — tune (1 • 1 I 1 kg »3 8 mol) and Pear 1 man 1 1 1 in fluoroacetic acid Media (0 • 5 5 kg f 5 0% wet weight) of the mixture in the reaction volume 1 1 container »the container is vented to the atmosphere eight times > and then the Most is introduced to the gas eight times Η pumping true 1 1 air 9 to make the force reach 1 1 PS ig 0 Intensely heated at room temperature and I 1 for 24 hours. Thin layer chromatography confirms the conversion of m — 1 ketone 1 1 into (S) — 1 — hydroxy — 5 * 7 Mono-difluoro— 2 — C (fluoroethenyl 1 1 group) Amine — 3 4 Mono-dihydro- (2 Η) — Cai 0 1 1-107- 1 1 Applicable to China National Standards (CNS) A4 specifications (210X297 mm) 470741 Printed by A7 _B7_ of the Consumer Cooperatives of the Bureau of Intermediate Standards of the Ministry of Economic Affairs V. Invention Description () (f) Then add sulfuric acid (1.1 liters, 19.4 mols) (in 1 liter of trifluoro In acetic acid), hydrogen (125 ps ig) was passed at room temperature and the mixture was stirred for another 24 hours. Nitrogen was then passed into the reaction vessel and the mixture was filtered through Celite and washed with 1 liter of trifluoroacetic acid. The filtrate was mixed with 2.8 kg of sodium acetate trihydrate and 80 liters of water, and the mixture was cooled to 107 to obtain a crystalline substance. The material was separated by filtration, and the paper residue was washed with 10 liters of ice water and dried to obtain (S) -5,7-difluoro-[(trifluoroethylamido) amino] -1,2,3, Tetrahydronaphthalene (0.8 kg, 2.9 moles), melting point 159.9-160.9¾. C α -56 · 0 ° (c = 1,01, methanol). (g) Lithium hydroxide military hydrate (7.8 g, 0 · 2 mol) was added with (S) -5,7-difluoro-2-[(trifluoroacetamido) amino] -1,2 , 3,4-tetrahydronaphthalene (20.8 g, 74.5 mmol) in a solution of 187 ml of methanol and 21 ml of water. The mixture was stirred at reflux for 30 minutes and diluted with 200 ml of formazan. The diluted mixture was then mixed with 60 ml of water, 24 ♦ 8 ml of concentrated hydrochloric acid and 4 · 2 g of activated carbon Darco®. The mixture was stirred for 30 minutes, and then filtered through K 061 "6. The mash was distilled until the head temperature reached 75 < 0 ° to cool the remaining mixture and left for about 60 hours. Then the mixture was cooled in an ice bath to obtain crystallinity Substances are filtered and separated * The filter paper residue is washed with water, and the separated materials are dried under nitrogen and nitrogen at room temperature until the constant weight is obtained to obtain (S) — 5, 7 —difluoro-1, 2, 3,4 -tetrahydronaphthalene-2 -ylamine hydrochloride (14.8 g, 67 '6 -1 0 8-This paper size applies to Chinese national standard (CNS> A4 specification (210X297 mm) --- ------- t ------ 、玎 ------ Silk (Please read the precautions on the back before filling out this page) 470741 Printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 5 , Description of the invention ()

毫冥耳），熔點大於28〇υ。〔《 Ip '— 6 6 ♦ 2 ° ( C =0 ♦ 1 6 2 ，甲酵）。實例7 (R) - 5，7-二氟-1，2，3，4一四氫萘-2- 基甲烷磺酸鹽 Μ下係製備式5中η為1 ，t為2，5 —和7 —位置的R1為氟且L為甲磺酿氧基的化合物。如實例3所製備的（R) - 5，7—二氟一1 ，2， 3，4 一四氫一2 —羥基萘（59 . 0克，0 · 32莫耳 )和三乙胺（13 · 8M，74 . 2毫升，0 . 53莫耳 )混合物在1·78升二***中在甲醇/冰浴中冷卻。在氩氣中於5 — 1 0分鐘內加入甲烷磺豳氯化物（1 2 · 9 Μ，37 . 2毫升，0 . 48莫耳），然後在室溫下搅拌混合物1 8小時。混合物在水和醚之間分曆，分雛醚曆，用醚率取水層。混合物醚曆各被1 Ν氫氯酸，飽和碳酸氬納溶液•鹽水洗滌一次*然後Μ硫酸鎂乾煉之。蒸發之後，得到灰白色固體的（R) -5，7 —二氟一1 ，2，3 ，4 一四氫一萘一 2基甲烷磺酸鹽（87 · 12克），溶點 79 °C— 801， ία： 2 s = +16 - 77° ( c = 2 ♦ 0，氯仿）。依實例7進行*但是採用不同起始物霣取代（R) — 5，7 —二氟一 1 ，2，3，4 一四氣一 2 —羥基萘，製得K下的式5化合物： -109- 本紙張尺度適用中國國家榇準（CNS ) A4規格（2丨〇乂297公釐） ----------f------IT------# (請先閱讀背面之注意事項再填寫本覓) 470741 A7 B7 五、發明説明（）用1 ，2，3，4 —四氫—2_羥基萘取代，製得1 ，2 * 3，4 —四氣一萘~*2_基甲焼碌酸鹽；用（R) —1 ，2，3，4 —四氫一2 —羥基萘取代，製得（R) — 1 ，2，3，4 一四氫一萘一 2 —基甲烷磺酸鹽；用（R) —5 —氟—1 ，2，3，4 —四氫一 2 —羥基萘取代，製得（S) - 5 —氟—1 ，2，3，4 一四氫 —萘_2 —基甲烷磺酸鹽；用（R) — 6 —氟一1 ，2，3，4 —四氫一 2 —羥基萘取代，製得（S) — 6—氟—1 ，2，3，4 一四氫一萘一2—基甲烷磺酸鹽；用（R) — 7-氟一 1 ，2，3，4 —四氳-2—羥基萘取代，製得（S) — 7 —氟—1 ，2，3，4 一四氫 —萘一2—基甲烷磺酸鹽；用 6，7 —二氯-1 ，2 , 3，4 —四氫一 2 —羥基萘取代，製得2 — 6，7 —二氯—1 ，2，3，4一四氫一萘一2—基甲烷磺酸鹽；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填寫本頁) 用（一）6，7 —二氟一1 ，2，3，4 一四氫—2 —羥基萘取代，製得（一）一 6，7 —二氟-1 ，2， 3，4 一四氫—萘_2 一基甲烷磺酸鹽；用 6，7 -二氟一1 ，2，3，4 一四氫—2 -羥基萘取代，製得6，7_二氟—1 ，2，3 * 4 —四氫— 萘—2 —基甲烷磺酸鹽； -110- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 470741 經濟部中央標準局員工消費合作社印製 A7 B7五、發明説明（）用（S) — 5，7 —二氟一1 ，2，3，4-四氫— 2 -經基萘取代，製得（R) ~5，7 —二氯—1 ，2 ，3，4 —四氫一萘—2 —基甲烷磺酸鹽；用5，7 —二氟—1，2，3，4一四氫一 2_羥基萘取代，製得5，7—二氟—1 ，2，3，4一四氫—萘 —2 —基甲烷磺酸鹽；用6，8 —二氟—1 ，2，3，4 —四氫一 2 —羥基萘取代，製得6，8 -二氟—1 ，2，3，4 一四氫—萘一2—基甲烷磺酸鹽；用（R) — 6，8-二氟一1 ，2 * 3，4 一四氫一 2 -羥基萘取代，製得（S) — 6，8 -二氟—1 ，2， 3，4 一四氫一萘_2 —基甲烷磺酸鹽；用6，8 —二氟-1 ，2，3，4-四氫-2 —羥基 —7 —甲氧基萘取代，製得6，8 —二氟一1 ，2，3， 4 —四氫一7 —甲氧基萘—2-基甲烷磺酸鹽；用2 —羥基茚滿取代，製得茚滿—2 —基甲烷磺酸鹽 » 用4，6 —二氟—2 —羥基茚滿取代，製得4 * 6 — 二氟茚滿—2 —基甲烷磺酸鹽·，用5，6—二氟—2 —羥基茚滿取代，製得5，6 — 二氟茚滿一 2 —基甲烷磺酸鹽；用5，6 —二氟—1—羥基茚滿取代，製得5，6 — 二氟茚滿一1一基甲烷磺酸鹽； -111- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） (請先閱讀背面之注意事項再填寫本頁) 470741 A7 B7 經濟部中央標準局員工消費合作社印製五、發明説明（ ) 1 1 I 用 5 > 7 — 二氟 — 1 — 羥基茚滿取代 9 製得 5 f 7 一 1 1 1 二氟茚滿一 1 一基甲焼磺酸 m » 1 I 請 1 I 實例 8 先閱 1 1 ( S ) — 5 > 7 — 二氟 '— 1 % 2 3 » 4 一四氫萘 — 2 一讀背面 1 I 之 1 基胺氫氯化物注意 1 Μ 下係製備式 3 中 η 為 1 » t 為 2 位於 5 — 和 7 — 事項 1 I 再 I 位置的 R 1 為氟的化合物〇填寫本装 1 如實例 7 所製備的 ( R ) 一 5 参 7 一二氟 — 1 2 Ρ 頁 1 I 3 4 一四氫萘一 2 — 基甲焼磺酸鹽 ( 5 4 * 0 克 ) 和叠 1 | 氮鋰 ( 1 5 • 8 克 0 3 2 2 莫耳 ) 混合物在 4 0 0 毫 1 1 升二甲基甲 m 胺中於 5 0 °C 及氬氣中攪伴 1 6 小時 0 Κ 1 訂 2 0 0 毫升水驟冷反應 Μ 1 升戊烷萃取混合物〇 Μ 5 0 1 | 毫升洗滌萃取物硫酸 m 乾燥之 0 在減躔下及 3 5 V 蒸 1 I 發 > 得到粗製的黃色油殘留物 ( S ) 一 2 — 蠡氮基 — 5 * 1 1 7 — 二 — 1 2 3 ， 4 一四氫蔡 ( 5 9 • 8 克 ) 0 1 線叠氮殘留物溶於 1 • 2 升醋酸乙酿 » 於 1 0 % 炭上鈀 1 I ( 6 克 ) 氳化 6 小時每個小時再加入 kss* 凰氣 Η 除去產生的 1 1 I 風氣 0 然後 Ce 1 i t e 過漶混合物 Μ 醚類氯化氫 ( 1 Ν » 1 1 2 5 0 毫升 ) 予 Μ 攪拌 > 得到結晶性物質〇在 4 小時內過 1 1 m 分離該物質用醋酸乙酿洗滌滤紙殘留物 0 在真空中除 1 I 去殘留的溶劑 > 得到白色固體的 ( S ) — 5 t 7 二氟一 1 1 I 1 » 2 9 3 4 一四氫萘 — 2 一基胺氬氯化物 ( 4 8 • 2 1 1 克 t 0 • 2 2 萁耳 ) 熔點大於 2 8 0 V » C a ) Ζ 5 = 1 1 -112- 1 1 本紙張尺度適用中國國家標準（CNS ) A4規格（2IOX297公釐〉 470741 經濟部中央標準局員工消費合作社印製 A7 B7五、發明説明（） -60.15° (c=2*7，甲醇）° 依實例8進行，但是採用不同起始物質取代（R)-5，7 —二氟一1 ，2，3，4 —四氫萘一 2 —基甲烷磺酸鹽*製得Μ下的式3化合物：用1 ，2，3，4 —四氫萘-2 —基甲烷磺酸鹽取代，製得1 * 2，3，4-四氫萘一 2 -基胺氫氯化物，熔點 239°C — 242υ; 用（R) — 1 ，2，3，4一四氫萘一2—基甲烷磺酸鹽取代，製得（S) — 1 ，2，3，4_四氫萘—2_ 基胺氫氯化物，熔點2 4 1它一 2 4 4 Ό ; 用（R) - 5—氟一 1 ，2，3 >4 —四氫禁一2 - 基甲烷磺酸鹽取代，製得（S) — 5 —氟一 1 * 2，3， 4 —四氫萘—2 —基胺氫氯化物，熔點大於280 °C ; 用（R) — 6 —氟一1 ，2，3，4 —四氫萘一2 — 基甲烷磺酸鹽取代，製得（S) — 6 —氟一1 ，2，3， 4 一四氫萘一 2 —基胺氫氯化物，熔點264 °C -265¾ » 用（R) — 7—氟—1 ，2，3，4 一四氫禁一2 — 基甲烷磺酸鹽取代，製得（S) — 7 —氟一1 ，2，3， 4 一四氫萘一 2 —基胺氫氯化物，熔點大於280 °C ; 用6，7 —二氯—1 ，2，3，4 —四氫萘一 2—基甲烷磺酸鹽取代，製得6，7 —二氯一1 ，2，3，4 一四氫萘—2 —基胺氫氯化物，熔點大於2 80¾ ; -113- 本紙張尺度適用中國國家標準（CNS ) Α4規格（21 ΟΧ297公釐） (請先閱讀背面之注意事項再填寫本頁) 470741 A7 B7 經濟部中央標準局員工消費合作社印製五、發明説明（ ) 用 ( 一 ) 一 6 » 7 — 氟 — 1 9 2 ί 3 $ 4 — 四氫萘 — 2 — 基甲烷磺酸鹽取代製得 ( 一 ) 一 6 9 7 — 二氟一 1 9 2 » 3 9 4 一四氫萘 — 2 一基胺氫氯化物 * 用 6 > 7 一二氟 1 > 2 3 » 4 一四氫萘一 2 一基甲烷磺酸鹽取代製得 6 7 — 二氟 1 2 » 3 9 4 一四氫萘一 2 一基胺氫氯化物用 ( S ) — 5 7 一 ~- 氟 — 1 9 2 3 9 4 — 四氫萘 — 2 一基甲焼磺酸鹽取代製得 ( R ) 一 5 7 一二氟 —' 1 2 3 4 一四氫萘一 2 一基胺氫氯化物熔點大於 2 8 0 °C 用 5 7 一二氟一 1 2 3 4 一四氫萘一 2 — 基甲焼磺酸鹽取代製得 5 7 — __. 氟一 1 * 2 3 4 — 四氫萘 — 2 一基胺氫氯化物用 6 8 — 二氟一 1 2 3 4 一四氫萘一 2 一基甲烷磺酸鹽取代製得 6 8 — 二氟 — 1 * 2 3 4 一四氫萘 — 2 — 基胺氫氯化物用 ( R ) — 6 8 一二氟一 1 2 9 3 4 — 四氫萘 — 2 — 基甲烷磺酸鹽取代 > 製得 ( S ) — 6 f 8 — 二氟一 1 > 2 3 > 4 — 四氫萘 — 2 一基胺氫氯化物用 6 f 8 — 二氟 — 1 * 2 > 3 * 4 — 四氫一 7 — 甲氧基 m 一 2 — 基甲烷礎酸鹽取代 » 製得 6 t 8 — 二氟 — 7 —. 甲氧基一 1 ί 2 9 3 $ 4 一四氫 m 一 2 一基胺氫氯化物用 2 — η 滿一 2 一基甲烷磺酸鹽取代 » 製得 η 滿 — 2 •114- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 470741 經濟部中央標準局員工消費合作社印製 A7 B7五、發明説明（） -基胺氫氯化物；用4 * 6 —二氟茚滿一 2~基甲烷磺酸鹽取代，製得 4，6 —二氟茚滿一 2 —基胺；用5，6 —二氟茚滿一2—基甲烷磺酸鹽取代，製得 5，6 —二氟茚滿—2 —基胺氫氯化物，熔點大於280t： t 用5，6 —二氟茚滿—1 ~基甲烷磺酸鹽取代，製得 5，6 —二氟茚滿—1 一基胺氫氯化物；和用5 * 7 —二氟茚滿一 1 -基甲烷磺酸鹽取代，製得 5，7 -二氟茚滿—1 —基胺氫氯化物；實例9 5，7 —二氟—1- (1 ，2，3，4-四氫萘-2-基 )—1 ，3 —二氫眯唑—2 —硫酮 Μ下係製備式I (a)中η為1 * t為2，R3和 R4和R5為氫，位於5 —和7 —位置的R1為氟的化合物。如實例8所製備的（S) — 5，7 —二氟一 1 ，2， 3，4 —四氫萘一 2 -基胺（2 · 05克，1 1 . 2毫莫耳）和二甲氧基乙醛（1 · 73克，13 * 1毫莫耳）混合物在50毫升乙醇中於10%炭上鈀（500毫克）進行氫化1 8小時。過濾混合物*蒸發濃縮之。殘留物與在 30毫升1N氫氯酸和20毫升乙醇中的硫氰酸鉀（1 · 57克，16 ♦ 2毫莫耳）混合，混合物在70 — 80 °C -115- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） (請先閱讀背面之注意事項再填寫本頁) 470741 經濟部中央標準局員工消費合作社印裝 A7 B7五、發明説明（）加熱1 8小時。混合物在冰浴中冷卻，得到結晶性物質，經過滹分離，於醋酸乙酯/己烷中再結晶*製得1一（5 * 7 — 二氟一1 ，2，3，4_ 四氫蔡一 2 —基）一1 ， 3 —二氫眯唑—2_硫酮（1 . 27克，4 · 76奄莫耳 )，熔點 250t：— 251°C。依實例9進行，但是採用不同起始物質取代（S) — 5，7_二氟一 1 ，2，3，4 —四氫萘一2_基胺，製得K下的式I化合物：用7—氟一 1 ，2，3，4一四氫萘一 2_基胺取代，製得1一（7 —氟-1 ，2，3，4一四氫萘一2 —基 )—1 *3 —二氫咪唑—2_ 硫酮，熔點 215°C— 217°C l 用6，7 —二氟一 1 ，2 * 3，4 一四氫萘—2 —基胺取代，製得1— (6，7 —二氟—1 ，2，3，4 —四氫萘_2-基）一1 ，3-二氫眯唑一2—硫酮，熔點 Z4ZV-243V 用6，8 —二氟-1 ，2，3，4 —四氫萘-2—基肢取代，製得1— (6，8 —二氟—1 ，2，3，4 一四氫萘一 2 —基）—1 ，3 —二氫脒唑一 2 —硫酮，熔點 260V-261V 用5-甲氧基一 1 ，2，3，4一四氫萘一2 —基胺取代，製得1— (1 ，2，3，4 —四氫一 5 —甲氧基萘 —2 -基）一 1*3 —二氬咪唑~2 —硫酮，熔點233 °C -116- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） (請先閱讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 470741 A7 B7 五、發明説明（） -2 3 5 t!；用6 —甲氧基一 1 ，2，3，4一四氫萘一2 —基胺取代，製得1— (1 ，2，3，4 —四氫一 6 —甲氧基萘一2 —基）—1 ，3 —二氫咪唑一 2 —硫酮，熔點226 °C -2 2 7 V ；用7_甲氧基—1 ，2，3，4 一四氫萘一2 —基胺取代，製得1— (1 ，2，3，4 一四氫一7_甲氧基萘 —2 —基）-1 ，3 —二氫畔唑—2 -硫酮，熔點271 °C -2 7 3 "C ; 用8 —甲氧基—1 ，2，3，4 一四氫萘一 2 -基胺取代，製得1 一（1 ，2，3，4 —四氫一 8 —甲氧基萘 —2 -基）—1 ，3 —二氫咪唑—2 —硫酮，熔點249D -2 5 1 V ；用6，8 —二氟一7 —甲氧基一1 * 2，3，4 —四氫萘一 2 —基胺取代*製得1 一（6，8 —二氟—1 ，2 ，3 »4-四氫-7-甲氧基蔡-2-基）-1 ，3 -二氫咪唑—2 —硫酮，熔點228 °C— 230¾ ; 用5 -甲氧基—1 ，2，3，4 —四氫萘一1_基胺取代，製得1— (1 ，2，3 ，4 一四氫一5 —甲氧基萘一 1 一基）—1 ，3-二氩眯唑—2—硫酮，熔點176Ό -1 7 7 υ ；用6 —甲氧基-1 ，2，3，4 —四氫萘一1-基胺取代，製得1— (1 ，2，3，4 一四氫一6 —甲氧基萘 -117- 本紙張尺度適用中國國家標準（CNS ) Α4規格（210Χ：297公釐） ^衣訂矣 (請先閱讀背面之注意事項再填寫本頁) 470741 A7 B7 經濟部中央標準局員工消費合作社印製五、發明説明（ ) 1 1 I — 1 一基 ) 一 1 9 3 — 二氫咪唑 — 2 — 硫鬭 » 烙點 1 9 0 V 1 1 1 一 1 9 2 °C t 1 | 請 I I 用 7 一甲氧基 — 1 $ 2 » 3 > 4 一四氫萘一 1 — 基胺閱 1 I 取代製得 1 一 ( 1 9 2 3 4 一四氫 — 7 一甲氧基萘讀背 1 1 ΐδ I 一 1 — 基 ) — 1 i 3 一二氫眯唑一 2 一硫 _ » 熔點 1 4 2 °C 之注 1 I 意 I 一 1 4 3 V > 事項 1 I 再 1 | 用 4 » 6 — 二氣茚滿 ·— 2 一基胺取代 t 製得 1 一 ( 4 填 1 裝寫本 t 6 一二氟茚滿 — 2 一基 ) 一 1 3 — 二氫咪唑 — 2 — 硫頁 1 I 酮熔點 1 8 5 V 一 1 8 6 V 1 1 用 5 6 一二氟茚滿 2 一基胺取代製得 1 — ( 5 1 1 ， 6 一二氟茚滿一 2 — 基 ) 一 1 3 一二氫咪唑 — 2 — 硫 1 訂 1 I _ 熔點 2 5 5 °c 一 2 5 7 用 5 — 甲氧基茚滿一 1 一基胺取代 > 製得 1 — ( 5 一 1 1 | 甲氧基 m 滿 — 1 — 基 ) — 1 3 — 二氫咪唑 — 2 — 硫 _ * 1 1 熔點 1 9 5 — 1 9 6 c 1 線 1 I 用 ( — ) — 4 6 — 二氟茚滿一 1 一基胺取代製得 ( + ) — 1 — ( 4 6 — 二氟 η 滿 — 1 — 基 ) — 1 3 — 1 1 二氫蹄唑一 2 一硫酮熔點 1 9 1 V 一 1 9 3 V 1 1 用 ( + ) 一 4 6 一二氟 η 滿一 1 一基胺取代 1 製得 1 1 ( 一 ) — 1 — ( 4 6 一 ™- 氟 η 滿一 1 — 基 ) — 1 ， 3 一 1 I 二氫咪唑 — 2 一硫酮 f 熔點 1 8 1 1〇 — 1 9 1 °c 1 I 1 1 用 5 6 — 二氟茚滿一 1 — 基胺取代 » 製得 1 — ( 5 1 1 t 6 — 二氟茚滿 — 1 一基 ) — 1 9 3 — 二氫咪唑 — 2 — 硫 1 1 -118- 1 1 本紙張尺度適用中國國家標準（CNS〉A4規格（210X297公釐） 470741 經濟部中央標準局員工消費合作社印製 Α7 Β7 五、發明説明（）麵，熔點183υ_187υ;和用5，7 —二氟茚滿一 1 一基胺取代，製得1一（5 ，7—二氟茚滿一1-基）一1，3-二氫咪唑_2-硫酮，熔點212Ό— 實例1 0 (-)一 6，7 —二氟一2 —異硫氟基—1 * 2 * 3，4 一四氫萘 Μ下係製備式9中η為1 · t為2 *位於5 —和7 — 位置的R1為氟的化合物。如實例8所製備的（―）6，7 —二氟一 1 ，2，3 ，4 一四氫萘一 2 —基胺（0 . 56克，3 · 06奄莫耳 )和1 ，1' 一硫羰基二咪唑（0.82克·4. 59毫莫耳）混合物在1 5奄升醋酸乙酯中被攪拌*直到反應完全為止。蒸發除去溶劑，在矽膠上（沖提液為5%丙酮/ 甲撐氯化物）進行層析Κ純化殘留物，製得（―）_6， 7 —二氟一2 —異硫氰-1 ，2，3，4 一四氫萘（0 . 55 克，2. 42 毫奠耳）。〔ct〕p2S=15.5° (c = 1 . 0 ，甲醇）。依實例10進行，但是採用不囿起始物質取代（_) -6，7 —二氟-1 ，2，3，4一四氬萘一 2 -基胺 * 製得Μ下的式9化合物：用1 · 2，3，4 —四氫萘一2 —基胺取代，製得2 一異硫氰基一 1，2，3，4 一四氫萘（油）；和 -119- 本紙張尺度適用中國國家標準（CNS ) A4規格（21〇Χ297公釐） I— I— I I I n 訂 I (請先閱讀背面之注意事項再填寫本頁) 470741 A7 B7 經濟部中央標準局員工消費合作社印製五、發明説明（) 用（+ ) — 6，7 —二氟—1 ，2，3，4 一四氫萘一2 -基胺取代，製得（+ ) - 6，7 —二氟—2 -異硫氮基—1 * 2，3，4~四氫萘，熔點206 — 207Ό Ο 實例1 1 (—)一 6.7-二氣一1_ (1*2* 3 ’4 一四氫萘一 2 —基）—1 ，3 -二氫咪唑-2 —硫酮 K下係製備式（I) a中η為1 ，t為2，R3 ，r 4和R5各為氫，R1為氟且位於6~和7 —位置的化合物。如實例10所製備的（―）—6，7 —二氟—2 —異硫氰基—1 ，2，3，4 一四氫萘（0 ‘49克，2 · 2 毫莫耳）和2，2 —二甲氧基乙基胺（0 . 23克，2 · 2 毫莫耳）混合物在二甲基甲醯胺中於85¾加熱2 · 5小時，在減壓下除去溶劑*殘留物溶於2到3毫升的乙酵和 2 0毫升4N的氫氯酸中。在8 加熱溶液約4 8小時，冷卻之後得到結晶性物質。過濾分離該物質，乾燥之。在矽膠上K管柱層析（沖提液為3%甲醇/甲撐氯化物）進行純化，得到（_) — 6，7 —二氟一 1- (1 ，2， 3，4-四氫萘-2 —基）-1 ，3 —二氫眯唑—2 —硫酮（0 · 225克，0 · 84毫莫耳），熔點200Ό — 2 0 5 V > 〔a〕p、25 -77.90 (c=0.6，2: 1的氯仿/甲酵）。 -120- (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) A4規格（210Χ297公釐） 470741 經濟部中央標準局員工消費合作社印製 A7 _B7_五、發明説明（）依實例1 1進行，但是用（+ ) — 6，7 —二氟一2 -異硫氰基一 1 ，2 · 3，4 一四氫萘取代（一）一6 * 7 —二氟一 2 —異硫籤基—1 ，2，3，4 一四氫萘，製得（+ ) - 6*7 -二氟一1- (1，2，3,4 -四氫萘一 2 —基）一 1 ，3 —二氫咪唑一 2 —硫酮（0 . 225 克，0.84毫奠耳），熔點206"0 — 207Ό。〔cx〕D 2 5 86 . 98° (c = l · 06 ，2 : 1 的氯仿 /甲醇）。實例1 2 1— (4，6-二氟茚滿-1—基）一 1 ，3 —二氫咪唑一 2 —硫酮 Μ下係製備式（I) a中η為0 · t為2，R1為位於4一和6_位置的氟，R3 ，R4和R5各為氫的化合物。 4，6_ 二氟茚滿-1— _ (11 ‘3 克，67·2 6毫莫耳）*2，2 -二甲氧基乙基胺（7 . 〇 7克， 67 . 26毫莫耳）和氰硼氫化納（4 * 23克）混合物在7 5毫升甲醇中在溫和回流下攪拌加熱，並於氮氣中搜拌約1 8小時。另外加入氰硼氫化納（2 · 1 2克）*混合物在65t!加熱20小時。蒸發除去溶劑，在矽膠上進行管柱層析而純化（沖提液為2 ♦ 5%甲酵/甲撐氯化物1 )，製得（4，6—二氟茚滿_1一基）一（2，2~ 二甲氧基乙基）胺。 -121- (請先聞讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家榇準（CNS ) A4規格（2〗0X297公釐） 470741 Α7 Β7 五、發明説明（） (4，6 —二氟茚滿一1—基）一(2，2 -二甲氧基乙基）胺（1 1 · 68克，45 · 9毫奠耳）和硫氰化鉀（4 · 46克，45 · 9毫莫耳）混合物在21 · 6毫升1 2N氫氯酸，86毫升乙醇和86毫升水中，於80 到8 5 t加熱1 5小時。混合物在冰浴中冷卻· K水稀釋，得到結晶性物質。過漶分離該物質，濾紙殘留物被冷乙醇（2x25毫升）和50毫升二***洗滌。乾燥製得1 一（4，6_二氟茚滿—1 一基）—1 ，3_二氫咪唑_ 2 —硫酮（5 · 65克，22 · 2毫莫耳），熔點205 - 2 0 7 ¾° 依實例1 2進行，但是採用不同起始物質取代4，6 一二氟-茚滿一 1 一嗣，製得K下的式I化合物：用1 ，2 * 3，4 一四氫萘一 1—酮取代，製得1一 (1 ，2，3，4 —四氫萘一 1—基）一1 ，3—二氫蹄唑一2—硫酮，熔點188Ό—189υ ; 用6 -甲氧基一1 ，2，3，4 一四氫萘一1 一酮取代，製得1— (6 —甲氧基一1 ，2，3 ，4 —四氫蔡一經濟、邵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填寫本頁) 1—基）一 1 *3 —二氫咪唑—2 —硫酮，熔點190Ό -1 9 Ζ V ； 5 —甲氧基一 1 * 2，3，4 —四氫萘_1 一酮取代，製得1 一（5 —甲氧基一 1 ，2，3，4 一四氫萘—1 —基）_1 ，3 -二氫咪唑—2 —硫酮，熔點176Ό — 1 7 7 υ ； -122- 本紙張尺度適用中國國家標準（CNS ) Α4規格（210父2们公釐） 470741 Α7 Β7 經濟部中央標準局員工消費合作社印製五、發明説明（）用7 —甲氧基—1 ，2，3，4 —四氫萘一 1 一酮取代，製得1— (7 —甲氧基一1 ，2，3，4_四氫萘一 1—基）一 1 ，3 -二氫咪唑一 2 —硫酮，熔點142υ -1 4 3 Ό ；用茚滿一2— _取代，製得1 一（茚滿一 2 —基）一 1 ，3 —二氫咪唑—2 —硫酮，熔點210°C— 21 1Ό ;和用茚滿一 1 —酮取代，製得1 一（茚滿一 1 一基）一 1 ，3 —二氫眯唑—2 —硫酮，熔點136°C— 137C 〇實例1 3 1— (1 ，2，3，4一四氫—2 -基）咪唑 K下係製備式1 1中η為1 ，t為0的化合物。如實例7所製備的1 ，2 * 3，4 一四氫萘一 2 —基甲烷磺酸鹽（15 · 74克* 69 · 6毫莫耳）和眯唑（ 23 ♦ 68克，349毫莫耳）混合物在1 00毫升二甲基甲醯胺中，於80 °C - 90 °C及氩氣中加熱24小時。真空中於旋轉蒸發器除去溶劑，將殘留物溶於5 0 0毫升醋酸乙酯，Μ水（5x250毫升）洗滌溶液。混合的水曆被500毫升的醋酸乙酯萃取，萃取物然後被水洗漉（ 5x250毫升）。混合的醋酸乙酷萃取物被飽和氯化納溶液洗滌，於硫酸鎂乾燥，旋轉蒸發器濃縮。在矽膠上進行管柱層析而純化（沖提液為5%甲醇/甲撐氯化物）， -123- (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) Α4規格（210X297公釐） 470741 經濟部中央標準局員工消費合作社印製 A7 B7五、發明説明（）製得1一（1 ，2，3，4 一四氫-2 —基）咪唑（5 · 18 克，26· 1毫莫耳），熔點93υ_95υ。依實例1 3進行，但是採用4 一甲基咪唑取代咪唑， M2 —溴—1 ，2，3，4_四氫萘一 1 一酮取代1 ，2 ，3，4 一四氫萘一 2 -基甲烷磺酸鹽，然後遒原之，製得1- (1 ，2，3，4一四氫萘一2 —基）一4 一甲基眯唑。實例1 4 (S ) - Ν- 〔3 - (5，7-二氟-1*2，3，4- 四氫萘—2 —基）一2，3—二氫—1Η—咪哩一 4 —基甲基〕甲醯胺 Μ下係製備式1 1中η為1 ，t為2，R1為位於5 一和7 —位置的氟* R4為氫的化合物。如實例29所製備的甲醯胺（S) —N_ 〔3 — (5 ，7 —二氟—1 ，2，3 * 4—四氮蔡—2 —基）— 2 — 硫酮一 2，3 -二氫一 1H-眯唑-4-基甲基〕甲醯胺 (1 · 38克，4 · 27毫莫耳）和活性Raney®鎳（1 1 克）混合物在50毫升乙醇中於80Ό快速搜拌1小時。 MCelite過濾混合物，濾液蒸發成為白色固體（0 · 98 克）。此固體被醋酸乙酯/甲醇再結晶而得到（S) - N -〔3 - (5，7 -二氟-1 ，2，3，4 —四氫萘一 2 —基）一2，3 —二氫—1H —眯唑一 4 一基甲基〕甲醯胺，熔點 1941-195^0 -124- 本紙張尺度適用中國國家標準（CNS〉A4規格（210Χ29>?公釐） (請先閱讀背面之注意事項再填寫本頁) 470741 經濟部中央標準局員工消費合作社印裝 A7 B7五、發明説明（）依實例14進行，但是Μ不同起始物質取代（S) -Ν - C 3 - (5，7-二氟—1，2，3*4 — 四氫萘一 2-基）一2-硫酮_2，3—二氫—1Η—眯唑一4一基甲基〕甲醯胺，製得Κ下式1 1化合物：用（S) —5 —胺基甲基一1— (5，7 —二氟一1 ，2，3，4 一四氫萘一 2 —基）一1 ，3 —二氫眯唑一 2 —硫酮氫氯化物取代，製得（S) — 〔3 — （5，7_ 二氟—1 ，2 * 3，4 一四氫萘-2 — 基）-2，3_ 二氫一1Η —眯唑一4 一基甲基〕胺，熔點273Ό — 274Ό ;和用 1 一（5，7—二氟一1，2，3，4_四氫萘— 2 —基）-1 ，3 —二氫—咪唑-2 —硫酮取代，製得1 -(5，7 -二氟一1 ，2，3，4-四氫萘—2-基）一 1 ，3 _二氫眯唑。實例1 5 3 — 胺基一 1一（1 ，2，3，4 一四氫萘-2-基）- 1 ，3~二氫眯唑一2 —硫酮 Μ下係製備式I (a)中η為1 * t為0，R3為胺基，R4和R5為氫的化合物。如實例13所製備的1— (1 ，2，3，4 一四氫一 2 -基）咪唑（198毫克，1毫莫耳）和Ο— 1 ，3 * 5 —三甲基笨磺醯基羥基胺（2 15毫克，1毫莫耳）的混合物在乙腈中於氩氣中攪拌1 8小時，此反應混合物被 -125- 本紙張尺度適用中國國家標準（CNS〉A4規格（210><297公釐） (請先閱讀背面之注意事項再填寫本頁) 470741 Μ 經濟部中央標準局員工消費合作社印製 _ Β7五、發明説明（) 二***稀釋，得到油狀的沈濺物。溶劑被潷析，Μ二*** (2x10毫升）洗滌殘留物。在真空中蒸發殘留溶劑。殘留物和蟲漆硫（32毫克，1 ♦ 0奄莫耳）混合物於1 毫升砒啶和0 * 5毫升三乙胺中於約90t：及氩氣中加热 4小時。蒸發除去殘留物，殘留物與甲苯進行共蒸發。殘留物在矽膠上被甲撐氣化物沖提進行層析而純化殘留物，製得3 -胺基一1— (1，2，3 · 4 —四氫萘一 2 -基 )一 1 ，3_ 二氫眯唑一 2 —硫嗣（5 ♦ 18 克，26 . 1奄莫耳），熔點1871-189¾。依實例1 5進行，但是Μ不同起始物質取代0 — 1 ， 3，5 —三甲基苯磺醯基羥基胺和/或1 一（1 ，2，3 ，4 -四氫萘一 2 -基）眯唑*製得Μ下式I化合物：用溴醋酸三級丁酯取代，製得3~ (1 ，2，3 *4 —四氫萘-2-基）-2 —硫酮一 2 »3 —二氬一 1Η-咪唑一 1 一基醋酸三級丁酯；熔點1 67Ό — 1 691 ; 用4 一溴丁酸甲酯和1— (1 ，2，3，4 一四氣蔡一 2 -基）咪唑取代，製得4_ 〔3 - (1 ，2，3’4 —四氫萘一 2 —基）—2_硫酮_2，3 —二氫一 1Η-眯唑一 1 一基〕丁酸甲酿；用5 —溴甲基皮考啉酸甲酯和1 一（1 ，2，3’4 一四氫萘一 2 —基）咪唑取代，製得5 — 〔3 - （1 ’ 2 ，3，4一四氫蔡-2 —基）一2 —硫酮一 2 ’ 3 '氳 —1 H -咪唑一 1 一基甲基〕皮考啉酸甲酯（油）； -126- 本紙張尺度適用中國國家標準（CNS ) A4规格（210 X 297公釐） (請先閲讀背面之注意事項再填寫本頁) -装. 訂 -絲 470741 經濟部中央標準局員工消費合作社印製 A7 B7五、發明説明（）用4 —溴甲基苯酸甲酯和1 一（1 ，2 ，3 ，4 一四氫萘一 2 —基）咪唑取代*製得4_ 〔3 — ( 1 · 2 > 3 ，4 —四氫萘—2 -基）一 2-硫酮一 2，3 —二氫一 1 H —咪唑一 1—甲基〕笨酸甲酯，熔點133 — 1351C 用3 —溴甲基苯酸甲酯和1一（1 ，2，3，4 一四氫萘—2 —基）畔唑取代，製得3 — 〔3 — (1*2*3 »4 —四氫蔡一 2—基）—2—硫酮—2，3—二氫—1 H —咪唑—1—甲基]笨酸甲酿，熔點130 — 132 °C I 用3，4 一二甲氧基苄基氯化物和1_ (1 ，2，3 ，4 —四氫萘—2 —基）眯唑取代，製得3 — (3，4一二甲氧基苄基）一 1 一（1，2，3，4 —四氫萘—2 — 基）一 1 ，3 —二氫咪唑一 2 —硫嗣，熔點129 - 131¾ ♦ 用4 一溴甲基笨酸甲酯和1一（1 ，2，3，4 一四氫萘一2 —基）—4 一甲基咪唑取代，製得4 — 〔3 — （ 1 ，2，3 · 4 —四氮萘一 2 —基）_5 —甲基一2 -硫酮—2，3 —二氫一1H —咪唑_1—甲基〕苯酸甲酯，熔點 140 — 14115 用6 —二甲基胺基一 3 —溴嚏嗪和1 一（1 ，2，3 *4 —四氫萘一 2_基）咪唑取代，製得3 — （6 —二甲基胺基噠嗪—3-基）—1— (1 ，2，3，4 —四氫萘 -127- 本紙張尺度適用中國國家標率（CNS ) Α4規格（210><297公釐） (請先閱讀背面之注意事項再填寫本頁) 470741 A7 B7 經濟部中央標準局員工消費合作社印製五、發明説明（ ) — 2 一基 ) 一 1 • 3 — 二氫咪唑 — 2 一硫酮 t 熔點 1 9 8 一 1 9 9 V * 用 2 一溴乙基笨和 1 一 ( 1 » 2 9 3 9 4 *— 四氫萘一 2 — 基 ) 蹄唑取代製得 3 — ( 2 苯基乙基 ) 一 1 一 ( 1 2 3 » 4 四氫萘 — 2 — 基 ) — 1 » 3 — 二氳咪唑 — 2 — 硫酮熔點 1 4 0 — 1 4 2 t：用 4 — ( 2 一溴乙基 ) 笨酸甲酯和 1 一 ( 1 2 > 3 » 4 一四氫萘 — 2 — 基 ) 眯唑取代製得 4 { 2 — C 3 一 ( 1 2 3 9 4 一四氫萘 — 2 一基 ) — 2 一硫酮 — 2 $ 3 一二氫一 1 Η — 咪唑 — 1 — 基乙基 } 笨酸甲酯熔點 1 5 9 — 1 6 1 V 用 4 — ( 2 — 溴乙基 ) 笨酸和 1 ( 1 2 3 4 一四氫萘 — 2 一基 ) 眯唑取代製得 4 一 C 3 一 ( 1 Σ » 3 4 一四氫萘一 2 — 基 ) *— 2 硫酮 — 2 3 氫 — 1 Η 一咪唑一 1 — 基乙基 ] 苯酸熔點 2 2 7 V 一 2 3 0 V 用 3 4 — 二甲氧基 — 1 — ( 2 溴乙基 ) 笨和 1 — ( 1 > 2 3 t 4 一四氫 m — 2 — 基 ) 咪唑取代 » 製得 3 — C 2 一 ( 3 4 一二甲氧基苯基 ) 乙基一 1 一 ( 1 » 2 9 3 t 4 一四氫蔡 — 2 一基 ) 一 1 9 3 — 二氫眯唑一 2 一硫 m 熔點 9 7 一 1 0 1 ti 用 4 一 ( 2 溴乙基 ) 苯酸和 ( S ) — 1 — ( 5 7 — 二氟一 1 2 食 3 $ 4 一四氫蔡 2 — 基 ) 眯唑取代 9 128- 本紙張尺度適用中國國家標準（CNS〉A4規格（210X297公釐） 470741 A7 B7 經濟部中央榇準局員工消費合作社印製五、發明説明（ ) 製得 ( S ) — 4 一 { 2 — 3 一 ( 5 9 7 一二氟一 1 » 2 9 3 1 4 一四氫萘一 2 一基 ) 一 2 一硫酮一 2 9 3 一二氫一 1 Η 一咪唑 — 1 — 基 ) 乙基 } 苯酸 9 熔點 2 2 2 — 2 2 4 V 9 Μ 甲醇中的氫氧化鉀處理 > 蒸乾 > 於甲醇 / 異丙醇再結晶 9 製得 ( S ) — 4 — { 2 — 3 一 ( 5 > 7 二氟一 1 9 2 3 4 — 四氫萘一 2 — 基 ) — 2 一硫酮一 2 3 — 二氫 — 1 Η 一咪唑 — 1 一基乙基 } 苯酸鉀 » 熔點大於 2 8 0 tl 用 4 — ( 2 一溴乙基 ) 一 1 — 氰基笨和 ( S ) 一 1 一 ( 5 7 一二氟一 1 2 3 4 一四氫萘一 2 一基 ) 咪唑取代製得 ( S ) » 3 — [ 2 — ( 4 一氰基苯基 ) 乙基 ] 一 1 一 ( 5 7 一二氟 — 1 2 3 4 — 四氫萘 — 2 — 基 ) — 1 f 3 一二氫 — 眯唑 — 2 一硫 m 熔點 1 3 0 一 1 3 3 V· 用 4 一 ( 2 — 溴乙基 ) 苯和 ( S ) — 1 ( 5 7 一二氟 — 1 2 3 ， 4 — 四氫萘一 2 一基 ) 眯唑取代製得 ( S ) 一 3 一 C 2 — 苯基乙基 ) — 1 一 ( 5 7 一二氟一 1 > 2 9 3 4 一四氫萘一 2 一基 ) 一 1 3 — 二凰眯唑一 2 一硫酮熔點 1 3 1 _ 1 3 3 t! 用 4 — ( 2 — 溴乙基 ) — 1 — 氟基笨和 1 — ( 1 2 $ 3 t 4 一四氫萘 — 2 一基 ) 咪唑取代製得 3 — C 2 一 ( 4 — 氰基笨基 ) 乙基 — 1 一 ( 1 f 2 % 3 » 4 — 四氫蔡 — 2 一基 ) — 1 f 3 — 二氫咪唑 — 2 一硫酮 f 熔點 1 6 9 129- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 470741Milline ears), melting point is greater than 28〇υ. [《Ip '— 6 6 ♦ 2 ° (C = 0 ♦ 1 6 2, formazan). Example 7 (R)-5,7-Difluoro-1,2,3,4-tetrahydronaphthalen-2-ylmethanesulfonate M is prepared in the following formula: wherein η is 1 and t is 2,5 —and The compound at the 7-position where R1 is fluorine and L is methanesulfonyloxy. (R) -5,7-difluoro-1,2,3,4-tetrahydro-2-hydroxynaphthalene (59.0 g, 0.32 mol) and triethylamine (13 8M, 74.2 ml, 0.53 mole) The mixture was cooled in 1.78 liters of diethyl ether in a methanol / ice bath. Methanesulfonium chloride (12. 9 M, 37.2 ml, 0.48 mol) was added under argon over 5-10 minutes, and the mixture was stirred at room temperature for 18 hours. The mixture was divided between water and ether, and the ether was divided. The water layer was taken at the ether rate. The mixture ether was washed once with 1N hydrochloric acid, saturated argon carbonate solution, brine *, and then dried with magnesium sulfate. After evaporation, (R) -5,7-difluoro-1,2,3,4-tetrahydro-naphthalene- 2ylmethanesulfonate (87 · 12 g) was obtained as an off-white solid with a melting point of 79 ° C— 801, ία: 2 s = +16-77 ° (c = 2 ♦ 0, chloroform). Following Example 7 * but replacing (R)-5,7 -difluoro-1,2,3,4 -tetrakis -2 -hydroxynaphthalene with a different starting material 霣 to prepare a compound of formula 5 under K:- 109- This paper size applies to China National Standard (CNS) A4 (2 丨〇乂 297mm) ---------- f ------ IT ------ # ( Please read the notes on the back before filling in this search) 470741 A7 B7 V. Description of the invention () Substituted with 1,2,3,4-tetrahydro-2_hydroxynaphthalene to obtain 1,2 * 3,4--4 Gas-naphthalene ~ * 2-methylformyl chloride; Substituted with (R) —1,2,3,4-tetrahydro-2 —hydroxynaphthalene to obtain (R) —1,2,3,4— Tetrahydro-naphthalene- 2-methanesulfonate; Substituted with (R) —5-fluoro-1, 2,3,4-tetrahydro-2—hydroxynaphthalene to obtain (S) -5—fluoro-1 , 2,3,4-tetrahydro-naphthalene_2-ylmethanesulfonate; Substituted with (R) -6-fluoro-1,2,3,4-tetrahydro-2-hydroxynaphthalene to obtain (S ) — 6-fluoro-1,2,2,3,4-tetrahydro-naphthalene-2-ylmethanesulfonate; (R) -7-fluoro-1,2,2,3,4-tetramethyl-2-hydroxyl Naphthalene (S) -7-fluoro-1,2,3,4-tetrahydro-naphthalene-2-ylmethanesulfonate; 6,7-dichloro-1,2,3,4-4 Hydrogen-2-hydroxynaphthalene was substituted to produce 2-6,7-dichloro-1,1,2,3,4-tetrahydro-naphthalene-2-methanesulfonate; printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (Please read the notes on the back before filling this page) Substitute with (a) 6,7-difluoro-1,2,3,4-tetrahydro-2 -hydroxynaphthalene to obtain (a) -6,7 —Difluoro-1,2,3,4-tetrahydro-naphthalene_2 monomethyl methanesulfonate; substituted with 6,7-difluoro-1,2,3,4tetrahydro-2-naphtalene, 6,7_difluoro-1,2,3 * 4—tetrahydro-naphthalene-2—based methane sulfonate was prepared; -110- This paper size is applicable to China National Standard (CNS) A4 (210X297 mm) 470741 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention () Use (S) — 5, 7, —difluoro-1, 2, 2, 3, 4-tetrahydro — 2 — substituted with naphthalene to make (R) ~ 5,7-dichloro-1,2,3,4-tetrahydro-naphthalene-2 Methane sulfonate; substituted with 5,7-difluoro-1,2,3,4-tetrahydro-2-hydroxynaphthalene to obtain 5,7-difluoro-1,2,3,4-tetrahydro —Naphthalene-2 —ylmethane sulfonate; 6,8-difluoro-1, 2, 3, substituted with 6,8-difluoro-1, 2,3,4-tetrahydro-2-hydroxynaphthalene , 4 Tetrahydro-naphthalene-2-ylmethanesulfonate; Substituted with (R) -6,8-difluoro-1,2 * 3,4 tetrahydro-2-hydroxynaphthalene to obtain (S) — 6,8-difluoro-1,2,3,4-tetrahydro-naphthalene_2-ylmethanesulfonate; 6,8-difluoro-1,2,3,4-tetrahydro-2 — Substituted with hydroxy-7-methoxynaphthalene to obtain 6,8-difluoro-1,2,3,4-tetrahydro-7-methoxynaphthalene-2-ylmethanesulfonate; 2-hydroxyindene Fully substituted to produce indan-2-ylmethanesulfonate »Substituted with 4,6-difluoro-2-hydroxyindane to produce 4 * 6-difluoroindan-2-ylmethanesulfonate · And substituted with 5,6-difluoro-2-hydroxyindane to obtain 5,6-difluoroindane-2-ylmethanesulfonate; use 5,6-difluoro-1-hydroxyindane 5,6 —difluoroindane-1 1-based methane sulfonate; -111- This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) (Please read the notes on the back before filling (This page) 470741 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention () 1 1 I 5 with 5 > 7 —difluoro— 1 —hydroxyindane substituted with 5 5 7 1 1 1 1 Difluoroindan-1 monomethylmethanesulfonic acid m »1 I Please 1 I Example 8 First read 1 1 (S) — 5 > 7 — Difluoro '— 1% 2 3» 4 Tetrahydronaphthalene — 2 First reading on the back of 1 I amine hydrochloride Note that 1 M is prepared in the formula 3 in which η is 1 »t is 2 at 5 — and 7 — Item 1 R 1 in the I and I positions is a fluorine compound. (1) (R) prepared as in Example 7-5 ref. 7-difluoride — 1 2 P 1 I 3 4 Tetrahydronaphthalene-2 —methylformamidine sulfonate (5 4 * 0 g) and azide 1 | Lithium nitrogen (1 5 • 8 g 0 3 2 2 mole) mixture in 4 0 0 milli 1 1 liter of dimethylformamide at 50 ° C and argon for 16 hours 0 KK 1 order 200 ml of water to quench the reaction MU 1 liter of pentane extraction mixture OM 5 0 1 | ml washing The sulfuric acid of the extract was dried under reduced pressure and steamed at 3 5 V for 1 time. I got a crude yellow oil residue (S)-2-hydrazino-5 * 1 1 7-two-1 2 3, 4 Tetrahydrocae (5 9 • 8 g) 0 1 Wire azide residue dissolved in 1 • 2 liters of ethyl acetate »on 10% palladium on charcoal 1 I (6 g) tritiated for 6 hours per hour Add kss * phoenix gas to remove the 1 1 I air 0 and then Ce 1 ite through the mixture M ether hydrogen chloride (1 Ν »1 1 2 50 ml) Stir & get the crystalline material within 4 hours After 1 1 m The filter paper residue was washed with ethyl acetate in 0%. The solvent was removed by removing 1I in a vacuum.> (S) — 5 t 7 difluoro-1 1 I 1 »2 9 3 4 tetrahydronaphthalene — 2 Monoamine argon chloride (4 8 • 2 1 1 g t 0 • 2 2 萁) Melting point is greater than 2 8 0 V »C a) Zn 5 = 1 1 -112- 1 1 This paper size applies to Chinese national standards (CNS) A4 specification (2IOX297 mm) 470741 Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs A7 B7 V. Description of the invention () -60.15 ° (c = 2 * 7, methanol) ° According to Example 8, but different Substitution of (R) -5,7-difluoro-1,2,3,4-tetrahydronaphthalene- 2-methanesulfonate * for the starting material to obtain a compound of formula 3 under M: with 1, 2, 3 1,4-tetrahydronaphthalene-2 -yl methane sulfonate is substituted to obtain 1 * 2,3,4-tetrahydronaphthalene-2-ylamine hydrochloride, melting point 239 ° C — 242υ; using (R) — Substitution of 1,2,3,4-tetrahydronaphthalene- 2-methanesulfonate to obtain (S) — 1,2,3,4-tetrahydronaphthalene-2 —ylamine Chloride, melting point 2 4 1 1 2 4 4 Ό; Substituted with (R)-5-fluoro-1,2,3 > 4-tetrahydroan- 2-methanesulfonate to obtain (S) — 5 —fluoro-1 * 2,3,4-tetrahydronaphthalene-2-ylamine hydrochloride, melting point is greater than 280 ° C; (R) — 6 —fluoro-1, 2, 3, 4-tetrahydro Naphthalene- 2-methanesulfonate is substituted to obtain (S) -6-fluoro-1,2,3,4-tetrahydronaphthalene- 2-ylamine hydrochloride, melting point 264 ° C -265¾ »Use ( R) — 7-fluoro-1,2,3,4,4-tetrahydroban-1,2-methanesulfonate is substituted to produce (S) -7-fluoro-1,2,3,4-tetrahydronaphthalene- 2-Amine amine hydrochloride, melting point greater than 280 ° C; Substituted with 6,7-dichloro-1,2,3,4-tetrahydronaphthalene- 2-methanesulfonate to obtain 6,7-di Chlorine 1,2,3,4 Tetrahydronaphthalene-2-ylamine hydrochloride, melting point is greater than 2 80¾; -113- This paper size applies to China National Standard (CNS) A4 specification (21 0 × 297 mm) (please (Please read the notes on the back before filling out this page) 470741 A7 B7 (5) Description of the invention () Prepared by (1) a 6 »7 — fluorine — 1 9 2 ί 3 $ 4 — tetrahydronaphthalene — 2 — methylmethanesulfonate (6) 7 9 — Difluoro-1 9 2 »3 9 4 Tetrahydronaphthalene — 2 monoamine hydrochloride * 6 > 7 Monodifluoro 1 > 2 3» 4 Tetrahydronaphthalene 1 2 monomethyl methane sulfonate Substitution to obtain 6 7 —difluoro 1 2 »3 9 4 monotetrahydronaphthalene-1 2 monoamine hydrochloride (S) — 5 7 mono ~ -fluoro — 1 9 2 3 9 4 — tetrahydronaphthalene — 2 Monomethylformamidine sulfonate is substituted to obtain (R) a 5 7-difluoro- '1 2 3 4 tetrahydronaphthalene- 2 mono-amine hydrochloride with a melting point greater than 2 8 0 ° C with 5 7-difluoro 1 1 2 3 4 Tetrahydronaphthalene- 2 -methylformamidine sulfonate to obtain 5 7 — __. Fluorine 1 * 2 3 4 — Tetrahydronaphthalene — 2 Monoamine hydrochloride with 6 8 — 2 Fluorine 1 2 3 4 One Tetrahydronaphthalene-2 monomethyl methane sulfonate is substituted to obtain 6 8 —difluoro — 1 * 2 3 4 Monotetrahydronaphthalene — 2 —ylamine hydrochloride (R) — 6 8 difluoro-1 2 9 3 4 —Tetrahydronaphthalene — 2 —ylmethane sulfonate substitution > Preparation of (S) — 6 f 8 — Difluoro-1 > 2 3 > 4 —Tetrahydronaphthalene — 2 monoylamine hydrochloride Substituting 6 f 8 —difluoro — 1 * 2 > 3 * 4 —tetrahydro — 7 — methoxy m — 2 —methane basic acid salt to obtain 6 t 8 — difluoro — 7 —. A Oxygen-1 ί 2 9 3 $ 4 One tetrahydrom one 2 monoamine amine hydrochloride was replaced with 2 — ηman-1 2 monomethylmethanesulfonate »to make ηman — 2 • 114- This paper size applies China National Standard (CNS) A4 specification (210X297 mm) 470741 A7 B7 printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of the invention ()-Base amine hydrochloride; 4 * 6-difluoroindane 1 2 ~ Methane sulfonate substitution to obtain 4, 6-difluoroindan-2-ylamine; substituted with 5,6-difluoroindan-2-ylmethanesulfonate to obtain 5,6-difluoroindan-2-ylamine hydrochloride, Melting point is greater than 280t: t is replaced with 5,6-difluoroindan-1-ylmethanesulfonate to obtain 5,6-difluoroindan-1 monoylamine hydrochloride; and 5 * 7-di Substitution of fluoroindan-1-methanesulfonate to obtain 5,7-difluoroindan-1-ylamine hydrochloride; Example 9 5,7-difluoro-1- (1,2,3, 4-tetrahydronaphthalen-2-yl) -1,3-dihydrooxazole-2-thione M is prepared in the following formula I (a) where η is 1 * t is 2, R3 and R4 and R5 are hydrogen, Compounds in which R1 at the 5- and 7-positions are fluorine. (S) —5,7—difluoro-1,2,3,4-tetrahydronaphthalene-2—ylamine (2.05 g, 11.2 mmol) and dimethyl as prepared in Example 8 A mixture of oxyacetaldehyde (1.73 g, 13 * 1 mmol) was hydrogenated in 50 ml of ethanol on 10% carbon palladium (500 mg) for 18 hours. The mixture was filtered * and concentrated by evaporation. The residue is mixed with potassium thiocyanate (1.57 g, 16 ♦ 2 mmol) in 30 ml of 1N hydrochloric acid and 20 ml of ethanol. The mixture is at 70 — 80 ° C -115- This paper is for China National Standard (CNS) A4 specification (210X297 mm) (Please read the notes on the back before filling out this page) 470741 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 5. Description of the invention () Heating for 18 hours. The mixture was cooled in an ice bath to obtain a crystalline material, which was separated by tritium and recrystallized in ethyl acetate / hexane to obtain 1- (5 * 7-difluoro-1, 2, 2, 3, 4_ tetrahydro-Caiyi 2-based) -1,3-dihydrooxazole-2-thione (1.27 g, 4.76 mol), melting point 250t:-251 ° C. Example 9 was carried out, but (S) -5,7_difluoro-1,2,3,4-tetrahydronaphthalene-2-ylamine was substituted with different starting materials to obtain a compound of formula I under K: Substitution of 7-fluoro-1,2,3,4-tetrahydronaphthalene- 2-ylamine to obtain 1- (7-fluoro-1,2,3,4-tetrahydronaphthalene- 2-yl) -1 * 3-dihydroimidazole-2_thione, melting point 215 ° C-217 ° C l Substituted with 6,7-difluoro-1,2 * 3,4 tetrahydronaphthalene-2-ylamine to obtain 1- ( 6,7-difluoro-1,2,3,4-tetrahydronaphthalene_2-yl) -1,3-dihydrooxazole- 2-thione, melting point Z4ZV-243V with 6,8-difluoro- 1,2,3,4-tetrahydronaphthalene-2-substitutes to obtain 1- (6,8-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl) -1,3 —Dihydrooxazole—2—thione, melting point 260V-261V, substituted with 5-methoxy—1,2,3,4-tetrahydronaphthalene—2-ylamine to obtain 1— (1,2,3 , 4-tetrahydro-1, 5-methoxynaphthalene-2, 2-yl), 1 * 3, diargylimidazole ~ 2, thioketone, melting point 233 ° C -116- This paper size applies to China National Standard (CNS) A4 specifications (210X297 (%) (Please read the notes on the back before filling out this page) Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 470741 A7 B7 V. Description of the invention ()-2 3 5 t !; 6-methoxy-1, Substitution of 2,3,4-tetrahydronaphthalene- 2-ylamine to obtain 1- (1,2,3,4-tetrahydro-6-methoxynaphthalene- 2-yl) -1,3-dihydro Imidazol-2-thione, melting point 226 ° C -2 2 7 V; Substituted with 7-methoxy-1,2,3,4-tetrahydronaphthalene-2-ylamine to obtain 1- (1,2 , 3,4 Tetrahydro-7-methoxynaphthalene-2-yl) -1,3-dihydropanazol-2-thione, melting point 271 ° C -2 7 3 "C; use 8-methyl Oxy-1,2,3,4-tetrahydronaphthalene- 2-ylamine substitution to obtain 1- (1,2,3,4-tetrahydro-8-methoxynaphthalene-2-yl) -1 , 3-dihydroimidazole-2-thione, melting point 249D-2 5 1 V; 6,8-difluoro-7-methoxy-1 * 2, 3, 4-tetrahydronaphthalene-2-amine Substituting * produces 1- (6,8-difluoro-1,2,3 »4-tetrahydro-7-methoxycae-2-yl) -1,3-dihydroimidazole-2-thione, Melting point 228 ° C— 230¾; Substituted with 5-methoxy-1,2,3,4-tetrahydronaphthalene- 1-ylamine to obtain 1- (1,2,3,4-tetrahydro-5-methyl Oxynaphthalene-1, 1-yl) -1,3-dihydroxazol-2-thione, melting point 176Ό -1 7 7 υ; using 6-methoxy-1, 2,3,4-tetrahydronaphthalene-1 Substituted by 1-ylamine to obtain 1- (1,2,3,4-tetrahydro-6-methoxynaphthalene-117-) This paper size applies the Chinese National Standard (CNS) A4 specification (210 ×: 297 mm) ^ Clothing order (please read the notes on the back before filling this page) 470741 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention () 1 1 I — 1 1 base) 1 1 3 — 2 Hydroimidazole — 2 —Thionine »Burning point 1 9 0 V 1 1 1 1 9 2 ° C t 1 | Please use II 7 methoxy — 1 $ 2» 3 > 4 tetrahydronaphthalene 1 — 1 1 (1 9 2 3 4 monotetrahydro — 7 monomethoxynaphthalene read back 1 1 ΐδ I — 1 — ) — 1 i 3 dihydroxazole-2 monosulfide_ »Melting point 1 4 2 ° C Note 1 I meaning I-1 4 3 V > Item 1 I again 1 | Use 4» 6-Digas indane · — 2 mono-amines are substituted for t to obtain 1- (4 filled in 1 textbook t 6 difluoroindane—2-one-based) — 1 3 —dihydroimidazole — 2 — sulfur page 1 I ketone melting point 1 8 5 V 1 1 8 6 V 1 1 is substituted with 5 6 difluoroindan 2 monoylamine to obtain 1 — (5 1 1, 6 difluoroindan 1 2-yl) 1 1-dihydroimidazole 2 — Sulfur 1 Order 1 I _ Melting point 2 5 5 ° c-2 5 7 Substituted with 5 -methoxyindan-1 1-ylamine > to obtain 1-(5-1 1 | methoxym 1-1- ) — 1 3 — dihydroimidazole — 2 — sulfur — * 1 1 Melting point 1 9 5 — 1 9 6 c 1 Line 1 I Substituted by (—) — 4 6 — difluoroindan-1 monoamine ( +) — 1 — (4 6 — difluoroηman — 1 —yl) — 1 3 — 1 1 dihydrothiazole-2 monothione melting point 1 9 1 V-1 9 3 V 1 1 with (+)- 4 6 difluoro η 1-1 amine substituted 1 to obtain 1 1 (1) — 1 — (4 6 1 ™-fluoro η 1-1)-1, 3-1 I dihydroimidazole — 2 Monothione f Melting point 1 8 1 10— 1 9 1 ° c 1 I 1 1 Substituted with 5 6 —difluoroindane-1 1-ylamine to obtain 1 — (5 1 1 t 6 —difluoroindane — 1 1 base) — 1 9 3 — Dihydroimidazole — 2 — Sulfur 1 1 -118- 1 1 This paper size applies to Chinese national standards (CNS> A4 specification (210X297 mm) 470741 Employee Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Print A7 B7 V. Description of the invention () plane, melting point 183υ_187υ; and substituted with 5,7-difluoroindan-1 1-ylamine to obtain 1- (5,7-difluoroindan-1-yl) -1,3-dihydroimidazole_2-thione, melting point 212Ό — Example 1 0 (-)-6,7 —difluoro-2 —isothiofluoro-1 * 2 * 3,4 Tetrahydronaphthalene M is a compound in which n is 1 · t is 2 in formula 9 * R1 at the 5-and 7-positions is a fluorine compound. (-) 6,7-difluoro-1,2,3,4-tetrahydronaphthalene-2-ylamine (0.56 g, 3.06 mol) and 1,1 'prepared as in Example 8. A mixture of monothiocarbonyldiimidazole (0.82 g. 4.59 mmol) was stirred in 15 ml of ethyl acetate * until the reaction was complete. The solvent was removed by evaporation, and the residue was purified by chromatography on silica gel (eluent: 5% acetone / methylene chloride) to obtain (―) _ 6, 7 —difluoro—2 —isothiocyanate-1, 2 , 3,4 tetralin (0.55 g, 2.42 millimoles). 〔Ct〕 p2S = 15.5 ° (c = 1.0, methanol). Following Example 10, but substituting (_)-6,7-difluoro-1,2,3,4-tetrahydronaphthalene- 2-ylamine * with a non-starting material, a compound of formula 9 was obtained: Substituted with 1,2,3,4-tetrahydronaphthalene-2-ylamine to produce 2-isothiocyanato-1,2,3,4-tetrahydronaphthalene (oil); and -119- Applicable to China National Standard (CNS) A4 specification (21 × 297 mm) I—I—III n Order I (please read the precautions on the back before filling this page) 470741 A7 B7 Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs V. Description of the invention () Substituting (+) — 6,7 —difluoro-1, 2,3,4 tetrahydronaphthalene — 2-ylamine to obtain (+) — 6,7 —difluoro-2 -Isothioazepine—1 * 2,3,4 ~ tetrahydronaphthalene, melting point 206—207Ό 〇 Example 1 1 (—)-6.7-digas-1_ (1 * 2 * 3 '4-tetrahydronaphthalene-2 —Base) —1,3-dihydroimidazole-2—thione K is prepared under the formula (I) in which η is 1, t is 2, R3, r 4 and R 5 are each hydrogen, R 1 is fluorine and is located at 6 ~ And 7-position compounds. (-)-6,7-difluoro-2-isothiocyanato-1, 2,3,4 tetrahydronaphthalene (0 '49 g, 2.2 mmol) and 2 prepared as in Example 10 The mixture of 2,2-dimethoxyethylamine (0.23 g, 2.2 mmol) was heated in dimethylformamide at 85¾ for 2.5 hours, and the solvent was removed under reduced pressure. In 2 to 3 ml of acetic acid and 20 ml of 4N hydrochloric acid. The solution was heated at 8 for about 4 to 8 hours. After cooling, a crystalline substance was obtained. The material was isolated by filtration and dried. Purified by K column chromatography on silica gel (eluent: 3% methanol / methylene chloride) to obtain (_) — 6,7 —difluoro-1 — (1,2,3,4-tetrahydro Naphthalene-2 -yl) -1,3 -dihydrooxazole-2 -thione (0.225 g, 0.884 mmol), melting point 200 Ό — 2 0 5 V > [a] p, 25- 77.90 (c = 0.6, 2: 1 chloroform / formaldehyde). -120- (Please read the precautions on the back before filling this page) This paper size applies to Chinese National Standard (CNS) A4 (210 × 297 mm) 470741 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economy A7 Explanation () was carried out according to Example 11, but (1) 6 * 7-2 was replaced by (+) — 6,7 —difluoro — 2 —isothiocyanato — 1, 2, 3, 4 —tetralin Fluoro-2 —isothiol—1,2,3,4-tetrahydronaphthalene, (+)-6 * 7-difluoro-1- (1,2,3,4 -tetrahydronaphthalene-2 —Base) —1,3-dihydroimidazole—2-thione (0.225 g, 0.84 mmol), melting point 206 " 0—207 °. [Cx] D 2 5 86. 98 ° (c = 1.06, 2: 1 chloroform / methanol). Example 1 2 1- (4,6-difluoroindan-1-yl) -1,3-dihydroimidazol-2-thione M is prepared in the following formula (I): a in which η is 0 · t is 2, R1 is a fluorine compound at the 4- and 6-positions, and R3, R4, and R5 are each a compound of hydrogen. 4,6_ difluoroindane-1 — _ (11 '3 g, 67.26 mmol) * 2,2-dimethoxyethylamine (7.07 g, 67.26 mmol) ) And sodium cyanoborohydride (4 * 23 g) in 75 ml of methanol under gentle reflux and heated under stirring, and searched under nitrogen for about 18 hours. Additional sodium cyanoborohydride (2.12 g) * mixture was added and heated at 65t! For 20 hours. The solvent was removed by evaporation, and column chromatography was performed on silica gel to purify it (the extract was 2 ♦ 5% formic acid / methylene chloride 1) to obtain (4,6-difluoroindane_1-yl). (2,2 ~ dimethoxyethyl) amine. -121- (Please read the precautions on the back before filling this page) This paper size is applicable to China National Standard (CNS) A4 specification (2〗 0X297 mm) 470741 Α7 Β7 5. Description of the invention () (4, 6 —Difluoroindan-1-yl)-(2,2-dimethoxyethyl) amine (1 1.68 g, 45.9 mmol) and potassium thiocyanide (4.46 g, 45 · 9 mmol) in 21.6 ml of 1 2N hydrochloric acid, 86 ml of ethanol and 86 ml of water and heated at 80 to 85 t for 15 hours. The mixture was cooled in an ice bath and diluted with K water to obtain a crystalline substance. The material was separated by centrifugation, and the filter paper residue was washed with cold ethanol (2 x 25 ml) and 50 ml of diethyl ether. Dry 1- (4,6_difluoroindane-1-yl) -1,3_dihydroimidazol-2-thione (5. 65 g, 22.2 mmol), melting point 205-2 0 7 ¾ ° was carried out according to Example 12, but using different starting materials instead of 4,6 difluoro-indane-1 1 嗣, to obtain the compound of formula I under K: 1, 2 * 3, 4 1-4 1- (1,2,3,4-tetrahydronaphthalene- 1-yl) -1,3-dihydrotetrazole- 2-thione, with melting point 188Ό-189υ; 6-Methoxy-1,2,3,4-tetrahydronaphthalene-1 monoketone is substituted to obtain 1- (6-methoxy-1,2,3,4-tetrahydrocaine Printed by the Consumer Cooperatives of the Bureau of Standards (please read the precautions on the back before filling in this page) 1-based) 1 * 3 —dihydroimidazole — 2 — thione, melting point 190Ό -1 9 Z V; 5 —methoxy 1- (1,2,3,4-tetrahydronaphthalene_1-one) is substituted to obtain 1- (5-methoxy-1,2,3,4-tetrahydronaphthalene-1-yl) _1,3- Dihydroimidazole—2 —thione, melting point 176Ό — 1 7 7 υ; -122- This paper size applies to Chinese national standards CNS) Α4 specification (210 fathers and 2 mm) 470741 Α7 Β7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention () Use 7-methoxy-1, 2, 3, 4-tetrahydronaphthalene-1 1-ketone substitution to obtain 1- (7-methoxy-1,2,3,4-tetrahydronaphthalene-1-yl) -1,3-dihydroimidazol-2-thione, melting point 142υ -1 4 3 Ό; Substituted with indane-1 2- _ to obtain 1- (indane-2-yl) -1,3-dihydroimidazole-2-thione, melting point 210 ° C-21 1Ό; and indene Manganese 1-ketone substitution to produce 1- (indane-1 1-yl) -1,3-dihydrooxazole-2-thione, melting point 136 ° C- 137C. Example 1 3 1- (1,2 , 3,4-tetrahydro-2-yl) imidazole K is used to prepare a compound of formula 1 in which η is 1 and t is 0. 1,2 * 3,4-tetrahydronaphthalene-2-ylmethanesulfonate (15.74 g * 69.6 mmol) and oxazole (23.68 g, 349 mmol) prepared as in Example 7 Ear) The mixture was heated in 100 ml of dimethylformamide and heated at 80 ° C-90 ° C under argon for 24 hours. The solvent was removed on a rotary evaporator in vacuo, and the residue was dissolved in 500 ml of ethyl acetate, and the solution was washed with MW water (5 x 250 ml). The combined water was extracted with 500 ml of ethyl acetate, and the extract was washed with water (5 x 250 ml). The combined ethyl acetate extract was washed with a saturated sodium chloride solution, dried over magnesium sulfate, and concentrated on a rotary evaporator. Purify by column chromatography on silica gel (eluent is 5% methanol / methylene chloride), -123- (Please read the precautions on the back before filling this page) This paper size applies to Chinese national standards (CNS ) A4 specification (210X297 mm) 470741 A7 B7 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention () 1 1 (1, 2, 3, 4 tetrahydro-2 -yl) imidazole (5 · 18 grams, 26.1 millimoles), melting point 93υ_95υ. It was carried out according to Example 13 except that 4-methylimidazole was used instead of imidazole, and M2-bromo-1,2,3,4_tetrahydronaphthalene-1 was replaced by ketone 1,2-, 3,4-tetrahydronaphthalene-2- Methane sulfonate, and then sulfonium, to obtain 1- (1,2,3,4-tetrahydronaphthalene- 2-yl) -4 methyl oxazole. Example 1 4 (S)-Ν- [3-(5,7-difluoro-1 * 2,3,4-tetrahydronaphthalene-2 -yl) -2,3-dihydro-1Η-mi-mile-1 —Methylmethyl] formamidine M is prepared in the formula 11 in which n is 1 and t is 2 and R1 is fluorine at the 5 and 7 positions * R4 is a hydrogen compound. Formamidine (S) prepared as in Example 29 [N — [3 — (5,7 —difluoro-1, 2, 3 * 4 —tetrazine — 2 —yl) — 2 — thione — 2, 3 -A mixture of dihydro-1H-oxazol-4-ylmethyl] formamidine (1.38 g, 4.27 mmol) and active Raney® nickel (1 1 g) in 50 ml of ethanol at 80 ° C for rapid Search for 1 hour. MCelite filtered the mixture and the filtrate evaporated to a white solid (0.98 g). This solid was recrystallized from ethyl acetate / methanol to obtain (S)-N-[3-(5,7 -difluoro-1,2,3,4-tetrahydronaphthalene-2 -yl) -2,3- Dihydro-1H-oxazole-4 monomethylmethyl] methanamine, melting point 1941-195 ^ 0 -124- This paper size applies to Chinese national standards (CNS> A4 specifications (210 × 29 >? mm)) (Please read first Note on the back, please fill in this page again) 470741 Printed by A7 B7, Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention () According to Example 14, but M is replaced by different starting substances (S) -N-C 3-( 5,7-difluoro-1,2,3 * 4 — tetrahydronaphthalene- 2-yl)-2-thione_2,3-dihydro-1 Η-oxazole-4-ylmethyl] methanamine The compound of formula 1 is prepared as follows: Using (S) -5-aminoaminomethyl-1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl) -1 , 3-Dihydrooxazole-2-thione hydrochloride substitution to obtain (S) — [3 — (5,7_ difluoro-1, 2 * 3,4 tetrahydronaphthalene-2 —yl)- 2,3_ dihydro-1Η-oxazole-4 4-ylmethyl] amine, melting point 273Ό-274Ό; and 1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl) -1,3-dihydro-imidazole-2-thione substitution to obtain 1- (5,7-di Fluoro-1,2,3,4-tetrahydronaphthalene-2-yl) -1,3-dihydroxazole. Example 1 5 3-Amine- 1- (1,2,3,4-tetrahydronaphthalene -2-yl) -1,3 ~ dihydrooxazole-1 2-thione M is prepared in the formula I (a) wherein η is 1 * t is 0, R3 is an amine group, and R4 and R5 are hydrogen compounds. 1- (1,2,3,4-tetrahydro-2-yl) imidazole (198 mg, 1 mmol) and 0-1,3 * 5-trimethylbenzylsulfonyl as prepared in Example 13 A mixture of hydroxylamine (2 15 mg, 1 mmol) was stirred in acetonitrile in argon for 18 hours, and the reaction mixture was -125- This paper size is applicable to Chinese national standards (CNS> A4 specification (210 > < 297 mm) (Please read the notes on the back before filling out this page) 470741 Μ Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Β7 V. Description of the invention () Diethyl ether was diluted to obtain oily splash . The solvent was decanted and the residue was washed with M diethyl ether (2 x 10 ml). The residual solvent was evaporated in vacuo. A mixture of the residue and shellac sulfur (32 mg, 1 ♦ 0 mol) was heated in 1 ml of pyridine and 0 * 5 ml of triethylamine at about 90 t: and argon for 4 hours. The residue was removed by evaporation, and the residue was co-evaporated with toluene. The residue was purified by chromatography on a silica gel with a methane gaseous compound, and the residue was purified to obtain 3-amino-1— (1,2,3 · 4-tetrahydronaphthalene-2—yl) -1,3— Dihydrooxazole-1, 2-thizone (5 ♦ 18 g, 26.1 mol), melting point 1871-189¾. It was carried out according to Example 15, but different starting materials were substituted for 0-1, 3, 5-trimethylbenzenesulfonylhydroxylamine and / or 1- (1,2,3,4-tetrahydronaphthalene-2- Group) oxazole * to obtain a compound of the formula I: Substituted with tert-butyl bromoacetate to obtain 3 ~ (1,2,3 * 4 -tetrahydronaphthalen-2-yl) -2 -thione-2 »3-Diargon-1Η-imidazole-1 1-butyl tertiary acetic acid; melting point 1 67Ό — 1 691; 4 methyl bromobutyrate and 1- (1,2,3,4 1-4 2 -yl) imidazole substitution to obtain 4_ [3-(1,2,3'4 -tetrahydronaphthalene-2 -yl) -2 -thione_2,3 -dihydro-1, 1 -oxazole-1 1 Methyl] butyrate; substituted with 5-bromomethylpicolinic acid methyl ester and 1- (1,2,3'4-tetrahydronaphthalene-2-yl) imidazole to obtain 5— [3-( 1'2,3,4-tetrahydrocae-2 —yl) — 2 —thione — 2 '3' fluorene — 1 H -imidazole — 1 monomethyl] picolinic acid methyl ester (oil);- 126- This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) (Please read the precautions on the back before filling this page)-Packing. -Silk 470741 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention () Use methyl 4-bromomethylbenzoate and 1- (1,2,3,4-tetrahydronaphthalene-2 ) Substitute * for imidazole to obtain 4_ [3- — (1 · 2 > 3,4-tetrahydronaphthalene-2-yl)-2-thione-2,3-dihydro-1H-imidazole-1-methyl ] Methyl methaneate, melting point 133-1351C is substituted with methyl 3-bromomethylbenzoate and 1- (1,2,3,4-tetrahydronaphthalene-2-yl) panazole to obtain 3-[3 — (1 * 2 * 3 »4 —tetrahydrocae 2-yl) — 2-thione — 2, 3 —dihydro — 1 H — imidazole — 1 —methyl] methane acid, melting point 130 — 132 ° CI is substituted with 3,4-dimethoxybenzyl chloride and 1- (1,2,3,4-tetrahydronaphthalene-2-yl) oxazole to obtain 3- (3,4-dimethoxy Benzyl)-1- (1,2,3,4-tetrahydronaphthalene-2-yl) -1,2,3-dihydroimidazole- 2-thizone, melting point 129-131¾ ♦ Use 4 monobromomethylbenzyl Acid methyl ester and 1- (1,2,3,4-tetrahydronaphthalene-2 -yl) -4 methylimidazole substitution to obtain 4- [3- — (1,2,3,4-tetranaphthalene-2-yl) _5-methyl-2, thione-2,3-dihydro-1H-imidazole_1-methyl] methyl benzoate The melting point is 140-14115, which is substituted with 6-dimethylamino-3-bromopyrazine and 1- (1,2,3 * 4-tetrahydronaphthalene- 2-yl) imidazole to obtain 3- (6-di Methylaminopyridazin-3-yl) —1 -— (1,2,3,4-tetrahydronaphthalene-127-) This paper is sized for China National Standard (CNS) A4 Specification (210 > < 297 mm) (Please read the notes on the back before filling out this page) 470741 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention () — 2 1 base) 1 1 • 3 — Dihydro Imidazole — 2 Monothione t Melting point 1 9 8 — 1 9 9 V * Prepared by substituting 2 monobromoethylbenzyl and 1 ((1 »2 9 3 9 4 * —tetrahydronaphthalene 2 —yl)) 3 — (2 phenylethyl) 1 1 1 (1 2 3 »4 tetrahydronaphthalene — 2 —yl) — 1» 3 — diimidazole — 2 — thione melting point 1 4 0 — 1 4 2 t: used 4- (2-bromoethyl) benzate and 1- (1 2 > 3 »4-tetrahydronaphthalene-2-yl) oxazole substituted to obtain 4 {2-C 3-(1 2 3 9 4 Tetrahydronaphthalene — 2 monoyl) — 2 monothione — 2 $ 3 monodihydro-1 hydrazone — imidazole — 1 —ylethyl} Melting point of methyl muteate 1 5 9 — 1 6 1 V with 4 — (2-bromoethyl) benzoic acid and 1 (1 2 3 4 a Tetrahydronaphthalene — 2 monoyl) oxazole substituted to obtain 4 —C 3 — (1 Σ »3 4 Tetrahydronaphthalene — 2 —yl) * — 2 Thione — 2 3 Hydrogen — 1 Η Imidazole — 1 — Methyl] benzoic acid melting point 2 2 7 V-2 3 0 V with 3 4 —dimethoxy — 1 — (2 bromoethyl) and 1 — (1 > 2 3 t 4 tetrahydrom — 2 —yl) imidazole substitution »to obtain 3 — C 2 mono (3 4 -dimethoxyphenyl) ethyl 1 1 (1» 2 9 3 t 4 tetrahydrocae — 2 mono) 1 1 9 3 — dihydrooxazole — 2 —sulfur m — melting point 9 7 — 1 0 1 ti with 4 (2 bromoethyl) benzoic acid and (S) — 1 — (5 7 — difluoro-1 2 2 food 3 $ 4 Tetrahydrocae 2 — base) oxazole replaced 9 128- This paper size applies to Chinese national standards (CNS> A4 size (210X297 mm) 470741 A7 B7 ) Make (S) — 4 a {2 — 3 a ( 5 9 7 Difluoro-1 1 »2 9 3 1 4 Tetrahydronaphthalene- 2 1-yl) 1 2 Monothione 1 2 9 3 1-Dihydro-1 1 Η 1-imidazole — 1-yl) ethyl} benzoic acid 9 melting point 2 2 2 — 2 2 4 V 9 Μ treatment of potassium hydroxide in methanol > evaporation to dryness > recrystallization from methanol / isopropanol 9 to obtain (S) — 4 — {2 — 3 1 (5 > 7 difluoro-1 9 2 3 4 —tetrahydronaphthalene-2 —yl) — 2 monothioketone 2 3 — dihydro — 1 Ηimidazole — 1 monoethyl} potassium benzoate »melting point greater than 2 8 0 tl was prepared by substituting 4-(2 -bromoethyl)-1 -cyanobenzyl and (S)-1-(5 7 -difluoro-1 2 3 4 -tetrahydronaphthalene-2 -yl) imidazole ( S) »3 — [2 — (4 -cyanophenyl) ethyl]-1 1 (5 7 -difluoro — 1 2 3 4 — tetrahydronaphthalene — 2 —yl) — 1 f 3 -dihydro — Oxazole — 2 monosulfur m melting point 1 3 0 — 1 3 3 V · with 4 mono (2-bromoethyl) And (S) — 1 (5 7 -difluoro-1 2 3, 4-tetrahydronaphthalene-2 -yl) oxazole substituted to obtain (S)-3-C 2-phenylethyl) — 1-( 5 7 Monodifluoro-1 > 2 9 3 4 Tetrahydronaphthalene-1 2 1) 1 1 3-Diphosphazol-2 Monothione Melting point 1 3 1 _ 1 3 3 t! Use 4 — (2 —Bromoethyl) — 1 — Fluorobenzyl and 1 — (1 2 $ 3 t 4 Tetrahydronaphthalene — 2 mono) imidazole substitution to prepare 3 — C 2 mono (4 —cyanobenzyl) ethyl — 1 1 (1 f 2% 3 »4 — Tetrahydrocai — 2 1 base) — 1 f 3 — Dihydroimidazole — 2 Monothione f Melting point 1 6 9 129- This paper size applies to China National Standard (CNS) A4 Specifications (210X297 mm) 470741

經濟部中央標準局員工消費合作社印I A7 B7五、發明説明（） -1 7 0 °C ；用4 — (2 —溴乙基）苯酸和（S) — N — 〔3 —( 5，7 —二氟一 1 ，2，3，4 —四氫萘一 2 —基）—2 ，3 —二氫一1 Η —咪唑—4 —基甲基〕甲醯胺取代，製得（S) — 4 — {2 — 〔4 一甲醯基胺基甲基—3 — (5 ，7 —二氟一1 ，2，3，4 一四氬萘一2 —基）一 2 — 硫酮一 2，3 —二氫—1Η —脒唑—1—基]乙基}苯酸 ;和用3 —溴丙酸乙酯和（S) — Ν — 〔3 — （5，7 — 二氟一 1 ，2，3 >4 —四氫萘—2_ 基）一 2，3 -二氫—1 Η —咪唑-4-基甲基〕甲醯胺取代，製得（S) —3 — 〔4 一甲醯基胺基甲基一3 — (5，7—二氟一1 ，2，3，4 —四氫萘—2-基）-2 —硫酮-2，3-二氫一 1Η —咪唑—1—基〕丙酸乙酯。實例1 6 1— (1，2，3，4_ 四.氮蔡—2—基）一 1 ·3 一二氫咪唑_ 2 —硫酮 Μ下係製備式I (a)中η為1 ，t為0，R3 ， R4和R5各為氫的化合物。如實例13所製備的1 一（1 ，2，3，4 —四氫一 2 -基）畔唑（1 * 6克，8 · 1毫莫耳）於30毫升四氫呋喃所形成溶液冷卻到_78·Ό，在1 5分鐘内加入正丁基錫（6毫升* 9 · 7毫莫耳）。混合物在—78¾攪 -1 3 0 - 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） (請先閱讀背面之注意事項再填寫本頁) 470741 A7 B7 五、發明説明（）拌1小時，加入蟲漆硫（0 . 34克，10 . 5毫奠耳〉，混合物在一 7 8 再攪拌2小時·然後使其回溫到室溫。混合物倒入1 00奄升水中，得到结晶性物質。過澳分雛該物質，用***洗滌，乾燥之。用甲撐氯化物萃取滤液 (2χ 1 00毫升），用鹽水洗滌萃取物，Μ硫酸納乾燥，蒸發澹縮之。殘留物在矽膠上被管柱層析純化（沖提液物1 · 5%甲醇（含2%濃氫氧化納）〕。混合結晶性物，得到 1— (1 ，2，3，4 一四氫萘一 2 —基）一 1 ， 3 —二氬咪唑一 2 —硫醜質（〇 . 8 1克，3 . 5毫莫耳 )，熔點 233D— 234υ〇實例1 7 5 —胺基一 1一（1 ，2，3，4一四氬萘—基 )_1 ，3 -二氳咪唑—2 —硫劂以下係製備式I (a)中η為1 ，t為0，R3和 R4為氳，R5為胺基的化合物。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填寫本頁) 如實例1 0所製備的2 —異硫氟基一 1 ，2，3，4 一四氬萘（1 · 92克，10 . 1奄莫耳）和胺基乙腈氫氮化物（0 · 94克，10 · 1毫莫耳）混合物在1 ·41 毫升三乙胺中於60¾加熱1小時。蒸發溶劑，殘留物被驟急曆析純化（沖提液為甲撐氯化物，接著為3%甲醇（甲撐氯化物中））。純化的殘留物於醋酸乙酯/己烷再结晶。殘留物（1 ♦ 06克）和44毫升0 ♦ 1N氫氧化鉀在氮氣中攪拌1 5分鐘。過滹分雛殘留物，用水洗滌*空 -131- 本紙張尺度適用中國國家樣準（CNS ) A4規格（210x297公釐） 470741 A7 B7 經濟部中央標準局員工消費合作社印製五、發明説明（）氣乾燥，然後與甲撐氯化物搅拌。過漶，乾煉，製得5 — 胺基一 1— (1 ，2，3，4 一四氫萘一 2 —基）_1 ， 3_二氫眯唑一 2 —硫酮，熔點169Ό — 171t：。實例1 8 (S ) -5 —羥基甲基一1— (5，7 -二氟一 1 ， 2，3，4 —四氫萘一 2 -基）一 1 ，3 —二氫眯唑一 2 -硫酮 Μ下係製備式I (a)中η為1 ，t為2，5_和7 -位置的R1為氟，R5為羥基甲基的化合物。硫氰酸鉀（15 ♦ 9克，162 · 6奄莫耳）在氮氣中被加熱到1 7 510而乾燥，然後在真空中通入數次氮氣而冷卻之。二羥基丙酮（1 5 . 9克，1 76 · 7毫莫耳 )和如實例6所製備的（S) — 5，7 —二氟一 1 ，2， 3，4_四氫萘一 2 —基胺氫氯化物（30 . 0克，137 . 〇毫其耳）混合物（於540毫升醋酸乙酯中）加入乾煉硫鼠酸鉀。反應容器通入氮氣，加入40 · 83克冰醋酸。反應混合物在3 5¾攪拌1 5分鐘，然後在冰浴中冷卻* 加入2 . 5M氫氧化納直到混合物pH為7。先後用50 毫升飽和碳酸氫納水溶液和5 0毫升鹽水洗滌有機層。蒸餾有機層使濃縮到48 0毫升，混合物冷卻到6Ό ·使其靜置1 2小時，得到結晶性物質。過滹分離該物質，用冷醋酸乙酯洗滌漶紙殘留物’乾燥分離的物質。該物質溶於6 5 0毫升醋酸乙酯和2 5奄升水中，蒸 -132- (請先聞讀背面之注意事項再填寫本頁) .裝. '、11 -絲本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 470741 A7 B7 五、發明説明（）餾混合物直到除去5 0 0毫升的揮發物。冷卻混合物到室溫，攪拌45分鐘，得到结晶性物質。過濾分離該物質，用冷醋酸乙酯洗滌濾紙殘留物。在真空中通入氮氣使乾燥，製得（S) — 5 —羥基甲基一 1 一（5，7 —二氟一 1 ，2，3，4一四氫萘一2 —基）一1 ，3 —二氬咪唑一 2 —硫酮（30 ·4克，107 ·4毫莫耳），熔點20 6-2071， [ α ]ρ2 5 -40ο (C = 0.682，甲醇）。依類似實例18方式進行，但是用（S) — 6，7 - 二氟_1 ，2，3，4 一四氫萘一 2-基胺氫氯化物取代 (S ) — 5，7 —二氟-1 ，2，3，4 一四氫萘—2_ 基胺氫氯化物，製得（S) — 5 —羥基甲基—1 一（6， 7 —二氟 _1 ，2，3，4 一四氫蔡—2 —基）一 1 ，3 一二氫眯唑一 2 —硫酮，熔點247°C — 248t：。實例1 9 (S ) — 5—氰基一 1— (5，7—二氟—1，2，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填寫本1) 3，4 —四氫萘—2 —基）—1 ，3-二氬咪唑一 2 —硫酮 Μ下係製備式I (a)中η為1 ，t為2，5 —和7 —位置的R1為氟，R3和R4為氫，Rs為氟基的化合物0 如實例8所製備的（S) — 5，7-二氟一1 · 2， 3，4 一四氫萘一 2 —基胺氫氯化物（50 · 3克，0 . 23 -133- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 470741 A7 B7 經濟部中央#準局員工消費合作社印製五、發明説明（ ) 1 1 I 莫耳 ) 和氫氧化納 ( 1 0 • 0 克 0 • 2 5 η 耳 ) 在 4 5 0 1 1 1 毫升水中所形成的溶液被加熱到 5 0 °C 9 然後加入甲醛亞 1 I 硫酸納錯合物 ( 3 0 • 8 克 • 0 f 2 3 莫耳 ) 0 攪拌混合請 kj 閱讀背 1 I 物 3 0 分鐘加入氰化鉀 ( 1 5 « 0 克 > 0 * 2 3 莫耳 ) 1 1 面 I 0 加熱混合物到 8 0 V 9 攪拌 1 小時 9 冷卻到室溫 9 然後之注 1 I 意 1 I 用醋酸乙酯萃取〇蒸發得到油狀殘留物 ( 5 1 3 克 ) 0 事項 1 I 再 1 在矽膠上進行管柱曆析純化 ( 沖提液為 5 % 甲醇 / 甲撐氯 § 1 寫本 f 化物 ) 製得 ( S ) 一 ( 5 7 — 二氟 — 1 2 3 4 頁 1 一四氫萘 — 2 — 基 — 胺基 ) 乙腈 ( 3 9 4 克 ) 和 ( S ) 1 1 一 ( 5 7 一二氟 — 1 2 3 4 — 四氫萘 — 2 一基胺 1 I ( 7 1 2 克 ) 0 依上述類似方式進行循環回收起始物 I 訂質混合後得到 ( S ) 一 ( 5 7 一二氟一 1 2 3 » 1 I 4 一四氫萘 — 2 — 基一胺基 ) 乙腈 ( 4 4 * 8 克 0 • 2 1 1 0 莫耳 ) 熔點 7 3 一 7 6 1C C a 〕0 Z 5 =· -58 0 4° 1 1 ( C = 1 6 氯仿 ) 〇 1 絲 ( S ) 一 ( 5 7 — 二氟一 1 2 3 4 — 四氫萘 1 一 2 — 基一胺基 ) 乙腈在甲酸丁酿 ( 8 7 Μ 9 2 4 0 毫 1 1 升 2 • 1 0 莫耳 ) 中所形成的溶液被加熱到回流 » 在氮 1 1 氣中撹拌 1 9 小時 0 在減壓下除去溶劑 » 加入甲苯 9 然後 1 I 蒸發〇乾燥後得到油狀殘留物 ( S ) — N 一 ( 概基甲基 ) 1 1 一 N 一 ( 5 » 7 — 二氟一 1 » 2 » 3 * 4 一四氫萘 — 2 一 1 1 基 ) 甲醢胺 ( 5 3 • 2 克 ) 〇將甲醯胺 ( 5 3 * 2 克 ) 和 1 1 甲酸乙酯 ( 1 2 • 4 Μ 9 4 8 • 7 毫升， 0 • 6 0 4 莫耳 1 | - 134- 1 1 本紙張尺度適用中國國家標準（CNS )八4規格（2丨OX297公釐） 470741 經濟部中央標準局員工消費合作社印裝 A7 B7 __五、發明説明（） )在0♦925升無水四氫呋哺中所形成的攪拌混合物冷卻到一1 5C。在2 0分鐘内加入三級丁氧化鉀在四氫呋喃（1 . ΟΜ，302奄升，0 · 302莫耳）中所形成的溶液，攪拌混合物1 8小時。蒸發溶劑》得到殘留物 (S ) - Ν - (1一氰基一 2 —氧乙烯基）一Ν — ( 5 » 7 —二氟一 1 ，2，3，4 一四氫萘-2 —基）甲豳胺。 (S) — Ν - (1-氰基一2 —氧乙烯基）一 Ν - ( 5，7-二氟一1 ，2 * 3，4-四氣蔡一 2 —基）甲_ 胺鉀和硫氰酸鉀（78 · 1克，0 · 80莫耳）混合物在 0·99升1Ν氫氯酸和0·497升乙酵中被加熱到 85Ό，攒拌1 35分鐘。然後混合物在冰浴中冷卻，形成沈澱，收集成為泥狀物。在包裝於己烷的矽膠上進行管柱層純化（沖提液為10%丙酮/甲撐氛化物），製得 (S) — 5_ 氰基一 1- (5，7 —二氟一1，2，3， 4 —四氬萘一 2 -基）一1 ，3-二氫咪唑—2 -硫暇（ 18 . 1 克，0 . 06 冥耳），熔點 241-249C， [a ) D 25=-69.1。（C = 1.20，DMS0 )0 依實例1 9進行*但是用不同起始物質取代（S> — 5，7 —二氟一 1 ，2，3 , 4 —四氫萘一 2 —基胺氫氛化物，製得K下式I化合物：用5，7 —二氟一1 · 2，3，4 —四氫萘一 2-基胺取代，製得5-氰基-1 一（5，7-二氟—1 ，2， -135- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） (請先閱讀背面之注意事項再填寫本頁) 470741 A7 B7 五、發明説明（）經濟部中央標準局員工消費合作社印製 3 9 4 — 四氫 m — 2 — 基 ) — 1 > 3 一二氫咪唑 — 2 一硫酮 i 熔點 2 5 5 ( 分解 ) 5 用 ( R ) 一 5 > 7 — 二氟一 1 > 2 > 3 » 4 — 四氫萘 — 2 — 基胺取代製得 ( R ) 一 5 — 氰基一 1 — ( 5 * 7 — 二氟 — 1 9 2 > 3 » 4 — 四 m 萘一 2 一基 ) 一 1 t 3 — 二氫眯唑 — 2 — 硫酮 * * 用 ( S ) — 7 — 氟 — 1 2 3 > 4 — 四氫萘 — 2 — 基胺取代 » 製得 ( S ) — 5 一氰基 — 1 — ( 7 — 氟一 1 ， 2 3 » 4 — 四每 m 萘 — 2 — 基 ) 一 1 > 3 — 二氫咪唑 — 2 — 硫酮 > 用 ( S ) — 6 — 氟 — 1 > 2 > 3 » 4 — 四氫萘 — 2 一基胺取代 > 製得 ( S ) — 5 — 氟基 — 1 一 ( 6 — 氟一 1 9 2 $ 3 t 4 -— 四氫萘 — 2 — 基 ) 一 1 P 3 — 二氫咪唑 — 2 — 硫酮 > 用 ( S ) — 5 —. 氟一 1 2 3 9 4 — 四氫萘 — 2 一基胺取代 > 製得 ( S ) 一 5 一氰· 基 — 1 — ( 5 — 氟一 1 > 2 3 9 4 — 四氫 m — 2 — 基 ) — 1 » 3 — -' 氫咪唑 — 2 — 硫嗣 » 用 ( S ) — 1 > 2 3 4 — 四氫萘 — 2 一基胺取代 t 製得 ( S ) — 5 一氰基 — 1 — ( 1 » 2 » 3 9 4 一四氫萘 — 2 — 基 ) — 1 i 3 一 —-- 氫咪唑 — 2 — 硫酮 $ 用 6 « 7 — 二氟 — 1 • 2 • 3 > 4 — 四氫蔡 — 2 — 基胺取代 * 製得 5 — 氰基一 1 一 ( 6 9 7 一 . 氟一 1 > 2 » -136- (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 470741 經濟部中央標準局員工消費合作社印製 Μ Β7五、發明説明（） 3，4 —四氫萘一 2 —基）一 1 ，3 —二氫咪唑—2 —硫酮；用（S) — 6，7— 二氟一 1 ，2，3，4~ 四氫萘 —2 —基胺取代，製得（S) — 5 —氰基一 1— (6，7 —二氟一 1 ，2，3，4 —四氫蔡一 2— 基）—1 ，3 — 二氫眯唑一 2 —硫酮；和用5 * 6 —二氟茚滿一 2 —基胺取代，製得5 —氰基 —1- (5*6 —二氟一茚滿一2_ 基）一 1 ，3 —二氫咪唑_ 2 —硫酮。實例2 0 (S ) — 5-胺基甲基一 1— (5，7 —二氟一1 ， 2，3，4 —四氫萘一 2 —基）一 1 ，3_二氫咪唑—2 一硫酮氫氯化物 K下係製備式I (a)中η為1 ，t為2，5 —和7 一位置的R1為氟，R3和R4為氫，R5為胺基甲基的化合物。如實例19所製備的（S) — 5 —氰基一 1_ (5， 7 —二氟一1 ，2，3，4 —四氫萘一2 —基）一1 ，3 —二氫咪唑_2 —硫酮（5 · 0克，0 · 017奠耳）在 7 5毫升四氫呋喃所形成的溶液在氩氣中於冰浴中攪拌，在10分鐘内滴加LAH在四氫呋喃（1 · OM，34 · 3 毫升，34 · 3毫莫耳）中所形成的溶液。混合物冷卻到 Ο Ό，攪拌3 0分鐘，使其回溫到室溫，靜置1 · 5小時 -137- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） (請先閱讀背面之注意事項再填寫本頁) 470741 經濟部中央標準局員工消費合作社印製 A7 B7_五、發明説明（）。混合物冷卻到oc*然後加人足量的飽和酒石酸納鉀溶液，使混合物自由搅拌。另外加人3 0毫升飽和1酒石酸納鉀溶液和200毫升10%甲醇（甲撐氯化物中）。分雛有機曆，水相被10%甲醇（甲撐氯化物中）宰取二次（ 2x125毫升），混合的萃取物被75毫升水洗濂•被硫酸鎂乾燥，蒸發濃縮成殘留物（5 ♦ 2克）。在矽膠 (沖提液為5%甲鹉/甲撐氯化物）上進行管柱層析純化，製得（S) — 5 —胺基甲基一1— (5，7 —二氟一 1 ，2 , 3，4 —四氫萘—2 —基）一 1 ，3 —二氫咪唑— 2 —硫酮（2. 92克，10.0毫莫耳）° (S ) - 5-胺基甲基一 1— (5，7-二氟一 1 * 2，3，4_四氫禁_2 —基）一 1 ，3 —二氫咪唑—2 一硫酮溶於甲醇中，用1 ‘ 5當量無水氯化氫（***中）處理，與醋酸乙酯進行共蒸發，除去溶劑，製得（S) _ 5 -胺基甲基一1 一（5，7-二氟一1 ，2 ’ 3，4一四氫萘一 2 —基）一 1 ，3 —二氫咪唑—2 —硫酮氫氯化物，熔點 245D，〔<χ〕ρ25=11·30° (C = 0 · 5 · D M S 0 ) 0 如實例2 0方式進行，但是用不同的起始物質取代 (S) — 5 —氮基—1 一（5，7 -二氣一1 ，2’3’ 4 —四氫萘-2 —基）—1 ，3-二氫眯唑—2 —硫酮，製得Μ下式I化合物：用 5 —氰基一1 一（5，7 —二氟一 1 ，2，3，4 -138- 本紙張;Cl適用中國國家標準（CNS ) Α4規格（210Χ297公釐） I---------t------IT------,# (請先閱讀背面之注意事項再填寫本頁) 470741 經濟部中央標準局員工消費合作社印製 A7 B7五、發明説明（）一四氫萘一2 —基）_1 ，3 —二氫晞唑一2 —硫酮取代，製得5 —胺基甲基一1— (5，7 —二氟一1 ，2，3 ，4 —四氫蔡—2 -基）一1 ，3 —二氫咪唑—2 —硫酮，熔點172它一178Ό，和5 —胺基甲基一1— (5 ，7-•二氟-1 ，2，3，4-四氫蔡一2 -基）-1 ， 3 —二氫眯唑一 2 —硫酮氫氯化物，熔點265^— 2 7 0¾ » 用（R) — 5 —氰基—1- (5，7 — 二氟一1 ，2 ，3，4_四氫萘一2 —基）一 1 ，3 —二氫咪唑一 2 — 硫酮取代，製得（R) — 5—胺基甲基一1 一（5，7 — 二氟—1 ，2，3，4 -四氫萘—2 -基）—1 ，3 -二氫咪唑一 2 —硫酮氫氯化物；用（S) — 5 —氮基—1 一（7 —氟一1 ，2，3， 4 —四氫萘一2 —基）一1 ，3 —二氫咪唑一 2 —硫酮取代，製得（S) — 5-胺基甲基一 1— (7 —氟—1 ，2 ，3，4一四氫萘一2 —基）一1 ，3 —二氫眯唑—2 — 硫酮氫氯化物，熔點237 — 247¾ ; 用（S) — 5 —氰基—1— (6 —氟—1 ，2，3， 4 —四氫萘—2 —基）一 1 ，3 —二氫咪唑一 2 —硫酮取代，製得（S) — 5_胺基甲基一 1— (6 —氟一 1 ，2 ，3，4—四氣蔡一 2 —基）—1 ，3 —二氫畔啤—2 — 硫酮氬氯化物，熔點240 — 249C ; 用（S) -5 —氰基-1— (5 -氟一1 ，2，3， -139- 本紙張尺度適用中國國家標準（CNS )八4規格（210 X297公釐） (請先閱讀背面之注意事項再填寫本頁) 470741 經濟部中央標準局員工消費合作社印製 A7 B7五、發明説明（） 4 一四氣蔡—2 —基）一 1 ，3—二氫蹄啤一 2 —硫酮取代，製得（S) — 5—胺基甲基—1_ (5 —氟一1 ，2 ，3，4 —四氫蔡—2 —基）一 1 ，3—二氫咪唑—2 — 硫酮氫氯化物*熔點2 73 — 276 °C ; 用（S) — 5 —氰基一1— (1 ，2*3*4 -四氫萘一 2 —基）—1 ，3 -二氫眯唑_2 —硫酮取代，製得 (S ) 一 5 —胺基甲基一 1— (1 ，2，3，4一四氫萘 —2 —基）一 1 ，3 -二氫咪唑—2 —硫酮氫氯化物，熔點 255-258P; 用 5 —氰基—1— (6，7 —二氟一 1 ，2，3，4 一四氫萘一 2 —基）—1 >3 —二氫眯唑—2 —硫酮取代，製得5 —胺基甲基—1— (6，7—二氟一 1 ，2，3 ，4 —四氫蔡—2 —基）—1 ，3_二氫牌哩—2 —硫酮氫氯化物，熔點260 — 263Ό(分解）；用（S) -5—氰基一 1- (6，7 —二氟-1 ，2 ，3，4 一四氫萘—2 —基）—1 ，3 —二氫晞唑—2 — 硫酮取代，製得（S) — 5 —胺基甲基一 1一（6，7_ 二氟—1 ，2，3，4 —四氫萘一 2 —基）—1 ，3 —二氫咪唑—2 —硫酮氫氛化物，熔點253 — 27〇υ ;和用 5 —氰基—1一（5，6 -二氟—1 ，2，3，4 一四氫萘—2 —基）一 1 ，3 —二氫脒唑—2 —硫酮取代，製得5 —胺基甲基一 1— (5，6 —二氟-1 ，2，3 ，4一四氫萘—2 —基）—1 ，3 —二氫咪唑一2 —硫_ -140- 本紙張尺度適用中國國家標準（CNS ) Α4規格（210X297公釐〉 (請先間讀背面之注意事項再填寫本頁) 470741 A7 B7 五、發明説明（）氫氯化物，熔點大於280 °C。實例2 1 1— (5 * 7 — 二氟一 1 ，2，3，4 —四氳萘一2 —基）一5 (1H) -四唑一5 —基—1 ，3 —二氫眯唑 —2 _硫酮 Μ下係製備式I (a)中η為1 ，t為2，5 —和7 —位置的R1為氟，R5為1H —四唑_5 —基的化合物〇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填寫本頁) 如實例19所製備的5 —氰基一1一（5，7 —二氟 —1 ，2，3，4 —四氫萘—2—基）一1 ，3 —二氫蹄唑—2 —硫酮（0 · 554克，1 · 9毫莫耳）在1 * 6 毫升三丁基錫蠱氮中的混合物在130¾的氮氣中被加熱 2 · 5小時，然後加入1 0毫升甲苯。混合物冷卻到室溫，約加入5毫升的二***。混合物冷卻到Ο °C，然後用 10毫升1N氯化氫（二***中）處理約15分鐘。混合物倒入氟化鉀單水合物（15 ·0克）在15到20毫升水和7 5毫升醋酸乙酯中所形成的溶液。用2N氫氧化納萃取醋酸乙酯層，用甲撐氯化物洗滌水層6次。用濃氫氯酸酸化水層，然後用醋酸乙酯萃取之。蒸發溶劑，製得1 -(5，7 —二氟-1 ，2，3 >4 —四氫萘-2-基） —5 (1H)—四唑一 5-基-1 ，3 —二氫咪唑—2 — 硫酮（0 · 57克* 1 · 7毫莫耳），熔點214Ό — 2 15¾° -141- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 470741 經濟部中央標準局員工消費合作社印製 Μ Β7五、發明説明（）依實例2 1進行，但是用不同起始物質取代5 -氟基 —1— (5，7 —二氟一1 ，2，3，4 一四氫蔡—2 — 基）—1 ，3 -二氫咪唑一 2 —硫_，製得K下式I化合物：用5 —氣基—1— (5，6 —二氟節滿一 2 —基）— 1 ，3 —二氫咪唑一 2 —硫嗣取代，製得1— (5，6 — 二氟茚滿_2 —基）一 5 ( 1 Η ) _四唑一 5 —基一1 · 3 -二氫眯唑—2 —硫酮，熔點142Π— 147Ό;和用 5 —氰基-1— (6，7 —二氟-1 ，2，3，4 一四氳萘—2 —基）—1 ，3 —二氫咪唑一 2 —硫酮，製得 1- (6，7 —二氟-1 ，2，3，4 —四氫萘-2 — 基）—5 (1Η)—四唑一5 —基一 1 ，3 —二氫脒唑一 2 -硫酮，熔點 195 - 212 °C。實例2 2 3 - (1 ，2，3，4 —四氫萘一 2 —基）_2 —硫代一2，3—二氫一 1H —咪唑一 5 — 5 —卡巴醛 Μ下係製備式I (a)中η為1 ，t為0，R3和 R5為氫* R4為甲醯基的化合物。如實例1 0所製備的2-異硫氟基—1 ，2，3，4 一四氬萘（1 . 89克，10奄莫耳）和D — ( + )葡萄胺（1 · 78克，10毫莫耳）混合物在90 °C攒拌直到均勻為止，然後加入0·8毫升醋酸。混合物在9〇υ攪 -142- 本紙張尺度適用中國國家標準（CNS ) Α4規格（210Χ297公釐） (請先閱讀背面之注意事項再填寫本頁) 470741 經濟部中央標準局員工消費合作社印製 A7 B7五、發明説明（）拌30分鐘，然後冷卻之。用旋轉蒸發器除去溶劑，殘留物與甲苯（2x25毫升）共蒸發。殘留物溶於醋酸，在 9〇υ — 1 00 °C加熱30分鐘。冷卻混合物，用丙酮研製*得到結晶性物質。過濾分離該物質，用丙酮洗滌濾紙殘留物*乾燥得到4 - (1R，2R，3S，4)—四羥基丁一 1—基）一1 (1，2，3，4_ 四氫萘一 2 —基 )—1 ，3 —二氫眯唑一 2 —硫嗣（1 .48 克 *4. 23 莫耳）。 4 - (1R，2R，3S*4) _ 四羥基丁一 1-基 )-1 (1 ，2，3，4 一四氫蔡一 2—基）一1 *3 — 二氫眯唑一 2 —硫酮（0 · 252克，0 · 72毫莫耳）和四醋酸铅（0 · 85克，1 * 92毫奠耳）在15毫升 3 3%醋酸/笨中的懸浮物被攪拌直到3 0分鐘後混合物圼均勻為止。反應混合物倒入1 2 5奄升飽和碳酸納溶液 •過滤混合物。分離有機層，Μ硫酸鎂乾燥，濃縮之。殘留物溶於4 0毫升四氫呋喃和2毫升亞硫酸（6%S〇2 )。蒸發溶劑，製得3 — (1，2，3*4 —四氮萘—2 —基）—2—硫代一2，3 —二氫一1H —畔啤—5—卡巴醛（0 · 1 5克，0 * 59毫莫耳），熔點206Ό — 2 10 1° 依實例22進行，但是用（S) — 2 —異硫氰基—5 ，7 —二氟_1 ，2，3，4 —四氫萘取代2 —異硫氰基 —1，2，3，4_ 四氫萘，製得（S) - 3 - (5*7 -143- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） (請先閱讀^：面之注意事項再填寫本頁) 470741 A7 _B7_ 五、發明説明（） —二氟一1 ，2，3 *4-四氳萘—2 -基）-2-硫代 —2，3-二氫一 1 Η -咪唑—5 —卡巴醛，熔點大於 2 8 5 1° 實例2 3 〔（5，7-二氟一1 · 2，3，4 一四氳萘一 2-基）（甲醢基）胺基〕醋酸乙酯 Μ下係製備式17中η為1 ，t為2，5 —和7 —位置的R1為氟，R3 2為乙氧基羰基。如實例8所製備的5，7 —二氟一 1 ，2 * 3，4 一四氫萘一 2~基胺（6 * 0克，32 . 8毫莫耳）和二羥基醋酸乙酯（4 · 6克，36 · 0毫莫耳 > 混合物在30 0毫升乙酵中於10%炭上鈀（0 . 75克）氫化 10 小時。遇濾绲合物，蒸發濃縮之。殘留物在矽膠（沖提液為30%醋酸乙酯/己烷）進行管柱層析鈍化，製得〔（ 5，7-二氟一 1，2，3，4 —四氫萘一 2 —基）胺基〕醋酸乙酯（7 . 5克，27 . 9毫莫耳）之油。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填寫本頁) 〔（5，7 —二氟 _1 ，2，3 *4 — 四氫萘- 2-基）胺基〕醋酸乙酯（7 . 15克，25 . 6毫莫耳）在 2 0毫升甲撐氯化物中所形成的溶液在氬氣中冷卻到約〇將冷卻到0C的醋酸甲酸酐（9 · 7毫升，67 · 3 毫莫耳）加入，混合物在〇°C攪拌2小時，然後使其回溫到室溫。與甲苯（3x50毫升）共蒸發以除去溶劑。在 -1 4 4 ·" 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 470741 Μ Β7 五、發明説明（）高度真空中結晶殘留物，得到〔（5，7 —二氟一 1 ，2 ，3，4-四氫萘—2 —基）（甲醯基）胺基〕醋酸乙酯 (7.68克，25.0毫莫耳）。依實例23進行，但是用不同起始物質取代5，7~ 二氟_1 ，2，3，4-四氫萘一2 —基胺，製得K下的式1 7化合物：用6，8 —二氟—1 ，2，3，4 —四氫萘一 2 —基胺取代，製得〔（6，8 —二氟—1 ，2，3，4 一四氫萘一2_基）（甲醯基）胺基〕醋酸乙酯；用4，6 —二氟茚滿—2 —基胺取代，製得〔（4， 6 —二氟茚滿—2 —基）（甲醯基）胺基〕醋酸乙酯；用5，7 —二氟茚滿一2 —基胺取代，製得〔（5， 7 —二氟茚滿一2 —基）（甲醯基）胺基〕醋酸乙酯；和用5 * 6 —二氟茚滿一 2 —基胺取代，製得〔（5， 6 -二氟茚滿一 2 —基）（甲醯基）胺基〕醋酸乙酯。實例2 4 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填寫本貢) 3 — 〔5，7 — 二氟一 1 ，2，3，4 —四氫萘一 2 —基）—2-硫代—2，3 —二氫—1H —咪唑一 4 一羧酸乙酯 Μ下係製備式I (a)中η為1 ，t為0，5 —和7 一位置的R1為氟，R3和R4為氫，R5為乙氧基羰基 Ο 製備如實例23的〔5，7 -二氟—1 ，2，3，4 -145- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 470741 A7 B7 經濟部中央標準局舅工消費合作社印製五、發明説明（ ) 1 1 I 一四氫萘一 2 — 基 ) ( 甲醢基 ) 胺基 3 醋酸乙酷 ( 7 • 5 8 1 1 I 克 9 2 4 • 7 奄莫耳 ) 和甲酸乙酯 ( 5 • 9 1 毫升 » 7 2 · 7 1 | 請 1 | 毫冥耳 ) 混合物在 6 0 毫升四氬呋喃中及氣氣中冷卻到 k» 閱 1 I 一 1 0 V 〇加入在 4 5 毫升四氬呋喃中的三級丁氧化鉀 ( 讀背 1 1 I 4 0 8 克 3 6 * 4 毫奠耳 ) ，混合物在 — 1 0 V 攪拌之注 | 意 I 2 小時 0 使混合物回溫到室溫再攪拌 4 小時〇蒸發除去事項 1 I 再 1 | 溶劑 » 殘留物溶於 7 5 毫升 1 Ν 氫氯酸和 5 0 毫升乙醇中 4 1 裝克毫寫本〇加入硫氰酸鉀 ( 2 6 5 7 5 莫耳 ) 混合物在頁 1 I 8 5 V 搜拌 1 5 小時 0 冷卻混合物 > Μ 1 2 5 毫升水稀釋 1 1 之用醋酸乙酯萃取 0 萃取物被硫酸銕乾燥用旋轉蒸發 1 | 器除去醋酸乙酯〇殘留物在矽膠 ( 沖提液為 2 5 % 甲醇 1 訂 / 甲撐氯化物 ) 上進行管柱層析純化製得 3 一 C 5 7 1 一二氟一 1 2 3 4 — 四氫萘 — 2 一基 ) — 2 一硫代 1 1 一 2 3 —* 二氫一 1 Η — 咪唑一 4 — 羧酸乙酯 ( 8 0 7 1 I 克 2 4 6 毫奠耳 ) 熔點 1 5 9 TC 一 1 6 1 1C 0 1 絲依實例 2 4 進行 1 但是用不同起始物質取代 C ( 5 » 1 7 一二氟 — 1 2 3 » 4 — 四氫萘一 2 — 基 ) 一 ( 甲醢 1 1 基 ) 胺基 ] 醋酸乙醮 9 製得 Μ 下式 I 化合物： 1 1 用 C ( 6 > 8 一二氟 — 1 2 » 3 t 4 一' 四氫第 —. 2 1 I 一基 ) — ( 甲醢基 ) 胺基 ] 醋酸乙醅取代 1 製得 3 一 ( 6 1 1 * 8 — 二氟一 1 t 2 ， 3 $ 4 一四氫萘 — 2 一基 ) — 2 一 1 1 硫代一 2 3 — 二氫 — 1 Η — 眯唑一 4 一羧酸乙酷 » 熔點 1 1 1 8 7 V — 1 8 9 V 1 I 146- 1 1 1 本紙張尺度適用中國國家標準（CNS ) A4規格（2!OX 297公釐〉 470741 經濟部中央標準局員工消費合作社印製 A7 B7五、發明説明（）用（1 ，2，3，4一四氫萘-2 —基）一（甲醯基 )胺基〕醋酸乙酯取代，製得3 — (1 * 2，3，4 一四氫萘-2 —基）—2-硫代_2，3 -二氬-1 Η —眯唑一4_羧酸乙酯，熔點70t：— 72¾ ; 用（7 —氟-1 ，2，3，4 -四氫萘—2 —基）一 (甲醯基）胺基〕醋酸乙酿取代，製得3 — (7_氟一 1 ，2，3，4一四氫萘-2-基）-2-硫代—2，3 — 二氫一 1 H—咪唑—4 —羧酸乙酯；用（4，6 —二氟茚滿一 2 —基）一（甲醯基）胺基〕醋酸乙酯取代，製得3 — (4，6 -二氟茚滿一 2 —基 )—2—硫代—2，3—二氫—1H —咪哇—4 一後酸乙酯；用（5，7 —二氟茚滿一 2 —基）一（甲醢基）胺基〕醋酸乙酯取代，製得3 — （5，7-二氟茚滿一 2 —基 )—2—硫代—2，3 —二氫—1H—畔哩—4—梭酸乙酯；和用（5，6 —二氟茚滿一 2 —基）一（甲醯基）胺基〕醋酸乙酯取代*製得3 - （5，6 —二氟茚滿一 2 -基 )—2—硫代-2，3 —二氫—1H —咪唑一 4 一羧酸乙酉旨。實例2 5 3 - 〔1 ，2，3，4 -四氫萘一2 —基）一5 —甲 -147- (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) A4規格（210 X 297公釐） 470741 Α7 Β7 經濟部中央標準局員工消費合作衽印製五、發明説明（）基一 2 —硫代一 2，3—二氫一 1 Η —咪唑一 4 一羧酸乙酯 Κ下係製備式I (a)中η為1 ，t為0，R3為氫，R4為甲基* R5為乙氧基羰基。二異丙基胺（1 · 54奄升，1 1毫奠耳）在30毫升無水四氫肤喃中所形成的溶液在氩氣中冷卻到0"0，加入正丁基鋰（6 . 25毫升，10毫莫耳）°混合物冷卻到一78C，在1 5分鐘內將在20毫升四氫呋喃中的實例23所製備的〔5，7 —二氟一 1 ，2，3，4 一四氫萘一基）（甲豳基）胺基〕醋酸乙酿（1 · 33克， 5 · 〇毫莫耳）加入混合物，混合物在—7 8 υ攪拌1小時，在5分鐘內加入乙醯氯化物（0 · 427毫升，6 · 0 毫莫耳）。混合物在—78Ό攪拌3小時，在1小時內回溫到室溫。蒸發除去溶劑，殘留物溶於2 5毫升1 Ν氫氯酸25毫升乙酵中。加入硫氰酸鉀（1 · 94克，20橐莫耳），混合物在75t：— 8 0¾攒拌18小時。冷卻混合物》用水稀釋· Μ醋酸乙酯萃取二次。將醋酸乙酯湄縮成為黑色油。殘留物在砂膠（沖提液為2%甲醇/甲撐氯化物）上進行管柱層析純化》Μ醋酸乙酿/異丙醚研製，製得淺黃色固體的3 - 〔1 ，2，3，4 一四氫萘—2 — 基）一5 —甲基一 2 —硫代一2，3 —二氫一1 Η —蹄唑一 4 —羧酸乙酯，熔點225Ό - 227*0。依實例25進行，但是用不同起始物質取代〔（1 ， -148- 本紙張；1度適用中國國家標準（(：]^)人4規格（210父297公釐） (請先閱讀背面之注意事項再填寫本頁) 470741 經濟部中央標準局員工消費合作社印製 A7 B7五、發明説明（） 2，3，4-四氫萘—2 —基）一（甲醯基）胺基〕醋酸乙酯和/或乙醯氮化物，製得Μ下式I化合物：用異丁醯氯化物取代，製備3_ 〔1 ，2，3，4 一四氫萘~2 —基）—5 —丙基一2 —硫代一 1 * 3 —二氫 —1 Η —咪唑一 4 —羧酸乙酯，熔點1 95°C— 1 97υ > 用三甲基乙醯氯化物取代，製備3 — 〔1 ，2，3， 4 —四氫萘一2 —基）一5 — (1 ，1-二甲基乙基）一 2 —硫代一1 ，3 —二氫一 1Η —咪唑一 4 一羧酸乙酯的泡沫；用（5，7 —二氟—1 ，2，3，4 —四氫萘—2 — 基）（甲醯基）胺基醋酸乙酯取代，製備3 — 〔5，7 — 二氟一 1 ，2，3，4 —四氫萘一 2 —基）一 5 —丙基一 2 —硫代—1 ，3 —二氫—1Η —咪唑一 4 —羧酸乙酯* 熔點 207υ— 209°C;和用乙基草醯氯化物取代*製備3 - (5，7 -二氟一 1 ，2，3，4一四氫萘一 2 —基）一5 —乙氧基羰基一 2—硫代一 1 ，3—二氣—1 Η -畔哩一4 —梭酸乙酯，熔點 160 °C — 161¾。實例2 6 5 —胺基甲基一 4 — 〔1 ，2，3，4 一四氫萘一 2 •基）-2，4 —二氫〔1 ，2 *4〕三嗖—3 — 硫酮 -149- 本紙張尺度適用中國國家標準（CNS ) A4規格（2丨0X297公釐） (請先閱讀背面之注意事項再填寫本1) 470741 A7 B7 經濟部中央標準局員工消費合作社印製五、發明説明 ( ) 1 1 I K 下係製備式 I ( b ) 中 η 為 1 t 為 0 R 7 為胺 1 1 基甲基的化合物 0 1 I 氰基請 1 1 製備如實例 1 0 的 2 一異硫一 1 2 » 3 4 先閱 I 四氫萘 ( 0 1 9 克 » 1 0 毫奠耳 ) 和 ( 三級丁基氧基背 1 1 I 羰基 ) 胺基乙醜基肼 ( 0 • 1 9 克 1 1 毫莫耳 ) 混合之注音物在 5 毫升二甲基甲醢中於氮氣中在 8 0 V 加熱 2 5 事項 1 I 下再 1 I 小時〇用旋轉蒸發器除去溶劑殘留物在通氮氣的室溫 f 1 本 V 攪拌加入 4 5 毫升乙氧化鈉混合物 ( 製備於 0 4 6 頁 1 I 克納和 4 5 毫升乙酵 ) 〇反應混合物在氮氣下回流約 2 4 1 1 小時使其冷卻然後過濾〇用旋轉蒸發器除去溶劑殘 1 1 留物溶於水中〇用 1 0 % 氫氯酸將溶液酸化到 P Η 3 然 1 訂 1 I 後過濾 0 在減壓下蒸發水得到 5 — ( 三級丁基氧基羰基）胺基甲基一 4 — ( 1 2 3 4 一四氫萘 — 2 一基 ) 一 1 1 I 2 4 一二氫 ( 1 2 4 3 三唑一 3 一硫鬭 ( 0 2 0 3 1 1 克 0 5 6 奄莫耳 ) 〇 ί 將無水氯化氫 ( 4 2 2 克 ) 通入 1 5 毫升在冰甲醇 1 I 浴中的醋酸乙酯加入 5 — ( 三級丁基氧基羰基 ) 胺基甲 1 基 — 4 — ( 1 2 3 4 — 四氫萘一 2 — 基 ) 一 2 9 4 1 一二氫 ( 1 2 4 ) 唑一 3 — 硫酮 ( 0 1 7 8 克 1 1 1 0 4 9 毫其耳 ) f 混合物在室溫下搜拌〇加入醚混合 1 I 物在氮氣中過灌〇在減壓下蒸發溶劑得到 5 — 胺基甲基 1 — 4 — ( 1 9 2 9 3 t 4 一四氫萘 — 2 一基 ) 一 2 » 4 一 1 1 二氫 ( 1 9 2 » 4 ] 三唑 — 3 一硫酮氫氯化物 ( 0 ♦ 1 2 5 1 1 150- 1 1 本紙張尺度適用中國國家標準（CMS ) A4規格（210X 297公釐） 470741 經濟部中央標準局員工消費合作社印製 A7 B7五、發明説明（）克，0 · 4 1毫莫耳）*熔點279P-28 ID。依實例2 6進行*但是用不同起始物質取代2 -異硫氰基-1 ，2，3，4-四氫萘和/或（三級丁基氧基羰基）胺基乙醯基肼，製得Μ下式I化合物：用2 —異硫氰基一 1 ，2，3，4_四氫萘和4 —甲基#嗪一1—基乙醯基肼，製備5 — （4 一甲基哌嗪一 1 一基）_4 一〔1 ，2，3，4 一四氫萘一2 —基）—2 •4-二氫〔1 ，2，4〕***—2—硫酮，熔點217¾ —2 1 8 °C ;和用（S) — 5，7 -二氟—2 —異硫氟基一1 ，2， 3，4 -四氫萘和（三級丁基氧基羰基）胺基乙醯基肼，製備（S) — 5 —胺基甲基一4 — (5，7 —二氟一1 , 2，3，4 —四氫萘—2 —基）-2*4 —二氫〔1，2 ，4〕***一3 —硫酮和（S) — 5 —胺基甲基一 4 —( 5，7 —二氟 _1 ，2，3，4 —四氫萘一2 —基）一2 ，4一二氫〔1，2，4〕***一 3-硫酮氫氯化物，熔點大於2 8 0 I。實例2 7 2_ 〔1 ，2，3，4-四氫萘-2 —基）-2，4 一二氫〔1 ，2，4〕***一 3 -硫酮 Μ下係製備式I (c)中η為1 ，t為0，R8為氫的化合物。 -151- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） (請先閱讀背面之注意事項再填寫本頁) 470741 經濟部中央標準局員工消費合作社印製 A7 B7五、發明説明（） 1 ，2，3，4一四氫萘一 2 酮（3 .5 克，24.0 毫冥耳）和甲酸肼（1 · 56克，26 · 0毫莫耳）混合物在25毫升乙醇和1滴濃氫氯酸中*於70Ό加熱1小時。混合物冷卻到室溫，得到結晶性物質，過濾分離此物質，Μ乙醇洗滌之。乾燥後得到2 —甲醢胼叉一 1 ，2 * 3，4-四氫萘（3 . 5克，8 ♦ 7毫莫耳）。 2 —甲醯肼叉一1，2，3，4-四氫萘（3 · 0克 • 16 · 0毫奠耳）和氫化硼納（1 ，2克，31. 6毫莫耳）混合物在2 5毫升乙醇中，於室溫下攪拌2 0小時。用水驟冷混合物，然後用醋酸乙酯（2x25毫升）萃取之。用鹽水洗滌混合的醋酸乙酯萃取物，Κ硫酸納乾燥，濃縮之。殘留物在急驟曆析（沖提液為2%甲醇/甲撐氯化物）進行純化，得到2 —甲醢胼叉一 1 ，2 , 3 , 4 一四氫萘（2.0克，10.7毫莫耳）。 2 -甲醯胼叉一 1，2，3，4 —四氫萘（2 ♦ 0克，1 0 · 7毫莫耳）和三甲基甲矽烷輿硫氟酸鹽（2 . 8 克，21 . 0毫莫耳）混合物在20毫升甲苯中，於60Ό 一 6 5 °C攪拌2 0小時，得到結晶性物質，過濾分離，乾燥後得到N — 〔（1 ，2，3，4 一四氫萘—2 —基）（胺基硫_羰基）胺基〕甲酿胺（0 . 6克，2 .4毫莫耳 )0 N - 〔（1 ，2，3，4 一四氳萘一 2 -基）（胺基硫-羰基）胺基〕甲醯胺（0 . 6克，2 . 4毫莫耳）在 -152- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） ----------W-- (請先閱讀背面之注意事項再填寫本頁) 訂 470741 A7 B7 經濟部中央標準局員工消費合作社印製五、發明説明 ( ) 1 1 | 1 0毫升 1 0 % 氫氧化納中所形成的溶液在 7 0 t! 加熟 1 1 | 3 0分鐘 0 冷卻溶液 $ 用稀氫氯酸酸化溶液 > 用醋酸乙酯 r-V 1 | 萃取之 0 用鹽水洗滌醋酸乙酯萃取物 9 以硫酸納乾燥 > 濃請先 1 1 閲 | 縮之0 殘留物在醋酸酷 /己焼中再结晶 t 過漶後得到 2 讀 # | I — C 1 » 2 9 3 > 4 一四氫萘 — 2 - 基 ) — 2 9 4 一二氫之注 1 1 意 1 | t 1， 2 > 4 三唑一 3 一硫酮 (0 • 2 5 克 1 • 0 6 事項 1 I 毫莫耳 ) 熔點 2 0 0 • 5 V 〇再填 1 1 馬本頁 1 I 實例2 8 1 1 4 一胺基 — 2 一 C 1 ，2 3， 4 一四氫萘 — 2 — 基 1 1 ) -2 4 — 二氫 [ 1 2， 4 〕三唑一 3 一硫酮 1 訂 Μ 下係製備式 I ( C )中 η 為1 » t 為 0 R 8 為胺 1 基的化合物〇 1 1 2 一溴 — 1 2 3 ，4 — 四氫萘 ( 1 0 6 克 5 1 I 毫其耳 ) 和 4 一胺基 C 1 ，2 t 4〕三唑 ( 2 • 1 克 1 / 2 5奄莫耳 ) 混合物在 8 毫升二甲基甲釅胺中 » 於 9 0 V 1 加熱並搅拌 2 小時〇蒸發除去溶劑，殘留物溶於 5 毫升吡 1 1 啶中〇加入蟲漆硫 ( 0 16 克 * 5 奄莫耳 ) 和 2 • 5 毫 1 1 升三乙基胺 9 混合物在氣氣中及約9 0 V 加熱攪拌 4 小時 1 I 〇蒸發除去溶劑 9 殘留物與甲笨共蒸發 > 以急驟層析 (沖 1 1 提液為 5 % 甲醇 / 甲撐氯化物 ) 進行純化 » 製得 4 — 胺基 1 1 — 2 - C 1 » 2 f 3 > 4 -四氫蔡— 2 — 基 ) 一 2 4 — 1 1 二氫〔 1 % 2 4 ) 三唑 -3 一硫酮 ( 0 * 3 5 克 9 1 • 4 2 1 | -153- 1 1 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 470741 經濟部中央標準局員工消費合作社印製 A7 _B7_五、發明説明（）毫莫耳），熔點147—150¾。實例2 9 (S ) -N -〔3 — (5，7 -二氟-1，2，3， 4 —四氫萘—2—基）—2 —硫代一 2，3 —二氫—1 Η 一眯唑一4一基甲基〕甲醢胺 Μ下係製備式I (a)中η為1 ，t為2，5 —和7 一位置的R1為氟* R5為甲醯胺基甲基的化合物。甲酿胺（250毫升，6 . 3毫莫耳）被加熱到175 °C ，在30分鐘內將製備如實例18的（S) — 5 —羥基甲基一 1一（5，7 —二氟一 1 ，2，3，4 —四氣蔡—2 一基）一 1，3 —二氫咪唑_2 —硫酮（25 . 0克， 88·3毫莫耳）分數次加入，反應混合物在氮氣中攪拌 1小時。冷卻混合物到5 0 t：，加入2 ♦ 5克活生碳 (Darco®)。冷卻混合物到30°C，以Celite 過濾之，Μ 25毫升甲醯胺洗滌。加熱瀘液到95Ό，然後滴加入1升水。使混合物冷卻，然後在室溫下攪拌1 2 小時。混合物冷卻到0 •得到結晶性物質。過滤分離該物質，乾燥之。該物質與約5倍重量的7 0%四氫肤喃/3 0%己烷攪拌5分鐘。過漶分離該物質，用5 0%四氫呋喃/5 0% 己烷洗滌漶紙殘留物•乾燥到恆重，得到（S ) — N — 〔 3 - （5，7 — 二氟一 1，2，3，4 一四氫萘—2 -基 "15 4- 本紙張^度適用中國國家標準（〇奶）八4規格（210父297公釐） ----------'裝------訂------ (請先閲讀背面之注意事項再填寫本頁) 470741 經濟部中央標準局—工消費合作社印製 A7 B7五、發明説明（） )—2 —硫代一 2，3 —二氫一 1H—蹄哩一 4 —基甲基〕甲醯胺（19 · 5克，62 · 7毫莫耳），熔點245 -2 4 6 Ό ° 〔a〕p +48.9° (c = 0.613， D M S Ο ) 〇依實例2 9進行，但是用不同的起始物質取代（S) 一 5 —羥基甲基一1— (5 ，7 — 二氟一 1 ，2，3，4 —四氫萘一 2 —基）一1 ，3 —二氫咪唑一 2 —硫_或甲醯胺，製得Μ下式I ( a )化合物：用（S) — 5 —羥基甲基一1 一（6，7 —二氟一 1 ，2，3，4 —四氫萘一 2 —基）_1 ，3—二氩咪唑一 2 —硫酮取代，製得（S) — N — 〔3 — （6，7 -二氟一1 ，2，3，4-四氫萘一2 —基）一2 —硫代—2， 3 —二氫一 1H —眯唑一4 —基甲基〕甲醯胺；和用尿素取代，製得（S) _5 —胧甲基一 1 一（5, 7 -二氟 _1 ，2，3，4 一四氫萘一 2 —基）一 1 ，3 一二氫咪唑一 2 —酮，熔點258 — 260它，[α + 34.3° (c = 0.574，DMSO)。實例3 Ο (S) -N —〔3 - (5，7-二氟-1 * 2，3， 4—四氫萘_2—基）一2-硫代一2，3-二氫—11^ 一咪唑一4 一基甲基〕甲醯胺 Μ下係製備式I (a)中η為1 ，t為2 * 5 —和7 -155- 本紙張尺度適用中國國家標準（CNS ) A4規格（210 X 297公釐） (請先閱讀背面之注意事項再填寫本頁) ·— A. 470741 經濟部中央標準局員工消費合作社印製 A7 B7五、發明説明（） _位置的R1為氟，R5為甲醯胺基甲基的化合物。製備如實例18的（S) — 5 —羥基甲基一1_ (5 ，7-二氟一 1 ，2，3，4 —四氳萘-2 —基）-1 ， 3 -二氫咪唑—2 -硫酮（1 · 0克，3 * 5毫莫耳）和甲醢胺的混合物在約1 2 5 υ攪拌1小時，然後加熱混合物到約1 3 8 C，再攪拌3 5分鐘。用2 5毫升水稀釋混合物，使其冷卻到室溫。使混合物老化（aging)約1 8小時，得到結晶性物質。過漶分離該物質*用水洗滌漶紙殘留物*乾燥到恆簠，得到（S ) - N — 〔 3 — ( 5，7 —二氟一 1 ，2，3，4 —四氫萘一2_ 基）一 2 -硫2 ，3 —二氫一1H —噃唑一 4 一基甲基〕甲醯胺（0，9 2克，2. 96毫莫耳）。依實例30進行，但是用醋酸銨取代甲醯銨，（S) -N - C 3 - (5，7 -二氟-1 ，2，3，4一四氫萘一 2‘一基）—2 — 硫代一 2，3 -二氫—1H —噃唑—4 —基甲基〕乙醢胺，熔點275 — 276¾，〔α〕ρ = + 41-3° (c = l -00»DMS0)。實例3 1 (S) -5 -胺基甲基一1— (5，7—二氟一1， 2，3，4 —四氫萘—2 —基）—1 ，3_二氫眯唑—2 -硫画氫氯化物 K下係製備式I (a)中η為1 * t為2，5 —和7 -156- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） ----------裝訂 ^ (請先閱讀背面之注意事項再填寫本頁) 470741 A7 B7 經濟部中央標準局員工消費合作社印製五、發明説明 ( ) 1 i 1 — 位置的 R 1 為氟 » R 5 為胺基甲基的化合物〇 1 1 1 如實例 3 0 所製備的 ( S ) 一 Ν — C 3 一 ( 5 t 7 '— V 1 1 二氟一 1 > 2 9 3 9 4 — 四氫蔡一 2 一基 ) — 2 一硫代 — 請先閲 1 I 2 3 一二氫一 1 Η 一眯唑一 4 一基甲基 3 甲醢胺 ( 1 9 背 1 1 I • 1 克 > 5 9 • 0 毫莫耳 ) 和 2 5 毫升濃氫氯酸 ( 1 2 * 之注意 I 0 Μ 2 5 毫升 3 0 0 毫莫耳 ) 混合物在 4 0 0 毫升異事項 1 I 蒸再 1 I 丙酵中概加熱到回流 1 2 分疆 $ 攪拌 1 釔時 4 0 分鐘〇寫 1 If 餾混合物 Μ 除去 1 5 0 毫升異丙酵〇逐漸冷卻混合物到室本頁 λ 1 1 溫攬拌 3 小時 4 5 分鐘 0 過濾分離此物質用 7 5 毫升 1 1 異丙醇洗滌濾紙殘留物 0 在 1 1 0 1 2 5 並通入氮氣 1 1 的真空中乾燥製得 ( S ) _ 5 一胺基乙基一 1 ( 5 > 1 訂 7 一二氟 — 1 2 3 4 — 四氫萘一 2 — 基 ) ~ 1 f 3 1 1 — 二氫脒唑 — 2 — 硫嗣氫氛化物 ( 1 5 6 克 t 4 7 Γ 1 1 1 毫莫耳 ) 熔點 2 5 1 ♦ 9 °c C OC Η h L 0 2。 1 1 ( C = 0 5 0 0 D Μ S 0 ) 0 1 κ 依賁例 3 1 進行 9 但是用不同起始物質取代 ( S ) 一 s ) I N 一 C 3 一 ( 5 i 7 — —* 氟一 1 f 2 3 4 一四氫萘 — 1 ! 2 一基 ) 一 2 — 硫代一 2 » 3 — 二氫一 1 Η — 蹄唑一 4 — 1 1 基甲基 3 甲醢胺 1 製得以下式 I 化合物： 1 I 用 ( S ) —* N — C 3 — ( 6 ， 7 — —·. 氟一 1 » 2 9 3 1 1 I 4 一四氫 m — 2 — 基 ) 一 2 一硫酮 — 2 > 3 一二氫 — 1 1 1 Η — 咪唑 — 4 — 基甲基 ) 甲醯胺製得 ( S ) 一 5 一胺基 1 1 甲基 — 1 一 ( 6 $ 7 — 二氟 — 1 2 f 3 % 4 — 四氫蔡 — 1 I 157- 1 1 本紙張尺度適用+國國家標準（CNS ) A4規格（210 X297公釐） 470741 經濟部中央標準局員工消費合作社印製 A7 B7五、發明説明（） 2 -基）—1 ，3-二氫眯唑—2 -硫酮氫氯化物，熔點 1 9 Ο υ (分解）；用（S) - 4 - { 2 - 〔4 —甲醯基胺基甲基一3 —(5，7—二氟—1 ，2，3，4一四氫萘—2—基）一 2 —硫代一 2，3 -二氫一 1Η —咪唑—1 一基〕乙基 )苯酸，製得（S) —4—〖2— 〔4一胺基甲基一3- (5，7 — 二氟一 1 ，2，3，4 一四氫萘一 2 —基）一 2 -硫嗣—2，3 —二氫1Η —蹄唑—1 一基〕乙基}笨酸氫氯化物，熔點246 — 248 °C):和用（S) — 3 — 〔4 —甲醯基胺基甲基一 3 — (5, 7 —二氟—1. ，2，3，4 —四氫萘—2—基）—2—硫代—2，3 —二氫一 1H —咪唑-1—基〕丙酸，製得（ S ) — 3 — 〔4 —胺基甲基一3 — (5，7 —二氟一1 * 2，3，4 一四氫萘一 2 - 基）一 2 —硫酮—2，3 —二氫一 1H —咪唑—1~基〕丙酸，熔點191°C)(蒸發 )° 實例3 2 (S ) - 1 - (5，7 -二氟-1，2，3，4 —四氫萘—2 —基）一 5 -吡咯烷—1—基甲基一 1，3—二氫眯唑—2 —硫麵以下係製備式I (a)中η為1 ，t為2 · 5 —和7 一位置的R1為氟，R3和R4為氫，R5為毗咯烷一 1 -158- 本紙張尺度適用中國國家標準（CNS ) A4规格（210X297公釐) I---------裝—-----訂------線 (請先閱讀背面之注意事項再填寫本頁) 470741 A7 B7 經濟部中央標準局員工消費合作社印製五、發明説明 ( ) 1 1 | 一基甲基的化合物 0 1 1 | 如實例 1 8 所製備的 ( S ) — 1 一 ( 5 » 7 - 二氟 — 1 1 1 > 2 ，3 > 4 一四氫萘 — 2 一基 ) — 5 一羥基甲基一 1 請先 1 1 閱 | » 3 — 二氫咪唑 2 一硫酮 ( 1 4 0 毫克 t 0 .4 7 奄莫讀背 | © I 耳 ) 在 2 0 毫升四 ksst S 呋喃和 1 滴二甲基甲臞胺中所形成的之 1 I 液冷卻意 1 I 溶被到 0 和 5 t：在氮氣中滴加亞硫氯化物 ( 1 3 事項 1 1 • 7 Μ * 1 0 9 微升 f 1 4 9 奄莫耳 ) * 混合物在室溫再填 I ) % 士下搅拌 0 . 5 小時 9 然後冷卻混合物到 0 和 5 °C » 滴加吡頁 1 咯烷 ( 12 0 Μ 9 8 1 8 微升 9 * 8 奄莫耳） 0 在回 1 1 流下 m 拌混合物 1 * 5 小時蒸發除去溶劑用水稀釋殘 1 I 留物〇將醋酸乙酯加入稀釋物調整混合物 Ρ Η到 7 0 乾 I 1 訂燥醋酸乙酯層藉蒸發濃縮之〇 Μ 管柱曆析純化殘留物， 1 製得 ( S ) — 1 — ( 5 7 — 二氟 — 1 2 3， 4 一四 1 1 氫萘一 2 - 基 ) 一 5 一吡咯烧 — 1 — 基甲基一 1 · 3 — 二 1 I 氫眯唑 -2 — 硫酮 ( 1 0 0 毫克 0 2 9 毫莫耳 ) 0 1 1 h [ a ] D - -10 9 6 ° (C = : 1 L 3 D M S 0 ) k 1 用 2其耳當量的 1 Μ «<rn* SR 水氯化氫 ( 二乙醚中）處理 t 1 1 製得 ( S ) 一 1 — ( 5 7 — 二氟 — 1 f 2 Ρ 3， 4 — 四 1 I 氫蔡一 2 - 基 ) — 5 — 吡咯烷一 1 — 基甲基 - 1， 3 一二 1 I 氫眯唑 -2 一硫酮氫氯化物 ( 1 0 0 毫克 > 0 .2 6 毫奠 1 1 耳 ) 熔點 1 8 7 °C 一 1 8 9 V 〇 1 1 依實例 3 2 進行 t 但是用不同起始物質取代（ S ) 一 1 i 5 一羥基甲基 1 — ( 5 9 7 一二氟 — 1 $ 2 ，3 9 4 — i I •159- 1 1 1 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 470741 經濟部中央標準局員工消費合作社印製 A7 B7五、發明説明（）四氫萘_2-基）一 1 ，3—二氫咪唑—2 —硫酮，製得 Μ下式I化合物：用甲基胺取代，製得（S) -1 — （5，7 —二氟— 1 ，2，3 ，4一四氫萘一2 —基）一5 -(甲基胺基甲基）—1 ，3 —二氫眯唑—2 —硫酮，熔點250 — 26 0¾，和（S) - 1 - (5，7 —二氟一1 ，2*3，4 —四氫萘一2 —基）一5 —(甲基胺基甲基）一1 ，3_ 二氫咪唑—2 —硫酮氫氯化物，熔點250¾。 [a ) D 25+7.7。（c=2.4，DMS0)； )；用二甲基胺取代，製得（S) — 1— (5，7 —二氟一 1 ，2，3，4 一四氫萘一2 —基）一5 —(二甲基胺基甲基）一1 ，3 —二氫咪唑—2 —硫_和（S) —1 — (5，7 —二氟-1 ，2，3，4一四氫萘一 2 -基）— 5 -(二甲基胺基甲基）_1 ，3 —二氫咪唑_2 —硫麵氫氯化物，熔點207_208O°C ; 用吡啶取代，製得（S) — 1一（5，7 —二氟—1 ，2，3，4 —四氫萘-2 —基）一 5 —(吡啶一1一基甲基）一1 ，3 —二氫咪唑一2—硫酮和（S) -1-( 5，7 —二氟一1 , 2，3，4 —四氫萘一 2 —基）—5 —(毗啶一1—基甲基）一1 ，3 —二氫咪唑—2 —硫酮氫氯化物，熔點1691-170^5 用嗎啉取代，製得（S) _1 — （5，7 —二氟一 1 -160- 本紙張尺度適用中國國家標準（CNS ) A4規格（210 X 297公釐） (請先閱讀背面之注意事項再填寫本頁) 470741 經濟部中央標準局員工消費合作社印製 A7 B7五、發明説明（），2，3 * 4 —四氫蔡-2 —基）一 5 — （嗎啉一 4 —基甲基）一1 ，3-二氫咪唑—2-硫酮，熔點198Ρ~ 201¾，[ a ] D 25一7.56。（c=2.38， D M S Ο )，和（S) — 1- (5，7—二氟一1，2， 3，4一四氫萘—2 —基）一5 —(嗎啉一4 一基甲基） —1 ，3 —二氫眯唑—2 —硫酮氫氯化物，熔點182"Ό -1 8 4 1 0C ;和用1—甲基哌嗪取代，製得（S) — 1— (5*7- 二氟一 1 ，2，3，4 —四氫萘一2 —基）一5 — (4-甲基顿嚷一 1 —基甲基）—1 ，3 —二氫晞唑一 2 —硫_ ，和（S) — 1 — (5，7 —二氟一1 ，2，3，4 一四氫萘一2 —基）一5 — (4 —甲基一1— #嗪一 1-基甲基）一 1 ，3 —二氫眯唑一 2 —硫酮氫氯化物，熔點237¾ -245¾° 實例3 3 1— (1 ，2，3，4 —四氫萘—2 —基）一4，5 二（羥基甲基）—1 ，3 —二氫脒唑一 2 —硫酮 K下係製備式I (a)中η為1 · t為0，R3為氫，R4和R5為羥基甲基的化合物。氫化硼納（0 · 22克* 5 · 8毫莫耳）和無水氯化鈣（0 · 34克，3 . 1毫莫耳）混合物在10毫升無水四氫呋喃中於約25t：搅拌1小時，然後加入在1 0毫升 -1 6 1 - 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） (請先閱讀背面之注意事項再填寫本頁) 訂 470741 經濟部中央標準局負工消費合作社印製 A7 B7五、發明説明（）無水四氫呋喃中的製備如實例25的3— （1 ，2，3, 4 一四氫萘—2 —基）—5—乙氧基羰基一硫酮—1 ，3 —二氫—1H -咪唑一 4 一羧酸乙酯（0 . 37克， 1毫莫耳）。混合物在501¾攬拌約72小時•然後濃縮之。用20毫升10%氫氧化納和50毫升醋酸乙酯處理殘留物，過濾之，水層再度被醋酸乙酯萃取（3x50毫升）。混合的萃取物被硫酸鎂乾燥，濃縮。殘留物與甲撐氯化物/甲醇（93 : 7)攪拌，過漶混合物。蒸乾K上水相，殘留物與甲醇一起攬拌。過濾甲醇混合物*然後與甲撐氯化物/甲醇滹液混合，混合的混合物濃縮，殘留物在矽膠上（沖提液為9 3 : 7的甲撐氯化物/甲醇）進行急驟層析Μ純化殘留物，製得1— (1 ，2，3，4 一四氫萘一2 —基）一 4，5二（羥基甲基）一 1 ，3 —二氫咪唑—2 —硫酮（35毫克，0 ♦ 12毫奠耳），熔點 1 99°C-2001C° 實例3 4 3 — 〔3 — （1 *2，3，4-四氫萘-2 —基）-2_硫代一 2，3 —二氫—1Η —眯唑—1—基〕丙酸乙酯 Μ下係製備式I (a)中η為1 * t為0，R3為2 —乙氧基羰基乙基，R4和R5為氫的化合物。如實例9所製備的1一（1 ，2，3，4 一四氫萘一 -162- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） (請先閲讀背面之注意事項再填寫本頁) 470741 A7 B7 經濟部中央標準局員工消費合作社印製五、發明説明 ( ) 2 — 基 ) 一 1 3 一二氫一咪唑一 2 一硫酮 ( 1 3 克 » 5 6 毫其耳 ) 在 1 4 毫升乙醇中的丙烯酸乙酯 ( 3 * 1 毫升 2 8 2 毫莫耳 ) 和在甲酵中的 1 2 8 毫升 Ν 一苄基三甲基氫氧化銨 ( 2 • 8 毫莫耳 ) 的混合物在 8 0 t：及氮氣中加熱 2 小時 0 混合物冷卻 Μ 旋轉蒸發器濃縮之〇殘留物在矽膠上 (沖提液為 3 ： 1 的己焼 / 醋酸乙醮 ) 進行層析純化製得 3 一 C 3 — ( 1 2 3 4 一四氫 m 一 2 — 基 ) 一 2 一硫代 — 2 3 — 二氫一 1 Η — 眯唑一 1 一基丙酸乙酯 ( 1 2 克 3 7 毫莫耳 ) 熔點 7 1 一 7 3 v 〇依實例 3 4 進行但是用不同起始物質取代 1 一 ( 1 9 2' 3 4 — 四氫萘 2 — 基 ) 一 1 3 — 二氫一眯唑一 2 — 硫酮製得下式 I 化合物用 4 — ( 1 2 3 4 一四氫萘 — 2 一基 ) 一 5 — 硫嗣一 1 5 一二氫 C 1 2 4 三唑 — 3 一基甲基胺基甲酸三级丁酯製得 3 — C 4 一 ( 1 2 3 4 一四氫萘 — 2 一基 ) 一 3 一 ( = 級丁氧基羰基胺基甲基 ) — 5 — 硫醒 — 1 5 — 二氫 C 1 2 4 3 三唑 — 1 一基 ] 丙酸乙醋和用 ( S ) — ( 1 一 ( 5 7 — 二 Jksf 親 — 1 2 3 4 — 四氫萘 — 2 — 基 ) — 1 3 — 二氫咪唑 — 2 — 硫酮取代 9 製得 ( S ) — 3 — C 3 一 ( 5 7 — 二氟 — 1 2 3 ί 4 一四氫 m — 2 — 基 ) — 2 — 硫銅一 2 » 一二氫一 1 - 163- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 470741 經濟部中央標準局員工消費合作社印t. A7 B7五、發明説明（） H —眯唑—1—基〕丙酸乙海，熔點1〇5弋—107¾ 0 實例3 5 3 - 〔3~ (1·，2，3，4 —四氫蔡一 2 -基）-4 —二甲碁胺基甲基一2—硫代一2 ，3 —二氳一1Η-咪唑一1 一基〕丙酸乙酯 Μ下係製備式I (a)中η為1 * t為0，R3為2 —(乙氧基羰基）乙基，R4為氫，R5為二甲基胺基甲基的化合物。如實例34所製備的3 — 〔3 — （1 ，2，3，4 一四氫蔡——基）一 2 —硫代一2，3 —二氫—1 Η —蹄唑—1 一基〕丙酸乙酯（0 . 5克，1 . 5毫奠耳）和Ν ，Ν—二甲基甲撐氯化銨（0.17克，1.8毫萁耳）混合物在7毫升二甲基甲醯中於8 0 °C及氮氣中加熱1 6 小時。混合物在飽和碳酸氫鈉溶液和醋酸乙酯之間分層。分離有機層，用鹽水洗滌，Μ硫酸納乾燥，過濾，濃縮。殘留物在矽膠上（沖提液為醋酸乙酯/己烷）管柱層析純化，製得3 — 〔3 — (1，2，3，4 —四氫萘一 2 —基 )一 4 一二甲基胺基甲基一 2 —硫代一2 ，3—二氫一1 Η —咪唑一1 一基〕丙酸乙酯（277毫克，0 . 7毫莫耳），熔點 128t：~130t：。依實例35進行，但是用4— 〔3— （1 ，2，3, -164- 本紙張尺度適用中國國家標準（CNS ) A4規格（210x297公釐） (請先閱讀背面之注意事項再填寫本頁) ..V- 訂 470741 經濟部中央標準局員工消費合作社印製 A7 B7五、發明説明（） 4-四氫萘一 2-基）一 5-甲基—2-硫代一 2，3-二氫—1 H —眯唑—1 —基〕苯酸甲酯取代，製得泡沫體的 3 — 〔3 — （1 ，2，3，4 -四氫萘 _2- 基）一2 ―硫嗣一2，3 -二M_1H—蹄哇—1—基〕丙酸乙醋 Ο 實例3 6 1一（1 ，2，3，4一四氫萘一 2 —基）一4，5 —二（二甲基胺基）一1 ，3_二氫咪唑一 2 —硫酮 Μ下係製備式I (a)中η為1 ，t為0，R3為氫，R4和R5為二甲基胺基甲基的化合物。如實例9所製備的1 一（1 ，2，3，4 一四氫萘— 2 —基）一 1 ，3 —二氫眯唑一2 —硫酮（1克，4 * 3 毫莫耳），丙烯酸乙酯（4 · 7毫升，4 ♦ 3毫莫耳）和氫氯酸（在醚中為1N，8 · 7毫升，8 · 7毫莫耳）混合物於2 0毫升乙醇中，在8 0 °C及氮氣中約加熱5小時。使混合物冷卻，濃縮並於飽和碳酸氫鈉溶液和甲撐氯化物之間分層。分離有機層，用碳酸鉀乾燥之，過濾，濃縮之。殘留物在矽膠上（沖提液為99 : 1的甲撐氯化物/ 甲醇）進行管柱層析純化，製得3— 〔1— (1 ，2，3 ，4 一四氫萘一2 —基）咪唑—2 —基一硫基〕丙酸乙酯 (1·36克，4·1毫莫耳）。 3_ 〔1 一（1 ，2，3，4-四氫萘一 2 —基）眯 -165- (請先閲讀背面之注意事項再填寫本頁) 本纸張尺度適用中國國家標準（CNS ) Α4規格（210X297公釐） 470741 Α7 Β7 經濟部中央標準局員工消費合作社印製五、發明説明（）唑—2_基—硫基〕两酸乙酯（1 ‘ 36克，4 . 1毫莫耳）和N，N —二甲基甲撐氯化銨（1 · 66克，17 . 毫莫耳）混合物於25毫升二甲基甲醯胺中，在1〇〇。〇及氮氣中約加熱2 2小時。反應混合物冷卻到約9 〇 p , 然後加入額外的N，N -二甲基甲撐氯化銨（0 . 83克，8 · 8毫莫耳）。加熱混合物31 . 5小時，然後於碳酸氫納和醋酸乙酯之間分層。分離有機層，用豳水洗猫，用碳酸鉀乾燥，過濾，濃縮之。殘留物在矽膠上（沖提液為_5—10%甲酵（甲撐氯化物中）.）進行管柱層析純化，製得 3 — 〔1— (1 ，2，3，4一四氫萘—2 —基） —4，5 —二（二甲基胺基甲基）咪唑一2~基一硫基〕丙酸乙酿（0.55克，1.2毫莫耳）。 3 - 〔1-_(1 ，2，3，4 -四氫蔡-2 基）—4 ' 5 —* ( —*甲基胺基甲基）畔睡一 2 一基一硫基〕丙酸乙酯（0 . 55克，1 . 2毫其耳）和乙氧化納（3 . 5 毫升的溶液，係製備於4 5 0毫克納和4 5毫升乙醇， 1 · 4毫莫耳）混合物在5毫升乙醇中，在約25Ό攒拌 1 . 7 5小時。濃縮混合物，於水和醋酸乙酯之間分層。分離有機層，用鹽水洗滌，Μ碳酸砰乾燥，過滤，濃縮之。殘留物在矽膠上（沖提液為9 7 : 3的甲撐氯化物/甲醇）進行管柱層析純化，製得1— (1 , 2，3，4 一四氫萘一 2-基）一4，5-二（二甲基胺基）一1 ，3 — 二氫咪唑—2-硫酮（〇 . 24克，〇 . 7毫莫耳），熔 -16 6" 本紙張尺度適用中國國家標準（CNS ) Α4規格（210X297公釐） -----II II I I I ^ I ~ (請先閲讀背面之注意事項再填寫本頁) 470741 經濟部中夬檩準局員工消費合作社印製 A7 B7 i、發明説明（) 點 182-184¾° 實例3 7 3 - (5，7_ 二氟一1 ，2，3，4-四氫萘一 2 -基）一2 —硫代一2，3 —二氫一 1H —眯唑一 4 一羧酸 Μ下係製備式I (a)中η為1 ，t為2，5 —和7 —位置的R1為氟，R3和R4為氫，Rs為羧基的化合物。如實例24所製備的3 — （5，7 —二氟一 1 ，2， 3，4 —四氣莱一2 —基）一2 —硫代一2，3 — 一 Μ ~ 1Η —眯唑一 4 一羧酸乙酯（4 ♦ 6克，1 3 . 6毫莫耳 )和氫氧化鉀（3 . 14克，47 . 6毫莫耳）混合物在 130毫升乙醇/水（10: 3)中，於85 — 90¾攪拌5小時。蒸發除去溶劑，殘留物溶於水沖。用1 N氫氯酸酸化溶液到P Η為1 ，製得结晶性物質。過滹分離該物質，製得3 — （5，7 —二氟一1 ，2，3，4 —四氫萘一 2 —基）一2_硫代一2，3-二氫—111一眯哩一4 —羧酸（3 . 86克，12 . 5毫萁耳），熔點250 — 2 5 2 ¾° 依實例3 7進行，但是用不同起始物質取代3 — ( 5 ,7-二氟一 1 ，2 , 3，4 一四氫萘一 2 -基）一 2 — 硫代一 2，3 —二氫一 1 H_咪唑一 4 —羧酸乙酯’製得 -167- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） I 裝訂線 (請先閱讀背面之注意事項再填寫本頁) 470741 A7 B7 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填寫本頁) 五、發明説明（) K下式I ( a ) 用 3 — (1 硫代一2，3 — 製得3 — (1 ，代 _ 2，3 —二 2 3 1 - 2 3 2 用 3 - ( 7 )—2 —硫代— 酯取代，製得3 2 -基）-2 -羧酸，熔點2 0 用 3 - ( 6 2 -基）-2 -羧酸乙酯取代， 4 —四氫萘一2 一眯唑一 4 _羧 (甲醇中）處理 3 — ( 6，8 — )一 2 —硫代— ，熔點1 6 0 — 用 3 - ( 4 2，3 —二氣— 一（<4 , 6 —二化合物： 9 2 » 3 f 4 — 四氫二氫一 1 Η — 眯哩 — 2 3 > 4 — 四氫萘氫 1 Η — 眯唑 — 4 °c ( 分解 ) — 氟 — 1 $ 2 3 > 2 9 3 — 二氫一 1 Η — ( 7 — 氟 — 1 2 硫代 — 2 9 3 — 二氫 7 — 2 0 9 » 8 — 二氟 — 1 t 2 硫代 — 2 » 3 — 二氫製得 3 — ( 6 8 — — 基 ) — 2 — 硫代 — 酸 » 熔點 2 0 7 — 2 蒸乾 $ 於甲醇 / 異二 m. — 1 » 2 9 3 > 2 > 3 — 二氫一 1 Η 1 6 3 f 6 — 二氟 η 滿 — 1 1 Η — 咪唑 — 4 — 狻氟 m 滿 — 2 — 基 ) 一 -168- 萘一2 — 基）—2 — 4 —羧酸乙酯取代， —2 — 基）一 2 —硫 -羧酸乙酯，熔點 4—四氳萘—2—基 -咪唑一4一羧酸乙，3，4 —四氫萘一 —1 H —咪唑一 4 — ，3，4 _四氫蔡_ _1H—咪唑一4一二氟-1，2，3， 2，3 -二氫-1 Η 08C，用氫氧化鉀丙醇中再結晶，得到 4 —四氫萘一 2 —基 —咪唑一 4 一羧酸鉀 —基）一 2 _硫代一酸乙酯取代，製得3 2 —硫代—2，3 本紙張尺度適用中國國家標準（CNS ) Α4規格（210X297公釐） 470741 A7 B7 經濟部中央標準局>貝工消費合作社印製五、發明説明（ ) 1 1 I 一二氫一 1 Η — 眯唑 — 4 一羧酸用氫氧化鉀 ( 甲醇中 ) 1 1 1 處理蒸乾於甲醇/異丙醇中再结晶，得到 3 一 ( 4 9 /«—V I I 請 1 6 一二氟茚滿一 2 一基 ) 一 2 — 硫代 — 2，3 — 二氫一 1 先閱 I I Η 一畔唑 _ 4 一羧酸鉀熔點 1 6 3 0 -1 7 3 9 讀背 1 1 面 1 用 3 — ( 5 7 — 二氟茚滿 — 1 一基）一 2 一硫代 — 冬 1 I 2 3 一二氫一 1 Η — 眯唑一 4 — 羧酸乙酯取代 9 製得 3 事項 1 I 再 1 1 —· ( 5 7 一二氟茚滿 — 2 - 基 ) — 2 -硫代一 2 3 — 1 馬本二氫一 1 Η 一眯唑 — 4 一羧酸熔點 2 3 0- 2 3 2 9 頁 Sw*· 1 I 用氫氧化鉀 ( 甲醇中 ) 處理，蒸乾於甲醇/異丙醇中再 1 1 结晶得到 3 — ( 5 7 一二飛茚滿 — 2 —基 ) — 2 一硫 1 1 代一 2 3 — 二氫 — 1 Η 一咪唑一 4 — 羧酸鉀熔點 1 訂 1 I 1 7 0 — 1 7 4 用 3 ( 5 6 — 二氟茚滿一 1 一基）— 2 一硫代 — 1 1 I 2 3 — 二氫一 1 Η — 咪哩一 4 — 羧酸乙酯取代製得 3 1 1 — ( 5 6 — 二氟茚滿一 2 - 基 ) — 2 —硫代一 2 3 — 1 綠二镜 — 1 Η 一眯唑 — 4 — 羧酸熔點 2 3 3 - 2 3 4 1 I 用 3 — [ 3 — ( 1 2 * 3 4 一四氫萘 — 2 — 基 ) 1 1 — 2 — 硫代一 2 3 一二氫一 1 Η — 眯唑一1 — 基甲基 1 1 苯酸甲酯和氫氧化納取代，製得3 — C 3 -( 1 2 J 3 1 1 9 4 一四氯邊 — 2 — 基 ) -2 — 硫代 — 2，3 一二氫 — 1 1 I Η — 眯唑一 1 — 基甲基〕笨酸 * 熔點2 5 2 - 2 5 4 V 1 1 | 用 4 — C 3 — ( 1 2， 3 4 — 四氫萘 — 2 — 基 ) 1 1 一 2 一硫代 — 2 9 3 — 二氫- 1 Η 一眯唑一 1 — 基甲基 ] 1 1 -169- 1 1 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 470741 A7 B7 經濟部中央標準局貞工消費合作社印製五、發明説明（）苯酸甲酯和氫氧，4 一四氫萘一 H ~·畔哇一 1 — 用 4 —〔 3 —2 -硫代—2 丁酸甲酯取代，萘_ 2 -基）— 1 一基甲基〕丁用 5 -〔 3 —2 —硫代一 2 皮考林酸酯取代得 5 —〔 3 —( 一硫代~ 2，3 林酸氫氯化物，用 3 -〔3 —2 —硫代—2 甲酯取代，製得 2 -基）-2 -基]丙酸，熔點用 4 - 〔 3 —5 _甲基一2 一基甲基〕笨酸，4 —四氫萘一化納取代 f 製得 4 一 2 一基 ) 一 2 — 硫代基甲基 ) 苯酸 > 熔點 — ( 1 » 2 > 3 * 4 » 3 — 二氫一 1 Η — 製得 4 C 3 — ( 1 2 一硫代 — 2 • 3 一酸 » 熔點 1 5 6 — 1 — ( 1 » 2 9 3 > 4 » 3 — 二氫一 1 Η — » 於氫氯酸在乙酵中 1 # Σ i 3 * 4 — 四 — 二氫一 1 Η — 脒唑熔點 2 0 4 一 2 0 5 一 ( 1 > 2 > 3 * 4 » 3 — 二氫 — 1 Η — 3 — ( 3 — ( 1 » 2 硫代 — 2 9 3 — 二氫 1 6 7 — 1 6 8 9 — ( 1 i 2 9 3 i 4 — 硫代 — 2 » 3 — 二甲 m 取代 t 製得 4 — 2 一基 ) 一 5 一甲基 -170- 〔3 - (1，2，3 —2，3 —二氫—1 211-212V；一四氫萘一 2 -基）咪唑一1 —基甲基〕，2，3，4 一四氫二氫一 1 Η —咪唑一 5 8 ^ ； -四氫萘一2_基）咪唑一 1 一基甲基〕的溶液中再結晶，製氫萘一2 —基）—2 —1 —基甲基〕皮考 °C ； —四氫萘-2 —基）眯唑一1 一基〕丙酸，3，4 —四氫萘— -1 Η —眯唑—1 一 —四氫萘—2 —基）氫-1Η —咪唑-1 〔3 - ( 1，2，3 —2—硫代—2，3 (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) Α4規格（210X297公釐）經濟部中央標準局員工消費合作社印製 470741 A7 B7五、發明説明（） —二氫—1 Η —脒唑-1 _基甲基〕笨酸，熔點18 1-1 8 2 V I 用 3_ 〔4 — (1 ，2，3，4 一四氫萘—2-基） —3 —(三级丁氧基羰基胺基甲基）-5-硫代-1 ，5 一二氫〔1 ，2，4〕***一1 一基〕丙酸乙酯取代，製得 3 — 〔4 - (1 ，2，3，4一四氫萘-2—基）一 3 _(三級丁氧基羰基胺基甲基）—5 -硫代一1 ，5 —二氫〔1 ，2，4〕***-1 一基〕丙酸，熔點76-78Ό 用（S) — 3 — 〔5，7_ 二氣一 1 ，2，3，4 — 四氫萘—2 —基）-2—硫代一2，3 -二氫一1Η —眯唑—1 一基〕丙酸乙酯取代，製得（S) - 3 - C 3 -( 5，7 —二氟一1 ，2，3，4一四氫萘 _2 — 基）一2 -硫代-2，3 -二氫-1Η -眯唑-1-基〕丙酸，熔點 182-184t：; 用 3 — 〔3 — (1 ，2，3，4~ 四氫萘—2 - 基）一 4 -二甲基胺基一甲基一2_硫代一 2，3 —二氫一 1 Η_眯唑一 1—基〕丙酸乙酯取代，製得3 — 〔3 — (1 ，2，3，4 一四氫萘一2 —基）一4 一二甲基胺基甲基 —2—硫代—2，3 —二氫一 1Η —蹄唑一1—基〕丙酸，熔點 171 — 1741; 用（S) - 4 - { 2 - 〔3 — (1 *2，3，4 —四氨蔡一 2—基）—2 —硫代一 2，3_二氫一 1Η —蹄唾 -171- (請先閱讀背面之注意事項再填寫本頁) 本纸張尺度適用中國國家標率（CNS ) Α4規格（210Χ297公釐） 470741 經濟、部中央襟準局員工消費合作社中製 A7 B7五、發明説明（） —4 —基甲基胺基〕乙基}苯酸甲酯取代，製得（S)— 4 — {2_ 〔3 - (1 ，2，3，4一四氫萘一2 —基） —2 —硫代一2，3 —二Μ — 1 H —蹄哩一4 一基甲基胺基〕乙基）苯酸氫氯化物，熔點240 - 241Ό; 用（S) - 3 - 〔4 一甲醯基胺基甲基一3 — （5, 7 -二氟—1 ，2，3，4 一四氫萘一 2 —基）一2 -硫代—2，3 -二氫_1H —畔唑一1 一基〕丙酸乙酯取代，製得（S) — 3_ 〔4 一甲醯胺胺基甲基一 3 — （5, 7 —二氟一 1 ，2，3，4 -四氫萘一2 -基）一2 —硫代一 2，3—二Μ — 1H —蹄哩_1_基〕丙酸。依實例37進行，但是用不同起始物質取代3— （5 ，7-二氟一 1 ，2，3，4 一四氫萘一2 —基）一2 — 硫代一2，3 —二氫_1H_咪唑一4 一羧酸乙酯，並進行酸觸媒水解，製得以下式I (a)化合物：用 3_ (1 ，2，3，4 —四氫萘一 2 —基）一 2 — 硫代—2，3-二氫一 1H—咪唑—1—基醋酸三级丁酯和三氟醋酸取代，製得3 - （1 ，2，3，4 一四氫萘— 2 —基）—2—硫代 _2，3_ 二氨—1H -蹄哦一1 — 基〕醋酸，熔點228 — 230 °C; 用 1- (5，7-二氟一 1 * 2，3，4 —四氫萘— 2—基）—2—硫代—2，3-二氫_11^—味唑一4一基甲基胺基醋酸三级丁酯和氬氯酸取代，製得1 一（5, 7-二氟-1 ，2，3，4 —四氫萘-2 —基）一2 —硫 -172- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） (請先閲讀背面之注意事項再填寫本頁) 470741 經濟部中央標準局員工消費合作社印製 A7 B7五、發明説明（）代—2，3 —二氫一 1 H —咪唑一 4 一基甲基肢基醋酸，熔點 214-216υ; 用（S) —1— (5*7 -二氟一1 ，2，3，4- 四氫萘—2 —基）一2 —硫代一 2，3 —二氫一1 Η —晞唑- 4 一基甲基胺基醋酸三级丁酯和氫氯酸取代，製得（ S ) - 1 - (5，7_ 二氟一 1 ，2，3，4 -四氫萘一 2 - 基）—2—硫代—2，3 —二氮—1 Η -蹄哩— 4 — 基甲基胺基醋酸氫氯化物，熔點214 (蒸發）；和用 1_ (1 ，2，3，4 一四氫萘—2 — 基）—2 — 硫代—2，3 —二氫一1 Η -眯唑—4 一基甲基胺基醋酸三級丁酯和氫氯酸取代，製得1— (1 ，2，3，4 —四氫萘—2_基）一2 —硫代一2，3-二氫一111一眯唑 —4 -基甲基胺基醋酸氫氯化物，熔點20 8 — 2 1 1 υ 〇實例3 8 4 - 〔 3 - (1 ，2，3，4 一四氫萘一 2 —基）— 2 —硫代一 2，3 —二氫—1Η —蹄唑_1一基）丁醯胺 Κ下係製備式I (a)中η為1 ，t為0，R3為4 一（氨基甲藤）丙基，R4和R5為氫的化合物。製備如實例37的4— 〔3— （1， 2，3，4 —四氫萘一2 —基）一 2 —硫嗣—2，3 —二氫-1H -咪唑—1—基〕丁酸（100毫克，0 · 32 -173- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） (請先閲讀背面之注意事項再填寫本頁) 470741 經濟部中央標準局員工消費合作社印製 A7 — B7五、發明説明（）其耳）和箄醢氯化物（2M，〇 . 32毫升，0 . 64莫耳）和5滴二甲基甲醯胺的混合物於1〇毫升甲撐氯化物中搜拌2小時。蒸發除去過量的草醯氯化物和溶劑’用5 毫升3 0%氫氧化銨水溶液處理殘留物，並攪拌1 S小時。將混合物倒入碳酸氫鈉水溶液’用甲撐氯化物萃取之。萃取物被硫酸納乾燥，並濃縮之。殘留物在矽膠上（沖提液為99:1到96:4的甲撐氯化物/甲醇）進行急驟層析鈍化，製得泡沫體的4 一〔3 — (1，2，3，4一四氫萘一 2 —基）一2 —硫代_2，3 —二氫_1H —咪唑一 1 一基）丁醯胺（70毫克，〇 . 22毫蓂耳）。依實例3 8進行，但是用不同起始物質取代4_ 〔3 一（1 ，2，3 , 4 - 四氫萘 —基）一 2 —硫代一2 ，3 -二氫—1 Η -眯唑一 1 _基）丁酸，製得以下式I 化合物：用 4 一〔3 - （1，2，3，4 —四氫萘一 2 — 基）一 2 —硫代一2，3 —二氯一1. Η -蹄啤一 1 基乙基] 苯酸取代，製得4一〔3- （1，2，3，4一四氫萘— 2 —基）一 2 —硫代一 2，3_ 二氫一 1Η - 眯唑一 1 一基乙基）苄基醸胺，熔點158 — 16〇υ;和用 3 - 〔3 — (1 ，2，3，4 一四氫萘一 2~'基） —2 —硫代一2，3 —二氫一1Η_眯唑一基〕丙酸取代，製得3— 〔3— (1，2，3，4_四氫萘一2- 基）一2 -硫代一2，3 —二氫—1Η —咪唑一 1—基乙 -1 74-本纸張Α度適用中國國家標準（CNS ) Α4規格（210Χ297公釐） (請先閲讀背面之注意事項再填寫本頁) 470741 經濟部中央標準局員工消費合作社印製 A7 B7五、發明説明（）基）丙醯胺，熔點180 - 181 °C。實例3 9 3 — 〔2- (4 (1H) —四唑一5 —基苯基）乙基〕一（1 ，2，3，4 —四氫萘-2-基）一1 ，3 —二氫眯唑—2 —硫酮 Μ下係製備式I (a)中η為1 ，t為Ο，R3為2 —(4 (1H)—四唑—5 -基苯基）乙基，R4和R5 為氫的化合物。如實例15製備的3- 〔2— （4一氰基苯基）乙基〕-1- (1 ，2，3，4 —四氫萘—2—基）一 1 ，3 -二氫脒唑—2 —硫酮（0 . 5克，1 · 4毫莫耳）和三丁基錫蠱氮（1 · 39克，4 · 2毫奠耳）混合物在3毫升二甲苯中，於1 20¾及氮氣中加熱約1 6小時。混合物在矽膠上（沖提液為甲撐氯化物/甲醇）進行層析純化，製得3 — 〔2 - （4 (1Η) —四唑一 5 —基苯基）乙基〕-(1 ，2，3，4 一四氫萘—2-基）一1 ，3 — 二氫眯唑_2—硫_ (0 · 5克，1 ·4毫莫耳），熔點 218-220^° 實例4 0 (S ) 一 4 — (1—羥基）乙基一1- (5，7 —二氟一1 ，2，3，4 —四氫萘—2 -基）一1 ，3 —二氫 -175- 本纸張尺度適用中國國家標準（CNS ) Α4規格（2丨0X297公釐） (請先閱讀背面之注意事項再填寫本頁) 470741 經濟部中央標準局員工消費合作社印製 A 7 B7五、發明説明（）咪唑一 2 _硫酮以下係製備式I (a)中η為1 ，t為0，R3和 R5為氫，R4為1—羥基乙基的化合物。如實例22所製備的（S) -3 — （5，7 —二氟一 1 ，2，3，4 —四氫萘一 2 —基）_2 — 硫代一 2，3 一二氫—1H-咪唑—5 —卡巴醛（178毫克，0 . 6 毫莫耳）和甲基氯化鎂（3M，0 · 4毫升，1 · 2毫莫耳）潖合物在約Ο亡攪拌1小時，另外在約2 5 C攪拌1 小時。用5毫升稀硫酸處理混合物，Κ醋酸乙酯萃取（2 次）。用硫酸鎂乾燥混合的萃取物，濃縮之，殘留物在砂膠上（沖提液為9 8 : 2的甲撐氯化物/甲醇）進行急驟層析純化，製得（S) - 4 — (1—羥基）乙基一1 一（ 5，7 —二氣—1 ，2，3，4 —四 S 蔡一2 —基）一1 ，3 —二氫咪唑_2 —硫_ (22毫克，Ο · 1毫莫耳） * 熔點 210-21 It：。依實例4 0進行，但是用正丙基氯化鎂取代甲基氯化鎂，製得（S) - 4 - (1 一羥基）丁一 1—基 _ (5, 7 —二氟 _1 ，2，3，4一四氫萘-2 —基）_1 ，3 —二氫蹄唑一 2 —硫酮，熔點1 54 — 1 56Ό。實例4 1 Ν-1Η-四唑一5-基一3 - (5，7 —二氟一 1 ，2，3，4一四氫萘一2_ 基）—2 - 硫代-2，3- -176- 本紙張尺度適用中國國家標準（CNS ) ( 210X297公釐） (請先閲讀背面之注意事項再填寫本頁) 470741 A7 --- -B7 _ 五、發明説明（）二氫咪唑一4一羧醯胺 K下係製備式I (a)中η為1 ，t為2，5 —和7 ~位置的R1為氟，Rs為111-·四哩一 5 —基一氨基甲驢的化合物。如實例37所製備的3 - （5，7 -二氟一 1 , 2，經濟部中央標準局員工消費合作社印製 (請先闖讀背面之注意事項再填寫本頁) 3，4 一四氫萘一 2 —基）一2 -硫代—2，3 —二氫-1H —蹄唑—4 —接酸（1克，3 . 33毫莫耳）溶於1 5毫升草藤氯化物和1滴二甲基甲醯胺中，該溶液在氮氣中攪拌3小時。在旋轉蒸發器中除去過量的草醯氯化物，殘留物與四氯化碳（2x25毫升）進行共蒸發。殘留物冷卻到0¾，加入乾燥的5-胺基一 1H —四哩（〇 . 8 5克，10毫莫耳）和2 5毫升吡啶。混合物回溫到室溫，然後攪拌1 6小時。蒸發除去溶劑，殘留物與甲笨進行共蒸發。殘留物在矽膠（裝有含1 %醋酸的5%甲醇/甲撐氯化物）進行管柱層析纯化，製得〇 . 9克的不純產物。將不純產物溶於碳酸鉀水溶液中，K醋酸乙酯萃取該溶劑。酸化水層得到一固體物質。過濾分離該物質，得到淺橙色固體的N-1H —四嗖一 5 —基一3— （5，7 —二氟一1，2 ’ 3 ’ 4 —四氫蔡一2 —基）一2_硫代—2 ，3 -二氣畔哩—4—接醯胺（〇 . 54克，1 . 56毫莫耳），熔點228-230¾。實例4 2 -1 77- 本紙張又度適用中國國家標準（CNS ) A4規格（210X297公釐） 470741 A7 ____B7_ 五、發明説明（） (4_甲基呢嗪一1一基）〔3— （5，7—二氟一 1，2，3，4 一四氫蔡一 2 —基）一2 - 硫代一 2，3 一二氫咪唑一1 Η —眯唑一 4 一基〕甲萌 Μ下係製備式1(a)中η為1 ，t為2，5 —和7 —位置的R1為氟* R5為4-甲基一哌嗪一 1 -基羰基的化合物。如實例37所製備的3 - （5，7 -二氟一1 ，2， 3，4 一四氫萘一 2 —基）一2_硫_— 2 * 3 —二氫一 1H -咪唑一4 一羧酸（0 . 75克，2 . 42毫莫耳）和1，1'—羰基二眯唑（0 .43克，2 . 65毫奠耳 )混合物於6毫升四氫肤喃中，在氬氣及室溫下攪拌約 18小時。加入N —甲基呢嗪（0 · 29克，2 . 65毫莫耳），混合物在氩氣中及室溫下攪拌約18小時。混合物於甲撐氯化物和水之間分層，用水洗滌甲撐氯化物層4 次，Μ硫酸鎂乾燥，蒸發濃縮之。殘留物於醋酸乙酯/甲醇中再结晶，製得（4一甲基哌嗪一1_基）〔3— （5 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填寫本頁) ，7— 二氟一 1 ，2，3，4 一四氫萘一2 —基）一2 — 硫代一 2，3_二氫眯唑一 1Η_咪唑一 4 —基]甲_ ( 0 . 69 克，1 . 76 毫莫耳），熔點 248 — 25〇υ 〇依實例42進行，但是用不同起始物質取代3- (5 ，7-二氟一 1 ，2，3，4 一四氫萘一2-基）一2-硫代_2，3—二氫一 1Η —眯唑一 4 —羧酸和/或Ν_ -17 8" 本紙張尺!度適用中國國家標準（CNS ) Α4規格（210x297公釐） 470741 經濟部中央標準局員工消費合作社印製 A7 B7五、發明説明（）甲基哌嗪，製得以下式I化合物：用 3 — （6，8 —二氟一 1 ，2，3，4一四氫萘一 2 —基）一 2 -硫代—1 ，3 -二氫—1H —咪唑一 4_ 羧酸取代，製得（4 —甲基呢嗪—1—基）〔3 — （6, 8 -二氟一1 ，2，3，4 -四氫萘—2 -基）一2 —硫代一 2，3—二氫咪唑—1H —晞唑-4 —基〕甲酮（油 )；用 3 - （5，7 —二氣一1 ，2，3，4 —四氯蔡— 2_ 基）一 2_ 硫代-2，3 —二氫一1H —眯唑—4 — 羧酸和N，N —二甲基乙烯二胺取代，製得N —(二甲基胺基乙基）一3 - (5，7 -二氟一1 ，2，3，4 -四 Μ萘—2 —基）一2 —硫代一2，3 —二氫蹄哩一 1H — 咪唑_4一羧釀胺，熔點125Ό; 用 3 — （5，7 —二氟 _1 ，2，3，4 一四氫萘一 2_ 基）一 2_ 硫代—1 ，3 —二氨—1Η —畔哩 _4_ 羧酸和對一甲基磺醯胺基苯胺取代，製得Ν_ [ 4 -(甲基磺醯胺基）笨基〕一 3 - （5，7—二氟一 1 ，2，3 ，4 —四氫萘—2 —基）—2 —硫代—2，3 —二氫眯唑 -1 Η—眯唑一 4 一羧醯胺，熔點225 — 2301 ; 用 3_ (5，7 —二氟一1 ，2，3 *4 —四氫萘一 2 —基）一 2 —硫代—1 ，3- 二Μ—1Η—蹄哩 ~4一羧酸和二甲基胺基乙烷硫赶氫氯化物及二氯己基羧醯亞胺取代，製得3 — (5，7 —二氟一 1 ，2，3，4 —四氫 -1 7 9 - 本紙張尺度適用中國國家標準（CNS ) Α4規格（210Χ297公釐） (請先閱讀背面之注意事項再填寫本頁) 470741 A7 B7 經濟部中央標準局員工消費合作社印製五、發明説明（）萘—2 -基）—2 —硫代一 2，3 -二氫—1H —眯唑一羧硫代酸和S — (2 —二甲胺基乙基）酷，熔點204 -2 0 6 Ό ;和用 3_ (6，8 —二氟 _1 ，2，3，4 一四氫萘一 2 —基）—硫代 ~*1 ，3 —二氫—1H —味唑一4 一羧酸和二甲基胺基乙烷硫赶氫氯化物及二氯己基羧醢亞胺取代，製得3 — (6，8—二氟一 1 ，2，3，4 一四氫萘—2 —基）—2 +硫代一 2，3—二氫眯哩一 4 一接硫代酸和S— （2—二甲胺基乙基）酯，熔點275— 2 7 7 V ° 實例4 3 3 - (3，4 一二羥基苄基）一(1 ，2，3，4一四氫禁一2—基）一1，3—二氫眯唾一2—硫嗣 Μ下係製備式I (a)中η為1 * t為〇 , R3為3 ，4 —二羥基苄基，R4和Rs為氫的化合物。如實例1 5所製備的3 - （3，4一二甲氧基苄基）一 1_ (1 ，2，3，4一四氫萘一2 —基）一1 ，3 — 二氫眯哇_2 -硫酮（900毫克* 2 . 37毫莫耳）在甲撐氯化物中所形成的溶液在氮氣中冷卻到0¾，然後滴加三溴化硼（1M* 7.1毫升，7.1毫莫耳）（在另外10毫升甲撐氯化物中）。混合物冷卻到室溫，攪拌 1 6小時，然後慢慢加入水中。分離有機層，用鹽水洗滌 -1 8 0 - (請先聞讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 470741 Α7 Β7 五、發明説明（) ’ Μ硫酸納乾燥，濃縮之。殘留物在矽膠（沖提液為9 6 :4的甲撐氯化物/甲醇）進行急驟析層鈍化，然後在甲酵/乙醇/己烷中再结晶，製得3 — (3，4 —二羥基苄基）一(1 ，2，3，4 一四氫萘一2 —基）一 1 ，3 -二氫咪唑一 2 —硫酮（520毫克），熔點173— 174Ό Ο 依實例43進行，但是用不同起始物質取代3— (3 ，4一二甲氧基苄基）-1 一（1 ，2，3，4 一四氫萘 —2 —基）一 1 ，3 —二氫咪唑一2_硫酮，製得Κ下式 I化合物：用3_ 〔2 — （3，4 一二甲氧基苯基）乙基〕一 1 —(1 ，2，3，4 —四氫萘一2-基）-1 ，3— 二氫眯唑一2 —硫酮取代，製得3 — 〔2 — （3, 4_二羥基笨基）乙基〕—（1，2，3，4一四氫萘一2—基）一 1 ，3_二氫眯唑一 2 —硫嗣，熔點165 - 1671C; 經濟部中央標準局員工消費合作社印製 (請先閲讀背面之注意事項再填寫本頁) 用1_ (5 —甲氧基茚滿一1 一基）一 1 ，3-二氫眯唑一2_硫萌取代，製得1一（5-羥基茚滿一1一基 )_1，3 —二氫咪唑_2 -硫酮，熔點208 - 209"Ό 用1- (1 ，2，3，4-四氫一 6 —甲氧基萘一1 一基）一 1 ，3 —二氫眯唑一 2 —硫釅取代，製得1一（ 1，2，3 * 4-四氫一 6 —羥基萘一 1 一基）-1，3 一二氫咪唑一 2 —硫酮，熔點2 1 3 — 2 1 5它； -1 8 1 - 本紙張尺度適用中國國家標準（CNS ) Α4規格（210乂29<7公釐） 470741 經濟部中央標準局員工消費合作社印製 A7 B7五、發明説明（）用1 一（1 ，2，3，4 —四氫一5 -甲氧基萘_1 一基）一1 ，3 -二氫咪唑一2 -硫酮取代，製得1 一（ 1 ，2，3，4 —四氫一5 —羥基萘—1—基）-1 ，3 一二氫咪唑—2 -硫酮，熔點1 88 — 1 90°C ; 用1_ (1 ，2，3，4 —四氫一7 —甲氧基萘一1 —基）一 1 ，3 —二氫咪唑—2 —硫酮取代，製得1—( 1 ，2，3，4 一四氫一7 —羥基萘一 1—基）一 1 ，3 —二氫噃唑一2 -硫酮，熔點1 95 - 1 96 °C ; 用1 一（1 ，2，3，4 —四氫一5 —甲氧基萘一2 —基）一1 ，3 -二氫咪唑一2 -硫酮取代，製得1一（ 1 ，2，3，4一四氫一5 -羥基萘—2 — 基）-1 ，3 —二氫咪唑一 2 -硫酮，熔點263 — 26 5Ό ; 用1_ (1 ，2，3，4 —四氫一 6 —甲氧基萘—2 —基）一 1 ，3 —二氫眯唑一 2 —硫_取代，製得1—( 1 ，2，3，4_ 四氫-6-羥基萘-2-基）—1 ，3 一二氫眯唑一 2 —硫酮，熔點240 — 24 1°C ; 用1 一（1 ，2，3，4 —四氫一7 —甲氧基萘一2 —基）一1 ，3 —二氫眯唑—2 —硫酮取代，製得1—( 1 ，2，3，4 —四氫-7—羥基萘-2-基）一1 ，3 一二氫咪唑—2 —硫酮，熔點248 — 25 〇υ ; 用1 一（1 ，2，3，4 —四氫一8 —甲氧基萘一2 一基）一 1 ，3 —二氫眯唑_2 —硫酮取代，製得1_ ( 1 ，2，3，4 —四氫-8—羥基萘—2 —基）一 1 ，3 -1 8 2 - 本紙張尺度適用中國國家標準（CNS〉Α4規格（210Χ297公釐） (請先聞讀背面之注意事項再填寫本頁) 470741 經濟部中央標準局員工消費合作社印製 A7 B7五、發明説明（）一二氫眯唑—2 —硫酮，熔點274 — 276¾ ;和用 1— (6，8 —二氣—1 ，2，3，4 一四氯一7 一甲氧基萘一 2 —基）一1 ，3 —二氫眯唑一2 —硫酮取代，製得 1— (6，8-二氟一 1 ，2，3，4_ 四氫一 6-羥基萘—2 —基）一 1 ，3-二氫咪唑一2 —硫_ ，熔點 258 - 260 °C。實例4 4 (S ) - N- 〔3 - (5，7-二氟-1，2，3, 4 —四氫萘_2_基）一2—硫代一2，3—二氫一1^1 —眯唑-4 一基甲基〕—4 一丁基苄醯胺 K下係製備式I (a)中η為1 ，t為2，5_和7 -位置的R1為氟，R5為4 — 丁基苯醯胺基甲基的化合物如實例31所製備的（S) — 5 —胺基甲基一1—( 5，7 —二氟一1 ，2，3，4一四氫萘—2 —基）一1 ，3 —二氫眯唑一 2 —硫酮（0 · 30克，1毫莫耳）和 4 — 丁基苯醯氯化物（0，21毫升，1 · 1毫莫耳）混合物在1 〇毫升無水吡啶中，在氬氣及約ου攪拌1小時，然後另外在25D攪拌2小時。濃縮混合物，用水處理殘留物。用醋酸乙酯萃取混合物三次，用硫酸鎂乾燥混合的萃取物，濃縮之。殘留物於醋酸乙酯中再结晶，得到（ 5 ) - Ν - 〔3_ (5，7 —二氟一1 ，2，3，4 —四 -183- 本纸張尺度適用中國國家揉準（CNS ) Α4規格（210Χ297公釐） (請先閱讀背面之注意事項再填寫本頁) 470741 經濟部中央標準局員工消費合作社印製 A7 B7五、發明説明（）氫萘一2—基）一2—硫酮一2，3—二氫一1?1_眯唑 —4 一基甲基〕一 4 — 丁基苄醯胺（0 · 25克，0 . 5 5毫莫耳），熔點242-243 °C。依實例44進行，但是用不同起始物質取代（S)-5 -胺基甲基一1— (5，7 — 二氟一1 ，2，3，4 — 四氫萘一 2 -基）一1 ，3 —二氫眯唑—2_硫嗣和/或 4 -丁基苯醯氯化物，製得Μ下式I化合物：用菸鹼醯取代，製得（S) - Ν — 〔3 - （5，7 — 二氟一 1 ，2，3，4 一四氫萘一2 —基）一2 —硫代一 2，3 —二氫-1 Η —咪唑一 4 一基甲基〕菸鹼醯胺，熔點 218_221它；用苯醯氯化物取代*製得（S) - Ν - [ 3 - (5, 7 —二氟一 1 ，2，3，4 —四氫萘—2—基）一 2~ 硫代一 2，3 —二氫一1 Η —咪唑一 4 一基甲基〕苄醯胺，熔點 260 — 26ΐυ; 用二甲基氨基甲醯取代*製得（S) — Ν_ 〔3 -( 5，7 —二氟-1 ，2，3，4一四氫萘一2 —基）~2 -硫代一2，3 —二氫一1Η —眯唑一4 -基甲基〕二甲基脲，熔點218 — 220C; 用氯甲酸甲酯取代，製得（S) — Ν — 〔3 - (5, 7 —二氟一 1 ，2，3，4 —四氫萘-2-基）—2 -硫代一2，3 —二氫一1 Η —咪唑—4 -基甲基〕氨基甲酸甲酯，熔點220 — 222 °C;*18 4- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） (請先閱讀背面之注意事項再填寫本頁) 470741 經濟部中央標準局員工消費合作社印製 A7 B7五、發明説明（）用（S) — 3 —胺基一1一（1 ，2，3，4一四氫萘—2 —基）—1 ，3 -二氫咪唑—2—硫酮和醋酸酐取代，製得N- 〔3 — （1 ，2，3，4一四氫萘一 2 —基 )—2—硫代一 2，3 —二氫—1H —眯唑一4 一基〕乙醯胺，熔點196 — 200^0; 用2 —呋喃羧酸氯化物取代，製得（S) — Ν — 〔3 -(5，7 —二氟—1 ，2，3，4 -四氫萘一2 —基） —2 —硫代-2，3 —二氫—1Η —晞唑-4 一基甲基〕 —2 —呋喃羧醯肢，熔點227 — 231¾ ;和用4 一胺基一2 — (1 ，2，3，4 —四氫萘一2- 基）—2，4 -二氫〔1 ，2，4〕***_3-硫酮和醋酸酐取代，製得Ν— 〔1— (1 ，2，3，4 一四氫萘一 2 —基）一 5 —硫代一4，5 —二氨―1Η — 〔1 ，2， 4〕***一 4_基〕乙醯胺，熔點199 — 201Π。實例4 5 (S ) - Ν- 〔3 - (5，7 —二氟-1，2，3, 4—四氫萘—2 -基）—2 -硫代一2，3_二氫—1 Η —咪唑_4_基甲基〕皮考林醯胺 Κ下係製備式I (a)中η為1 ，t為2，5 —和7 —位置的R1為氟，R5為皮考林醜胺基甲基的化合物。如實例31所製備的（S) — 5 —胺基甲基—1—( 5，7 —二氟一1 ，2，3，4 一四氫萘—2—基）一1 -185- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） (請先閲讀背面之注意事項再填寫本頁) 470741 經濟部中央標準局員工消費合作社印製 A7 ___ B7_五、發明説明（），3 —二氫眯唑_2-硫酮（295毫克，1毫莫耳），皮考林酸（123毫克，1毫莫耳）和ByBOP (62 0毫克，1·2毫莫耳）混合物於1〇毫升無水二甲基甲醯胺中，於氩氣中及約2 5C攪拌5分鐘，然後加入N， Ν -二異丙基乙基胺（0 . 58毫升，3 . 3毫莫耳）。用醋酸乙酯（3x10毫升）萃取水層，用水洗滌混合的萃取物，以硫酸鎂乾燥，濃縮之。殘留物在矽膠上（沖提液為1:1到8:2的己烷/四氫呋喃）進行急驟層析纯化，製得（S) — Ν - 〔3 - (5，7 - 二氟一1 *2， 3，4 —四氫萘一 2 —基）一2 —硫代一 2，3 —二氫一 1Η—咪唑一 4 一基甲基〕皮考林醯胺（80毫克，0 . 2 毫莫耳），熔點216 — 217t。依實例4 5進行，但是用不同起始物質取代皮考林酸，製得以下式I化合物：用N-(三级丁氧基羰基）甘氨酸取代並去保護，製得（S) - N - [ 3 - (5，7-二氟一1，2，3，4 一四氫萘一 2 —基）一2 —硫代一2，3 —二氫一1 Η — 眯唑—4 一基甲基〕胺基乙醯胺，熔點144-153¾ > 用N - （三级丁氧基羰基）- 2 —甲基丙氨酸取代並去保護*製得（5)-1^—〔3—（5，7-二氟一1， 2，3，4 一四氫萘一 2-基）一 2 - 硫代一 2，3 -二氫一 1 Η —眯唑一 4 —基甲基〕一2-胺基一 2 —甲基丙 -1 8 6 - 本紙張尺度適用中國國家標準（CNS ) Α4規格（210 X 297公釐） (請先閲讀背面之注意事項再填寫本頁) 470741 經濟部中央標準局員工消費合作社印製 A7 B7五、發明説明（）醯胺三氟醋酸鹽，熔點1 ;和用5 —丁基皮考林酸取代*製得（S) — Ν — 〔3 — (5，7— 二氟—1 ，2，3，4 一四氫萘—2 — 基）一 2 —硫代—2，3 —二氳一1 Η —眯唑一4 —基甲基〕一 5 - 丁基皮考林醯胺，熔點99 一 1 04 °C。實例4 6 (S ) - N-〔3 - (5，7 -二氟-1，2，3, 4 -四氫萘—2 —基）一2 -硫代_2，3 —二氫一1 Η —眯唑一 4 一基甲基〕乙基脲 Κ下係製備式I (a)中η為1 ，t為2，5 —和7 一位置的R1為氟，R5為乙基脲基甲基的化合物。如實例3 1所製備的（S) — 5 —胺基甲基_1—( 5，7-二氟-1 ，2，3，4 —四氫萘—2 —基）一1 ，3 -二氫咪唑—2 -硫酮（294毫克，1毫莫耳）和異氰酸乙酯（0 ♦ 16毫升，2毫莫耳）混合物於10毫升四氫呋喃中，在氩氣中及約5 0 υ攪拌約6 0小時。過滤混合物，經過濾的固體於醋酸乙酯/甲醇中再結晶，製得（S) "™ Ν — 〔3- （5，7 —二氟一 1 ，2，3*4 一四氫萘一 2 —基）一 2 —硫代—2，3 -二氣一 1Η — 眯唑一 4 一基甲基〕乙基脲（1 10毫克，0 · 3毫莫耳 )，熔點 219 — 220 °C。 _ 1 8 7 ~ 本紙張尺度適用中國國家襟準（CNS ) A4規格（210X297公釐） (請先閱讀背面之注意事項再填寫本頁) 470741 經濟部中央標準局員工消費合作社印製 A7 _ B7五、發明説明（）實例4 7 4 —胺基甲基一1- (1 ，2，3，4 —四氫萘一2 —基）一 1，3 -二氫咪唑—2 -硫酮 Μ下係製備式1(a)中η為1 ，t為Ο，R3和 Rs為氫，R4為胺基甲基的化合物。 3 - (1，2，3，4 —四氫萘—2—基）一2 —硫代~2，3 —二氫一 1 Η —眯唑一4 一卡巴醛（Ό · 25 克，1 · 0毫莫耳）*羥基胺氫氯化物（0 * 09克， 1 · 3毫莫耳）和氫氧化鈉（0 · 046克，1 · 6毫莫耳）混合物於2毫升乙醇和2毫升水中，於60*0攪拌1 小時。混合物冷卻後得到结晶性物質。過濾分離此物質，乾燥之。混合结晶性物質，得到1 一（ 1 ，2，3，4 一四氫萘—2 —基）一2—硫代—2，3 —二氯一1Η —畔唑一 5 -卡巴醛肟（0 · 186克，0 . 68毫莫耳）。如實例22所製備的3 — （1 ，2，3，4 一四氫萘一 2 —基）—2 - 硫代—2，3. - 二氯—1Η —畔哩一 5 一卡巴醛肟（0 · 158克，0 · 58毫莫耳）於20毫升四氫呋喃所形成的懸浮物冷卻到0Ό，慢慢加入在四氫呋喃中的LAH (1 . 0Μ，1 . 16毫升，1 · 16毫莫耳。混合物在0°C攪拌1小時，然後加入飽和氯化銨，水和醋酸乙酯。分離水層，用醋酸乙酯萃取之。混合的醋酸乙酯於硫酸鎂乾燥，並蒸發濃縮。殘留物經急驟層析純化得到4_胺基甲基一1- (1 ，2，3，4 —四氫萘— -1 8 8 - 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） (請先閱讀背面之注意事項再填寫本頁) 470741 經濟部中央標準局員工消費合作社印製 A7 B7五、發明説明（） 2 —基）-1 ，3~二氫脒唑—2 —硫酮，熔點197 — 2 0 0 它 ° 實例4 8 (S ) — 1— (5*7 —二氣一 1 *2，3，4 一四氫萘一2 —基）一 4 - (2 —苯基乙基）胺基甲基一 1 ， 3 -二氫眯唑—2 -硫_ K下係製備式I (a)中η為1 ，t為2，5 —和7 一位置的R1為氟，R4為2 —(苯基）乙基胺基甲基的化合物。如實例22所製備的（S) — 3 — （5，7 —二氟一 1 ，2，3，4 -四氫萘—2—基）—2—硫代 _2，3 —二氫一1H -咪唑一5-卡巴醛（147毫克，0 . 5 毫莫耳），苯乙基胺（75微升，0 · 6毫莫耳）和氟基硼氫化硼（47毫克，0 · 75毫莫耳）混合物於10毫升甲醇中，在約60 °C攪拌2小時。濃縮混合物，殘留物在矽膠（沖提液為97:3的甲撐氯化物/甲醇）進行急驟層析純化，純化的產物經濃縮，轉化成氫氯化物鹽，再於醋酸乙醅/甲醇中再结晶，得到（S) — 1— (5，7 一二氣一1 ，2，3，4 —四 Μ 蔡一2 —基）—4 — (2 —苯基乙基）胺基甲基一 1 ，3 —二氫眛唑一 2 —硫酮氫氯化物（68毫克，0 · 2毫莫耳），熔點227 — 229 °C 〇 -189- 本紙張A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填寫本頁) 470741 經濟部中央標準局員工消費合作社印製 A7 B7五、發明説明（）依實例48進行，但是用不同起始物質取代（S)-3 — (6，7_ 二氟一1 ，2，3，4 —四氫萘一2 -基 )一 2 —硫代一 2，3 —二氫一 1H —晞唑一5_卡巴醛和/或苯乙基胺，得到K下式I化合物：用 3 — （5，7 —二氟—1 ，2，3，4 —四氫萘一 2 —基）一 2 —硫代一2，3— 二氯一1H —蹄哇一5_ 卡巴醛和甘氨酸三级丁基酯氫氯化物取代，製得3 - (5 ，7- 二氟一 1 ，2，3，4_ 四氫萘一 2 —基）一2 — 硫代一2，3 -二氫—1H—咪唑—5 —基甲基胺基醋酸三级丁酯；用（S) — 3 — (5，7—二氣_1，2，3，4_ 四氫萘—基）—2 -硫代一 2，3 —二氫一1H —眯唑-5 _卡巴醛和甘氨酸三级丁基酯氫氯化物取代，製得 (S ) - 3— (5，7 -二氣-1 ，2，3，4-四氫萘一 2_ 基）_2 —硫代 _2，3_ 二氨一 1 H —畔哩—5 —基甲基胺基醋酸三级丁酯；用 3 - （1 ，2，3，4 一四氫萘一 2 —基）一2- 硫代—2，3 —二氫一1 Η —眯唑一 5 —卡巴醛和甘氨酸三级丁基酯氫氯化物取代，製得3_ (1 ，2，3，4 — 四氫萘一 2 —基）—2—硫代—2，3—二氫—1Η—咪唑-5_基甲基胺基醋酸三级丁酯；用甘氨醯胺取代，製得（S) — 3 - （5，7 —二氟 —1 ，2，3，4 —四氫萘一2 —基）—2 —硫代一 2， -1 90- 本纸張尺度適用中國國家標準（CNS ) Α4規格（210Χ297公釐） (請先閱讀背面之注意事項再填寫本頁) 470741 經濟部中央標準局員工消費合作社印製 A7 B7五、發明説明（） 3 —二氫一 1 H —咪唑—5—基甲基胺基乙醯胺，熔點 212 — 213它；和用4一（2—胺基乙基）苯酸甲酯取代，製得（S) -4- {2 - 〔3- (5，7-二氟-1，2，3，4_ 四氬萘一 2 —基）一 2 —硫代一2，3 —二氫一 1H —咪唑一 5_基甲基胺基〕乙基}苯酸甲酯，熔點159 — 16 0° 實例4 9 (S ) - N 3 - 〔3 - (5，7 -二氟—1 ，2，3 ，4 —四氯蔡_2 —基）—2—硫代—2，3 —二氯一 1 Η —咪唑_4 一基甲基〕一N1 ，Ν2 —二（三级丁氧基羰基）甲脒 Μ下係製備式I (a)中η為1 ，t為2，5 —和7 —位置的R1為氟，Rs SN1 ，N2 —二（三级丁氧基羰基）脒基胺基甲基的化合物。如實例31所製備的（S) — 1— (5，7 -二氟一 1 ，2，3，4 一四氫萘-2 —基）-5 —胺基甲基—1 ，3-二氫咪唑—2_硫酮（0 . 6克，2毫莫耳）和 N 1 ，N2 —二（三级丁氧基羰基）甲基硫胖（0 · 65 克，2 · 2毫莫耳）混合物於15毫升四氫呋喃和0 * 3 毫升水中，於約5 0¾及氬氣中攪拌4小時。濃縮混合物，殘留物與5%碳酸氫納水溶液混合，用醋酸乙酯萃取混 -191- 本纸張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） (請先閱讀背面之注意事項再填寫本頁) 470741 A7 —__ 五'發明説明（）合％，Μ硫酸鎂乾燥萃取物，並濃縮之。殘留物在矽膠上 (沖提液為99:1的甲撐氯化物/甲醇）進行急驟層純化，得到（S) — Ν3 — 〔3 - （5，7 —二氟一 1 ，2 ，3，4_四氫萘一 2 —基）—2 —硫代一2，3 —二氫 ~1 Η —咪唑一 4 一基甲基〕一Ν1 ，Ν2 —二（三级丁氧基羰基）甲脒（0 . 54克，1毫奠耳），熔點155¾ (蒸發）。依實例49進行，但是用不同起始物質取代N 1 ， N2 ~二（三级丁氧基羰基）甲基硫脒，製得K下式I化合物：用N1 ，N2 -二（乙醢基）甲基硫脒取代，製得 (S ) — N ^ — 〔3 — (5，7 —二氣一 1 ’2’3，4 一四氫萘一 2 —基）一 2 -硫代一 2，3 —二氫一1H -4 —基甲基〕一 Ν1 ,Ν2 _二（乙醯基）甲胖，熔點 213-214Π;和經濟部中央標準局員工消費合作社印製 (請先閣讀背面之注意事項再填寫本頁) 用Ν1 — （三级丁氧基羰基）甲基硫胖取代，製得 (S ) 一 Ν3 — 〔3 - （5，7—二氣_1 ’2’3’4 —四氫蔡 _2 —基）一 2 —硫代—2，3 —二 M—l Η — 4~基甲基〕一Ν1—二（三級丁氧基羰基）甲脒，熔點大於2 8 0 t：。實例5 0 (S ) - N 3 -〔3 - (5，7_ 二氟 _1，2，3 -192- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 470741 經濟部中央標準局員工消費合作社印製 A7 B7五、發明説明（），4 —四氣蔡一 2_基）一 2 —硫代—2，3 —二氮—1 H—眯唑一 4 -基甲基〕甲脒 Μ下係製備式I (a)中η為1 ，t為2，5 —和7 一位置的R1為氟，Rs為脒胺基甲基的化合物。如實例49所製備的（S) — N3 — 〔3 — (5，7 —二氣—1 ’ 2，3，4一四氫萘—2 —基）一2 -硫代 _2，3 — 二氫一1H — 咪唑一4 —基甲基〕- N1， N 2 —二（三级丁氧基羰基）甲脒於2 0毫升三氟醋酸中所形成的溶液在約25 °C攪拌1 · 5小時。濃縮溶液，殘留物與1 00毫升二***混合。潷析二***，殘留物與1 00 毫升二***混合。過濾混合物，經過濾殘留物溶於醋酸乙酯，濃縮溶液，脫真空，所形成的泡沫經二***處理，過濾混合物，製得（S) - N 3 - 〔3 — (5，7 —二氟一 1 ，2，3，4 -四氫萘一2 —基）一2 —硫代一 2，3 —二氫一1H-眯唑一4 —基甲基]甲脒（0 . 28克， ◦ •6毫莫耳），熔點103D (蒸發）。實例5 1 2S -胺基-3 - (3Η —咪唑一4-基）一 Ν —〔 3 — (5，7 -二氟-1 ，2，3，4 —四氫萘—2 —基 )—2 —硫代—2* 3 —二氫—1Η —眯唑一4 —基甲基〕丙醯胺氬氯化物 Μ下係製備式I I中η為1 ，t為2，5 —和7 —位 -193- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） (請先閱讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 470741 A7 B7五、發明説明（）置的R1為氟，R1 8為式（d)中R2 1為L —組氨醃胺基甲基的化合物。如實例3 1所製備的（R) — 5 —胺基甲基—1_ ( 5，7 —二氣 _1 ，2，3，4 —四氫蔡一2—基）一1 ，3 —二氫眯唑—2 —硫酮（0 . 55克，1 . 86毫莫耳），（S) —2—(三级丁氧基羰基）胺基一3— (3 —三級丁氧基羰基一 3H咪唑一4 —基）丙酸（0 · 76 克，1 .86 毫莫耳）和 PyBOP (1 · 07 克，2. 05 毫莫耳）混合物於6 · 2毫升二甲基甲醯胺中，於氬氣中攪拌，直到均匀為止。加入二乙基異丙基乙基胺（1 · 07 毫升，6 · 1 5毫莫耳），攪拌混合物約1 8小時。混合物於水和醋酸乙酯之間分層，用水洗滌有機層二次，K硫酸鎂乾燥*蒸發濃縮之。殘留物在管柱層析（沖提液為 5%甲醇/甲撐氯化物）進行純化，製得泡沫的2S (二級丁氧基羰基）胺基—3 - (3-三级丁氧基羰基—3H —睐唑—4 —基）—N — 〔3 - （5，7-二氟一 1，2 ，3，4 —四氨蔡—2R—基）—2_ 硫代一 2，3 —二氫一 1H —眯唑—4 一基甲基〕丙醯胺（1 · 003克）〇將2S—(三级丁氧基羰基）胺基一3_ (3 —三级丁氧基羰基—3H —眯唑-4 一基）一 N — 〔3 — (5 ，7 —二氟 _1 ，2，3，4 —四氫萘— 2R —基）一2 _硫代一 2，3 —二氫一 1H —眯唑一 4 一基甲基〕丙醯 -194- (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 470741 經濟部中央標準局員工消費合作社印製 A7 B7五、發明説明（）胺（0 . 935克）溶於45毫升30%無水氯化氫/醋酸乙酯中，攪拌混合物1 8小時，得到结晶性物質。過據分離該物質，在60 °C及真空中乾燥，得到2S -胺基一 3 — (3H —脒唑—4 —基）一N - 〔3 — (5，7 —二氟一1 ，2，3，4 —四氫萘一2 —基）一2 —硫代—2 ，3 —二氫—1H —咪唑_4_基甲基〕丙醯胺氫氯化物 (0 . 655克，1 · 24毫莫耳），熔點228υ; 依實例5 1進行，但是用不同起始物質取代（R)-5_ 胺基甲基一1— (5，7 —二氟一1 ，2，3，4一四氫萘一 2 -基）一 1 ，3 —二氫眯唑—2 —硫麵和（S )-2 -(三级丁氧基羰基）胺基—3_ (3 —三级丁氧基羰基-3Η)眯唑一4 —基）丙酸，製得Κ下式I I化合物：用5 —胺基甲基一 1 一（5，7 —二氟一1 ，2，3 ，4 -四氫萘一2-基）一 1 ，3 -二氫咪唑-2 -硫酮和（S) - 3 —(三級丁氧基羰基）一 2 —三级丁氧基鑛基胺基丙酸取代，製得3S -胺基—Ν — 〔3— （5，7 一二氟一 1 ，2，3，4 —四氫萘_2_基）—2 —硫代 —2，3 —二氫—1Η —咪唑一4 —基^甲基〕琥珀醯胺酸氫氯化物，熔點220Ό; 用5 —胺基甲基一1_ (5，7 —二氣一1 ，2，3 ，4 —四氬萘—2 -基）-1 ，3-二氫眯唑一2 —硫酮和（S) - 3 -(三级丁氧基羰基）一3 - （三級丁氧基 -195- 本紙張尺度適用中國國家標準（CNS ) Α4規格（210Χ297公釐） (請先閱讀背面之注意事項再填寫本頁) 470741 經濟部中央標準局員工消費合作社印製 A7 B7五、發明説明（）羰基胺基）丙酸取代，製得2S —胺基一 N — 〔3 - （5 ，7 — 二氣一1 ，2，3，4 —四氣蔡—2—基）—2 — 硫代一 2，3 —二氫一1H —脒唑—4 —基甲基〕琥珀醯胺酸氫氯化物，熔點2 20t); 用5_胺基甲基一1一（5，7 —二氟一1 ，2，3 ，4 -四氫萘一2 —基）一1 ，3 -二氫咪哩一2 —硫酮和（S) - 2，5 -二（三级丁氧基羰基胺基）戊酸取代，製得 2S，5 —二胺基-Ν— 〔3 — （5，7 —二氟— 1 ，2，3，4 -四氫萘一2 —基）—2—硫代一2，3 一二氫—1Η -蹄唑—4 —基甲基〕戊醯胺酸氫氯化锪，熔點 212 — 216 °C; 用胺基甲基一1— (1 ，2，3，4 —四氫萘一 2 —基）一 1 ，3 -二氫眯唑—2 —硫酮和（S) — 2, 5 -二（三级丁氧基羰基胺基）戊酸取代，製得2S，5 —二胺基一N — 〔3 — (1 ，2，3，4 —四氨蔡—2—· 基）一 2 -硫代—2，3 —二氫一 1H —眯唑一4-基甲基〕戊醯胺酸氫氯化物，溶點191 —205 °C; 用5 -胺基甲基一 1一（1 ，2，3，4 一四氫萘— 2 -基）一 1 ，3—二氫眯唑—2-硫酮和（S) - 2 - (三级丁氧基羰基胺基）_5_ (三级丁氧基羰基）胍基戊酸取代，製得2S —胺基一N — 〔3— （1 ，2，3， 4 —四氫萘—2 —基）一2 —硫代—2，3 —二氫—1 Η —眯唑—4 一基甲基〕_5 —胍基戊醯胺酸氫氯化物，熔 -196- 本紙張尺度適用中國國家標準（CNS ) Α4規格（210Χ297公釐） (請先閣讀背面之注意事項再填寫本頁) 470741 經濟部中央標準局員工消費合作社印製 A7 B7五、發明説明（）點 1 6 Ο Ό ; 用3 —胺基—1_ (1 ，2 * 3 ’4 —四氫蔡—2 — 基）一 1 ，3 —二氫脒唑—2 —硫酮和（S) - 2 -(三級丁氧基羰基）胺基- 3 — (3 —三級丁氧基羰基—3Η —咪唑—4 一基）丙酸取代，製得2 S —胺基一3 — 3Η —咪唑 _4 一基）—Ν - 〔3 — (1 ，2，3，4 一四氫蔡一 2 —基）一2 —硫代_2，3—二氫一1Η —蹄哩― 1 —基〕丙醯胺酸氫氯化物，熔點1 97 — 205 °C ; 用5 —胺基甲基一1 一（5，7 -二氟一1 ，2，3 ，4 —四氫萘—2 —基）—1 ，3 -二氫咪唑一 2 —硫酮和（S) - 2 -(三級丁氧基羰基）胺基一 3 - （3 -三級丁氧基羰基一 3 Η -咪唑_4 一基）丙酸取代，製得2 S —胺基 _3— （3Η -畔唑一4 一基）—Ν — 〔3 - ( 5，7 — 二氟一 1 ，2，3，4一四氫萘一2_ 基）一2 —硫代，3 —二氫一1Η —咪唑—1—基甲基〕丙醯胺酸氫氯化物，熔點1 95 — 238 °C; 用（S) — 5 —胺基甲基一 1— (5，7—二氟_1 ，2，3，4 —四氫萘—2 —基）一1 ，3 —二氫眯唑-2_硫酮和（S) — 2 —三趿丁氧基羰基—胺基—3 —( 3 —三鈒丁氧基羰基一 3H-咪唑一 4 —基）丙酸取代，製得2S —胺基—3_ (3H—蹄啤—4—基）—〔 3 — (5，7 —二氟—1 ，2，3，4-四氫萘—2 —基 )—2—硫代—2，3 —二氫一 1H —咪唑—4 一基甲基 -197- (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) A4規格（2I0X297公釐） 470741 經濟部中央標隼局員工消費合作社印製 A7 B7五、發明説明（) 〕丙醯胺酸氫氯化物，熔點225 °C; 用（S) — 5 —胺基甲基一 1 一（5，7 —二氟一1 ，2，3，4 —四氫萘—2—基）一 1 ，3 —二氫眯哇一 2_硫酮和（S) — 4 -乙醢基胺基—4_三級丁氧基羰基丁酸取代，製得2S -乙醯基胺基—4 一〔3 — (5, 7-二氟一1 ，2，3，4 —四氬萘一2S —基）一2 — 硫代一2，3 —二氫—1 Η —咪唑一 4 一基甲基胺基羰基〕丁酸，溶點1 5 9 t ; 用（S) — 5 —胺基甲基一1— (5，7_二氟一1 ，2，3，4 —四氫萘一 2 —基）一1 ，3-二氫咪唑-2 —硫酮和（S) — 2，5 —二（三級丁氧基羰基胺基）戊酸取代，製得2S，5—二胺基—N - 〔3 — (5，7 一二氟-1 ，2，3，4 一四氫萘-2S —基）一2 —硫代—2 · 3_二氫一1H —咪唑一 4 一基甲基〕戊醯胺氫氯化物*熔點233—2371; 用（R) — 5 —胺基甲基一1 一（5，7 —二氟一1 ，2，3，4 —四氫萘一2 —基）-1 ，3 —二氫咪唑_ 2 —硫酮和（S) — 2，5 —二（三級丁氧基羰基胺基）戊酸，製得 2S，5-二胺基—N — 〔3 — (5，7 —二氟一 1 ，2，3，4 —四氫蔡—2R —基）—2—硫代一 2，3 —二氫一1 Η —咪唑一4 一基甲基〕戊醯胺氫氯化物，熔點 128— 150 °C; 用（S) — 5 —胺基甲基一 1— (5，7-二氟一1 "19 8~ (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 470741 A7 B7 五、發明説明（），2，3，4 一四氫萘一 2 -基）一 1 ，3 -二氫咪唑— 2-硫酮和（S) — 3_ (三級丁氧基羰基）一 2 — （三級丁氧基羰基胺基）丙酸，製得2S—胺基—N— 〔3~ (5，7 -二氟—1，2，3，4-四氫萘一 2S -基） —2 —硫代—2，3 —二氫—1H —眯唑一4 —基甲基〕琥珀酸氫氯化物，熔點1 941 ; 用（R) -5 -胺基甲基一1 一（5，7 —二氟一1 ，2 * 3 * 4 —四氫萘一 2 —基）一1 ，3 —二氫眯唑一 2 —硫酮和（S) —3 —(三級丁氧基羰基）一 2 —(三級丁氧基羰基胺基）丙酸，製得2S —胺基—Ν — 〔3 - (5 * 7 —二氟—1 ，2，3，4 -四氫萘—2R —基） —2—硫代一 2，3~二氫—1 Η —畔唑一4 —基甲基〕琥珀醢胺酸氫氯化物，熔點1 9 3 υ ; 用 4 —胺基一 2_ (5，7 —二氟—1 ，2，3 *4 一四氫萘一2 —基）一 2，4一二氫〔1 ，2，4〕*** —3_硫酮和（S) — 2，5 —二（三級丁氧基羰基胺基 )戊酸，製得 2S，5 —二胺基一 Ν — 〔1 一 (5*7- 經濟部中央標準局負工消費合作社印製 (請先閱讀背面之注意事項再填寫本頁) 二氟—1 * 2，3，4 一四氫萘一 2 —基）—5 —硫代— 4，5 —二氫一1Η 〔1 ，2，4〕***一4 —基〕戊醯胺氫氯化物；用 4 一胺基—2_ (5，7 —二氟—1 ，2，3，4 —四氫萘_2 —基）—2，4 —二氫〔1 ，2，4]三哩 —3—硫酮和（S) — 2 — （三級丁氧基羰基）胺基_3 -1 99- 本紙張尺度適用中國國家標準（CNS ) Α4規格（210><297公釐） 470741 經濟部智慧財產局員工消費合作社印製 f‘允訓: 五、發明說明（ A7 B7Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs I A7 B7 V. Description of the invention () -1 7 0 ° C; Use 4 — (2-bromoethyl) benzoic acid and (S) — N — 〔3 — (5, 7-difluoro-1,2,3,4-tetrahydronaphthalene- 2-yl) -2,3-dihydro-1 fluorene-imidazol-4-ylmethyl] formamidine to obtain (S) — 4 — {2 — [4 Monomethylaminoaminomethyl-3 — (5,7 —difluoro-1,2,3,4 —tetrahydronaphthalene — 2 —yl) — 2 —thione — 2 , 3-dihydro-1,1-oxazolyl-1-yl] ethyl} benzoic acid; and ethyl 3-bromopropionate and (S) —N— [3— (5,7—difluoro-1, 2,3 > 4-tetrahydronaphthalene-2-yl) -2,3-dihydro-1 fluorene-imidazol-4-ylmethyl] formamidine to obtain (S) —3 — [4 monomethyl Fluorenylaminomethyl- 3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl) -2 -thione-2,3-dihydro-1,1-imidazole- 1-yl] ethyl propionate. Example 1 6 1— (1,2,3,4_ Tetra.azaca-2-yl) -1.3-dihydroimidazol 2-thione M is prepared in the following formula I (a) where η is 1, t Is a compound in which R3, R4 and R5 are each hydrogen. The solution of 1- (1,2,3,4-tetrahydro-2-yl) panazole (1 * 6 g, 8.1 mmol) in 30 ml of tetrahydrofuran prepared in Example 13 was cooled to -78 · Well, add n-butyltin (6 ml * 9 · 7 mmol) over 15 minutes. The mixture is at -78¾ stir -1 3 0-This paper size applies Chinese National Standard (CNS) A4 specification (210X297mm) (Please read the precautions on the back before filling this page) 470741 A7 B7 V. Description of the invention () After 1 hour, shellac sulfur (0.34 g, 10.5 mmol) was added, and the mixture was stirred at 7.8 for another 2 hours and then allowed to warm to room temperature. The mixture was poured into 100 liters of water to obtain A crystalline substance. The substance was dried, washed with diethyl ether, and dried. The filtrate (2 × 100 ml) was extracted with methylene chloride, and the extract was washed with brine, dried over sodium sulfate, and evaporated to shrink. The residue Purified by column chromatography on silica gel (eluent 1 · 5% methanol (containing 2% concentrated sodium hydroxide)]. The crystalline material was mixed to obtain 1- (1,2,3,4-tetrahydronaphthalene -2 -yl)-1, 3-diimidazole-2-sulfur ugly (0.81 g, 3.5 mmol), melting point 233D-234 υ Example 1 7 5-amine 1-1 ( 1,2,3,4-tetrahydronaphthalene-yl) _1,3-dioximidazole-2-sulfanil is prepared by the following formula I (a) where η is 1, t is 0, R3 and R4 is fluorene and R5 is amine-based compound. Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) As in Example 10 2—Isothiofluoro-1, A mixture of 2,3,4 tetrahydronaphthalene (1.92 g, 10.1 mole) and aminoacetonitrile hydronitride (0.94 g, 10.1 mmol) in 1.41 ml of triethyl The amine was heated at 60¾ for 1 hour. The solvent was evaporated and the residue was purified by flash chromatography (the extract was methyl chloride, followed by 3% methanol (methylene chloride)). The purified residue was in ethyl acetate Ester / hexane recrystallized. Residue (1 ♦ 06 g) and 44 ml of 0 ♦ 1N potassium hydroxide was stirred in nitrogen for 15 minutes. Pass the residue and wash with water. * Empty-131- This paper size applies China National Standard (CNS) A4 (210x297 mm) 470741 A7 B7 Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of the invention () Air-dried and then stirred with methylene chloride. Preparation of 5-amino-1— (1,2,3,4-tetrahydronaphthalene-2—yl) _1, 3-dihydro Oxazole-2 —thione, melting point 169 ° — 171t: Example 1 8 (S) -5 -hydroxymethyl-1-(5,7 -difluoro-1, 2,3,4 -tetrahydronaphthalene-2 -Yl) -1,3-dihydrooxazole- 2 -thione M is prepared in the following formula I (a) where η is 1 and t is 2,5_ and 7-position R1 is fluorine and R5 is hydroxymethyl Compounds. Potassium thiocyanate (15 ♦ 9 g, 162 · 6 mol) was dried in nitrogen by heating to 1 7 510, and then cooled by passing nitrogen through the vacuum several times. Dihydroxyacetone (15.9 g, 1 76 · 7 mmol) and (S) prepared as in Example 6-5,7 -difluoro-1,2,3,4_tetrahydronaphthalene-2- A mixture of ammonium hydrochloride (30.0 g, 137.0 milliliters) (in 540 ml of ethyl acetate) was added to dry refined potassium thioratate. The reaction vessel was purged with nitrogen and 40.83 g of glacial acetic acid was added. The reaction mixture was stirred at 3 5¾ for 15 minutes, then cooled in an ice bath * 2.5 M sodium hydroxide was added until the pH of the mixture was 7. The organic layer was washed with 50 ml of a saturated aqueous sodium hydrogen carbonate solution and then 50 ml of brine. The organic layer was distilled to be concentrated to 4800 ml, and the mixture was cooled to 6 ° F. The mixture was allowed to stand for 12 hours to obtain a crystalline substance. This material was separated by centrifugation, and the paper residue was washed with cold ethyl acetate to dry the separated substance. The substance is dissolved in 650 ml of ethyl acetate and 25 liters of water, and steamed -132- (please read the precautions on the back before filling this page). Packing. ', 11-Silk paper size is applicable to China Standard (CNS) A4 size (210X297 mm) 470741 A7 B7 V. Description of the invention () Distill the mixture until 500 ml of volatiles are removed. The mixture was cooled to room temperature and stirred for 45 minutes to obtain a crystalline substance. The material was separated by filtration, and the filter paper residue was washed with cold ethyl acetate. Nitrogen was introduced into the vacuum for drying to obtain (S) -5-hydroxymethyl-1 1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalene-2 2-yl) -1, 3-Diargylimidazole-2-thione (30 · 4 g, 107 · 4 mmol), melting point 20 6-2071, [α] ρ 2 5 -40ο (C = 0.682, methanol). Performed in a similar manner to Example 18, except that (S) -6,7-difluoro_1,2,3,4-tetrahydronaphthalene-2-ylamine hydrochloride was used instead of (S) -5,7-difluoro -1,2,3,4-tetrahydronaphthalene-2-ylamine hydrochloride to obtain (S) —5-hydroxymethyl-1 — (6, 7 —difluoro_1 — 2, 2, 3, 4 — Tetrahydrocai-2-yl) -1,3-dihydrooxazole-2-thione, melting point 247 ° C-248t :. Example 1 9 (S) — 5—cyano 1— (5,7—difluoro—1,2, printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling in this 1) 3 , 4-tetrahydronaphthalene-2-yl) -1,3-diargylimidazole 2-thione M is prepared in the following formula I (a) where η is 1 and t is 2,5-and 7-position R1 Are fluorine, R3 and R4 are hydrogen, and Rs is a fluoro-based compound 0 (S) — 5,7-difluoro-1, 2, 3, 4 tetrahydronaphthalene — 2-ylamine hydrogen prepared in Example 8 Chloride (50 · 3 g, 0.23 -133- This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) 470741 A7 B7 Printed by the Central Consumers ’Cooperative Bureau of the Ministry of Economic Affairs # 5. Description of invention ( ) 1 1 I mole) and sodium hydroxide (1 0 • 0 g 0 • 2 5 η ear) in 4 5 0 1 1 1 ml of water was heated to 50 ° C 9 and then formaldehyde was added 1 I sodium sulfate complex (3 0 • 8 g • 0 f 2 3 mol) 0 stirring and mixing please kj read the back 1 I matter 30 minutes add potassium cyanide (1 5 «0 g > 0 * 2 3 mol) 1 1 side I 0 Heat the mixture to 80 V 9 Stir for 1 hour 9 Cool to room temperature 9 Then note 1 I means 1 I extract with ethyl acetate. An oily residue was obtained by evaporation (5 1 3 g). 0 Matter 1 I Re 1 Purification by column chromatography on silica gel (eluent: 5% methanol / methylene chloride § 1 f) (S) Mono (5 7 —difluoro— 1 2 3 4 page 1 monotetrahydronaphthalene — 2 —yl — amine) acetonitrile (3 9 4 g) and (S) 1 1 (5 7 —difluoro — 1 2 3 4 — Tetrahydronaphthalene — 2 monoylamine 1 I (7 1 2 g) 0 Recycle the starting material I in a similar manner as above to obtain (S)-(5 7-difluoro-1 2 3 » 1 I 4 Tetrahydronaphthalene-2 -yl-amino) acetonitrile (4 4 * 8 g 0 • 2 1 1 0 Mol) Melting point 7 3 7 6 1C C a] 0 Z 5 = · -58 0 4 ° 1 1 (C = 1 6 chloroform) 〇1 silk (S) one (5 7 — difluoro-1 1 2 3 4 — tetrahydronaphthalene 1 1 2 — Mono-amino group) Acetonitrile in butyl formate (87 M 9 2 4 0 milliliter 1 1 liter 2 • 10 mole) was heated to reflux »stir in nitrogen 1 1 gas for 19 hours 0 The solvent was removed under reduced pressure »Toluene 9 was added and then 1 I was evaporated. After drying, an oily residue (S) — N- (n-methyl) 1 1-N— (5» 7 — difluoro-1 1 » 2 »3 * 4 tetralin-2-1 1yl) formamidine (5 3 • 2 g) 0 formamidine (5 3 * 2 g) and 1 1 ethyl formate (1 2 • 4 Μ 9 4 8 • 7 ml, 0 • 6 0 4 Mole 1 |-134- 1 1 This paper size is applicable to China National Standard (CNS) 8-4 specifications (2 丨 OX297 mm) 470741 Employee Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Printing A7 B7 __V. Description of the invention )) At 0 ♦ 925 L of anhydrous tetrahydrofuran was stirred in the feed mixture was cooled to a 1 5C. A solution of tertiary potassium butoxide in tetrahydrofuran (1.0 M, 302 liters, 0 · 302 mol) was added over 20 minutes, and the mixture was stirred for 18 hours. Evaporation of the solvent "gives the residue (S)-Ν-(1 -cyano-2-oxoethylene) -N-(5» 7 -difluoro-1,2,3,4 -tetrahydronaphthalene-2 -yl ) Formamidine. (S) — Ν-(1-cyano-2-oxoethenyl) -N-(5,7-difluoro-1, 2 * 3,4-tetrakisene-2-yl) methylamine and The mixture of potassium thiocyanate (78.1 g, 0. 80 mol) was heated to 85 ° F in 0.99 liters of 1N hydrochloric acid and 0.497 liters of acetic acid, and stirred for 1 35 minutes. The mixture was then cooled in an ice bath to form a precipitate, which was collected as a mud. Purification on a column layer on silica gel packed in hexane (eluent is 10% acetone / methane atmosphere) to obtain (S) — 5_ cyano 1 — (5, 7 — difluoro-1, 2,3,4-tetrahydronaphthalene- 2-yl) -1,3-dihydroimidazol-2-sulfan (18.1 g, 0.06 stilb), melting point 241-249C, [a) D 25 = -69.1. (C = 1.20, DMS0) 0 according to Example 19 * but substituted with different starting materials (S > — 5,7 —difluoro-1,2,3,4 —tetrahydronaphthalene 2 —ylamine hydrogen atmosphere Compounds to obtain K compounds of the formula I: Substituted with 5,7-difluoro-1,2,3,4-tetrahydronaphthalene- 2-ylamine to obtain 5-cyano-1-(5,7- Difluoride 1,2, -135- This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling this page) 470741 A7 B7 V. Description of Invention () Economy Printed by the Consumer Cooperatives of the Ministry of Standards of the People's Republic of China 3 9 4 —tetrahydrom — 2 —based) — 1 > 3 monodihydroimidazole — 2 monothioketone i melting point 2 5 5 (decomposition) 5 used (R) a 5 > 7 — difluoro-1 > 2 > 3 »4 — tetrahydronaphthalene — 2 —ylamine substitution to obtain (R) — 5 — cyano 1 — (5 * 7 — difluoro — 1 9 2 > 3 »4—tetram naphthalene-2 mono) 1 t 3 —dihydrooxazole — 2 —thione * * with (S) — 7 —fluoro — 1 2 3 > 4 — Tetrahydronaphthalene — 2 —ylamine substitution »to obtain (S) — 5 monocyano — 1 — (7 — fluoro-1 1, 2 3» 4 — tetranaphthalene — 2 —yl) — 1 > 3 — Dihydroimidazole — 2 — thioketones> (S) — 5 — Fluorine with (S) — 6 — Fluoro — 1 > 2 > 3 »4 — Tetrahydronaphthalene — 2 monoylamine substitution > 1 — 1 (6 — Fluorine 1 9 2 $ 3 t 4 — — Tetrahydronaphthalene — 2 — 1) 1 P 3 — Dihydroimidazole — 2 — Thione> (S) — 5 —. Fluorine 1 1 2 3 9 4 —tetrahydronaphthalene — 2 monoylamine substitution > to obtain (S) 5 5 cyano · 1 — (5 — fluorine — 1 > 2 3 9 4 — tetrahydrom — 2 — —) — 1 »3 —-'Hydroimidazole — 2 —Thizone» (S) — 5 monocyano substituted with (S) — 1 > 2 3 4 — tetrahydronaphthalene — 2 monoylamine — 1 — (1 »2» 3 9 4 Tetrahydronaphthalene — 2 —yl) — 1 i 3 One--Hydroimidazole — 2 — Ketone $ Substituted with 6 «7 — difluoro — 1 • 2 • 3 > 4 — tetrahydrocae — 2 — ylamine to make 5 — cyano-1 1 (6 9 7 1. Fluoro-1 > 2 »-136- (Please read the notes on the back before filling out this page) This paper size is applicable to Chinese National Standard (CNS) A4 (210X297 mm) 470741 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. Explanation () 3,4-tetrahydronaphthalene-2-yl) -1,3-dihydroimidazole-2-thione; (S) -6,7-difluoro-1,2,3,4 ~ four Hydronaphthalene-2-ylamine substitution to obtain (S) -5—cyano-1— (6,7—difluoro-1, 2,3,4—tetrahydrocae-2—yl) —1, 3 — Dihydrooxazole-2-thione; and substitution with 5 * 6-difluoroindan-2-ylamine to give 5-cyano-1- (5 * 6-difluoroindan-2-yl ) A 1,3-dihydroimidazol-2-thione. Example 2 0 (S) — 5-Aminomethyl-1— (5,7—difluoro-1, 2,3,4-tetrahydronaphthalene-2—yl) -1,3—dihydroimidazole-2 Monothione hydrochloride K is a compound prepared by formula I (a) in which η is 1 and t is 2, 5- and 7; R1 is fluorine, R3 and R4 are hydrogen, and R5 is aminomethyl. (S) —5-cyano-1— (5,7—difluoro-1,2,3,4—tetrahydronaphthalene—2-yl) —1,3-dihydroimidazole_2 as prepared in Example 19 -A solution of thioketone (5.0 g, 0.017 mol) in 75 ml of tetrahydrofuran was stirred in an ice bath under argon, and LAH was added dropwise over 10 minutes to tetrahydrofuran (1.OM, 34. 3 ml, 34.3 mmol). The mixture is cooled to 0 ° C, stirred for 30 minutes to return to room temperature, and left to stand for 1.5 hours -137- This paper size applies to China National Standard (CNS) A4 (210X297 mm) (please read the back first) Please note this page, please fill in this page) 470741 A7 B7 printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs V. Invention Description (). The mixture was cooled to oc * and a sufficient amount of a saturated sodium potassium tartrate solution was added to allow the mixture to stir freely. Add 30 ml of a saturated sodium potassium tartrate solution and 200 ml of 10% methanol (methylene chloride). In the organic calendar, the water phase was slaughtered twice with 10% methanol (methylene chloride) (2x125 ml), and the mixed extract was washed with 75 ml of water. • It was dried over magnesium sulfate and evaporated to a residue (5 ♦ 2 g). Purification by column chromatography on silica gel (eluent: 5% methylammonium / methylene chloride) to obtain (S) -5-aminomethyl-1- (5,7-difluoro-1), 2, 3,4-tetrahydronaphthalene-2-yl) -1,3-dihydroimidazole-2-thione (2.92 g, 10.0 mmol) ° (S)-5-aminomethyl- 1- (5,7-difluoro-1 * 2,3,4_tetrahydroan-2-yl) -1,3-dihydroimidazole-2 monothione is dissolved in methanol and used 1 '5 equivalents of anhydrous Treated with hydrogen chloride (in ether), co-evaporated with ethyl acetate, and removed the solvent to obtain (S) _5-aminomethyl-1 1- (5,7-difluoro-1,2'3,4-14 Hydronaphthalene- 2-yl) -1,3-dihydroimidazole-2-thione hydrochloride, melting point 245D, [ < χ] ρ25 = 11 · 30 ° (C = 0 · 5 · DMS 0) 0 Performed as in Example 20, but replacing (S) with a different starting material — 5 —nitro group — 1 (5, 7-Digas-1,2'3'4-tetrahydronaphthalene-2-yl) -1,3-dihydrooxazole-2-thione, to obtain a compound of the formula I below: 5 -cyano-1 1 one (5,7 —difluoro-1,1,2,3,4 -138- this paper; Cl applicable to China National Standard (CNS) A4 specification (210 × 297 mm) I --------- t- ----- IT ------, # (Please read the notes on the back before filling out this page) 470741 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Invention Description () Tetralin -2 -yl) _1, 3-dihydrooxazole-2 -thione substitution, 5-amino methyl 1-(5,7-difluoro-1, 2, 3, 4-tetrahydrocae —2 -yl) -1,3-dihydroimidazole-2-thione, melting point 172 to 178 °, and 5-aminomethyl-1— (5,7- • difluoro-1,2,3, 4-tetrahydrocae-2-yl) -1, 3-dihydrooxazole- 2-thione hydrochloride, melting point 265 ^ -2 7 0¾ »With (R) — 5 —cyano — 1- ( 5,7-difluoro-1,2,3,4-tetrahydronaphthalene- 2-yl) -1,3-dihydroimidazole- 2-thione substitution to obtain (R) -5 -aminomethyl One 1 one (5,7 —difluoro-1,2,2,3,4-tetrahydronaphthalene-2-yl) —1,3 —dihydroimidazole — 2 —thione hydrochloride; (S) — 5 —Amino—1— (7—fluoro—1,2,3,4—tetrahydronaphthalene—2—yl] —1,3—dihydroimidazole—2—thione is substituted to obtain (S) — 5- Aminomethyl 1- (7-fluoro-1,2,3,4-tetrahydronaphthalene- 2-yl) -1,3-dihydrooxazole-2 -thione hydrochloride, melting point 237-247¾ ; Substituted with (S) — 5 —cyano — 1 — (6-fluoro-1, 2, 3, 4-tetrahydronaphthalene — 2 —yl) — 1, 3 —dihydroimidazole — 2 —thione, to make (S) —5-Aminomethyl-1— (6-fluoro-1,2,3,4-tetrakis-Caiyi 2—yl) —1,3—dihydropan beer—2—thione argon Chloride, melting point 240 — 249C; with (S) -5 —cyano-1 — (5-fluoro-1, 2, 3, -139-) This paper size applies to China National Standard (CNS) 8-4 specifications (210 X297 mm) (Please read the precautions on the back before filling out this page) 470741 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Invention Description () 4 Yi Si Cai 2—Base) 1 ， 3 —Dihydrotetramethyl-2-thione substitution to produce (S) —5-aminoamino-1— (5-fluoro-1,2,3,4-tetrahydrocae-2—yl) -1, 3—dihydroimidazole—2 —thione hydrochloride * Melting point 2 73 — 276 ° C; (S) — 5 —cyano-1 — (1,2,3 * 3 * 4 —tetrahydronaphthalene 2 —yl ) -1,3-dihydrooxazole_2-thione substitution, to obtain (S) -5-aminomethyl-1- (1,2,3,4-tetrahydronaphthalene-2-yl)- 1,3-dihydroimidazole-2-thione hydrochloride, melting point 255-258P; 5-cyano-1- (6,7-difluoro-1,2,3,4-tetrahydronaphthalene-2 —Base) — 1 > 3-dihydrooxazole — 2 —thione substitution to produce 5-aminomethyl — 1 — (6,7—difluoro-1, 2, 3, 4 — tetrahydrocae —2 —based) — 1, 3_dihydro brand — 2 —thione hydrochloride, melting point 260 — 263Ό (decomposition); (S) -5 — cyanide 1- (6,7-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl) -1,3-dihydrooxazole-2 -thione substitution to obtain (S) — 5-Aminomethyl-1,1- (6,7_difluoro-1,2,3,4-tetrahydronaphthalene-2, yl) -1,3-dihydroimidazole-2, thioketone hydrogen odorant, melting point 253 — 27〇υ; and 5-cyano-1- (5,6-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl) -1,2,3-dihydrooxazole-2 —Thionone substitution to obtain 5-aminomethyl-1— (5,6-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl) -1,3-dihydroimidazole-2 —Sulfur_ -140- The size of this paper applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) (please read the precautions on the back before filling this page) 470741 A7 B7 5. Description of the invention () Hydrochloride, Melting point is greater than 280 ° C. Example 2 1 1— (5 * 7—difluoro-1,2,3,4-tetranaphthalene-2—yl) -5 (1H) -tetrazol-5-yl-1,3-dihydrooxazole —2 —Thionone M is prepared in the formula I (a) in which η is 1 and t is 2, 5- and 7-positions. R1 is fluorine, and R5 is 1H-tetrazol-5-based compound. Printed by the Consumer Bureau of the Bureau of Standards (please read the precautions on the back before filling this page) The 5-cyano-1 1- (5,7-difluoro-1, 2, 3, 4--4) prepared in Example 19 Hydronaphthalene-2-yl) -1,3-dihydrotetrazole-2-thione (0.554 g, 1.9 mmol) in 1 * 6 ml of tributyltin hydrazine under 130 ¾ of nitrogen The mixture was heated for 2.5 hours, and then 10 ml of toluene was added. The mixture was cooled to room temperature and about 5 ml of diethyl ether was added. The mixture was cooled to 0 ° C and then treated with 10 ml of 1N hydrogen chloride (in diethyl ether) for about 15 minutes. The mixture was poured into a solution of potassium fluoride monohydrate (15.0 g) in 15 to 20 ml of water and 75 ml of ethyl acetate. The ethyl acetate layer was extracted with 2N sodium hydroxide, and the aqueous layer was washed 6 times with methylene chloride. The aqueous layer was acidified with concentrated hydrochloric acid and then extracted with ethyl acetate. The solvent was evaporated to obtain 1- (5,7-difluoro-1,2,3 > 4-tetrahydronaphthalen-2-yl) -5 (1H) -tetrazol-5-yl-1,3-di Hydroimidazole — 2 — thioketone (0 · 57 g * 1 · 7 mmol), melting point 214 2 — 2 15¾ ° -141- This paper size applies to China National Standard (CNS) A4 (210X297 mm) 470741 Ministry of Economic Affairs Printed by the Consumer Standards Cooperative of the Central Bureau of Standards. B. B. V. Description of the invention () It was carried out according to Example 21, but the 5-fluoro-1— (5,7—difluoro-1, 2, 3, was replaced with a different starting material. 4-tetrahydrocae-2-yl) -1,3-dihydroimidazol-2-sulfur is used to prepare a compound of formula I as follows: Using 5-amino- 1- (5,6-difluoromethane) 2 —yl) — 1, 3 —dihydroimidazole — 2 —thizone substitution to obtain 1 — (5,6 — difluoroindan_2 —yl) — 5 (1 Η) — tetrazol — 5 —yl 1-3 -dihydrooxazole-2 -thione, melting point 142Π-147Ό; and 5 -cyano-1-(6,7 -difluoro-1, 2,3,4-tetranaphthalene-2 —Base) —1,3-dihydroimidazole—2—thione to produce 1- (6,7—difluoro-1, 2, 3, 4 Tetrahydronaphthalen-2 '- yl) -5 (1Η) - a-tetrazol 5 - yl - 1, 3 - dihydro-oxazole an amidine 2 - thione, m.p. 195 - 212 ° C. Example 2 2 3-(1,2,3,4-tetrahydronaphthalene-2-yl) _2-thioxo-2,3-dihydro-1H-imidazole-5-5-carbaaldehyde M (a) A compound in which η is 1, t is 0, R3 and R5 are hydrogen, and R4 is a methylamino group. 2-Isothiofluoro-1,1,2,3,4 tetrahydronaphthalene (1. A mixture of 89 g, 10 mol) and D — (+) glucosamine (1.78 g, 10 mmol) was stirred at 90 ° C until homogeneous, and then 0.8 ml of acetic acid was added. The mixture is stirred at 〇υυ-142- This paper size applies Chinese National Standard (CNS) Α4 specification (210 × 297 mm) (Please read the precautions on the back before filling this page) A7 B7 V. Description of the invention () Mix for 30 minutes, and then cool it. The solvent was removed on a rotary evaporator and the residue was co-evaporated with toluene (2 x 25 mL). The residue was dissolved in acetic acid and heated at 90 ° to 100 ° C for 30 minutes. The mixture was cooled and triturated with acetone to obtain a crystalline material. The material was separated by filtration, and the residue of the filter paper was washed with acetone * and dried to obtain 4-(1R, 2R, 3S, 4) -tetrahydroxybutan-1-yl) -1 (1,2,3,4_ tetrahydronaphthalene-2- Radical) -1,3-dihydrooxazole-2-thizone (1. 48 g * 4. 23 Moore). 4-(1R, 2R, 3S * 4) _ tetrahydroxybutan-1-yl) -1 (1,2,3,4 -tetrahydrocae-2-yl) -1 * 3-dihydrooxazole -2 — Suspension of Thione (0. 252 g, 0. 72 mmol) and lead tetraacetate (0.85 g, 1 * 92 mmol) in 15 ml of 3 3% acetic acid / benzyl agitate until 30 After minutes the mixture was homogeneous. The reaction mixture was poured into 1 2 5 liters of saturated sodium carbonate solution. • The mixture was filtered. The organic layer was separated, dried over magnesium sulfate, and concentrated. The residue was dissolved in 40 ml of tetrahydrofuran and 2 ml of sulfurous acid (6% S02). Evaporate the solvent to obtain 3 — (1,2,3 * 4 —tetrazapene — 2 —yl) — 2 —thioxo-2, 3 —dihydro-1H — pan beer — 5 — carbaldehyde (0 · 1 5 grams, 0 * 59 millimoles), melting point 206 2 — 2 10 1 ° according to Example 22, but with (S) — 2 —isothiocyanato — 5, 7 —difluoro — 1, 2, 3, 4 —Tetrahydronaphthalene is substituted for 2 —Isothiocyano—1,2,3,4_ Tetrahydronaphthalene to obtain (S)-3-(5 * 7 -143- This paper size applies to China National Standard (CNS) A4 specifications (210X297 mm) (please read ^: the above precautions before filling out this page) 470741 A7 _B7_ V. Description of the invention () — difluoro-1, 2, 3 * 4-tetranaphthalene — 2 -yl)- 2-thio-2,3-dihydro- 1 hydrazone-imidazole-5 -carbaldehyde, melting point is greater than 2 8 5 1 ° Example 2 3 [(5,7-difluoro-1, 2, 3, 4 one four Benzene naphthalene 2-yl) (methylamido) amino] ethyl acetate M is prepared in the following formula 17 in which η is 1, t is 2,5- and 7-positions R1 is fluorine, R3 2 is ethoxy Carbonyl. 5,7-difluoro-1,2 * 3,4-tetrahydronaphthalene-2 ~ ylamine (6 * 0 g, 32. 8 millimoles) and dihydroxyethyl acetate (4.6 g, 36.0 millimoles) in a mixture of 300 ml of acetic acid on 10% carbon palladium (0. 75 g) hydrogenated for 10 hours. When it meets the filter compound, it is concentrated by evaporation. The residue was passivated by column chromatography in silica gel (eluent: 30% ethyl acetate / hexane) to obtain [(5,7-difluoro-1,2,3,4 —tetralin-1 — (Amino) amino] ethyl acetate (7. 5 grams, 27. 9 millimoles). Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page) [(5,7 —difluoro_1, 2,3 * 4 — tetrahydronaphthalene-2-yl) amine 〕 Ethyl acetate (7. 15 grams, 25. 6 millimoles) in 20 mL of methylene chloride was cooled to about 0 in argon. Acetic acid formic anhydride (9.7 mL, 67.3 millimoles) cooled to 0C was added to the mixture. Stir at 0 ° C for 2 hours, then allow to warm to room temperature. Co-evaporated with toluene (3x50 ml) to remove the solvent. -1 4 4 · " This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 470741 Μ B7 V. Description of the invention () Crystallize the residue in a high vacuum to obtain [(5,7 —difluoro -1,2,3,4-tetrahydronaphthalene-2-yl) (methylamido) amino] ethyl acetate (7. 68 grams, 25. 0 millimoles). Example 23 was carried out, but 5,7 ~ difluoro_1,2,3,4-tetrahydronaphthalene-2-ylamine was replaced with different starting materials to obtain a compound of formula 17 under K: using 6,8 —Difluoro-1,2,2,3,4-tetrahydronaphthalene-2-ylamine substitution to obtain [(6,8 —difluoro-1,2,3,4-tetrahydronaphthalene-2 —yl) ( Formamyl) amino] ethyl acetate; Substituted with 4,6-difluoroindan-2-ylamine to obtain [(4,6-difluoroindan-2-yl) (methylfluorenyl) amine []] Ethyl acetate; Substituted with 5,7-difluoroindan-2-ylamine to obtain [(5,7-difluoroindan 2-yl) (methylamido) amino] ethyl acetate And substituted with 5 * 6-difluoroindan-2-ylamine to obtain [(5,6-difluoroindan-2-yl) (methylamido) amino] ethyl acetate. Example 2 4 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling out the tribute) 3 — [5,7 — difluoro-1, 2, 3, 4 — tetrahydronaphthalene — 2 — Group) —2-thio-2,3-dihydro-1H—imidazole—4—monoethyl carboxylate M is prepared in the following formula I (a) where η is 1 and t is 0, 5 — and 7-position R1 is fluorine, R3 and R4 are hydrogen, and R5 is ethoxycarbonyl group 0 [5,7 -difluoro-1, 2,3,4 -145- as prepared in Example 23- This paper size applies to Chinese National Standard (CNS) A4 specifications (210X297 mm) 470741 A7 B7 Printed by the Central Laboratories of the Ministry of Economic Affairs, Masonry Consumer Cooperative, V. Description of the invention (7 • 5 8 1 1 g 9 2 4 • 7 mol) and ethyl formate (5 • 9 1 ml »7 2 · 7 1 | please 1 | millineur) mixture in 60 ml of tetrahydrofuran Cool to k in neutral gas. Read 1 I-10 V 〇 Add in 4 5 ml of tetrahydrofuran Tertiary potassium butoxide (read 1 1 I 4 0 8 grams 3 6 * 4 millimoles), the mixture is stirred at -10 V | Note I 2 hours 0 Allow the mixture to warm to room temperature and stir for 4 hours 〇 Removal by evaporation 1 I again 1 | Solvents »The residue was dissolved in 7 5 ml of 1 Ν hydrochloric acid and 50 ml of ethanol 4 1 gram of milligram 〇 added potassium thiocyanate (2 6 5 7 5 mol) The mixture is on page 1 I 8 5 V Search for 15 hours 0 Cool the mixture > Μ 1 2 5 ml water dilution 1 1 Extraction with ethyl acetate 0 Extracts are dried with sulphuric acid and rotary evaporation 1 | Remove ethyl acetate 〇Residue was purified by column chromatography on silica gel (eluent: 25% methanol, methanol / methylene chloride) to obtain 3—C 5 7 1—difluoro—1 2 3 4 — tetrahydronaphthalene — 2 a base) — 2 a sulfur 1 1 1 2 3 — * Dihydro-1 1 Η — Imidazole 4 — Ethyl carboxylate (8 0 7 1 I g 2 4 6 mmol) Melting point 1 5 9 TC 1 16 1 1C 0 1 2 4 Perform 1 but replace C (5 »1 7 -difluoro — 1 2 3» 4-tetralin-2 -yl) mono (formamidine 1 1 -amino) amine] ethyl acetate 9 with a different starting material 9 Preparation of a compound of the formula I: 1 1 with C (6 > 8 a difluoro — 1 2 »3 t 4 a 'tetrahydrodi —. 2 1 I mono)-(methylformyl) amino] Substituted 1 with ethyl acetate to obtain 3 mono (6 1 1 * 8 — difluoro-1 t 2, 3 $ 4 monotetrahydronaphthalene — 2 mono) — 2 1 1 1 Thio 2 3 — Dihydro — 1 hydrazone — oxazole — 4 ethyl carboxylate »melting point 1 1 1 8 7 V — 1 8 9 V 1 I 146- 1 1 1 Applicable to this paper size Chinese National Standard (CNS) A4 specification (2! OX 297 mm> 470741 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention () Use (1,2,3,4-tetrahydronaphthalene-2 — () (Monomethyl) amino] acetic acid ethyl ester to obtain 3- (1 * 2,3,4-tetrahydronaphthalene-2-yl) -2-thio-2,3-diargon -1 fluorene-oxazole-4-carboxylic acid ethyl ester, melting point 70t:-72¾; using (7-fluoro-1,2,3,4-tetrahydronaphthalene-2-yl)-(methylamido) amino ] Ethyl acetate was substituted to obtain 3- (7_fluoro-1,2,3,4-tetrahydronaphthalen-2-yl) -2-thioxo-2,3-dihydro-1H-imidazole-4 —Ethyl carboxylate; (4,6-difluoroindane 2-()-(methylamino) amino] ethyl acetate was substituted to obtain 3- (4,6-difluoroindan-2-yl) -2-thioxo-2,3-dihydro-1H —Miwa-4 ethyl acetate; Substituted with (5,7-difluoroindan-2-yl)-(methylamido) amino] acetate to obtain 3- (5,7-di Fluoroindan-2-yl) -2—thio-2,3-dihydro-1H—panil-4-ethyl fumarate; and (5,6-difluoroindan-2-yl) -1 (Methylformyl) amino] ethyl acetate is substituted for * to obtain 3-(5,6-difluoroindan-2-yl) -2-thio-2,3-dihydro-1H-imidazole-4 1 Ethyl Acetate of Carboxylic Acid. Example 2 5 3-[1,2,3,4 -tetrahydronaphthalene-2 -yl] -5 -methyl-147- (Please read the precautions on the back before filling this page) This paper size Applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 470741 Α7 Β7 Printed by the consumer cooperation of the Central Standards Bureau of the Ministry of Economy 1 Η-imidazole-4 monocarboxylic acid ethyl ester K is prepared in formula I (a) where η is 1 , T is 0, R3 is hydrogen, R4 is methyl * R5 is ethoxycarbonyl. A solution of diisopropylamine (1.54 milliliters, 11 millimoles) in 30 milliliters of anhydrous tetrahydrofuran was cooled to 0 in argon and added with n-butyllithium (6. 25 ml, 10 mmol), the mixture was cooled to -78C, and [5,7-difluoro-1,2,3,4 -tetrahydro] prepared in Example 23 in 20 ml of tetrahydrofuran within 15 minutes Naphthyl) (methylamino) amino] acetic acid ethyl acetate (1.33 g, 5.0 mmol) was added to the mixture, and the mixture was stirred at -7 8 υ for 1 hour, and acetamidine chloride was added within 5 minutes (0 · 427 ml, 6.0 · moles). The mixture was stirred at -78 Torr for 3 hours and allowed to warm to room temperature within 1 hour. The solvent was removed by evaporation and the residue was dissolved in 25 ml of 1N hydrochloric acid and 25 ml of acetic acid. Potassium thiocyanate (1.94 g, 20 橐 Mor) was added, and the mixture was stirred at 75t: -8 0¾ 攒 for 18 hours. The mixture was cooled, diluted with water, and extracted twice with ethyl acetate. Ethyl acetate was reduced to a black oil. The residue was purified by column chromatography on a sand gel (eluent: 2% methanol / methylene chloride), and developed by ethyl acetate / isopropyl ether to obtain 3-[1,2, a light yellow solid. 3,4 Tetrahydronaphthalene-2 —yl) — 5 —methyl — 2 —thio — 2,3 —dihydro — 1 Η — oxazole — 4 —carboxylic acid ethyl ester, melting point 225 Ό-227 * 0. Follow Example 25, but replace [(1, -148- this paper; 1 degree with Chinese national standard ((:] ^) person 4 specification (210 father 297 mm)) with different starting materials (please read the back Note: Please fill in this page again) 470741 Printed by A7 B7, Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention () 2,3,4-tetrahydronaphthalene-2-yl)-(methylamido) amino] acetic acid Ethyl and / or acetamidine nitrides to prepare M compounds of the following formula I: Substituted with isobutyrium chloride to prepare 3_ [1,2,3,4-tetrahydronaphthalene ~ 2-yl) -5-propyl -2-thio- 1 * 3-dihydro-1 Η-imidazole-4-carboxylic acid ethyl ester, melting point 1 95 ° C-1 97 υ > Substituted with trimethylacetamidine chloride to prepare 3-[1 , 2,3,4-tetrahydronaphthalene- 2-yl)-5-(1,1-dimethylethyl)-2 -thio-1,3-dihydro-1 hydrazone -imidazole- 4 -carboxylic acid Ethyl foam; Substituted with (5,7-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl) (methylamido) aminoethyl acetate to prepare 3— [5,7 — Difluoro-1,2,3,4-tetrahydro Naphthalene-2 -yl) -5 -propyl -2 -thio-1, 3 -dihydro-1, -imidazole-4-carboxylic acid ethyl ester * Melting point 207-209 ° C; and ethyl chloroacetate chloride Substitute * to prepare 3-(5,7 -difluoro-1,2,3,4-tetrahydronaphthalene-2 -yl) -5 -ethoxycarbonyl -2 -thio-l 1,3-digas-1 Η -Pan-1-ethyl fumarate, melting point 160 ° C-161¾. Example 2 6 5 —Aminomethyl-4— [1,2,3,4-tetrahydronaphthalene-2 • yl) -2,4-dihydro [1,2 * 4] trifluorene-3—thione -149- This paper size applies to Chinese National Standard (CNS) A4 (2 丨 0X297 mm) (Please read the notes on the back before filling in this 1) 470741 A7 B7 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Description of the invention () 1 1 IK is used to prepare a compound of formula I (b) where η is 1 t is 0 R 7 is an amine 1 1 methyl group 0 1 I cyano please 1 1 Sulfur 1 2 »3 4 Read first I tetrahydronaphthalene (0 1 9 g» 1 0 millimolar) and (tertiary butyloxy back 1 1 I carbonyl) amino ethyl hydrazine (0 • 1 9 G 1 1 mM) Mix the phonetic substance in 5 ml of dimethylformamidine under nitrogen at 80 V and heat it for 2 5 items at 1 I for another 1 h. Using a rotary evaporator Remove the solvent residues at room temperature f 1 with nitrogen and stir. Add 4 5 ml of sodium ethoxide mixture (prepared on page 1 to 4 and 1 5 g of acetic acid). The reaction mixture is refluxed under nitrogen for about 2 4 1 Let it cool for 1 hour and then filter it. Remove the solvent residue with a rotary evaporator. 1 The retentate is dissolved in water. The solution is acidified to P with 10% hydrochloric acid. Evaporate water to give 5- (tertiary-butyloxycarbonyl) aminomethyl-4- (1 2 3 4 tetrahydronaphthalene-2 2-yl)-1 1 I 2 4 -dihydro (1 2 4 3 Triazole-3 trithizone (0 2 0 3 1 1 g 0 5 6 mol) 〇ί Add anhydrous hydrogen chloride (4 2 2 g) to 15 ml of ethyl acetate in a 1 methanol bath of ice. 5 — (tertiary butyloxycarbonyl) aminomethyl 1 — 4 — (1 2 3 4 — tetrahydronaphthalene-2 Based)-2 9 4 1-dihydro (1 2 4) azole-3-thione (0 1 7 8 g 1 1 1 0 4 9 mil) f The mixture is searched at room temperature. Added ether mixed 1 I was overfilled in nitrogen, and the solvent was evaporated under reduced pressure to obtain 5-aminomethyl 1-4 (1 9 2 9 3 t 4 -tetrahydronaphthalene-2 2-yl)-2 »4-1 1 2 Hydrogen (1 9 2 »4] Triazole — 3 monothione hydrochloride (0 ♦ 1 2 5 1 1 150- 1 1 This paper size is applicable to the Chinese National Standard (CMS) A4 specification (210X 297 mm) 470741 Economy Printed by the Consumer Standards Cooperative of the Ministry of Standards of the People's Republic of China A7 B7 V. Description of the invention (g, 0.41 millimolar) * Melting point 279P-28 ID. According to Example 26 * but replacing 2-isothiocyano-1, 2,3,4-tetrahydronaphthalene and / or (tertiary butyloxycarbonyl) aminoacetamidohydrazine with different starting materials, A compound of the formula I is prepared as follows: 5-isothiocyano-1,2,3,4-tetrahydronaphthalene and 4-methyl # azine-1-ylacetamidohydrazine are used to prepare 5- (4-methyl Piperazine-1, 1-yl) _4, [1,2,3,4-tetrahydronaphthalene-2, 2-yl) -2 • 4-dihydro [1,2,4] triazole-2-thione, melting point 217¾ —2 1 8 ° C; and (S) —5,7 -difluoro-2 —isothiofluoro-1,2,3,4-tetrahydronaphthalene and (tertiary butyloxycarbonyl) amine Ethyl hydrazine, Preparation of (S) -5-aminoaminomethyl-4- (5,7-difluoro-1, 2,3,4-tetrahydronaphthalene-2-yl) -2 * 4-2 Hydrogen [1,2,4] triazole-3-thione and (S) -5-aminomethyl-1 4- (5,7-difluoro_1,2,3,4-tetrahydronaphthalene-2 —Yl) -1,2,4-dihydro [1,2,4] triazole-3-thione hydrochloride, with a melting point greater than 280 I. Example 2 7 2_ [1,2,3,4-tetrahydronaphthalene-2 -yl) -2,4-dihydro [1,2,4] triazole-3-thione M is prepared in the following formula I (c A compound in which η is 1, t is 0, and R8 is hydrogen. -151- This paper size is in accordance with Chinese National Standard (CNS) A4 (210X297 mm) (Please read the notes on the back before filling this page) 470741 Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Invention Description () 1,2,3,4-tetrahydronaphthalene-2 ketone (3. 5 grams, 24. 0 milliliters) and hydrazine formate (1.56 g, 26.0 millimoles) in 25 ml of ethanol and 1 drop of concentrated hydrochloric acid * heated at 70 ° C for 1 hour. The mixture was cooled to room temperature to obtain a crystalline material, which was separated by filtration and washed with ethanol. After drying, 2-formamidine-1,2,3,4-tetrahydronaphthalene (3. 5 grams, 8 ♦ 7 millimoles). 2-Methylhydrazine-1,2,3,4-tetrahydronaphthalene (3.0 g • 16.0 mmol) and borohydride (1,2 g, 31. 6 mmol) in 25 ml of ethanol and stirred at room temperature for 20 hours. The mixture was quenched with water and extracted with ethyl acetate (2x25 ml). The combined ethyl acetate extract was washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by flash calendar analysis (eluent: 2% methanol / methylene chloride) to obtain 2-methaneidene-1, 2, 3, 4-tetrahydronaphthalene (2. 0 grams, 10. 7 millimoles). 2 -formamidine-1,2,3,4-tetrahydronaphthalene (2 0 0 g, 10 · 7 mmol) and trimethylsilyl thiofluorate (2. 8 grams, 21. 0 mmol) in 20 ml of toluene and stirred at 60 ° C. to 65 ° C. for 20 hours to obtain a crystalline substance, which was separated by filtration and dried to obtain N — [(1,2,3,4-tetrahydronaphthalene —2 —yl) (aminothio_carbonyl) amino] methylamine (0. 6 grams, 2. 4 millimoles) 0 N-[(1,2,3,4-tetramethylnaphthalene- 2-yl) (aminothio-carbonyl) amino] methanamine (0. 6 grams, 2. 4 millimoles) at -152- This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) ---------- W-- (Please read the precautions on the back before filling in this Page) Order 470741 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention () 1 1 | 10 ml 10% solution formed in sodium hydroxide at 7 0 t! Add cooked 1 1 | 3 0 minutes 0 Cooling solution $ Acidify the solution with dilute hydrochloric acid > Extract with ethyl acetate rV 1 | Extraction 0 Wash the ethyl acetate extract with brine 9 Dry with sodium sulfate > Concentrate first 1 1 Read | Condensed 0 The residue was recrystallized in acetic acid / hexane, and 2 was obtained after reading # | I — C 1 »2 9 3 > 4 Tetrahydronaphthalene — 2 -yl) — 2 9 4 Dihydrogen Note 1 1 meaning 1 | t 1, 2 > 4 triazole-3 monothione (0 • 2 5 g 1 • 0 6 matter 1 I mol) melting point 2 0 0 • 5 V 〇 refill 1 1 Page 1 1 I Example 2 8 1 1 4 Monoamino — 2 —C 1, 2 3, 4 Tetrahydronaphthalene — 2 — 1 1) -2 4 — Dihydro [1 2, 4] triazole 1 3 Monothione 1 The following formulae are used to prepare compounds of formula I (C) where η is 1 »t is 0 and R 8 is an amine 1 group. 0 1 1 2 Monobromo— 1 2 3, 4 —Tetralin 6 g of 5 1 I michelel) and 4 monoamine C 1, 2 t 4] triazole (2 • 1 g 1/2 1/2 mol) in 8 ml of dimethylformamide »on 9 0 V 1 Heat and stir for 2 hours. Evaporate to remove the solvent. The residue is dissolved in 5 ml of pyridine. Add shellac sulfur (0 16 g * 5 mol) and 2 • 5 milliliters of 1 1 triethyl. The amine 9 mixture was heated and stirred in the air at about 90 V for 4 hours. 1 I 〇 Evaporation to remove the solvent 9 Co-evaporation of the residue with methylbenzyl chloride> Chromatography (punching 1 1 extract with 5% methanol / Methylene chloride) for purification »to obtain 4-amino 1 1-2-C 1» 2 f 3 > 4-tetrahydrocae-2 -yl)-2 4 — 1 1 dihydro [1% 2 4) Triazole-3 monothione (0 * 3 5 g 9 1 • 4 2 1 | -153- 1 1 This paper size applies to China National Standard (CNS) A4 (210X297 mm) 470741 Central Bureau of Standards, Ministry of Economic Affairs A7 _B7_ printed by the employee consumer cooperative. V. Description of the invention () mol), melting point 147-150¾. Example 2 9 (S) -N-[3 — (5,7 -difluoro-1,2,3,4-tetrahydronaphthalene-2-yl) -2—thioxo-2,3-dihydro-1 Η mono-oxazole-4-ylmethyl] formamidine M is prepared in the following formula I (a) where η is 1 and t is 2, 5-and 7 R 1 is fluorine * R 5 is formamidomethyl Compounds. Methylamine (250 ml, 6. (3 mmol) was heated to 175 ° C, and (S) 5-hydroxymethyl-1 1- (5,7-difluoro-1,2,3,4- Siqi Cai-2 Yiji) -1,3-dihydroimidazole_2-thione (25. 0 g, 88.3 millimoles) was added in portions, and the reaction mixture was stirred under nitrogen for 1 hour. Cool the mixture to 50 t: add 2 ♦ 5 g of live carbon (Darco®). The mixture was cooled to 30 ° C, filtered through Celite, and washed with 25 ml of formamidine. Heat the mash to 95 ° F, then add 1 liter of water dropwise. The mixture was allowed to cool and then stirred at room temperature for 12 hours. The mixture is cooled to 0. A crystalline material is obtained. The material was separated by filtration and dried. This material was stirred with about 5 times the weight of 70% tetrahydrofuran / 3 0% hexane for 5 minutes. Isolate the material through tritium, and wash the paper residue with 50% tetrahydrofuran / 50% hexane. • Dry to constant weight to obtain (S) — N — [3-(5, 7 — difluoro-1, 2, 2, 3,4 Tetrahydronaphthalene-2 -based " 15 4- This paper is compliant with China National Standard (〇奶) 8 4 specifications (210 father 297 mm) ---------- 'pack ------ Order ------ (Please read the notes on the back before filling out this page) 470741 Printed by the Central Standards Bureau of the Ministry of Economic Affairs—Industrial and Consumer Cooperatives A7 B7 V. Invention Description ()) —2 — Thio-2,3-dihydro-1H-methyl-1, 4-methylmethyl] formamide (19.5 g, 62.7 mmol), melting point 245 -2 4 6 Ό ° [a] p +48. 9 ° (c = 0. 613, DMS 0) 〇 According to Example 29, but (S) 5-hydroxymethyl-1-(5,7-difluoro-1, 2, 3, 4-tetrahydro) was replaced with a different starting material Naphthalene-2-yl) -1,3-dihydroimidazol-2-sulforamide or formamidine to prepare a compound of formula I (a) below: (S) -5 -hydroxymethyl-1 1- (6 (7) -Difluoro-1,2,3,4-tetrahydronaphthalene- 2-yl) _1,3-diargylimidazole-2-thione substitution to obtain (S) — N — [3 — (6, 7-difluoro-1,2,3,4-tetrahydronaphthalene- 2-yl)-2 -thio-2, 3 -dihydro- 1H -oxazole- 4-methylmethyl] formamide; and Substituted with urea to obtain (S) _5 —Orylmethyl-1 1 (5, 7 -difluoro_1, 2,3,4 -tetrahydronaphthalene-2 -yl) -1,3 -dihydroimidazole- 2-ketone, melting point 258-260 it, [α + 34. 3 ° (c = 0. 574, DMSO). Example 3 Ο (S) -N — [3-(5,7-difluoro-1 * 2,3,4-tetrahydronaphthalene_2-yl)-2-thio-2,3-dihydro-11 ^ Imidazole-4 monomethyl] formamidine M is prepared in the following formula I (a) where η is 1 and t is 2 * 5 —and 7 -155— This paper size applies to Chinese National Standard (CNS) A4 specifications (210 X 297 mm) (Please read the notes on the back before filling this page) · A. 470741 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs A7 B7 V. Description of the invention () _ Position R1 is fluorine and R5 is a methylaminomethyl compound. (S) -5-hydroxymethyl-1_ (5,7-difluoro-1,1,2,3,4-tetramethylnaphthalene-2-yl) -1,3-dihydroimidazole-2 as in Example 18 was prepared -A mixture of thioketone (1.0 g, 3 * 5 mmol) and formamidine is stirred at about 1 2 5 v for 1 hour, then the mixture is heated to about 1 3 8 C, and stirred for 3 5 minutes. The mixture was diluted with 25 ml of water and allowed to cool to room temperature. The mixture was aged for about 18 hours to obtain a crystalline material. Isolate this material by washing * Washing the paper residue with water * Drying to constant hydration to obtain (S)-N — [3 — (5, 7 —difluoro-1, 2, 2, 3, 4 — tetrahydronaphthalene — 2 — group) ) 2-sulfur 2, 3-dihydro-1H-oxazole-4-methylmethyl] formamide (0, 9 2 g, 2. 96 millimoles). Example 30 was carried out, but ammonium acetate was replaced with ammonium acetate, (S) -N-C 3-(5,7 -difluoro-1,2,3,4-tetrahydronaphthalene-2'-yl) -2 — Thio-2,3-dihydro-1H —oxazole-4 —ylmethyl] acetamidine, melting point 275 — 276¾, [α] ρ = + 41-3 ° (c = l -00 »DMS0) . Example 3 1 (S) -5 -aminomethyl-1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl) -1,3_dihydrooxazole- 2-Sulfur hydrochloride K is prepared under the formula I (a) where η is 1 * t is 2, 5 — and 7 -156- This paper size applies to China National Standard (CNS) A4 (210X297 mm)- --------- Binding ^ (Please read the notes on the back before filling this page) 470741 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention () 1 i 1 — Position R 1 is fluorine »R 5 is amine methyl compound 0 1 1 1 (S) -N — C 3-(5 t 7 '— V 1 1 difluoro-1 > 2 9 prepared as in Example 30 3 9 4 — Tetrahydrocai 2 1 base) — 2 monothio — Please read 1 I 2 3 1 dihydro 1 1 hydrazine 1 4 monomethyl 3 formamidine (1 9 back 1 1 I • 1 g > 5 9 • 0 mmol) and 25 ml concentrated hydrochloric acid (1 2 * Note I 0 Μ 2 5 ml 3 0 0 mmol (Ear) The mixture was heated to reflux in 400 ml 1 I steamed and 1 I propionate was heated to reflux 1 2 fen $ $ stirred 1 yttrium 40 minutes 〇 write 1 If the mixture was distilled off 150 ml isopropion was removed 〇 Cool the mixture gradually to the chamber page λ 1 1 Warm for 3 hours 4 5 minutes 0 Filter to separate this material. Wash the filter paper residue with 7 5 ml 1 1 Isopropanol 0 1 1 0 1 2 5 and pass in nitrogen 1 (S) _5 monoaminoethyl-1 (5 > 1 order 7 difluoro-1 — 2 2 3 4 — tetrahydronaphthalene 2 —yl) ~ 1 f 3 1 1 — Dihydrooxazole — 2 —thionine hydrogen odorant (156 g t 4 7 Γ 1 1 1 mmol) Melting point 2 5 1 ♦ 9 ° c C OC Η h L 0 2. 1 1 (C = 0 5 0 0 D Μ S 0) 0 1 κ According to Example 3 1 Perform 9 but replace (S)-s) with a different starting material IN-C 3-(5 i 7 —-* Fluorine 1 1 f 2 3 4 Tetrahydronaphthalene — 1! 2 1 radical) 2 — thio-1 2 »3 — dihydro-1 1 fluorene — oxazole 4 — 1 1 methylmethyl 3 Formamide Compounds of the following formula I: 1 I Use (S) — * N — C 3 — (6, 7 — — ·. Fluoro-1 »2 9 3 1 1 I 4 Tetrahydrom — 2 —yl) 2 Monothione — 2 > 3 Dihydro — 1 1 1 hydrazone — imidazole — 4 —methylmethyl) formamidine Obtained (S) -5 monoamine 1 1 methyl — 1 mono (6 $ 7 — difluoro — 1 2 f 3% 4 — tetrahydrocae — 1 I 157- 1 1 This paper size applies + national standards (CNS) A4 specification (210 X297 mm) 470741 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention () 2-based) -1,3-dihydrooxazole-2 -thione hydrochloride Compound, melting point 1 9 Ο υ (decomposition); using (S)-4-{2-[4-methylamidoaminomethyl- 3-(5,7-difluoro-1, 2, 3, 4- Tetrahydronaphthalene-2-yl)-2 -thio-2,3-dihydro-1,1-imidazole-1 -yl] benzoic acid to obtain (S) —4— 〖2— [4-monoamine Methylmethyl 3- (5,7 —difluoro-1,2,3,4—tetrahydronaphthalene—2-yl) —2-thizone-2,3—dihydro1—1-oxazole—1 radical ] Ethyl} Panoic acid hydrochloride, melting point 246-248 ° C): and (S) - 3 - [4 - methyl acyl amino methyl-3 - (5,7 - bis-Fluoro-1. , 2,3,4-tetrahydronaphthalene-2-yl) -2-thio-2,3-dihydro-1H-imidazole-1-yl] propanoic acid to obtain (S) — 3 — [4 — Aminomethyl-3— (5,7—difluoro-1 * 2,3,4—tetrahydronaphthalene-2—yl) —2—thione—2,3—dihydro-1H—imidazole—1 ~ Group] propanoic acid, melting point 191 ° C) (evaporation) ° Example 3 2 (S)-1-(5,7 -difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)-5- Pyrrolidine-1-ylmethyl-1,3-dihydrooxazole-2 is prepared below the sulfur surface in formula I (a) where η is 1 and t is 2 · 5 — and 7 R1 at a position is fluorine, R3 and R4 are hydrogen, and R5 is pyrrolidine 1 -158- This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) I --------- packing ------- Order ------ line (please read the notes on the back before filling this page) 470741 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention () 1 1 | Monomethyl compounds 0 1 1 | (S) — 1 one (5 »7-difluoro — 1 1 1 > 2 prepared as in Example 1 8 3 > 4-tetrahydronaphthalen-a - 2 a-yl) - 5-hydroxy-a-methyl-a 1 to 1 Please read 1 | »3 - dihydro-imidazol-2-thione (140 mg t 0. 4 7 奄莫读背 | © I ear) 1 in 2 ml of tetra-ksst S furan and 1 drop of dimethylformamide 1 I liquid cooling means 1 I dissolved to 0 and 5 t: under nitrogen Add sulfurous chloride dropwise (13 items 1 1 • 7 μM * 1 0 9 μl f 1 4 9 μmol) * The mixture was filled at room temperature and then stirred at 0%%. 5 hours 9 Then cool the mixture to 0 and 5 ° C »Add pyrrolidone 1 tol (12 0 Μ 9 8 1 8 µl 9 * 8 mol) 0 mix in the mixture 1 * 5 hours The solvent was removed by evaporation, and the residue was diluted with water. Ethyl acetate was added to the dilution to adjust the mixture to 70 to dry. The dried ethyl acetate layer was concentrated by evaporation, and the residue was purified by column chromatography. Obtain (S) — 1 — (5 7 — difluoro — 1 2 3, 4 1-4 1 1 hydronaphthalene 2 —yl) — 5 — pyrrolidine — 1 — methylmethyl — 1 · 3 — di 1 I hydrogen Oxazole-2 — thione (100 mg 0 2 9 mmol) 0 1 1 h [a] D--10 9 6 ° (C =: 1 L 3 DMS 0) k 1 with 2 ear equivalents 1 Μ « < rn * SR Hydrogen chloride (in diethyl ether) treated with t 1 1 to obtain (S)-1-(5 7-difluoro-1 f 2 ρ 3, 4-tetra 1 I hydrogen CAI-2 -yl)- 5 —pyrrolidine-1 —ylmethyl — 1, 3, 12 1 I Hydroxazol-2 monothione hydrochloride (100 mg > 0.26 mmol 1 1 ear) Melting point 1 8 7 ° C-1 8 9 V 〇1 1 According to Example 3 2 but t (S)-1 i 5-hydroxymethyl 1 — (5 9 7-difluoro — 1 $ 2, 3 9 4 — i I • 159- 1 1 1 This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) 470741 Printed by A7 B7, Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of invention () Tetralin 2-yl) -1,3-dihydroimidazol-2-thione, to obtain a compound of formula I below: Substituted with methylamine to obtain (S) -1 — (5,7 —difluoro — 1, 2,3,4-tetrahydronaphthalene- 2-yl) -5-(methylaminomethyl) -1, 3-dihydrooxazole-2 -thione, Points 250 — 26 0¾, and (S)-1-(5,7 —difluoro-1, 2 * 3,4 —tetrahydronaphthalene — 2 —yl) — 5 — (methylaminomethyl) — 1 , 3_ dihydroimidazole-2-thione hydrochloride, melting point 250¾. [a] D 25 + 7.7. (C = 2.4, DMS0);); Substituted with dimethylamine to obtain (S) — 1 — (5,7 —difluoro-1, 2, 3, 4 — tetrahydronaphthalene — 2 —yl) — 5- (dimethylaminomethyl) -1,3-dihydroimidazole-2-sulfur and (S) -1— (5,7-difluoro-1, 2,3,4-tetrahydronaphthalene -2 -yl) — 5-(dimethylaminomethyl) _1, 3-dihydroimidazole_2 —sulfide hydrochloride, melting point 207_208O ° C; Substituted with pyridine to obtain (S) — 1- (5,7-difluoro-1,2,2,3,4-tetrahydronaphthalene-2 -yl)-5-(pyridine-1 -ylmethyl)-1, 3-dihydroimidazole-2-thione and (S) -1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalene- 2-yl) -5- (pyridine-1-ylmethyl) -1,3-dihydro Imidazole-2-thione hydrochloride, melting point 1691-170 ^ 5, substituted with morpholine to obtain (S) _1 — (5,7 —difluoro-1 -160-) This paper is in accordance with the Chinese National Standard (CNS) A4 size (210 X 297 mm) (Please read the notes on the back before filling out this page) 470741 Printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 Description (), 2, 3 * 4-tetrahydrocae-2-yl) -5— (morpholine-4-ylmethyl) -1,3-dihydroimidazole-2-thione, melting point 198P ~ 201¾ [A] D 25-7.56. (C = 2.38, DMS 〇), and (S) — 1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalene-2 —yl) — 5 — (morpholine—4-yl) (Methyl) —1,3 —dihydrooxazole —2 —thione hydrochloride, melting point 182 " fluorene -1 8 4 1 0C; and substitution with 1-methylpiperazine to obtain (S) — 1- (5 * 7-difluoro-1,2,3,4-tetrahydronaphthalene- 2-yl) -5- (4-methylpentamidine-1-ylmethyl) -1,3-dihydroxazole -2 -sulfur_, and (S)-1-(5,7 -difluoro-1,2,3,4 -tetrahydronaphthalene -2 -yl) -5-(4 -methyl-1-#azine 1-ylmethyl) -1,3-dihydrooxazole-1 2-thione hydrochloride, melting point 237¾ -245¾ ° Example 3 3 1- (1,2,3,4 -tetrahydronaphthalene-2- Group) -4,5 bis (hydroxymethyl) -1,3-dihydrooxazole-1 2-thione K is prepared under the formula I (a) where η is 1 · t is 0, R3 is hydrogen, R4 and R5 is a hydroxymethyl compound. A mixture of sodium borohydride (0.22 g * 5.8 mmol) and anhydrous calcium chloride (0.34 g, 3.1 mmol) in 10 ml of anhydrous tetrahydrofuran at about 25t: Stir for 1 hour, then Added in 10 ml-1 6 1-This paper size applies to China National Standard (CNS) A4 (210X297 mm) (Please read the precautions on the back before filling this page) Order 470741 Central Standards Bureau of the Ministry of Economic Affairs Cooperative printed A7 B7 V. Description of the invention () Preparation in anhydrous tetrahydrofuran as in Example 25 3- (1,2,3,4-tetrahydronaphthalene-2-yl) -5—ethoxycarbonyl monothione— 1,3-dihydro-1H-imidazole-4 monocarboxylic acid ethyl ester (0.37 g, 1 mmol). Mix the mixture at 501¾ for about 72 hours • Then concentrate. The residue was treated with 20 ml of 10% sodium hydroxide and 50 ml of ethyl acetate, filtered, and the aqueous layer was extracted again with ethyl acetate (3 x 50 ml). The combined extracts were dried over magnesium sulfate and concentrated. The residue was stirred with methylene chloride / methanol (93: 7) and the mixture was stirred. The aqueous phase was evaporated to dryness and the residue was stirred with methanol. The methanol mixture was filtered * and then mixed with methylene chloride / methanol solution. The mixed mixture was concentrated. The residue was purified on silica gel (eluent: methylene chloride / methanol 9 3: 7) to purify the residue. To produce 1- (1,2,3,4-tetrahydronaphthalene-2-yl) -4,5-bis (hydroxymethyl) -1,3-dihydroimidazole-2-thione (35 mg, 0 ♦ 12 millimoles), melting point 1 99 ° C-2001C ° Example 3 4 3 — [3 — (1 * 2,3,4-tetrahydronaphthalene-2 —yl) -2_thioxo-2,3 —Dihydro-1, —oxazole — 1-yl] ethyl propionate is prepared in the following formula I (a) where η is 1 * t is 0, R3 is 2-ethoxycarbonylethyl, R4 and R5 are Compounds of hydrogen. 1- (1,2,3,4-tetrahydronaphthalene-162-) prepared as in Example 9 This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before (Fill in this page) 470741 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the Invention () 2-Base) 1 1 3 Dihydro-imidazole- 2 Monothione (1 3 g »5 6 mil ) Ethyl acrylate in 14 ml of ethanol (3 * 1 ml of 2 8 2 mmol) and 1 28 ml of N-benzyltrimethylammonium hydroxide (2 • 8 mmol) ) The mixture was heated at 80 t: under nitrogen for 2 hours. 0 The mixture was cooled. The residue was concentrated on a rotary evaporator. The residue was purified on silica gel (eluent: 3: 1 hexane / acetic acid acetate) and purified by chromatography. This gives 3 -C 3 — (1 2 3 4 -tetrahydrom -2 -yl) -2 -thio- 2-3 -dihydro-1 1-oxazole-1 -yl propionate (1 2 G 3 7 mmol) Melting point 7 1-7 3 v 〇 Followed Example 3 4 but replaced with a different starting material 1 1 (1 9 2 '3 4-tetrahydronaphthalene 2 -yl)-1 3-dihydro Monoxazole- 2 -thione is used to prepare the compound of formula I with 4-(1 2 3 4 -tetrahydronaphthalene-2 -yl)-5 -thiazole-1 5 -dihydro C 1 2 4 triazole-3 Monomethylaminocarbamic acid tert-butyl ester is prepared to 3-C 4-(1 2 3 4 -tetrahydronaphthalene-2 -yl) -3-(= butoxycarbonylaminomethyl)-5- Sulfate — 1 5 — Dihydro C 1 2 4 3 Triazole — 1 mono] Ethyl propionate and (S) — (1 1 (5 7 — Di Jksf Pro — 1 2 3 4 — Tetrahydronaphthalene — 2 —yl) — 1 3 —dihydroimidazole — 2 —thione to replace 9 to obtain (S) — 3 — C 3 mono (5 7 —difluoro — 1 2 3 ί 4 tetrahydrom — 2 —yl) — 2 — Sulfur copper 2 »One dihydro one 1-163- This paper size applies Chinese National Standard (CNS) A4 (210X297 mm) 470741 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs t. A7 B7 V. Description of the invention () H-oxazole-1-based Ethyl propionate, melting point 105-107¾ 0 Example 3 5 3-[3 ~ (1, 2, 2, 3, 4-tetrahydrocae-2-yl) -4 -dimethylformaminomethyl- 2-thiothio-2,3-dioxo-1Η-imidazole-1yl] ethyl propionate is prepared in the following formula I (a) where η is 1 * t is 0 and R3 is 2-(ethoxy Carbonyl) ethyl, a compound in which R4 is hydrogen and R5 is dimethylaminomethyl. 3- [3— (1,2,3,4-tetrahydrocae —yl) — 2 —thio-2,3 —dihydro-1 — hydrazone — 1-yl] prepared as in Example 34 Ethyl propionate (0.5 g, 1.5 mil) and N, N-dimethylmethylene ammonium chloride (0.17 g, 1.8 mil) were mixed in 7 ml of dimethylformamidine Heat at 80 ° C under nitrogen for 16 hours. The mixture was partitioned between saturated sodium bicarbonate solution and ethyl acetate. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate / hexane) to obtain 3-[3-(1,2,3,4 -tetrahydronaphthalene-2 -yl) -4- Dimethylaminomethyl-2, thio-2,3-dihydro-1, 1Η-imidazole-1, 1-yl] ethyl propionate (277 mg, 0.7 mmol), melting point 128t: ~ 130t :. Follow the example 35, but use 4— [3— (1,2,3, -164-) This paper size applies the Chinese National Standard (CNS) A4 specification (210x297 mm) (Please read the precautions on the back before filling in this Page) .. V-Order 470741 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention -Dihydro-1 H -oxazole-1 -yl] benzoate to obtain methyl 3- [3-(1,2,3,4-tetrahydronaphthalene_2-yl)-2- Thioxan-2,3 -di-M_1H-oxo-1-yl] acetic acid ethyl ester Example 3 6 1- (1,2,3,4-tetrahydronaphthalene-2 -yl) -4,5--2 (Dimethylamino)-1,3-dihydroimidazole- 2-thione M is prepared in the following formula I (a) where η is 1, t is 0, R3 is hydrogen, R4 and R5 are dimethylamine Methyl compounds. 1- (1,2,3,4-tetrahydronaphthalene-2-yl) -1,2-dihydrooxazole-2-thione (1 g, 4 * 3 mmol) prepared as in Example 9 , A mixture of ethyl acrylate (4.7 ml, 4 mM) and hydrochloric acid (1N in ether, 8.7 ml, 8.7 mmol) in 20 ml of ethanol at 8 Heat at 0 ° C and nitrogen for about 5 hours. The mixture was allowed to cool, concentrated and separated between saturated sodium bicarbonate solution and methylene chloride. The organic layer was separated, dried over potassium carbonate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (eluent: 99: 1 methylene chloride / methanol) to obtain 3— [1— (1,2,3,4, tetrahydronaphthalene-2— Propyl) imidazol-2-yl-thio] ethyl propionate (1.36 g, 4.1 mmol). 3_ 〔1 (1,2,3,4-tetrahydronaphthalene-2-yl) 眯 -165- (Please read the precautions on the back before filling this page) The paper size applies to Chinese National Standard (CNS) Α4 Specifications (210X297 mm) 470741 Α7 Β7 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention ) And N, N-dimethylmethylene ammonium chloride (1.66 g, 17. mmol) in 25 ml of dimethylformamide at 100 ° C. 〇 and heating in nitrogen for about 2 2 hours. The reaction mixture was cooled to about 90 p, and then additional N, N-dimethylmethylene ammonium chloride (0.83 g, 8.8 mmol) was added. The mixture was heated for 31.5 hours and then separated between sodium bicarbonate and ethyl acetate. The organic layer was separated, the cat was washed with water, dried over potassium carbonate, filtered, and concentrated. The residue was purified on silica gel (the extract solution was _5-10% formazan (methylene chloride).) And purified by column chromatography to obtain 3 — [1— (1, 2, 3, 4—14 Hydronaphthalene-2-yl) -4,5-bis (dimethylaminomethyl) imidazole-2 ~ yl-thio] Propionate (0.55 g, 1.2 mmol). 3-[1 -_ (1,2,3,4-tetrahydrocae-2yl) — 4 '5 — * (— * methylaminomethyl) propionate-2-1-monothio] propionic acid A mixture of ethyl acetate (0.55 g, 1.2 mils) and sodium ethoxylate (3.5 ml solution, prepared at 450 mg sodium and 4.5 ml ethanol, 1.4 mmol) In 5 ml of ethanol, stir for about 1.5 hours at about 25 ° C. The mixture was concentrated and the layers were separated between water and ethyl acetate. The organic layer was separated, washed with brine, dried over M carbonate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (eluent: 9 7: 3 methylene chloride / methanol) to obtain 1- (1,2,3,4-tetrahydronaphthalene-2-yl). One 4,5-bis (dimethylamino) -1,3-dihydroimidazole-2-thione (0.24 g, 0.7 mmol), fused-16 6 " This paper size applies to China National Standard (CNS) Α4 Specification (210X297 mm) ----- II II III ^ I ~ (Please read the notes on the back before filling out this page) 470741 Printed by the Consumers Cooperative of the China Standards Bureau of the Ministry of Economic Affairs A7 B7 i. Description of the invention () Point 182-184¾ ° Example 3 7 3-(5,7_ difluoro-1,2,3,4-tetrahydronaphthalene- 2-yl)-2 -thio-2,3- Dihydro-1H-oxazole-4 monocarboxylic acid is prepared under the formula I (a) in which η is 1 and t is 2,5- and 7-positions R1 is fluorine, R3 and R4 are hydrogen, and Rs is carboxyl compound of. 3- (5,7-difluoro-1,2,3,4-tetrakilai-2-yl) -2-thioxo-2,3--1M ~ 1Η-oxazole-1 prepared as in Example 24 A mixture of 4 ethyl monocarboxylate (4.6 g, 13.6 mmol) and potassium hydroxide (3.14 g, 47.6 mmol) in 130 ml of ethanol / water (10: 3) Stir at 85-90¾ for 5 hours. The solvent was removed by evaporation and the residue was dissolved in water. The solution was acidified with 1 N hydrochloric acid to a pH of 1 to obtain a crystalline substance. The substance was separated by tritium to obtain 3- (5,7-difluoro-1,2,3,4-tetrahydronaphthalene-2 2-yl)-2-thio-2,3-dihydro-111-fluorene. Mile one 4-carboxylic acid (3.86 g, 12.5 mTorr), melting point 250-2 5 2 ¾ °, carried out according to Example 37, but replacing 3 — (5, 7-difluoro with different starting materials -1,2,3,4-tetrahydronaphthalene-2 -yl)-2 -thio-2,3-dihydro- 1 H_imidazole- 4 -carboxylic acid ethyl ester 'to obtain -167- paper size Applicable to China National Standard (CNS) A4 specification (210X297 mm) I gutter (please read the notes on the back before filling this page) 470741 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the notes on the back first) Please fill in this page again.) 5. Description of the invention () K The following formula I (a) is obtained by using 3 — (1 thio-1,2,3 — to obtain 3 — (1, generation_ 2, 3 — 2 2 3 1-2 3 2 is substituted with 3-(7) -2 -thio-ester to obtain 3 2 -yl) -2-carboxylic acid, melting point 2 0 is substituted with 3-(6 2 -yl) -2-carboxylic acid ethyl ester , 4-tetrahydronaphthalene-2, 2-oxazole, 4_carboxy (in methanol) treatment 3-(6, 8 —) — 2 —thio—, melting point 1 6 0 — with 3-(4 2, 3 — two gases — 1 ( < 4, 6 —Two compounds: 9 2 »3 f 4 — Tetrahydrodihydro-1 Η — Miles — 2 3 > 4 — Tetrahydronaphthalene hydrogen 1 Η — Oxazole — 4 ° c (decomposition) — Fluorine — 1 $ 2 3 > 2 9 3 — Dihydro-1 Η — (7 — Fluoro — 1 2 Thio — 2 9 3 — Dihydro 7 — 2 0 9 »8 — Difluoro — 1 t 2 Thio — 2 »3 — Dihydro to obtain 3 — (6 8 — — radical) — 2 — Thio — acid» Melting point 2 0 7 — 2 Evaporate to dryness in methanol / isodim. — 1 »2 9 3 > 2 > 3 —dihydro-1 Η 1 6 3 f 6 —difluoro ηman — 1 1 Η — imidazole — 4 — fluorinated m man — 2 —yl) 1-168- naphthalene 1 2 -yl) -2 — 4 —Ethyl carboxylic acid substituted, —2 —yl) —2-thio-carboxylic acid ethyl ester, melting point: 4-tetralinaphthalene-2-yl-imidazole—4-monocarboxylic acid ethyl, 3,4-tetrahydronaphthalene 1—1 H—imidazole—4—, 3,4_tetrahydrocae — _1H—imidazole—4—difluoro-1,2,3,2,3—dihydro-1 Η 08C, potassium hydroxide propanol And recrystallized to obtain 4-tetrahydronaphthalene-2 -Imidazole-4 monopotassium carboxylate- 2)-2-thiomonomonoethyl ester to obtain 3 2-thio-2, 3 This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) ) 470741 A7 B7 Printed by the Central Bureau of Standards of the Ministry of Economic Affairs > Printed by Shellfish Consumer Cooperatives 5. Description of the invention () 1 1 I 1-dihydro-1 1 Η — oxazole — 4 potassium hydroxide for monocarboxylic acid (in methanol) 1 1 1 treatment and evaporation to dryness in methanol / isopropanol and recrystallization to obtain 3 1 (4 9 / «— VII please 16 1 difluoroindan 1 2 1 base) 1 2 —thio — 2 3 —dihydro 1 1 Read II Η Izobazole_ 4 Potassium monocarboxylate Melting point 1 6 3 0 -1 7 3 9 Read back 1 1 Side 1 with 3 — (5 7 — difluoroindane — 1 mono) — 2 monosulfide Generation — winter 1 I 2 3 dihydro-1 1 一 — oxazole — 4 — ethyl carboxylate substituted 9 to obtain 3 items 1 I then 1 1 — · (5 7 difluoroindan — 2 -yl) — 2 -thioxo 2 3 — 1 Mabendihydro- 1 Η mono-oxazole — 4 monocarboxylic acid Melting point 2 3 0- 2 3 2 9 Page Sw * · 1 I Treat with potassium hydroxide (in methanol) and evaporate to dryness in methanol / isopropanol 1 1 crystallized to give 3 — (5 7 diphenydandan — 2 —yl) — 2 monosulfur 1 1 substitution — 2 3 — dihydro — 1 Η imidazole 4 — potassium carboxylate melting point 1 order 1 I 1 7 0 — 1 7 4 Prepared by substituting 3 (5 6 —difluoroindan-1 1-yl) — 2 monothio — 1 1 I 2 3 — dihydro-1 1 — hydrazine 4 — ethyl carboxylate 3 1 1 — (5 6 —difluoroindan-2-yl) — 2 —thioxo 2 3 — 1 green dimirr — 1 hydrazine — 4 — melting point of carboxylic acid 2 3 3-2 3 4 1 I use 3-[3-(1 2 * 3 4 -tetrahydronaphthalene-2 -yl) 1 1-2-thio-2 3-dihydro-1 fluorene-oxazole-1-yl methyl 1 1 benzene Substitute methyl acid ester and sodium hydroxide to obtain 3 — C 3-(1 2 J 3 1 1 9 4 tetrachloro edge — 2 —yl) -2 — thio — 2 3 dihydro — 1 1 I Η — oxazole — 1 —methylmethyl] benzoic acid * Melting point 2 5 2-2 5 4 V 1 1 | Use 4 — C 3 — (1 2, 3 4 — tetrahydronaphthalene — 2 — base) 1 1-2 monothio — 2 9 3 — dihydro-1 hydrazone-imidazol — 1 —methyl] 1 1 -169- 1 1 This paper is sized to Chinese National Standard (CNS) A4 Specifications (210X297 mm) 470741 A7 B7 Printed by Zhengong Consumer Cooperative, Central Bureau of Standards, Ministry of Economic Affairs 5. Description of the invention () Methyl benzoate and hydrogen, 4 Tetrahydronaphthalene 1 H ~ · Panwa 1-Use 4 — [3 — 2 -thio-2 methyl butyrate substitution, naphthalene 2-yl) — 1 monomethyl] butanyl 5 — [3 —2 —thio-2 picolinate substituted to 5 — [3 — (monothio ~ 2,3 linoleic acid hydrochloride, substituted with 3-[3- -2-thiothio-2 methyl ester to obtain 2-yl) -2-yl] propionic acid, melting point used 4-[3-5 -methyl-2 -ylmethyl] stearic acid, 4-tetrahydronaphthalene-sodium substituted by f to obtain 4-2-1 -yl)-2-thiomethyl) benzoic acid > Melting point — (1 » 2 > 3 * 4 »3 — dihydro-1 hydrazone — to produce 4 C 3 — (1 2 monothio — 2 • 3 monoacid» melting point 1 5 6 — 1 — (1 »2 9 3 > 4 »3 — Dihydro-1 Η —» Hydrochloric acid in acetic acid 1 # Σ i 3 * 4 — tetra-dihydro-1 Η — oxazole melting point 2 0 4 1 2 0 5 1 (1 > 2 > 3 * 4 »3 — Dihydro — 1 Η — 3 — (3 — (1» 2 Thio — 2 9 3 — Dihydro 1 6 7 — 1 6 8 9 — (1 i 2 9 3 i 4 — Thio — 2 »3 — Dimethyl m in place of t to give 4 — 2 mono) — 5 monomethyl — 170 — [3-(1,2,3 —2,3 —dihydro — 1 211-212V; -Tetrahydronaphthalene-2 -yl) imidazole-1 -ylmethyl], 2,3,4 -tetrahydrodihydro-1 hydrazone -imidazole-5 8 ^; -tetrahydronaphthalene-2 -yl) imidazole-1 Recrystallized from a solution of monomethyl] to produce naphthyl-2-yl) -2-yl-1-ylmethyl] pico ° C; --tetrahydronaphthalene-2yl) oxazole-1yl Acid, 3,4-tetrahydronaphthalene — -1 Η —oxazole — 1 —tetrahydronaphthalene — 2 — hydrogen Imidazole-1 〔3-(1,2,3—2—thioxo-2,3 (Please read the precautions on the back before filling out this page) This paper size applies to China National Standard (CNS) Α4 size (210X297 mm) ) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 470741 A7 B7 V. Description of the invention () — Dihydro-1 — hydrazone — oxazole-1 _methylmethyl] Stearic acid, melting point 18 1-1 8 2 VI 3_ 〔 4 — (1,2,3,4 tetrahydronaphthalene-2-yl) —3 — (tertiary butoxycarbonylaminomethyl) -5-thio-1,5 dihydro [1,2 , 4] triazole-1,1-yl] ethyl propionate to obtain 3- [4- (1,2,3,4-tetrahydronaphthalene-2-yl) -3- (tertiary butoxycarbonyl) Aminomethyl) -5 -thio-1,5-dihydro [1,2,4] triazole-1 monoyl] propanoic acid, melting point 76-78. (S) — 3 — [5,7_ di Gas-1,2,3,4-tetrahydronaphthalene-2-yl) -2-thio-2,3-dihydro-1,1-oxazole-1 1-yl] propionic acid ethyl ester was substituted to obtain (S )-3-C 3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalene_2-yl)-2 -thio-2,3-dihydro-1Η- 眯-1-yl] propanoic acid, melting point 182-184t :; using 3- [3- (1,2,3,4 ~ tetrahydronaphthalene-2 -yl)-4-dimethylamino monomethyl-2 _Thio-2,3-dihydro-1, 1 __oxazole-1, yl] propionate was substituted to obtain 3- [3, (1,2,3,4 tetrahydronaphthalene-2 ) A 4-Dimethylaminomethyl-2-thio-2,3-dihydro-1,1-oxazole-1-yl] propanoic acid, melting point 171-1741; with (S)-4-{2 -〔3 — (1 * 2,3,4 —tetraaminocaine 2-yl) — 2 —thioxo 2,3_dihydro-1 1Η — hoof saliva-171- (Please read the precautions on the back before (Fill in this page) This paper scale is applicable to China National Standards (CNS) A4 specifications (210 × 297 mm) 470741 Employees' Cooperatives of the Ministry of Economy, Ministry of Economic Development, Consumer Cooperatives, A7, B7, V. Description of the invention ()-4-methyl Amino] ethyl} methyl benzoate substitution to obtain (S) — 4 — {2_ [3-(1,2,3,4-tetrahydronaphthalene-2 —yl) —2 —thioxo-2, 3 —DiM — 1 H —Hydroxyl-4 monomethylmethylamino] ethyl) benzoic acid hydrochloride, melting point 240-241Ό; used S)-3-[4 monomethylamidoaminomethyl 3 — (5, 7 -difluoro-1, 2,3,4 -tetrahydronaphthalene -2 -yl) -2 -thio-2, Substituting 3 -dihydro_1H —panazole-1 1yl] ethyl propionate to obtain (S) — 3_ [4 monomethylamidoaminomethyl 3 — (5, 7 —difluoro-1 1, 2,3,4-tetrahydronaphthalene- 2-yl)-2 -thio-2,3-di-M 1 -H 1 -yl] propanoic acid. Following Example 37, but replacing 3- (5,7-difluoro-1,2,3,4-tetrahydronaphthalene- 2-yl)-2 -thio-2,3-dihydro with different starting materials _1H_imidazole-4 monocarboxylic acid ethyl ester, and subjected to acid catalyst hydrolysis, to obtain the following compound of formula I (a): using 3_ (1,2,3,4-tetrahydronaphthalene-2-yl) -2 — Substituted with thio-2,3-dihydro-1H-imidazol-1-yl acetate and trifluoroacetic acid to obtain 3-(1,2,3,4-tetrahydronaphthalene-2-yl) —2—thio_2,3_ diamino—1H—shodium 1 —yl] acetic acid, melting point 228 — 230 ° C; with 1- (5,7-difluoro-1 1 * 2,3,4 —four Hydronaphthalene — 2-yl) — 2 —thio — 2,3-dihydro — 11 ^ — Weizole 4 4-ylmethylaminoacetic acid tert-butyl ester and argon chloro acid were substituted to obtain 1 1 (5 , 7-difluoro-1,2,3,4 —tetrahydronaphthalene-2 —yl) — 2 —sulfur-172- This paper size applies to China National Standard (CNS) A4 (210X297 mm) (Please read first Note on the back, please fill in this page again) 470741 Printed by the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs A7 B7 ) —2,3 —dihydro-1 H —imidazole-4 4-methylmethyl acetic acid, melting point 214-216υ; using (S) —1— (5 * 7-difluoro-1, 2, 3, 4-tetrahydronaphthalene-2-yl)-2 -thio-2,3-dihydro-1 1 fluorene-oxazole-4 4-ylmethylaminoacetic acid tert-butyl ester and hydrochloric acid to obtain ( S)-1-(5,7_ difluoro-1,2,3,4-tetrahydronaphthalene-2 -yl) -2 -thio-2,3 -diazepine-1 hydrazone-4 -yl Methylaminoacetic acid hydrochloride, melting point 214 (evaporation); and 1- (1,2,3,4-tetrahydronaphthalene-2-yl) -2—thio-2,3-dihydro-1 Η -Oxazole-4 monomethylmethylaminoacetic acid tert-butyl ester and hydrochloric acid were substituted to obtain 1- (1,2,3,4-tetrahydronaphthalene-2-yl)-2 -thioxo-2 , 3-Dihydro-111-oxazolyl-4-ylmethylaminoacetic acid hydrochloride, melting point 20 8-2 1 1 υ 〇 Example 3 8 4-[3-(1, 2, 3, 4 one four Hydronaphthalene- 2 -yl)-2 -thio-2,3-dihydro-1,1--oxazole_1 -yl) butanamide K is prepared in the following formula I (a) where η is 1 and t is 0, R3 is 4 a (ammonia Vine hydrogen methyl) propyl, R4 and R5. 4- [3- (1,2,3,4-tetrahydronaphthalene-2-yl) -2-thizone-2,3-dihydro-1H-imidazole-1-yl] butanoic acid as in Example 37 was prepared (100 mg, 0 · 32 -173- This paper size is applicable to Chinese National Standard (CNS) A4 specifications (210X297 mm) (Please read the precautions on the back before filling out this page) 470741 Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Preparation of A7 — B7 V. Description of the invention () its ear) and osmium chloride (2M, 0.32 ml, 0.64 mol) and 5 drops of dimethylformamide in 10 ml of methyl chloride Search the mixture for 2 hours. The excess chloramidine chloride and solvent were removed by evaporation, and the residue was treated with 5 ml of a 30% aqueous ammonium hydroxide solution and stirred for 1 S hour. The mixture was poured into an aqueous solution of sodium bicarbonate 'and extracted with methylene chloride. The extract was dried over sodium sulfate and concentrated. The residue was passivated on silica gel (methylene chloride / methanol with an eluent of 99: 1 to 96: 4) to passivate the chromatograph to obtain 4— [3 — (1, 2, 3, 4— Tetrahydronaphthalene- 2-yl)-2 -thio_2,3-dihydro_1H -imidazole- 1 -yl) butanamide (70 mg, 0.22 millineur). Proceeding as in Example 38, but replacing 4_ with a different starting material [3-(1,2,3,4-tetrahydronaphthalene-yl) -2 -thio-2,3-dihydro-1 fluorene-oxazole -1 -yl) butyric acid to prepare a compound of the following formula I: 4-[3-(1,2,3,4-tetrahydronaphthalene-2 -yl) -2 -thio-2,3-dichloro -1. Η-hoof beer-1 yl ethyl] benzoic acid substitution to obtain 4-[3- (1,2,3,4-tetrahydronaphthalene-2 -yl)-2 -thio -2,3_ Dihydro-1,1-oxazole-1,1-ethylethyl) benzylfluorenamine, melting point 158 — 16〇υ; and 3-[3-(1,2,3,4 tetrahydronaphthalene-2 ~ 'group ) —2 —Thio-2,3-dihydro-1,1-oxazole-yl] propionic acid substitution to obtain 3- [3— (1,2,3,4_tetrahydronaphthalene-2-yl) — 2 -Thio-2,3-dihydro-1Η-imidazole-1 1-ethyl-1-1 74-This paper A degree applies to Chinese National Standard (CNS) A4 specification (210 × 297 mm) (Please read the note on the back first Please fill in this page again for matters) 470741 Printed by the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs A7 B7 V. Invention Description () Basic) Amine, melting point 180-181 ° C. Example 3 9 3 — [2- (4 (1H) —Tetrazol-5 —ylphenyl) ethyl]-(1,2,3,4-tetrahydronaphthalen-2-yl) -1,3-bis Hydroxazole-2-thione M is prepared under the formula I (a) where η is 1, t is 0, and R3 is 2- (4 (1H) -tetrazol-5-ylphenyl) ethyl, R4 and R5 is a compound of hydrogen. 3- [2- (4-Cyanophenyl) ethyl] -1- (1,2,3,4-tetrahydronaphthalene-2-yl) -1,3-dihydrooxazole prepared as in Example 15 —2 —Thionone (0.5 g, 1.4 mmol) and tributyltin hydrazine (1.39 g, 4.2 mmol) in 3 ml of xylene, 1 20¾ and nitrogen Heat for about 16 hours. The mixture was purified by chromatography on silica gel (eluent: methylene chloride / methanol) to obtain 3-[2-(4 (1Η) -tetrazol-5 -ylphenyl) ethyl]-(1, 2,3,4-tetrahydronaphthalene-2-yl) -1,3-dihydrooxazole_2-sulfur (0.5 mg, 1.4 mmol), melting point 218-220 ^ ° Example 4 0 (S) 4- (1-hydroxy) ethyl-1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalene-2 -yl) -1,3-dihydro-175 -This paper size applies to Chinese National Standard (CNS) Α4 specification (2 丨 0X297 mm) (Please read the precautions on the back before filling this page) 470741 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Description of the invention () The following compounds are prepared from imidazole 2-thione in formula I (a): η is 1, t is 0, R3 and R5 are hydrogen, and R4 is 1-hydroxyethyl. (S) -3-(5,7 -difluoro-1,2,3,4 -tetrahydronaphthalene-2 -yl) _2-thio-2,3 -dihydro-1H- The mixture of imidazole-5-carbaldehyde (178 mg, 0.6 mmol) and methylmagnesium chloride (3M, 0.4 ml, 1.2 mmol) was stirred at about 0 h for 1 hour, and Stir at 2 5 C for 1 hour. The mixture was treated with 5 ml of dilute sulfuric acid and extracted with EtOAc (2 times). The mixed extract was dried with magnesium sulfate, concentrated, and the residue was purified by flash chromatography on sand gel (eluent: 9 8: 2 methylene chloride / methanol) to obtain (S)-4 — ( 1-Hydroxy) ethyl 1- (5,7-digas-1,2,3,4-tetra-S-Cai-2-2-yl) -1,3-dihydroimidazole_2-sulfur (22 mg, 〇 · 1 millimolar) * Melting point 210-21 It :. It was carried out according to Example 40, but the methyl magnesium chloride was replaced with n-propyl magnesium chloride to obtain (S) -4-(1-hydroxy) butan-1-yl- (5, 7-difluoro_1, 2, 3, 4-tetrahydronaphthalene-2 -yl) _1,3-dihydrotetrazole-2 -thione, melting point 1 54-56. Example 4 1 Ν-1Η-Tetrazol-5-yl- 3-(5,7 -difluoro-1,2,3,4-tetrahydronaphthalene-2 -yl) -2 -thio-2,3-- 176- This paper size applies to Chinese National Standards (CNS) (210X297 mm) (Please read the precautions on the back before filling out this page) 470741 A7 --- -B7 _ 5. Description of the invention () Dihydroimidazole 1 4 1 Carboxamide K is a compound of formula I (a) in which η is 1, t is 2, 5- and 7-positions R1 is fluorine, and Rs is 111- · 4-mile-5-yl-carbamidine. 3-(5,7 -difluoro-1, 2 prepared in Example 37, printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) 3,4 tetrahydro Naphthalene- 2-yl)-2 -thio-2,3-dihydro-1H-oxazole-4 -acid (1 g, 3.33 mmol) dissolved in 15 ml of grass vine chloride and 1 In dimethylformamide, the solution was stirred under nitrogen for 3 hours. The excess grasshopper chloride was removed on a rotary evaporator and the residue was co-evaporated with carbon tetrachloride (2 x 25 ml). The residue was cooled to 0¾, and dried 5-amino-1H-four miles (0.85 g, 10 mmol) and 25 ml of pyridine were added. The mixture was warmed to room temperature and then stirred for 16 hours. The solvent was removed by evaporation and the residue was co-evaporated with methylbenzyl. The residue was purified by column chromatography in silica gel (containing 5% methanol / methylene chloride containing 1% acetic acid) to obtain 0.9 g of an impure product. The impure product was dissolved in an aqueous potassium carbonate solution, and the solvent was extracted with ethyl acetate. Acidifying the aqueous layer gave a solid material. This material was separated by filtration to obtain N-1H-tetrahydro-5-yl-3- (5,7-difluoro-1,2,3'4-tetrahydrocai-2-yl)-2_ Thio-2,3,2-difluorocarbon-4,4-amidine (0.54 g, 1.56 mmol), melting point 228-230¾. Example 4 2 -1 77- This paper is again applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) 470741 A7 ____B7_ V. Description of the invention () (4_methylmorphazine-1 1-based) [3— ( 5,7-difluoro-1,2,3,4-tetrahydrocaine- 2-yl)-2 -thio-2,3 -dihydroimidazole- 1 Η -oxazole- 4 -yl] Meng M The following system prepares a compound in which η is 1 and t is 2, 5- and 7-positions in Formula 1 (a), and R1 is fluorine * R5 is 4-methylmonopiperazine-1-ylcarbonyl. 3-(5,7 -difluoro-1,2,3,4 -tetrahydronaphthalene-2 -yl) -2_sulfur-2 * 3 -dihydro-1H -imidazole-4 prepared as in Example 37 A mixture of a monocarboxylic acid (0.75 g, 2.42 mmol) and 1,1'-carbonyldioxazole (0.43 g, 2.65 mmol) in 6 ml of tetrahydrofuran. Stir for about 18 hours at argon and room temperature. N-methylmorphazine (0.29 g, 2.65 mmol) was added and the mixture was stirred under argon at room temperature for about 18 hours. The mixture was layered between methylene chloride and water. The methylene chloride layer was washed 4 times with water, dried over magnesium sulfate, and concentrated by evaporation. The residue was recrystallized from ethyl acetate / methanol to obtain (4-methylpiperazine-1-yl) [3— (5 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before (Fill in this page), 7-difluoro-1,2,3,4-tetrahydronaphthalene- 2-yl)-2 -thio-2,3_dihydrooxazole-1 1_imidazole- 4-yl] methyl _ (0.69 g, 1.76 mmol), melting point 248-25 〇υ 〇 according to Example 42, but with 3- (5,7-difluoro-1,2,3, 4-tetrahydronaphthalene- 2-yl) -2-thio-2,3-dihydro-1,1-oxazole-4, carboxylic acid and / or N_-17 8 " This paper rule applies to Chinese national standards ( CNS) A4 size (210x297 mm) 470741 A7 B7 printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention () Methylpiperazine to obtain the compound of formula I -1,2,3,4-tetrahydronaphthalene-2-yl) -2-thio-1,3-dihydro-1H-imidazole-4 carboxylic acid substitution to obtain (4-methylmorphazine-1 —Base] [3 — (6, 8-two -1,2,3,4-tetrahydronaphthalene-2-yl)-2 -thio-2,3-dihydroimidazole-1H -oxazole-4 -yl] methanone (oil); use 3-( 5,7 —digas-1,2,3,4 —tetrachlorocae — 2_yl) — 2_thio-2,3 —dihydro-1H —oxazole — 4 —carboxylic acid and N, N —dimethyl N- (dimethylaminoethyl)-3-(5,7 -difluoro-1,2,3,4-tetramethylnaphthalene-2-yl)-2 -sulfur Substituted 2,3-dihydroquinone-1H-imidazole_4-carboxamide, melting point 125Ό; using 3- (5,7-difluoro_1,2,3,4-tetrahydronaphthalene-2_yl) A 2_ thio-1, 3-diamino-1 Η — mile_ 4_ carboxylic acid and p-methylsulfonamidoaniline are substituted to obtain N_ [4- (methylsulfonamido) benzyl] a 3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl) -2-thioxo-2,3-dihydrooxazole-1 hydrazone-oxazole-4 4-carboxy Amidine, melting point 225 — 2301; 3_ (5,7 —difluoro-1,2,3 * 4 —tetrahydronaphthalene 2 —yl) — 2 —thio-1,3-diM—1 fluorene — hoof Mi ~ 4 monocarboxylic acid and dimethyl Substituted amine sulfide hydrochloride and dichlorohexylcarboximide to obtain 3 — (5,7 —difluoro-1,2,3,4 —tetrahydro-1 7 9-Applicable to this paper size China National Standard (CNS) Α4 specification (210 × 297 mm) (Please read the notes on the back before filling out this page) 470741 A7 B7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention () Naphthalene-2 ) —2—thio-2,3-dihydro-1H—oxazole-carboxythiocarboxylic acid and S— (2-dimethylaminoethyl), melting point: 204—2 0 6 Ό; and 3_ ( 6,8 —difluoro_1, 2,3,4 -tetrahydronaphthalene -2 -yl) -thioxo ~ * 1, 3 -dihydro-1H -weizol-4 monocarboxylic acid and dimethylamine Ethyl sulfide hydrochloride and dichlorohexylcarboximide were substituted to obtain 3 — (6,8-difluoro-1,2,3,4 tetrahydronaphthalene-2 —yl) -2 + thio -2,3-Dihydrofluoric acid-4 One is thio acid and S-(2-dimethylaminoethyl) ester, melting point 275-2 7 7 V ° Example 4 3 3-(3,4 one two Hydroxybenzyl)-(1,2,3,4-tetrahydroinhibit-2-yl) -1,2-bis A 2-thio-blind saliva Μ the Si-based Formula I (a) is in η 1 * t is square, 3, 4 R3 is - dihydroxy benzyl, R4 and Rs are hydrogen. 3- (3,4-dimethoxybenzyl)-1_ (1,2,3,4-tetrahydronaphthalene- 2-yl) -1,3-dihydroquinone prepared as in Example 15 A solution of 2-thione (900 mg * 2.37 mmol) in methylene chloride was cooled to 0¾ in nitrogen, and then boron tribromide (1M * 7.1 ml, 7.1 mmol) was added dropwise. (In another 10 ml of methylene chloride). The mixture was cooled to room temperature, stirred for 16 hours, and then slowly added to water. Separate the organic layer and wash with brine-1 0 0-(Please read the precautions on the back before filling out this page) This paper size applies to China National Standard (CNS) A4 (210X297 mm) 470741 Α7 Β7 V. Description of the invention () 'M sodium sulfate is dried and concentrated. The residue was passivated in a silica gel (eluent: 9 6: 4 methylene chloride / methanol), and then recrystallized in formic acid / ethanol / hexane to obtain 3 — (3, 4 — 2 Hydroxybenzyl)-(1,2,3,4-tetrahydronaphthalene- 2-yl) -1,3-dihydroimidazole- 2-thione (520 mg), melting point 173- 174Ό ο according to Example 43, However, 3— (3,4-dimethoxybenzyl) -1— (1,2,3,4-tetrahydronaphthalene-2-yl) —1,3-dihydroimidazole— 2-thione to prepare a compound of the formula I: 3- [2- (3,4-dimethoxyphenyl) ethyl]-1- (1,2,3,4-tetrahydronaphthalene-2 -Yl) -1,3-dihydrooxazole-2-thione substitution to obtain 3- [2- (3,4-dihydroxybenzyl) ethyl]-(1,2,3,4-1.4 Hydronaphthalene- 2-yl) -1,3_dihydrooxazole-2-thizone, melting point 165-1671C; printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) 1- (5-methoxyindane-1 1-yl) -1,3-dihydrooxazole-2 _Sulfur substitution to produce 1- (5-hydroxyindane-1 1-yl) _1,3-dihydroimidazole_2-thione, melting point 208-209 " Ό Use 1- (1, 2, 3, 4 -Tetrahydro-6-methoxynaphthalene-1yl) -1,3-dihydrooxazole-2thione substitution to obtain 1- (1,2,3 * 4-tetrahydro-6-hydroxyl Naphthalene-1, 1-yl) -1,3-dihydroimidazol-2, 2-thione, melting point 2 1 3-2 1 5 it; -1 8 1-This paper size applies to China National Standard (CNS) A4 specification (210 乂) 29 < 7 mm) 470741 A7 B7 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (1) (1, 2, 3, 4 -tetrahydro-5 -methoxynaphthalene_1-one) ) -1,3-dihydroimidazole-2-thione substitution to obtain 1- (1,2,3,4-tetrahydro-5-hydroxynaphthalene-1-yl) -1,3 dihydroimidazole-- 2-thione, melting point 1 88 — 1 90 ° C; 1_ (1, 2, 3, 4 —tetrahydro-7 —methoxynaphthalene 1 —yl) — 1, 3 —dihydroimidazole — 2 — Substituted by thioketone to obtain 1- (1,2,3,4-tetrahydro-7-hydroxynaphthalene-1-yl) -1,3-dihydrooxazole-2 2-thione, melting point 1 95-1 96 ° C; Substituted with 1- (1,2,3,4-tetrahydro-5-methoxynaphthalene-2 2-yl) -1,3-dihydroimidazole-2 2-thione to obtain 1- (1 , 2,3,4-tetrahydro-5 -hydroxynaphthalene-2-yl) -1,3-dihydroimidazol-2-thione, melting point 263-26 5Ό; use 1_ (1, 2, 3, 4- Tetrahydro-6-methoxynaphthalene-2-yl) -1,3-dihydrooxazole-2-sulfur-substituted to obtain 1- (1,2,3,4_tetrahydro-6-hydroxynaphthalene- 2 -Base) —1,3—dihydrooxazole—2—thione, melting point 240—24 1 ° C; 1— (1,2,3,4—tetrahydro—7—methoxynaphthalene—2— Radical) -1,3-dihydrooxazole-2-thione substitution to obtain 1- (1,2,3,4-tetrahydro-7-hydroxynaphthalene-2-yl) -1,3-dihydro Imidazole—2—thione, melting point 248—25 〇υ; using 1- (1,2,3,4-tetrahydro-8-methoxynaphthalene-2 2-yl) -1,3-dihydrooxazole_ 2—thione substitution to produce 1_ (1,2,3,4—tetrahydro-8-hydroxynaphthalene-2—yl) —1,3 -1 8 2-This paper applies Chinese national standards (CNS> Α4) Specifications (210 × 297 mm) (Please read the notes on the back before filling out this page) 470741 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs A7 B7 V. Description of the invention () Dihydroxazole-2—thione, Melting point 274 — 276¾; and 1— (6,8—digas—1,2,3,4—tetrachloro-7—methoxymethoxynaphthalene—2-yl) —1,3-dihydrooxazole—2 —Thionone substitution to obtain 1- (6,8-difluoro-1,2,3,4_tetrahydro-6-hydroxynaphthalene-2 —Base) —1,3-dihydroimidazole—2—sulfur —, melting point 258-260 ° C. Example 4 4 (S)-N- [3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalene_2_yl) -2-thioxo-2,3-dihydro-1 ^ 1-oxazole-4 monoylmethyl] -4 monobutylbenzylamine K is prepared in the following formula I (a) where η is 1, t is 2, 5- and 7-positions R1 is fluorine, R5 The compound which is 4-butylphenylphosphoniumaminomethyl was prepared as in Example 31. (S) -5-aminomethyl-1- (5,7-difluoro-1,1,2,3,4-tetrahydro Naphthalene-2-yl) -1,3-dihydrooxazole-1, 2-thione (0. 30 g, 1 mmol) and 4-butylphenylphosphonium chloride (0, 21 ml, 1.1 mmol) Mol) The mixture was placed in 10 ml of anhydrous pyridine, stirred under argon for about 1 hour, and then stirred at 25D for another 2 hours. The mixture was concentrated and the residue was treated with water. The mixture was extracted three times with ethyl acetate, and the mixed extracts were dried over magnesium sulfate and concentrated. The residue was recrystallized from ethyl acetate to obtain (5)-Ν-[3_ (5,7 —difluoro-1,2,3,4 —tetra-183-). ) Α4 specification (210 × 297 mm) (Please read the precautions on the back before filling out this page) 470741 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention Thione-2,3-dihydro-1? 1-oxazole-4 monomethylmethyl] 4-butyl benzamidine (0.25 g, 0.5 5 mmol), melting point 242-243 ° C. Following Example 44 but substituting (S) -5 -aminomethyl- 1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalene- 2-yl)- 1, 3-dihydrooxazole-2-thizone and / or 4-butylphenylsulfonium chloride to prepare a compound of formula I below: Substituted with nicotine hydrazone to obtain (S)-Ν-[3- (5,7 —difluoro-1,2,2,3,4-tetrahydronaphthalene-2 —yl) — 2 —thio-2,3 —dihydro-1 Η —imidazole — 4-ylmethyl] nicotine Amidine, melting point 218_221 it; (S)-Ν-[3-(5, 7-difluoro-1, 2, 2, 3, 4-tetrahydronaphthalene-2-yl)- 2 ~ Thio-2,3-dihydro-1 Η -imidazole-4 monomethyl] benzamidine, melting point 260-26ΐυ; substituted with dimethylaminoformamidine * to obtain (S) — Ν_ 〔3 -(5,7-difluoro-1,2,3,4-tetrahydronaphthalene- 2-yl) ~ 2 -thio-2,3-dihydro-1,1-oxazole-4-methylmethyl] di Methyl urea, melting point 218 — 220C; Substituted with methyl chloroformate to obtain (S) — Ν — [3-(5, 7 —difluoro-1, 2, 2, 3, 4-tetrahydronaphthalene-2-yl ) —2-thiothio-2,3-dihydro-1 hydrazone—imidazole—4-methylmethyl] carbamate, melting point 220 — 222 ° C; * 18 4- This paper size applies to Chinese National Standard (CNS ) A4 size (210X297 mm) (Please read the precautions on the back before filling out this page) 470741 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention () Use (S) — 3 —Amine 1 1- (1,2,3,4-tetrahydronaphthalene-2-yl) -1,3-dihydroimidazole-2-thione and acetic anhydride were substituted to obtain N- [3 — (1,2,3 , 4-tetrahydronaphthalene- 2-yl) -2-thio-2,3-dihydro-1H-oxazole-4 4-yl] acetamidine, melting point 196-200 ^ 0; with 2-furancarboxylic acid (S) — Ν — [3-(5,7 —difluoro-1,2,3,4 -tetrahydronaphthalene-2 —yl) —2 —thio-2,3 —di Hydrogen-1,1-oxazole-4 monomethyl], 2-furancarboxymethyl, melting point 227-231¾; and 4-monoamino- 2-(1,2,3,4-tetrahydronaphthalene-2 ) -2,4-dihydro [1,2,4] triazol-3-thione and acetic anhydride Preparation of N— [1— (1,2,3,4-tetrahydronaphthalene-2—yl) —5—thioxo-4,5—diamine—1Η— [1,2,4] triazole—4 _Yl] Ethylamine, melting point 199-201Π. Example 4 5 (S)-Ν- [3-(5,7 -difluoro-1,2,3,4-tetrahydronaphthalene-2 -yl) -2 -thio-2,3_dihydro-1 Η —imidazole_4-ylmethyl] picoline amine K k is prepared in the following formula I (a) in which η is 1 and t is 2, 5 and 7-position R1 is fluorine, R5 is picolin ugly Aminomethyl compounds. (S) 5-Aminomethyl-1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)-1-185- this paper prepared as in Example 31 Standards are applicable to China National Standard (CNS) A4 specifications (210X297 mm) (Please read the notes on the back before filling out this page) 470741 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 ___ B7_ V. Description of Invention (), A mixture of 3-dihydrooxazole_2-thione (295 mg, 1 mmol), picolinic acid (123 mg, 1 mmol) and ByBOP (62 0 mg, 1.2 mmol) In 10 ml of anhydrous dimethylformamide, stir in argon at about 25 ° C for 5 minutes, and then add N, N-diisopropylethylamine (0.58 ml, 3.3 mmol) . The aqueous layer was extracted with ethyl acetate (3x10 ml), and the combined extracts were washed with water, dried over magnesium sulfate, and concentrated. The residue was purified by flash chromatography on silica gel (eluent: hexane / tetrahydrofuran from 1: 1 to 8: 2) to obtain (S) — Ν-[3-(5,7 -difluoro-1 1 * 2,3,4-tetrahydronaphthalene-2-yl) 2-thiothio-2,3-dihydro-1,1-imidazole-4 4-ylmethyl] picolinin (80 mg, 0.2 mmol) Moore), melting point 216-217t. It was carried out according to Example 45, but replacing picolinic acid with different starting materials to obtain the compound of the formula I: Substituting and deprotecting with N- (tertiary butoxycarbonyl) glycine to obtain (S) -N- [3-(5,7-Difluoro-1,2,3,4-tetrahydronaphthalene- 2-yl)-2 -thio-2,3-dihydro-1 1 Η-oxazole-4 -ylmethyl Group] amino ethyl amine, melting point 144-153¾ > Substituted with N-(tertiary butoxycarbonyl) -2-methylalanine and deprotected * to obtain (5) -1 ^ — [3— (5,7-difluoro-1,2,3,4-tetrahydronaphthalene- 2-yl)-2 -thio-2,3 -dihydro-1 1 Η -oxazole-4-ylmethyl]- 2-Amine-2 —Methylpropane-1 8 6-This paper size applies to Chinese National Standard (CNS) A4 (210 X 297 mm) (Please read the precautions on the back before filling this page) 470741 Ministry of Economic Affairs Printed by the Consumer Standards Cooperative of the Central Bureau of Standards A7 B7 V. Description of the invention () Ammonium trifluoroacetate, melting point 1; and obtained by replacing * with 5-butylpicolinic acid (S) — Ν — [3 — ( 5,7-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl) 1 2 -thio-2,3 -dioxo-1 1 Η -oxazole -4-ylmethyl]-5-butylpicolinin, melting point 99-1 04 ° C. Example 4 6 (S)-N- [3-(5,7 -difluoro-1,2,3,4-tetrahydronaphthalene-2-yl)-2 -thio_2,3-dihydro-1 Hydrazone-oxazole-4 monomethyl] ethylurea K is prepared in formula I (a) where η is 1 and t is 2,5-and 7 R1 at one position is fluorine and R5 is ethylurea Compounds. (S) -5-Aminomethyl_1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl) -1,3, -2, prepared as in Example 31 Hydroimidazole-2-thione (294 mg, 1 mmol) and ethyl isocyanate (0 ♦ 16 ml, 2 mmol) were mixed in 10 ml of tetrahydrofuran and stirred under argon at about 50 υ About 60 hours. The mixture was filtered, and the filtered solid was recrystallized from ethyl acetate / methanol to obtain (S) " ™ Ν — [3- (5,7 —difluoro-1, 2, 2, 3 * 4, tetrahydronaphthalene— 2-based)-2 -thio-2,3 -digas- 1Η-oxazole-4 -ylmethyl] ethylurea (1 10 mg, 0.3 mmol), melting point 219-220 ° C . _ 1 8 7 ~ This paper size is applicable to China National Standard (CNS) A4 size (210X297 mm) (Please read the precautions on the back before filling this page) 470741 Printed by A7 _B7 V. Description of the invention () Example 4 7 4 —Aminomethyl-1— (1,2,3,4-tetrahydronaphthalene-2—yl) —1,3-dihydroimidazol-2-thione M In the formula (a), η is 1, t is 0, R3 and Rs are hydrogen, and R4 is an aminomethyl compound. 3-(1,2,3,4-tetrahydronaphthalene-2-yl)-2 -thio ~ 2,3 -dihydro-1 1 Η -oxazole-4 -carbaldehyde (Ό · 25 g, 1 · 0 millimolar) * hydroxylamine hydrochloride (0 * 09 grams, 1.3 millimoles) and sodium hydroxide (0.046 grams, 1.6 millimoles) in 2 ml of ethanol and 2 ml of water , Stir at 60 * 0 for 1 hour. After the mixture was cooled, a crystalline substance was obtained. This material was separated by filtration and dried. The crystalline materials were mixed to obtain 1- (1,2,3,4-tetrahydronaphthalene-2-yl) -2-thioxo-2,3-dichloro-1, 1-pyrazole-1,5-carbamaldoxime (0 · 186 grams, 0.68 millimoles). 3- (1,2,3,4-tetrahydronaphthalene-2-yl) -2 2-thio-2,3.-dichloro-1—-dichloro-1-5 carbaaldoxime ( 0. 158 g, 0.58 mol) in 20 ml of tetrahydrofuran was cooled to 0 Ό, and LAH (1.0 M, 1.16 ml, 1.16 mM) in tetrahydrofuran was slowly added. The mixture was stirred at 0 ° C for 1 hour, then saturated ammonium chloride, water and ethyl acetate were added. The aqueous layer was separated and extracted with ethyl acetate. The mixed ethyl acetate was dried over magnesium sulfate, and concentrated by evaporation. The residue was concentrated by evaporation. Purification by flash chromatography yielded 4-aminomethyl 1- (1,2,3,4-tetrahydronaphthalene) -1 8 8-This paper is sized to the Chinese National Standard (CNS) A4 (210X297 mm) ( Please read the notes on the back before filling out this page) 470741 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Invention Description (2)-1-3-Dihydrooxazole-2-Thione, Melting point 197 — 2 0 0 It ° Example 4 8 (S) — 1— (5 * 7 —Digas—1 * 2,3,4—Tetrahydronaphthalene—2—Base) —4— (2 —Benzene Ethyl) aminomethyl-1,3-dihydrooxazole-2-sulfur-K is prepared in the following formula I (a) where η is 1 and t is 2,5-and 7 R1 at one position is fluorine, R4 is a 2- (phenyl) ethylaminomethyl compound. (S) 3- (5,7-difluoro-1,2,3,4-tetrahydronaphthalene-2) prepared as in Example 22 —Base) —2—thio_2,3-dihydro-1H-imidazole-5 carbaaldehyde (147 mg, 0.5 mmol), phenethylamine (75 μl, 0.6 mmol) Ear) and fluoroboroborohydride (47 mg, 0.75 mmol) in 10 ml of methanol and stirred at about 60 ° C for 2 hours. The mixture was concentrated and the residue was concentrated in silica gel (eluent 97: 3 Methylene chloride / methanol) was purified by flash chromatography. The purified product was concentrated, converted into hydrochloride salt, and recrystallized from ethyl acetate / methanol to obtain (S) — 1— (5,7— Two gas one 1,2,3,4-tetra-M Cai Yi 2-yl) 4- 4- (2-phenylethyl) aminomethyl-1 1,3-dihydrooxazole-2 2-thioketone hydrochloride Compound (68 mg, 0.2 mmol), melting point 227 — 229 ° C 〇-189- paper A degree applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) (Please read the precautions on the back before filling this page) 470741 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Invention Description Following Example 48, but replacing (S) -3 — (6,7_difluoro-1,2,2,3,4-tetrahydronaphthalene-2 —yl) — 2 —thio-2, 3 with different starting materials —Dihydro-1H —oxazole- 5-carbaldehyde and / or phenethylamine to give K a compound of the formula I: using 3- (5,7-difluoro-1,2,3,4-tetrahydronaphthalene -2 -yl)-2-thio-2, 3-dichloro-1H-oxo 5-carbaaldehyde and glycine tert-butyl ester hydrochloride substitution to obtain 3-(5, 7- difluoro- 1,2,3,4_ tetrahydronaphthalene- 2-yl)-2 -thio- 2,3-dihydro-1H-imidazole-5 -ylmethylaminoacetic acid tert-butyl ester; (S)- 3 — (5,7—digas_1,2,3,4_tetrahydronaphthalene —yl) —2 —thio-2,3 —dihydro-1H —oxazole-5 —carbaaldehyde and glycine tertiary butyl (S)-3-(5,7-digas-1) 2,3,4-tetrahydronaphthalene- 2 -yl) _2 -thio_2,3_ diamino-1 H -Panyl-5- 5-methylmethylaminoacetic acid tert-butyl ester; 3-(1,2 , 3,4 Tetrahydronaphthalene- 2-yl)-2-thio-2,3-dihydro- 1 hydrazone -oxazole-5-carbaaldehyde and glycine tert-butyl ester hydrochloride substituted to obtain 3_ (1,2,3,4-tetrahydronaphthalene-2-yl) -2-thioxo-2,3-dihydro-1Η-imidazol-5-ylmethylaminoacetic acid tert-butyl ester; Substituting amidoxamine to obtain (S) — 3-(5,7 —difluoro-1,2,3,4 —tetrahydronaphthalene — 2-yl) — 2 —thioxo-2, -1 90-benzyl Paper size applies to Chinese National Standard (CNS) A4 specification (210 × 297 mm) (Please read the notes on the back before filling out this page) 470741 Printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Invention Description () 3 —Dihydro-1 H —imidazol-5-ylmethylamidoacetamidine, melting point 212 — 213 it; and substitution with methyl 4-mono (2-aminoethyl) benzoate to obtain (S)- 4- {2-[3- (5,7-difluoro-1,2,3,4_ tetrahydronaphthalene-1 — )-2 -thio-2,3-dihydro-1H -imidazole-5 -ylmethylamino] ethyl} methyl benzoate, melting point 159 — 16 0 ° Example 4 9 (S)-N 3- [3-(5,7 -Difluoro-1,2,2,3,4-tetrachlorocae_2-yl) -2 -thioxo-2,3 -dichloro-1 hydrazone -imidazole_4-monomethyl ] One N1, N2-bis (tertiary butoxycarbonyl) formaldehyde is prepared in the following formula I (a) where η is 1 and t is 2, 5- and 7-positions R1 is fluorine, Rs SN1, N2 -Bis (tertiary butoxycarbonyl) fluorenylaminomethyl compounds. (S) — 1 — (5,7 -difluoro-1,2,2,3,4 -tetrahydronaphthalene-2 —yl) —5 —aminomethyl — 1, 3-dihydro as prepared in Example 31 Mixture of imidazole-2-thione (0.6 g, 2 mmol) and N 1, N 2 -di (tertiary butoxycarbonyl) methylsulfan (0.65 g, 2.2 mmol) In 15 ml of tetrahydrofuran and 0 * 3 ml of water, stir for about 4 hours under about 502 and argon. Concentrate the mixture, mix the residue with 5% sodium bicarbonate aqueous solution, and extract with ethyl acetate -191- This paper size applies to China National Standard (CNS) A4 (210X297 mm) (Please read the precautions on the back before reading) (Fill in this page) 470741 A7 —__ Description of the invention (5) Combined, M magnesium sulfate dried extract, and concentrated. The residue was subjected to flash layer purification on silica gel (eluent: 99: 1 methyl chloride / methanol) to obtain (S) — Ν3 — [3-(5,7 —difluoro-1, 2, 3, 4-tetrahydronaphthalene-2-yl) -2-thiothio-2,3-dihydro ~ 1 Η—imidazole-4 methyl yl] -N1, Ν2-bis (tertiary butoxycarbonyl) formamidine (0.54 g, 1 mil), melting point 155¾ (evaporation). Example 49 was carried out, but N 1, N 2 ~ di (tertiary butoxycarbonyl) methylthiofluorene was replaced with different starting materials to obtain a compound of formula I with K: using N 1, N 2 -bis (ethenyl) Substituted by methylthiofluorene to obtain (S) —N ^ — [3- — (5,7—digas-1′2′3,4—tetrahydronaphthalene-2—yl) —2—thioxo-2, 3-dihydro-1H-4-methylmethyl] -N1, N2_di (ethenyl) methyl fat, melting point 213-214Π; and printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the first Note: Please fill in this page again.) Substitute with N1 — (tertiary butoxycarbonyl) methylsulfanium to obtain (S) —N3 — [3-(5,7—digas_1 '2'3'4 —Tetrahydrocae —2 —yl) — 2 —thio-2, 3 —diM—l — — 4 ~ ylmethyl] —N1 —di (tertiary butoxycarbonyl) formamidine, melting point greater than 2 8 0 t:. Example 5 0 (S)-N 3-[3-(5,7_ difluoro_1,2,3 -192- This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) 470741 Central Standard of the Ministry of Economic Affairs A7 B7 printed by the Bureau ’s Consumer Cooperatives. V. Description of the invention (), 4—Siqi—Caiyi 2_ji) —2—Thioxo-2, 3—Diazine-1 H—oxazole—4-methyl group] Formamidine is a compound in which I is 1 in formula I (a), t is 2, 5- and 7 and R1 is fluorine and Rs is amidinomethyl. (S) — N3 — [3 — (5,7 —digas — 1 ′ 2,3,4 tetrahydronaphthalene — 2 —yl) — 2 —thio_2,3 — 2 as prepared in Example 49 A solution of hydrogen-1H-imidazole-4-ylmethyl] -N1, N2-bis (tertiary butoxycarbonyl) formamidine in 20 ml of trifluoroacetic acid was stirred at about 25 ° C for 1.5 hours. hour. The solution was concentrated and the residue was mixed with 100 ml of diethyl ether. The diethyl ether was decanted and the residue was mixed with 100 ml of diethyl ether. The mixture was filtered, the filtered residue was dissolved in ethyl acetate, the solution was concentrated, and the vacuum was removed. The formed foam was treated with diethyl ether, and the mixture was filtered to obtain (S)-N 3-[3 — (5, 7 — difluoro). -1,2,3,4-tetrahydronaphthalene- 2-yl)-2 -thio-2,3-dihydro- 1H-oxazole- 4-ylmethyl] formamidine (0.28 g, ◦ • 6 millimolar), melting point 103D (evaporation). Example 5 1 2S -amino-3-(3'-imidazol-4-yl) -N-[3-(5,7 -difluoro-1, 2,3,4 -tetralin-2 -yl)- 2-thio- 2 * 3 -dihydro-1Η-oxazole-4-ylmethyl] propanamidinium argon chloride M is prepared in the formula II where η is 1 and t is 2,5-and 7-positions -193- This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) (Please read the precautions on the back before filling out this page) Printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 470741 A7 B7 V. Invention Description (1) R1 is fluorine, and R1 8 is a compound in which R2 1 in formula (d) is L-histamine salted aminomethyl. (R) —5 —aminomethyl — 1 — (5,7 —digas — 1,2,3,4 —tetrahydrocae —2 —yl) —1,3 —dihydro as prepared in Example 31 Oxazole—2—thione (0.55 g, 1.86 mmol), (S) —2— (tertiary butoxycarbonyl) amino—3- (3-tert-butoxycarbonyl— A mixture of 3H imidazole- 4-yl) propionic acid (0.76 g, 1.86 mmol) and PyBOP (1.07 g, 2.05 mmol) in 6.2 ml of dimethylformamide , Stir in argon until uniform. Diethylisopropylethylamine (1.07 ml, 6.15 mmol) was added and the mixture was stirred for about 18 hours. The mixture was partitioned between water and ethyl acetate. The organic layer was washed twice with water, dried over magnesium sulfate and concentrated by evaporation. The residue was purified by column chromatography (eluent: 5% methanol / methylene chloride) to obtain foamed 2S (secondary butoxycarbonyl) amino-3-(3-tertiary butoxy Carbonyl — 3H — oxazole — 4 —yl) — N — [3-(5,7-difluoro-1, 2, 3, 4 —tetraammine — 2R —yl) — 2 — thio — 2, 3 — Dihydro-1H —oxazole-4 monoylmethyl] propanamide (1.03 g) 〇 2S— (tertiary butoxycarbonyl) amino group 3- (3-tertiary butoxycarbonyl-3H —Oxazole-4 monoyl) -N — [3 — (5,7 —difluoro_1 1,2,3,4 —tetrahydronaphthalene — 2R —yl) — 2 —thioxo 2,3 —dihydro 1H-oxazole-4 monomethylmethyl] propanyl-194- (Please read the notes on the back before filling this page) This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) 470741 Ministry of Economic Affairs A7 B7 printed by the Consumers' Cooperative of the Central Bureau of Standards 5. Description of the invention () Amine (0.935 g) was dissolved in 45 ml of 30% anhydrous hydrogen chloride / ethyl acetate, and the mixture was stirred for 18 hours to obtain a crystalline substance. The material was separated and dried under vacuum at 60 ° C to obtain 2S-amino-3- (3H-oxazole-4-yl) -N- [3— (5,7-difluoro-1, 2 , 3,4-tetrahydronaphthalene- 2-yl)-2 -thio-2,3-dihydro-1H -imidazol-4-ylmethyl] propanamidin hydrochloride (0.665 g, 1 · 24 millimoles), melting point 228υ; carried out according to Example 51, but replacing (R) -5_aminomethyl-1— (5,7—difluoro-1,1,2,3,4— Tetrahydronaphthalene- 2-yl) -1,3-dihydrooxazole-2-sulfanium and (S) -2-(tertiary butoxycarbonyl) amino-3_ (3-tertiary butoxycarbonyl) -3)) oxazole-4-yl) propanoic acid to prepare a compound of formula II using K-aminomethyl-1 1- (5,7-difluoro-1,1,2,3,4-tetrahydronaphthalene -2-yl) -1,3-dihydroimidazol-2-thione and (S) -3-(tertiary butoxycarbonyl) -2-tertiary butoxymine aminoaminopropionic acid 3S-amino-N- [3— (5,7-difluoro-1,2,3,4-tetrahydronaphthalene_2_yl) -2—thioxo-2,3—dihydro-1Η — mum A 4-methyl ^ methyl] succinimidine hydrochloride, melting point 220Ό; using 5-aminomethyl-1_ (5,7-digas-1,1,2,3,4-tetrahydronaphthalene-2- Base) -1,3-dihydrooxazole-1, 2-thione and (S) -3-(tertiary butoxycarbonyl) -3-(tertiary butoxy-195-) This paper applies Chinese national standards (CNS) A4 specification (210 × 297 mm) (Please read the notes on the back before filling out this page) 470741 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention () Carbonylamino) Propionic acid substitution, 2S —amino-N — [3-(5,7 —digas-1,2,3,4 —tetracaine-2 —yl) — 2 —thioxo-2,3 —dihydro-1H —Oxazole-4 —ylmethyl] succinimidine hydrochloride, melting point 2 20t); with 5-aminomethyl-1 1- (5,7-difluoro-1, 2, 3, 4-tetra Hydronaphthalene- 2-yl) -1,3-dihydroimido-1-thione and (S) -2,5-di (tertiary butoxycarbonylamino) valeric acid were substituted to obtain 2S, 5 —Diamino-N— [3 — (5,7 —difluoro — 1, 2, 3, 4-tetrahydronaphthalene Mono- 2 -yl)-2 -thio-2,3-dihydro-1,1 -oxazole -4 -ylmethyl] ammonium ammonium hydrochloride, melting point 212-216 ° C; using amino methyl 1- (1,2,3,4-tetrahydronaphthalene-2-yl) -1,3-dihydrooxazole-2-thione and (S) -2, 5 -di (tertiary butoxy Carbonylamino) valeric acid substitution to obtain 2S, 5-diamino-N— [3 -— (1,2,3,4-tetraaminocae-2--2-yl) —2-thioxo-2,3 —Dihydro-1H —oxazole-4-ylmethyl] pentamidine hydrochloride, melting point 191 —205 ° C; with 5-aminomethyl-1 1- (1,2,3,4— Tetrahydronaphthalene-2 -yl) -1,3-dihydrooxazole-2-thione and (S)-2-(tertiary butoxycarbonylamino) -5_ (tertiary butoxycarbonyl) guanidino Valeric acid substitution to obtain 2S —amino-N — [3 -— (1,2,3,4-tetrahydronaphthalene-2—yl) —2—thioxo-2,3—dihydro—1 Η — 眯Azole-4 monomethyl]] 5-guanidinopentylamine hydrochloride, fused -196- This paper size applies to Chinese National Standard (CNS) A4 specification (210 × 297 mm) (please read first) Please fill in this page again for details) 470741 Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention () Point 1 6 Ο Ό; Tetrahydrocae-2-yl) -1,3-dihydrooxazole-2-thione and (S) -2-(tertiary butoxycarbonyl) amino-3-(3-tertiary butoxy Carbonyl-3Η-imidazole-4 monoyl) propionic acid substitution to obtain 2S-amino- 3-33-imidazole-4 monoyl) -N-[3 — (1,2,3,4-tetrahydrocaine) 1 2 -yl)-2 -thio_2,3 -dihydro-1, 1 -yl-1 -yl] propionate hydrochloride, melting point 1 97-205 ° C; 5-amino methyl One 1 one (5,7 -difluoro-1,2,3,4-tetrahydronaphthalene-2-yl) -1,3 -dihydroimidazol-2-thione and (S)-2-(tertiary Butoxycarbonyl) amino group 3-(3-tertiary butoxycarbonyl group 3 Η -imidazol-4-yl) propionic acid substitution to obtain 2 S —amino_3 — (3 Η -panzol-4 One group) —N — [3-(5,7 —difluoro-1,2,3,4-tetrahydronaphthalene-2 —yl) —2 —thio 3-dihydro-1,1-imidazol-1-ylmethyl] propanamidate hydrochloride, melting point 1 95-238 ° C; using (S) -5 -aminomethyl-1-(5,7- Difluoro_1,2,3,4-tetrahydronaphthalene-2-yl) -1,3-dihydrooxazole-2-thione and (S) -2-trifluorobutoxycarbonyl-amino group- 3— (3 -trimethylbutoxycarbonyl—3H-imidazole—4-yl) propanoic acid was substituted to obtain 2S —amino —3 — (3H—hoe beer —4 —yl) — [3 — (5,7 —Difluoro-1,2,2,3,4-tetrahydronaphthalene-2 —yl — 2 —thio-2,3 —dihydro-1H —imidazole — 4 monomethyl-197- (please read the back first) Please pay attention to this page before filling in this page) This paper size applies Chinese National Standard (CNS) A4 specification (2I0X297 mm) 470741 Printed by A7 B7, Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of the invention () Hydrochloride, melting point 225 ° C; using (S) —5-aminomethyl-1 1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl) -1, 3 —dihydrofluorinone 2-thione and (S) — 4-ethylaminoamino — 4-tertiary butoxycarbonyl Butyric acid substitution to obtain 2S-ethenylamino-4— [3 — (5, 7-difluoro-1, 2, 2, 3, 4-tetrahydronaphthalene- 2S —yl) — 2 — thio-2 , 3-dihydro-1, hydrazone, 4-imidazole-4 monomethylmethylaminocarbonyl] butanoic acid, melting point 1 5 9 t; (S)-5 -aminomethyl 1-(5,7_ di Fluoro-1,2,3,4-tetrahydronaphthalene- 2-yl) -1,3-dihydroimidazol-2-thione and (S) -2,5-di (tertiary butoxycarbonylamino) ) Substituted by valeric acid to obtain 2S, 5-diamino-N-[3 — (5,7-difluoro-1,2,3,4-tetrahydronaphthalene-2S-yl)-2 -thio- 2 · 3-dihydro-1H-imidazole-4 monomethyl] pentamidine hydrochloride * Melting point 233-2331; using (R) -5 -aminomethyl-1 1- (5,7-difluoro -1,2,3,4-tetrahydronaphthalene- 2-yl) -1,3-dihydroimidazol-2-thione and (S) -2,5-di (tertiary butoxycarbonylamino) Valeric acid to obtain 2S, 5-diamino-N — [3 — (5,7 —difluoro-1,2,3,4 —tetrahydrocae-2R —yl) —2 —thioxo-2, 3 —dihydro-1 hydrazone —imidazole-4 Methyl] pentamidine hydrochloride, melting point 128-150 ° C; using (S) -5-aminomethyl-1— (5,7-difluoro-1 1 " 19 8 ~ (Please read first Note on the back page, please fill in this page again) This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) 470741 A7 B7 V. Description of the invention (), 2, 3, 4 Tetrahydronaphthalene 2-based) 1,3 -dihydroimidazole-2-thione and (S)-3-(tertiary butoxycarbonylamino)-2-(tertiary butoxycarbonylamino) propionic acid to obtain 2S -amino- N— [3 ~ (5,7 -difluoro-1,2,3,4-tetrahydronaphthalene-2S-yl) —2 —thio-2,3 —dihydro-1H —oxazole-4-yl Methyl] succinate hydrochloride, melting point 1 941; using (R) -5 -aminomethyl-1 1- (5,7-difluoro-1, 2 * 3 * 4-tetrahydronaphthalene-2 -yl )-1,3-dihydrooxazole- 2-thione and (S) -3- (tertiary butoxycarbonylamino) -2- (tertiary butoxycarbonylamino) propionic acid to obtain 2S — Amino group —N — [3-(5 * 7 —difluoro-1, 2, 3, 4-tetrahydronaphthalene-2R —yl) — 2 —thioxo-2 3 ~ dihydro-1, hydrazone-panazole-4-ylmethyl] succinylamine hydrochloride, melting point 1 9 3 υ; using 4-amino- 2-(5,7 -difluoro-1 1,2, 3 * 4 Tetrahydronaphthalene-2-yl) -2,4-dihydro [1,2,4] triazol-3-thione and (S) -2,5-di (tertiary butoxycarbonyl) Amino) valeric acid to produce 2S, 5-diamine-N — [1 1 (5 * 7-Printed by the Consumers ’Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page) Difluoro-1 * 2,3,4 tetrahydronaphthalene-2-yl) -5—thioxo-4,5-dihydro-1 hydrazone [1,2,4] triazol-4-yl] pentamidine Hydrochloride; use 4-monoamino-2_ (5,7-difluoro-1, 2,3,4-tetrahydronaphthalene_2-yl) -2,4-dihydro [1,2,4] tris Mile—3-thioketone and (S) — 2— (tertiary butoxycarbonyl) amino group_3 -1 99- This paper size applies to China National Standard (CNS) Α4 specification (210 > < 297 mm) 470741 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs f ’Training: V. Invention Description (A7 B7

一（3 —三级丁氧基羰基一 3H —咪唑一 4 —基）丙酸* 製得2S —胺基一3 — (3H —眯唑一4 一基）一N — [1 — (5，7—二氟一1 ，2’3，4 —四氫萘一2 — 基）-5—硫代一 4，5 — 二氫一1H — 〔1 ，2 ，4] ***一 4 —基〕戊醯胺氫氯化物，熔點22 1 — 224D 用（S) — 5 —甲基胺基甲基一 1- (5，7—二氟 —1 ，2 ，3，4 一四氫萘一2 —基）一1 ，3—二氫脒唑-2 —硫酮和（S) — 3 —(三級丁氧基羰基）—2 — (三級丁氧基羰基胺基）丙酸，製得3S—胺基一N—〔 1 ，2，3 ，4 一四氫蔡一2S — 3 -二氫—1 H —咪唑—4 —基— 3 ~ (5，7 —二氟一基）—2 —硫代一 2, 甲基〕一甲基琥珀醯胺酸氫氯化物；和 (5，7-二氟-1，2，3，4 2，4一二氫〔1，2，4]*** 用4 —胺基一2-四氫蔡一2； —基）一 3 —硫酮和（S) — 3 —(三级丁氧基羰基） 3 —( 三級丁氧基羰基胺基）丙酸，製得2S—胺基一N- 〔1 —(5 ，7—二氟—1 ，2 ，3 ，4 —四氫蔡一2 —基） —5 —硫代-4，5 —二氫一 1H 〔1 ，2，4〕***一 4一基]琥珀醯胺酸氫依前述之步驟進行氯化物，熔點1 ，可獲得化合物Mono (3-tert-butoxycarbonyl- 3H-imidazol-4-yl) propionic acid * to obtain 2S-amino-3- (3H-oxazole-4-yl) -N- [1 — (5, 7-difluoro-1,2'3,4-tetrahydronaphthalene- 2-yl) -5-thio-4,5-dihydro-1H- [1,2,4] triazole-4-yl] Amylamine hydrochloride, melting point 22 1 — 224D (S) — 5 —methylaminomethyl — 1 — (5,7 —difluoro — 1, 2, 3, 4 — tetrahydronaphthalene — 2 — Group)-1,3-dihydrooxazole-2 -thione and (S) 3-(tertiary butoxycarbonylamino) -2-(tertiary butoxycarbonylamino) propionic acid to obtain 3S —Amine-N— [1,2,3,4—Tetrahydrocae 2S — 3 —Dihydro — 1 H —Imidazole — 4 —Base — 3 ~ (5,7 —Difluoromono) — 2 — Thio-2, methyl] monomethylsuccinimine hydrochloride; and (5,7-difluoro-1,2,3,4 2,4-dihydro [1,2,4] triazole With 4-amino-2-tetrahydrocae-2; -yl) -3-thioketone and (S) -3-(tertiary butoxycarbonylamino) 3- Acid to make 2S-amino N- 〔1 — (5,7-difluoro-1,2,3,4—tetrahydrocaine 2-yl) —5 —thio-4,5 —dihydro-1H [1,2,4] Triazol-4-yl] Hydrogen succinimine is chlorided according to the previous steps, melting point 1 to obtain the compound

S) - 5，7 -二氟-1，2，3, )-2-硫代一 2，3— 二氫一1H 4 9 3 - 1 9 6 1° 1-((3-(( —四氫萘一 2 _基咪唑一 4 一基甲基 F--1^1 n n «^1 n m ^^1 n n t n I n i— n n ^^1 I .1 UK Bn n ^^1 ϋ I tc 4 <請先閱讀背面之注意事項再ΐ寫本頁) 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐）經濟部智慧財產局員工消費合作社印製〕~胺基甲醢基]環戊基一氯化銨，熔點212 ‘ 5 — 2 2 5 °C 〇實例5 2 2R —胺基一 3 — 〔1— (4，6—二氟郎滿一1_ 基）—1 Η —咪唑—2 —基二硫酸酐基]丙酸氫氯化物 W下傜製備式I I I中η為0 ，t為2 ，5 —和7 — 位置的R1為氟，R2 7為式（a)中R4和RS為氫， R2 8為2 —胺基一 2 —羧基乙基的化合物。 (R，R') 一3，3' _二硫酸酐基雙〔2— （三級丁氧基羰基）胺基丙酸三級丁酯〕（1.06克，2.0 毫莫耳）在5毫升乙烯二氯化物中的溶液在氩氣中冷卻到 —2 3 °C ◊滴加溴（5 1 ，3微升* 1 . 0毫莫耳），攬拌混合物約2 0分鐘，然後用額外的2毫升乙烯二氯化物稀釋之。肽醯亞胺鉀（370毫克，2 * 0毫莫耳）在5 毫升乙烯二氯化物中所形成的懸浮物被冷卻到約一2 3Ό ’加入二硫化物混合物。該混合物在_ 2 3 C攪拌1小時，然後回溫到室溫達4 5分鐘。過濾混合物，於真空中濃縮。殘留物溶於苯中，經過層析純化，製得（R ) — Ν — 〔2 —(三级丁氧基羰基胺基）一2 —(三級丁氧基羰基 )乙基硫酸酐基〕肽醯亞胺（684毫克）（油）。 (R ) - Ν - C 2 -(三級丁氧基羰基胺基）一2 — (三级丁氧基羰基）乙基硫酸酐基]肽醯亞胺（660毫 -20 1- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） — — — — —-------1 -------^訂-----1—丨-- (請先閱讀背面之注意事項再填寫本頁) 470741 Α7 Β7 五、發明說明（） (請先閱讀背面之注意事項再填寫本頁) 克，1 . 61毫莫耳）和如實例9所製備的1 一（4，6 —二氟茚滿一1 一基）一 1 *3 —二氫咪唑一2 —硫酮 (400毫克* 1 · 59毫莫耳）混合物在8毫升醋酸乙酯中，於氬氣中加熱回流1小時。冷卻混合物到室溫，得到结晶性沈澱，然後在減壓下蒸發溶劑。用苯研製殘留的半固體，過濾苯混合物。蒸發濃縮苯溶液，殘留物經層析純化，製得2R—(三級丁氧基羰基）胺基一3— 〔1— (4，6 -二氟郎滿一 1 一基）—1H-咪唑一 2—基二硫酸酐基〕丙酸三級丁酯（672毫克）。 2R-(三级丁氧基羰基）胺基—3 — 〔1— (4， 6 —二氟茚滿一 1 一基）—1 Η —眯唑—2 —基二硫酸酐基〕丙酸三級丁酯（672毫克）與15毫升三氟醋酸和 1 5毫升甲撐氯化物之混合物在氮氣中及室溫下攪拌2小時。蒸發除去溶劑，殘留物與醋酸乙酯（2x50毫升）進行共蒸發。用醚的氯化氫加Μ處理*製得固體的2 R —胺基一3 —〔5 —胺基甲基一（1— (4，6 —二氟茚滿一1—基經濟部智慧財產局員工消費合作社印製S)-5,7 -difluoro-1,2,3,) -2-thioxo-2,3-dihydro-1H 4 9 3-1 9 6 1 ° 1-((3-((- Hydronaphthalene-2 _ylimidazole-4 monomethyl F--1 ^ 1 nn «^ 1 nm ^^ 1 nntn I ni— nn ^^ 1 I .1 UK Bn n ^^ 1 ϋ I tc 4 < (Please read the precautions on the back before copying this page) This paper size is applicable to the Chinese National Standard (CNS) A4 (210 X 297 mm) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs] ~ Aminomethanyl Cyclopentyl monoammonium chloride, melting point 212 '5 — 2 2 5 ° C 〇 Example 5 2 2R —Amine 3 — [1— (4,6-difluorolangman 1-yl) — 1 Η — imidazole —2- —disulfic anhydride group] propionate hydrochloride W is prepared from formula III in which η is 0, t is 2, 5 and 7, and R1 is fluorine, and R2 7 is R4 and R4 in formula (a). RS is hydrogen, and R 2 8 is a 2-amino-2-carboxyethyl compound. (R, R ') 3,3'_disulfonic anhydride bis [2- (tertiary butoxycarbonyl) amino group A solution of tertiary butyl propionate] (1.06 g, 2.0 mmol) in 5 ml of ethylene dichloride was cooled to -2 3 ° C in argon, and bromine (5 1 3 μl * 1.0 mmol), stir the mixture for about 20 minutes, and then dilute it with an additional 2 ml of ethylene dichloride. Potassium imide potassium (370 mg, 2 * 0 mmol) The suspension formed in 5 ml of ethylene dichloride was cooled to about 2-3 ° C. The disulfide mixture was added. The mixture was stirred at 2-3 C for 1 hour, then warmed to room temperature for 4 5 minutes. Filtered The mixture was concentrated in vacuo. The residue was dissolved in benzene and purified by chromatography to obtain (R) -N- [2- (tertiary-butoxycarbonylamino)-2- (tertiary-butoxycarbonyl) ) Ethylsulfate anhydride] Peptidyl imine (684 mg) (oil). (R)-Ν-C 2-(tertiary butoxycarbonylamino)-2-(tertiary butoxycarbonyl) ethyl Sulfuric acid anhydride group] Peptidyl imine (660 milligrams 20 1- This paper size applies to China National Standard (CNS) A4 specifications (210 X 297 mm) — — — — — ------- 1- ----- ^ Order ----- 1— 丨-(Please read the notes on the back before filling this page) 470741 Α7 Β7 V. Description of the invention () (Please read the notes on the back before filling in this (Page) grams 1.61 mmol) and 1- (4,6-difluoroindane-1 1-yl)-1 * 3 -dihydroimidazole- 2 -thione (400 mg * 1 · 59 The mol) mixture was heated in 8 ml of ethyl acetate under reflux for 1 hour under argon. The mixture was cooled to room temperature to obtain a crystalline precipitate, and then the solvent was evaporated under reduced pressure. The residual semi-solid was triturated with benzene and the benzene mixture was filtered. The benzene solution was concentrated by evaporation, and the residue was purified by chromatography to obtain 2R— (tertiary butoxycarbonyl) amino—3— [1— (4,6-difluorolangman 1—1yl) —1H-imidazole. A 2-yldisulfic anhydride group] tert-butyl propionate (672 mg). 2R- (tertiary butoxycarbonyl) amino-3— [1- (4,6-difluoroindane-1 1-yl) -1 fluorene-oxazole—2-disulfonic anhydride group] propionic acid tris A mixture of grade butyl ester (672 mg) with 15 ml of trifluoroacetic acid and 15 ml of methylene chloride was stirred under nitrogen at room temperature for 2 hours. The solvent was removed by evaporation and the residue was co-evaporated with ethyl acetate (2x50 mL). Treatment with hydrogen chloride in ether and M to obtain solid 2 R —amino — 3 — [5-aminomethyl — (1 — (4,6 —difluoroindane — 1 —based employee of Intellectual Property Bureau, Ministry of Economic Affairs) Printed by Consumer Cooperatives

)—1Η —咪唑一 2 —基二硫酸酐基]丙酸氫氛化物 (768毫克，1.74毫莫耳），熔點147 — 154 °C 〇依實例5 2進行，但是用不同起始物質取代（R，R ')—3，3' —二硫酸酐基雙〔2 —(三級丁氧基羰基 )胺基丙酸三级丁酯]和/或1 一（ 4，6 —二氟茚滿— - 2 0 2 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐）經濟部智慧財產局員工消費合作社印製 mu a? _B7_ 五、發明說明（）基）—1 ，3 —二氫咪唑—2 —硫_，製得K下式 I I I化合物；用（R，R' ) — 3，3'—二硫酸酐基雙〔2 — ( 三級丁氧基羰基）胺基丙酸甲酯取代，製得2R-胺基-3 — [5 —胺基甲基一 1— (4，6 —二氟郎滿一 1 一基 )咪唑一 2 —基二磺胺基〕丙酸甲酯氫氯化物，熔點15 5 — 1 5 7 "C ° 用3，3'—二硫酸酐基雙〔2 — （三级丁氧基羰基 )胺基乙基乙基〕取代，製得2~ 〔2 —胺基乙基二磺胺基）—1— (4，6 —二氟茚滿一1_基）咪唑氫氯化物，熔點 175 — 177 °C; 用（R，R' ) — 3，3' —二硫酸酐基雙〔2 — （三氟乙醯基）胺基丙酸甲酯取代，製得2_ (三氟乙醯基 )胺基—3 — 〔1一（4，6 -二氟茚滿一 1—基）咪唑 —2—基二磺胺基〕胺基丙酸甲酯（油）·，用（R，R' ) -3，3'—二硫酸酐基雙〔2 — ( 三級丁氧基羰基）胺基丙酸三鈒丁酯取代，製得2 R -胺基一3 — 〔1一（4，6 —二氟茚滿_2 —基）咪唑一2 一基二磺胺基〕胺基丙酸氫氯化物，熔點145-1501 * 用 1— (4，5 —二氟茚滿一 2 —基）一1 ，3 —二氫眯唑一2 —硫酮取代，製得2R —胺基一 3~ 〔1—( 4，5 —二氟茚滿—2 —基）一 1H —眯唑一2 —基二硫 - 2 0 3 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） I I-----丨 — 丨--1 "^4---II---訂-丨----- (請先間讀背面之注意事項再填寫本頁) 470741 8a 9. ί8 經濟部智慧財產局員工消費合作社印製 A7 B7_五、發明說明（）酸酐基〕丙酸氫氯化物，熔點140t：; 用 1 一（5 ，7 —二氟一1 ，2 ，3 ，4 —四氫萘一 2 —基）一1 ，3~二氫咪唑一2 —硫酮取代，製得2R —胺基— 3·— 〔1— (5，7 —二氟一 1 ，2，3，4 — 四萘一2 —基）—1Η —咪唑—2 —基二硫酸酐基〕丙酸氫氯化物，熔點1 3 0 °C ; 用 1— (6，8 —二氟一1 ，2，3，4 —四氫蔡一 2 —基）—1 * 3~二氫脒唑—2 —硫_取代*製得2R —胺基 ~3 - 〔1~ (6，8_ 二氟—1，2，3，4_ 四萘—2 —基）一 1H —咪唑一2 —基二硫酸酐基]丙酸氫氯化物，熔點1 4 1 t ; 用 1— (6 ，7 —二氟一1 ，2 ，3 ，4一四氫蔡一 2 —基）—1 ，3 —二氫咪唑—2 —碲酮取代，製得2R —胺基—3— [ 1 ~ (6，7 —二氟 _1 ，2，3，4·— 四萘一 2 —基）—1H —咪唑一 2 —基二硫酸酐基〕丙酸氫氯化物，熔點1 3 0 °C ; 用 1— (5 ，7 — 二氟一1 ，2 ，3 ，4 一四氫萘一 2 —基）一2 —硫代—1 ，3 —二氫一咪唑—5 —羧酸取代，製得2R —胺基—3 — 〔5 —羧基—1 一（5，7 — 二氟一1 ，2 ，3 ，4 一四萘一2 —基）眯唑一2 —基二硫酸酐基〕丙酸氫氯化物，熔點1 29— 1 38 °C; 用 1— (4，5—二氟邦滿—2 —基）—1 ，3 —二氫咪唑—2 —碲嗣和（S，S' ) — 4，4'—二硫酸酐 - 2 0 4 - ϋϋ度ίϊ用中國國家標準（CNS)A4規格（210 X 297公釐）： ' II1IIII1 — — — — ' · I I I I I I I ·111!1111 . (請先閱讀背面之注意事項再填寫本頁) 470741 89. 9, | A7 B7 經濟部智慧財產局員工消費合作社印製五、發明說明（）基雙〔2— （三級丁氧基羰基）胺基丁酸三级丁酯〕取代，製得2S —胺基一4 — 〔1— (4，5 —二氟茚滿一2 —基）咪唑一 2 —基二磺胺基〕丁酸氫氯化物，熔點59 °C ♦ 用 1 一（4，5 —二氟茚滿一2 —基）一 1 ，3 —二氫咪唑一 2 —硫酮和（S，S' ) — 3 ，3'—二硫酸酐基雙〔2 — （三級丁氧基羰基）胺基一 3 —甲基丁酸三鈒丁酯]取代，製得2S —胺基一 3 — 〔1— (4，5 —二氟郎滿—2 -基）一 1H—眯唑—2 —基二硫酸酐基〕一 3 —甲基丁酸氫氯化物，熔點143 — 149¾ ; 用 1— (5 ，7 —二氟一 1 ，2 ，3 ，4 —四氫蔡一 2 —基）一5 (1H)—四唑一5— 基一1 ，3 — 二氫咪唑一 2 —硫_和3 ，3' -二硫酸酐基雙〔2 —(三級丁氧基羰基）胺基乙基〕取代，製得2 — (2 —胺基乙基二硫酸酐基）一1一（5，7 — 二氟一 1 *2，3，4 —四氫蔡一 2 —基）一 5 ( 1 Η )—四唑一5 —基一1 ，3 — 二氫咪唑氫氯化物，熔點1 6 5 °C (分解）；和用（S) — 5 —(三級丁氧基羰基）胺基甲基一1 一 (5 ，7 —二氟一1 ，2，3，4一四氫蔡一 2 —基）一 1 ，3~ 二氫咪唑一2 —硫_和（R ，R' ) 一 3 ，3' 一二硫酸酐基雙〔2 — （三級丁氧基羰基）胺基丙酸三級丁酷〕取代，製得2R_胺基—3 — 〔5 —胺基甲基一1 -(5 ，7 -二氟一1 ，2，3 ，4_ 四氫萘一2 —基） - 2 0 5 - (請先閱讀背面之注音？事項再填寫本頁) )->/ ----訂----I---1 1 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 470741 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明（）一 1 Η —咪唑—2 —基二硫酸酐基〕丙酸氫氯化物，熔點 179 — 180°C (分解）。實例5 3 N —(三氟乙醯基）一L 一門冬氨酸酐三氟醋酸酐（7，7公斤，5 * 3升，37 · 5莫耳 )被加熱到回流溫度，在30分鐘内將L一門冬氨酸（ 2 · 0公斤* 1 5 * 0莫耳）於9升三氟醋酸中所形成的溶液（製備於逐漸加熱到65¾，並攪拌3小時）加入回流中的三氟醋酸酐。然後蒸餾混合物*除去9升的三氟醋酸。在氮氣中將殘留的混合物加入8升冰冷的己烷，己烷混合物在冰浴中攪拌3小時，得到结晶性物質。過濾分離該物質，用約2 5升己烷洗滌濾紙殘留物，在5 0 °C的真空烘箱中通入氮氣下乾燥到恆重，得到N —(三氟乙醯基 )—L —門冬氨酸酐（2·9公斤，13·7莫耳），熔點 140-141。。，〔a〕D-2：7-4° (c=3，28，四氫呋哺）。實例5 4 (S ) — 2 —〔（三氟乙醯基）胺基〕一4 — (2*4- 二氟苯基）一4一氧基丁酸 Μ下係製備式31中η為0，t為2，2 —和4 —位置的R 1為氟的化合物。 - 2 0 6 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） ----- - - - - -------I I I — I 訂---------I (請先閱讀背面之注意事項再填寫本頁) 470741 89. 9. 18 A7 B7 經濟部智慧財產局員工消費合作社印製五、發明說明（〉 1 ，3-二氟苯（2 . 3公斤，20 . 0莫耳）於5 升甲撐氯化物中所形成的溶液被加入如霣例5 3所製備的 N -(三氟乙醯基）一L —門冬氨酸酐（4. 2公斤，2 〇 . 〇莫耳），氯化鋁（7 . 4公斤，5 5 . 5莫耳）和 2 5升甲撐氯化物的混合物中。在1 . 5小時内將反應混合物溫度逐漸提高，並另外維持在回流達3小時。然後將混合物冷卻，在良好攪拌下加入2 0升的6N氫氯酸。分離甲撐氮化物層，先後用水和鹽水洗滌，在大氣壓力下藉蒸餾除去揮發物。將殘留物溶於40升甲苯，在真空中蒸餾混合物而除去8升揮發物。將溶液加熱到50 °C，加入8升己烷。然後在2 5 t攪拌混合物3小時，得到結晶性物質。過濾分離該物質，用己烷（3x10升）洗滌濾紙殘留物，在釋出氮氣及室溫下於真空烘箱乾燥到恆重，得到（S ) - 2 —〔（三氟乙醯基）胺基〕一 4 — (2 ，4 —二氟苯基） —4 —氧基丁酸（5 . 2公斤，16 · 0莫耳），熔點 82.4-84.0。。。〔a〕D+15.2。（c = 〇.9 5 6 ，甲酵）。實例5 5 (S) — 2 — [(三氟乙醯基）胺基〕一4 — (2，4一二氟苯基）丁酸 Μ下係製備式30中η為1 ，t為2，2 —和4 一位 - 2 0 7 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） --II---— — — — — — 丨 — — I I I — 訂.— — — — —--- (請先閱讀背面之注意事項再填寫本頁) 470741 89. 9. 3 8 A7 ___ 五經濟部智慧財產局員工消費合作社印製發明說明（）置的R 1為氟的化合物。如實例5 4所製備的（S ) — 2 —〔（三氟乙醯基） (請先閱讀背面之注意事項再填寫本頁) 胺基〕一4 — (2，4 —二氟苯基）一 4 一氧基丁酸（ 4 . 8公斤，14 · 7莫耳）和活性碳Darco® ( 0 · 4公斤）混合物於5升醋酸中，在室溫攪拌1小時。混合物被過漶到 Pearl man觸媒（0 ‘ 5公斤，5 0 %濕重），K 1 5升冰醋酸予Μ洗滌。1升冰醋酸中的硫酸（ 1 ，2升，2 1 ，8莫耳）被過濾到混合物中，以2 · 8 升冰醋酸洗滌。反應容器在先後真空通入氮氣三次然後通入六次氫氣氣抽真空，使壓力達到IOps i g。在通入氫氣的大氣壓力及室溫下激烈攪拌混合物達2 4小時◊然後將氮氣通入反應容器，過漶混合物到4 · 6公斤的醋酸納三水合物。用1 0升冰醋酸洗滌·據紙，在真空中蒸餾除去冰醋酸。殘留物在20升甲撐氯化物和40升水中分層，水層被1 0升甲撐氯化物萃取，混合的甲撐氯化物被1 0升水洗滌，然後甲撐氯化物在硫酸納（1 0公斤）乾燥，過濾。在真空中除去溶劑，殘留物溶於5升的甲撐氛化物中。在通入氮氣中將溶液加入1 5升的己烷，其加入速率使己烷混合物的溫度維持在0 °C和5 Ό之間。使混合物靜置1 小時，得到结晶性物質。過濾並分離該物質，以1 0升己焼洗滌濾過的殘留物•在2 5 °C及通入氮氣的真空烘箱中乾燥到恆重，得到（S ) — 2 — 〔（三氟乙醯基）胺基〕 - 2 0 8 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐）經濟部智慧財產局員工消費合作社印製 470741 ㈣.iis A7 B7 五、發明說明（） -4 - (2，4—二氟苯基）丁酸（3 . 3 公斤，1〇 .4 莫耳），熔點62 — 83. 5Ό。分析上純樣品的熔點為 86t：-89 0C° ία) D +6，8° (c=〇.995 ，甲醇）。實例5 6 (S ) 一5，7 —二氟一 2 — 〔（二氟乙醯基广胺基〕一 3，4一二氫一1 (2H) -mm Μ下係製備式29中η為1 ，t為2，5 —和7 —位置的R 1為氟的化合物。將五氯化磷（2 · 2公斤，1 0 · 6莫耳）在1 2升甲撐氯化物中所形成的懸浮物冷卻到5 °C，在20分鐘内加入製備於實例5 5的（S ) - 4 - ( 2，4 -二氟苯基 )一 2 —〔（三氟乙臨钍）胺基〕丁酸（3 · 1公斤， 9，9莫耳）（12升甲撐氛化物中）。薄層層析（甲醇驟冷）證實丁酸已轉換成相對應的酸氯化物。搜拌混合物3 0分鐘，然後被加入氛化鋁（4 · 3公斤）在38 * 8升甲撐氯化物中所形成的泥狀物，添加速率使泥狀物溫度維持在1 t：和5 °C之間。授拌反應混合物 1小時，然後被加入2 8公斤的冰和5 · 3公斤濃氫氯酸中。搜拌混合物1小時，使溫度回升到2 0 t：。分離水相，Μ甲撐氯化物萃取（2x15升），用水洗滌甲撐氯化物層，與甲撐氯化物萃取物混合。然後用水 - 2 0 9 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -----------— -味衣-----— I I 訂--------- (請先閱讀背面之注意事項再填寫本頁) 470741 A7 B7 五、發明說明（） (請先閱讀背面之注意事項再填寫本頁) 洗滌混合的甲撐氯化物。添加碳酸氫納水溶液Μ調整水相的ρ Η。再分別用水和鹽水洗滌甲撐氯化物層。Μ硫酸納乾燥甲撐氯化物。在大氣壓下蒸發濃縮混合物，殘留物溶於1 5升甲醇中。蒸餾甲酵溶液Μ除去殘留的甲撐氯化物，然後加入9 * 9升水。使混合物回溫到5 6 °C，使其冷卻到室溫，然後約攪拌1 2小時。過濾分離而製得結晶性物質。用1 5升水洗滌漶紙殘留物，在真空中及室溫下通人氮氣K乾燥分離的物質到呈恆重為止。在90t：將該物質溶於5升甲苯中，在801與1 0 升的庚烷混合。混合物的溫度在1 ‘ 5小時内逐漸降低，然後在5 °C攪拌混合物約1 2小時，得到结晶性物質。過裢分離該物質，用1 5升庚烷洗滌濾紙殘留物，在真空及室溫下通入氮氣使乾燥分離的物質到圼恆重為止，製得（ S ) 一 5，7 —二氟—2 —〔（三氟乙醢基）胺基]一3 ，4 一二.氫一（2H)—蔡一 1—酮（2.0 公斤，6. 8 莫耳），熔點 142. 4 — 144.6 °C。〔ct〕D —5 9.4° (c = 0.994，甲醇）。經濟部智慧財產局員工消費合作社印製實例5 7 (S) — 5，7 —二氟一 2 — 〔（三氟乙醯基）胺基]— 1 ，2，3，4 一四氫萘 Μ下係製備式28中η為1 ，t為2 ，5 —和7 —位置的R1為氟的化合物。 -2 10- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 470741 S9. 9, 18 A7 經濟部智慧財產局員工消費合作社印製 B7____ 五、發明說明（）含製備如實例56的（S) — 5，7 —二氟一 2 —〔 (三氟乙醯基）胺基〕一 3，4 一二氫一（2H)—萘一 1-酮（1 ，1公斤，3 · 8莫耳）和Peariman觸媒（ 0 . 55公斤，50%濕重）混合物及1 1升三氟醋酸的反應容器在通入氮氣八次然後通入氫氣氣八次抽真空，使壓力達到1 1 p s i g。在通入氫氣的及室溫下激烈攪拌混合物24小時。薄層層析證實萘一1 —嗣轉換成（S) —1 一羥基一5，7 —二氟一2 —〔（三氟乙釀基）胺基 3 了3，4 —二M— ( 2 Η )—蔡。然後加入硫酸（1 · 1升，19 · 4莫耳）（在1升三氟醋酸中），在室溫下通入氫氣（125psig)，攪拌混合物24小時。然後將氮氣通入反應容器，Μ C e 1 i t e過漶混合物，Μ 1 1升三氟醋酸洗滌。濾液與2 · 8 公斤醋酸納三水合物和8 0升水混合，混合物冷卻到1 0 °C 7 ，得到結晶性物質。過滤分離該物質，用1 〇升冰水洗滌濾紙殘留物，乾燥製得（S) — 5 ，7 —二氟一 2 - 〔 (三氟乙醯基）胺基〕一1 ，2 ，3，4 一四氫萘（〇 * 8 公斤，2 ‘9 莫耳），熔點 159. 9— 160.9 °C。〔a〕D— 5.6-0。（c = l- 〇l，.甲酵）。實例5 8 (S) — 5 ，7 —二氟一 1 ，2 ，3 ，4 一四氫蔡一 2 — 基胺氫氯化物 -211- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） ---- I-------— I ------— —訂 —-------I (請先閱讀背面之注意事項再填寫本頁) 470741 89. ?8 A7 B7 經濟部智慧財產局員工消費合作社印*1衣五、發明說明（） K下係製備式3中ri為1 ，t為2 ，5 —和7 —位置的R 1為氟的化合物。氫氧化鋰單水合物（7 ‘ 8克’ 〇 · 2莫耳）加入（ S) — 5 ，7 —二氟一2 - 〔（三氟乙驢基）胺基〕一1 ，2，3，4 一四氳蔡（20 . 8克’ 74 ♦ 5毫莫耳）在1 8 7毫升甲醇和2 1毫升水中所形成的溶液中。在回流下攪拌混合物3 0分鐘，K 2 0 0毫升甲醇稀釋之。然後將稀釋後的混合物與60毫升水，24 · 8毫升濃氫氯酸和4 . 2克活性碳D a r c ο ®混合。撹拌混合物3 0分鐘，然後K C e 1 i t e過濾。蒸餾濾液直到頭溫度達7 5 Ό。使殘留的混合物冷郤，並靜置約6 0小時。然後使混合物在冰浴中冷卻，得到结晶性物質。過濾分離該物質，用水洗滌濾紙殘留物，在真空及室溫下通入氮氣以乾燥分離的物質到呈恆重為止，製得（S) — 5 ，7 —二氟一 1 ，2 ，3 ，4 —四氫萘—2 —基胺氫氯化物（14 * 8克，67 * 6 毫莫耳），熔點大於280°0。〔〇(〕0—66.2° ( c =0 . 1 6 2 ，甲酵）。實例5 9 (S ) 一 5 —羥基甲基一1 一（5，7 —二氟一1 ，2， 3，4 —四氫蔡一2 —基）_1 ，3 —二氫味嗤一2—硫嗣 Κ下係製備式27中η為1 ，t為2，5 —和7 —位 -212- 本紙張尺度適用中國國家標準（CNS)A4規格（210 χ‘297公釐） ------------- I------訂---------. (請先閱讀背面之注意事項再填寫本頁) 470741) —1Η—imidazole—2-disulfonic anhydride] hydrogen propionate (768 mg, 1.74 mmol), melting point 147 — 154 ° C 〇 According to Example 52, but replaced with different starting materials ( R, R ')-3,3'-disulfic anhydride bis [2- (tertiary butoxycarbonyl) amino propionate tert-butyl ester] and / or 1- (4,6-difluoroindane —-2 0 2-This paper size is in accordance with China National Standard (CNS) A4 (210 X 297 mm) printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs. A. _B7_ V. Description of the invention () Base) -1, 3-dihydroimidazole-2-sulfo-, to obtain a compound of formula III below K; (R, R ')-3,3'-disulfonic anhydride bis [2- (tertiary butoxycarbonyl) amino group Substituting methyl propionate to obtain 2R-amino-3— [5-aminomethyl-1— (4,6-difluorolangman-1—1-yl) imidazole—2-yldisulfonyl] propanoic acid Methyl ester hydrochloride, melting point 15 5 — 1 5 7 " C ° prepared by substituting 3,3′-disulfic anhydride bis [2- (tertiary butoxycarbonyl) amino ethylethyl] 2 ~ [2-Aminoethyldisulfonyl) -1 (4,6-difluoroindan-1-yl) imidazole hydrochloride, melting point 175 — 177 ° C; (R, R ') — 3,3' —disulfic anhydride based bis [2 — (trifluoro Ethyl) methylaminopropionate was substituted to obtain 2- (trifluoroethylfluorenyl) amino-3— [1- (4,6-difluoroindan-1-yl) imidazol-2-yl-2 Sulfonyl] amino propionate methyl ester (oil), using (R, R ') -3,3'-disulfonic anhydride bis [2- (tertiary butoxycarbonyl) amino propionate Ester substitution to obtain 2 R -amino- 3-[1-(4,6-difluoroindan_2 -yl) imidazole-2-1-disulfonamido] amino propionate hydrochloride, melting point 145- 1501 * Substituted with 1- (4,5-difluoroindan-2-yl) -1,3-dihydrooxazole-2thione to obtain 2R-amino-3 ~ [1— (4, 5 —Difluoroindan-2-yl) —1H —oxazole — 2 —disulfide — 2 0 3 — This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) I I-- --- 丨-丨 --1 " ^ 4 --- II --- Order- 丨 ----- (Please read the precautions on the back before filling this page) 470741 8a 9. ί8 A7 B7 printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs of the People's Republic of China. V. Description of the invention () Anhydride group] propionate hydrochloride, melting point 140t :; —Tetrahydronaphthalene-2—yl) —1,3 ~ dihydroimidazole—2—thione substitution to obtain 2R —amino — 3 · — [1— (5,7 —difluoro-1, 2, 3 , 4-tetranaphthalene-2-yl) -1Η-imidazol-2-yl disulfonic anhydride group] propanoic acid hydrochloride, melting point 1 3 0 ° C; 1- (6,8-difluoro-1, 2 ， 3,4 —tetrahydrocai 2 —yl) — 1 * 3 ~ dihydrooxazole — 2 —sulfur_substitution * to produce 2R —amino ~ 3-[1 ~ (6,8_ difluoro-1, 2,3,4_ tetranaphthalene-2-yl) -1H-imidazol-2-yldisulfic anhydride group] propionic acid hydrochloride, melting point 1 4 1 t; with 1- (6,7-difluoro-1, 2,3,4-tetrahydrocae-2-yl) -1,3-dihydroimidazole-2 and tellurone substitution to produce 2R-amino-3— [1 ~ (6,7 —difluoro_1 ， 2,3,4 · —tetranaphthalene-2-yl) —1H—imidazol-2-yl disulfonic anhydride group] propionate hydrochloride, melting point 1 3 0 ° C ; Substituted with 1— (5,7—difluoro-1,2,3,4—tetrahydronaphthalene—2-yl) —2—thio-1, 3—dihydro-imidazole-5—carboxylic acid, to make 2R —amino—3— [5-carboxy-1— (5,7—difluoro—1,2,3,4—tetranaphthalene—2—yl) oxazole—2—disulfonic anhydride]] propene Acid hydrochloride, melting point 1 29-1 38 ° C; use 1- (4,5-difluorobonman-2-yl) -1,3-dihydroimidazole-2—tellurium and (S, S ' ) — 4,4'—Disulfic anhydride-2 0 4-For the use of Chinese National Standard (CNS) A4 (210 X 297 mm): 'II1IIII1 — — — —' · IIIIIII · 111! 1111. ( Please read the precautions on the back before filling out this page) 470741 89. 9, | A7 B7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 5. Description of the invention () Basic bis [2- (tertiary butoxycarbonyl) amine Tert-butyl butyrate] substitution to obtain 2S-amino-4— [1- (4,5-difluoroindan-2-yl) imidazol-2-yldisulfonyl] butyric acid hydrochloride , Melting point 59 ° C ♦ Use 1 one (4, 5 — two Indane-2-yl) -1,3-dihydroimidazole-2thione and (S, S ')-3,3'-disulfonic anhydride bis [2- (tertiary butoxycarbonyl) amine -3 -trimethylbutyl butyrate] substitution to obtain 2S -amino- 3-[1-(4,5 -difluorolangman-2-yl) -1H -oxazole-2 -yl Disulfonic anhydride group] -3-methylbutanoic acid hydrochloride, melting point 143-149¾; using 1- (5,7-difluoro-1,2,3,4-tetrahydrocae-2-yl) -5 (1H) -tetrazol-5-yl-1,3-dihydroimidazol-2-sulfide and 3,3'-disulfonic anhydride bis [2- (tertiary butoxycarbonyl) aminoethyl] Substitute to obtain 2- (2-aminoethyldisulfonic anhydride group)-1- (5,7-difluoro-1 * 2,3,4-tetrahydrocae-2-yl) -5 (1 Η ) -Tetrazol-5-yl-1,3-dihydroimidazole hydrochloride, melting point 16 5 ° C (decomposition); and (S) 5-(tertiary butoxycarbonyl) aminomethyl 1 1 1 (5,7 —difluoro-1,2,3,4 —tetrahydrocae 2 —yl) —1,3 ~ dihydroimidazole 2 —sulfur and (R ， R ′)-3 ， 3′-disulfonic anhydride group bis [2- (tertiary butoxycarbonyl) amino propionic acid tertiary butyl] substitution to obtain 2R_amino-3— [5 —amine Methylmethyl-1-(5,7-difluoro-1,2,3,4_tetralina-2-yl)-2 0 5-(Please read the note on the back first? Please fill in this page for more details))-> / ---- Order ---- I --- 1 1 This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 470741 Intellectual Property of the Ministry of Economic Affairs Printed by the Consumer Cooperatives of the Bureau A7 B7 V. Description of the invention (1) 1 咪 —imidazole — 2 —disulfonic anhydride group] propionate hydrochloride, melting point 179 — 180 ° C (decomposition). Example 5 3 N — (trifluoroacetamidyl) -L-aspartic acid anhydride trifluoroacetic anhydride (7,7 kg, 5 * 3 liters, 37.5 moles) was heated to reflux temperature, and the solution was heated in 30 minutes. A solution of L-aspartic acid (2.0 kg * 1 5 * 0 mole) in 9 liters of trifluoroacetic acid (prepared by gradually heating to 65¾ and stirring for 3 hours) was added to the trifluoroacetic anhydride in reflux . The mixture was then distilled * to remove 9 liters of trifluoroacetic acid. The remaining mixture was added to 8 liters of ice-cold hexane under nitrogen, and the hexane mixture was stirred in an ice bath for 3 hours to obtain a crystalline substance. The material was separated by filtration, and the filter paper residue was washed with about 25 liters of hexane, and dried in a vacuum oven at 50 ° C to constant weight under nitrogen to obtain N- (trifluoroacetamidyl) -L-aspart Amino acid (2.9 kg, 13.7 mol), melting point 140-141. . [A] D-2: 7-4 ° (c = 3, 28, tetrahydrofuran). Example 5 4 (S) — 2 — [(trifluoroethylfluorenyl) amino]-4 — (2 * 4-difluorophenyl) -4 4-oxybutyric acid M is prepared in formula 31 where η is 0 , T is a compound in which R 1 at the 2, 2- and 4- positions is fluorine. -2 0 6-This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) ---------------- III — I Order ------ --- I (Please read the notes on the back before filling this page) 470741 89. 9. 18 A7 B7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 5. Description of the invention (> 1, 3-difluorobenzene (2 3 kg, 20.0 mol) in 5 liters of methyl chloride was added to N- (trifluoroacetamido) -L-aspartic anhydride (4 2 kg, 2.0 mol), aluminum chloride (7.4 kg, 55.5 mol) and 25 liters of methylene chloride. The temperature of the reaction mixture was within 1.5 hours Gradually increase and maintain at reflux for another 3 hours. Then cool the mixture and add 20 liters of 6N hydrochloric acid with good stirring. Separate the methylene nitride layer, wash with water and then brine, and distill at atmospheric pressure Remove the volatiles. Dissolve the residue in 40 liters of toluene and distill the mixture in vacuo to remove 8 liters of volatiles. Heat the solution to 50 ° C and add 8 liters of hexane. Then at 25 t The mixture was stirred for 3 hours to obtain a crystalline substance. The substance was separated by filtration, the residue of the filter paper was washed with hexane (3x10 liters), and dried in a vacuum oven to constant weight at room temperature under the release of nitrogen, to obtain (S)-2- [(Trifluoroacetamido) amino] 4- (2,4-difluorophenyl) -4-oxybutyric acid (5.2 kg, 16.0 mole), melting point 82.4-84.0. [A] D + 15.2. (C = 0.95 6, formazan). Example 5 5 (S) — 2 — [(trifluoroacetamido) amino] — 4 — (2, 4, 12 Fluorophenyl) butyric acid M is prepared in formula 30 in which η is 1 and t is 2, 2 — and 4 digits-2 0 7-This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) ) --II ---— — — — — — 丨 — — III — Order. — — — — — —-- (Please read the notes on the back before filling out this page) 470741 89. 9. 3 8 A7 ___ The Consumer Property Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs has printed a description of the invention () where R 1 is a fluorine compound. (S) — 2 — [(trifluoroethylfluorenyl) prepared as in Example 54 (please read the back first) Precautions (Fill in this page) Amine]-4-(2,4-difluorophenyl)-4 monooxybutyric acid (4.8 kg, 14.7 mol) and activated carbon Darco® (0.4 kg) The mixture was stirred in 5 liters of acetic acid at room temperature for 1 hour. The mixture was washed to Pearl Man catalyst (0 ′ 5 kg, 50% wet weight), and K 1 5 liters of glacial acetic acid was washed with M. Sulfuric acid (1,2 liters, 21, 8 mol) in 1 liter of glacial acetic acid was filtered into the mixture and washed with 2.8 liters of glacial acetic acid. The reaction vessel was purged with nitrogen three times in succession and then purged with hydrogen gas six times, so that the pressure reached 10 ps i g. The mixture was stirred vigorously under the atmospheric pressure of hydrogen gas at room temperature for 24 hours, and then the nitrogen gas was passed into the reaction vessel, and the mixture was passed through to 4.6 kg of sodium acetate trihydrate. The paper was washed with 10 liters of glacial acetic acid, and the glacial acetic acid was distilled off in a vacuum. The residue was separated into 20 liters of methylene chloride and 40 liters of water. The aqueous layer was extracted with 10 liters of methylene chloride. The mixed methylene chloride was washed with 10 liters of water. 0 kg) dried and filtered. The solvent was removed in vacuo, and the residue was dissolved in 5 liters of a methylated atmosphere. Under nitrogen, the solution was added to 15 liters of hexane at a rate such that the temperature of the hexane mixture was maintained between 0 ° C and 5 Torr. The mixture was allowed to stand for 1 hour to obtain a crystalline substance. The material was filtered and separated, and the filtered residue was washed with 10 liters of hexane. • Dry to constant weight in a vacuum oven at 25 ° C and nitrogen, to obtain (S) — 2 — [(trifluoroethylfluorenyl) ） Amine group]-2 0 8-This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 470741 ii.iis A7 B7 V. Description of the invention -4-(2,4-difluorophenyl) butanoic acid (3.3 kg, 10.4 moles), melting point 62-83.5. The melting point of the analytically pure sample was 86t: -89 0C ° ία) D +6, 8 ° (c = 0.995, methanol). Example 5 6 (S) -5,7 -difluoro-2-[(difluoroethylfluorenyl glutamine) -3,4 -dihydro-1 (2H) -mm Μ The following formula η is 1, t is 2, 5 and 7, and R 1 is a fluorine compound. Phosphorus pentachloride (2.2 kg, 10.6 mol) was formed in 12 liters of methylene chloride. The suspension was cooled to 5 ° C, and (S)-4-(2,4-difluorophenyl)-2-[(trifluoroethylimino) amino] butyl, prepared in Example 5 5 was added over 20 minutes. Acid (3.1 kg, 9,9 moles) (in 12 liters of methylated atmosphere). Thin-layer chromatography (methanol quench) confirmed that butyric acid had been converted to the corresponding acid chloride. Mixture 30 0 Minutes were then added to the sludge formed by the aluminized aluminum (4.3 kg) in 38 * 8 liters of methylene chloride at a rate that maintained the temperature of the sludge between 1 t: and 5 ° C. The reaction mixture was stirred for 1 hour, and then added to 28 kg of ice and 5.3 kg of concentrated hydrochloric acid. The mixture was searched for 1 hour to bring the temperature back to 20 t: The aqueous phase was separated, and the methyl chloride was separated. Extraction (2x15 liters), washing the methane with water Compound layer, mixed with methylene chloride extract, and then water-2 0 9-This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) ------------- -Taste -----— Order II --------- (Please read the notes on the back before filling this page) 470741 A7 B7 V. Description of the invention () (Please read the notes on the back first Fill in this page again) Wash the mixed methylene chloride. Add sodium bicarbonate solution M to adjust the pH of the aqueous phase. Then wash the methylene chloride layer with water and brine separately. M sodium sulfate to dry the methylene chloride. At atmospheric pressure The mixture was concentrated by evaporation, and the residue was dissolved in 15 liters of methanol. The formazan solution M was distilled to remove the remaining methylene chloride, and then 9 * 9 liters of water was added. The mixture was warmed to 5 6 ° C and allowed to cool to room temperature. Then, it was stirred for about 12 hours. It was separated by filtration to obtain a crystalline substance. The paper residue was washed with 15 liters of water, and the separated substance was dried under nitrogen and nitrogen at room temperature until constant weight was reached. At 90t : This material was dissolved in 5 liters of toluene, and mixed with 10 liters of heptane at 801. The temperature of the mixture was between Gradually lower within 1 'to 5 hours, and then stir the mixture at 5 ° C for about 12 hours to obtain a crystalline substance. The substance was separated by centrifugation, the filter paper residue was washed with 15 liters of heptane, and passed in under vacuum at room temperature. Nitrogen is used to dry the separated material until the constant weight of osmium is obtained, and (S) -5,7-difluoro-2 — [(trifluoroethylfluorenyl) amino]-3,4-2.2. Hydrogen- (2H) —Cai Yi 1-one (2.0 kg, 6.8 mol), melting point 142.4 — 144.6 ° C. [Ct] D —5 9.4 ° (c = 0.994, methanol). Printed by the Consumers' Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 5 7 (S) — 5,7 —Difluoro-2 — [(trifluoroethylamido) amino] — 1,2,3,4 Tetrahydronaphthalene M In the following, a compound in which η is 1 and t is 2, and R1 at the 5- and 7-positions in Formula 28 is fluorine is prepared below. -2 10- This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) 470741 S9. 9, 18 A7 Printed by the Consumers' Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs B7____ 5. Description of the invention () (S) —5,7 —difluoro-2 — [(trifluoroacetamido) amino] -3,4—dihydromono (2H) —naphthalene-1—one (1, 1 kg, 3. 8 mol) and Peariman catalyst (0.55 kg, 50% wet weight) and 11 liters of trifluoroacetic acid. The reaction vessel was evacuated with nitrogen gas eight times and then with hydrogen gas eight times to evacuate. Reached 1 1 psig. The mixture was stirred vigorously under hydrogen at room temperature for 24 hours. Thin layer chromatography confirmed the conversion of naphthalene-1, fluorene to (S) -1,1, hydroxy-5,7-difluoro-2, [(trifluoroethyl) amino 3,3,4-di M— (2 Η) —Cai. Then, sulfuric acid (1.1 liter, 19.4 mol) (in 1 liter of trifluoroacetic acid) was added, and hydrogen gas (125 psig) was passed at room temperature, and the mixture was stirred for 24 hours. Nitrogen was then passed into the reaction vessel, MCe1ite was passed through the mixture, and M1 1 liter of trifluoroacetic acid was washed. The filtrate was mixed with 2.8 kg of sodium acetate trihydrate and 80 liters of water, and the mixture was cooled to 10 ° C 7 to obtain a crystalline substance. The material was separated by filtration, and the residue of the filter paper was washed with 10 liters of ice water, and dried to obtain (S) -5,7-difluoro-2-[(trifluoroacetamido) amino] -1,2,3, 4 Tetrahydronaphthalene (0 * 8 kg, 2 '9 mol), melting point 159.9-160.9 ° C. [A] D- 5.6-0. (C = l-〇l ,. formazan). Example 5 8 (S) —5,7—Difluoro-1,2,3,4—Tetrahydrocae-2—Base amine hydrochloride-211- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) ---- I -------— I -------- —Order —------- I (Please read the notes on the back before filling this page) 470741 89.? 8 A7 B7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs * 1 Yi Wu, the description of the invention () In the formula K below, ri is 1 and t is 2, 5 and 7-the position R 1 is Fluorine compounds. Lithium hydroxide monohydrate (7 '8 g' 0.2 mole) was added with (S) -5,7-difluoro-2-[(trifluoroethylammonyl) amine] -1, 2, 3, 4 1 4 氲 Cai (20.8 g '74 ♦ 5 mmol) in a solution of 187 ml of methanol and 21 ml of water. The mixture was stirred under reflux for 30 minutes, and diluted with K 2 0 ml methanol. The diluted mixture was then mixed with 60 ml of water, 24.8 ml of concentrated hydrochloric acid and 4.2 g of activated carbon Darco. The mixture was stirred for 30 minutes, then filtered through K C e 1 it t e. The filtrate was distilled until the head temperature reached 7 5 ° F. The remaining mixture was cooled and left to stand for about 60 hours. The mixture was then cooled in an ice bath to obtain a crystalline material. The material was separated by filtration, and the residue of the filter paper was washed with water, and nitrogen was passed under vacuum and room temperature to dry the separated material until constant weight was obtained to obtain (S) -5,7-difluoro-1,2,3, 4-tetrahydronaphthalene-2-ylamine hydrochloride (14 * 8 g, 67 * 6 mmol), melting point is greater than 280 ° 0. [〇 (] 0-66.2 ° (c = 0. 1 6 2, formazan). Example 5 9 (S)-5-hydroxymethyl-1 1-(5,7 -difluoro-1, 2, 3, 4-tetrahydrocaine 2-base) _1, 3-dihydro miso-1 2-thizone κ in the following formula 27 in which η is 1 and t is 2, 5 — and 7 —position -212- paper size Applicable to China National Standard (CNS) A4 specification (210 χ'297 mm) ------------- I ------ Order ---------. (Please (Please read the notes on the back before filling out this page) 470741

9. IB A7 _____B7__ 五、發明說明（）置的R1為氟的化合物。硫氰酸鉀（15 · 9克，162 . 6毫莫耳）在氮氣中被加熱到1 7 5°C而乾燥，然後在通入數次氮氣的真空下冷卻。二羥基丙_ (15 . 9克，176 . 7毫冥耳）和如實例58所製備的（S) — 5，7 —二氟一 1 ，2， 3，4 一四氫萘一 2 -基胺氫氯化物（30 ‘ 0克，1 37 毫莫耳）混合物（於540毫升醋酸乙酯中）加入乾燥硫氰酸鉀。反應容器通入氮氣，加人40♦83克冰醋酸。反應混合物在3 5 °C攪拌1 5分鐘，然後在冰浴中冷卻， ο 蒸 5 0 用層後機先有〇滌 7 洗為水 H鹽 P 升物毫合 ο 混 5 到和直液納溶化水氧鈉氫氫 Μ 酸 5 碳 . 和 2 飽入升加毫其冷使用 Ρ 質 6 物到該卻離冷分物癍合過混。 ’ 質升物毫性 ο 晶 8 結 4 到到得縮，濃時使小層 2 機 1 有置餾靜蒸中水升〇毫質 5 物 2 的和離酿分乙燥酸乾醋 ’ 升物毫留 ο 殘 5 紙 6 濾於滌溶洗質酯物乙該酸醋 ---------- I----------訂--------- (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製室，燥到質乾物物中合該空混離真卻分的冷S氣。過氮物。入發質通揮物在的性。升晶物毫結留 ο 到殘 ο 得紙 5 , 0 去鐘滌除分洗到 5 酯直 4 乙物拌酸合攪醋混，冷餾溫用 - 基基 -甲 2 基一羥萘 I 氫 5 四 I -) 4 S ， ( 3 得 ’ 製 2 , 5 克 CvJ 4 ] α o rL 3 ， (cc 嗣 7 硫 ο i 2 2 i 醇 5 3 - 唑氟咪二氫- 二 7 _ 耳莫毫 4 7 ο 11- 6 ο 2 點熔 6 49. IB A7 _____B7__ V. Description of the invention () R1 is a fluorine compound. Potassium thiocyanate (15.9 grams, 162.6 millimoles) was heated to 175 ° C in nitrogen to dry, and then cooled under a vacuum of nitrogen several times. Dihydroxypropane (15.9 g, 176.7 milliliters) and (S) -5,7-difluoro-1,2,3,4-tetrahydronaphthalene-2 -yl as prepared in Example 58 A mixture of amine hydrochloride (30'0 g, 1 37 mmol) (in 540 ml of ethyl acetate) was added to dry potassium thiocyanate. The reaction vessel was purged with nitrogen, and 40.83 g of glacial acetic acid was added. The reaction mixture was stirred at 3 5 ° C for 15 minutes, and then cooled in an ice bath, ο steamed 5 0 using a layer after the machine was washed, washed with water, H salt, P, and the mixture was mixed. Dissolve water, sodium hydroxide, hydrogen acid, 5 carbons, and 2 liters. Add 2 liters of chilled cold matter using the P substance 6 to the cold mixture and mix. 'The quality of the material is very low ο Crystal 8 junction 4 to the shrinkage, when concentrated, make the small layer 2 Machine 1 has a distillation still steam water liter 0 milligram 5 of the product 2 and dry acetic acid dry vinegar' liter Leave nothing ο Residual 5 Paper 6 Filtered on polyester esters of the solubilized acid vinegar ---------- I ---------- Order -------- -(Please read the notes on the back before filling out this page) The printing room of the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs has dried the dry air to the dry and dry air. Nitrogen. Into the hair quality and sex. The crystals remain intact ο to the residue ο get the paper 5, 0 to remove and wash to 5 esters straight 4 ethyl matter mixed with acid and vinegar, cold distillation temperature--yl-methyl 2-hydroxynaphthalene I hydrogen 5 Tetra I-) 4 S, (3 to get 2, 5 grams of CvJ 4] α o rL 3, (cc 嗣 7 sulfur ο i 2 2 i alcohol 5 3-azoflumiddihydro-di 7 _ mol Mark 4 7 ο 11- 6 ο 2 Spot melting 6 4

C ο 2 8 6 甲本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 470741 經濟部智慧財產局員工消費合作社印製 A7 B7_ 五、發明說明（）實例6 0 (S ) — N —〔3 — (5，7 —二氟—1，2，3， 4 一四氫蔡一2—基）—2—硫代一2 ’ 3—二氬一1H —咪唑一4_基甲基〕甲醢胺 Μ下係製備式26中η為1 ’ t為2，5 —和7 —位置的R1為氟，R2為氫的化合物。甲醢胺（250毫升，6 * 3毫莫耳）被加熱到1751C ，在30分鐘内將製備如實例59的（S) —5—羥基甲基一1一（5，7 —二氟一1 ，2，3，4 -四氫萘一2 一基）一1 ，3 —二氫眯唑一2 —疏酮（25·0克， 88 * 3毫莫耳）分數次加入，反應混合物在氮氣中攪拌 1小時。冷卻混合物到5 0 °C，加入2 · 5克活生碳 (D a r c ο ® )。冷卻混合物到 3 0 °C，M C e 1 i t e 過據之，以2 5毫升甲醯胺洗滌。加熱濾液到9 5 D，然後滴加入1升水。使混合物冷卻，然後在室溫下攪拌1 2 小時。混合物冷卻到0 °C，得到结晶性物質。過據分離該物質，乾燥之。該物質與約5倍重量的7 0%四氫肤喃/3 0%己烷攪拌5分鐘。過濾分離該物質，用5 0%四氫呋喃/5 0% 己烷洗滌濾紙殘留物，乾燥到恆重，得到（S ) — N _ 〔 3 — (5 ’ 7 —二氟一1 ，2，3，4 —四氫蔡一2 —基 )—2 —硫酮—2，3 —二氫一1H —咪唑一4 一基甲基 -214- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） ------------I I------^ ---------I. (請先閱讀背面之注意事項再填寫本頁) 470741 A7 B7 五、發明說明（）〕甲_胺（19 · 5克，62 · 7毫莫耳），熔點245 ~ 2 4 6 V 〇〔cx〕D+48-9° (c=0.613， D M S Ο )。依類似實例6 Ο方式進行，但是用脲取代甲醯胺（S )-5-脲基甲基一1— (5，7 —二氟一1 ，2，3, 4 —四氫萘—2 —基）一1 >3 —二氫咪唑—2 —硫嗣，熔點 258 — 260 °C; 〔a]D+34.3° (c = 0 5 7 4 * D M S Ο )。實例6 1 (S ) — N — [ 3 — (5，7 —二氟一 1»2，3，4 — 四氫萘一2 —基）一 2 —硫代—2，3 —二氫一1 Η —眯唑一4 一基甲基〕甲醢胺以下係製備式26中η為1 ，t為2 ，5 —和7 —位置的R1為氟*R2為氫的化合物。如實例59所製備的（S) — 5 —羥基甲基一1一（ 5 ，7 —二氟一1 ，2，3 ，4 —四氫萘一2 —基）一1 ，3 -二氫咪唑一2 —硫酮（1 . 0克，3 . 5毫莫耳）C ο 2 8 6 The paper size of this paper applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 470741 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs A7 B7_ V. Description of the invention () Example 6 0 (S) — N — [3 — (5,7 —difluoro—1,2,3,4 —tetrahydrocae —2 —yl) — 2 —thio — 2 ′ 3 —diargon — 1H —imidazole — 4 —yl Methyl] formamidine M is a compound in Formula 26 in which η is 1 ′ t is 2, 5- and 7-positions, R1 is fluorine, and R2 is hydrogen. Formamidine (250 ml, 6 * 3 mmol) was heated to 1751C, and (S) -5-hydroxymethyl-1-1 (5,7-difluoro-1) as in Example 59 was prepared in 30 minutes. , 2,3,4-tetrahydronaphthalene-2, 1-yl) -1,3-dihydrooxazole-2, 2-morone (25.0 g, 88 * 3 mmol) were added in portions, and the reaction mixture was under nitrogen Stir for 1 hour. Cool the mixture to 50 ° C and add 2.5 grams of live carbon (D a r c ο ®). The mixture was cooled to 30 ° C, M C e 1 i t e was used, and washed with 25 ml of formamidine. The filtrate was heated to 95 D, and 1 liter of water was added dropwise. The mixture was allowed to cool and then stirred at room temperature for 12 hours. The mixture was cooled to 0 ° C to give a crystalline material. The material was separated according to the data and dried. This material was stirred with about 5 times the weight of 70% tetrahydrofuran / 3 0% hexane for 5 minutes. The material was separated by filtration, and the filter paper residue was washed with 50% tetrahydrofuran / 50% hexane and dried to constant weight to obtain (S) — N _ [3 — (5 '7 —difluoro-1, 2, 3, 4 —tetrahydrocaine 2 —yl) — 2 —thione — 2, 3 —dihydro 1H — imidazole 4 —ylmethyl — 214 — This paper is sized for China National Standard (CNS) A4 (210 X 297 mm) ------------ I I ------ ^ --------- I. (Please read the notes on the back before filling this page) 470741 A7 B7 V. Description of the invention ()] Methylamine (19.5 g, 62.7 mmol), melting point 245 ~ 2 4 6 V 〇 [cx] D + 48-9 ° (c = 0.613, DMS 〇 ). It was carried out in a similar manner to Example 6 except that urea was used to replace formamidine (S) -5-ureidomethyl-1— (5,7—difluoro-1, 2,3,4—tetrahydronaphthalene—2 — A) 1 > 3 -dihydroimidazole-2 -thizone, melting point 258-260 ° C; [a] D + 34.3 ° (c = 0 5 7 4 * DMS Ο). Example 6 1 (S) — N — [3 — (5,7 —difluoro-1 »2,3,4 —tetrahydronaphthalene-2 —yl) — 2 —thioxo-2,3 —dihydro-1 The hydrazone-oxazole-4 monomethyl] formamidine is prepared in the following formula 26 in which η is 1 and t is 2, 5- and 7-positions where R1 is fluorine and R2 is hydrogen. (S) 5-Hydroxymethyl-1 1- (5,7-difluoro-1,2,3,4-tetrahydronaphthalene-2-yl) -1,3-dihydroimidazole prepared as in Example 59 One 2-thioketone (1.0 g, 3.5 mmol)

和甲酸銨（10克，158 · 6毫莫耳）之混合物在約 1 2 5 °C攪拌1小時，然後加熱混合物到約1 3 8 °C，另外攪拌3 5分鐘。用2 5毫升水稀釋混合物，使其冷卻到室溫。老化混合物約1 8小時，得到结晶性物質。過漶分離該物質，用水洗滌濾紙殘留物。乾燥到恆重，得到（S -2 15- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -------------'裝--- (請先閱讀背面之注意事項再填寫本頁)And a mixture of ammonium formate (10 g, 158.6 millimoles) was stirred at about 125 ° C for 1 hour, then the mixture was heated to about 138 ° C, and stirred for another 3 5 minutes. The mixture was diluted with 25 ml of water and allowed to cool to room temperature. The mixture was aged for about 18 hours to obtain a crystalline material. The material was separated by centrifugation, and the filter paper residue was washed with water. Dry to constant weight to get (S -2 15- This paper size applies to China National Standard (CNS) A4 specifications (210 X 297 mm) ------------- 'pack --- ( (Please read the notes on the back before filling out this page)

1 . I 線- 經濟部智慧財產局員工消費合作社印製 470741 A7 B7 五、發明說明（） )—N - 〔3 — (5，7~·二氟一1 ，2，3，4 一四氫 (請先閱讀背面之注意事項再填寫本頁) 萘—2 -基）—2_硫代—2，3_二氫~1Η —咪唑一 4_基甲基〕甲醯胺（〇 . 92克，2 ‘ 96毫莫耳）。依類似實例6 1方式進行，但是用醋酸銨取代甲酸銨 ’製得（S) — Ν — 〔3 — (5,7 —二氟一1 ，2，3 ，4一四氫萘一2 —基）一2—硫代一 2，3 —二氫一 1 Η —陳唑一 4 —基甲基乙醢胺，熔點275 . 5 — 276 °C (分解）；〔tt〕j)+41.3。（c = 1.00, D M S 〇 ) 〇實例6 2 (S) — 5 —胺基甲基—(5，7 —二氟一 1 , 2 , 3 ’ 4 —四氫蔡—2 —基）一2，3 —二氫一 2 —硫代一 1 Η —咪唑氫氯化物 Μ下係製備式25中η為1 ，t為2，5 —和7 —位置的R1為氟的化合物。經濟部智慧財產局員工消費合作社印製如實例60所製備的（s) - N - [ 3 - (5·7-二氟一1 ，2，3 ’4 -四氫萘一2-基）一2 —硫代一 2，3_二氫眯唑一4 —基甲基〕甲醯胺（19 .1克，59，0毫莫耳）和在400毫井異丙醇中的 25毫升濃氫氮酸（12 . 0M，25毫升，300毫.莫耳）的混合物加熱到回流1 2分鐘，撹拌1小時4 0分鐘。蒸餾混合物除去1 5 0毫升異丙醇。混合物逐漸冷卻到 -216- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 470741 A7 89. 9. 18 B7___ 五、發明說明（）室溫，攪拌3小時45分鐘。過濾分離該物質，用75毫升異丙醇洗猫濾紙殘留物。在1 1 Ο — 1 25 °C及通入氮氣的真空下乾燥，得到（S) — 5 —胺基甲基一1 一（5 ，7_ 二氟—1 ，2，3，4 一四氫萘一2 —基）2，3 一二氫—2 —硫代一1H —咪唑氫氯化物（15 . 6克， 47.1毫莫耳），熔點251.9Ό。 C a ] D +10.20 (c = 0.500，DMS0 )。實例6 3 活體外度巴明羥基酶之抑制以下敘述一種活體外評鑑方法，以證實抑制度巴明/3 羥基酶（D B Η )的化合物。此評鑑係依賴氫基對乙酚經度巴明々羥基酶觸媒轉化成為八巴明（octopamine)K及試驗化合物的度巴明；8羥基酶活性的抑制作用。一包含牛腎上腺度巴明/3羥基酶（1 3 · 8毫單位/ 毫升），銅離子（2mM)，抗壞血酸（lOmM)，過氧化氫酶（200微克/毫升）和試驗化合物的混合物在〇 * 65毫升的50mM醋酸納媛衝液（PH4 · 5)中，於3 7 °C培養1 0分鐘。加入氫基對乙鼢，反應混合物在37 °C培養10分鐘。反應在加入0 * 1毫升濃氫氧化銨之後驟冷，八巴明產物在添加0 ‘ 2毫升的2 %變性過碘酸納並另外培養4分鐘之後被氣化成對羥基苄醛。過量 -2 17- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -------------裝--------訂i n n I n I tn I 線' (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 470741 89, 1 A7 B7 經濟部智慧財產局員工消費合作社印製五、發明說明（）的變性過碘酸鈉被0 < 2毫升1 0%亞硫酸鈉還原，而以分光光度計測定3 3 3 0 nm波長Μ檢測對羥基苄醛濃度 0 或者，一包含牛腎上腺度巴明/3羥基酶（0 · 02毫單位/毫升），0 * 1 25Μ醋酸納，1 OmM富馬酸鹽 * 0 * 5mM硫酸銅，100微克/毫升的過氣化氫酶和 10mM的氫基對乙酚銅離子（2mM)的混合物在30 t培養5分鐘，然後加入N，N —二由基—1 ，4 —苯撐二胺（D Μ P D ) Μ起始反應。其吸收情況係Μ光度計監控5 1 5nm波長。評鑑多種濃度範圍的試驗化合物，並 Μ内插法求得產生抑制5 0 %度巴明/3羥基酶所需要的化合物濃度（IDs。）。依實例63進行，測試本發明化合物，發現其具備抑制度巴明/3羥基酶的活性。例如，5 -(S ) 一胺基甲基一 1- (5，7 —二氟一1 ，2，3 ，4 —四氫萘_2 —基）一 1 ，3 —二氬眯唑一2 —硫嗣氫氯物的I Ds 〇為8 . 5nM。實例6 4 活體内度巴明点一羥基酶的抑制 K下敘述一種活體内評鑑方法，K證實抑制度巴明Θ 羥基酶（D B Η )的化合物。此評鑑係依賴度巴明和腎上腺皮質素濃度Μ及試驗化合物效應。雄性大鼠（正常血壓或自發性高血壓）被投Μ載媒（ -2 18- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） n n n n -n n -H I ί -i I · l n —I— n i-J 1 n 一 δι · I 1 a^i t 4. ' (請先閱讀背面之注意事項再填寫本頁) 470741 aa 9., ιβ A7 B7 i、發明說明（ /公斤）或試驗化合物，途徑為口服或靜脈鼠在2 4天内每天被投Μ 1到2次。在投Μ 小時後，Κ鹵烷類（halothane)麻醉大鼠，並速取得選擇組織（例如大腦皮質，骨髓，膠心室），稱重，置於0 · 4毫升冰冷過氯酸 C和電化學檢測方法測定度巴明和腎上腺皮度0 廣的劑童評鑑試驗化合物，與對照組比較效羥基酶的抑制被界定為正腎上腺素在統計上 .05)減少的濃度，伴隨減少的度巴明濃對正腎上腺素比例的增加。 4進行，本發明化合物經測試後發現具備度巴明/3經基酶抑制活性。5 — （S)—胺基甲基一 1 一（經濟部智慧財產局員工消費合作社印製 1到1 注射。最後劑切下頭糸膜動中。用質素的 Μ 應。度顯著（度Μ及依 0毫升某些大量的2 部。快脈和左 Η P L 組織濃範圍很巴明/3 ρ运0 度巴明實例6 (請先閱讀背面之注意事項再填寫本頁) 5，7 —二氟-1 ，2，3，4-四氫萘一 2 -基）-1 ，3 —二氫眯唑一 2 —硫酮氫氯化物對相隔12小時相繼投K三次口服劑量的自發性高血壓大鼠左心室的度巴明和腎上腺皮質素（組織的克/克）以及對度巴明/腎上腺皮質素比例（克/克）效應，簡述於下表中。數值平均值（每組9隻大鼠）土標準誤差。劑量腎上腺度巴明度巴明/腎上腺皮質素 (毫克/公斤）皮質素〇 1.30±0.18 0·02士 0.01 〇 · 〇2 ± 0.00 3 1 . 26± 0 . 6 4 0 . 0 6 土 0 . 〇 1 0.05±0.02 -2 1 9 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 470741 89.1. Line I-printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 470741 A7 B7 V. Description of the invention ())-N-〔3 — (5,7 ~ · Difluoro-1,1,2,3,4-tetrahydro (Please read the precautions on the back before filling this page) Naphthalene-2-yl) —2_thio-2,3_dihydro ~ 1Η —imidazol-4-ylmethyl] formamide (0.92g , 2 '96 millimoles). It was carried out in a similar manner to Example 61 except that ammonium acetate was used instead of ammonium formate to obtain (S) — Ν — [3 — (5,7 —difluoro-1, 2, 3, 4-tetrahydronaphthalene — 2-yl). )-2 -thio-2,3-dihydro-1 1 Η-Chenazole-4-methylmethylacetamide, melting point 275.5-276 ° C (decomposition); [tt] j) + 41.3. (C = 1.00, DMS 〇) 〇 Example 6 2 (S) — 5 —aminomethyl — (5,7 —difluoro-1, 2, 3 ′ 4 —tetrahydrocae — 2 —yl) — 2, 3-Dihydro-2, thio-1, hydrazone-imidazole hydrochloride M is prepared in the formula 25 in which η is 1, and t is 2, 5- and 7-position R1 is fluorine. (S)-N-[5-(5 · 7-difluoro-1,2,3'4-tetrahydronaphthalene- 2-yl) -1 prepared in Example 60 by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 2-thio-2,3-dihydrooxazole-4-ylmethyl] formamidine (19.1 g, 59.0 mmol) and 25 ml of concentrated hydrogen in 400 mmol of isopropanol A mixture of nitric acid (12.0 M, 25 ml, 300 mmol. Mol) was heated to reflux for 12 minutes, and stirred for 1 hour and 40 minutes. The mixture was distilled to remove 150 ml of isopropanol. The mixture is gradually cooled to -216- This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) 470741 A7 89. 9. 18 B7___ V. Description of the invention () At room temperature, stir for 3 hours and 45 minutes. The material was separated by filtration, and the cat filter paper residue was washed with 75 ml of isopropanol. Drying at 1 1 0 — 1 25 ° C under vacuum with nitrogen to give (S) — 5 -aminomethyl-1 1 (5,7_difluoro-1,2,3,4-tetrahydronaphthalene -2-based) 2,3 dihydro-2 -thio- 1H-imidazole hydrochloride (15.6 g, 47.1 mmol), melting point 251.9. C a] D +10.20 (c = 0.500, DMS0). Example 6 3 Inhibition of tobamin hydroxylase in vitro The following describes an in vitro evaluation method to confirm a compound that inhibits tobamin / 3 hydroxylase (D B Η). This review is based on the hydrogen group's ability to inhibit the conversion of acetol to octopamine K and octopamine K and test compounds by the amine hydroxyamylase enzyme; the inhibitory effect of 8-hydroxylase activity. A mixture containing bovine adrenal dubamine / 3 hydroxylase (13.8 mmol / ml), copper ion (2 mM), ascorbic acid (10 mM), catalase (200 μg / ml) and test compound. * In 65 ml of 50 mM Nawon acetate acetate solution (PH4 · 5), incubate at 37 ° C for 10 minutes. Hydrogenated p-acetamidine was added, and the reaction mixture was incubated at 37 ° C for 10 minutes. The reaction was quenched after the addition of 0 * 1 ml of concentrated ammonium hydroxide, and the octabamine product was gasified to p-hydroxybenzaldehyde after addition of 0 ' 2 ml of 2% denatured sodium periodate and incubation for an additional 4 minutes. Excess-2 17- This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) ------------- Installation -------- Order inn I n I tn I Line '(Please read the notes on the back before filling out this page) Printed by the Employees' Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 470741 89, 1 A7 B7 Printed by the Employees' Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs The denatured sodium periodate was reduced by 0 < 2 ml of 10% sodium sulfite, and measured spectrophotometrically at a wavelength of 3 3 30 nm to detect the concentration of p-hydroxybenzaldehyde 0 or, Enzyme (0. 02 milliunits / ml), 0 * 1 25M sodium acetate, 1 OmM fumarate * 0 * 5mM copper sulfate, 100 micrograms / ml perhydrogenase and 10mM copper p-ethylphenolate The mixture of ions (2 mM) was incubated at 30 t for 5 minutes, and then N, N-dioxo-1,4-phenylenediamine (DMPD) was added to initiate the reaction. The absorption is monitored by a 5 photometer with a wavelength of 5 1 5 nm. Test compounds in various concentration ranges were evaluated, and M interpolation was used to determine the concentration of compounds (IDs) required to produce 50% dormamine / 3 hydroxylase inhibition. The compound of the present invention was tested according to Example 63 and found to have the activity of inhibiting dobamin / 3 hydroxylase. For example, 5- (S) -aminomethyl-l- (5,7-difluoro-1,2,3,4-tetrahydronaphthalene_2-yl) -1,3-dihydroxazole-2 —The thiophosphonium hydrochloride has an I Ds 0 of 8.5 nM. Example 6 4 In vivo inhibition of tobamin point-hydroxylase An in vivo evaluation method is described below, and K confirms a compound that inhibits tobamin θ hydroxylase (D B Η). This review relies on dubamine and adrenocortical hormone concentration M and test compound effects. Male rats (normal blood pressure or spontaneous hypertension) were injected with M vehicle (-2 18- This paper size applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) nnnn -nn -HI ί -i I · Ln —I— n iJ 1 n-δι · I 1 a ^ it 4. '(Please read the notes on the back before filling out this page) 470741 aa 9., ιβ A7 B7 i, invention description (/ kg) or Test compounds are administered either orally or intravenously to mice 1 to 2 times per day for 24 days. After 24 hours of administration, the rats are anesthetized with Khalothanes and selected tissues (eg, cerebral cortex, bone marrow) are quickly obtained , Gel ventricle), weighed, placed in 0.4 ml of ice-cold perchloric acid C and electrochemical detection method to measure dubamine and adrenal cortex 0. The test agent was evaluated by comparing with the control group, compared with the control group It was defined as a statistically reduced concentration of orprenaline. 05), with an increase in the ratio of reduced dobaminide to orprenaline. 4, the compound of the present invention was tested and found to have dubamine / 3 melanase inhibitory activity. 5 — (S) —Aminomethyl-1 1 (Printed from 1 to 1 by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs. The final injection is to cut off the membrane of the head and move. Use the quality of M. Degree is significant (degree M And some 2 in large quantities according to 0 ml. The concentration range of fast tissue and left sacral PL tissue is very lammin / 3 ρ and 0 degrees bamin Example 6 (Please read the precautions on the back before filling this page) 5, 7 — Difluoro-1,2,3,4-tetrahydronaphthalene- 2-yl) -1,3-dihydrooxazole- 2-thione hydrochloride has high spontaneous spontaneous doses of K three oral doses 12 hours apart The effects of dubamine and adrenocorcin (g / g of tissue) and the ratio of dubamine / adrenocorticin (g / g) in the left ventricle of blood pressure rats are briefly described in the table below. Rats) soil standard error. Dose adrenal bamin dobamin / adrenocortexin (mg / kg) cortisol 〇1.30 ± 0.18 0 · 02 ± 0.01 〇2 ＋ 0.00 3 1. 26 ± 0. 6 4 0. 0 6 soil 0. 〇1 0.05 ± 0.02 -2 1 9-This paper size is applicable to China National Standard (CNS) A4 (210 X 297) %) 470 741 89.

IB A7 B7 經濟部智慧財產局員工消費合作社印製五、發明說明（） 10 1 . 04土 0 , .37 0 , .09 土 0 1.02 0 . 09 士 0 , .02 30 1 . 95 土 0 , ,21 0 . ,1 4 土 0 .03 0 . 15 土 0 , .03 100 0 · 85 土 0 , ,17 0 . ,18土 0 .02 0 . 22 土 0 . ,04 實例6 5 Μ下所述係鑑定降血壓的化合物。雄性自發性高血壓大鼠被麻醉，將管子***股骨或頸動脈，Μ連孃監控血壓。麻醉大鼠30到60分鐘之後，開始測其基礎血壓。大鼠被投以載媒（1 〇毫克/公斤）或試驗化合物90.3到30毫克/公斤），投Μ方式為口服或靜脈注射，並觀察4到6小時。以範圍很廣的劑量評鑑試驗化合物，降血壓活性被界定為與載媒處理大鼠比較之統計上顯著（ρδ〇·〇5) 血壓下降。依實例6 5進行，本發明化合物經測試後發現具備降血壓活性。5 — (S)—胺基甲基一 1— (5，7_二氟 —1 ，2 ，3 ，4 —四氫萘一2 —基）一1 ，3 —二氫眯唑-2 -硫酮氫氯化物對被投Μ受制自發性占相隔1 2小時相繼投Μ三次口服劑量的自發性高血壓大鼠在劑量前到投與後4小時的平均動脈血壓變化效應，簡述於下表中。劑量（毫克/公斤）平均動脈血壓變化〇 20毫米汞柱 - 2 2 0 - 冢|氏張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） " II ----- - - - - - - 4^---I i I I I 訂- 111 — — — —· — (請先閱讀背面之注意事項再填寫本頁) 470741 89. 9, 18 A7 B7 五、發明說明（ 10 27毫米汞柱 32毫米汞柱 41毫米汞柱 53毫米汞柱實例6 6 毒性 5 — ( S ) 一胺基甲基一1— (5，7 —二氟一1 2，3，4 —四氫萘_2 —基）一1 ，3 —二氫咪唑一2 -硫嗣氫氯化物在一系列評鑑中不會造成遺傳突變。化合物的有毒口服劑量為小鼠的1 0 0 0毫克/公斤，大鼠和狗分別為大於2 5 0 0和4 0 0毫克/公斤。實例6 7 以下為代表性的含式I化合物的藥學組成物。口服組成物口服投與的代表性溶液包含： (請先閱讀背面之注意事項再填寫本頁) --裝訂·--------線. 經濟部智慧財產局員工消費合作社印製式I化合物擰樣酸單水合物氫氧化納增味劑水靜脈注射組成物 70 — 700毫克 1 0 5毫克 1 8毫克添加到1 0 0毫升 -221- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 470741 fl A7 B7 五、發明說明（）靜脈投與組成物的代表性溶液：式I化合物 2 5 % 微结晶性纖維素 5 4 % 硬脂酸 2 0 % 膠體二氧化矽 1 % 依實例6 7進行，可Μ製備含式I I或I I I化合物的代表性藥學組成物。 (請先閱讀背面之注意事項再填寫本頁) -1 ^^1 m I— n an m 訂---------線. 經濟部智慧財產局員工消費合作社印製 - 2 2 2 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐）IB A7 B7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs V. Invention Description () 10 1. 04 soil 0, .37 0, .09 soil 0 1.02 0. 09 people 0, .02 30 1. 95 soil 0, , 21 0., 1 4 soil 0 .03 0. 15 soil 0, .03 100 0 · 85 soil 0,, 17 0., 18 soil 0 .02 0. 22 soil 0., 04 Example 6 5M This line identifies compounds that lower blood pressure. Male spontaneously hypertensive rats were anesthetized, a tube was inserted into the femur or carotid artery, and the blood pressure was monitored by ML. After anesthetizing the rats for 30 to 60 minutes, the basal blood pressure was measured. Rats were administered vehicle (10 mg / kg) or test compound (90.3 to 30 mg / kg) by M orally or intravenously and observed for 4 to 6 hours. The test compounds were evaluated at a wide range of doses, and blood pressure lowering activity was defined as a statistically significant (ρδ0.05) blood pressure drop compared to vehicle-treated rats. Following Example 65, the compound of the present invention was tested and found to have blood pressure lowering activity. 5- (S) -aminomethyl- 1- (5,7_difluoro-1,2,3,4-tetrahydronaphthalene- 2-yl) -1,3-dihydrooxazole-2 -sulfur The effect of ketohydrochloride on the change in mean arterial blood pressure of spontaneously hypertensive rats administered with three oral doses after 12 hours of controlled spontaneous administration at 12 hours intervals is briefly described in the table below. in. Dose (mg / kg) Mean arterial blood pressure change 020 mmHg-2 2 0-The gravel scale is applicable to the Chinese National Standard (CNS) A4 (210 X 297 mm) " II ------ -----4 ^ --- I i III Order-111 — — — — · (Please read the notes on the back before filling out this page) 470741 89. 9, 18 A7 B7 V. Description of the invention (10 27 Mm Hg 32 mm Hg 41 mm Hg 53 mm Hg Example 6 Toxicity 5 — (S) Monoaminomethyl 1 — (5,7 —difluoro 1 12 3,4 —tetrahydronaphthalene _2-based) -1,3-dihydroimidazole-2-thizone hydrochloride does not cause genetic mutations in a series of reviews. The toxic oral dose of the compound is 100 mg / kg in mice, Rats and dogs were greater than 2500 and 400 mg / kg, respectively. Example 67 The following are representative pharmaceutical compositions containing a compound of formula I. Oral compositions Representative solutions for oral administration include: (Please (Please read the notes on the back before filling this page)-Binding · -------- Line. Printed acid form of the compound of compound I printed by the Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs Compound sodium hydroxide flavor enhancer water intravenous injection composition 70 — 700 mg 105 mg 18 mg added to 100 ml -221- This paper size applies to China National Standard (CNS) A4 (210 X 297 male) (Centi) 470741 fl A7 B7 V. Description of the invention () Representative solution for intravenous administration: Compound of Formula I 25% Microcrystalline cellulose 54% Stearic acid 20% Colloidal silica 2% According to examples 6 7 can be performed to prepare a representative pharmaceutical composition containing a compound of formula II or III. (Please read the precautions on the back before filling out this page) -1 ^^ 1 m I— n an m Order ----- ---- Line. Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs-2 2 2-This paper size applies to China National Standard (CNS) A4 (210 X 297 mm)

Claims

470741 經濟部智慧財產局員工消費合作社印製 (A8 ,.B8 C? 841040 申請專利範圍種式I化合物 (R'lt R1470741 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs (A8, .B8 C? 841040 Scope of Patent Application, Compound of Formula I (R'lt R1

(CHi). 其中： η為0，1或2 ; t 為 0 ，1 ，2 或 3 ; R1個自獨立為鹵素，羥基或（Ci — C4 )烷基氧基；和當R 2被接於α位置，且為選自式（a ) ，（ b )和 (c )之基團： RJ R4 T / S、 N 丫 \ 1 N R7 八/ (a) (b) (c) R< -1- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） (請先閱讀背面之注意事項再填寫本頁) 470741 ABCD 經濟部智慧財產局員工消費合作杜印制取 ^·申請專利範圍其中： R4為氫，R3為氫或一（CH2 ) qR 3 {其中q為〇，1，2，3或4，且尺9為狻基，（Ct— C4)烷基氧基羰基，氨基甲醯或選自苯基，吡啶基或噠嗪基（該基團選擇性再被一到二個獨立選自羥基，（C i - C 4 )烷基氧基，氰基，1. Η —四唑一5 —基，羧基或（C! — C4) 烷基氧基羰基之取代基所取代）},R5為氫或一 NHz ;或 R 4和R s均為氫，R 3為一 N H SR 1 0 (其中R 1 〇為氬或（C i — C 4 )烷醢基）；或 Rs為氫，R3為氳或一（CH2)q R 9 (其中q 和R9定義同上），R4為（Ci — C4 )烷基，二（Ct -C 4 )烷基胺基甲基，甲醯基，1 一羥基（Ct — C4 )烷基或一 C Η 2 N H R 1 3 (其中R i 3為氫，（Ci —C 4 )烷基，羧基（C i — C 4 )烷基，氨基甲籐，氨基甲醯（Ci - C 4 )烷基或笨基（Ct —C4 )烷基 (選擇性被羧基或（Ci -C4 )烷基氧基羰基取代）} ;或 R 3為氫，R 4為氫，'且R 5為氰基，羥基甲基， —四唑一5 —基，4，5-二氫咪唑—2 -基，吡咯烷一1—基甲基，哌啶一1—基甲基，嗎啉一 4 — 基甲基，呢嗪一1—基甲基，4 一（Ci — C 4 )院基喊嗪一 1—基甲基，一C ( 0 ) R 1 4 {其中Ri4為本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） ------------------------------ (請先閱讀背面之注意事項再填寫本頁) 470741 A8 B8 C8 D8 ^、申請專利範圍 2 — （二甲基胺基）乙基胺基，4 —甲基哌嗪一 1—基， 2 — ί二甲基胺基）乙基氫硫，4 一（甲基磺醯基胺基） (請先閱讀背面之注意事項再填寫本頁) 苯胺基，1 — Η —四唑一5 —基胺基），一 C ( Ν Η ) NR15 R 1 6 (其中R1 5和尺16個自獨立為氫， (C 1 — C4 )烷基或三氟（C! - C 4 )烷基）或 -C Η 2 N R 1 0 R 1 7 {其中 R 1 0 為氫，（C !— C 4 )烷醯基，氨基甲醯，(C , - C 4 )烷基氧基羰基，（C: 一（：4 )烷基氨基甲醯，二（Ct — C4 ) 烷基氨基甲醯，胺基（Ct — C4 )烷醯基，或選自苯醯基，皮考林醯胺，菸鹼醯胺和2 —呋醯基，或— C(NRil)NHR12 (其中 R11 和 R1^ 獨立為氫，乙_基或三级丁氧基羰基），R 1 7為氫或 ((^—(:+丨烷基）};或經濟部智慧財產局員工消費合作社印製 R3為氫，R4為—C4 )烷基，且尺5為氰基，羥基甲基，1H —四唑一5 —基，4，5 —二氫眯唑一 2 —基，吡咯烷一1 —基甲基，#啶一 1 —基甲基，嗎啉一 4 一基甲基，哌嗪一1 一基甲基，4 — ( C ί -C 4 )烷基咪嗪一1 —基甲基，一 C ( Ο ) R 1 4 (其中 R1 4為胺基，羥基，（Ct -C4 )烷基氧基* 2 — （二甲基胺基）乙基胺基，4 一甲基锨嗪一1—基，2 — （二甲基胺基）乙基氫硫，4 —甲基磺醯基胺基）苯胺基，1 一 H —四唑一5 —基胺基），一C (NH) NR15R1S (其中Ri 5和個自獨立為氫，（Ci - C 4 )烷本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 470741 A8 B8 C8 D8 六經濟部智慧財產局員工消費合作社印製申請專利範圍基或三氟（Ct —C4 )烷基）或一CHz NR10 R 1 7 (其中R1 °為氫* (C! — C4 )烷醯基，氨基甲醯， (請先閱讀背面之注意事項再填寫本頁) (C , — C 4 )烷基氧基羰基，（C t — C 4 )烷基氨基甲醯，二（Ci -C4 )烷基氨基甲醯，胺基（Cl —C4 )烷藤基，或選自苯藤基，皮考林醯胺，菸鹼醯胺和2— 呋醯基，或一C ( N R 1 1 ) N H R 1 2 (其中R 1 1和 R1 2獨立為氫，乙醯基或三级丁氧基羰基），R1 7為氫或（C i — C 4 )烷基）};或 R3為氫，R4為一C (0) R 1 4 (其中R1*為 (C ! - C 4 )烷基氧基），且Rs為氮基，羥基甲基， 1 Η -四唑—5 —基，4，5 —二氫咪唑—2 —基，吡咯垸一1 —基甲基，哌啶一1 —基甲基，嗎啉一4 —基甲基，哌嗪一1-基甲基，4 — (Ci —C4 )烷基哌嗪一1 一基甲基，一C (0) R14 (其中R14為胺基，羥基，2 — （二甲基胺基）乙基胺基，4 —甲基哌嗪一 1—基，2 — （二甲基胺基）乙基氫硫，4 —(申基磺醢基胺基）苯胺基，1 一 H —四唑—5 —基胺基），一 C (NH) N R 1 5 R 1 6 (其中R 1 5和R 1 6個自獨立為氫，（C t -C 4 )烷基或三氟（Ct — C4 )烷基）或一 CH2 N R 1 0 R 1 7 {其中R 1 0為氫，（C i 一 C 4 )烷酿基，氨基甲醯，（Ct— C4)烷基氧基羰基，（Ct— C4 )烷基氨基甲醯，二（Ct — C4 )烷基氨基甲醯，胺基 (Cl — C4 )焼藤基，或選自苯髓基I皮考抹驢胺，Μ -4-本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 470741 A8 B8 C8 D8 申請專利範圍 2 X 和 R ，胺中 } 藤其基驗 ί 羰 R Ν /V C - 或基醯呋三 ) 或基基烷 0 ) 乙 4 ， C 氫 I 為丨立 C 獨 ί 2 或 1 氣 R 為和 7 i 1 X R 2 基 1 氧 R 丁 Η 級 Ν 或 q \ly 2 Η c rl\ I 為 3 R R 義定 9 R 和 q 中其上 i 同 R 氫丨為 R 4 中 R 其為 c c 為 ) 5 o R /IV C ) - 基氧或基基烷烷} N—^- 4 4 C C I 4 I 4 ,β$> 基# 基 I , 甲 5 基基 I 甲 I 唑基 1 四 I I I 1 嗪 Η - 派 1 垸，，咯基基fth甲甲，基基基 I 羥 -4 ， 2 -基 I 啉氟唑嗎 5 基 C 眯氫基二甲 ---------------- (請先閱讀背面之注意事項再填寫本頁) C R i 基 R 氧 } 基 ο 垸 /«V C 4 - C J I 基 1 甲 C 基 ί I ) 1 基 I 羥嗪，咪基基胺烷為中其 2 . 4 4 ) , ，基基硫胺胺氫基基基 I 乙乙 5 \—/ \—/ 一基基唑胺胺四基基 I 甲甲H 二二 I 嗪呢基甲基 2 基胺基醢磺基甲 /V R Ν Η Ν Γν c s C /IV i R 氟中三其或 ( 基 R 4 ο C 1 1 R 1 N c Z (Η ， C 氬一為立,~, 獨基自综個 } 6 4 1 C 或 R 烷 7 -線為 ο 1 R 中其經濟部智慧財產局員工消費合作社印製 C 4 C 氫烷 C C 醯烷醯甲基 0 烷或立 1 , 獨 C 基 2 ί 醢 1 或呋 R 氫羰烷基丨氧基丨基 4 醯 C 苯 I 自 1 選 C 或 C 氫為 C 基 C 氣 } , 4 基 C (β 基鹼胺 ί於醯胺甲醯基林氨考基皮 , 基 C _ 醯氨 I 2 甲基 1 和基烷 C 胺 R R 中，其} 丨基 2 羰 1 基 R 氧 Η 一—ί Ν 級 ) 三 } 1 或 } 1 基基 R _ 烷 Ν乙 \—, 或本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐）和為 470741 A8 B8 C8 D8 申請專利範圍 R 上同 ) 立 2 獨 Η 自 C 個 /V 5 I R 或和氫 4 為 R Q R 二為義定 9 R 和 Q 中其啶哌基甲基基啉嗎基甲基 C 4 4 C 胺基烷甲基羥或基甲基基 ; 甲基基乙 -基 1 羧 -I 嗪 2# 或 ’ 氫氫為為 6 7 R R C 4 C 嗪基烷或基甲基 Η C 烷 \)/· 4 C I C /V 或氫為 1 氫 R 為中 7 其 1 ( R 7 且 1 > R 基〇羰 1 基 R 氧 Ν 基 -------------- --- (請先閱讀背面之注意事項再填寫本頁) R 4 C R Η Ν I ; 或 } 氫基為醯 8 烷 R 中其 C /|\ 或氫為 a /IV 式自選為且置位 7 或 θ· 於：接團被基 Ζ 之 R -) 當 C R, R, 訂· 1.線_(CHi). Wherein: η is 0, 1 or 2; t is 0, 1, 2 or 3; R1 is independently halogen, hydroxy or (Ci-C4) alkyloxy; and when R2 is connected to α position, and is a group selected from the formulas (a), (b) and (c): RJ R4 T / S, N y \ 1 N R7 eight / (a) (b) (c) R < -1 -This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) (Please read the precautions on the back before filling out this page) 470741 ABCD Printed by the Intellectual Property Bureau of the Ministry of Economic Affairs for consumer cooperation. The scope of the patent is as follows: R4 is hydrogen, R3 is hydrogen or mono (CH2) qR 3 {wherein q is 0,1,2,3, or 4, and chi9 is fluorenyl, (Ct-C4) alkyloxycarbonyl, Carbamate or selected from phenyl, pyridyl, or pyridazinyl (the group is optionally one or two independently selected from hydroxyl, (C i-C 4) alkyloxy, cyano, 1. Η —Tetrazol —5 —yl, substituted with carboxyl or (C! — C4) alkyloxycarbonyl)), R5 is hydrogen or —NHz; or R 4 and R s are both hydrogen and R 3 is — NH SR 1 0 (wherein R 1 〇 is argon or (C i —C 4) alkylfluorenyl Or Rs is hydrogen, R3 is fluorene or mono (CH2) q R 9 (wherein q and R9 have the same definitions as above), R4 is (Ci-C4) alkyl, and di (Ct-C4) alkylaminomethyl, Formamyl, 1-hydroxy (Ct — C4) alkyl or 1CΗ2 NHR 1 3 (where R i 3 is hydrogen, (Ci —C 4) alkyl, carboxy (C i —C 4) alkyl, Carbamate, carbamate (Ci-C 4) alkyl or benzyl (Ct —C4) alkyl (optionally substituted by carboxyl or (Ci -C4) alkyloxycarbonyl)}; or R 3 is hydrogen , R 4 is hydrogen, and R 5 is cyano, hydroxymethyl, —tetrazol-5 —yl, 4,5-dihydroimidazol-2-yl, pyrrolidine 1 —ylmethyl, piperidine — 1-methylmethyl, morpholine 4-ylmethyl, morphazine 1-ylmethyl, 4-mono (Ci — C 4) yloxazine-1-ylmethyl, 1 C (0) R 1 4 {Where Ri4 is the paper size and applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) -------------------------- ---- (Please read the precautions on the back before filling this page) 470741 A8 B8 C8 D8 ^, patent application scope 2-(dimethylamino) ethylamine, 4-methyl Piperazine 1-yl, 2 — dimethylamino) ethyl hydrogen sulfide, 4 mono (methylsulfonamido) (Please read the precautions on the back before filling this page) Aniline, 1 — Η —tetrazol —5 —ylamino), C (NR) NR15 R 1 6 (where R1 5 and 16 are independently hydrogen, (C 1 — C4) alkyl or trifluoro (C!- C 4) alkyl) or -C Η 2 NR 1 0 R 1 7 {where R 1 0 is hydrogen, (C! —C 4) alkylfluorenyl, carbamate, (C, -C 4) alkyloxy Carbonyl, (C: mono (: 4) alkylcarbamidine, bis (Ct—C4) alkylcarbamidine, amine (Ct—C4) alkylamidine, or selected from phenylammonyl, picolin Sulfonamide, nicotinamide and 2-furfuryl, or —C (NRil) NHR12 (where R11 and R1 ^ are independently hydrogen, ethyl or tertiary butoxycarbonyl), and R 1 7 is hydrogen or ( (^ — (: + 丨 alkyl)}; or printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, R3 is hydrogen, R4 is -C4) alkyl, and ruler 5 is cyano, hydroxymethyl, 1H-tetrazole A 5-yl group, 4,5-dihydrooxazole- 2-yl group, pyrrolidine- 1-ylmethyl group, # pyridine-1 -ylmethyl group , Morpholine-4 monomethyl, piperazine-1 monomethyl, 4- (C ί -C 4) alkylimidazine-1-ylmethyl, C (Ο) R 1 4 (where R1 4 is amine, hydroxyl, (Ct-C4) alkyloxy * 2-(dimethylamino) ethylamino, 4 monomethylpyrazine mono-1-yl, 2- (dimethylamino ) Ethyl hydrogen sulfide, 4-methylsulfonylamino) aniline, 1-H-tetrazol-5-ylamino), C (NH) NR15R1S (wherein Ri 5 and A are independently hydrogen, (Ci-C 4) The size of the paper is applicable to the Chinese National Standard (CNS) A4 (210 X 297 mm) 470741 A8 B8 C8 D8 Six employees of the Intellectual Property Bureau of the Ministry of Economic Affairs printed a patent application scope or trifluoro ( Ct —C4) alkyl) or a CHz NR10 R 1 7 (where R1 ° is hydrogen * (C! — C4) alkyl carbamoyl, carbamate, (Please read the precautions on the back before filling this page) (C , —C 4) alkyloxycarbonyl, (C t —C 4) alkylcarbamidine, bis (Ci -C4) alkylcarbamidine, amine (Cl —C4) alkylpentyl, or selected from Benzyl, picolinium, nicotine and 2 Furfuryl, or C (NR 1 1) NHR 1 2 (wherein R 1 1 and R1 2 are independently hydrogen, ethylfluorenyl or tertiary butoxycarbonyl), R1 7 is hydrogen or (C i — C 4 ) Alkyl)}; or R3 is hydrogen, R4 is a C (0) R 1 4 (where R1 * is (C!-C 4) alkyloxy), and Rs is nitrogen, hydroxymethyl, 1 Hydrazone-tetrazol-5-yl, 4,5-dihydroimidazol-2-yl, pyrrolidine-1-ylmethyl, piperidine-1-ylmethyl, morpholine 4-ylmethyl, piperazine 1-ylmethyl, 4- (Ci-C4) alkylpiperazine-1 1-methyl, 1-C (0) R14 (where R14 is amine, hydroxyl, 2- (dimethylamino) ethyl Methylamino, 4-methylpiperazine-1-yl, 2- (dimethylamino) ethylhydrosulfide, 4- (shenylsulfonylamino) aniline, 1-H-tetrazole- 5-Amino group), a C (NH) NR 1 5 R 1 6 (wherein R 1 5 and R 1 6 are independently hydrogen, (C t -C 4) alkyl or trifluoro (Ct — C4) Alkyl) or mono-CH2 NR 1 0 R 1 7 {wherein R 1 0 is hydrogen, (C i -C 4) alkanol, carbamate, (Ct—C4) alkyloxycarbonyl, (Ct—C4 Alkyl ammonia Formamidine, bis (Ct—C4) alkylaminoformamidine, amine (Cl—C4) amidine, or selected from benzyme I, picolinol, M -4- This paper size applies to Chinese national standards (CNS) A4 specification (210 X 297 mm) 470741 A8 B8 C8 D8 Patent application scope 2 X and R, in amines} Benzene radical test carbonyl R NR / VC-or methylfurfuryl) or alkane 0 ) B 4, C hydrogen I is Li C or 2 or 1 gas R is and 7 i 1 XR 2 radical 1 oxygen R but Η grade N or q \ ly 2 Η c rl \ I is 3 RR define 9 R and where i is the same as R hydrogen in q and R is R in R 4 which is cc) 5 o R / IV C)-alkoxy or alkane} N — ^-4 4 CCI 4 I 4, β $ > Radical # radical I, methyl 5 radical I, methyl I, oxazolyl 1 tetra III 1 hydrazine hydrazone-pie 1 hydrazone, alkynyl fth methyl, aryl I hydroxy-4, 2-yl I fluorofluorozole 5 C 眯 Hydrogen Dimethyl ---------------- (Please read the notes on the back before filling this page) CR i radical R oxygen} radical ο «/« VC 4- CJI group 1 methylC group I) 1 group I hydroxyzine, imidylamine In which 2. 4 4),, thiothiamine hydrolyl I ethylene 5 \ — / \ — / monoylazolamine amine tetrayl I methyl methyl H bis I oxazinyl methyl 2 Aminoaminosulfomethyl / VR Ν Η Ν Γν cs C / IV i R Three or more in fluorine (R 4 ο C 1 1 R 1 N c Z (Η, C Ar Self-contained} 6 4 1 C or R alkanes 7-line is ο 1 R printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, C 4 C hydrogen alkanes, CC, alkanes, methyl 0 alkanes, or 1 alkanes, only C radicals 2 醢醢 1 or furo R hydrocarbonylalkyloxyl group 4 醯 C benzene I select C or C hydrogen from C group C gas}, 4 group C (β-based base amine 醯 amine formamidine Linamoxipin, in the group C _ ammonium I 2 methyl 1 and alkane C amine RR, its} 丨 2 carbonyl 1 carbonyl R oxo 1-ί N) three} 1 or} 1 group R _ Kan N B \ —, or this paper size applies Chinese National Standard (CNS) A4 specifications (210 X 297 mm) and 470741 A8 B8 C8 D8 patent scope R same as above) From C / V5 IR or and hydrogen 4 is RQR, the meaning is 9 R and Q. Its pyridylmethylmethyl morpholine methyl C 4 4 C amino alkyl methyl hydroxy or methyl methyl group; A Phenylethyl-yl 1 carboxy-I hydrazine 2 # or 'hydrogen and hydrogen are 6 7 RRC 4 C azinylalkane or methylmethyl hydrazine C) /) 4 CIC / V or hydrogen is 1 hydrogen R is medium 7 Its 1 (R 7 and 1 > R group 0 carbonyl 1 group R oxy N group -------------- --- (Please read the precautions on the back before filling this page) R 4 CR Η Ν I; or} hydrogen group is 醯 8 alkane R whose C / | \ or hydrogen is a / IV formula can be selected and set to 7 or θ. In: R of the bond group Z-) when CR , R, order 1. line_

y 經濟部智慧財產局員工消費合作社印製弋b) ^ /|\ 丫 A(c) 中其本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 470741 經濟部智慧財產局員工消費合作社印製 A8 B8 C8 D8 、申請專利範圍 R4為氫，R3為氳或一（CH2 ) qR 9 {其中q為 0，1，2，3或4，尺9為羧基，（C!— C4)烷基氧基羰基，氨基甲醯或選自苯基，吡啶基或嚙嗪基（該基團選擇性再被一到二個獨立選自羥基，（Ci — C4 )烷基氧基，氰基，1H —四唑—5 -基，羧基或（C! — C4 ) 烷基氧基羰基之取代基所取代）},RS為氫或一NH2 ;或 R4和R5均為氫，R3為一NHR1 〇 (其中Ri 〇為氫或（Ct—C*)烷醢基）；或 R5為氫，R3為氫或一（CH2)q R 9 (其中q 和R9定義同上），：R4為（C! -C4 )烷基，二（C! -C 4 )烷基胺基甲基，甲醯基，1-羥基（Ct — C4 )烷基或—CH2NHR13 {其中R1 3為氫，（Ci -C 4 )烷基，羧基（Ct — C4 )烷基，氨基甲醯，氨基甲醢（Ci —C4 )烷基或苯基（C! — C4 )烷基 (選擇性被羧基或（Ci — C4 )烷基氧基羰基取代）） :或 R3為氫或一（CH2)q R 9 (其中q和R9定義同上），R 4為氫，（C - C 4 )烷基或 —C (〇） R 1 4 (其中R14為（Ci-C*)烷基氧基），RS為氰基，羥基甲基，1 Η —四唑~5~基，4，5 —二氫咪唑一2 —基，毗咯烷一1 —基甲基，锨啶—1 一基甲基，嗎啉一4 —基甲基，顿嗪一1—基甲基，4 — ( C t - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） ---------------------訂·-------I (請先閱讀背面之注意事項再填寫本頁) 470741 A8 B8 C8 D8 經濟部智慧財產局員工消費合作社印制^ ^、申請專利範圍 C 4 ) 院基哌嗪 — 1 — 基甲基 > — C ( 0 ) R 1 4 ( 其中 R I 4 為胺基 r 羥基 > ( C 1 — C 4 ) 院基氧基 t 2 — ( 二甲基胺基 ) 乙基胺基 » 4 — 甲基呢嗪 — 1 — 基 » 2 — ( 二甲基胺基 ) 乙基氫硫 > 4 — (甲基磺醯基肢基）苯胺基，1 — Η — 四唑 — 5 — 基胺基 ) t — C ( Ν Η ) Ν R 1 5 R 1 6 ( 其中 R 1 5 和 R 1 G 個白獨立為氫 > ( c 1 — c 4 ) 烧基或三氟 ( C 1 — C 4 ) 院基 ) 或 — C Η 2 Ν R 1 0 R i 7 { 其中 R 1 0 為氫 9 ( C ί — C 4 ) 烷醯基 » 氨基甲藤 t ( C 1 — C 4 ) 烷基氧基羰基 f ( C 1 — c 4 ) '院基氨基甲醯 t 二 ( C 1 — C 4 ) 烷基氨基甲醯 t 胺基 ( C I — C 4 ) 醯基 9 或選白苯醯基 9 皮考林 _ 胺 9 Μ 驗 m 胺和 2 — 呋醯基 > 或 — C ( N R X 1 ) N Η R 1 z ( 其中 R 1 1 和 R1 2獨立為氫，乙醯基或三級丁氧基羰基），R1 7為氫或（C , 一 C 4 )烷基）};或 R3為氫或一（CH2 ) q R9 (其中〇和R9定義同上），R4和R5個自獨立為二（C, —C4 )烷基胺基甲基，#啶一 1 —基甲基，嗎啉一4 一基甲基或羥基甲基； R6為氫或2 —羧基乙基； R7為氫，哌嗪一1—基甲基，一 C4 )烷基 #嗪一1—基甲基或一CH2 NR1 0 R1 7 (其中R1 〇為氫或（C t — C 4 )烷基氧基羰基，且R 1 7為氫）；本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） ---------------------訂-----I--- (請先閱讀背面之注意事項再填寫本頁) 470741 A8 B8 C8 D8 申請專利範圍 R R Η Ν R 中其 C Γν 或氫。為物〇合 1 混物構異其和物構異 '，別 _ ) 個或基 ’ 氫醯鹽為烷受 8 } 接 4 可 C 上 I 學中其物合化的項第 ’’ 圍 2 範或利 1 專 > 請 ο 申為如 η 2 ο 為 3 或 2 C /|\ 或基羥素鹵為立獨自個 R C 氧基烷 ----------------- (請先閱讀背面之注意事項再填寫本頁) 基 a /|\ 式自選為且置位 7 或於接：被團 2 基 R 之 C b · R5y Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 弋 b) ^ / | \ YA A (c) The paper size in this paper applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) Employee Consumer Cooperatives printed A8 B8 C8 D8, patent application scope R4 is hydrogen, R3 is 氲 or one (CH2) qR 9 {where q is 0,1,2,3 or 4, and foot 9 is carboxyl, (C! — C4) alkyloxycarbonyl, carbamate or selected from phenyl, pyridyl or pyrazinyl (this group is optionally further selected from one to two independently selected from hydroxyl, (Ci-C4) alkyloxy, Cyano, 1H-tetrazol-5-yl, substituted by carboxyl or (C! — C4) alkyloxycarbonyl)}, RS is hydrogen or mono-NH2; or R4 and R5 are both hydrogen and R3 is -NHR1 0 (where Ri 0 is hydrogen or (Ct-C *) alkyl); or R5 is hydrogen, R3 is hydrogen or-(CH2) q R 9 (where q and R9 are the same as defined above), and R4 is ( C! -C4) alkyl, di (C! -C 4) alkylaminomethyl, formamyl, 1-hydroxy (Ct — C4) alkyl or —CH2NHR13 {wherein R1 3 is hydrogen, (Ci- C 4) alkyl, carboxy (Ct — C4) alkane , Carbamate, carbamate (Ci — C4) alkyl or phenyl (C! — C4) alkyl (optionally substituted by carboxyl or (Ci — C4) alkyloxycarbonyl)): or R3 is hydrogen Or a (CH2) q R 9 (wherein q and R9 are as defined above), R 4 is hydrogen, (C-C 4) alkyl or —C (〇) R 1 4 (where R 14 is (Ci-C *) alkane Alkoxy), RS is cyano, hydroxymethyl, 1 Η -tetrazol ~ 5 ~, 4,5 -dihydroimidazole-2 -yl, pyrrolidine-1 -ylmethyl, pyridin-1 Monomethyl, morpholine 4- 4-methyl, tetrazine 1-methyl, 4 — (C t-This paper size applies to China National Standard (CNS) A4 (210 X 297 mm)- ------------------- Order · ------- I (Please read the notes on the back before filling in this page) 470741 A8 B8 C8 D8 Ministry of Economy Wisdom Printed by the Consumer Cooperative of the Property Bureau ^ ^, applied for patent range C 4) Cipropiperazine — 1 —methylmethyl> — C (0) R 1 4 (where RI 4 is an amino r hydroxyl group) (C 1 — C 4) Nolyloxy t 2 — (dimethylamino) ethylamino »4 — methylmorphazine — 1 — group »2 — (dimethylamino) ethylhydrosulfide > 4 — (methylsulfonyllimyl) aniline, 1 — fluorene — tetrazol — 5 —ylamino) t — C (Ν Η) Ν R 1 5 R 1 6 (where R 1 5 and R 1 G are independently hydrogen) (c 1-c 4) alkyl or trifluoro (C 1-C 4) base) or — C Η 2 NR R 1 0 R i 7 {where R 1 0 is hydrogen 9 (C ί — C 4) alkylfluorenyl »carbamate t (C 1 — C 4) alkyloxycarbonyl f (C 1 — c 4) 'Chenylcarbamidine t bis (C 1 — C 4) alkylcarbamidine t amine (CI — C 4) fluorenyl 9 or selected benzamidine 9 picolin amine 9 amine test m amine and 2 —furfuryl> or — C (NRX 1) N Η R 1 z (wherein R 1 1 and R1 2 are independently hydrogen, ethylfluorenyl or tertiary butoxycarbonyl), and R1 7 is hydrogen Or (C, -C4) alkyl)}; or R3 is hydrogen or one (CH2) q R9 (wherein 0 and R9 have the same definitions as above), and R4 and R5 are independently di (C, —C4) alkylamines Methyl, #pyridinyl 1-methyl, morpholine 4-yl R6 is hydrogen or 2-carboxyethyl; R7 is hydrogen, piperazine-l-ylmethyl, one C4) alkyl # azine-l-ylmethyl or one CH2 NR1 0 R1 7 ( Wherein R1 0 is hydrogen or (C t — C 4) alkyloxycarbonyl group, and R 1 7 is hydrogen); This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) ---- ----------------- Order ----- I --- (Please read the notes on the back before filling this page) 470741 A8 B8 C8 D8 Patent Application RR RR NR in which C Γν or hydrogen. For the object 0 in 1, the structure of the mixture is different from the structure of the object, and don't _) or the group of the hydrogen sulfonium salt is an alkyl group. Fan or Li 1 Special> Please ο apply for such as η 2 ο is 3 or 2 C / | \ or hydroxyl halogen is a single RC oxyalkane -------------- --- (Please read the notes on the back before filling in this page) The radical a / | \ can be selected and set to 7 or connected: C b · R5 of radical 2

7r R, rb) r /—-、 N/ Νr'3 --線經濟部智慧財產局員工消費合作社印製中其 2 Η ， c 基 ( 羧一為或 9 氫 R 為， 3 4 R 或 . 3 氫 ’ 為 2 4 , R '—*_ 〇 R Q 為 Q 中其 C 基烷 \—/ 4 C 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 470741 A8 B8 C8 D8 t、申請專利範圍經濟部智慧財產局員工消費合作社印制衣氧基羰基，氨基甲 1¾¾ 或選 § 苯基，〇比啶基或 m 嗪基 ( 該基團選木明 1辛性再被一到二個獨選 i 羥基 1 ( C 1 — C 4 ) 烷基氧基 > 氰基 > 1 Η — 四唑 — 5 — 基 t 羧基或 ( C 1 一 C 4 ’院棊氧基羰基之取代基所取代） } » R 5 為 — N Η Z 或 R 4 和 R 5 均為氫 R 3 為 — N Η R 1 0 ( 其中 R V 0 為 Μ 或 ( C 1 — C 4 ) 院藤基 ) > 或 R 5 為氫 » R 3 為氫或 — ( C Η 2 \ q R 9 (其中Q 和 R 9 定義同上 ) ， R 4 為 ( C X — C 4 ) 烷基 f 二 ( C 1 — C 4 ) 烷基胺基甲基甲釀基 1 1 — 羥基 ( C X — C 4 ) 烧基或 — C Η 2 Ν Η R 1 { 其中 R 1 3 為氫 9 ( C 1 — C 4 ) 焼基 > 狻基 ( C 1 — C 4 ) 烧基氨基甲醯 f 氨基甲聽 ( C 1 — C 4 ) 烷基或苯基 ( C 1 — C 4 ) 烷基 ( 選 4-ΏΤ 1辛性被羧基或 ( C 1 — C 4 ) 焼基氧基羰基取代 ) } t 或 R 3 為氫或 — ( C Η 2 ) q R 9 (其中Q和R 9 定義同上 ) » R 4 為氫 t ( C 1 — C 4 ) 烷基或 — C ( 0 ) R 1 4 ( 其中 R 1 4 為 ( C t 一 C 4 ) 烷基氧基 R 5 為氰基 > 羥基甲基， 1 Η — 四唑一 5 — 基 f 4 ， 5 — 二氫咪唑 — 2 — 基 > 吡咯烷 — 1 — 基甲基 > 呢啶 — 1 — 基甲基 t 嗎啉 — 4 — 基甲基 > 嗪 — 1 一基甲基 * 4 — ( C 1 — r-* Ο 4 ) 烷基嗪 — 1 — 基甲基 t — C ( 0 ) R 1 4 ( 其中 R 1 4 為胺基 1 羥基 t ( C 1 — C 4 ) 院基氧基 t 2 — ( _— 甲基胺基 ) 乙基胺基 > 4 — 甲基哌嗪 — 1 — 基 2 一 ( (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 470741 A8 B8 C8 D8 ^、申請專利範圍經濟部智慧財產局員工消費合作社印制农二甲基胺基 ) 乙基氫硫 1 4 一甲基磺醯基胺基 )苯胺基， ‘ 1 — Η — 四唑 — 5 — 基胺基 ) f — C ( N Η ) N R 1 5 R 1 6 ( 其中 R I .5 和 R 1 6 個白獨立為氫 t ( c l — C 4 ) 焼基或三氟 ( C Ϊ — C 4 ) 烧基 ) 或 — C Η 2 N R 1 0 R 1 7 Γ 1 其中 R 1 0 為氫 > ( C ί — C 4 ) 燒醯基 * 氨基甲 Try? 福 > ( C 1 — C 4 ) 基氧基羰基 J ( C 1 — c 4 ) 烧基氨基甲醯 t 二 ( C 1 — C 4 ) 烷基氨基甲釀 t 胺基 ( C 1 — C 4 ) 烧藤基 > 或選白苯 ns><» 福基 9 皮考林醢胺 9 菸驗 _ 胺和 2 — 呋醯基 t 或 — C ( N R i 1 ) N Η R 1 z ( 其中 R 1 1 和 R 1 2 獨，、了為氫 t 乙藤基或三级丁氧基羰基 ) 9 R 1 7 為氫或 ( C \ — C 4 ) 烧基 ) ·- 或 R 3 為氫或 — ( C Η 2 ) q R 3 (其中q和R 9 定義同上 ) > R 4 和 R 5 個白獨立為二 ( C I — C 4 ) 焼基胺基甲基 ) 哌啶 — 1 — 基甲基嗎啉 — 4 — 基甲基或羥基甲基 R 6 為氫或 Σ — 羧基乙基 7 R 7 為氫 > 哌嗪 — 1 — 基甲基 > ( c 1 — C 4 ) 烷基嗪 — 1 — 基甲基或 — C Η 2 N R i 0 R L 7 ( 其中 R 1 0 為氫或 ( C 1 — C 4 ) 烷基氧基羰基 9 R i 7 為氫 ) > R 8 為氫或 — N Η R 0 ( 其中 R ί 〇為氫或 ( C 1 — C 4 \ 烧醯基 ) 和藥學上可接受鹽，個別異構物和其異構物混合物 0 -11- (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 470741 A8 B8 C8 D8 t、申請專利範圍 3 *如申請專利範圍第2項的化合物，其中R 2為式（a )*且係連接於/3位置。 4 ·如申請專利範圚第3項的化合物，其中η為0或1 ， RS為二（C. 1 - C 4 )烷基胺基甲基，吡咯烷一1 一基甲基，哌啶一 1 _基甲基，嗎啉一 4 —基甲基，呢嗪一 1 —基甲基，4 — (Ct — C4 )烷基#嗪一1—基甲基或 -C Η 2 N H R 1 0 〇 .(請先閱讀背面之注意事項再填寫本頁) R 中其物合 ο 化基的甲項基 4胺第基圍醯範乙利或專基請甲申基如胺 5 基甲基脲為 1 為 η 中其物合化的項 5 第圍。範氟利為專 1 請 R 申個如每 6 2 為位 I 7 和 I 5 中其物合化的項 6 第圍範利。專氟請為申 1 如 R . 的 7 置經濟部智慧財產局員工消費合作社印製 I 唑彡氟咪 R 二氫中 I 二其 7 I * ， 3 物 5 , 合 ί 1 化 1 1 的 1 } 項 I 基 7 基 1 第甲 2 圍基 i 範胺萘利一氫。專 5 四物請是一化申就4氯如也，氫 * ’ 3 酮 8 基，硫甲基胺為 2 2 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 470741 A8 B8 C8 D8t、申請專利範圍 1 Ο ·如申請專利範圍第7項的化合物，其中R s為脲基甲基，也就是5 —脲基甲基一1— (5，7 —二氟一1 ， 2 ，3 ，4 —四氫萘一 2 —基）_ 1 ，3 —二氫咪唑一2 一硫酮。 11 •如申請專利範園第1 0項的化合物，其係（S )— 5 —脲基甲基一1— (5 ，7 —二氟一1 ，2 ，3 ，4一四氫萘一2 —基）一 1 ，3 —二氫咪唑一2 —硫酮。 1 2 ·如申請專利範圍第7項的化合物，其中R 5為乙藤基胺基甲基，也就是N— 〔3 — (5，7 -二氟一1 ，2 ，3，4 —四氫萘一 2 —基）—2 —硫代—2，3-二氫 —1H —眯唑一4 —基甲基]乙醯胺。經濟部智慧財產局員工消費合作社印製 )萘4 S 氫 -丨四唑係 | 咪其4-, , Η 物 3 1 合， I 化 2 氫的，二項 1 - 2 _ 3 1 氟，第二 2 圍 - I 範 7 代利，硫。專 5 I 胺請 ί 2 醯申 - I 乙如 3 3 1 . t 基基 3 I I 甲 i N 2 基式為 2 R 中其物合化的項 2 ο 第置圍位範点利於專接請連申且如 ’ . 基 4 ) -—! b 或 ο 為 Π 中其物合化的項 4 r—1 第圍範 nu 禾專請甲如 5 1 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） ---------------------訂---------線 (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 470741 A8 B8 C8 D8 ^、申請專利範圍 1 ，R7為顿嗪一 1 一基甲基，4 — (C! — C4)烷基哌嗪一 1 一基甲基或一CH2NHR10 。 1 6 ·如申請專利範圍第1 5項的化合物，其中n為1 ， t為2 ，每個R 1為氟。 ί 7 ·如申請專利範圍第1 6項的化合物，其中5 —和7 一位置的R 1為氟。 1 8 ·如申請專利範圍第1 7項的化合物，其中R 6為氫，R7為胺基甲基，也就是5 -胺基甲基一4 一（5 ，7 一二氟一1 ，2，3，4 —四氫萘一2 —基）一2，4 — 二氫〔1 ，2，4〕***一 3 —硫酮和其藥學上可接受鹽 0 +1 9 ·如申請專利範圍第1 8項的化合物，其係（S )— 5 —胺基甲基一4 - (5 ，7 —二氟一1 ，2 ，3 ，4一四氫萘一2—基）一2，4 —二氫〔1 ，2，4〕***一 3 —硫酮氫氛化物。 2 0 ·如申請專利範圍第2項的化合物，其中R 2為式（ c)基，且連接於/3位置。 -14- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -------------y^·--------訂·-------- (請先閱讀背面之注意事項再填寫本頁) 470741 經濟部智慧財產局員工消費合作社印製 A8 B8 C8 D8 、申請專利範圍 2 1 *如申請專利範圍第2 0項的化合物，其中η為0或 1 ，R 8為胺基。 22 .如申請專利範圍第2 1項的化合物，其中η為1.或 t為2 ，R 1為氟。 23 .如申請專利範圍第22項的化合物，其中5 —和7 —位置的尺1為氟，也就是4 —胺基_2—（5，7—二氟一1 ，2，3 ，4 —四氫蔡一2—基）一 2 ’ 4—.一& 〔1 ，2，4 ]***一 3 —硫嗣。 2 4 ·如申請專利範圍第2 3項的化合物，其係為（S ) —4 -胺基一2 — （5，7-二氟一1 ’ 2，3，4 -四氫萘一2 —基）一2，4 一二氫〔1 ，2，4〕***—3 一硫嗣。 2 5 * —種用於治療抑制度巴明/3 —羥基酶的藥物所能改善疾病的藥學組成物，其包括有效治療數量的如申請專利範圍第1項的化合物。 2 6 . —種用於治療抑制度巴明卢一羥基酶的藥物所能改善疾病的藥學組成物，其包括有效治療數量的如申請專利第3項的化合物。 -15- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公爱） ^^1 n n I ί 1 - -- ϋ I · 1^1 m It— t— I I— - ^ I n n m n Hi ^^1 I (請先閱讀背面之注意事項再填寫本頁) 470741 A8 B8 C8 D8 六、申請專利範圍 2 7 · —種用於治療抑制度巴明/3 —羥基酶的藥物所能改善疾病的藥學組成物，其包括有效治療數量的如申請專利範圍第1 4項的化合物。 2 8 · —種用於治療抑制度巴明/3 —羥基酶的藥物所能改善疾病的藥學組成物，其包括有效治療數量的如申請專利範圍第2 0項的化合物。 2 9 *如申請專利範圍第2 5至2 8項中任一項的藥學組成物，其中該疾病為充血性心臟病。 3 0 * —種申請專利範圍第1項之化合物的前劑，其係為式I I化合物， ------------I --------訂 - -------- (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製或， -~一〇 > 為 o t 為 η7r R, rb) r / —-, N / NRr'3-Printed by the Consumer Property Cooperative of the Intellectual Property Bureau of the Ministry of Line Economy in the 2Η, c-based (carboxyl- or 9-hydrogen R-, 3 4 R or. 3 Hydrogen 'is 2 4, R' — * _ 〇 RQ is its C-based alkane in Q \ // 4 C This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 470741 A8 B8 C8 D8 t. Scope of application for patents. Printing of oxocarbonyl, carbamoyl 1¾¾, or § phenyl, 0-pyridinyl or mazinyl (this group is selected from Mu Ming 1 and acrid by To two independently selected hydroxy 1 (C 1 —C 4) alkyloxy > cyano > 1 Η — tetrazol — 5 —yl t carboxyl or (C 1 -C 4 ′ Substituted by a substituent)} »R 5 is — N Z or R 4 and R 5 are both hydrogen R 3 is — N 1 R 1 0 (where RV 0 is M or (C 1 — C 4) Yuan Fujiji) > or R 5 is hydrogen »R 3 is hydrogen or — (C Η 2 \ q R 9 (where Q and R 9 have the same definition ), R 4 is (CX — C 4) alkyl f bis (C 1 — C 4) alkylamino methyl methyl 1 1 — hydroxy (CX — C 4) alkyl or — C Η 2 Ν Η R 1 {where R 1 3 is hydrogen 9 (C 1 — C 4) fluorenyl > fluorenyl (C 1-C 4) carbamoylcarbamate f carbamoyl (C 1 — C 4) alkyl or benzene (C 1 —C 4) alkyl (selected 4-ΏΤ 1 octyl substituted by carboxyl or (C 1 —C 4) fluorenyloxycarbonyl)} t or R 3 is hydrogen or — (C Η 2) q R 9 (where Q and R 9 are as defined above) »R 4 is hydrogen t (C 1 —C 4) alkyl or — C (0) R 1 4 (where R 1 4 is (C t -C 4) alkyl Oxygen R 5 is cyano > hydroxymethyl, 1 Η — tetrazol-5 —yl f 4, 5 —dihydroimidazol — 2 —yl — pyrrolidine — 1 —methylmethyl> pyridin — 1 —Methylmethyl t morpholine — 4 —methylmethyl> azine — 1 monomethyl * 4 — (C 1 — r- * Ο 4) alkylazine — 1 — methylmethyl t — C (0 ) R 1 4 (where R 1 4 is amine 1 hydroxy t (C 1 — C 4) alkyloxy t 2 — (_ —methylamino) ethylamino> 4 — methylpiperazine — 1 — Base 2 1 ((Please read the notes on the back before filling this page) This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 470741 A8 B8 C8 D8 ^ Ministry of Economic Affairs, Patent Application Scope Printed by the Intellectual Property Bureau Employee Cooperatives Co., Ltd. Agrodimethylamine) Ethylhydrosulfide 1 4 Monomethylsulfonamidoamino) Aniline, '1 — Η — Tetrazol — 5 — Aminoamine) f — C (N Η) NR 1 5 R 1 6 (where RI .5 and R 1 6 are independently hydrogen t (cl — C 4) fluorenyl or trifluoro (C Ϊ — C 4) alkyl) or — C Η 2 NR 1 0 R 1 7 Γ 1 where R 1 0 is hydrogen > (C ί — C 4) sulfanyl group * carbamate Try? Fu & (C 1 — C 4) alkoxycarbonyl J (C 1 — C 4) alkylaminocarbamate t bis (C 1 — C 4) alkylcarbamate amino group (C 1 — C 4) alkylamine> or Phenyl ns > < »Focky 9 Picolinamine 9 Smoke test _ amine and 2-furyl t or — C (NR i 1) N Η R 1 z (wherein R 1 1 and R 1 2 are alone,了 is hydrogen t ethenyl or tertiary butoxycarbonyl) 9 R 1 7 is hydrogen or (C \ — C 4) alkyl) ·-or R 3 is hydrogen or — (C Η 2) q R 3 (Wherein q and R 9 have the same definitions as above) > R 4 and R 5 are independently bis (CI — C 4) fluorenylaminomethyl) piperidine — 1 —methylmethylmorpholine — 4 —ylmethyl Or hydroxymethyl R 6 is hydrogen or Σ — carboxyethyl 7 R 7 is hydrogen> piperazine — 1 —methylmethyl> (c 1 — C 4) alkylazine — 1 — methylmethyl or — C Η 2 NR i 0 RL 7 (where R 1 0 is hydrogen or (C 1 —C 4) alkyloxycarbonyl 9 R i 7 is hydrogen) > R 8 is hydrogen or — N Η R 0 (where R ί 〇 is hydrogen or (C 1-C 4 \ alkyl) and pharmaceutically acceptable salts, individual isomers and their isomers Material mixture 0 -11- (Please read the precautions on the back before filling this page) This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) 470741 A8 B8 C8 D8 t, patent scope 3 * For example, the compound in the second scope of the patent application, wherein R 2 is the formula (a) * and is connected to the / 3 position. 4 · The compound according to item 3 of the patent application, wherein η is 0 or 1, RS is bis (C. 1-C 4) alkylaminomethyl, pyrrolidine-1 monomethyl, piperidine-1 1-ylmethyl, morpholine 4-ylmethyl, morphazine 1-ylmethyl, 4- (Ct-C4) alkyl # azine-1-ylmethyl or -C Η 2 NHR 1 0 〇 . (Please read the notes on the back before filling out this page) The compound in R is a chemical group of a methylamino group, a 4-amino group, a fan group, or a special group, such as an amino group, such as amine 5-methyl methyl urea. 1 is the item 5 of η which is compounded. Fan Fuli is a special one. R is requested to apply for the 6th range of the compound of I 7 and I 5 in every 6 2. Special fluorine please apply for printing 1 as R. Printed by the Consumers' Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, I, oxazolium, fluoroimide, R, dihydro, I, 7, I *, 3, 5, 1, 1, 1 } Item I, group 7, group 1 and group 2 and group 2 i. Specialty 5 The four things please apply for 4 chlorine Ruye, hydrogen * '3 ketone 8 group, thiomethylamine is 2 2 This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) 470741 A8 B8 C8 D8t, the scope of patent application 1 〇 · For the compound in the seventh scope of the patent application, in which R s is ureidomethyl, which is 5-ureidomethyl-1— (5,7—difluoro-1 , 2,3,4-tetrahydronaphthalene- 2-yl) _ 1, 3-dihydroimidazole-2 monothione. 11 • The compound of item 10 in the patent application park, which is (S) —5-ureidomethyl-1— (5,7—difluoro-1, 2, 3, 4—tetrahydronaphthalene—2 —Base) —1,3-dihydroimidazole—2-thione. 1 2 · The compound according to item 7 in the scope of patent application, wherein R 5 is ethenylaminomethyl, that is, N— [3 — (5,7 -difluoro-1,2,3,4-tetrahydro Naphthalene-2-yl) -2-thio-2,3-dihydro-1H-oxazole-4-ylmethyl] acetamidinium. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs) Naphthalene 4 S Hydrogen- 丨 Tetrazole Series | Miqi 4-,, Phenyl 3 1-H, I 2 H 2, Binomial 1-2 _ 3 1 Fluorine, No. Twenty-two Wai-I Fan 7 Daily, Sulfur. Special 5 I amine please ί 2 醯 Shen-I B such as 3 3 1. T radical 3 II A i N 2 the basic formula is 2 R of its compounded item 2 ο the range of the range point is conducive to the special invitation Continuous application such as'. Base 4) -—! B or ο is the item of its combination in Π 4 r-1 范范 nu 禾和 A special request such as 5 1 This paper size applies Chinese National Standard (CNS) A4 Specifications (210 X 297 mm) --------------------- Order --------- Line (Please read the precautions on the back before filling (This page) Printed by the Consumers ’Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 470741 A8 B8 C8 D8 ^, the scope of patent application 1, R7 is doxazine-1 monomethyl, 4- (C! — C4) alkylpiperazine-1 One methyl group or one CH2NHR10. 16 · The compound according to item 15 of the claims, wherein n is 1 and t is 2 and each R 1 is fluorine. 7. For example, the compound in the 16th scope of the patent application, wherein R 1 in the 5- and 7 positions is fluorine. 1 8 · The compound according to item 17 in the scope of patent application, in which R 6 is hydrogen and R 7 is aminomethyl, that is, 5-aminomethyl-4 4- (5,7-difluoro-1, 2, 3,4-tetrahydronaphthalene-2-yl) -2,4-dihydro [1,2,4] triazol-3-thione and pharmaceutically acceptable salts thereof 0 + 1 9 The compound of item 18, which is (S) -5 -aminomethyl- 4-(5,7 -difluoro-1,2,3,4-tetrahydronaphthalene-2 -yl) -2,4- Dihydro [1,2,4] triazol-3-thione hydrogenated compound. 2 0. The compound according to item 2 of the scope of patent application, wherein R 2 is a group of formula (c) and is attached to the / 3 position. -14- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) ------------- y ^ · -------- Order ·- ------ (Please read the precautions on the back before filling this page) 470741 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs A8 B8 C8 D8, patent application scope 2 1 * If the number of patent application scope item 20 A compound in which n is 0 or 1, and R 8 is an amine group. 22. The compound according to item 21 of the scope of patent application, wherein η is 1. or t is 2 and R 1 is fluorine. 23. The compound according to item 22 of the scope of patent application, wherein the ruler 1 at the 5- and 7-positions is fluorine, that is, 4-amino-2- (5,7-difluoro-1,2,3,4- Tetrahydrocaine 2-yl)-2 '4--. &Amp; [1,2,4] triazole-3-thizone. 2 4 · The compound according to item 23 of the scope of patent application, which is (S) -4 -amino- 2-(5,7-difluoro-1 '2,3,4-tetrahydronaphthalene-2- Radical) -2,4 -dihydro [1,2,4] triazole-3 -thithione. 2 5 * A pharmaceutical composition for treating a disease that can be improved by a drug that inhibits dobamin / 3-hydroxylase, and includes an effective therapeutic amount of a compound such as the first item in the scope of patent application. 26. A pharmaceutical composition for treating diseases that can be treated by a drug that inhibits dubaminglu-hydroxylase, including a therapeutically effective amount of a compound such as the third item of the patent application. -15- This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 public love) ^^ 1 nn I ί 1--ϋ I · 1 ^ 1 m It— t— II—-^ I nnmn Hi ^^ 1 I (Please read the precautions on the back before filling out this page) 470741 A8 B8 C8 D8 VI. Application for patent scope 2 7 · — A drug used to treat dubamin / 3 — hydroxylase can improve the disease A pharmaceutical composition comprising an effective therapeutic amount of a compound such as item 14 of the scope of patent application. 28. A pharmaceutical composition capable of improving a disease by treating a drug that inhibits dubamin / 3-hydroxylase, including an effective therapeutic amount of a compound such as the 20th item in the scope of patent application. 2 9 * The pharmaceutical composition according to any one of claims 25 to 28, wherein the disease is congestive heart disease. 3 0 * — A prodrug of a compound in the scope of patent application No. 1 which is a compound of formula II, ------------ I -------- order- --- ----- (Please read the notes on the back before filling this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs or,-~ 一〇 > is ot is η

II 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 470741 A8 B8 C8 D8 、申請專利範圍 R1個自獨立為鹵素，羥基或（C, —C4 )烷基氧基；和 (請先閱讀背面之注意事項再填寫本頁) R1 8被接於cr ，卢或7位置，且為選自式（d), (e )和（f )之基團：II This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) 470741 A8 B8 C8 D8, patent application scope R1 is independently halogen, hydroxyl or (C, —C4) alkyloxy; and (Please read the notes on the back before filling this page) R1 8 is connected to cr, Lu or 7 and is a group selected from formulas (d), (e) and (f):

Cd ) (e) R2「j為氫，R19為氫或一（CH2)qR3 (其中 Q 為〇，1 ，2，3或4，尺9為羧基，（C! — C4) 烷基氧基羰基，氨基甲醯或選自苯基+，吡啶基或噠嗪基（經濟部智慧財產局員工消費合作社印製該基圑選擇性再被一到二個獨立選自羥基，（C i - C 4 )烷基氧基，氰基，1 Η—四唑一 5 —基，狻基或（C1 一C4)烷基氧基羰基之取代基所取代）}，及R2 1為一 2 5 R 2 6 (其中R2 5為氫或（Ci — C4)烷基，R2 6為L 一丙氨醯，L —精氨醢，L—門冬醯，L — « —門冬氨醯，-門冬氨醢，L —半胱氨醯，L — 谷髓氧基，L~a —谷藤基，L 一 7 -谷藤基，N —( C.i — C 4 )烧藤基一L — ot —谷藤基，N — (Ci — C 4 -17- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 470741 A8 B8 C8 D8 t、申請專利範圍經濟部智慧財產局員工消費合作社印制衣 ) 烷藤基 — L — 7 一谷髓基 t 甘氨酸基 L — 組氨觸 » L — 異白氨 DSX m > L — 白氨 TT^-r 臨 t L — 賴氨醯 t L — 蛋氨醯 > L — 鳥氨醯基 t L — 苯基丙氨醯 L — 脯氨醯 > L — 絲氨藤 9 L — 蘇氨醢 1 L — 色氨醯， L — 賂氨釀 » L — 纈氨驢 f i — 胺基 — 環丙基羰基 > 1 — 胺基環丁基羰基 t 1 一胺基 rsa ί« 戊基羰基 ) 9 1 一胺基環己基羰基 ) ，或 R 2 〇和 R Ζ 1 均為氫 1 R X 9 為一 N R Z 5 R G ( 苴中 R Z 5 和 R Z 6 定義同上 ) > 或 R 2 X 為氫 * R 1 9 為氫或 ~ ( C Η 2 ) qR 9 (其中 q 和 R 9 定義同上 ) > R 2 0 為 — C Η 2 N R 2 5 R Z 6 ( 其中 R Z S 和 R 2 6 定義同上 ) t 或 R 1 9 為氫或 — ( C Η 2 ) q R 9 (其中q和R 9 定義同上、) t R Z 0 為氫 ( C 1 一 C 4 ) 烧基或 — C ( 0 ) R 1 4 ( 其中 R 1 4 為 ( C 1 — C 4 ) 烷基氧基 ) > R 2 1 為 — C Η 2 N R 2 5 R Z 6 ( 其中 R 2 S 和 R 2 6定義同上 ) $ R 2 2 為氫或 2 — 羧基乙基 R Z 3 為 — C Η 2 N R Z 5 R Z 6 ( 其中 R Z 5 和 R 2 定義同上 ) 和 R 2 4 為一 N R 2 5 R 2 6 ( 其中 R Z 5 和 R Z 6 定義同上 ) > 和藥學上可接受鹽 f 個別異構物和其異構物混合物。 _ 1 8 _ 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） ---------------------訂*-------- (請先閱讀背面之注意事項再填寫本頁) 470741 A8 B8 C8 D8 、申請專利範圍 3 1 ·如申請專利範圍第3 0項的前劑，其中R 1 8為式 (d )，且連接於/S位置。 3 2 *如申請專利範圍第3 1項的前劑，其中η為〇或1 ，每個 R1 為氟，R2 1 為一CH2 NHR2 6 〇 3 3 ·如申請專利範圍第3 2項的前劑，其中5 —和7 — 位置的R 1為氟，R 2 6為L —精氨醯基，L — 門冬氨醯基，L 一組氨醯基或L 一鳥氨醯基。 3 4 ·如申請專利範圍第3 3項的前劑，其中R 2 s為 L — α —門冬氨醯基，也就是3S —胺基一N— 〔3 —( 5 ，7 —二氟一1 ，2，3 ，4 —四氫萘一2 —基）一2 —硫代一 2 ，3 —二氫一1 Η —咪唑一 4 —基一甲基]琥珀醯肢酸和其藥學上可接受鹽。 3 5 ·如申請專利範圍第3 4項的前劑，其係3 S —胺基 -------------.裝·-------訂·-------- (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作杜印製蔡4 氫 I 四唑 _ 咪 4 _ ， Η 3 1 , I 2 氫I 二。 1 _ 物 I 3 化氟，氯二 2 氫 - _ 酸 7 代胺 , 硫醯 5 I 珀 ί 2 琥 - I ] 3 ) 基 t 基甲 I - I N 2 基 L _ 為4 6 ' I 2 唑 R 蹄中 -其 Η . 3 Ην /IV 劑前 -的 3 項 - 3 基 3 胺第 I 圍 S 範 2 利是專就請也申 ) 如基 ‘ 0 6 氨 3 組本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 470741 A8 B8 C8 D8 申請專利範圍 }醯基丙 -J 2 基 I I 蔡 1 氫 -四唑 - 咪 4 I , Η 0〇一—. I 1 2 氫 » 二。 1 I 鹽 ί 3 受 - ，接 3 2 可 [ _ 上 I 代學 Ν 硫藥 _ I 其 -— 2 和基-胺 7 3 3 劑 I 前Ν 的 -項 } 6 基 3 I 第4 圍 -範唑利眯專 -請Η 申 3 如 ί 基胺 - S 2 係其 3 2 氫二 I 3 2 ο _ 物代化硫氯 _ 氫 2 二 I 胺 } 醯基丙 _ rj S 基 2 -I 1 萘 I 氫唑四咪 - - 4 Η 8 I Ζ R 中 C 其 I ， Ν 劑一前基的胺項二 3 I 3 5 第，圍 S 範 2 利是專就請也申，如基 . 醯 8 氨 3 鳥 3 --------------Mi衣·— (請先閱讀背面之注意事項再填寫本頁) L 為 5 硫藥 1 其 2 和 - 胺 } 醯基戊 - J 2 基 I - 萘 4 氫 -四唑 _ 蹄 4 I , Η 3 1 » 1 2 氫 , 二。 1 I 鹽 I 3 受氟，接二 2 可 I I 上 7 代學線' 經濟部智慧財產局員工消費合作社印製範一利 3 專 t 請 - I J 申 N 2 基如 - - I . 基禁 4 9 胺氫 I 3 二四唑劑 I 前氣的二項 I 8 7 3 , 第 5 S 2係其 2 3 5 4 氫二 I 3 2 ο I 物代化硫氯 - 氫 2 二 _ 胺 )0 基戊眯 I Η 改利能專所請物申藥如的的酶量基數羥療 _ 治 θ. 效明有巴括度包制其抑，。療物劑治成前於組的用學項種藥 ο 一的 3 . 病第 ο 疾圍 4善範本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 470741 A8 B8 C8 D8 六、申請專利範圍改利能專所請物申藥如的的酶量基數羥療 I 治 ^.效明有巴括度包制其抑’ 療物治成。於組劑用學前種藥的 1 的項 • 病 4 -~~疾 3 4 善第改利能專所請物申藥如的的酶量基數羥療 - 治卢效明有巴括度包制其抑，。療物劑治成前於組的用學項種藥 6 j 的 3 . 病第 2 疾圍 4善範改利能專所請物申藥如的的酶量基數羥療 - 治卢效明有巴括度包制其抑，。療物劑治成前於組的用學項種藥 8 1 的 3 . 病第 3 疾圍 4 善範中項 3 ο 4病至臟 ο 心 4 性第血圍充範為利病專疾請該 Φ 中如其 4 物 4 成組學藥的項 ----I------------ (請先閱讀背面之注意事項再填寫本頁) 訂： •線經濟部智慧財產局員工消費合作社印製 5 式 4 下為係其劑前的物合化之項 1 第圍範利 ·· 專物請合申化種 ICd) (e) R2 "j is hydrogen, R19 is hydrogen or mono (CH2) qR3 (wherein Q is 0, 1, 2, 3 or 4, and Chi9 is carboxyl, (C!-C4) alkyloxycarbonyl Carbamate or selected from phenyl +, pyridyl, or pyridazinyl (printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, this base is optionally selected by one or two hydroxyl groups, (C i-C 4 ) Alkyloxy, cyano, 1'-tetrazol-5-yl, substituted with fluorenyl or (C1-C4) alkyloxycarbonyl)}, and R2 1 is 2 5 R 2 6 (Where R2 5 is hydrogen or (Ci — C4) alkyl, R2 6 is L-alanine, L—arginine, L—aspartam, L — «— aspartate,-aspartam , L — cysteine, L — glutamyl oxygen, L ~ a — glutenyl, L 7-glutinyl, N — (Ci — C 4) burnt vinel — L — ot — glutinyl, N — (Ci — C 4 -17- This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) 470741 A8 B8 C8 D8 t, patent application scope, printed by the consumer consumer cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, clothing printing) Fujimoto — L — 7 glutamate t glycine Acid group L — Histamine »L — Isoammonium DSX m > L — White ammonia TT ^ -r Pro t L — Lysine Lt L — Methionine> L — Ornithine t t L — Benzene Alanine L — Proline #> L — Serine 9L — Threonine 1 L — Tryptophan, L — Ammonia »L — Valine donkey fi — Amino group — Cyclopropylcarbonyl group> 1 — Aminocyclobutylcarbonyl t 1 monoamino rsa ί «pentylcarbonyl) 9 1 monoaminocyclohexylcarbonyl), or R 2 0 and R Z 1 are both hydrogen 1 RX 9 is a NRZ 5 RG (The definition of RZ 5 and RZ 6 in 苴 is the same as above) > or R 2 X is hydrogen * R 1 9 is hydrogen or ~ (C Η 2) qR 9 (where q and R 9 are defined as above) > R 2 0 is- C Η 2 NR 2 5 RZ 6 (where RZS and R 2 6 are as defined above) t or R 1 9 is hydrogen or — (C Η 2) q R 9 (where q and R 9 are as defined above) t RZ 0 is hydrogen (C 1 -C 4) alkyl or — C (0) R 1 4 (where R 1 4 is (C 1 —C 4) alkyloxy) > R 2 1 is — C Η 2 NR 2 5 RZ 6 (where R 2 S and R 2 6 have the same definitions as above) $ R 2 2 is hydrogen or 2 —carboxyethylethyl RZ 3 is — C Η 2 NRZ 5 RZ 6 (Wherein RZ 5 and R 2 have the same definitions as above) and R 2 4 is NR 2 5 R 2 6 (wherein RZ 5 and RZ 6 have the same definitions as above) > and pharmaceutically acceptable salts f individual isomers and their isomers mixture. _ 1 8 _ This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) --------------------- Order * ---- ---- (Please read the notes on the back before filling out this page) 470741 A8 B8 C8 D8, patent application scope 3 1 · If the prodrug of the 30th patent application scope, where R 1 8 is formula (d) And connected to the / S position. 3 2 * If the prodrug of item 31 of the patent application, where η is 0 or 1, each R1 is fluorine, and R2 1 is a CH2 NHR2 6 〇3. Where R 1 at the 5-and 7-positions is fluorine, R 2 6 is L-argininoyl, L-aspartyl, L is a group of amido or L-ornithino. 3 4 · The prodrug of item 33 in the scope of patent application, wherein R 2 s is L — α —aspartyl group, that is, 3S —amino group N — [3 — (5, 7 —difluoro 1 1,2,3,4-tetrahydronaphthalene- 2-yl)-2 -thio-2,3-dihydro- 1 Η -imidazole-4-yl-methyl] succinic acid and its pharmaceutically Accept salt. 3 5 · If the prodrug of item 34 of the scope of the application for a patent, it is 3 S —amino group -------------. ----- (Please read the notes on the back before filling out this page) Consumption cooperation between employees of the Intellectual Property Bureau of the Ministry of Economic Affairs Du printed Cai 4 Hydrogen I tetrazole _ Mi 4 _, Η 3 1, I 2 Hydrogen I 2. 1 _ I I Fluoride, chlorodi 2 hydrogen-_ acid 7 amine, thiazole 5 I Persyl 2 succinate-I] 3) t tylmethyl I-IN 2 group L _ is 4 6 'I 2 azole R 中中-其 Η. 3 Ην / IV agent before-3 items-3 bases 3 amines I I S S 2 2 (please also apply for special) (such as the base '0 6 ammonia 3 group This paper size applies to China Standard (CNS) A4 specification (210 X 297 mm) 470741 A8 B8 C8 D8 Patent application scope} Aromatic propane-J 2 radical II Tsai 1 Hydrogen-tetrazole-imid 4 I, Η 0〇一 —. I 1 2 Hydrogen »II. 1 I salt ί 3 accept-, then 3 2 can [_ I generation Ν thio drug _ I its--2 and base-amine 7 3 3 agent I before N-item} 6 base 3 I No. 4- Fanzolyl-Special-please apply 3 such as ylamine-S 2 is its 3 2 hydrogen di I 3 2 ο _ phytochemical sulfur chloride _ hydrogen 2 di I amine} fluorenyl propyl_ rj S group 2 -I 1 Naphthalene I Hydrozole tetraimide--4 Η 8 I Z R in C, its I, N agent one amine of the pre-group 2 3 I 3 5 first, encircle S Fan 2 please apply for it, such as the base.醯 8 Ammonia 3 Bird 3 -------------- Mi clothing · — (Please read the precautions on the back before filling this page) L is 5 Sulfur Medicine 1 Its 2 and-Amine} 醯Pentyl-J 2 radical I-naphthalene 4 hydrogen-tetrazolium_tetracycline 4 I, hydrazone 3 1 »1 2 hydrogen, two. 1 I salt I 3 is subject to fluorine, followed by 2 2 can be II on the 7th generation education line 'printed by Fan Yili, employee consumer cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, 3 special t please-IJ Shen N 2 Jiru--I. 9 Amine hydrogen I 3 Tetrazole agent I Binary I 8 7 3, 5 S 2 series 2 3 5 4 hydrogen di I 3 2 ο I thiosulfate-hydrogen 2 di_amine) 0 Benzyl pentoxide I Η Change the amount of enzymes in the application for drug application, such as the base of hydroxyl therapy _ treatment θ. The efficacy has a degree of restraint to limit its effect. The medicines used in the treatment group were used before the treatment. One of the three. The disease. The disease is good. The four good templates. The paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm). 470741 A8 B8 C8 D8 Sixth, the scope of application for patents has been changed to apply for the enzyme base of the drug application, such as hydroxyl therapy I treatment ^. Effectiveness has a degree of control to control its treatment. 1 item of pre-school medicine for group medications • Disease 4-~~ Disease 3 4 Enzyme-based enzymatic amount of hydroxytherapy applied by Shan Di Gai Li Neng Specialty Medicine-Zhilu Xiaoming has a degree of restraint to limit its effect . The therapeutic agent was used to treat the group of drugs 6 j 3 before the treatment of the disease. The second disease, the second disease, the fourth, and the energy can be applied to the application of the drug, such as hydroxytherapy-Zhilu Xiaoming Contain its suppression,. The therapeutic agent is used to treat the group of medicines used before the group of medicines 8 1 of 3. The disease is the 3rd disease and the 4th is good. The middle item is 3 ο 4 is the disease to the viscera. Φ Items such as 4 things and 4 groups of medicines ---- I ------------ (Please read the notes on the back before filling this page) Order: • Intellectual Property of the Ministry of Economics Printed by the Bureau's Consumer Cooperatives 5 Formula 4 The item below is the combination of chemical substances before its agent

11 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 470741 A8 B8 C8 D8 ^、申請專利範圍其中： (請先閱讀背面之注意事項再填寫本頁) η為0 ，1或2 ; t 為 Ο ，1 ，2 或 3 ; 個自獨立為鹵素，羥基或（C! — C4 )烷基氧基；和 R 2 7被接於α ，/3或7位置，且為選自式（g )， (h )和（i )之基團： SRa I SRa 1 SRa S N S N 丫 1 V R3 R7 八 (?) U) (: R4為氫，Rs為氫或一NH2 ，或（Ci - C 4 ) 烷_基；或經濟部智慧財產局員工消費合作杜印制农 R 5為氫，R 4為（C t — C4 )烷基’二（Ci — C4 )烷基胺基甲基，甲醯基， 1—羥基（Ci - C 4 )烷基或—CHz N H R 1 3 (其中R13為氫，（C! —C4 )烷基，羧基（Ci — C4 )烷基，氨基甲醢，氨基甲醯（Ci — C4 )烷基或苯基 -22- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 470741 AS B8 C8 D8 t、申請專利範圍經濟部智慧財產局員工消費合作社印制机 ( C 1 — C 4 ) 烷基 ( 選擇性再被羧基或 ( C 1 一 C 4 ) 烷基氧基氨基甲藤取代 ) } > 或 R 4 為氫 ( C 1 — C 4 ) 烧基或 — C ( 0 ) R ί 4 ( 其中 R 1 4 為 ( C 1 — C 4 ) 烷基氧基 ) ， R 5 為氰基 t 羥基甲基 > 1 Η — 四唑 — 5 — 基 t 4 9 5 — 二氫眯唑 — 2 — 基 t 吡喀烷 — 1 — 基甲基顿啶 — 1 — 基甲基嗎啉 — 4 — 基甲基，嗪一 1 — 基甲基 > 4 — ( C 1 — C 4 ) 甲基嗪 — 1 — 基甲基 t — C ( 0 ) R 1 4 ( 其中 R 1 4 為胺基 9 羥基 9 ( C 1 — C 4 ) 烧基氧基 t 2 — ( 二甲基胺基 ) 乙基胺基 ) 4 — 甲基哌嗪 — 1 — 基， 2 — ( 二甲基胺基 ) 乙基氫硫 > 4 — ( 甲基磺醢基胺基 ) 苯胺基 1 1 Η — 四唑 — 5 — 基胺基 ) f — C (N Η ) Ν R 1 5 R 1 6 ( 其中 R i S 和 R 1 6 個白獨立為氫 5 ( C 1 — C 4 ) 烷基或 ___- 氟 ( C t — C 4 ) 综基 ) 或 — C Η Ζ N R 1 0 R i 7 ( 其中 R L 0 為氫 7 ( C 1 — C 4 ) 焼基 * 氨基甲 m ( C 1 — C 4 ) 基氧基羰基 » ( C 1 — C 4 ) 院基氨基甲醢，二 ( C 1 — C 4 ) 烷基氛基甲 1C* 釅 9 胺基 ( C 1 — C ) 燒醯基 * 或選 g 苯醯基 » 皮考林醯胺 > 於鹼 m 胺和 2 — 呋 n?A 觸基 S 或 — C ( N R 1 I ) N Η R 1 Ζ ( 其中 R 1 i 和 R i Z 獨立為氫乙醯基或三級丁氧基羰基 ) > R 1 7 為氫或 ( C 1 — C 4 ) 烷基 ) } > 或 R 4 和 R 5 獨為二 ( C 1 — C 4 ) 烷基胺基乙基，哌啶 — 1 — 基甲基 > 嗎啉 — 4 一基甲基或羥基甲基 > -23- ---------------------訂·-------- (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS)A4规格（210 X 297公釐）經濟部智慧財產局員工消費合作社印製 470741 A8 B8 C8 D8 六、申請專利範圍 Rv為氫，顿嗪一1_基甲基，（Ct — C4 )烷基咪嗪一 1 一基甲基或一 (其中R1 為氫或（C ! — C 4 )烷基氧基羰基，R 1 7為氫）：和 R 2 8為（c 2 - C 6 )烷基{該烷基再被一到二個獨立選自一 N ( R 2 9 ) 2 ，一 C ( 0 ) 0 R 3 〇 (其中每個R 2 3獨立為氫，乙醯基或三氟乙醯基，R 3 °為氫或(C r C 5 )烷基）的取代基所取代};和藥學上可接受鹽，個別異構物和其異構物混合物。 46 ·如申請專利範圍第45項的前劑，其中R2 7為式 (g )，且連接於/3位置。 47 «如申請專利範圍第46項的前劑，其中η為0或1 ，1:為2，每個1^1為氟。 4 8 ·如申請專利範圍第4 7項的前劑，其中5 —和7 — 位置的R 1為氟。 49 ·如申請專利範圍第48項的前劑，其中R2 3為選自乙基，1 ， 1一二甲基乙基和丙（該基進一步被一到二個取代基取代，該取代基係選自羧基，甲氧基羰基，胺基和三氟乙醯基胺基）。 -24- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） ---------------------訂·-------- (請先閱讀背面之注意事項再填寫本頁) 470741 A8 B8 C8 D8 申請專利範圍 ο 5 R 為 2 S 1 R R 中丨其 ’ ’ 基劑乙前基的羰項 I 9 基 4氧第甲圍 -範 2 利 I 專基請胺申 I 如 2 基胺 1 I 基 2 3 0 - I 乙 } 基氟 S 胺三 { I - ， 3 2 基或 1 乙基 } 基乙 R 胺基 ( I 甲 , 2 二基， -乙基 1 基乙，羧基 1 -羰 I 。 2 基基基一氧羧 I 基甲 I 1 胺 - 2 I 2 - 丙基基胺羧改利能專所請物申藥如的的酶量基數羥療 i 治 β 效明有巴括度包制其抑， ο 療物劑治成前於組的用學項種藥 5 1 的4 . 病第 1 疾圍 5 善範疾該中其物成組學藥的項 1—! 5 第圍範。利病專臟請心申性如血 . 充 2 為病 3 5 法方的劑前其或物合化 I 式備製種 --------------裝— (請先閱讀背面之注意事項再填寫本頁) 訂：線經濟部智慧財產局員工消費合作社印製中其11 This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) 470741 A8 B8 C8 D8 ^, patent application scope Among them: (Please read the precautions on the back before filling this page) η is 0, 1 Or 2; t is 0, 1, 2, or 3; each is independently halogen, hydroxyl, or (C! — C4) alkyloxy; and R 2 7 is attached to the α, / 3, or 7 position, and is optional Groups of formula (g), (h) and (i): SRa I SRa 1 SRa SNSN ya 1 V R3 R7 eight (?) U) (: R4 is hydrogen, Rs is hydrogen or -NH2, or (Ci -C 4) Alkyl; or consumer cooperation of the Intellectual Property Bureau of the Ministry of Economic Affairs, Du Yin Nong R 5 is hydrogen, R 4 is (C t — C4) alkyl′di (Ci — C4) alkylaminomethyl , Methylamino, 1-hydroxy (Ci-C4) alkyl or -CHz NHR 1 3 (where R13 is hydrogen, (C! -C4) alkyl, carboxy (Ci-C4) alkyl, carbamate, Carbamate (Ci — C4) alkyl or phenyl-22- This paper size is applicable to the Chinese National Standard (CNS) A4 (210 X 297 mm) 470741 AS B8 C8 D8 t. Member of the Intellectual Property Bureau of the Ministry of Economic Affairs Consumer Cooperative Printing Machine (C 1-C 4) Alkyl (optionally replaced by carboxyl or (C 1 -C 4) Alkyloxycarbamate)} > or R 4 is hydrogen (C 1 — C 4 ) Alkyl or — C (0) R ί 4 (where R 1 4 is (C 1 —C 4) alkyloxy), R 5 is cyano t hydroxymethyl> 1 Η — tetrazole — 5 — T 4 9 5 —dihydrooxazole — 2 —yl t-pyrrolidine — 1 —methylmethylpyridine — 1 —methylmethylmorpholine — 4 —ylmethyl, azine 1 —ylmethyl> 4 — (C 1 — C 4) methylazine — 1 —ylmethyl t — C (0) R 1 4 (where R 1 4 is amine 9 hydroxy 9 (C 1 — C 4) alkoxyl t 2- (dimethylamino) ethylamino) 4-methylpiperazine-1-yl, 2- (dimethylamino) ethylhydrosulfide> 4-((methylsulfonamido) amino ) Anilino 1 1 Η — tetrazol — 5 —ylamino) f — C (N Η) NR 1 5 R 1 6 (where R i S and R 1 6 are independent Hydrogen 5 (C 1 — C 4) alkyl or ___- fluoro (C t — C 4) heptyl) or — C Η Zn NR 1 0 R i 7 (where RL 0 is hydrogen 7 (C 1 — C 4 ) Fluorenyl * carbamyl m (C 1 — C 4) oxyoxycarbonyl »(C 1 — C 4) alkylcarbamidine, bis (C 1 — C 4) alkylaminomethyl 1C * 酽 9 amine (C 1 — C) sulfanyl group * or g benzyl group »picolinyl amine> base amine and 2 -furfurn? A contact group S or — C (NR 1 I) N Η R 1 Zn (wherein R 1 i and R i Z are independently hydrogenethenyl or tertiary butoxycarbonyl) > R 1 7 is hydrogen or (C 1-C 4) alkyl)} > or R 4 and R 5 is exclusively di (C 1 —C 4) alkylaminoethyl, piperidine — 1 —ylmethyl> morpholine — 4 monomethyl or hydroxymethyl> -23- ---- ----------------- Order · -------- (Please read the precautions on the back before filling out this page) This paper size applies to Chinese National Standards (CNS) A4 size (210 X 297 mm) Employees of Intellectual Property Bureau, Ministry of Economic Affairs Printed by Fei Cooperative 470741 A8 B8 C8 D8 6. The scope of the patent application is hydrogen, donazine-1-methyl, (Ct-C4) alkylimidazine- 1-methyl or 1 (where R1 is (C! — C 4) alkyloxycarbonyl, R 1 7 is hydrogen): and R 2 8 is (c 2 -C 6) alkyl {The alkyl group is independently selected from one to two N ( R 2 9) 2, one C (0) 0 R 3 〇 (wherein each R 2 3 is independently hydrogen, ethylfluorenyl or trifluoroethylfluorenyl, and R 3 ° is hydrogen or (C r C 5) alkyl ); And pharmaceutically acceptable salts, individual isomers and mixtures of isomers thereof. 46. The prodrug according to item 45 of the patent application, wherein R2 7 is of formula (g) and is connected to the / 3 position. 47 «The prodrug of item 46 of the patent application, wherein η is 0 or 1, 1: is 2, each 1 ^ 1 is fluorine. 4 8 · The prodrug according to item 47 of the patent application, wherein R 1 at the 5-and 7-positions is fluorine. 49. The prodrug of item 48 in the scope of patent application, wherein R 2 3 is selected from ethyl, 1, 1, dimethyl ethyl and propyl (the group is further substituted with one or two substituents, and the substituent is Selected from carboxyl, methoxycarbonyl, amine and trifluoroacetamido). -24- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) --------------------- Order · ----- --- (Please read the precautions on the back before filling this page) 470741 A8 B8 C8 D8 Patent application scope 5 R is 2 s 1 RR 丨 its '' carbonyl item of the ethyl before group I 9 group 4 oxygen Section A-Fan 2 Li I Specialist please amine application I such as 2 base amine 1 I group 2 3 0-I B} fluoro fluoride S amine tri {I-, 3 2 group or 1 ethyl} group ethyl R amino group (I methyl, 2 diyl, -ethyl 1 ethyl ethyl, carboxyl 1-carbonyl I. 2 yl monooxy carboxyl I methyl 1 1 amine-2 I 2-propyl amine The application of the drug is based on the amount of enzymes in the base of hydroxyl therapy. The treatment of β has the effect of enclosing its inhibitory effect. Ο The therapeutic agent is treated with the group of medicines 5 1 4 before the disease. 5 Good Fan Diseases The items in the group of medicines 1—! 5 No. 5 Fan Wei. Special diseases, please apply heartily like blood. Fill 2 for the disease 3 5 before the prescription of the medicine or its combination I prepared Species -------------- install-(please read first Note to fill out the back of this page) book: line Ministry of Economic Affairs Intellectual Property Office employees consumer cooperatives in its printed

I 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 470741 ABCD 申請專利範圍 η為0 ，1或2 ; t,為 Ο ，1 ，2 或 3 ; R1個自獨立為鹵素，羥基或（C 基；和 C 4 )烷基氧 R 2被接於《，/6或7位置，且為選自式（ (b )和（C )之基團： V \ Μ // / Λ· (請先閱讀背面之注意事項再填寫本頁) ：a ) c ) 經濟部智慧財產局員工消費合作社印制衣其中： R4為氫，R3為氫或— （CH2 ) qR 9 (其中Cl為〇，1，2，3或4，尺9為羧基，（Ci— C4)烷基氧基羰基，氨基甲藤或選自苯基，姐嗤基或_嗪基（該基團選擇性再被一到二個獨立選自羥基，（C ! — C 4 )烷基氧基，氰基，1H-四唑-5 —基，羧基或（Ci — C4 烷基氧基羰基之取代基所取代）} ，R s為一Ν Η 2 ;或 R4和R5均為氫，R3為一NHR10 (其中Ri〇為氫或（C! 一C4)烷醯基）；或 R 3為氫，R 3為氫或一（c Η 2 ) q R 9 (其中Q -26- 本紙張尺度適用中國國家標準（CNS)A4規格（210 χ 297公釐) 470741 A8 B8 C8 D8 六、申請專利範圍經濟部智慧財產局員工消費合作社印製和 R g 定義同上 ) R 4 — C 4 \ 烷基胺基甲基 \ 院基或 — C Η 2 N Η R — C 4 ) 基 9 羧基 ( C 基甲釀 ( C 1 — C 4 ) 烷 (選擇性被羧基或 ( C 1 t 或 R 3 為氫或 — ( C Η 同上 ) 1 R 4 為氫 > ( C R 1 4 ( 其中 R X 4 為 ( 氟基 t 羥基甲基 1 Η — 唑 — 2 — 基，吡咯燒 — 1 嗎啉 — 4 — 基甲基 > 顿嗪 C 4 ) 垸基哌嗪 — 1 — 基 R 1 4 為胺基 t 羥基 y ( 二甲基胺基 ) 乙基胺基 1 二甲基胺基 ) 乙基氫硫 t — Η — 四唑 — 5 — 基胺基 ( 其中 R 1 5 和 R 1 β 個基或三氟 ( C I - C 4 ) r 1 其中 R 1 0 為氫 ( C ( C Ϊ — C 4 ) 烷基氧基甲醯 > 一 ( C I — C 4 ) 為（Ct —C4 )烷基，二（C! 甲_基，1—羥基（Ct - C4 1 3 {其中R13為氫，（Ci t — C4 )烷基，氨基甲醯，氨基或苯基（Ci - C 4 )烷基一c4 )烷基氧基羰基取代）） 2 ) q R 9 (其中Q和R9定義 1— C4)烷基或—C(O) Ci — C4 )烷基氧基，Rs為四唑一5 —基，4，5 —二氫咪 —基甲基，顿啶一1 —基甲基， —1—基甲基，4 — (Ci — 甲基，一C(〇)R14 (其中 C! -C4 )烷基氧基，2 - （ 4-甲基#嗪一 1—基，2 —( 4_甲基磺_基胺基）苯胺基，1 )>-C (NH) NR15 R16 自獨立為氫，（C t — C 4 )烷烷基）或一CH2 NR1 0 R1 7 t — C 4 )烷醯基，氨基甲醯，羰基，（C — C 4 )烷基氨基烷基氨基甲醯，胺基（Ci - C4 -27- X 297公釐〉— (請先閱讀背面之注意事項再填寫本頁) 國國家標準（CNS) A4規格（210 470741 A8 B8 C8 D8 ^、申請專利範圍 )烷醯基，或選自苯蘸基，皮考林醯胺，菸鹼醯胺和2-呋醯基，或一C (NR1 1 ) NHR12 (其中R1 1和 R 1 2獨立為氫，乙醯基或三級丁氧基羰基），R 1 7為氫或（C t _ C 4 )烷基）}:或 V/ R 3為氫或一（C Η 2 ) q R 9 (其中q和R 3定義同上），R 4和R 5個自獨立為二（C 1 — C 4 )烷基胺基甲基，哌啶一1 —基甲基，嗎啉一4 —基甲基或羥基甲基； R6為氫或2 —羧基乙基； R7為氫，#嗪-1—基甲基，（Ct -C4 )烷基 a||嗪一 1 一基甲基或一CHz NR1 ° R1 7 (其中R1 c 為氫或（Ci — C4 )烷基氧基羰基，R1 7為氫）； R8為氫或—NHR1 ° (其中R1 °為氫或（C! —C4 )烷醯基）；和藥學上可接受鹽，画別異構物和其異構物混合物；該方法包括： (a )使下式3化合物 I ---I I I I I — III . I I I ----« — Ι — illil (請先閱讀背面之注意事項再填寓本頁) 經濟部智慧財產局員工消費合作社印製I This paper size is applicable to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 470741 ABCD. The scope of patent application η is 0, 1 or 2; t, 0, 1, 2, or 3; R1 is independently halogen , A hydroxyl group or (C group; and C 4) alkyloxy R 2 is attached to the ", / 6 or 7 position, and is a group selected from the formulas ((b) and (C): V \ M // / Λ · (Please read the precautions on the back before filling this page): a) c) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs where R4 is hydrogen, R3 is hydrogen or — (CH2) qR 9 (where Cl It is 0, 1, 2, 3 or 4, and Chi9 is a carboxyl group, (Ci-C4) alkyloxycarbonyl, carbamotyl or selected from phenyl, hydrazone or _azinyl (this group is One or two independently selected from hydroxy, (C! -C4) alkyloxy, cyano, 1H-tetrazol-5-yl, carboxyl or (Ci-C4 alkyloxycarbonyl substituted with a substituent) }, R s is an N Η 2; or R4 and R5 are both hydrogen, R3 is an NHR10 (where Ri0 is hydrogen or (C! -C4) alkylfluorenyl); or R 3 is hydrogen and R 3 is hydrogen Or one (c Η 2) q R 9 (where Q -26- the paper rule Applicable to China National Standard (CNS) A4 specification (210 χ 297 mm) 470741 A8 B8 C8 D8 VI. Application scope of patents Printed by the Intellectual Property Bureau of the Ministry of Economic Affairs and printed by the Consumer Cooperatives and the same definition of Rg) R 4 — C 4 Aminoaminomethyl \ radixyl or — C Η 2 N Η R — C 4) 9 carboxyl (C methyl alcohol (C 1-C 4) alkane (optionally by carboxyl or (C 1 t or R 3 as Hydrogen or — (C Η ibid.) 1 R 4 is hydrogen> (CR 1 4 (where RX 4 is (fluoro t hydroxymethyl 1 Η — azole — 2 —yl, pyrrolidin — 1 morpholine — 4 —yl Methyl > donazine C 4) fluorenylpiperazine — 1 — group R 1 4 is amine t hydroxy y (dimethylamino) ethylamino 1 dimethylamino) ethyl hydrogen sulfur t — Η — tetrazol — 5 —ylamino (where R 1 5 and R 1 β groups or trifluoro (CI-C 4) r 1 where R 1 0 is hydrogen (C (C Ϊ — C 4) alkyloxy Methylformamidine> mono (CI —C 4) is (Ct —C4) alkyl, di (C! Methyl_, 1-hydroxyl ( Ct-C4 1 3 {where R13 is hydrogen, (Ci t — C4) alkyl, carbamate, amino or phenyl (Ci-C 4) alkyl-c4) alkyloxycarbonyl substituted)) 2) q R 9 (wherein Q and R 9 define 1—C4) alkyl or —C (O) Ci—C4) alkyloxy, Rs is tetrazol-5-yl, 4,5-dihydroimidyl-methyl, Pentimidine-l-ylmethyl, —1-ylmethyl, 4- (Ci-methyl, mono-C (〇) R14 (where C! -C4) alkyloxy, 2- (4-methyl # Azine-1-yl, 2- (4-methylsulfonylamino) aniline, 1) > -C (NH) NR15 R16 is independently hydrogen, (Ct-C4) alkylalkyl) or -CH2 NR1 0 R1 7 t — C 4) alkylamido, carbamate, carbonyl, (C — C 4) alkylaminoalkylcarbamoamide, amino (Ci-C4 -27- X 297 mm> — (Please read the precautions on the back before filling out this page) National Standard (CNS) A4 Specification (210 470741 A8 B8 C8 D8 ^, patent application scope) Alkyl, or selected from benzene diphenyl, picolin Amine, nicotinamide and 2-furanyl, or mono-C (NR1 1) NHR12 (wherein R1 1 and R 1 2 are independently hydrogen and ethenyl Tertiary butoxycarbonyl), R 1 7 is hydrogen or (C t _ C 4) alkyl)}: or V / R 3 is hydrogen or one (C Η 2) q R 9 (wherein q and R 3 are defined Same as above), R 4 and R 5 are independently bis (C 1 -C 4) alkylaminomethyl, piperidine-1-ylmethyl, morpholine-4-ylmethyl or hydroxymethyl; R6 Is hydrogen or 2-carboxyethyl; R7 is hydrogen, # azine-1-ylmethyl, (Ct -C4) alkyl a || azine- 1 monomethyl or CHz NR1 ° R1 7 (where R1 c Is hydrogen or (Ci — C4) alkyloxycarbonyl, and R1 7 is hydrogen); R8 is hydrogen or —NHR1 ° (where R1 ° is hydrogen or (C! —C4) alkylfluorenyl); and pharmaceutically acceptable Salt, isomeric isomers and mixtures of isomers thereof; the method includes: (a) using the compound of formula 3 I --- IIIII — III. III ---- «— Ι — illil (please read the (Notes are included on this page) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs

-28- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐〉 470741 A8 B8 C8 D8 f、申請專利範圍其中每個η ，t和R 1定義同M上的式I ，與二烷基氧基乙醛在一化學遷原劑存在下或觸媒氫化中反應，然後用硫氰酸處理，製得式I中R2為式（a)基中R3 ，R4和 R 5均為氫的化合物；或 (b )使式3化合物或其酸加成鹽（其中每個η ，t和 R 1定義同K上的式I )與硫氰酸和二羥基丙嗣反應，接著選擇性用硫酸處理反應混合物，製得式I中R 3和R 4 為氫，R 5為羥基甲基的化合物；或 (c )使式5化合物 (請先閱讀背面之注意事項再填寫本頁)-28- This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) 470741 A8 B8 C8 D8 f. The scope of patent application where each η, t and R 1 are defined as Formula I on M, and The dialkyloxyacetaldehyde is reacted in the presence of a chemical migrating agent or in the catalytic hydrogenation, and then treated with thiocyanate to obtain R2 in formula I is R3 in the group of formula (a), and R4 and R5 are both A compound of hydrogen; or (b) reacting a compound of formula 3 or an acid addition salt thereof (wherein each η, t and R 1 are defined as formula I on K) with thiocyanic acid and dihydroxypropane, followed by selectivity Treat the reaction mixture with sulfuric acid to prepare compounds of formula I in which R 3 and R 4 are hydrogen and R 5 is hydroxymethyl; or (c) make a compound of formula 5 (please read the precautions on the back before filling this page)

5 />. 經濟部智慧財產局員工消費合作社印製其中每個η ，t和R1定義同Μ上的式I ，與1 ，2 ，4 一***一4 一基胺基反應，然後硫化而製得式I中R2為式（c )(其中R 3為胺基）的化合物；或 d )使式7化合物5 / >. Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, where each η, t and R1 are defined with the formula I on M, reacted with 1, 2, 4, 4-triazole-4 4-aminoamine groups, and then vulcanized And a compound of formula I in which R2 is formula (c) (wherein R3 is an amine group) is prepared; or d) a compound of formula 7

7 -2 9- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 470741 A8 B8 C8 D8 τ、申請專利範圍其中每涸η ，t和R 1定義同Κ上的式I ，與2 ，2 ，一二垸基氧基乙基胺在一化學還原劑化中或者觸媒氫化中反應，然後用硫氰酸處理，製得式I中R 2為式（a )(其中R 3 ，R 4和R 5為氫）的化合物；或 e )使式9化合物 (請先閱讀背面之注意事項再填寫本頁)7 -2 9- The size of this paper is applicable to Chinese National Standard (CNS) A4 (210 X 297 mm) 470741 A8 B8 C8 D8 τ, the scope of patent application where each 涸 η, t and R 1 are defined as the formula I on K , And react with 2, 2, 1-dioxoyloxyethylamine in a chemical reducing agent or catalytic hydrogenation, and then treated with thiocyanic acid to obtain R 2 in formula I of formula (a) (where R 3, R 4 and R 5 are hydrogen); or e) make the compound of formula 9 (please read the precautions on the back before filling this page)

經濟部智慧財產局員工消費合作社印*'双其中每個η ，t和R 1定義同K上的式I ，與2 ，2 —二烷基氧基乙基胺反應，然後用酸處理，製得式I中R 2為式（a)(其中R3 ，R4和rs為氫）的化合物；或 (f )使式9與胺基乙腈氫氯化物反應，然後用鹼處理，製得式I中R2為式（a)(其中R3和R4為氫，rs 為胺基）的化合物；或 (g )使式9化合物與D — ( + )—葡萄胺反應，然後氧化，製得式I中R 2為式（a )中R 3和R s為氫，r 4 為甲醢基的化合物；或 (h )使式9化合物與式Η 2 N Η N C ( Ο ) R 3 4 (其 -30- 本紙張尺度適用中國國家標準（CNS)A4規格（210 χ 297公釐）經濟部智慧財產局員工消費合作社印刹衣 470741 A8 B8 C8 D8 f、申請專利範圍中R.3 4為氫，胺基甲基，哌嗪一1 一基甲基或4 — ( C t —C 4 )烷基#嗪—1 —基甲基）的化合物或其保護衍生物反應，然後用鹼處理，視需要去保護，製得式I中R 2 為式（b )(其中R 6為氫，R 7為氳，胺基甲基，b浓嗪 —1 一基甲基或4 一（C〖一C4 )烷基锨嗪一1—基甲基的化合物；或 (1 )使式1 1的化合物The consumer cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs of the People's Republic of China, each of η, t and R 1 is defined as the formula I on K, reacted with 2,2-dialkyloxyethylamine, and then treated with acid to produce Compounds of formula I in which R 2 is formula (a) (wherein R 3, R 4 and rs are hydrogen) are obtained; or (f) reacting formula 9 with aminoacetonitrile hydrochloride and then treating with base to obtain formula I R2 is a compound of formula (a) (wherein R3 and R4 are hydrogen and rs is an amine group); or (g) a compound of formula 9 is reacted with D — (+) -grapeamine and then oxidized to obtain R in formula I 2 is a compound of formula (a) in which R 3 and R s are hydrogen, and r 4 is methylamidino; or (h) a compound of formula 9 and formula Η 2 N Η NC (〇) R 3 4 (whose -30- This paper size is in accordance with Chinese National Standard (CNS) A4 (210 χ 297 mm). The employee's consumer cooperative of India ’s Intellectual Property Bureau 470741 A8 B8 C8 D8 f. In the scope of the patent application, R.34 is hydrogen and amine Methyl, piperazine-l-methyl or 4- (Ct-C4) alkyl # azin-1-ylmethyl) compounds or their protected derivatives are reacted, then treated with a base and deprotected if necessary ,system In formula I, R 2 is formula (b) (wherein R 6 is hydrogen, R 7 is fluorene, aminomethyl, b concentrated azine-1 monomethyl or 4- (C 〖-C4) alkyl oxazine- A 1-methylmethyl compound; or (1) a compound of formula 1 1

其中每個η ，t和R 1 ，R 4和R s定義同Μ上的式I ，與一強鹼反應，然後硫化，製得式I中R 3為氫的化合物 :或 (J)使式1 1中每個n，t «R1 ，R4和R5定義同 Μ上的式I與式L — ( C Η 2 ) qR 9 (其中L為一離去基，每個q和R 9定義同式I )反應，然後硫化，製得式I 中R 2為式（a )(其中R 3為一（C Η 2 ) qR 9 )的化合物；或 (k )使式1 1中R 4和R 5為氫，每個^ ，t和R 1定義同Μ上的式I的化合物與胺基芳基磺酸鹽或烷基磺酸鹽 -3 1- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） --------訂 ---I ------ (請先閱讀背面之注意事項再填寫本頁) 470741 A8 B8 C8 D8 t、申請專利範圍反應，製得式I中R2為式（a)(其中R3為胺基）的化合物；或 (1 )用適當的N ，N —二取代甲撐銨鹽烷基化式1 1中 R 4和R 5為氫，每個η ，t和R Α定義同以上的式I的化合物，然後硫化，製得式I中R 2為式（a )(其中R s為二（Ci — C4 )烷基胺基甲基，喊啶一1-基甲基或嗎琳一4 —基甲基的化合物；或 (m )使式1 6化合物 (請先閱讀背面之注意事項再填寫本頁)Wherein each η, t and R 1, R 4 and R s are defined as the formula I on M, reacted with a strong base, and then vulcanized to obtain a compound of formula I in which R 3 is hydrogen: or (J) make the formula Each n, t «R1, R4, and R5 in 1 1 is defined as Formula I and Formula L — (C Η 2) qR 9 (where L is a leaving group, and each q and R 9 define the same formula I) react and then vulcanize to obtain a compound of formula I wherein R 2 is formula (a) (wherein R 3 is mono (C Η 2) qR 9); or (k) such that R 4 and R 5 in formula 1 1 Is hydrogen, each ^, t and R 1 are the same as those of the compound of formula I and amine aryl sulfonate or alkyl sulfonate on M. 3 1- This paper size applies to China National Standard (CNS) A4 specifications (210 X 297 mm) -------- Order --- I ------ (Please read the notes on the back before filling this page) 470741 A8 B8 C8 D8 To obtain a compound of formula I in which R2 is formula (a) (wherein R3 is an amine group); or (1) R 4 and R in formula 1 1 are alkylated with an appropriate N, N-disubstituted methylammonium salt 5 is hydrogen, and each of η, t and R A is defined as the compound of formula I above, and then vulcanized to obtain R 2 in formula I as formula (a) (Wherein R s is a di (Ci-C4) alkylaminomethyl group, a compound of 1-ylmethyl group or morphine 4-ylmethyl group; or (m) a compound of formula 16 (please first (Read the notes on the back and fill out this page)

經濟部智慧財產局員工消費合作社印制衣其中R3 2為氰基或（C! —C4 )烷基氧基羰基，每個 η ，t和R 1定義同Κ上的式I ，與式R 3 3 c ( 0 ) L 化合物反應，然後用硫氰酸處理，製得式I中R 2為式（ a )(其中R3為氫，Rs為氰基或（C! -C4 )烷基氧基羰基，R4為氫，（Ct — C4 )烷基氧基羰基或（ C ! — C 4 )烷基的化合物；或 (η )使式2 4化合物 -32- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 470741 A8 B8 C8 D8 六、申請專利範圍Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, where R3 2 is cyano or (C! —C4) alkyloxycarbonyl, and each η, t, and R 1 are defined as Formula I on K and Formula R 3 The 3 c (0) L compound is reacted and then treated with thiocyanate to obtain R 2 in formula I of formula (a) (where R 3 is hydrogen and Rs is cyano or (C! -C4) alkyloxycarbonyl). , R4 is hydrogen, (Ct — C4) alkyloxycarbonyl or (C! — C 4) alkyl compounds; or (η) makes the compound of formula 2 4 -32- This paper applies the Chinese National Standard (CNS) A4 specifications (210 X 297 mm) 470741 A8 B8 C8 D8 6. Scope of patent application

CIO 24 經濟部智慧財產局員工消費合作社印製後用 )的 (〇 )R 中R )烷 (C 燒基水解鹽； (P 得式 t和Ri定義同Μ上的式I ，與異硫氟酸鹽反應，然鹼處理，製得式I中R 2為式（c )(其中R _3為氫化合物；或 )使式I中R 5為羥基甲基的化合物與式Η 2 Ν (0 3 1的化合物或式ΜΗ4 + ~ 0 C (0) R s 1 (其為氫 C C )烷基或三氟（C! — C 基）的銨鹽反應，製得式I中R5為甲醯胺基甲基 —C 4 烷基羰基胺基甲基或三氟（Ci —c4 羰基胺基甲基的化合物，該化合物可另外選擇性地被成式I中R3和R4為氫，R5為胺基甲基的酸加成或 )使式ί中R s為羥基甲基的化合物與尿素反應，製 I中R5為脲基甲基的化合物；或 )使式I中R 5為氰基的化合物與蠱氮酸反應’製得式1中R 5為1 Η —四唑—5 —基的化合物；或 (r )瘥原式I中R 為胺基甲基的化合物 (s )水解式I中R 為氰基的化合物，製得式I中R s 為氰基的化合物，製得式I中R s -33- 本紙張尺度適用中國國家標準（CNS)A4規格（210 297公釐） ---------------------訂-------- (請先閱讀背面之注意事項再填寫本頁) 470741 A8 B8 C8 D8 、申請專利範圍為氨基甲醯的化合物；或 (t )使式I中R 5為氟基的化合物與乙烯二胺反應，製得式I中R 5為4 ，5 —二氫咪唑一2 —基的化合物；或 (u )使式I中R 5為氟基的化合物與式（C Η 3 ) 2 A 1 R N 1 ^ R 1 6的化合物反應，製得式I中R s為一C (N Η ) N R 1 5 R 1 6的化合物；或 (v) 還原式I中R5或R4和Rs同為乙氧基羰基的化合物，製得式I中R5或R4和R5同為羥基甲基的化合物；或 (w) 將式I中RS為羥基甲基的化合物轉換成式28的化合物 ------------I --------訂·-------- (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製其中 L 為 _. 離去基 1 η j t 和 R 1 定義同 M 上發明概要的式 I 使式 2 8 的化合物與式 Η N R 3 6 R 3 7 { 其中 R 3 6 和 R 3 7 個自獨為 ( C 1 — C 4 ) 院基或 — 起為 — ( C Η 2 ) 4 — > — ( C Η 2 ) 5 — > — ( C Η 2 ) 2 〇 ( C Η Ζ \ 2 — 或 — ( C Η 2 ) Z N R 3 8 ( C Η 2 ) 2 一 1 其中 R 3 8 為氫或 ( C 1 — C 4 ) 焼基 ) 的胺反應 -34-CIO 24 (used after printing by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs) (0) R in R) alkane (C-alkyl hydrolyzed salt); Acid salt reaction and then alkali treatment to obtain a compound of formula I in which R 2 is formula (c) (where R _3 is a hydrogen compound; or) a compound in which R 5 in formula I is a hydroxymethyl group and formula Η 2 Ν (0 3 1 or a compound of formula MΗ4 + ~ 0 C (0) R s 1 (which is hydrogen CC) alkyl or trifluoro (C! -C group) ammonium salt reaction to obtain R5 in formula I is a methylamine group Methyl-C 4 alkylcarbonylaminomethyl or trifluoro (Ci-c4 carbonylaminomethyl) compounds, which can be optionally further formed into the formula I where R3 and R4 are hydrogen and R5 is aminomethyl Acid addition of a group or) react a compound in which R s is a hydroxymethyl group with urea to produce a compound in which R 5 is a ureidomethyl group; or) make a compound in which R 5 is a cyano group with 蛊Nitric acid reaction 'to prepare a compound in which R 5 in Formula 1 is 1 Η -tetrazol-5-yl; or (r) 瘥 The compound in formula I where R is amino methyl (s) is hydrolyzed in formula I where R is A cyano compound in which R s in formula I is cyano Compound of formula I to obtain R s -33 in formula I- This paper size applies to Chinese National Standard (CNS) A4 (210 297 mm) ------------------ --- Order -------- (Please read the precautions on the back before filling out this page) 470741 A8 B8 C8 D8, the compound whose patent application scope is carbamate; or (t) make R in formula I 5 is a fluoro-based compound and ethylenediamine to produce a compound in which R 5 is 4,5-dihydroimidazol-2-yl in formula I; or (u) a compound in which R 5 is fluoro-based in formula I is A compound of formula (C Η 3) 2 A 1 RN 1 ^ R 1 6 is reacted to obtain a compound of formula I in which R s is a C (N Η) NR 1 5 R 1 6; or (v) reduction in formula I A compound in which R5 or R4 and Rs are both ethoxycarbonyl groups to obtain a compound in which R5 or R4 and R5 are both hydroxymethyl groups; or (w) converting a compound in which RS is a hydroxymethyl group into a formula 28 compounds ------------ I -------- Order · -------- (Please read the precautions on the back before filling out this page) Ministry of Economy Wisdom Printed by the Consumer Cooperative of the Property Bureau where L is _. Leaving base 1 η jt and R 1 have the same definition as M above. The formula I makes the compound of formula 2 8 and formula Η NR 3 6 R 3 7 {wherein R 3 6 and R 3 7 are unique (C 1 — C 4) or — from — (C Η 2) 4 — > — (C Η 2) 5 — > — (C Η 2) 2 〇 (C Η Zn \ 2 — or — (C Η 2) ZNR 3 8 (C Η 2) 2-1 where R 3 8 is an amine reaction of hydrogen or (C 1-C 4) fluorenyl) -34-

本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 470741 六經濟部智慧財產局員工消費合作社印製 A8 B8 C8 D8 ----------一、_請專利範圍 ,製得式1中只5為胺基甲基，（Ci —CU )烷基胺基甲基，二（C, —C4 )烷基胺基甲基，吡咯烷一1 一基甲基，#啶一1 一基甲基，嗎啉一4 —基甲基，顿嗪一 1 —基甲基，4一（C! —C4)院基顿_一】一基甲基的化合物；或 (X )使式I中R 4為甲醯基的化合物與羥基胺氫氯化物反應，然後還原製得式1中R 4為胺基甲基的化合物；或 (y)使式I中R4為甲醯基的化合物與式NH2 R1 3 的胺在一化學還原劑存在下或在觸媒氫化中，製得式I 中R4為一CHzNHR1〗（其中R1 3為氫，（c! -C4 )烷基*羧基（Ci — C4 )烷基，氨基甲醯，氨基甲醯（Cl — C4 )烷基或苯基（C, — C4 )烷基（選擇性再被羧基或（Ci — c4 )烷基氧基羰基取代）；或 (z )烷基化式I中R 4為甲醯基的化合物，製得式I中 R 4為1 一羥基（C , _ c 4 )烷基的化合物；或 (a a)使式I中R5為胺基甲基的化合物與一適當取代脒反應，製得式I中R5為一CHzNHC (NR1 *) N H R 1 2 (其中R11為氫，乙醯基或三级丁氧基羰基，R 1 2為乙醯基或三級丁氧基羰基）的相對應化合物反應；$ (b b )用酸與式I中尺5為一 CH2 NHC (NR1 1 )N H R 1 2 (其中R11為氫，乙醯基或三级丁氧基羰 -3δ- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） --11111------- 1 —--I--訂- -- ------ (請先閱讀背面之注意事項再填寫本頁) 470741 A8 B8 C8 D8 t、申請專利範圍 (請先閱讀背面之注意事項再填寫本頁) 基，R 1 2為乙醯基或三级丁氧基羰基）的化合物反應，製得式I中R5為—CH2NHC (NH) NH2的化合物；或 (c c )用一合適的醯化劑或其保護衍生物醯化式I中 R 3為胺基或R 4或R 5為胺基甲基的化合物，然後視需要去保護，製得式I中R 3為一 N H R 1 °的相對應化合物，其中R10為（C! — C4)烷醯基，或R4為 -C Η 2 N H R 1 3 ，其中R1 3為氨基甲醯或rs為 -C Η 2 N H R 1 0 ，其中 R10 為（Ci-C*)烷醯基，氨基甲醯，（C,— C4)烷基氧基羰基，（Ci — C4 )烷基氨基甲醢，二（C, —C4 )烷基氨基甲醯，胺基（Ci —C4 )烷醯基，或選自苯醯基，皮考林醯胺，菸鹼_胺和2—呋醯基； (dd)式I中RS為胺基甲基的化合物與（Cl 一〇4 )烷基異氰酸鹽反應，製得式I中為一 CH2 NHR1 〇 (其中R1 Q為（C! —C4 )烷基氨基甲醯）的化合物 > 經濟部智慧財產局員工消費合作社印制机 (e e )用一合適的N，N -二取代甲撐銨鹽烷基化式I 中R 3 ，R 4和R 5為氫的化合物，製得式I中R 3和 R5為氫，R4為二（Ct — C4 )烷基胺基甲基的化合物；或 (f f )用一合適的N，N —二取代甲撐銨鹽烷基化式I 中R 4為氫，R 3不為氫的化合物，製得式I中R s為二本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 470741 經濟部智慧財產局員工消費合作社印製 A8 B8 C8 D8 六、申請專利範圍 (ct ~c4 )烷基胺基甲基，吡咯烷一1—基甲基或嗎啉一4 —基甲基的相對應化合物；或 (g S )用硫赶保護基保護式1中R 3為氫的化合物，用一合適的N，N —二取代甲撐銨鹽烷基化，然後去保護，製得式I中R3為氫，R*和R5同為二（（：1 — C4 ) 烷基胺基甲基，#啶_ 1 一基甲基或嗎啉一1 一基甲基的化合物；或 (h h )使式I中R 5為羧基或其酸衍生物與一合適的胺或硫赶反應，製備式I中R5為1 Η —四唑一 5 —基氨基甲藤，2-(二甲基胺基）乙基氨基甲醯，4 —甲基#嗪一 1—基羰基或2 — （二甲基胺基）乙基氫硫；或 (i i)使式I中R3為氫的化合物與（Ct — C4 )烷 y基丙烯酸酯反應，製得式I中R3為2 — (Ci - C 4 ) 烷基氧基羰基乙基的化合物；或 (jj)水解式I中R3 - R 4 ，尺5或只6為（（：1_ C4 )烷基氧基羰基或另外被（Ci — C4 )烷基氧基羰基取代基取代的基團的化合物，製得式I中R 3 ，R 4 ， R 5或R 6為羧基或另外被羧基取代基取代的基團的化合物； (kk)胺化式I中R3 ，R4或R5為羧基或另外被羧基取代基取代的基團的化合物，製得式I中R 3 ，R 4或 R 5為氨基甲醯或另外被氨基甲醯取代基取代的基團的化合物；或 -37- 本紙張尺度適用中國國家標準（CNS)A4規格（210 x 297公髮） ---— — — — —-----------II 訂— — — — — — (請先閲讀背面之注意事項再填寫本頁) 470741 經濟部智慧財產局員工消費合作社印製 A8 B8 C8 D8 六、申請專利範圍 (1 I )使式I中R 3 1 R 4 ，R s或R 7為羧基或另外被羧基取代基取代的基團的化合物與（c i 一 C 4 )醇反應，製得式I中R3 , R 4 ，R5或R7為（Ci 一 C4 )烷基氧基羰基或另外被（C ! — C 4 )烷基氧基氨基甲醯取代基取代的基團的化合物；或 (mm)對式I中R1為甲氧基和/或其中式I中R3為 —(C Η 2 ) qRg中R9為苯基，吡啶基或1^嗪基（再被一或二個甲氧基取代基取代）進行脫甲基反應，製得式I 中R1為羥基和/或R3為一（CH2) qR9 ，其中R9 為苯基，毗啶基或_嗪基（再被一或二個羥基取代基所取代）的化合物； (nn)使式I中R3為一（CH2 ) qR 9 (其中R9為苯基，吡啶基或_嗪基（再被氮基取代取代））的化合物與曼氮酸衍生物反應，製得式I中R3為—（？H2) qR9 (其中R9為苯基，毗啶基或_嗪基（再被1 Η —四唑一 5 -基取代基所取代）的化合物；或 (〇〇)使式I化合物相對應非鹽形態與一藥學上可接受無機或有機酸或鹼反應，製得藥學上可接受鹽或 (ρ ρ )使式1化合物相對應酸加成鹽或鹼加成鹽分別與一合適鹼或酸反應，製得自由態酸或鹼；或 (Qq)分離式I化合物的立體異構物混合物’得到單一立體異構物；或 (r r )使L -胺基酸的保護衍生物與式1化合物 -38- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公楚） ---------------------訂--------- (請先閱讀背面之注意事項再填寫本頁) 470741 (R'V R1This paper size applies to China National Standard (CNS) A4 specifications (210 X 297 mm) 470741 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs A8 B8 C8 D8 Range, to obtain only 5 in the formula 1 are aminomethyl, (Ci — CU) alkylamino methyl, di (C, —C4) alkylamino methyl, pyrrolidine — 1 monomethyl, # Pyridine-1 monomethyl, morpholine 4-ylmethyl, triazine-1 1-methylmethyl, 4-mono (C! -C4) diketon_a] monomethyl compounds; or ( X) reacting a compound in which R 4 is a methyl group in formula I with hydroxylamine hydrochloride, and then reducing to obtain a compound in which R 4 is an amino methyl group in formula 1; or (y) allowing R 4 in formula I to be a methyl group A fluorenyl compound and an amine of the formula NH2 R1 3 in the presence of a chemical reducing agent or in the hydrogenation of a catalyst yield R4 in formula I as CHzNHR1 (where R1 3 is hydrogen, (c! -C4) alkyl * Carboxy (Ci — C4) alkyl, carbamate, carbamate (Cl — C4) alkyl or phenyl (C, — C4) alkyl (optionally replaced by carboxy or (Ci — c4) alkyloxy Carbonyl substitution); or (z) alkylation of formula I A compound in which R 4 is a methyl group, to obtain a compound in which R 4 in Formula I is a 1-hydroxy (C, _ c 4) alkyl group; or (aa) a compound in which R 5 in formula I is an aminomethyl group, and An appropriate substitution reaction of fluorene to obtain R5 in formula I is CHzNHC (NR1 *) NHR 1 2 (where R11 is hydrogen, ethylfluorenyl or tertiary butoxycarbonyl, and R 1 2 is ethylfluorenyl or tertiary butyl The corresponding compound of oxycarbonyl group) is reacted; $ (bb) with an acid and CH 5 NHC (NR1 1) NHR 1 2 (where R11 is hydrogen, ethenyl or tertiary butoxycarbonyl) 3δ- This paper size is in accordance with China National Standard (CNS) A4 (210 X 297 mm) --11111 ------- 1 --- I--Order --- ------ (Please Read the precautions on the back before filling this page) 470741 A8 B8 C8 D8 t, patent application scope (please read the precautions on the back before filling out this page), R 1 2 is ethenyl or tertiary butoxycarbonyl ) To obtain a compound of formula I in which R5 is -CH2NHC (NH) NH2; or (cc) using a suitable halogenating agent or a protected derivative thereof, wherein R3 is an amine group or R4 Or a compound in which R 5 is an aminomethyl group, and Deprotection is required to prepare the corresponding compound in formula I where R 3 is -NHR 1 °, where R 10 is (C! — C4) alkylfluorenyl, or R 4 is -C Η 2 NHR 1 3, where R 1 3 is amino Formamidine or rs is -C Η 2 NHR 1 0, where R10 is (Ci-C *) alkylfluorenyl, carbamate, (C, — C4) alkyloxycarbonyl, (Ci — C4) alkylamino Formamidine, bis (C, —C4) alkylcarbamidine, amine (Ci—C4) alkylamido, or selected from phenylamido, picolinium, nicotine_amine, and 2-furamyl ; (Dd) a compound in which RS is an aminomethyl group in formula I is reacted with (Cl-10) alkyl isocyanate to obtain a CH2 NHR1 in formula I (where R1 Q is (C! -C4 ) Alkylcarbamidine) Compounds > The Consumer Cooperative Printing Machine (ee) of the Intellectual Property Bureau of the Ministry of Economic Affairs alkylates R 3, R 4 in Formula I with a suitable N, N -disubstituted methylammonium salt A compound wherein R 5 and R 5 are hydrogen to obtain a compound of formula I in which R 3 and R 5 are hydrogen and R 4 is a di (Ct — C4) alkylaminomethyl group; or (ff) a suitable N, N —di Alkylation of Substituted Methylene Ammonium Salts In Formula I, R 4 is hydrogen and R 3 is not hydrogenated. R s in formula I is two paper sizes. Applicable to China National Standard (CNS) A4 specifications (210 X 297 mm) 470741 Printed by A8, B8, C8, D8, Consumer Cooperatives of Intellectual Property Bureau of the Ministry of Economic Affairs 6. Patent application Corresponding compounds in the range (ct ~ c4) alkylaminomethyl, pyrrolidine-l-ylmethyl or morpholine-4-ylmethyl; or (g S) Protecting R in Formula 1 with a sulfur protecting group Compounds in which 3 is hydrogen are alkylated with a suitable N, N-disubstituted methylammonium salt, and then deprotected to obtain formula I in which R3 is hydrogen, and R * and R5 are both di ((: 1-C4 ) Alkylaminomethyl, # pyridine-1 or morpholine-1monomethyl; or (hh) making R5 in formula I a carboxyl group or an acid derivative thereof and a suitable amine Or sulfur reaction, in the formula I R5 is 1 Η -tetrazol-5 -ylcarbamidine, 2- (dimethylamino) ethylcarbamidine, 4 -methyl # hydrazine 1 -ylcarbonyl group or 2- (dimethylamino) ethylhydrosulfide; or (ii) reacting a compound in which R3 is hydrogen in formula I with a (Ct-C4) alkyl y acrylate to obtain R3 in formula I as 2-( Ci-C 4) alkyl Carbonylcarbonylethyl compounds; or (jj) hydrolysis of R3-R4 in Formula I, or 5 or 6 is ((: 1-C4) alkyloxycarbonyl or additionally (Ci-C4) alkyloxycarbonyl A compound of a substituent-substituted group to obtain a compound in which R 3, R 4, R 5 or R 6 in the formula I is a carboxyl group or another group substituted with a carboxyl substituent; (kk) amination of R3 in the formula I, A compound in which R4 or R5 is a carboxyl group or another group substituted with a carboxyl substituent to obtain a compound in which R 3, R 4 or R 5 in formula I is a carbamate or a group further substituted with a carbamate substituent; Or -37- This paper size applies to China National Standard (CNS) A4 (210 x 297). --------------------- II Order------ (Please read the precautions on the back before filling this page) 470741 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs A8 B8 C8 D8 VI. The scope of patent application (1 I) makes R 3 1 R 4, R s or A compound in which R 7 is a carboxyl group or another group substituted with a carboxyl substituent is reacted with (ci-C 4) alcohol to obtain R 3, R 4, R 5 or R 7 in formula I (Ci-C 4 ) An alkyloxycarbonyl group or a compound additionally substituted with a (C! -C4) alkyloxycarbamidine substituent; or (mm) for R1 in formula I is methoxy and / or wherein R3 in I is-(C Η 2) R9 in qRg is phenyl, pyridyl or 1 ^ azinyl (replaced by one or two methoxy substituents) to perform demethylation reaction to obtain R1 in formula I Is a compound in which hydroxyl and / or R3 is mono (CH2) qR9, wherein R9 is phenyl, pyridinyl or _azinyl (replaced by one or two hydroxyl substituents); (nn) makes R3 in formula I A compound that is mono (CH2) qR9 (wherein R9 is phenyl, pyridyl or _azinyl (replaced by nitrogen)) is reacted with a nitric acid derivative to obtain R3 in formula I as-(? H2) a compound of qR9 (wherein R9 is phenyl, pyridinyl or _azinyl (replaced by 1 Η -tetrazol-5 -yl substituent); or (〇〇) corresponding to the compound of formula I is not a salt The form reacts with a pharmaceutically acceptable inorganic or organic acid or base to prepare a pharmaceutically acceptable salt or (ρ ρ) so that the compound of formula 1 corresponds to an acid addition salt or a base addition salt and reacts with a suitable base or acid respectively To obtain a free acid or base; or (Qq) to separate a mixture of stereoisomers of a compound of formula I to obtain a single stereoisomer; or (rr) to make a protected derivative of L-amino acid and a compound of formula 1- 38- This paper size applies to China National Standard (CNS) A4 (210 X 297 cm) --------------------- Order ------- -(Please read the notes on the back before filling this page) 470741 (R'V R1

A8 B8 C8 D8 、申請專利範圍 I 或其藥學可接受鹽，其個別異構物或異構物混合物反應，其中η ，t和R1定義如申請專利範圍第30項的式I I 化合物；和 R 2係連接於α ，/3或7位置，且為選自式（a )， (b )和（c )之基團： ------------13^·-------訂 ---------- (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製中其 y/(a) ) Y$b wR, / N Ay N Μ / N V $/ 氫為 4 R 或氫為 3 R 2 Η c R 為 Q 中其本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 470741 A8 B8 C8 D8 τ、申請專利範圍經濟部智慧財產局員工消費合作社印製和 R 9 定義同上 ) > R 5 為一 N Η R 1 〇 ( 其中 R 1 0 為氫或 ( C 1 — C 4 ) 综基 ) R 4 和 R 5 各為氫 1 R 3 為 — Ν Η R 1 〇 ( 其中 R 1 0 為氫或 ( 1 一 C 4 ) 焼基 ) » 或 R 5 為氫 t R 3 為氫或 — ( C Η 2 ) q ] R s 1 (其中| 3和 R 9 定義同上 ) ， R 4 為 — C Η Ζ Ν Η R 1 〇 ( 其中 R 1 0 為氫或 ( C 一 C 4 ) 燒基 ) 或 R 3 為氫或 — ( C Η 2 ) qR 9 (其中< 3和R 9 定義同上 ) 9 R 4 為氫 * ( C 1 — C 4 ) 烧基或 — C ( 0 ) R 1 為 ( C i 一 C 4 ) 燒基氧基 ) 9 Κ 5 為 — C Η 2 N Η R 1 0 ( 其中 R 1 0 為氫或 ( C 1 一 c 4 ) 焼基 ) > 和 R 6 為氫或 2 — 羧乙基 t R 7 為 — C Η 2 Ν Η 1 0 ( 其中 R X 0 為氫或 ( C 1 — C 4 ) 焼基 ) 和 R Q 為 — N Η R 1 0 ( 其中 R i 0 為氫或 ( C I — C 4 ) 烷基 ) Μ 形成如申請專利範圍第 3 0 項式 I I 的 XX. 刖劑進 ___. 步選擇性的使式 I I 化合物的相對懕非鹽形式與 __. 藥學上可接受無機或有機酸或鹼反懕得到藥學上可接受鹽，或選擇性再使式 I I 化合物的相對 ntxs 懕酸加成鹽或鹼加成 m jxn 形成分別與 -* 合適鹼或酸反應，得到由態酸或由態驗 » 或選擇性地分雛式 I I 化合物的 BM 體異構物混合物，得到單一立體異構物 9 或 ( S S ) 使式 4 7 化合物 -40- -------------裝--------訂---------線 (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用_國國家標準（CNS)A4規格（210 X 297公釐） 470741 A8 B8 C8 D8 經濟部智慧財產局員工消費合作社印制^ 申請專利範圍A8 B8 C8 D8, patent application scope I or a pharmaceutically acceptable salt thereof, and individual isomers or mixtures of isomers thereof, wherein η, t and R1 are defined as the compound of formula II as defined in item 30 of the scope of patent application; and R 2 Is connected to the α, / 3 or 7 position, and is a group selected from the formulas (a), (b) and (c): ------------ 13 ^ · ---- --- Order ---------- (Please read the precautions on the back before filling out this page) y / (a) in the print by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economy Y \ (b wR , / N Ay N Μ / NV \) / hydrogen is 4 R or hydrogen is 3 R 2 Η c R is Q. Its paper size is applicable to Chinese National Standard (CNS) A4 (210 X 297 mm) 470741 A8 B8 C8 D8 τ, the scope of patent application, printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, and the definition of R 9 is the same as above) > R 5 is a N Η R 1 〇 (where R 1 0 is hydrogen or (C 1-C 4) comprehensive R 4 and R 5 are each hydrogen 1 R 3 is —N Η R 1 〇 (where R 1 0 is hydrogen or (1 -C 4) fluorenyl) »or R 5 is hydrogen t R 3 is hydrogen or — ( C Η 2) q] R s 1 (where | 3 and R 9 have the same definitions as above), R 4 is — C Η ZO Η R 1 〇 (where R 1 0 is hydrogen or (C-C 4) alkyl) or R 3 is hydrogen or — (C Η 2) qR 9 (wherein < 3 and R 9 have the same meanings as above) 9 R 4 is hydrogen * (C 1 — C 4) alkyl or — C (0) R 1 is (C i -C 4) alkyloxy) 9 KK 5 is-C Η 2 N Η R 1 0 (where R 1 0 is hydrogen or (C 1 -c 4) fluorenyl) > and R 6 is hydrogen or 2 — Carboxyethyl t R 7 is — C Η 2 Ν Η 1 0 (where RX 0 is hydrogen or (C 1 — C 4) fluorenyl) and RQ is — N Η R 1 0 (where R i 0 is hydrogen or (CI — C 4) alkyl) Μ forms XX. II as formula II in the scope of the patent application. The elixir can be used to selectively make the relative non-salt form of the compound of formula II and __. Pharmacy Inorganic or organic acids or bases are acceptable to give pharmaceutically acceptable salts, or the compound of formula II may be selectively combined. The relative ntxs of arsenic acid addition salt or base addition m jxn formation respectively react with-* suitable base or acid to obtain the BM isomer from the acid or by the test »or optionally the compound of formula II Mixture to give a single stereoisomer 9 or (SS) make the compound of formula 4 7 -40 ------------- install -------- order ------ --- line (please read the precautions on the back before filling this page) This paper size is applicable _ National Standard (CNS) A4 (210 X 297 mm) 470741 A8 B8 C8 D8 Employee Consumption Cooperative of Intellectual Property Bureau Printing ^ Patent Application Scope

Μ-Sr29 或其係護衍生物，其中R 2 8定義如式I II ，與式I化合物M-Sr29 or a protective derivative thereof, wherein R 2 8 is defined as Formula I II, and a compound of Formula I

(CHA 或其藥學可接受鹽，其個別異構物或異構物混合物反應，其中η ，t和R 1定義同上，R 2係連接於α ，/3或γ位置，且為選自式（a) - (b)和（c)之基團： -4 1- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） --------------- (請先閱讀背面之注意事項再填寫本頁) 470741 A8 B8 C8 D8 申請專利範圍 S、 N V (a) R(b) (c) 其中R3 ，R6和R8為氫，R4 ，：RS和R7定義如式 I I I ;視需要去保護，K形成如申請專利範園第4 5項的式I I I的前劑，進一步選擇性的使式I I I化合物的相對應非鹽形式與一藥學上可接受無機或有機酸或鹼反應，得到藥學上可接受鹽；或選擇性再使式I I I化合物的相對應酸加成鹽或鹼加成鹽形成分別與一合適鹼或酸反應，得到自由態酸或自由態鹼；或選擇性地分離式I I I化合物的立體異構物混合物，得到單一立體異構物。 ---------------------訂--------- (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作杜印製 5 4 種下式化合物 42- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 470741 A8 B8 C8 D8 t、申請專利範圍也就是（S) - 5 ，7 —二氟-1 ，2 ，3 ，4一四氫蔡一 2 —基胺。 5 5 * —種製備式3 ( a )的S —對映異構物的方法： (請先閱讀背面之注意事項再填寫本頁)(CHA or a pharmaceutically acceptable salt thereof, and the individual isomers or mixtures of isomers thereof react, wherein η, t and R 1 have the same definitions as above, and R 2 is connected to the α, / 3, or γ position, and is selected from the formula ( a)-The groups of (b) and (c): -4 1- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) ------------- -(Please read the notes on the back before filling this page) 470741 A8 B8 C8 D8 Patent application scope S, NV (a) R (b) (c) where R3, R6 and R8 are hydrogen, R4: RS and R7 is defined as formula III; if necessary, deprotected, K forms a prodrug of formula III as described in item 45 of the patent application park, and further selectively matches the corresponding non-salt form of the compound of formula III with a pharmaceutically acceptable inorganic Or organic acid or base reaction to obtain a pharmaceutically acceptable salt; or alternatively, the corresponding acid addition salt or base addition salt of the compound of formula III is formed to react with a suitable base or acid respectively to obtain a free acid or free acid Base; or selectively separate stereoisomer mixtures of compounds of formula III to obtain a single stereoisomer. --------- (Please read the precautions on the back before filling out this page) The consumer cooperation of the Intellectual Property Bureau of the Ministry of Economic Affairs has printed 5 4 compounds of the following formula. 42- This paper applies Chinese national standards (CNS ) A4 specification (210 X 297 mm) 470741 A8 B8 C8 D8 t, the scope of patent application is also (S) -5,7-difluoro-1,2,3,4-tetrahydrocae-2-ylamine. 5 5 * — A method for preparing S —enantiomer of formula 3 (a): (Please read the precautions on the back before filling this page)

經濟部智慧財產局員工消費合作社印制农其中 t為0 ，1 ，2或3 ;和 R1個自獨立為鹵素，羥基或（Ci —C4 )烷氧基；其包括： (a)在2S —二甲基胺基一1R —苯基丙醇和2 —乙基胺基吡啶存在下還原式7 (b)化合物 -43- .本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 470741 A8 B8 C8 D8 申請專利範圍Ministry of Economic Affairs, Intellectual Property Bureau, Employee Consumer Cooperative Printed Farms where t is 0, 1, 2, or 3; and R1 is independently halogen, hydroxy, or (Ci-C4) alkoxy; it includes: (a) in 2S — Reduction of compound 7 (b) -43- in the presence of dimethylamino-1R-phenylpropanol and 2-ethylaminopyridine. This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) ) 470741 A8 B8 C8 D8

映 i 對 } I S /|\ \—/ R 的 /tv \|7 的 a /fv \i/ c 4 i 式 6 到式得理 ’ 處應物反化鹽氯氮醯疊磺與烷後甲然物用，構 } 物異 b 構映 ί 異對 ---------------------訂·------— I (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製Map i to} IS / | \ \ — / R of / tv \ | 7 of a / fv \ i / c 4 i Natural use, structure} 物异 b 映映异异 ——------------------- Order · ------— I (Please read the back first (Please note this page before filling out this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs

本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 470741 A8 B8 C8 D8 申請專利範圍第氟圍為範 1 。利 R 之專的原請置遷申位 ) 如一 C . 7 6 和和 5 _ 5 2 為 t 中其法方的項 -------------ML-衣--------訂---------線 (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製本紙張尺度適用中國國家標準（CNS)A4規格（210 χ 297公釐）This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) 470741 A8 B8 C8 D8 Patent Application Scope No. 1 is the fluorine range. Please apply for relocation of the original R). For example, C. 7 6 and 5 _ 5 2 are the terms of their law in t ------------- ML-yi --- ----- Order --------- line (Please read the notes on the back before filling out this page) Printed by the Consumers' Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs This paper applies Chinese National Standard (CNS) A4 Specifications (210 x 297 mm)