TW200523234A - Chemical compounds - Google Patents

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TW200523234A
TW200523234A TW093130165A TW93130165A TW200523234A TW 200523234 A TW200523234 A TW 200523234A TW 093130165 A TW093130165 A TW 093130165A TW 93130165 A TW93130165 A TW 93130165A TW 200523234 A TW200523234 A TW 200523234A
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alkyl
phenyl
amino
hydrogen
het1
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TW093130165A
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Roger John Butlin
Gordon Stuart Currie
Harold Gaskin
Rodney Brian Hargreaves
Paul David Kemmitt
Nathaniel George Martin
Richard Andrew Ward
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Astrazeneca Ab
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    • C07C237/24—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
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    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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Abstract

The invention relates to compounds of the formula (I) or pharmaceutically-acceptable salts thereof, wherein Ar, R1, R2, R3, R4, R5, R6, R7 and R8 have any of the meanings defined in the description, which possess dipeptidyl peptidase IV (DPP-IV) inhibitory activity and accordingly have value in the treatment of disease states associated with DPP-IV activity, such as diabetes mellitus. Processes for the preparation of said compounds, intermediates in said processes, pharmaceutical compositions containing said compounds or salts, and the use of said compounds or salts are also described.

Description

200523234 九、發明說明： 【發明所屬之技術領域】 本發明係關於抑制二肽基肽酶IV(DPP-IV)活性的化合 物，其製法，含此等化合物作為活性成分的醫藥組合物， 治療由DPP-IV活性所致的疾病的方法，及其用於製成抑制 溫血動物如人的DPP-IV活性的藥物上的用途。特定地說， 本發明係關於治療溫血動物，如人，的糖尿病的化合物， 更特定地說，係關於此等化合物在製成藥物以治療溫血動 物如人的糖尿病上的用途。 【先前技術】 DPP-IV是見於全身的絲胺酸蛋白酶，其降解並調整人體 内的數種調節肽的活性，包括胰高血糖素樣肽-UGLP-1)，GLP-2，GHRH(生長激素釋出激素）及GIP(胰高血糖素 相互作用肽）。GLP-1是一種肽激素，係由腸道壁分泌入血 流以反應餐飲，對餐後葡萄糖代謝體強大影響。當餐後葡 萄糖量升高時，GLP-1直接作用於胰/3-細胞以增強胰島素 釋出並促進新胰島素的生物合成。同時，GLP-1也延遲胃 空，進一步抑制與餐食有關的血漿葡萄糖的升高。現已顯 示（Rachman，J. et al，（1997)，40，205-211; Nauck, M.A. et al, (1996), Diabetologia, 39, 1546-1553; Gutniak, M.K. et al5 (1994), Diatetes Care, 17, 1039-1045; Rachman J· et al，（1996) 45，1524-1530)，以皮下 或靜脈注入液給予GLP-1會改善糖尿病病人的葡萄糖耐受 性，但一般認為每天給予GLP-1不是一個合意的治療方 9615l.doc 200523234 式。200523234 IX. Description of the invention: [Technical field to which the invention belongs] The present invention relates to a compound that inhibits the activity of dipeptidyl peptidase IV (DPP-IV), a preparation method thereof, and a pharmaceutical composition containing these compounds as an active ingredient. A method for diseases caused by DPP-IV activity, and its use for preparing a medicament for inhibiting DPP-IV activity of warm-blooded animals such as humans. In particular, the present invention relates to compounds for treating diabetes in warm-blooded animals, such as humans, and more particularly, to the use of these compounds in the manufacture of medicaments for treating diabetes in warm-blooded animals, such as humans. [Prior art] DPP-IV is a serine protease found throughout the body, which degrades and regulates the activity of several regulatory peptides in the human body, including glucagon-like peptide-UGLP-1), GLP-2, GHRH (growth Hormones release hormones) and GIP (glucagon-interacting peptides). GLP-1 is a peptide hormone that is secreted into the bloodstream by the intestinal wall in response to meals and has a strong effect on post-prandial glucose metabolites. When glucose levels increase after a meal, GLP-1 acts directly on pancreatic / 3-cells to enhance insulin release and promote the biosynthesis of new insulin. At the same time, GLP-1 also delays gastric emptying, further suppressing the increase in plasma glucose associated with meals. Now shown (Rachman, J. et al, (1997), 40, 205-211; Nauck, MA et al, (1996), Diabetologia, 39, 1546-1553; Gutniak, MK et al5 (1994), Diatetes Care , 17, 1039-1045; Rachman J. et al, (1996) 45, 1524-1530), GLP-1 administered subcutaneously or intravenously will improve glucose tolerance in diabetic patients, but it is generally believed that GLP- 1 is not a desirable treatment formula 9615l.doc 200523234.

DPP-IV降解血流中循環的GLP-l，而DPP-iv活性的抑制 導致GLP-1的半衰期增加，因而增加其活性。此外，DPP-IV抑制劑對胰衰竭有有益的效果：Ribel U.等人（(2001)於DPP-IV degrades circulating GLP-1 in the blood stream, and inhibition of DPP-iv activity results in an increase in GLP-1 half-life, thereby increasing its activity. In addition, DPP-IV inhibitors have beneficial effects on pancreatic failure: Ribel U. et al. ((2001) in

01汪匕61:〇1〇^1&，44，人192，73 8)說明〇??_1\^抑制劑11比17各化線 胺酸（valine pyrrolidide)(VP)於60%的切除胰臟的鼠促進新 /3細胞的分化。所以給予DPP-IV抑制劑應會導致内生性 GLP-1活性的的延長，是以臨床上明顯地降低糖尿病性的 血糖過高。DPP-IV抑制劑有可能用於預防、延緩或治療2-型（非胰島素依賴型）糖尿病。01 Wang Jian 61: 〇1〇 ^ 1 & 44, Human 192, 73 8) Description ?? _ 1 \ ^ inhibitor 11 to 17 each valine pyrrolidide (VP) in 60% of the pancreas Dirty mice promote the differentiation of new / 3 cells. Therefore, the administration of DPP-IV inhibitors should lead to the prolongation of endogenous GLP-1 activity in order to clinically significantly reduce diabetic hyperglycemia. DPP-IV inhibitors have the potential to prevent, delay or treat type 2 (non-insulin-dependent) diabetes.

此技藝已說明過新穎DPP-IV抑制劑。多數是2-氰基吡咯 烷衍生物，於氮環上鍵合有不同的取代基（見例如WO 98/19998， WO 00/34241，WO 01/96295，WO 01/40180)，或含此構 造（見例如WO 01/68603，其揭示稠合有環丙基的氰基吡咯 烧）。其他的是氰基°塞嗤（cyanothiazolidine)(見例如美國專 利 6110949號，美國專利 61073 17號，WO 99/61431 號），其 也於氮環上鍵合有各種取代基。另一些包括ϋ比咯烧，六氫 吡啶，或嗎福啉環，其可於環碳原子上而非氰基上含取代 基（見例如 W0 03/000181 及 WO 03/000180)。 【發明内容】 申請人出人意外地發現一類新構造的DPP-IV抑制劑。 因之，本發明提供式（I)化合物或其醫藥上可接受的鹽， 96151.doc 200523234This technique has demonstrated novel DPP-IV inhibitors. Most are 2-cyanopyrrolidine derivatives with different substituents bonded to the nitrogen ring (see, for example, WO 98/19998, WO 00/34241, WO 01/96295, WO 01/40180), or contain this structure (See, for example, WO 01/68603, which discloses cyanopyrrole fused with cyclopropyl). Others are cyanothiazolidine (see, for example, U.S. Patent No. 6110949, U.S. Patent No. 6107317, and WO 99/61431), which also has various substituents bonded to the nitrogen ring. Others include pyrrolidine, hexahydropyridine, or morpholine rings, which may contain substituents on the ring carbon atom instead of the cyano group (see, for example, WO 03/000181 and WO 03/000180). SUMMARY OF THE INVENTION The applicant unexpectedly discovered a new class of DPP-IV inhibitors. Accordingly, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, 96151.doc 200523234

(I) - 其中：(I)-where:

Ar是視需要經獨立選自R9的1，2，3，4或5個基團取代 的苯基； R9是選自鹵，（1-6C)烷基（視需要以1-5個鹵取代的）’（1-6C)烷氧基（視需要以1-5個鹵取代的）及氰基； R1是選自氫及（1-6C)烷基； R2是選自氫，（1-6C)烷基，（3-8C)環烷基’（5-12C)雙環 烷基，（6-12C)三環烷基，AR1，HET1，-(1-6C)烷基 AR1，-(1-6C)烷基 AR2，-(1-6C)烷基（3-8C)環烷基，-(1-6C)烷基 HET1，-(1-6C)烷基 HET2，-(1-6C)烷基 C02(1-6C) 烷基，-(1-6C)烷基C〇2(3-8C)環烷基，-(1-6C)烷基 C02AR1，-(1-6C)烧基 C02HET1，-(卜6C)烧基 OCO(l-6C) 烷基，-(1-6C)烷基OCO(3-8C)環烷基，-(1-6C)烷基 OCOAR1，-(1-6C)烧基 OCOHET1，-(1-6C)烧基 CO(l-6C)炫 基，-(1-6C)烷基 CO(3-8C)環烷基，-(1-6C)烷基 COAR1， -(1-6C)烷基 COHET1，_(1-6C)烷基 NHCO(l-6C)烷基，-(卜 6C)烷基NHCO(3-8C)環烷基，-(1-6C)烷基NHCOAR1，-(1-6C)烷基 CONH(l-6C)烷基，-(1-6C)烷基 CONH(3-8C)環烷 . 基，-(1-6C)烷基 CON-二（1-6C)烷基，-(1-6C)烷基 、 CONHAR1，-(1-6C)烧基 NH(1-6C)烧基，-(1-6C)烧基 N-二 (1-6C)烷基，-(1-6C)烷基 NHAR1 ，-(1-6C)烷基 96151.doc 200523234 NH(HETl)，-(1-6C)烧基 NHS〇2(l-6C)院基，-(1-6C)烧基 S02NH(1-6C)烷基，-(1-6C)烷基 S02(1-6C)烷基，-S02(1-6C)烷基及（1-6C)烷基 S02N-二（1-6C)烷基； 或 R1及R2可共同與其相聯的氮形成HET1或HET3所界定的 環；其中含R1及R2的環是視需要由1或2個取代基取代的， 此等取代基係獨立選自鹵，（1-6C)烷基，鹵（1-6C)烷基， (1-6C)烷氧基，氰基，羧基，羧基（1-6C)烷基，-CO(l-6C) 烷基，-C02(1-6C)烷基，（1-6C)烷基胺基，二-(1-6C)烷基 胺基，-NHCO((l-6C)烷基，-CONH(l-6C)烷基，-CON二-(1-6C)烷基及 HET1 ; R3及R4係獨立選自氫，（1-6C)烷基，（3-8C)環烷基，（3-8C)環烯基，（5_12C)雙環烷基，-(1_6C)烷基（3_8C)環烷 基 ’ -(1_6C)烷基（3_8C)環烯基，AR1，AR2，HET1， HET2，_(i_6C)烷基 AR1 …（1-6C)烷基 AR2，烷基 HET1，及 _〇_6C)烷基 hET2 ;或 R及R4共同形成以（3-8C)環烷基，AR2，HET1或HET2 所界定的環； R5 ’ R6，R7及R8是獨立選自氫及（1_6C)烷基； 其中任-由Rl，R2, R3, R4, R5, R6, R7或R8内所界定的 (1 烧基是視需要由1或2個取代基取代的，此等取代基 係獨立選自羥基及氟； 其中R2 ’ R3或R4内所界定的任一（3_8C)環烧基，（3_8c)環 烯基，（5-12C)雙環烧基或（6_12C)三環院基是視需要經取 96151.doc 200523234 « 代的； AR1是視需要經苯基取代的； AR2是視需要經取代的8_，9_或1〇_員的， 观和的，部 - 分或全部飽和的雙環碳環形環； HET1是視需要經取代的3_，4-，弘或6 只的，不飽和 的，部分或全部飽和的單環雜環基環，含達四個雜原子 此等雜原子係獨立選自〇，N及S(但不含〇_〇，n。二Ar is phenyl optionally substituted with 1, 2, 3, 4 or 5 groups independently selected from R9; R9 is selected from halogen, (1-6C) alkyl (substituted with 1-5 halogens as required) ) '(1-6C) alkoxy (substituted with 1-5 halogens as needed) and cyano; R1 is selected from hydrogen and (1-6C) alkyl; R2 is selected from hydrogen, (1- 6C) alkyl, (3-8C) cycloalkyl '(5-12C) bicycloalkyl, (6-12C) tricycloalkyl, AR1, HET1,-(1-6C) alkyl AR1,-(1 -6C) alkyl AR2,-(1-6C) alkyl (3-8C) cycloalkyl,-(1-6C) alkyl HET1,-(1-6C) alkyl HET2,-(1-6C) Alkyl C02 (1-6C) alkyl,-(1-6C) alkyl Co2 (3-8C) cycloalkyl,-(1-6C) alkyl C02AR1,-(1-6C) alkyl C02HET1 ,-(Bu 6C) alkyl OCO (l-6C) alkyl,-(1-6C) alkyl OCO (3-8C) cycloalkyl,-(1-6C) alkyl OCOAR1,-(1-6C ) Alkyl OCOHET1,-(1-6C) alkyl CO (l-6C) xyl,-(1-6C) alkylCO (3-8C) cycloalkyl,-(1-6C) alkyl COAR1, -(1-6C) alkyl COHET1, _ (1-6C) alkylNHCO (l-6C) alkyl,-(114C) alkylNHCO (3-8C) cycloalkyl,-(1-6C) Alkyl NHCOAR1,-(1-6C) alkyl CONH (l-6C) alkyl,-(1-6C) alkyl CONH (3-8C) cycloalkane.yl,-(1-6C) alkane Con-di- (1-6C) alkyl,-(1-6C) alkyl, CONHAR1,-(1-6C) alkenyl NH (1-6C) alkenyl,-(1-6C) alkenyl N- Di (1-6C) alkyl,-(1-6C) alkylNHAR1,-(1-6C) alkyl 96151.doc 200523234 NH (HETl),-(1-6C) alkyl NHS〇2 (l- 6C) courtyard,-(1-6C) alkyl S02NH (1-6C) alkyl,-(1-6C) alkyl S02 (1-6C) alkyl, -S02 (1-6C) alkyl and ( 1-6C) alkyl S02N-di (1-6C) alkyl; or the nitrogen to which R1 and R2 can be linked together form a ring defined by HET1 or HET3; the ring containing R1 and R2 is optionally composed of 1 or 2 substituents, these substituents are independently selected from halogen, (1-6C) alkyl, halo (1-6C) alkyl, (1-6C) alkoxy, cyano, carboxyl, carboxyl ( 1-6C) alkyl, -CO (l-6C) alkyl, -C02 (1-6C) alkyl, (1-6C) alkylamino, di- (1-6C) alkylamine,- NHCO ((l-6C) alkyl, -CONH (l-6C) alkyl, -CON di- (1-6C) alkyl and HET1; R3 and R4 are independently selected from hydrogen, (1-6C) alkyl , (3-8C) cycloalkyl, (3-8C) cycloalkenyl, (5_12C) bicycloalkyl,-(1_6C) alkyl (3_8C) cycloalkyl '-(1_6C) alkyl (3_8C) cycloolefin Base, AR1, AR2, HET1, HET2, _ (i_6C) alkane Group AR1… (1-6C) alkyl AR2, alkyl HET1, and _0_6C) alkyl hET2; or R and R4 together form a (3-8C) cycloalkyl, AR2, HET1 or HET2 defined Ring; R5 'R6, R7 and R8 are independently selected from hydrogen and (1-6C) alkyl; wherein any-defined by R1, R2, R3, R4, R5, R6, R7 or R8 (1 alkyl group is considered as Need to be substituted by 1 or 2 substituents, these substituents are independently selected from hydroxyl and fluorine; wherein any of (3-8C) cycloalkenyl, (3-8c) cycloalkenyl, as defined in R2'R3 or R4, ( 5-12C) bicyclic alkyl or (6_12C) tricyclic radical is selected as needed by 96151.doc 200523234 «generation; AR1 is substituted with phenyl as needed; AR2 is substituted with 8_, 9_ or as needed 10-membered, superficial, partially or fully saturated bicyclic carbocyclic ring; HET1 is optionally substituted with 3, 4, 4-, or 6, unsaturated, partially or fully saturated monocyclic A cycloheterocyclyl ring containing up to four heteroatoms. These heteroatoms are independently selected from 0, N and S (but not containing 0_0, n. two

vJ * 〇 S - S 鍵）’如果環不因而季銨化（qUaternised)，是經環碳原子咬 環氮原子相聯，且其中任一碳，硫或氮原子可以是經氧化 的； HET2是視需要經取代的8-，9-或10-員的，不飽和的， 部分或全部飽和的雙環雜環，含達四個獨立選自〇，s 的雜原子（但不含0-0，Ο-S或S-S鍵），並經由含雙環系統 的環内的環碳原子鍵合； HET3是N-鍵合的飽和的雙環或三環環系統，含達12個 環原子，包括鍵合的氮原子； 其中（3-8C)環烷基，（5-12C)雙環烷基，（6-12C)三環烷 基，AR1，AR2，HET1及HET2上適宜的取代基是1，2, 3，4或5個取代基，獨立選自苯基（視需要以鹵，三氟甲 基，（1-4C)烷基或（1-4C)烷氧基取代的），鹵，（1-6C)烷 基，鹵（1-6C)烷基，二鹵（1-6C)烷基，三氟甲基，（1-6C)烷 • · 氧基，羧基（1-6C)烷基，羧基（1-6C)烷氧基，羥基，胺基’ ^ (1-6C)烷基胺基，二（1-6C)烷基胺基，-CONH2，-CONH(l-6C) 烷基，-CON二（1-6C)烷基，-NHCO(l_6C)烷基，-S〇2(l-6C)烧 9615l.doc -10- 200523234 基，-S(0)2NH2，-S02NH(1-6C)烷基，-S02N 二（1-6C)烧基 及-NHS02(1-6C)烷基。 本發明又一具體實施例包括式⑴化合物或其醫藥上可接 • 受的鹽，其中： Αι*是視需要經1，2，3，4或5個獨立選自R9的基團取代 的苯基； R9是選自鹵，（1-6C)烷基（視需要是以1-5個鹵取代的）’ (1-6C)烷氧基（視需要是以1-5個鹵取代的）及氰基； R1是選自氫及（1-6C)烷基； R2是選自氫，（1-6C)烷基，（3-8C)環烷基，（5-12C)雙環 烷基，（6-12C)三環烷基，AR1，HET1，-(1-6C)烷基 AR1，-(1-6C)烷基 AR2，_(1-6C)烷基（3-8C)環烷基，-(1-6C)烷基 HET1，-(1-6C)烷基 HET2，-(1-6C)烷基 C02(1-6C) 烷基，-(1-6C)烷基C02(3-8C)環烷基，-(1-6C)烷基 C02AR1，-(1-6C)烧基 C02HET1，-(1-6C)烧基 〇CO(l-6C) 烷基，-(1-6C)烷基OCO(3-8C)環烷基，-(1-6C)烷基 OCOAR1，-(1-6C)烧基 OCOHET1，-(1-6C)烧基 CO(l-6C) 烷基，-(1_6C)烷基CO(3-8C)環烷基，-(1-6C)烷基 COAR1，-(1-6C)烧基 COHET1，-(1-6C)烧基 NHCO(l-6C) 烷基，-(1-6C)烷基NHCO(3-8C)環烷基，-(1-6C)烷基 NHCOAR1，-(UC)烧基 CONH(l-6C)烧基，-(1-6C)烧基 • CONH(3-8C)環烷基，-(1-6C)烷基 CON-二（1-6C)烷基，-(1-6C)烷基 CONHAR1，-(1-6C)烷基 NH(1-6C)烷基，-(1-6C) 烷基 N-二（1-6C)烷基，-(1-6C)烷基 NHAR1，-(1-6C)烷基 96151.doc -11 - 200523234 NH(HETl)，-(1-6C)烧基 NHS〇2(l-6C)烧基，-(1-6C)烧基 S02NH(卜6C)院基及-(1-6C)烧基 S02N-二（1-6C)烧基； 或 R1及R2可共同與其相聯的氮形成HET1所界定的環’其 中含R1及R2的環是視需要由1或2個取代基取代的，此等取 代基係獨立選自鹵，（KC)烧基’鹵（1-6C)烧基’（1-6C)烧 氧基，氰基，羧基，羧基（1-6C)烷基，-CO((l-6C)炫基， -C〇2(l-6C)烷基，（1-6C)烷基胺基，二-(1-6C)烷基胺基’ •NHCO(卜6C)院基，-CONH(l-6C)烧基，-CON二-(卜6C)烧 基及HET1 ; R3及R4係獨立選自氫，（1-6C)烷基，-(1-6C)烷基（3-8C) 環烷基，-(1-6C)烷基（3-8C)環烯基，-(1-6C)烷基AR1， -(1-6C)烷基 AR2，-(1-6C)烷基 HET1，及-(1-6C)烷基 HET2 ;或 R3及R4共同形成如（3-8C)環烷基，AR2，HET1或HET2 所界定的壞， R5，R6，R7及R8是獨立選自氫及（1-6C)烷基； AR1是視需要經取代的苯基； AR2是視需要經取代的8-，9-或10-員的，不飽和的’部 分或全部飽和的雙環碳環形環； HET1是視需要經取代的3-，4-，5-或6-員的，不飽和 的，部分或全部飽和的單環雜環基環，含達四個雜原子’ 此等雜原子係獨立選自〇，N及S(但不含〇-〇 ’ 〇-s或S-S 鍵），如果環不因而季銨化（quaternised)，是經環碳原子或 96151.doc -12- 200523234 環氮原子相聯，且其中任一碳，硫或氮原子可以是經氧化 的； HET2是視需要經取代的8-，9-或10-員的，不飽和的， 部分或全部飽和的雙環雜環，含達四個獨立選自Ο，N及S 的雜原子（但不含〇-〇，Ο-S或S-S鍵），並經由含雙環系統 的環内的環碳原子鍵合； 其中AR1，AR2，HET1及HET2上適宜的取代基是1， 2，3，4或5個取代基，獨立選自鹵，（1-6C)烷基，鹵（1_ 6C)烷基，二鹵（1_6C)烷基，三氟甲基，（1_6C)烷氧基，羧 基（1-6C)烷基，羧基（1-6C)烷氧基，羥基，胺基，（1-6C)烷 基胺基，二（1-6C)烷基胺基，-CONH2，-CONH(l-6C)烷 基，-CON 二（1-6C)烷基，-NHCO(l-6C)烷基，-S(0)2NH2， -S02NH(1-6C)烷基，-S02N 二（1-6C)烷基及-NHS02(1-6C) 烷基。 為免於懷疑，須了解到於此說明中，以’前所界定的，或 ’如後界定的，所修飾的基團，包括第一次出現時及最廣義 的定義以及每一及所有該基團的特定的定義。 應了解到’在取代基包括烧基鏈上的二個取代基，其中 二者是以雜原子（例如烷氧基取代基）相聯，則此二取代基 不是烷基鏈同一碳原子上的取代基。 於此說明中’ π烧基’，一詞包括直鏈及支鏈的烧基，但在 • 提及個別的烷基如”丙基，，時，則只意謂直鏈。同樣的習用 ν 語適用於其他屬性詞。除非另有說明，，，烷基”一詞較佳是 意謂1-6個碳原子的鏈，較佳是ι_4個碳原子的。 96151.doc -13- 200523234 於此說明中，”烷氧基”一詞意謂聯於氧原子的前述的烧 基。 應了解到，任何基團上的有時出現的取代基，除非另有 - 說明，可聯於任何存在的原子上，包括雜原子，如果此等 雜原子不因而季銨化的話。 於此說明内使用組合詞說明含多個官能的基團，如_(1_ 6C)烷基NHS〇2(l-6C)烷基。此類詞是根據精於此技藝者熟 知的意義解釋。例如-(1-6C)烷基NHS〇2(l-6C)烷基包括-甲 基胺基石黃醯基甲基，-甲基胺基石黃醯基乙基，-乙基胺基確 醯基甲基，及-丙基胺基磺醯基丁基。 在有時存在的取代基是選自”0，1，2或3"個基團時，應 了解到此定義包括由此等特定基團之一所選取的所有取代 基’或是此等取代基是選自此特定基團的二個或二個以上 的基團。類似習用語也適用於選自"〇，1或2個”基團，，，〇 或1個”基團的取代基及”1或2個”基團的取代基。 取代基可存在於任何適宜的，例如，烷基的位置。所以 爹莖基取代的（1-6C)烧基包括經基甲基，1-經基乙基，2 -經 基乙基及3 -經基丙基。 (1-4C)烧基的例包括甲基，乙基，丙基及異丙基；（工_ 6C)烷基的例包括甲基，乙基，丙基，異丙基，第三-丁 基，戊基，異-戊基，1-2-二甲基丙基及己基；（3-8C)環烷 • 基的例包括環丙基，環丁基，環戊基及環己基；（3-8C)環 、 烯基的例包括環丙烯基，環丁烯基，環戊烯基及環己烯 基；（5-12C)雙環烧基的例包括正冰片基，萘燒基（雙環 96151.doc -14- 200523234 [4,4,〇]癸基（正式及反式），雙環[5,3,0]癸基及茚烷基（雙環 [4,3,〇]壬基；（6-12C)三環烷基的例包括金剛烷基（三環 [3,3，1，1]癸基），高金剛烷基（三環[4,3，1，1]十一烷基）及菲 烷異構物；-(1_6C)烷基（3_8C)環烷基的例包括-(1-4C)烷基 (3-6C)環烷基，如環丙基甲基，環丙基乙基，環丙基丙 基，環丙基丁基，環丁基甲基，環戊基乙基，環己基甲 基，環己基丙基及環己基丁基；-(1-6C)烷基（3-8C)環烯基 的例包括-(1-4C)烷基（3-6C)環烯基，如環丙烯基甲基，環 丙烯基乙基，環丙烯基丙基，環丙烯基丁基，環丁烯基甲 基，環戊烯基乙基，環己烯基甲基及環己二烯基甲基；（1-6C)烷氧基的例包括甲氧基，乙氧基，丙氧基，異丙氧 基，第三-丁氧基及戊氧基；鹵的例包括氣，溴，氟及 碘；鹵（1-6C)烷基的例包括氟乙基及氟甲基；二鹵（1-6C) 烷基的例包括二氟甲基，1，2-二氟乙基及1，1-二氟乙基； 羥基（1-6C)烷基的例包括羥基甲基，1-羥基乙基，2-羥基 乙基及3-羥基丁基；敌基（1-6C)烧基的例包括羧基甲基， 1-羧基乙基，2-羧基乙基，2-羧基丙基及3-羧基丙基；羧 基（1-6C)烧氧基的例包括緩基甲氧基，1-竣基乙氧基，2-羧基乙氧基，2-羧基丙氧基及3-羧基丙氧基；（1-6C)烷基 胺基的例包括甲基胺基，乙基胺基及丙基胺基；二-((I 6C)烧基）胺基的例包括二甲基胺基，N-乙基-N-甲基胺 基，二乙基胺基，N-甲基-N-丙基胺基及二-異丙基胺基； CO(l-6C)烷基的例包括-CO(l-4C)烷基如曱基羰基，乙基 羰基，丙基羰基，異丙基羰基及第三-丁基羰基；_C〇2(i_ 96151.doc -15- 200523234 6C)烷基的例包括-C02(1-4C)烷基如甲氧基羰基，乙氧基 羰基，丙氧基羰基，異丙氧基羰基及第三-丁氧基羰基； -NHCO(l-6C)烷基的例包括-NHCO(l-4C)烷基，如甲基羰 基胺基，乙基羰基胺基，丙基羰基胺基，異-丙基羰基胺 基及第三-丁基羰基胺基；-CONH(l-6C)烷基的例包 括-CONH(l-4C)烷基，如甲基胺基羰基，乙基胺基羰基， 丙基胺基羰基，異丙基胺基羰基及第三-丁基胺基羰 基；-CON二（1_6C)烷基的例包括-CON二（1-4C)烷基，如 二甲基胺基羰基，N-甲基-N-乙基胺基羰基，二乙基胺基 羰基，N-甲基-N-丙基胺基羰基及二-異丙基胺基羰 基；-S02NH(1-6C)烷基的例包括_S02NH(1-4C)烷基，如 甲基胺基磺醯基，乙基胺基磺醯基，丙基胺基磺醯基， 異-丙基胺基磺醯基及第三-丁基胺基磺醯基；-so2n二（1-6C)烷基的例包括-S02N二（1-4C)烷基，如二甲基胺基磺 酿基，N-甲基-N-乙基胺基石黃酿基，二乙基胺基石黃酿 基，N-甲基-N-丙基胺基磺醯基及二-異丙基胺基磺醯 基；-NHS02(1-6C)烷基的例包括-NHS02(1-4C)烷基如甲 基石黃酿基胺基，乙基續S篮基胺基，丙基礦酿基胺基， 異-丙基磺醯基胺基及第三-丁基磺醯基胺基；-(1-6C)烷基 CO(l-6C)烷基的例包括-(1-4C)烷基CO(l-4C)烷基如甲基 羰基曱基，甲基羰基丁基，乙基羰基甲基，丙基羰基丁 基，異-丙基羰基甲基及第三-丁基羰基甲基；-(1-6C)烷基 CO(3-8C)環烷基的例包括-(1-4C)烷基CO(3-6C)環烷基， 如環丙基羰基甲基，環丙基羰基丁基，環丁基羰基甲基， 96151.doc -16- 200523234 環戊基羰基羰基丁基，環己基羰基甲基及環己基羰基甲 基；-(1-6C)烷基OCO(l-6C)烷基的例包括-(1-4C)烷基 OCO(l-4C)烷基如甲基羰基氧基甲基，甲基羰基氧基丁 基’乙基幾基氧基甲基’丙基幾基氧基丁基’異-丙基幾 基氧基甲基及第三-丁基羰基氧基甲基；-(1-6C)烷基 OCO(3_8C)環烷基的例包括-(1-4C)烷基OCO(3-6C)烷基如 環丙基羰基氧基甲基，環丙基羰基氧基丁基，環丁基羰基 氧基甲基，環戊基羰基氧基丁基，環己基羰基氧基甲基及 環己基羰基氧基甲基；-(1-6C)烷基C02(1-6C)烷基的例包 括-(1-4C)烷基C02(1-4C)烷基如甲氧基羰基甲基，甲氧基 羰基丁基，乙氧基羰基甲基，丙氧基孩基甲基，異-丙氧 基羰基甲基及第三-丁氧基羰基甲基；-(1_6C)烷基CChP-SC) 環烷基的例包括-(1-4C) 烷基 C02(3-6C) 環烷基 ，如環丙 基氧基羰基甲基，環丙基氧基羰基丁基，環丁基氧基羰基 甲基，環戊基氧基羰基甲基，環己基氧基羰基甲基及環己 基氧基羰基甲基；-(1-6C)烷基]VHCO(l-6C)烷基的例包括-(1-4C)烷基NHCO(l-4C)烷基如甲基羰基胺基甲基，甲基羰 基胺基丙基，乙基幾基胺基甲基，丙基魏基胺基甲基， 異-丙基羰基胺基甲基及第三-丁基羰基胺基曱基；-(1-6C) 烷基NHCO(3-8C)環烷基的例包括-(1-4C)烷基NHCO(3-6C) 環烷基如環丙基羰基胺基甲基，環丙基羰基胺基丙基，環 丁基羰基胺基甲基，環戊基羰基胺基曱基，環己基羰基胺 基甲基及環己基羰基胺基乙基；-(1-6C)烷基CONH(l-6C) 烷基的例包括-(1-4C)烷基CONH(l-4C)烷基如甲基胺基羰 96151.doc -17- 200523234vJ * 〇S-S bond) 'If the ring is not quaternized (qUaternised), it is linked by ring carbon atoms and ring nitrogen atoms, and any of the carbon, sulfur or nitrogen atoms can be oxidized; HET2 is Optionally substituted 8-, 9- or 10-membered, unsaturated, partially or fully saturated bicyclic heterocyclic rings containing up to four heteroatoms independently selected from 0, s (but not 0-0, 〇-S or SS bond), and bonded via a ring carbon atom in a ring containing a bicyclic system; HET3 is an N-bonded saturated bicyclic or tricyclic ring system, containing up to 12 ring atoms, including bonded Nitrogen atom; of which (3-8C) cycloalkyl, (5-12C) bicycloalkyl, (6-12C) tricycloalkyl, AR1, AR2, HET1 and HET2 are suitable substituents 1, 2, 3 , 4 or 5 substituents, independently selected from phenyl (optionally substituted with halogen, trifluoromethyl, (1-4C) alkyl or (1-4C) alkoxy), halogen, (1-6C ) Alkyl, halo (1-6C) alkyl, dihalo (1-6C) alkyl, trifluoromethyl, (1-6C) alkane ·· oxy, carboxy (1-6C) alkyl, carboxy ( 1-6C) alkoxy, hydroxy, amino '^ (1-6C) alkylamino, di (1-6C) alkyl Amine, -CONH2, -CONH (l-6C) alkyl, -CONdi (1-6C) alkyl, -NHCO (l-6C) alkyl, -S02 (l-6C) burn 9615l.doc -10 -200523234 group, -S (0) 2NH2, -S02NH (1-6C) alkyl, -S02N di (1-6C) alkyl and -NHS02 (1-6C) alkyl. Yet another embodiment of the present invention includes a compound of formula (I) or a pharmaceutically acceptable salt thereof, in which: A * is a benzene substituted with 1, 2, 3, 4 or 5 groups independently selected from R9 as needed R9 is selected from halogen, (1-6C) alkyl (optionally substituted with 1-5 halogens) '(1-6C) alkoxy (optionally substituted with 1-5 halogens) And cyano; R1 is selected from hydrogen and (1-6C) alkyl; R2 is selected from hydrogen, (1-6C) alkyl, (3-8C) cycloalkyl, (5-12C) bicycloalkyl, (6-12C) tricycloalkyl, AR1, HET1,-(1-6C) alkyl AR1,-(1-6C) alkyl AR2, _ (1-6C) alkyl (3-8C) cycloalkyl ,-(1-6C) alkylHET1,-(1-6C) alkylHET2,-(1-6C) alkylC02 (1-6C) alkyl,-(1-6C) alkylC02 (3- 8C) cycloalkyl,-(1-6C) alkyl CO 2AR1,-(1-6C) alkyl C02HET1,-(1-6C) alkyl OC (l-6C) alkyl,-(1-6C) Alkyl OCO (3-8C) cycloalkyl,-(1-6C) alkyl OCOAR1,-(1-6C) alkyl OCOHET1,-(1-6C) alkyl CO (l-6C) alkyl,- (1-6C) alkyl CO (3-8C) cycloalkyl,-(1-6C) alkyl COAR1,-(1-6C) alkyl COOHET1,-(1-6C) alkyl NHCO (l-6C) alkyl ,-(1-6C) alkylNHCO (3-8C) cycloalkyl,-( 1-6C) alkyl NHCOAR1,-(UC) alkenyl CONH (l-6C) alkenyl,-(1-6C) alkenyl • CONH (3-8C) cycloalkyl,-(1-6C) alkyl CON-di (1-6C) alkyl,-(1-6C) alkyl CONHAR1,-(1-6C) alkylNH (1-6C) alkyl,-(1-6C) alkyl N-di ( 1-6C) alkyl,-(1-6C) alkylNHAR1,-(1-6C) alkyl 96151.doc -11-200523234 NH (HETl),-(1-6C) alkylNHS 2 (l -6C) alkynyl,-(1-6C) alkynyl S02NH (Bu 6C) courtyard and-(1-6C) alkynyl S02N-di (1-6C) alkynyl; or R1 and R2 can be connected to it together The nitrogen forms the ring defined by HET1 ', wherein the ring containing R1 and R2 is optionally substituted by 1 or 2 substituents, and these substituents are independently selected from halogen, (KC) alkyl'halo (1-6C ) Alkyl, (1-6C) alkyl, cyano, carboxyl, carboxyl (1-6C) alkyl, -CO ((l-6C) alkyl, -C02 (l-6C) alkyl, (1-6C) alkylamino, di- (1-6C) alkylamino '• NHCO (Bu 6C) alkyl, -CONH (1- 6C) alkyl, -CON di- (Bu 6C) And HET1; R3 and R4 are independently selected from hydrogen, (1-6C) alkyl,-(1-6C) alkyl (3-8C) cycloalkyl,-(1-6C) alkyl (3-8C ) Cycloalkenyl,-(1-6C) alkyl AR1,-(1-6C) alkyl AR2,-(1-6C) HET1, and-(1-6C) alkyl HET2; or R3 and R4 together form a bad group as defined by (3-8C) cycloalkyl, AR2, HET1 or HET2, R5, R6, R7 and R8 are independently selected From hydrogen and (1-6C) alkyl; AR1 is optionally substituted phenyl; AR2 is optionally substituted 8-, 9- or 10-membered, unsaturated 'partially or fully saturated bicyclic carbon Cyclic ring; HET1 is optionally substituted 3-, 4-, 5- or 6-membered, unsaturated, partially or fully saturated monocyclic heterocyclyl ring containing up to four heteroatoms The atomic system is independently selected from 0, N and S (but not containing 0-〇 '0-s or SS bond), if the ring is not thus quaternised, it is a ring carbon atom or 96151.doc -12- 200523234 Ring nitrogen atoms are linked, and any of the carbon, sulfur or nitrogen atoms may be oxidized; HET2 is optionally substituted 8-, 9- or 10-membered, unsaturated, partially or fully saturated bicyclic Heterocyclic ring containing up to four heteroatoms independently selected from 0, N and S (but not containing 0-〇, 0-S or SS bond), and bonded via a ring carbon atom in a ring containing a bicyclic system; wherein AR1, AR2, HET1 and HE Suitable substituents on T2 are 1, 2, 3, 4 or 5 substituents independently selected from halo, (1-6C) alkyl, halo (1-6C) alkyl, dihalo (1-6C) alkyl, three Fluoromethyl, (1-6C) alkoxy, carboxy (1-6C) alkyl, carboxy (1-6C) alkoxy, hydroxyl, amine, (1-6C) alkylamino, di (1-6C ) Alkylamino, -CONH2, -CONH (l-6C) alkyl, -CON di (1-6C) alkyl, -NHCO (l-6C) alkyl, -S (0) 2NH2, -S02NH ( 1-6C) alkyl, -S02N di (1-6C) alkyl and -NHS02 (1-6C) alkyl. For the avoidance of doubt, it must be understood that in this description, the groups modified by 'previously defined' or 'as defined later, including the first occurrence and the broadest definition, and each and all of the Specific definition of group. It should be understood that 'the substituent includes two substituents on the alkyl chain, where the two are linked by a heteroatom (such as an alkoxy substituent), so this disubstituent is not on the same carbon atom of the alkyl chain. Substituents. In this description, the term 'πalkenyl' includes both straight and branched alkyl radicals, but when referring to individual alkyl groups such as "propyl," it only means straight chain. The same customary v The term applies to other attribute words. Unless otherwise stated, the term "alkyl" preferably means a chain of 1 to 6 carbon atoms, more preferably 4 to 4 carbon atoms. 96151.doc -13- 200523234 In this description, the term "alkoxy" means the aforementioned alkyl group attached to an oxygen atom. It should be understood that the sometimes occurring substituents on any group, unless otherwise specified, may be attached to any atom present, including heteroatoms, if such heteroatoms are not thus quaternized. In this description, a combination word is used to describe a group containing multiple functional groups, such as _ (1_6C) alkylNHS0 (1-6C) alkyl. Such words are interpreted according to meanings familiar to those skilled in the art. For example,-(1-6C) alkylNHS0 (1-6C) alkyl includes -methylaminosulfaroxanylmethyl, -methylaminosulfoxanthenylethyl, -ethylaminosulfanylmethyl, and -Propylaminosulfonylbutyl. When the substituents sometimes present are selected from "0, 1, 2 or 3" groups, it should be understood that this definition includes all substituents selected by one of these specific groups, or such substitutions. A group is two or more groups selected from this particular group. Similar idioms also apply to the substitution of "0, 1 or 2" groups, and 0 or 1 "groups. And "1 or 2" groups of substituents. Substituents can be present at any suitable position, for example, the position of an alkyl group. Therefore, the substituted (1-6C) alkyl group includes a methyl group, 1 -Ethylethyl, 2-Ethylethyl, and 3-Ethylpropyl. (1-4C) Examples of the alkyl group include methyl, ethyl, propyl, and isopropyl; (I-6C) alkyl Examples include methyl, ethyl, propyl, isopropyl, tert-butyl, pentyl, iso-pentyl, 1- 2-dimethylpropyl and hexyl; (3-8C) cycloalkane • Examples of the group include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; (3-8C) Examples of the ring and alkenyl include cyclopropenyl, cyclobutenyl, cyclopentenyl, and cyclohexenyl; (5-12C) Examples of bicyclic alkyl groups include norbornyl and naphthyl Bicyclic 96151.doc -14- 200523234 [4,4, 〇] decyl (formal and trans), bicyclic [5,3,0] decyl and indenyl (bicyclo [4,3, 〇] nonyl; Examples of (6-12C) tricycloalkyl include adamantyl (tricyclo [3,3,1,1] decyl), homoadamantyl (tricyclo [4,3,1,1] undecane) Groups) and phenanthrene isomers; examples of-(1-6C) alkyl (3-8C) cycloalkyl include-(1-4C) alkyl (3-6C) cycloalkyl, such as cyclopropylmethyl, cyclopropyl Ethyl, cyclopropylpropyl, cyclopropylbutyl, cyclobutylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylpropyl and cyclohexylbutyl;-(1-6C) alkyl ( Examples of 3-8C) cycloalkenyl include-(1-4C) alkyl (3-6C) cycloalkenyl, such as cyclopropenylmethyl, cyclopropenylethyl, cyclopropenylpropyl, cyclopropenylbutene Group, cyclobutenylmethyl, cyclopentenylethyl, cyclohexenylmethyl and cyclohexadienylmethyl; examples of (1-6C) alkoxy include methoxy, ethoxy, Propoxy, isopropoxy, tert-butoxy and pentoxy; examples of halogen include gas, bromine, fluorine and iodine; examples of halogen (1-6C) alkyl include fluoroethyl and fluoromethyl ; Dihalogen (1-6C) Examples of the group include difluoromethyl, 1,2-difluoroethyl and 1,1-difluoroethyl; examples of the hydroxy (1-6C) alkyl group include hydroxymethyl, 1-hydroxyethyl, 2- Hydroxyethyl and 3-hydroxybutyl; examples of di (1-6C) alkyl include carboxymethyl, 1-carboxyethyl, 2-carboxyethyl, 2-carboxypropyl, and 3-carboxypropyl; Examples of the carboxyl (1-6C) alkoxy group include a slow methoxy group, a 1-octylethoxy group, a 2-carboxyethoxy group, a 2-carboxypropoxy group, and a 3-carboxypropoxy group; (1- 6C) Examples of alkylamino groups include methylamino, ethylamino and propylamino; examples of di-((I 6C) alkyl) amino include dimethylamino, N-ethyl- N-methylamino, diethylamino, N-methyl-N-propylamino and di-isopropylamino; examples of CO (l-6C) alkyl include -CO (l-4C ) Alkyl groups such as fluorenylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl and tert-butylcarbonyl; examples of -C02 (i_96151.doc -15-200523234 6C) alkyl include -C02 ( 1-4C) alkyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl and third-butoxycarbonyl; examples of -NHCO (l-6C) alkyl include -NHCO (l-4C) Groups such as methylcarbonylamino, ethylcarbonylamino, propylcarbonylamino, iso-propylcarbonylamino and tertiary-butylcarbonylamino; examples of -CONH (l-6C) alkyl include -CONH (l-4C) alkyl, such as methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, isopropylaminocarbonyl and third-butylaminocarbonyl; -CON di (1-6C Examples of alkyl groups include -CON di (1-4C) alkyl, such as dimethylaminocarbonyl, N-methyl-N-ethylaminocarbonyl, diethylaminocarbonyl, N-methyl- N-propylaminocarbonyl and di-isopropylaminocarbonyl; examples of -S02NH (1-6C) alkyl include -S02NH (1-4C) alkyl, such as methylaminosulfonyl, ethyl Aminosulfonyl, propylaminosulfonyl, iso-propylaminosulfonyl and tertiary-butylaminosulfonyl; Examples of -so2n di (1-6C) alkyl include -S02N Di (1-4C) alkyl, such as dimethylaminosulfonyl, N-methyl-N-ethylaminosulfuryl, diethylaminosulfuryl, N-methyl-N- Propylaminosulfonyl and di-isopropylaminosulfonyl; examples of -NHS02 (1-6C) alkyl include -NHS02 (1-4C) alkyl such as methyl azinylamino, Ethyl Continued S-basic amino group, propyl mineral amino group, iso-propylsulfonylamino group and tertiary-butylsulfonylamino group;-(1-6C) alkylCO (l-6C) Examples of alkyl include-(1-4C) alkylCO (l-4C) alkyl such as methylcarbonylfluorenyl, methylcarbonylbutyl, ethylcarbonylmethyl, propylcarbonylbutyl, iso-propyl Examples of carbonylmethyl and third-butylcarbonylmethyl;-(1-6C) alkylCO (3-8C) cycloalkyl include-(1-4C) alkylCO (3-6C) cycloalkyl , Such as cyclopropylcarbonylmethyl, cyclopropylcarbonylbutyl, cyclobutylcarbonylmethyl, 96151.doc -16- 200523234 cyclopentylcarbonylcarbonylbutyl, cyclohexylcarbonylmethyl and cyclohexylcarbonylmethyl; Examples of-(1-6C) alkyl OCO (l-6C) alkyl include-(1-4C) alkyl OCO (l-4C) alkyl such as methylcarbonyloxymethyl, methylcarbonyloxybutane 'Ethyl-Echyloxymethyl'propyl-Ethyloxybutyl'iso-propyl-Ethyloxymethyl and tertiary-butylcarbonyloxymethyl;-(1-6C) alkyl Examples of OCO (3-8C) cycloalkyl include-(1-4C) alkyl OCO (3-6C) alkyl such as cyclopropylcarbonyloxymethyl, cyclopropylcarbonyloxybutyl, cyclobutylcarbonyloxy Methyl, cyclopentylcarbonyl Butyl, cyclohexylcarbonyloxymethyl and cyclohexylcarbonyloxymethyl; examples of-(1-6C) alkylC02 (1-6C) alkyl include-(1-4C) alkylC02 (1 -4C) Alkyl such as methoxycarbonylmethyl, methoxycarbonylbutyl, ethoxycarbonylmethyl, propoxymethyl, iso-propoxycarbonylmethyl and tert-butoxy Carbonylmethyl;-(1-6C) alkylCChP-SC) Examples of cycloalkyl include-(1-4C) alkylC02 (3-6C) cycloalkyl, such as cyclopropyloxycarbonylmethyl, cyclopropyl Oxycarbonylbutyl, cyclobutyloxycarbonylmethyl, cyclopentyloxycarbonylmethyl, cyclohexyloxycarbonylmethyl and cyclohexyloxycarbonylmethyl;-(1-6C) alkyl] Examples of VHCO (l-6C) alkyl include-(1-4C) alkyl NHCO (l-4C) alkyl such as methylcarbonylaminomethyl, methylcarbonylaminopropyl, ethylepiamino Methyl, propylweilylaminomethyl, iso-propylcarbonylaminomethyl and tertiary-butylcarbonylaminofluorenyl;-(1-6C) alkylNHCO (3-8C) cycloalkyl Examples include-(1-4C) alkylNHCO (3-6C) cycloalkyl such as cyclopropylcarbonylaminomethyl, cyclopropylcarbonylaminopropyl, cyclobutylcarbonylaminomethyl, cyclopentyl base Carbonylaminomethyl, cyclohexylcarbonylaminomethyl and cyclohexylcarbonylaminoethyl; examples of-(1-6C) alkylCONH (l-6C) alkyl include-(1-4C) alkylCONH (l-4C) alkyl such as methylaminocarbonyl 96151.doc -17- 200523234

基甲基，甲基胺基羰基丙基，乙基胺基羰基甲基，丙基胺 基羰基甲基，異-丙基胺基羰基甲基及第三-丁基胺基羰基 甲基；-(1-6C)烷基CON二（1-6C)烷基的例包括-(1-4C)烷基 CON二（1-4C)烷基如二甲基胺基羰基甲基，二甲基胺基羰 基丙基，N-甲基乙基胺基羰基甲基，二乙基胺基羰基 甲基，N-甲基-N-丙基胺基羰基甲基及二—異丙基胺基羰基 甲基；-(1_6C)烷基CONH(3_8C)環烷基的例包括例如-(1-4C)烷基CONH(3-6C)環烷如環丙基胺基羰基甲基，環丙基 胺基羰基丙基，環丁基胺基羰基甲基，環戊基胺基羰基甲 基，環己基胺基羰基甲基及環己基胺基羰基乙基；-(1-6C) 烷基NH(1-6C)烷基的例包括-(1-4C)烷基NH(1-4C)烷基如 甲基胺基甲基，甲基胺基丙基，乙基胺基甲基，丙基胺基 甲基，異-丙基胺基甲基及第三-丁基胺基甲基；-(1-6C)烷 基N二（1-6C)烷基的例包括-(1-4C)烷基N二（1-4C)烷基如二 甲基胺基甲基，二甲基胺基丙基，N-甲基-N-乙基胺基甲 基’二乙基胺基甲基’ N-甲基-N-丙基胺基甲基及二異丙 基胺基甲基；-(1-6C)烷基S02NH(1_6C)烷基的例包括-（1-4C)烷基S02NH(1-4C)烷基如甲基胺基磺醯基甲基，甲基胺 基績酿基丙基，乙基胺基績醯基甲基，丙基胺基石黃酸基甲 基，異丙基胺基磺醯基甲基及第三-丁基胺基磺醯基甲基 胺基磺醯基曱基；-(1-6C)烷基S02N: (1_6C)烷基的例包 括-(1-4C)烷基S02N:(1-4C)烷基如二甲基胺基磺醯基甲 基，二甲基胺基磺醯基丙基，N-甲基_N-乙基胺基磺醯基 甲基，二乙基胺基磺醯基甲基，N-甲基-N-丙基胺基磺醯 96151.doc -18 - 200523234 基甲基及二-異丙基胺基磺醯基甲基；-(1-6C)烷基 NHS02(1-6C)烷基的例包括-(1-4C)烷基NHS02(1-4C)烷基 如甲基磺醯基胺基甲基，甲基磺醯基胺基丙基，乙基磺醯 基胺基丙基甲，丙基磺醯基胺基甲基，異-丙基磺醯基胺 基甲基及第三-丁基磺醯基胺基甲基；-(1-6C)烷基S02(1-6C)烷基的例包括-(1-4C)烷基S02(1-4C)烷基如甲基磺醯基 甲基，甲基磺醯基丙基，乙基磺醯基甲基，丙基磺醯基甲 基，異-丙基磺醯基甲基及第三-丁基磺醯基甲基；-so2(i-6C)烷基的例包括S02(1-4C)烷基如甲基磺醯基乙基磺醯 基，丙基，異丙基磺醯基及第三-丁基磺醯基。 -(1-6C)烷基AR1的例包括（每一例是視需要經取代的）苄 基，苯基乙基及苯基丁基。-(1-6C)烷基COAR1的例包括 (每一例是視需要經取代的）苯氧基羰基甲基，苯氧基羰基 乙基，苯氧基羰基丙基及苯氧基羰基丁基。-(1-6C)烷基 C02AR1之實例包括（各實例視情況經取代）苯氧羰基甲基， 苯氧羰基乙基，苯氧羰基丙基及苯氧羰基丁基。-(1-6C)烷 基OCOAR1之實例包括（各實例視情況經取代）苯氧羰氧基 甲基，苯氧羰氧基乙基，苯氧羰氧基丙基及苯氧羰氧基丁 基。-(1-6C)烷基NHCOAR1的例包括（每一例是視需要經取 代的）苯基魏基胺基甲基，苯基魏基胺基乙基，苯基幾基 胺基丙基及苯基羰基胺基丁基。-(1_6C)烷基CONHAR1的 例包括（每一例是視需要經取代的）苯基胺基羰基甲基，苯 基胺基羰基乙基，苯基胺基羰基丙基及苯基胺基羰基甲 基。-(1-6C)烷基NHAR1的例包括（每一例是視需要經取代 96151.doc -19- 200523234 的）苯基胺基甲基，苯基胺基乙基，苯基胺基丙基及苯基 胺基丁基。 AR2的特定例包括，例如，萘基，茚滿基，茚烯基，二 氫萘基及1，2,3,4-四氫萘基。 -(1-6C)烷基AR2的例包括（每一例是視需要經取代的）萘 基甲基，萘基乙基，茚滿基甲基，茚滿基乙基，茚滿基丙 基，茚滿基丁基，茚烯基甲基，茚烯基乙基，二氫萘基甲 基，二氫萘基丙基及1，2,3,4-四氫萘基甲基。 HET1的特疋值包括，例如（每一例是視需要經取代的） 呋喃基，吡咯基，噻吩基，吡唑基，咪唑基，吡啶基，嘧 σ定基’ σ比唤基’璉唤基’ 1，2,3-三嗪基，ι，2,4_三ϋ秦基， 1，3,5-二嗪基’ 1，2,3-及1，2,4-三唾基，四峻基，嗔峻基， 異噁唑基，噁嗪基，噁二唑基，噻唑基，異嗟峻基， 1，2，4 -及1，3，4 -σ塞一 σ坐基’ σ惡唾琳’ n塞唾琳二氫σ比洛基（特 別是2,5-二氫吡咯-4-基），四氫吡啶基（特別是丨，2,5,6•四氫 口比啶-4-基），四氫咬喃基，四氫噻吩基，丨_氧代四氫嗟吩 基，1，1-二氧代四氫養吩基，吡咯啶基，2_氧代吡洛。定 基，噁唑烷，噻唆烧，嗎福啉基，硫代嗎福啉基，六氫吡 嗪基，咪唑基，六氫吡啶基，2-氧代六氫吡啶基，丨，弘二 氧茂烧-4-基，1，3-二°惡烧-4-基，1，3_二。惡烧_5_基及1，4_二 。惡烧-2 -基。 其他ΗΕΤ1的特定值包括（每一值都是視需要經取代的）呋 喃基，吡咯基，噻吩基，吡唑基，咪唑基，吡啶基，嘧啶 基，吨嗪基，噠嗪基’ 1，2,3-及1，2,4-三唑基，四唑基，嗔 96151.doc -20- 200523234 唑基，異噁唑基，噁嗪基，噁二唑基，噻唑基，異噻喷 基，1，2,4_及1，3,4-σ塞二唾基，°惡嗤琳，嗟峻淋，六氫。比嗓 基及味17坐基。 ΗΕΤ1其他特定值包括（每一值都是視需要經取代的）二氣 吡咯基（特別是2,5-二氫吡咯-4-基），四氫吡啶基（特別是 1，2,5,6-四氫吡啶-4-基），四氫呋喃基，四氫噻吩基，1_氧 代四氫噻吩基，1,1-二氧代四氫噻吩基，吡咯啶基，噁唉 烷，噻唑烷，嗎福啉基，硫代嗎福啉基，六氫吡啶基， 1，3-二氧茂烷-4-基，1，3-二噁烷-4-基，1，3-二噁烷-5-基及 1，4-二噁烷-2-基。 ΗΕΤ1其他特定值包括（每一值都是視需要經取代的）咬喃 基，噻吩基，吼啶基，噁唑基，異噁唑基，噻唑基，異嗟 唑基，四氫呋喃基，四氫嘧吩基，1 -氧代四氫噻吩基， 1，1-二氧代四氫噻吩基，吡咯啶基，2_氧代吡咯啶基，嗎 福啉基，硫代嗎福啉基，六氫吡嗪基，六氫吡啶基及2_氧 代六氫°比啶基。 ΗΕΤ1其他特定值包括（每一值都是視需要經取代的）σ夫喃 基，噻吩基，吡啶基’噻唑基，四氫噻吩基，1 _氧代四氫 噻吩基，1，1_二氧代四氫噻吩基，咣咯啶基，2-氧代吡，各 啶基，嗎福啉基，硫代嗎福啉基及六氫吡σ定基。 ΗΕΤ1其他特定值包括（每一值都是視需要經取代的）呋喃 基，噻吩基，吡啶基，噻唑基，二氧代四氩噻吩基， 吡咯啶基，2-氧代吡咯啶基，嗎福啉基及六氫吡啶基。 應了解到，當R1及R2共同與其相聯的氮形成環HET1 96151.doc -21 - 200523234 時，環HET1必須是這樣的環，其容許使環經由氮原子聯 於其相聯的羰基上，而且此環在相聯時氮原子不會季銨 化。此處所述特定的HET1的適宜值包括，例如，σ比洛 基，σ比唆基，味嗤基，四唾基，二氫σ比嘻基，四氫σ比口各 基，吡咯啶基，2-氧代吡咯啶基，噁唑啶基，噻唑啶基， 嗎福琳基，硫代嗎福淋基，六氫σ比唤基，六氫°比咬基或2-氧代六氫吼σ定基。 -(1-6C)烷基ΗΕΤ1的例包括上述聯於任何（1-6C)烷基上 的ΗΕΤ1的特定值，所以包括例如（視需要經取代的）吡啶甲 基，°比°定乙基，^比σ定丙基，°比°定丁基及°比°定己基。 -(1-6C)烷基COHET1之實例包括經由羰基連接於任何 (1-6C)烷基值的任一特定ΗΕΤ1值，因此包括例如（視需要 經取代的）吡啶基羰基甲基，吡啶基羰基乙基，吡啶基羰 基丙基、吡啶羰基丁基及吼啶基羰基己基。 -(1-6C)烷基C02HET1的例包括經由氧基羰基聯於任何 (1-6C)烷基值的上述特定HET1的值，所以包括例如（視需 要經取代的）吡啶基氧基羰基甲基，吡啶基氧基羰基乙 基，σ比啶基氧基羰基丙基，吼啶基氧基羰基丁基及σ比啶基 氧基魏基己基。 -(1-6C)烷基OCOHET1的例包括經由羧基聯於任何（1- 6C)烷基值上的上述任何ΗΕΤ1值，所以包括例如（視需要經 取代的”比啶基羧基甲基，吡啶基羧基乙基，吡啶基羧基 丙基，σ比啶基羧基丁基及吨啶基羧基己基。 -(1-6C)烷基NH(HETl)的例包括經由胺基聯於任何（1- 96151.doc -22- 200523234 6C)烷基值上的上述任何HET1值，所以包括例如（視需要經 取代的）吡啶基胺基甲基，吡啶基胺基乙基，吡啶基胺基 丙基，σ比啶基胺基丁基及α比啶基胺基己基。 HEΤ2的特定值包括，例如，叫| σ朵，苯并吱喃基，苯并 嗟吩基，笨并咪唑基，苯并噻唑基，苯并異噻唑基，苯并 嗔σ坐基’苯并異噁唑基，喹啉基，異喹啉基，喹喏啉基， 喹唑啉基，二氮雜萘基，噌啉基，二氫吲哚基，i，2,3,4_ 四氫1琳基，2，3 - 一氫苯并u夫喃基，苯并二氫σ比喊基，異 苯并二氫处喃基，2,3-二氫苯并噻唑基，2,3·二氫苯并咪 嗤基’笨并二氧戊環基，嘌呤基及二氮雜萘基。 另外些特疋ΗΕΤ2值包括，例如，,嗓，苯并吱喃 基’苯并噻吩基，喹啉基及異喹啉基。 ΗΕΤ2的又一些特定值包括雙環雜芳基環系統，有至少 一個橋頭（bridgehead)氮及視需要有的丨_3個選自氧，硫及 氮的雜原子。此類環系統的特定例包括，例如，吡咯 并[l，2-a]吨咯基，吡咯并⑻外塞唑基，lH“米唑并[1 吡咯基，m-咪唑并n，2_a]咪唑基，1Η，3Η_π比咯并Methyl, methylaminocarbonylpropyl, ethylaminocarbonylmethyl, propylaminocarbonylmethyl, iso-propylaminocarbonylmethyl and tertiary-butylaminocarbonylmethyl; Examples of (1-6C) alkylCONdi (1-6C) alkyl include-(1-4C) alkylCONdi (1-4C) alkyl such as dimethylaminocarbonylmethyl, dimethylamine Carbonylcarbonylpropyl, N-methylethylaminocarbonylmethyl, diethylaminocarbonylmethyl, N-methyl-N-propylaminocarbonylmethyl and di-isopropylaminocarbonylmethyl Examples of-(1-6C) alkyl CONH (3_8C) cycloalkyl include, for example,-(1-4C) alkyl CONH (3-6C) cycloalkane such as cyclopropylaminocarbonylmethyl, cyclopropylamino Carbonylpropyl, cyclobutylaminocarbonylmethyl, cyclopentylaminocarbonylmethyl, cyclohexylaminocarbonylmethyl and cyclohexylaminocarbonylethyl;-(1-6C) alkylNH (1- 6C) Examples of alkyl include-(1-4C) alkylNH (1-4C) alkyl such as methylaminomethyl, methylaminopropyl, ethylaminomethyl, propylaminomethyl Group, iso-propylaminomethyl and tertiary-butylaminomethyl; examples of-(1-6C) alkylN di (1-6C) alkyl include-(1-4C) alkylN Di (1-4C) alkyl such as di Aminoaminomethyl, dimethylaminopropyl, N-methyl-N-ethylaminomethyl'diethylaminomethyl 'N-methyl-N-propylaminomethyl and Examples of diisopropylaminomethyl;-(1-6C) alkylS02NH (1-6C) alkyl include-(1-4C) alkylS02NH (1-4C) alkyl such as methylaminosulfonyl Methyl, methylamino, methylpropyl, ethylamino, methylmethyl, propylamino, luteinyl methyl, isopropylaminosulfomethyl, and tert-butylamine Sulfosulfanylmethylaminosulfofluorenylfluorenyl;-(1-6C) alkyl S02N: Examples of (1-6C) alkyl include-(1-4C) alkyl S02N: (1-4C) alkyl such as Dimethylaminosulfomethyl, dimethylaminosulfopropyl, N-methyl_N-ethylaminosulfomethyl, diethylaminosulfomethyl, N-methyl-N-propylaminosulfonium 96151.doc -18-200523234 methyl and di-isopropylaminosulfonylmethyl;-(1-6C) alkylNHS02 (1-6C Examples of) alkyl include-(1-4C) alkylNHS02 (1-4C) alkyl such as methylsulfonylaminomethyl, methylsulfonylaminopropyl, ethylsulfonylamino Propylmethyl, propylsulfonylaminomethyl, iso-propylsulfonyl Aminomethyl and tertiary-butylsulfonylaminomethyl; examples of-(1-6C) alkyl S02 (1-6C) alkyl include-(1-4C) alkyl S02 (1-4C ) Alkyl groups such as methylsulfonylmethyl, methylsulfonylpropyl, ethylsulfonylmethyl, propylsulfonylmethyl, iso-propylsulfonylmethyl and tert-butyl Examples of -sulfosulfanylmethyl; -so2 (i-6C) alkyl include S02 (1-4C) alkyl such as methylsulfonylethylsulfonyl, propyl, isopropylsulfonyl and Tri-butylsulfonyl. Examples of-(1-6C) alkyl AR1 include (each is optionally substituted) benzyl, phenylethyl and phenylbutyl. Examples of-(1-6C) alkyl COAR1 include (each is optionally substituted) phenoxycarbonylmethyl, phenoxycarbonylethyl, phenoxycarbonylpropyl, and phenoxycarbonylbutyl. Examples of-(1-6C) alkyl C02AR1 include (each example optionally substituted) phenoxycarbonylmethyl, phenoxycarbonylethyl, phenoxycarbonylpropyl, and phenoxycarbonylbutyl. Examples of-(1-6C) alkyl OCOAR1 include (each case is substituted as appropriate) phenoxycarbonyloxymethyl, phenoxycarbonyloxyethyl, phenoxycarbonyloxypropyl and phenoxycarbonyloxybutyl base. Examples of-(1-6C) alkyl NHCOAR1 include (each case is substituted as necessary) phenylweilylaminomethyl, phenylweilylaminoethyl, phenylepiaminopropyl and benzene Carbonylaminoaminobutyl. Examples of-(1_6C) alkyl CONHAR1 include (each case is substituted as necessary) phenylaminocarbonylmethyl, phenylaminocarbonylethyl, phenylaminocarbonylpropyl and phenylaminocarbonylmethyl base. Examples of-(1-6C) alkyl NHAR1 (each case is substituted as required by 95151.doc -19-200523234) phenylaminomethyl, phenylaminoethyl, phenylaminopropyl and Phenylaminobutyl. Specific examples of AR2 include, for example, naphthyl, indanyl, indenenyl, dihydronaphthyl, and 1,2,3,4-tetrahydronaphthyl. Examples of-(1-6C) alkyl AR2 include (each is optionally substituted) naphthylmethyl, naphthylethyl, indanylmethyl, indanylethyl, indanylpropyl, Indanylbutyl, indenenylmethyl, indenenylethyl, dihydronaphthylmethyl, dihydronaphthylpropyl and 1,2,3,4-tetrahydronaphthylmethyl. The specific values of HET1 include, for example, (each case is substituted as necessary) furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, pyridyl, pyrimidine, and sigma group. 1,2,3-triazinyl, ι, 2,4-trisinophenyl, 1,3,5-diazinyl '1,2,3- and 1,2,4-trisialyl, tetramethylene Radical, isoxazolyl, isoxazolyl, oxazinyl, oxadiazolyl, thiazolyl, isoxazolyl, 1,2,4-and 1,3,4- -sigma-sigma 'sigma Sialin 'n sialin dihydroσbiloki (especially 2,5-dihydropyrrole-4-yl), tetrahydropyridyl (especially 丨, 2,5,6 • tetrahydropyridine- 4-yl), tetrahydropyranyl, tetrahydrothienyl, oxo-tetrahydrofluorenyl, 1,1-dioxotetrahydrophenyl, pyrrolidinyl, 2-oxopyrrolo. Amidyl, oxazolidine, thienyl, morpholinyl, thiomorpholinyl, hexahydropyrazinyl, imidazolyl, hexahydropyridyl, 2-oxohexahydropyridyl, Benzol-4-yl, 1,3-di ° oxazol-4-yl, 1,3-bis. Smoldering _5_ base and 1,4_ 2. Smoldering -2 -yl. Other specific values of ΗET1 include (each value is optionally substituted) furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, toxazinyl, pyridazinyl '1, 2,3- and 1,2,4-triazolyl, tetrazolyl, fluorene 96151.doc -20- 200523234 oxazolyl, isoxazolyl, oxazinyl, oxadiazolyl, thiazolyl, isothiazole Base, 1,2,4_ and 1,3,4-σ cydiasialyl, ° Epirin, 嗟 Junlin, hexahydro. Than the base and taste 17 base. Other specific values of QET1 include (each value is optionally substituted) dipyrrole (especially 2,5-dihydropyrrole-4-yl), tetrahydropyridyl (especially 1, 2, 5 ,, 6-tetrahydropyridin-4-yl), tetrahydrofuranyl, tetrahydrothienyl, 1-oxotetrahydrothienyl, 1,1-dioxotetrahydrothienyl, pyrrolidinyl, oxapinane, thiazolidine , Morpholinyl, thiomorpholinyl, hexahydropyridyl, 1,3-dioxocane-4-yl, 1,3-dioxan-4-yl, 1,3-dioxane -5-yl and 1,4-dioxan-2-yl. Other specific values of QET1 include (each value is substituted as necessary) sulfanyl, thienyl, iridinyl, oxazolyl, isoxazolyl, thiazolyl, isoxazolyl, tetrahydrofuranyl, tetrahydro Pyridinyl, 1-oxotetrahydrothienyl, 1,1-dioxotetrahydrothienyl, pyrrolidinyl, 2-oxopyrrolidinyl, morpholinyl, thiomorpholinyl, six Hydropyrazinyl, hexahydropyridyl and 2-oxohexahydro ° pyridyl. Other specific values of QET1 include (each value is optionally substituted) sigmafuranyl, thienyl, pyridyl'thiazolyl, tetrahydrothienyl, 1-oxotetrahydrothienyl, 1,1-di Oxotetrahydrothienyl, pyrrolidinyl, 2-oxopyridyl, each pyridyl, morpholinyl, thiomorpholinyl and hexahydropyridine sigmadenyl. Other specific values of QET1 include (each value is optionally substituted) furanyl, thienyl, pyridyl, thiazolyl, dioxotetraldienyl, pyrrolidinyl, 2-oxopyrrolidin, Fluorolinyl and hexahydropyridyl. It should be understood that when R1 and R2 together form a ring HET1 96151.doc -21-200523234, the ring HET1 must be a ring that allows the ring to be linked to its associated carbonyl group through a nitrogen atom, Moreover, the nitrogen atom will not be quaternized when this ring is linked. Suitable values for the specific HET1 described herein include, for example, σbilocyl, σbifluorenyl, miso, tetrasialyl, dihydroσbicycloyl, tetrahydroσbiyl, pyrrolidinyl , 2-oxopyrrolidyl, oxazolyl, thiazolyl, morpholinyl, thiomorpholinyl, hexahydrosigma, hexahydro ° specificity or 2-oxohexahydro Roar σ fixed base. -Examples of (1-6C) alkyl ΗET1 include the above-mentioned specific values of 联 ET1 linked to any (1-6C) alkyl group, and thus include, for example, (substituted if necessary) pyridyl, °°°° ethyl , ^ Than σ fixed propyl, ° than ° fixed butyl and ° than ° fixed hexyl. -Examples of (1-6C) alkyl COHET1 include any particular ΗET1 value attached to any (1-6C) alkyl value via a carbonyl group, and thus include, for example (substituted if necessary) pyridylcarbonylmethyl, pyridyl Carbonylethyl, pyridylcarbonylpropyl, pyridylcarbonylbutyl, and pyridylcarbonylhexyl. -Examples of (1-6C) alkyl C02HET1 include the above-mentioned specific HET1 value linked to any (1-6C) alkyl value via an oxycarbonyl group, and thus include, for example (substituted if necessary) pyridyloxycarbonylmethyl Group, pyridyloxycarbonylethyl, σ-pyridinyloxycarbonylpropyl, carbamoyloxycarbonylbutyl and σ-pyridyloxyweilylhexyl. -Examples of (1-6C) alkyl OCOHET1 include any of the above FET1 values linked to any (1- 6C) alkyl value via a carboxyl group, so include, for example (substituted as needed) than pyridylcarboxymethyl, pyridine Carboxylethyl, pyridylcarboxypropyl, σ-pyridylcarboxybutyl and tolylcarboxyhexyl. Examples of (1-6C) alkylNH (HETl) include any .doc -22- 200523234 6C) Any of the above HET1 values on the alkyl value, so include for example (substituted as necessary) pyridylaminomethyl, pyridylaminoethyl, pyridylaminopropyl, σ Pyridylamino butyl and α-pyridylaminohexyl. Specific values for HET2 include, for example, sigma | benzo, benzopyranyl, benzofluorenyl, benzimidazolyl, benzothiazolyl , Benzoisothiazolyl, benzofluorene sigma'benzoisoxazolyl, quinolinyl, isoquinolinyl, quinazoline, quinazolinyl, diazanaphthyl, fluorinyl, Dihydroindolyl, i, 2,3,4_ tetrahydro 1 linyl, 2,3-monohydrobenzoufuranyl, benzodihydrosigmayl, isobenzodihydroanyl, 2,3-dihydrobenzothia Group, 2,3 · dihydrobenzimidyl ', benzodioxolyl, purinyl, and diazanaphthyl. Other special ET2 values include, for example, benzo, benzocranyl' Benzothienyl, quinolinyl, and isoquinolinyl. Some other specific values of ET2 include a bicyclic heteroaryl ring system, at least one bridgehead nitrogen and optionally __3 selected from oxygen and sulfur. And nitrogen heteroatoms. Specific examples of such ring systems include, for example, pyrrolo [l, 2-a] tyrrolyl, pyrrolopyrazolyl, lH "mizolo [1 pyrrolyl, m- Imidazon, 2_a] imidazolyl, 1Η, 3Η_π ratio pyrrole

噁唑基，1Η-咪唑并[i，5-a]吡咯基，吡咯 ’ C ^ I ,, 开Li，2-b]異噁唑 基，咪唑开[5，l-b]噻唑基，咪唑并Rbb]噻唑基，中，『 基，咪唑并[l，2-ap比啶基，咪唑并 :虱印 [1，5青比°定基，。比洛并[1，叫噠嗪基，„比„各 ^ 开 Ll，2-c]0密口定 各开[1，2_a]m，_并m [2，l-c]-s-三唑基，s-三唑[丨，^]吡啶基，咪唑并 咬基’㈣并[糾比嗪基，咪唾并π，2_，。定基’，：: 96151.doc -23- 200523234 并[l，5-a]°比嗪基，咪唑并[i，5-a]a比唤基，咪唑并[1，2_6]噠 嗪基，s-二唑并[4,3-a]嘧啶基，咪唑并[5，1-b]噁唑基及咪 嗤并[2,1 -b]噁唑基。此類環系統之其他特定例包括，例 如，[1H]-吨咯并[2’bc]噁嗪基，[3Η]_噁唑并[3，扣a]g比啶 基，[6H]-吼咯并[2,卜c]噁嗪基及吼啶并[2，l-c][l，4]噁嗪 基。其他5/5-雙ί哀糸統的特定例是味σ坐并σ惡嗤基或咪哇并 σ塞嗤基，特別是咪嗤并[5，l-b]嗟唾基，咪σ坐并[2，i-b]^n^ 基，咪唑并[5，l-b]噁唑基或咪唑并[2，l-b]噁唑基。 -(1-6C)烷基HET2的例包括聯於任何（KC)烷基值上的 上述HET2特定值之一，所以包括例如（視需要經取代的）吲 吲哚基甲基，吲哚基乙基，吲哚基丙基，吲哚基丁基及吲 0木基己基。此處所用命名見於，例如，”Heterocyclic Compounds (Systems with bridgehead nitrogen)W.L. Mosby (Interscience Publishers Inc·，New York), 1961，Parts 1 and 2 〇 HET3的特定值包括，例如，α引σ朵基，苯并味σ坐基，二 氫吲哚基，1，2,3,4-四氫嗤琳基，2,3_二氫°塞嗤基，2,3-二 氫苯并σ米11坐基及票吟基。 AR1，AR2，HET1及HET2上有時存在的取代基的特定 值是1，2,3,4或5個取代基，其係獨立選自氰基，鹵，（1-6C) 烷基，鹵（1-6C)烷基，二鹵（1-6C)烷基，三氟甲基，（1-6C) 烷氧基，羧基（1-6C)烷基，羧基（1-6C)烷氧基，羥基， 胺基，（1-6C)烷基胺基，二（1-6C)烷基胺基，-CONH2， -CONH(l-6C)烷基，-CON 二（1-6C)烷基，_NHCO(l-6C)烷 96151.doc -24- 200523234 基，-S(0)2NH2，-S02NH(1-6C)烷基，-S02N 二（1-6C)烷 基，-NHS02(1-6C)烷基，-CO(l_6C)烷基，_C02(1-6C)烷基 及-OCO(l-6C)烷基。 AR1，AR2，HET1及HET2上其他的有時存在的取代基的 特定值是1，2或3個取代基，其係獨立選自氰基，鹵，（1-6C)烧基，鹵（1-6C)烧基，二鹵（1-6C)院基’三氟甲基’（1-6C)烷氧基，羧基（1-4C)烷基，羧基（1-6C)烷氧基，羥 基，胺基，（1-6C)烷基胺基，-CONH2，-CONH(l-6C)烷 基，-CON 二（1-6C)烷基，-NHCO(l-6C)烷基，-S(0)2NH2， -S02NH(1-6C)烷基，-NHS02(1-6C)烷基。 AR1，AR2，HET1及HET2上其他的有時存在的取代基 的特定值是1或2個取代基，其係獨立選自氰基，鹵，甲 基，乙基，氟甲基，二氟甲基，氣甲基，三氟甲基，甲氧 基，羧基曱基，羧基曱氧基，羥基，胺基，甲基胺基，乙 基胺基，-CONH2，-CONHMe，-NHCOMe，-S(0)2NH2， _S02NHMe及-NHS02Me。 AR1，AR2，HET1及HET2上其他的有時存在的取代基 的特定值是1或2個取代基，其係獨立選自氰基，氟， 氣，甲基，乙基，氟曱基，二氟甲基，氣甲基，三氟曱 基，甲氧基，羧基甲基，羧基甲氧基，羥基，-CONH2及 -S(0)2NH2。 如果無另外說明，特定基團的適宜的有時存在的取代基 是此處所述類似基團的取代基。 式（I)化合物可形成安定的酸或鹼鹽，在此情形下以鹽給 96151.doc -25- 200523234 予化合物是適宜的，而醫藥上可接受的鹽可以下述習用方 法製備。 適宜的醫藥上可接受的鹽包括酸加成鹽，如甲燒錯酸 鹽，甲苯磺酸鹽，α-甘油磷酸鹽，富馬酸鹽，鹽酸鹽，梓 檬酸鹽，馬來酸鹽，酒石酸鹽及（較不宜的）氫溴酸鹽。也 適宜的是與磷酸及硫酸生成的鹽。另一方面，適宜的鹽是 鹼鹽，如鹼金屬鹽，例如鈉鹽，鹼土金屬鹽，例如辑或鎮 鹽，有機胺鹽，例如三乙基胺鹽，嗎福啉鹽，Ν_甲基六氫 吡啶鹽，Ν-乙基六氫吡啶鹽，普魯卡因鹽，二苄基胺鹽， Ν，Ν-二苄基乙基胺鹽，參羥基乙基）胺鹽，队甲基冬葡 糖胺鹽及胺基酸如賴胺酸鹽。視所載電荷及陽離子或陰離 子的價而異，可有一個以上的陽離子或陰離子。較佳的醫 藥上可接受的鹽是鈉鹽。 但在製備過程中，為易於分離出鹽，不論是醫藥上可接 受的或不接受的鹽，較佳是不易溶於選擇的溶劑的鹽。 應了解到，在本發明内，式⑴化合物或其鹽會展現互變 異構現象，本說明内所晝的構造式只代表一種互變異構物 形式。應了解到，本發明包括展現Dpp_IV活性的任何互變 異構物，並不限於本說明所繪出的構造式。 、精於此技藝者會了解到，某些式⑴化合物含不對稱經取 代的碳及/或硫原子，因之可以光學活性及外消旋形式存 在或:離出。應了解到，本發明包括任何外消旋、光學活 丨夕日日I或立體異構物形式’此等形式具抑制活 性的性質 如，以重結晶技術Oxazolyl, 1'-imidazo [i, 5-a] pyrrolidinyl, pyrrole 'C ^ I ,, Li, 2-b] isoxazolyl, imidazo [5, lb] thiazolyl, imidazolyl Rbb ] Thiazolyl, medium, "group, imidazo [l, 2-ap than pyridyl, imidazo: lice imprint [1,5 cyanidyl]. Biloxa [1, called pyridazinyl, [b] ^^^^ Ll, 2-c] 0 densely set [1,2_a] m, _ and m [2, lc] -s-triazolyl , S-triazole [丨, ^] pyridyl, imidazopyridyl'pyrido [pyridazinyl, imidopyridyl, 2_ ,. Amine ', :: 96151.doc -23- 200523234 and [l, 5-a] ° biazinyl, imidazo [i, 5-a] a bisulfonyl, imidazo [1,2_6] pyridazinyl, s-diazolo [4,3-a] pyrimidinyl, imidazo [5,1-b] oxazolyl and imidazo [2,1-b] oxazolyl. Other specific examples of such ring systems include, for example, [1H] -ton-pyrrolo [2'bc] oxazinyl, [3Η] _oxazolo [3, button a] g than pyridyl, [6H]- Heirro [2, bc] oxazinyl and heiro [2, lc] [l, 4] oxazinyl. The other specific examples of the 5 / 5-double sorrow system are sigma sigma and σ oxanyl or miwa sigma syl, especially sigma [5, lb] sialyl, sigma sigma [ 2, ib] ^ n ^ group, imidazo [5, lb] oxazolyl or imidazo [2, lb] oxazolyl. -Examples of (1-6C) alkyl HET2 include one of the above-mentioned HET2 specific values linked to any (KC) alkyl value, so include, for example (substituted as needed) indolinylmethyl, indolyl Ethyl, indolylpropyl, indolylbutyl and indolylhexyl. The nomenclature used here is found in, for example, "Heterocyclic Compounds (Systems with bridgehead nitrogen) WL Mosby (Interscience Publishers Inc., New York), 1961, Part 1 and 2 〇HET3 specific values include, for example, α-introduction σ dodecyl, Benzo sigma group, dihydroindolyl group, 1,2,3,4-tetrahydrofluorenyl group, 2,3_dihydro ° stilbene group, 2,3-dihydrobenzo sigma 11 group The specific values of the substituents sometimes present on AR1, AR2, HET1 and HET2 are 1, 2, 3, 4 or 5 substituents, which are independently selected from cyano, halo, (1- 6C) alkyl, halo (1-6C) alkyl, dihalo (1-6C) alkyl, trifluoromethyl, (1-6C) alkoxy, carboxy (1-6C) alkyl, carboxy (1 -6C) alkoxy, hydroxyl, amino, (1-6C) alkylamino, di (1-6C) alkylamino, -CONH2, -CONH (l-6C) alkyl, -CON di ( 1-6C) alkyl, _NHCO (l-6C) alkane 91151.doc -24-200523234, -S (0) 2NH2, -S02NH (1-6C) alkyl, -S02N di (1-6C) alkyl , -NHS02 (1-6C) alkyl, -CO (l-6C) alkyl, -C02 (1-6C) alkyl and -OCO (l-6C) alkyl. Others on AR1, AR2, HET1 and HET2 Existing substitution The specific value of the group is 1, 2 or 3 substituents, which are independently selected from the group consisting of cyano, halo, (1-6C) alkyl, halo (1-6C) alkyl, dihalo (1-6C) 'Trifluoromethyl' (1-6C) alkoxy, carboxy (1-4C) alkyl, carboxy (1-6C) alkoxy, hydroxyl, amine, (1-6C) alkylamino,- CONH2, -CONH (l-6C) alkyl, -CON di (1-6C) alkyl, -NHCO (l-6C) alkyl, -S (0) 2NH2, -S02NH (1-6C) alkyl, -NHS02 (1-6C) alkyl. AR1, AR2, HET1 and other sometimes existing substituents on HET2 have a specific value of 1 or 2 substituents, which are independently selected from cyano, halo, methyl, Ethyl, fluoromethyl, difluoromethyl, gas methyl, trifluoromethyl, methoxy, carboxymethyl, carboxymethyl, hydroxy, amine, methylamino, ethylamino,- CONH2, -CONHMe, -NHCOMe, -S (0) 2NH2, _S02NHMe and -NHS02Me. The specific value of other sometimes existing substituents on AR1, AR2, HET1 and HET2 is 1 or 2 substituents, which are independent Selected from cyano, fluorine, gas, methyl, ethyl, fluorofluorenyl, difluoromethyl, gas methyl, trifluorofluorenyl, methoxy, carboxymethyl, carboxymethyl Group, hydroxy, -CONH2 and -S (0) 2NH2. Unless otherwise stated, suitable sometimes present substituents for a particular group are substituents similar to those described herein. The compound of formula (I) can form a stable acid or base salt, in which case it is suitable to give the compound 96151.doc -25-200523234, and the pharmaceutically acceptable salt can be prepared by the following conventional method. Suitable pharmaceutically acceptable salts include acid addition salts such as mesylate, tosylate, alpha-glyceryl phosphate, fumarate, hydrochloride, citrate, maleate , Tartrate and (less preferred) hydrobromide. Also suitable are salts with phosphoric acid and sulfuric acid. On the other hand, suitable salts are alkali salts, such as alkali metal salts, such as sodium salts, alkaline earth metal salts, such as chlorate or town salts, organic amine salts, such as triethylamine salts, morpholine salts, N_methyl Hexahydropyridine salt, Ν-ethylhexahydropyridine salt, procaine salt, dibenzylamine salt, Ν, Ν-dibenzylethylamine salt, p-hydroxyethyl) amine salt, team methyl dong Glucosamine salts and amino acids such as lysine salts. Depending on the charge and valence of the cation or anion, there may be more than one cation or anion. The preferred pharmaceutically acceptable salt is the sodium salt. However, in the preparation process, in order to easily separate the salt, whether it is a pharmaceutically acceptable or unacceptable salt, a salt that is not easily soluble in the selected solvent is preferred. It should be understood that, in the present invention, the compound of formula (I) or a salt thereof exhibits the phenomenon of tautomerism, and the structural formula in this specification represents only one tautomeric form. It should be understood that the present invention includes any tautomers exhibiting Dpp_IV activity and is not limited to the structural formulae drawn in this description. 2. Those skilled in this art will understand that some compounds of formula ⑴ contain asymmetrically substituted carbon and / or sulfur atoms, and therefore can exist or be isolated in optically active and racemic forms. It should be understood that the present invention includes any racemic, optically active form I or a stereoisomer form. These forms have activity-inhibiting properties such as, for example, by recrystallization techniques

如何製備光學活性形式（例 96\5l.doc -26- 200523234 解析外>肖旋形式，以光學活性起始物f合成，以對掌性人 成，以酶解析，或以對掌固定相作色層分離）及如何^ 述標準試驗測^DPIMV的抑制活性，都是此技#已知的: -般較佳是碳原子上帶有RW的⑻構形的化合物。 也應了解到’某些式⑴化合物及其鹽可以溶劑合物，例 如水合物’或非溶劑合物形式存在。應了解到本發明包括 所有此類具抑制DPP-IV活性的溶劑合物形式。 如岫所述，發明人等已發現具良好Dpp — IV抑制活性的一 類化σ物。一般而言，此類化合物具有良好物理及/或醫 藥性質。下述化合物具有良好醫藥及/或物理及/或藥物動 力學性質。 一方面，本發明包括式⑴化合物，或其醫藥上可接受的 鹽，其中取代基Ar，Ri至R9及上述其他取代基有如前所界 疋的值或下述的任何值（其適用於此前或後述具體實施例 之定義）： 與本發明一具體實施例中，提供式（I)化合物，於另一具 體實施例中，提供式⑴化合物的醫藥上可接受的鹽。 各基團的特定值如下。此等值適宜時可與此前或後述之 任何其他的值，定義，申請範圍或具體實施例使用。 1) Ar是未經取代的苯基 2) Ar是以1個R9基團取代的苯基 3) Ar是以2個獨立選自R9的基團取代的苯基 4) Ar是以4個獨立選自R9的基團取代的苯基 5) R9是鹵，較佳是氟 96151.doc -27- 200523234 6) R9是（1-6C)烷基（視需要以1-5個鹵取代），例如（1-4C) 烷基（視需要以1-5個ifi取代），如甲基，氟甲基，二氟甲基 或三氟甲基 7) R9是（1-6C)烷氧基（視需要以1-5個鹵取代），例如（卜 4C)烷氧基（視需要以1-5個鹵取代），如甲氧基，氟甲氧 基’《—氣甲氧基或二氣甲氧基 8) R9是氰基 9) R1是氫 10) R1是（1-6C)烷基，例如（1-4C)烷基，如甲基 11) R5是氫或甲基 12) R5是氫 13) R6是氫或甲基 14) R6是氫 15) R7是氫或甲基 16) R7是氫 17) R8是氫或甲基 18) R8是氫 19) R3及R4共同形成一環，如AR2，HET1或HET2所界定 20) R3及R4共同形成一環，如AR2所界定 21) R3及R4共同形成一環，如heTI所界定 22) R3及R4共同形成一環，如HET2所界定 23) R3及R4係獨立選自氫，（1-6C)烷基，气1-6C)烷基（3-8C)環烧基，_(1-6C)烷基（3-8C)環烯基，-(1-6C)烷基 AR1 ’ -(1-6C)烷基 AR2，-(1-6C)烷基 HET1 及-(1-6C)烷基 96151.doc -28- 200523234 HET2 24) R3是氫及R4是-(1-6C)烷基AR1如苄基 25) R3是氫及R4是-(1-6C)烷基AR2 26) R3是氫及R4是-(1-6C)烷基HET1 27) R3是氫及R4是-(1-6C)烷基HET2 28) R3是（1-6C)烷基，如（1-4C)烷基，例如甲基及R4是選 自-(1-6C)烷基（3-8C)環烷基，-(1-6C)烷基（3-8C)環烯 基，（1-6C)烷基 AR1，-(1-6C)烷基 AR2，-(1-6C)烷基 HET1 及- (1-6C)炫基 HET2 29) R3是氫及R4是選自-(1-6C)烷基（3-8C)環烷基’ -(1-6C) 烷基（3-8C)環烯基，（1-6C)烷基AR1，_(1-6C)烷基 AR2，-(1-6C)烷基 HET1 及·（卜 6C)烷基 HET2 30) R1是氫及R2是（3-8C)環烷基，（5-12C)雙環烷基，（6-12C)三環烷基環或HET1所界定的環；其中含R1及r2的環 是視需要以1或2個取代基取代的，此等取代基獨立選自 鹵，（1-6C)烷基，鹵（1-6C)烷基，（1-6C)烷氧基，氰基，羧 基，羧基（1-6C)烷基，-CO(l-6C)烷基，-C02(1-6C)烧基’ (1-6C)烷基胺基，二-(1-6C)烷基胺基，-NHCO(l_6C)烧 基，-CONH(l-6C)烷基，-CON 二-(1-6C)烷基及 HET1 31) R2是選自氫，（1-6C)烷基，（3-8C)環烧基，（5-12C)雙 環烷基及（6-12C)三環烷基 32) R2 是選自 AR1，HET1，-(1-6C)烷基 AR1，-(1-6C)烧基 AR2，-(1-6C)烷基（3-8C)環烷基，-(1-6C)烷基 HET1 及 _(1- 6C)烷基 HET2 96151.doc -29- 200523234 33) R 是選自 '(1-6C)烷基 C02(1-6C)烷基，-(1-6C)烷基 C〇2(3-8C)環烷基，-(1-6C)烧基 C02AR1，-(1-6C)烷基 C02HET1 ’，（1_6C)烷基 〇c〇(1-6C)烷基，-(1-6C)烷基 〇C〇(3-8C)環烷基，-(1-6C)烷基 OCOAR1 及 _(1-6C)烷基 OCOHET1 34) R2 是選自 _(1_6C)烧基 CO(l-6C)烷基，-(1-6C)烷基 C〇(3-8C)環烷基，-(1-6C)烧基 COAR1 及-(1-6C)烷基 COHET1 35) R2 是選自、（1-6C)烷基 NHCO(l-6C)烷基，_(1-6C)烷基 NHCO(3-8C)環烷基，-(1-6C)烷基NHCOAR1，-(1-6C)烷基 C0NH(1-6C)烷基，-(1-6C)烷基 CONH(3_8C)環烷基，-(1-6C)烧基 C〇N_二（1_6C)烧基及 _(1_6C)烧基 CONHAR1 36) R2是選自-(1_6〇烷基NH(1-6C)烷基，-(1-6C)烷基N-二 (1-6C)烷基，-(1-6C)烷基NHAR1 及-(1-6C)烷基NH(HETl) 37) R2 是選自-(1-6C)烷基 NHS02(1-6C)烷基，-(1-6C)烷基 S02NH(1-6C)烷基及-(1-6C)烷基 S02N-二（1-6C)烷基 38) R2是選自氫，（1-6C)烷基，（3-8C)環烷基，（5-12C)雙 環烷基，（6-12C)三環烷基，AR1，HET1，-(1-6C)烧基 AR1，-(1-6C)烷基 NHCO(l-6C)烷基，-(1-6C)烧基 NHCOAR1，-(卜6C)烷基 CONH(l-6C)烷基，-(1-6C)烷基 CON-二（1-6C)烷基，-(1-6C)烷基 CONHAR1，-(1_6C)烷基 NH(1-6C)烷基，-(KC)烷基 N-二（1-6C)烷基，-(1-6C)烧基 NHAR1，-(1-6C)炫基 NH(HETl)，-(1-6C)烧基 NHS02(1-6C)烷基，-(1-6C)烷基 S02NH(1-6C)烷基及-(1-6C)烧基 96151.doc -30- 200523234 S02N-二（1-6C)烷基 39) R2是選自（1-6C)烷基，（3-8C)環烷基，（5-12C)雙環烷 基，（6-12C)三環烷基，AR1，HET1，-(1-6C)烷基 AR1，-(1-6C)烷基 NHCO(l-6C)烷基，-(1-6C)烷基 NHCOAR1，-(1-6(:)¾ 基 CONH(l-6C)烧基，-(1-6C)烧基 CONHAR1，-(1-6C)烷基 NH(1-6C)烷基，-(1-6C)烷基 NHAR1，-(1-6C)烧基 NH(HETl)，-(1-6C)烧基 NHS〇2〇-6C)烷基及-(1-6C)烷基S02NH(1-6C)烷基 40) R2是選自（1-6C)烷基，環己基，降冰片烷基，金剛炫 基，苯基（視需要經1或2個取代基取代的，取代基選自 氟，氣，三氟甲基，甲烷磺醯胺基，羧曱基，-SChNH2 及-S02NHMe)，苄基（視需要經1或2個取代基取代的’ 取代基選自氟，氯，三氟甲基，甲烷磺醯胺基’羧甲 基，_S02NH2 及-S02NHMe)，_(1-4C)烷基 CONH(l-4C)炫 基，-(1-4C)烷基CONHPh(視需要經1或2個取代基取代的’ 取代基選自氟，氣，三氟甲基，甲烷磺醯胺基，羧甲基’ -S02NH2 及-S02NHMe)及-(卜 4C)烷基 NHS02(1-4C)烷基 41) R1及R2共同與其相聯的氮形成HET1所界定的環，是祝 需要經1或2個取代基取代的，取代基選自鹵’ 基，鹵（1-6C)烷基，（1-6C)烷氧基，氰基，羧基，羧基（卜 6C)烷基，-CO(l-6C)烷基，-C02(1-6C)烷基，（1-6C)炫基 胺基，二-(1-6C)烷基胺基，-NHCO(l-6C)炫基 ’ -CONH(卜 6C)烷基，-CON 二-(1-6C)烷基及 HET1 42) R1及R2共同與其相聯的氮形成HET3所界定的環 96151.doc -31- 200523234 43) R1是Η及R2是呋喃基，α比咯基，噻吩基，吡唑基，味 σ坐基，σ比u定基，。密σ定基，咐;p井基，達σ秦基，1，2,3-及1，2,4-三17坐基，四σ坐基，喔σ坐基，異tr惡峻基，^惡σ秦基’ °惡一 σ坐 基，噻唑基，異噻唑基，1，2,4-及1，3,4-嘍二唑基，噁唑 琳，嗟哇琳，二氫α比洛基（特別是2,5_二氫°比17各-4-基）’四 氫吡啶基（特別是1，2,5,6-四氫吡啶基），四氫呋喃基，四 氫噻吩基，1-氧代四氫噻吩基，二氧代四氫噻吩基， °比洛σ定基，喔嗤院，售σ坐烧，嗎福琳基，硫代嗎福琳基’ 六氫吼嗪基，味唆基，六氫π比咬基，1，3-二氧戊環-4-基’ 1，3-二噁烧-4-基，1，3-二噁燒-5-基或1,4-二噁烧-2-基環， 視需要是如前述經取代的 44) R1是Η及R2是呋喃基，吡咯基，噻吩基，吡唑基，咪 唑基，吡啶基，嘧啶基，噁唑琳，噻唑琳，二氫吡咯基 (特別是2,5-二氫σ比洛-4·基），四氫β比唆基（尤其是1，2,5,6-四氫吡啶-4-基），四氫呋喃基，四氫噻吩基，1 -氧代四氫 噻吩基，1，1 -二氧代四氫噻吩基，吡咯啶基，噁唑烷，噻 。坐烧，嗎福琳基，硫代嗎福琳基，六氫σ比嗓基，味唾基或 六氫吡啶基環，視需要是如前述經取代的 45) R1及R2共同與其相聯的氮形成二氫。比咯基（特別是2,5-二氫°比°各-4-基），四氫°比σ定基（特別是1，2,5,6_四氫^比咬_4-基），四氫吱喃基，四氫°塞吩基，1 -氧代四氫嗟吩基，1，1 _ 二氧代四氫噻吩基，吡咯啶基，噁唑烷，噻唑烷，嗎福琳 基，硫代嗎福啉基，六氫°比嗪基或六氫吡啶基環，視需要 疋、經1或2個取代基取代的’此專取代基疋獨立選自氰基， 96151.doc -32- 200523234 鹵，（1-6C)烷基，鹵（1-6C)烷基，二鹵（1-6C)烷基，三氟甲 基，（1-6C)烷氧基，羧基（1-4C)烷基，羧基（1-6C)烷氧基， 羥基，胺基，（卜6C)烷基胺基，-CONH2 ’ -CONH(l-6C)燒 基，-CON二（1-6C)烷基，-NHCO(l-6C)烷基，-S(0)2NH2 ’ -S02NH(1-6C)烷基及-NHS02(1-6C)烷基 46) R1及R2共同與其相聯的氮形成四氫σ比啶基（特別是 1，2,5,6-四氫吡啶-4-基），四氫呋喃基，吡咯啶基，噁唑 烧，σ塞嗤烧，嗎福琳基，硫代嗎福淋基’六氫°比σ秦基’或 六氫吡啶基環，視需要是經1或2個取代基取代的，此等取 代基是獨立選自氰基，鹵，（1-6C)烷基，鹵（1-6C)烷基’ 二鹵（1-6C)烷基，三氟甲基，（1-6C)烷氧基，羧基（1-4C)烷 基，羧基（1-6C)烷氧基，羥基，胺基，（1-6C)烷基胺 基，-CONH2，-CONH(l-6C)烷基，-CON二（1-6C)烷 基，-NHCO(l-6C)烷基，-S(0)2NH2，-S02NH(1-6C)烷 基及-NHS02(1-6C)烷基 47) R1及R2共同與其相聯的氮形成0比咯啶基，或六氫σ比啶 基環，視需要是經1或2個取代基取代的，此等取代基是獨 立選自氰基，鹵，（1-6C)烷基，鹵（1_6C)烷基，二鹵（1-6C) 烷基，三氟甲基，（1-6C)烷氧基，羧基（1-4C)烷基，羧基 (1-6C)烷氧基，羥基，胺基，（1_6C)烷基胺基，-CONH2， -CONH(l-6C)烷基，-CON 二（1-6C)烷基，-NHCO(l-6C)烷 基，-S(0)2NH2, -S02NH(1-6C)烷基及 _NHS02(1-6C)烷基 48) R1及R2共同與其相聯的氮形成吡咯啶基，或六氫吡啶 基環，視需要是經1或2個取代基取代的，此等取代基是獨 96151.doc -33- 200523234 立選自氰基，鹵，甲基，乙基，氟甲基，二氟甲基，氣甲 基，三氟甲基，甲氧基，羧基甲基，羧基甲氧基，羥基， 胺基，甲基胺基，乙基胺基，-CONH2，-CONHMe， -NHCOMe，-S(0)2NH2，-S02NHMe及-NHS02Me 49) R1是氫 50) R1是甲基 51) Ar是以三個獨立選自R9的基團，特別是三個氟基團取 代的苯基 52) Ar是2-氟苯基 53) Ar是2,4-二氟苯基 54) Ar是2,5-二氟苯基 55) R2是（1-4C)烷基，例如甲基 56) R2 是氫，（1-6C)烷基，（1-6C)烷基 S02(1-6C)烷基，（1-6C)烷基 CONH(l-6C)烷基，-S02(1-6C)烷基，（1-6C)烷基 (3-8C)環烷基，（1-6C)烷基 NHS02(1-6C)烷基，（1-6C)烷基 CONHAR1 或（1-6C)烧基 HRT1 此處所界定的任一組化合物中的另一些本發明化合物是 其中R3為氫或（1-6C)烷基及R4是氫之外的基團或（1-6C)烷 基的化合物，其中帶有R3及R4的碳原子有（R)-構形。 此處所界定的任一組化合物中的另一些本發明化合物是 其含HET1基團的化合物，其中HET1含單一雜原子。 本發明一方面提供式（I)化合物或其醫藥上可接受的鹽， 其中How to prepare an optically active form (Example 96 \ 5l.doc -26- 200523234 Analytical > Xiao Xuan form, synthesized with an optically active starting material f, to form a human, enzymatic, or to a stationary phase The separation of the color layer) and how to measure the inhibitory activity of DPIMV by standard tests are known in this technique:-Generally preferred are compounds with a fluorene configuration of RW on the carbon atom. It will also be appreciated that ' certain compounds of formula (I) and their salts may exist in solvate, e.g., hydrate ' or unsolvate forms. It should be understood that the present invention includes all such solvate forms having DPP-IV inhibitory activity. As described in 岫, the inventors have found a class of sigma compounds having good Dpp-IV inhibitory activity. In general, such compounds have good physical and / or medical properties. The following compounds have good medical and / or physical and / or pharmacokinetic properties. In one aspect, the invention includes a compound of formula VII, or a pharmaceutically acceptable salt thereof, in which the substituents Ar, Ri to R9, and the other substituents described above have a value as previously defined, or any value described below (which applies to the previous Or the definition of a specific embodiment described later): In a specific embodiment of the present invention, a compound of formula (I) is provided, and in another specific embodiment, a pharmaceutically acceptable salt of a compound of formula VII is provided. Specific values of each group are as follows. These values may be used with any other values, definitions, application scopes, or specific embodiments described before or after, as appropriate. 1) Ar is unsubstituted phenyl 2) Ar is phenyl substituted with 1 R9 group 3) Ar is 2 substituted phenyl groups independently selected from R9 4) Ar is 4 independent groups Group selected from R9 is substituted phenyl 5) R9 is halogen, preferably fluorine 96151.doc -27- 200523234 6) R9 is (1-6C) alkyl (substituted with 1-5 halogens if necessary), For example (1-4C) alkyl (substituted with 1-5 ifi as needed), such as methyl, fluoromethyl, difluoromethyl or trifluoromethyl 7) R9 is (1-6C) alkoxy ( Substitute with 1-5 halogens if necessary), such as (Bu 4C) alkoxy (substitute with 1-5 halogens if necessary), such as methoxy, fluoromethoxy, "-methoxy or digas Methoxy 8) R9 is cyano 9) R1 is hydrogen 10) R1 is (1-6C) alkyl, for example (1-4C) alkyl, such as methyl 11) R5 is hydrogen or methyl 12) R5 is 13) R6 is hydrogen or methyl 14) R6 is hydrogen 15) R7 is hydrogen or methyl 16) R7 is hydrogen 17) R8 is hydrogen or methyl 18) R8 is hydrogen 19) R3 and R4 together form a ring, such as AR2, HET1 or HET2 defined 20) R3 and R4 together form a ring, as defined by AR2 21) R3 and R4 together form a ring, as defined by heTI 22) R3 and R4 together form a ring , As defined by HET2 23) R3 and R4 are independently selected from hydrogen, (1-6C) alkyl, gas 1-6C) alkyl (3-8C) cycloalkyl, _ (1-6C) alkyl (3 -8C) cycloalkenyl,-(1-6C) alkyl AR1 '-(1-6C) alkyl AR2,-(1-6C) alkyl HET1 and-(1-6C) alkyl 96151.doc -28 -200523234 HET2 24) R3 is hydrogen and R4 is-(1-6C) alkyl AR1 such as benzyl 25) R3 is hydrogen and R4 is-(1-6C) alkyl AR2 26) R3 is hydrogen and R4 is-( 1-6C) alkyl HET1 27) R3 is hydrogen and R4 is-(1-6C) alkyl HET2 28) R3 is (1-6C) alkyl, such as (1-4C) alkyl, such as methyl and R4 Is selected from-(1-6C) alkyl (3-8C) cycloalkyl,-(1-6C) alkyl (3-8C) cycloalkenyl, (1-6C) alkyl AR1,-(1- 6C) alkyl AR2,-(1-6C) alkyl HET1 and-(1-6C) hexyl HET2 29) R3 is hydrogen and R4 is selected from-(1-6C) alkyl (3-8C) cycloalkane -'(1-6C) alkyl (3-8C) cycloalkenyl, (1-6C) alkyl AR1, _ (1-6C) alkyl AR2,-(1-6C) alkyl HET1 and · ( 6C) alkyl HET2 30) R1 is hydrogen and R2 is (3-8C) cycloalkyl, (5-12C) bicycloalkyl, (6-12C) tricycloalkyl ring or ring defined by HET1; Rings containing R1 and r2 are optionally substituted with 1 or 2 substituents. These substitutions Independently selected from halo, (1-6C) alkyl, halo (1-6C) alkyl, (1-6C) alkoxy, cyano, carboxy, carboxy (1-6C) alkyl, -CO (l- 6C) alkyl, -C02 (1-6C) alkyl '(1-6C) alkylamino, di- (1-6C) alkylamino, -NHCO (l-6C) alkyl, -CONH (l- 6C) alkyl, -CON di- (1-6C) alkyl and HET1 31) R2 is selected from hydrogen, (1-6C) alkyl, (3-8C) cycloalkyl, (5-12C) bicycloalkane And (6-12C) tricycloalkyl 32) R2 is selected from AR1, HET1,-(1-6C) alkyl AR1,-(1-6C) alkyl AR2,-(1-6C) alkyl ( 3-8C) cycloalkyl,-(1-6C) alkylHET1 and _ (1-6C) alkylHET2 96151.doc -29- 200523234 33) R is selected from '(1-6C) alkylC02 ( 1-6C) alkyl,-(1-6C) alkylC02 (3-8C) cycloalkyl,-(1-6C) alkylC02AR1,-(1-6C) alkylC02HET1 ', (1-6C ) Alkylocco (1-6C) alkyl,-(1-6C) alkylocco (3-8C) cycloalkyl,-(1-6C) alkyl OCOAR1 and _ (1-6C) Alkyl OCOHET1 34) R2 is selected from _ (1_6C) alkyl CO (l-6C) alkyl,-(1-6C) alkyl Co (3-8C) cycloalkyl,-(1-6C) alkyl COAR1 and-(1-6C) alkyl COHET1 35) R2 is selected from (1-6C) alkylNHCO (l-6C) alkyl, _ (1-6C) NHCO (3-8C) cycloalkyl,-(1-6C) alkylNHCOAR1,-(1-6C) alkylCONH (1-6C) alkyl,-(1-6C) alkylCONH (3_8C) Cycloalkyl,-(1-6C) alkyl C_N_di (1_6C) alkyl and _ (1_6C) alkyl CONHAR1 36) R2 is selected from-(1-6_alkylalkylNH (1-6C) alkyl ,-(1-6C) alkylN-di (1-6C) alkyl,-(1-6C) alkylNHAR1 and-(1-6C) alkylNH (HETl) 37) R2 is selected from-( 1-6C) alkylNHS02 (1-6C) alkyl,-(1-6C) alkylS02NH (1-6C) alkyl and-(1-6C) alkylS02N-di (1-6C) alkyl 38) R2 is selected from hydrogen, (1-6C) alkyl, (3-8C) cycloalkyl, (5-12C) bicycloalkyl, (6-12C) tricycloalkyl, AR1, HET1,-( 1-6C) Alkenyl AR1,-(1-6C) alkyl NHCO (l-6C) alkyl,-(1-6C) alkenyl NHCOAR1,-(bu 6C) alkylCONH (l-6C) alkyl ,-(1-6C) alkylCON-di (1-6C) alkyl,-(1-6C) alkylCONHAR1,-(1-6C) alkylNH (1-6C) alkyl,-(KC) alkane N-di (1-6C) alkyl,-(1-6C) alkyl NHAR1,-(1-6C) alkyl NH (HETl),-(1-6C) alkyl NHS02 (1-6C) alkane Group,-(1-6C) alkyl S02NH (1-6C) alkyl and-(1-6C) alkyl 96151.doc -30- 200523234 S02N-di (1-6C) alkyl 39) R2 is selected from (1-6C) alkyl, (3-8 C) cycloalkyl, (5-12C) bicycloalkyl, (6-12C) tricycloalkyl, AR1, HET1,-(1-6C) alkyl AR1,-(1-6C) alkylNHCO (l -6C) alkyl,-(1-6C) alkylNHCOAR1,-(1-6 (:) ¾ CONH (l-6C) alkyl,-(1-6C) alkyl CONHAR1,-(1-6C ) Alkyl NH (1-6C) alkyl,-(1-6C) alkyl NHAR1,-(1-6C) alkyl NH (HET1),-(1-6C) alkyl NHS〇2〇-6C) Alkyl and-(1-6C) alkyl S02NH (1-6C) alkyl 40) R2 is selected from (1-6C) alkyl, cyclohexyl, norbornyl, adamantyl, phenyl (as required Substituted with 1 or 2 substituents, the substituents are selected from the group consisting of fluorine, gas, trifluoromethyl, methanesulfonamido, carboxyfluorenyl, -SChNH2 and -S02NHMe), benzyl (if necessary, 1 or 2 Substituent-substituted 'substituents are selected from the group consisting of fluorine, chlorine, trifluoromethyl, methanesulfonamido'carboxymethyl, _S02NH2 and -S02NHMe), _ (1-4C) alkyl CONH (l-4C) xyl ,-(1-4C) alkyl CONHPh (optionally substituted with 1 or 2 substituents 'substituents are selected from the group consisting of fluorine, gas, trifluoromethyl, methanesulfonamido, carboxymethyl' -S02NH2 and- S02NHMe) and-(B4C) alkylNHS02 (1-4C) alkyl41) R1 and R2 are nitrogens associated with it To form a ring as defined by HET1, it needs to be substituted with 1 or 2 substituents. The substituents are selected from halo ', halo (1-6C) alkyl, (1-6C) alkoxy, cyano, and carboxyl. , Carboxy (B6C) alkyl, -CO (l-6C) alkyl, -C02 (1-6C) alkyl, (1-6C) alkylamino, di- (1-6C) alkylamino , -NHCO (l-6C) Hexyl'-CONH (Bu6C) alkyl, -CON di- (1-6C) alkyl and HET1 42) R1 and R2 together with the nitrogen associated with them form a ring defined by HET3 96151.doc -31- 200523234 43) R1 is fluorene and R2 is furyl, α-pyrrolyl, thienyl, pyrazolyl, sigma sitting group, and sigma u group. Dense σ fixed base, p well base, up to σ Qinji, 1,2,3- and 1,2,4-three 17 bases, four σ bases, oo σ bases, different tr bases, ^ Evil σ-Qinyl '° Evil-σ sitting group, thiazolyl, isothiazolyl, 1,2,4- and 1,3,4-oxadiazolyl, oxazoline, oxazoline, dihydroa-bilox (Especially 2,5-dihydro ° than 17 each 4-yl) 'tetrahydropyridyl (especially 1,2,5,6-tetrahydropyridyl), tetrahydrofuranyl, tetrahydrothienyl, 1 -Oxotetrahydrothienyl, dioxotetrahydrothienyl, ° Biloxi stilbyl, oh yin yuan, sigma sitting, morpholinyl, thiomorpholinyl 'hexahydrorazinyl, flavor Fluorenyl, hexahydropi ratio, 1,3-dioxolane-4-yl '1,3-dioxan-4-yl, 1,3-dioxan-5-yl or 1,4 -Dioxan-2-yl ring, optionally substituted as previously described 44) R1 is fluorene and R2 is furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, oxazole Lin, thiazoline, dihydropyrrolyl (especially 2,5-dihydroσ bilo-4 · yl), tetrahydropyridinyl (especially 1,2,5,6-tetrahydropyridine-4- ), Tetrahydrofuranyl, tetrahydrothiophene Group, 1-oxotetrahydrothienyl, 1,1-dioxotetrahydrothienyl, pyrrolidinyl, oxazolidine, thio. Sit-burn, morpholinyl, thiomorpholinyl, hexahydrosigma, sialyl or hexahydropyridyl ring, optionally substituted as described above 45) R1 and R2 are associated with it Nitrogen forms dihydrogen. Pyrrolyl (especially 2,5-dihydro °°°° each -4-yl), tetrahydro ° ratio σ fixed group (especially 1,2,5,6_tetrahydro ^ specific _4-yl), Tetrahydrocranyl, tetrahydro ° phenenyl, 1-oxotetrahydrofluorenyl, 1,1-dioxotetrahydrothienyl, pyrrolidinyl, oxazolidine, thiazolidine, morpholinyl , Thiomorpholine, hexahydro ° biazinyl or hexahydropyridyl ring, if necessary, 疋, substituted with 1 or 2 substituents ′ This special substituent 疋 is independently selected from cyano, 96151.doc- 32- 200523234 halo, (1-6C) alkyl, halo (1-6C) alkyl, dihalo (1-6C) alkyl, trifluoromethyl, (1-6C) alkoxy, carboxyl (1- 4C) alkyl, carboxy (1-6C) alkoxy, hydroxyl, amine, (6C) alkylamino, -CONH2'-CONH (l-6C) alkyl, -CONdi (1-6C) Alkyl, -NHCO (l-6C) alkyl, -S (0) 2NH2 '-S02NH (1-6C) alkyl and -NHS02 (1-6C) alkyl46) Nitrogen that R1 and R2 together are associated with Formation of tetrahydrosigmapyridyl (especially 1,2,5,6-tetrahydropyridin-4-yl), tetrahydrofuranyl, pyrrolidinyl, oxazole, sigmathione, morpholinyl, thio Modalin base 'hexahydro ° ratio σ Qinji' or Hexahydropyridyl ring, optionally substituted with 1 or 2 substituents, these substituents are independently selected from cyano, halo, (1-6C) alkyl, halo (1-6C) alkyl ' Halo (1-6C) alkyl, trifluoromethyl, (1-6C) alkoxy, carboxy (1-4C) alkyl, carboxy (1-6C) alkoxy, hydroxyl, amine, (1- 6C) alkylamino, -CONH2, -CONH (l-6C) alkyl, -CONdi (1-6C) alkyl, -NHCO (l-6C) alkyl, -S (0) 2NH2, -S02NH (1-6C) alkyl and -NHS02 (1-6C) alkyl47) R1 and R2 together form a 0-pyrrolidinyl, or hexahydroσ-pyridinyl ring with the nitrogen associated with it, optionally via 1 or 2 substituents, these substituents are independently selected from cyano, halo, (1-6C) alkyl, halo (1-6C) alkyl, dihalo (1-6C) alkyl, trifluoromethyl, (1-6C) alkoxy, carboxy (1-4C) alkyl, carboxy (1-6C) alkoxy, hydroxyl, amine, (1-6C) alkylamino, -CONH2, -CONH (l-6C ) Alkyl, -CON di (1-6C) alkyl, -NHCO (l-6C) alkyl, -S (0) 2NH2, -S02NH (1-6C) alkyl and _NHS02 (1-6C) alkane 48) R1 and R2 together form a pyrrolidinyl or hexahydropyridyl ring with the nitrogen associated with it, as required If substituted with 1 or 2 substituents, these substituents are only 96151.doc -33- 200523234 selected from cyano, halo, methyl, ethyl, fluoromethyl, difluoromethyl, gas methyl , Trifluoromethyl, methoxy, carboxymethyl, carboxymethoxy, hydroxy, amine, methylamino, ethylamino, -CONH2, -CONHMe, -NHCOMe, -S (0) 2NH2, -S02NHMe and -NHS02Me 49) R1 is hydrogen 50) R1 is methyl 51) Ar is three phenyl groups independently selected from R9, especially three fluoro groups substituted by phenyl 52) Ar is 2-fluorobenzene 53) Ar is 2,4-difluorophenyl 54) Ar is 2,5-difluorophenyl 55) R2 is (1-4C) alkyl, for example methyl 56) R2 is hydrogen, (1-6C ) Alkyl, (1-6C) alkylS02 (1-6C) alkyl, (1-6C) alkylCONH (l-6C) alkyl, -S02 (1-6C) alkyl, (1-6C ) Alkyl (3-8C) cycloalkyl, (1-6C) alkylNHS02 (1-6C) alkyl, (1-6C) alkyl CONHAR1 or (1-6C) alkyl HRT1 Other compounds of the present invention in a group of compounds are those in which R3 is hydrogen or (1-6C) alkyl and R4 is a group other than hydrogen or (1-6C) alkyl, wherein R3 and R4 are The carbon atom has (R)- Configuration. Other compounds of the invention in any of the groups of compounds defined herein are compounds containing a HET1 group, wherein HET1 contains a single heteroatom. One aspect of the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

Ar是視需要以1或2個獨立選自R9的基團取代的苯基； 96151.doc -34- 200523234 R9是選自鹵，甲基，甲氧基及三氟甲基； R1是氫或甲基； R5是氫； R6是氫； R7是氫； R8是氫； R3及R4共同形成如AR2，HET1或HET2所界定的環； R2是選自（1-6C)烷基，（3-8C)環烷基，（5-12C)雙環烷基， (6-12C)三環烷基，AR1，HET1，-(1-6C)烷基 AR1，-(1-6C)烷基 NHCO(l-6C)烷基，-(1-6C)烷基 NHCOAR1，-(1-6C)烷基 CONH(l-6C)烷基，-(1_6C)烷基 NHCOAR1，-(1-6C)烷基 CONH(l-6C)烷基，-(1-6C)烷基 CONHAR1，-(1-6C)烷基 NH(1-6C)烷基，-(1-6C)烷基 NHAR1，-(1-6C)烷基 NH(HETl)，-(1-6C)烷基 NHS02(1-6C)烷基及-(1-6C)烷基 S02NH(1-6C)烷基。 本發明另一方面提供式（I)化合物或其醫藥上可接受的 鹽，其中Ar is phenyl optionally substituted with 1 or 2 groups independently selected from R9; 96151.doc -34- 200523234 R9 is selected from halogen, methyl, methoxy and trifluoromethyl; R1 is hydrogen or Methyl group; R5 is hydrogen; R6 is hydrogen; R7 is hydrogen; R8 is hydrogen; R3 and R4 together form a ring as defined by AR2, HET1 or HET2; R2 is selected from (1-6C) alkyl, (3- 8C) cycloalkyl, (5-12C) bicycloalkyl, (6-12C) tricycloalkyl, AR1, HET1,-(1-6C) alkyl AR1,-(1-6C) alkyl NHCO (l -6C) alkyl,-(1-6C) alkylNHCOAR1,-(1-6C) alkylCONH (l-6C) alkyl,-(1-6C) alkylNHCOAR1,-(1-6C) alkylCONH (l-6C) alkyl,-(1-6C) alkyl CONHAR1,-(1-6C) alkylNH (1-6C) alkyl,-(1-6C) alkylNHAR1,-(1-6C ) Alkyl NH (HET1),-(1-6C) alkylNHS02 (1-6C) alkyl and-(1-6C) alkylSO2NH (1-6C) alkyl. Another aspect of the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

Ar是視需要以1或2個獨立選自R9的基團取代的苯基； R9是選自鹵，甲基，甲氧基及三氟甲基； R5是氫； R6是氫； R7是氫； R8是氫； R3及R4共同形成如AR2所界定的環； 96151.doc -35- 200523234 R2是選自（1-6C)烷基，（3-8C)環烷基，（5-12C)雙環烷基， (6-12C)三環烷基，AR1，HET1，-(1-6C)烷基 AR1，-(1-6C)烷基 NHCO(l-6C)烷基，-(1-6C)烷基 NHCOAR1，-(1-6C)烷基 CONH(l-6C)烷基，-(1-6C)烷基 CONHAR1，-(1-6C)烷基 NH(1-6C)烷基，-(1-6C)烷基 NHAR1，-(1-6C)烷基 NH(HETl)，-(1-6C)烧基 NHS02(卜 6C)烧基及-(1-6C)烷基 S02NH(1-6C)烷基。 本發明另一方面提供式⑴化合物或其醫藥上可接受的 鹽，其中Ar is phenyl optionally substituted with 1 or 2 groups independently selected from R9; R9 is selected from halogen, methyl, methoxy and trifluoromethyl; R5 is hydrogen; R6 is hydrogen; R7 is hydrogen R8 is hydrogen; R3 and R4 together form a ring as defined by AR2; 96151.doc -35- 200523234 R2 is selected from (1-6C) alkyl, (3-8C) cycloalkyl, (5-12C) Bicycloalkyl, (6-12C) tricycloalkyl, AR1, HET1,-(1-6C) alkyl AR1,-(1-6C) alkylNHCO (l-6C) alkyl,-(1-6C ) AlkylNHCOAR1,-(1-6C) alkylCONH (l-6C) alkyl,-(1-6C) alkylCONHAR1,-(1-6C) alkylNH (1-6C) alkyl,- (1-6C) alkylNHAR1,-(1-6C) alkylNH (HETl),-(1-6C) alkylNHS02 (Bu 6C) alkyl and-(1-6C) alkylS02NH (1- 6C) alkyl. Another aspect of the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

Ar是視需要以1或2個獨立選自R9的基團取代的苯基； R9是選自鹵，甲基，甲氧基及三氟甲基； R1是氫或甲基； R5是氫； R6是氫； R7是氫； R8是氫； R3及R4共同形成茚滿基環； R2是選自（1-6C)烷基，（3-8C)環烷基，（5-12C)雙環烷基， (6-12C)三環烷基，AR1，HET1，-(1-6C)烷基 AR1，-(1-6C)烷基 NHCO(l-6C)烷基，_(1-6C)烷基 NHCOAR1，-(1-6C)烷基 CONH(l-6C)烷基，-(1-6C)烷基 CONHAR1，-(1-6C)烷基 NH(1-6C)烷基，-(1-6C)烷基 NHAR1，-(1-6C)烷基 NH(HETl)，-(1-6C)烷基 NHS〇2(l-6C)烷基及-(1-6C)烷基 S02NH(1-6C)烷基。 96151.doc • 36- 200523234 本發明另一方面提供式⑴化合物或其醫藥上可接受的 鹽，其中Ar is phenyl substituted with 1 or 2 groups independently selected from R9 as needed; R9 is selected from halogen, methyl, methoxy and trifluoromethyl; R1 is hydrogen or methyl; R5 is hydrogen; R6 is hydrogen; R7 is hydrogen; R8 is hydrogen; R3 and R4 together form an indanyl ring; R2 is selected from (1-6C) alkyl, (3-8C) cycloalkyl, (5-12C) bicycloalkane , (6-12C) tricycloalkyl, AR1, HET1,-(1-6C) alkyl AR1,-(1-6C) alkylNHCO (l-6C) alkyl, _ (1-6C) alkane NHCOAR1,-(1-6C) alkylCONH (l-6C) alkyl,-(1-6C) alkylCONHAR1,-(1-6C) alkylNH (1-6C) alkyl,-(1 -6C) alkylNHAR1,-(1-6C) alkylNH (HETl),-(1-6C) alkylNHS〇2 (l-6C) alkyl and-(1-6C) alkylS02NH (1 -6C) alkyl. 96151.doc • 36- 200523234 Another aspect of the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein

Ar是苯基，氟苯基或二氟苯基； R1是氫； R5是氫； R6是氫； R7是氫； R8是氫； R3及R4共同形成茚滿基環； R2是選自（1-6C)烷基，環己基，降冰片烷基，金剛烷 基，苯基（視需要是1或2個選自氟，氯，三氟甲基， 甲烷磺醯胺基，羧甲基，-S02NH2& -S〇2NHMe的取 代基取代的）’苄基（視需要是1或2個選自氟，氯，三 氟甲基，甲烷磺醯胺基，羧曱基，-S02NH2及 -S02NHMe的取代基取代的），-(1-4C)烷基CONH(l-4C)烷基，-U-4C)烷基CONHPh(視需要是1或2個選自 氟，氯，三氟甲基，甲烷磺醯胺基，羧甲基， -S02NH2及-s〇2NHMe的取代基取代的），及-(1-4C)烷 基 NHS02(1-4C)烷基。 本發明另一方面提供式⑴化合物或其醫藥上可接受的鹽 其中Ar is phenyl, fluorophenyl or difluorophenyl; R1 is hydrogen; R5 is hydrogen; R6 is hydrogen; R7 is hydrogen; R8 is hydrogen; R3 and R4 together form an indanyl ring; R2 is selected from (1 -6C) alkyl, cyclohexyl, norbornyl, adamantyl, phenyl (optionally 1 or 2 selected from fluorine, chlorine, trifluoromethyl, methanesulfonylamino, carboxymethyl,- S02NH2 & -S02NHMe substituted with a substituent '' benzyl (optionally 1 or 2 selected from fluorine, chlorine, trifluoromethyl, methanesulfonamido, carboxyfluorenyl, -S02NH2 and -S02NHMe (Substituent substituted),-(1-4C) alkyl CONH (l-4C) alkyl, -U-4C) alkyl CONHPh (optionally 1 or 2 selected from fluorine, chlorine, trifluoromethyl, Methanesulfonamido, carboxymethyl, -S02NH2 and -s02HMe substituted with-), and-(1-4C) alkylNHS02 (1-4C) alkyl. Another aspect of the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof

Ar是視需要以1或2個獨立選自R9的基團取代的苯基； R9是選自鹵’甲基’甲氧基及三氟甲基； R1是氫或甲基； 96l51.doc -37- 200523234 R5是氫； R6是氫； R7是氫； R8是氩； R3是氫及R4是選自-(1-4C)烷基（3-8C)環烷基，-(1-4C)烷基 (3-8C)環烯基，-(1-4C)烷基 AR1，-(idC)烷基 AR2，-(1-4C)烷基HET1 及-(1-4C)烷基HET2 ; R2是選自（1-6C)烷基，（3-8C)環烷基，（5-12C)雙環 烷基，（6-12C)三環烷基，AR1，HET1，-(1-6C)烷基 AR1，-(1-6C)烷基 NHCO(l-6C)烷基，-(1-6(3)烷基 NHCOAR1，-(1-6C)烷基 CONH(l-6C)烷基，-(1-6C) 烷基 CONHAR1，-(1-6C)烷基 NH(1-6C)烷基，-(1-6C)烷基 NHAR1，-(1-6C)烷基 NH(HETl)，-(1-6C)烷 基 NHS02(1-6C)烷基及-(1-6C)烷基 S02NH(1-6C)烷 基。 本發明另一方面提供式⑴化合物或其醫藥上可接受的鹽 其中Ar is phenyl substituted with 1 or 2 groups independently selected from R9 as needed; R9 is selected from halo'methyl'methoxy and trifluoromethyl; R1 is hydrogen or methyl; 96l51.doc- 37- 200523234 R5 is hydrogen; R6 is hydrogen; R7 is hydrogen; R8 is argon; R3 is hydrogen and R4 is selected from-(1-4C) alkyl (3-8C) cycloalkyl,-(1-4C) Alkyl (3-8C) cycloalkenyl,-(1-4C) alkyl AR1,-(idC) alkyl AR2,-(1-4C) alkyl HET1 and-(1-4C) alkyl HET2; R2 Is selected from (1-6C) alkyl, (3-8C) cycloalkyl, (5-12C) bicycloalkyl, (6-12C) tricycloalkyl, AR1, HET1,-(1-6C) alkane Alkyl AR1,-(1-6C) alkylNHCO (l-6C) alkyl,-(1-6 (3) alkylNHCOAR1,-(1-6C) alkylCONH (l-6C) alkyl,- (1-6C) alkyl CONHAR1,-(1-6C) alkylNH (1-6C) alkyl,-(1-6C) alkylNHAR1,-(1-6C) alkylNH (HET1),- (1-6C) alkylNHS02 (1-6C) alkyl and-(1-6C) alkylS02NH (1-6C) alkyl. Another aspect of the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof. among them

Ar是視需要以1或2個獨立選自R9的基團取代的苯基； R9是選自鹵，甲基，甲氧基及三氟甲基； R1是氫或甲基； R5是氫； R6是氫； R7是氫； R8是氫； 9615l.doc -38- 200523234 R3是氫及R4是選自-(1-4C)烷基ARl，-(1-4C)烷基AR2， -(1-4C)烷基 HET1 及-(1-4C)烷基 HET2 ; R2是選自（1-6C)烷基，（3-8C)環烷基，（5-12C)雙環烷 基，（6-12C)三環烷基，AR1，HET1，-(1-6C)烷基 AR1，-(1-6C)烷基 NHCO(l_6C)烷基，-(1-6C)烷基 NHCOAR1，-(1-6C)烧基 CONH(l-6C)烧基，-(1-6C)烧基 CONHAR1，-(1-6C)烷基 NH(1-6C)烷基，-(1-6C)烷基 NHAR1，-(1-6C)烧基 NH(HETl)，-(1-6C)烧基 NHS02(1-6C)烷基及-(1-6C)烷基 S02NH(1-6C)烷基。 本發明另一方面提供式（I)化合物或其醫藥上可接受的鹽 其中Ar is phenyl optionally substituted with 1 or 2 groups independently selected from R9; R9 is selected from halo, methyl, methoxy and trifluoromethyl; R1 is hydrogen or methyl; R5 is hydrogen; R6 is hydrogen; R7 is hydrogen; R8 is hydrogen; 9615l.doc -38- 200523234 R3 is hydrogen and R4 is selected from-(1-4C) alkyl AR1,-(1-4C) alkyl AR2,-(1 -4C) alkyl HET1 and-(1-4C) alkyl HET2; R2 is selected from (1-6C) alkyl, (3-8C) cycloalkyl, (5-12C) bicycloalkyl, (6- 12C) Tricycloalkyl, AR1, HET1,-(1-6C) alkyl AR1,-(1-6C) alkylNHCO (l-6C) alkyl,-(1-6C) alkylNHCOAR1,-(1- 6C) alkyl (H-6C) alkyl,-(1-6C) alkyl CONHAR1,-(1-6C) alkylNH (1-6C) alkyl,-(1-6C) alkylNHAR1, -(1-6C) alkenyl NH (HET1),-(1-6C) alkenyl NHS02 (1-6C) alkyl and-(1-6C) alkylS02NH (1-6C) alkyl. Another aspect of the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof

Ar是視需要以1或2個獨立選自R9的基團取代的苯基； R9是選自鹵，甲基，甲氧基及三氟甲基； R1是氫或甲基； R5是氩； R6是氫； R7是氫； R8是氫； R3是氫及R4是選自苄基，（視需要是以1或2個選自氰基 氟，氯，甲基，乙基，氟甲基，二氟甲基，氯甲基，三氟 曱基，曱氧基，羧甲基，羧基甲氧基，羥基，-CONH2& -S(0)2NH2取代基取代的； R2是選自（1-6C)烷基，（3-8C)環烷基，（5-12C)雙環烷基， (6-12C)三環烷基，AR1，HET1，-(1-6C)烷基 AR1，-(1- 96151.doc -39- 200523234 6C)烷基 NHCO(l_6C)烷基，-(1-6C)烷基 NHCOARl，-(1· 6C)烷基 CONH(l-6C)烷基，-(1-6C)烷基 CONHAR1，-(1-6C)烷基 NH(1-6C)烷基，-(1-6C)烷基 NHAR1，-(1-6C)烷基 NH(HETl)，-(1-6C)烷基 NHS02(卜6C)烷基及-(1-6C)烷基 S02NH(1-6C)烷基。 本發明另一方面提供式（I)化合物或其醫藥上可接受的鹽 其中Ar is phenyl optionally substituted with 1 or 2 groups independently selected from R9; R9 is selected from halogen, methyl, methoxy and trifluoromethyl; R1 is hydrogen or methyl; R5 is argon; R6 is hydrogen; R7 is hydrogen; R8 is hydrogen; R3 is hydrogen and R4 is selected from benzyl, (if necessary, 1 or 2 selected from cyanofluoro, chlorine, methyl, ethyl, fluoromethyl, Difluoromethyl, chloromethyl, trifluorofluorenyl, fluorenyl, carboxymethyl, carboxymethoxy, hydroxy, -CONH2 & -S (0) 2NH2 substituted; R2 is selected from (1- 6C) alkyl, (3-8C) cycloalkyl, (5-12C) bicycloalkyl, (6-12C) tricycloalkyl, AR1, HET1,-(1-6C) alkyl AR1,-(1 -96151.doc -39- 200523234 6C) alkyl NHCO (l-6C) alkyl,-(1-6C) alkyl NHCOARl,-(1.6C) alkylCONH (l-6C) alkyl,-(1- 6C) alkyl CONHAR1,-(1-6C) alkylNH (1-6C) alkyl,-(1-6C) alkylNHAR1,-(1-6C) alkylNH (HETl),-(1- 6C) alkyl NHS02 (6C) alkyl and-(1-6C) alkyl S02NH (1-6C) alkyl. Another aspect of the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof

Ar是苯基，氟苯基或二氟苯基； R1是氫； R5是氫； R6是氫； R7是氫； R8是氫； R3是氫； R4是苄基； R2是選自（1-6C)烷基，環己基，降冰片烷基，金剛烷基， 苯基（是視需要由1或2個選自氟，氣，三氟甲基，曱烷磺 醯胺基，羧甲基，-S02NH2及-S02NHMe的取代基取代 的），苄基（是視需要由1或2個選自氟，氯，三氟甲基，甲 烷磺醯胺基，羧甲基，-S02NH2及-S02NHMe的取代基取代 的），-(1-4C)烷基 CONH(l-4C)烷基，-(1-4C)烷基 CONHPh(是視需要由1或2個選自氟，氣，三氟甲基，甲烷 磺醯胺基，羧甲基，-S02NH2及-S02NHMe的取代基取代 的）及-(1-4C)烷基 NHS02(1-4C)烷基。 96i5l.doc -40- 200523234 本發明另一方面提供式（i)化合物或其醫藥上可接受的鹽 其中Ar is phenyl, fluorophenyl or difluorophenyl; R1 is hydrogen; R5 is hydrogen; R6 is hydrogen; R7 is hydrogen; R8 is hydrogen; R3 is hydrogen; R4 is benzyl; R2 is selected from (1- 6C) alkyl, cyclohexyl, norbornyl, adamantyl, phenyl (which is optionally selected from 1 or 2 of fluorine, gas, trifluoromethyl, pinanesulfonamido, carboxymethyl, -S02NH2 and -S02NHMe substituted), benzyl (is optionally selected from 1 or 2 selected from fluorine, chlorine, trifluoromethyl, methanesulfonamido, carboxymethyl, -S02NH2 and -S02NHMe (Substituent substituted),-(1-4C) alkyl CONH (l-4C) alkyl,-(1-4C) alkyl CONHPh (optionally from 1 or 2 selected from fluorine, gas, trifluoromethyl Group, methanesulfonamido, carboxymethyl, substituted with -SO2NH2 and -SO2NHMe substituents) and-(1-4C) alkylNHS02 (1-4C) alkyl. 96i5l.doc -40- 200523234 Another aspect of the present invention provides a compound of formula (i) or a pharmaceutically acceptable salt thereof

Ar是經1，2或3個氟取代的苯基； R1是氫； R2是選自（1-6C)烷基，（3-8C)環烷基，（5-12C)雙環 烷基，（6-12C)三環烷基，AR1，HET1，-(l-6c)烧 基 AR1，-(1-6C)烷基 NHCO(l-6C)烷基，-(1-6C)燒基 NHCOAR1，-(1-6C)烷基 CONH(l-6C)烷基，-(i_6c) 烷基 CONHAR1，-(1-6C)烷基 NH(1-6C)烷基， 6C)烷基 NHAR1 及-(1-6C)烷基 NH(HETl)，_(1-6C)烧 基 NHS02(1-6C)烷基及-(1-6C)烷基 S02NH(1-6C)烧 基； R3是氫； R4是 CH2-AR1，CH2_HET1 或 CH2-HET2 ;及 R5，R6，R7及R8都是氫。 本發明另一方面提供式⑴化合物或其醫藥上可接受的鹽 其中Ar is phenyl substituted with 1, 2 or 3 fluorines; R1 is hydrogen; R2 is selected from (1-6C) alkyl, (3-8C) cycloalkyl, (5-12C) bicycloalkyl, ( 6-12C) tricycloalkyl, AR1, HET1,-(l-6c) alkyl AR1,-(1-6C) alkylNHCO (l-6C) alkyl,-(1-6C) alkyl NHCOAR1, -(1-6C) alkyl CONH (l-6C) alkyl,-(i-6c) alkyl CONHAR1,-(1-6C) alkylNH (1-6C) alkyl, 6C) alkylNHAR1 and-( 1-6C) alkyl NH (HETl), _ (1-6C) alkyl NHS02 (1-6C) alkyl and-(1-6C) alkylS02NH (1-6C) alkyl; R3 is hydrogen; R4 CH2-AR1, CH2_HET1 or CH2-HET2; and R5, R6, R7 and R8 are all hydrogen. Another aspect of the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof

Ar是經1，2或3個氟取代的苯基； R1是氫； R2是氫，（1-4C)烷基，-(1-4C)烷基AR1或-(1-4C)烷基 CONH(l-4C)烷基； R3是氫； R4 是 CH2-AR1 或 CH2-HET1 ;及 R5，R6，R7及R8都是氫。 96151.doc -41 - 200523234 【實施方式】 本發明特定化合物是式（ΙΑ)化合物··Ar is phenyl substituted with 1, 2 or 3 fluorines; R1 is hydrogen; R2 is hydrogen, (1-4C) alkyl,-(1-4C) alkyl AR1 or-(1-4C) alkyl CONH (l-4C) alkyl; R3 is hydrogen; R4 is CH2-AR1 or CH2-HET1; and R5, R6, R7 and R8 are all hydrogen. 96151.doc -41-200523234 [Embodiment] The specific compound of the present invention is a compound of formula (IA) ...

R2 (ΙΑ) 其中Ar，R1至R8如前述或後述之紅 — 交述之任一疋義，具體實施例或 各方面所界定。 另一方面，本發明化合物是任一實例之化合物，或其醫 藥上可接受的鹽。 製法 式⑴化合物及其醫藥上可接受的鹽可以任何已知的用於 製備化學上有關的化合物的製法製備。此種製法，在用以 製備式⑴化合物或其醫藥上可接受的鹽時，視為本發明的 又一特色。 另一方面，本發明也提供式⑴化合物及其醫藥上可接受 的鹽的如下製備步驟(其中各變數，除非另有說明，如前 述或後述之定義）： j a)用式（II)化合物（或其活化衍生物）（其中p是適宜的保古蔓 基）與式（III)化合物偶合，然後除去保護基p ;R2 (ΙΑ) where Ar, R1 to R8 are as defined in any of the preceding or following red — descriptions, specific embodiments or aspects. In another aspect, the compound of the present invention is a compound of any one of the examples, or a pharmaceutically acceptable salt thereof. Method of Preparation The compound of formula (I) and its pharmaceutically acceptable salts can be prepared by any known method for preparing chemically relevant compounds. This method is considered to be another feature of the present invention when used to prepare a compound of formula (I) or a pharmaceutically acceptable salt thereof. In another aspect, the present invention also provides the following preparation steps of the compound of formula (I) and a pharmaceutically acceptable salt thereof (wherein each variable, unless otherwise specified, is as defined above or below): Or an activated derivative thereof) (where p is a suitable Baogumanyl) is coupled to a compound of formula (III), and then the protecting group p is removed;

96i51.doc -42- 200523234 或b)以式（IV)化合物（或其活化衍生物）與式（V)化合物偶 合，再除去保護基P;96i51.doc -42- 200523234 or b) coupling a compound of formula (IV) (or an activated derivative thereof) with a compound of formula (V), and then removing the protective group P;

(IV) (V) 然後’如有必要(IV) (V) and then ‘if necessary

⑴將式（I)化合物以習用官能基團修改轉化成另一式⑴化合 物，及/或 (Π)視需要生成醫藥上可接受的鹽。 式（Π)化合物是商業上可購得的或可以此技藝已知方法 製得的。例如，式（Π)化合物可藉偶合式（IV)化合物（或立 活化衍生物）與式（V)化合物製得，其中pl是適宜的保護(I) Converting a compound of formula (I) into another compound of formula (I) with modification of conventional functional groups, and / or (Π) forming a pharmaceutically acceptable salt, if necessary. Compounds of formula (Π) are commercially available or can be prepared by methods known in the art. For example, a compound of formula (Π) can be prepared by coupling a compound of formula (IV) (or a stereoactivated derivative) with a compound of formula (V), where pl is a suitable protection

OP1 〇 (V)OP1 〇 (V)

然後在適宜條件下除去pi。 式（no化合物-般是商業上可講得的，或可以此技藝 =製備心胺基酸的方法製得。保護基p較佳是胺基甲 =4基’如獄基團。其他製跡胺基酸的方法見專 甲咱案 WO 03/000181。 式（V)化合物一般是商 業上可購得的 或可以此技藝已 96151.doc -43- 200523234 知的製備經保護的胺基酸的方法製得。適宜的保護基p1較 佳是烧基，如甲基。 步驟b)或步驟c)的適宜的偶合條件是此技藝已知的任何 偶合酸及驗的條件，例如此技藝已知的標準肽偶合試劑或 例如羰基二咪唑，b乙基_3气3-二甲基胺基丙基）碳化二亞 醯胺鹽酸鹽（EDCI)及二環己基-碳化二亞醯胺（DCCI)，有 時是有催化劑如丨_羥基苯并三唑，二甲基胺基π比啶或比 咯啶基吡啶，視需要在有鹼如三乙基胺，二-異丙基乙基 胺 比疋或2,6 - 一烧基·。比17定如2,6_廬剔咬或2,6 -二-第三_ 丁基吡α疋之存在。適宜的溶劑包括二甲基乙醯胺，二氣甲 烷笨，四氫呋喃及二甲基甲醯胺。偶合反應可於_4〇 π 至4〇°c溫度範圍内進行。式（Π)或（IV)化合物”活化的衍生 物疋扣，例如，適於此偶合反應的酐或醯基鹵。 保羞基P之除去可以任何此技藝已知方法完成。在保護 基P1是烧基時，可在酸或驗性條件下水解自旨，例如用驗金 屬驗如氫氧化鈉或氫氧化鋰。 保屢基P之除去可以任何此技藝已知方法完成。在p是胺 基甲酸基團如BOC時，B〇c基團的水解可用酸的水溶液達 成例如用一噁烷内的HC1水溶液。適於除去保護基p的條 件’如SHC1酸處理，可導致生成式⑴化合物的鹽，此鹽 可視而要再加以處理得自由態驗，或得另—形式的（醫藥 上可接受的）鹽。 士果商業上不把購得’上述所需起始物質可藉標準有機 化子技術工序衣侍’此等技術與已知的構造類似的化合物 96151.doc -44- 200523234 的合成技術相同，此等技術已如上述，此等技術與上述工 序或與實例中所述工序相同。 應注意到，上述合成方法所需起始物質是商業上可購得 的及/或科學文獻上廣為報告的，或可用報告上所述工序 以商業上可購得的化合物製備的。讀者可進一步參考 Advanced Organic Chemistry，4th Edition，Jerry March著， John Wiley & Sons 1992出版，作反應條件及試劑的參考。 應了解到，有些式（I)化合物的中間體是新穎的，此等中 間體為本發明另一獨立面。有些式（II)化合物是新穎的， 也是本發明的另一獨立面。有些式（III)化合物是新穎的， 也是本發明的另一獨立面。有些式（IV)化合物是新穎的， 也是本發明的另一獨立面。有些式（V)化合物是新穎的， 也是本發明的另一獨立面。 有些特定式（II)，（III)，（IV)及（V)是這樣的化合物，其 中Ar是經1，2或3個氟取代的苯基；R5，R6，R7及R8都是 氫；R3是氫及 R4是 CH2-AR1，CH2-Hetl 或 CH2-Het2，R1 是 氫而R2是選自（1-6C)烷基，（3-8C)環烷基，（5-12C)雙環 烷基，（6-12C)三環烷基，AR1，HET1，-(1-6C)烷基 AR1，-(1-6C)烷基 NHC0(1-6C)烷基，-(1-6C)烷基 NHC0AR1，-(1-6C)烧基 C0NH(1-6C)烧基，-(1-6C)烧基 C0NHAR1，-(1-6C)烷基 NH(1-6C)烷基，-(1-6C)烷基 NHAR1，-(1-6C)烧基 NH(HETl)，-(1-6C)烧基 NHS02(1-6C)烷基及-(1-6C)烷基 S02NH(1-6C)烷基。 應了解到，在有些此處所述反應中，有時須/需保護化 96l51.doc -45- 200523234 合物中易反應的基團。何時須/需保護及適宜的保護方法 是此技藝已知的。根據標準操作選用習用的保護基（說明 見 T.W. Greene，Protective Groups in Organic Synthesis， John Wiley and Sons，1991) ° 保遵基可藉由文獻所載或精於化學者所知之任何適於移 除所要移除之保護基的簡便方法除去，所選擇的方法能有 效除去保護基而對分子内的其他基團產生極少的擾亂。 所以，如果反應物中包含如胺基，羧基或羥基之類的基 團’須要在前述反應中保護此基團。 羥基的適宜的保護基的例是，例如，醯基，例如烷醯基 如乙醯基，芳醯基如苯甲醯基，曱矽烷基如三甲基甲矽烷 基，或芳基甲基如苄基。上述保護基的去保護條件視所選 保護基而異。是以，例如醯基如烷醯基或芳醯基可藉，例 如，用適宜的鹼如鹼金屬氫氧化物，例如氫氧化鋰或鈉， 作水解除去。或者是，甲我基如三甲基甲_烧基可用例 如氟化物或酸水溶液除去；或者，如芳基甲基如苄基可 用，例如，在有催化劑如鈀/碳之存在下行氫化除去。 胺基的適宜的保護基是，例如，醯基，例如烷醯基如乙 驢基’燒氧基爹炭基，例如甲氧基幾基，乙氧基魏基，或第 、 氧基‘基’芳基甲氧基幾基，例如苄基氧基幾基， 或=醯基，例如苯甲醯基。上述保護基的除去條件視所選 保4基而異。是以，醯基如烷醯基或烷氧基羰基或芳醯 基，可藉，例如，用適宜的鹼如鹼金屬氫氧化物如氫氧化 鋰或鈉’仃水解除去。另外，醯基如第三-丁氧基羰基 96151.doc 200523234 可，例如，用適宜的酸如鹽酸，硫酸或磷酸或三氟醋酸處 理除去，而芳基甲氧基羰基如节基氧基羰基可藉，处 用催化劑如鈀/碳，行氫化除去，或用路易氏酸，例如參 (三氟醋酸）硼處理除去。初級胺基的適宜的保護基是，例 如，鄰苯二甲録，其可藉用，例如，烷基胺如二甲基胺 基丙基胺或2-羥基乙基胺，或用肼處理除去。 羧基的適且的保護基是，例如，酯化基團，例如甲基哎 乙基4可用驗Μ列如氫氧化納，行水解除去，或者:例 如’第三-丁基，可用，例如，酸如三氟醋酸處理除去， 或者例如节基，其可用，例如，絶/碳催化劑行氣化除 去。 樹脂也可用作保護基。 此保濩基可於合成的任何方便階段以化學技藝已知的技 術除去，或在後期反應步驟或收取時除去。。 技巧的有機化學家應能❹上述信息及上述參考文獻及 所附實例與此處所述實例以製得必需的起始物質及產物。 ㈣基之除去及醫藥上可接受的鹽的生成是—般有機化 工作者能以-般技術作做的。此等步驟的詳情前已提供。 在需本發明光學活性化合物時’其可藉使用一種上述方 μ光#㈣起始物質製得（例如’適宜反應步驟中的不 對稱誘導），u標準工序解析外消旋形的化合物，或將 非鏡像立體異構物（製得時）作色層分析製得。製備光學活 性化合物及/或中間體時也可用酶技術。 同樣，在需要本發明化合物的區異構物（regioisomer) 96151.doc -47- 200523234 時，其可藉使用上述工序之一用純區異構物作為起始物質 製得，或以標準工序藉解析區異構物或中間體的混合物製 - 根據本發明另一方面，提供一種醫藥組合物，其含上述 式（I)化合物或其醫藥上可接受的鹽與醫藥上可接受的賦形 劑或載劑。 本發明組合物可以是供口服的形式（例如錠，糖衣錠， 硬或軟膠囊，水性或油性懸浮液，乳液，可分散的散 粒，糖漿或酏），供局部使用的形式（例如霜，膏，凝膠， 或水性或油性溶液或懸浮液），供吸入給予的形式（例如磨 細的粉或液體氣溶膠）、藉吹入投藥（例如細粉形式）或供非 經腸給予的形式（例如滅菌的水性或油性溶液作靜脈，皮 下’肌肉内給藥或作為塞劑供直腸給藥）。 本發明醫藥組合物習用工序以此技藝周知的習用醫藥賦 形劑製得。是以，用於口服的組合物可含，例如，一或多 種增色劑，甘味劑，續味劑及/或防腐劑。一方面，本發 明組合物為適於口服的形式。 錠調配物的適宜的醫藥上可接受的賦形劑包括，例如， 惰性稀釋劑，如乳糖，碳酸鈉，磷酸鈣或碳酸鈣，成顆粒 及分散劑如玉米澱粉或藻酸；結合劑如澱粉；滑潤劑如硬 脂酸鎮，硬脂酸或滑石粉；防腐劑如^苯甲酸乙酯或丙酯 • 及抗氧化劑如抗壞血酸。錠調配物可以是未塗覆的或塗覆 ' 的，用以修正其崩解及在胃腸道内吸收活性成分，或用以 增進其女疋性及/或外觀，這都是使用此技藝習用的塗覆 96151.doc -48· 200523234 劑及工序。 供口服的組合物可以是硬明膠膠囊的形式，其内以活性 成分與惰性固體稀釋劑，例如，碳酸鈣，磷酸鈣或高嶺土 混合’或是軟明膠膠囊的形式，於其内活性劑是與水或油 如花生油，液體石蠟或撖欖油混合。 水性懸浮液一般含磨成細粉的活性成分及一或多種懸浮 劑’如緩甲基纖維素鈉，曱基纖維素，羥基丙基甲基纖維 素’澡酸鈉，聚乙烯-吡咯酮，黃蓍膠及阿拉伯膠；分散 或濕潤劑如卵磷脂或氧化烯與脂肪酸的縮合物（例如硬脂 酉文氧乙稀醋），或環氧乙烷與長鏈脂肪醇例如十七乙烯 氧不蠟醇的縮合產物，或環氧乙烷與衍生自脂肪酸及己醇 的部分酯的縮合產物如聚氧乙烯山梨糖醇單油酸鹽，或環 氧乙烷與長鏈脂肪醇例如十七乙烯氧京蠟醇的縮合產物， 或環環氧乙烧與衍生自脂肪酸及己醇的部分醋的縮合產物 如聚氧乙烯山梨糖醇單油酸鹽，或環氧乙烷與衍生自脂肪 酸及己醇的部分酷的縮合產物如聚氧乙稀山梨糖醇單油酸 鹽。水性懸浮液也可含-或多種防腐劑（如對i基苯甲酸 乙^丙酯抗氧化劑(如抗壞血·增色劑，橋味劑及 /或甘味劑（如蔗糖，糖精或阿斯帕他米（aspaname))。 油性懸浮液可藉將活性成分懸浮於植物油（如花生油， 撖欖油，芝麻油或椰子油)或礦物油(諸如液體内調 配。油性懸浮液也可含增稠劑如蜂壤， ^ 又七嘴或京蠛基 醇。可加上述甘味劑及矯味劑以製出合口 ^ 木的製劑。此箄 組合物可藉加抗氧化劑如抗壞血酸以防腐。 寸 96151.doc • 49- 200523234 適於藉加水製成水性懸浮液之可分散的散劑及顆粒一般 含活性劑與分散劑或濕潤劑，懸浮劑及一或多種防腐劑。 適宜的分散劑或濕潤劑及懸浮劑之例如上述者。也可含其 . 他的賦形劑，如乾味劑，矯味劑及增色劑。 本發明醫藥組合物也可以是水包油的乳液形式。油相可 、疋植物油，如撖欖油或化生油，或礦物油，如液體石蠛 或等成分的混合物。適宜的乳化劑可以是，例如，天然的 膠，如阿拉伯膠或黃蓍膠，天然的磷脂如大豆，卵磷脂， 何生自脂肪酸及己醇酐的酯或部分酯（如單油酸山梨糖醇） 及該部分酯與環氧乙烷的縮合產物，如聚氧乙烯山梨糖醇 單油酸鹽。此乳液也可含甘味劑，矯味劑及防腐劑。 糖裝及酿可用甘味劑如甘油，丙二醇，山梨糖醇，阿斯 他米或蔗糖調配，也可含潤藥（demulcent)，防腐劑，矯味 劑及/或增色劑。 此醫藥組合物也可是滅菌的可注射的水性或油性懸浮液 的形式，其可根據已知方法用前述一或多種適宜的分散劑 或濕潤及懸浮劑調配。滅菌的可注射的製劑也可以是無 毒的非經腸給予接受的稀釋液或溶劑内的滅菌的可注射的 溶液或懸浮液，例如於丨，3_丁烷二醇内的溶液。 藉吸入給予的組合物可以是習用的加壓的喷霧劑的形 式，其含磨細的固體或液體小滴。可使用習用的喷霧推進 ，劑如揮發性氣化的煙屬或烴屬，噴霧裝置較佳是裝成能投 ^ 送計量的活性成分。 關於進一步的調配信息讀者可參考chapter 25.2 in 96151.doc -50- 200523234Pi is then removed under appropriate conditions. Compounds of formula (no) are generally commercially available, or can be prepared by this technique = method of preparing amino acids. The protecting group p is preferably aminomethyl = 4 groups such as jail groups. Other traces The method of amino acids is described in WO 03/000181. Compounds of formula (V) are generally commercially available or can be prepared by the technique known as 96151.doc -43- 200523234. It is prepared by a method. A suitable protecting group p1 is preferably a calcined group, such as a methyl group. A suitable coupling condition of step b) or step c) is any coupling acid known in the art and the conditions tested, for example, the technology is known Standard peptide coupling reagents or for example carbonyldiimidazole, bethyl_3-gas 3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) and dicyclohexyl-carbodiimide (DCCI ), Sometimes there is a catalyst such as __hydroxybenzotriazole, dimethylamino π than pyridine or pyrrolidinylpyridine, if necessary in the presence of a base such as triethylamine, di-isopropylethylamine Than 疋 or 2,6-one burned base ·. Than 17 is fixed as the presence of 2,6_lu tick or 2,6-di-third_butylpyridine α 疋. Suitable solvents include dimethylacetamide, digasmethane, tetrahydrofuran and dimethylformamide. The coupling reaction can be performed at a temperature ranging from -40 π to 40 ° C. "Activated derivatives of compounds of formula (Π) or (IV) are snapped, for example, anhydrides or fluorenyl halides suitable for this coupling reaction. Removal of the pouch group P can be accomplished by any method known in the art. At the protective group P1 When it is calcined, it can be hydrolyzed under acid or test conditions, such as using a metal test such as sodium hydroxide or lithium hydroxide. Removal of Phenyl P can be accomplished by any method known in the art. Where p is an amine In the case of carbamate groups such as BOC, the hydrolysis of the Boc group can be achieved with an aqueous solution of an acid, such as an aqueous solution of HC1 in monooxane. Conditions suitable for removal of the protecting group p, such as treatment with SHC1 acid, can lead to the formation of compounds of formula This salt can be treated freely, or it can be treated in another form (pharmaceutically acceptable). Shiguo does not commercially purchase the above-mentioned required starting materials by standard organic Chemical technology process: These techniques are the same as the known synthetic compounds 96151.doc -44- 200523234. These techniques are as described above. These techniques are the same as those described above or in the examples. It should be noted that the above combination The starting materials required for the method are commercially available and / or widely reported in the scientific literature, or can be prepared from commercially available compounds using the procedures described in the report. Readers may refer to Advanced Organic Chemistry for further information. 4th Edition by Jerry March, published by John Wiley & Sons 1992, as a reference for reaction conditions and reagents. It should be understood that some intermediates of compounds of formula (I) are novel, and these intermediates are another of the present invention Independent aspects. Some compounds of formula (II) are novel and are another independent aspect of the present invention. Some compounds of formula (III) are novel and also another independent aspect of the present invention. Some compounds of formula (IV) are novel Is also another independent aspect of the present invention. Some compounds of formula (V) are novel and also another independent aspect of the present invention. Some specific formulae (II), (III), (IV) and (V) are like this Compounds where Ar is phenyl substituted with 1, 2 or 3 fluorines; R5, R6, R7 and R8 are all hydrogen; R3 is hydrogen and R4 is CH2-AR1, CH2-Hetl or CH2-Het2, and R1 is hydrogen And R2 is selected from (1-6C) alkyl and (3-8C) cycloalkane , (5-12C) bicycloalkyl, (6-12C) tricycloalkyl, AR1, HET1,-(1-6C) alkylAR1,-(1-6C) alkylNHC0 (1-6C) alkyl ,-(1-6C) alkylNHC0AR1,-(1-6C) alkylC0NH (1-6C) alkyl,-(1-6C) alkylCONARAR1,-(1-6C) alkylNH (1- 6C) alkyl,-(1-6C) alkylNHAR1,-(1-6C) alkylNH (HETl),-(1-6C) alkylNHS02 (1-6C) alkyl and-(1-6C ) AlkylS02NH (1-6C) alkyl. It should be understood that in some of the reactions described herein, it is sometimes necessary / protected to react easily in the compound. When to / when protection is needed and appropriate protection methods are known in the art. Customary protective groups are selected according to standard procedures (see TW Greene, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991) ° The conformance group can be removed by any suitable material contained in the literature or known to the chemist The convenient method of removing the protecting group to be removed, the selected method can effectively remove the protecting group and cause little disturbance to other groups in the molecule. Therefore, if the reactant contains a group such as an amine group, a carboxyl group or a hydroxyl group, it is necessary to protect this group in the aforementioned reaction. Examples of suitable protecting groups for hydroxyl groups are, for example, fluorenyl groups, such as alkyl fluorenyl groups such as ethyl fluorenyl, aryl fluorenyl groups such as benz fluorenyl, fluorenyl silyl groups such as trimethylsilyl, or arylmethyl groups such Benzyl. The conditions for deprotection of the aforementioned protecting groups differ depending on the selected protecting group. Therefore, for example, a fluorenyl group such as an alkyl fluorenyl group or an aryl fluorenyl group can be removed by, for example, hydrolysis using a suitable base such as an alkali metal hydroxide such as lithium hydroxide or sodium hydroxide. Alternatively, a methyl group such as trimethylmethylsulfanyl can be removed by, for example, fluoride or an acid aqueous solution; or, an arylmethyl group such as benzyl can be used, for example, by hydrogenation in the presence of a catalyst such as palladium / carbon. Suitable protecting groups for amine groups are, for example, fluorenyl groups, such as alkyl fluorenyl groups such as ethynyl'alkyloxy, e.g. methoxyalkyl, ethoxyweiyl, or thienyloxy ' 'Arylmethoxyalkyl, such as benzyloxyalkyl, or = fluorenyl, such as benzamyl. The removal conditions of the above protecting groups differ depending on the selected protecting group. Therefore, a fluorenyl group such as an alkylfluorenyl group or an alkoxycarbonyl group or an arylfluorenyl group can be removed by, for example, hydrolysis with a suitable base such as an alkali metal hydroxide such as lithium hydroxide or sodium'fluorene. Alternatively, fluorenyl groups such as tertiary-butoxycarbonyl 96151.doc 200523234 can be removed, for example, by treatment with a suitable acid such as hydrochloric acid, sulfuric acid or phosphoric acid or trifluoroacetic acid, while arylmethoxycarbonyl groups such as benzyloxycarbonyl It can be removed by treatment with a catalyst such as palladium / carbon, hydrogenation, or treatment with a Lewis acid, such as ginseng (trifluoroacetic acid) boron. Suitable protecting groups for primary amine groups are, for example, phthalate, which can be borrowed, for example, alkylamines such as dimethylaminopropylamine or 2-hydroxyethylamine, or removed by treatment with hydrazine . Suitable protecting groups for carboxyl groups are, for example, esterification groups, such as methyl ethyl 4 can be removed by hydrolysis such as sodium hydroxide, or: for example, 'third-butyl, available, for example An acid such as trifluoroacetic acid may be removed by treatment, or, for example, a benzyl group, which may be removed by, for example, gasification of an absolute / carbon catalyst. Resin can also be used as a protective group. This stilbene can be removed at any convenient stage of the synthesis by techniques known in the chemical arts, or at a later reaction step or upon collection. . A skilled organic chemist should be able to use the above information and the above references, as well as the accompanying examples and examples described herein, to produce the necessary starting materials and products. Removal of amidines and the formation of pharmaceutically acceptable salts are as organic as a worker can do with ordinary techniques. Details of these steps were previously provided. When the optically active compound of the present invention is needed, it can be prepared by using one of the above-mentioned square μ 光 # ㈣ starting materials (for example, 'asymmetric induction in a suitable reaction step), the standard procedure for analyzing racemic compounds, or Non-mirrored stereoisomers (when prepared) were prepared by color analysis. Enzymatic techniques can also be used in the preparation of optically active compounds and / or intermediates. Similarly, when the regioisomer 96151.doc -47- 200523234 of the compound of the present invention is required, it can be prepared by using one of the above procedures using pure regioisomers as starting materials, or by standard procedures. Made of a mixture of resolution isomers or intermediates-According to another aspect of the present invention, a pharmaceutical composition is provided, which contains the compound of the above formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient Or carrier. The composition of the invention may be in the form for oral administration (for example, lozenges, dragees, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible granules, syrups or tinctures), for topical use (for example creams, ointments) , Gel, or aqueous or oily solution or suspension), in the form for administration by inhalation (eg, ground powder or liquid aerosol), by injectable administration (eg, in the form of fine powder), or in the form of parenteral administration ( Such as sterile aqueous or oily solutions for intravenous, subcutaneous' intramuscular administration or rectal administration as suppositories). The conventional process of the pharmaceutical composition of the present invention is prepared by conventional pharmaceutical excipients known in the art. Therefore, the composition for oral administration may contain, for example, one or more color enhancers, sweeteners, flavor extenders and / or preservatives. In one aspect, the composition of the invention is in a form suitable for oral administration. Suitable pharmaceutically acceptable excipients for pastille formulations include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and dispersing agents such as corn starch or alginic acid; binding agents such as starch Lubricants such as stearic acid, stearic acid or talc; preservatives such as ethyl or propyl benzoate • and antioxidants such as ascorbic acid. Tablet formulations can be uncoated or coated to correct their disintegration and absorption of active ingredients in the gastrointestinal tract, or to enhance their son-in-law and / or appearance, both of which are customary using this technique Coating 96151.doc -48 · 200523234 agent and process. Compositions for oral administration may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or in the form of soft gelatin capsules in which the active agent is Mix with water or oil such as peanut oil, liquid paraffin or olive oil. Aqueous suspensions generally contain finely ground active ingredients and one or more suspending agents 'such as sodium methylcellulose sodium, fluorenyl cellulose, hydroxypropyl methylcellulose' sodium salt, polyvinyl-pyrrolidone, Tragacanth and gum arabic; dispersing or wetting agents such as condensates of lecithin or alkylene oxides with fatty acids (such as stearyl ethoxylate) or ethylene oxide with long-chain fatty alcohols such as heptaethylene oxide Condensation products of wax alcohols, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexanol, such as polyoxyethylene sorbitol monooleate, or ethylene oxide with long-chain fatty alcohols such as heptaethylene Condensation products of oxetyl alcohol, or condensation products of cycloethylene glycol and partial vinegar derived from fatty acids and hexanol, such as polyoxyethylene sorbitol monooleate, or ethylene oxide with fatty acids and hexane derived Partially cool condensation products of alcohols such as polyoxyethylene sorbitol monooleate. Aqueous suspensions may also contain-or more preservatives (such as ethyl p-propyl benzoate antioxidants (such as ascorbate · coloring agents, bridge flavors and / or sweeteners (such as sucrose, saccharin or aspar Oily suspensions can be obtained by suspending the active ingredients in vegetable oils (such as peanut oil, olive oil, sesame oil or coconut oil) or mineral oils (such as liquid formulations. Oily suspensions can also contain thickening agents such as Honeycomb, ^ and seven mouth or Gingeryl alcohol. The sweeteners and flavoring agents mentioned above can be added to make the preparation of Hekou ^ wood. This pupa composition can be preserved by adding antioxidants such as ascorbic acid. Inch 96151.doc • 49 -200523234 Dispersible powders and granules suitable for making aqueous suspensions by adding water generally contain active agents and dispersants or wetting agents, suspending agents and one or more preservatives. Examples of suitable dispersing or wetting agents and suspending agents are The above may also contain other excipients, such as dry flavoring agents, flavoring agents, and color enhancers. The pharmaceutical composition of the present invention may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, such as olive oil. Oil or chemical oil, or mineral oil, Liquid stone chrysanthemum or a mixture of such ingredients. Suitable emulsifiers can be, for example, natural gums such as gum arabic or tragacanth, natural phospholipids such as soybeans, lecithin, esters of fatty acids and hexanol anhydrides, or Partial esters (such as sorbitol monooleate) and condensation products of the partial esters with ethylene oxide, such as polyoxyethylene sorbitol monooleate. This emulsion can also contain sweeteners, flavoring agents and preservatives. Sugar and stuffing can be formulated with sweeteners such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and can also contain demulcent, preservatives, flavoring agents and / or color enhancers. The pharmaceutical composition can also be In the form of a sterile injectable aqueous or oily suspension, it can be formulated according to known methods using one or more of the foregoing suitable dispersing or wetting and suspending agents. The sterile injectable preparation may also be administered non-toxic parenterally Acceptable diluents or solvents are sterile injectable solutions or suspensions, such as those in 3-butanediol. Compositions administered by inhalation may be in the form of a conventional pressurized spray It contains finely ground solid or liquid droplets. Conventional spray propellants can be used, such as volatile vaporized Nicotiana or Hydrocarbons, and the spray device is preferably mounted to be able to deliver a metered amount of active ingredient. About further For deployment information, please refer to chapter 25.2 in 96151.doc -50- 200523234

Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board)，Pergamon Press 1990。 產生單位劑形的與一或多種賦形劑合併的活性成分的量 可視要治療的病主及特定給予途徑而變化。例如，意圖供 經口給予人的調配物一般含，例如，0.5毫克至2克活性劑 化合物及適量的賦形劑，其可佔總組合物重量的約百分之 5至約百分之98。單位劑形可含約1毫克至約500毫克活性 劑。關於給予途徑及給藥方案的進一步信息讀者可參考 Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board)， Pergamon Press 1990 〇 根據本發明另一方面，提供前述式（I)化合物或其醫藥上 可接受的鹽供用於治療人或動物身體之方法。 發明人等發現本發明化合物抑制DPP-IV活性，在降低血 葡萄糖效果上是有益的。 本發明另一特點是式（I)化合物及其醫藥上可接受的鹽供 用作藥物。 式（I)化合物或其醫藥上可接受的鹽方便用作藥物供溫血 動物如人產生DPP-IV活性抑制作用。 特別是，式（I)化合物或其醫藥上可接受的鹽供用作藥物 以治療溫血動物如人之糖尿病。 是以，根據本發明另一方面，提供式（I)化合物或其醫藥 上可接受的鹽在製成藥物以產生溫血動物如人的DPP-IV活 96151.doc -51 - 200523234 性受抑制的用途。 疋以’根據本發明另一 上可接受、 X月另一方面，提供式（I)化合物或其醫藥 的用途。、在製成藥物以治療溫血動物如人的糖尿病上 根據本發明κ . ^ rTU,. 一方面，提供一種醫藥組合物，其含前述 ;s物或其醫藥上可接受的鹽及與其相混合的醫藥上 广的職形劑或载劑，供溫血動物如人產生D 抑制效果。 本I月另一方面κ共-種醫藥組合物，其含前述 式⑴化合物或其醫藥上可接受的鹽及與其相混合的醫華上 可接受的賦形劑或載劑，供用於治療溫血動物如人之糖尿 病0 根據本發明另-特點，提供—種方法供需此治療的溫企 動物如人產生DPP-IV活性抑制，包括給予該動物有效量的 前述式（I)化合物或其醫藥上可接受的鹽。 根據本發明另-特點，提供—種供治療需此治療的溫血 動物如人的糖尿病的方法，包括給予該動物有效量的前述 式（I)化合物或其醫藥上可接受的鹽。 如前所H療或預防特定疾病情況的劑量大小應視要 治療的病主、給予途徑及疾病嚴重程度而異。較佳是每曰 使用的劑量範圍為1-5G毫克/公斤。但此每日劑量應視要治 療的病主、給予途徑及疾病嚴重程度而異，因之，適宜的 劑量應由治療特定病人的醫生決定。 如前所述，本發明所界定的化合物在其抑制Dpp_IV活性 9615l.doc -52- 200523234 上是有益的。所以本發明化合物可用於預防、延遲或治療 —類疾病，包括糖尿病，特定的說是2型糖尿病（t2dm)及 其合併症（例如視網膜病變，神經病變及腎臟病變），葡萄 糖耐受性受損（IGT)，空腹葡萄糖受損情況，代謝性酸中 毒’酮病，代謝障礙病徵’關節炎，骨質疏鬆，肥胖及與 肥胖有關的疾病，週邊血管疾病（包括間歇性跛行），心臟 衰竭及某些心肌病變，心肌缺血，大腦缺血及消腫，肌肉 無力，血脂過高，愛茲海默氏病，粥狀動脈硬化，不孕， :囊性卵巢病徵’各帛免疫調節疾病(如牛皮癖)，hiv感 染’發炎性腸病徵，發炎性腸疾病（如克郎氏病及潰癌性 結腸炎）。 另方面，式⑴化合物或其醫藥上可接受的鹽可與其他 療d 〇併給予以預防、延遲或治療各種涉及DPP-IV活性 的疾病，包括但不限於上列疾病。 例如，為要預防、延遲或治療2型糖尿病，本發明化合 物或其醫藥上可接受的鹽可與治療有效量的其他一或多種 式⑴化合物及/或一或多種下列劑合併給予： υ胰島素及胰島素類似物； )胰島素促分泌劑，包括磺醯脲，膳食葡萄糖調節劑 及葡糖激酶活化劑； 3)増進腸降血糖素的劑（例如GLP-1拮抗劑）； )胰島素敏感化劑，包括PPART拮抗劑及合併ppARa 及T活性的的劑； )調節肝葡萄糖平衡的劑（例如雙縮胍，果糖1，6二磷 9615l.doc 200523234 酸酶抑制劑，糖原磷酸化酶抑制劑，糖原合成激酶 抑制劑，葡糖激酶活化劑）； 6) 用以減少腸吸收葡萄糖的劑（例如以葡糠普酶抑制 劑）； 7) 防止腎臟再吸收葡萄糖的劑（鈉葡萄糖轉運蛋白抑制 劑）； 8) 用以/α療長期高血糖合併症的劑（例如盤糖還原酶抑 制劑’蛋白質激酶C抑制劑）； 9) 用以治療肥胖（例如食欲抑制劑）或增進能消耗的劑； 10) 抗血脂障礙劑，如HMG-CoA還原酶抑制劑，ppARa 激動劑（例如fibrates)，ppAR 5激動劑，膽酸螯合 劑’膽固醇吸收抑制劑，膽酸吸收抑制劑，CETP抑 制劑，脂分解抑制劑； π)抗南血壓劑，如口阻斷劑，ACE抑制劑，鈣拮抗劑， 血官緊張素受體拮抗劑，α受體拮抗劑及利尿劑； 12) 止血凋節劑如抗凝血劑，纖維蛋白溶解活化劑及抗 jk小板劑’凝血酶拮抗劑，因子抑制劑，因子 Vila抑制劑，抗血小板劑及抗血凝劑； 13) 拮抗騰尚血糖素作用的劑；及 14) 抗發炎劑’如非類固醇抗發炎藥物及類固醇抗發炎 劑。 除了用作~療藥物外，式⑴化合物及其醫藥上可接受之 鹽亦可作為西療工具，發展用以評估實驗室動物如貓、 狗、兔、狼、大氣及小鼠之DPP-IV抑制劑活性效果的體外 96151.doc 200523234 及體内測試系統並將其標準化，成為新穎療劑之一部分研究。 如前文所述，所有的此等化合物及其醫藥上可接受的鹽 可用於抑制DPP-IV。式⑴化合物及其對應的醫藥上可接 受的鹽抑制DPP-IV的能力可用caco-2DPP-IV鑑定顯示，此 鑑定測定試驗化合物抑制人結腸癌細胞萃取物之DPP-IV的 能力。人結腸癌細胞系Caco-2是得自American Type Culture Collection (ATCC HTB 37)。細胞之分化誘發 DPP-IV表達可如 Reisher 等人（Proc· Natl· Acad· Sci·，V〇1.90，頁 5757-5761 (1993))所述完成。細胞萃取物是用溶於i〇 mM Tris Hen，0·15 M Nacn，0.04 t.i.u·抑酶肽，0」％11〇1^(16卜 P40，pH 8.0，的細胞製備，以35,000 g於4 °C離心30分 鐘移除細胞碎屑。Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990. The amount of active ingredient that is combined with one or more excipients to produce a unit dosage form will vary depending upon the subject to be treated and the particular route of administration. For example, formulations intended for oral administration to humans generally contain, for example, 0.5 mg to 2 grams of active compound and an appropriate amount of excipients, which may comprise from about 5 to about 98 percent of the total composition weight . The unit dosage form may contain from about 1 mg to about 500 mg of the active agent. For further information on the route of administration and dosing regimen, readers may refer to Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990. According to another aspect of the present invention, the aforementioned compound of formula (I) is provided Or a pharmaceutically acceptable salt thereof for use in a method of treating the human or animal body. The inventors have found that the compounds of the present invention are effective in inhibiting the activity of DPP-IV and are beneficial in reducing blood glucose. Another feature of the invention is the use of a compound of formula (I) and a pharmaceutically acceptable salt thereof as a medicament. The compound of formula (I) or a pharmaceutically acceptable salt thereof is conveniently used as a drug for warm-blooded animals, such as humans, to inhibit the DPP-IV activity. In particular, the compound of formula (I) or a pharmaceutically acceptable salt thereof is used as a medicament for the treatment of diabetes in a warm-blooded animal such as a human. Therefore, according to another aspect of the present invention, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided as a medicament to produce a DPP-IV activity in a warm-blooded animal such as a human 96151.doc -51-200523234. the use of. According to another aspect, according to the present invention, in another aspect, a compound of formula (I) or a pharmaceutical use thereof is provided. In accordance with the present invention, a drug is prepared to treat diabetes in a warm-blooded animal such as a human. In one aspect, a pharmaceutical composition is provided, which contains the foregoing; s substance or a pharmaceutically acceptable salt thereof and its phase Mixed medically-available formulations or carriers for warm-blooded animals such as humans to produce D-suppressive effects. Another aspect of this month is a kappa-co-pharmaceutical composition containing the aforementioned compound of formula (I) or a pharmaceutically acceptable salt thereof and a medically acceptable excipient or carrier mixed therewith for the treatment of Blood animals such as human diabetes 0 According to another feature of the present invention, a method is provided for warming animals such as humans in need of this treatment to produce DPP-IV activity inhibition, including administering to the animal an effective amount of the aforementioned compound of formula (I) or a medicine thereof Acceptable salt. According to another feature of the present invention, there is provided a method for treating diabetes in a warm-blooded animal in need of such treatment, such as human, comprising administering to the animal an effective amount of the aforementioned compound of formula (I) or a pharmaceutically acceptable salt thereof. As previously mentioned, the dose size for the treatment or prevention of specific disease conditions should vary depending on the subject to be treated, the route of administration and the severity of the disease. It is preferred to use a dose ranging from 1 to 5 mg / kg per day. However, this daily dose should vary depending on the patient to be treated, the route of administration, and the severity of the disease, so the appropriate dose should be determined by the doctor treating the particular patient. As mentioned previously, the compounds defined by the present invention are beneficial in their inhibition of Dpp_IV activity 9615l.doc -52- 200523234. Therefore, the compounds of the present invention can be used for the prevention, delay or treatment of diseases, including diabetes, specifically type 2 diabetes (t2dm) and its comorbidities (such as retinopathy, neuropathy and kidney disease), impaired glucose tolerance. (IGT), impaired fasting glucose, metabolic acidosis 'ketosis, metabolic disorder symptoms' arthritis, osteoporosis, obesity and obesity-related diseases, peripheral vascular disease (including intermittent claudication), heart failure and some Some myocardial diseases, myocardial ischemia, cerebral ischemia and swelling, muscle weakness, hyperlipidemia, Alzheimer's disease, atherosclerosis, infertility, cystic ovarian disease, 'immunomodulatory diseases (such as Psoriasis), HIV infection, inflammatory bowel symptoms, inflammatory bowel disease (such as Krone's disease and ulcerative colitis). On the other hand, the compound of formula (I) or a pharmaceutically acceptable salt thereof can be treated with other drugs to prevent, delay or treat various diseases involving DPP-IV activity, including but not limited to the diseases listed above. For example, to prevent, delay or treat type 2 diabetes, a compound of the invention or a pharmaceutically acceptable salt thereof may be administered in combination with a therapeutically effective amount of one or more other compounds of formula (I) and / or one or more of the following: insulin And insulin analogs;) insulin secretagogues, including sulfonylurea, dietary glucose regulators, and glucokinase activators; 3) agents for intestinal glucagon (such as GLP-1 antagonists);) insulin sensitizers , Including PPART antagonists and agents that combine ppARa and T activity;) agents that regulate hepatic glucose balance (such as biguanide, fructose 1,6 diphosphate 9615l.doc 200523234 acidase inhibitors, glycogen phosphorylase inhibitors , Glycogen synthesis kinase inhibitors, glucokinase activators); 6) agents to reduce the intestinal absorption of glucose (such as glucosporin inhibitors); 7) agents to prevent kidney reabsorption of glucose (sodium glucose transporter) Inhibitors); 8) Agents used to treat long-term hyperglycemia (for example, a dextrose reductase inhibitor 'protein kinase C inhibitor); 9) Used to treat obesity (for example, an appetite suppressant) Or agents that increase energy consumption; 10) antilipidemia agents, such as HMG-CoA reductase inhibitors, ppARa agonists (such as fibrates), ppAR 5 agonists, bile acid sequesterers, cholesterol absorption inhibitors, bile acid absorption inhibitors Agents, CETP inhibitors, lipolysis inhibitors; π) antihypertensive agents, such as oral blockers, ACE inhibitors, calcium antagonists, angiotensin receptor antagonists, alpha receptor antagonists and diuretics; 12) Hemostatic agents such as anticoagulants, fibrinolytic activators and anti-jk platelets' thrombin antagonists, factor inhibitors, factor Vila inhibitors, antiplatelet agents and anticoagulants; 13) Antagonism Agents that act on tenglucan; and 14) anti-inflammatory agents such as non-steroidal anti-inflammatory drugs and steroid anti-inflammatory agents. In addition to being used as therapeutic drugs, the compounds of formula (I) and its pharmaceutically acceptable salts can also be used as western therapeutic tools to develop DPP-IV for evaluating laboratory animals such as cats, dogs, rabbits, wolves, the atmosphere, and mice. The inhibitory effect of in vitro 96151.doc 200523234 and in vivo testing systems and standardization have become part of the study of novel therapeutic agents. As previously mentioned, all these compounds and their pharmaceutically acceptable salts can be used to inhibit DPP-IV. The ability of the compound of formula (I) and its corresponding pharmaceutically acceptable salt to inhibit DPP-IV can be shown by caco-2DPP-IV identification, and this identification measures the ability of the test compound to inhibit DPP-IV of human colon cancer cell extracts. The human colon cancer cell line Caco-2 was obtained from the American Type Culture Collection (ATCC HTB 37). Cell differentiation-induced DPP-IV expression can be accomplished as described by Reisher et al. (Proc. Natl. Acad. Sci., V. 1.90, pages 5757-5761 (1993)). Cell extracts were prepared from cells dissolved in 10 mM Tris Hen, 0.15 M Nacn, 0.04 tiu · aprotinin, 0 %% 〇1 ^ (16 P40, pH 8.0, 35,000 g in 4 Centrifuge at ° C for 30 minutes to remove cell debris.

此比色鑑定是藉將於終容積10微升鑑定緩衝液（25 mMThis colorimetric assay is based on a final volume of 10 μl of identification buffer (25 mM

Tris HC1 pH 7.4，140 mM NaCl，10 mM KC1，0.1%Tris HC1 pH 7.4, 140 mM NaCl, 10 mM KC1, 0.1%

Triton-x-100)内的20微克溶解的Caco-2蛋白質，20毫微克 重組人DPPIV或純化的豬腎DPP-IV完成。於室溫培養1〇分 鐘後，加10微升0.5mM基質（H-Glycine-Proline-pNA;pNA 是對-硝基苯胺）引發反應。終鑑定容積為100微升。反應於 室溫進行10分鐘，然後加1〇微升容積的醋酸鈉緩衝液pH 4.5 停止反應。試驗化合物一般是加10微升。用0-500 μΜ自由 ρΝΑ於鑑定緩衝液内的溶液產生自由態對-硝基苯胺的標準 曲線。所生成的曲線為線性的，用於插入基質消耗（毫莫 耳基質裂解/分鐘催化活性）。於Labsytems微滴定碟讀計内 以405 nm藉測定吸光度測出終點。 96151.doc -55- 20052323420 micrograms of dissolved Caco-2 protein in Triton-x-100), 20 nanograms of recombinant human DPPIV or purified pig kidney DPP-IV. After incubating at room temperature for 10 minutes, 10 microliters of 0.5 mM substrate (H-Glycine-Proline-pNA; pNA is p-nitroaniline) was added to initiate the reaction. The final identified volume was 100 microliters. The reaction was performed at room temperature for 10 minutes, and then a 10 microliter volume of sodium acetate buffer pH 4.5 was added to stop the reaction. The test compound is typically 10 microliters. A solution of 0-500 μM free ρNA in the identification buffer was used to generate a standard curve for free-state p-nitroaniline. The resulting curve is linear for matrix insertion (millimolar matrix cleavage / min catalytic activity). The end point was determined by measuring absorbance at 405 nm in a Labsytems microtiter plate reader. 96151.doc -55- 200523234

CaCo2萃取物活性也以 Kubota 等人（Clin· Exp. Immunol·， Vol.89頁，192-197(1992))所述修改的鑑定方法測定。此鑑 定是藉將10微克溶解的Caco-2蛋白質，於10微升終容積鑑 定緩衝液（25 mM HEPES，140 mM NaCl，80 mM MgCl2， 0.1% TritonX-100，pH 7.4)内，加於微滴定碟内進行。將 此碟於室溫培養10分鐘後，藉加含〇·5 mM基質（H-Glycine-Proline-AMC ; AMC為7-胺基-40-甲基香豆素）10微升開 始反應。該等碟於室溫（黑暗中）歷經10分鐘。試驗化合物 一般添加量為10 /xl，最終檢定緩衝劑體積為1 〇〇 μΐ。反應 藉添加10 μΐ 0.5 mM基質Gly-Pro-7-胺基-4-三氟甲基香豆 素歷經10分鐘而起始，之後添加1〇 W體積乙酸鈉緩衝劑 pH 4.5而終止反應。反應10分鐘後，用Tecan Ultra熒光計 (興奮360 nm，發射465 nm)測定開花期（florescence)。使用 鑑定緩衝液内的0-50 μΜ自由態AMC溶液生成自由態AMC 標準曲線。所生曲線為線性，用基質消耗的插入（毫莫耳 基質裂解/分鐘催化活性）。作為DPP-IV抑制劑的試驗化合 物的效價以IC50表示，使用4參數對數函數由11-點計算出 劑量反應曲線。 此鑑定顯示出化合物一般活性為IC5Q < 100 μΜ。實例1 顯示IC5G= 0_46 μΜ，實例 10顯示IC5〇= 0.45 μΜ。 式I化合物及其對應的醫藥上可接受的鹽抑制DPP-IV的 能力也可藉以修改的上述鑑定方法測定於人及鼠血漿試驗 化合物對DPP-IV活性的效果。簡言之，將5-10微升血漿代 替CaCo2萃取物加於96-凹平底微滴定碟内，終鑑定容積為 96151.doc -56- 200523234 wo从升。以前述鐘定測得，作為Dpp_lv抑制劑的試驗化 二物的效價’以IC5g表示，使用4參數對數函數由η'點計 异出劑量反應曲線。 上述醫藥組合物、製法、用途及藥物製造特點也適用於 此處所述本發明其他化合物的具體實施例。 實例 今以下述實例說明本發明，其中，除非另有說明： ⑴溫度以攝氏度fC)表示；操作是於室溫或週邊溫度進 行，即在18-25 c溫度範圍及惰性氣體如氬氣下進行； (ii) 有機溶液是於無水硫酸鎂上乾燥；溶劑之蒸發是用迴 旋蒸發器在減壓（600-4000帕；4.5-30毫米汞柱）於浴溫達 6(TC下進行； ’皿 (iii) 色層分析意謂二氧化矽膠上的閃色層分析；在使用 BioUge筒時是指含KP-Siltm二氧化矽膠，6〇人，顆粒大小 32-63毫米，購自Biotage，其為Dyax c〇rp 一部門，㈧ Avon Street Extended ^ Charlottesville ^ VA 22902 ^ USA ； (iv) —般而言，反應過程以TLC追蹤，反應時間只供說 明； (V)產出只供說明，並非精巧方法所得；如果需要更多物質 可重複製備； (vi)如有表示，NMR數據dH)是主要診斷質子的5值，以 相對於四甲基甲矽烷（TMS)的每百萬分比（ppm)作為内標準 表示，用全氘二甲基亞砜（DMSO-δ6)作為溶劑於3〇〇 MHz (除非另有說明）測定；s =單峰，d =雙峰，sept =七重 96151.doc -57- 200523234 峰，q =四重峰，t =三重峰，dd=二雙峰，（11:=二三重 峰，m=多重峰，brs =廣單峰； (vii) 化學符號有其一般意義；使用SI單位及符號； (viii) 溶劑比以容積：容積（v/v)表示； (ix) 質譜（MS)是以70電子伏特於化學離子化（CI)型表示， 使用直接曝露探針；在所示離子化受電子撞擊（EI)影響 時，使用快原子撞擊（FAB)或電喷（ESP);示出m/z值；一 般只報告顯示母質量的離子； (X)使用如下縮寫：CaCo2 extract activity was also determined by a modified identification method described in Kubota et al. (Clin. Exp. Immunol., Vol. 89, 192-197 (1992)). This identification was performed by adding 10 micrograms of dissolved Caco-2 protein to 10 microliters of final volume identification buffer (25 mM HEPES, 140 mM NaCl, 80 mM MgCl2, 0.1% TritonX-100, pH 7.4) and adding Perform the titration in a dish. After incubating the dish at room temperature for 10 minutes, the reaction was started by adding 10 microliters containing 0.5 mM substrate (H-Glycine-Proline-AMC; AMC is 7-amino-40-methylcoumarin). The dishes lasted 10 minutes at room temperature (in the dark). The test compound is generally added in an amount of 10 / xl, and the final assay buffer volume is 100 μΐ. The reaction was initiated by adding 10 μΐ of 0.5 mM matrix Gly-Pro-7-amino-4-trifluoromethylcoumarin over 10 minutes, and then the reaction was terminated by adding a 10 W volume of sodium acetate buffer pH 4.5. After 10 minutes of reaction, the florescence was measured using a Tecan Ultra fluorometer (excitation 360 nm, emission 465 nm). A 0-50 μM free-state AMC solution in the identification buffer was used to generate a free-state AMC standard curve. The resulting curve is linear, with matrix depleted insertion (millimolar matrix cleavage / min catalytic activity). The potency of the test compound as a DPP-IV inhibitor was expressed as IC50, and a dose response curve was calculated from an 11-point using a 4-parameter logarithmic function. This identification showed that the compound generally has an activity of IC5Q < 100 μM. Example 1 shows IC5G = 0_46 μM, and Example 10 shows IC50 = 0.45 μM. The ability of a compound of formula I and its corresponding pharmaceutically acceptable salt to inhibit DPP-IV can also be tested in human and murine plasma to test the effect of the compound on DPP-IV activity by the modified identification method described above. In short, 5-10 microliters of plasma was used instead of the CaCo2 extract in a 96-concave flat-bottomed microtiter dish, and the final identification volume was 96151.doc -56- 200523234. The measured potency of the test substance Dpp_lv inhibitor as IC5g was measured by the aforementioned method, and was expressed as IC5g, and the dose response curve was calculated from the η 'point using a 4-parameter logarithmic function. The above-mentioned pharmaceutical composition, preparation method, use and pharmaceutical manufacturing characteristics are also applicable to specific examples of other compounds of the present invention described herein. EXAMPLES The present invention will now be illustrated by the following examples, wherein, unless otherwise stated: ⑴ The temperature is expressed in degrees Celsius fC); the operation is performed at room temperature or ambient temperature, that is, under the temperature range of 18-25 c and inert gas such as argon (Ii) The organic solution is dried over anhydrous magnesium sulfate; the evaporation of the solvent is performed using a rotary evaporator under reduced pressure (600-4000 Pa; 4.5-30 mm Hg) at a bath temperature of 6 (TC; (iii) Color layer analysis means flash layer analysis on silicon dioxide; when using a BioUge cartridge, it means KP-Siltm silicon dioxide containing 60 people, particle size 32-63 mm, purchased from Biotage, which is Dyax c〇rp One department, ㈧ Avon Street Extended ^ Charlottesville ^ VA 22902 ^ USA; (iv)-In general, the reaction process is tracked by TLC, and the reaction time is for explanation only; (V) The output is for explanation only, not delicate Obtained by the method; if more materials are needed, the preparation can be repeated; (vi) If indicated, the NMR data dH) is the 5 value of the main diagnostic proton, in terms of parts per million (ppm) relative to tetramethylsilane (TMS) ) As an internal standard, using deuterium dimethyl sulfoxide (DM SO-δ6) was measured as a solvent at 300 MHz (unless stated otherwise); s = singlet, d = doublet, sep = sevenfold 96151.doc -57- 200523234 peak, q = quadruple, t = triplet Peak, dd = two double peaks, (11: = two triplet, m = multiple peak, brs = wide singlet; (vii) chemical symbols have their general meanings; use SI units and symbols; (viii) solvent ratio to Volume: Volume (v / v) representation; (ix) Mass spectrometry (MS) is expressed at 70 electron volts over chemical ionization (CI) type, using a direct exposure probe; ionization is shown to be affected by electron impact (EI) When using fast atomic impact (FAB) or electrospray (ESP); show m / z value; generally only report the ion showing the parent mass; (X) use the following abbreviations:

Et2〇 醚/二乙醚 DMF 二甲基甲醯胺 DCM 二氣甲烷 DME 二甲氧基乙烷 MeOH 甲醇 EtOH 乙醇 h2o 水 TFA 三氟醋酸 THF 四氫呋喃 DMSO 二甲基亞砜 HOB1 1-羥基苯并三唑 EDCI 1-乙基-3-(3-二甲基胺基丙基）碳化 二亞醯胺鹽酸鹽 DIPEA 二異丙基乙基胺 DEAD 二乙基氮二羧酸酯 96151.doc -58- 200523234 第三-丁氧基羰基 下述每一實例作為本發明分別的及獨立的方面提供。 實例1 · 2-{[(3R)_3-胺基·4_(2_氟苯基）丁醯基】胺基}_N•苄 基茚滿-2_叛甲醯胺鹽酸鹽Et20 ether / diethyl ether DMF dimethylformamide DCM Digasmethane DME dimethoxyethane MeOH methanol EtOH ethanol h2o water TFA trifluoroacetic acid THF tetrahydrofuran DMSO dimethyl sulfoxide HOB1 1-hydroxybenzotriazole EDCI 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride DIPEA diisopropylethylamine DEAD diethylazadicarboxylic acid ester 96151.doc -58- 200523234 Third-butoxycarbonyl Each of the examples below are provided as separate and independent aspects of the invention. Example 1 2-{[((3R) _3-Amino · 4_ (2_fluorophenyl) butylfluorenyl] amino}) _ N • benzylindane-2_metamidine hydrochloride

將二噁烷内的4 M HC1加於[(iR)_3_(2_[(苄基胺基）羰基卜 2,3-二氩·1Η-茚烯-2-基）胺基卜^(2-氟苄基）-3_氧丙基]胺基 甲酸第三-丁酯（中間體1，104毫克，〇191毫莫耳）内，將 此此合物攪拌2小時。減壓蒸發溶劑，殘餘物用_研磨。 蒸發醚，得標題化合物，為無色固體（88毫克，96%)。MS ESP+ m/z 360, 362; ESP- m/z 336, 338 〇 lU NMR(DMSO)： 2.78-2.85(m，2H)，2.95-3.02(m，2H)，3.10-3.25(m，3H)， 3.51-3.57(m，5H)，4.23-4.27(m，2H)，7.05-7.27(m，13H)， 8.16(brs 2H) , 8.37(t，lH)，8.63(s，lH) ; MS m/z 445(MH)+。 實例2-4 以類似實例1方法完成如下實例。起始物質係如下述製 備中間體1方法製得，但使用適宜的胺起始物質（實例3及4 所用者可由商業購得；實例2所用者見專利申請案WO 2003045382之反應物 CAS no.[479586-24-8]-反應物）以代替 苄基胺。 實例2 : [4-({[(2-{[(3R)_3-胺基-4-(2-氟苯基）丁醯基]胺基}- 96151.doc -59- 200523234 2,3-二氫·1Η-茚烯-2·基）羰基】胺基}甲基）苯基I乙酸 實例3 : 2_{[(3R)_3_胺基-4-(2-氟苯基）丁醯基]胺基卜Ν-{2· [(丙基磺醯基）胺基】乙基}茚烷-2-羧醯胺 實例4 : 2-{[(3R)-3-胺基-4-(2-氟苯基）丁醯基】胺基卜Ν_{2· [4-(胺基磺醯基）苯基】乙基}茚烷-2-羧醯胺Add 4 M HC1 in dioxane to [(iR) _3_ (2 _ [(benzylamino) carbonylcarbonyl2,3-diargon · 1'-inden-2-yl) amino group ^ (2- Fluorobenzyl) -3-oxopropyl] aminocarboxylic acid tertiary-butyl ester (Intermediate 1,104 mg, 191 1 mol), this mixture was stirred for 2 hours. The solvent was evaporated under reduced pressure and the residue was triturated under reduced pressure. Evaporation of the ether gave the title compound as a colorless solid (88 mg, 96%). MS ESP + m / z 360, 362; ESP- m / z 336, 338 0.1U NMR (DMSO): 2.78-2.85 (m, 2H), 2.95-3.02 (m, 2H), 3.10-3.25 (m, 3H) , 3.51-3.57 (m, 5H), 4.23-4.27 (m, 2H), 7.05-7.27 (m, 13H), 8.16 (brs 2H), 8.37 (t, lH), 8.63 (s, lH); MS m / z 445 (MH) +. Examples 2-4 The following examples were completed in a similar manner to Example 1. The starting materials were prepared as described below for the preparation of Intermediate 1, but using suitable amine starting materials (Examples 3 and 4 are commercially available; those used in Example 2 are listed in CAS no., Reactant of patent application WO 2003045382. [479586-24-8]-reactants) in place of benzylamine. Example 2: [4-({[(2-([(3R) _3-Amino-4- (2-fluorophenyl) butylamidino] amino)}-96151.doc -59- 200523234 2,3-dihydro · 1'-Indenene-2 · yl) carbonyl] amino} methyl) phenyl I acetic acid Example 3: 2 _ {[((3R) _3_Amino-4- (2-fluorophenyl) butyridinyl] amino group) Ν- {2 · [(propylsulfonyl) amino] ethyl} indane-2-carboxamide Example 4: 2-{[((3R) -3-amino-4- (2-fluorobenzene Group) Butyridyl] amino group N_ {2 · [4- (Aminosulfonyl) phenyl] ethyl} indane-2-carboxamide

實例 R lHNMR(DMSO) MS m/z 2 2.35-2.41 (m, 2H), 2.70-2.80 (m, 1H), 2.90-2.97 (m, 1H), 3.08-3.23 (m, 2H), 3.35-3.60 (m, 5H), 4.20-4.24 (m，lH)，7.05-7.32 (m，12H)， 7.95 (brs，2H)，8.30 (t，1H)，8.57 (s， 1H) 504 (MH)+ 3 H 0.95 (t5 3H), 1.60-1.70 (m, 2H), 2.41-2.43 (m，2H)，2.77-2.84 (m，1H)， 2.90-2.95 (m, 5H), 3.07-3.17 (m, 4H), 3.38-3.48 (m, 2H), 3.60-3.66 (m，1H)，6.95 (t，1H)，7.07-7.17 (m， 6H)，7.22-7.33 (m，2H)，7.87 (t，1H)， 8.04 (brs，2H)，8·61 (s，1H) 505 (MH)+ 4 ^as,〇 b、NU2 2.39-2.41 (m，2H)，2.70-2.79 (m， 2H)，2.94-3.10 (m，2H)，3.25-3.37 (m, 2H), 3.35-3.40 (m, 4H), 3.60-3.62 (m, 1H), 7.06-7.17 (m, 6H), 7.71 (d，2H)，7.90 (t，1H)，8.06 (brs， 2H)，8.54 (s，1H) 538 _)+ 實例2所用中間體 {4-({[2-{[(3R)-3-丨第三-丁氧基羰基）胺基】_4-(2_氟苯基）丁 醯基]胺基}-2,3-二氩_1H_茚烯-2-基）羰基】胺基}曱基}苯基} 乙酸第三-丁酯 咕 NMR (DMSO): 1.23 (s，9H)，1.36 (s，9H) 2.25 (d，1H)， 2.55-2.62 (m，1H)，2.73-2.77 (m，1H)，3.12-3.21 (m，1H)， 96151.doc •60- 200523234 3.44-3.52 (m, 4H)，3.94-4.03 (m，1H)，（KM (m，2h) 6.61 (d, 1H), 7.03-7.20 (m,l2H),8.16(t)1H) 8 25 (s MS m/z 682 (M+Na)。 ’ ’ 實例3所用中間體 [(lR)-l-(2-氣节基）-3-氧代(丙基磺醯基）胺基】乙 基}胺基）羰基卜2,3-二氫-1H-節烯_2_基}胺基丙基】胺基甲酸 第三-丁酯 iH NMR (CDC13): 0.94 (t，3H)，1.25 (s，9H)，1.59-1.67 (m，2H)，2·23 (d，2H)，2.59-2.62 (m，1H)，2.72-2.76 (m， 1H)，2.89-2.94 (m，4H)，3.10-3.14 (m，4H)，3.41-3.50 (m， 2H)，3.94-3.97 (m，lH)，6.58(d，lH)，6.88(t，lH)，7.01-7.21 (m，8H)，7.71 (brs，1H)，8.30 (s，1H); MS m/z 627 (M+Na)。 實例4所用中間體 [(lR)-3-({2_[({2_[4-(胺基磧醯基）苯基】乙基}胺基）羰基]-2,3-二氫-1H-茚烯-2-基}胺基）-1-(2-氟苄基）-3-氧代丙基】胺 基甲酸第三-丁酯 lH NMR (CDC13): 1.23 (s, 9H), 2.22 (d5 2H), 2.59-2.63 (m? 1H)? 2.71-2.76 (m, 3H)5 3.03-3.10 (m, 2H), 3.32-3.47 (m，4H)，3·96_4·00 (m，1H)，6.61 (d，1H)，7.04-7.17 (m， 8H)，7,24 (s，1H)，7.33 (d，2H)，7.69-7.72 (m，3H)，8.19 (s， 1H); MS m/z 661 (M+Na)。 實例5 : (R)-3_胺基-N-((R)_1-苄基胺甲醯基_2-苯基-乙基）-4-(2-氟苯基）-丁醯胺鹽酸鹽 96151.doc -61 - 200523234Examples R lHNMR (DMSO) MS m / z 2 2.35-2.41 (m, 2H), 2.70-2.80 (m, 1H), 2.90-2.97 (m, 1H), 3.08-3.23 (m, 2H), 3.35-3.60 (m, 5H), 4.20-4.24 (m, lH), 7.05-7.32 (m, 12H), 7.95 (brs, 2H), 8.30 (t, 1H), 8.57 (s, 1H) 504 (MH) + 3 H 0.95 (t5 3H), 1.60-1.70 (m, 2H), 2.41-2.43 (m, 2H), 2.77-2.84 (m, 1H), 2.90-2.95 (m, 5H), 3.07-3.17 (m, 4H ), 3.38-3.48 (m, 2H), 3.60-3.66 (m, 1H), 6.95 (t, 1H), 7.07-7.17 (m, 6H), 7.22-7.33 (m, 2H), 7.87 (t, 1H) ), 8.04 (brs, 2H), 8.61 (s, 1H) 505 (MH) + 4 ^ as, OB, NU2 2.39-2.41 (m, 2H), 2.70-2.79 (m, 2H), 2.94 3.10 (m, 2H), 3.25-3.37 (m, 2H), 3.35-3.40 (m, 4H), 3.60-3.62 (m, 1H), 7.06-7.17 (m, 6H), 7.71 (d, 2H), 7.90 (t, 1H), 8.06 (brs, 2H), 8.54 (s, 1H) 538 _) + Intermediate used in Example 2 {4-({[2-{[(3R) -3- 丨 third-but Oxycarbonyl) amino group] _4- (2-fluorophenyl) butylfluorenyl] amino group} -2,3-diargon_1H_indenen-2-yl) carbonyl] amino group} fluorenyl} phenyl} acetic acid Tertiary-butyl ester NMR (DMSO): 1.23 (s, 9H), 1.36 (s, 9H) 2.25 (d, 1H), 2.5 5-2.62 (m, 1H), 2.73-2.77 (m, 1H), 3.12-3.21 (m, 1H), 96151.doc • 60- 200523234 3.44-3.52 (m, 4H), 3.94-4.03 (m, 1H) ), (KM (m, 2h) 6.61 (d, 1H), 7.03-7.20 (m, l2H), 8.16 (t) 1H) 8 25 (s MS m / z 682 (M + Na). 'Example 3 Intermediates used [(lR) -l- (2-Aristoloyl) -3-oxo (propylsulfonyl) amino] ethyl} amino) carbonyl group 2,3-dihydro-1H-section Alkenyl-2-yl} aminopropyl] aminocarboxylic acid third-butyl ester iH NMR (CDC13): 0.94 (t, 3H), 1.25 (s, 9H), 1.59-1.67 (m, 2H), 2 · 23 (d, 2H), 2.59-2.62 (m, 1H), 2.72-2.76 (m, 1H), 2.89-2.94 (m, 4H), 3.10-3.14 (m, 4H), 3.41-3.50 (m, 2H) ), 3.94-3.97 (m, 1H), 6.58 (d, 1H), 6.88 (t, 1H), 7.01-7.21 (m, 8H), 7.71 (brs, 1H), 8.30 (s, 1H); MS m / z 627 (M + Na). Intermediate used in Example 4 [(lR) -3-({2 _ [({2_ [4- (Aminoamido) phenyl] ethyl} amino) carbonyl] -2,3-dihydro-1H- Indenen-2-yl} amino) -1- (2-fluorobenzyl) -3-oxopropyl] aminocarboxylic acid tert-butyl ester 1H NMR (CDC13): 1.23 (s, 9H), 2.22 (d5 2H), 2.59-2.63 (m? 1H)? 2.71-2.76 (m, 3H) 5 3.03-3.10 (m, 2H), 3.32-3.47 (m, 4H), 3.96_4 · 00 (m, 1H ), 6.61 (d, 1H), 7.04-7.17 (m, 8H), 7,24 (s, 1H), 7.33 (d, 2H), 7.69-7.72 (m, 3H), 8.19 (s, 1H); MS m / z 661 (M + Na). Example 5: (R) -3_Amino-N-((R) _1-benzylaminomethylamidino_2-phenyl-ethyl) -4- (2-fluorophenyl) -butylammonium salt Acid salt 96151.doc -61-200523234

將二噁烷内的4 M HC1加於（R)-3-胺基-N-((R)-1-苄基胺 甲醯基-2-苯基·乙基）-4-(2-氟-苯基）-丁醯胺（中間體4 , l〇6 毫克，0.191毫莫耳）内，將此混合物攪拌16小時。減壓蒸 發溶劑，殘餘物用醚研磨。蒸發醚，得標題化合物，為無 色固體（90毫克，96%)。4 NMR (DMSO): 2.20-2.40 (m， 2H)，2.60-2.78 (m，2H)，2.84 (dd，1H)，3.00 (dd，1H)，3.50 (m，1Η)，4.18-4.30 (m，2Η)，4.56 (m，1Η)，7.05-7.38 (m， 14H)，7.94 (brs 2H)，8.44 (d，1H)，8.58 (t，1H); MS m/z 434 (MH)+ 〇 實例6至9 以商業上可購得的適宜的胺代替苄基胺用類似實例5方 法合成如下實例，但以如下方法分離充自由態鹼： 將鹽酸鹽溶於DCM(l〇毫升），相繼用2 M Na〇H(2x2〇毫 升）及水（20毫升）洗，有機層於MgSCU上乾燥，真空除去 DCM，得自由態鹼，為無色固體。 實例6 : (R)-3-胺基-4-(2-氣-苯基）^⑻小甲基胺甲醯基_ 2-苯基-乙基）-丁醯胺 實例7 : (R)-3-胺基甲基_丙基胺甲醯 基）·2.苯基-乙基]-4-(2-敗·苯基）丁醯胺 實例8 : (R)-3-胺基-4-(2-氟-苯基卜叫⑷·^甲基胺甲醯基 96151.doc •62- 200523234 甲基-胺甲酿基-苯基·乙基】-丁酿胺 實例 9 ·· (R)-3-胺基-4_(2_ 氟-苯基）_N-{(R)_2-苯基-1_[2-(丙 烷-1-磺醯基胺基）-乙基胺甲醯基】-乙基卜丁醯胺4M HC1 in dioxane was added to (R) -3-amino-N-((R) -1-benzylaminomethylmethyl-2-phenyl · ethyl) -4- (2- This mixture was stirred for 16 hours in fluoro-phenyl) -butanamide (Intermediate 4, 106 mg, 0.191 mmol). The solvent was evaporated under reduced pressure, and the residue was triturated with ether. Evaporation of the ether gave the title compound as a colorless solid (90 mg, 96%). 4 NMR (DMSO): 2.20-2.40 (m, 2H), 2.60-2.78 (m, 2H), 2.84 (dd, 1H), 3.00 (dd, 1H), 3.50 (m, 1Η), 4.18-4.30 (m , 2Η), 4.56 (m, 1Η), 7.05-7.38 (m, 14H), 7.94 (brs 2H), 8.44 (d, 1H), 8.58 (t, 1H); MS m / z 434 (MH) + 〇 Examples 6 to 9 The following examples were synthesized in a similar manner to Example 5 with commercially available suitable amines in place of benzylamine, but the free base was isolated as follows: The hydrochloride was dissolved in DCM (10 ml), It was washed successively with 2 M NaOH (2 x 20 ml) and water (20 ml). The organic layer was dried over MgSCU and the DCM was removed in vacuo to give the free base as a colorless solid. Example 6: (R) -3-Amino-4- (2-Gas-phenyl) ^ Small methylamine methylamidino-2-phenyl-ethyl) -butanidine Example 7: (R) -3-Aminomethyl-propylaminomethylamidino) · 2.Phenyl-ethyl] -4- (2-Apiphenyl) butamidamine Example 8: (R) -3-amino- 4- (2-Fluoro-phenyl) is called ⑷ · ^ methylaminomethylamino 96151.doc • 62- 200523234 methyl-aminomethylamino-phenyl · ethyl] -butylaminoamine Example 9 ·· ( R) -3-amino-4_ (2_fluoro-phenyl) _N-{(R) _2-phenyl-1_ [2- (propane-1-sulfonylamino) -ethylaminemethyl} -Ethylbubutamine

FF

R 實例 R lRNUR8: MS m/z 6 之Me 2.19 (dd, 1H), 2.40 (dd, 1H), 2.62-2.82 (m，5H)，3·0_3·16 (m，2H)，3.40 (m，1H)， 4.64 ((apparent q，1H)，6.60 (brs，1H), 6.96-7.35 (9H, m), 7.64 (brd 1H) 358 (MH)+ 7 (CDC13)： 0.78 (d, 3H), 0.88 (d, 3H), 1.58 (1H + water), 2.12 (dd, 1H), 2.38 (dd, 1H), 2.62 (dd, 1H), 2.75 (dd, 1H), 3.03 (dd, 1H), 3.11 (dd, 1H), 3.34 (m, 1H), 3.73 (m, 1H), 4.58 (apparent q, 1H), 5.79 (brd，1H)，6.98-7.32 (m，9H)，7.77 (d， 1H) 414 (MH)+ 8 0 Η (CDCI3): 2.14 (dd, 1H), 2.39 (dd, 1H), 2.64 (dd, 1H), 2.66-2.80 (m, 4H), 3.02 (dd, 1H), 3.21 (dd, 1H), 3.26 (m, 1H), 3.75 (dd, 1H), 3.86 (dd, 1H), 4.60 (m, 1H)，6.72 (m，1H)，6.90-7.32 (m，9H)， 7·65 (d，1H)，7.95 (t，1H) 415 _)+ 9 Η (DMSO): 0.96 (t, 3H), 1.64 (sex, 2H), 2.32 (dd, 1H), 2.40-3.30 (m 11H), 3.49 (m, 1H), 4.42 (m5 1H), 7.02-7.38 (m, 9 H), 8.11 (brs, 3H), 8.20 (t, 1H), 8.32 (d, 1H) 493 _)+Examples R lRNUR8: MS m / z 6 Me 2.19 (dd, 1H), 2.40 (dd, 1H), 2.62-2.82 (m, 5H), 3.0 · 3 · 16 (m, 2H), 3.40 (m, 1H), 4.64 ((apparent q, 1H), 6.60 (brs, 1H), 6.96-7.35 (9H, m), 7.64 (brd 1H) 358 (MH) + 7 (CDC13): 0.78 (d, 3H), 0.88 (d, 3H), 1.58 (1H + water), 2.12 (dd, 1H), 2.38 (dd, 1H), 2.62 (dd, 1H), 2.75 (dd, 1H), 3.03 (dd, 1H), 3.11 (dd, 1H), 3.34 (m, 1H), 3.73 (m, 1H), 4.58 (apparent q, 1H), 5.79 (brd, 1H), 6.98-7.32 (m, 9H), 7.77 (d, 1H) 414 (MH) + 8 0 Η (CDCI3): 2.14 (dd, 1H), 2.39 (dd, 1H), 2.64 (dd, 1H), 2.66-2.80 (m, 4H), 3.02 (dd, 1H), 3.21 (dd, 1H), 3.26 (m, 1H), 3.75 (dd, 1H), 3.86 (dd, 1H), 4.60 (m, 1H), 6.72 (m, 1H), 6.90-7.32 (m, 9H), 7.65 (d, 1H), 7.95 (t, 1H) 415 _) + 9 Η (DMSO): 0.96 (t, 3H), 1.64 (sex, 2H), 2.32 (dd, 1H), 2.40-3.30 ( m 11H), 3.49 (m, 1H), 4.42 (m5 1H), 7.02-7.38 (m, 9 H), 8.11 (brs, 3H), 8.20 (t, 1H), 8.32 (d, 1H) 493 _) +

中間體1 : [(1R)_3_(2-丨（苄基胺基）羰基】_2,3_二氫-1H-茚烯-2_基}胺基）-1-(2-氟苄基）-3·氧代丙基】胺基甲酸第三丁酯 將EDC1(51毫克，〇·27毫莫耳）繼之將HOBt(36毫克， 〇·27亳莫耳）加於2-{(3R)-3-[第三-丁氧基羰基）胺基]-4-(2- 96151.doc -63- 200523234Intermediate 1: [(1R) _3_ (2- 丨 (benzylamino) carbonyl] _2,3_dihydro-1H-indenen-2-yl} amino) -1- (2-fluorobenzyl) -3. Oxopropyl] tertiary butyl aminoformate EDC1 (51 mg, 0.27 mmol) followed by HOBt (36 mg, 0.27 mmol) to 2-{(3R ) -3- [Third-butoxycarbonyl) amino] -4- (2- 96151.doc -63- 200523234

氟苯基）丁醯基卜茚烧-2-羧酸（中間體2，〇. ιοί克，0.22毫 莫耳）於DCM内的溶液中。將此混合物擾拌2 — 3分鐘，然後 加三乙基胺（30微升，0.22毫莫耳）及苄基胺（2〇微升，0.22 写莫耳）。此反應混合物於週邊溫度擾拌16小時。然後相繼用 2 M HC1(50毫升）及鹽水（50毫升）洗。分離有機層，以硫酸 鎂乾燥，減壓濃縮，得無色固體。殘餘物以閃二氧化矽膠 色層分析純化（醋酸乙g旨：異己烧2 : 3 )，得標題化合物 (104毫克，86%)，為無色固體。4 NMR (DMSO) δ : 1.23 0，9Η)，2.25 (d，2Η)，2.55-2.62 (m，1Η)，2.70-2.77 (m，lH)， 3.13-3.25 (m，2H)，3.44_3·53 (m，2H)，3·94_4·04 (m，1H)， 4.16-4.35 (m，1H)，6.61 (d，1H)，7.01-7.18 (m，13H)，8.17 (t，1H)，8.25 (s，1H); MS m/z 568 (M+Na)。 中間體2 : 2-{(3R)-3-[第三-丁氧基羰基）胺基】-4-(2_氟苯基） 丁酿基}-茚烧-2-叛酸A solution of fluorophenyl) butanyl indole-2-carboxylic acid (Intermediate 2, 0.1 g, 0.22 mmol) in DCM. Stir this mixture for 2-3 minutes, then add triethylamine (30 µl, 0.22 mmol) and benzylamine (20 µl, 0.22 write Mol). The reaction mixture was stirred at ambient temperature for 16 hours. It was then washed successively with 2 M HC1 (50 ml) and brine (50 ml). The organic layer was separated, dried over magnesium sulfate, and concentrated under reduced pressure to obtain a colorless solid. The residue was purified by flash silica gel chromatography (ethyl acetate g: isohexane 2: 3) to obtain the title compound (104 mg, 86%) as a colorless solid. 4 NMR (DMSO) δ: 1.23 0, 9Η), 2.25 (d, 2Η), 2.55-2.62 (m, 1Η), 2.70-2.77 (m, 1H), 3.13-3.25 (m, 2H), 3.44_3 · 53 (m, 2H), 3.94_4 · 04 (m, 1H), 4.16-4.35 (m, 1H), 6.61 (d, 1H), 7.01-7.18 (m, 13H), 8.17 (t, 1H), 8.25 (s, 1H); MS m / z 568 (M + Na). Intermediate 2: 2-{(3R) -3- [Third-butoxycarbonyl) amino] -4- (2-fluorophenyl) butynyl} -indeno-2-acid

將2-{(3R)-3·[第三-丁氧基羰基）胺基]-4-(2-氟苯基）丁醯 基卜茚烷-2-羧酸甲酯甲基酯（中間體3，0.292克，0.598毫 莫耳）於THF(l〇毫升）及水（3毫升）内的溶液以水合氫氧化鋰 (50¾克’ 1.19毫莫耳）於水（1毫升）内的溶液處理。此反應 混合物於週邊溫度攪拌16小時。再將混合物減壓濃縮，水 性殘餘物用硫酸氫舒酸化至pH 2。水層用醋酸乙酯（2X1 〇〇 愛升）萃取’分離有機相。用硫酸鎮將合併之有機物乾 燥，減壓濃縮，得標題化合物，為無色固體（〇 241克， 94%piHNMR(DMSO):1.23(s，9H)，2.22(d，2H)，2.55-2.62 (m，1H)，2.70-2.82 (m，2H)，3.11-3.25 (m，2H)，3.39- 96151.doc -64- 200523234 3·53 (m，2H)，3·91-4_01 (brm，1H)，6·60 (d，1H)，7.03-7.20 (m，8H)，8·44 (s，1H)，12.29 (brs，1H); MS m/z 455 (ΜΗ).。 中間體3 : 2-{(3R)-3_[第三-丁氧基羰基）胺基】_4_(2-氟苯基） 丁醯基卜茚烷-2-羧酸甲酯甲基酯 於攪拌的（R)-3-第三-丁氧基羰基胺基-4-(2-氟-苯基）-丁 酸（0.296克，1.0毫莫耳）於DCM(20毫升）内的溶液中相繼加 HOBt(0.16克，1.2毫莫耳），EDC1(0.23克，1.2毫莫耳），2-胺基-茚烧-2-綾酸甲基 g旨（Kotha，S and Kuki，A Tetrahedron Lett” 1992，33,（12) 1565)(0.277 克，1·0 毫莫耳）及三乙基 胺（0·28毫升，2.0毫莫耳）。此混合物於週邊溫度攪拌16小 時。反應混合物然後用2 M HC1(50毫升）之碳酸氫鈉水溶 液（50毫升）及鹽水（1〇〇毫升）洗。分離有機相，用硫酸鎂乾 燥’減壓濃縮，得黃色膠體。此殘餘物作閃二氧化石夕膠色 層分析純化（醋酸乙酯），得標題化合物（325毫克，69%)， 為無色固體。4 NMR (CDC13): 1.35 (s，9H)，2.26-2.45 (m， 2H)，2.88-2.92 (m，2H)，3·20-3·29 (m5 2H)，3.62-3.71 (m， 2H)，3.76 (s，3H)，6·32 (brs，1H)，6.95-7.02 (m，2H)，7.14 -7.20 (m，6H); MS m/z 493 (M+Na)。 中間鱧4 : [(R)-2-((R)-l_苄基胺甲醯基-2-苯基乙基胺甲醯 基氟-苯基）乙基]胺基甲酸第三-丁基酯 於N-[(3R)-3-胺基-4-(2-氟苯基）丁醯基]笨基苯胺（中 間體5，0.1〇〇克，〇.23毫莫耳）於00“（5毫升）内的溶液中 相繼加HOBt(0.037克，0.27毫莫耳），苄基胺（25微升， 0.23毫莫耳），三乙基胺（63微升，0.45毫莫耳）及 96L51.doc -65- 2005232342-{(3R) -3 · [Third-butoxycarbonyl) amino] -4- (2-fluorophenyl) butyridinyl indane-2-carboxylic acid methyl ester (Intermediate 3 A solution of 0.292 g, 0.598 mmol in THF (10 ml) and water (3 ml) was treated with a solution of lithium hydroxide hydrate (50 ¾ g '1.19 mmol) in water (1 ml). The reaction mixture was stirred at ambient temperature for 16 hours. The mixture was concentrated under reduced pressure, and the aqueous residue was acidified to pH 2 with bisulfate. The aqueous layer was extracted with ethyl acetate (2 × 100 liters) and the organic phase was separated. The combined organics were dried over sulfuric acid and concentrated under reduced pressure to give the title compound as a colorless solid (0241 g, 94% piHNMR (DMSO): 1.23 (s, 9H), 2.22 (d, 2H), 2.55-2.62 ( m, 1H), 2.70-2.82 (m, 2H), 3.11-3.25 (m, 2H), 3.39- 96151.doc -64- 200523234 3.53 (m, 2H), 3.91-4_01 (brm, 1H ), 6.60 (d, 1H), 7.03-7.20 (m, 8H), 8.44 (s, 1H), 12.29 (brs, 1H); MS m / z 455 (ΜΗ). Intermediate 3: 2-{(3R) -3_ [Third-butoxycarbonyl) amino group] _4_ (2-fluorophenyl) Butyridinyl indane-2-carboxylic acid methyl ester of methyl ester (R) -3 -To a solution of the third-butoxycarbonylamino-4- (2-fluoro-phenyl) -butyric acid (0.296 g, 1.0 mmol) in DCM (20 ml) was added HOBt (0.16 g, 1.2 millimoles), EDC1 (0.23 g, 1.2 millimoles), 2-amino-indeno-2-acetic acid methyl ester (Kotha, S and Kuki, A Tetrahedron Lett "1992, 33, (12 ) 1565) (0.277 g, 1.0 mmol) and triethylamine (0.28 ml, 2.0 mmol). The mixture was stirred at ambient temperature for 16 hours. The reaction mixture was then washed with 2 M HC1 (50 mL Carbon Aqueous sodium hydrogen solution (50 ml) and brine (100 ml) were washed. The organic phase was separated, dried over magnesium sulfate, and concentrated under reduced pressure to obtain a yellow colloid. The residue was purified and analyzed by flash chromatography of silica gel (acetic acid). Ethyl ester) to give the title compound (325 mg, 69%) as a colorless solid. 4 NMR (CDC13): 1.35 (s, 9H), 2.26-2.45 (m, 2H), 2.88-2.92 (m, 2H), 3.20-3 · 29 (m5 2H), 3.62-3.71 (m, 2H), 3.76 (s, 3H), 6.32 (brs, 1H), 6.95-7.02 (m, 2H), 7.14 -7.20 ( m, 6H); MS m / z 493 (M + Na). Intermediate hydrazone 4: [(R) -2-((R) -1-benzylaminemethylamidino-2-phenylethylaminecarboxamidine Fluoro-phenyl) ethyl] aminocarboxylic acid tert-butyl ester in N-[(3R) -3-amino-4- (2-fluorophenyl) butylfluorenyl] benzylaniline (Intermediate 5, 0.100 g, 0.23 mmol) in a solution of 00 "(5 ml) followed by the addition of HOBt (0.037 g, 0.27 mmol), benzylamine (25 µl, 0.23 mmol), Triethylamine (63 μl, 0.45 mmol) and 96L51.doc -65- 200523234

EDC1(0.052克，0.27毫莫耳）。此混合物於週邊溫度攪拌16 小時，然後相繼用2 M HCl(2xlO毫升），飽和碳酸氫鈉水 溶液（10毫升）及水（10毫升）洗。分離有機相，用硫酸鎂乾 燥，減壓濃縮，得無色固體，以閃二氧化矽膠色層分析純 化，用（DCM至10% MeOH/DCM)洗離，得標題化合物 (0.106克，89%)，為無色固體。b NMR (DMSO): 1.22 (s， 9H)，2·18-2·35 (m，2H)，2·44-2·62 (m，2H+水），2·80 (dd， 1H)，3·02 (dd，1H)，3.92 (m，1H)，4.06 (d，2H)，4·60 (m， 1H)，6.57 (d，1H)，7.00-7.30 (m，14H)，8.14 (d，1H)，8.40 (t， 1H)。 中間體5 : N-[(3R)-3-第三-丁氧基羰基胺基-4-(2_氟苯基） 丁醯基】-D-苯基苯胺EDC1 (0.052 g, 0.27 mmol). The mixture was stirred at ambient temperature for 16 hours, and then washed successively with 2 M HCl (2 x 10 ml), saturated aqueous sodium bicarbonate solution (10 ml) and water (10 ml). The organic phase was separated, dried over magnesium sulfate, and concentrated under reduced pressure to give a colorless solid, which was purified by flash silica gel chromatography and washed with (DCM to 10% MeOH / DCM) to give the title compound (0.106 g, 89%) , Is a colorless solid. b NMR (DMSO): 1.22 (s, 9H), 2.18-2 · 35 (m, 2H), 2.44-2 · 62 (m, 2H + water), 2.80 (dd, 1H), 3 · 02 (dd, 1H), 3.92 (m, 1H), 4.06 (d, 2H), 4.60 (m, 1H), 6.57 (d, 1H), 7.00-7.30 (m, 14H), 8.14 (d , 1H), 8.40 (t, 1H). Intermediate 5: N-[(3R) -3-Third-butoxycarbonylamino-4- (2-fluorophenyl) butylfluorenyl] -D-phenylaniline

將2-[(R)-3 -第三-丁氧基幾基胺基-4-(2-氟-苯基）·丁醯基 胺基]-3-苯基-丙酸曱基酯（中間體6，2.90克，5.88毫莫耳） 於THF(50毫升）及MeOH(3毫升）内的溶液以2 Μ氫氧化納水 溶液（16 · 1毫升）處理。此反應混合物於週邊溫度授拌16小 時。將反應混合物減壓濃縮，水性殘餘物用2 M HC1酸化 至pH 2，此時有大量白色沉澱物形成，濾除沉澱物，用水 及二乙醚洗。將固體真空乾燥，得標題化合物，為無色固 體（0.241 克，94%)。1HNMR(DMSO):l·23(s，9H)，2 18 2.35 (m，2H)，2.44-2.62 (m，2H)，2.87 (dd，1H)，3.06 (dd， 1H)，3.96 (m，1H)，4.46 (m，1H)，6.55 (d，1H)，7.00-7 3〇 (m，9H)，8.22 (d，1H); MS m/z 467 (M+Na)。 中間體6 : 2-[(R)-3_第三-丁氧基叛基胺基苯基）_ 96151.doc • 66 - 200523234 丁醯基胺基】-3-苯基-丙酸甲基酯 於攪拌的（R)-3-第三-丁氧基羰基胺基·4_(2_氟-苯基）_ 丁 酸（2.00克’ 6.75¾莫耳）於D C Μ (10 〇宅升）内之溶液中相繼 加HOBt(l.l〇克，8.11毫莫耳），D-苯基胺吉丙酸甲酯（1·46 克，6_75毫莫耳），三乙基胺（1.88毫升，13.5毫莫耳）及 EDC1(1.55克，8.11毫莫耳）。此混合物於週邊溫度擾拌16 小時。反應混合物然後相繼用2 M HC1(50毫升），碳酸氫 鈉水溶液（50毫升）及鹽水（1〇〇毫升）洗。分離有機相，用硫 酸鎂乾燥，減壓濃縮，得白色膠體。殘餘物作閃二氧化矽 膠色層分析（用DCM至10% MeOH/DCM洗離），得2-[(R)-3-第三-丁氧基羰基胺基-4-(2-氟-苯基）-丁醯基胺基]-3-苯基-丙酸甲基酯（2.91克，94%)，為無色固體。4 NMR (CDC13): 1.38 (s，9H)，2_32 (dd，1H)，2.42 (dd，1H)，2.82_ 2.96 (m，2H)，3_06 (dd，1H)，3·14 (dd，1H)，3.76 (s，3H)， 4.10 (m，1Η)，4.84 (m，1Η)，5·38 (brs，1Η)，6·02 (brd，1Η) 及 6.94 —7.36 (m，9H); MS m/z 481 (M+Na)。 實例10 : (R)-3-胺基-4_(2·氟-苯基）-N-((R)-l-甲基-1_甲基 胺甲醯基-2-苯基-乙基）-丁醯胺鹽酸鹽2-[(R) -3 -Third-butoxyepiaminoamino-4- (2-fluoro-phenyl) · butyridinylamino] -3-phenyl-propionate fluorenyl ester (intermediate A solution of 6, 2.90 g, 5.88 mmol) in THF (50 ml) and MeOH (3 ml) was treated with a 2 M aqueous sodium hydroxide solution (16.1 ml). The reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the aqueous residue was acidified to pH 2 with 2 M HC1. At this time, a large amount of white precipitate was formed. The precipitate was filtered off and washed with water and diethyl ether. The solid was dried under vacuum to give the title compound as a colorless solid (0.241 g, 94%). 1HNMR (DMSO): 1.23 (s, 9H), 2 18 2.35 (m, 2H), 2.44-2.62 (m, 2H), 2.87 (dd, 1H), 3.06 (dd, 1H), 3.96 (m, 1H), 4.46 (m, 1H), 6.55 (d, 1H), 7.00-7 3o (m, 9H), 8.22 (d, 1H); MS m / z 467 (M + Na). Intermediate 6: 2-[(R) -3_Third-butoxyalkylaminophenyl) _ 96151.doc • 66-200523234 Butanylamino] -3-phenyl-propionic acid methyl ester in (R) -3-Third-butoxycarbonylamino · 4- (2-fluoro-phenyl) _butyric acid (2.00 g '6.75 mol) in DC M (100 liters) To the solution were sequentially added HOBt (110 g, 8.11 mmol), D-phenylamine methyl propionate (1.46 g, 6-75 mmol), and triethylamine (1.88 mL, 13.5 mmol). ) And EDC1 (1.55 g, 8.11 mmol). This mixture was stirred at ambient temperature for 16 hours. The reaction mixture was then washed successively with 2 M HC1 (50 ml), aqueous sodium bicarbonate solution (50 ml) and brine (100 ml). The organic phase was separated, dried over magnesium sulfate, and concentrated under reduced pressure to give a white colloid. The residue was analyzed by flash silica gel chromatography (washed off with DCM to 10% MeOH / DCM) to give 2-[(R) -3-third-butoxycarbonylamino-4- (2-fluoro- Phenyl) -butylamidoamino] -3-phenyl-propionic acid methyl ester (2.91 g, 94%) as a colorless solid. 4 NMR (CDC13): 1.38 (s, 9H), 2_32 (dd, 1H), 2.42 (dd, 1H), 2.82_ 2.96 (m, 2H), 3_06 (dd, 1H), 3.14 (dd, 1H) ), 3.76 (s, 3H), 4.10 (m, 1Η), 4.84 (m, 1Η), 5.38 (brs, 1Η), 6.02 (brd, 1Η) and 6.94 —7.36 (m, 9H); MS m / z 481 (M + Na). Example 10: (R) -3-amino-4 ((2-fluoro-phenyl) -N-((R) -1-methyl-1_methylaminomethylmethyl-2-phenyl-ethyl ) -Butamidine hydrochloride

於攪拌的（R)-2-第三-丁氧基羰基胺基-2-甲基-3-苯基—丙 酸（838毫克，3.0毫莫耳）於DCM(20毫升）内的溶液中加 96151.doc -67- 200523234 HOBt(500毫克，3·26毫莫耳），EDC1(633毫克，3.3毫莫 耳），DIPEA(1.15毫升，6·6毫莫耳）及甲基烷鹽酸鹽（223毫 克，3.3毫莫耳）。此混合物於室溫攪拌16小時，蒸發，將 殘餘物於醋酸乙酯及水間分開。有機相相繼用1N擰檬酸水 溶液，水及鹽水洗。以硫酸鎂乾燥後，蒸發溶液，得（(R)-1-甲基-1-甲基胺甲醯基-2-苯基-乙基）-胺基甲酸第三-丁基 酯，為白色固體（880毫克）。此物質於室溫在4N HC1/二噁 烷（10 ml)中攪拌2小時，蒸發，用醚研磨，得（R)-2-胺基-2，N_二甲基-3-苯基-丙醯胺，鹽酸鹽，為白色固體（760毫 克）。於此固體於DCM(20毫升）内的攪拌的溶液中加（R)-3-第三·丁氧基羰基胺基-4-(2-氟-苯基）-丁酸（970毫克，3.26 毫莫耳），HOBT(500毫克，3.26毫莫耳），EDC1(626.4毫 克，3.26毫莫耳），DIPEA( 1.14毫升，6.5毫莫耳）。此混合 物於室溫攪拌16小時，蒸發，殘餘物於醋酸乙酯及水間分 開。有機萃取物相繼用水，1 N檸檬酸，水，1 N氫氧化鈉 水溶液，水及鹽水洗。以硫酸鎂乾燥後，蒸發溶液，得 {(R)-2-(2-氟-苯基-甲基-卜甲基甲醯胺基_2-苯 基·乙基胺甲醯基）-甲基]-乙基卜胺基甲酸第三-丁基酯，為 白色固體。將此固體於4 N HC1/二噁烷内於室溫攪拌1小 時’蒸發，以醚研磨，得標題化合物，為白色固體（35〇毫 克 ’ 26.4%)。4 NMR (DMSO d6) δ: 1.18 (s，3H)，2.52 (d， 3H)，2.85-2.98 (m，1H)，2.98-3.1 (m，2H)，3.28 (s，2H)， 3.58-3.7 (b，1H)，7·02 (d，2H)，7.12-7.4 (m，9H)，7.7 (d， 1H)，7.95 (s，1H)，8.25 (bs5 3H); MS m/z 372 (MH+)。 96151.doc -68- 200523234 實例11 : (R)-3-胺基-(2-氟·苯基）_N_((R)_1-甲基胺甲醯基-2 -苯硫-2-基-乙基）-丁酿胺鹽酸鹽A stirred solution of (R) -2-Third-butoxycarbonylamino-2-methyl-3-phenyl-propionic acid (838 mg, 3.0 mmol) in DCM (20 ml) Add 96151.doc -67- 200523234 HOBt (500 mg, 3.26 mmol), EDC1 (633 mg, 3.3 mmol), DIPEA (1.15 ml, 6.6 mmol) and methylalkanoic acid Salt (223 mg, 3.3 mmol). The mixture was stirred at room temperature for 16 hours and evaporated to separate the residue between ethyl acetate and water. The organic phase was washed successively with 1N aqueous citric acid solution, water and brine. After drying over magnesium sulfate, the solution was evaporated to obtain ((R) -1-methyl-1-methylaminomethylamidino-2-phenyl-ethyl) -aminocarboxylic acid third-butyl ester, which was white Solid (880 mg). This material was stirred in 4N HC1 / dioxane (10 ml) at room temperature for 2 hours, evaporated, and triturated with ether to give (R) -2-amino-2, N_dimethyl-3-phenyl- Propylamine, hydrochloride, as a white solid (760 mg). To a stirred solution of this solid in DCM (20 ml) was added (R) -3-tert-butoxycarbonylamino-4- (2-fluoro-phenyl) -butanoic acid (970 mg, 3.26 Millimoles), HOBT (500 mg, 3.26 millimoles), EDC1 (626.4 mg, 3.26 millimoles), DIPEA (1.14 ml, 6.5 millimoles). The mixture was stirred at room temperature for 16 hours, evaporated, and the residue was partitioned between ethyl acetate and water. The organic extract was washed successively with water, 1 N citric acid, water, 1 N aqueous sodium hydroxide solution, water and brine. After drying over magnesium sulfate, the solution was evaporated to obtain {(R) -2- (2-fluoro-phenyl-methyl-bumethylformamido-2--2-phenyl · ethylaminoformamyl) -methyl] -Third-butylethylethylaminoformate as a white solid. This solid was stirred in 4 N HC1 / dioxane at room temperature for 1 hour 'to evaporate and triturated with ether to give the title compound as a white solid (350,000 mg' 26.4%). 4 NMR (DMSO d6) δ: 1.18 (s, 3H), 2.52 (d, 3H), 2.85-2.98 (m, 1H), 2.98-3.1 (m, 2H), 3.28 (s, 2H), 3.58-3.7 (b, 1H), 7.02 (d, 2H), 7.12-7.4 (m, 9H), 7.7 (d, 1H), 7.95 (s, 1H), 8.25 (bs5 3H); MS m / z 372 ( MH +). 96151.doc -68- 200523234 Example 11: (R) -3-amino- (2-fluoro · phenyl) _N _ ((R) _1-methylaminomethylmethyl-2 -phenylthio-2-yl- Ethyl) -butyramine hydrochloride

於（R)-3-第三-丁氧基羰基胺基-4-(2-氟-苯基）-丁酸2,5-二 氧代-吡咯烷-1_基酯（中間體8 ; 0.515克，1.3毫莫耳）於 DCM(20毫升）内的攪拌的溶液中相繼加DIPEA(0.23毫升， 1 ·3宅莫耳）及（R)-2-胺基-N-甲基-3-苯硫-2-基丙醯胺鹽酸鹽 (中間體7，0.288克，1·3毫莫耳）。此混合物於週邊溫度攪 拌16小時。然後將反應混合物過濾，固體餅用DCM(50毫 升）及水（50毫升）洗，然後再於60°C真空乾燥過夜，得 {(R)-2-(2-氟苯基）-l-[((R)-l·甲基胺甲醯基-2-苯硫-1_基-乙 基胺甲醯基）-甲基]-乙基}-胺基甲酸第三-丁基酯（3 80毫 克，63.1%)，為白色固體。將此物質（195毫克，0.420毫莫 耳）於4 N HC1/二噁烷内之溶液於室溫攪拌1小時。真空下 蒸發除去溶劑，殘餘物用醚研磨，得標題化合物（130毫 克，85.3%) 〇 咕 NMR (DMSO-d6) δ: 2.32-2.52 (m，2H)， 2.58 (d，3H)，2.7-2.82 (m，1H)，2.88-3.01 (q，2H)，3.15-3.25 (dd，1H)，3.59 (b，1H)， 4.38 (b，1H)，6.79-6.86 (m，2H)， 7.12-7.39 (m，5H)，8.01 (d，1H)，8.15 (b，3H)，8.5 (d，1H); MS m/z 364 (MH+)。 實例12 : (R)_3_胺基_N-((R)-1_胺甲醯基-2-環戊基-乙基）_ 96151.doc -69- 200523234 4-(2-氟-苯基）-丁醯胺鹽酸鹽In (R) -3-third-butoxycarbonylamino-4- (2-fluoro-phenyl) -butyric acid 2,5-dioxo-pyrrolidine-1_yl ester (Intermediate 8; 0.515 g, 1.3 mmol) in a stirred solution in DCM (20 ml) was added DIPEA (0.23 ml, 1.3 μmol) and (R) -2-amino-N-methyl-3 -Phenylthio-2-ylpropionamine hydrochloride (Intermediate 7, 0.288 g, 1.3 mmol). This mixture was stirred at ambient temperature for 16 hours. The reaction mixture was then filtered, the solid cake was washed with DCM (50 mL) and water (50 mL), and then dried under vacuum at 60 ° C overnight to give {(R) -2- (2-fluorophenyl) -l- [((R) -1 · methylaminomethylamidino-2-phenylsulfan-1-yl-ethylaminomethylamidino) -methyl] -ethyl} -aminocarboxylic acid third-butyl ester ( 3 80 mg, 63.1%) as a white solid. A solution of this material (195 mg, 0.420 mmol) in 4 N HC1 / dioxane was stirred at room temperature for 1 hour. The solvent was removed by evaporation under vacuum, and the residue was triturated with ether to give the title compound (130 mg, 85.3%). NMR (DMSO-d6) δ: 2.32-2.52 (m, 2H), 2.58 (d, 3H), 2.7- 2.82 (m, 1H), 2.88-3.01 (q, 2H), 3.15-3.25 (dd, 1H), 3.59 (b, 1H), 4.38 (b, 1H), 6.79-6.86 (m, 2H), 7.12- 7.39 (m, 5H), 8.01 (d, 1H), 8.15 (b, 3H), 8.5 (d, 1H); MS m / z 364 (MH +). Example 12: (R) _3_amino_N-((R) -1_aminomethylmethyl-2-cyclopentyl-ethyl) _ 96151.doc -69- 200523234 4- (2-fluoro-benzene -) Butanamine hydrochloride

將中間體8(0.394克，1.0毫莫耳），⑻冬胺基_3_環戊基_ 丙酸（0.157毫克，1.0毫莫耳）及三乙基胺（〇139毫升，1〇 毫莫耳）於二嗔烧内之溶液於15(rc在微波爐内加熱1〇分 鐘。冷卻後，將混合物於醋酸乙酯（25毫升）及水（25毫升） 間分開’有機相相繼用1 Μ擰檬酸，水及鹽水洗。有機萃 取物再用硫酸議乾燥，蒸發。固體殘餘物用Ν-羥基丁二亞 醯胺（115毫克，1·〇毫莫耳）及edc1(192毫克，1.0毫莫耳） 於DCM(20毫升）内於室溫攪拌16小時。蒸發後，將殘餘物 於錯酸乙S旨及水間分開。有機相相繼用水及鹽水洗，用硫 酸錯乾燥，過遽，蒸發。固體殘餘物用二噁烷（2〇毫升）及 濃氨水溶液（5毫升）混合物攪拌16小時。過濾所得沉澱物， 用水洗’真空乾燥。所得固體用4 n HC1/二噁烷於室溫挽 拌2小時。將溶液蒸發，殘餘物用醚研磨，得標題化合 物’為固體（164毫克，48·96%)。iH nmR (DMSO d6) δ: 0.95-1.18(b，2H)，1.37_U2(b，9H)，2.4-2.6(m，2H)，2.8- 2.9 (dd，1H)，2.98-3.1 (dd，1H)，3 62 (b，1H)，4 13 (b，1H) 6.92-7.44 (m，6H)，8·〇5_8 35 (m，4H) MS m/z 336 (MH+)。 實例13-19 以類似實例10方法製得如下實例之鹽酸鹽；起始物質如 下所述。 96151.doc 200523234 實例⑻3·胺基·4·(2·氟·苯基）-N-[(R)-2-(lH-崎喝 基)小甲基胺甲醯基_乙基卜丁醯胺 起始物質是（R)_2 •第三丁氧基羰基胺基_3_(1H-吲哚-3 基）丙酸，商業上 可購得。 實例14 基_4_(2氟苯基）養((r)小甲基胺子酿 基-2-萘-2-基·乙基）_ 丁醯胺 起始物質是叫2_第三丁氧基Μ基胺基-3-萘-2-基-丙 酸，商業上可購得。 實例15 · (R)_3_胺基-N_[(R)-2_(4_氣苯基)小甲基胺肀醢 基-乙基）-4-(2-氟，基）_ 丁醯胺 起始物質是（r)_2_第三丁氧基羰基胺基_3_(4_氣-苯基）-丙 酸，商業上可購得。 實例16 · (R)-3•胺基-N-【(R)-2-(4-甲基-苯基）-1-甲基胺肀 醯基-乙基]_4-(2-氟-苯基卜丁醯胺 起始物質是（R)_2-第三丁氧基羰基胺基-3_(4_甲基-苯基）_ 丙酸，商業上可購得。 實例 17 : (R)_3_ 胺基-N_[(R)_2_(3,4-二氟·苯基甲基胺 f 醯基-乙基卜4-(2_氟_笨基）_丁醯胺 起始物質是（R)_2_第三丁氧基羰基胺基-3-(3,4-二氟-笨 基）-丙酸，商業上可購得。 實例18 : (R)_3-胺基_4-(2,4-二氟苯基）-N_((R)-l-甲基胺甲 醯基-2-苯基·乙基）_丁醯胺 起始物質是（R)-2-第三丁氧基羰基胺基-3-笨基-丙酸’商 業上可購得。起始物質（3R)-3-[(第三-丁氧基羰基）胺基]-4- 96151.doc -71 - 200523234 (2,4-二氟苯基）丁酸是根據R.F.W· Jackson等人厂0巧· Chem·，1999, 64, 7579-7585所述製備。 實例19 ·· (R)-3-胺基-4-(2,5-二氟-苯基）-N-((R)-l-甲基胺甲 醯基-2-苯基-乙基）-丁醯胺 起始物質是（R)-2-第三丁氧基羰基胺基-3-苯基-丙酸，商 業上可購得。起始物質（3R)-3-[(第三-丁氧基羰基）胺基]-4-(2,5-二 IL 苯基）丁酸是根據 N. Ikemoto 等人 J· Amer. Chem. Soc·，2004, 126,（10) 3048-3049所述製備。Combine intermediate 8 (0.394 g, 1.0 mmol), aspartame_3_cyclopentyl_propionic acid (0.157 mg, 1.0 mmol) and triethylamine (0139 mL, 10 mmol) (Ear) The solution in Ergoya was heated at 15 (rc in a microwave oven for 10 minutes. After cooling, the mixture was separated between ethyl acetate (25 ml) and water (25 ml). The organic phase was sequentially screwed with 1 μM Wash with citric acid, water and brine. The organic extract was dried over sulphuric acid and evaporated. The solid residue was treated with N-hydroxysuccinimide (115 mg, 1.0 mmol) and edc1 (192 mg, 1.0 mmol). Mol) was stirred in DCM (20 ml) at room temperature for 16 hours. After evaporation, the residue was separated between ethyl acetate and water. The organic phase was washed successively with water and brine, dried over sulfuric acid, and dried over 遽, Evaporate. The solid residue is stirred with a mixture of dioxane (20 ml) and concentrated ammonia solution (5 ml) for 16 hours. The resulting precipitate is filtered, washed with water and dried under vacuum. The solid obtained is then washed with 4 n HC1 / dioxane in the chamber. Warm to stir for 2 hours. The solution was evaporated and the residue was triturated with ether to give the title compound 'as a solid (164 mmol , 48 · 96%). IH nmR (DMSO d6) δ: 0.95-1.18 (b, 2H), 1.37_U2 (b, 9H), 2.4-2.6 (m, 2H), 2.8-2.9 (dd, 1H), 2.98-3.1 (dd, 1H), 3 62 (b, 1H), 4 13 (b, 1H) 6.92-7.44 (m, 6H), 8.05_8 35 (m, 4H) MS m / z 336 (MH + ). Examples 13-19 The hydrochloride of the following example was prepared in a similar manner to that of Example 10; the starting materials are described below. 96151.doc 200523234 Example ⑻ 3. Amino group · 4 · (2 · Fluorine · phenyl) -N- [(R) -2- (lH-sakimyl) small methylaminomethylamidino_ethylbutamidamine The starting material is (R) _2 • Third butoxycarbonylamino_3_ (1H- Indole-3yl) propionic acid, which is commercially available. Example 14 Methyl-4- (2fluorophenyl) sulfate ((r) small methylamine methyl-2-naphthyl-2-yl · ethyl) _ Butylamine starting material is called 2_ third butoxy M-aminoamino-3-naphth-2-yl-propionic acid, which is commercially available. Example 15 · (R) _3_amino-N_ [(R) -2_ (4-Gasphenyl) small methylaminofluorenyl-ethyl) -4- (2-fluoro, yl) _ Butanidine The starting material is (r) _2_Third-butyl Oxycarbonylamino-3- (4-gas-phenyl) -propionic acid is commercially available. Example 16 · (R) -3 • amino-N-[(R) -2- (4-methyl-phenyl) -1-methylaminofluorenyl-ethyl] _4- (2-fluoro- The starting material for phenylbutamidine is (R) _2-third-butoxycarbonylamino-3_ (4-methyl-phenyl) _propionic acid, which is commercially available. Example 17: (R) _3_ Amino-N _ [(R) _2_ (3,4-difluoro · phenylmethylamine f fluorenyl-ethylbenzene 4- (2_fluoro_benzyl) _butamidamine The starting material is (R ) _2_Third-butoxycarbonylamino-3- (3,4-difluoro-benzyl) -propionic acid, commercially available. Example 18: (R) _3-Amino_4- (2 , 4-Difluorophenyl) -N _ ((R) -l-methylaminemethylamidino-2-phenyl · ethyl) _butamidamine The starting material is (R) -2-third butoxy Carbonylamino-3-benzyl-propanoic acid 'is commercially available. The starting material (3R) -3-[(third-butoxycarbonyl) amino] -4- 96151.doc -71- 200523234 (2,4-difluorophenyl) butanoic acid was prepared according to RFW Jackson et al. Chem., 1999, 64, 7579-7585. Example 19 (R) -3-amino group -4- (2,5-Difluoro-phenyl) -N-((R) -l-methylaminomethylmethyl-2-phenyl-ethyl) -butanidine The starting material is (R) -2-Third-butoxycarbonylamino-3-phenyl- Propionic acid is commercially available. The starting material (3R) -3-[(third-butoxycarbonyl) amino] -4- (2,5-diIL phenyl) butanoic acid is based on N. Prepared by Ikemoto et al. J. Amer. Chem. Soc., 2004, 126, (10) 3048-3049.

實例 R11 R12 R14 R15 R16 iHNMRpMSO) δ: MS m/z 13 ch3 F H H 2.22-2.45(m, 2H)，2.55(d, 3H)， 2.7-3.1(m，4H)，3.55(b，1H)， 4.42(m, 1H), 6.85-7.35(m, 8H), 7.55(d，1H)，7.98(d，1H)，8.1(bs, 3H)，8.4(d，1H)，10.77(b，1H) 397 14 ch3 F H H 2.27-2.34 (m，2H)，2.56 (d，3H)， 2.47-2.89 (m, 2H), 3.10-3.16 (m, 2H), 3.42-3.48 (m, 1H), 4.48-4.55 (m，lH)，7.06-7.13(m，3H)，7.32-7.41 (m, 3H), 7.65 (s, 1H), 7.70-7.76 (m, 3H), 8.02 (d, 2H), 8.51 (d, 1H). 408 96151.doc -72- 200523234 15 ch3 ^TCI F H H 2.27-2.34 (m，1H)，2.41-2.43 (m， 1H)，2.55 (d，3H)，2.59-2.70 (m， 2H), 2.82-2.97 (m, 2H), 3.47-3.49 (m, 1H), 4.36-4.44 (m, 1H), 7.11-7.25 (m，8H)，7.28-7.35 (m，1H)， 7.99-8.04 (m，2H)，8.45 (d，1H). 392 16 ch3 F H H 2.09 (s，3H)，2.26-2.33 (m，2H)， 2.55 (d，3H)，2.60-2.65 (m，2H)， 2.76-2.83 (m5 1H), 2.88-2.97 (m, 1H)，3.44-3.48 (m，1H)，4.35-4.43 (m，1H)，6.94 (d，2H)，7.03 (d， 2H), 7.11-7.23 (m, 3H), 7.30-7.35 (m，1H)，7.97 (d，1H)，8.03 (brs， 2H)，8.40 (d，1H). 372 17 ch3 A： F H H 2.25-2.35 (m，2H)，2.56 (d，3H)， 2.60-2.70 (m, 2H), 2.81-2.88 (m, 1H)，2.2-2.98 (m，1H)，3.44-3.51 (m, 1H), 4.38-4.46 (m, 1H), 6.98-7.01 (m，1H)，7.11-7.25 (m，6H)， 7.28-7.34 (m，1H)，8.02 (brs，1H)， 8.46 (d, 1H). 394 18 ch3 X) F F H 2.30-2.46 (m，2H)，2.58 (d，3H)， 2.66-2.84 (m, 2H), 2.94-3.10 (m, 2H)，3.41-3.48 (m，1H)，4.40-4.46 (m，1H)，7.02 (t，1H)，7.10 (t，1H)， 7.17-7.28 (m，6H), 7.80 (brs，2H)， 7.96-7.98 (m, 1H), 8.42-8.45 (m, 1H). 376 19 ch3 F H F 2.30-2.42 (m，2H)，2.55 (d，3H)， 2.59-2.72 (m，2H)，2.80-2.87 (m， 1H)，2.93-3.07 (m，2H)，4.38-4.46 (m, 1H)，7.06-7.24 (m，8H)，7.99 (d，1H)，8.07 brs，2H)，8.46 (d， 1H). 376 實例20-30 如實例11類似方法用中間體8製得下列實例的鹽酸鹽， 其起始物質如下。 96l51.doc -73- 200523234 實例20 : (R)-3_胺基-4·(2-氟-苯基）_N-((R)-1-甲基胺甲醯 基-2-吡啶-3_基-乙基）_丁醯胺 起始物質一見中間體9 實例21 : (R)-3-胺基-4-(2-氟-苯基）-N-((R)-1-甲基胺甲醯 基-2 _ ϋ比咬-4 -基-乙基）-丁酿胺 起始物質一見中間體10 實例22 : (R)-3_胺基-N-[(R)-2-(4-溴-苯基）-1-甲基胺甲醯 基-乙基】- 4-(2 -氣-苯基）-丁酿胺 起始物質一見中間體11 實例23 : (R)-3-胺基-4-(2-氟-苯基）-N_((R)-1-甲基胺甲醯 基-2-苯硫-3-基-乙基）-丁酿胺 起始物質一見中間體12 實例24 : (R)-3-胺基-4-(2-氟-苯基）-N-((R)_1-甲基胺甲醯 基-3-苯基-丙基）-丁酿胺 起始物質一見中間體13 實例25 : (R)-3-胺基-4_(2·氟-苯基）_N-[(R)-2_(4-甲氧基-苯 基）-1-甲基胺甲醯基-乙基】-丁醯胺 起始物質一見中間體14 實例26 : (R)-3-胺基-4-(2•氟-苯基）-N-[(R)_1-甲基胺甲醯 基-2-(3-三敗甲基-苯基）_乙基]-丁釀胺 起始物質一見中間體15 實例27 : (R)-3-胺基-4_(2-氟-苯基）-N-((R)-1-甲基胺甲醯 基-2-噻唑-4-基-乙基）-丁醯胺 起始物質一見中間體16 96151.doc -74- 200523234 實例28 : (R)_3-胺基·4_(2_氟-苯基）_N-(1-甲基胺甲醯基-2-喹啉-4-基-乙基）-丁醯胺 起始物質一 2-胺基甲基-3-喹啉-4-基-丙醯胺 實例29 : (3R)-3_胺基_4_(2_氟苯基）-N-[(lR)-2-(甲基胺基）_ 1-(1-萘基甲基）-2-氧代乙基】丁醯胺 起始物質一（R)-2-胺基-N-甲基·3-萘-1-基-丙醯胺 實例30 : (R)-3_胺基-4-(2-氟-苯基）_N-((R)-1·甲基胺甲醯 基-2-吡啶-2-基-乙基）-丁醯胺 起始物質一（R)-2-胺基-N-甲基-3-吡啶-2-基-丙醯胺 „12Example R11 R12 R14 R15 R16 iHNMRpMSO) δ: MS m / z 13 ch3 FHH 2.22-2.45 (m, 2H), 2.55 (d, 3H), 2.7-3.1 (m, 4H), 3.55 (b, 1H), 4.42 (m, 1H), 6.85-7.35 (m, 8H), 7.55 (d, 1H), 7.98 (d, 1H), 8.1 (bs, 3H), 8.4 (d, 1H), 10.77 (b, 1H) 397 14 ch3 FHH 2.27-2.34 (m, 2H), 2.56 (d, 3H), 2.47-2.89 (m, 2H), 3.10-3.16 (m, 2H), 3.42-3.48 (m, 1H), 4.48-4.55 ( m, lH), 7.06-7.13 (m, 3H), 7.32-7.41 (m, 3H), 7.65 (s, 1H), 7.70-7.76 (m, 3H), 8.02 (d, 2H), 8.51 (d, 1H). 408 96151.doc -72- 200523234 15 ch3 ^ TCI FHH 2.27-2.34 (m, 1H), 2.41-2.43 (m, 1H), 2.55 (d, 3H), 2.59-2.70 (m, 2H), 2.82-2.97 (m, 2H), 3.47-3.49 (m, 1H), 4.36-4.44 (m, 1H), 7.11-7.25 (m, 8H), 7.28-7.35 (m, 1H), 7.99-8.04 (m , 2H), 8.45 (d, 1H). 392 16 ch3 FHH 2.09 (s, 3H), 2.26-2.33 (m, 2H), 2.55 (d, 3H), 2.60-2.65 (m, 2H), 2.76-2.83 (m5 1H), 2.88-2.97 (m, 1H), 3.44-3.48 (m, 1H), 4.35-4.43 (m, 1H), 6.94 (d, 2H), 7.03 (d, 2H), 7.11-7.23 ( m, 3H), 7.30-7.35 (m, 1H), 7.97 (d, 1H), 8.0 3 (brs, 2H), 8.40 (d, 1H). 372 17 ch3 A: FHH 2.25-2.35 (m, 2H), 2.56 (d, 3H), 2.60-2.70 (m, 2H), 2.81-2.88 (m , 1H), 2.2-2.98 (m, 1H), 3.44-3.51 (m, 1H), 4.38-4.46 (m, 1H), 6.98-7.01 (m, 1H), 7.11-7.25 (m, 6H), 7.28 -7.34 (m, 1H), 8.02 (brs, 1H), 8.46 (d, 1H). 394 18 ch3 X) FFH 2.30-2.46 (m, 2H), 2.58 (d, 3H), 2.66-2.84 (m, 2H), 2.94-3.10 (m, 2H), 3.41-3.48 (m, 1H), 4.40-4.46 (m, 1H), 7.02 (t, 1H), 7.10 (t, 1H), 7.17-7.28 (m, 6H), 7.80 (brs, 2H), 7.96-7.98 (m, 1H), 8.42-8.45 (m, 1H). 376 19 ch3 FHF 2.30-2.42 (m, 2H), 2.55 (d, 3H), 2.59- 2.72 (m, 2H), 2.80-2.87 (m, 1H), 2.93-3.07 (m, 2H), 4.38-4.46 (m, 1H), 7.06-7.24 (m, 8H), 7.99 (d, 1H), 8.07 brs, 2H), 8.46 (d, 1H). 376 Examples 20-30 The hydrochloride salts of the following examples were prepared in the same manner as in Example 11 using Intermediate 8. The starting materials are as follows. 96l51.doc -73- 200523234 Example 20: (R) -3_amino-4 · (2-fluoro-phenyl) _N-((R) -1-methylaminomethylmethyl-2-pyridine-3 _Yl-ethyl) _butamidamine starting material See intermediate 9 Example 21: (R) -3-amino-4- (2-fluoro-phenyl) -N-((R) -1-methyl Methylaminomethyl-2, 4-methyl- 4-methyl-ethyl) -butylamine starting material See intermediate 10 Example 22: (R) -3_amino-N-[(R) -2 -(4-Bromo-phenyl) -1-methylamine formamidine-ethyl]-(4- (2-Gas-phenyl) -butyramine starting material See intermediate 11 Example 23: (R) -3-Amino-4- (2-fluoro-phenyl) -N _ ((R) -1-methylaminomethylmethyl-2-phenylthio-3-yl-ethyl) -butylamine See the substance at Intermediate 12 Example 24: (R) -3-amino-4- (2-fluoro-phenyl) -N-((R) _1-methylaminomethylmethyl-3-phenyl-propyl ) -Butanamine starting material See intermediate 13 Example 25: (R) -3-amino-4 ((2 · fluoro-phenyl) _N-[(R) -2_ (4-methoxy-phenyl) ) -1-methylamine formamidine-ethyl] -butylamidine starting material See intermediate 14 Example 26: (R) -3-amino-4- (2 • fluoro-phenyl) -N- [(R) _1-Methylaminomethylmethyl-2- (3-tridecylmethyl-phenyl) _ethyl] -butylamine Intermediate 15 Example 27: (R) -3-amino-4- (2-fluoro-phenyl) -N-((R) -1-methylaminomethylmethylmethyl-2-thiazol-4-yl-ethyl See also Intermediate 16 96151.doc -74- 200523234 Example 28: (R) _3-Amino · 4- (2-fluoro-phenyl) _N- (1-methylamine formamidine 2-quinolin-4-yl-ethyl) -butyramine starting material 2-aminomethyl-3-quinolin-4-yl-propanilamine Example 29: (3R) -3_ Amino_4_ (2_fluorophenyl) -N-[(lR) -2- (methylamino) _ 1- (1-naphthylmethyl) -2-oxoethyl] butamidine Starting material mono (R) -2-amino-N-methyl · 3-naphthalen-1-yl-propanamide Example 30: (R) -3_amino-4- (2-fluoro-phenyl) _N-((R) -1 · methylaminomethylamidinyl-2-pyridin-2-yl-ethyl) -butanidine starting material mono (R) -2-amino-N-methyl-3 -Pyridin-2-yl-propanilamine 12

實例 R11 R12 1HNMR(DMSO) MS m/z 20 ch3 2.25-2.63 (m, 2H), 2.58 (d, 3H), 2.65-2.8 (dd，1H)，2.9-3.05 (m，2H)，3.2-3.35 (dd， 1H)，3.55 (b，1H)，4.55 (m，1H)，7.1-7.2 (m， 2H)，7.25-7.38 (m，2H)，7.95 (dd，1H) 8.25(b，4H)，8.45(d，1H)，8.65(d，1H)， 8.75(d，1H)，8.85(s，1H) 359 21 ch3 225-2.5(m，2H)，2.53(d，3H)，2.66-2.8(dd， 1H), 2.9-3.05(m, 2H), 3.2-3.35(dd, 1H), 3.55(b，1H)，4.58(m，1H)，7.1-7.38(m，4H), 7.82(d, 2H), 8.2(bs, 4H), 8.65(d, 1H), 8.73(d, 2H) 359 96151.doc -75- 200523234 22 ch3 2.25-2.58(m，2H)，2.59(d, 3H)，2.6-2.7(m， 2H)，2.8-3.0(m，2H)，3.5(b，1H)，4.4(m， 1H)，7.1-7.4(m，8H)，8.05(d，1H)，8.13(bs， 3H)，8.5(d，1H) 436/438 23 ch3 2.25-2.45(m，2H)，2.58(d，3H)，2.7-2.82(m， 2H)，2.9-3.05(m，2H)，3.55(m，1H)，4.4(m， 1H)，6.92(d, 1H)，7.1-7.39(m，7H)，8.0(d， 1H)，8.15(bs，3H)，8_45(d，1H) 364 24 ch3 -CH2Ph 1.65-1.95(m, 2H), 2.4-2.65(m, 4H), 2.56(d, 3H), 2.8-3.l(m, 2H), 3.68(m, 1H), 4.15(m, IH)，7.1-7.4(m，9H), 7.9(d, 1H)，8.22(bs， 3H), 8.4(d, 1H) 372 25 ch3 2.26-2.53(m，2H)，2.58(d，3H)，2.6-2.7(m， 2H)，2.8-2.98(m，2H)，3.5(m，1H)，4.38(m， 1H)，6.7(d，2H)，7.05-7.38(m，6H)，8.0(d， 1H)，8.15(bs，3H)，8.45(d，1H) 388 26 ch3 cf3 2.22-2.38(m，lH)，2.4-2.68(d，5H)，2.7-2.9(m，2H)，3.0-3.15(m，1H)，3.5(b，1H)， 4.45(m，1H)，7.05-7.6(m，8 H)，8.1(b, 4H)， 8.55(d，1H) 426 27 ch3 ^Cs 2.38-2.58(m，5H)，2.75-3.22(m，4H)，3.6(b， 1H)，4.55(m，1H)，7.1-7_4(m，5H)，7.95(d， 1H)，8.15(b，3H)，8.5(d，1H)，9.08(s，IH) 365 28 ch3 00 409 96151.doc -76- 200523234 29 ch3 2.27- 2.34 (m，2H)，2.54 (d，3H)，2.81-2.86 (m，2H)，3.06-3.15 (m，2H)，3.63-3.67 (m， 1H)，4.53-4.58 (m，1H)，7.12-7.18 (m，4H)， 7.28- 7.30 (m, 3H), 7.46-7.49 (m, 2H), 7.68-7.71 (m, 1H), 7.82-7.85 (m, 1H), 7.96-8.01 (m，2H)，8.13-8.15 (m，1H)，8.53 (d，1H). 408 30 ch3 2.34 (m，1H)，2.58 (m，3H)，2.68-3.04 (m， 2H)，3.41-3.64(m，3H)，4.73(m，lH)，7.10-7.22 (m, 2H), 7.23-7.38 (m, 2H), 7.83 (m, 2H)，8.09-8.59 (m，5H)，8.65-8.82 (m，2H) 359 實例31 : (S)-2-[(R)-3-胺基-4-(2·氟-苯基）_ 丁醜基胺基】-4-甲基-戊酸甲基醯胺Examples R11 R12 1HNMR (DMSO) MS m / z 20 ch3 2.25-2.63 (m, 2H), 2.58 (d, 3H), 2.65-2.8 (dd, 1H), 2.9-3.05 (m, 2H), 3.2-3.35 (dd, 1H), 3.55 (b, 1H), 4.55 (m, 1H), 7.1-7.2 (m, 2H), 7.25-7.38 (m, 2H), 7.95 (dd, 1H) 8.25 (b, 4H) , 8.45 (d, 1H), 8.65 (d, 1H), 8.75 (d, 1H), 8.85 (s, 1H) 359 21 ch3 225-2.5 (m, 2H), 2.53 (d, 3H), 2.66-2.8 (dd, 1H), 2.9-3.05 (m, 2H), 3.2-3.35 (dd, 1H), 3.55 (b, 1H), 4.58 (m, 1H), 7.1-7.38 (m, 4H), 7.82 (d , 2H), 8.2 (bs, 4H), 8.65 (d, 1H), 8.73 (d, 2H) 359 96151.doc -75- 200523234 22 ch3 2.25-2.58 (m, 2H), 2.59 (d, 3H), 2.6-2.7 (m, 2H), 2.8-3.0 (m, 2H), 3.5 (b, 1H), 4.4 (m, 1H), 7.1-7.4 (m, 8H), 8.05 (d, 1H), 8.13 ( bs, 3H), 8.5 (d, 1H) 436/438 23 ch3 2.25-2.45 (m, 2H), 2.58 (d, 3H), 2.7-2.82 (m, 2H), 2.9-3.05 (m, 2H), 3.55 (m, 1H), 4.4 (m, 1H), 6.92 (d, 1H), 7.1-7.39 (m, 7H), 8.0 (d, 1H), 8.15 (bs, 3H), 8_45 (d, 1H) 364 24 ch3 -CH2Ph 1.65-1.95 (m, 2H), 2.4-2.65 (m, 4H), 2.56 (d, 3H), 2.8-3.l (m, 2H), 3.68 (m, 1H), 4.15 ( m , IH), 7.1-7.4 (m, 9H), 7.9 (d, 1H), 8.22 (bs, 3H), 8.4 (d, 1H) 372 25 ch3 2.26-2.53 (m, 2H), 2.58 (d, 3H ), 2.6-2.7 (m, 2H), 2.8-2.98 (m, 2H), 3.5 (m, 1H), 4.38 (m, 1H), 6.7 (d, 2H), 7.05-7.38 (m, 6H), 8.0 (d, 1H), 8.15 (bs, 3H), 8.45 (d, 1H) 388 26 ch3 cf3 2.22-2.38 (m, lH), 2.4-2.68 (d, 5H), 2.7-2.9 (m, 2H) , 3.0-3.15 (m, 1H), 3.5 (b, 1H), 4.45 (m, 1H), 7.05-7.6 (m, 8 H), 8.1 (b, 4H), 8.55 (d, 1H) 426 27 ch3 ^ Cs 2.38-2.58 (m, 5H), 2.75-3.22 (m, 4H), 3.6 (b, 1H), 4.55 (m, 1H), 7.1-7_4 (m, 5H), 7.95 (d, 1H), 8.15 (b, 3H), 8.5 (d, 1H), 9.08 (s, IH) 365 28 ch3 00 409 96151.doc -76- 200523234 29 ch3 2.27- 2.34 (m, 2H), 2.54 (d, 3H), 2.81-2.86 (m, 2H), 3.06-3.15 (m, 2H), 3.63-3.67 (m, 1H), 4.53-4.58 (m, 1H), 7.12-7.18 (m, 4H), 7.28- 7.30 (m , 3H), 7.46-7.49 (m, 2H), 7.68-7.71 (m, 1H), 7.82-7.85 (m, 1H), 7.96-8.01 (m, 2H), 8.13-8.15 (m, 1H), 8.53 (d, 1H). 408 30 ch3 2.34 (m, 1H), 2.58 (m, 3H), 2.68-3.04 (m, 2H), 3.41-3.64 (m , 3H), 4.73 (m, 1H), 7.10-7.22 (m, 2H), 7.23-7.38 (m, 2H), 7.83 (m, 2H), 8.09-8.59 (m, 5H), 8.65-8.82 (m , 2H) 359 Example 31: (S) -2-[(R) -3-Amino-4- (2 · fluoro-phenyl) _butaconylamino] -4-methyl-valeric acid methylamidamine

此實例係如類似實例11方法製成鹽酸鹽，使用中間體8 及L-亮胺酸-Ν-甲基醯胺（CAS no.64569-68-2)。後者可用 R.W. Feenstra et al·，Tetrahedron 1990, 46(5)，1745-56所述 工序製備。 MS m/z 324 (MH+)。 實例32 · (R)_3_胺基-N-((S)_1_苄基嗎福啉-4-基-2-氧代_ 乙基）_4-(2-氟·苯基）_丁醯胺This example was prepared as a hydrochloride salt in a similar manner to Example 11, using intermediate 8 and L-leucine-N-methylamidamine (CAS no. 64569-68-2). The latter can be prepared by the procedure described by R.W.Feenstra et al., Tetrahedron 1990, 46 (5), 1745-56. MS m / z 324 (MH +). Example 32 · (R) _3_amino-N-((S) _1_benzylmorpholine-4-yl-2-oxo_ethyl) _4- (2-fluoro · phenyl) _butane amine

此實例係一類似實例法製得，為其鹽酸鹽，使用中 96151.doc -77- 200523234 間體8及（S)-2-胺基-1-嗎福琳-4-基-3-苯基丙烧- l-_鹽酸 鹽。此胺可以類似WO 9528416用於合成對映體（CAS ηο·17186-57-1)方法製備。 MS m/z 414(MH+)。 實例34 : (R)-3-胺基-N-(l_胺甲醯基-2_呋喃-2-基-乙基）-4-(2-氟-苯基）-丁醯胺 於中間體17(266毫克，1.3毫莫耳）於DCM(l〇毫升）内的 搜拌的溶液中加（R)-3-第三-丁氧基羰基胺基_4-(2-氟-苯 基）-丁酸（386毫克，1.3毫莫耳），h〇BT(199毫克，1.3毫莫 耳），EDC1(249 毫克，1.3 毫莫耳）及 DIPEA(0.45 毫升，2.6 毫莫耳）。此混合物於室溫攪拌16小時得白色沉澱物，過 渡分離出，用DCM及水洗。然後將固體真空乾燥，得i9〇 毫克無色固體。此固體用二噁烷/HC1於室溫授拌2小時。 蒸發後，將殘餘物用驗研磨，過遽，得固體（12 〇毫克）； !H NMR (DMSO-d6) δ: 2.3-2.55(m5 2H)5 2.7-3.l(m? 4H), 3.6(b，1H)，4.45(m，1H)，6.02-6.38(dd，2H)，7.05-7.55(m， 7H)，8.15(bs，3H)，8.02(t，1H); MS m/z 334 (MH+)。 實例33，35及36 下列實例係以類似實例12方法製得其鹽酸鹽，使用中間 體8及如下所示商業上可購得的胺基酸為起始物質。This example is prepared by a similar example method as its hydrochloride salt. 96151.doc -77- 200523234 Intermediate 8 and (S) -2-amino-1-morpholin-4-yl-3-benzene Propyl-l-_hydrochloride. This amine can be prepared analogously to WO 9528416 for the synthetic enantiomer (CAS ηο · 17186-57-1). MS m / z 414 (MH +). Example 34: (R) -3-amino-N- (l-aminomethylamidino-2_furan-2-yl-ethyl) -4- (2-fluoro-phenyl) -butanidine in the middle (R) -3-Third-butoxycarbonylamino_4- (2-fluoro-benzene) was added to a stirred solution of body 17 (266 mg, 1.3 mmol) in DCM (10 ml) ) -Butyric acid (386 mg, 1.3 mmol), HOBT (199 mg, 1.3 mmol), EDC1 (249 mg, 1.3 mmol) and DIPEA (0.45 ml, 2.6 mmol). The mixture was stirred at room temperature for 16 hours to obtain a white precipitate, which was separated off after being washed with DCM and water. The solid was then dried under vacuum to give i90 mg of a colorless solid. This solid was stirred with dioxane / HC1 at room temperature for 2 hours. After evaporation, the residue was triturated with a test tube and dried to obtain a solid (120 mg);! H NMR (DMSO-d6) δ: 2.3-2.55 (m5 2H) 5 2.7-3.l (m? 4H), 3.6 (b, 1H), 4.45 (m, 1H), 6.02-6.38 (dd, 2H), 7.05-7.55 (m, 7H), 8.15 (bs, 3H), 8.02 (t, 1H); MS m / z 334 (MH +). Examples 33, 35, and 36 The following examples were prepared in a similar manner to that of Example 12 using Intermediate 8 and commercially available amino acids as shown below as starting materials.

實例33 : (R)_3-胺基-N((R)|苯并[b】苯硫|基+胺甲醯 基-乙基）_‘(2·氟·苯基）-丁醯胺 96151.doc -78- 200523234 起始物質~ 3-苯并噻吩基丙胺酸 實例35 : (R)_3-胺基-N-((R)_2-聯苯-4-基-1-胺甲醯基-乙 基）-4-(2-氟-苯基）_丁醯胺 起始物質一 4-聯苯基-D-丙胺酸 實例36 : (R)-3_胺基-4-(2•氟-苯基）-N-((R)-1_甲基胺甲醯 基-2-喹啉-2-基-乙基）-丁醯胺 起始物質一 2-喹啉基-D-丙胺酸 實例 R11 R12 1HNMR(DMSO)5: MS m/z 33 Η P 2.3-2.6(m，2H)，2.64-3.3(m，4H)，3.5(b， 1H)，4.55(m, 1H)，7.05-7.48(m，8H)，7.6(bs， 1H), 7.9(m, 2H), 8.15(bs, 3H), 8.53(d, 1H) 399 35 Η 2.05-2.9(m, 5H), 3.0-3.1(dd, 1H), 3.5(b, 1H), 4.5(m, 1H), 7.02-7.6(m, 15H), 8.05(bs, 3H), 8.45(d, 1H) 420 36 ch3 2.3-2.6(m, 2H), 2.73(d, 3H), 2.8-3.8(m, 5H), 4.9(m, 1H), 7.03-8.35(m, 13H), 8.75(d, 1H), 8.85(bs, 1H) 409 實例37 : (R)-3-胺基-N-((R)-1-苄基-2-甲烷磺醯基胺基-2-氧代-乙基）-4-(2•氟·苯基）-丁醯胺，鹽酸鹽Example 33: (R) _3-Amino-N ((R) | benzo [b] phenylthio | yl + aminomethylamidino-ethyl) _ '(2 · fluoro · phenyl) -butyralamine 96151 .doc -78- 200523234 Starting material ~ 3-benzothienylalanine Example 35: (R) _3-Amino-N-((R) _2-biphenyl-4-yl-1-aminomethylamino) -Ethyl) -4- (2-fluoro-phenyl) _butamidamine starting material 4-biphenyl-D-alanine Example 36: (R) -3_amino-4- (2 • Fluoro-phenyl) -N-((R) -1-methylaminomethylamidinyl-2-quinolin-2-yl-ethyl) -butanamide starting material 2-quinolinyl-D- Examples of alanine R11 R12 1HNMR (DMSO) 5: MS m / z 33 Η P 2.3-2.6 (m, 2H), 2.64-3.3 (m, 4H), 3.5 (b, 1H), 4.55 (m, 1H), 7.05-7.48 (m, 8H), 7.6 (bs, 1H), 7.9 (m, 2H), 8.15 (bs, 3H), 8.53 (d, 1H) 399 35 Η 2.05-2.9 (m, 5H), 3.0- 3.1 (dd, 1H), 3.5 (b, 1H), 4.5 (m, 1H), 7.02-7.6 (m, 15H), 8.05 (bs, 3H), 8.45 (d, 1H) 420 36 ch3 2.3-2.6 ( m, 2H), 2.73 (d, 3H), 2.8-3.8 (m, 5H), 4.9 (m, 1H), 7.03-8.35 (m, 13H), 8.75 (d, 1H), 8.85 (bs, 1H) 409 Example 37: (R) -3-amino-N-((R) -1-benzyl-2-methanesulfonamido-2-oxo-ethyl) -4- (2 • fluoro · Phenyl) -butanamide, Salt

將中間體18(58毫克，0.11毫莫耳）與4 M HC1於二噁烷於 至溫授拌16小時。將此混合物減壓濃縮，再用醚濃縮二 96151.doc -79- 200523234 次’得標喊化合物，為無色固體。1h NMR (300 MHz， DMSO) δ: 2.36-2.45 (m5 1H)，2_60 - 3·08 (m，4H)，3·16 (d， 2H)，3.43-3.51 (m，1H)，4.53 (m，1H)，7.06-7.39 (m， 10H)，8·11 (s，3H)，8.61 (t，1H); MS m/z 422 (MH)+。 中間體7 : (R)-2·胺基甲基苯硫基-丙醯胺逢酸鹽Intermediate 18 (58 mg, 0.11 mmol) was mixed with 4 M HC1 in dioxane at room temperature for 16 hours. This mixture was concentrated under reduced pressure, and concentrated with ether 96151.doc -79- 200523234 times' to obtain the title compound as a colorless solid. 1h NMR (300 MHz, DMSO) δ: 2.36-2.45 (m5 1H), 2_60-3.08 (m, 4H), 3.16 (d, 2H), 3.43-3.51 (m, 1H), 4.53 (m , 1H), 7.06-7.39 (m, 10H), 8.11 (s, 3H), 8.61 (t, 1H); MS m / z 422 (MH) +. Intermediate 7: (R) -2 · Aminomethylphenylthio-propionamine

將（R)-2-第三-丁氧基羰基胺基|苯硫_2•基_丙酸（542毫 克，2毫莫耳）與甲基胺，鹽酸鹽（1485毫克，2·2毫莫耳）， HOBT(3 37 毫克，2·2 毫莫耳），EDCI(421.8 毫克，2.2 毫莫 耳）及DIPEA(0.77毫升，2.2毫莫耳）於DCM(20毫升）内攪拌 16小時。將混合物蒸發，殘餘物於醋酸乙酯及水間分開。 將有機萃取物相繼用水，1 ·〇 N檸檬酸，水及鹽水洗。於 硫酸鎂上乾燥後，將混合物過濾並蒸發，得固體（450毫 克）。此固體用4 N HC1/二噁烷（20毫升）於室溫攪拌16小 時。蒸發去溶劑，殘餘物用v/v醋酸乙酯/異己烷研磨，得 標題化合物，為白色固體（300毫克，68%) MS m/z 185 (MH+) 〇 中間艘8 : (R)-3-第三·丁氧基羰基胺基-4-(2-氟-苯基）-丁酸 2,5_二氧代-吡咯啶-1-基酯 96151.doc •80- 200523234(R) -2-Third-butoxycarbonylamino | phenylthio_2 • yl_propionic acid (542 mg, 2 mmol) with methylamine, hydrochloride (1485 mg, 2.2 MM), HOBT (3 37 mg, 2.2 mol), EDCI (421.8 mg, 2.2 mol) and DIPEA (0.77 ml, 2.2 mol) were stirred in DCM (20 ml) for 16 hours . The mixture was evaporated and the residue was partitioned between ethyl acetate and water. The organic extract was washed successively with water, 1.0 N citric acid, water and brine. After drying over magnesium sulfate, the mixture was filtered and evaporated to give a solid (450 mg). This solid was stirred with 4 N HC1 / dioxane (20 ml) at room temperature for 16 hours. The solvent was removed by evaporation, and the residue was triturated with v / v ethyl acetate / isohexane to give the title compound as a white solid (300 mg, 68%) MS m / z 185 (MH +). Middle vessel 8: (R) -3 -Third · butoxycarbonylamino-4- (2-fluoro-phenyl) -butyric acid 2,5-dioxo-pyrrolidin-1-yl ester 96151.doc • 80- 200523234

將（R)_3_B〇〇胺基_4-(2，-氟苯基丁酸（10·0克，33·8毫莫 耳）及N-羥基丁二亞醯胺（4.09克，35·5毫莫耳）於DCM(125 毫升）内之混合物用EDAC(7.78克，40.6毫莫耳）處理。此 混合物於室溫攪拌過夜。此混合物以DCM稀釋，相繼用 1M HC1及碳酸氫鈉水溶液洗。將有機溶液乾燥（MgS〇4)， 減壓濃縮。所得固體以MPLC於二氧化矽（Isco Companion⑧；用100% DCM至20%醋酸乙酯/DCM洗離）， 得（R)-3-第三-丁氧基羰基胺基_4-(2-氟-苯基）-丁酸2,5-二氧 代-吡咯啶-1-基酯，為無色固體（7·28克，55%)。4 NMR (CDC13) 1.380 (s，9Η)，2_85 (s，6Η)，2.92-3.12 (m，2Η)， 4·22-4·38 (m，1H)，4.90-5.08 (m，1H)，6.99-7.13 (m，2H)， 7.18-7.30 (m，2H); MS m/z 417 (M+Na)+。Add (R) _3_B〇〇amino_4- (2, -fluorophenylbutyric acid (10.0 g, 33.8 mmol) and N-hydroxysuccinimide (4.09 g, 35.5 A mixture of mM) in DCM (125 ml) was treated with EDAC (7.78 g, 40.6 mM). The mixture was stirred at room temperature overnight. The mixture was diluted with DCM and washed successively with 1M HC1 and aqueous sodium bicarbonate solution. The organic solution was dried (MgS04) and concentrated under reduced pressure. The obtained solid was subjected to MPLC in silica (Isco Companion (R); washed with 100% DCM to 20% ethyl acetate / DCM) to obtain (R) -3- Third-butoxycarbonylamino_4- (2-fluoro-phenyl) -butyric acid 2,5-dioxo-pyrrolidin-1-yl ester as a colorless solid (7.28 g, 55% ). 4 NMR (CDC13) 1.380 (s, 9Η), 2_85 (s, 6Η), 2.92-3.12 (m, 2Η), 4 · 22-4 · 38 (m, 1H), 4.90-5.08 (m, 1H) ), 6.99-7.13 (m, 2H), 7.18-7.30 (m, 2H); MS m / z 417 (M + Na) +.

中間體9-17係根據中間體7工序製得的其鹽酸鹽，使用 適宜的商業上可購得的沁第三-丁氧基羰基胺基酸。 中間體9 : (R)_2-胺基_Ν_甲基_3-吡啶基·丙醯胺 中間體10 : (R)-2_胺基-心曱基吡啶基·丙醯胺 中間體11 : (R)-2-胺基_3_(心溴_苯基）甲基-丙醯胺 96151.doc -81 - 200523234 中間體12 : (R)-2-胺基甲基_3_苯硫-3-基·丙醯胺 中間體13 : (R)-2-胺基-N-甲基-4-苯基-丁醢胺 中間體14 ·· (R)-2-胺基-3-(4-甲氧基-苯基）-N-甲基-丙醯胺 中間體15 : (R)-2-胺基甲基-3-(3-三氟甲基-苯基）丙醯胺 中間體16 : (R)-2-胺基甲基-3-噻唑-4·基-丙醯胺 中間體17: (R)-2-胺基-3-呋喃-2-基-丙醯胺Intermediate 9-17 is the hydrochloride obtained according to the procedure of Intermediate 7, and a suitable commercially available cin third-butoxycarbonylamino acid is used. Intermediate 9: (R) _2-Amino_N_methyl_3-pyridyl · propanilamine intermediate 10: (R) -2_Amino-cardiacylpyridyl · propanilamine intermediate 11 : (R) -2-Amino_3_ (cardibromo_phenyl) methyl-propanamide 96151.doc -81-200523234 Intermediate 12: (R) -2-Aminomethyl_3_benzenesulfide -3-yl-propionamine intermediate 13: (R) -2-amino-N-methyl-4-phenyl-butanidine intermediate 14 · (R) -2-amino-3- (4-methoxy-phenyl) -N-methyl-propanilamine intermediate 15: (R) -2-aminomethyl-3- (3-trifluoromethyl-phenyl) propanilamine Intermediate 16: (R) -2-aminomethyl-3-thiazol-4-yl-propionamine Intermediate 17: (R) -2-amino-3-furan-2-yl-propionamine

h2n人f〇 _〜NH 中間體 R12 R11 MS: M+ 9 σ ch3 180 10 ch3 180 11 ch3 257/259 12 (f ch3 185 13 Cu ch3 193 14 ch3 209 96151.doc -82- 200523234 15 (7 cf3 ch3 247 16 ch3 186 17 pyf ch3 169 (R)-2-胺基甲基-3_喹啉-4-基_丙醯胺h2n human f〇_ ~ NH intermediate R12 R11 MS: M + 9 σ ch3 180 10 ch3 180 11 ch3 257/259 12 (f ch3 185 13 Cu ch3 193 14 ch3 209 96151.doc -82- 200523234 15 (7 cf3 ch3 247 16 ch3 186 17 pyf ch3 169 (R) -2-aminomethyl-3_quinolin-4-yl_propylamine

(R)-2-胺基甲基_3_喹啉_4-基-丙醯胺是根據中間體7 方法用（R)-2-第三·丁氧基羰基胺基-3_喹啉-‘基-丙酸製成 其鹽酸鹽。所製得者為黃色收濕性固體；MS m/z 230(MH)+。 (R)-2_胺基_N-甲基_3_莕小基_丙醯胺 (R)-2-胺基-N-甲基-3-莕-1-基-丙醯胺係依中間體7之方 法自（R)-2_第三-丁氧基羰基胺基-3-莕-1-基丙酸製成其鹽 酸鹽。得到無色發泡物；MS m/z 251(M+Na)+，229 (MH)+。 (R)-2_胺基_Ν·甲基-3_吡啶-2-基-丙醯胺(R) -2-Aminomethyl-3_quinolin_4-yl-propionamine is used according to the method of Intermediate 7 -'Yl-propionic acid makes its hydrochloride. The obtained was a yellow hygroscopic solid; MS m / z 230 (MH) +. (R) -2_Amino_N-methyl_3_fluorenyl_propanilamine Intermediate 7 is prepared from (R) -2-tert-butoxycarbonylamino-3-fluoren-1-ylpropionic acid as its hydrochloride. Colorless foam was obtained; MS m / z 251 (M + Na) +, 229 (MH) +. (R) -2_Amino_N · methyl-3_pyridin-2-yl-propionamine

(R)-2-胺基-N-甲基-3-吡啶-2-基-丙醯胺是用（R)-2-第三-丁氧基羰基胺基-3-吡啶-2-基-丙酸製成其TFA鹽。所用方 法與製備中間體7相同，唯在去保護步驟中用2 : 1 DCM : TFA代替4 N HC1/二噁烷。製得者為棕色油體；MS m/z 202 (M+Na)+，180(MH)+。 中間體18 :丨(R)-1-[((R)-1_苄基-2-甲烷磺醯基胺基_2-氧代-乙基胺甲醯基）-甲基】-2-(2 -象-苯基）-乙基】-胺基甲酸第三· 丁酯 96151-doc -83- 200523234(R) -2-Amino-N-methyl-3-pyridin-2-yl-propionamine is (R) -2-third-butoxycarbonylamino-3-pyridin-2-yl -Propionic acid is made into its TFA salt. The method used was the same as for the preparation of intermediate 7, except that 4 N HC1 / dioxane was replaced by 2: 1 DCM: TFA in the deprotection step. The product was a brown oil body; MS m / z 202 (M + Na) +, 180 (MH) +. Intermediate 18: ((R) -1-[((R) -1_benzyl-2-methanesulfonamidoamino_2-oxo-ethylaminomethylamidino) -methyl] -2- (2-Like-Phenyl) -Ethyl] -carbamic acid tert-butyl ester 96151-doc -83- 200523234

於中間體5(200¾克，0.45¾莫耳）於X)CM(5毫升）内的授 拌的溶液中加DMAP(489毫克，1.8毫莫耳），甲烷磺醯胺 (51毫克，0.54毫莫耳）及EDC1(331毫克，〇54毫莫耳）。將 此此合物於室溫攪拌16小時，蒸發，殘餘物於DCM&1 M 鹽酸間分開。瘵發有機萃取物至乾。殘餘物用MPLc於二 氧化石夕（Isco Companion® ;用 5% Me〇H/DCM 洗離）上純 _ 化’得膠體。此膠體進一步用Is〇luted)RNHdi，用20%甲 醇/DCM洗，並用5%乙酸：1〇%甲醇：85〇/〇 DCM洗離純 化。經用醚再濃縮後，所得標題化合物為無色固體（58毫 克，25%)。4 NMR (3〇〇 MHz, DMSO) δ: 1·13 (s，9H)， 2.13-2.33 (m? 2H)，2.53 (s，m)，2.67-2.85 (m，2H)，2.92- 3.10(m，4H)，3.92(s，lH)，4.44(m，lH)，6.57(t，lH)，6.96-7.29 (m，9H)，8.02 (m，1H)，12 〇7 (s，1H);⑽ m/z 544 · (M+Na)+，522 (MH)+。 實例38 · 1-{【(3R)_3_胺基_4_(2_氟苯基）丁醯基】胺基丨N_甲 基環戊烷羧醯胺鹽酸豊To a stirred solution of intermediate 5 (200 ¾ g, 0.45 ¾ mole) in X) CM (5 ml) was added DMAP (489 mg, 1.8 mmol) and methanesulfonamide (51 mg, 0.54 mmol). Mol) and EDC1 (331 mg, 054 millimoles). The mixture was stirred at room temperature for 16 hours, evaporated, and the residue was partitioned between DCM & 1 M hydrochloric acid. Burst the organic extract to dryness. The residue was purified with MPLc on silica (Isco Companion®; washed off with 5% MeOH / DCM) to obtain a colloid. This colloid was further purified with Isolute) RNHdi, washed with 20% methanol / DCM, and washed with 5% acetic acid: 10% methanol: 850 / 〇 DCM. After reconcentration with ether, the title compound was obtained as a colorless solid (58 mg, 25%). 4 NMR (300 MHz, DMSO) δ: 1.13 (s, 9H), 2.13-2.33 (m? 2H), 2.53 (s, m), 2.67-2.85 (m, 2H), 2.92- 3.10 ( m, 4H), 3.92 (s, 1H), 4.44 (m, 1H), 6.57 (t, 1H), 6.96-7.29 (m, 9H), 8.02 (m, 1H), 12 07 (s, 1H) ⑽ m / z 544 · (M + Na) +, 522 (MH) +. Example 38 · 1-{[(3R) _3_amino_4_ (2_fluorophenyl) butylfluorenyl] amino group N-methylcyclopentanecarboxamidine hydrochloride 豊

將[(lR)-l-(2-氟节基⑴κ甲基胺基）緩基]環戊基}胺 基）-3-氧代丙基]胺加甲酸第三_ 丁酯於4 ν HC1及二噁烷内 96l51.doc -84- 200523234 之溶液於室溫攪拌1小時。經真空蒸發並用醚研磨後後分 離出標題化合物（131毫克，1〇〇%)。4 NMR (DMSO d6): 1.56 (m，4H)，1.66-1.99 (m，4H)，2,47-2.52 (m，2H)，2·50 (s，3H)，2.79-2.86 (m，1H)，2.97-3.03 (m，1H)，3.61-3.68 (m，1H)，7.15-7.21 (m，2H)，7.29-7.35 (m，2H)，7.52-7.54 (m，1H)，8.13 (brs，2H)，8.25 (s，1H); MS m/z 322 (MH+)。 中間體21 : 1-{[(3Κ)-3·[(第三·丁氧基羰基）胺基卜4-(2-氟苯 基）丁酿基]胺基}環戊烷羧酸甲酯 於（3R)-3-[(第三，丁氧基羰基）胺基]_4_(2·氟苯基）丁酸 (0.813克，2.80毫莫耳）於DCM(30毫升）内之溶液中加聚合 物支撐的碳化二亞醯胺（4.38克，5·60毫莫耳），聚苯乙烯 二異丙基胺基甲基（2.2克，8.40毫莫耳），HOBt(0.56克， 4·20毫莫耳）及1-胺基環戊烷羧酸甲酯鹽酸鹽（0.50克，2.80 毫莫耳）。任此反應混合物於週邊溫度攪拌丨8小時，過 濾’濾過物用碳酸氫鈉（1〇〇毫升）洗，乾燥（MgS〇4)，濃 縮。殘餘物於40克Biotage二氧化矽上純化，用EtOAc-異 己烧（8-2)洗離，得標題化合物（1 ·〇克，85%)。ipj NMR (CDC13): 1.37 (s, 9H), 1.77-1.80 (m, 4H), 1.89-1.99 (m? 2H)，2.22-2.48 (m，4H)，2.92(d，2H)，3.73(s，3H)，4.05-4·14 (m，1H)，5·42 (brs，1H)，6_13 (brs，1H)，6.98-7.09 (m， 2H)，7.17-7.28 (m，2H) ; MS m/z 445 (M+Na)。 中間體20 : l-{[(3R)-3_[(第三_ 丁氧基羰基）胺基】_4-(2_氟苯 基）丁醯基】胺基}環戊烷羧酸 於l-{[(3R)-3-[(第三-丁氧基羰基）胺基>‘（2·氟苯基）丁 96151.doc •85- 200523234 醯基]胺基}環戊烷羧酸甲酯（中間體21，1〇克，2·36毫莫 耳）於THF(36毫升）及水（1〇毫升）内之溶液中加$水合氮氧 化鐘（0.19克，4.74宅莫耳）於水（7毫升）内之溶液。任反應 混合物於室溫攪拌18小時，蒸發除去揮發性物質，殘餘物 用1N硫酸氫鉀酸化至pH 2。將此水溶液萃取入 EtOAC(2xl50毫升）内，合併有機萃取物，乾燥（MgS〇4)， 濃縮，得標題化合物（0.873克，91%)。lH NMR (DMS〇 d6):1.25(s，9H)，1.61(m，4H)，1.79-1.85 (m，2H)，1.93-2.05 (m，2H)，2.22 (d，2H)，2.57-2.64 (m，1H)，2.78-2.84 (m，1H)，3.95-3.97 (m，1H)，6.58 (d，1H)，7.06 (t，2H)， 7·19-7·23 (m，2H)，8.06 (s，1H)，12.03 (s，1H); MS m/z 431 (M+Na) 〇 中間體19 · [(1R)-1_(2-氟苄基[(甲基胺基）羰基】環 戊基}胺基）-3-氧代丙基】胺基甲酸第三-丁酯Add [(lR) -l- (2-fluorobenzyl ⑴κmethylamino) branyl] cyclopentyl} amino) -3-oxopropyl] amine to tert-butyl formate at 4 ν HC1 And a solution of 96l51.doc -84- 200523234 in dioxane was stirred at room temperature for 1 hour. The title compound (131 mg, 100%) was isolated after evaporation in vacuo and trituration with ether. 4 NMR (DMSO d6): 1.56 (m, 4H), 1.66-1.99 (m, 4H), 2,47-2.52 (m, 2H), 2.50 (s, 3H), 2.79-2.86 (m, 1H ), 2.97-3.03 (m, 1H), 3.61-3.68 (m, 1H), 7.15-7.21 (m, 2H), 7.29-7.35 (m, 2H), 7.52-7.54 (m, 1H), 8.13 (brs , 2H), 8.25 (s, 1H); MS m / z 322 (MH +). Intermediate 21: 1-{[((3Κ) -3 · [(Third · butoxycarbonyl) amino group 4- (2-fluorophenyl) butynyl] amino group} methyl cyclopentanecarboxylate To a solution of (3R) -3-[(third, butoxycarbonyl) amino] -4- (2 · fluorophenyl) butanoic acid (0.813 g, 2.80 mmol) in DCM (30 ml) was added Polymer-supported carbodiimide (4.38 g, 5.60 mmol), polystyrene diisopropylaminomethyl (2.2 g, 8.40 mmol), HOBt (0.56 g, 4.20 Mmol) and methyl 1-aminocyclopentanecarboxylate hydrochloride (0.50 g, 2.80 mmol). The reaction mixture was allowed to stir at ambient temperature for 8 hours, filtered, and the filtrate was washed with sodium bicarbonate (100 ml), dried (MgS04), and concentrated. The residue was purified on 40 g of Biotage silica and washed off with EtOAc-isohexane (8-2) to give the title compound (1.0 g, 85%). ipj NMR (CDC13): 1.37 (s, 9H), 1.77-1.80 (m, 4H), 1.89-1.99 (m? 2H), 2.22-2.48 (m, 4H), 2.92 (d, 2H), 3.73 (s , 3H), 4.05-4 · 14 (m, 1H), 5.42 (brs, 1H), 6_13 (brs, 1H), 6.98-7.09 (m, 2H), 7.17-7.28 (m, 2H); MS m / z 445 (M + Na). Intermediate 20: l-{[((3R) -3 _ [(third_butoxycarbonyl) amino group] _4- (2_fluorophenyl) butylfluorenyl] amino group} cyclopentanecarboxylic acid in l-{[ (3R) -3-[(Third-butoxycarbonyl) amino group> '(2.fluorophenyl) butane 96151.doc • 85- 200523234 fluorenyl] amino} cyclopentanecarboxylic acid methyl ester ( Intermediate 21, 10 g, 2.36 millimoles) in a solution of THF (36 ml) and water (10 ml) was added with hydrated nitrogen oxide bell (0.19 g, 4.74 mol) in water 7 ml). The reaction mixture was stirred at room temperature for 18 hours, the volatile materials were removed by evaporation, and the residue was acidified to pH 2 with 1N potassium hydrogen sulfate. This aqueous solution was extracted into EtOAC (2 x 150 ml), the organic extracts were combined, dried (MgS04), and concentrated to give the title compound (0.873 g, 91%). lH NMR (DMSOd6): 1.25 (s, 9H), 1.61 (m, 4H), 1.79-1.85 (m, 2H), 1.93-2.05 (m, 2H), 2.22 (d, 2H), 2.57-2.64 (m, 1H), 2.78-2.84 (m, 1H), 3.95-3.97 (m, 1H), 6.58 (d, 1H), 7.06 (t, 2H), 7.19-7 · 23 (m, 2H) , 8.06 (s, 1H), 12.03 (s, 1H); MS m / z 431 (M + Na) 〇 Intermediate 19 · [(1R) -1_ (2-fluorobenzyl [(methylamino) carbonyl ] Cyclopentyl} amino) -3-oxopropyl] aminocarboxylic acid third-butyl ester

以類似中間體21所述工序用{第三-丁氧基羰 基）胺基]-4-(2-氟苯基）丁醯基]胺基}環戊烷羧酸（中間體 20 ’ 0.218克，0.534毫莫耳）及甲基胺鹽酸鹽（37.2毫克， 0.513毫莫耳）製得標題化合物（〇142克，63%)。iH NMR (CDC13): 1.38 (s，9H)，1.68-1.77 (m，4H)，1.90-1.98 (m， 2H)，2.21-2.51 (m，2H)，2.41-2.51 (m，2H)，2·79 (d，3H)， 2.91 (d，2H)，4.05-4.15 (m，1H)，5.24 (d，1H)，6.06 (s，1H)， 6.87 (brs，1H)，7.00-7.11 (m，2H)，7.21-7.23 (m，2H); MS m/z 578 (M+Na)。 實例39 : 1_{[(3R)_3-胺基_4_(2-氟苯基）丁醯基】胺基卜N-苄 96151.doc -86 - 200523234 基環戊烷羧醯胺 實例40 ·· l-{[(3R)-3_胺基_4-(2-氟苯基）丁醯基】胺基卜Ν-{2· [(丙基磺醯基）胺基】乙基}環戊烷羧醯胺 實例41 : l-{[(3R)-3-胺基-4-(2_氟苯基）丁醯基】胺基}-Ν-{2-[4-(胺基磺醯基）苯基】乙基}環戊烷羧醯胺 實例39，40及41係如實例38所述，分別用中間體22，23 及24製得。{Third-butoxycarbonyl) amino] -4- (2-fluorophenyl) butylfluorenyl] amino} cyclopentanecarboxylic acid (intermediate 20 '0.218 g, 0.534 Mmol) and methylamine hydrochloride (37.2 mg, 0.513 mmol) to give the title compound (1422 g, 63%). iH NMR (CDC13): 1.38 (s, 9H), 1.68-1.77 (m, 4H), 1.90-1.98 (m, 2H), 2.21-2.51 (m, 2H), 2.41-2.51 (m, 2H), 2 79 (d, 3H), 2.91 (d, 2H), 4.05-4.15 (m, 1H), 5.24 (d, 1H), 6.06 (s, 1H), 6.87 (brs, 1H), 7.00-7.11 (m , 2H), 7.21-7.23 (m, 2H); MS m / z 578 (M + Na). Example 39: 1 _ {[(3R) _3-Amino_4_ (2-fluorophenyl) butylfluorenyl] amino group N-benzyl 96151.doc -86-200523234 Examples of cyclopentanecarboxamides 40 ·· l- {[((3R) -3_amino_4- (2-fluorophenyl) butyryl)] amino group N- {2 · [(propylsulfonyl) amino] ethyl} cyclopentanecarboxamide Example 41: l-{[(3R) -3-amino-4- (2-fluorophenyl) butylfluorenyl] amino} -N- {2- [4- (aminosulfonyl) phenyl] ethyl Cyclopentanecarboxamide Examples 39, 40 and 41 were prepared as described in Example 38 using intermediates 22, 23 and 24, respectively.

實例 R11 lHNMR(DMSO) MS m/z 39 -CH2Ph 1.59 (m，4H)，1.75-2.13 (m，4H)，2.78-2.86 (m， 1H), 2.94-3.01 (m, 1H), 3.28-3.35 (m, 2H), 3.61-3.69 (m，1H)，4.21 (t，1H)，7.09-7.35 (m， 9H), 8.08 (brs, 2H), 8.17 (t, 1H), 8.32 (s,lH). 398 (MH)+ 40 -(CH2)2NHS02Pr 0.93 (t, 3H), 1.56-1.81 (m, 8H), 1.88-2.03 (m, 2H)，2.83-3.09 (m，8H)，3.25-3.31 (m，2H)， 3.61-3.65 (m，1H)，6.95 (t, 1H)，7.14-7.21 (m， 2H)，7.30-7.35 (m，2H), 7.69 (t，1H)，8.10 (brs， 2H)，8.34 (s，1H)， 457 (MH)+ 41 1.56 (m，4H)，1.67-2.00 (m，4H)，2.72 (t，2H)， 2.81-2.89 (m，1H)，2.97-3.04 (m，1H)，3.53-3.68 (m，3H)，7.15-7.21 (m，2H)，7.26-7.36 (m，4H)， 7.71 (d，2H)，8.12 (brs，2H)，8.25 (s，1H). 491 (MH)+ # 中間體22 : [(1R)-3_({1-[(苄基胺基）羰基】環戊基}胺基）-1- (2 -氣节基）-3-氧代丙基】胺基曱酸第三-丁 S旨 中間艘23 : [(1R)_1_(2_氣节基）-3•氧代_3_({1-[({2 -丙基確酿 9615l.doc -87- 200523234 基）胺基】乙基}胺基）羰基】環戊基}胺基）丙基】胺基甲酸第三 丁酯 中間體24 :【（lR)_3-({l_【（{2-[4_(胺基磺醯基）苯基】乙基}胺 基）羰基】環戊基}胺基）_1-(2-氟苄基）-3-氧代丙基】胺基甲酸 第三-丁酯 中間體22-24是根據中間體19所述方法用中間體20及有 關商業上可購得的胺（中間體22及24所用）或N-(2-胺基乙 基）丙烧-1-石黃醯胺（CAS No:53673-27-l; M.S. Large and L.H. Smith，J· Med· Chem. 1982, 25，1286)(中間體23所用） 製備。N-(2-胺基乙基）丙烷-1-磺醯胺可以類似Eur· Pat· Appl·，EP259092所述製備N-(2-胺基乙基）丙烷-1-磺醯胺方 法製備。Example R11 lHNMR (DMSO) MS m / z 39 -CH2Ph 1.59 (m, 4H), 1.75-2.13 (m, 4H), 2.78-2.86 (m, 1H), 2.94-3.01 (m, 1H), 3.28-3.35 (m, 2H), 3.61-3.69 (m, 1H), 4.21 (t, 1H), 7.09-7.35 (m, 9H), 8.08 (brs, 2H), 8.17 (t, 1H), 8.32 (s, lH ). 398 (MH) + 40-(CH2) 2NHS02Pr 0.93 (t, 3H), 1.56-1.81 (m, 8H), 1.88-2.03 (m, 2H), 2.83-3.09 (m, 8H), 3.25-3.31 (m, 2H), 3.61-3.65 (m, 1H), 6.95 (t, 1H), 7.14-7.21 (m, 2H), 7.30-7.35 (m, 2H), 7.69 (t, 1H), 8.10 (brs , 2H), 8.34 (s, 1H), 457 (MH) + 41 1.56 (m, 4H), 1.67-2.00 (m, 4H), 2.72 (t, 2H), 2.81-2.89 (m, 1H), 2.97 -3.04 (m, 1H), 3.53-3.68 (m, 3H), 7.15-7.21 (m, 2H), 7.26-7.36 (m, 4H), 7.71 (d, 2H), 8.12 (brs, 2H), 8.25 (s, 1H). 491 (MH) + # Intermediate 22: [(1R) -3 _ ({1-[(benzylamino) carbonyl] cyclopentyl} amino) -1--1- (2- Group) -3-oxopropyl] amino sulfonic acid third-butyric acid intermediate group 23: [(1R) _1_ (2_Aristoloyl) -3 • oxo_3 _ ({1-[({ 2-propyl group 9615l.doc -87- 200523234 group) amino group} ethyl} amino group) carbonyl ] Cyclopentyl} Amino) propyl] Thirty-Butyl Carbamate Intermediate 24: [(lR) _3-({l _ [({2- [4_ (Aminosulfonyl) phenyl) ethyl] } Amine) carbonyl] Cyclopentyl} Amine) _1- (2-fluorobenzyl) -3-oxopropyl] aminocarboxylic acid third-butyl ester intermediates 22-24 are described according to intermediate 19 Method uses Intermediate 20 and related commercially available amines (used for Intermediates 22 and 24) or N- (2-aminoethyl) propan-1-carboxamine (CAS No: 53673-27- l; MS Large and LH Smith, J. Med. Chem. 1982, 25, 1286) (used for Intermediate 23). N- (2-aminoethyl) propane-1-sulfonamide can be prepared similarly to the method described in Eur. Pat. Appl., EP259092 for the preparation of N- (2-aminoethyl) propane-1-sulfonamide.

中間體 R11 lHNMR(CDCl3) MS m/z 22 -CH2Ph 1.37 (s, 9H), 1.73-2.00 (m, 6H), 2.26-2.44 (m, 4H), 2.81 (d, 2H), 3.88-3.92 (m，1H)，4.36-4.52 (m，2H)，4.88 (d， 1H)，6.07 (s，1H)，6.98-7.23 (m，8H). 520 M+Na 23 -(CH2)2NHS02Pr 1.05 (t，3H)，1.37 (s，9H)，1.67-1.90 (m， 9H), 2.23-2.35 (m, 2H), 2.47-2.53 (m, 1H)，2.63-2.74 (m，1H)，2.89-3.04 (m， 579 M+Na 96151.doc -88- 200523234 4H)，3.25-3.38 (m，3H)，4.09 (m，1H)， 5.50 (brs，1H)，5.58 (brs，1H)，6.43 (brs， 1H)，6.69 (brs，1H)，6.99-7.01 (m，2H)， 7.20-7.22 (m, 2H). 24 "XL so2nh2 (DMSO): 1.26 (s, 9H), 1.54-1.59 (m, 4H), 1.73-1.81 (m, 2H), 1.89-1.97 (m, 2H)，2.24 (d，2H)，2.68-2.80 (m，4H)， 3.20-3.28 (m，2H)，3.94-4.01 (m，1H)， 6.62 (d, 1H), 7.09 (t, 2H), 7.18-7.24 (m, 4H)，7.32 (d，2H)，7.49-7.53 (m，1H)， 7.69 (d，2H)· 613 M+NaIntermediate R11 lHNMR (CDCl3) MS m / z 22 -CH2Ph 1.37 (s, 9H), 1.73-2.00 (m, 6H), 2.26-2.44 (m, 4H), 2.81 (d, 2H), 3.88-3.92 ( m, 1H), 4.36-4.52 (m, 2H), 4.88 (d, 1H), 6.07 (s, 1H), 6.98-7.23 (m, 8H). 520 M + Na 23-(CH2) 2NHS02Pr 1.05 (t , 3H), 1.37 (s, 9H), 1.67-1.90 (m, 9H), 2.23-2.35 (m, 2H), 2.47-2.53 (m, 1H), 2.63-2.74 (m, 1H), 2.89-3.04 (m, 579 M + Na 96151.doc -88- 200523234 4H), 3.25-3.38 (m, 3H), 4.09 (m, 1H), 5.50 (brs, 1H), 5.58 (brs, 1H), 6.43 (brs , 1H), 6.69 (brs, 1H), 6.99-7.01 (m, 2H), 7.20-7.22 (m, 2H). 24 " XL so2nh2 (DMSO): 1.26 (s, 9H), 1.54-1.59 (m , 4H), 1.73-1.81 (m, 2H), 1.89-1.97 (m, 2H), 2.24 (d, 2H), 2.68-2.80 (m, 4H), 3.20-3.28 (m, 2H), 3.94-4.01 (m, 1H), 6.62 (d, 1H), 7.09 (t, 2H), 7.18-7.24 (m, 4H), 7.32 (d, 2H), 7.49-7.53 (m, 1H), 7.69 (d, 2H ) 613 M + Na

實例42 : 1-[(R)_3_胺基-4-(2-氟-苯基）-丁醯基胺基]-環己烷 羧酸4-氟-节基醯胺 實例43 : l-[(R)-3_胺基-4-(2-氟-苯基）-丁醯基胺基卜環己烷 羧酸異丙基醯胺Example 42: 1-[(R) _3-Amino-4- (2-fluoro-phenyl) -butylamidinoamino] -cyclohexanecarboxylic acid 4-fluoro-benzylamidoamine Example 43: l-[( R) -3_Amino-4- (2-fluoro-phenyl) -butylamidinoaminocyclohexanecarboxylic acid isopropylamidoamine

實例44 : 1 -[(R)-3-胺基- 4-(2 -氣-本基）-丁酿基胺基】"環己烧 羧酸[2-(4-胺磺醯基·苯基）已基】-醯胺 實例45 : l-[(R)-3-胺基-4-(4-氟-苯基）_丁醯基胺基卜環己烷 羧酸丨2-(4-胺磺醯基-笨基）_乙基】-醯胺 實例46 : l-[(R)-3-胺基_4-(2-氟-苯基）-丁醯基胺基】·環己烷 羧酸環丙基甲基醯胺 實例47 : l-[(R)-3-胺基氟-苯基）-丁醯基胺基】-環己烷 羧酸甲基醯胺 實例42-47是以實例以所述相同方法分別用中間體25_30 製備。 96151.doc -89- 14 200523234Example 44: 1-[(R) -3-amino group 4- (2 -gas-benzyl) -butynylamino group] " Cyclohexyl carboxylic acid [2- (4-aminesulfonyl group · Phenyl) hexyl] -fluorenamine Example 45: l-[(R) -3-amino-4- (4-fluoro-phenyl) _butanylaminocyclocyclocarboxylic acid 丨 2- (4- Aminosulfenyl-benzyl) _ethyl] -fluorenamine Example 46: l-[(R) -3-amino_4- (2-fluoro-phenyl) -butanylamino]] cyclohexanecarboxyl Acid Cyclopropylmethylamidamine Example 47: l-[(R) -3-aminofluoro-phenyl) -butylamidinoamino] -cyclohexanecarboxylic acid methylamidamine Examples 42-47 are examples The same method was prepared using intermediates 25-30, respectively. 96151.doc -89- 14 200523234

RR

RR

實例 R11 R12 R13 R14 lR NMR (DMSO) MS m/z 42 F H H 1.00-1.64 (m，8H)，1.84-1.99 (dd， 2H)，2.47-2.52 (m，2H)，2.76-2.82 (m, 1H), 2.90-2.95 (m, 1H), 3.51-3.58 (m，1H)，4.12-4.17 (m，2H)， 6.99 (t，2H)，7.08-7.17 (m，4H)， 7.23-7.28 (m，2H)，7.90 (s，1H)， 8.02-8.05 (m，3H). 429 _)+ 43 -ch(ch3)2 F H H 1.01 (t，6H)，0.99-1.68 (m，8H)， 1.90-2.01 (dd，2H), 2.56 (d，2H)， 2.88-2.97 (m, 1H), 3.00-3.04 (m, 1H)，3.61-3.66 (m，1H)，3.77-3.81 (m, 1H), 7.17-7.24 (m, 3H), 7.33-7.39 (m, 2H), 7.81 (s, 1H), 8.15 (brs, 2H). 364 (MH)+ 44 F H H 1.06-1.64 (m, 10H), 1.76-1.97 (m, 2H), 2.73 (t, 2H), 2.83-2.93 (m, 1H), 2.96-3.03 (m, 1H), 3.22-3.24 (m, 2H), 3.62-3.66 (m, 1H), 7.16-7.23 (m5 2H), 7.26 (s, 1H), 7.30-7.37 (m, 4H)，7.62-7.66 (m，1H), 7.71 (d， 2H)，7.88 (s，1H)，8.06 (brs，3H). 504 (MH)+ 96151.doc -90- 200523234Examples R11 R12 R13 R14 lR NMR (DMSO) MS m / z 42 FHH 1.00-1.64 (m, 8H), 1.84-1.99 (dd, 2H), 2.47-2.52 (m, 2H), 2.76-2.82 (m, 1H ), 2.90-2.95 (m, 1H), 3.51-3.58 (m, 1H), 4.12-4.17 (m, 2H), 6.99 (t, 2H), 7.08-7.17 (m, 4H), 7.23-7.28 (m , 2H), 7.90 (s, 1H), 8.02-8.05 (m, 3H). 429 _) + 43 -ch (ch3) 2 FHH 1.01 (t, 6H), 0.99-1.68 (m, 8H), 1.90- 2.01 (dd, 2H), 2.56 (d, 2H), 2.88-2.97 (m, 1H), 3.00-3.04 (m, 1H), 3.61-3.66 (m, 1H), 3.77-3.81 (m, 1H), 7.17-7.24 (m, 3H), 7.33-7.39 (m, 2H), 7.81 (s, 1H), 8.15 (brs, 2H). 364 (MH) + 44 FHH 1.06-1.64 (m, 10H), 1.76- 1.97 (m, 2H), 2.73 (t, 2H), 2.83-2.93 (m, 1H), 2.96-3.03 (m, 1H), 3.22-3.24 (m, 2H), 3.62-3.66 (m, 1H), 7.16-7.23 (m5 2H), 7.26 (s, 1H), 7.30-7.37 (m, 4H), 7.62-7.66 (m, 1H), 7.71 (d, 2H), 7.88 (s, 1H), 8.06 (brs , 3H). 504 (MH) + 96151.doc -90- 200523234

so2nh2so2nh2

47 CH,47 CH,

FF

H H H U8-1.64 (m，10H)，1.86-1.98 (m， 2H), 2.71-2.82 (m, 3H), 2.91-2.98 (m，lH)，3.21-3.27(m，2H)，3.57-3.59 (m，1H)，7.16 (t，2H)，7.26-7.28 (m，4H)，7.33 (d，2H)，7.64 (t，1H)， 7.71 (d，2H)，7.87 (s，1H)，8.01 (brs， 2H). 504 (MH)+ 0.02-0.04 (m，2H)，0.18-0.22 (m， 376 2H), 0.70-0.78 (m, 1H), 1.05-1.58 _)+ (m，9H)，1.76-1.93 (dd，2H)，2.44 (d， 2H), 2.76-2.94 (m, 3H), 3.49-3.54 (m，lH)，7.02-7.12(m，2H)，7.22- 7.28 (m，2H)，7.40 (t，1H)，7.77 (s， 1H)，8.02 (brs，2H)· 1.13-1.69 (m，8H)，1.90-2.02 (dd， 336 2H), 2.53-2.60 (m, 5H), 2.86-2.95 (MH)+ (m, 1H), 3.01-3.06 (m, 1H), 3.62- 3.67 (m，1H)，7.19-7.24 (m，2H)， 7.33-7.43 (m，2H)，7.48-7.50 (m， 1H)，7.91 (s，1H)，8.15 (brs，2H). 貫例25，26，29及3〇县田山 ^ 疋用中間體47及有關的商業上可購 得的胺以中間體1 9所沭ia m + 吓述相冋方法製備，例外的是： 〇化合物疋以反相色層分析5·95%乙腈，95_5%水， 0J%TFA純化。 0於中間體30中，有去保護出現。 中間體27及28是以類似方法用1-胺基-環己烷羧酸[2-(4-胺磺醯基·苯基）·乙基]•醯胺製備 96151.doc -91· 200523234HHH U8-1.64 (m, 10H), 1.86-1.98 (m, 2H), 2.71-2.82 (m, 3H), 2.91-2.98 (m, lH), 3.21-3.27 (m, 2H), 3.57-3.59 ( m, 1H), 7.16 (t, 2H), 7.26-7.28 (m, 4H), 7.33 (d, 2H), 7.64 (t, 1H), 7.71 (d, 2H), 7.87 (s, 1H), 8.01 (brs, 2H). 504 (MH) + 0.02-0.04 (m, 2H), 0.18-0.22 (m, 376 2H), 0.70-0.78 (m, 1H), 1.05-1.58 _) + (m, 9H) , 1.76-1.93 (dd, 2H), 2.44 (d, 2H), 2.76-2.94 (m, 3H), 3.49-3.54 (m, lH), 7.02-7.12 (m, 2H), 7.22- 7.28 (m, 2H), 7.40 (t, 1H), 7.77 (s, 1H), 8.02 (brs, 2H), 1.13-1.69 (m, 8H), 1.90-2.02 (dd, 336 2H), 2.53-2.60 (m, 5H ), 2.86-2.95 (MH) + (m, 1H), 3.01-3.06 (m, 1H), 3.62- 3.67 (m, 1H), 7.19-7.24 (m, 2H), 7.33-7.43 (m, 2H) , 7.48-7.50 (m, 1H), 7.91 (s, 1H), 8.15 (brs, 2H). Examples 25, 26, 29 and 30 of Tianshan County 疋 中间体 Intermediate 47 and related commercially available The amine was prepared by the method of ia m + in the intermediate 19, with the following exceptions: 〇 Compound 疋 analysis by reverse phase chromatography 5.95% acetonitrile, 95_5% water, 0J% TFA purification. 0 In intermediate 30, deprotection occurs. Intermediates 27 and 28 were prepared in a similar manner using 1-amino-cyclohexanecarboxylic acid [2- (4-aminesulfonyl · phenyl) · ethyl] • fluorenamine 96151.doc -91 · 200523234

中間體 R11 R12 R13 R14 ^NMRCDMSO) MS m/z 25 % F H H 1.19-1.26 (m, 10H), 1.43-1.62 (m, 7H)，1.91-2.07 (dd，2H)，2.24-2.41 (m, 2H), 2.61-2.67 (m, 1H), 2.78-2.85 (m, 1H), 2.78-2.85 (m, 1H), 3.95-4.00 (m, 1H), 4.14-4.24 (m, 2H)，6.63 (d，1H)，7.01-7.11 (m， 4H)，7.17-7.22 (m，4H)，7.43 (s， 1H)，7.92 (t，1H). 552 M+Na « 26 -CH(CH3)2 F H H 0.97 (d，6H)，U9-1.61 (m，17H)， 2.21-2.38 (m, 2H), 2.62-2.70 (m, 1H)，2.80-2.86 (m，1H)，3.71-3.81 (m，1H)，3.96-4.03 (m, 1H)，6.63 (d，1H)，6·98 (d，1H)，7.09 (t，2H)， 7.19-7.26 (m, 3H). 486 M+Na 41 27 F H H 603 M-H 28 H F H 603 M-H 29 >〇<] F H H 0.00-0.04 (m，2H)，0.19-0.25 (m， 2H), 0.72-0.78 (m, 1H), 1.13-1.53 498 M+Na 96151.doc -92- 200523234 (m，17H)，1.83-1.96(m，2H)，2.19-2.30 (m，2H)，2.56-2.63 (m，1H)， 2.73-2.86 (m，3H)，3.91-3.95 (m， 1H)，6.57 (d，1H)，7.03 (t，2H)， 7.15 (t，2H)，7.24 (t，1H)，7.28 (s， 1H) 30 -ch3 F H H 458 M+NaIntermediate R11 R12 R13 R14 ^ NMRCDMSO) MS m / z 25% FHH 1.19-1.26 (m, 10H), 1.43-1.62 (m, 7H), 1.91-2.07 (dd, 2H), 2.24-2.41 (m, 2H ), 2.61-2.67 (m, 1H), 2.78-2.85 (m, 1H), 2.78-2.85 (m, 1H), 3.95-4.00 (m, 1H), 4.14-4.24 (m, 2H), 6.63 (d , 1H), 7.01-7.11 (m, 4H), 7.17-7.22 (m, 4H), 7.43 (s, 1H), 7.92 (t, 1H). 552 M + Na «26 -CH (CH3) 2 FHH 0.97 (d, 6H), U9-1.61 (m, 17H), 2.21-2.38 (m, 2H), 2.62-2.70 (m, 1H), 2.80-2.86 (m, 1H), 3.71-3.81 (m, 1H) , 3.96-4.03 (m, 1H), 6.63 (d, 1H), 6.98 (d, 1H), 7.09 (t, 2H), 7.19-7.26 (m, 3H). 486 M + Na 41 27 FHH 603 MH 28 HFH 603 MH 29 > 〇 <] FHH 0.00-0.04 (m, 2H), 0.19-0.25 (m, 2H), 0.72-0.78 (m, 1H), 1.13-1.53 498 M + Na 96151.doc -92- 200523234 (m, 17H), 1.83-1.96 (m, 2H), 2.19-2.30 (m, 2H), 2.56-2.63 (m, 1H), 2.73-2.86 (m, 3H), 3.91-3.95 ( m, 1H), 6.57 (d, 1H), 7.03 (t, 2H), 7.15 (t, 2H), 7.24 (t, 1H), 7.28 (s, 1H) 30 -ch3 FHH 458 M + Na

中間體48 : l_{[(3R)-3-[(第三-丁氧基羰基）胺基】_4_(2_氟苯 基）丁醯基】胺基}環己烷羧酸甲酯 根據中間體21所述方法用（3R)-3-[(第三·丁氧基羰基）胺 基]-4-(2-氟苯基）丁酸及1-胺基環己烷羧酸甲酯（CAS No : 4507-57-7，見 Synthesis 2002，14，2023-2036)製備，產出 率 77%。4 NMR (CDC13): 1.37 (s，9H)，1.40-1.51 (m，6H)， 1.80-2.05 (m，4H)，2.35-2.51 (m，2H)，2.93 (d，2H)，3.72 (s， 3H)，4.06-4.16(m，lH)，5.40(brs，lH)，5.91(brs，lH)，6.99-7·〇9 (m，2H)，7.17-7.29 (m，2H); MS m/z 459 (M+Na)。 中間體47 : 1_{[(3R)_3_[(第三·丁氧基幾基）胺基】_4_(2_氣苯 基）丁醜基】胺基}環己垸竣暖 根據中間體20所述方、、土 m ι 去用中間體48製備，產出率83%。 H NMR (DMSO d6)： i ls , •i5、1.19(m，lH)，1.26(s，9H)，1.46- L63 (m5 7H)5 1.85-1.99 r / ”（rn，2H)，2.28 (d，2H)，2.58-2.66 (m，1H)，2.81-2.85 (m 1 v 5 3.95-3.97 (m, 1H), 6.60 (d, (m，2H)，7·74 (s，1H); MS m/z 1H)，7.07 (t，2H)，7·2(Μ·24 421(ΜΗ·) 〇 96151.doc -93. 200523234 1-胺基-環己烷羧酸[2-(4-胺磺醯基-苯基）_乙基】_醯胺 將HC1於二噁烷内的溶液（4M，4毫升）加於胺磺 醯基-苯基乙基胺甲醯基扒環己基}_胺基甲酸第三_丁基酯 (338毫克’ 0.795毫莫耳）内。此混合物於室溫攪拌3小時， 然後蒸發去溶劑，得蠟樣固體，將其載於1〇克％又柱體上 純化，用甲醇洗及用甲醇氨洗離。此工序所製之胺為無色 固體（245 毫克，95%)。MS m/z 326(MH+)。 {l-[2-(4-胺磺醯基-苯基 > 乙基胺甲醯基】_環己基卜胺基甲 酸第三-丁基酯 於第二-丁氧基戴基-1-胺基-1-環己烧竣酸（〇· 243克，1.0 毫莫耳）於乙腈（5毫升）内的攪拌的溶液中加η〇βτ(0.162 克，1.2毫莫耳），EDC1(0.230克，12毫莫耳），三乙基胺 (〇·3毫升’ 2·2毫莫耳）及4-(2-胺基乙基）苯磺醯胺（0·20克， 1 ·0毫莫耳）。此反應混合物於微波爐内加熱5分鐘。混合物 用醋酸乙酯稀釋，用！ ！^硫酸氫鉀水溶液（100毫升）洗。將 所得懸浮液過濾，有機層相繼用碳酸氫鈉水溶液及鹽水 洗。然後將溶液用硫酸鎂乾燥，蒸發，得無色固體（〇.338 克’80%)。咕應尺（麗8〇(16):1〇9_126(111，2印，129- 1.47 (m，13Η)，1.50-1.67 (m，2Η)，1.74-1.94 (m，2Η)，2.74 (t，2H)，3.20-3.37(m，2H)，6.51(s，iH)，7.25(s，2H)，7.32- 7.48 (m，3H)，7.71 (d，2H); MS m/z 448 (M+Na)。 實例48 : 1_{[(3R>3_胺基冬(2-氣苯基）丁醯基]胺基卜N_甲 基_4_苯基環己烷羧醯胺 96151.doc -94· 200523234Intermediate 48: l _ [[(3R) -3-[(Third-butoxycarbonyl) amino group] _4_ (2_fluorophenyl) butylfluorenyl] amino group} methyl cyclohexanecarboxylate according to intermediate 21 The method uses (3R) -3-[(third · butoxycarbonyl) amino] -4- (2-fluorophenyl) butanoic acid and 1-aminocyclohexanecarboxylic acid methyl ester (CAS No : 4507-57-7, see Synthesis 2002, 14, 2023-2036), yield 77%. 4 NMR (CDC13): 1.37 (s, 9H), 1.40-1.51 (m, 6H), 1.80-2.05 (m, 4H), 2.35-2.51 (m, 2H), 2.93 (d, 2H), 3.72 (s , 3H), 4.06-4.16 (m, 1H), 5.40 (brs, 1H), 5.91 (brs, 1H), 6.99-7.09 (m, 2H), 7.17-7.29 (m, 2H); MS m / z 459 (M + Na). Intermediate 47: 1 _ {[(3R) _3 _ [(Third · butoxyquinyl) amino group] _4_ (2_Gaphenyl) butyryl group) Amine group} Cyclohexane is completed according to the method described in Intermediate 20 , And soil m ι were prepared with intermediate 48, and the yield was 83%. H NMR (DMSO d6): i ls, • i5, 1.19 (m, lH), 1.26 (s, 9H), 1.46- L63 (m5 7H) 5 1.85-1.99 r / ”(rn, 2H), 2.28 (d , 2H), 2.58-2.66 (m, 1H), 2.81-2.85 (m 1 v 5 3.95-3.97 (m, 1H), 6.60 (d, (m, 2H), 7.74 (s, 1H); MS m / z 1H), 7.07 (t, 2H), 7.2 (M · 24 421 (ΜΗ ·) 〇96151.doc -93. 200523234 1-amino-cyclohexanecarboxylic acid [2- (4-amine Sulfonyl-phenyl) _ethyl] _fluorenamine A solution of HC1 in dioxane (4M, 4 ml) was added to the amine sulfonyl-phenylethylamine methylsulfanylcyclohexyl} _amine Tert-butyl carbamate (338 mg '0.795 mmol). The mixture was stirred at room temperature for 3 hours, and then the solvent was evaporated to give a waxy solid, which was loaded on a 10 g% column. Purified, washed with methanol and washed with methanol ammonia. The amine produced in this step was a colorless solid (245 mg, 95%). MS m / z 326 (MH +). {L- [2- (4-Aminesulfonium -Phenyl > ethylaminomethyl] -Cyclohexylpyridinecarboxylic acid third-butyl ester in the second-butoxydynyl-1-amino-1-cyclohexanoic acid (〇 · 243 g, 1.0 mmol) in acetonitrile (5 ml) To the stirred solution were added ηββτ (0.162 g, 1.2 mmol), EDC1 (0.230 g, 12 mmol), triethylamine (0.3 mL '2.2 mmol) and 4- ( 2-Aminoethyl) benzenesulfonamide (0.20 g, 1.0 mmol). The reaction mixture was heated in a microwave oven for 5 minutes. The mixture was diluted with ethyl acetate and used! ^ Potassium hydrogen sulfate aqueous solution (100 ml). The resulting suspension was filtered, and the organic layer was washed successively with an aqueous solution of sodium bicarbonate and brine. The solution was then dried over magnesium sulfate and evaporated to give a colorless solid (0.338 g '80%). (Li 80 (16): 10-9_126 (111, 2 India, 129-1.47 (m, 13Η), 1.50-1.67 (m, 2Η), 1.74-1.94 (m, 2Η), 2.74 (t, 2H) , 3.20-3.37 (m, 2H), 6.51 (s, iH), 7.25 (s, 2H), 7.32- 7.48 (m, 3H), 7.71 (d, 2H); MS m / z 448 (M + Na) Example 48: 1 _ {[(3R > 3-Amino (2-aminophenyl) butylfluorenyl] amino group N_methyl_4_phenylcyclohexanecarboxamide 96151.doc -94 · 200523234

實例48是用中間體35以實例38所述方法製備，產出率 74%。W NMR (DMSO d6): 1.60-1.83 (m，7H)，2·08 (d，1H)，2.22 (m，1H)， 2.55 (d, 3H), 2.59-2.61 (m5 2H)5 2.86-2.94 (m? 1H), 3.00-3.07 (m5 1H), 3.63-3.66 (m，1H)，7.13-7.40 (m，8H)，7.56 (d，1H)，8·00 (s，1H)，8.12 (brs，2H); MS m/z 412 (MH+)。 中間體31 ·· 1-{[(9H-芴-9-基甲氧基）羰基】胺基}_4-苯基環己 烷羧酸Example 48 was prepared using Intermediate 35 using the method described in Example 38 with a yield of 74%. W NMR (DMSO d6): 1.60-1.83 (m, 7H), 2.08 (d, 1H), 2.22 (m, 1H), 2.55 (d, 3H), 2.59-2.61 (m5 2H) 5 2.86-2.94 (m? 1H), 3.00-3.07 (m5 1H), 3.63-3.66 (m, 1H), 7.13-7.40 (m, 8H), 7.56 (d, 1H), 8.00 (s, 1H), 8.12 ( brs, 2H); MS m / z 412 (MH +). Intermediate 31 ·· 1-{[(9H-fluoren-9-ylmethoxy) carbonyl] amino} 4-phenylcyclohexanecarboxylic acid

Xin-jie; Danho， Waleed; Swistok，Joseph; Wang， Yao; Yagaloff，Keith Alan，WO 2002018437所述方法製備。 中間體32 : 1-胺基-4·苯基環己烷羧酸甲酯Xin-jie; Danho, Waleed; Swistok, Joseph; Wang, Yao; Yagaloff, Keith Alan, WO 2002018437. Intermediate 32: methyl 1-amino-4 · phenylcyclohexanecarboxylate

將三甲基甲矽烷基二氮甲烷（於己烷内2Μ溶液；2.3毫 升，4_59毫莫耳）加於卜{[(9Η-芴-9-基甲氧基）羰基]胺基卜 4-苯基環己烷羧酸（中間體31，1.35克，3.06毫莫耳）於甲醇 (14毫升）及甲苯（20毫升）内的溶液中。任此反應混合物於 週邊溫度攪拌3小時，加乙酸，蒸發去揮發性物質，得卜 {[(9H-苟-9-基甲氧基）羰基]胺基}_4_苯基環己烷羧酸曱醋 (1.29克，93%)，為固體；MS m/z 456(MH+)。 此物質用20%六氫啦σ定於DMF内的溶液（50毫升）於週邊 溫度處理2小時。加水（100毫升），將混合物萃取入 96151.doc -95· 200523234Trimethylsilyldiazomethane (2M solution in hexane; 2.3 ml, 4-59 mmol) was added to [{(9Η- 芴 -9-ylmethoxy) carbonyl] amino group 4- A solution of phenylcyclohexanecarboxylic acid (Intermediate 31, 1.35 g, 3.06 mmol) in methanol (14 ml) and toluene (20 ml). Allow the reaction mixture to stir at ambient temperature for 3 hours, add acetic acid, and evaporate the volatile materials to obtain {[(9H-Glu-9-ylmethoxy) carbonyl] amino} _4-phenylcyclohexanecarboxylic acid Rhenium vinegar (1.29 g, 93%) as a solid; MS m / z 456 (MH +). This material was treated with a 20% solution of hexahydrolaz in DMF (50 ml) at ambient temperature for 2 hours. Add water (100 ml) and extract the mixture into 96151.doc -95 · 200523234

EtOAc(3xlOO毫升），合併有機萃取物，乾燥（MgS04)，濃 縮，得固體。將其於40克二氧化矽Biotage柱上純化，用 EtOAc-異己烷（1:1)洗離，得標題化合物（0.303克，46%)。 'H NMR(DMSO d6): 1.52-1.97(m5 9H), 3.62(s5 3H) ^ 6.97-7.29(m，5H) ; MS m/z 234(MH+)。 中間體33 : l-{[(3R)-3-[(第三·丁氧基羰基）胺基】-4-(2-氟苯 基）丁醯】胺基卜4-苯基環己烷羧酸甲酯EtOAc (3 x 100 mL), combined organic extracts, dried (MgSO4), and concentrated to give a solid. It was purified on a 40 g silica dioxide Biotage column and washed off with EtOAc-isohexane (1: 1) to give the title compound (0.303 g, 46%). 'H NMR (DMSO d6): 1.52-1.97 (m5 9H), 3.62 (s5 3H) ^ 6.97-7.29 (m, 5H); MS m / z 234 (MH +). Intermediate 33: l-{[(3R) -3-[(Third · butoxycarbonyl) amino group] -4- (2-fluorophenyl) butyridine] amino group 4-phenylcyclohexane Methyl carboxylate

於（3R)-3_[(第三-丁氧基羰基）胺基]-4-(2-氟苯基）丁酸 (0.386克，1.30毫莫耳）於DCM(40毫升）内的攪拌的溶液中 加 HOBT(0_210 克，1.56 毫莫耳），EDC1(0.299 克，1.56 毫莫 耳）’三乙基胺（0·22毫升，1.56毫莫耳）及1-胺基-4-苯基環 己烷羧酸甲酯（中間體32，0.303克，1.3毫莫耳）。任此反 應混合物於週邊溫度擾拌16小時，用水，1 ν硫酸氫钟水 溶液（100毫升），碳酸氫鈉（1〇〇毫升）及鹽水（1〇〇毫升）洗。 以硫酸鎮乾燥後，將溶液蒸發，得粗製產物。此粗製產物 於40克二氧化矽Bi〇tage柱上純化，用EtOAc-異己烧（1:1) 洗離’得標題化合物（0.451克，68%)。4 NMR (DMS0 d6): 1.25 (s，9H)，1·65-1·81 (m，7H)，2.11 (d，1H)，2.19 (d， 1H)，2.31-2.42 (m，2H)，2.65-2.70 (m，1H)，2.84-2.88 (m， lH)，3.56(s，3H)，4.01-4.05(m，lH)，6.63(d，lH)，7.08-7.30 (m，9H)，8·〇5 (s，1H); MS m/z 535 (M+Na)。 中間體34 : 1_{[(3R)_3_[(第三_丁氧基羰基）胺基】冰(2敗苯 基）丁酿]胺基卜4-苯基環己烷羧酸 標題化合物係以b{[(3R)-3-[(第三-丁氧基羰基）胺基]-4_ 96151.doc -96- 200523234 (2-氟苯基）丁醯]胺基卜4-苯基環己烷羧酸甲酯（中間體33) 以中間體20所述方法水解製得，產出率82%。4 NMR (DMSO d6): 1.22 (s，9H)，1.52-1.77 (m，7H)，2.11 (d，1H)， 2.22 (d，1H)，2.32-2.39 (m，2H)，2.63-2.70 (m，1H)，2.82義 2·89 (dd，1H)，3.96-4.06 (m，1H)，6.62 (d，1H)，7.05-7.28 (m，9H)，7.88 (s，1H); MS m/z 521 (M+Na)。 中間體35 : [(1R)-1_(2-氟苯基）_3-({l-[(甲基胺基）羰基】-4-苯基環己基}胺基）-3-氧代丙基】胺基甲酸第三_丁酯 將1 - {[(3R)-3-[(第三-丁氧基幾基）胺基]_4_(2 -氟苯基）丁 醯]胺基卜4-苯基環己烷羧酸（中間體34，0.117克，0.3 53毫 莫耳），HOBt(0.038 克，0.281 毫莫耳），EDC1(0.054 克， 0.281毫莫耳），三乙基胺（〇·〇6毫升，〇·498毫莫耳）及曱基 胺鹽酸鹽（0.018克，0.234毫莫耳）於乙腈（5毫升）内的混合 物於100°C在微波爐内加熱5分鐘。加EtOAc(80毫升），此 混合物用1 N硫酸氫鉀水溶液（5〇毫升），碳酸氫鈉（5〇毫升） 及鹽水（50毫升）洗。以硫酸鎂乾燥後，將溶液蒸發，得粗 製產物。此產物於反相HPLC柱5-95%乙腈純化，得標題化 合物（0.100克，83%)。4 NMR (DMSO d6): 1.24 (s，9H)， 1.58-1.78 (m，7H)，2.12-2.15 (m，2H)，2.31-2.40 (m，2H)， 2.53 (d, 3H), 2.65-2.72 (m, 1H)5 2.81-2.91 (m, 1H), 4.00- 4.06 (m，1H)，6.63 (d，1H)，7.07-7.30 (m，l〇H)，7.54 (s， 1H); MS m/z 534 (M+Na) 〇 中間體36 : {(lR)-l-(2-氟苯基）·3_[(1_{【(4_氟节基）胺基】羰 基}-4-苯基環己基）胺基】_3_氧代丙基丨胺基甲酸第三_丁酯 96151.doc -97- 200523234 關的Stir in (3R) -3 _ [(third-butoxycarbonyl) amino] -4- (2-fluorophenyl) butanoic acid (0.386 g, 1.30 mmol) in DCM (40 ml) Add HOBT (0_210 g, 1.56 mmol), EDC1 (0.299 g, 1.56 mmol), triethylamine (0.22 ml, 1.56 mmol) and 1-amino-4-phenyl to the solution. Methyl cyclohexanecarboxylate (Intermediate 32, 0.303 g, 1.3 mmol). The reaction mixture was left to stir at ambient temperature for 16 hours, and washed with water, a 1 ν hydrogen bisulfate water solution (100 ml), sodium bicarbonate (100 ml) and brine (100 ml). After drying over sulfuric acid, the solution was evaporated to obtain a crude product. This crude product was purified on a 40 g silica dioxide Biotage column and washed off with EtOAc-isohexane (1: 1) to give the title compound (0.451 g, 68%). 4 NMR (DMS0 d6): 1.25 (s, 9H), 1.65-1 · 81 (m, 7H), 2.11 (d, 1H), 2.19 (d, 1H), 2.31-2.42 (m, 2H), 2.65-2.70 (m, 1H), 2.84-2.88 (m, 1H), 3.56 (s, 3H), 4.01-4.05 (m, 1H), 6.63 (d, 1H), 7.08-7.30 (m, 9H), 8.05 (s, 1H); MS m / z 535 (M + Na). Intermediate 34: 1 _ {[((3R) _3 _ [(Third_butoxycarbonyl) amino group] Ice (2-phenylphenyl) butanyl] amino group 4-phenylcyclohexanecarboxylic acid b {[((3R) -3-[(Third-butoxycarbonyl) amino)]-4_ 96151.doc -96- 200523234 (2-fluorophenyl) butylamidine] amino group 4-phenylcyclohexyl Methyl alkanecarboxylate (Intermediate 33) was prepared by hydrolysis according to the method described in Intermediate 20, and the yield was 82%. 4 NMR (DMSO d6): 1.22 (s, 9H), 1.52-1.77 (m, 7H), 2.11 (d, 1H), 2.22 (d, 1H), 2.32-2.39 (m, 2H), 2.63-2.70 ( m, 1H), 2.82, 2.89 (dd, 1H), 3.96-4.06 (m, 1H), 6.62 (d, 1H), 7.05-7.28 (m, 9H), 7.88 (s, 1H); MS m / z 521 (M + Na). Intermediate 35: [(1R) -1_ (2-fluorophenyl) _3-({l-[(methylamino) carbonyl] -4-phenylcyclohexyl} amino) -3-oxopropyl ] Thirty-butyl aminoformate 1-{[((3R) -3-[(Third-butoxyalkenyl) amino] -4_ (2-fluorophenyl) butylammonium] amino group 4- Phenylcyclohexanecarboxylic acid (Intermediate 34, 0.117 g, 0.3 53 mmol), HOBt (0.038 g, 0.281 mmol), EDC1 (0.054 g, 0.281 mmol), triethylamine ( A mixture of 0.06 ml, 0.498 mmol and 0.5% amine hydrochloride (0.018 g, 0.234 mmol) in acetonitrile (5 ml) was heated in a microwave oven at 100 ° C for 5 minutes. EtOAc (80 mL) was added, and the mixture was washed with 1 N aqueous potassium hydrogen sulfate (50 mL), sodium bicarbonate (50 mL) and brine (50 mL). After drying over magnesium sulfate, the solution was evaporated to obtain a crude product. This product was purified on a reversed-phase HPLC column with 5-95% acetonitrile to give the title compound (0.100 g, 83%). 4 NMR (DMSO d6): 1.24 (s, 9H), 1.58-1.78 (m, 7H), 2.12-2.15 (m, 2H), 2.31-2.40 (m, 2H), 2.53 (d, 3H), 2.65- 2.72 (m, 1H) 5 2.81-2.91 (m, 1H), 4.00- 4.06 (m, 1H), 6.63 (d, 1H), 7.07-7.30 (m, 10H), 7.54 (s, 1H); MS m / z 534 (M + Na) 〇 Intermediate 36: {(lR) -1- (2-fluorophenyl) · 3 _ [(1 _ {[(4-fluorobenzyl) amino] carbonyl} -4 -Phenylcyclohexyl) amino group] _3_oxopropyl 丨 aminocarboxylic acid third_butyl ester 96151.doc -97- 200523234

0 N. R11 中間體 R11 36 37 MS m/z 628 M+Na 704 M+Na 實例49 ·· 1-{[(3R)_3-胺基_4-(2_氟苯基）丁醯基】胺基卜N-(4-氣节基）-4-苯基環己基叛酿胺 實例50 : 1-{[(3R)_3-胺基-4_(2-氣苯基）丁醯基】胺基}-Ν·{2- [4-(胺基績酿基）本基】乙基}-4 -苯基環己基敌酿胺 實例49及50是以實例38所述方法，分別以中間體36及37 起始製備。0 N. R11 intermediate R11 36 37 MS m / z 628 M + Na 704 M + Na Example of N- (4-Acetyl) -4-phenylcyclohexyl benzylamine 50: 1-{[((3R) _3-Amino-4_ (2-Gaphenyl) butyridinyl] amino} -N · {2- [4- (Amino group) benzyl] ethyl} -4-phenylcyclohexyl diamine amine Examples 49 and 50 are the methods described in Example 38, starting with intermediates 36 and 37 respectively Start preparation.

s、R” 96151.doc •98- 200523234 實例 R11 lH NMR (DMSO) MS m/z 49 1.63-1.89 (m，7H)，2.10 (d，1H)，2.28 (d，1H)， 506 2.61-2.63 (m, 2H), 2.85-2.92 (dd, 1H), 2.98-3.05 (dd, 1H), 3.61-3.64 (m, 1H), 4.16-4.30 (m，2H)，7.04-7.34 (m，12H)，8.06 (s，1H)， 8.09 (brs, 2H), 8.19 (t, 1H). (MH)+ 50 1.58-1.78 (m, 7H), 2.03-2.07 (m, 1H), 2.17- 581 ^^^so2nh2 2.21(m，lH)，2.61(d，lH)，2.76(t，2H)，2.88-2.95 (dd, 2H), 3.00-3.07 (dd, 2H), 3.25-3.28 (m, 2H), 3.61-3.70 (m, 1H), 7.13-7.40 (m, 12H), 7.71 (d, 2H), 8.00 (s, 1H), 8.13 (brs, 2H). (MH). 實例51 : (R)-2_[(R)-3-胺基-4_(2_氟_苯基）_ 丁醯基胺基】· 1，2,3,4-四氩萘_2_羧酸甲基醯胺s, R "96151.doc • 98- 200523234 Examples R11 lH NMR (DMSO) MS m / z 49 1.63-1.89 (m, 7H), 2.10 (d, 1H), 2.28 (d, 1H), 506 2.61-2.63 (m, 2H), 2.85-2.92 (dd, 1H), 2.98-3.05 (dd, 1H), 3.61-3.64 (m, 1H), 4.16-4.30 (m, 2H), 7.04-7.34 (m, 12H) , 8.06 (s, 1H), 8.09 (brs, 2H), 8.19 (t, 1H). (MH) + 50 1.58-1.78 (m, 7H), 2.03-2.07 (m, 1H), 2.17- 581 ^^ ^ so2nh2 2.21 (m, lH), 2.61 (d, lH), 2.76 (t, 2H), 2.88-2.95 (dd, 2H), 3.00-3.07 (dd, 2H), 3.25-3.28 (m, 2H), 3.61-3.70 (m, 1H), 7.13-7.40 (m, 12H), 7.71 (d, 2H), 8.00 (s, 1H), 8.13 (brs, 2H). (MH). Example 51: (R)- 2 _ [(R) -3-Amino-4_ (2_fluoro_phenyl) _butamidinoamino]] 1,2,3,4-tetraargonaphthalene_2_carboxylic acid methylamidamine

實例51係如實例38所述用中間體49製備，產出率98%。 lE NMR (DMSO d6): 1.87-1.97 (m? 1H)? 2.26-2.30 (m, 1H), 2.40-2.42 (m? 2H), 2.56 (d? 3H), 2.64-2.68 (m? 2H), 2.73-2.81 (m? 1H), 2.93-3.01 (m5 2H)? 3.11-3.16 (m, 1H), 3.58-3.63 (m，1H)，7.03-7.21 (m，7H)，7.26-7.33 (m，1H)，7·64-7.66 (m，1H)，8.09 (brs，2H)，8·15 (s，1H); MS m/z 384 (MH+)。 中間體49 : [(lR)_l-(2-氟苄基）-3-({(2S)-2-[(甲基胺基）羰 96151.doc -99- 200523234 基】-1，2,3,4 -四氩萘-2_基}胺基）-3-氧代丙基】胺甲甲酸第三-丁酯 根據實例34所述工序用（3R)-3-[(第三-丁氧基羰基）胺 基]-4-(2-氟苯基）丁酸及（11)-2-胺基-1，2,3,4-四氫-萘-2-羧酸 甲基醯胺製備，產出率32% ; MS m/z 484(MH+)。 (R)-2-胺基-1，2,3,4_四氩-萘-2_羧酸甲基醯胺Example 51 was prepared as described in Example 38 using intermediate 49 with a yield of 98%. lE NMR (DMSO d6): 1.87-1.97 (m? 1H)? 2.26-2.30 (m, 1H), 2.40-2.42 (m? 2H), 2.56 (d? 3H), 2.64-2.68 (m? 2H), 2.73-2.81 (m? 1H), 2.93-3.01 (m5 2H)? 3.11-3.16 (m, 1H), 3.58-3.63 (m, 1H), 7.03-7.21 (m, 7H), 7.26-7.33 (m, 1H), 7.64-7.66 (m, 1H), 8.09 (brs, 2H), 8.15 (s, 1H); MS m / z 384 (MH +). Intermediate 49: [(lR) _1- (2-fluorobenzyl) -3-({(2S) -2-[(methylamino) carbonyl 96151.doc -99- 200523234 group) -1, 2, 3,4-tetrahydronaphthalene-2-yl} amino) -3-oxopropyl] carbamate tert-butyl ester According to the procedure described in Example 34, (3R) -3-[(third-butyl (Oxycarbonyl) amino] -4- (2-fluorophenyl) butanoic acid and (11) -2-amino-1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid methylamidamine Preparation, yield 32%; MS m / z 484 (MH +). (R) -2-Amino-1,2,3,4-tetraargon-naphthalene-2_carboxylic acid methylamidamine

以精於此技藝者所知標準工序（Μ· Bodansky，’Principles of Peptide Chemistry’，Springer-Verlag，New York，1984)用 (R)-2-胺基-1，2,3,4-四氫-萘-2_羧酸製備。 (R)_2_胺基-1，2,3,4·四氫-萘 _2-羧酸（CAS no. 104974-44-9)可根據文獻方法（J. Aldrich，Q Zheng，T.F. Murray， Chirality (2001)，13(3)，125-129)製得。 實例52 : l-{[(3R)-3-胺基-4-(2-氟苯基）丁醯基】胺基}_N-甲 基環丙烷羧醯胺鹽酸鹽(R) -2-amino-1,2,3,4-tetramethane is used in standard procedures known to those skilled in the art (M. Bodansky, 'Principles of Peptide Chemistry', Springer-Verlag, New York, 1984) Preparation of hydrogen-naphthalene-2_carboxylic acid. (R) _2_amino-1,2,3,4 · tetrahydro-naphthalene_2-carboxylic acid (CAS no. 104974-44-9) can be obtained according to literature methods (J. Aldrich, Q Zheng, TF Murray, Chirality (2001), 13 (3), 125-129). Example 52: l-{[(3R) -3-amino-4- (2-fluorophenyl) butyridinyl] amino} _N-methylcyclopropanecarboxamide hydrochloride

實例52係如實例38所述，用{(R)-2-(2-氟苯基）-1-[(1-甲 基胺甲醯基-環丙基胺甲醯基）-甲基]-乙基卜胺基甲酸第三-丁基酯起始製備。1H NMR (DMSO d6): 0.67-0.71 (m，1H)，0.78-0.83 (m，1H)，1.10-1.21 (m，2H)，2.42-2.44 (m，2H)，2.52 (d，3H)，2.79-2·86 (m， 1H)，2.99-3.05 (m，1H)，3.62-3.68 (m，1H)，7.14-7.16 (m，2H)，7.29-7.35 (m， 2H)，7.73 (d，1H)，8.16 (brs，2H)，8·59 (s，1H); MS m/z 294 (MH+)。 {(R)-2-(2_氟苯基甲基胺甲醯基·環丙基胺甲醯基 96151.doc -100- 200523234 甲基】-乙基}•胺基甲酸第三_ 丁基醋 根據中間體21所述方法用中間體38及甲基胺合成。MS m/z 417(M+Na)+。 中間體39 : l_{[(3R)-3-[(第三·丁氧基羰基）胺基卜4-(2-氟苯 基）丁酿基】胺基}環丙燒瘦酸甲醋Example 52 was as described in Example 38 using {(R) -2- (2-fluorophenyl) -1-[(1-methylamine formamyl-cyclopropylamine formamyl) -methyl] -Ethyl-p-aminocarboxylic acid tertiary-butyl ester was prepared initially. 1H NMR (DMSO d6): 0.67-0.71 (m, 1H), 0.78-0.83 (m, 1H), 1.10-1.21 (m, 2H), 2.42-2.44 (m, 2H), 2.52 (d, 3H), 2.79-2 · 86 (m, 1H), 2.99-3.05 (m, 1H), 3.62-3.68 (m, 1H), 7.14-7.16 (m, 2H), 7.29-7.35 (m, 2H), 7.73 (d 1H), 8.16 (brs, 2H), 8.59 (s, 1H); MS m / z 294 (MH +). {(R) -2- (2-fluorophenylmethylaminomethylamido · cyclopropylaminomethylamido 96151.doc -100- 200523234 methyl] -ethyl} • aminocarboxylic acid tertiary-butyl Vinegar was synthesized using intermediate 38 and methylamine according to the method described in intermediate 21. MS m / z 417 (M + Na) +. Intermediate 39: l _ {[(3R) -3-[(third · butoxy Carbonyl group) amino group 4- (2-fluorophenyl) butanyl group] amine group} cyclopropane ketone

(3R)-3-[(第三-丁氧基羰基）胺基]·4_(2-氟苯基）丁酸及卜 胺基環丙烧羧酸甲酯鹽酸鹽（CAS No 72784-43-1 JACS 1998, 120(37)，9452-9459)根據中間體21所述方法偶合得標 題化合物’產出率78%。4 NMR (CDC13): 1.10-1.17 (m， 2H)，1.37 (s，9H)，1.257-1.58 (m，2H)，2·32-2·49 (m，2H)， 2.95 (d，2H)，3·70 (s，3H)，4.06-4.18 (m，1H)，5.42 (brs， 1H)，6.25 (brs，1H)，6.98-7.09 (m，2H)，7.16-7.29 (m，2H); MS m/z 417 (M+Na) 〇 中間體38 : 1_{[(3R)_3_[(第三-丁氧基羰基）胺基】-4-(2-氟苯 基）丁醯基】胺基}環丙烷羧酸 以中間體20所述方法將第三-丁氧基羰基） 胺基]-4-(2-氟苯基）丁醯基；]胺基}環丙烷羧酸甲酯（中間體 39)水解，得標題化合物。1H NMR (DMSO d6): 0.89-0.90 (m，2H)，0.99-1.04 (m，1H)，1.15-1.19 (m，1H)，1.25 (s， 9H)，2.21 (d，2H)，2.57-2.65 (m，1H)，2.78-2.85 (dd，1H)， 3.94-4.03 (m，1H)，6.61 (d，1H)，7.06 (t，2H)，7.19-7.24 (m， 2H)，8.36 (s，1H)，12.22 (s，1H); MS m/z 381 (MH+)。 實例53 : 1_{[(3R)_3_胺基-4-(2-氟苯基）丁醯基】胺基}-N-{2-[(丙基確醯基）胺基】乙基丨環丙烷羧醯胺鹽酸鹽 96151.doc -101 - 200523234(3R) -3-[(Third-butoxycarbonyl) amino] · 4- (2-fluorophenyl) butanoic acid and methylaminocyclopropanecarboxylic acid methyl ester hydrochloride (CAS No 72784-43 -1 JACS 1998, 120 (37), 9452-9459) was coupled according to the method described in Intermediate 21 to obtain the title compound '78% yield. 4 NMR (CDC13): 1.10-1.17 (m, 2H), 1.37 (s, 9H), 1.257-1.58 (m, 2H), 2.32-2 · 49 (m, 2H), 2.95 (d, 2H) , 3.70 (s, 3H), 4.06-4.18 (m, 1H), 5.42 (brs, 1H), 6.25 (brs, 1H), 6.98-7.09 (m, 2H), 7.16-7.29 (m, 2H) ; MS m / z 417 (M + Na) 〇Intermediate 38: 1 _ {[((3R) _3 _ [(third-butoxycarbonyl) amino group] -4- (2-fluorophenyl) butylfluorenyl] amino group) } Cyclopropanecarboxylic acid is tertiary-butoxycarbonyl) amino] -4- (2-fluorophenyl) butylfluorenyl;] amino} methylcyclopropanecarboxylic acid (Intermediate 39 ) Hydrolysis to give the title compound. 1H NMR (DMSO d6): 0.89-0.90 (m, 2H), 0.99-1.04 (m, 1H), 1.15-1.19 (m, 1H), 1.25 (s, 9H), 2.21 (d, 2H), 2.57- 2.65 (m, 1H), 2.78-2.85 (dd, 1H), 3.94-4.03 (m, 1H), 6.61 (d, 1H), 7.06 (t, 2H), 7.19-7.24 (m, 2H), 8.36 ( s, 1H), 12.22 (s, 1H); MS m / z 381 (MH +). Example 53: 1 _ {[(3R) _3_Amino-4- (2-fluorophenyl) butylfluorenyl] amino} -N- {2-[(propylpropyl) amino] ethyl 丨 cyclopropane Carboxamide hydrochloride 96151.doc -101-200523234

實例53係如實例38所述用中間體50製備，產出率98%。 4 NMR (DMSO d6): 0.69-0.73 (m，1H)，0.80-0.91 (m，1H)， 0.94 (t? 3H), 1.12-1.20 (m? 2H), 1.55-1.67 (m, 2H), 2.39-2.44 (m，2H)，2.78-3.11 (m，8H)，3.62-3.71 (m，1H)，7.06 (t， 1H)，7.14-7.18 (m，2H)，7.29-7.36 (m，2H)，7.87 (t，1H)， 8.08 (brs，2H)，8·61 (s，1H); MS m/z 429 (MH+) 中間體50 ·· [(R)-l_(2-氟苄基）-3-氧代-3-({l_【（{2_[(丙基磺 醯基）胺基】乙基}胺基）羰基】環丙基}胺基）丙基】胺基甲酸第 三-丁酯 根據中間體21所述方法用中間體38及N-(2-胺基乙基）丙Example 53 was prepared as described in Example 38 using intermediate 50 with a yield of 98%. 4 NMR (DMSO d6): 0.69-0.73 (m, 1H), 0.80-0.91 (m, 1H), 0.94 (t? 3H), 1.12-1.20 (m? 2H), 1.55-1.67 (m, 2H), 2.39-2.44 (m, 2H), 2.78-3.11 (m, 8H), 3.62-3.71 (m, 1H), 7.06 (t, 1H), 7.14-7.18 (m, 2H), 7.29-7.36 (m, 2H) ), 7.87 (t, 1H), 8.08 (brs, 2H), 8.61 (s, 1H); MS m / z 429 (MH +) intermediate 50 · [(R) -1_ (2-fluorobenzyl ) -3-oxo-3-({l _ [({2 _ [(propylsulfonyl) amino] ethyl} amino) carbonyl] cyclopropyl} amino) propyl] aminocarboxylic acid third -Butyl ester with intermediate 38 and N- (2-aminoethyl) propane according to the method described in intermediate 21.

院-1-石黃醯胺（CAS No 53673-27-1 J.Med.Chem·，（1982)， 25(11)，1286-92)製備，產出率55〇/〇 ; ms m/z 551(M+Na)。 實例54 · 1-[(R)_3_胺基]-(2_敗-苯基丁醯基胺基卜2普 氣-本基）-環丙燒致酸曱基酿胺Yuan-l-baicalin (CAS No 53673-27-1 J. Med. Chem., (1982), 25 (11), 1286-92) was prepared with a yield of 55 / 〇; ms m / z 551 (M + Na). Example 54 · 1-[(R) _3-Amine]-(2-A-phenylbutyrylamidoamino 2a-benzyl) -Cyclopropane-acid-based ammonium amine

二:是如實例38所述方… 98/〇 , MS m/z 404 (MH+) 〇 二=叫3·(4-氣笨基…^ 基}胺基)小(2初基)-氧代丙基歸甲酸第三- 9615l.doc -102. 200523234 根據中間體21所述方法用第三-丁氧基羰基）胺 基]_4_(2_氟苯基）丁酸及丨_胺基·氯苯基）善甲基環丙 烧致醯胺（CAS No : 669058-61-1 J· Org· Chem·，2004, 69(4)，1262-1269)製備，產出率9〇/0 ; MS m/z 526 (M+Na)。 實例55 : (3R)-3-胺基_N_{(1R)-1_環己基_2-[(4·氟苄基）胺 基]·2_氧代乙基}-4_(2-氟苯基）丁醯胺 實例56 : (3R)-3-胺基_n_【（1R)_i_環己基-2-(異丙基胺基）-2_氧代乙基】-4-(2-氟苯基）丁酿胺 實例57 : (3R)-3-胺基_N-[(lR)_2_({2_[4-(胺基磺醯基）苯基】 乙基}胺基）·1-環己基-2_氧代乙基】-4-(2-氟苯基）丁醯胺 實例58 : (3R)-3-胺基·ν](1Κ)_1_環己基_2·[(環丙基甲基） 胺基】-2-氧代乙基}_4_(2-氟苯基）丁醯胺 實例59 ·· (3R)-3-胺基環己基-2-(甲基胺基）-2-氧代乙基】-4-(2 -氟苯基）丁酿胺 實例55至59係以實例38所述工序分別以中間體42至46起 始製備：Two: is as described in Example 38 ... 98 / 〇, MS m / z 404 (MH +) 〇 == called 3 · (4-aminobenzyl ... ^ yl} amino group) small (2 primary group)-oxo Propyl carboxylic acid tertiary-9615l.doc -102. 200523234 tertiary-butoxycarbonyl) amino group according to the method described in Intermediate 21] 4- (2-fluorophenyl) butanoic acid and 丨 amino · chloro Phenyl) sulfanilamide induced by sulfanilamide (CAS No: 669058-61-1 J · Org · Chem ·, 2004, 69 (4), 1262-1269), yield 90/0; MS m / z 526 (M + Na). Example 55: (3R) -3-amino_N _ {(1R) -1_cyclohexyl_2-[(4 · fluorobenzyl) amino] · 2-oxoethyl} -4_ (2-fluoro Phenyl) butylammonium amine Example 56: (3R) -3-amino_n _ [(1R) _i_cyclohexyl-2- (isopropylamino) -2-oxoethyl] -4- (2 -Fluorophenyl) Butylamine Example 57: (3R) -3-amino_N-[(lR) _2 _ ({2_ [4- (aminosulfofluorenyl) phenyl] ethyl} amino) · 1-cyclohexyl-2_oxoethyl] -4- (2-fluorophenyl) butylammonium amine Example 58: (3R) -3-amino group · ν] (1Κ) _1_cyclohexyl_2 · [ (Cyclopropylmethyl) amino] -2-oxoethyl} -4_ (2-fluorophenyl) butanamide Example 59 · (3R) -3-aminocyclohexyl-2- (methylamine ) -2-oxoethyl] -4- (2-fluorophenyl) butyramine Examples 55 to 59 are prepared starting from intermediates 42 to 46 using the procedure described in Example 38, respectively:

實例 R11 ^NMRiDMSO) MS m/z 55 0.92-1.12 (m, 5H), 1.46-1.66 (m, 6H), 2.42-2.57 (m, 2H), 2.81-2.88 (m, 1H), 2.95-3.00 (m, 1H), 3.66 (brs, 1H), 4.12-4.17 (m, 1H), 444 (MH)+ 200523234 4.23-4.26 (m, 1H), 7.08-7.40 (m, 8H), 7.96 (brs，2H)，8.20-8.27 (m，1H)，8.48-8.52 (m， 1H). 56 -ch(ch3)2 57 0.77-1.07 (m，5H)，1.38-1.64 (m，6H)，2.35- 519 so2nh2 2.47 (m，2H)，2.75-2.88 (m，3H)，2.95-3.00 (m，1H)，3.21-3.28 (m，1H)，3.37-3.46 (m， 1H), 3.65 (m, 1H), 4.04-4.07 (m, 1H), 7.16-7.40 (m，8H)，7.71 (m，2H)，7.94 (brs，2H)， 8.09-8.20 (m，2H). (MH)+ 58 -0.02-0.02 (m, 2H), 0.21-0.27 (m, 2H), 0.69-1.02 (m, 6H), 1.38-1.54 (m, 6H), 2.27-2.45 (m, 2H), 2.67-2.89 (m, 4H), 3.51 (brs, 1H), 3.97 (t, 1H), 7.02-7.08 (m, 2H), 7.17-7.23 (m，2H)，7.82 (brs，2H)，7.91 (t, 1H)， 8.02 (d，1H). 390 (MH)+ 59 -ch3 0.90-1.17 (m, 5H), 1.45-1.66 (m, 6H)? 2.36-2.39 (m, 1H), 2.56-2.60 (m, 3H), 2.67-2.77 (m，1H)，2.82-2.88 (m，1H)，2.97-3.04 (m， 1H)，3.65 (brs，1H)，4.02-4.08 (m，1H)， 7.16-7.22 (m, 2H), 7.32-7.37 (m, 2H), 7.90-7.92 (m, 1H), 8.04 (brs, 2H), 8.17-8.21 (m, 1H) 350 (MH)+ 中間體41 : (2R)-{[(3R)_3-[(第三-丁氧基羰基）胺基】_4_(2-氟苯基）丁醯基】胺基}(環己基）乙酸甲酯R11 ^ NMRiDMSO) MS m / z 55 0.92-1.12 (m, 5H), 1.46-1.66 (m, 6H), 2.42-2.57 (m, 2H), 2.81-2.88 (m, 1H), 2.95-3.00 ( m, 1H), 3.66 (brs, 1H), 4.12-4.17 (m, 1H), 444 (MH) + 200523234 4.23-4.26 (m, 1H), 7.08-7.40 (m, 8H), 7.96 (brs, 2H ), 8.20-8.27 (m, 1H), 8.48-8.52 (m, 1H). 56 -ch (ch3) 2 57 0.77-1.07 (m, 5H), 1.38-1.64 (m, 6H), 2.35-519 so2nh2 2.47 (m, 2H), 2.75-2.88 (m, 3H), 2.95-3.00 (m, 1H), 3.21-3.28 (m, 1H), 3.37-3.46 (m, 1H), 3.65 (m, 1H), 4.04-4.07 (m, 1H), 7.16-7.40 (m, 8H), 7.71 (m, 2H), 7.94 (brs, 2H), 8.09-8.20 (m, 2H). (MH) + 58 -0.02-0.02 (m, 2H), 0.21-0.27 (m, 2H), 0.69-1.02 (m, 6H), 1.38-1.54 (m, 6H), 2.27-2.45 (m, 2H), 2.67-2.89 (m, 4H) , 3.51 (brs, 1H), 3.97 (t, 1H), 7.02-7.08 (m, 2H), 7.17-7.23 (m, 2H), 7.82 (brs, 2H), 7.91 (t, 1H), 8.02 (d , 1H). 390 (MH) + 59 -ch3 0.90-1.17 (m, 5H), 1.45-1.66 (m, 6H)? 2.36-2.39 (m, 1H), 2.56-2.60 (m, 3H), 2.67- 2.77 (m, 1H), 2.82-2.88 (m, 1H), 2.97-3.04 (m, 1H), 3.65 (brs, 1H), 4.02 -4.08 (m, 1H), 7.16-7.22 (m, 2H), 7.32-7.37 (m, 2H), 7.90-7.92 (m, 1H), 8.04 (brs, 2H), 8.17-8.21 (m, 1H) 350 (MH) + Intermediate 41: (2R)-{[((3R) _3-[(Third-butoxycarbonyl) amino group) _4_ (2-fluorophenyl) butylfluorenyl] amino group} (cyclohexyl) Methyl acetate

此標題化合物是用中間體8(1.0克，2.53毫莫耳）及（2R)-胺基（環己基）乙酸甲酯鹽酸鹽（Van Boeckel，et al WO 96l51.doc -104- 200523234 98/07308)(0.43克，2.53毫莫耳）以實例丨丨所述方法（只是以 乙腈代替DCM作溶劑）製備，得標題化合物（〇.894克， 79%)。咕 NMR (DMSO d6): 〇·96-1·19 (m，5H)，} 26 (s， 9H)，1.48-1.66 (m，6H)，2.22-2.39 (m，2H)，2.57-2 65 (m， 1H)，2.75-2.81 (m，1H)，3.59 (s，3H)，3.95畴3.96 (m，1H)， 4·13 (t，1H)，6.59 (d，1H)，7.07 (t，2H)，7.19 (m，2H)，8.13 (d，1H); MS m/z 473 (M+Na) 〇 中間體40 : (2R)-{[(3R)-3_[(第三-丁氧基羰基）胺基】_4-(2-氟苯基）丁醯基]胺基}(環己基）乙酸 標題化合物是用中間體20所述方法，藉水解（2R)_ {[(3R)-3-胺基-4-(2-氟苯基）丁醯基]胺基}(環己基）乙酸甲 酯（中間體41)製得，產出率100%。1HNMR(DMSOd6)·· 0.88-1.19 (m，5H)，1·26 (s，9H)，1_54_1·73 (m，6H)，2·27-2.35 (m5 2H), 2.58-2.66 (m, 1H), 2.75-2.81 (m, 1H), 3.96-4.04(m，lH)，4.11(t，lH)，6.60(d，lH)，7.06(t，2H)，7.19-7·24 (m，2H)，7.98 (d，1H); MS m/z 459 (M+Na)。 中間體42 : [(1R)_3-({(1R)_1-環己基_2_[(4-氟节基）胺基】-2-氧代乙基}胺基）-1-(2-氟苄基）-3-氧代丙基]胺基甲酸第三-丁酯 中間體43 : [(R)-1-{[((R)-環己基·異丙基胺甲醯基-甲基）-胺甲醯基卜甲基卜2-(2_氟-苯基）-乙基]-胺基甲酸第三-丁酯 中間體44 : [(lR)-3-{[(lR)-2-({2-[4-(胺基磺醯基）苯基】乙 基}胺基）-1-環己基-2_氧代乙基]胺基}-1-(2-氟苄基）-3-氧代 丙基】胺基甲酸第三丁酯 96151.doc -105- 200523234 中間體45 : 環己基_2_[(環丙基甲基）胺 基】·2-氧代乙基}胺基）4-(2-氟苄基）_3-氧代丙基】胺基甲酸 第二-丁酉旨 中間艘46 : 環己基_2气甲基胺基）-2-氧代 乙基】胺基卜1-(2-氟苄基）-3-氧代丙基】胺基甲酸第三-丁酯 中間體42至46是用中間體35所述方法用中間體40及適寬 的胺製備，但過濾粗製產物並直接行去保護步驟。This title compound was prepared using intermediate 8 (1.0 g, 2.53 mmol) and (2R) -amino (cyclohexyl) methyl acetate hydrochloride (Van Boeckel, et al WO 96l51.doc -104- 200523234 98 / 07308) (0.43 g, 2.53 mmol) was prepared by the method described in Example (but using acetonitrile instead of DCM as the solvent) to give the title compound (.894 g, 79%). NMR (DMSO d6): 0.96--1.19 (m, 5H), 26 (s, 9H), 1.48-1.66 (m, 6H), 2.22-2.39 (m, 2H), 2.57-2 65 (m, 1H), 2.75-2.81 (m, 1H), 3.59 (s, 3H), 3.95 domain 3.96 (m, 1H), 4.13 (t, 1H), 6.59 (d, 1H), 7.07 (t , 2H), 7.19 (m, 2H), 8.13 (d, 1H); MS m / z 473 (M + Na) 〇 Intermediate 40: (2R)-{[(3R) -3 _ [(third-but Oxycarbonyl) amino] _4- (2-fluorophenyl) butylfluorenyl] amino} (cyclohexyl) acetic acid The title compound was prepared by the method described in Intermediate 20 by hydrolysis of (2R) _ {[(3R) -3 -Amino-4- (2-fluorophenyl) butylamidino] amino} (cyclohexyl) acetate (intermediate 41) was prepared with a yield of 100%. 1HNMR (DMSOd6) ·· 0.88-1.19 (m, 5H), 1.26 (s, 9H), 1_54_1 · 73 (m, 6H), 2.27-2.35 (m5 2H), 2.58-2.66 (m, 1H ), 2.75-2.81 (m, 1H), 3.96-4.04 (m, lH), 4.11 (t, lH), 6.60 (d, lH), 7.06 (t, 2H), 7.19-7 · 24 (m, 2H ), 7.98 (d, 1H); MS m / z 459 (M + Na). Intermediate 42: [(1R) _3-({(1R) _1-cyclohexyl_2 _ [(4-fluorobenzyl) amino] -2-oxoethyl} amino) -1- (2-fluoro Benzyl) -3-oxopropyl] aminocarboxylic acid tertiary-butyl ester intermediate 43: [(R) -1-{[((R) -Cyclohexyl · isopropylaminomethylmethyl-methyl ) -Carbamate methylmethyl 2- (2-fluoro-phenyl) -ethyl] -aminocarboxylic acid tertiary-butyl ester intermediate 44: [(lR) -3-{[(lR) -2- ({2- [4- (Aminosulfonyl) phenyl] ethyl} amino) -1-cyclohexyl-2_oxoethyl] amino} -1- (2-fluorobenzyl)- 3-oxopropyl] third butyl aminoformate 96151.doc -105- 200523234 intermediate 45: cyclohexyl_2 _ [(cyclopropylmethyl) amino] · 2-oxoethyl} amino ) 4- (2-fluorobenzyl) _3-oxopropyl] aminocarboxylic acid second-butanthine intermediate vessel 46: cyclohexyl_2 gas methylamino) -2-oxoethyl] amino group 1- (2-Fluorobenzyl) -3-oxopropyl] aminocarboxylic acid third-butyl ester intermediates 42 to 46 were prepared using intermediate 40 and a suitable amine using the method described in intermediate 35, but The crude product was filtered and deprotected directly.

中間體 R11 MS m/z 42 566 M+Na 43 CH(CH3)2 500 M+Na 44 r^as,〇 !、nh2 641 M+Na 45 512 M+Na 46 ch3 472 M+Na 實例60 : 2-{[(3R)-3_胺基_4_(2_氟苯基）丁醯基]胺基卜N]2_ [4_(曱基磺醯基）苯基】乙基}茚烷-2-羧醯胺 96151.doc -106- 200523234 實例61 : 2-{[(3R)-3-胺基-4-(2-氣苯基）丁酿基I胺基卜N_{-[(甲基確醜基）胺基】丙基}茚烧-2-叛醯胺 實例62 ·· 2-{[(3R)-3-胺基-4-(2-氣苯基）丁酿基]胺基卜N]3-[(丙基項酿基）胺基】丙基}節烧-2-叛酿胺 實例63 ·· 2_U(3R)-3_胺基_4-(2-氟苯基）丁醯基】胺基卜N_ {[4_(丙基確酿基）六氫β比变-4 _基】甲基}茚烧-2-叛酿胺 實例64 : 2-{[(3R)-3-胺基-4_(2-氟苯基）丁醯基】胺基卜Ν-{[1-(甲基磺醯基）六氩吡啶-4_基]甲基}茚烷-2-羧醯胺 實例65 : 2-{[(3R)-3_胺基_4_(2-氣苯基）丁醯基】胺基}-Ν-[4· (甲基碟酿基）节基】茚烧·2-敌醯胺 實例66 : [4-(2-U(2-{[(3R)-3-胺基氟苯基）丁醯基】胺 基}-2,3-二氩·1Η-節烯基）羰基】胺基}乙基）苯氧基】乙酸 實例67 : 2-{[(3R)-3_胺基-4_(2_敗苯基）丁醯基】胺基卜Ν-【4-(三氟甲基）苄基】茚燒_2_致醜胺 實例68 : 2_{【（3R)_3-胺基_4 〇备# 丞4_(2-氟苯基）丁醯基]胺基卜N_[2- # (f基胺基）-2-氧代乙基】茚烷緩酿胺 7 <方法用中間體52_60·借。Intermediate R11 MS m / z 42 566 M + Na 43 CH (CH3) 2 500 M + Na 44 r ^ as, 〇 !, nh2 641 M + Na 45 512 M + Na 46 ch3 472 M + Na Example 60: 2 -{[((3R) -3_amino_4_ (2-fluorophenyl) butylfluorenyl] amino} N] 2_ [4_ (fluorenylsulfonyl) phenyl] ethyl} indane-2-carboxyfluorene Amine 96151.doc -106- 200523234 Example 61: 2-{[((3R) -3-amino-4- (2-aminophenyl) butynyl I amino group N _ {-[(methyl ceryl group ) Amino] propyl} indane-2-benzylamine Example 62 ·· 2-{[((3R) -3-amino-4- (2-aminophenyl) butynyl] amino group N] Examples of 3-[(propyl-terminated) amino] propyl} benzyl-2-benzylamine 63 ·· 2_U (3R) -3_amino_4- (2-fluorophenyl) butanyl] amine Kib N_ {[4_ (propyl alkynyl) hexahydroβ ratio change-4 _yl] methyl} indole-2-benzylamine Example 64: 2-{[((3R) -3-amino- 4- (2-fluorophenyl) butyridinyl] amino group N-{[1- (methylsulfonyl) hexahydropyridin-4-yl] methyl} indane-2-carboxamide Example 65: 2- {[((3R) -3_Amine_4_ (2-Gasphenyl) butyryl}] amino}}-N- [4 · (Methylpyridyl) benzyl] Indene · 2-antimidine Example 66 : [4- (2-U (2-{[((3R) -3-aminofluorophenyl) butylfluorenyl] amino}}-2,3- Diargon · 1Η-benzyl) carbonyl] amino} ethyl) phenoxy] acetic acid Example 67: 2-{[((3R) -3_amino-4_ (2-decylphenyl) butyryl)] amino Ν- [4- (trifluoromethyl) benzyl] indene_2_Uglyamine Examples 68: 2 _ {[(3R) _3-amino_4 〇 备 # 丞 4_ (2-fluorophenyl) Butanyl] amino group N_ [2- # (f-basedamino) -2-oxoethyl] indane slow amine 7 < Intermediate 52-60 for borrowing.

實例60至68是以實例38所 96151.doc -107- 200523234 實例 R11 !Η NMR (DMSO) MS m/z 60 2.41 (d, 2Η), 2.77-2.85 (m, 3Η), 2.95-3.10 (m，3H)，3J6(s，3H)， 3.36-3.48 (m, 2H), 3.58-3.62 (m, 1H)? 7.06-7.17 (m, 6H), 7.22-7.32 (m，2H)，7·42 (d，2H)，7.81 (d， 2H)，7.91 (t，1H)，8.10 (brs，2H)， 8.55 (s, 1H). 538 (MH)+ 61 0\\,p Η 1.51-1.60 (m，2H)，2.41-2.42 (m， 2H)，2.81-2.94 (m，6H)，3.00-3.18 (m, 5H), 3.36-3.52 (m, 2H), 3.59-3.64 (m, 1H), 6.86 (t, 1H), 7.06-7.33 (m, 8H), 7.80 (t, 1H), 8.03 (brs, 2H)5 8.57 (s, 1H). 491 (MH)+ 62 9、,,〇 Η 0.95 (t，3H)，1.52-L70 (m，4H)， 2.41 (d，2H)，2.77-3.21 (m，10H)， 3.40-3.51 (m, 2H), 3.60-3.63 (m, 1H), 6.90 (t, 1H), 7.06-7.30 (m, 9H)，7.80 (t，1H)，8.06 (brs，2H)， 8.57 (s5 1H). 491 (MH)+ 63 0.95 (t, 3H), 1.21-1.35 (m, 2H), 1.58-1.68 (m, 3H), 1.77-1.81 (m, 1H), 2.39 (d，2H), 2.70-3.22 (m， 13H), 3.37-3.45 (m, 2H), 3.58-3.68 (m，1H)，7.06-7.30 (m，8H)， 8.11 (brs，2H)，8.71 (s，1H). 559 (MH)+ 64 γ>ό 1.21-1.34 (m, 2H), 1.63-1.81 (m, 3H)，2.38 (d，2H)，2.80-2.84 (m， 531 (MH)+ 96l5l.doc -108- 200523234 4H)，2.86 (s，3H)，2.95-3.22 (m， 5H), 3.35-3.51 (m, 3H), 3.58-3.66 (m，1H)，7.03-7.31 (m，8H)，8.08 (brs，2H)，8.71 (s，1H). 65 2.44 (m，2H)，2.77-2.85 (m, 1H)， 2.94-3.01 (m, 1H), 3.09-3.24 (m, 2H), 3.15 (s, 3H), 3.32-3.48 (m, 2H)，3.61-3.66 (m，1H)，4.34 (t， 2H)，7.05-7.30 (m，8H)，7.46 (d， 2H)，7.82 (d，2H)，8.09 (brs，2H)， 8.52 (t，1H)，8.69 (s，1H) 524 _)+ 66 ^.0^/C02H 2.38-2.41 (m，2H)，2.59 (t，2H)， 2.70-2.81 (m，1H)，2.94-3.20 (m， 5H), 3.33-3.49 (m, 2H), 3.59-3.63 (m，1H)，4.60 (s，2H)，6.70 (d， 2H)，7.04-7.32 (m，10H)，7.82 (t， 1H)，8.04 (brs，2H)，8.52 (s，1H). 534 (MH)+ 67 >XTCF3 2.41-2.44 (m，2H)，2.77-2.84 (m， 1H), 2.93-3.00 (m, 1H), 3.09-3.24 (m, 2H), 3.39-3.45 (m, 2H), 3.59-3.63 (m，1H), 4.25-4.41 (m，2H)， 7.05-7.32 (m，8H)，7.41 (d，2H)， 7.62 (d，2H)，8.08 (brs，2H)，8.50 (t，1H)，8.68 (s，1H). 514 _)+ 68 2.41-2.43 (m，2H)，2.57 (d，3H), 2.79-2.99 (m, 2H), 3.01-3.17 (m, 3H)? 3.48-3.67 (m, 4H), 7.08-7.31 (m, 8H), 7.41-7.42 (m, 1H), 8.08 427 (MH)+ 96151.doc -109- 200523234 (brs5 2H)，8.20 (t，1H)，8.89 (s， 1H)· 中間體52 : [(R)_2-(2-氟-苯基）-l-({2-[2-(4-甲烷磺醯基-苯 基）-乙基胺甲醯基卜茚-2-基胺甲醯基卜甲基）-乙基卜胺基甲 酸第三-丁酯 中間體53 : ((R)-2-(2-氟-苯基）-1-{[2-(3-甲烷磺醯基胺基-丙基胺甲酿基）-節-2 -基胺甲酿基】-甲基}-乙基）-胺基甲酸第Examples 60 to 68 are shown in Example 38 96151.doc -107- 200523234 Example R11! Η NMR (DMSO) MS m / z 60 2.41 (d, 2Η), 2.77-2.85 (m, 3Η), 2.95-3.10 (m , 3H), 3J6 (s, 3H), 3.36-3.48 (m, 2H), 3.58-3.62 (m, 1H)? 7.06-7.17 (m, 6H), 7.22-7.32 (m, 2H), 7.42 (d, 2H), 7.81 (d, 2H), 7.91 (t, 1H), 8.10 (brs, 2H), 8.55 (s, 1H). 538 (MH) + 61 0 \\, p Η 1.51-1.60 ( m, 2H), 2.41-2.42 (m, 2H), 2.81-2.94 (m, 6H), 3.00-3.18 (m, 5H), 3.36-3.52 (m, 2H), 3.59-3.64 (m, 1H), 6.86 (t, 1H), 7.06-7.33 (m, 8H), 7.80 (t, 1H), 8.03 (brs, 2H) 5 8.57 (s, 1H). 491 (MH) + 62 9 ,,, 〇 0.95 (t, 3H), 1.52-L70 (m, 4H), 2.41 (d, 2H), 2.77-3.21 (m, 10H), 3.40-3.51 (m, 2H), 3.60-3.63 (m, 1H), 6.90 (t, 1H), 7.06-7.30 (m, 9H), 7.80 (t, 1H), 8.06 (brs, 2H), 8.57 (s5 1H). 491 (MH) + 63 0.95 (t, 3H), 1.21- 1.35 (m, 2H), 1.58-1.68 (m, 3H), 1.77-1.81 (m, 1H), 2.39 (d, 2H), 2.70-3.22 (m, 13H), 3.37-3.45 (m, 2H), 3.58-3.68 (m, 1H), 7.06-7.30 (m, 8H), 8.11 (brs, 2H), 8.71 (s, 1H). 559 (MH) + 64 γ > ό 1.21-1.34 (m, 2H), 1.63-1.81 (m, 3H), 2.38 (d, 2H), 2.80-2.84 (m, 531 (MH) + 96l5l.doc -108- 200523234 4H), 2.86 (s, 3H), 2.95-3.22 (m, 5H), 3.35-3.51 (m, 3H), 3.58-3.66 (m, 1H), 7.03-7.31 (m, 8H), 8.08 (brs, 2H), 8.71 (s, 1H). 65 2.44 (m, 2H), 2.77-2.85 (m, 1H), 2.94-3.01 (m, 1H), 3.09-3.24 (m, 2H), 3.15 (s, 3H), 3.32 -3.48 (m, 2H), 3.61-3.66 (m, 1H), 4.34 (t, 2H), 7.05-7.30 (m, 8H), 7.46 (d, 2H), 7.82 (d, 2H), 8.09 (brs , 2H), 8.52 (t, 1H), 8.69 (s, 1H) 524 _) + 66 ^ .0 ^ / C02H 2.38-2.41 (m, 2H), 2.59 (t, 2H), 2.70-2.81 (m, 1H), 2.94-3.20 (m, 5H), 3.33-3.49 (m, 2H), 3.59-3.63 (m, 1H), 4.60 (s, 2H), 6.70 (d, 2H), 7.04-7.32 (m, 10H), 7.82 (t, 1H), 8.04 (brs, 2H), 8.52 (s, 1H). 534 (MH) + 67 > XTCF3 2.41-2.44 (m, 2H), 2.77-2.84 (m, 1H) , 2.93-3.00 (m, 1H), 3.09-3.24 (m, 2H), 3.39-3.45 (m, 2H), 3.59-3.63 (m, 1H), 4.25-4.41 (m, 2H), 7.05-7.32 ( m, 8H), 7.41 (d, 2H), 7.62 (d, 2H), 8.08 (brs, 2H), 8.5 0 (t, 1H), 8.68 (s, 1H). 514 _) + 68 2.41-2.43 (m, 2H), 2.57 (d, 3H), 2.79-2.99 (m, 2H), 3.01-3.17 (m, 3H)? 3.48-3.67 (m, 4H), 7.08-7.31 (m, 8H), 7.41-7.42 (m, 1H), 8.08 427 (MH) + 96151.doc -109- 200523234 (brs5 2H), 8.20 ( t, 1H), 8.89 (s, 1H) · Intermediate 52: [(R) _2- (2-fluoro-phenyl) -l-({2- [2- (4-methanesulfonyl-phenyl-phenyl ) -Ethylaminomethylindenyl-2-inylaminomethylammonylmethyl) -Ethylaminotricarboxylic acid tert-butyl intermediate 53: ((R) -2- (2-fluoro-phenyl ) -1-{[2- (3-Methanesulfonylamino-propylaminomethyl) -Methyl-2-methylaminomethyl] -methyl} -ethyl) -aminocarboxylic acid

三-丁酯 中間體54 ··【(R)_2_(2-氟-苯基）-1-({2-[3-(丙烷-1-磺醯基-胺 基）-丙基胺甲醯基】_茚-2-基胺甲醯基卜甲基）-乙基】-胺基甲 酸第三-丁酯 中間體55 : {(R)-2_(2-氟-苯基）-1-[(2-{[1-(丙烷-1-磺醯基）-六氫《比啶-4-基甲基卜胺甲醯基}-茚-2-基胺甲醯基）-甲基】-乙基}-胺基甲酸第三·丁酯Tri-butyl ester intermediate 54 ·· [(R) _2_ (2-fluoro-phenyl) -1-({2- [3- (propane-1-sulfonyl-amino) -propylamine formamidine Group] _inden-2-ylaminoformamylmethyl) -ethyl] -aminocarboxylic acid third-butyl ester intermediate 55: {(R) -2_ (2-fluoro-phenyl) -1-[( 2-{[1- (propane-1-sulfofluorenyl) -hexahydro [pyridin-4-ylmethylbenzamidine} -inden-2-ylaminemethane) -methyl] -ethyl Butyl} -carbamic acid tert-butyl ester

中間體 56 : {(R)_2-(2-氟-苯基）-1_[(2_{2_[1·(丙烷-1_磺醯 基）-六氫啦啶-4-基]乙基胺甲醯基卜茚-2-基胺甲醯基）-甲 基】·乙基卜胺基甲酸第三-丁酯 中間體57 : ((R)-2_(2-氟-苯基）-1_{[2_(4-甲烷磺醯基-苄基 胺甲醯基）-茚-2-基胺甲醮基卜甲基卜乙基）-胺基甲酸第三-丁酯 中間體58 : {4_[2_({2_[(R)-3-第三-丁氧基羰基胺基-4_(2-氣-苯基）-丁酿基胺基】-茚烧-2-幾基}胺基）-乙基】-苯氧基}-乙酸 中間體59 : ((R)-2-(2-氟-苯基）-1-{[2-(4-三氟甲基-苄基胺 96151.doc -110- 200523234 甲醯基）-茚-2-基胺甲醯基】-甲基卜乙基）-胺基甲酸第三-丁 酯 中間體60 : ((R)-2-(2·氟-苯基）-1-{[2-(甲基胺甲醯基甲基-胺甲醯基）-茚-2-基胺甲醯基]-甲基卜乙基）-胺基甲酸第三-丁酯 中間體52-60是用中間體2及適宜的胺起始物質以中間體 1所述合成方法製備。此等產物直接行去保護步驟。Intermediate 56: {(R) _2- (2-fluoro-phenyl) -1 _ [(2_ {2_ [1 · (propane-1_sulfonyl) -hexahydrolaridin-4-yl] ethylamine Formamylindenyl-2-ylamine formamidine) -methyl] · ethyltribenzylcarboxylic acid tertiary-butyl ester intermediate 57: ((R) -2_ (2-fluoro-phenyl) -1_ {[2_ (4-Methanesulfonyl-benzylaminomethylmethyl) -inden-2-ylaminomethylmethylmethylethyl) -aminocarboxylic acid third-butyl intermediate 58: {4_ [2 _ ({ 2 _ [(R) -3-Third-butoxycarbonylamino-4_ (2-Gas-phenyl) -butynylamino] -indenyl-2-quinyl} amino) -ethyl] -Phenoxy} -acetic acid intermediate 59: ((R) -2- (2-fluoro-phenyl) -1-{[2- (4-trifluoromethyl-benzylamine 96151.doc -110- 200523234 Formamyl) -inden-2-ylaminoformamyl] -methylbuthyl) -carbamic acid tertiary-butyl ester intermediate 60: ((R) -2- (2 · fluoro-phenyl)- 1-{[2- (methylaminomethylmethylmethyl-carbamoyl) -inden-2-ylaminomethylmethyl] -methylbuthyl) -aminocarboxylic acid third-butyl intermediate 52- 60 is prepared using intermediate 2 and a suitable amine starting material by the synthetic method described in intermediate 1. These products are directly deprotected.

中間體 R11 MS m/z 52 660 (M+Na) 53 0、\,P Η 613 (M+Na) 54 9w,0 613 H (M+Na) 55 681 山 (M+Na) 56 r>.\0 653 (M+Na) 96151.doc -111 - 200523234 57 646 (M+Na) 58 656 (M+Na) 59 636 (M+Na) 60 H 549 (M+Na) [1-(丙基磺醯基）-六氫吡啶_4_基】-甲基胺里酸鹽 製備以上化合物所用中間體係如下製得：_ 於六氫吡啶-4-基甲基-胺基甲酸第三·丁基酯（57〇毫克， 2.66毫莫耳）於〇01^(10毫升）内之溶液中加三乙基胺（〇41毫 升’ 2.93毫莫耳）及1-丙烷磺醯氣（0.33毫升，2.93毫莫 耳）。任此反應混合物於週邊溫度攪拌16小時，然後相繼 用碳酸氫鉀（50毫升）及鹽水（50毫升）洗。將有機相乾燥 (MgS04)並濃縮，得無色膠體。將此殘餘物於40克Biotage 二氧化矽柱上純化，用EtOAc-異己烷（8-2)洗離，得[l-(丙 烷-1-磺醯基）-六氫吡啶-4-基甲基]-胺基甲酸第三-丁基酯 (809毫克，95%)，為無色膠體。於部分此膠體（695毫克， 2.17毫莫耳）内加4 M HC1於1，4-二噁烷内的溶液（5毫升）， 將所得懸浮液於週邊溫度攪拌1.5小時。然後除去揮發性 物質，得標題化合物（770毫克，定量），為橘棕色固體； NMR (300 MHz, DMS0) δ 0.95 (t? 3Η), 1.20 - 1.39 (m? 2H)，1.64 (六重峰，2H)，1·79 (d，2H)，2.70 - 2·87 (m，5H)， 96l5l.doc -112- 200523234 2.94 (t, 2H), 3.16 - 3.27 (m, 2H), 7.12 (t, 1H), 8.63 (s, 1H), 8.92 (s，1H); MS m/z 220 (M+H)+ 〇 &(3_胺基丙基）丙烧-1_續醜胺鹽睃鹽 於（3-胺基-丙基）-胺基甲酸第三·丁基酯（1〇克，5·73毫莫 耳）於DCM(20毫升）内的溶液中加吼啶（0·51毫升，6 31毫莫 耳）及1-丙基磺醯氣（0.71毫升，6 31毫莫耳）。任此反應混 合物於週邊溫度攪拌5小時，然後相繼用碳酸氫鉀（5()毫升） 及鹽水（50毫升）洗。將有機相乾燥（MgS〇4)並濃縮，得黃 色膠體。將此殘餘物於40克Biotage二氧化矽柱上純化，用 EtOAc-異己烧（8-2)洗離，得[3-(丙烧-1-石黃醯基胺基）_丙 基]_胺基甲酸第三-丁基酯（717毫克，45%)，為無色膠體。 於此膠體内加4 M HC1於1，4-二嗔烧内的溶液（5毫升），將 所得懸浮液於週邊溫度攪拌2小時。然後除去揮發性物 質，得標題化合物（495毫克，91%)，為乳色固體；4 NMR (300 MHz，DMSO) δ 0.96 (t，3Η)，1.58 - 1.78 (m， 4H)，2·74 - 2.85 (m，2H)，2·92 _ 3·02 (m，4H)，7.13 (t，1H)， 7·91 (s，3H); MS m/z 180 (M+H)+。 N-(3_胺基丙基）甲烷磺醯胺鹽酸鹽 此N-(3-胺基丙基）甲烷磺醯胺鹽酸鹽（CAS NO : 88334-76-3)係如N-(3-胺基丙基）丙烷-1-磺醯胺鹽酸鹽般製備，只 是用甲烷磺醯氯代替1-丙基磺醯氯；MS m/z 153 (MH+)。 [1-(曱基磺醯基）六氩吼啶-4-基】甲基胺鹽酸鹽 此[1-(曱基磺醯基）六氫吡啶-4-基]甲基胺鹽酸鹽（cAS No 325 153-03-5)是如製備[1-(丙基磺醯基）-六氫吡啶-4- 96151.doc -113- 200523234 基]-甲基胺鹽酸鹽般製備，只是用甲烷磺醯氣代替1 -丙基 磺醯氯；MS m/z 193 (MH+)。 {2-[4-(甲基磺醯基）苯基】乙基}胺 此{2_[4-(甲基磺醯基）苯基]乙基W$Cas NO: 153402-45-0 係如 Niu，Jinkui; Lawrence, David S. Journal of Biological 1997, 272(3)，1493-1499所述製備。 實例69 : 2-{[(3R)-3-胺基-4-苯基丁醯基】胺基}-N_苄基茚 烷-2-羧醯胺 實例70 : 2_{[(3R)-3_胺基-4-苯基丁醯基】胺基卜N-{2-[(丙基 磺醯基）胺基】乙基}茚烷-2-羧醯胺 實例69至70是以實例38所述方法分別用中間體61及62製 備。Intermediate R11 MS m / z 52 660 (M + Na) 53 0, \, P Η 613 (M + Na) 54 9w, 0 613 H (M + Na) 55 681 Mountain (M + Na) 56 r >. \ 0 653 (M + Na) 96151.doc -111-200523234 57 646 (M + Na) 58 656 (M + Na) 59 636 (M + Na) 60 H 549 (M + Na) [1- (propyl Sulfonyl) -hexahydropyridine_4-yl] -methylamine glutamate The intermediate system used to prepare the above compounds was prepared as follows: _ In hexahydropyridin-4-ylmethyl-aminocarboxylic acid third To a solution of the ester (57 mg, 2.66 mmol) in 0.01 (10 ml) was added triethylamine (0.41 ml '2.93 mmol) and 1-propanesulfonium (0.33 ml, 2.93). Mol). The reaction mixture was allowed to stir at ambient temperature for 16 hours, and then washed successively with potassium bicarbonate (50 ml) and brine (50 ml). The organic phase was dried (MgS04) and concentrated to give a colorless colloid. The residue was purified on a 40 g Biotage silica column and washed off with EtOAc-isohexane (8-2) to obtain [l- (propane-1-sulfonyl) -hexahydropyridine-4-ylmethyl Tris-butylaminocarbamate (809 mg, 95%) as a colorless colloid. A solution (5 ml) of 4 M HC1 in 1,4-dioxane was added to a portion of this colloid (695 mg, 2.17 mmol), and the resulting suspension was stirred at ambient temperature for 1.5 hours. The volatiles were then removed to give the title compound (770 mg, quantitative) as an orange-brown solid; NMR (300 MHz, DMS0) δ 0.95 (t? 3Η), 1.20-1.39 (m? 2H), 1.64 (sixfold peak , 2H), 1.79 (d, 2H), 2.70-2.87 (m, 5H), 96l5l.doc -112- 200523234 2.94 (t, 2H), 3.16-3.27 (m, 2H), 7.12 (t , 1H), 8.63 (s, 1H), 8.92 (s, 1H); MS m / z 220 (M + H) + 〇 & (3-aminopropyl) propane-1_continuous amine salt 睃To a solution of (3-amino-propyl) -carbamic acid tert-butyl ester (10 g, 5.73 mmol) in DCM (20 ml) was added amidin (0.51 Ml, 6 31 millimoles) and 1-propylsulfonium (0.71 ml, 6 31 millimoles). The reaction mixture was allowed to stir at ambient temperature for 5 hours, and then washed successively with potassium bicarbonate (5 () ml) and brine (50 ml). The organic phase was dried (MgS04) and concentrated to give a yellow colloid. The residue was purified on a 40 g Biotage silica column and washed off with EtOAc-isohexane (8-2) to obtain [3- (propan-1-sulfazylamino) _propyl] _amino group. Tertiary-butyl formate (717 mg, 45%) is a colorless colloid. A solution (5 ml) of 4 M HC1 in 1,4-dioxane was added to this colloid, and the resulting suspension was stirred at ambient temperature for 2 hours. The volatiles were then removed to give the title compound (495 mg, 91%) as a cream-colored solid; 4 NMR (300 MHz, DMSO) δ 0.96 (t, 3Η), 1.58-1.78 (m, 4H), 2.74 -2.85 (m, 2H), 2.92 _ 3.02 (m, 4H), 7.13 (t, 1H), 7.91 (s, 3H); MS m / z 180 (M + H) +. N- (3-Aminopropyl) methanesulfonamide hydrochloride This N- (3-aminopropyl) methanesulfonamide hydrochloride (CAS NO: 88334-76-3) is such as N- ( 3-Aminopropyl) propane-1-sulfamidamide hydrochloride was prepared, except that 1-propylsulfazone was replaced by methanesulfonyl chloride; MS m / z 153 (MH +). [1- (fluorenylsulfonyl) hexazol-4-yl] methylamine hydrochloride This [1- (fluorenylsulfonyl) hexahydropyridin-4-yl] methylamine hydrochloride (CAS No 325 153-03-5) is prepared like [1- (propylsulfonyl) -hexahydropyridine-4- 96151.doc -113- 200523234 group] -methylamine hydrochloride, except that Methanesulfonium gas was used instead of 1-propylsulfonium chloride; MS m / z 193 (MH +). {2- [4- (methylsulfonyl) phenyl] ethyl} amine {2_ [4- (methylsulfonyl) phenyl] ethyl W $ Cas NO: 153402-45-0 Niu, Jinkui; Lawrence, David S. Journal of Biological 1997, 272 (3), 1493-1499. Example 69: 2-{[((3R) -3-Amino-4-phenylbutylfluorenyl] amino group) -N-benzylindenane-2-carboxamidine Example 70: 2 _ {[(3R) -3_ Amino-4-phenylbutylfluorenyl] amino N- {2-[(propylsulfonyl) amino] ethyl} indenane-2-carboxamide Examples 69 to 70 are described in Example 38 Prepared using intermediates 61 and 62, respectively.

實例 R11 ^NMR (DMSO) MS m/z 69 ^X) 2.39-2.41 (m，2H)，2.67-2.75 (m， 1H), 2.90-2.96 (m, 1H), 3.12-3.21 (m，2H)，3.37-3.48 (m，2H)，3.59 (m， 1H), 4.19-4.30 (m, 2H), 7.12-7.28 (m，14H)，8.02 (brs，2H)，8.36 (t， 1H)，8.59 (s，1H) 428 _)+ 70 Η 0.95 (t, 3H), 1.57-1.69 (m, 2H), 2.35-2.40 (m, 2H), 2.68-2.75 (m, 1H), 486 (MH)+ 96151.doc -114- 200523234 2.90-2.95 (m, 5H), 3.04-3.22 (m, 4H), 3.39-3.60 (m, 2H)? 3.59-3.62 (m，1H)，6.95 (t，1H)，7.15-7.26 (m， 9H)，7·89 (t，1H)，8.00 (brs，2H)，8.61 (s，1H)Example R11 ^ NMR (DMSO) MS m / z 69 ^ X) 2.39-2.41 (m, 2H), 2.67-2.75 (m, 1H), 2.90-2.96 (m, 1H), 3.12-3.21 (m, 2H) , 3.37-3.48 (m, 2H), 3.59 (m, 1H), 4.19-4.30 (m, 2H), 7.12-7.28 (m, 14H), 8.02 (brs, 2H), 8.36 (t, 1H), 8.59 (s, 1H) 428 _) + 70 Η 0.95 (t, 3H), 1.57-1.69 (m, 2H), 2.35-2.40 (m, 2H), 2.68-2.75 (m, 1H), 486 (MH) + 96151.doc -114- 200523234 2.90-2.95 (m, 5H), 3.04-3.22 (m, 4H), 3.39-3.60 (m, 2H)? 3.59-3.62 (m, 1H), 6.95 (t, 1H), 7.15-7.26 (m, 9H), 7.89 (t, 1H), 8.00 (brs, 2H), 8.61 (s, 1H)

中間艘61 : [(R)-l-苄基_2-(2-苄基胺甲醜基-茚基胺甲酿 基）_乙基】-胺基甲酸第三-丁基酯 中間體62 : ((R)-1-苄基-2-{2-【2-(丙烷-1_磺醯基胺基）_乙基胺 甲醯基卜茚-2-基胺甲醯基}-乙基）-胺基甲酸第三·丁基醋 中間體61及6 2係用中間體2及適宜的胺以中間體b所述 ，產品直接行去保護步驟。 中間體 R11 MS m/z 61 550 M+Na 62 ,9wP Η 608 M+Na 96151.doc 115-Middle Ship 61: [(R) -l-benzyl_2- (2-benzylaminomethyl-indenylaminomethyl) -ethyl] -aminocarboxylic acid third-butyl ester intermediate 62 : ((R) -1-benzyl-2- {2- [2- (propane-1_sulfonamidoamino) _ethylaminemethylamidomethylindane-2-ylaminemethylamido}}-ethyl ) -Amino carboxylic acid tertiary-butyl acetic acid intermediates 61 and 62. The intermediate 2 and a suitable amine are described in intermediate b, and the product is directly subjected to a deprotection step. Intermediate R11 MS m / z 61 550 M + Na 62, 9wP Η 608 M + Na 96151.doc 115-

Claims (1)

200523234 十、申請專利範圍· 1. 一種式（I)化合物或其醫藥上可接受的鹽200523234 X. Scope of patent application 1. A compound of formula (I) or a pharmaceutically acceptable salt thereof 其中： Ar是視需要經獨立選自r9的1 ’ 2 ’ 3 ’ 4或5個基團取 代的苯基； R9是選自鹵，（1-6C)烷基（視需要以1_5個鹵取代的）’ (1-6C)烷氧基（視需要以卜5個鹵取代的）及氰基； R1是選自氫及（UC)烷基； R2是選自氫、（1-6C)烷基、（3-8C)環烷基、（5-12C)雙 環烷基、（6-12C)三環烷基、AR1、HET1、-(1-6C)烧基 AR1、-(1-6C)烧基 AR2、-(1-6C)烧基（3-8C)環烧基、-(1-6C)烷基 HET1、-(1-6C)烷基 HET2、-(1-6C)烧基 C02(1-6C)烷基、-(1-6C)烷基 C02(3-8C)環烧基、-(1-6C)烧基 C02AR1、-(卜 6C)烧基 C02HET1、-(1-6C)烧基 OCO(l-6C) 烷基、-(1-6C)烷基〇CO(3-8C)環烷基、-(1-6C)烷基 OCOAR1、-(1-6C)烷基 OCOHET1、-(1-6C)烷基 CO(l-6C) 烷基、-(1-6C)烷基CO(3-8C)環烷基、-(1-6C)烷基 COAR1、-(1-6C)烷基 COHET1、-(1-6C)烷基 NHCO(l-6C) 烷基、-(1-6C)烷基NHCO(3-8C)環烷基、_(1_6C)烷基 NHCOAR1、-(1-6C)烧基 CONH(l-6C)炫基、-(1-6C)烧基 96151.doc 200523234 CONH(3-8C)環烷基、-(1-6C)烷基 CON-二（1-6C)烷 基、-(1-6C)烷基 CONHAR1、-(1-6C)烷基 NH(1-6C)烷 基、-(1-6C)烷基 N_ 二（1-6C)烷基、-(1-6C)烷基 NHAR1、 -(1-6C)烷基 NH(HETl)、-(1_6C)烷基 NHS02(1-6C)烷 基、-(1-6C)烷基 S02NH(1-6C)烷基、-(1-6C)烷基 S02(1-6C)烷基、-S02(1-6C)烷基及（1-6C)烷基 S02N-二（1-6C)烷 基； 或 R1及R2可共同與其相聯的氮形成HET1或HET3所界 定的環；其中包含R1及R2的環是視需要由1或2個取代基 取代的，此等取代基係獨立選自鹵、（1-6C)烷基、鹵（1-6C)烷基、（1-6C)烷氧基、氰基、羧基、羧基U-6C)烷 基、-CO(l-6C)烷基、C02(1-6C)烷基、（1-6C)烷基胺 基、二-(1-6C)烷基胺基、_NHCO((l-6C)烷基、_CONH(l-6C)烷基、-CON 二-(1-6C)烷基及 HET1 ; R3及R4係獨立選自氫、（1-6C)烷基、（3-8C)環烷基、 (3-8C)環烯基、（5-12C)雙環烷基、-(1-6C)烷基（3-8C)環 烷基、-(1-6C)烷基（3-8C)環烯基、AR1、AR2、HET1、 HET2、-(1-6C)烷基 AR1、_(1-6C)烷基 AR2、-(1-6C)烷基 HET1 及-(1-6C)烷基HET2;或 R3及R4共同形成以（3-8C)環烷基、AR2、HET1或HET2 所界定的環； R5、R6、R7及R8是獨立選自氫及（1-6C)烷基，其中任 一由 R1、R2、R3、R4、R5、R6、R7 及 R8 内所界定的（1- 96151.doc 200523234 6C)炫基是視需要由_個取代基取代的，此等取代基係 獨立選自羥基及氟；其中r2' R3或尺4内所界定的任一(弘 8C)環烷基、（3_8C)環烯基、（5_12C)雙環烷基或（6_ιχ) 三環烷基是視需要經取代的； AR1是視需要經取代的苯基； AR2是視需要經取代的8·、9-或1〇_員的，不飽和的， 部分或全部飽和的雙環碳環形環； HET1是視需要經取代的3_、4一 5-或6-貝#，不飽和 的，部分或全部飽和的單環雜環基環，含達四個雜原 子，此等雜原子係獨立選自〇、s(但不含〇_〇、〇_ s、或S-S鍵），如果環不因而季銨化（quaternised)，是經 環碳原子或環氮原子相聯，且其中任一碳，硫或氮原子 可以是經氧化的； HET2是視需要經取代的8…9-或員的，不飽和 的，部分或全部飽和的雙環雜環，含達四個獨立選自 〇，N及S的雜原子（但不含〇-〇、〇-S或s — s鍵），並經由含 雙環系統的環内的環碳原子鍵合； HET3是N-鍵合的飽和的雙環或三環環系統，含達12 個環原子，包括鍵合的氮原子； 其中（3-8C)環烷基、（5-12C)雙環烷基、（6-12C)三環烷 基、AR1、AR2、HET1及HET2上適宜的取代基是1、2、 3、4或5個取代基，獨立選自苯基（視需要以鹵、三氟甲 基、（1-4C)烷基或（1-4C)烷氧基取代的）、鹵、（1-6C)烷 基、鹵（1-6C)烷基、二鹵（1-6C)烷基、三氟甲基、（1-6C) 96151.doc 200523234 烷氧基、羧基（1-6C)烷基、羧基（1-6C)烷氧基、羥基、胺 基、（1_6C)烷基胺基、二（1-6C)烷基胺基、-CONH2、 -CONH(l-6C)烷基、-CON 二（1-6C)烷基、-NHCO(l-6C) 烷基、-S02(1-6C)烷基、-S(0)2NH2、-S02NH(1-6C)烷 基、-S02N:(1-6C)烷基及 _NHS〇2(l-6C)烷基。 2·根據請求項1之化合物，其為式（IA)化合物Wherein: Ar is a phenyl substituted with 1 ′ 2 ′ 3 ′ 4 or 5 groups independently selected from r9 as needed; R9 is selected from halogen, (1-6C) alkyl (substituted with 1-5 halogens as required) ) '(1-6C) alkoxy (substituted with 5 halogens as needed) and cyano; R1 is selected from hydrogen and (UC) alkyl; R2 is selected from hydrogen, (1-6C) alkane Group, (3-8C) cycloalkyl, (5-12C) bicycloalkyl, (6-12C) tricycloalkyl, AR1, HET1,-(1-6C) alkynyl AR1,-(1-6C) Alkenyl AR2,-(1-6C) alkenyl (3-8C) cycloalkenyl,-(1-6C) alkyl HET1,-(1-6C) alkyl HET2,-(1-6C) alkenyl C02 (1-6C) alkyl,-(1-6C) alkyl C02 (3-8C) cycloalkyl,-(1-6C) alkyl C02AR1,-(Bu 6C) alkyl C02HET1,-(1-6C ) Alkyl OCO (l-6C) alkyl,-(1-6C) alkyl OCO (3-8C) cycloalkyl,-(1-6C) alkyl OCOAR1,-(1-6C) alkylOCOHET1 ,-(1-6C) alkylCO (l-6C) alkyl,-(1-6C) alkylCO (3-8C) cycloalkyl,-(1-6C) alkylCOAR1,-(1- 6C) alkyl COHET1,-(1-6C) alkylNHCO (l-6C) alkyl,-(1-6C) alkylNHCO (3-8C) cycloalkyl, _ (1_6C) alkylNHCOAR1,- (1-6C) Carbonyl CONH (l-6C) Hexyl,-(1-6C) Carbonyl 96151.doc 200523 234 CONH (3-8C) cycloalkyl,-(1-6C) alkylCON-di (1-6C) alkyl,-(1-6C) alkylCONHAR1,-(1-6C) alkylNH ( 1-6C) alkyl,-(1-6C) alkylN_di (1-6C) alkyl,-(1-6C) alkylNHAR1,-(1-6C) alkylNH (HETl),-( 1-6C) alkylNHS02 (1-6C) alkyl,-(1-6C) alkylS02NH (1-6C) alkyl,-(1-6C) alkylS02 (1-6C) alkyl, -S02 ( 1-6C) alkyl and (1-6C) alkyl S02N-di (1-6C) alkyl; or the nitrogen to which R1 and R2 can be linked together form a ring defined by HET1 or HET3; including R1 and R2 The ring is optionally substituted with 1 or 2 substituents, and these substituents are independently selected from halogen, (1-6C) alkyl, halo (1-6C) alkyl, (1-6C) alkoxy , Cyano, carboxyl, carboxyl U-6C) alkyl, -CO (l-6C) alkyl, C02 (1-6C) alkyl, (1-6C) alkylamino, di- (1-6C) Alkylamino, _NHCO ((l-6C) alkyl, _CONH (l-6C) alkyl, -CON di- (1-6C) alkyl and HET1; R3 and R4 are independently selected from hydrogen, (1- 6C) alkyl, (3-8C) cycloalkyl, (3-8C) cycloalkenyl, (5-12C) bicycloalkyl,-(1-6C) alkyl (3-8C) cycloalkyl,- (1-6C) alkyl (3-8C) cycloalkenyl, AR1, AR2, HET1 HET2,-(1-6C) alkyl AR1, _ (1-6C) alkyl AR2,-(1-6C) alkyl HET1 and-(1-6C) alkyl HET2; or R3 and R4 together form ( 3-8C) ring defined by cycloalkyl, AR2, HET1 or HET2; R5, R6, R7 and R8 are independently selected from hydrogen and (1-6C) alkyl, any of which is represented by R1, R2, R3, R4 (1-96151.doc 200523234 6C) as defined in R, R5, R6, R7, and R8 are optionally substituted with _ substituents, these substituents are independently selected from hydroxyl and fluorine; where r2 'R3 Or any of the (Hong 8C) cycloalkyl, (3_8C) cycloalkenyl, (5_12C) bicycloalkyl, or (6_ιχ) tricycloalkyl defined in Rule 4 is substituted as needed; AR1 is Substituted phenyl; AR2 is optionally substituted 8 ·, 9- or 10-membered, unsaturated, partially or fully saturated bicyclic carbocyclic ring; HET1 is optionally substituted 3_, 4-5 -Or 6- 贝 #, an unsaturated, partially or fully saturated monocyclic heterocyclyl ring, containing up to four heteroatoms, these heteroatoms are independently selected from 〇, s (but excluding 〇_〇, 〇 _ s, or SS bond), if the ring is not quaternised, Linked by a ring carbon atom or a ring nitrogen atom, and any one of the carbon, sulfur or nitrogen atoms may be oxidized; HET2 is optionally substituted 8 ... 9- or less, unsaturated, partially or fully saturated Bicyclic heterocycle containing up to four heteroatoms independently selected from 0, N and S (but not containing 0-〇, 0-S or s-s bond), and via a ring carbon atom in a ring containing a bicyclic system Bonding; HET3 is an N-bonded saturated bicyclic or tricyclic ring system containing up to 12 ring atoms, including bonded nitrogen atoms; of which (3-8C) cycloalkyl, (5-12C) bicycloalkane (6-12C) tricycloalkyl, AR1, AR2, HET1 and HET2 are suitable substituents of 1, 2, 3, 4 or 5 substituents independently selected from phenyl (halo, tri Fluoromethyl, (1-4C) alkyl or (1-4C) alkoxy substituted), halo, (1-6C) alkyl, halo (1-6C) alkyl, dihalo (1-6C) Alkyl, trifluoromethyl, (1-6C) 96151.doc 200523234 alkoxy, carboxy (1-6C) alkyl, carboxy (1-6C) alkoxy, hydroxyl, amine, (1-6C) alkyl Amine, di (1-6C) alkylamino, -CONH2, -CONH (l-6C) alkyl -CON di (1-6C) alkyl, -NHCO (l-6C) alkyl, -S02 (1-6C) alkyl, -S (0) 2NH2, -S02NH (1-6C) alkyl, -S02N : (1-6C) alkyl and -NHS02 (l-6C) alkyl. 2. The compound according to claim 1, which is a compound of formula (IA) (IA) 或其醫藥上可接受的鹽，其中R1、R2、R3、R4、R5、 R6、R7及R8具如請求項1所界定的意義。 3.根據請求項1或2之化合物或其醫藥上可接受的鹽，其 中： Ar是視需要經1、2、3、4或5個獨立選自R9的基團取 代的苯基； R9是選自鹵、（1-6C)烷基（視需要是以1-5個鹵取代 的）、（1-6C)烷氧基（視需要是以1-5個鹵取代的）及氰基； R1是選自氫及（1-6C)烷基； R2是選自氫、（1-6C)烷基、（3-8C)環烷基、（5-12C)雙 環烷基、（6-12C)三環烷基、AR1、HET1、-(1-6C)烷基 AR1、-(1-6C)烷基 AR2、-(1-6C)烷基（3-8C)環烷基、-(1-6C)烷基 HET1、-(1-6C)烷基 HET2、_(i-6C)烷基 C02(1-6C)烷基、-(1-6C)烷基 C02(3-8C)環烷基、_(1_6C)烷基 96151.doc 200523234 C02AR1、-(1-6C)烧基 C02HET1、-(1-6C)烧基 〇CO(l-6C) 烷基、-(1-6C)烷基〇CO(3-8C)環烷基、-(1-6C)烷基 OCOAR1、-(1-6C)烧基 OCOHET1、-(1-6C)燒基 CO(l-6C) 烷基、-(1-6C)烷基CO(3-8C)環烷基、-(1-6C)烷基 COAR1、-(1-6C)貌基 COHET1、-(1-6C)炫基 NHCO(l-6C) 烷基、-(1-6C)烷基NHCO(3-8C)環烷基、-(1-6C)烷基 NHCOAR1、-(1-6C)烷基 CONH(l-6C)烷基、-(1-6C)烷 基 CONH(3-8C)環烷基、-(1-6C)烷基 CON-二（1-6C)烷 基、-(1-6C)烷基 CONHAR1、-(1-6C)烷基 NH(1-6C)烷 基、-(1-6C)烷基 N-二（1-6C)烷基、-(1-6C)烷基 NHAR1、-(1-6C)烧基 NH(HETl)、-(1-6C)烧基 NHS02(1-6C)烷基、_(1-6C)烷基 S02NH(1-6C)烷基及-(1-6C)烷基 S02N-二（1-6C)烷基； 或 R1及R2可共同與其相聯的氮形成HET1所界定的環； 其中含R1及R2的環是視需要由1或2個取代基取代的， 此等取代基係獨立選自鹵、（！-6C)烷基、鹵（i_6C)烷 基、（1-6C)烧氧基、氰基、竣基、竣基（KC)烧基、 -CO(l-6C)烷基、-C02(1-6C)烷基、（1-6C)烷基胺基、二-(1-6C)烷基胺基、-NHCO(l-6C)烷基、-CONH(l-6C)烷 基、-CON-二（1-6C)烷基及 HET1 ; R3及R4係獨立選自氫、（1-6C)烷基、-(1-6C)烷基（3-8C)環烷基、-(1-6C)烷基（3-8C)環烯基、-(1-6C)烷基 AR1、-(1-6C)烷基 AR2、-(1-6C)烷基 HET1 及-(1-6C)烷基 96151.doc 200523234 HET2 ;或 R及R共同形成如（3-8C)環烷基、AR2、ίίΕΤΙ或HET2 所界定的環； R、R、R7及R8是獨立選自氫及（1_6C)烷基； AR1是視需要經取代的笨基； AR2是視需要經取代的8_、9·或1〇_員的，不飽和的， 部分或全部飽和的雙環碳環形環； HET1是視需要經取代的3_、4·、5_或卜員的，不飽和 的’部分或全部飽和的單環雜環基環，含達四個雜原 子’此等雜原子係獨立選自〇，N及s(但不含0-0，0-S 或s-s鍵），如果環不因而季銨化（quaternised),是經環碳 原子或環氮原子相聯，且其中任一碳、硫或氮原子可以 是經氧化的； HET2是視需要經取代的8-、9-或10-員的，不飽和 的，部分或全部飽和的雙環雜環，含達四個獨立選自 Ο、N及S的雜原子（但不含〇-〇、〇-S或S-S鍵），並經由含 雙環系統的環内的環碳原子鍵合； 其中AR1、AR2、HET1及HET2上適宜的取代基是1、 2、3、4或5個取代基，獨立選自鹵、（1-6C)烷基、鹵（1-6C)烷基、二鹵（1_6C)烷基、三氟甲基、（1-6C)烷氧基、 羧基（1-6C)烷基、羧基（1-6C)烷氧基、羥基、胺基、（1-6C)烷基胺基、二（1-6C)烷基胺基、-CONH2、-CONH(l_ 6C)烷基、-CON 二（1-6C)烷基-NHCO(l-6C)烷基、 -S(0)2NH2、-S02NH(1-6C)烷基、_S02N二（1-6C)烷基及 96151.doc 200523234 -NHS02(1-6C)烷基。 4. 根據請求項1或2之化合物或其醫藥上可接受的鹽，其中 Ar是視需要以1或2個獨立選自R9的基團取代的苯基； R9是選自鹵、甲基、甲氧基及三氟甲基； R1是氫或甲基； R5是氫； R6是氫； R7是氫； R8是氫； R3及R4共同形成由AR2、HET1或HET2所界定的環；及 R2是選自（1-6C)烷基、（3-8C)環烷基、（5-12C)雙環烷 基、（6-12C)三環烷基、AR1、HET1、-(1-6C)烷基 AR1、-(1-6C)烷基 NHCO(l-6C)烷基、-(1-6C)烷基 NHCOAR1、-(1-6C)烧基 CONH(l-6C)烧基、-(1-6C)烧基 CONHAR1、-(1-6C)烧基 NH(1-6C)烧基、-(1-6C)烧基 NHAR1、-(1-6C)烧基 NH(HETl)、-(1-6C)烧基 NHS02(1 -6C)烷基及-(1-6C)烷基 S02NH(1-6C)烷基。 5. 根據請求項1或2之式（I)化合物或其醫藥上可接受的鹽， 其中 Ar是視需要以1或2個獨立選自R9的基團取代的苯基； R9是選自鹵，甲基，甲氧基及三氟曱基； R1是氫或曱基； R5是氫； R6是氫； 96151.doc 200523234 R7是氫； R8是氫； R3是氫及R4是選自-(丨-4(^)烧基（3-8C)環烧基、-(1-4C) 烷基（3-8C)環烯基、-(1-4C)烷基AR1、-(1-4C)烷基 AR2、-(1-4C)烷基 HET1 及（1-4C)烷基 HET2 ;及 R2是選自（1-6C)烷基、（3-8C)環烷基、（5-12C)雙環燒 基、（6-12C)三環烷基、AR1、HET1、_(1-6C)烷基 AR1、-(1-6C)烷基 NHCO(l-6C)烷基、-(1-6C)烷基 NHCOAR1、-(卜 6C)烷基 CONH(l-6C)烷基、，(卜 6C)烷基 CONHAR1、-(1-6C)貌基 NH(1-6C)烧基、-(1-6C)烧基 NHAR1、-(1-6C)烧基 NH(HETl)、-(1-6C)烧基 NHS02(1-6C)烧基及- (1-6C)烧基 S〇2NH( 1-6C)烧基。 6.根據請求項1或2之化合物或其醫藥上可接受的鹽’其中 Ar是經1、2或3個氟取代的苯基； R1是氫； R2是選自（1-6C)烷基、（3-8C)環烷基、（5-12C)雙環烷 基、（6-12C)三環烷基、AR1、HET1、_(1-6C)烷基 AR1、-(1-6C)烷基 NHCO(l-6C)烷基、_(1_6C)烷基 NHCOAR1、-(卜 6C)烧基 CONH(l-6C)烧基、-(1-6C)烧基 CONHAR1、-(1-6C)烧基 NH(1-6C)院基、-(1-6C)烧基 NHAR1、-(1-6C)烧基 NH(HETl)、-(1-6C)烧基 NHS02(1-6C)烷基及-(1-6C)烷基 S02NH(1-6C)烷基、 R3是氫； R4是 CH2-AR1、CH2-HET1 或 CH2-HET2 ;及 96151.doc 200523234 R5、R6、R7及R8都是氫。 7·根據請求項1或2之化合物或其醫藥上可接受的鹽，其中 Ar是以1、2或3個氟取代的苯基； R1是氫； R2是選自氫、（1-4C)烷基、（i_4C)烷基AR1或-(1-4C)烷基 CONH(l-4C)烷基； R3是氫； R4是 CH2-AR1 或 CH2-HET1 ;及 R5、R6、R7及R8都是氫。 8·根據請求項5之化合物或其醫藥上可接受的鹽，其中帶有 R3及R4的碳原子有（R)-構形。 9.根據請求項1之化合物，其係選自 (R)-3-胺基-N-((R)-1-苄基胺甲醯基-2-苯基-乙基）-4-(2-氟-苯基）-丁醯胺； (R)-3 -胺基-4-(2·亂-本基）-N_((R)-1-曱基胺甲酿基-2 -苯 基-乙基）-丁醯胺； (R)-3-胺基-4-(2-氟-苯基:)-Ν-[(Γ〇-1-(甲基胺甲醯基甲基-胺曱醯基）-2-苯基-乙基]-丁醯胺； (R)-3-胺基-4-(2-氟-苯基）-N-((R)-1-甲基胺甲醯基-2-苯 硫-2-基-乙基）-丁醯胺； (R)-3-胺基-4-(2-氟-苯基）-N-((R)-2_(1H_吲哚-3-基）-1-甲 基胺甲醯基-乙基）-丁醯胺； (R)-3-胺基-N-[(R)-2-(4-氯-苯基）-1-甲基胺甲醯基-乙基]-4-(2-氟-苯基）-丁醯胺； 96l51.doc -9- 200523234 (R)-3-胺基-N-[(R)-2_(4-甲基-苯基）-1-甲基胺甲醯基-乙 基]-4-(2-氟-苯基）-丁醯胺； (R)-3-胺基-4-(2-氟-苯基:)-Ν-((ΙΙ)-1-甲基胺甲醯基-2-¾ 啶-3-基-乙基）-丁醯胺； (R)-3-胺基-4-(2-氟-苯基:)-Ν-((ΙΙ)-1-甲基胺甲醯基-2-。比 啶-4-基-乙基）-丁醯胺； (R)-3_胺基-N-[(R)-2-(4-溴-苯基）-1-甲基胺甲醯基-乙基]_ 4-(2-氟-苯基）-丁醯胺； (R)-3-胺基-4-(2-氟·苯基）_N-((R)-1-甲基胺甲醯基-2-笨 硫-3-基-乙基）-丁醯胺； (R)-3-胺基-4-(2-氟-苯基）-N-((R)-1-甲基胺甲酿基-2_°比 。定-2 -基-乙基）-丁酿胺，及 (R)-3-胺基-N-(l-胺甲醯基_2_吱喃_2_基-乙基）-4-(2-氟-笨 基）-丁醯胺；或其醫藥上可接受的鹽。 10· —種根據請求項1之式（I)化合物或其鹽的製備方法，其 包括 a)用式（II)化合物或其活化衍生物，其中p是胺基保護 基，與式（III)化合物偶合，然後除去保護基p ;(IA) or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, R7 and R8 have the meanings as defined in claim 1. 3. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein: Ar is a phenyl group optionally substituted with 1, 2, 3, 4 or 5 groups independently selected from R9; R9 is Selected from halogen, (1-6C) alkyl (optionally substituted with 1-5 halogens), (1-6C) alkoxy (optionally substituted with 1-5 halogens), and cyano; R1 is selected from hydrogen and (1-6C) alkyl; R2 is selected from hydrogen, (1-6C) alkyl, (3-8C) cycloalkyl, (5-12C) bicycloalkyl, (6-12C ) Tricycloalkyl, AR1, HET1,-(1-6C) alkyl AR1,-(1-6C) alkyl AR2,-(1-6C) alkyl (3-8C) cycloalkyl,-(1 -6C) alkyl HET1,-(1-6C) alkyl HET2, _ (i-6C) alkylC02 (1-6C) alkyl,-(1-6C) alkylC02 (3-8C) cycloalkane Group, _ (1_6C) alkyl group 96151.doc 200523234 C02AR1,-(1-6C) alkyl group C02HET1,-(1-6C) alkyl group CO (l-6C) alkyl group,-(1-6C) alkyl group 〇CO (3-8C) cycloalkyl,-(1-6C) alkyl OCOAR1,-(1-6C) alkyl OCOHET1,-(1-6C) alkylCO (l-6C) alkyl,-( 1-6C) alkylCO (3-8C) cycloalkyl,-(1-6C) alkyl COAR1,-(1-6C) morphocohet1,-(1-6C) hexylNHCO (l-6C) Alkyl,-(1-6C) alkylNHCO (3-8C) cycloalkane ,-(1-6C) alkylNHCOAR1,-(1-6C) alkylCONH (l-6C) alkyl,-(1-6C) alkylCONH (3-8C) cycloalkyl,-(1- 6C) alkyl CON-di (1-6C) alkyl,-(1-6C) alkyl CONHAR1,-(1-6C) alkylNH (1-6C) alkyl,-(1-6C) alkyl N-di (1-6C) alkyl,-(1-6C) alkylNHAR1,-(1-6C) alkyl NH (HETl),-(1-6C) alkyl NHS02 (1-6C) alkyl , _ (1-6C) alkylS02NH (1-6C) alkyl and-(1-6C) alkylS02N-di (1-6C) alkyl; or R1 and R2 can jointly form nitrogen with it to form HET1 A ring defined by R1 and R2 which are optionally substituted by 1 or 2 substituents, and these substituents are independently selected from halogen, (! -6C) alkyl, halogen (i_6C) alkyl, (1-6C) oxy group, cyano group, end group, end group (KC) group, -CO (l-6C) alkyl, -C02 (1-6C) alkyl, (1-6C) alkyl Amine, di- (1-6C) alkylamino, -NHCO (l-6C) alkyl, -CONH (l-6C) alkyl, -CON-di (1-6C) alkyl and HET1; R3 And R4 are independently selected from hydrogen, (1-6C) alkyl,-(1-6C) alkyl (3-8C) cycloalkyl,-(1-6C) alkyl (3-8C) cycloalkenyl, -(1-6C) alkyl AR1,-(1-6C) alkyl AR2,-(1-6C) alkyl HET1 and-(1-6C) alkane 96151.doc 200523234 HET2; or R and R together form a ring as defined by (3-8C) cycloalkyl, AR2, ίΕΙ or HET2; R, R, R7 and R8 are independently selected from hydrogen and (1-6C) alkyl AR1 is a substituted benzyl as needed; AR2 is an optionally substituted 8-, 9 · or 10-membered, unsaturated, partially or fully saturated bicyclic carbocyclic ring; HET1 is optionally substituted 3_, 4 ·, 5_, or bifurcated, unsaturated 'partially or fully saturated monocyclic heterocyclyl ring containing up to four heteroatoms' These heteroatoms are independently selected from 0, N and s (but Does not contain 0-0, 0-S or ss bond), if the ring is not quaternised, it is linked via a ring carbon atom or a ring nitrogen atom, and any of the carbon, sulfur or nitrogen atoms may be Oxidized; HET2 is optionally substituted 8-, 9- or 10-membered, unsaturated, partially or fully saturated bicyclic heterocyclic ring containing up to four heteroatoms independently selected from 0, N and S ( But does not contain 〇-〇, 〇-S or SS bond), and is bonded via a ring carbon atom in a ring containing a bicyclic system; wherein AR1, AR2, HET1 and HET2 are suitable substituents Are 1, 2, 3, 4 or 5 substituents independently selected from halo, (1-6C) alkyl, halo (1-6C) alkyl, dihalo (1-6C) alkyl, trifluoromethyl, ( 1-6C) alkoxy, carboxy (1-6C) alkyl, carboxy (1-6C) alkoxy, hydroxyl, amine, (1-6C) alkylamino, di (1-6C) alkyl Amine, -CONH2, -CONH (l-6C) alkyl, -CON di (1-6C) alkyl-NHCO (l-6C) alkyl, -S (0) 2NH2, -S02NH (1-6C) alkane _S02N di (1-6C) alkyl and 96151.doc 200523234-NHS02 (1-6C) alkyl. 4. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein Ar is a phenyl group optionally substituted with 1 or 2 groups independently selected from R9; R9 is selected from halogen, methyl, Methoxy and trifluoromethyl; R1 is hydrogen or methyl; R5 is hydrogen; R6 is hydrogen; R7 is hydrogen; R8 is hydrogen; R3 and R4 together form a ring defined by AR2, HET1 or HET2; and R2 Is selected from (1-6C) alkyl, (3-8C) cycloalkyl, (5-12C) bicycloalkyl, (6-12C) tricycloalkyl, AR1, HET1,-(1-6C) alkane Group AR1,-(1-6C) alkylNHCO (l-6C) alkyl,-(1-6C) alkylNHCOAR1,-(1-6C) alkyl, CONH (l-6C) alkyl,-(1 -6C) Carbonyl CONHAR1,-(1-6C) alkyl NH (1-6C) alkyl,-(1-6C) alkyl NHAR1,-(1-6C) alkyl NH (HETl),-(1 -6C) alkyl NHS02 (1 -6C) alkyl and-(1-6C) alkyl S02NH (1-6C) alkyl. 5. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein Ar is a phenyl group optionally substituted with 1 or 2 groups independently selected from R9; R9 is selected from halogen , Methyl, methoxy and trifluorofluorenyl; R1 is hydrogen or fluorenyl; R5 is hydrogen; R6 is hydrogen; 96151.doc 200523234 R7 is hydrogen; R8 is hydrogen; R3 is hydrogen and R4 is selected from-(丨 -4 (^) alkyl (3-8C) cycloalkyl,-(1-4C) alkyl (3-8C) cycloalkenyl,-(1-4C) alkyl AR1,-(1-4C) Alkyl AR2,-(1-4C) alkyl HET1 and (1-4C) alkyl HET2; and R2 is selected from (1-6C) alkyl, (3-8C) cycloalkyl, (5-12C) Bicycloalkyl, (6-12C) tricycloalkyl, AR1, HET1, _ (1-6C) alkyl AR1,-(1-6C) alkylNHCO (l-6C) alkyl,-(1-6C ) Alkyl NHCOAR1,-(Bu 6C) alkyl CONH (l-6C) alkyl, (Bu 6C) alkyl CONHAR1,-(1-6C) alkyl NH (1-6C) alkyl,-(1 -6C) alkyl NHAR1,-(1-6C) alkyl NH (HETl),-(1-6C) alkyl NHS02 (1-6C) alkyl and-(1-6C) alkyl 〇2NH (1 -6C) alkyl. 6. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein Ar is phenyl substituted with 1, 2 or 3 fluorines; R1 is hydrogen; R2 is selected from (1-6C) alkyl, (3-8C) cycloalkyl, (5-12C) bicycloalkyl, (6-12C) tricycloalkyl, AR1, HET1, _ ( 1-6C) alkyl AR1,-(1-6C) alkylNHCO (l-6C) alkyl, _ (1-6C) alkylNHCOAR1,-(bu 6C) alkyl CONH (l-6C) alkyl,- (1-6C) Carbonyl CONHAR1,-(1-6C) Carbonyl NH (1-6C) Codium,-(1-6C) Carbonyl NHAR1,-(1-6C) Carbonyl NH (HET1),- (1-6C) alkyl NHS02 (1-6C) alkyl and-(1-6C) alkyl S02NH (1-6C) alkyl, R3 is hydrogen; R4 is CH2-AR1, CH2-HET1 or CH2-HET2 And 96151.doc 200523234 R5, R6, R7 and R8 are all hydrogen. 7. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein Ar is benzene substituted with 1, 2 or 3 fluorines R1 is hydrogen; R2 is selected from hydrogen, (1-4C) alkyl, (i_4C) alkylAR1 or-(1-4C) alkylCONH (l-4C) alkyl; R3 is hydrogen; R4 is CH2-AR1 or CH2-HET1; and R5, R6, R7 and R8 are all hydrogen. 8. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein the carbon atoms bearing R3 and R4 have an (R) -configuration. 9. A compound according to claim 1, which is selected from (R) -3-amino-N-((R) -1-benzylaminomethylamido-2-phenyl-ethyl) -4- ( 2-fluoro-phenyl) -butanidine; (R) -3 -amino-4- (2 · ran-benzyl) -N _ ((R) -1-amidinomethylmethyl-2-benzyl) -Ethyl) -butanidine; (R) -3-amino-4- (2-fluoro-phenyl:)-N-[(Γ〇-1- (methylaminomethylmethylmethyl- Aminomethyl) -2-phenyl-ethyl] -butylamidamine; (R) -3-amino-4- (2-fluoro-phenyl) -N-((R) -1-methyl Carboxamidine-2-phenylthio-2-yl-ethyl) -butanamide; (R) -3-amino-4- (2-fluoro-phenyl) -N-((R) -2_ (1H_indol-3-yl) -1-methylamine formamidine-ethyl) -butanidine; (R) -3-amino-N-[(R) -2- (4-chloro -Phenyl) -1-methylaminomethylamidino-ethyl] -4- (2-fluoro-phenyl) -butanidine; 96l51.doc -9- 200523234 (R) -3-amino-N -[(R) -2_ (4-methyl-phenyl) -1-methylamine formamidine-ethyl] -4- (2-fluoro-phenyl) -butanamide; (R) -3 -Amino-4- (2-fluoro-phenyl:)-N-((III) -1-methylaminomethylmethyl-2--2-pyridin-3-yl-ethyl) -butanidine; ( R) -3-amino-4- (2-fluoro-phenyl:)-N-((II) -1-methylaminomethylmethyl-2-.pyridin-4-yl-ethyl)- Butamidine (R) -3_Amino-N-[(R) -2- (4-bromo-phenyl) -1-methylamine formamyl-ethyl] 4- (2-fluoro-phenyl) -Butanidine; (R) -3-amino-4- (2-fluoro · phenyl) _N-((R) -1-methylaminomethylmethyl-2-benzylthio-3-yl-ethyl ) -Butylamine; (R) -3-amino-4- (2-fluoro-phenyl) -N-((R) -1-methylamine methylamino-2 ° ratio. Ding-2 -Yl-ethyl) -butylamine, and (R) -3-amino-N- (l-aminomethylamido_2_crean_2_yl-ethyl) -4- (2-fluoro -Benzyl) -butanamide; or a pharmaceutically acceptable salt thereof. 10. A method for preparing a compound of formula (I) or a salt thereof according to claim 1, comprising a) using a compound of formula (II) or Its activated derivative, wherein p is an amine protecting group, coupled with a compound of formula (III), and then removing the protecting group p; (π) (III) 或b)以式（IV)化合物或其活化衍生物，其中p是胺基保護 基，與式（V)化合物偶合，再除去保護基p ; 96151.doc -10 - 200523234 /P(π) (III) or b) a compound of formula (IV) or an activated derivative thereof, wherein p is an amine protecting group, coupled with a compound of formula (V), and then removing the protecting group p; 96151.doc -10-200523234 / P HN 〇 R7ί r^R6 (IV) 然後，如有必要 (i) 將式（I)化合物以習用官能基團修改轉化成另一式⑴化 合物；及/或 (ii) 視需要生成醫藥上可接受的鹽；及其中Ar、Ri、R2、 R、R、R、R、R及R8有任何請求項1界定的意義。 11 · 一種醫藥組合物’其含根據請求項1或2之式⑴或（ία)化 合物或其醫藥上可接受的鹽及與其混合的醫藥上可接受 的賦形劑或載劑。 12·根據請求項1或2之式（I)或（IA)化合物或其醫藥上可接受 的鹽供用作藥物。 13·根據請求項1或2之式（I)或（IA)化合物或其醫藥上可接受 的鹽在製備藥物供於溫血動物產生DPP_IV活性抑制上 的用途。 96151.doc -11 - 200523234 七、 指定代表圖·· (一) 本案指定代表圖為：（無） (二) 本代表圖之元件符號簡單說明： 八、 本案若有化學式時，請揭示最能顯示發明特徵的化學式:HN 〇R7ί r ^ R6 (IV) Then, if necessary (i) convert the compound of formula (I) into another compound of formula (I) with conventional functional group modification; and / or (ii) if necessary, produce a pharmaceutically acceptable Salt; and Ar, Ri, R2, R, R, R, R, R, and R8 have the meaning defined in any claim 1. 11. A pharmaceutical composition 'comprising the compound of formula (I) or (ία) or a pharmaceutically acceptable salt thereof according to claim 1 or 2 and a pharmaceutically acceptable excipient or carrier mixed therewith. 12. A compound of formula (I) or (IA) or a pharmaceutically acceptable salt thereof according to claim 1 or 2 for use as a medicament. 13. Use of a compound of formula (I) or (IA) or a pharmaceutically acceptable salt thereof according to claim 1 or 2 for the preparation of a medicament for the production of DPP_IV activity inhibition in a warm-blooded animal. 96151.doc -11-200523234 VII. Designated representative map ... (I) The designated representative map in this case is: (none) (II) The component symbols of this representative map are briefly explained: 8. If there is a chemical formula in this case, please disclose the best Chemical formula showing features of the invention: 96151.doc96151.doc
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