TW200401634A

TW200401634A - Novel glucagon antagonists

Info

Publication number: TW200401634A
Application number: TW091135050A
Authority: TW
Inventors: Janos Tibor Kodra; Prter Madsen; Jesper Lau; Anker Steen Jorgensen; Inge Thoger Christensen
Original assignee: Novo Nordisk As
Priority date: 2002-07-18
Filing date: 2002-12-03
Publication date: 2004-02-01

Abstract

Novel compounds that act to antagonize the action of the glucagon petide hormone on the glucagon receptor. More particularly, it relates to glucagon antagonists or inverse agonists.

Description

200401634 玖、發明說明【發明所屬之技術領域】本發明係有關拮抗在胰增血糖素受體上胰增血糖肽激素作用之試劑。更特別的是有關胰增血糖素拮抗劑或反激動劑。發明背景胰增血糖素（Glucagon)是一種主要激素劑，其與胰島素合作，進行血液中葡萄糖量的穩定調節。當血糖含量降低時胰增血糖素藉由刺激某些細胞（大部份肝細胞）作用以釋放葡萄糖。胰增血糖素之作用和胰島素相反，當血糖含量升高時刺激細胞攝取和儲存葡萄糖。胰增血糖素和胰島素兩者都是肽激素。胰增血糖素在阿爾發（α )胰島細胞中產生，胰島素在貝它（/3 )胰島細胞中產生。糖尿病是一般葡萄糖新陳代謝之疾病，特徵在高血糖，且可分類型第I型糖尿病，胰島素依賴型，或第I I型糖尿病，其特徵上是一種非胰島素依賴型的型式。有第I型糖尿病之患者之症狀是高血糖和血胰島素過少（hypoinsulinemic)，傳統治療此疾病的方式爲提供胰島素。然而，在一些患有第I型或第II型糖尿病之病人中，絕對或相對提高的胰增血糖素含量已顯示產生高血糖狀態。在健康動物和在第I和I I類型糖尿病動物的模型兩者中，使用選擇性和特定抗體除去循環胰增血糖素已經造成血糖（glycemic)量的減少。這些硏究建議胰增血糖素抑制或抗胰增血糖素作用可被有效地和傳統糖尿 200401634 病患的高血糖治療配合。胰增血糖素的作用可藉由提供括抗劑或反激動劑達成，抑制或防止胰增血糖激素誘發反應之物質。拮抗劑可爲天然肽或非肽。天然胰增血糖素爲含 2 9個胺酸之肽，其具有序列：200401634 (ii) Description of the invention [Technical field to which the invention belongs] The present invention relates to an agent that antagonizes the effect of glucagon on the glucagon receptor. More specifically, it is related to glucagon antagonists or anti-agonists. BACKGROUND OF THE INVENTION Glucagon is a major hormonal agent that cooperates with insulin to stably regulate the amount of glucose in the blood. When the blood glucose level decreases, glucagon releases glucose by stimulating the action of certain cells (most liver cells). Glucagon works the opposite of insulin, stimulating cells to take up and store glucose when blood glucose levels rise. Both glucagon and insulin are peptide hormones. Glucagon is produced in islet (α) islet cells, and insulin is produced in beta (/ 3) islet cells. Diabetes is a general glucose metabolism disease that is characterized by hyperglycemia and can be classified into type I diabetes, insulin-dependent, or type I diabetes, which is characterized by a non-insulin-dependent type. Patients with type 1 diabetes are hyperglycemic and hypoinsulinemic. Traditionally, the disease is treated with insulin. However, in some patients with type I or type II diabetes, absolute or relatively elevated glucagon levels have been shown to produce hyperglycemia. The removal of circulating pancreatic glucagon using selective and specific antibodies has resulted in a reduction in the amount of glycemic in both healthy animals and in models of type I and II animals with diabetes. These studies suggest that glucagon-inhibiting or anti-glucagon effects can be effectively combined with traditional hyperglycemic treatment in patients with diabetes 200401634. The effects of glucagon can be achieved by providing antagonists or inverse agonists, substances that inhibit or prevent glucagon-induced responses. The antagonist may be a natural peptide or a non-peptide. Natural glucagon is a peptide containing 29 amino acids, which has the sequence:

His-Scr-Glu-Gly-Thr-Phc-Thr-Scr-Asp-Tyr-Ssr-Lys-Tyr-Lcu-Asp-Scr-Arg-Arg-Ala-Gln-Asp-Phc-V&l~Gln-Trp-Lcu-Mct-Asn-Thr-OH 胰增血糖素藉由結合和活化其受體而發揮它的作用，其爲偶合至受體族之7 -跨膜G -蛋白質的胰增血糖素-分泌活素支鏈的部份。受體藉由腺嘌呤核苷醯基環化酶第二信使系統的活化而作用，結果增加c A Μ P含量。【先前技術】幾種刊物揭示可當作胰增血糖素拮抗劑的肽。或許，被最徹底描述的拮抗劑爲DesHis1 [Glu9]-胰增血糖素醯胺 (Unson 等人，肽類 10，1171(1989) ; Post 等人，Proc.His-Scr-Glu-Gly-Thr-Phc-Thr-Scr-Asp-Tyr-Ssr-Lys-Tyr-Lcu-Asp-Scr-Arg-Arg-Ala-Gln-Asp-Phc-V & l ~ Gln- Trp-Lcu-Mct-Asn-Thr-OH glucagon exerts its function by binding and activating its receptor, which is a glucagon- 7-transmembrane G-protein coupled to the receptor family- The part that secretes activin branches. The receptor acts through the activation of the second messenger system of adenine nucleotide cyclase, resulting in an increase in c A M P content. [Prior art] Several publications have disclosed peptides that can be used as glucagon antagonists. Perhaps the most thoroughly described antagonist is DesHis1 [Glu9] -glucagonamine (Unson et al., Peptide 10, 1171 (1989); Post et al., Proc.

Natl. Acad. Sci.USA 90，1662(1993))。其他的拮抗劑爲例如DesHis1，Phe6[Glu9]-胰增血糖素醯胺（Azizh等人，生物有機和醫學化學文獻（Bioorganic & Medicinal Chem.Lett.)，16，1849(1995))及 Nleu9，Ala1 1 ’ 1 6-胰增血糖素醯胺（Unson 等人，J. Biol· Chem. 269(17)， 12548(1994))。肽激素之掊抗劑通常十分有效的；然而，因爲生理酶降解，和體內分佈性的不佳，所以一般的認知是不可口服的。因此，可以口服之肽激素的非肽拮抗劑爲較佳。在非 200401634 肽胰增血糖素拮抗劑之中，—種喹噁啉衍生物，（2 -苯乙烯基一 3 —〔3 -（二甲胺基）丙基甲基胺基〕一 6， 7 -二氯喹唑啉被發現可取代來自鼠肝受體的胰增血糖素( 柯林斯，：LL.等人，（1992)生物有機和醫學化學文獻2(9) :915-918)。WO 94/ 14426揭示使用醌茜素（skyrin)當做胰增血糖素括抗劑（The Wellcome Foundation Limited)，其爲一種天然產物’包3 通連丨女的9，1 0 -恩二丽基，和其合成類似物。美國專利第4，359，474號（Sandoz)揭示卜苯基毗唑衍生物之胰增血糖素拮抗性質。美國專利第4， 374，130號（Sandoz)，揭示經取代二矽環己烷當做胰增血糖素拮抗劑。W0 98/ 04528 (拜耳公司）揭示經取代之毗啶和聯苯當做胰增血糖素拮抗劑。美國專利第5，776，954( Merck & Co.， Inc)揭示經取代之毗啶基毗唑當做胰增血糖素拮抗劑和W0 98 / 21957，W〇98/22108， W0 98/22109 和美國專利第 5，880，139 ( Merck & Co 公司）揭示2，4 一二芳基一 5 -吡啶基咪唑當做胰增血糖素拮抗劑。除此之外，W〇97/16442，美國專利第5，837，719 (Merck & Co·， Inc·)揭示2，5 -取代的芳基吡咯當作胰增血糖素拮抗劑。W〇98/24780， W0 98/24782，W0 99/24404及W099/32448 (Amgen Inc·)揭示經取代的嘧啶酮及D[t陡酮化合物，及經取代的喃陡化合物，分別具有胰增血糖素拮抗活性。Madsen et al (J. Med. Chem. 1998 (41) 5151-7)揭示一系列的2 —（苯咪唑一 2 —基硫）一 1 一（ 3，4 一二羥基苯基）一 1 一乙酮當作競爭性胰增血糖素 200401634 受體掊抗劑。W〇 99/01423 和 WO 00/39088 (Novo Nordisk A/S)揭示一系列醯基腙當作胰增血糖素拮抗劑/反激動劑。W〇 00/69810， W〇 02/00612， W〇 02/40444， WO 02/40445 和 WO 02/40446 (Novo Nordisk A/S)揭示另一類的胰增血糖素拮抗劑。這些習知胰增血糖素拮抗劑與本發明化合物結構不同定義下列係用以描述本發明化合物之術語的詳細定義： π鹵素"定義爲一種選自包括F，C 1，B r或I的原子。術語-烷基”在本文中代表一含支鏈或直鏈的烴基，具有從1至6個碳原子。代表性例子包括，但非限制性的，甲基，乙基，正-丙基，丁基，異丁基，第二一丁基，第三一丁基，正一戊基，異戊基，新戊基，第三一戊基，正一己基，異己基和類似群基。術語“C2-6 -烯基”在此代表一含支鏈或直鏈的烴基，具有從2至6個碳原子及至少一雙鍵。這些群基的例子包括，但非限制性的，乙烯基，1 -丙烯基，2 -丙烯基，異一丙烯基，1，3 -丁二烯基，1 一丁烯基，2-丁烯基，3 —丁烯基，2 -甲基—1 一丙烯基，1—戊烯基，2 -戊烯基，3 -戊烯基，3 -戊烯基，4 一戊烯基 ’ 3 —甲基一 2 -丁嫌基，1 一己燦基’ 2 -己嫌基’ 3 —己烯基，2，4 一己二烯基，5 -己烯基及類似群基。 200401634 術語“ C 2 — 6 —炔基”在此代表一含支鏈或直鏈的烴基，具有從2至6個碳原子，及至少一三鍵。這些群基的例子包括，但非限制性的，乙炔基，1 一丙炔基，2 -丙炔基，1 一丁炔基，2 - 丁炔基，3 - 丁炔基，1 一戊炔基，2 —戊炔基，3 -戊炔·基，4-戊炔基，1—己炔基，2 —己炔基，3 —己炔基，5 —己炔基，2，4 一己二炔基和類似群基。術語“ C 1 — 6 —烷氧基”在此代表一一〇—C 1 _ 6 — 烷基，其中C 1 - 6 -烷基是如上所定義者。代表性例子爲甲氧基，乙氧基，正一丙氧基，異丙氧基，丁氧基，第二一丁氧基，第三-丁氧基，戊氧基，異戊氧基，己氧基，異己氧基和類似群基。術語“ C 3 - 8 -環烷基”在此代表一碳環基，具有從 3至8個碳原子。代表性例子爲環丙基，環丁基，環戊基，環己基，環庚基，環辛基和類似群基。術語“C4_8 -環烯基”在此代表一非芳香系之碳環基，具有從4至8個碳原子及至少一雙鍵。代表性例子爲 1 一環戊烯基，2 -環戊烯基，3 -環戊烯基，1—環己烯基，2 -環己烯基，3 -環己烯基，2 -環庚烯基，3 一環庚烯基，2 -環辛烯基，1，4 一環辛二烯基和類似群基。術語“雜環基”在此代表一非芳香系3至1 0元環，含有一個或多個選自氮，氧及硫的雜原子，及選擇性的含有一個或兩個雙鍵。代表性例子爲吡咯啶基，锨啶基，呢 200401634 嗪基，嗎啉基，硫代嗎啉基，吖啶基，四氫呋喃基和類似群基。術語“芳基（aryl)” 一詞在此包括碳環芳香族環系統，像6元單環及9至14-元雙-及三環之碳環芳香族系統，代表例子爲苯基，聯苯基，萘基，憩基，菲基，氟烯基，茚基，甘菊環基（azulenyl)，及類似群基。芳基也包括部份氫化的上述碳環系統衍生物。這些部份氫化衍生物的非限制性例子爲1，2，3，4 —四氫萘基，1，4 —二氫萘基及類似群基。術語“芳撐（arylene)” 一詞在此包括二價碳環芳香族環系統，像6元單環及9至1 4 一元雙-及三環之二價碳環芳香族系統，代表例子爲苯撐，聯苯撐，萘撐，憩撐，菲撐，氟烯撐，茚撐，甘菊環基（azulenyl)，及類似群基。芳撐也包括部份氫化的上述碳環系統衍生物。這些部份氫化衍生物的非限制性例子爲1，2，3，4一四氫萘撐， 1，4 —二氬萘撐及類似群基。術語“芳氧基”一詞在此代表一式-〇一芳基，其中芳基是如上所定義者。術語“芳醯基” 一詞在此代表一式一 C (〇）一芳基，其中芳基是如上所定義者。術語“CV6-烷醯基”一詞在此代表一—c (〇）—Ci —6 -院基，其中C 1-6 -院基是如上所定義者。術語“雜芳基”一詞在此包括芳香族雜環系統，包含一個或多個選自氮，氧，及硫的雜原子，像含有~個或多 11 200401634 個選自氮，氧及硫雜原子之5至7元單環及8至1 4元雙 -及三環芳香族雜環系統，代表例子爲呋喃基，噻嗯基，吡咯基，噁唑基，噻唑基，咪唑基，異噁唑基，異噻唑基，1，2，3 —***基，1，2，4 一***基，吡喃基，吡啶基，噠嗪基，嘧啶基，毗嗪基，1，2，3 —三嗪基，1，2，4 一三嗪基，1，3，5 —三嗪基，1，2， 3 -噁二唑基，1，2，4 —噁二唑基，1，2，5 —噁二唑基，1，3，4 —噁二唑基，1，2，3 —噻二哇基，1，2，4 —噻二唑基，1，2，5—_二唑基，1， 3，4 一噻二唑基，四唑基，噻二嗪基，吲哚基，異吲哚基，苯並呋喃基，苯並噻嗯基，苯並暖吩基（噻憩基），吲唑基、苯並咪唑基，苯並瞳唑基，苯並異噻唑基，苯並噁唑基，苯並異噁唑基，嘌呤基，喹唑啉基，喹啉嗪基，喹啉基，異喹啉基，喹噁啉基，萘啶基，蝶啶基，卡唑基，吖庚因基，二吖庚因基，吖啶基和類似群基。雜芳基也包括上述雜環系統的部份氫化衍生物。這些部份氫化衍生物的非限制性例子爲2，3 -二氫苯並呋喃基，吡咯，吡唑基，吲哚基，噁唑啉基，噁吖庚因基（oxazolinyl)和類似群基。術語“雜芳撐”一詞在此包括芳香族雜環系統，包含一個或多個選自氮，氧，及硫的雜原子，像含有一個或多個選自氮，氧及硫雜原子之5至7元單環及8至1 4元雙 -及三環芳香族雜環系統，代表例子爲呋喃撐，噻嗯撐，吡咯撐，噁唑撐，噻唑撐，咪唑撐，異噁唑撐，異噻唑撐 12 200401634 ，1，2，3 —***撐，1，2，4 一***撐，吡喃撐，吡啶撐，噠嗪撐，嘧啶撐，吡嗪撐，1，2，3 -三嗉撐，1，2，4 —三嗪撐，1，3，5-三嗪撐，ι，2, 3 -噁二唑撐，1，2，4 一噁二唑撐，1，2，5 —螺二唑撐，1，3，4 一噁二唑撐，1，2，3 -噻二唑撐，1，2，4-噻二唑撐，1，2，5 —噻二唑撐，1， 3，4 一噻二唑撐，四唑撐，噻二嗪撐，吲哚撐，異吲口朵撐，苯並呋喃撐，苯並噻嗯撐，苯並噻吩撐（噻憩撐），吲唑撐，苯並咪唑撐，苯並噻唑撐，苯並異噻唑撐，苯並噁唑撐，苯並異噁唑撐，嘌呤撐，喹唑啉撐，喹啉嗪撐，喹啉撐，異喹啉撐，喹噁啉撐，萘啶撐，蝶啶撐，卡唑撐，吖庚因撐，二吖庚因撐，吖啶撐和類似群基。雜芳撐也包括上述雜環系統的部份氫化衍生物。這些部份氫化衍生物的非限制性例子爲2，3 —二氫苯並呋喃撐，吡咯撐，毗唑撐，吲哚撐，噁唑啉撐，噁吖庚因撐（〇xaz〇linyl)和類似群基。 “芳基—C 1 — 6 -烷基”，“雜芳基一 C 1 — 6 —烷基，，，“芳基—C 2 - 6 —烯基，，等意指上述之C i - 6 —院基或C 2-6 -烯基，經由一上述之芳基或雜芳基取代的’例如：Natl. Acad. Sci. USA 90, 1662 (1993)). Other antagonists are, for example, DesHis1, Phe6 [Glu9] -glucagonamine (Azizh et al., Bioorganic & Medicinal Chem. Lett., 16, 1849 (1995)) and Nleu9 Ala11'16-glucagonamine (Unson et al., J. Biol. Chem. 269 (17), 12548 (1994)). Peptide hormone antagonists are usually very effective; however, due to the degradation of physiological enzymes and poor distribution in the body, general recognition is not oral. Therefore, non-peptide antagonists of peptide hormones that can be taken orally are preferred. Among the non-200401634 peptide glucagon antagonists, a quinoxaline derivative, (2-styryl-3- [3- (dimethylamino) propylmethylamino] -6, 7 -Dichloroquinazoline was found to replace glucagon from rat liver receptors (Collins: LL. Et al. (1992) Bioorganic and Medical Chemistry 2 (9): 915-918). WO 94 / 14426 discloses the use of quinine as a glucagon antagonist (The Wellcome Foundation Limited), which is a natural product including 3, 10, and 20-eniliki, and its synthesis Analogs. U.S. Patent No. 4,359,474 (Sandoz) discloses glucagon antagonistic properties of a phenylpyrazole derivative. U.S. Patent No. 4,374,130 (Sandoz) discloses a substituted disilicon ring Hexane acts as a glucagon antagonist. WO 98/04528 (Bayer) discloses substituted bipyridines and biphenyls as glucagon antagonists. US Patent No. 5,776,954 (Merck & Co., Inc) reveals substituted pyrimidinylpyrazole as a glucagon antagonist and WO 98/21957, WO 98/22108, WO 98/22 109 and U.S. Patent No. 5,880,139 (Merck & Co.) disclose 2,4-diaryl-5-pyridylimidazole as a glucagon antagonist. In addition, WO97 / 16442, U.S. Patent No. 5,837,719 (Merck & Co., Inc.) discloses 2,5-substituted arylpyrroles as glucagon antagonists. WO98 / 24780, WO 98/24782, WO 99 / 24404 and W099 / 32448 (Amgen Inc.) disclose that substituted pyrimidinone and D [t acanone compounds, and substituted aranone compounds have glucagon antagonistic activity, respectively. Madsen et al (J. Med. Chem. 1998 (41) 5151-7) revealed a series of 2- (benzimidazole-2-ylthio)-1- (3,4-dihydroxyphenyl)-1-ethyl ketone as a competitive pancreatic blood glucose 200401634 receptor antagonists. WO99 / 01423 and WO 00/39088 (Novo Nordisk A / S) reveal a series of amidines as glucagon antagonists / inverse agonists. WO00 / 69810, WO 02/00612, WO 02/40444, WO 02/40445 and WO 02/40446 (Novo Nordisk A / S) disclose another class of glucagon antagonists. These conventional glucagon antagonists differ in structure from the compounds of the present invention. The following is a detailed definition of the terms used to describe the compounds of the present invention: π halogen " is defined as one selected from the group consisting of F, C 1, B r or I. atom. The term "alkyl" herein refers to a branched or straight chain hydrocarbon group having from 1 to 6 carbon atoms. Representative examples include, but are not limited to, methyl, ethyl, n-propyl, Butyl, isobutyl, second-butyl, third-butyl, n-pentyl, iso-pentyl, neopentyl, third-pentyl, n-hexyl, isohexyl and similar groups. "C2-6-alkenyl" here represents a branched or straight chain hydrocarbon group having from 2 to 6 carbon atoms and at least one double bond. Examples of these groups include, but are not limited to, vinyl , 1-propenyl, 2-propenyl, iso-propenyl, 1,3-butadienyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1 Propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 3-pentenyl, 4-pentenyl '3-methyl-2-butanyl, 1-pentanyl' 2 -Hexyl '3-hexenyl, 2,4-hexadienyl, 5-hexenyl and similar groups. 200401634 The term "C 2-6 -alkynyl" here means a branched or straight chain A hydrocarbyl group having from 2 to 6 carbon atoms, and One less triple bond. Examples of these groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl , 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 5-hexynyl, 2,4 Hexadiynyl and similar groups. The term "C 1-6 -alkoxy" here stands for 110 -C 1-6 -alkyl, where C 1-6 -alkyl is as defined above Representative examples are methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, second-butoxy, third-butoxy, pentyloxy, isopentyloxy Groups, hexyloxy, isohexyloxy and similar groups. The term "C 3-8 -cycloalkyl" here stands for a carbocyclic group, having from 3 to 8 carbon atoms. A representative example is cyclopropyl, Cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and similar groups. The term "C4-8-cycloalkenyl" here stands for a non-aromatic carbocyclic group, having from 4 to 8 carbons Atom and at least one double bond. A representative example is 1 1 Pentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 2-cycloheptenyl, 3 monocycloheptenyl Group, 2-cyclooctenyl, 1,4 monocyclic octadienyl and similar groups. The term "heterocyclyl" here means a non-aromatic 3 to 10 membered ring containing one or more selected from nitrogen , Oxygen and sulfur heteroatoms, and optionally contains one or two double bonds. Representative examples are pyrrolidinyl, pyridinyl, oxazine 200401634 azinyl, morpholinyl, thiomorpholinyl, acrylyl , Tetrahydrofuranyl and similar groups. The term "aryl" includes carbocyclic aromatic ring systems, such as 6-membered monocyclic and 9 to 14-membered bi- and tricyclic carbocyclic aromatic systems. Representative examples are phenyl, Phenyl, naphthyl, aryl, phenanthryl, fluoroalkenyl, indenyl, azulenyl, and similar groups. Aryl also includes the aforementioned carbocyclic system derivatives which are partially hydrogenated. Non-limiting examples of these partially hydrogenated derivatives are 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl and the like. The term "arylene" includes bivalent carbocyclic aromatic ring systems such as 6-membered monocyclic and 9 to 1 4-bivalent and tricyclic bivalent carbocyclic aromatic systems. Representative examples are: Phenylene, biphenylene, naphthalene, stilbene, phenanthrene, fluorene, indylene, azulenyl, and similar groups. Arylene also includes derivatives of the aforementioned carbocyclic systems which are partially hydrogenated. Non-limiting examples of these partially hydrogenated derivatives are 1,2,3,4-tetrahydronaphthylene, 1,4-diargyrylene and similar groups. The term "aryloxy" herein stands for the formula -0-aryl, where aryl is as defined above. The term "arylfluorenyl" herein stands for the formula -C (0) -aryl, where aryl is as defined above. The term "CV6-alkylfluorenyl" here stands for -c (0) -Ci-6-sinyl, where C1-6-sinyl is as defined above. The term "heteroaryl" here includes aromatic heterocyclic systems containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, such as containing ~ or more 11 200401634 selected from nitrogen, oxygen, and sulfur Heteroatom 5- to 7-membered monocyclic and 8 to 1 4-membered bi- and tricyclic aromatic heterocyclic systems, representative examples are furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, iso Oxazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4 monotriazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2, 3-triazinyl, 1,2,4-monotriazinyl, 1,3,5-triazinyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1, 2,5—oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiawyl, 1,2,4-thiadiazolyl, 1,2,5-—di Oxazolyl, 1, 3, 4 monothiadiazolyl, tetrazolyl, thiadiazinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl, benzothienyl (thia (Divyl group), indazolyl, benzimidazolyl, bendizolyl, benzoisothiazolyl, benzoxazolyl, Benzoisoxazolyl, purinyl, quinazolinyl, quinolinazinyl, quinolinyl, isoquinolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, azepinyl , Diazepine, acridinyl and similar groups. Heteroaryl also includes partially hydrogenated derivatives of the above heterocyclic systems. Non-limiting examples of these partially hydrogenated derivatives are 2,3-dihydrobenzofuranyl, pyrrole, pyrazolyl, indolyl, oxazoline, oxazolinyl and similar groups . The term "heteroarylene" includes here aromatic heterocyclic systems containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, as if containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur. 5- to 7-membered monocyclic and 8 to 1 4-membered bi- and tricyclic aromatic heterocyclic ring systems. Representative examples are furanyl, thienyl, pyrrolidene, oxazole, thiazolyl, imidazole, and isoxazole. , Isothiazolyl 12 200401634, 1,2,3-triazole, 1,2,4 monotriazole, pyranyl, pyridine, pyridazine, pyrimidine, pyrazine, 1, 2, 3 -Trimethylene, 1,2,4-triazine, 1,3,5-triazine, 1,2,3 -oxadiazole, 1,2,4 monooxadiazole, 1,2 , 5-spirodiazole, 1,3,4 oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole Support, 1, 3, 4 monothiadiazolyl, tetrazolyl, thiadiazine, indole, isoindole, benzofuranyl, benzothienyl, benzothienyl (thiophene Support), indazole, benzimidazole, benzothiazolyl, benzoisothiazolyl, benzoxazole, benzene Acyloxazolyl, purine, quinazoline, quinolinazine, quinoline, isoquinoline, quinoxaline, naphthyridine, pteridine, carbazole, azepine, Diazepine, acridine and similar groups. Heteroarylenes also include partially hydrogenated derivatives of the above heterocyclic systems. Non-limiting examples of these partially hydrogenated derivatives are 2,3-dihydrobenzofuranyl, pyrrolidyl, pyrazolyl, indole, oxazoline, and oxazolinyl. And similar group base. "Aryl-C 1-6 -alkyl", "heteroaryl-C 1-6 -alkyl,", "aryl -C 2-6 -alkenyl," and the like mean the above Ci-6 —Chenyl or C 2-6 -alkenyl, substituted by an aryl or heteroaryl group as described above, for example:

“選擇性取代的，，一詞在此是指未經取代的’或經由 13 200401634 一個或多個所定義之取代基取代的。當該群基是由超過一個取代基所取代時，則取代基可是相同或不同的。上述所定義的特定名詞在結構式中出現超過一次以上時，每一次出現皆是彼此獨立的。除此之外，必須瞭解的是“互不相關的是”及“互不關的選自”一詞可是相同的或是不同的。 “治療”此一名詞在此意指處理及照顧一患者’以達到治癒疾病，病痛或狀況的目的，此名詞包括延緩疾病，病痛或狀況的惡化，減輕或解除症狀或倂發症，及/或治魯癒或排除疾病，病痛或狀況。被治療的患者較佳的是哺乳動物，特別是人類。【發明內容】本發明的詳述本發明關於一種式⑴化合物，"Selectively substituted," as used herein, means unsubstituted or substituted by one or more of the substituents defined in 13 200401634. When the group is substituted with more than one substituent, the substituent But the same or different. When the specific nouns defined above appear more than one time in the structural formula, each occurrence is independent of each other. In addition, you must understand that "unrelated to each other" and "mutually The word "irrelevantly selected" may be the same or different. The term "treating" here refers to the treatment and care of a patient 'to achieve the purpose of curing a disease, pain or condition, and this term includes delaying the disease, pain Or worsening of the condition, reducing or relieving symptoms or eruption, and / or curing or eliminating disease, pain or condition. The patient to be treated is preferably a mammal, especially a human. [Summary of the Invention] The present invention DETAILED DESCRIPTION OF THE INVENTION The invention relates to a compound of formula (I),

其中 A是Where A is

m是0或1， 14 200401634 η 是〇，1，2 或 3，但其前提是m及η不能同時爲0， R 4是氫，鹵素或一（C Η 2 )。一〇R 5，〇是0或1， R5是氫，Cl — 6 -院基’ Cl-6 -院醯基，芳基或芳基—C 1 — 6—烷基， R1和R2互不相關的分別是氫，鹵素或C 1 —6一烷基，或R 1和R 2—起形成一雙鍵， R3是氫’ Ci — 6—院基或鹵素’或R3及R2 —^起形成一鍵結至氧的雙鍵， X是芳撐或雜芳撐，其可選擇性的經一個或二個選自 —CN ，一 CF3 ，一 OCFg ，— OCHFg ，— N〇2 ， —OR8，一 NR8R9&C1 — 6 —烷基之R6和R7群基所取代的， R 8和R 9互不相關的分別是氫或C 1 _ 6 -烷基’ Y 是一C(〇）一，一〇一，一 NRi〇，一 S —，一 s (〇）一，一s (〇）2 —或—CRiiRi2—， R1G是氫或C 1 — 6 -院基’ R 1 1和R 1 2互不相關的分別是氫，C 1 — 6 -烷基或羥基，或R 1 1和R 1結合形成一雙鍵’及R 1 2是氫’ c 1 —6 -院基或經基’ 2是一(：(〇）一(〇1^131114)1)—，一〇一（〇1^13尺14)1)一， -S-(CR13R14)P-，-S (〇）-（cr13r14)p-， —S (〇）2—（CR13R14)p—，一NR15— (CR13R14)P—或 15 200401634 -(CR13R14) p-， p是0，1或2， R13和R14互不相關的分別選自氫，一 CF3 ’ 一〇 CF 3及Cl— 6 —院基， R 1 5是氫或C 1 — 6 -烷基， D是芳基或雜芳基，其可是選擇性的經一個或多個取代基 R 1 6，R 1 7，R 1 8，R 1 9，R 2 ◦及 R 2 1 所取代的，其中 R 1 6，R 1 7，R 1 8及R 1 9互不相關的分別是氫，鹵素，一CN，一CH2CN，一CHF2,一CF3， —OCHF2 5 — OCH2CF3 J —OCF2CHF2 J —S(〇）2CF3, 一 SCF3，一NOS，一〇R22， -NR22R23，—SR22，—NR22S (〇）2R23， —S (〇）2nr22r23，一S (〇）nr22r23， —S (〇）R22，一S (〇）2R22，一 C (〇）NR22R23, 一〇C (〇）NR22R23， —NR22C (〇）R23, 一 CH2C (〇）NR22R23，一〇CH2C (〇）NR22R23, 一 CH2〇R23， -CH2NR22R23，一〇C (〇）R22，一C (〇）R22或 —C (〇）〇R22， .C工_ 6 —院基，C 2 - 6 -細基或C 2 - 6 —块基，m is 0 or 1, 14 200401634 η is 0, 1, 2 or 3, but the premise is that m and η cannot be 0 at the same time, and R 4 is hydrogen, halogen, or one (C Η 2). 〇R 5, 〇 is 0 or 1, R5 is hydrogen, Cl-6-Cycloyl'Cl-6-Cycloyl, aryl or aryl-C1-6-alkyl, R1 and R2 are not related to each other Are hydrogen, halogen or C 1-6 alkyl, or R 1 and R 2 together form a double bond, and R 3 is hydrogen 'Ci -6-courtyard or halogen' or R 3 and R 2 together form a A double bond bonded to oxygen, X is arylene or heteroarylene, which can be optionally selected via one or two of -CN, -CF3, -OCFg, -OCHFg, -NO2, -OR8,- NR8R9 & C1-6-alkyl is substituted by the R6 and R7 group groups, and R8 and R9 are unrelated to each other hydrogen or C1-_6-alkyl 'Y is a C (〇) 一, 〇 One, one NRi〇, one S —, one s (〇) one, one s (〇) 2 — or —CRiiRi2 —, R1G is hydrogen or C 1 — 6-R & D 'R 1 1 and R 1 2 do not The relevant ones are hydrogen, C 1-6 -alkyl or hydroxy, or R 1 1 and R 1 combine to form a double bond 'and R 1 2 is hydrogen' c 1-6-nodyl or via group '2 is a (: (〇) 一 (〇1 ^ 131114) 1) —, 101 (〇1 ^ 13foot 14) 1) —, -S- (CR13R14) P-, -S (〇)-(cr13r14) p - —S (〇) 2— (CR13R14) p—, one NR15— (CR13R14) P— or 15 200401634-(CR13R14) p—, p is 0, 1, or 2, R13 and R14 are independent of each other and are selected from hydrogen , CF3'-10CF3 and Cl-6-institution, R 1 5 is hydrogen or C 1- 6-alkyl, D is aryl or heteroaryl, which may be optionally substituted by one or more The groups R 1 6, R 1 7, R 1 8, R 1 9, R 2 ◦ and R 2 1 are substituted. Among them, R 1 6, R 1 7, R 1 8 and R 1 9 are irrelevant. Hydrogen, halogen, one CN, one CH2CN, one CHF2, one CF3, —OCHF2 5 — OCH2CF3 J —OCF2CHF2 J —S (〇) 2CF3, one SCF3, one NOS, one 10R22, -NR22R23, —SR22, —NR22S (〇) 2R23, —S (〇) 2nr22r23, -S (〇) nr22r23, -S (〇) R22, -S (〇) 2R22, -C (〇) NR22R23, -0C (〇) NR22R23, -NR22C (〇) R23, -CH2C (〇) NR22R23, -0CH2C (〇) NR22R23, -CH2〇R23, -CH2NR22R23, -0C (〇) R22, -C (〇) R22 or -C (〇) 〇R22 , .C 工 _ 6 —yuan foundation, C 2-6-fine foundation or C 2-6-block foundation,

其可選擇性的經一個或多個選自鹵素，一 c N，一 c FIt is optionally selected from one or more of halogen, a c N, a c F

〇C F 16 200401634 一〇CHF2 ’ 一 N〇2 ’ 一〇R22，一 NR22R23 及 C i _ 6 -烷基的取代基取代的， • C 3-8-環院基，C 4-8-環烯基，雜環基，C 3_8-環院基- C 1-6 _火兀基’ C 3 —8 -每知:基一 c 1-6 -院氧基’ C 3 —8—環院氧基，C3_8-環烷基-。卜6-烷硫基，C3 —8-環烷基烷硫基， C 3_8—環垸基—C 2_6-烯基，C 3_8-環烷基—C 2 —6—炔基， C 4 — 8 -環烯基-C丄_ 6 -烷基，C 4 _ 8 -環烯基-C 2 一 6 -烯基， C 4-8-環烯基-C 2-6-炔基，雜環基-C卜6-院基，雜環基-C 2 - 6 —烯基’雜環基—C 2 — 6 -炔基，芳基，芳氧基，芳氧基簾基，芳醯基，芳基—Ci —6-烷氧基，芳基—Ci —6—烷基，芳基— C 2-6-烯基’芳基—C 2-6-炔基，雜芳基，雜芳基—C卜6—院基，雜芳基—C 2__6 —烯基或雜芳基—C 2 —e —炔基，其中芳香系及非-芳香系環系統可選擇性的經一個或多個選自鹵素，一C (〇）〇R22，_cn，一 cf3，一〇 CF3 ，一〇CHF2 ，一 N〇2 ，一〇R22 ，一 NR22 R 2 3及C 1 — 6 —烷基的取代基取代的， R 22和R 2 3互不相關的分別是氫，C 1 — 6 -烷基，芳基一 C 1 — 6 —烷基或芳基，或R 2 2及R 2 3 —起鍵結至相同的氮原子上時，則其和氮原子形成一 3至8元雜環，且此雜環可選擇性的含有一個或二個其它選自氮，氧及硫的雜原子，及選擇性的含有一個或二個雙鍵，或R 1 6至R 1 9中的任二個群基是在相鄰位置時，其可一起形成一架橋基一（CR24R25) a — 〇一（CR26 R 2 7 ) c — 〇一， 17 200401634 a是0，1或2， c是1或2， R 2 4，R 2 5，R 2 6和R 2 7互不相關的分別是氫，c 1 — 6 -院基或氟， R 2 ◦和R 2 1互不相關的分別是氫，C 1 _ 6 -烷基， C 3-8 -環院基或 C 3 — 8—垣院基—C^ — g-院基， E是 C 3 — 8 -環烷基或C 4 — 8 -環烯基，其可選擇性的經一個或二個取代基 R 2 8和R 2 9取代的，而此取代基是互不相關的分別選自：氫，鹵素，一 CN，一 CF3，一〇CF3，一〇CHF2，一 OR33, —NR33R34，Ci—6—烷基，c3 —8一環烷基，C4 —8一環烯基，雜芳基及芳基，其中該雜芳基及芳基是選擇性的經一個或多個選自鹵素，一CN，一CF3，一〇CF3，一〇CHF2, 一 N〇2，一〇R33，一 NR33R34 及 Ci — 6 -烷基取代的， R 33和R 3 4互不相關的分別是氫或C —烷基，或R 3 3及R 3 4—起鍵結至相同的氮原子上時，則其和該氮原子可形成一 3至8元雜環，且此雜環可選擇性的含有一個或二個其它選自氮，氧及硫的雜原子，及選擇性的含有一個或二個雙鍵， 18 200401634 芳基，雜芳基，芳基一 C2_6烯基或芳基一 C2 — 6- 炔基，其中該芳基及雑芳基可選擇性的經一個或多個取代基 R 2 8，R 2 9，R 3 〇，R 3 1 及 R 3 2 取代的，其中R28和是如上所定義者，及R3Q，R31和 R 3 2互不相關的分別選自 •氫，鹵素，一chf2，一cf3,一〇cf3，一〇chf2，一〇ch2cf3,一〇cf2chf2,一 scf3，一〇R35， —NR35R36, 一 SR35，一S (〇）R35，一S (〇）2R35， —c (〇）nr35r36，一〇c (〇）nr35r36， —NR35C (〇）R36，一〇CH2C (〇）NR35R36， -C (〇）R35 及一 C (〇）OR35， C i _ 6 —院基，c 2 - 6 -烯基及C 2 — 6 -炔基，〇CF 16 200401634 〇CHF2 ′ -No 2 ′ 〇R22, NR22R23 and C i _ 6-alkyl substituents, • C 3-8-cycloalkyl, C 4-8-cycloolefin Group, heterocyclyl, C 3_8-cyclodynyl-C 1-6 _flavoyl 'C 3-8 , C3_8-cycloalkyl-. Alkyl 6-alkylthio, C3-8-cycloalkylalkylthio, C 3-8-cyclofluorenyl-C 2-6-alkenyl, C 3-8-cycloalkyl-C 2-6-alkynyl, C 4-8 -Cycloalkenyl-C 丄 _6-alkyl, C 4-8 -cycloalkenyl-C 2 -6-alkenyl, C 4-8-cycloalkenyl-C 2-6-alkynyl, heterocyclyl -C 1-6-yl, heterocyclyl-C 2-6 -alkenyl'heterocyclyl-C 2-6 -alkynyl, aryl, aryloxy, aryloxycuryl, arylfluorenyl, aryl —Ci —6-alkoxy, aryl—Ci —6—alkyl, aryl — C 2-6-alkenyl'aryl—C 2-6-alkynyl, heteroaryl, heteroaryl— Cb 6—Chenyl, heteroaryl—C 2__6 —alkenyl or heteroaryl—C 2 —e —alkynyl, wherein the aromatic and non-aromatic ring systems are optionally selected from one or more selected from Halogen, C (〇) 〇R22, _cn, cf3, 〇CF3, 〇CHF2, 〇2, 〇22, NR22 R 2 3 and C 1 -6-alkyl substituted R 22 and R 2 3 are unrelated to each other, hydrogen, C 1-6 -alkyl, aryl-C 1-6 -alkyl or aryl, or R 2 2 and R 2 3-are bonded to On the same nitrogen atom, then Atoms form a 3- to 8-membered heterocyclic ring, and this heterocyclic ring may optionally contain one or two other heteroatoms selected from nitrogen, oxygen, and sulfur, and optionally one or two double bonds, or R 1 When any two groups from 6 to R 1 9 are in adjacent positions, they can form a bridge group together (CR24R25) a — 〇a (CR26 R 2 7) c — 〇1, 17 200401634 a is 0 , 1 or 2, c is 1 or 2, R 2 4, R 2 5, R 2 6 and R 2 7 are unrelated to each other, hydrogen, c 1-6-courtyard or fluorine, R 2 ◦ and R 2 1 unrelated to each other are hydrogen, C 1 _ 6 -alkyl, C 3-8-ring courtyard or C 3-8-Yuanyuan-C ^-g-courtyard, E is C 3-8- Cycloalkyl or C 4-8 -cycloalkenyl, which is optionally substituted with one or two substituents R 2 8 and R 2 9, and this substituent is independently selected from: hydrogen, Halogen, one CN, one CF3, one CF3, one CHF2, one OR33, —NR33R34, Ci-6-alkyl, c3-8 cycloalkyl, C4--8 cycloalkenyl, heteroaryl and aryl, Wherein the heteroaryl group and the aryl group are optionally selected from one or more halogens, CN, -CF3, -0CF3, -0CHF2, -N02, -OR33, -NR33R34 and Ci-6-alkyl substituted, R 33 and R 3 4 are unrelated to each other hydrogen or C- When an alkyl group, or R 3 3 and R 3 4-are bonded to the same nitrogen atom, they may form a 3 to 8-membered heterocyclic ring with the nitrogen atom, and the heterocyclic ring may optionally contain one or Two other heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds, 18 200401634 aryl, heteroaryl, aryl-C2-6 alkenyl or aryl-C2-6-alkyne Group, wherein the aryl group and the aryl group are optionally substituted with one or more substituents R 2 8, R 2 9, R 3 0, R 3 1 and R 3 2, wherein R28 and R are as defined above , And R3Q, R31 and R 3 2 are independently selected from the group consisting of hydrogen, halogen, chf2, cf3, 〇cf3, 〇chf2, 〇ch2cf3, 〇cf2chf2, 〇cf3, 〇R35 — —NR35R36, —SR35, —S (〇) R35, —S (〇) 2R35, —c (〇) nr35r36, —OC (〇) nr35r36, —NR35C (〇) R36, —〇CH2C (〇) NR35R36 , -C (〇) R35 and a C (〇) OR35, C i _ 6 —sinyl, c 2-6 -alkenyl and C 2 — 6 -alkynyl,

其可是選擇性的經一個或多個選自鹵素，一 C N，一 C F 3 ’一〇CFg ’ 一 0 C H F 2 5 一 N〇2 ，一〇R35 ，一 n R 3 5 R 3 6及C 1 _ 6 —烷基取代的， ◦ 3 —8—環院基，C 4 —8-環烯基，雜環基，C 3_8~環院基一 c 1-6 —院基’ C 3 —8—環院基—C 2 —6—烯基，C 3 —8—環院基—c 9 _ 炔基’ C4_8—環烯基—Cu—院基，C4_8—環烯基——广燦基’ C 4-8—環烯基一 C 2-6—炔基，雜環基一 C i — 院基，雜環其 —◦ 2-6 —細基，雜環基—C 2 — 6 —炔基，芳基，芳氧基，芳基，芳基—C 1-6—丨兀氧基’方基一 C u-院基’芳基一 C 2 —6~燦其，芳基—C 2-6-炔基，雜芳基，雜芳基—(^ — 6-烷基，雜芳基一稀基及雑方基一 C 2e 一快基，其中該方香系及非-芳香系環系統選擇性的可經〜個或夕 19 200401634 個選自鹵素，一CN，一 CF3，一〇CF3，〇CHF2 ，一 N〇2，一 OR35， —N R 3 5 R 3 6及C 1 _ 6 —烷基取代的，其中R35和R36互不相關的分別是氫’ Cl-6 -院基或芳基，或當R 3 5和R 3 6鍵結至相同的氮原子上時’則其和該氮原子一起形成一 3至8元雜環，且此雜環選擇性的包含一個或二個其它選自氮，氧及硫的雜環子，且選擇性的包含一個或二個雙鍵，或當取代基R 3 ◦，R 3 1和R 3 2中的二個鍵結至相同的碳原子或相鄰環之碳原子上時，則其可一起形成一架橋基一〇一（CH2) t — CR37R38 — (CH2) 1 —〇一，一 (CH2) t - CR37R38 - (CH2) 1 -或一 S - (CH2) t-CR37R38 — (CH2) i - S —， t和1互不相關的爲0，1，2，3，4或5， R 37和R 3 8互不相關的爲氫或C i-6 -烷基，以及任何其非對映異構物或對映異構物或互變型式異構物，包括這些異構物的混合物或其藥學上可接受的鹽。在另一具體實例中，A是It may optionally be selected from one or more of halogen, -CN, -CF 3 '-0CFg' -0 CHF 2 5 -N02, -OR35, -nR 3 5 R 3 6 and C 1 _ 6 —Alkyl-substituted, ◦ 3 —8-Cycloyl, C 4 —8-cycloalkenyl, heterocyclyl, C 3_8 ~ Cyclo-1 — 1-6 —Cyclo 'C 3 —8— Cycloalkyl—C 2 —6—alkenyl, C 3 —8—Cyclosyl—c 9 _ alkynyl 'C4_8—Cycloalkenyl—Cu—Cycloyl, C4_8—Cycloalkenyl—Guangcanji' C 4-8-cycloalkenyl-C 2-6-alkynyl, heterocyclyl-C i -institution, heterocyclic its -◦ 2-6 -fine, heterocyclyl-C 2-6 -alkynyl, Aryl, aryloxy, aryl, aryl—C 1-6— 丨 oxy 'square group-C u-Cycloyl' aryl-C 2-6 ~ Chanqi, aryl-C 2-6 -Alkynyl, heteroaryl, heteroaryl-(^-6-alkyl, heteroaryl-diluted and fluorenyl-C 2e-acyl, wherein the aromatic and non-aromatic ring systems are selected Sexuality can be ~ ~ or ~ 19 200401634 selected from halogen, one CN, one CF3, one CF3, one CHF2, one No2, one OR35, —NR 3 5 R 3 6 and C 1 _ 6 — Group substituted, in which R35 and R36 are unrelated to each other, hydrogen'Cl-6-sinyl or aryl, or when R 3 5 and R 3 6 are bonded to the same nitrogen atom, then it and the nitrogen The atoms together form a 3- to 8-membered heterocyclic ring, and the heterocyclic ring optionally includes one or two other heterocyclic rings selected from nitrogen, oxygen, and sulfur, and optionally includes one or two double bonds, or when When the substituent R 3 ◦, two of R 3 1 and R 3 2 are bonded to the same carbon atom or a carbon atom of an adjacent ring, then they can form a bridge group 010 (CH2) t — CR37R38 — (CH2) 1 —〇 One, one (CH2) t-CR37R38-(CH2) 1-or one S-(CH2) t-CR37R38 — (CH2) i-S —, t and 1 are not related to each other as 0, 1, 2, 3, 4 or 5, R 37 and R 3 8 independently of each other are hydrogen or Ci-6-alkyl, and any of its diastereomers or enantiomers or each other Variant isomers, including mixtures of these isomers or a pharmaceutically acceptable salt thereof. In another specific example, A is

其中m，η和R4具有如式（I )中之定義者。在另一具體實例中，Α是 20 200401634 h〇ACh2/ch 广 ο 在另一具體實例中，Α是〇人 /CH「 ΗΟ 2Where m, η and R4 have the same meanings as defined in formula (I). In another specific example, A is 20 200401634 h〇ACh2 / ch Guang ο In another specific example, A is 〇 person / CH "ΗΟ 2

OH ο 在另一具體實例中，Α是OH ο In another specific example, A is

在另一具體實例中，X是單環芳撐或雜芳撐，其可選擇性的如式（I )所述取代的。在另一具體實例中，X是 R6In another specific example, X is a monocyclic arylene or heteroarylene, which is optionally substituted as described in formula (I). In another specific example, X is R6

其中R6和R7具有如式（I )中所述之定義者。在另一具體實例中，X是 R6Wherein R6 and R7 have the same meanings as defined in formula (I). In another specific example, X is R6

21 200401634 其中R6和R7具有如式（I )中所述之定義者。在另一具體實例中，R6和R7兩者皆爲氫。在另一具體實例中，E是21 200401634 wherein R6 and R7 have the definitions as described in formula (I). In another specific example, both R6 and R7 are hydrogen. In another specific example, E is

其中 R28，R29，R3Q，R31 和 R32 是如式（][ )中所定義者。在另一具體實例中，E是Where R28, R29, R3Q, R31 and R32 are as defined in the formula () [). In another specific example, E is

22 200401634 其中R28，r29，R30，R31和R32是如式（i )中所定義者。在另一具體實例中，E是22 200401634 wherein R28, r29, R30, R31 and R32 are as defined in formula (i). In another specific example, E is

其中R 3 0，R 3 1和R 3 2是如式（I )中所定義者。在另一具體實例中，E是Wherein R 3 0, R 3 1 and R 3 2 are as defined in formula (I). In another specific example, E is

其中R3Q，R31和R32是如式（I )中所定義者。在另一具體實例中，E是Where R3Q, R31 and R32 are as defined in formula (I). In another specific example, E is

其中R28，R29，R3〇，R31和R32是如式（I )中所定義者。在另一具體實例中，R 3 ◦，R 3 1和R 3 2互不相關的分別爲氫鹵素，一〇CF3，一SCF3 或一CF3， 23 200401634 C 1 — 6 —烷基，其是選擇性的經一個或多個選自下述之取代基取代的：氟，—CN，一 CF3，—〇CF3，— 〇R35 和一 NR35R36， C 3 — 8 -環烷基或C 4 — 8 —環烯基，其可選擇性的經一個或多個選自氟，一 CN，一 CF3，一〇CF3，一〇 R 3 5，一 N R 3 5 R 3 6及c 1 _ 6 —烷基的取代基取代的 •芳基，芳氧基或芳基一 Cl — 6 -烷氧基，其中該芳基可選擇性的經一個或多個選自鹵素，一 c N，一 C F 3， —〇CF3 ，一NOS，一 R35 ，一NR35R36 及 C i - 6 -烷基的取代基取代的， R 3 5和R 3 6互不相關的分別爲氫，C 1 — 6 —烷基或芳基，或當R 3 5及R 3 6鍵結至相同的氮原子上時，則其和該氮原子可形成一3至8元雜環’且此雜環選擇性的含有一個或二個其它選自氮，氧及硫的雜原子，且選擇性的含有一個或二個雙鍵。在另一具體實例中，R 3 ◦，R 3 1和R 3 2互不相關的分別是 _氫 •鹵素，〇cf3，或一scf3， C 1 _ 6 —烷基，其可選擇性的經一個或多個選自氟， -CN，一CF3，一〇CF3，一〇R35 及 —N R 3 5 R 3 6取代的， 24 200401634 • ί哀己基或ί哀己- 1 -嫌基’其可選擇性的經一個或多個選自氣 ’ 一CN ’ 一 CF3，一〇CF3，一〇R35， — NR 3 5R36及C ι_6—烷基取代的， •苯基，其可選擇性的經一個或多個選自鹵素，一 C N，一 CF3 ，一〇CF3 ，一N〇2 ，一〇R35 ，一 NR 3 5R36及C ι — 6 -烷基取代的， •苯氧基或苯甲氧基，其中該苯基可選擇性的經一個或多個選自鹵素，一CN，一 CF3，一〇CF3，一 N〇2 ，一〇R35，— NR35R36及Ci_6 一烷基取代的， R 35和R 3 6互不相關的分別爲氫或C 1 — 6 -烷基。在另一具體實例中，R3 ◦和32兩者皆爲氫，及R31 不是氫。在另一具體實例中，E是Wherein R28, R29, R30, R31 and R32 are as defined in formula (I). In another specific example, R 3 ◦, R 3 1 and R 3 2 which are unrelated to each other are hydrogen halide, 10CF3, SCF3 or CF3, 23 200401634 C 1 6-alkyl, which are selected It is substituted by one or more substituents selected from the group consisting of: fluorine, —CN, —CF3, —〇CF3, —OR35 and —NR35R36, C 3 —8-cycloalkyl, or C 4 — 8 — Cycloalkenyl, optionally via one or more selected from fluorine, -CN, -CF3, -0CF3, -OR 3 5, -NR 3 5 R 3 6 and c 1-6 -alkyl • Substituent-substituted aryl, aryloxy or aryl-Ci-6-alkoxy, wherein the aryl is optionally selected from one or more of halogen, -cN, -CF3,-. CF3, a NOS, a R35, a NR35R36 and a Ci-6-alkyl substituent, R 3 5 and R 3 6 are hydrogen, C 1-6 -alkyl or aryl, which are independent of each other, Or when R 3 5 and R 3 6 are bonded to the same nitrogen atom, then they and the nitrogen atom can form a 3 to 8 membered heterocyclic ring ', and the heterocyclic ring optionally contains one or two other selected from Heteroatoms of nitrogen, oxygen and sulfur, Selectively contain one or two double bonds. In another specific example, R 3 ◦, R 3 1 and R 3 2 are _ hydrogen • halogen, 0cf3, or a scf3, C 1 _ 6-alkyl, which are not related to each other. One or more selected from fluorine, -CN, -CF3, 10CF3, 10R35 and -NR 3 5 R 3 6 substituted, 24 200401634 Optionally substituted by one or more selected from the group consisting of gaseous-one CN 'one CF3, one CF3, one RR35, -NR 3 5R36 and C 1-6 alkyl,-phenyl, which can be optionally Or more selected from halogen, one CN, one CF3, one 10CF3, one No2, one R35, one NR 3 5R36 and C 6-6 alkyl substituted, phenoxy or phenoxy Wherein the phenyl group is optionally substituted with one or more selected from halogen, -CN, -CF3, -0CF3, -NO2, -OR35, -NR35R36 and Ci_6 alkyl, R35 and R 3 6 independently of each other is hydrogen or C 1-6 -alkyl. In another specific example, R3 and 32 are both hydrogen, and R31 is not hydrogen. In another specific example, E is

25 20040163425 200401634

在另一具體實例中，E是In another specific example, E is

在另一具體實例中，E是 26 200401634In another specific example, E is 26 200401634

ο 在另一具體實例中，Ε是ο In another specific example, E is

其中R3Q是如式（I )中所定義者。在另一具體實例中，R30是鹵素或 •雜芳基，其可選擇性經一個或多個選自鹵素，一 C N，一 CF3 ，一N〇2 ，一〇R35 ，— NR35R36 及 C i __ 6 一院基取代的， R 35和R 3 6互不相關的分別是氫或C ι_6-烷基，或當R 3 5及R 3 6鍵結至相同的氮原子上時，則其和該氮原子可形成一 3至8元雜環’此雜環選擇性的含有一個或二個其它選自氮，氧及硫的雜原子’及選擇性的含有一個或二個雙鍵。在另一具體實例中，R 3 〇是 •鹵素，或噻嗯基，其可選擇性經一個或多個選自鹵素’一 C N ’ —CFq，一N〇2 ，一0 r35，一NR35R36 及 ό c i-6 -烷基取代的’ 27 200401634 R 35和R 3 6互不相關的分別是氫或C ι — 6 —烷基，或當R 3 5及R 3 6鍵結至相同的氮原子上時，則其和該氮原子可形成一 3至8元雜環，此雜環選擇性的含有一個或二個其它選自氮，氧及硫的雜原子，及選擇性的含有一個或二個雙鍵。在另一具體實例中’ E是Where R3Q is as defined in formula (I). In another specific example, R30 is halogen or heteroaryl, which can be optionally selected from one or more of halogen, -CN, -CF3, -NO2, -OR35,-NR35R36 and C i __ 6 is substituted by a radical, and R 35 and R 3 6 are unrelated to each other hydrogen or C 6_ 6 alkyl, or when R 3 5 and R 3 6 are bonded to the same nitrogen atom, then it and the The nitrogen atom can form a 3- to 8-membered heterocyclic ring 'this heterocyclic ring optionally contains one or two other heteroatoms selected from nitrogen, oxygen and sulfur' and optionally contains one or two double bonds. In another specific example, R 3 0 is a halogen, or thienyl, which can be optionally selected via one or more halogens selected from the group consisting of halogen '-CN'-CFq, -N02, -0 r35, -NR35R36 and ό c i-6 -alkyl substituted '27 200401634 R 35 and R 3 6 are unrelated to each other hydrogen or C 1-6 alkyl, or when R 3 5 and R 3 6 are bonded to the same nitrogen When atomic, it and the nitrogen atom can form a 3- to 8-membered heterocyclic ring. This heterocyclic ring optionally contains one or two other heteroatoms selected from nitrogen, oxygen and sulfur, and optionally contains one or Two double bonds. In another specific example, 'E is

在另一具體實例中，Y是一 C (〇）一，一 ◦一，一 S (〇）2 —，一 NH —或一CH2-。在另一具體實例中，Y是一 CHRii —，其中Rii是和R 1結合，形成一雙鍵。在另一具體實例中，Y是一 C (〇）一。在另一具體實例中，R1和R2兩者皆爲氫。在另一具體實例中，R1和R 2結合在在一起形成一雙鍵。在另一具體實例中，R3是氫。在另一具體實例中，Z是一 C (〇）一（CR13R14 )p-，-〇-（CR"R“）p-， -NRi5 — (CR"ri” p 一或 -S(〇）2 - (CR"R“）p-，其中p，Rl3，R14和R15是如式（I )中所定義者。 28 200401634 在另一具體實例中，Z是一 NR15— (CR13R14 )p —或一 C (〇）一（CR13R14) p —，其中 p 是如式（I)中所定義者，及R13和R1 4互不相關的分別選自氫，一CF3，一〇CF3及Ci_6—烷基及R15是氫。In another specific example, Y is a C (〇)-, a ◦-, a S (〇) 2-, a NH-, or a CH2-. In another specific example, Y is a CHRii — where Rii is combined with R 1 to form a double bond. In another specific example, Y is -C (0)-. In another specific example, both R1 and R2 are hydrogen. In another specific example, R1 and R2 are bonded together to form a double bond. In another specific example, R3 is hydrogen. In another specific example, Z is -C (〇)-(CR13R14) p-, -〇- (CR " R ") p-, -NRi5 — (CR " ri" p one or -S (〇) 2 -(CR " R ") p-, where p, R13, R14, and R15 are as defined in formula (I). 28 200401634 In another specific example, Z is a NR15— (CR13R14) p—or a C (〇) 一 (CR13R14) p —, where p is as defined in formula (I), and R13 and R1 4 are unrelated to each other selected from hydrogen, -CF3, -0CF3 and Ci_6-alkyl and R15 is hydrogen.

在另一具體實例中，Z是一 NH (CH2) p或一 C 〇）一（CH2) P —，其中P是如式（I)中所定義者在另一具體實例中，Z是NH或一 C (〇）一。在另一具體實例中，Z是一 C (〇）一。在另一具體實例中，D是In another specific example, Z is -NH (CH2) p or -C0)-(CH2) P-, where P is as defined in formula (I). In another specific example, Z is NH or -C (〇) 一. In another specific example, Z is -C (0)-. In another specific example, D is

，16, 16

N R18N R18

N-R20N-R20

其中 R16，R17，R18，R19，R2Q 和 R21 是如式（I )中所定義者。在另一具體實例中，D是Where R16, R17, R18, R19, R2Q and R21 are as defined in formula (I). In another specific example, D is

其中R16，R17和R18是如式（I )中所定義者。 29 200401634 在另一具體實例中，R 1 6，R 1 7和R 1 8分別是氫，鹵素，—CN，一CH2CN，—CHF2，一CF3，一〇chf2, 一〇ch2cf3, 一〇cf2chf2， —S (〇）2CF3，一SCF3, 一N〇2，一〇R22， —NR22R23，—SR22，—NR22S (〇）2R23， —s (〇）2nr22r23，一s (〇）nr22r23， —S (〇）R22，一S (〇）2R22， —C (〇）NR22R23，一〇C (〇）NR22R23，一NR22C (〇）R23，一CH2C (〇）NR22R23，一〇CH2C (〇）NR22R23, 一 CH2〇R23， —CH2NR22R23，一〇C (〇）R22，一C (〇）R22或 —C (〇）〇R22， C 1 _ 6 —烷基，其可選擇性的經一個或多個選自氟，一 CN，一 CF3，一〇CF3，一〇R22 及一 N R 2 2 R 2 3的取代基取代的， _ C 3 _ 8 —環烷基，其可選擇性的經一個或多個選自氟，一 C (〇）〇R24，— CN，一 CF3，一〇CF3, 一〇r22，一 Nr22r23及Ci — 6 —烷基的取代基取代的，芳基或芳氧基，其可選擇性的經一個或多個選自氟’一 C (〇）〇R24，— CN，一 CF3，一〇CF3，一 N〇2，一 OR22，一 NR22R23 及 Cl — 6 — 烷基的取代基取代的， R 22和R 2 3互不相關的分別是氫，C 1-6—烷基，芳 30 200401634 基一 C i — 6 —烷基或芳基，或當R 2 2及R 2 3鍵結至相同的氮原子上時，則其和該氮原子一起形成一 3至8元的雜環，且此雜環選擇性的含有一個或二個其它選自氮，氧及硫的雜原子’且選擇性的含有一個或二個雙鍵’ 或當R 1 6至R 1 8中的二個位於相鄰位置時，則其可一起形成一架橋基 —(CR24R25) a_〇 — （CR26R27) c_〇_， a是0，1或2， C是1或2， R 2 4，R 2 5，R 2 6及R 2 7互不相關的分別是氫，c 1 — 6 一院基或氣。在另一具體實例中，R 1 6，R 1 7和R 1 8互不相關的分別是氫，鹵素，一CF3，一〇CF3，一 SCF3，Ci_6 一烷基，Ci — 6 -烷氧基，苯基，環戊基，環己基或苯氧基， •或當R 1 6至R 1 8中的二個位於相鄰位置時，其可一起形成一架橋基 —〇一（CF2) 2 一 ◦一，一 CF 2 — 〇一CF 2 — 〇一或一〇一 CH2 — 〇一。在另一具體實例中，R16是氫，及R17和R18不是氫。在另一具體實例中，R16和R17是氫，及R18不是 31 200401634 氫。在另一具體實例中，本發明關於一種式（I 4 )化合物Where R16, R17 and R18 are as defined in formula (I). 29 200401634 In another specific example, R 1 6, R 1 7 and R 1 8 are hydrogen, halogen, —CN, —CH2CN, —CHF2, —CF3, —Ochf2, —Och2cf3, —Ocf2chf2, —S (〇) 2CF3, —SCF3, —No2, —OR2, —NR22R23, —SR22, —NR22S (〇) 2R23, —s (〇) 2nr22r23, —s (〇) nr22r23, —S (〇 ) R22, -S (〇) 2R22, -C (〇) NR22R23, -0C (〇) NR22R23, -NR22C (〇) R23, -CH2C (〇) NR22R23, -CH2C (〇) NR22R23, -CH2. R23, —CH2NR22R23, 10C (〇) R22, 1C (〇) R22 or —C (〇) 〇R22, C 1 -6 —alkyl, which can be optionally selected from one or more of fluorine, One CN, one CF3, one 10CF3, one 10R22 and one NR 2 2 R 2 3 substituent, _C 3 _ 8-cycloalkyl, which is optionally selected from one or more fluorine groups , C (〇) OR24, —CN, —CF3, —CF3, —OR22, —Nr22r23, and Ci-6 —alkyl substituted with aryl or aryloxy groups, which are optional Via one or more selected from fluorine'-C ( ) 〇R24, —CN, —CF3, —CF3, —NO2, —OR22, —NR22R23, and Cl-6 —alkyl substituents, R 22 and R 2 3 are unrelated to each other and are hydrogen , C 1-6-alkyl, aryl 30 200401634 radical-C i — 6-alkyl or aryl, or when R 2 2 and R 2 3 are bonded to the same nitrogen atom, then it and the nitrogen atom Together form a 3 to 8 membered heterocyclic ring, and this heterocyclic ring optionally contains one or two other heteroatoms selected from nitrogen, oxygen and sulfur 'and optionally contains one or two double bonds' or when R When two of 16 to R 1 are located adjacent to each other, they can form a bridge base together— (CR24R25) a_〇— (CR26R27) c_〇_, where a is 0, 1, or 2, and C is 1 or 2, R 2 4, R 2 5, R 2 6 and R 2 7 are unrelated to each other, hydrogen, c 1-6 a radical or gas. In another specific example, R 1 6, R 1 7 and R 1 8 are irrelevant to each other hydrogen, halogen, -CF3, -CF3, -SCF3, Ci_6 alkyl, Ci-6 -alkoxy , Phenyl, cyclopentyl, cyclohexyl, or phenoxy, or when two of R 1 to R 1 8 are located adjacent to each other, they can form a bridge group together— 〇一 (CF2) 2 一◦ One, one CF 2 — 〇 One CF 2 — 〇1 or 100 — CH2 — 〇1. In another specific example, R16 is hydrogen, and R17 and R18 are not hydrogen. In another specific example, R16 and R17 are hydrogen, and R18 is not 31 200401634 hydrogen. In another specific example, the invention relates to a compound of formula (I 4)

其中R6，R7，E和D是如式（I )中所定義者，或如前述任一具體實例中所定義者，以及其任何非對映或對映異構物或包括這些異構物混合物的互變異構物，或其藥學上可接受的鹽。在其它具體實例中，本發明關於一種式（I 5 )化合物Where R6, R7, E and D are as defined in formula (I), or as defined in any of the foregoing specific examples, and any diastereomers or enantiomers thereof or mixtures of these isomers Tautomers, or pharmaceutically acceptable salts thereof. In other specific examples, the invention relates to a compound of formula (I 5)

(|5) 其中R6，R7，E和D是如式（I )中所定義者，或如前述任一具體實例中所定義者，以及其任何非對映或對映異構物或包括這些異構物混合物的互變異構物，或其藥學上可接受的鹽。在其它具體實例中，本發明關於一種式（I 5 a )化合物， 32 200401634(| 5) wherein R6, R7, E and D are as defined in formula (I), or as defined in any of the foregoing specific examples, and any diastereomers or enantiomers thereof or include these Tautomers of a mixture of isomers, or a pharmaceutically acceptable salt thereof. In other specific examples, the present invention relates to a compound of formula (I 5 a), 32 200401634

其中R6，R7，E和D是如式（I )中所定義者，以及其任何非對映或對映異構物或包括這些異構物混合物的互變異構物，或其藥學上可接受的鹽。在其它具體實例中，本發明關於一種式（I 5 b )化合物，Where R6, R7, E and D are as defined in formula (I), and any diastereomers or enantiomers thereof or tautomers including mixtures of these isomers, or a pharmaceutically acceptable Of salt. In other specific examples, the present invention relates to a compound of formula (I 5 b),

其中R6，R7，E和D是如式（I )中所定義者，以及其任何非對映或對映異構物或包括這些異構物混合物的互變異構物，或其藥學上可接受的鹽。在其它具體實例中，本發明關於一種式（I 6 )化合物Where R6, R7, E and D are as defined in formula (I), and any diastereomers or enantiomers thereof or tautomers including mixtures of these isomers, or a pharmaceutically acceptable Of salt. In other specific examples, the present invention relates to a compound of formula (I 6)

其中R6，R7，E和D是如式（I )中所定義者，或如前述任一具體實例中所定義者，以及其任何非對映或對映異構物或包括這些異構物混合物的互變異構物，或其藥學上可接受的鹽。本發明的化合物可具有不對稱中心，且任何對映異構 33 200401634 物（呈分離，純或部份純化之對映異構物）或其消旋混合物皆包含在本發明的範圍中。此外，當一個雙鍵或完全或部份飽和環系統，或超過一個非對稱中心，或限制旋轉度的鍵存在於一分子中時，則可能形成一非對映異構物。在此將任何非對映異構物，呈分離，純或部份純化的非映異構物或其混合物包含在本發明的範圍中。再者，一些本發明的化合物可以能夠形成的不同互變異構物形式存在，在此將此化合物包括在本發明的範圍之內。本發明也關於本發明化合物之藥學上可接受的鹽，這些鹽類包括藥學上可接受的酸加成鹽，藥學上可接受的金屬鹽，銨和烷基化銨鹽。酸加成鹽包括無機酸及有機酸的鹽，合適無機酸的代表例子爲氫氯酸，氫溴酸，氫碘酸，磷酸，硫酸，硝酸，和類似的酸。合適有機酸的代表例子爲甲酸，乙酸，三氯乙酸，三氟乙酸，丙酸，苯甲酸，肉桂酸，檸檬酸，富馬酸，乙二醇酸，乳酸，順丁烯二酸，蘋果酸，丙二酸，扁桃酸，乙二酸，苦味酸，丙酮酸，水楊酸，丁二酸，甲烷磺酸，乙烷磺酸，酒石酸，抗壞血酸，雙經萘酸（pamoic )，雙甲撐水楊酸，乙院二磺酸，葡糖酸，檸康酸，天冬酸，硬脂酸，棕櫚酸，E D T A，乙二醇酸，p —胺基苯甲酸，谷氨酸，苯磺酸，p -甲苯磺酸，硫酸鹽，硝酸鹽，磷酸鹽，過氯酸鹽，硼酸鹽，乙酸鹽，苯甲酸鹽，羥基萘酸鹽，丙三氧基磷酸鹽，酮戊二酸 34 200401634 鹽和類似物。其它藥學上可接受無機或有機酸加成鹽的例子包括列於：i. Pharm. Sci. 1977， 66 ’ 2 ’的藥學上可接受的鹽，在此倂入本發明作爲參考。金屬鹽的例子包括鋰，鈉，鉀，鎂鹽和類似物。銨和烷基化銨鹽的例子包括銨，甲基銨，二甲基銨，三甲基銨，乙基銨，羥基乙基銨，二乙基銨，正一丁基銨，第二一丁基銨，叔一丁基銨，四甲基銨鹽和類似物。其它本發明化合物可形成之藥學上可接受的酸加成鹽是水合物。再者，藥學上可接受鹽包括鹼性胺基酸鹽，像離氨基酸（lysine )，阿金氨基酸（arginine )和鳥氨基酸（ ornithine)。酸加成鹽可由化合物合成的直接產物獲得。另一方面，游離鹼可溶於適當含有恰當酸的溶劑中，且鹽可由蒸發溶劑，或者分離鹽和溶劑的方式分離出。本發明的化合物可和標準低分子量溶劑，使用此項領域內習知的方法形成溶劑化物。這些溶劑化物也包括在本發明的範圍之內。本發明也關於本發明化合物的前藥（prodrugs)，施用時’在其變成活性藥理成份前會由新陳代謝的程序產生化學轉變。一般而言，這些前藥是本發明式（I )化合物的功能性衍生物，其在體內易於轉變爲所需之式（I )化合物。選擇和製備合適前藥衍生物的傳統步驟描述於，例如 Design of Prodrugs1' 5 ed. H. Bundgaard 5 Elsevier， 35 200401634 1985。本發明也關於本發明化合物的新陳代謝產物。本發明的化合物具有拮抗胰增血糖素的作用，因此可用於治療及/或預防該拮抗作用是有利之疾病。本發明的化合物較佳的具有I C 5 〇値不超過5 // Μ，更佳地小於1 // Μ，愈佳地小於5 0 0 ηΜ，像小於1 〇〇 ηΜ (由在此所揭示之胰增血糖素結合試驗（I )或胰增血糖素結合試驗（I I )測定）。因此，本發明化合物可適用於治療高血糖，I G Τ ( 葡萄糖容忍度的損害），抗胰島素徵候群，徵候群X，類型I糖尿病，類型I I糖尿病，血內脂過多，脂肪代謝障礙（dyslipidemia)，高三酸甘油脂血症（hypertriglyceridemia) ，高脂蛋白血症（hyperlipoproteinemia)，高膽固醇血症，包括動脈粥瘤硬化的動脈硬化疾病，高糖素瘤，急性的胰臟炎，心臟血管的疾病，高血壓，心臟肥大，胃腸疾病，肥胖症，肥胖導致的糖尿病，糖尿病引起的血脂代謝障礙。此外，他們可適用於當做診斷劑以識別具有胰增血糖素受體的缺點之病人，當做增加胃酸分泌的治療劑，及由於投予胰增血糖素所產生之腸蠕動減緩的治療。其也可在結合試驗中用作標示型式的工具或參考分子，如輻射標示，以確認新穎胰增血糖素拮抗劑。因此，本發明另一個特徵爲關於一種用作藥物的本發明化合物。本發明也關於一種藥學組成物，包括當作活性成份之 36 200401634 至少一本發明的化合物’及一種或多種藥學上可接受的載體或輔助劑。此藥學組成物較佳的是單位劑量型式，包括從約〇.〇5 毫克至約1000毫克，較佳的從約0.1毫克至約500毫克，特別佳的從約0.5毫克至約200毫克的本發明化合物。再者，本發明也關於本發明化合物於製備可治療其中胰增血糖素拮抗作用是有利疾病的藥學組成物的應用。本發明也關於治療其中胰增血糖素拮抗作用是有利之疾病的方法’包括施與該患者一有效量之本發明化合物。在一較佳實施例中，本發明的化合物用於製造可用於治療預防高血糖之藥物。在另一較佳實施例中，本發明的化合物是用於製造可降低哺乳動物血糖的藥物。本發明的化合物可有效的降低血糖，包括在斷食及膳食後的階段。在另一較佳實施例中，本發明的化合物是用於製造可治療I G T的藥物。在另一較佳實施例中，本發明的化合物是用於製造可治療第2型糖尿病的藥物。在另一較佳實施例中，本發明的化合物是用於製造可延緩或預防I G T發展爲第2型糖尿病的藥學組成物。在另一較佳實施例中，本發明的化合物可用於製造爲用於延緩或預防不需胰島素之第I I型糖尿病惡化爲需胰島素之第II型糖尿病之藥學組成物。在另一較佳實施例中，本發明的化合物是用於製造可 37 200401634 治療第i型糖尿病的藥學組成物。該治療一般是配合胰島素治療。在另一較佳實施例中，本發明的化合物是用於製造可治療肥胖症的藥學組成物。在另一較佳實施例中，本發明的化合物是用於製造可治療脂肪新陳代謝疾病的藥學組成物，像脂肪代謝障礙。在另一較佳實施例中，本發明的化合物是用於製造可治療食慾調節或能量消耗疾病的藥學組成物。本發明的另一個特徵爲以本發明化合物治療病人時可和飮食及/或運動配合施用。本發明的其它特徵爲本發明的化合物也可和一種或多種其它藥理活性物質，以適當的比例一起配合施用，這些其它活性物質爲如抗糖尿病劑，抗高血脂劑，抗肥胖劑，抗高血壓劑，用於治療由糖尿病引起或相關倂發症的藥劑〇合適的抗糖尿病劑包括胰島素，胰島素類似物及衍生物，像揭示於 E P 7 9 2 2 9 0 (Novo Nordisk A/S)的物質，如ΝεΒ29—十四烷醯基（B30)，人體胰島素，EP214 826及 ΕΡ 705 275 (Novo Nordisk A/S)，如 AspB28 人體胰島素，118-5，504，188 (Eli Lilly)，如 LysB28ProB29 人體胰島素，EP368 187(Aventis)，如Lantus®，所有這些物質在此併入本發明作爲參考，G L P - 1和G L P — 1衍生物，像那些描述於W 0 98/08871 ( Novo Nordisk A/S )的化合物，在此將其倂入本發明作爲參考，及口服活性低血糖劑。 38 200401634 口服活性的降血糖作用劑較佳地包括咪唑咐；磺醯脲，·雙，胍類；氯茴苯酸類（meglitinide);噁二哩卩定二酮；噻唑啶二酮；胰島素增敏劑；糖苷酶抑制劑；作用於/5細胞的ATP-依賴性鉀通道之作用劑（例如，鉀通道開放劑），例如，揭露於 WO 97/26265、WO 99/03861 及 WO 00/37474 (Novo Nordisk A/S)之作用劑，其以引用方式納入本文中；或米提格列奈（ mitiglinide);或鉀通道阻斷劑，例如，BTS-67582 ;那格列奈 (nateglinide );胰增血糖素拮抗劑，例如，揭露於WO ^ 99/01423 及 WO 00/39088 (Novo Nordisk A/S 及 Agouron 製藥公司）之拮抗劑，其以引用方式納入本文中；glp-1激動劑，例如，揭露於 wo 00/42026 (Novo Nordisk A/S 及 Agouron 製藥公司）之激動劑，其以引用方式納入本文中；DPP-IV (二胜肽基胜肽酶-IV)抑制劑；PTP酶（蛋白質酪胺酸磷酸酶）抑制劑；涉及刺激葡萄糖生成及/或糖原分解的肝臟酵素之抑制劑；葡萄糖攝取調節劑；GSK-3 (糖原合成酶激酶-3)抑制劑；修飾脂質代謝之化合物，例如，抗脂質增高作用劑；降低食物攝取 φ 之化合物；PPAR (過氧化物酶體增生活化受體）及rxr (視黃醇類X受體）激動劑，例如，ALRT-268、LG-1268或LG-1069 。在一具體實例中’本發明的化合物可和胰島素或胰島素類似物或衍生物一起配合施用，像Ν ε B29 -十四烷醯 des(B30)人體胰島素’ AspB28人體胰島素，LysB28ProB29人體胰島素 ’ LysB29-(N ε ( 7 -glutamyl-N α litocholyl)des(B30)人體胰島素’ Lantus，或包括一種或多種這些物質的混合製備物 39 200401634 在本發明的另一具體實例中，本發明之化合物是與磺醯脲結合而投藥，例如，甲磺丁脲（tolbutamide)、氯磺丙脲（ chlorpropamide )、妥拉磺脲（tolazamide )、格列本（ glibenclamide)、格列班脲(glyburide)、格列D比嗪（glypizide) 、格列甲ϋ秦(glimepride)、格列齊特（glicazide)。在本發明的另一實施例中，本發明的化合物是和雙胍類一起施用，如二甲雙胍（metformin)。在本發明的又一實施例中，本發明的化合物是和梅格萘得（meglitinide) —起施用，如雷帕列奈片（repaglinide)或那格列奈片（nateglinide)。在本發明的另一具體實例中，本發明之化合物是與噻哇B定二酮胰島素增敏劑結合而投藥，例如，卓格列酮（ troglitazone )、環格列酮（ciglitazone )、卩比格列酮（ pioglitazone )、羅西格列酮（rosiglitazone )、伊莎格列酮 (isaglitazone )、達格列酮（darglitazone )、恩格列酮（ englitazone) 、CS-011/C1-1037 或 T174，或是揭露於 W〇 97/41097、W〇 97/41119、WO97/41120、W〇 00/41121 及 W〇 98/45292 (Reddy博士硏究基金會）之化合物。在另一實施例中，本發明的化合物可和胰島素敏感劑配合使用，像 GI 262570，YM-440，MCC-555， JTT-501 ，Ar-H039242， KRP-297， GW-409544， CRE-16336， AR-H-049020， LY510929， LY465608， MBX-102， CLX-940， GW-501516， tesaglitazar (AZ 242)或揭示於 200401634 W099/19313 ， W〇 00/50414 ， WO 00/63191 5 WO 00/63192， W〇 00/63193 的化合物，像 ragaglitazar (NN 622 或（-)DRF 2725)(Dr. Reddy’s Research Foundation)及 W〇 00/23425， W〇 00/23415， WO 00/2345：!， WO 00/23445 ^ WO 00/23417 ^ W〇 00/23416 ， W〇 00/63153 ， WO 00/63196， W〇 00/63209， W〇 00/63190 和 W〇 00/63189 (Novo Nordisk A/S) o 在本發明的另一具體實例中，本發明之化合物是與a-糖苷酶抑制劑結合而投藥，例如，伏格列波糖（voglibose)、乙格列酯（emiglitate )、米格列醇（miglitol )或阿卡波糖（ acarbose) 〇在本發明的另一具體實例中，本發明之化合物是與作用於冷細胞的ATP-依賴性鉀通道之作用劑結合而投藥，例如，甲磺丁脲、格列本、格列毗嗪、格列齊特、BTS-67582或瑞格列奈〇在本發明的另一具體實例中，本發明之化合物是與抗高脂血作用劑或抗脂質增高作用劑結合而投藥，例如，考來烯胺（cholestyramine )、考來替泊（colestipol )、氯貝特（clofibrate )、吉非羅齊（gemfibrozil )、洛伐他汀（ lovastatin )、普伐他汀（pravastatin )、辛伐他汀（ simvastatin )、普羅布考（probucol )或右旋甲狀腺素（ dextrothyroxine) 〇在本發明的另一實施例中，本發明的化合物是和超過一種上述的化合物配合使用，如和二甲雙胍（metf〇rmin)及 41 200401634 磺醯脲類（sulphonylurea)配合’像格列本（glibenclamide) 或格列班脲（glyburide);磺醯脲類和阿卡波糖（acarbose)配合 :二甲雙胍及氯茴苯酸類（meglitinide)配合，像瑞格列萘 (repaglinide);阿卡波糖（acarbose)和二甲雙胍配合；磺醯尿類，二甲雙胍及卓格列酮（troglitazone)配合；磺醯脲類，二甲雙胍及卩比格列酮（pioglitazone)配合；磺醯脲類，二甲雙胍及胰島素敏感劑配合，像揭示於W0 00/63189或W〇 97/41097的敏感劑；氯茴苯酸類（meglitinide)(像瑞格列萘 (repaglinide))，二甲雙胍及卓格列酮（troglitazone)配合；氯茴苯酸類（meglitinide)(像瑞格列萘（repaglinide))，二甲雙胍及毗格列酮（pioglitazone)配合；氯茴苯酸類（meglitinide)( 像瑞格列萘（repaglinide))，二甲雙胍及一胰島素敏感劑（像揭示於W0 00/63189或W0 97/41097)配合；胰島素及磺醯脲配合；胰島素和氯茴苯酸類（meglitinide)(像瑞格列萘 (repaglinide))配合；胰島素和二甲雙胍配合；胰島素’二甲雙狐和氯茴苯酸類（meglitinide)(像瑞格列萘（repaglinide))配合；胰島素，二甲雙胍及磺醯脲配合；胰島素和 troglitazone配合；胰島素和毗格列酮（pioglitazone)配合；胰島素和胰島素敏感劑（像揭示於W0 00/63189或W〇 97/41097 )配合；胰島素和lovastatin配合；胰島素類似物或衍生物，二甲雙胍及一氯茴苯酸類（meglitinide)(像瑞格列萘（repaglinide))配合；胰島素類似物或衍生物，二甲雙胍及磺醯脲配合；胰島素類似物或衍生物及卓格列酮 (troglitazone)配合；胰島素類似物或衍生物及卩it格列酮 42 200401634 (pioglitazone)配合；胰島素類似物或衍生物及一胰島素敏感劑（像揭示於W0 00/63189或W0 97/41097 )配合；胰島素類似物或衍生物及洛伐他汀（lovastatin)配合；等等。除此之外，本發明的化合物可和一種或多種抗肥胖劑或食慾調節劑一起施用。這些藥劑爲選自CART (古柯鹼安菲太明調節轉錄本（***e amphetamine regulated transcript )激重力劑， NPY (神經肽 Y ( neuropeptide Y))括抗劑，MC4 ( 黑色皮質素4 (melanocortin4))激動劑，阿立新拮抗劑（ orexin antagonists )，H3組織胺拮抗劑，T N F (腫瘤壞死因子（tumor necrosis factor))調節劑，C R F (親皮質素釋放因子（corticotropin releasing factor)激動劑，C R F BP (親皮質素釋放因子結合蛋白（corticotropin releasing factor binding protein)诘抗劑，尿皮質素激動劑（ urocortin agonists ) ，3 激動劑，像 CL-316243， AJ- 9677， GW-0604，LY377267 或 AZ-40140，M S H (黑色素細胞刺激激素（melanocyte-stimulating hormone ))激動劑，M C Η (黑色素細胞濃縮激素（melanocyteconcentrating hormone ) 拮抗劑， C C K (激膽囊素（ cholecystokinin)激動劑，血淸素（serotonin)再攝取抑止劑，像 fluorxetine， seroxate 或 citalopram，血淸素和正腎上腺素（noradrenaline )再攝取抑止劑，5 Η T (血淸素）激動劑，邦巴辛激動劑（bombesin agonists )，甘丙素拮抗劑（galanin antagonists)，生長激素，生長激素釋放化合 43 200401634 物，T R Η (親甲狀腺釋放激素（thyreotropin releasing hormone ))激動劑，U C P 2或3 (解偶聯蛋白2或3 (uncoupling protein 2 or 3))調節劑，萊普亭激動劑（ leptri agonists ) ，D A 激動劑（溴隱亭（bromocriptin )，嗎乙苯吡酮（doprexin))，脂肪酶/澱粉酶抑止劑，P P A R調節劑，R X R (視黃醛衍生物X受體（retinoid X receptor )調節劑或T R /3激動劑。在本發明另一個實施例中，抗肥胖劑是十安菲太明（ φ dexamphetamine )或安菲太明(amphetamine ) 〇在本發明另一個實施例中，抗肥胖劑是氟***（ fenfluramine )或十氟***（dexfenfluramine )。在本發明的另一個實施例中，抗肥胖劑是蘇木他明（ sibutramine) 0 在本發明的另一實施例中，抗肥胖劑是歐力士塔（ orlistat) 〇在本發明的另一實施例中，抗肥胖劑是氯苯咪吲哚（ φ mazindol)或苯丁胺（phentermine )。再者，本發明的化合物可和一種或多種抗高血壓藥劑配合使用，抗高血壓藥劑的例子爲/3 -嵌段劑，像/3 -感受體遮斷劑（alprenolol )，安田心安（atenolol )，噻嗎心安（timolol ) ，DM； U朵心安（pindolol )，心得安（ propranolol )和美多心安（met〇pr〇l〇l )，A C E (血管緊張素轉化酶）抑止劑，像吲哚心安（benazepril)，毓甲丙脯酸（captopril ) ’乙氧苯丙脯酸（enaiaprii)，氟辛丙脯 44 200401634 酸（fosinopril )，麗辛丙脯酸（lisinopril)，喹喔丙脯酸 (quinapril )和藍咪丙脯酸（ramipril )，鉀道嵌段劑，像硝苯D比卩定（nifedipine)，菲略Dtt卩定（felodipine)，尼卡卩比陡（nicardipine )，依斯拉卩ϋ陡（isradipine )，尼摩卩比陡 (nimodipine )，蒂提亞（diltiazem)和非拉潘（verapamil) ，及α —嵌段劑，像多哇辛（doxazosin )，優皮蒂 (urapidil)，呢哩 β秦（prazosin )和四哇嗪（terazosin )。其它參考資料爲 Remington : The Science and Practice of Pharmacy 19th Edition， Gennaro ， Ed. ， MackWhere R6, R7, E and D are as defined in formula (I), or as defined in any of the foregoing specific examples, and any diastereomers or enantiomers thereof or mixtures of these isomers Tautomers, or pharmaceutically acceptable salts thereof. The compounds of the present invention may have asymmetric centers, and any enantiomer 33 200401634 (enantiomers that are isolated, pure or partially purified) or racemic mixtures thereof are included within the scope of the present invention. In addition, when a double bond or a fully or partially saturated ring system, or more than one asymmetric center, or a bond that restricts rotation is present in a molecule, a diastereomer may be formed. Any diastereomers, isolated, pure or partially purified, or mixtures thereof are included herein within the scope of the invention. Furthermore, some of the compounds of the present invention may exist in different tautomeric forms that can be formed, and this compound is included within the scope of the present invention. The present invention also relates to pharmaceutically acceptable salts of the compounds of the present invention. These salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salts. Acid addition salts include salts of inorganic and organic acids. Representative examples of suitable inorganic acids are hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, nitric acid, and similar acids. Representative examples of suitable organic acids are formic acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, propionic acid, benzoic acid, cinnamic acid, citric acid, fumaric acid, glycolic acid, lactic acid, maleic acid, malic acid , Malonic acid, mandelic acid, oxalic acid, picric acid, pyruvic acid, salicylic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, tartaric acid, ascorbic acid, pamoic acid, bismethylene Salicylic acid, acetic acid, gluconic acid, citraconic acid, aspartic acid, stearic acid, palmitic acid, EDTA, glycolic acid, p-aminobenzoic acid, glutamic acid, benzenesulfonic acid , P-toluenesulfonic acid, sulfate, nitrate, phosphate, perchlorate, borate, acetate, benzoate, hydroxynaphthoate, glyceryl phosphate, ketoglutarate 34 200401634 Salt and analogs. Other examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in: i. Pharm. Sci. 1977, 66 '2', which is incorporated herein by reference. Examples of metal salts include lithium, sodium, potassium, magnesium salts and the like. Examples of ammonium and alkylated ammonium salts include ammonium, methyl ammonium, dimethyl ammonium, trimethyl ammonium, ethyl ammonium, hydroxyethyl ammonium, diethyl ammonium, n-butylammonium, and second monobutyl Ammonium, tert-butylammonium, tetramethylammonium salts and the like. Other pharmaceutically acceptable acid addition salts that can be formed from the compounds of the present invention are hydrates. Furthermore, pharmaceutically acceptable salts include basic amino acids such as lysine, arginine and ornithine. Acid addition salts can be obtained from the direct products of compound synthesis. On the other hand, the free base can be dissolved in a solvent suitably containing an appropriate acid, and the salt can be separated by evaporating the solvent or by separating the salt and the solvent. The compounds of the present invention can be solvated with standard low molecular weight solvents using methods known in the art. These solvates are also included in the scope of the present invention. The present invention also relates to prodrugs of the compounds of the present invention, which, when administered, are chemically transformed by a metabolic process before they become active pharmacological components. In general, these prodrugs are functional derivatives of the compound of formula (I) of the present invention, which are easily converted into the desired compound of formula (I) in vivo. Traditional procedures for selecting and preparing suitable prodrug derivatives are described, for example, in Design of Prodrugs 1 '5 ed. H. Bundgaard 5 Elsevier, 35 200401634 1985. The invention also relates to the metabolites of the compounds of the invention. The compound of the present invention has an effect of antagonizing glucagon, and thus can be used for treating and / or preventing a disease in which the antagonism is advantageous. The compounds of the present invention preferably have an IC50 of not more than 5 // M, more preferably less than 1 // M, and more preferably less than 500 nM, like an image less than 100nM (as disclosed herein Glucagon binding test (I) or glucagon binding test (II)). Therefore, the compounds of the present invention are suitable for the treatment of hyperglycemia, IGT (impairment of glucose tolerance), anti-insulin syndrome, syndrome X, type I diabetes, type II diabetes, hyperlipidemia, and dyslipidemia. , Hypertriglyceridemia, hyperlipoproteinemia, hypercholesterolemia, atherosclerotic diseases including atherosclerosis, hyperglycosoma, acute pancreatitis, cardiovascular disease , Hypertension, cardiac hypertrophy, gastrointestinal diseases, obesity, obesity-induced diabetes, diabetes-induced dyslipidemia. In addition, they are suitable for use as a diagnostic agent to identify patients with shortcomings of glucagon receptors, as a therapeutic agent for increasing gastric acid secretion, and as a treatment for slowing intestinal motility due to glucagon administration. It can also be used as a labeling tool or reference molecule in binding experiments, such as radiation labeling, to identify novel glucagon antagonists. Therefore, another feature of the present invention relates to a compound of the present invention for use as a medicament. The present invention also relates to a pharmaceutical composition comprising, as active ingredients, 36 200401634 at least one compound of the present invention 'and one or more pharmaceutically acceptable carriers or adjuvants. The pharmaceutical composition is preferably in a unit dosage form, including from about 0.05 mg to about 1000 mg, preferably from about 0.1 mg to about 500 mg, and particularly preferably from about 0.5 mg to about 200 mg of Invention compounds. Furthermore, the present invention also relates to the use of the compound of the present invention in the preparation of a pharmaceutical composition that can treat diseases in which glucagon antagonistic effects are beneficial. The invention also relates to a method of treating a disease in which glucagon antagonism is advantageous, comprising administering to the patient an effective amount of a compound of the invention. In a preferred embodiment, the compounds of the present invention are used in the manufacture of a medicament useful for the treatment and prevention of hyperglycemia. In another preferred embodiment, the compounds of the invention are used in the manufacture of a medicament for lowering blood glucose in a mammal. The compounds of the present invention are effective in lowering blood glucose, including during fasting and post-dietary stages. In another preferred embodiment, the compounds of the invention are used in the manufacture of a medicament for the treatment of IGT. In another preferred embodiment, the compounds of the invention are used in the manufacture of a medicament for the treatment of type 2 diabetes. In another preferred embodiment, the compounds of the present invention are used to make a pharmaceutical composition that can delay or prevent the development of I G T to type 2 diabetes. In another preferred embodiment, the compounds of the present invention are useful in the manufacture of a pharmaceutical composition for delaying or preventing the progression of type I diabetes without insulin to type II diabetes requiring insulin. In another preferred embodiment, the compounds of the present invention are used to make a pharmaceutical composition that can treat type i diabetes. This treatment is usually combined with insulin treatment. In another preferred embodiment, the compound of the present invention is used for the manufacture of a pharmaceutical composition for treating obesity. In another preferred embodiment, the compounds of the present invention are useful in the manufacture of a pharmaceutical composition, such as a fat metabolism disorder, that is useful in the treatment of fat metabolism disorders. In another preferred embodiment, the compound of the present invention is a pharmaceutical composition for the manufacture of an appetite-regulated or energy-consuming disease. Another feature of the invention is that it can be administered in combination with fasting and / or exercise when treating a patient with a compound of the invention. Other features of the present invention are that the compounds of the present invention can also be administered in combination with one or more other pharmacologically active substances in appropriate proportions, such as anti-diabetic agents, anti-hyperlipidemic agents, anti-obesity agents, anti-high Blood pressure agents, agents used to treat diarrhea caused by or related to diabetes. Suitable antidiabetic agents include insulin, insulin analogs and derivatives, such as those disclosed in EP 7 9 2 2 9 0 (Novo Nordisk A / S) Substances such as NεB29-tetradecanyl (B30), human insulin, EP214 826 and EP 705 275 (Novo Nordisk A / S), such as AspB28 human insulin, 118-5, 504, 188 (Eli Lilly), such as LysB28ProB29 Human insulin, EP368 187 (Aventis), such as Lantus®, all of which are incorporated herein by reference, GLP-1 and GLP-1 derivatives, like those described in WO 98/08871 (Novo Nordisk A / S ) Compounds, incorporated herein by reference, and orally active hypoglycemic agents. 38 200401634 Oral active hypoglycemic agents preferably include imidazolium; sulfonylurea, bis, guanidines; meglitinide; oxadiazinedione; thiazolidinedione; insulin sensitization Agents; glycosidase inhibitors; agents acting on the ATP-dependent potassium channels of / 5 cells (eg, potassium channel openers), for example, as disclosed in WO 97/26265, WO 99/03861, and WO 00/37474 ( Novo Nordisk A / S), which is incorporated herein by reference; or mitiglinide; or potassium channel blockers, for example, BTS-67582; nateglinide; pancreas Glucagon antagonists, such as those disclosed in WO ^ 99/01423 and WO 00/39088 (Novo Nordisk A / S and Agouron Pharmaceuticals), which are incorporated herein by reference; glp-1 agonists, such as , An agonist disclosed at wo 00/42026 (Novo Nordisk A / S and Agouron Pharmaceuticals), which is incorporated herein by reference; DPP-IV (Dipeptidyl Peptidase-IV) Inhibitor; PTPase ( Protein tyrosine phosphatase) inhibitors; involved in stimulating glucose production and / or Inhibitors of protolytic liver enzymes; Glucose uptake regulators; GSK-3 (Glycogen synthase kinase-3) inhibitors; Compounds that modify lipid metabolism, for example, antilipid increasing agents; Compounds that reduce food intake φ; PPAR (peroxisome proliferator) and rxr (retinol X receptor) agonists, such as ALRT-268, LG-1268, or LG-1069. In a specific example, 'the compound of the present invention can be administered in combination with insulin or an insulin analog or derivative, such as εεB29-tetradecane 醯 des (B30) human insulin' AspB28 human insulin, LysB28ProB29 human insulin 'LysB29- (N ε (7 -glutamyl-N α litocholyl) des (B30) human insulin 'Lantus, or a mixed preparation comprising one or more of these substances 39 200401634 In another embodiment of the invention, the compound of the invention is Sulfadiazine is administered in combination, for example, tolbutamide, chlorpropamide, tolazamide, glibenclamide, glyburide, and glib Glypizide, glimepride, glicazide. In another embodiment of the invention, the compounds of the invention are administered with biguanides, such as metformin In yet another embodiment of the present invention, the compound of the present invention is administered together with meglitinide, such as repaglinide or naglitaide teglinide). In another specific embodiment of the present invention, the compound of the present invention is administered in combination with a thiabodidinone insulin sensitizer, for example, troglitazone, ciglitazone. , Pioglitazone, pioglitazone, rosiglitazone, isaglitazone, darglitazone, englitazone, CS-011 / C1- 1037 or T174, or compounds disclosed in WO97 / 41097, WO97 / 41119, WO97 / 41120, WO00 / 41121, and WO98 / 45292 (Dr. Reddy Research Foundation). In another implementation In the examples, the compounds of the present invention can be used in combination with insulin sensitizers, such as GI 262570, YM-440, MCC-555, JTT-501, Ar-H039242, KRP-297, GW-409544, CRE-16336, AR-H -049020, LY510929, LY465608, MBX-102, CLX-940, GW-501516, tesaglitazar (AZ 242) or disclosed in 20041634 W099 / 19313, W00 / 50414, WO 00/63191 5 WO 00/63192, W. 00/63193 compounds like ragaglitazar (NN 622 or (-) DRF 2725) (Dr. Reddy's Research F oundation) and WO 00/23425, WO 00/23415, WO 00/2345:!, WO 00/23445, WO 00/23417, WO 00/23416, WO 00/63153, WO 00/63196, W 00/63209, WO 00/63190 and WO 00/63189 (Novo Nordisk A / S) o In another embodiment of the present invention, the compound of the present invention is administered in combination with an a-glucosidase inhibitor, For example, voglibose, emiglitate, miglitol or acarbose. In another embodiment of the invention, the compound of the invention is Administered in combination with agents that act on ATP-dependent potassium channels that act on cold cells, such as metsulfuron, gliben, glipizide, gliclazide, BTS-67582, or reglitazone In another embodiment of the present invention, the compound of the present invention is administered in combination with an antihyperlipidemic agent or an antilipid increasing agent, for example, cholestyramine, colestipol, chlorine Clofibrate, gemfibrozil, lovastatin, pravastatin vastatin), simvastatin, probucol, or dextrothyroxine. In another embodiment of the present invention, the compound of the present invention is used in combination with more than one of the aforementioned compounds, such as Combine with metformin (metformin) and 41 200401634 sulphonylurea (like glibenclamide or glyburide); sulfonylurea and acarbose: metformin And meglitinide, like repaglinide; acarbose and metformin; sulfonylurea, metformin and troglitazone; sulfonylurea , Metformin and pioglitazone; sulfonylurea, metformin and insulin sensitizers, such as those disclosed in WO 00/63189 or WO 97/41097; meglitinide (meglitinide) ( Like repaglinide), metformin and troglitazone; meglitinide (like repaglinide), metformin and Combination of pioglitazone; meglitinide (like repaglinide), metformin and an insulin sensitizer (like disclosed in WO 00/63189 or WO 97/41097); insulin With sulfonylurea; insulin and meglitinide (like repaglinide); insulin and metformin; insulin 'metafox and meglitinide (like rigglinide) Repaglinide); insulin, metformin and sulfonylurea; insulin and troglitazone; insulin and pioglitazone; insulin and insulin sensitizers (as disclosed in WO 00/63189 or W097) / 41097); insulin and lovastatin; insulin analogs or derivatives, metformin and meglitinide (like repaglinide); insulin analogs or derivatives, metformin and sulfonium Urea complex; insulin analog or derivative and troglitazone complex; insulin analog or derivative and 卩 glitazone 42 200401634 (pioglitazone); insulin analogs or derivatives and an insulin sensitizer (as disclosed in WO 00/63189 or WO 97/41097); insulin analogs or derivatives and lovastatin; and so on. In addition, the compounds of the present invention may be administered with one or more anti-obesity agents or appetite regulators. These agents are selected from CART (***e amphetamine regulated transcript) stimulants, NPY (neuropeptide Y) antagonists, MC4 (melanocortin4) ) Agonists, orexin antagonists, H3 histamine antagonists, TNF (tumor necrosis factor) modulators, CRF (corticotropin releasing factor) agonists, CRF BP (Corticotropin releasing factor binding protein) antagonist, urocortin agonists, 3 agonists, like CL-316243, AJ-9677, GW-0604, LY377267 or AZ- 40140, MSH (melanocyte-stimulating hormone) agonist, MCΗ (melanocyteconcentrating hormone) antagonist, CCK (cholecystokinin agonist, serotonin) Uptake inhibitors like fluorxetine, seroxate or citalopram, heparin and ortho-kidney Noradrenaline reuptake inhibitor, 5 Η T (heparin) agonist, bombesin agonists, galanin antagonists, growth hormone, growth hormone release compound 43 200401634 compounds, TR Η (thyreotropin releasing hormone) agonist, UCP 2 or 3 (uncoupling protein 2 or 3) modulator, leptri agonists, DA Agonists (bromocriptin, doprexin), lipase / amylase inhibitors, PPAR modulators, RXR (retinoid X receptor) modulators or TR / 3 agonist. In another embodiment of the present invention, the anti-obesity agent is ten dexamphetamine or amphetamine. In another embodiment of the present invention, the anti-obesity agent is fenfluramine or Dexfenfluramine. In another embodiment of the invention, the anti-obesity agent is sibutramine. 0 In another embodiment of the invention, the anti-obesity agent is orlistat. In another implementation of the invention In the example, the anti-obesity agent is chloromimidindol (φmazindol) or phentermine (phentermine). Furthermore, the compounds of the present invention can be used in combination with one or more antihypertensive agents. Examples of antihypertensive agents are / 3-block agents, such as / 3-receptor blockers (alprenolol), and atenolol ), Timolol, DM; U pindolol, propranolol and metoprol, ACE (angiotensin converting enzyme) inhibitors, like indole Benazepril, captopril, ethiaprii, fluoropropion 44 200401634, fosinopril, lisinopril, quinapril and blue Ramipril, potassium blocker, like nifedipine, felodipine, nicardipine, and iselapine isradipine), nimodipine, diltiazem and verapamil, and alpha-blocking agents like doxazosin, urapidil, β 秦 (prazosin) and tetrazosin (terazosin). Other references are Remington: The Science and Practice of Pharmacy 19th Edition, Gennaro, Ed., Mack

Publishing Co.， Easton.， PA， 1995 o 必須瞭解的是任何本發明化合物和一種或多種前述化合物，及選擇性之一種或多種其它藥理活性物質的組合物皆是在本發明的範疇之內。藥學組成物本發明的化合物可單獨施與或和藥學上可接受的載體或輔劑一起施與，可以單一劑量型式或多劑量型式存在。本發明的藥學組成物可和藥學上可接受載體或稀釋劑，及其它任何習知佐藥和輔劑，依據傳統技藝一起配方，像揭示於 Remington : The Science and Practice of Pharmacy 19th Edition， Gennaro， Ed.， Mack Publishing Co.， Easton. ，PA ， 1995 。本發明的藥學組成物特別可配方成適當路徑施與，像口服，直腸，鼻，肺，局部（包括頰內和舌下），經皮，腦內，會陰內，***內和非經腸道（包括皮下，肌肉內，椎 45 200401634 管內，靜脈內和皮內）投藥治療’口服路徑爲較佳。應了解的是較佳路徑將會因接受者之情況’欲治療情況的性質，和所選擇之活性成分而改變。適合於口服投予之藥學組成物包括固體劑量配方，像膠囊，錠劑，糖衣錠，藥九，錠劑，粉末，及顆粒狀。假使適當的，其可塗覆塗覆物’像腸溶衣塗覆物，或其可配方成控制釋放活性成份的配方’像傳統習知技藝之持續釋放或延緩釋放配方。適用於口服施與的液體劑量包括溶液，乳液，懸浮液，糖漿和佐劑。用於非經腸施與的藥學組成物包括滅菌水溶液及非水溶液之可注射溶液，分散液’懸浮液或乳液，及在使用前可溶於無菌可注射溶液或分散液中的滅菌粉末。積存可注射配方也包括在本發明的範圍內。其它合適的施與型式包括塞藥’霧狀噴劑，軟膏，乳液，凝膠，吸藥，皮膚貼布，植入物等。基本口服劑量是在從約0 · 0 0 1至約1 0 0毫克/ 公斤體重/天，較佳的從約0 · 0 1至約5 0毫克/公斤體重/天，更佳地從約0 · 0 5至約1 0毫克/公斤體重 /天，施與時是1劑量或多劑量施用，像1至3劑量。正確的劑量將依據施用的頻率及型式，性別，年齡，體重及患者一般狀況，癥狀的性質及嚴重性，及任何倂發症及其它此項技藝領域內習知的明顯因素而定。施用配方可方便的以此項領域內習知的方法製成單位 46 200401634 劑量型式。基本適用於每天施與1次或多次，像1至3次之口服施與配方的單位劑量包括從〇 · 0 5至約1 〇〇〇毫克’較佳的從約0 · 1至約5 0 0毫克，及更佳地從約〇·5毫克至約200毫克。對非經腸道路徑，例如靜脈內，椎管內，肌肉內和相似的投予方式，典型地使用於口服投予的約1/2劑量。本發明的化合物通常以游離物質利用或以其藥學地可接受的鹽使用。一個實施例是化合物具有游離酸利用性之的鹼加成鹽。當式（I )的化合物包含游離酸時，該鹽是以傳統方式藉由以化學相對等之一藥學上可接受鹼，例如，處理式（I )之游離酸的溶液或懸浮液製得。代表性例子爲如上所述者。對於非經腸道的投予，可使用新穎式（I )化合物於滅菌水溶液，水性丙二醇，維生素E水溶液或於芝麻或花生油中的溶液。該水溶液應該是適合於緩衝的，如果必需的話，首先液態稀釋劑以充份鹽水或葡萄糖提供等張壓力。該等水溶液特別適合於靜脈內，肌肉內，皮下和腹膜內投予。所使用之滅菌水性介質全部可藉由該諳熟該技藝者所習知之標準技術快速獲得。適當的藥劑載體包括惰性固體稀釋劑或塡充劑，滅菌水溶液和各種有機溶劑。固體載體的實例爲乳糖，白土，蔗糖，環糊精，滑石，明膠，瓊脂，果膠，金合歡，硬脂酸鎂，硬脂酸或纖維素的低級烷基醚。液態載體的實例爲糖漿，花生油，橄欖油，磷脂，脂肪酸，脂肪酸胺，聚氧 47 200401634 乙撐或水。同樣地，載體或稀釋劑可包括任何該技藝已知的緩釋物質，例如甘油基單硬脂酸酯或甘油基二異硬脂酸酯，單獨或和蠘混合。該等藉由組合式（I )新穎化合物和藥學地可接受載體所形成的藥學組成物然後可以適合於所揭示路徑的多種劑量形式投予。該等配方可藉由在藥學技藝中已知的方法方便地以單位劑量形式存在。本發明適合於口服投予之配方可以例如膠囊或錠劑的不連續單位存在，且每一種包含一預定數量之活性成分，和可包括適當的賦形劑。除此之外，這些口服配方可粉末或顆粒之形式，於水性或非水性液體中之溶液或懸浮液型式，或油在水中或水在油中之液態乳液型式。如果固體載體使用於口服投予，該製劑可被製錠，放置在硬明膠膠囊之粉末或片劑形式，或其可能於藥片或菱形之形式。固體載體的數量將會廣泛地改變，但通常爲約 2 5毫克到約1克。如果使用液態載體，製劑可於糖漿，乳液，軟明膠膠囊或滅菌可注射液體的形式例如水性或非水性液態懸浮液或溶液。可藉由習知製錠技術製備之典型錠劑可包含：核心：活性化合物（爲游離化合物或其鹽） 5.0毫克Publishing Co., Easton., PA, 1995. It must be understood that any combination of a compound of the present invention with one or more of the foregoing compounds, and optionally one or more other pharmacologically active substances, is within the scope of the present invention. Pharmaceutical composition The compounds of the present invention may be administered alone or together with a pharmaceutically acceptable carrier or adjuvant, and may be present in a single dose or multiple doses. The pharmaceutical composition of the present invention can be formulated with a pharmaceutically acceptable carrier or diluent, and any other conventional adjuvants and adjuvants, according to traditional techniques, as disclosed in Remington: The Science and Practice of Pharmacy 19th Edition, Gennaro, Ed. ., Mack Publishing Co., Easton., PA, 1995. The pharmaceutical composition of the present invention can be specially formulated to be administered in an appropriate route, such as oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), percutaneous, brain, perineal, intravaginal and parenteral (Including subcutaneous, intramuscular, vertebral 45 200401634 tube, intravenous and intradermal) Administration of the oral route is better. It should be understood that the preferred route will vary depending on the condition of the recipient ', the nature of the condition being treated, and the active ingredient chosen. Pharmaceutical compositions suitable for oral administration include solid dosage formulations, such as capsules, lozenges, dragees, medicines, lozenges, powders, and granules. If appropriate, it can be coated with coatings 'like enteric coatings, or it can be formulated with a controlled release active ingredient' formula like a conventional release or sustained release formulation. Suitable liquid dosages for oral administration include solutions, emulsions, suspensions, syrups and adjuvants. Pharmaceutical compositions for parenteral administration include injectable solutions, dispersions' suspensions or emulsions of sterile aqueous and non-aqueous solutions, and sterile powders which are soluble in sterile injectable solutions or dispersions before use. Accumulated injectable formulations are also included within the scope of the present invention. Other suitable types of administration include suppository sprays, ointments, creams, emulsions, gels, inhalants, skin patches, implants, and the like. The basic oral dose is from about 0. 01 to about 100 mg / kg body weight / day, preferably from about 0. 01 to about 50 mg / kg body weight / day, and more preferably from about 0. 0.5 to about 10 mg / kg body weight / day, when administered in 1 or more doses, like 1 to 3 doses. The correct dosage will depend on the frequency and type of administration, gender, age, weight and general condition of the patient, the nature and severity of symptoms, and any scurvy and other obvious factors known in the art. Administration formulas can be conveniently prepared into units in a manner well known in the art. 46 200401634 Dosage form. Basically suitable for one or more administrations per day, like 1 to 3 times for oral administration. The unit dose of the formulation includes from 0.05 to about 1,000 mg ', preferably from about 0.1 to about 5 0.00 mg, and more preferably from about 0.5 mg to about 200 mg. For parenteral routes, such as intravenous, intraspinal, intramuscular and similar administration, typically about 1/2 dose is administered orally. The compounds of the present invention are generally utilized as a free substance or as a pharmaceutically acceptable salt thereof. One example is a base addition salt of a compound having free acid utilization. When the compound of formula (I) contains a free acid, the salt is prepared in a conventional manner by treating a solution or suspension of the free acid of formula (I) with one of the pharmaceutically acceptable bases in a chemical equivalent. A representative example is the one described above. For parenteral administration, a solution of the novel compound of formula (I) in a sterile aqueous solution, an aqueous propylene glycol, an aqueous vitamin E solution, or a sesame or flower oil can be used. The aqueous solution should be suitable for buffering. If necessary, the liquid diluent first provides isotonic pressure with sufficient saline or glucose. These aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. All sterilized aqueous media used can be quickly obtained by standard techniques familiar to those skilled in the art. Suitable pharmaceutical carriers include inert solid diluents or elixirs, sterile aqueous solutions and various organic solvents. Examples of solid carriers are the lower alkyl ethers of lactose, clay, sucrose, cyclodextrin, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid or cellulose. Examples of liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxygen 47 200401634 ethylene or water. Likewise, the carrier or diluent may include any slow-release material known in the art, such as glyceryl monostearate or glyceryl diisostearate, alone or mixed with rhenium. These pharmaceutical compositions formed by combining a novel compound of formula (I) and a pharmaceutically acceptable carrier can then be administered in a variety of dosage forms suitable for the disclosed routes. Such formulations may conveniently be presented in unit dosage form by methods known in the pharmaceutical art. Formulations suitable for oral administration of the present invention may exist in discrete units such as capsules or lozenges, each of which contains a predetermined amount of active ingredient, and may include appropriate excipients. In addition, these oral formulations can be in the form of powders or granules, solutions or suspensions in aqueous or non-aqueous liquids, or liquid emulsions in oil or water or water in oil. If a solid carrier is used for oral administration, the preparation may be tabletted, placed in the form of a powder or tablet of a hard gelatin capsule, or it may be in the form of a tablet or diamond. The amount of solid carrier will vary widely, but is usually about 25 mg to about 1 g. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution. A typical lozenge that can be prepared by conventional tableting techniques may include: Core: Active compound (is a free compound or its salt) 5.0 mg

Lactosum Ph. Eur. 67_8 毫克纖維素，微晶（AviCel) 31.4毫克Lactosum Ph. Eur. 67_8 mg cellulose, microcrystalline (AviCel) 31.4 mg

Amberlite⑧IRP88* 1·〇毫克硬脂酸鎂Ph. Eur Q.s. 200401634 塗層：羥基丙基甲基纖維素大約9毫克Amberlite⑧IRP88 * 1.0 mg Magnesium stearate Ph. Eur Q.s. 200401634 Coating: hydroxypropyl methyl cellulose approx. 9 mg

MywaCett 9-40T** 大約 0.9 毫克 *Polacrilin 鉀 NF，錠劑崩解劑，Rohm 及 Haas **乙醯化單甘油酸酯當做薄膜塗層的增塑劑。假使需要，本發明的藥學組成物可包括式（I )化合物，配合其它藥理活性物質，如那些前述的物質。【實施方式】實例以下實例和一般步驟是關於在說明書及合成反應機制中之中間化合物及最終產物。本發明化合物的製備使用以下實例作進一步淸楚描述，但此處所述之化學反應只是關於製備本發明胰增血糖素拮抗劑的一般應用方法。一般而言，本發明的化合物可以不同於下述實例的方法製得，如一些化合物可以數種方法製得。有時候不是所有的反應皆能適用於本發明範圍內的每個化合物，這對於習於此項技藝之人來說將是很容易確認的。在此種情況下，此反應可以此項領域內熟知的方法修正而成功的進行反應，亦即適當的保護干擾基團，改變爲其它傳統反應劑，或改變反應途徑的反應條件。另一方面，其它在此所述的反應或者其它傳統反應方法可用於製備本發明的化合物。在所有製備方法中，所有的起始物質是習知的，或可由習知起始物質輕易的製得。所有此處所述的溫度除非另外指示，否則爲 49 200401634 攝氏溫度，當份數和百分比係關於產量時是以重量計，但關於溶劑和洗提劑時爲以體積計算。一些下述實例中所揭示的NMR資料只是經選擇的資料。在實例中，以下的名詞具有如下所述之定義： D B U : 1，8 —二口丫雙環[5，4 —0H---5 —烯 DCM:二氯甲烷，甲撐氯化物 D I P E A : N，N—二異丙基乙基胺 DMF : N，N—二甲基甲醯胺 DMS〇··二甲基亞碉，甲基亞碾 EDAC : 1 —乙基一3 —(3—二甲基胺基丙基)碳二醯亞胺氫氯化物 F m ◦ c : 9—氟烯甲氧基羰基 NMP : N—甲基一2—D比略烷酮 T F A :四氫呋喃 H〇B t : 1 —羥基苯並*** HP L C—MS (方法A): 使用以下的設備：MywaCett 9-40T ** Approximately 0.9 mg * Polacrilin potassium NF, lozenge disintegrator, Rohm and Haas ** Ethylated monoglycerides are used as plasticizers for film coatings. If desired, the pharmaceutical composition of the present invention may include a compound of formula (I) in combination with other pharmacologically active substances, such as those previously mentioned. [Embodiment] Examples The following examples and general procedures are related to the intermediate compounds and final products in the description and the synthetic reaction mechanism. The preparation of the compounds of the present invention is further described using the following examples, but the chemical reactions described herein are only related to the general application method of preparing the glucagon antagonists of the present invention. In general, the compounds of the present invention can be prepared by methods other than those described in the following examples. For example, some compounds can be prepared by several methods. Sometimes not all reactions are applicable to every compound within the scope of the present invention, which will be easily confirmed by those skilled in the art. In this case, the reaction can be successfully modified by methods well known in the art, that is, appropriate protection of interference groups, change to other traditional reactants, or change the reaction conditions of the reaction pathway. On the other hand, other reactions described herein or other conventional reaction methods can be used to prepare the compounds of the present invention. In all preparation methods, all starting materials are known or can be easily prepared from known starting materials. All temperatures stated herein are 49 200401634 Celsius unless otherwise indicated. Parts and percentages are by weight when referring to yield, but are by volume when referring to solvents and eluents. The NMR data disclosed in some of the examples below are only selected data. In the examples, the following terms have the following definitions: DBU: 1,8—two-mouthed bicyclo [5,4—0H --- 5—ene DCM: dichloromethane, methylene chloride DIPEA: N, N-diisopropylethylamine DMF: N, N-dimethylformamidine DMS. Dimethyl sulfenyl, methylimine EDAC: 1-ethyl-1 3- (3-dimethyl Aminopropyl) carbodiimide hydrochloride F m ◦ c: 9-fluoroenylmethoxycarbonyl NMP: N-methyl-2-D-pyrrolidone TFA: tetrahydrofuran HOB t: 1 — Hydroxybenzotriazole HP LC-MS (Method A): Use the following equipment:

Hewlett Packard 系歹丨J1100 G1312A Bin PumpHewlett Packard system 丨 J1100 G1312A Bin Pump

Hewlett Packard 系列 1100，管柱間隔Hewlett Packard Series 1100, column spacing

Hewlett Packard 系歹[J 1100 G13 15A DAD 二極體矩陣偵測器Hewlett Packard system [J 1100 G13 15A DAD Diode Matrix Detector

Hewlett Packard 系歹丨J1100 MSD 儀器是由HP Chemstation軟體控制。 HPLC泵是連結至兩洗提劑貯存器中，而此貯存器含有： A ： 0.01% T FA/水 50 200401634 B : 0.01%TFA/乙腈此分析是在溫度4 0 °C下進行，進行時將適當體積的樣品（較佳的1毫升）注入管柱中，接著以乙腈梯度洗提劑洗提。 Η P L C條件，偵測器設定及質譜設定見於下表：管柱 Waters Xterra 100A MS C-18 3.5μηι » 3.0mm x 50mm 梯度洗提劑 10%-100%乙腈線性洗提劑（時間7.5分鐘），流速 1.0毫升/分鐘偵測 UV : 210nm (二極體矩陣） MS 離子化模式：API-ES Scan 100-1000 amu 步進 O.lamu HPLC—MS (方法Β): 使用以下的設備：The Hewlett Packard Series J1100 MSD instrument is controlled by HP Chemstation software. The HPLC pump is connected to two eluent reservoirs, and this reservoir contains: A: 0.01% T FA / water 50 200401634 B: 0.01% TFA / acetonitrile. This analysis was performed at a temperature of 40 ° C. An appropriate volume of sample (preferably 1 ml) is injected into the column, followed by elution with an acetonitrile gradient eluent. Η PLC conditions, detector settings and mass spectrometer settings are shown in the following table: Waters Xterra 100A MS C-18 3.5 μηι »3.0mm x 50mm gradient eluent 10% -100% acetonitrile linear eluent (time 7.5 minutes) UV detection: 210nm (diode matrix) MS ionization mode: API-ES Scan 100-1000 amu step O.lamu HPLC-MS (method B): Use the following equipment:

Hewlett Packard 系歹[]1100 MSD G1946A 單一四孑L質譜 Hewlett Packard 系歹丨J1100 MSD G1312A Bin 泵 Hewlett Packard 系歹丨J1100 MSD G1313A Als 自動取樣器 Hewlett Packard 系歹[]1100 MSD G1315A 二極體矩陣偵測器(DAD) 使用HP LC/MSD ChemStation控制軟體在一 HP Vetra電腦上操作控制儀器及取得數據。 HPLC泵是連結至兩洗提劑貯存器中，而此貯存器含有 A : 0.01% TFA/水 B : 0.01%TFA/乙腈此分析是在室溫下進行，進行時將1毫升體積的樣品 51 200401634 溶液注入管柱中，接著以乙腈0.01 %ΤΕΑ度洗提劑洗提。 Η P L C 條1 牛，偵測器設定及質譜設定見於下表= 管柱 Waters Xterra 100A MS C-18 3.5μπι ? 3.0mm x 50mm 梯度洗提劑 1〇％-100%乙腈-0.05%TFA線性洗提劑（時間4.5分鐘），流速1.5毫升/分鐘偵測 UV : 210nm (二極體矩陣） MS 離子化模式：API-ES 實驗：開始·· lOOarnu，停止·· lOOOamu，步進 0.1 amu HPLC—MS (方法C): 使用以下的設備：Hewlett Packard System [] 1100 MSD G1946A Single Quadrupole Mass Spectrometry Hewlett Packard System 丨 J1100 MSD G1312A Bin Pump Hewlett Packard System 丨 J1100 MSD G1313A Als Autosampler Hewlett Packard System [] 1100 MSD G1315A Diode Matrix The Detector (DAD) uses HP LC / MSD ChemStation control software to operate control instruments and acquire data on an HP Vetra computer. The HPLC pump was connected to two eluent reservoirs, which contained A: 0.01% TFA / water B: 0.01% TFA / acetonitrile. This analysis was performed at room temperature. A 1 ml volume of sample 51 was performed. 200401634 The solution was injected into the column and then eluted with acetonitrile 0.01% TEA degree eluent. Η PLC strip 1 N, detector settings and mass spectrometer settings are shown in the following table = Waters Xterra 100A MS C-18 3.5μm? 3.0mm x 50mm gradient eluent 10% -100% acetonitrile-0.05% TFA linear washing Extraction (time 4.5 minutes), flow rate 1.5 ml / min UV detection: 210nm (diode matrix) MS ionization mode: API-ES experiment: start · lOOarnu, stop · lOOamu, step 0.1 amu HPLC— MS (Method C): Use the following equipment:

Sciex API 100單-四孔質譜 Perkin Elmer 系歹[j 200Quard 泵 Perkin Elmer系歹[]200自動取樣器 Applied Biosystems 785Α UV 偵測器 Sedex 55蒸發式光散射偵測器Sciex API 100 single-four-well mass spectrometer Perkin Elmer system [j 200Quard pump Perkin Elmer system] [] 200 autosampler Applied Biosystems 785Α UV detector Sedex 55 evaporative light scattering detector

Valeo管柱，開關以泵時間控制的Valeo啓動器控制使用 Sciex Sample 控制軟體，在 Macintosh PowerPC 7200 上操作控制儀器及收集資料。 HPLC泵是連結至四洗提劑貯存器中，而此貯存器含有： A:乙腈 B :水Valeo tubing, Valeo starter controlled by pump time control. Use Sciex Sample control software to operate control instruments and collect data on a Macintosh PowerPC 7200. The HPLC pump is connected to a four-eluent reservoir, which contains: A: acetonitrile B: water

D C : 0.5%TFA/水 :0.02M乙酸銨 52 200401634 樣品的需求爲於一適當溶劑中含有大約5 0 0微克/ 毫升的待分析化合物，溶劑的例子爲像甲醇，乙醇，乙腈，THF，水和其混合物。（在低乙腈濃度下，高濃度的強洗提劑會干擾圖譜）。DC: 0.5% TFA / water: 0.02M ammonium acetate 52 200401634 The requirement of the sample is about 500 micrograms / ml of the compound to be analyzed in a suitable solvent. Examples of the solvent are methanol, ethanol, acetonitrile, THF, water. And its mixture. (At low acetonitrile concentrations, high concentrations of strong eluents can interfere with the spectrum).

此分析是在室溫下進行，進行時將2 0微升樣品溶液注入管柱中，接著以乙腈梯度洗提劑（0.05%TFA或0.002M 乙酸酯）洗提。依據分析的方法，改變所使用的洗提條件〇由管柱洗出的洗提液流經一分叉T -連接管，讓大約 20微升/分鐘流經大約1公尺75 //二氧化矽毛細管，再至 ΑΠ干擾的API 100光譜計上。剩下的1.48毫升/分鐘的洗出液流經UV偵測器，連結到ELS偵測器上。 LC-分析時，同時收集質譜儀、U V偵測器和E L S偵測器的數據。所使用L C條件，偵測器設定及質譜儀的設定見於下表：管柱 YMC ODS-A 12〇Α 8-5μ 3mm x 50mm id 梯度洗提劑 5%-90%乙腈/〇.〇5%TFA線性洗提劑（時間7.5分鐘 )，流速1.5毫升/分鐘偵測 UV : 214nm ELS ： 40°C MS 實驗：開始：lOOamu停止：800amu，步進：〇.2amu Dwell : 0.571 msec 方法：Scan 284次二9.5分鐘 53 200401634 Η P L C —M S (方法 D): 使用以下的設備：The analysis was performed at room temperature. 20 μl of the sample solution was injected into the column, followed by elution with an acetonitrile gradient eluent (0.05% TFA or 0.002M acetate). According to the analytical method, change the eluent conditions used. The eluent from the column flowed through a bifurcated T-connection tube, allowing about 20 microliters / minute to flow through about 1 meter 75 // dioxide. Silica capillaries, then on API 100 spectrometer with ΑΠ interference. The remaining 1.48 ml / min of eluate flows through the UV detector and is connected to the ELS detector. During LC-analysis, data from the mass spectrometer, UV detector, and EL detector were collected simultaneously. The LC conditions, detector settings, and mass spectrometer settings are shown in the following table: Column YMC ODS-A 12〇Α 8-5μ 3mm x 50mm id Gradient eluent 5% -90% acetonitrile / 0.05% TFA linear eluent (time 7.5 minutes), flow rate 1.5 ml / min UV detection: 214nm ELS: 40 ° C MS experiment: start: 100amu stop: 800amu, step: 0.2 amu Dwell: 0.571 msec method: Scan 284 Second time 9.5 minutes 53 200401634 Η PLC —MS (Method D): Use the following equipment:

Hewlett Packard 系歹[J 1100 G1312A Bin PumpHewlett Packard system [J 1100 G1312A Bin Pump

Hewlett Packard 系歹ij 1100，管柱間隔Hewlett Packard system 歹 ij 1100, column spacing

Hewlett Packard 系歹[]iioo G13 15A DAD 二極體矩陣偵測器Hewlett Packard System [] iioo G13 15A DAD Diode Matrix Detector

Hewlett Packard 系歹[j iioo MSDHewlett Packard Department [j iioo MSD

Sedere 75 Evaporative 光散射偵測器儀器是由HP Chemstation軟體控制。 HPLC泵是連結至兩洗提劑貯存器中，而此貯存器含有： A : 0.01% TF A/水 B : 0.01%TFA/乙腈此分析是在溫度4 0 °C下進行，進行時將適當體積的樣品（較佳的1微升）注入管柱中，接著以乙腈梯度洗提劑洗提。 Η P L C條件，偵測器設定及質譜設定見於下表: 管柱 Waters Xterra MS C-18 x3 mm id 5μτη 梯度洗提劑 5%-100%乙腈線性洗提劑（時間7.5分鐘），流速 1.5毫升/分鐘偵測 UV : 210nm (由DAD類比輸出） ELS(由ELS類比輸出） MS 離子化模式：API-ES Scan 100-1000 amu 步進 O.lamu 在經過 DAD後，將洗出物分隔，產生大約1毫升/分鐘至ELS，及0.5毫升/分鐘至MS。 54 200401634 建造嵌段以下部份爲關於用於製備式（I I )中間物的嵌段的建造：Sedere 75 Evaporative Light Scattering Detector The instrument is controlled by HP Chemstation software. The HPLC pump is connected to two eluent reservoirs, and this reservoir contains: A: 0.01% TF A / water B: 0.01% TFA / acetonitrile. This analysis is performed at a temperature of 40 ° C. A volume of the sample (preferably 1 microliter) is injected into the column and then eluted with an acetonitrile gradient eluent. Η PLC conditions, detector settings, and mass spectrometer settings are shown in the following table: Waters Xterra MS C-18 x 3 mm id 5μτη column gradient eluent 5% -100% acetonitrile linear eluent (time 7.5 minutes), flow rate 1.5 ml UV detection per minute: 210nm (analog output from DAD) ELS (analog output from ELS) MS ionization mode: API-ES Scan 100-1000 amu step O.lamu After DAD, the eluate is separated to produce Approximately 1 ml / min to ELS and 0.5 ml / min to MS. 54 200401634 Building blocks The following section is about the building of blocks used to prepare intermediates of formula (I I):

式(II) 其中E和D是如上所定義者。用於建造製備式（I I )中間物嵌段的起始物質， 4 -環己基苯甲醛此化合物可依據一修正過的文獻步驟（L Org. Chem.， 37，No. 24，（1972)，3972— 3974)合成而得。環己基苯（112.5克，0.702莫耳）及六甲撐四胺（99.3克，0.708莫耳）一起混合於TFA(375毫升）中，在氮氣氣氛及 90°C下攪拌3天，之後冷卻至室溫，及將混合物倒入冰水 (3600毫升）中，及攪拌1小時。所得溶液以Na2C〇3(2M的水溶液）中和及以DCM萃取（2.5升），有機相層以Na2S04乾燥，及在真空下移去溶劑，殘留油狀物以分餾法純化，可得標題化合物（51克，39%)。 55 200401634 iHNMR (CDC13) : (?9.96(s，1H)，7.80(d，2H)，7，35(d，ffi)，2.58(m ，1H)，L94—1.70(m，5H)，1.51 —1.17(m，5H)。用於建造製備式（I I )中間物嵌段的起始物質 4 一（ 2，2 —二甲基丙基）苯甲醛Formula (II) wherein E and D are as defined above. The starting material for the preparation of the intermediate block of formula (II), 4-cyclohexylbenzaldehyde. This compound can follow a revised literature procedure (L Org. Chem., 37, No. 24, (1972), 3972-3974). Cyclohexylbenzene (112.5 g, 0.702 mol) and hexamethylenetetramine (99.3 g, 0.708 mol) were mixed together in TFA (375 ml), stirred under a nitrogen atmosphere at 90 ° C for 3 days, and then cooled to room temperature. Warm and pour the mixture into ice water (3600 ml) and stir for 1 hour. The resulting solution was neutralized with Na2CO3 (2M aqueous solution) and extracted with DCM (2.5 liters). The organic phase layer was dried over Na2S04, and the solvent was removed under vacuum. The residual oil was purified by fractional distillation to obtain the title compound. (51 g, 39%). 55 200401634 iHNMR (CDC13): (? 9.96 (s, 1H), 7.80 (d, 2H), 7, 35 (d, ffi), 2.58 (m, 1H), L94-1.70 (m, 5H), 1.51- 1.17 (m, 5H). Starting material for the preparation of intermediate blocks of formula (II) 4 mono (2,2-dimethylpropyl) benzaldehyde

此化合物可依據一修正過的文獻步驟（L Med. Chem.， ^ 36，23 (1993)，3700 - 3704)合成而得。將（2，2—二甲基丙基）苯（9.33克，6.33毫莫耳 )溶於二氯甲烷（50毫升）中及在一冰浴中冷卻至0°C，激烈攪拌，經由一注射器加入SnCl4(28.66克，110毫莫耳）(一次全部加入），接著以液滴的方式加入二氯甲基甲基醚（7.24克，63毫莫耳），加入時間爲10分鐘，20分鐘後，移去冰浴，及加入冰水（100毫升）淬冷此混合物。倒掉水溶液層，有機液層以水（3x25毫升），3N氫氯酸（3x25毫升），及飽和氯 φ 化鈉水溶液（2x25毫升）洗滌，然後以活性碳處理有機相，乾燥（硫酸鎂），過濾和在真空下濃縮，如此可得標題化合物，產率：7.49 克（62%)。 iHNMR (CDC13) : 5〇.94(s，9Η)，2.57(s，2Η)，7.28(d，2Η)，7.8〇(d， 2H)，9.98(s，1H)。用於建造製備式（I I )中間物嵌段的起始物質茚滿—5 -醛 56 200401634This compound can be synthesized according to a modified literature procedure (L Med. Chem., ^ 36, 23 (1993), 3700-3704). Dissolve (2,2-dimethylpropyl) benzene (9.33 g, 6.33 mmol) in dichloromethane (50 ml) and cool to 0 ° C in an ice bath, stir vigorously, and pass through a syringe Add SnCl4 (28.66 grams, 110 millimoles) (all at once), and then add dichloromethyl methyl ether (7.24 grams, 63 millimoles) in the form of droplets for 10 minutes. After 20 minutes Remove the ice bath and add ice water (100 ml) to quench the mixture. The aqueous layer was decanted. The organic layer was washed with water (3x25 ml), 3N hydrochloric acid (3x25 ml), and saturated aqueous sodium chloride solution (2x25 ml). The organic phase was treated with activated carbon and dried (magnesium sulfate) , Filtered and concentrated under vacuum to give the title compound in a yield of 7.49 g (62%). iHNMR (CDC13): 50.94 (s, 9Η), 2.57 (s, 2Η), 7.28 (d, 2Η), 7.80 (d, 2H), 9.98 (s, 1H). Starting material for the preparation of intermediate blocks of the formula (I I) Indan-5 -aldehyde 56 200401634

此標題化合物可由茚滿及二氯甲基甲基酯，使用前述的步驟反應製得，所得爲一茚滿一 4 -醛及茚滿一 5 —醛的1 : 2混合物。接下來，此混合物可用於轉化成查爾酮 (建造嵌段7 )，不需進一步純化。下述資料只是標題化合物的，（主要異構物）。 iHNMR (DMS〇一d6) : 52.05(q，2H)，2.90(m，4H)，7.41(d，1H)， 7.67(d，1H)，7.70 (s，1H)，9.95(s，1H)。HPLC—MS(方法 D): m/z=147(M+l) ; Rt=3.53 分鐘。用於建造製備式（I I )中間物嵌段的起始物質 4 —環己一 1 —烯基一苯甲醛將鎂屑（14.6克，600毫莫耳）置入一乾燥4一頸燒瓶中，加入無水THF(50毫升）及碘結晶物，接著緩慢加入一含2 —(4 —溴苯基）—[1，3]—二嘿院（Tetrahedron，57，No. 28， (2001)，5991 - 6002)(135 克，589 毫莫耳）溶於無水 THF(200 毫升）的混合物，以起始反應。在反應開始後，持續加入2 一（4一溴化苯基）一 [1，3]-二噁烷，加入速度爲維持反應溫度在35和4(TC間。加入完成後，攪拌反應混合物2小時 57 200401634 ，然後在一冰浴中冷卻至5°C，接著以液滴的方式加入環己酮（57.8克，580毫莫耳），同時維持反應溫度低於l〇°C。在室溫下攪拌反應混合物18小時，及在真空下移去三分之二的THF，殘留物倒入一含氯化銨（65克）溶於冰水（1升）的混合物中，及以乙酸乙酯萃取，有機液層以水洗滌，乾燥（硫酸鎂），過濾和在真空下蒸發。殘留油狀物於石油醚中攪拌成泥狀物，可得48克的1 一（4 — [ 1，3 ]二卩惡院一 2 —基一本基）環己醇，其爲一固體。 HPLC—MS(方法 A) : m/z=231 (M+l) ; Rt=3.27 分鐘。 1 一（4一[1，3]二噁烷一 2—基一苯基）—環己醇（45克）及 p —甲苯磺酸（3.4克）溶於300毫升的甲苯中，在一 Dean-Stark 條件下迴流 3 小時，冷卻後，加入乙酸乙酯及飽和碳酸氫鈉溶液，有機液層以水洗滌兩次，乾燥（硫酸鎂），過濾和在真空下濃縮，殘留油狀物溶於冰醋酸（250毫升），及加入1M氫氯酸（25毫升），及在溫度50°C下攪拌混合物2小時，冷卻後，混合物在真空下濃縮，接著以乙酸乙酯和水分離殘留油狀物，有機液層以水洗滌三次，乾燥（硫酸鎂）’ 過濾和在真空下濃縮，殘留油狀物在真空下蒸餾，及收集沸點在120— 13(TC間的分餾物（0.2mmHg)，可得4.7克的標題化合物。 NMR (CDC13) : 51.72(m，4H)，2.25(m，2H)，2.43(m，2H)， 6.30(m，1H)，7.53(d，2H)，7.82(d，2H)，9.98(s，1H)。用於建造製備式（I I )中間物嵌段的起始物質 1 一（3，5—二氯化苯基）乙酮 58 200401634The title compound can be prepared from indane and dichloromethyl methyl ester using the previous steps to obtain a 1: 2 mixture of indane-4-aldehyde and indane-5-aldehyde. This mixture was then used to convert to chalcone (building block 7) without further purification. The following information is for the title compound only (major isomers). iHNMR (DMSO-d6): 52.05 (q, 2H), 2.90 (m, 4H), 7.41 (d, 1H), 7.67 (d, 1H), 7.70 (s, 1H), 9.95 (s, 1H). HPLC-MS (method D): m / z = 147 (M + 1); Rt = 3.53 minutes. The starting material for the preparation of the intermediate block of formula (II) 4-cyclohexyl-1-alkenyl-benzaldehyde Put magnesium dust (14.6 g, 600 mmol) into a dry 4-necked flask, Anhydrous THF (50 ml) and iodine crystals were added, followed by a slow addition of 2- (4-bromophenyl)-[1,3] -diheyuan (Tetrahedron, 57, No. 28, (2001), 5991). -6002) (135 g, 589 mmol) dissolved in a mixture of anhydrous THF (200 ml) to initiate the reaction. After the reaction started, 2 (4-bromophenyl)-[1,3] -dioxane was continuously added at a rate to maintain the reaction temperature between 35 and 4 (TC. After the addition was completed, the reaction mixture 2 was stirred. Hr 57 200401634, then cooled to 5 ° C in an ice bath, then cyclohexanone (57.8 g, 580 mmol) was added in droplets while maintaining the reaction temperature below 10 ° C. At room temperature The reaction mixture was stirred for 18 hours, and two-thirds of the THF was removed under vacuum. The residue was poured into a mixture containing ammonium chloride (65 g) in ice water (1 liter), and ethyl acetate. After extraction, the organic liquid layer was washed with water, dried (magnesium sulfate), filtered and evaporated under vacuum. The residual oil was stirred into petroleum ether to form a mud, and 48 g of 1- (4-[1, 3 ] Dioxin 2-a-yl-yl) cyclohexanol, which is a solid. HPLC-MS (Method A): m / z = 231 (M + l); Rt = 3.27 minutes. 1 1 (4 Mono [1,3] dioxane-2-yl-phenyl) -cyclohexanol (45 g) and p-toluenesulfonic acid (3.4 g) were dissolved in 300 ml of toluene under a Dean-Stark condition Under reflux for 3 hours, after cooling, ethyl acetate and saturated sodium bicarbonate solution were added. The organic layer was washed twice with water, dried (magnesium sulfate), filtered and concentrated under vacuum. The residual oil was dissolved in glacial acetic acid ( 250 ml), and 1M hydrochloric acid (25 ml) was added, and the mixture was stirred at a temperature of 50 ° C for 2 hours. After cooling, the mixture was concentrated under vacuum, and the remaining oil was separated with ethyl acetate and water. The liquid layer was washed three times with water, dried (magnesium sulfate) ', filtered and concentrated under vacuum, the remaining oil was distilled under vacuum, and the fractional boiling point between 120-13 (TC between 0.2mmHg) was collected to obtain 4.7 G of the title compound. NMR (CDC13): 51.72 (m, 4H), 2.25 (m, 2H), 2.43 (m, 2H), 6.30 (m, 1H), 7.53 (d, 2H), 7.82 (d, 2H) ), 9.98 (s, 1H). Starting material for the preparation of intermediate blocks of formula (II) 1 mono (3,5-dichlorophenyl) ethanone 58 200401634

將3 ’ 5-二氯苯甲酸（19.10克，100毫莫耳）溶於無水 THF(165毫升）及在冰浴中冷卻至，接著激烈攪拌，然後經由注射器，在時間30分鐘內，以液滴的方式加入138 毫升（210毫莫耳）的甲基鋰（1.6M，二***），1小時後，將混合物倒入冰水（500毫升）中，水溶液相以二***萃取（4x50 毫升）’結合不同的有機液層，及以飽和碳酸氫鈉水溶液 (2x50毫升）及飽和氯化鈉水溶液（2x50毫升）洗滌，及乾燥有機相（硫酸鎂），過濾和在真空下移去溶劑，可得17.06克的標題化合物，其含有18%重量百分比的2-（3，5-二氯苯基）丙-2-醇，此化合物可用於下一步驟，不需進一步純化。 ^NMIKCDCy : (52.62(s，3H)，7.92(s，2H)，7.94(s，1H)。用於建造製備式（I I )中間物嵌段的起始物質 1 一（2，2，3，3 —四氟一 2，3—二氫苯並[1，4]二氧普一 6—基）乙酮Dissolve 3 '5-dichlorobenzoic acid (19.10 g, 100 mmol) in anhydrous THF (165 ml) and cool in an ice bath, followed by vigorous stirring, and then pass the syringe over a period of 30 minutes. 138 ml (210 millimoles) of methyl lithium (1.6 M, diethyl ether) were added dropwise. After 1 hour, the mixture was poured into ice water (500 ml), and the aqueous phase was extracted with diethyl ether (4 x 50 ml). 'Combine different organic liquid layers and wash with saturated aqueous sodium bicarbonate (2x50 ml) and saturated aqueous sodium chloride (2x50 ml), and dry the organic phase (magnesium sulfate), filter and remove the solvent under vacuum. This gave 17.06 g of the title compound containing 18% by weight of 2- (3,5-dichlorophenyl) propan-2-ol, which was used in the next step without further purification. ^ NMIKCDCy: (52.62 (s, 3H), 7.92 (s, 2H), 7.94 (s, 1H). The starting materials used to construct the intermediate block of formula (II) 1-(2, 2, 3, 3-tetrafluoro-2,3-dihydrobenzo [1,4] dioxo-6-yl) ethanone

所有的設備在一烤箱中以溫度12(TC乾燥數小時。在氮氣氣氛之下，於一乾燥的三頸500毫升圓底燒瓶( 59 200401634 裝置有分液漏斗及冷凝器）中加入鎂片（7.31克，0.30莫耳) 及二乙醇（20毫升）。以磁性攪拌器攪拌，接著以液滴的方式加入碘化甲烷（4.7毫升，75毫莫耳）至Mg上開始反應，然後緩慢加入碘化甲烷（14毫升，0.22莫耳）/二***（30毫升 )，同時維持迴流溫度。完成加入後，攪拌混合物1又1/2 小時’將6-氯基—2’ 2’ 3 ’ 3 —四氣一 1 ’ 4 —苯並一嚼稀 (35克，0.15莫耳）溶於甲苯（60毫升），及加入至反應混合物中。加熱混合物至80°C持續1小時（不凝縮）移去二*** 。另外再加入6—氰基一2, 2, 3, 3 —四氟—1，4—苯並二噁烯（25克，0.11莫耳），及迴流加熱混合物16小時。以冰浴冷卻，及小心加入氫氯酸（6M，150毫升），然後迴流加熱混合物1.5小時，冷卻後，混合物以乙酸乙酯和水分離，及以碳酸氫鈉水溶液洗滌。結合不同的有機液層，及以硫酸鎂乾燥和在真空下濃縮，殘留油狀物在矽膠上以層析法純化，洗提劑爲乙酸乙酯和庚烷（2 : 8)的混合物，可得標題化合物（22克，34%)。 iHNMRCCDClJ : 57.80(dd，1H)，7.77(d，1H)，7.23(d，1H)，2.69(s ，3H) ; HPLC—MS(方法 A) : m/z=251 (M+l) ; Rt=4.27 分鐘。一般程序（A) 溶液相合成式（II)建造嵌段化合物的一般程序（A):All equipment was dried in an oven at a temperature of 12 ° C for several hours. Under a nitrogen atmosphere, a dry three-necked 500 ml round bottom flask (59 200401634 equipped with a separatory funnel and condenser) was charged with magnesium flakes ( 7.31 g, 0.30 mol) and diethanol (20 ml). Stir with a magnetic stirrer, then add methyl iodide (4.7 ml, 75 mmol) as a drop to Mg to start the reaction, then slowly add iodine Methane (14 ml, 0.22 moles) / diethyl ether (30 ml) while maintaining the reflux temperature. After the addition was complete, the mixture was stirred for 1 1/2 hours 'and the 6-chloro group was 2' 2 '3' 3- Four gases, one 1 '4-benzobenzoate (35 g, 0.15 mole) was dissolved in toluene (60 ml) and added to the reaction mixture. The mixture was heated to 80 ° C for 1 hour (non-condensing) and removed Diethyl ether. An additional 6-cyano-2, 2, 3, 3-tetrafluoro-1, 4-benzodioxene (25 g, 0.11 mole) was added, and the mixture was heated at reflux for 16 hours. The ice bath Cool and carefully add hydrochloric acid (6M, 150 ml), then heat the mixture at reflux for 1.5 hours After cooling, the mixture was separated with ethyl acetate and water and washed with aqueous sodium bicarbonate solution. The different organic liquid layers were combined, dried over magnesium sulfate and concentrated under vacuum. The residual oil was purified by chromatography on silica gel. The eluent was a mixture of ethyl acetate and heptane (2: 8) to obtain the title compound (22 g, 34%). IHNMRCCDClJ: 57.80 (dd, 1H), 7.77 (d, 1H), 7.23 (d , 1H), 2.69 (s, 3H); HPLC-MS (Method A): m / z = 251 (M + 1); Rt = 4.27 minutes. General Procedure (A) Solution Phase Synthesis Formula (II) Building Block General procedure for compounds (A):

F 丄兄 aq Na〇H II 、CH〇 + H cAd -^ (II) 3 ΒΟΗ 60 200401634 此程序在建造嵌段1中說明。建造嵌段1(一般程序（A)) 3 —（4 一環己基苯基）一 1 一（4 一三氟甲基磺胺基苯基）丙烯酮F 丄 brother aq Na〇H II, CH〇 + H cAd-^ (II) 3 ΒΟΗ 60 200401634 This procedure is explained in the construction block 1. Building Block 1 (General Procedure (A)) 3 — (4-Cyclohexylphenyl)-1- (4-Trifluoromethylsulfonylphenyl) propenone

scf3 將4—(三氟甲基磺胺基）乙醯酮（2.34克，10.6毫莫耳) 及4-環己基苯甲醛（2克，10.6毫莫耳）混合物乙醇（3毫升) 中，將NaOH(0.425克，10.6毫莫耳）溶於水（2毫升），及加入至此混合物中，在室溫下攪拌混合物，10分鐘後可得一沈澱物，再另外加入乙醇（5毫升），同時維持攪拌另30分鐘。將混合物倒入水（100毫升），過濾出沈澱物及乾燥。粗產物的純度足以用於下一步驟，不需進一步純化（2.64克， 64%)。另一方面，其能由庚烷中再結晶，製得純產物。 HPLC—MS(方法 A) : m/z=391(M+l) ; Rt=6.68 分鐘。建造嵌段2( —般程序（A)) 3 — (4 -環己一 1 一烯基苯基）—1 — (4 —三氟甲氧基苯基 )丙烯酮scf3 In a mixture of 4- (trifluoromethylsulfonyl) acetone (2.34 g, 10.6 mmol) and 4-cyclohexylbenzaldehyde (2 g, 10.6 mmol) in ethanol (3 ml), NaOH (0.425 g, 10.6 mmol) was dissolved in water (2 ml), and added to the mixture, and the mixture was stirred at room temperature. A precipitate was obtained after 10 minutes, and an additional ethanol (5 ml) was added while maintaining Stir for another 30 minutes. The mixture was poured into water (100 ml), the precipitate was filtered off and dried. The crude product was pure enough for the next step without further purification (2.64 g, 64%). On the other hand, it can be recrystallized from heptane to obtain a pure product. HPLC-MS (Method A): m / z = 391 (M + 1); Rt = 6.68 minutes. Building Block 2 (General Procedure (A)) 3 — (4-Cyclohexane-1 Alkenylphenyl) — 1 — (4-trifluoromethoxyphenyl) acrylone

將4—(三氟甲氧基）乙醯苯酮（5.18克，24.9毫莫耳）和 4一環己一 1一烯基苯甲醛（4.63克，24.9毫莫耳）混合物乙醇 61 200401634 (7毫升），將NaOH(1.0克，25毫莫耳）溶於水（5毫升），及加入至此混合物中。在室溫下攪拌此混合物，10分鐘後，可觀察到沈澱物的形成，接著再另外加入乙醇（10毫升），及再攪拌混合物30分鐘。將混合物倒入水（100毫升），過濾出沈澱物，及乾燥。粗產物的純度足以用於下一步驟，不需進一步純化（9.18克，99%)。另一方面，其可由庚烷中再結晶，製得純產物。 ^[NMIUDMSO —d6) : 51.60-1.68(m，2H)，1.72—1.80(m，2H)， 2.23(m，2H)，2.40(m，2H)，6.35(t，1H)，7.50(d，2H)，7.58(d，2H)，7.77(d ，1H)，7.86(d，2H)，7.93(d，1H)，8.30(d，2H); HPLC—MS(方法 C) : m/z=373 (M+l) : Rt=8.90 分鐘。建造嵌段3( —般程序（A)) 3 —（4一環己基苯基）一 1 一（3, 5—二氯苯基）丙烯酮A mixture of 4- (trifluoromethoxy) acetophenone (5.18 g, 24.9 mmol) and 4-cyclohexyl-11-alkenylbenzaldehyde (4.63 g, 24.9 mmol) was used. 61 200401634 (7 ml ), NaOH (1.0 g, 25 mmol) was dissolved in water (5 ml) and added to the mixture. The mixture was stirred at room temperature, and after 10 minutes, the formation of a precipitate was observed, followed by further addition of ethanol (10 ml), and the mixture was stirred for another 30 minutes. The mixture was poured into water (100 ml), the precipitate was filtered off and dried. The crude product was pure enough for the next step without further purification (9.18 g, 99%). On the other hand, it can be recrystallized from heptane to obtain a pure product. ^ [NMIUDMSO —d6): 51.60-1.68 (m, 2H), 1.72—1.80 (m, 2H), 2.23 (m, 2H), 2.40 (m, 2H), 6.35 (t, 1H), 7.50 (d, 2H), 7.58 (d, 2H), 7.77 (d, 1H), 7.86 (d, 2H), 7.93 (d, 1H), 8.30 (d, 2H); HPLC-MS (Method C): m / z = 373 (M + l): Rt = 8.90 minutes. Building Block 3 (General Procedure (A)) 3- (4-Cyclohexylphenyl)-1- (3,5-Dichlorophenyl) propenone

^NMIUDMSO—d6) : 51.21 —1.51(m，5H)，1.72—1.97(m，5H)， 155(m，1H)，7.27(d，2H)，7.35(d，1Η)，7.55(s，1H)，7.59(d，2H)，7.84(d ，1H)，7.86(s，2H)。建造嵌段4(一般程序（A)) 3-二苯基一 4一基一 1一（4一氯化苯基）丙烯酮 200401634 ^[NMIUDMSO —d6) : 57·43—7·56(Μ，6H)，7.60 —7.69(m，4H)， 7.74(d，2Η)，7.86(d，1Η)，7.98(d，2Η)。HPLC-MS(方法 C) : m/z=(319); Rt=6.86 分鐘。建造嵌段5( —般程序（A)) 3 -二苯基—4一基—萘一 2-基丙烯酮^ NMIUDMSO-d6): 51.21 —1.51 (m, 5H), 1.72—1.97 (m, 5H), 155 (m, 1H), 7.27 (d, 2H), 7.35 (d, 1Η), 7.55 (s, 1H ), 7.59 (d, 2H), 7.84 (d, 1H), 7.86 (s, 2H). Building block 4 (general procedure (A)) 3-diphenyl-4 4-yl-1 1- (4-chlorochlorinated phenyl) ketone 200401634 ^ [NMIUDMSO —d6): 57 · 43-7 · 56 (Μ , 6H), 7.60-7.69 (m, 4H), 7.74 (d, 2Η), 7.86 (d, 1Η), 7.98 (d, 2Η). HPLC-MS (method C): m / z = (319); Rt = 6.86 minutes. Building Block 5 (General Procedure (A)) 3-Diphenyl-4-yl-naphthalene-2-acrylketone

iHNMIUDMSO —d6) : (57.47(m，2H)，7.54 — 7.74(m，6H)，7.76(m， 3H)，7.90(d，2H)，7.95(d，2H)，8.00(d，1Η)，8.41(d，1Η)，8.55(s，1H)。 HPLC—MS(方法 C) : m/z=335(M+l) ; Rt=6.83 分鐘。建造嵌段6( —般程序（A)) 1 一（4一環己基苯基）一 3 -（4一異丙基苯基）丙烯酮iHNMIUDMSO —d6): (57.47 (m, 2H), 7.54—7.74 (m, 6H), 7.76 (m, 3H), 7.90 (d, 2H), 7.95 (d, 2H), 8.00 (d, 1Η), 8.41 (d, 1Η), 8.55 (s, 1H). HPLC-MS (Method C): m / z = 335 (M + 1); Rt = 6.83 minutes. Building block 6 (-General procedure (A)) 1- (4-Cyclohexylphenyl)-3-(4-Isopropylphenyl) propenone

^NMIUDMSCi —d6) : 51_27(d，6H)，1.35 —1.53(m，5H)，1.78(m， 1H)，1.89(m，4H)，2.57(m，1Η)，2.94(m，1Η)，7.27(d，2H)，7.34(d，2H) ，7.50(d，1H)，7.58(d，2H)，7.90(d，1H)，7.95(d，2H)。HPLC—MS(方法 C) : m/z=333(M+l) ; Rt=7.93 分鐘。建造嵌段7( —般程序（A)) 3 -茚滿一 5—基一 1 一（4 —三氟甲氧基苯基）丙烯酮 63 200401634^ NMIUDMSCi —d6): 51_27 (d, 6H), 1.35—1.53 (m, 5H), 1.78 (m, 1H), 1.89 (m, 4H), 2.57 (m, 1Η), 2.94 (m, 1Η), 7.27 (d, 2H), 7.34 (d, 2H), 7.50 (d, 1H), 7.58 (d, 2H), 7.90 (d, 1H), 7.95 (d, 2H). HPLC-MS (method C): m / z = 333 (M + 1); Rt = 7.93 minutes. Building Block 7 (General Procedure (A)) 3-Indan-1 5-yl-1 1 (4-trifluoromethoxyphenyl) propenone 63 200401634

iHNMRCDMSO-dJ : 52·11(ρ，2H)，2.94(t，4H)，7.26(d，1H)， 7.27(d，1H)，7.34(s，1H)，7.45(d，1H)，7.49(d，2H)，7.84(d，1H)，8.06(d ，2H) ; HPLC—MS(方法 A) : m/z=333(M+l) ; Rt=5.98 分鐘。建造嵌段8( —般程序（A)) 3 — [4 一（2, 2—二甲基丙基）苯基]—1 一（4—三氟化甲氧基苯基）丙烯酮iHNMRCDMSO-dJ: 52 · 11 (ρ, 2H), 2.94 (t, 4H), 7.26 (d, 1H), 7.27 (d, 1H), 7.34 (s, 1H), 7.45 (d, 1H), 7.49 ( d, 2H), 7.84 (d, 1H), 8.06 (d, 2H); HPLC-MS (Method A): m / z = 333 (M + 1); Rt = 5.98 minutes. Building Block 8 (-General Procedure (A)) 3-[4 mono (2,2-dimethylpropyl) phenyl] -1 mono (4-trifluoromethoxyphenyl) propenone

iHNMRCDMSO —d6) : 50.92(s，9H)，2.54(s，2H)，7.17(d，2H)， 7.33(d，2H)，7.45(d，1H)，7.55(d，2H)，7.84(d，1H)，8.07(d，2H) ; HPLC —MS(方法 A) : m/z=363(M+l) ; Rt=6.56 分鐘。建造嵌段9(一般程序（A)) 1 一苯並[1，3]二氧醇—5-基一 3—(4—環己基苯基）丙烯酮iHNMRCDMSO —d6): 50.92 (s, 9H), 2.54 (s, 2H), 7.17 (d, 2H), 7.33 (d, 2H), 7.45 (d, 1H), 7.55 (d, 2H), 7.84 (d , 1H), 8.07 (d, 2H); HPLC-MS (method A): m / z = 363 (M + 1); Rt = 6.56 minutes. Building Block 9 (General Procedure (A)) 1 Monobenzo [1,3] dioxol-5-yl-1 3- (4-cyclohexylphenyl) propenone

iHNMR^MSO — dj ·· 51.17 —1.50(m，5H)，1.69 —1.95(m，5H)， 2.52(m，1H)，6.07(s，2H)，6.88(d，1H)，7.24(d，2H)，7.44(d，1H)，7.51(d 64 200401634 ，1H)，7.55(d，2H)，7.64(dd，1Η)，7.88(d，1H)。建造嵌段10( —般程序（A)) 3 —（4一環己基苯基）一 1 一（4一異丙基苯基）丙烯酮iHNMR ^ MSO — dj ·· 51.17 — 1.50 (m, 5H), 1.69 — 1.95 (m, 5H), 2.52 (m, 1H), 6.07 (s, 2H), 6.88 (d, 1H), 7.24 (d, 2H), 7.44 (d, 1H), 7.51 (d 64 200401634, 1H), 7.55 (d, 2H), 7.64 (dd, 1H), 7.88 (d, 1H). Building Block 10 (General Procedure (A)) 3 — (4-Cyclohexylphenyl) 1 1 (4-Isopropylphenyl) Acrylone

1HNMR(DMS〇一d6):51.19—1.49(m，5H)，1.30(d，6H)，1.68 — 1.95(m，5H)，2.54(m，1H)，2.99(m，1H)，7.26(d，2H)，7.35(d，2H)， 7.47(d，1H)，7.57(d，2H)，7.78(d，1H)，7.95(d，2H)。建造嵌段11(一般程序（A)) 1，3-雙一（4一環己基苯基）丙烯酮1HNMR (DMS〇-d6): 51.19-1.49 (m, 5H), 1.30 (d, 6H), 1.68-1.95 (m, 5H), 2.54 (m, 1H), 2.99 (m, 1H), 7.26 (d , 2H), 7.35 (d, 2H), 7.47 (d, 1H), 7.57 (d, 2H), 7.78 (d, 1H), 7.95 (d, 2H). Building Block 11 (General Procedure (A)) 1,3-Bis (4-Cyclohexylphenyl) Acrylonone

^NMIUDMSO—dd : (51.21 —1.56(m，10H)，1.70-1.98(m，10H)， 2.45 —2.66(m，2H)，7.25(d，2H)，7.33(d，2H)，7.51(d，1H)，7.58(d，2H)， 7.80(d，1H)，7.95(d，2H)。建造嵌段12( —般程序（A)) 1 一（4-異丁基苯基）- 3 -（4一三氟化甲氧基苯基)丙烯酮^ NMIUDMSO-dd: (51.21 —1.56 (m, 10H), 1.70-1.98 (m, 10H), 2.45 —2.66 (m, 2H), 7.25 (d, 2H), 7.33 (d, 2H), 7.51 (d , 1H), 7.58 (d, 2H), 7.80 (d, 1H), 7.95 (d, 2H). Building block 12 (general procedure (A)) 1- (4-isobutylphenyl) -3 -(4-trifluoromethoxyphenyl) propenone

65 200401634 iHNMIUDMSO-c^) : 50.93(d，6H)，1.93(m，1H)，2.55(d，2H)， 7.24(d，2H)，7.29(d，2H)，7.51(d，1H)，7.67(d，2H)，7.77(d，1H)，7.95(d ，2H) ; HPLC—MS(方法 D) ·· m/z=349 (M+l) ; Rt=5.97 分鐘。建造嵌段13( —般程序(A)) 1 一（4 一環戊基苯基）- 3 -（4一三氟化甲氧基苯基)丙烯酮65 200401634 iHNMIUDMSO-c ^): 50.93 (d, 6H), 1.93 (m, 1H), 2.55 (d, 2H), 7.24 (d, 2H), 7.29 (d, 2H), 7.51 (d, 1H), 7.67 (d, 2H), 7.77 (d, 1H), 7.95 (d, 2H); HPLC-MS (Method D) · m / z = 349 (M + 1); Rt = 5.97 minutes. Building Block 13 (General Procedure (A)) 1 Mono (4-Cyclopentylphenyl) -3-(4-Trifluoromethoxyphenyl) propenone

iHNMRCDMSO—d6) : (Π.57 —1.87(m，6H)，2.02-2.18(m，2H)， 3.07(p，1Η)，7.25(d，2H)，7.38(d，2H)，7.51(d，1H)，7.66(d，2H)，7.78(d ，1H)，7.95(d，2H) ; HPLC—MS(方法 D) ·· m/z=361(M+l) ; Rt=6.06 分鐘。建造嵌段14(一般程序（A)) 1 一苯基一 3 —（4 一三氟化甲氧基苯基）丙烯酮iHNMRCDMSO-d6): (Π.57 —1.87 (m, 6H), 2.02-2.18 (m, 2H), 3.07 (p, 1Η), 7.25 (d, 2H), 7.38 (d, 2H), 7.51 (d 1H), 7.66 (d, 2H), 7.78 (d, 1H), 7.95 (d, 2H); HPLC-MS (Method D) · m / z = 361 (M + 1); Rt = 6.06 minutes. Building block 14 (general procedure (A)) 1 monophenyl-3-(4-trifluoromethoxyphenyl) acrylone

iHNMIUDMSO —d6) : 57.27(d，2H)，7.45—7.63(m，4H)，7.67(d 2H)，7.77(d，1Η)，8.00(d，2H) ; HPLC—MS(方法 D) : m/z=293(M+l); Rt=4.97 分鐘。建造嵌段15( —般程序（A)) l — ρ—甲苯基一 3—（4一三氟化甲氧基苯基）丙烯酮 66 200401634iHNMIUDMSO —d6): 57.27 (d, 2H), 7.45-7.63 (m, 4H), 7.67 (d 2H), 7.77 (d, 1Η), 8.00 (d, 2H); HPLC-MS (Method D): m / z = 293 (M + l); Rt = 4.97 minutes. Building Block 15 (General Procedure (A)) l-ρ -tolyl- 3-(4-trifluoromethoxyphenyl) propenone 66 200401634

^[NMR (DMS〇一d6) : 52.45(s，3H)，7.25(d，2H)，7.31(d，2H)， 7.49(d，1H)，7.67(d，2H)，7.77(d，1H)，7.92(d，2H) : HPLC—MS(方法 D) :m/z=307(M+l) ; Rt=5.22 分鐘。建造嵌段16( —般程序（A)) 1 一（4一甲氧基苯基）一 3 —（4一三氟化甲氧基苯基)丙烯酮^ [NMR (DMS〇-d6): 52.45 (s, 3H), 7.25 (d, 2H), 7.31 (d, 2H), 7.49 (d, 1H), 7.67 (d, 2H), 7.77 (d, 1H ), 7.92 (d, 2H): HPLC-MS (Method D): m / z = 307 (M + 1); Rt = 5.22 minutes. Building Block 16 (General Procedure (A)) 1-(4-methoxymethoxyphenyl)-3-(4-trifluoromethoxyphenyl) acrylone

^NMIUDMSO —d6) : 53.90(s，3H)，6.99(d，2H)，7.25(d，2H)， 7.50(d，1H)，7.67(d，2H)，7.77(d，1Η)，8.04(d，2H) ; HPLC—MS(方法 D) :m/z=323(M+l) ; Rt=4.93 分鐘。建造嵌段17( —般程序（A)) 3 -（4一環己基苯基）一 1 一（4一三氟化甲氧基苯基）丙烯酮馨^ NMIUDMSO-d6): 53.90 (s, 3H), 6.99 (d, 2H), 7.25 (d, 2H), 7.50 (d, 1H), 7.67 (d, 2H), 7.77 (d, 1Η), 8.04 ( d, 2H); HPLC-MS (method D): m / z = 323 (M + 1); Rt = 4.93 minutes. Building Block 17 (General Procedure (A)) 3-(4-Cyclohexylphenyl)-1-(4-trifluoromethoxyphenyl) acrylone

iHNMIUCDC^) : 5 8.08(d，2H)，7.83(d，1H)，7.58(d，2H)，7.45(d， 1H)，7.32(d，2H) ; 7.28(2，1H)，2.54(m，1H)，1.95 —1.73(m，5H)，1.50— 1.20(m，5H) ; HPLC—MS(方法 A) : m/z=375 (M+l) ; Rt=6.70 分鐘。建造嵌段18( —^般程序（A)) 二苯基一 4—基一 1 — (4 一三氟化甲氧基苯基）丙烯酮 67 200401634iHNMIUCDC ^): 5 8.08 (d, 2H), 7.83 (d, 1H), 7.58 (d, 2H), 7.45 (d, 1H), 7.32 (d, 2H); 7.28 (2, 1H), 2.54 (m , 1H), 1.95-1.73 (m, 5H), 1.50-1.20 (m, 5H); HPLC-MS (Method A): m / z = 375 (M + 1); Rt = 6.70 minutes. Building Block 18 (-General Procedure (A)) Diphenyl-1 4-yl-1 1- (4-trifluoromethoxyphenyl) propenone 67 200401634

^NMIUCDCIJ : 5 8.09(d，2H)，7.87(d，1H)，7.75-7.60(m，6H)， 7.52(d，1H)，7.49—7.29(m，5H) ; HPLC—MS(方法 A) : m/z=369(M+l); Rt=6.00 分鐘。建造嵌段19(一般程序（A)) 3-二苯基一4一基一 1 一 (4一三氟化甲基磺胺基苯基)丙烯酮^ NMIUCDCIJ: 5 8.09 (d, 2H), 7.87 (d, 1H), 7.75-7.60 (m, 6H), 7.52 (d, 1H), 7.49-7.29 (m, 5H); HPLC-MS (Method A) : m / z = 369 (M + l); Rt = 6.00 minutes. Building Block 19 (General Procedure (A)) 3-Diphenyl-4 4-yl-1 1- (4-trifluoromethylsulfonylphenyl) acrylone

HPLC—MS(方法 A) : m/z=385(M+l) ; Rt=6.18 分鐘。建造嵌段20( —般程序（A)) 3 —二苯基—4 —基—1— (2，2，3，3-四氟—2，3 —二氫苯並[1，4]二氧芑一 6—基）丙烯酮HPLC-MS (method A): m / z = 385 (M + 1); Rt = 6.18 minutes. Building Block 20 (General Procedure (A)) 3-Diphenyl-4-yl-1- (2,2,3,3-tetrafluoro-2,3-dihydrobenzo [1,4] di Oxo-6-yl) propenone

HPLC—MS(方法 A) : m/z=415(M+l) ; Rt=6.22 分鐘。建造程序21( —般程序（A)) 3 —（4 —環己基苯基）—1 — (2, 2, 3, 3 —四氟—2, 3 — 二氫苯並[1，4]二氧普一 6-基）丙烯酮 68 200401634 〇HPLC-MS (Method A): m / z = 415 (M + 1); Rt = 6.22 minutes. Construction Procedure 21 (General Procedure (A)) 3 — (4-cyclohexylphenyl) — 1 — (2, 2, 3, 3 —tetrafluoro-2, 3 — dihydrobenzo [1,4] di Xopro-6-yl) propenone 68 200401634 〇

HPLC—MS(方法 A) : m/z=421(M+l) ; Rt=6.76 分鐘。建造嵌段22( —般程序（A)) 3 —（4一環己基苯基）一 1-(3—三氟化甲氧基苯基）丙烯酮 HPLC—MS(方法 A) : m/z=375(M+l) ; Rt=6.54 分鐘。建造嵌段23( —般程序（A)) 3 -（4 一叔一丁基苯基）一 1 一（4一三氟化甲基磺胺基苯基）丙烯酮HPLC-MS (Method A): m / z = 421 (M + 1); Rt = 6.76 minutes. Building block 22 (General procedure (A)) 3-(4-Cyclohexylphenyl) 1- (3-trifluoromethoxyphenyl) acrylone HPLC-MS (method A): m / z = 375 (M + 1); Rt = 6.54 minutes. Building Block 23 (General Procedure (A)) 3-(4-tert-butylphenyl)-1-(4-trifluoromethylsulfonylphenyl) acrylone

h3c h3c HPLC—MS(方法 A) : m/z=365(M+l) ; Rt=6.32 分鐘。建造嵌段24( —般程序（A)) 3 -二苯基—4一基一 1 一（3-溴化苯基）丙烯酮〇h3c h3c HPLC-MS (Method A): m / z = 365 (M + 1); Rt = 6.32 minutes. Building Block 24 (General Procedure (A)) 3-Diphenyl-4 4-yl-1 1- (3-bromophenyl) propenone

Br 69 200401634 HPLC —MS(方法 A) : m/z=363(M+l) ; Rt=5.91 分鐘。建造嵌段25( —般程序（A)) 3—二苯基一 4 一基一 1 一（3 —二氣化甲基苯基）丙嫌酉同〇Br 69 200401634 HPLC-MS (Method A): m / z = 363 (M + 1); Rt = 5.91 minutes. Building block 25 (general procedure (A)) 3-diphenyl-1, 4-yl-1, 1- (3-digasified methylphenyl) propanone is the same

cf3 建造嵌段26( —般程序（A)) 3—(4—溴化_吩—2 —基）一1 — (4 一三氟化甲氧基苯基 )丙烯酮cf3 building block 26 (-general procedure (A)) 3-(4-bromo-phen-2-yl)-1-(4-trifluoromethoxyphenyl) acrylone

HPLC—MS(方法 A) : m/z=377(M+l) ; Rt=5.50 分鐘。建造嵌段27( —般程序（A)) 1，3—雙一（4 一三氟化甲氧基苯基）丙烯酮〇HPLC-MS (Method A): m / z = 377 (M + 1); Rt = 5.50 minutes. Building Block 27 (General Procedure (A)) 1,3-Bis (4-trifluoromethoxyphenyl) propenone

^NMR (CDC13) : 5 8.31(d，2H)，8.〇5(d，2H)，7.99(d，1H)，7.80(d， 1H)，7.56(d，2H)，7.47(d，2H) ; HPLC—MS(方法 A) ·· m/z=377(M+l); Rt=5.83 分鐘。建造嵌段28( —^般程序（A)) 70 200401634 3 —（4一叔一丁基苯基）一 1 一（4一三氟化甲氧基苯基)丙烯酮^ NMR (CDC13): 5 8.31 (d, 2H), 8.05 (d, 2H), 7.99 (d, 1H), 7.80 (d, 1H), 7.56 (d, 2H), 7.47 (d, 2H) ); HPLC-MS (Method A) · · m / z = 377 (M + 1); Rt = 5.83 minutes. Building Blocks 28 (General Procedure (A)) 70 200401634 3-(4-t-tert-butylphenyl)-1-(4-trifluoromethoxyphenyl) acrylone

iHNMIUCDCy : (5 8.07(d，2H)，7.82(d，1H)，7.60(d，2H)，7.46(m ，3H)，7.34(d，2H)，1.36(s，9H) ; HPLC—MS(方法 A) : m/z=349(M+l); Rt=6.35 分鐘。建造嵌段29( —般程序（A)) 3 —（4一苯氧基苯基）一 1 一（4一三氟化曱氧基苯基)丙烯酮iHNMIUCDCy: (5 8.07 (d, 2H), 7.82 (d, 1H), 7.60 (d, 2H), 7.46 (m, 3H), 7.34 (d, 2H), 1.36 (s, 9H); HPLC-MS ( Method A): m / z = 349 (M + l); Rt = 6.35 minutes. Building block 29 (-general procedure (A)) 3-(4-phenoxyphenyl)-1-(4-3 (Fluorinated methoxyphenyl) acrylone

iHNMIUCDCy : 5 8.07(d，2H)，7.79(d，1H)，7.61(d，2H)，7.4 — 7.3(m，5H)，7.18(t，1Η)，7.1—7.0(m，4H) ; HPLC—MS(方法 A): m/z=385(M+l) ; Rt=6.12 分鐘。建造嵌段30( —般程序（A)) 3 —（3—苯氧基苯基）一 1 一（4-三氟化甲氧基苯基)丙烯酮iHNMIUCDCy: 5 8.07 (d, 2H), 7.79 (d, 1H), 7.61 (d, 2H), 7.4-7.3 (m, 5H), 7.18 (t, 1Η), 7.1-7.0 (m, 4H); HPLC —MS (Method A): m / z = 385 (M + 1); Rt = 6.12 minutes. Building Block 30 (General Procedure (A)) 3- (3-phenoxyphenyl)-1- (4-trifluoromethoxyphenyl) propenone

iHNMIUDMSO—dJ ·· 5 8.31(d，2H)，7.97(d，1H)，7.76(d，1H)， 7.7(m，2H)，7.55—7.35(m，5H)，7.15(t，1H)，7.1—7.0(m，3H) ; HPLC — MS(方法 A) : m/z=385(M+l) ; Rt=6.09 分鐘。 71 200401634 建造嵌段31( —般程序（A)) 3 —（4一苯甲氧基苯基）一 1 一（4一三氟甲氧基苯基)丙烯酮iHNMIUDMSO-dJ · 8.31 (d, 2H), 7.97 (d, 1H), 7.76 (d, 1H), 7.7 (m, 2H), 7.55-7.35 (m, 5H), 7.15 (t, 1H), 7.1-7.0 (m, 3H); HPLC-MS (Method A): m / z = 385 (M + 1); Rt = 6.09 minutes. 71 200401634 Building block 31 (-general procedure (A)) 3-(4-benzophenoxyphenyl)-1-(4-trifluoromethoxyphenyl) acrylone

1HNMR(CDCl3):5 8.05(d，2H)，7.78(d，lH)，7.60(d，2H)，7.45 — 7.3〇(m，8H)，7.00(d，2H)，5.13(s，2H) ; HPLC—MS(方法 A): m/z=399(M+l) ; Rt=6.04 分鐘。建造嵌段32( —般程序（A)) 3 —（4—環己基苯基）一 1—(3，4一二氟苯基）丙烯酮1HNMR (CDCl3): 5 8.05 (d, 2H), 7.78 (d, 1H), 7.60 (d, 2H), 7.45-7.3 (m, 8H), 7.00 (d, 2H), 5.13 (s, 2H) ; HPLC-MS (method A): m / z = 399 (M + 1); Rt = 6.04 minutes. Building Block 32 (General Procedure (A)) 3- (4-cyclohexylphenyl)-1- (3,4-difluorophenyl) propenone

iHNMRCCDClJ : 57.90 —7.80(m，3H)，7.60(d，2H)，7.43(d，1H)， 7.3(m，1H)，2.55(m，1Η)，1.9—1.75(m，5H)，1.5(m，5H) ; HPLC—MS(方法 A) : m/z=327(M+l) ; Rt=6.20 分鐘。建造嵌段33( —般程序（A)) 1 — (4 一第二一丁基苯基）一 3 — (3-苯氧基苯基）丙烯酮iHNMRCCDClJ: 57.90—7.80 (m, 3H), 7.60 (d, 2H), 7.43 (d, 1H), 7.3 (m, 1H), 2.55 (m, 1Η), 1.9-1.75 (m, 5H), 1.5 ( m, 5H); HPLC-MS (Method A): m / z = 327 (M + 1); Rt = 6.20 minutes. Building Block 33 (General Procedure (A)) 1-(4-second butylphenyl)-3-(3-phenoxyphenyl) acrylone

HPLC—MS(方法 A) : m/z=357(M) ; Rt=7.16 分鐘。 72 200401634 建造嵌段34( —般程序（A)) 3 — [3—(4—氯化苯氧基）苯基]—1 — (5 ’ 6 ’ 7 ’ 8—四氣萘一 2—基）丙烯酮HPLC-MS (Method A): m / z = 357 (M); Rt = 7.16 minutes. 72 200401634 Building block 34 (General procedure (A)) 3 — [3- (4-chlorophenoxy) phenyl] -1 — (5 '6' 7 '8-tetranaphthalene-2 ) Acrylone

HPLC—MS(方法 A) : m/z=389(M+l)Rt=7.68 分鐘。建造嵌段35( —般程序（A)) 3 —（4一苯甲氧基苯基）一 1 — (3-溴化苯基）丙烯酮HPLC-MS (Method A): m / z = 389 (M + 1) Rt = 7.68 minutes. Building Block 35 (General Procedure (A)) 3-(4-benzyloxyphenyl)-1-(3-bromophenyl) acrylone

HPLC—MS(方法 A) : m/z=393(M+l) : Rt=6.82 分鐘。建造嵌段36( —般程序（A)) 1-二苯基一 4 一基一 3 — (4-環己基苯基）丙烯酮HPLC-MS (method A): m / z = 393 (M + 1): Rt = 6.82 minutes. Building Block 36 (General Procedure (A)) 1-diphenyl-1, 4-yl-1, 3- (4-cyclohexylphenyl) propenone

^NMIUDMSO—d) : (5 1.20—1.50(5H，m)，1.65 —1·85(5Η，m)， 7·33(2Η，d)，7.45(2H，d)，7·53(2Η，dd)，7.53—7·92(6Η，m)，8·25(1Η，d) ;HPLC—MS(方法 C) : m/z=367(M+l) ; Rt=9.18 分鐘。 73 200401634 建造嵌段37( —般程序（A)) 1 一（2-氯化苯基）一 3 -（4一環己基苯基）丙烯酮^ NMIUDMSO-d): (5 1.20—1.50 (5H, m), 1.65—1.85 (5Η, m), 7.33 (2Η, d), 7.45 (2H, d), 7.53 (2Η, dd), 7.53-7.92 (6Η, m), 8.25 (1Η, d); HPLC-MS (Method C): m / z = 367 (M + 1); Rt = 9.18 minutes. 73 200401634 Construction Block 37 (General Procedure (A)) 1- (2-Chlorophenyl) -3- (4-Cyclohexylphenyl) propenone

iHNMIUDMSO—c^) : 51.15 —1.48(5H，m)，1.62—1.85(5H，m)， 7.17—7·30(5Η，m)，7·37(1Η，d)，7·49(1Η，d)，7·56(2Η，dd)，7·67(1Η，d) ，8·21(1Η，s)，8·53(1Η，t) ; HPLC—MS(方法 C) : m/z=325(M+l) ; Rt=8.47 分鐘。建造嵌段38( —般程序（A)) 3 -（4-環己基苯基）一 1 一（2-三氟化甲基苯基）丙烯酮iHNMIUDMSO-c ^): 51.15 —1.48 (5H, m), 1.62 — 1.85 (5H, m), 7.17 — 7.30 (5Η, m), 7.37 (1Η, d), 7.49 (1Η, d), 7.56 (2Η, dd), 7.67 (1Η, d), 8.21 (1Η, s), 8.53 (1Η, t); HPLC-MS (Method C): m / z = 325 (M + l); Rt = 8.47 minutes. Building Block 38 (General Procedure (A)) 3-(4-cyclohexylphenyl)-1-(2-trifluoromethylphenyl) acrylone

iHNMIUDMSO — c^) : 51.15 —1·48(5Η，m)，1.65 —1.88(5H，m)， 7·22(1Η，s)，7·30(3Η，d)，7.66(3H，d)，7.72—7·82(2Η，m)，7·89(1Η，d); HPLC—MS(方法 C) : m/z=359 (M+l) ; Rt=8.47 分鐘。建造嵌段39( —般程序（A)) 1 一（4 一叔一丁基苯基）一 3 -（4 一環己基苯基）丙烯酮iHNMIUDMSO — c ^): 51.15 —1.48 (5Η, m), 1.65 —1.88 (5H, m), 7.22 (1Η, s), 7.30 (3Η, d), 7.66 (3H, d) , 7.72-7.82 (2Η, m), 7.89 (1Η, d); HPLC-MS (Method C): m / z = 359 (M + 1); Rt = 8.47 minutes. Building block 39 (general procedure (A)) 1 mono- (4-tert-butylphenyl) 3- 3- (4-cyclohexylphenyl) propenone

74 200401634 iHNMiUDMSO-dJ : 51.25 —1·47(14Η，m)，1·65-1·85(5Η，m)， 7·31(2Η，d)，7·58(2Η，d)，7·65-7·90(4Η，m)，8·07(2Η，d) ; HPLC—MS( 方法 C) : m/z=347(M+l) ; Rt=9.22 分鐘。建造嵌段40( —般程序（A)) 3 — (4-環己基苯基）一 1 一（4一苯氧基苯基）丙烯酮74 200401634 iHNMiUDMSO-dJ: 51.25 —1.47 (14Η, m), 1.65-1 · 85 (5Η, m), 7.31 (2Η, d), 7.58 (2Η, d), 7 · 65-7 · 90 (4Η, m), 8.07 (2Η, d); HPLC-MS (Method C): m / z = 347 (M + 1); Rt = 9.22 minutes. Building Block 40 (General Procedure (A)) 3- (4-cyclohexylphenyl)-1- (4-phenoxyphenyl) propenone

iHNMIUDMSO-cU : (51·2—1·5(5Η，m)，1·7 — 1·85(5Η，m)， 7·08(2Η，d)，7·14(2Η，d)，7·31(3Η，m)，7.47(2H，dd)，7.67—7·90(4Η，m) ，7.20(2H，d) ; HPLC—MS(方法 C) : m/z=383(M+l) ; Rt=9.13 分鐘。建造嵌段41(一般程序（A)) 3 — (4 —環己基苯基）一 1 一（4 —呢D定—1 —基苯基）丙餘爾iHNMIUDMSO-cU: (51 · 2—1 · 5 (5m, m), 1 · 7—1 · 85 (5Η, m), 7 · 08 (2Η, d), 7 · 14 (2Η, d), 7 · 31 (3Η, m), 7.47 (2H, dd), 7.67-7 · 90 (4Η, m), 7.20 (2H, d); HPLC-MS (Method C): m / z = 383 (M + l ); Rt = 9.13 minutes. Building block 41 (general procedure (A)) 3 — (4-cyclohexylphenyl) — 1 — (4-naphthalene—1-phenylphenyl) propionol

1HNMR(DMS〇一d6):5 1.20—1.50(5H，m)，1.59(6H，s)，1.62— 1·83(5Η，m)，3·40(4Η，s)，6·98(2Η，d)，7.29(2H，d)，7·62(1Η，d)， 7·76(2Η，d)，7·84(1Η，d)，8.02(2H，d) ; HPLC-MS(方法 C): m/z=374(M+l) ; Rt=8.30 分鐘。建造嵌段42( —般程序（A)) 75 200401634 3 —（4一三氟化甲氧基苯基）一 1 一（4 一三氟化甲基磺胺基苯基）丙嫌酮1HNMR (DMS〇-d6): 5 1.20—1.50 (5H, m), 1.59 (6H, s), 1.62- 1.83 (5Η, m), 3.40 (4Η, s), 6.98 (2Η , D), 7.29 (2H, d), 7.62 (1Η, d), 7.76 (2Η, d), 7.84 (1Η, d), 8.02 (2H, d); HPLC-MS (method C): m / z = 374 (M + 1); Rt = 8.30 minutes. Building Block 42 (General Procedure (A)) 75 200401634 3-(4-trifluoromethoxyphenyl)-1-(4-trifluoromethylsulfonylphenyl) propanone

CF3〇/ SCF3 HPLC—MS(方法 A) : m/z=393(M+l) ; Rt=6.05 分鐘。建造嵌段43( —般程序（A)) 1 一（3—三氟化甲氧基苯基）一 3 —（4 一三氟化甲氧基苯基）丙烯酮CF3〇 / SCF3 HPLC-MS (Method A): m / z = 393 (M + 1); Rt = 6.05 minutes. Building Block 43 (General Procedure (A)) 1 Mono (3-trifluoromethoxyphenyl)-3- (4-trifluoromethoxyphenyl) propenone

HPLC—MS(方法 A) : m/z=377(M+l) ; Rt=5.87 分鐘。建造嵌段44(一般程序（A)) 1 一 3 -（二苯基—4 一基）—1 一（4 一環己基苯基）丙烯酮〇HPLC-MS (Method A): m / z = 377 (M + 1); Rt = 5.87 minutes. Building block 44 (general procedure (A)) 1-3-(diphenyl-4 -yl)-1-(4-cyclohexylphenyl) propenone 〇

HPLC—MS(方法 A) : m/z=367(M+l) ; Rt=6.82 分鐘。建造嵌段45( —般程序（A)) 1 一（4 一叔一丁基苯基）一 3 -（4一三氟化甲氧基苯基）丙 76 200401634 烯酮HPLC-MS (method A): m / z = 367 (M + 1); Rt = 6.82 minutes. Building Block 45 (General Procedure (A)) 1 Mono (4-tert-butylphenyl) 3- (4-trifluoromethoxyphenyl) propane 76 200401634 ketene

^[NMIUDMSO —d6) : (51.33(s，9H)，7.43 —7.50(d，2H)，7.58 — 7.63(d，2H)，7.72—7.79(d，2H)，7.94(s，1H) ; 7.97-8，14(m，4H) ; HPLC 一MS(方法 C) : m/z=349(M+l) ; Rt=6.70 分鐘。建造嵌段46( —般程序（A)) 1一（2 ’ 2，3，3 —四氣—2，3— —^ 氣苯並[1，4]二氧普一 6—基）一 3 —（4 一三氟甲氧基苯基）一丙烯酮^ [NMIUDMSO —d6): (51.33 (s, 9H), 7.43 —7.50 (d, 2H), 7.58 — 7.63 (d, 2H), 7.72—7.79 (d, 2H), 7.94 (s, 1H); 7.97 -8,14 (m, 4H); HPLC-MS (Method C): m / z = 349 (M + 1); Rt = 6.70 minutes. Building block 46 (general procedure (A)) 1- (2 '2,3,3 —Four gas—2,3— — ^ Gas benzo [1,4] dioxo-6-yl) -3- (4-trifluoromethoxyphenyl) -propenone

iHNMIUDMSO—cU : (57.42—7.50(d，2H)，7.67—7.73(d，1H)，7.78 —7.76(d，1H)，7.99(s，1H)，8.03 —8.11(d，2H) ; 8.13 —8.18(d，1H)，8.33(s ，1H) ; HPLC—MS(方法 D) : m/z=423 (M+l) ; Rt=5.97 分鐘。建造嵌段47( —般程序（A)) 1 一（4一氯化苯基）一 3 -（4一環己基苯基）丙烯酮iHNMIUDMSO-cU: (57.42-7.50 (d, 2H), 7.67-7.73 (d, 1H), 7.78-7.76 (d, 1H), 7.99 (s, 1H), 8.03-8.11 (d, 2H); 8.13- 8.18 (d, 1H), 8.33 (s, 1H); HPLC-MS (method D): m / z = 423 (M + 1); Rt = 5.97 minutes. Building block 47 (general procedure (A)) 1 mono (4-monochlorophenyl) 3- (4-cyclohexylphenyl) propenone

77 200401634 ^NMIUDMSO — c^) : (51.18 —1.53(m，5H)，1.66—1.89(m，5H)， 2.51—2.62(m，1H)，7.27 - 7.36(d，2H)，7_60—7.69(d，2H)，7.70—7.93(m， 4H)，8.13 —8.23(d，2H) ; HPLC—MS(方法 C) : m/z=325(M+l) ; Rt=7.33 分鐘微分析：C21H21C1〇，0·25Η2〇的計算値：C，76.58% ; H，6.58% 發現値：C，76.24% ; H，6.53%。建造嵌段48( —般程序（A)) 3 — (4 —環己基苯基）—1— (5，6，7，8 —四氫萘一2 — 基）丙烯酮77 200401634 ^ NMIUDMSO — c ^): (51.18 —1.53 (m, 5H), 1.66—1.89 (m, 5H), 2.51—2.62 (m, 1H), 7.27-7.36 (d, 2H), 7_60—7.69 ( d, 2H), 7.70—7.93 (m, 4H), 8.13—8.23 (d, 2H); HPLC-MS (Method C): m / z = 325 (M + 1); Rt = 7.33 minutes. Microanalysis: C21H21C1 Calculated 値, 0 · 25Η20, C: C, 76.58%; H, 6.58% Found 値: C, 76.24%; H, 6.53%. Building block 48 (general procedure (A)) 3-(4-ring Hexylphenyl) -1- (5,6,7,8-tetrahydronaphthalene-2-yl) propenone

iHNMIUDMSO—cy : 51.20—1.52(m，5H)，1.68-1.86(m，9H)， 2.52—2.61(m，1H)，2.77 —2.87(m，4H)，7.21-7.26(d，1H) ; 7.28 —7.34(d， 2H)，7.64—7.73(d，1H)，7.78—7.90(m，5H) ; HPLC—MS(方法 A): m/z=345(M+l) ; Rt=7.04 分鐘。微分析·· C25H28〇，0.25H2〇的計算値：C，86.04% ; H，8.23% ;發現値：C，86.06% ; H，8.35%。建造嵌段49(一般程序（A)) 1— (5, 6, 7, 8 —四氫萘一2 —基）—3 — (4 —三氟化甲氧基苯基）丙烯酮 200401634 ^NMIUDMSO —d6) : (Π.72—1.83(m，4H)，2.74-2.89(m，4H)， 7.21—7.29(d，1H)，7.41 — 7.49(d，2H)，7.70 —7.80(d，1H)，7.80—7.99(m， 4H)，8.00—8.08(d，1H) ; HPLC—MS(方法 C) : m/z=347(M+l) ; Rt=7.07 分鐘iHNMIUDMSO-cy: 51.20-1.52 (m, 5H), 1.68-1.86 (m, 9H), 2.52-2.61 (m, 1H), 2.77-2.87 (m, 4H), 7.21-7.26 (d, 1H); 7.28 —7.34 (d, 2H), 7.64—7.73 (d, 1H), 7.78—7.90 (m, 5H); HPLC—MS (Method A): m / z = 345 (M + 1); Rt = 7.04 minutes. Micro-analysis ... Calculation of C25H28〇, 0.25H2O: C, 86.04%; H, 8.23%; Discovery: C, 86.06%; H, 8.35%. Building block 49 (general procedure (A)) 1— (5, 6, 7, 8 —tetralina-2-yl) — 3 — (4-trimethoxymethoxyphenyl) acrylonone 200401634 ^ NMIUDMSO —D6): (Π.72—1.83 (m, 4H), 2.74—2.89 (m, 4H), 7.21—7.29 (d, 1H), 7.41 — 7.49 (d, 2H), 7.70 —7.80 (d, 1H ), 7.80—7.99 (m, 4H), 8.00—8.08 (d, 1H); HPLC-MS (Method C): m / z = 347 (M + 1); Rt = 7.07 minutes

O 微分析：C2QH17F3〇2的計算値：C，69.36% ; H，4.95% ;發現値：C， 69.13% ; H，4.96%。建造嵌段50( —般程序（A)) 3 — (4-氯化苯基）一 1 一（4一環己基苯基）丙烯酮O Microanalysis: Calculation of C2QH17F302: 値: C, 69.36%; H, 4.95%; 値: C, 69.13%; H, 4.96%. Building Block 50 (General Procedure (A)) 3- (4-chlorophenyl)-1- (4-cyclohexylphenyl) acrylonone

1HNMR(DMS〇一d6) : (51.18-1.55(m，5H)，1.68 —1.91(m，5H)， 2.56 — 2.69(m，1H)，7.37 — 7.47(d，2H)，7.48—7.57(d，2H) ; 7.66—7/78(d， 1H)，7.88 —8.02(m，3H)，8.04 —8.14(d，2H) ; HPLC—MS(方法 C): m/z=325 (M+l) ; Rt=7.40 分鐘。微分析：C21H21C1〇，0·25Η2〇的計算値：C，76.58% ; H，6.58% ;發現値：C，76.54% ; Η，6.43%。建造嵌段51( —般程序（A)) 1 -—^苯基一 4一基一 3 -（4 一環己基苯基）丙嫌爾1HNMR (DMS〇-d6): (51.18-1.55 (m, 5H), 1.68 —1.91 (m, 5H), 2.56 — 2.69 (m, 1H), 7.37 — 7.47 (d, 2H), 7.48 — 7.57 (d , 2H); 7.66-7 / 78 (d, 1H), 7.88-8.02 (m, 3H), 8.04-8.14 (d, 2H); HPLC-MS (Method C): m / z = 325 (M + l ); Rt = 7.40 minutes. Micro-analysis: C21H21C10, Calculate 0.25: 20 値: C, 76.58%; H, 6.58%; 値: C, 76.54%; Η, 6.43%. Building block 51 (- General procedure (A)) 1-^^ phenyl-4 4-yl-3-(4-cyclohexylphenyl) propanone

NMR (CDC13) : 5 1.20—1.52(m，5H)，1.71 —1.95(m，5H)，2.49 — 79 200401634 2.61(m，lH)，7.30(d，lH)，7.37—7.52(m，5H);7.56—7.68(m，4H)，7.69 — 7.76(d，2H)，7.79 —7.87(d，1H)，8·05 —8.13(d，2H) ; HPLC—MS(方法 C): m/z=367(M+l) ; Rt=8.00 分鐘。建造嵌段52( —般程序（A)) 1 一（4一環己基苯基）一 3 -（4一三氟化甲氧基苯基)丙烯酮NMR (CDC13): 5 1.20—1.52 (m, 5H), 1.71 — 1.95 (m, 5H), 2.49 — 79 200401634 2.61 (m, 1H), 7.30 (d, 1H), 7.37—7.52 (m, 5H) ; 7.56-7.68 (m, 4H), 7.69-7.76 (d, 2H), 7.79-7.87 (d, 1H), 8.05-8.13 (d, 2H); HPLC-MS (Method C): m / z = 367 (M + l); Rt = 8.00 minutes. Building Block 52 (General Procedure (A)) 1-(4-Cyclohexylphenyl)-3-(4-Trifluoromethoxyphenyl) acrylone

HPLC—MS(方法 A) : m/z=375(M+l) ; Rt=6.60 分鐘。建造嵌段53( —般程序（A)) 1-二苯基一 4 一基一 3 -（4 一二氟甲氧基苯基）丙烯酮HPLC-MS (Method A): m / z = 375 (M + 1); Rt = 6.60 minutes. Building block 53 (general procedure (A)) 1-diphenyl-1 4-yl-1 3-(4-difluoromethoxyphenyl) acrylone

HPLC—MS(方法 A) : m/z=369(M+l) ; Rt=5.86 分鐘。建造嵌段54( —般程序（A)) 1 —(4一環己基苯基）一 3 -（3，5-二氯化苯基）丙烯酮HPLC-MS (Method A): m / z = 369 (M + 1); Rt = 5.86 minutes. Building Block 54 (General Procedure (A)) 1-(4-Cyclohexylphenyl)-3-(3,5-dichlorophenyl) propenone

HPLC —MS(方法 A)m/z=360(M+l) ; Rt=6.52 分鐘。 80 200401634 建造嵌段55( —般程序（A)) 3 —（3-溴化苯基）一 1 一（4一環己基苯基）丙烯酮HPLC-MS (method A) m / z = 360 (M + 1); Rt = 6.52 minutes. 80 200401634 Building block 55 (general procedure (A)) 3-(3-bromophenyl)-1-(4-cyclohexylphenyl) acrylone

HPLC —MS(方法 A) ·· m/z=369(M+l) ; Rt=6.39 分鐘。建造嵌段56( —般程序（A)) 3 -（4 一甲基苯基）一 1 一（4 一氯化苯基）丙烯酮HPLC-MS (Method A) · m / z = 369 (M + 1); Rt = 6.39 minutes. Building Block 56 (General Procedure (A)) 3-(4-monomethylphenyl)-1-(4-monochlorophenyl) acrylone

HPLC—MS(方法 A) : m/z=257(M+l) ; Rt=5.05 分鐘。此化合物是習知的(Tet. Lett. 39(16)，2235，（1998))。建造嵌段57( —般程序（Α)) φ 1，3 —雙一（4 一氯化苯基）丙烯酮HPLC-MS (method A): m / z = 257 (M + 1); Rt = 5.05 minutes. This compound is known (Tet. Lett. 39 (16), 2235, (1998)). Building Block 57 (General Procedure (A)) φ 1,3-bis (4-monochlorophenyl) propenone

此化合物是習知的(Chem· Ber. 42，1813，（1909))。建造嵌段58( —般程序（A)) 3 -（4 一環己基苯基）—1 — 滿一 5 —基丙嫌酮 81 200401634This compound is conventional (Chem. Ber. 42, 1813, (1909)). Building Block 58 (General Procedure (A)) 3-(4-Cyclohexylphenyl)-1-Mann 5 -propylpropanone 81 200401634

iHNMIUDMSO — dj : (51.20—1.51(m，5H)，1.70—1.97(m，5H)， 2·15(ρ，2H)，2.54(m，1H)，2.97(t，4H)，7.25(d，2H)，7.32(d，1H)，7.48(d ，1H)，7.55(d，2H)，7.78(d，1H)，7.86(s，1H)。 HPLC —MS(方法 C) : m/z=331(M+l) ; Rt=6.46 分鐘。建造嵌段59( —般程序（A)) 3 -（4一環己基苯基）一 1 一（4一異丁基苯基）丙烯酮iHNMIUDMSO — dj: (51.20—1.51 (m, 5H), 1.70—1.97 (m, 5H), 2.15 (ρ, 2H), 2.54 (m, 1H), 2.97 (t, 4H), 7.25 (d, 2H), 7.32 (d, 1H), 7.48 (d, 1H), 7.55 (d, 2H), 7.78 (d, 1H), 7.86 (s, 1H). HPLC-MS (Method C): m / z = 331 (M + l); Rt = 6.46 minutes. Building block 59 (general procedure (A)) 3-(4-cyclohexylphenyl)-1-(4-isobutylphenyl) acrylone

^NMRCDMSO—d6) : 50.95(d，6H)，1.21 —1.50(m，5H)，1.75(m， 1H)，1.78 —2.20(m，5H)，2.49(m，1Η)，2.57(d，2H)，7.25(d，2H)，7.27(d ，2H)，7.49(d，1H)，7.56(d，2H)，7.79(d，1H)，7.94(d，2H)。 HPLC—MS(方法 C) : m/z=347(M+l) ; Rt=6.69 分鐘。建造嵌段60( —般程序（A)) 3 -（4一環己基苯基）一1 一（4 一環戊基苯基）丙烯酮^ NMRCDMSO-d6): 50.95 (d, 6H), 1.21-1.50 (m, 5H), 1.75 (m, 1H), 1.78-2.20 (m, 5H), 2.49 (m, 1Η), 2.57 (d, 2H ), 7.25 (d, 2H), 7.27 (d, 2H), 7.49 (d, 1H), 7.56 (d, 2H), 7.79 (d, 1H), 7.94 (d, 2H). HPLC-MS (method C): m / z = 347 (M + 1); Rt = 6.69 minutes. Building Block 60 (General Procedure (A)) 3-(4-Cyclohexylphenyl)-1-(4-Cyclopentylphenyl) Acrylone

^NMIUDMSO — dJ : 51.22—L50(m，5H)，1.62—1.96(m，11H)， 2.04 —2.2〇(m，2H)，2.54(m，1Η)，3·07(ρ，1H)，7.25(d，2H)，7.38(d，2H) 200401634 ，7.50(d，1H)，7.56(d，2H)，7.80(d，1H)，7.95(d，2H)。 HPLC—MS(方法 C) : m/z=359(M+l) ; Rt=6.77 分鐘。建造嵌段4(一般程序（A)) 3 —（4 一環己基苯基）一 1 一苯基丙烯酮^ NMIUDMSO — dJ: 51.22—L50 (m, 5H), 1.62—1.96 (m, 11H), 2.04 — 2.20 (m, 2H), 2.54 (m, 1Η), 3.07 (ρ, 1H), 7.25 (d, 2H), 7.38 (d, 2H) 200401634, 7.50 (d, 1H), 7.56 (d, 2H), 7.80 (d, 1H), 7.95 (d, 2H). HPLC-MS (method C): m / z = 359 (M + 1); Rt = 6.77 minutes. Building Block 4 (General Procedure (A)) 3 — (4-Cyclohexylphenyl)-1-Phenylpropenone

iHNMIUDMSO—d6) ·· (Π.22 —1.54(m，5H)，1.71 —1.96(m，5H)， 2.46—2.63(m，1Η)，7.25(d，2H)，7.44—7.62(m，6H)，7.80(d，1Η)，8.02(d ^ 2H) ° HPLC—MS(方法 C) : m/z=291(M+l) ; Rt=5.91 分鐘。建造嵌段5( —般程序（A)) 3 -（4一環己基苯基）一 1 一（4一甲基苯基）丙烯酮iHNMIUDMSO-d6) (Π.22 —1.54 (m, 5H), 1.71 —1.96 (m, 5H), 2.46—2.63 (m, 1Η), 7.25 (d, 2H), 7.44—7.62 (m, 6H ), 7.80 (d, 1Η), 8.02 (d ^ 2H) ° HPLC-MS (Method C): m / z = 291 (M + 1); Rt = 5.91 minutes. Building block 5 (-General procedure (A )) 3-(4-Cyclohexylphenyl)-1- (4-methylphenyl) propenone

—d6) : 51.21— 1.55(m，5H)，1.69 —1.96(m，5H)， 2.43(s 5 3H) ^ 2.46-2.64(m ^ 1H) ^ 7.25(d 5 2H) ^ 7.30(d ^ 2H) ^ 7.49(d 5 1H) 5 7.57(d，2H)，7.80(d，1H)，7.93(d，2H)。 HPLC—MS(方法 A) : m/z=305(M+l) ; Rt=6.15 分鐘。建造嵌段6( —般程序（A)) 3 —（4—環己基苯基）一 1 一（4一甲氧基苯基）丙烯酮 83 200401634—D6): 51.21— 1.55 (m, 5H), 1.69 —1.96 (m, 5H), 2.43 (s 5 3H) ^ 2.46-2.64 (m ^ 1H) ^ 7.25 (d 5 2H) ^ 7.30 (d ^ 2H ) ^ 7.49 (d 5 1H) 5 7.57 (d, 2H), 7.80 (d, 1H), 7.93 (d, 2H). HPLC-MS (method A): m / z = 305 (M + 1); Rt = 6.15 minutes. Building Block 6 (General Procedure (A)) 3- (4-cyclohexylphenyl)-1- (4-methoxyphenyl) propenone 83 200401634

? ch3 "HNMIUDMSO —d6) : 51.19 — 1.54(m，5H)，1.68-1.95(m，5H)， 2.45—2.62(m，1H)，3.90(s，3H)，6.96(d ’ 2H)，7.25(d，2H)，7.50(d，1H)， 7.56(d，2H)，7.79(d，1H)，8.04(d，2H)。 HPLC—MS(方法 A) ·· m/z=321(M+l) ; Rt=5.85 分鐘。ch3 " HNMIUDMSO —d6): 51.19 — 1.54 (m, 5H), 1.68-1.95 (m, 5H), 2.45—2.62 (m, 1H), 3.90 (s, 3H), 6.96 (d '2H), 7.25 (d, 2H), 7.50 (d, 1H), 7.56 (d, 2H), 7.79 (d, 1H), 8.04 (d, 2H). HPLC-MS (Method A) · m / z = 321 (M + 1); Rt = 5.85 minutes.

建造嵌段61( —般程序（A)) 1 -（4一叔一丁基苯基）一 3 -（4一三氟化甲氧基苯基)丙烯酮Building Block 61 (General Procedure (A)) 1-(4-tert-butylphenyl)-3-(4-trifluoromethoxyphenyl) acrylone

將4一（三氟化甲氧基）苯甲醛（16.5克，87毫莫耳）及4 φ —叔-丁基乙醯苯酮（15.3克，87毫莫耳）溶於乙醇99%(25 毫升）中，接著於此溶液中加入氧化鈉（8N，16.2毫升），及攪拌反應混合物1又1/2小時，加入水稀釋（1〇〇毫升），2 又1/2小時後過濾，及以水洗滌。產物在真空下乾燥，然後懸浮於乙醇（80毫升）中，及在溫度2(TC下攪拌1又1/2小時。接著將混合物放入冰箱中16小時，過濾出沈澱物，及以冰一冷卻的99%乙醇洗滌，可得11.5克（38%)的1 一（4 一叔-丁基苯基）- 3-（4-三氟化甲氧基苯基）丙烯酮。 84 200401634 HPLC—MS(方法 C) : m/z=349(M+l) ; Rt=7.10 分鐘。建造嵌段62( —般程序（A)) 1 一（3，5—雙一三氟化甲基苯基）一 3—（4 一環己基苯基 )丙烯酮Dissolve 4 mono (trifluoromethoxy) benzaldehyde (16.5 g, 87 mmol) and 4 φ-tert-butylacetophenone (15.3 g, 87 mmol) in 99% ethanol (25 Ml), then to this solution was added sodium oxide (8N, 16.2 ml), and the reaction mixture was stirred for 1 1/2 hours, diluted with water (100 ml), filtered after 2 1/2 hours, and Wash with water. The product was dried under vacuum, then suspended in ethanol (80 ml) and stirred at a temperature of 2 (TC for 1 1/2 hours. The mixture was then placed in the refrigerator for 16 hours, the precipitate was filtered off, and ice Washed with cooled 99% ethanol to obtain 11.5 g (38%) of 1- (4-tert-butylphenyl) -3- (4-trifluoromethoxyphenyl) propenone. 84 200401634 HPLC— MS (Method C): m / z = 349 (M + l); Rt = 7.10 minutes. Building block 62 (general procedure (A)) 1- (3,5-bis-trifluoromethylphenyl) ) 3- (4-cyclohexylphenyl) propenone

F 將3’，5’一雙（三氟化甲基）乙醯苯酮（9.3克，36.3毫莫耳）及4 一環己基苯甲醛（6_83克，36.3毫莫耳）溶於NMP(18 毫升）中，加入乙酸鋅（11)(398毫克，1.8毫莫耳），及2，2’ 一二吡啶（283毫克，1.81毫莫耳），及在溫度100°C及氮氣氣氛之下下加熱此混合物16小時，冷卻後，以庚烷（250毫升）和水（250毫升）分離混合物，有機相以NaS04乾燥，及蒸發至乾，可得粗產物，再由庚烷結晶，可得純標題化合物，其爲一固體，產量：5.8克（38%)。 HPLC—MS(方法 D) : m/z=427(M+l) ; Rt=6Jl 分鐘。一般程序（B) 固相合成式（15)化合物的一般程序（B):F Dissolve 3 ', 5'-bis (methyl trifluoride) acetophenone (9.3 g, 36.3 mmol) and 4-cyclohexylbenzaldehyde (6-83 g, 36.3 mmol) in NMP (18 ml ), Zinc acetate (11) (398 mg, 1.8 mmol) and 2,2'-dipyridine (283 mg, 1.81 mmol) were added and heated at 100 ° C under a nitrogen atmosphere This mixture was allowed to stand for 16 hours. After cooling, the mixture was separated with heptane (250 ml) and water (250 ml). The organic phase was dried over NaSO4 and evaporated to dryness to obtain the crude product, which was then crystallized from heptane to obtain the pure title. Compound as a solid, yield: 5.8 g (38%). HPLC-MS (Method D): m / z = 427 (M + l); Rt = 6Jl min. General procedure (B) General procedure for solid-phase synthesis of compound of formula (15) (B):

85 20040163485 200401634

其中X，D，E，m，η和R4是如式⑴中所定義者，及樹脂爲一聚苯乙嫌樹脂，其載有一 Wang—連結基。步驟1 : 此反應是習知的（Wang S.L，Am. Chem. Soc. 95， 1328，1973 )，且通常是由攪拌載有一連結基的聚苯乙烯樹脂，像載有Wang連結基的聚苯乙烯樹脂，及4一 10莫耳過量的Fmoc-保護的胺基酸（以2-5莫耳過量的二異丙基碳二醯亞胺，二環己基碳二醯亞胺或1 一 [3 -（二甲基胺基）丙基]- 3-乙基碳二醯亞胺氫氯化物活化），在一觸媒的存在下，像N，N-4-二甲基胺基吡啶的存在下進行反應。酯化反應是在一溶劑中進行，像THF，二噁烷，DCM， DMF，NMP或這些溶劑的二個或多個的混合物，反應溫度是從0°C至80°C間，較佳地是在2(TC和40°C。當酯化反應完成時，過量的反應劑可過濾掉。接著所得樹脂順序以反應所使用的溶劑洗滌，接著以甲醇洗滌。此樹脂鍵結的產物可進一步乾燥及分析。步驟2 : N-氟烯甲基羰基保護的群基可經由以20-50%的二級胺溶液，像溶於極性溶劑（像DMF或NMP(Carpino L.，Han 86 200401634 G.，J.〇rg. Chem. 37，3040，1972)中的呃啶溶液處理此樹脂鍵結的衍生物而移除。此反應的反應溫度爲20°C至180 °C之間，較佳地是在20°C至40°C之間。當反應完成時’過量的反應劑可過濾移除，所得樹脂依序以反應所使用的溶液洗滌。結果樹脂鍵結的中間物以酸醯化。醯化反應是熟知的（The combinatorial index，Ed. Bunin B.A.，1998， Acedemic press，p. 78)，且一般是由攪拌該樹脂鍵結的中間物和2-5莫耳過量的酸（以2-5莫耳過量的二異丙基-碳二醯亞胺，二環己基碳二醯亞胺或1 一 [3 -（二甲基胺基）丙基]- 3-乙基碳二醯亞胺氫氧化物活化）在一側反應抑止劑存在下，像N-羥基苯並***存在下進行反應。醯化反應可在一溶劑中，像THF，二噁烷，甲苯，DCM，DMF， NMP，或這些溶劑中的二種或多種的混合物，反應溫度爲在0°C至80°C間，較佳地從20°C至40°C。當酯化反應完成時，過濾移去過量的反應劑，接著以甲醇洗滌。此樹脂鍵結產物能進一步乾燥和分析。步驟3 ：此反應先前並沒有被報導過可在一固體支持物上進行，但其是一溶液相步驟的修正反應（316价1*11.，：&1^801^· J. Heterocyclic. Chem. 14，573，1977)。將醒加至一活化雙鍵上一般是由攪拌此醛及該含有一活化雙鍵的化合物，像一經取代的丙烯酮，在一觸媒的存在下進行，觸媒的例子爲像氰化鈉或鉀，或_唑鑰鹽(thiazolium salts)，像3，4一二甲基—5 — (2 —羥基乙基）碘化噻哇錄鹽，3—苯甲基一 5 — 87 200401634 (2—羥基乙基）—4 —甲基一 1，3—氯化噻唑鎗鹽，3—乙基一 5—(2—羥基乙基）一 4 —甲基—1，3—溴化噻唑鑰鹽或維生素I。當使用噻唑鎗鹽爲觸媒時，可加入一非親核胺鹼，像三乙胺，N，N—二異丙基乙基胺或DBU。加入時是在一溶劑中進行，像二噁烷，DMSO，NMP或DMF，或這些溶劑中的二種或多種的混合物。反應溫度是在50°C至120 °(：間，較佳地是在50°C至80°C之間。當反應完成時，過量的反應劑可過濾移去，所得樹脂依序以反應所使用的溶劑洗滌，接著以甲醇洗滌。此樹脂鍵結的產物能進一步純化及分析。步驟4 : 此反應是習知的（The combinatorial index，Ed. Bunin B.A.，1998，Acedemic press，p. 21)，且一般是由攪拌步驟3所得的樹脂鍵結中間物及50- 95%TFA溶液進行。最後裂解步驟是在一溶劑中進行，像THF，DCM，1，2 -二氯乙烷，1，3 —二氯丙烷，甲苯或這些溶劑中的二種或多種混合物。反應溫度爲從〇°C至80°C間，較佳地是從20°C 至40°C間。當反應完成時，過濾出產物。所得樹脂依序以 DCM洗滌，收集產物及洗滌物，移去溶劑，及在真空下乾燥產物。此程序將在以下實例中說明。實例1(一般程序（B)) 3 — {4 — [2-二苯基一 4—基一 4 一氧—4—(4—三氟化甲氧基苯基）丁醯]苯甲醯胺基}丙酸 88 200401634Among them, X, D, E, m, η and R4 are as defined in formula ⑴, and the resin is a polystyrene resin, which carries a Wang-linking group. Step 1: This reaction is conventional (Wang SL, Am. Chem. Soc. 95, 1328, 1973), and is usually carried out by stirring a polystyrene resin with a linker, such as polybenzene with a Wang linker. Vinyl resin, and 4 to 10 mol excess of Fmoc-protected amino acid (with 2-5 mol excess of diisopropylcarbodiimide, dicyclohexylcarbodiimide or 1- [3 -(Dimethylamino) propyl]-3-ethylcarbodiimide hydrochloride activation), in the presence of a catalyst, like the presence of N, N-4-dimethylaminopyridine The reaction was carried out. The esterification reaction is performed in a solvent, such as THF, dioxane, DCM, DMF, NMP or a mixture of two or more of these solvents. The reaction temperature is from 0 ° C to 80 ° C, preferably It is at 2 ° C and 40 ° C. When the esterification reaction is completed, the excess reactant can be filtered off. Then the resin obtained is sequentially washed with the solvent used for the reaction, and then washed with methanol. The resin-bonded product can be further Drying and analysis. Step 2: N-fluoroalkenylcarbonyl protected groups can be dissolved in a secondary amine solution of 20-50%, like soluble in polar solvents (like DMF or NMP (Carpino L., Han 86 200401634 G). ., J. Org. Chem. 37, 3040, 1972), the resin-bound derivative is removed by treatment with the eridine solution. The reaction temperature of this reaction is between 20 ° C and 180 ° C, preferably The ground is between 20 ° C and 40 ° C. When the reaction is complete, 'excess reactants can be removed by filtration, and the resulting resin is sequentially washed with the solution used for the reaction. As a result, the resin-bonded intermediate is acidified. The tritiation reaction is well known (The combinatorial index, Ed. Bunin BA, 1998, Acedemic press, p. 78), and This is usually accomplished by stirring the resin-bonded intermediate and a 2-5 molar excess of acid (diisopropyl-carbodiimide, dicyclohexylcarbodiimide or 2-5 molar excess). Mono [3-(dimethylamino) propyl] -3-ethylcarbodiimide hydroxide is activated) in the presence of a side reaction inhibitor, like N-hydroxybenzotriazole The tritiation reaction can be in a solvent, such as THF, dioxane, toluene, DCM, DMF, NMP, or a mixture of two or more of these solvents. The reaction temperature is between 0 ° C and 80 ° C. It is preferably from 20 ° C to 40 ° C. When the esterification reaction is completed, the excess reactant is removed by filtration and then washed with methanol. The resin-bonded product can be further dried and analyzed. Step 3: This reaction was previously It has not been reported that it can be performed on a solid support, but it is a modified reaction of a solution phase step (316 valence 1 * 11.,: &Amp; 1 ^ 801 ^ · J. Heterocyclic. Chem. 14, 573, 1977 ). Adding a wake to an activated double bond is usually made by stirring the aldehyde and the compound containing an activated double bond, like a substituted acrylone. Examples of catalysts are sodium or potassium cyanide, or thiazolium salts, such as 3,4-dimethyl-5- (2-hydroxyethyl) thiawadide. Recording salt, 3-benzyl-5—87 200401634 (2-hydroxyethyl) —4-methyl-1,3-thiazole chloride salt, 3-ethyl-5— (2-hydroxyethyl) A 4-methyl-1,3-bromothiazole key salt or vitamin I. When using thiazole gun salt as a catalyst, a non-nucleophilic amine base such as triethylamine, N, N-diisopropylethylamine or DBU can be added. The addition is performed in a solvent such as dioxane, DMSO, NMP or DMF, or a mixture of two or more of these solvents. The reaction temperature is between 50 ° C and 120 ° C :, preferably between 50 ° C and 80 ° C. When the reaction is completed, excess reactants can be removed by filtration, and the resulting resin is sequentially The solvent used was washed followed by methanol. The resin-bonded product can be further purified and analyzed. Step 4: This reaction is conventional (The combinatorial index, Ed. Bunin BA, 1998, Acedemic press, p. 21) It is generally carried out by stirring the resin-bonded intermediate obtained in step 3 and a 50-95% TFA solution. The final cleavage step is performed in a solvent such as THF, DCM, 1,2-dichloroethane, 1, 3-Dichloropropane, toluene or two or more of these solvents. The reaction temperature is between 0 ° C and 80 ° C, preferably between 20 ° C and 40 ° C. When the reaction is complete, The product was filtered off. The resulting resin was washed sequentially with DCM, the product and washings were collected, the solvent was removed, and the product was dried under vacuum. This procedure will be illustrated in the following example. Example 1 (General Procedure (B)) 3 — { 4 — [2-diphenyl-4—yl-4 4-oxy-4— (4-trifluoromethoxy Yl) butan-acyl] benzoyl amino} propanoic acid 88 200 401 634

步驟1和步驟2 :樹脂鍵結的3 —（4一甲醯苯甲醯胺基) 丙酸依據描述於WO 00/69810的步驟合成一鍵結至Wang樹脂的3—(4—甲醯苯甲醯胺基）丙酸樹脂（帶有大約0.2—0.8 毫莫耳/克）。步驟 3和步驟4:製備 3—{4—「2 — 一苯基—4 —基—4 一氧一 4 一（4 一三氟甲氧基苯基）一丁醯1苯甲醯胺基丨丙酸上述樹脂鍵結的3 —（4 一甲醯苯甲醯胺基）丙酸（496毫克樹脂）懸浮於一 NMP(10毫升）中。加入3，4一二甲基一 5 — (2—羥基乙基）碘化噻唑鎗（432毫克，1.5毫莫耳），3—二苯基一 4 一基—1 一（4 一三氟化甲氧基苯基）丙烯酮（1.05克， 2.7毫莫耳）及DBU(225微升，1.50毫莫耳），及在溫度70°C 下攪拌此懸浮液16小時。過濾分離出此樹脂，及以 DMF(3xl0毫升），乙醇（2x10毫升），DCM(10xl0毫升）洗滌。所得樹脂鍵結的3 — {4 - [ 2 — 一苯基—4 一基一 4 一氧一 4 一（4-三氟化甲氧基苯基）-丁醯]苯甲胺基}丙酸以 50%TFA/DCM(10毫升）溶液處理0.5小時（溫度爲25°C)。過瀘混合物，及以DCM(10毫升）洗滌樹脂，收集不同濾液，及在真空下濃縮，可得一油狀物，在矽膠上進行管柱層析 89 200401634 純化後，洗提劑爲DCM/甲醇/乙酸（95 : 4 : 1)，可得標題化合物。 'HNMRCCDCy ·· (5 8.07(d，2H)，8.02(d，2H)，7.79(d，2H)，7.55 —7.48(m，4H)，7·42 —7.24(m，7H) ; 7.05(t，1H)，5.32(dd，1H)，4.20(dd ，1H)，3.68(q，2H)，3.30(dd，1H)，2.64(t，2H); HPLC — MS(方法 A) : m/z=590(M+l) ; Rt=5_15 分鐘。以下實例爲如以上所述的製備。實例2 ( —般程序（B)) 3 — {4 — [2 —二苯基—4 一基一 4 —氧—4 — (3-三氟甲基苯基）丁醯]苯甲醯胺基}丙酸Step 1 and Step 2: Resin-bonded 3- (4-methylanilide benzamidine) propionic acid According to the procedure described in WO 00/69810, a 3- (4-methylanilide) bonded to Wang resin is synthesized. Formamidine) propionic acid resin (with about 0.2-0.8 mmol / g). Step 3 and Step 4: Preparation of 3- {4— "2-monophenyl-4-yl- 4 -oxo-4-(4 -trifluoromethoxyphenyl) -butane-1benzylamine 丨Propanoic acid 3- (4-methylanilide benzamido) propionic acid (496 mg resin) suspended in a NMP (10 ml) of the above resin. 3,4-dimethyl- 5-(2 —Hydroxyethyl) thiazole iodide gun (432 mg, 1.5 mmol), 3-diphenyl-4 4-yl-1 (4-trimethoxymethoxyphenyl) propenone (1.05 g, 2.7 Millimoles) and DBU (225 μl, 1.50 millimoles), and the suspension was stirred at 70 ° C for 16 hours. The resin was separated by filtration, and DMF (3x10ml), ethanol (2x10ml) , DCM (10x10 ml). The resulting resin-bonded 3- {4-[2-phenyl-4-1-4-oxygen-4-(4-trifluoromethoxyphenyl)-butanidine ] Benzamido} propanoic acid was treated with a 50% TFA / DCM (10 ml) solution for 0.5 hours (at a temperature of 25 ° C). The mixture was filtered, and the resin was washed with DCM (10 ml). The different filtrates were collected, and Concentrated under vacuum to give an oily After purification by column chromatography on silica gel 89 200401634, the eluent was DCM / methanol / acetic acid (95: 4: 1) to obtain the title compound. 'HNMRCCDCy · (5 8.07 (d, 2H), 8.02 (d, 2H), 7.79 (d, 2H), 7.55—7.48 (m, 4H), 7.42—7.24 (m, 7H); 7.05 (t, 1H), 5.32 (dd, 1H), 4.20 (dd , 1H), 3.68 (q, 2H), 3.30 (dd, 1H), 2.64 (t, 2H); HPLC — MS (Method A): m / z = 590 (M + 1); Rt = 5-15 minutes. The following The example is the preparation as described above. Example 2 (General Procedure (B)) 3 — {4 — [2-diphenyl-4 4-yl-4 —oxy-4 — (3-trifluoromethylphenyl) ) Butanidine] benzamidine amino} propanoic acid

iHNMRCCDCy : 5 8.24(s，1H)，8.17(d，1H)，8.09(d，2H)，7.85 —7.75(m，3H)，7.64 —7.49(m，5H) ; 7.44 —7.30(m，5H)，6.82(t，1H)， 5.35(dd，1H)，4.26(dd，1H)，3.71(q，2H)，3.36(dd，1H)，2.70(t，2H); HPLC —MS(方法 A) : m/z=574(M+l) ; Rt=5.04 分鐘。實例3 ( —般程序（B)) 3 — {4 — [2 — (4 —環己基苯基）—4 —氧—4 — (4 —二氣化甲基磺胺基苯基）丁醯]苯甲醯胺基}丙酸 90 200401634iHNMRCCDCy: 5 8.24 (s, 1H), 8.17 (d, 1H), 8.09 (d, 2H), 7.85—7.75 (m, 3H), 7.64—7.49 (m, 5H); 7.44—7.30 (m, 5H) , 6.82 (t, 1H), 5.35 (dd, 1H), 4.26 (dd, 1H), 3.71 (q, 2H), 3.36 (dd, 1H), 2.70 (t, 2H); HPLC-MS (Method A) : m / z = 574 (M + l); Rt = 5.04 minutes. Example 3 (General Procedure (B)) 3 — {4 — [2 — (4-cyclohexylphenyl) -4 —oxy-4 — (4-digasified methylsulfonylphenyl) butanyl] benzene Formamido} propanoic acid 90 200401634

^NMRCCDCIJ : 5 8.04(d，2H)，7.97(d，2H)，7.76(d，2H)，7.72(d ，2H)，7.20(d，2H) ; 7.14(d，2H)，6.88(t，1H)，5.24(dd，1H)，4.17(dd， 1H)，3.70(q，2H)，3.25(dd，1H)，2.68(t，2H)，2.42(m，1H)，1.85 —1.68(m ，5H)，1.45 —1.15(m，5H) ; HPLC—MS(方法 A) : m/z=612(M+l) ; Rt=5.78 分鐘。實例4 ( 一般程序（B)) 3 - {4 一 [4 一（3，5—雙三氟化甲基苯基）一 2 — (4 —環己基苯基）- 4-氧丁醯]苯甲醯胺基}丙酸^ NMRCCDCIJ: 5 8.04 (d, 2H), 7.97 (d, 2H), 7.76 (d, 2H), 7.72 (d, 2H), 7.20 (d, 2H); 7.14 (d, 2H), 6.88 (t, 1H), 5.24 (dd, 1H), 4.17 (dd, 1H), 3.70 (q, 2H), 3.25 (dd, 1H), 2.68 (t, 2H), 2.42 (m, 1H), 1.85—1.68 (m , 5H), 1.45-1.15 (m, 5H); HPLC-MS (Method A): m / z = 612 (M + 1); Rt = 5.78 minutes. Example 4 (General Procedure (B)) 3-{4 mono [4 mono (3,5-bistrifluoromethylphenyl) -2- (4-cyclohexylphenyl)-4-oxobutane] benzene Formamido} propionic acid

'HNMI^DMSO —d6) : 5 8.69(t，1H)，8.61(s，2H)，8.43(s，1H)， 8.14(d，2H)，7.90(d，2H) ; 7.34(d，2H)，7.17(d，2H)，5.42(dd，1H)， 4.29(dd，1H)，3.64(dd，1H)，1.78 —1.64(m，5H)，1.38 —1.25(m，5H); HPLC—MS(方法 A) ·· m/z=648(M+l) ; Rt=5.77 分鐘。實例5 ( —般程序（B)) 3— {4 — [2-二苯基一 4 一基一 4 — (3 —溴化苯基）—4 一 91 200401634 氧丁醯]苯甲醯胺基}丙酸'HNMI ^ DMSO —d6): 5 8.69 (t, 1H), 8.61 (s, 2H), 8.43 (s, 1H), 8.14 (d, 2H), 7.90 (d, 2H); 7.34 (d, 2H) , 7.17 (d, 2H), 5.42 (dd, 1H), 4.29 (dd, 1H), 3.64 (dd, 1H), 1.78—1.64 (m, 5H), 1.38—1.25 (m, 5H); HPLC-MS (Method A) ·· m / z = 648 (M + 1); Rt = 5.77 minutes. Example 5 (General Procedure (B)) 3- {4- — [2-diphenyl-4 4-yl-4 — (3-bromophenyl) — 4-91 200401634 oxetamine] benzamidine } Propionic acid

WNMRPMSO —d6) : 5 8.65(t，1H)，8.19(m，3H)，8.06(d，1H)， 7.93—7.83(m，3H)，7.60(m，4H) ; 7.50(m，3H)，7.43(m，2H)，7.34(m， 1H)，5.50(dd，1H)，4.20(dd，1H) ; HPLC—MS(方法 A) : m/z=586(M+l); Rt=4.99 分鐘0 實例6 ( —般程序（B)) 3 — {4— [2 - —^苯基—4 —基—4 —氧一 4 一（2，2，3，3 一四氟—2, 3—二氫苯並[1，4]二氧芑一6 —基）丁醯]苯甲醯胺基}丙酸WNMRPMSO —d6): 5 8.65 (t, 1H), 8.19 (m, 3H), 8.06 (d, 1H), 7.93—7.83 (m, 3H), 7.60 (m, 4H); 7.50 (m, 3H), 7.43 (m, 2H), 7.34 (m, 1H), 5.50 (dd, 1H), 4.20 (dd, 1H); HPLC-MS (Method A): m / z = 586 (M + l); Rt = 4.99 Minutes 0 Example 6 (General procedure (B)) 3 — {4— [2-— ^ phenyl-4 —yl — 4 —oxy-1 4 ((2, 2, 3, 3 — tetrafluoro-2, 3 —Dihydrobenzo [1,4] dioxo-6-yl) butyrene] benzylamino} propanoic acid

WNMI^CDCID : 5 8.09(d，2H)，7.86—7.75(m，4H)，7.55-7.5〇(m ，4H)，7.45 —7.30(m，5H)，7.23(d，2H) ; 6.78(t，1H)，5.83(dd，1H)， 4.18(dd，1H)，3.72(q，2H)，3.28(dd，1H)，2.71(t，2H) ; HPLC—MS(方法 A) : m/z=636(M+l) ; Rt=5.30 分鐘。WNMI ^ CDCID: 5 8.09 (d, 2H), 7.86-7.75 (m, 4H), 7.55-7.50 (m, 4H), 7.45-7.30 (m, 5H), 7.23 (d, 2H); 6.78 (t , 1H), 5.83 (dd, 1H), 4.18 (dd, 1H), 3.72 (q, 2H), 3.28 (dd, 1H), 2.71 (t, 2H); HPLC-MS (Method A): m / z = 636 (M + l); Rt = 5.30 minutes.

微分析：C34H25F4N〇7，0.75H2O的計算値： 92 200401634 C，62.92% ; Η，4.11%，N，2.16%。發現値： C，62.94% ; Η，3.99% ; N，2.25%。實例7 ( —般程序（Β)) 3 — {4—[2—(4 —環己基苯基）—4 —氧—4—(2’ 2’ 3 ’ 3 一四氟一 2, 3_二氫苯並[1，4]二氧芑一 6—基）丁醯]苯甲醯胺基}丙酸Micro analysis: C34H25F4N07, 0.75H2O calculation: 92 200401634 C, 62.92%; Η, 4.11%, N, 2.16%.値: C, 62.94%; Η, 3.99%; N, 2.25%. Example 7 (— General Procedure (B)) 3 — {4— [2— (4-cyclohexylphenyl) —4—oxy-4— (2 ′ 2 ′ 3 ′ 3—tetrafluoro—2, 3 — 2 Hydrobenzo [1,4] dioxo-6-yl) butyrene] benzylamino} propanoic acid

^NMRCCDCk) : 5 8.04(d，2Η)，7.82—7.70(m，4Η)，7.23—7.10(m ，5H)，6.82(t，1H)，5.23(dd，1Η) ; 4.13(dd，1H)，3.72(brq，2H)，3.20(dd ，1H)，2.70(brt，2H)，2.44(m，1H)，1.85 —1.70(m，5H)，1.46—1.15(m， 5H)。實例8 ( —般程序（B)) _ 3 — {4 — [2—二苯基-4—基-4—(3, 5—雙—三氟化甲基苯基）- 4-氧丁醯]苯甲醯胺基}丙酸^ NMRCCDCk): 5 8.04 (d, 2Η), 7.82-7.70 (m, 4Η), 7.23-7.10 (m, 5H), 6.82 (t, 1H), 5.23 (dd, 1Η); 4.13 (dd, 1H) , 3.72 (brq, 2H), 3.20 (dd, 1H), 2.70 (brt, 2H), 2.44 (m, 1H), 1.85-1.70 (m, 5H), 1.46-1.15 (m, 5H). Example 8 (—General Procedure (B)) _ 3 — {4 — [2-diphenyl-4-yl-4 ((3, 5-bis-trifluoromethylphenyl)) 4-oxobutane ] Benzamidine amino} propionic acid

]HNMR(DMSO —d6) : 5 8.64(m，3H)，8.42(s，1H)，8.20(d，2H)， 93 200401634 7.92(d，2H)，7.62(m，4H) ; 7.54(m，2H)，7.42(m，2H)，7.31(m，1H)， 5.52(dd，1H)，4.34(dd，1H) ; HPLC -MS(方法 A) : m/z=642(M+l) ; Rt=5.31 分鐘。實例9 ( 一般程序（B)) 3 — {4 - [2 -（4 一叔—丁基苯基）—4 —氧—4—(4 —二氟化甲基磺胺基苯基）丁醯]苯甲醯胺基}丙酸] HNMR (DMSO-d6): 5 8.64 (m, 3H), 8.42 (s, 1H), 8.20 (d, 2H), 93 200401634 7.92 (d, 2H), 7.62 (m, 4H); 7.54 (m, 2H), 7.42 (m, 2H), 7.31 (m, 1H), 5.52 (dd, 1H), 4.34 (dd, 1H); HPLC-MS (Method A): m / z = 642 (M + 1); Rt = 5.31 minutes. Example 9 (General Procedure (B)) 3 — {4-[2-(4-t-tert-butylphenyl) -4—oxy-4— (4-difluoromethylsulfonylphenyl) butane] Benzamidine} propionic acid

eNMRpMSO —d6) ·· 58.64(t，1H)，8.13(m，4H)，7.90(m，4H)， 7.33(s，4H)，7.62(m，4H)，5.43(dd，1H)，4.12(dd，1H) ; HPLC—MS(方法 A) : m/z=586(M+l) ; Rt=5.43 分鐘。eNMRpMSO —d6) · 58.64 (t, 1H), 8.13 (m, 4H), 7.90 (m, 4H), 7.33 (s, 4H), 7.62 (m, 4H), 5.43 (dd, 1H), 4.12 ( dd, 1H); HPLC-MS (Method A): m / z = 586 (M + 1); Rt = 5.43 minutes.

實例1 0 (—般程序（B)) 3 - {4 一 [2 -（4 一漠化瞳吩—2 —基）一 4—(3，4 一二氯化苯基）一 4-氧丁醯]苯甲醯胺基}丙酸Example 1 0 (—general procedure (B)) 3-{4 1 [2-(4 aridinyl quinone-2-yl)-4-(3,4-dichlorophenyl)-4-oxetane醯] benzylamino} propionic acid

'HNMRpMSO —d6) : (58.71(t，1H)，8.27(s，1H)，8.20(d，2H)， 7.96(m，3H)，7.81(d，1Η)，7.53(s，1Η)，7.20(s，1H) ; HPLC-MS(方法 A) :m/z=583(M+l) ; Rt=4.81 分鐘。 94 200401634 實例1 1 ( 一般程序（B)) 3 — {4—[2—(4—溴化噻吩—2—基）一4一（4—氯—3-甲基苯基）一 4-氧丁醯]苯甲醯胺基}丙酸'HNMRpMSO —d6): (58.71 (t, 1H), 8.27 (s, 1H), 8.20 (d, 2H), 7.96 (m, 3H), 7.81 (d, 1Η), 7.53 (s, 1Η), 7.20 (s, 1H); HPLC-MS (Method A): m / z = 583 (M + 1); Rt = 4.81 minutes. 94 200401634 Example 1 1 (General Procedure (B)) 3 — {4— [2— (4-Bromothiophene-2-yl) -4- (4-chloro-3-methylphenyl) -4-oxobutanyl] benzylamino} propanoic acid

MNMRPMSO —d6) : 5 8.68(t，1H)，8.18(d，2H)，8.04(d，1H)， 7.95(d，2H)，7.87(dd，1H)，7.55(m，2H)，7.17(s，1H)，5.75(dd，1H)， 4.10(dd，1H) ; HPLC—MS(方法 A) ·· m/z=563(M+l) ; Rt=4.81 分鐘。實例1 2 ( —般程序（B)) 3 — {4 一 [2 — (4 — 叔一丁基苯基）—4 —氧—4— (3-三氟化甲基苯基）丁醯]苯甲醯胺基}丙酸MNMRPMSO —d6): 5 8.68 (t, 1H), 8.18 (d, 2H), 8.04 (d, 1H), 7.95 (d, 2H), 7.87 (dd, 1H), 7.55 (m, 2H), 7.17 ( s, 1H), 5.75 (dd, 1H), 4.10 (dd, 1H); HPLC-MS (Method A) · m / z = 563 (M + 1); Rt = 4.81 minutes. Example 1 2 (—General Procedure (B)) 3 — {4 mono [2 — (4-tert-butylphenyl) -4 —oxy-4 — (3-trifluoromethylphenyl) butanidine] Benzamidine} propionic acid

HPLC—MS(方法 A) : m/z=554(M+l) ; Rt=5.14 分鐘。實例1 3 ( —般程序（B)) 3 — {4 — [2 —二苯基—4 一基一 4 —氧一4 一（4 —三氟化甲基磺胺基苯基）丁醯]苯甲醯胺基丨丙酸 95 200401634HPLC-MS (Method A): m / z = 554 (M + 1); Rt = 5.14 minutes. Example 1 3 (—General Procedure (B)) 3 — {4 — [2-diphenyl-4 4-yl-4 —oxy-4 — 4- (4-trifluoromethylsulfonylphenyl) butanyl] benzene Formamidine 丨 propionic acid 95 200401634

WNMI^CDCy : 5 8.08(d，2H)，8.0〇(d，2H)，7.80—7.68(m，5H)， 7.56—7.48(m，4H)，7.42-7.32(m，4H)，6.97(t，1H)，5.32(dd，1H); 4.22(dd，1H)，3.71(q，2H)，3.32(dd，1H)，2.70(t，2H) ; HPLC—MS(方法 B) : m/z=606(M+l) ; Rt=5.34 分鐘。實例1 4 ( 一般程序（B)) 3— {4 — [2 —（4 —苯甲氧基苯基）一4 —氧—4 一（4 —三氟化甲氧基苯基）丁醯]苯甲醯胺基}丙酸WNMI ^ CDCy: 5 8.08 (d, 2H), 8.00 (d, 2H), 7.80-7.68 (m, 5H), 7.56-7.48 (m, 4H), 7.42-7.32 (m, 4H), 6.97 (t , 1H), 5.32 (dd, 1H); 4.22 (dd, 1H), 3.71 (q, 2H), 3.32 (dd, 1H), 2.70 (t, 2H); HPLC-MS (Method B): m / z = 606 (M + l); Rt = 5.34 minutes. Example 1 4 (General Procedure (B)) 3 — {4 — [2 — (4-benzyloxyphenyl) — 4-oxo-4 — (4-trifluoromethoxyphenyl) butane] Benzamidine} propionic acid

^NMRCCDCy : (57.95(m，4H)，7.68(d，2H)，7.4—7.15(m，10H)， 6.85(m，2H)，5.15(d，1Η)，4.93(s，2H)，4.K)(m，2H) ; HPLC-MS(方法 A) :m/z=620(M+l) ; Rt=5.04 分鐘。實例1 5 ( —般程序（B)) 3 — {4 — [4 一氧一 2 —（4 一苯氧基苯基）—4 一（4 一三氟化甲氧基苯基）丁醯]苯甲醯胺基}丙酸 96 200401634NMRCCDCy: (57.95 (m, 4H), 7.68 (d, 2H), 7.4 to 7.15 (m, 10H), 6.85 (m, 2H), 5.15 (d, 1H), 4.93 (s, 2H), 4. K) (m, 2H); HPLC-MS (Method A): m / z = 620 (M + 1); Rt = 5.04 minutes. Example 1 5 (General procedure (B)) 3 — {4 — [4 monooxo 2 — (4-phenoxyphenyl) — 4 mono (4-trifluoromethoxyphenyl) butanthone] Benzamidine} propionic acid 96 200401634

實例1 6 ( —般程序（B)) 3 - {4 — [2—(4- 叔—丁基苯基）—4 —氧—4 一（4 —二氣化甲氧基苯基）丁醯]苯甲醯胺基}丙酸Example 1 6 (General Procedure (B)) 3-{4 — [2- (4-tert-butylphenyl) -4—oxy-4—mono (4-digasified methoxyphenyl) butane ] Benzamidine amino} propionic acid

HPLC—MS(方法 A) : m/z=570(M+l) ; Rt=5.42 分鐘。實例1 7 (—般程序（B)) 3—{4 — [4 一氧—2 -（3-苯氧基苯基）一 4一（4 —三氟化甲氧基苯基）丁醯]苯甲醯胺基}丙酸HPLC-MS (Method A): m / z = 570 (M + 1); Rt = 5.42 minutes. Example 1 7 (—General Procedure (B)) 3— {4 — [4 Dioxo-2- (3-phenoxyphenyl) -4— (4-trifluoromethoxyphenyl) butyrene] Benzamidine} propionic acid

200401634 HPLC—MS(方法 A) : m/z=606(M+l) ; Rt=5.20 分鐘。實例1 8 (—般程序（B)) 3 — {4 — [2 — —^ 苯基一 4 一基一 4—(4 —氯化苯基）—4 一氧丁醯]苯甲醯胺基}丙酸200401634 HPLC-MS (Method A): m / z = 606 (M + 1); Rt = 5.20 minutes. Example 1 8 (—General Procedure (B)) 3 — {4 — [2 — — ^ Phenyl-4 4-yl-4— (4-chlorinated phenyl) -4 dioxetane]] benzamidine } Propionic acid

HPLC—MS(方法 A) : m/z=540(M) ; Rt=4.85 分鐘。HPLC-MS (Method A): m / z = 540 (M); Rt = 4.85 minutes.

實例1 9 ( 一般程序（B)) 3 - [4—(2 — —^苯基—4 —基—4 —奈—2 —基—4 —氧丁醯）苯甲醯胺基]丙酸Example 1 9 (General Procedure (B)) 3-[4- (2 — — ^ phenyl-4 —yl — 4 —naphthalene — 2 —yl — 4 —oxebutazone) benzamidine] propanoic acid

HPLC—MS(方法 A) : m/z=556(M) ; Rt=4.97 分鐘。HPLC-MS (Method A): m / z = 556 (M); Rt = 4.97 minutes.

實例2 0 ( —般程序（B)) 3 — {4—[4—(4 —第—丁基苯基）—4 —氧—2—(3 —苯氧基苯基）丁醯]苯甲醯胺基}丙酸 98 200401634Example 2 0 (—General Procedure (B)) 3 — {4— [4— (4—first-butylphenyl) —4—oxy-2— (3—phenoxyphenyl) butyrene] benzyl Amido} propionic acid 98 200401634

HPLC—MS(方法 A) : m/z=578(M) ; Rt=5.62 分鐘。實例2 1 ( —般程序（B)) 3 - {4 一 [2 - [3 -（4 一氯化苯氧基）苯基]一 4 —氧一 4 — (5 ，6，7，8 —四氫萘一2—基）丁醯]苯曱醯胺基}丙酸HPLC-MS (Method A): m / z = 578 (M); Rt = 5.62 minutes. Example 2 1 (General Procedure (B)) 3-{4-[2-[3-(4-monochlorophenoxy) phenyl] -4 -oxy -4-(5,6,7,8- Tetrahydronaphthalene- 2-yl) butyridine] phenylamido} propionic acid

HPLC—MS(方法 A) : m/z=610(M) ; Rt=5.56 分鐘。HPLC-MS (Method A): m / z = 610 (M); Rt = 5.56 minutes.

實例2 2 (—般程序（B)) 3 — {4 — [2 —（4 一苯甲氧基苯基）—4 — (3-漠化苯基）—4 -氧丁醯]苯甲醯胺基}丙酸Example 2 2 (—General Procedure (B)) 3 — {4 — [2 — (4-benzyloxyphenyl) — 4 — (3-desertylphenyl) — 4-oxetane] benzamidine Amine} propionic acid

99 200401634 HPLC—MS(方法 A) : m/z=616(M+l) ; Rt=5.07 分鐘。實例2 3 ( —般程序（B)) 3—{4 — [4 -（4 —環己基苯基）一 2 -（4一異丙基苯基）—4 -氧丁醯]苯甲醯胺基丨丙酸99 200401634 HPLC-MS (Method A): m / z = 616 (M + 1); Rt = 5.07 minutes. Example 2 3 (-General procedure (B)) 3-{4 — [4--(4-cyclohexylphenyl)-2-(4-isopropylphenyl)-4-oxetane]] benzamidine Propionate

HPLC—MS(方法 A) : m/z=554(M) ; Rt=6.04 分鐘。實例2 4 ( —般程序（B)) 3 - {4 — [4 —二苯基—4 —基一 2 — (4-環己基苯基）—4 -氧丁醯]苯甲醯胺基}丙酸HPLC-MS (Method A): m / z = 554 (M); Rt = 6.04 minutes. Example 2 4 (—General Procedure (B)) 3-{4 — [4-diphenyl-4 —yl — 2 — (4-cyclohexylphenyl) — 4-oxobutanyl] benzamidine} Propionic acid

^NMRCCDCIJ : 51.05— 1·42(5Η，m)，1.55 —1.89(5H，m)，2·41(1Η ，m)，2·62(2Η，m)，3·31(1Η，d)，3·63(2Η，m)，4·20(1Η，m)，5·23(1Η， m)，7·12(2Η，d)，7·21(1Η，d)，7.38(1Η，d)，7·42(2Η，d)，7·58 — 7·80(6Η， 100 200401634 m)，7.99(4H，dd) ; HPLC—MS(方法 C) : m/z=588(M+l) ; Rt=7.97 分鐘。實例2 5 (—般程序（B)) 3 - {4 — [4 一（2-氯化苯基）—2 — (4-環己基苯基）—4 — 氧丁醯]苯甲醯胺基}丙酸^ NMRCCDCIJ: 51.05—1.42 (5Η, m), 1.55-1.89 (5H, m), 2.41 (1Η, m), 2.62 (2Η, m), 3.31 (1Η, d), 3.63 (2Η, m), 4.20 (1Η, m), 5.23 (1Η, m), 7.12 (2Η, d), 7.21 (1Η, d), 7.38 (1 (, d ), 7.42 (2Η, d), 7.58—7 · 80 (6Η, 100 200401634 m), 7.99 (4H, dd); HPLC-MS (Method C): m / z = 588 (M + l ); Rt = 7.97 minutes. Example 2 5 (—General Procedure (B)) 3-{4 — [4 Mono (2-chlorophenyl) -2 — (4-cyclohexylphenyl) — 4 —oxetane] benzamidine } Propionic acid

WNMI^DMSO — c^) ·· 51.15 —1.45(6H，m)，1.63 —1·80(5Η，m)， 3·94(1Η，m)，5·40(1Η，m)，7.14(1Η，d)，7·30(2Η，dd)，7·47(1Η，d)， 7·54(3Η，m)，7·90(2Η，dd)，7·97(1Η，d)，8·14(1Η，d)，8·68(1Η，t)， 12.25(1H，bs) ; HPLC-MS(方法 C) : m/z=546(M+l) ; Rt=7.32+7.40 分鐘。實例2 6 ( —般程序（B)) 3 - {4 — [2-（4 一環己基苯基）一 4 一氧一 4 一（2—三氟化 _ 甲基苯基）丁醯]苯甲醯胺基}丙酸WNMI ^ DMSO — c ^) 51.15 —1.45 (6H, m), 1.63 — 1.80 (5Η, m), 3.94 (1Η, m), 5.40 (1Η, m), 7.14 (1Η , D), 7.30 (2Η, dd), 7.47 (1Η, d), 7.54 (3Η, m), 7.90 (2Η, dd), 7.97 (1Η, d), 8 14 (1Η, d), 8.68 (1Η, t), 12.25 (1H, bs); HPLC-MS (Method C): m / z = 546 (M + 1); Rt = 7.32 + 7.40 minutes. Example 2 6 (General Procedure (B)) 3-{4 — [2- (4-Cyclohexylphenyl)-4 Oxy-4-(2-trifluoro-methylphenyl) butyrene] Benzene Amido} propionic acid

^NMRpMSO — cy ·· 51.15 —1.40(5H，m)，1.65 —1·87(5Η，m)， 101 200401634 3·47(2Η，q)，3·99(1Η，m)，5·43(1Η，m)，7·14(2Η，d)，7·31(2Η，d)，7·65 —8·00(6Η，m)，8·15(2Η，d)，8·68(1Η，t)，12·23(1Η，bs) ; HPLC—MS(方法 C) : m/z=580(M+l) ; Rt=7.67 分鐘。實例2 7 ( —般程序（B)) 3 - {4 一 [4 一（4 一叔一丁基苯基）一 2 -（4 一環己基苯基) 一 4一氧丁醯]苯甲醯胺基}丙酸^ NMRpMSO — cy 51.15 — 1.40 (5H, m), 1.65 — 1.87 (5Η, m), 101 200401634 3.47 (2Η, q), 3.99 (1Η, m), 5.43 ( 1Η, m), 7.14 (2Η, d), 7.31 (2Η, d), 7.65-8.00 (6Η, m), 8.15 (2Η, d), 8.68 (1Η , T), 12 · 23 (1Η, bs); HPLC-MS (Method C): m / z = 580 (M + 1); Rt = 7.67 minutes. Example 2 7 (General Procedure (B)) 3-{4-[4-(4-t-tert-butylphenyl)-2-(4-cyclohexylphenyl) -4 -oxetane}] benzamide Propyl

iHNMRCDMSO — dO : 51.15 —1.40(14H，m)，1.65 —1.80(5H，m)， 3·47(2Η，q)，4·08(1Η，m)，5·38(1Η，m)，7·15(2Η，d)，7·31(2Η，d)， 7·53(2Η，d)，7.85 - 8·00(4Η，m)，8·13(2Η，d)，8·67(1Η，t) ; HPLC-MS(方法 C) : m/z=568(M+l) ; Rt=8.47 分鐘。實例2 8 ( —般程序（B)) 3—{4 - [2 — (4-環己基苯基）—4 —氧一 4 — (4—呢啶—1 -基苯基）丁醯]苯甲醯胺基}丙酸iHNMRCDMSO — dO: 51.15 —1.40 (14H, m), 1.65 — 1.80 (5H, m), 3.47 (2Η, q), 4.08 (1Η, m), 5.38 (1Η, m), 7 · 15 (2Η, d), 7.31 (2Η, d), 7.53 (2Η, d), 7.85-8.00 (4Η, m), 8.13 (2Η, d), 8.67 ( 1Η, t); HPLC-MS (method C): m / z = 568 (M + 1); Rt = 8.47 minutes. Example 2 8 (—General Procedure (B)) 3— {4-[2 — (4-Cyclohexylphenyl) — 4 —Oxygen 4 — (4-N-Pyridine-1 -ylphenyl) butyrene] benzene Formamido} propionic acid

102 200401634 eNMRpMSO — c^) : 51.15 —1·40(8Η，m)，1·50—1·80(12Η，m)， 2·42(1Η，m)，3·46(2Η，m)，4.99(1Η，q)，5·34(1Η，m)，6·92(2Η，d)， 7·15(2Η，d)，7·31(2Η，d)，7·82(2Η，d)，7·89(2Η，d)，8·12(2Η，d)， 8·66(1Η，t) ; HPLC—MS(方法 C) : m/z=595(M+l) ; Rt=6.70 分鐘。實例2 9 ( —般程序（B)) 3 - {4 一 [2—(4 —環己基苯基）一 4 —氧一 4 一（4 一苯氧基苯基）丁醯]苯甲醯胺基}丙酸102 200401634 eNMRpMSO — c ^): 51.15 —1.40 (8Η, m), 1.50-1.80 (12Η, m), 2.42 (1Η, m), 3.46 (2Η, m), 4.99 (1Η, q), 5.34 (1Η, m), 6.92 (2Η, d), 7.15 (2Η, d), 7.31 (2Η, d), 7.82 (2Η, d ), 7.89 (2Η, d), 8.12 (2Η, d), 8.66 (1Η, t); HPLC-MS (Method C): m / z = 595 (M + 1); Rt = 6.70 minutes. Example 2 9 (General Procedure (B)) 3-{4-[2- (4-Cyclohexylphenyl) -4-Oxy-4- (4-Phenyloxyphenyl) butyryl] benzamide Propyl

iHNMRpMSO — dJ : (51.15 —1.40(5H，m)，1·60—1·80(5Η，m)， 3·46(2Η，q)，4·06(1Η，m)，5·38(1Η，m)，7·02(2Η，d)，7·13(4Η，dd)， 7·32(3Η，m)，7·48(2Η，dd)，7·88(3Η，dd)，8·02(2Η，d)，8·12(2Η，d)， 8·66(1Η，t)，12·25(1Η，bs) ; HPLC—MS(方法 C) : m/z=604(M+l) ; Rt=8.13 分鐘。實例3 0 ( —般程序（B)) 3 — {4 — [4 — (4-環己基苯基）—4 —氧—2 — (4 —三氟化甲氧基苯基）丁醯]苯甲醯胺基}丙酸 103 200401634iHNMRpMSO — dJ: (51.15 —1.40 (5H, m), 1.60—1 · 80 (5Η, m), 3.46 (2Η, q), 4.06 (1Η, m), 5.38 (1Η , M), 7.02 (2Η, d), 7.13 (4Η, dd), 7.32 (3Η, m), 7.48 (2Η, dd), 7.88 (3Η, dd), 8 · 02 (2Η, d), 8.12 (2Η, d), 8.66 (1Η, t), 12.25 (1Η, bs); HPLC-MS (Method C): m / z = 604 (M + l); Rt = 8.13 minutes. Example 3 0 (—general procedure (B)) 3 — {4 — [4 — (4-cyclohexylphenyl) — 4 —oxy — 2 — (4 —methyl trifluoride Oxyphenyl) butylammonium] benzamidineamino} propionic acid 103 200401634

WNMRCCDCy : 51.20—1·50(5Η，m)，1.70 —1·90(5Η，m)，2·55(1Η ，m)，2·70(2Η，t)，3·32(1Η，dd)，3·72(2Η，q)，4·15(2Η，dd)，5·30(1Η， dd)，6.83(1Η，t)，7·14(2Η，d)，7·28(2Η，d)，7·36(2Η，d)，7·79(2Η，d); 7·90(2Η，d)，8·06(2Η，d) ; HPLC—MS(方法 A) : m/z=596(M+l) ; Rt=5.68 分鐘。 · 實例3 1 ( —般程序（B)) 3— {4 — [4 —二苯基一 4 —基—4 —氧—2 — (4 —三氟化甲氧基苯基）丁醯]苯甲醯胺基}丙酸WNMRCCDCy: 51.20-1.50 (5Η, m), 1.70-1.90 (5Η, m), 2.55 (1Η, m), 2.70 (2Η, t), 3.32 (1Η, dd) , 3.72 (2Η, q), 4.15 (2Η, dd), 5.30 (1Η, dd), 6.83 (1Η, t), 7.14 (2Η, d), 7.28 (2Η, d), 7.36 (2Η, d), 7.79 (2Η, d); 7.90 (2Η, d), 8.06 (2Η, d); HPLC-MS (Method A): m / z = 596 (M + l); Rt = 5.68 minutes. · Example 3 1 (—General Procedure (B)) 3 — {4 — [4-diphenyl-1 4-yl-4 —oxy-2 — (4-trifluoromethoxyphenyl) butyrene] benzene Formamido} propionic acid

iHNMI^CDCy : 52·70(2Η，t)，3.38(1H，dd)，3.73(2H，q)， 104 200401634 4·24(2Η，dd)，5·35(1Η，dd)，6·85(1Η，t)，7·16(2Η，d)，7·28(2Η，d)，7.35 —7·50(5Η，m)，7·61(2Η，d) ; 7·67(2Η，d)，7·80(2Η，d)，8·03(2Η，d)， 8.〇7(2Η，d) ; HPLC—MS(方法 A) ·· m/z=590(M+l) ; Rt=5.03 分鐘。實例3 2 ( —般程序（B)) 3 - {4 一 [4 一（4 一環己基苯基）一 2-（3, 5-二氯化苯基) 一 4-氧丁醯]苯甲醯胺基丨丙酸iHNMI ^ CDCy: 52 · 70 (2Η, t), 3.38 (1H, dd), 3.73 (2H, q), 104 200401634 4 · 24 (2Η, dd), 5.35 (1Η, dd), 6.85 (1Η, t), 7.16 (2Η, d), 7.28 (2Η, d), 7.35-7.50 (5Η, m), 7.61 (2Η, d); 7.67 (2Η, d), 7.80 (2Η, d), 8.03 (2Η, d), 8.07 (2Η, d); HPLC-MS (Method A) · m / z = 590 (M + 1) ; Rt = 5.03 minutes. Example 3 2 (General Procedure (B)) 3-{4 mono [4 mono (4 monocyclohexylphenyl) 2- (3, 5-dichlorophenyl) 4-oxobutanyl] benzidine Amino acid

^NMRCCDCy : 51·15-1·50(5Η，m)，1.70—1.95(5H，m)， 2·57(1Η，m)，2·70(2Η，t)，3·30(1Η，dd)，3·73(1Η，q)，4·13(1Η，dd)， 5·23(1Η，dd)，6·90(1Η，t)，7·24(3Η，s)，7·29(2Η，d)，7.80(2H，d)， 7·88(2Η，d)，8·03(2Η，d)。實例3 3 ( —般程序（B)) 3— {4 — [2 -（3 -溴苯基）—4 一（4 —環己基苯基）一 4 一氧丁醯]苯甲醯胺基}丙酸^ NMRCCDCy: 51 · 15-1 · 50 (5Η, m), 1.70—1.95 (5H, m), 2.57 (1Η, m), 2.70 (2Η, t), 3.30 (1Η, dd ), 3.73 (1Η, q), 4.13 (1Η, dd), 5.23 (1Η, dd), 6.90 (1Η, t), 7.24 (3Η, s), 7.29 (2Η, d), 7.80 (2H, d), 7.88 (2Η, d), 8.03 (2Η, d). Example 3 3 (—General Procedure (B)) 3— {4 — [2- (3-bromophenyl) -4— (4-cyclohexylphenyl) —4—oxetane}] benzylamino} Propionic acid

105 200401634 ^NMRCCDCy : 51·17-1·50(5Η，m)，1.70—1·92(5Η，m)， 2·55(1Η，m)，2·69(2Η，t)，3·29(1Η，dd)，3.70(1Η，q)，4·15(1Η，dd)， 5·24(1Η，dd)，6·97(1Η，t)，7·15(1Η，t)，7·20-7·30(3Η，m) ; 7·35(1Η， d)，7·49(1Η，s)，7·76(2Η，d)，7·88(2Η，d)，8·02(2Η，d)。實例3 4 (—般程序（B)) 3 - {4 一 [4 一苯並[1，3]二氧醇—5-基一 2 — (4 -環己基苯基）- 4-氧丁醯]苯甲醯胺基}丙酸105 200401634 ^ NMRCCDCy: 51 · 17-1 · 50 (5Η, m), 1.70-1 · 92 (5Η, m), 2.55 (1Η, m), 2.69 (2Η, t), 3.29 (1Η, dd), 3.70 (1Η, q), 4.15 (1Η, dd), 5.24 (1Η, dd), 6.97 (1Η, t), 7.15 (1Η, t), 7 · 20-7 · 30 (3Η, m); 7.35 (1Η, d), 7.49 (1Η, s), 7.76 (2Η, d), 7.88 (2Η, d), 8. · 02 (2Η, d). Example 3 4 (—general procedure (B)) 3-{4 mono [4 monobenzo [1,3] dioxol-5-yl-1 2- (4-cyclohexylphenyl)-4-oxobutane ] Benzamidine amino} propionic acid

WNMRCCDCy : (51.20—1.48(m，5H)，1.66—1.87(m，5H)，2.47(m ，1H)，2.64(t，2H)，3.65(q，2H)，5.20(dd，2H)，6.02(s，2H)，6.81(d，1Η) ，6.99(t，1H)，7.12(m，1H)，7.23(d，2H)，7.38(s，1H)，7.46(d，2H)， 7.62(d，1H)，7.73(d，2H)，8.02(d，2H) ; HPLC—MS(方法 A): m/z=556(M+l) ; Rt=5.11 分鐘。一般程序（C ) 固相合成式（I4)化合物的一般程序（C) 106 200401634WNMRCCDCy: (51.20—1.48 (m, 5H), 1.66—1.87 (m, 5H), 2.47 (m, 1H), 2.64 (t, 2H), 3.65 (q, 2H), 5.20 (dd, 2H), 6.02 (s, 2H), 6.81 (d, 1Η), 6.99 (t, 1H), 7.12 (m, 1H), 7.23 (d, 2H), 7.38 (s, 1H), 7.46 (d, 2H), 7.62 ( d, 1H), 7.73 (d, 2H), 8.02 (d, 2H); HPLC-MS (Method A): m / z = 556 (M + l); Rt = 5.11 minutes. General procedure (C) Solid phase General procedure for the synthesis of compounds of formula (I4) (C) 106 200401634

步驟 1step 1

HOHO

Η 樹脂、OH 步驟2Η Resin, OH Step 2

其中X，D，E，m，n和R4是如式（I)中所定義者，及樹脂是一載有Wang-連接基的聚苯乙烯樹脂。其步驟如以下實例中所述者。 _ 實例3 5 (—般程序（C )) (Z) - 3 - {4 — [2—（4 —環己基苯基）一 4 一氧—4 — (4 —三氟化甲氧基苯基）丁-2-烯醯基]苯甲醯胺基丨丙酸Where X, D, E, m, n and R4 are as defined in formula (I), and the resin is a polystyrene resin carrying a Wang-linking group. The steps are as described in the examples below. _ Example 3 5 (General procedure (C)) (Z)-3-{4 — [2- (4-cyclohexylphenyl)-4 monooxy-4 — (4-trifluoromethoxyphenyl ) But-2-enylamino] benzamidine amino propionate

200401634 步驟1 一步驟3 :製備樹脂鍵結的3-（4 一「2-（4 一環己基苯基）一 4 —氣一 4 一（4 一三氟化甲氧基苯基）丁醯1苯甲醯胺基丨丙酸此化合物依據一般程序（B)合成製得。步驟4和步驟5 :製備3-丨4 —「2-（4一環己基苯基ΙΑ—氧一 4 一（4 一三氟化甲氧基苯基）丁—2—烯醯 1苯甲醯胺基丨丙酸上述樹脂鍵結的3 - {4 一 [2 -（4 一環己基苯基）一 4 一氧一 4 — (4一三氟化甲氧基苯基）丁醯]苯甲醯胺基}丙酸（500毫克樹脂）懸浮於THF(10毫升）中，加入碘結晶物（344毫克， 1.35毫莫耳）及DBU(225微升）。在室溫下攪拌此懸浮液3.5 小時，及過濾出樹脂，及以THF(lxlO毫升），焦亞硫酸鈉 (2%水溶液）（1χ10 毫升），THF(2xlO 毫升），DCM(10xl0 毫升) 洗滌。再以50%TFA之DCM溶液（10毫升）處理此樹脂鍵結的3— {4 — [2 —（4 一環己基苯基）—4 一氧一4 一（4 一三氟化甲氧基苯基）丁-2-烯醯]苯甲醯胺基丨丙酸0.5小時，溫度爲 25°C，過濾混合物，及以DCM(10毫升）洗滌該樹脂。結合不同的濾液，及在真空下濃縮，可得一油狀物，再置於一矽膠管柱上層析純化，洗提劑爲DCM/甲醇/乙酸（95 : 4 : 1) ，可得3 - {4_[2—(4—環己基苯基）一 4 一氧一 4—(4 一三氟化甲氧基苯基）丁-2-烯醯]苯甲醯胺基}丙酸的E和Z混合物0 108 200401634 ^NMR^CDCy : 5 8.03—7.92(m，3H)，7.88—7.77(m，3H)，7.58 — 7.47(m，1H)，7.15(t，3H)，7.01(d，1H) ; 6.90—6.80(m，2H)，3.73(q，2H) ，2.72(t，2H)，2.37(m，1H)，1.78 —1.66(m，5H)，1.42—1.23(m，5H); HPLC—MS(方法 A) : m/z=594(M+l) ; Rt=5.44 分鐘。步驟：6(Z)—3-丨4—「2—(4—環己基苯基）一 4—氧—4 一（4-三氟化甲氣基苯基）-丁一 2—烯醯1苯甲醯胺某丨丙酸的製備將E和Z混合物重組反應爲Z-異構物可依據文獻記載（L Am. Chem. Soc.，75，5997 — 6002，1953)的修正方法完成。將3 — {4 — [2 — (4 —環己基苯基）—4_氧一 4 — (4 一二氯化甲氧基苯基）丁-2-烯醯]苯甲醯胺基}丙酸的E和Z混合物（155毫克，0.26毫莫耳）溶於甲苯（15毫升），加入濃 HC1(37%，3滴），及迴流加熱混合物1小時。蒸發移去溶劑，可得3 - {4 一 [2 -（4—環己基苯基）一 4_氧一 4 一（4—三氟化甲氧基苯基）-丁-2-烯醯]苯甲醯胺基丨丙酸的純Z—異構物。 WNMRCCDCIJ : 5 8.03(d，4H)，7.79(d，2H)，7.57(s，1H)，7.48(d， 2H)，7.30(d，2H) ; 7.24(d，2H)，6.84(t，1Η)，3Jl(q，2H)，2.70(t，2H)， 2.52(m，1H)，1.90—1.70(m，5H)，1.45 —1.17(m，5H) ; HPLC—MS(方法 A) :m/z=594(M+l) ; Rt=5.37 分鐘。微分析：C33H30F3N〇6，0.25H2〇的計算値： C，66.27% ; Η，5.14% ; N，2.34%。發現値： C，66.33% ; Η，5.20% ; N，2.57%。 109 200401634 實例3 6 (—般程序（C )) (Z) —3 - {4—[2 — (4 —環己基苯基）一 4 —氧一 4—(2，2 ，3，3—四氟一 2，3—二氫苯並[1，4]二氧芑一 6—基）丁一 2 —烯醯]苯甲醯胺基}丙酸200401634 Step 1 Step 3: Preparation of resin-bonded 3- (4-2-(4-cyclohexylphenyl)-4-gas-4-(4-trifluoromethoxyphenyl) butane 1 benzene Formamidine 丨 propionic acid This compound is prepared according to the general procedure (B). Step 4 and Step 5: Preparation 3- 丨 4- "2- (4-Cyclohexylphenyl IAA-O 4-(4-3 Fluorinated methoxyphenyl) But-2-ene-1-benzylamine 丨 propionic acid 3-{4-[2-(4-cyclohexylphenyl)-4-oxygen 4- (4-trifluoromethoxyphenyl) butyrazine] benzylamido} propionic acid (500 mg of resin) was suspended in THF (10 ml), and crystals of iodine (344 mg, 1.35 mmol) were added. And DBU (225 µl). The suspension was stirred at room temperature for 3.5 hours, and the resin was filtered off with THF (1 x 10 ml), sodium metabisulfite (2% aqueous solution) (1 x 10 ml), THF (2 x 10 ml), Wash with DCM (10xl0ml). Then treat this resin-bonded 3— {4 — [2 — (4-monocyclohexylphenyl) — 4 oxygen — 4 — (4 — 1) with 50% TFA in DCM (10 ml). Trifluoride Methoxyphenyl) but-2-enamidine] benzylamidopropionic acid for 0.5 hours at 25 ° C, the mixture was filtered, and the resin was washed with DCM (10 ml). The different filtrates were combined, and Concentrated under vacuum to obtain an oil, which was then purified by chromatography on a silica gel column. The eluent was DCM / methanol / acetic acid (95: 4: 1), and 3-{4_ [2— (4-Cyclohexylphenyl) -4,4-oxy-4,4- (4-trifluoromethoxyphenyl) but-2-enefluorene] benzylamino} propionate mixture of E and Z 0 108 200401634 ^ NMR ^ CDCy: 5 8.03-7.92 (m, 3H), 7.88-7.77 (m, 3H), 7.58-7.47 (m, 1H), 7.15 (t, 3H), 7.01 (d, 1H); 6.90-6.80 (m, 2H), 3.73 (q, 2H), 2.72 (t, 2H), 2.37 (m, 1H), 1.78—1.66 (m, 5H), 1.42-1.23 (m, 5H); HPLC-MS (Method A): m / z = 594 (M + 1); Rt = 5.44 minutes. Steps: 6 (Z) —3- 丨 4 -— “2- (4-cyclohexylphenyl) —4-oxy-4— ( 4-trifluoromethylaminophenyl) -butyr-2-ene-1benzylamine Preparation of a propionic acid The recombination of E and Z mixtures into Z-isomers can be documented (L Am. Chem. Soc., 75, 59 97 — 6002, 1953). Add 3 — {4 — [2 — (4-cyclohexylphenyl) — 4-oxo-4 — (4-dichloromethoxyphenyl) but-2-enyl}] benzylamino} propyl A mixture of acid E and Z (155 mg, 0.26 mmol) was dissolved in toluene (15 ml), concentrated HC1 (37%, 3 drops) was added, and the mixture was heated at reflux for 1 hour. The solvent was removed by evaporation, and 3-{4- [2- (4-cyclohexylphenyl) -4-oxy-4- (4-trifluoromethoxyphenyl) -but-2-enefluorene] was obtained. Pure Z-isomer of benzamidine and propionic acid. WNMRCCDCIJ: 5 8.03 (d, 4H), 7.79 (d, 2H), 7.57 (s, 1H), 7.48 (d, 2H), 7.30 (d, 2H); 7.24 (d, 2H), 6.84 (t, 1Η ), 3Jl (q, 2H), 2.70 (t, 2H), 2.52 (m, 1H), 1.90-1.70 (m, 5H), 1.45-1.17 (m, 5H); HPLC-MS (Method A): m / z = 594 (M + l); Rt = 5.37 minutes. Microanalysis: C33H30F3N06, 0.25H2O calculation: C, 66.27%; H, 5.14%; N, 2.34%.値: C, 66.33%; Η, 5.20%; N, 2.57%. 109 200401634 Example 3 6 (—general procedure (C)) (Z) —3-{4— [2 — (4-cyclohexylphenyl) —4—oxy—4— (2, 2, 3, 3—4 Fluoro-2,3-dihydrobenzo [1,4] dioxo-6-yl) butan-2-enyl] benzylamino} propanoic acid

E和Z混合物的數據，由一般步驟（C)步驟5所產生： iHNMRCCDCy ·· 5 8.01-7.92(m，2H)，7.83—7.45(m，6H)，7.26 — 7.00(m，3H)，6.94(brt，1H)，3.71(q，2H)，2.70(q，2H)，2.52(m，1H)， 1.88 —1.67(m，5H)，1.45 —1.17(m，5H)。標題化合物的數據： iHNMRCCDClD : 57.98(brd，2H)，7.88 — 7.70(m，4H)，7.50(t，3H) ，7.18(d，1H)，6.84(brs，1H)，3.71(brs，2H)，2.70(brs，2H)，2.52(m， 1H)，1_90 — 1.70(m，5H)，1·45 —1.15(m，5H)。實例3 7 (—般程序（C )) (Z) — 3—{4— [4 一（3，5 -雙三贏化甲基苯基）一 2—（4 一環己基苯基）- 4 -氧丁- 2-烯醯]苯甲醯胺基丨丙酸 110 200401634The data of the mixture of E and Z are generated by step 5 of general step (C): iHNMRCCDCy ·· 5 8.01-7.92 (m, 2H), 7.83-7.45 (m, 6H), 7.26-7.00 (m, 3H), 6.94 (brt, 1H), 3.71 (q, 2H), 2.70 (q, 2H), 2.52 (m, 1H), 1.88-1.67 (m, 5H), 1.45-1.17 (m, 5H). Data for the title compound: iHNMRCCDClD: 57.98 (brd, 2H), 7.88 — 7.70 (m, 4H), 7.50 (t, 3H), 7.18 (d, 1H), 6.84 (brs, 1H), 3.71 (brs, 2H) , 2.70 (brs, 2H), 2.52 (m, 1H), 1_90 — 1.70 (m, 5H), 1.45 — 1.15 (m, 5H). Example 3 7 (—general procedure (C)) (Z) — 3— {4— [4 one (3,5-bis-trimethylated methylphenyl)-2-(4-cyclohexylphenyl)-4- Oxetane-2-enefluorene] benzylamine 丨 propionic acid 110 200401634

^NMRCCDCy : 58.40(s，2H)，8.07(s，1H)，8.00(d，2H)，7.81(d， 2H)，7.58(s，1H)，7.52(d，2H)，7.29(d，2H)，6.93(brs，1H)，3.72(q，2H) ，2.69(t，2H)，2.52(m，1H)，1·90—1.72(m，5H)，1.48 —1.25(m，5H)。實例3 8 ( —般程序（C )) (Z)_ 3 — {4 一 [4一（3，5—雙（三氟化甲基）苯基）一2 — [2 ，2’]二苯硫基—5-基一 4 一氧丁一 2-烯醯]苯甲醯胺基}丙酸^ NMRCCDCy: 58.40 (s, 2H), 8.07 (s, 1H), 8.00 (d, 2H), 7.81 (d, 2H), 7.58 (s, 1H), 7.52 (d, 2H), 7.29 (d, 2H ), 6.93 (brs, 1H), 3.72 (q, 2H), 2.69 (t, 2H), 2.52 (m, 1H), 1.90 to 1.72 (m, 5H), 1.48 to 1.25 (m, 5H). Example 3 8 (-General procedure (C)) (Z) _ 3 — {4 mono [4-mono (3,5-bis (trifluoromethyl) phenyl)-2- [2,2 '] diphenyl Thio-5-yl-4 dioxetane-2-enefluorene] benzamidine amino} propionic acid

iHNMRCCDCy : 58.38(s，2H)，8.07(s，1H)，8.05(d，2H)，7.85(d， 2H)，7.38—7.32(m，2H)，7.18(d，2H)，7.12-7.05(m，2H)，6.84(brt，1H) ，3.74(ci，2H)，2.70(t，2H)。實例3 9 (—般程序（C )) (Z)_ 3 - {4一 [2 — (4-溴化苯硫—2-基）一 4 —氧一 4 — (4 一三氟化甲氧基苯基）丁- 2-烯醯]苯甲醯胺基}丙酸 111 200401634iHNMRCCDCy: 58.38 (s, 2H), 8.07 (s, 1H), 8.05 (d, 2H), 7.85 (d, 2H), 7.38-7.32 (m, 2H), 7.18 (d, 2H), 7.12-7.05 ( m, 2H), 6.84 (brt, 1H), 3.74 (ci, 2H), 2.70 (t, 2H). Example 3 9 (—General Procedure (C)) (Z) _ 3-{4— [2 — (4-Bromophenylsulfan-2-yl) —4—Oxygen 4— (4—Trifluoromethane Phenyl) butyl-2-enefluorene] benzamidine amino} propionic acid 111 200401634

^NMRCCDCy : (5 8.03(d，2H)，7.99(d，2H)，7.84(d，3H)，7.47(s， 1H)，7.38(s，1H)，7.31(s，1H)，7.02(s，1H)，6.84(m，1H)，3.74(q，2H)， 2.72(t，2H)。實例4 0 (—般程序（C )) (Z)— 3 - {4 — [2 — (4 —環己基苯基）—4 一氧—4 一（3 —三氟化甲氧基苯基）丁-2 -烯醯]苯甲醯胺基}丙酸^ NMRCCDCy: (5 8.03 (d, 2H), 7.99 (d, 2H), 7.84 (d, 3H), 7.47 (s, 1H), 7.38 (s, 1H), 7.31 (s, 1H), 7.02 (s , 1H), 6.84 (m, 1H), 3.74 (q, 2H), 2.72 (t, 2H). Example 4 0 (—general procedure (C)) (Z) — 3-{4 — [2 — (4 —Cyclohexylphenyl) -4 monooxy-4 mono (3-trifluoromethoxyphenyl) but-2-enene] benzylamino} propanoic acid

iHNMRCCDCU) : 58.01(d，2H)，7.90(d，1H)，7.80(d和 s，3H)， 7.58—7.38(m，5H)，7.22(s，1H)，7.28(d，1H)，6.82(brs，1H)，3.74(brs， 2H)，2.70(brs，2H)，2.53(brm，1H)，1.90—1.70(m，5H)，1.47 —1.20(m， 5H)。iHNMRCCDCU): 58.01 (d, 2H), 7.90 (d, 1H), 7.80 (d and s, 3H), 7.58-7.38 (m, 5H), 7.22 (s, 1H), 7.28 (d, 1H), 6.82 (brs, 1H), 3.74 (brs, 2H), 2.70 (brs, 2H), 2.53 (brm, 1H), 1.90-1.70 (m, 5H), 1.47-1.20 (m, 5H).

實例4 1 ( 一般程序（C )) (Z)—3— {4 — [2 -（4 一環己基苯基）一 4 —氧一 4 一（4 一三氟化甲基磺胺基苯基）丁- 2 -烯醯]苯甲醯胺基丨丙酸 112 200401634Example 4 1 (General Procedure (C)) (Z) —3— {4 — [2-(4-Cyclohexylphenyl) -4-Oxy-4— (4-Cyclomethylsulfonylphenyl) butane -2 -ene fluorene] benzamidine 丨 propionic acid 112 200401634

WNMRCCDCIJ : 5 8.02(d，2H)，7.98(d，2H)，7.80(d，2H)，7.73(d ，2H)，7.58(s，1H)，7.49(d，2H)，7.26(d，2H)，6.78(brt，1H)，3.73(q， 2H)，2.72(t，2H)，2.53(brm，1H)，1.90—1.70(m，5H)，1.46—1.25(m，WNMRCCDCIJ: 5 8.02 (d, 2H), 7.98 (d, 2H), 7.80 (d, 2H), 7.73 (d, 2H), 7.58 (s, 1H), 7.49 (d, 2H), 7.26 (d, 2H ), 6.78 (brt, 1H), 3.73 (q, 2H), 2.72 (t, 2H), 2.53 (brm, 1H), 1.90-1.70 (m, 5H), 1.46-1.25 (m,

5H) ; HPLC—MS(方法 B) : m/z=610(M+l) ; Rt=5.63 分鐘。實例4 2 ( —般程序（C )) (Z) - 3 — {4 一 [4 —二苯基一 4 一基—2 — (4-環己基苯基) 一 4 一氧丁一 2 -烯醯]苯甲醯胺基}丙酸5H); HPLC-MS (Method B): m / z = 610 (M + 1); Rt = 5.63 minutes. Example 4 2 (General Procedure (C)) (Z)-3 — {4 mono [4-diphenyl-4 4-yl-2 — (4-cyclohexylphenyl) 4-dioxetane 2-ene醯] benzylamino} propionic acid

WNMI^DMSO — c^) : (51.20—1·45(5Η，m)，1.65 — 1·85(5Η，m)， 2.48(低於 DMS〇訊號），3·45(2Η，q)，7.33(2H，d)，7.45(1H，d)，7·51(2Η， d)，7·61(2Η，d)，7·77(2Η，d)，7·87(4Η，dd)，7·95(1Η，d)，8·22(2Η，d)， 8·66(1Η，t)，12.20(1H，br) ; HPLC—MS(方法 C) : m/z=586(M+l) ; Rt=8.03 分鐘。實例4 3 ( —般程序（C )) (Z) — 3 — {4 — [4 -（2 —氯化苯基）一 2 -（4一環己基苯基）一 4一氧丁一 2-烯醯]苯甲醯胺基}丙酸 113 200401634WNMI ^ DMSO — c ^): (51.20—1.45 (5Η, m), 1.65 — 1.85 (5Η, m), 2.48 (less than DMS0 signal), 3.45 (2Η, q), 7.33 (2H, d), 7.45 (1H, d), 7.51 (2Η, d), 7.61 (2Η, d), 7.77 (2Η, d), 7.87 (4Η, dd), 7 · 95 (1Η, d), 8.22 (2Η, d), 8.66 (1Η, t), 12.20 (1H, br); HPLC-MS (Method C): m / z = 586 (M + l ); Rt = 8.03 minutes. Example 4 3 (General procedure (C)) (Z) — 3 — {4 — [4-(2-Chlorophenyl)-2-(4-Cyclohexylphenyl)-4 Dioxobutene-2-enefluorene] benzylamido} propionic acid 113 200401634

】HNMR(DMSO—d6) : 5 1.15 —1·42(5Η，m)，1.65 —1·80(5Η，m)， 3·46(2Η，q)，7.31(ffi，d)，7·48(1Η，d)，7·52(2Η，d)，7·59(2Η，d)， 7·68(1Η，d)，7·91(2Η，d)，7.98(2H，d)，8.69(1H，t)，12·23(1Η，bs); HPLC—MS(方法 C) : m/z=544(M+l) ; Rt=7.33 分鐘。實例4 4 (一般程序（C )) (Z) - 3 — {4一 [2—（4 —環己基苯基）一 4 —氧—4一（2- 氣化甲基苯基）丁- 2 -烯醯]苯甲醯胺基}丙酸] HNMR (DMSO-d6): 5 1.15-1 · 42 (5Η, m), 1.65-1 · 80 (5Η, m), 3.46 (2Η, q), 7.31 (ffi, d), 7.48 (1Η, d), 7.52 (2Η, d), 7.59 (2 (, d), 7.68 (1Η, d), 7.91 (2Η, d), 7.98 (2H, d), 8.69 (1H, t), 12 · 23 (1Η, bs); HPLC-MS (Method C): m / z = 544 (M + 1); Rt = 7.33 minutes. Example 4 4 (General Procedure (C)) (Z)-3 — {4-a [2- (4-cyclohexylphenyl) -4-oxy-4- (2-gasified methylphenyl) butane-2 -Ene 醯] benzamidine amino} propionic acid

^NMIUPMSO-dJ : 51.15 —1·45(5Η，m)，1.60 — 1.85(5H，m)， 3.47(2H，Q)，7.31(2H，d)，7.55(3H，m)，7.74(lH，d)，7.85(2H，d)，7.90— 8.05(4H，dd)，8·70(1Η，t)，12·23(1Η，bs) ; HPLC—MS(方法 C): m/z=578(M+l) ; Rt=7.43 分鐘。實例4 5 ( —般程序（C )) (Z) - 3 — {4 — [4 — (4-叔一丁基苯基）一 2 一（4一環己基苯基）一 4 一氧丁一 2 —烯醯]苯甲醯胺基）丙酸 114 200401634^ NMIUPMSO-dJ: 51.15 —1.45 (5Η, m), 1.60 — 1.85 (5H, m), 3.47 (2H, Q), 7.31 (2H, d), 7.55 (3H, m), 7.74 (lH, d), 7.85 (2H, d), 7.90-8.05 (4H, dd), 8.70 (1Η, t), 12.23 (1Η, bs); HPLC-MS (Method C): m / z = 578 (M + 1); Rt = 7.43 minutes. Example 4 5 (-General procedure (C)) (Z)-3 — {4 — [4 — (4-tert-butylbutyl)) 2-(4-cyclohexylphenyl)-4-oxetane-2 —Ene 醯] benzylamido) propionic acid 114 200401634

iHNMF^DMSO-dJ : 51.20—1·45(5Η，m)，1·31(9Η，s)，1.65 — 1·85(5Η，m)，3·46(2Η，q)，7·32(2Η，d)，7·57(4Η，m)，7·88(2Η，d)， 7·92(2Η，d)，8·05(2Η，m)，8·65(1Η，t)，12·23(1Η，bs) ; HPLC—MS(方法 C) : m/z=566(M+l) ; Rt:8.17 分鐘。實例4 6 ( —般程序（C )) (Z) - 3— {4 — [2 — (4-環己基苯基）一 4 一氧一 4 — (4 —苯氧基苯基）丁一 2-烯醯]苯甲醯胺基丨丙酸iHNMF ^ DMSO-dJ: 51.20-1.45 (5Η, m), 1.31 (9Η, s), 1.65-1.85 (5Η, m), 3.46 (2Η, q), 7.32 ( 2Η, d), 7.57 (4Η, m), 7.88 (2Η, d), 7.92 (2Η, d), 8.05 (2Η, m), 8.65 (1Η, t), 12 · 23 (1Η, bs); HPLC-MS (Method C): m / z = 566 (M + 1); Rt: 8.17 minutes. Example 4 6 (— General Procedure (C)) (Z)-3 — {4 — [2 — (4-cyclohexylphenyl) —4—oxy-4— (4-phenoxyphenyl) —butan-2 -Ene 醯] benzamidine aminopropionic acid

WNMRpMSO—d6) : (Π.15 —1.50(5H，m)，1.65 —1.90(5H，m)， 3.46(2Η，q)，7·05(2Η，d)，7·16(2Η，d)，7·31(3Η，m)，7·47(2Η，d)， 7·59(2Η，d)，7·85 —8·00(4Η，m)，8·17(2Η，d)，8·66(1Η，t)，12·25(1Η，bs) ;HPLC—MS(方法 C) : m/z=602(M+l) ; Rt=7.90 分鐘。實例4 7 ( —般程序（C )) (Z)—3— {4 — [2 -（4 一叔—丁基苯基）—4 一氧一 4 — (4 — 三氟化甲氧基苯基）丁-2 -烯醯]苯甲醯胺基}丙酸 115 200401634WNMRpMSO-d6): (Π.15 —1.50 (5H, m), 1.65 —1.90 (5H, m), 3.46 (2Η, q), 7.05 (2Η, d), 7.16 (2Η, d) , 7.31 (3Η, m), 7.47 (2Η, d), 7.59 (2Η, d), 7.85-8.00 (4Η, m), 8.17 (2Η, d), 8.66 (1Η, t), 12.25 (1Η, bs); HPLC-MS (method C): m / z = 602 (M + l); Rt = 7.90 minutes. Example 4 7 (General procedure ( C)) (Z) —3— {4 — [2-(4-t-tert-butylphenyl) -4 4-oxo-4— (4-trifluoromethoxyphenyl) but-2-enene ] Benzamidineamino} propionic acid 115 200401634

^NMR^DMSO —d6) ·· 5 8.70(t，1H)，8.26(d，2H)，8.0—7.9(m，5H) ，7.61(d，2H)，7.5(m，3H)，1.28(s，9H) ; HPLC—MS(方法 A): m/z=568(M+l) ; Rt=5.21 分鐘。實例4 8 ( —般程序（C )) (Z) - 3 — {4 - [4 —氧—2 -（4 —苯氧基苯基）一 4—(4 —二氟化甲氧基苯基）丁- 2-烯醯]苯甲醯胺基}丙酸^ NMR ^ DMSO —d6) 5 8.70 (t, 1H), 8.26 (d, 2H), 8.0-7.9 (m, 5H), 7.61 (d, 2H), 7.5 (m, 3H), 1.28 (s , 9H); HPLC-MS (Method A): m / z = 568 (M + 1); Rt = 5.21 minutes. Example 4 8 (-General procedure (C)) (Z)-3 — {4-[4-oxy-2-(4-phenoxyphenyl)-4- (4-difluoromethoxyphenyl) ) But-2-enofluorenyl] benzamidine amino} propionic acid

HPLC—MS(方法 A) : m/z=604(M+l) ; Rt=5.07 分鐘。實例4 9 (一般程序（C )) (Z)—3_ {4 - [4 —氧一 2 — (3—苯氧基苯基）—4 — (4 —三氟化甲氧基苯基）丁- 2-烯醯]苯甲醯胺基}丙酸HPLC-MS (Method A): m / z = 604 (M + 1); Rt = 5.07 minutes. Example 4 9 (General Procedure (C)) (Z) —3_ {4-[4-Oxy-2 — (3-Phenoxyphenyl) — 4 — (4-Trifluoromethoxyphenyl) Butadiene -2-enefluorene] benzylamido} propionic acid

200401634 WNMRCCDPD) : 5 8.16(d，2H)，7.98(d，2H)，7.86(m，3H)，7.4(m ，4H)，7.34(m，2H)，7.25(s，1H)，7.15—7.05(m，2H)，6_94(d，2H)， 3.65(m，2H)，2.65(m，2H) ; HPLC—MS(方法 A) : m/z=604(M+l) ; Rt=5.06 分鐘。實例5 0 (—般程序（C)) (Z) —3 —{4—[2—(4 —苯甲氧基苯基)一4—氧一4 —(4 一三氟甲氧基苯基)—丁—2-烯醯]苯甲醯胺基}丙酸200401634 WNMRCCDPD): 5 8.16 (d, 2H), 7.98 (d, 2H), 7.86 (m, 3H), 7.4 (m, 4H), 7.34 (m, 2H), 7.25 (s, 1H), 7.15-7.05 (m, 2H), 6-94 (d, 2H), 3.65 (m, 2H), 2.65 (m, 2H); HPLC-MS (Method A): m / z = 604 (M + 1); Rt = 5.06 minutes . Example 5 0 (—General Procedure (C)) (Z) —3 — {4— [2— (4-benzyloxyphenyl) —4-oxo-4— (4-trifluoromethoxyphenyl ) -But-2-enefluorenyl] benzylamino} propanoic acid

HPLC—MS(方法 A) : m/z=618(M+l) ; Rt=5.00 分鐘。實例5 1 (—般程序（C ) ) · (Z) — 3— {4 — [4 —氧—2，4一雙—（4一二氣化甲氧基苯基）丁-2 -烯醯]苯甲醯胺基}丙酸HPLC-MS (Method A): m / z = 618 (M + 1); Rt = 5.00 minutes. Example 5 1 (—General Procedure (C)) · (Z) — 3— {4 — [4 —Oxygen-2,4—Bis— (4-digasified methoxyphenyl) but-2-enene) ] Benzamidine amino} propionic acid

117 200401634 'HNMR^CDsOD) : 5 8.18(d，2H)，8.00(d，2H)，7.93(s，1H)，7.85(d ，2H)，7.79(d，2H)，7.42(d，2H)，7.36(d，2H)，3.62(t，2H)，2.63(t，2H) ;HPLC—MS(方法 A) : m/z=596(M+l) ; Rt=4.90 分鐘。實例5 2 (—般程序（C )) (Z)—3 — {4—[2 -（4 一環己基苯基）—4 一（3，4一一氯化苯基）- 4 —氧丁-2 -烯醯]苯甲醯胺基}丙酸117 200401634 'HNMR ^ CDsOD): 5 8.18 (d, 2H), 8.00 (d, 2H), 7.93 (s, 1H), 7.85 (d, 2H), 7.79 (d, 2H), 7.42 (d, 2H) , 7.36 (d, 2H), 3.62 (t, 2H), 2.63 (t, 2H); HPLC-MS (Method A): m / z = 596 (M + 1); Rt = 4.90 minutes. Example 5 2 (General Procedure (C)) (Z) —3 — {4— [2-(4-Cyclohexylphenyl) -4— (3,4—Chlorophenyl) —4-O-butane— 2-enefluorene] benzylamido} propionic acid

HPLC—MS(方法 A) : m/z=546(M+l) ; Rt=5.25 分鐘。HPLC-MS (Method A): m / z = 546 (M + 1); Rt = 5.25 minutes.

實例5 3 (—般程序（C )) (Z)—3 — {4 — [2 -二苯基一4 —基—4—氧一 4 一（4 一三氟化甲氧基苯基）丁- 2 -烯醯]苯甲醯胺基}丙酸Example 5 3 (—General Procedure (C)) (Z) —3 — {4 — [2-diphenyl-4—yl-4—oxy-4—4- (4-trifluoromethoxyphenyl) butane -2 -ene 醯] benzylamido} propionic acid

^NMRPMSO —d6) : 512.2(bs，1H)，8.69(t，1H)，8.30(d，2H)， 118 200401634 8.15(s，1Η)，7.99(d，2H)，7.90(d，2H)，7.73(d，2H)，7.4-7.55(m，8H)， 3.46(m，2H) ; HPLC—MS(方法 A) : m/z=588(M+l) ; Rt=5.08 分鐘。實例5 4 (—般程序（C )) (Z) 一 3 — {4—[2 — —^ 苯基—4 —基—4 —氧一 4 一（2，2，3 ，3 —四氟一 2, 3—二氫苯並[1，4]二氧芑一6—基）丁— 2 — 烯醯]苯甲醯胺基}丙酸^ NMRPMSO-d6): 512.2 (bs, 1H), 8.69 (t, 1H), 8.30 (d, 2H), 118 200401634 8.15 (s, 1Η), 7.99 (d, 2H), 7.90 (d, 2H), 7.73 (d, 2H), 7.4-7.55 (m, 8H), 3.46 (m, 2H); HPLC-MS (Method A): m / z = 588 (M + 1); Rt = 5.08 minutes. Example 5 4 (-General procedure (C)) (Z)-3 — {4— [2 — — ^ Phenyl-4 —yl — 4 —oxyl 4 1 (2, 2, 3, 3 — tetrafluoroa 2,3-dihydrobenzo [1,4] dioxo-6-yl) but-2- 2-enefluorene] benzamidinylamino} propionic acid

iHNMRCCDCy : 58.00(d，2H)，7.85 —7.75(m，3H)，7.63 —7.35(m ，10H)，7.23(d，1Η)，7.18(d，1H)，6.88(t，1H)，3J1(q，2H) ; 2.70(t，2H) ;HPLC—MS(方法 A) : m/z=634(M+l) ; Rt=5.07 分鐘。實例5 5 (—般程序（C )) (Z) — 3 — {4 - [4 — (4 一環己基苯基）一 4 —氧—2 — (4 —三氟化甲氧基苯基）丁- 2 -烯醯]苯甲醯胺基}丙酸 119 200401634iHNMRCCDCy: 58.00 (d, 2H), 7.85—7.75 (m, 3H), 7.63—7.35 (m, 10H), 7.23 (d, 1Η), 7.18 (d, 1H), 6.88 (t, 1H), 3J1 ( q, 2H); 2.70 (t, 2H); HPLC-MS (method A): m / z = 634 (M + 1); Rt = 5.07 minutes. Example 5 5 (—General Procedure (C)) (Z) — 3 — {4-[4 — (4-Cyclohexylphenyl) — 4 —Oxygen 2 — (4 —Trifluoromethoxyphenyl) Butyl -2 -ene} benzamidine} propanoic acid 119 200401634

iHNMRCCDCL) : 57.99(d，2H)，7.90(d，2H)，7.79(d，2H)，7.62(d ，2H)，7.30(d，2H)，7.23(d，2H)，6.82(brt，1H)，3.71(q，2H) ; 2.70(t， 2H)，2.57(brm，1H)，1.90—1.70(m，5H)，1.45 —1.20(m，5H) ; HPLC—MS( 方法 A) : m/z=594(M+l) ; Rt=5.45 分鐘。實例5 6 (—般程序（C )) (Z) — 3 — {4 — [4 —苯並[1，3]二氧醇—5 —基一 2 — (4 — 環己基苯基）- 4 -氧丁一 2-烯醯]苯甲醯胺基}丙酸iHNMRCCDCL): 57.99 (d, 2H), 7.90 (d, 2H), 7.79 (d, 2H), 7.62 (d, 2H), 7.30 (d, 2H), 7.23 (d, 2H), 6.82 (brt, 1H ), 3.71 (q, 2H); 2.70 (t, 2H), 2.57 (brm, 1H), 1.90-1.70 (m, 5H), 1.45-1.20 (m, 5H); HPLC-MS (Method A): m / z = 594 (M + l); Rt = 5.45 minutes. Example 5 6 (-General procedure (C)) (Z) — 3 — {4 — [4 —benzo [1,3] dioxanol-5 —yl — 2 — (4 —cyclohexylphenyl) — 4 -Oxetane-2-enefluorene] benzamidine amino} propionic acid

^NMRCCDCIJ : (Π.10 —1.45(m，5H)，1.67 —1.90(m，5H)，2.46(m ，1H)，2.64(t，2H)，3.70(q，2H)，6.03(s，2H)，6.84(brs，1H)，7.08(d， 2H)，7.19(d，2H)，7.40(s，1H)，7.47(d，1H)，7.56(s，1H)，7.69(d，1H)， 7.74(d，2H)，8.03(d，2H) ; HPLC-MS(方法 A) ·· m/z=554(M+l) ; Rt=4.95 分鐘。實例5 7 (—般程序（C )) 120 200401634 (Z) - 3— {4 - [2 — (4—環己基苯基）一 4一（4一異丙基苯基）一 4一氧丁一 2 -烯醯]苯甲醯胺基}丙酸^ NMRCCDCIJ: (Π.10 —1.45 (m, 5H), 1.67 —1.90 (m, 5H), 2.46 (m, 1H), 2.64 (t, 2H), 3.70 (q, 2H), 6.03 (s, 2H ), 6.84 (brs, 1H), 7.08 (d, 2H), 7.19 (d, 2H), 7.40 (s, 1H), 7.47 (d, 1H), 7.56 (s, 1H), 7.69 (d, 1H) , 7.74 (d, 2H), 8.03 (d, 2H); HPLC-MS (Method A) ·· m / z = 554 (M + 1); Rt = 4.95 minutes. Example 5 7 (General procedure (C) ) 120 200401634 (Z)-3— {4-[2 — (4-cyclohexylphenyl) -4- (4-isopropylphenyl) -4-oxobut-2-enophene] benzidine Propyl

WNMRCCDCy : 51.14—1.45(m，5H)，1.25(d，6H)，1.66—1.95(m ，5H)，2.50(m，1H)，2.65(t，2H)，2.95(m，1H)，3.67(q，2H)，6.95(br s， 1H)，7.13—7.34(m，4H)，7.47(d，2H)，7.62(s，1H)，7.74(d，2H)，7.89(d， 2H)，7.97(d，2H) ; HPLC—MS(方法 A) : m/z=552(M+l) ; Rt=5.82 分鐘。實例5 8 (—般程序（C )) (Z) - 3— {4 — [2, 4 —雙—（4 —環己基苯基）一 4 一氧丁一 2 —烯醯]苯甲醯胺基}丙酸WNMRCCDCy: 51.14—1.45 (m, 5H), 1.25 (d, 6H), 1.66—1.95 (m, 5H), 2.50 (m, 1H), 2.65 (t, 2H), 2.95 (m, 1H), 3.67 ( q, 2H), 6.95 (br s, 1H), 7.13-7.34 (m, 4H), 7.47 (d, 2H), 7.62 (s, 1H), 7.74 (d, 2H), 7.89 (d, 2H), 7.97 (d, 2H); HPLC-MS (method A): m / z = 552 (M + 1); Rt = 5.82 minutes. Example 5 8 (General Procedure (C)) (Z)-3— {4 — [2, 4 —bis— (4-cyclohexylphenyl) —4—oxobutane—2—ene}] benzamide Propyl

屯厕11仰03) : 5 1.08 —1.50(m，10H)，1.67 —1.95(m，10H)，Tuen 11 Yang 03): 5 1.08 —1.50 (m, 10H), 1.67 —1.95 (m, 10H),

2.54(m，2H)，2.65(t，2H)，3.67(q，2H)，7.00(brs，1H)，7·12—7.34(m，4H) ，7.47(d，2H)，7.63(s，1H)，7.75(d，2H)，7.89(d，2H)，7.98(d，2H); HPLC—MS(方法 A) : m/z=592(M+l) ; Rt=6.13 分鐘。 121 200401634 實例5 9 (—般程序（C )) (Z) — 3 — {4 — [2 — (4-環己基苯基）—4 — (3，5 —二氯化苯基）一 4一氧丁一 2 -烯醯]苯甲醯胺基}丙酸2.54 (m, 2H), 2.65 (t, 2H), 3.67 (q, 2H), 7.00 (brs, 1H), 7.12-7.34 (m, 4H), 7.47 (d, 2H), 7.63 (s, 1H), 7.75 (d, 2H), 7.89 (d, 2H), 7.98 (d, 2H); HPLC-MS (Method A): m / z = 592 (M + 1); Rt = 6.13 minutes. 121 200401634 Example 5 9 (—General Procedure (C)) (Z) — 3 — {4 — [2 — (4-cyclohexylphenyl) — 4 — (3,5 —dichlorophenyl) — 4 — Oxetane-2-enefluorene] benzylamido} propionic acid

^NMRCCDCID : 51.18—1.48(m，5H)，1.65 —1.94(m，5H)，2.50(m ，1Η)，2.66(t，2H)，3.67(q，2H)，6.94(brs，1H)，7.15(d，2H)，7.22(d， 2H)，7.49(m，3H)，7.86(m，3H)，7.94(d，2H) ; HPLC—MS(方法 A): m/z=578(M+l) ; Rt=5.60 分鐘。實例6 0 (—般程序（C )) (Z)—3 — {4 — [4 一（4 —異丁基苯基）一 4 一氧—2 -（4 一三氟化甲氧基苯基）丁- 2 -烯醯]苯甲醯胺基}丙酸^ NMRCCDCID: 51.18—1.48 (m, 5H), 1.65—1.94 (m, 5H), 2.50 (m, 1Η), 2.66 (t, 2H), 3.67 (q, 2H), 6.94 (brs, 1H), 7.15 (d, 2H), 7.22 (d, 2H), 7.49 (m, 3H), 7.86 (m, 3H), 7.94 (d, 2H); HPLC-MS (Method A): m / z = 578 (M + l); Rt = 5.60 minutes. Example 6 0 (—general procedure (C)) (Z) —3 — {4 — [4 mono (4-isobutylphenyl) -4 monooxy-2-(4-trifluoromethoxyphenyl ) But-2-ylene] benzamidine amino} propionic acid

HO 〇HO 〇

CH3 ^NME^CDCIJ : 50.90(d，6H)，1.88(m，1H)，2.54(d，2H)，2.69(t ，2H)，3.70(q，2H)，6.86(brs，1H)，7.24(m，4H)，7.62(m，3H)，7.78(d， 2H)，7.87(d，2H)，7.99(d，2H) ; HPLC—MS(方法 A) : m/z=568(M+l); Rt=6.03 分鐘。 122 200401634 實例61(—般程序（C)) (Z) — 3 — {4 - [4 一（4 一環戊基苯基）—4 —氧一 2 — (4 —三氟化甲氧基苯基）丁- 2 -烯醯]苯甲醯胺基}丙酸CH3 ^ NME ^ CDCIJ: 50.90 (d, 6H), 1.88 (m, 1H), 2.54 (d, 2H), 2.69 (t, 2H), 3.70 (q, 2H), 6.86 (brs, 1H), 7.24 ( m, 4H), 7.62 (m, 3H), 7.78 (d, 2H), 7.87 (d, 2H), 7.99 (d, 2H); HPLC-MS (Method A): m / z = 568 (M + l ); Rt = 6.03 minutes. 122 200401634 Example 61 (General Procedure (C)) (Z) — 3 — {4-[4 Mono (4-Cyclopentylphenyl) — 4 —Oxy 2 — (4 —Trifluoromethoxyphenyl ) But-2-ylene] benzamidine amino} propionic acid

^NMRCCDCy · 51.48 —1.89(m 5 6H) 5 1.99—2.15(m j 2H) 5 2.69(t 5 2H)，3.04(m，1H)，3.70((1，2H)，6.90(br s，1H)，7.20(d，2H)，7.32(d，2H) ，7.62(m，3H)，7.79(d，2H)，7.88(d，2H)，7.99(d，2H) ; HPLC—MS(方法 A) : m/z=580(M+l) ; Rt=5.08 分鐘。實例6 2 (—般程序（C )) (Z)—3 — {4 — [4 一氧一4 一苯基一 2 —（4—三氟化甲氧基苯基）丁一 2—烯醯]苯甲醯胺基}丙酸^ NMRCCDCy · 51.48 —1.89 (m 5 6H) 5 1.99—2.15 (mj 2H) 5 2.69 (t 5 2H), 3.04 (m, 1H), 3.70 ((1, 2H), 6.90 (br s, 1H), 7.20 (d, 2H), 7.32 (d, 2H), 7.62 (m, 3H), 7.79 (d, 2H), 7.88 (d, 2H), 7.99 (d, 2H); HPLC-MS (Method A): m / z = 580 (M + l); Rt = 5.08 minutes. Example 6 2 (—general procedure (C)) (Z) —3 — {4 — [4 monooxo-4 monophenyl — 2 — (4 —Trifluoromethoxyphenyl) butane-2-enefluorene] benzamidinylamino} propanoic acid

^NMRCCDCy : 52.71(t，2H)，3.73(q，2H)，6.87(brs，1H)，7.15(d ，2H)，7.23(d，2H)，7.47(d，2H)，7.64(m，3H)，7.83(d，2H)，8.00(m， 3H) ; HPLC—MS(方法 A) : m/z=512(M+l) ; Rt=5.09 分鐘。實例6 3 (—般程序（C )) 123 200401634 (Z) 一 3 一 {4 一 [4 一氧一 4 一 p —甲苯基一 2 —（4 一二氣化甲氧基苯基）丁-2-烯醯]苯甲醯胺基}丙酸^ NMRCCDCy: 52.71 (t, 2H), 3.73 (q, 2H), 6.87 (brs, 1H), 7.15 (d, 2H), 7.23 (d, 2H), 7.47 (d, 2H), 7.64 (m, 3H ), 7.83 (d, 2H), 8.00 (m, 3H); HPLC-MS (Method A): m / z = 512 (M + 1); Rt = 5.09 minutes. Example 6 3 (-General procedure (C)) 123 200401634 (Z)-3-{4-[4-oxygen-4-p -tolyl-2-(4-digasified methoxyphenyl) butyl- 2-enefluorene] benzylamido} propionic acid

^NMRCCDCU) : 52.44(s，3H)，2.69(t，2H)，3.74(q，2H)，6.96(brs ，1Η)，7.16(d，2H)，7.25(d，2H)，7.63(m，3H)，7.79(d，2H)，7.88(d，2H) ，8.00(d，2H) ; HPLC—MS(方法 A) : m/z=526(M+l) ; Rt=5.26 分鐘。實例6 4 (—般程序（C )) (Z) — 3 — {4 - [4 一（4 —甲氧基苯基）一 4 一氧一 2—（4 —二氟化甲氧基苯基）丁-2-烯醯]苯甲醯胺基}丙酸NMRCCDCU): 52.44 (s, 3H), 2.69 (t, 2H), 3.74 (q, 2H), 6.96 (brs, 1), 7.16 (d, 2H), 7.25 (d, 2H), 7.63 (m, 3H), 7.79 (d, 2H), 7.88 (d, 2H), 8.00 (d, 2H); HPLC-MS (Method A): m / z = 526 (M + 1); Rt = 5.26 minutes. Example 6 4 (—General Procedure (C)) (Z) — 3 — {4-[4 mono (4-methoxyphenyl)-4 monooxy-2— (4-difluoromethoxyphenyl) ) But-2-enefluorene] benzamidine amino} propionic acid

eNMRCCDClJ : 52.70(t，2H)，3.73(q，2H)，3.88(s，3H)，6.96(brs ，1H)，7.16(d，2H)，7.24(d，2H)，7.65(m，3H)，7.80(d，2H)，8.00(m， 4H) ; HPLC—MS(方法 A) : m/z=542(M+l) ; Rt=5.09 分鐘。實例6 5 (—般程序（C )) (Z) — 3 - {4 一 [2 — [4 — (2，2-二甲基丙基）苯基]—4 — 氧一 4一（4一三氟化甲氧基苯基）丁-2—烯醯]苯甲醯胺基} 124 200401634 丙酸eNMRCCDClJ: 52.70 (t, 2H), 3.73 (q, 2H), 3.88 (s, 3H), 6.96 (brs, 1H), 7.16 (d, 2H), 7.24 (d, 2H), 7.65 (m, 3H) , 7.80 (d, 2H), 8.00 (m, 4H); HPLC-MS (Method A): m / z = 542 (M + 1); Rt = 5.09 minutes. Example 6 5 (General procedure (C)) (Z) — 3-{4 a [2 — [4 — (2,2-dimethylpropyl) phenyl] — 4 — oxygen — 4 — (4 — Trifluoromethoxyphenyl) but-2-enyl] benzamidinyl} 124 200401634 propionic acid

WNMRCCDCIO : c50.88(s，9H)，2.51(s，2H)，2.68(t，2H)，3.70(q， 2H)，6.99(brs，1H)，7.15(d，2H)，7.27(d，2H)，7.47(d，2H)，7.60(s，1H) ，7.78(d，2H)，8.00(m，4H) ; HPLC—MS(方法 D) : m/z=582(M+l) ; Rt=5.21 分鐘。實例6 6 (—般程序（C )) (Z) - 3 — {4 — [2 — 滿—5 —基—4一氧—4 — (4 一二每化甲氧基苯基）丁- 2 -烯醯]苯甲醯胺基}丙酸WNMRCCDCIO: c50.88 (s, 9H), 2.51 (s, 2H), 2.68 (t, 2H), 3.70 (q, 2H), 6.99 (brs, 1H), 7.15 (d, 2H), 7.27 (d, 2H), 7.47 (d, 2H), 7.60 (s, 1H), 7.78 (d, 2H), 8.00 (m, 4H); HPLC-MS (Method D): m / z = 582 (M + l); Rt = 5.21 minutes. Example 6 6 (—general procedure (C)) (Z)-3 — {4 — [2 — Mann — 5 —yl — 4 —oxy — 4 — (4 dioxinated methoxyphenyl) butan-2 -Ene 醯] benzamidine amino} propionic acid

^NMRCCDCID : (52.〇l(m，2H)，2.64(t，2H)，2.84(m，4H)，3.64(q ，2H)，6.81(brs，1H)，7.14(d，1Η)，7.22(d，2H)，7.27(d，1H)，7.35(s， 1H)，7.53(s，1H)，7.71(d，2H)，7.94(m，4H) ; HPLC—MS(方法 A): m/z=552(M+l) ; Rt=4.75 分鐘。實例6 7 (—般程序（C )) 125 200401634 (Z)- 3 - {4 — [2-二苯基一 4 一基一 4—(4 一氯化苯基）一 4一氧丁 -2 —烯醯]苯甲醯胺基}丙酸^ NMRCCDCID: (52.01 (m, 2H), 2.64 (t, 2H), 2.84 (m, 4H), 3.64 (q, 2H), 6.81 (brs, 1H), 7.14 (d, 1H), 7.22 (d, 2H), 7.27 (d, 1H), 7.35 (s, 1H), 7.53 (s, 1H), 7.71 (d, 2H), 7.94 (m, 4H); HPLC-MS (Method A): m / z = 552 (M + l); Rt = 4.75 minutes. Example 6 7 (—general procedure (C)) 125 200401634 (Z)-3-{4 — [2-diphenyl-4 4-yl-4— (4-monochlorophenyl) -4-oxobut-2-eneene] benzylamino} propanoic acid

^NME^CDCy : 52.74(t，2H)，3.73(q，2H)，6.77(brs，1H)， 7.44(m，6H)，7.54(s，1H)，7.61(d，2H)，7.65(m，3H)，7.84(d，2H)，7.95(d ，2H)，8.05(d，2H) ; HPLC—MS(方法 A) : m/z=552(M+l) ; Rt=4.75 分鐘。實例6 8 ( —般程序（C )) (Z) —3 — [4 — (2 —二苯基—4 —基—4 —奈—2 —基氧丁 - 2-烯醯）苯甲醯胺基]丙酸^ NME ^ CDCy: 52.74 (t, 2H), 3.73 (q, 2H), 6.77 (brs, 1H), 7.44 (m, 6H), 7.54 (s, 1H), 7.61 (d, 2H), 7.65 (m , 3H), 7.84 (d, 2H), 7.95 (d, 2H), 8.05 (d, 2H); HPLC-MS (Method A): m / z = 552 (M + 1); Rt = 4.75 minutes. Example 6 8 (-General procedure (C)) (Z) —3 — [4 — (2-diphenyl-4 —yl — 4 —naphthalene — 2 —oxetane-2-enefluorene) benzamidine Propyl] propionic acid

WNMRCCDCy : 52.70(t，2H)，3.72(q，2H)，6.80(brs，1H)， 7.38(m，1Η)，7.45(d，2H)，7.57(m，2H)，7.62(m，2H)，7.67(m，3H)， 7.74(m，1H)，7.83(d，2H)，7.91(m，1H)，7.92(d，2H)，7.99(m，2H)， 8.10(d，2H)，8_56(m，1H) ; HPLC—MS(方法 A) : m/z=554(M+l) ; Rt=4.71 分鐘。 126 200401634 實例6 9 (—般程序（C )) (Z)— 3 — {4 — [4 -（4 —環己基苯基）一 2 -（4 —異丙基苯基）一 4一氧丁-2-烯醯]苯甲醯胺基}丙酸WNMRCCDCy: 52.70 (t, 2H), 3.72 (q, 2H), 6.80 (brs, 1H), 7.38 (m, 1Η), 7.45 (d, 2H), 7.57 (m, 2H), 7.62 (m, 2H) , 7.67 (m, 3H), 7.74 (m, 1H), 7.83 (d, 2H), 7.91 (m, 1H), 7.92 (d, 2H), 7.99 (m, 2H), 8.10 (d, 2H), 8_56 (m, 1H); HPLC-MS (Method A): m / z = 554 (M + 1); Rt = 4.71 minutes. 126 200401634 Example 6 9 (—General Procedure (C)) (Z) — 3 — {4 — [4-(4-cyclohexylphenyl) —2— (4-isopropylphenyl) —4-oxobutane -2-enefluorene] benzamidine amino} propionic acid

iHNMi^CDCy : (H.24(d，6H)，1.24—1.50(m，5H)，1.68 —1.95(m ，5H)，2.57(m，1H)，2.70(t，2H)，2.93(m，1Η)，3.70(q，2H)，6.85(br s， 1H)，7.20(d，2H)，7.50(d，2H)，7.64(s，1H)，7.77(d，2H)，7.90(d，2H)， 8.01(d，2H) ; HPLC—MS(方法 A) : m/z=552(M+l) ; Rt=5.84 分鐘。實例7 0 (—般程序（C )) (Z)— 3 — {4 — [4 —氧一2 — (4—三氟化甲氧基苯基）—4 一 (4-三氟化甲基磺胺基苯基）丁-2-烯醯]苯甲醯胺基丨丙酸iHNMi ^ CDCy: (H.24 (d, 6H), 1.24—1.50 (m, 5H), 1.68—1.95 (m, 5H), 2.57 (m, 1H), 2.70 (t, 2H), 2.93 (m, 1Η), 3.70 (q, 2H), 6.85 (br s, 1H), 7.20 (d, 2H), 7.50 (d, 2H), 7.64 (s, 1H), 7.77 (d, 2H), 7.90 (d, 2H), 8.01 (d, 2H); HPLC—MS (Method A): m / z = 552 (M + 1); Rt = 5.84 minutes. Example 7 0 (—general procedure (C)) (Z) — 3 — {4 — [4 —Oxy-2 — (4-trifluoromethoxyphenyl) — 4-mono (4-trifluoromethylsulfonylphenyl) but-2-enefluorene] benzamidine Propionate

HPLC—MS(方法 A) : m/z=612(M+l) ; Rt=4.94 分鐘。實例7 1 (—般程序（C )) 127 200401634 (Z)— 3 — {4—[4 一氧一2, 4一雙一（4 一三氟化甲氧基苯基）丁- 2 -烯醯]苯甲醯胺基}丙酸HPLC-MS (Method A): m / z = 612 (M + 1); Rt = 4.94 minutes. Example 7 1 (General procedure (C)) 127 200401634 (Z) — 3 — {4— [4 monooxo-2, 4-bis (4-trifluoromethoxyphenyl) but-2-ene醯] benzylamino} propionic acid

^NMR^DMSO —d6) : 52·5(2Η，低於 DMS〇—d6)，3.47(2H，q)， 7·50(2Η，d)，7·54(2Η，d)，7.85(2H，d)，7·89(2Η，d)，7·97(2Η，d)， 8·10(1Η，s)，8.28(2H，d)，8.68(1H，t) ; HPLC—MS(方法 A): m/z=596(M+l) ; Rt=4.97 分鐘。實例7 2 (—般程序（C )) (Z)—3—{4 — [4一氧一 4 一（3-三氟化甲氧基苯基）一 2 — (4-三氟化甲氧基苯基）丁- 2 -烯醯]苯甲醯胺基}丙酸^ NMR ^ DMSO-d6): 52 · 5 (2Η, lower than DMS 0-d6), 3.47 (2H, q), 7.50 (2Η, d), 7.54 (2Η, d), 7.85 (2H , D), 7.89 (2Η, d), 7.97 (2Η, d), 8.10 (1Η, s), 8.28 (2H, d), 8.68 (1H, t); HPLC-MS (method A): m / z = 596 (M + l); Rt = 4.97 minutes. Example 7 2 (—general procedure (C)) (Z) —3— {4 — [4-monooxy-4 (3-trifluoromethoxyphenyl) — 2 — (4-trifluoromethoxy Phenyl) but-2-ylene] benzylamino} propanoic acid

HPLC—MS(方法 A) : m/z=596(M+l) ; Rt=4.73 分鐘。實例7 3 ( —般程序（C )) (Z) - 3 — {4 一 [2 - 一苯基—4 —基—4—(4 —環己基苯基) 一 4一氧丁一 2 -烯醯]苯甲醯胺基}丙酸 128 200401634HPLC-MS (Method A): m / z = 596 (M + 1); Rt = 4.73 minutes. Example 7 3 (-General procedure (C)) (Z)-3 — {4 mono [2-monophenyl-4 -yl -4-(4-cyclohexylphenyl) -4 -oxetane 2 -ene醯] benzylamino} propanoic acid 128 200401634

HPLC—MS(方法 A) : m/z=588(M+l) ; Rt=5.83 分鐘。實例7 4 (—般程序（C )) (Z)—3 —{4 — [2—二苯基—4—基—4 一氧—4 一（4—三氟化甲氧基苯基）丁- 2-烯醯]苯甲醯胺基丨丙酸HPLC-MS (Method A): m / z = 588 (M + 1); Rt = 5.83 minutes. Example 7 4 (-General procedure (C)) (Z) —3 — {4 — [2-diphenyl-4-yl — 4 monooxy-4 —mono (4-trifluoromethoxyphenyl) butyl -2-enefluorene] benzamidine

iHNMR^DMSO —d6) : 52·5(2Η，低於 DMS〇一d6)，3.46(2H，q)， 7·73(2Η，d)，7·90(2Η，d)，7.99(2H，d)，8·16(1Η，s)，8·30(2Η，d)， 8.70(1H，t)，12.1(1H，bs) ; HPLC—MS(方法 A) : m/z=588(M+l) ; Rt=5.08 分鐘。 129 200401634 實例7 5 (—般程序（C )) (Z)—(3 - {4 一 [4 一二苯基一 4 —基—4 一氧—2 -（4 一二氟甲氧基苯基）丁- 2 -烯醯]苯甲醯胺基}丙酸iHNMR ^ DMSO-d6): 52 · 5 (2Η, lower than DMS〇-d6), 3.46 (2H, q), 7.73 (2Η, d), 7.90 (2Η, d), 7.99 (2H, d), 8.16 (1Η, s), 8.30 (2Η, d), 8.70 (1H, t), 12.1 (1H, bs); HPLC-MS (Method A): m / z = 588 (M + l); Rt = 5.08 minutes. 129 200401634 Example 7 5 (-General procedure (C)) (Z) — (3-{4 mono [4 diphenylphenyl 4- 4-yl-4 monooxy-2-(4-difluoromethoxyphenyl ) But-2-ylene] benzamidine amino} propionic acid

^NMRCCDCy ： 52.70(2H 5 t) 5 3.72(2H ^ q) J 6.84(1H ^ t) ^ 7.40-7.50(3H，m)，7.59—7.73(8H，m)，7.81(2H，d)，8.00-8·08(4Η，dd)。HPLC —MS(方法 A) : m/z=588(M+l) ; Rt=4.86 分鐘。實例7 6 (—般程序（C )) (Z)— 3 - {4 一 [2 — (4 —環己一1 —烯基苯基）一 4 一氧—4 -（4-三氟化甲氧基苯基）丁-2—烯醯]苯甲醯胺基}丙酸^ NMRCCDCy: 52.70 (2H 5 t) 5 3.72 (2H ^ q) J 6.84 (1H ^ t) ^ 7.40-7.50 (3H, m), 7.59-7.73 (8H, m), 7.81 (2H, d), 8.00 -8 · 08 (4Η, dd). HPLC-MS (method A): m / z = 588 (M + 1); Rt = 4.86 minutes. Example 7 6 (—General Procedure (C)) (Z) — 3-{4 1 [2 — (4 —cyclohexyl 1 —alkenylphenyl) — 4 —oxy-4 — (4-trifluoromethane Oxyphenyl) but-2-enefluorene] benzylamino} propanoic acid

此化合物可依據一般程序（B)，修正步驟3，在樹脂裂解前先在溫度7(TC下搖動攪拌3天，如此可產得氧化產品 ^NMRCCDCy ： (?1.60-h74(m ^ 2H) 5 1.75-1.83(m ^ 2H) ^ 2.18-2.27(m，2H)，2.37 —2.43(m，2H)，2.68-2.75(t，2H)，3.68 —3.78(q，2H)， 130 200401634 6.24(t，1Η)，6.83(t，1H)，7.30(d，2H)，7.42(d，2H)，7.50(d，2H)，7.61(s， 1H)，7.80(d，2H)，8.01(dd，4H) ; HPLC—MS(方法 C) : m/z=592(M+l); Rt=7.60 分鐘。實例7 7 (—般程序（C )) (Z)~ 3 - {4 — [4一（4一叔一丁基苯基）一 4一氧—2 — (4-三氟化甲氧基苯基）丁-2-烯醯]苯甲醯胺基}丙酸This compound can be modified in accordance with the general procedure (B), step 3, and stirred at temperature 7 (TC for 3 days before the resin is cracked, so that an oxidation product can be obtained. ^ NMRCCDCy: (? 1.60-h74 (m ^ 2H) 5 1.75-1.83 (m ^ 2H) ^ 2.18-2.27 (m, 2H), 2.37-2.43 (m, 2H), 2.68-2.75 (t, 2H), 3.68-3.78 (q, 2H), 130 200401634 6.24 (t , 1Η), 6.83 (t, 1H), 7.30 (d, 2H), 7.42 (d, 2H), 7.50 (d, 2H), 7.61 (s, 1H), 7.80 (d, 2H), 8.01 (dd, 4H); HPLC-MS (Method C): m / z = 592 (M + l); Rt = 7.60 minutes. Example 7 7 (General procedure (C)) (Z) ~ 3-{4 — [4 一(4-t-tert-butylphenyl) -4-oxo-2- — (4-trifluoromethoxyphenyl) but-2-enefluorenyl] benzylamino} propionic acid

^NMRCCDCU)選定：51.33(s，9H)，2.62-2.78(寬，2H)，3.62-3.79(寬，2H)，7.23(寬，1H(低於 CDC13))，7·44—7·52(寬，2H)，7·56-7.67( 寬，4H)，7.72-7.87(寬，2H)，7.88-8.04(寬，4H) ; HPLC-MS(方法 C): m/z=568(M+l) ; Rt=5.53 分鐘。^ NMRCCDCU) selected: 51.33 (s, 9H), 2.62-2.78 (width, 2H), 3.62-3.79 (width, 2H), 7.23 (width, 1H (less than CDC13)), 7.44-7.52 ( Width, 2H), 7.56-7.67 (width, 4H), 7.72-7.87 (width, 2H), 7.88-8.04 (width, 4H); HPLC-MS (method C): m / z = 568 (M + l); Rt = 5.53 minutes.

實例7 8 (—般程序（C ) ) _ (Z)—3— {4 — [4 一氧—4 一（2，2，3，3 —四氟一2，3 — 二氫苯並[1，4]二氧芑一 6—基）一 2—(4—三氟化甲氧基苯基）丁- 2 -烯醯]苯甲醯胺基}丙酸Example 7 8 (—general procedure (C)) _ (Z) —3— {4 — [4 monooxy-4— (2,2,3,3 —tetrafluoro—2,3 —dihydrobenzo [1 , 4] Dioxo-6-yl) -2- (4-trifluoromethoxyphenyl) but-2-enene] benzylamino} propanoic acid

131 200401634 iHNMRCCDCl;)選定：52.62—2.77(寬，2H)，3.62 —3.78(寬，2H)， 7.86-7.98(寬，1H)，7.24(寬，2H(低於 CDC13))，7.50 —7.58(寬，1H)，7.58 —7.68(寬，2H) ; 7.73—7.89(寬，4H)，7.94 —8.04(寬，2H) ; HPLC—MS(方法 C) : m/z=642(M+l) ; Rt=5.53 分鐘。實例7 9 (—般程序（C )) (Z)— 3 - {4 — [4 — (4 一氯化苯基）—2 -（4一環己基苯基) 一 4 一氧丁一 2 -烯醯]苯甲醯胺基}丙酸131 200401634 iHNMRCCDCl;) Selected: 52.62—2.77 (wide, 2H), 3.62-3.78 (wide, 2H), 7.86-7.98 (wide, 1H), 7.24 (wide, 2H (less than CDC13)), 7.50 —7.58 ( Width, 1H), 7.58—7.68 (width, 2H); 7.73—7.89 (width, 4H), 7.94—8.04 (width, 2H); HPLC-MS (method C): m / z = 642 (M + l) ; Rt = 5.53 minutes. Example 7 9 (-General procedure (C)) (Z) — 3-{4 — [4 — (4-monochlorophenyl) —2— (4-cyclohexylphenyl) —4-oxobutane 2-ene醯] benzylamino} propionic acid

】HNMR(DMSO —d6) : 51.15 —1.46(m，5H)，1.65-1.83(m，5H)， 2.5〇(m，3H(低於 DMS〇)），3.42—3.50((1，2H) ; 7.30—7.35(d，2H)，7.55 — 7.72(dd，4H)，7.85 —8.05(m，5H)，8.10 - 8.20(d，2H) ; 8.66(t，1H)，12.23(s ，1H) ; HPLC—MS(方法 C) : m/z=544(M+l) ; Rt=5.87 分鐘。實例8 0 (—般程序（C )) (Z) —3 — {4 — [2 — (4 —環己基苯基）一 4 —氧一 4 一（5，6 ，7, 8—四氫萘—2—基）丁— 2—烯醯]苯甲醯胺基}丙酸] HNMR (DMSO — d6): 51.15 — 1.46 (m, 5H), 1.65-1.83 (m, 5H), 2.5 0 (m, 3H (less than DMS 0)), 3.42-3.50 ((1, 2H); 7.30-7.35 (d, 2H), 7.55-7.72 (dd, 4H), 7.85-8.05 (m, 5H), 8.10-8.20 (d, 2H); 8.66 (t, 1H), 12.23 (s, 1H); HPLC-MS (Method C): m / z = 544 (M + 1); Rt = 5.87 minutes. Example 80 (General procedure (C)) (Z) —3 — {4 — [2 — (4 — Cyclohexylphenyl) 4-oxo-4 4- (5,6,7,8-tetrahydronaphthalene-2-yl) butan-2-enefluorenyl] benzylamino} propanoic acid

132 200401634 ^NMI^CDCIJ : (51.10-1.42(m，5H)，1.60—1.88(m，9H)，2.29 — 2.43(m，1H)，2.61 —2.83(m，6H)，3.62—3.79(q，2H)，6.86(s，1H)，6.97-7.11(m，4H)，7.13—7.24(d，2H)，7.50—7.62(m，2H)，7.75 —7.86(d，2H)， 7.92-8.04(d，2H) ; HPLC-MS(方法 C) : m/z=564(M+l) ; Rt=6.20 分鐘。實例81(—般程序（C))132 200401634 ^ NMI ^ CDCIJ: (51.10-1.42 (m, 5H), 1.60—1.88 (m, 9H), 2.29—2.43 (m, 1H), 2.61—2.83 (m, 6H), 3.62—3.79 (q, 2H), 6.86 (s, 1H), 6.97-7.11 (m, 4H), 7.13-7.24 (d, 2H), 7.50-7.62 (m, 2H), 7.75-7.86 (d, 2H), 7.92-8.04 ( d, 2H); HPLC-MS (method C): m / z = 564 (M + 1); Rt = 6.20 minutes. Example 81 (General procedure (C))

(Z)—3—{4—[4—氧—4—(5, 6, 7, 8—四氫萘—2—基 )一 2-（4 一三氟化甲氧基苯基）丁一 2-烯醯]苯甲醯胺基}丙酸(Z) —3— {4— [4—oxy-4— (5, 6, 7, 8-tetrahydronaphthalene-2-yl) —2- (4-trifluoromethoxyphenyl) butan-1 2-enefluorene] benzylamido} propionic acid

iHNMRpMSO — dd : 51.72—1.81(m，4H)，2.51(m，2H(低於 DMS〇)），2.74 — 2.84(m，4H)，3.42—3.50(q，2H0，7.20—7.26(d，1H)，7.45 —7.52(d，2H)，7.78—7.98(m，8H)，8.05(s，1H)，8.66(t，1H)，12.22(s， 1H) ; HPLC—MS(方法 C) : m/z=566(M+l) ; Rt=5.47 分鐘。實例8 2 (—般程序（C )) (Z) - 3 — {4 - [2 -（4 一氯化苯基）—4 — (4 一環己基本基) 一 4 -氧丁一 2—烯醯]苯甲醯胺基}丙酸iHNMRpMSO — dd: 51.72—1.81 (m, 4H), 2.51 (m, 2H (less than DMS)), 2.74 — 2.84 (m, 4H), 3.42 — 3.50 (q, 2H0, 7.20 — 7.26 (d, 1H) ), 7.45—7.52 (d, 2H), 7.78—7.98 (m, 8H), 8.05 (s, 1H), 8.66 (t, 1H), 12.22 (s, 1H); HPLC-MS (Method C): m / z = 566 (M + l); Rt = 5.47 minutes. Example 8 2 (—general procedure (C)) (Z)-3 — {4-[2-(4 monochlorophenyl) — 4 — ( 4 monocyclohexyl)-4-oxetane-2-enefluorene] benzamidine amino} propionic acid

133 200401634 ^NMRpMSO—d6) : (H.22-1.53(m，5H)，1.68 —1.87(m，5H)， 2.51(t，2H(低於 DMS〇)），3.41 —3.52(q，2H)，7.36 —7.43(d，2H)，7.52— 7.58(d，2H)，7.68—7.75(d，2H)，7.85—7.97(dd，4H)，8.02 —8.08(m，3H)， 8.62 —8.71(t，1H)，12.22(s，1H) ; HPLC—MS(方法 C) : m/z=544_); Rt=5.83 分鐘。實例8 3 (—般程序（C ))133 200401634 ^ NMRpMSO-d6): (H.22-1.53 (m, 5H), 1.68—1.87 (m, 5H), 2.51 (t, 2H (less than DMS〇)), 3.41—3.52 (q, 2H) , 7.36 — 7.43 (d, 2H), 7.52 — 7.58 (d, 2H), 7.68 — 7.75 (d, 2H), 7.85 — 7.97 (dd, 4H), 8.02 — 8.08 (m, 3H), 8.62 — 8.71 ( t, 1H), 12.22 (s, 1H); HPLC-MS (Method C): m / z = 544_); Rt = 5.83 minutes. Example 8 3 (—general procedure (C))

(Z) — 3 — {4 — [4 一（4 —氯化苯基）—4 —氧—2—ρ —甲苯基丁-2-烯醯]苯甲醯胺基}丙酸(Z) — 3 — {4 — [4-mono (4-chlorophenyl) -4—oxy-2—ρ —tolyl-2-enyl] benzylamino} propanoic acid

^NMR^DMSO —d6) : 52.33(3H，s)，2.5(低於 DMS〇），3.44(2H，q) ，7·29(2Η，d)，7·61(4Η，m)，7·90(4Η，dd)，8·01(1Η，s)，8·15(2Η，d)， 8·66(1Η，t)，12·2(1Η，bs)。HPLC—MS(方法 D) : m/z=476(M+l) ; Rt=4.11 分馨鐘。實例8 4 (—般程序（C )) (Z) - 3 — {4 - [2, 4 一雙—（4 一氯化苯基）—4 一氧丁一 2 一烯醯]苯甲醯胺基}丙酸 H0^ NMR ^ DMSO-d6): 52.33 (3H, s), 2.5 (less than DMS), 3.44 (2H, q), 7.29 (2Η, d), 7.61 (4Η, m), 7. · 90 (4Η, dd), 8.01 (1Η, s), 8.15 (2Η, d), 8.66 (1Η, t), 12.2 (1Η, bs). HPLC-MS (Method D): m / z = 476 (M + 1); Rt = 4.11 minutes. Example 8 4 (—General Procedure (C)) (Z)-3 — {4-[2, 4 Mono- (4-monochlorophenyl) -4 4-oxobutane-2 monoene] benzamidine Propylpropionate H0

CI 134 200401634 WNMI^DMSO — l) : (515(低於 DMS〇），3·44(2Η，q)，7·55(2Η，d) ，7·63(2Η，d)，7·91(4Η，“q”），8·07(1Η，s)，8·15(2Η，d)，8·65(1Η，t)， 12·3(1Η，bs)。HPLC(方法 D) : m/z=496(M+l) ; Rt=4.20 分鐘。實例8 5 (—般程序（C )) (Z) —3 — {4 — [2 — (4-環己基苯基）一 4一郎滿一 5 —基— 氧丁- 2—烯醯]苯甲醯胺基}丙酸CI 134 200401634 WNMI ^ DMSO — l): (515 (less than DMS), 3.44 (2Η, q), 7.55 (2Η, d), 7.63 (2Η, d), 7.91 ( 4Η, “q”), 8.07 (1Η, s), 8.15 (2Η, d), 8.65 (1Η, t), 12 · 3 (1bs, bs). HPLC (Method D): m / z = 496 (M + l); Rt = 4.20 minutes. Example 8 5 (—general procedure (C)) (Z) —3 — {4 — [2 — (4-cyclohexylphenyl) —4 1 Langman Mono-5-yl-oxetane-2-enefluorenyl] benzamidinylamino} propanoic acid

iHNMR^CDClD : (Π.00—1.46(m，5H)，1.54-1.97(m，5H)，2·12(ρ ，2Η)，2.67(t，2Η)，2.84(m，1Η)，2.94(t，4Η)，3.70(q，2Η)，6.98(m，1Η) ，7.13 —7.32(m，4H)，7.48(d，2H)，7.63(s，1H)，7.70—7.84(m，3H)， 8.00(d，2H)。册!^一“8(方法〇):1^=550(1^+1);见=5.35分鐘。實例8 6 (—般程序（C )) (Z) — 3 — {4 — [2 -（4 一環己基苯基）—4 — (4 —異丁基苯基）一 4一氧丁一 2 -烯醯]苯甲醯胺基}丙酸iHNMR ^ CDClD: (Π.00-1.46 (m, 5H), 1.54-1.97 (m, 5H), 2.12 (ρ, 2Η), 2.67 (t, 2Η), 2.84 (m, 1Η), 2.94 ( t, 4Η), 3.70 (q, 2Η), 6.98 (m, 1Η), 7.13—7.32 (m, 4H), 7.48 (d, 2H), 7.63 (s, 1H), 7.70—7.84 (m, 3H) , 8.00 (d, 2H). !! ^ a "8 (Method 0): 1 ^ = 550 (1 ^ + 1); see = 5.35 minutes. Example 8 6 (—general procedure (C)) (Z) — 3 — {4 — [2- (4-Cyclohexylphenyl) -4— (4-Isobutylphenyl) -4—oxobutane-2-enefluorenyl] benzylamino} propanoic acid

200401634 iHNMIUCDCID : 50.88(d，6H)，1.00 —1.46(m，5H)，1.64—1.96(m ，5H)，2.44(m，1H)，2.53(d，2H)，2.67(t，2H)，2.86(m，1H)，3.68(q，2H) ，6.93(m，1H)，7.06—7.30(m，4H)，7.46(d，2H)，7.61(s，1H)，7.68(d， 2H)，7.86(d，2H)，7.98(d，2H)，9.98(br s，1H)。實例8 7 ( —般程序（C )) (Z) —3 - {4 — [2 -（4 一環己基苯基）一 4 — (4 —環戊基苯基）一 4一氧丁一 2 -烯醯]苯甲醯胺基}丙酸200401634 iHNMIUCDCID: 50.88 (d, 6H), 1.00—1.46 (m, 5H), 1.64—1.96 (m, 5H), 2.44 (m, 1H), 2.53 (d, 2H), 2.67 (t, 2H), 2.86 (m, 1H), 3.68 (q, 2H), 6.93 (m, 1H), 7.06-7.30 (m, 4H), 7.46 (d, 2H), 7.61 (s, 1H), 7.68 (d, 2H), 7.86 (d, 2H), 7.98 (d, 2H), 9.98 (br s, 1H). Example 8 7 (—General Procedure (C)) (Z) —3-{4 — [2-(4-Cyclohexylphenyl) —4— (4-Cyclopentylphenyl) —4—Oxybutane 2— Diene] benzamidine amino} propanoic acid

'HNMRCCDCy ： 51.00-1.45(m ^ 5H) ^ 1.51-1.94(m ^ 11H) ^ 1.96-2.17(m，2H)，2.52(m，1H)，2.65(t，2H)，3·03(ρ，1H)，3.67(q，2H)， 7.04(m，1Η)，7.12 —7.35(m，4Η)，7.46(d，2Η)，7.60(s，1Η)，7.76(d，2Η)'HNMRCCDCy: 51.00-1.45 (m ^ 5H) ^ 1.51-1.94 (m ^ 11H) ^ 1.96--2.17 (m, 2H), 2.52 (m, 1H), 2.65 (t, 2H), 3.03 (ρ, 1H), 3.67 (q, 2H), 7.04 (m, 1Η), 7.12—7.35 (m, 4Η), 7.46 (d, 2Η), 7.60 (s, 1Η), 7.76 (d, 2Η)

，7.87(d，2H)，7.99(d，2H)。 HPLC—MS(方法 D) : m/z=578(M+l) ; Rt=5.81 分鐘。實例8 8 (—般程序（C )) (Z) — 3 — {4 — [2 — (4 —環己基苯基）一 4 —氧一4 —苯基丁一 2-烯醯]苯甲醯胺基}丙酸 136 200401634, 7.87 (d, 2H), 7.99 (d, 2H). HPLC-MS (method D): m / z = 578 (M + 1); Rt = 5.81 minutes. Example 8 8 (-General procedure (C)) (Z) — 3 — {4 — [2 — (4-cyclohexylphenyl) —4—oxy-4—phenylbutane-2-enefluorene] benzamidine Amine} propionic acid 136 200401634

^NMRCCDCID : 51.00—1.48(m，5H)，1.56—1.94(m，5H)，2.51(m ，1H)，2.65(t，2H)，3.67(q，2H)，7.04(m，1H)，7.10—7.27(m，4H)，7.37 —7.56(m，3H)，7.62(s，1H)，7.80(d，2H)，7.93(d，2H)，7.96(d，2H)， 10.47(br s，1H)。 HPLC(方法 D) : m/z=510(M+l) ; Rt=4.84 分鐘。實例8 9 (—般程序（C )) (Z)—3— {4 — [2 — (4 —環己基苯基）一 4 一氧一 4—p—甲苯基丁一 2—烯醯]苯甲醯胺基}丙酸^ NMRCCDCID: 51.00-1.48 (m, 5H), 1.56-1.94 (m, 5H), 2.51 (m, 1H), 2.65 (t, 2H), 3.67 (q, 2H), 7.04 (m, 1H), 7.10 —7.27 (m, 4H), 7.37 —7.56 (m, 3H), 7.62 (s, 1H), 7.80 (d, 2H), 7.93 (d, 2H), 7.96 (d, 2H), 10.47 (br s, 1H). HPLC (Method D): m / z = 510 (M + 1); Rt = 4.84 minutes. Example 8 9 (-General Procedure (C)) (Z) —3-—4- (2— (4-cyclohexylphenyl) —4—oxo—4—p-tolyl-butan-2-ene]] benzene Formamido} propionic acid

】HNMR(CDC13) : 51.01 —1.47(m，5H)，1.59—1.96(m，5H)，2.40(s， 3H)，2.51(m，1H)，2.65(t，2H)，3.66(q，2H)，7.04(m，1H)，7.12—7.27(m ，4H)，7.46(d，2H)，7.59(s，1H)，7.76(d，2H)，7.85(d，2H)，7.97(d，2H) 。HPLC—MS(方法 D) : m/z=524(M+l) ; Rt=5.06 分鐘。 137 200401634 實例9 0 (—般程序（C )) (Z) — 3 — {4 - [2 —（4 —環己基苯基）一 4一（4一甲氧基苯基）一 4一氧丁一 2-烯醯]苯甲醯胺基}丙酸] HNMR (CDC13): 51.01—1.47 (m, 5H), 1.59—1.96 (m, 5H), 2.40 (s, 3H), 2.51 (m, 1H), 2.65 (t, 2H), 3.66 (q, 2H) ), 7.04 (m, 1H), 7.12-7.27 (m, 4H), 7.46 (d, 2H), 7.59 (s, 1H), 7.76 (d, 2H), 7.85 (d, 2H), 7.97 (d, 2H). HPLC-MS (method D): m / z = 524 (M + 1); Rt = 5.06 minutes. 137 200401634 Example 9 0 (general procedure (C)) (Z) — 3 — {4-[2 — (4-cyclohexylphenyl) — 4 — (4-methoxyphenyl) — 4 —oxetane Mono-2-enefluorene] benzylamido} propionic acid

WNMRCCDCy : 51.00—1.39(m，5H)，1.56—1.96(m，5H)，2.51(m ，1H)，2.67(t，2H)，3.70(q，2H)，3.85(s，3H)，7.03(m，1H)，7.13—7.26(m ，4H)，7.46(d，2H)，7.60(s，1H)，7.82(d，2H)，7.95(d，2H)，8.00(d，2H) ，10.57(brs，1H)。HPLC-MS(方法 D) : m/z=540(M+l) ; Rt=4.87 分鐘。WNMRCCDCy: 51.00-1.39 (m, 5H), 1.56-1.96 (m, 5H), 2.51 (m, 1H), 2.67 (t, 2H), 3.70 (q, 2H), 3.85 (s, 3H), 7.03 ( m, 1H), 7.13-7.26 (m, 4H), 7.46 (d, 2H), 7.60 (s, 1H), 7.82 (d, 2H), 7.95 (d, 2H), 8.00 (d, 2H), 10.57 (brs, 1H). HPLC-MS (method D): m / z = 540 (M + 1); Rt = 4.87 minutes.

實例9 1 (E)—3 — {4—[2 -（4 —環己基本基）—4 —氧一 4 一（4 一三氟化甲氧基苯基）丁- 2 -烯醯]苯甲醯胺基}丙酸Example 9 1 (E) —3 — {4— [2- (4-cyclohexyl radical) —4—oxy-4— (4-trifluoromethoxyphenyl) but-2-enene] benzene Formamido} propionic acid

如一般程序（C)步驟1 一 5所述的方法製得一含E和Z -3 — {4 — [2 — (4 —環己基本基）—4— 一 4一（4一二氟化甲氧基苯基）丁一 2-烯醯]苯甲醯胺基）丙酸的混合物，接著以 HPLC(chiralcel OD，25x2cm，洗提劑爲異丙醇：庚烷：三 138 200401634 氟乙酸（20 : 880 : 0.1)，6毫升/分鐘），可得純E-異構物。 ^NMI^CDCy : 51.66 —2.05(m，5H)，2.41(m，1H)，2.51(m，2H) ，3.47(q，2H)，7.12(d，4H)，7.44(d，2H)，7.96 — 8.01(m，6H)，8.72(t，1H) 一般程序（D) 溶液相合成式（I3)化合物的一般程序（D)A method containing E and Z is prepared as described in steps 1 to 5 of the general procedure (C). — {4 — [2 — (4 —cyclohexyl radical) — 4 — one 4 one (4-difluorination A mixture of methoxyphenyl) butene-2-enefluorene] benzylamido) propionic acid, followed by HPLC (chiralcel OD, 25x2cm, eluent: isopropanol: heptane: tri 138 200401634 fluoroacetic acid ( 20: 880: 0.1), 6 ml / min), to obtain pure E-isomers. ^ NMI ^ CDCy: 51.66 — 2.05 (m, 5H), 2.41 (m, 1H), 2.51 (m, 2H), 3.47 (q, 2H), 7.12 (d, 4H), 7.44 (d, 2H), 7.96 — 8.01 (m, 6H), 8.72 (t, 1H) General procedure (D) General procedure (D) for solution phase synthesis of compound of formula (I3)

此程序以下述實例詳細說明= 實例9 2 (—般程序（D )) 4 — [2 — —*苯基一4一基—4一氧—4 — (3 —二氣化甲基苯基）丁醯]—N-（2H —四唑—5 —基）苯醯胺This procedure is explained in detail with the following examples = Example 9 2 (—general procedure (D)) 4 — [2 — — * phenyl-1 4-yl-4 4-oxy-4 — (3-digasified methylphenyl) Butanidine] —N- (2H —tetrazol-5-yl) benzidine

將4一甲醯—N—(2H-四唑—5—基）苯醯胺（128毫克）( 依據WO 00/69810所述的步驟合成），3-二苯基一 4—基一 1 一（3-三氟化甲基苯基）丙烯酮（223毫克）及3, 4一二甲基— 5 -（2-羥基乙基）噻唑鎗碘化物（89毫克）溶於無水DMF(2.2 139 200401634 毫升）中，加入三乙胺（0.180毫升），及在溫度70°C和氮氣氣氛之下攪拌3天。接著以矽藻土過濾反應混合物，洗提劑爲DCM/甲醇/乙酸（90 : 9 : 1)，蒸發移去溶劑，可得一油狀物。再以沸騰的庚烷（4毫升）洗滌此油狀物，殘留物質在矽膠管柱上層析純化，洗提劑爲DCM/甲醇/乙酸（95 : 4 : 1) ，可得標題化合物（30毫克，9%)。 WNMRCCDCy : 512.8(brs，1H)，8.38(d，2H)，8.30(s，1H)，8.26(d ，2H)，8.18(d，1H)，7.83(d，1H)，7.7—7.30(m，11H) ; 5.41(dd，1H)， 4.30(dd，1H)，3.42(dd，1H) ; HPLC—MS(方法 A) : m/z=570(M+l) ; Rt=5.12 分鐘。一般程序（E) 溶液相合成式（I5)化合物的一般程序（E)4-Amidino-N- (2H-tetrazol-5-yl) benzidine (128 mg) (synthesized according to the procedure described in WO 00/69810), 3-diphenyl-1, 4-yl, 1 1 (3-Trifluoromethylphenyl) propenone (223 mg) and 3,4-dimethyl-5- (2-hydroxyethyl) thiazole iodide (89 mg) were dissolved in anhydrous DMF (2.2 139 200401634 ml), triethylamine (0.180 ml) was added, and the mixture was stirred at 70 ° C under a nitrogen atmosphere for 3 days. The reaction mixture was then filtered through celite, the eluent was DCM / methanol / acetic acid (90: 9: 1), and the solvent was removed by evaporation to obtain an oil. The oil was washed with boiling heptane (4 mL), and the remaining material was purified by chromatography on a silica gel column. The eluent was DCM / methanol / acetic acid (95: 4: 1) to obtain the title compound (30 Mg, 9%). WNMRCCDCy: 512.8 (brs, 1H), 8.38 (d, 2H), 8.30 (s, 1H), 8.26 (d, 2H), 8.18 (d, 1H), 7.83 (d, 1H), 7.7-1.30 (m, 11H); 5.41 (dd, 1H), 4.30 (dd, 1H), 3.42 (dd, 1H); HPLC-MS (Method A): m / z = 570 (M + 1); Rt = 5.12 minutes. General Procedure (E) General Procedure (E) for Solution Phase Synthesis of Compounds of Formula (I5)

其中X，D，E，m，η和R4是如式⑴中所定義者，及 Pg是一標準酸保護基，像甲基，乙基，丙基，異丙基，叔一丁基或苯甲基。此程序以下述實例作詳細說明：步驟1 : 140 200401634 此反應是習知的，且已描述於WO 00/69810。經保護胺基酸的胺基的醯化反應一般是以二異丙基-碳二醯亞胺，二環己基碳二醯亞胺或1 一 [3 -（二甲基胺基）丙基]一 3-乙基碳二醯亞胺氫氯化物，選擇性的在側反應抑止劑存在下，像N-羥基苯並***存在下活化羧酸而進行，然後將此經保護的胺基（經，像甲基，乙基，丙基，異丙基，叔-丁基或苯甲基酯保護的）加至該活化狻酸中。當此經保護的胺基爲一錢鹽時，加入一非親核鹼，像三乙胺或二異丙基乙基胺。此醯化反應是在一溶劑中進行，像THF，二噁烷，甲苯，DCM，DMF，NMP或這些溶劑中兩個或多個的混合物。此反應的反應溫度是在20°C至40°C之間，所得產物可以此項技藝領域內熟知的技藝純化。步驟2 : 此反應是習知的（Stetter H.，Krasselt J. ；[. Heterocyclic. Chem· 14，573，1977)。醛加入至活化雙鍵上的反應一般是由攪拌此醛和一含有一活化雙鍵的化合物（像一經取代的丙烯酮），在一觸媒存在下（像氰化物，噻唑鑰鹽，如3，4 -二甲基一 5—(2—羥基乙基）噻唑鑰碘化物，3—苯甲基一 4一 (2—羥基乙基）一 4一甲基—1，3—噻唑鎗氯化物，3 一乙基一 5 —（2 -經基乙基）一 4 —甲基—1，3 -噻π坐錄溴化物或維生素B!)反應進行而得。當使用噻唑鑰鹽當作觸媒時，可加入一非親核胺驗，像二乙胺或DBU。加入反應是在一溶劑中進行，如乙醇，甲醇，1 —丙醇，2 -丙醇，二嚼院， DMS〇，NMP或DMF，或這些溶劑中的二個或多個的混合 141 200401634 物。此反應的反應溫度是在50°C至120°C間，較佳地是在 5〇°C至80°C間。所得產物可以此項技藝領域內熟知的方法純化。步驟3 : 標準酸保護基的移去是依據保護基的性質而定，但一般的方法描述於，例如（Protective Groups in Organic Chemistry. Greene T.W.，Wuts Ρ· G. M. 1999，Wiley — Interscience，p. 377) o 此步驟在以下實例中作更詳細的說明。實例9 3 (—般程序（E ))Where X, D, E, m, η and R4 are as defined in formula ⑴, and Pg is a standard acid protecting group like methyl, ethyl, propyl, isopropyl, tert-butyl or benzene methyl. This procedure is illustrated in detail with the following examples: Step 1: 140 200401634 This reaction is conventional and has been described in WO 00/69810. The amidine reaction of the protected amino group is generally diisopropyl-carbodiimide, dicyclohexylcarbodiimide or 1- [3- (dimethylamino) propyl] The monoethyl 3-ethylcarbodiimide hydrochloride is optionally activated by activating a carboxylic acid in the presence of a side reaction inhibitor, such as N-hydroxybenzotriazole, and then protecting the protected amine group ( (Protected by, for example, methyl, ethyl, propyl, isopropyl, tert-butyl or benzyl ester) to the activated osmic acid. When the protected amine is a monovalent salt, a non-nucleophilic base such as triethylamine or diisopropylethylamine is added. This tritiation is carried out in a solvent such as THF, dioxane, toluene, DCM, DMF, NMP or a mixture of two or more of these solvents. The reaction temperature of this reaction is between 20 ° C and 40 ° C, and the resulting product can be purified by techniques well known in the art. Step 2: This reaction is conventional (Stetter H., Krasselt J .; [. Heterocyclic. Chem. 14, 573, 1977). The reaction of aldehyde added to the activated double bond is generally by stirring the aldehyde and a compound containing an activated double bond (like a substituted acrylone) in the presence of a catalyst (like cyanide, thiazole key salt, such as 3 , 4-Dimethyl-5 (2-hydroxyethyl) thiazolium iodide, 3-benzyl-4- (2-hydroxyethyl) -4-methyl-1,3-thiazolium chloride , 3 -Ethyl-5-(2-Ethylethyl) -4-methyl-1,3-Thi-π bromide or vitamin B!) Reaction proceeds. When using thiazole key salts as a catalyst, a non-nucleophilic amine test such as diethylamine or DBU can be added. The addition reaction is carried out in a solvent such as ethanol, methanol, 1-propanol, 2-propanol, dioxin, DMS0, NMP or DMF, or a mixture of two or more of these solvents. 141 200401634 . The reaction temperature of this reaction is between 50 ° C and 120 ° C, preferably between 50 ° C and 80 ° C. The resulting product can be purified by methods well known in the art. Step 3: The removal of the standard acid protecting group depends on the nature of the protecting group, but the general method is described in, for example, (Protective Groups in Organic Chemistry. Greene TW, Wuts P · GM 1999, Wiley — Interscience, p. 377 ) o This step is explained in more detail in the following example. Example 9 3 (—General Procedure (E))

步驟1 : 3—(4—甲醯苯甲醯胺基）一 2R—羥某丙酸甲某酯在一 500毫升的圓底燒瓶中，將4一甲醯苯甲酸(7.5克，50毫莫耳）溶於DMF(80毫升），加入1 一羥基苯並***，水合物（8.11克，60毫莫耳，1.2當量）及N5—(3—二甲基胺基丙基）一 N-乙基碳二醯亞胺氫氯化物（9.59克，50毫莫耳，1當量），接著在N2下攪拌溶液3/4小時，然後加入R-異絲氨酸甲基酯氫氯化物（如W0 02/00612所述方法製備， 11.67克，75毫莫耳，1.5當量）及DIPEA(13.6毫升，80毫莫耳，1.6當量），及攪拌混合物過夜。蒸發反應混合物至 142 200401634 80毫升，然後以乙酸乙酯（200毫升）和水（200毫升）分離，水溶液相以乙酸乙酯（100毫升和80毫升）萃取二次，結合各個有機相及以0.2N HCl(3xl00毫升）和飽和氯化鈉：水（1 :1)(3χ100毫升）洗滌，乾燥（硫酸鎂）及蒸發至乾，所得化合物懸浮於乙酸乙基酯（30毫升）中及過濾。洗滌所得固體，結合各個濾液，及在真空下蒸發。殘留物以管柱層析法純化，洗提劑爲乙酸乙基酯：正一庚烷（95 : 5)，及乙酸乙基酯：甲醇（95 ·· 5)，可分離出3 —（4一甲醯苯甲醯胺基）一 2R—羥基丙酸甲基酯（2.24克，10%)。 iHNMRCCDCy : δ3·82(3Η，s)，3·80-3·94(1Η，m)，4·42—4.49(1Η， m)，4·69(1Η，br s)，6·78(1Η，br s)，7·92(4Η，s)。步驟 2:3—丨4—『4一（4—叔—丁基苯基）—2-（4—環R 基苯基）-4 -氧丁醯1苯甲醯胺基2R-羥基丙酸乙某酯於一含有1 一（4—叔—丁基苯基）一3_(4-環己基苯基) 丙烯酮（1.00克，2·91毫莫耳）溶於無水乙醇（99%，10毫升) 的混合物中，在氮氣氣氛之下以液滴的方式加入3，4 一二甲基—5—(2—羥基乙基）_唑鑰碘化物（165毫克，0.58毫莫耳）及三乙胺（0.325毫升，2.33毫莫耳），迴流加熱混合物1 小時，及迴流加熱混合物7天，讓其冷卻至室溫，及以 DCM(50毫升）及HC1水溶液（1Ν，50毫升）分離產物。水溶液相以DCM(50毫升）洗滌，結合各個有機相，及以Na2S〇4 乾燥和在真空下乾燥，殘留油狀物經矽膠管柱層析純化，洗提劑爲乙酸乙酯和庚烷（1 : 1)，可得純3 — {4 - [4一（4 ~ 叔一丁基苯基）一 2 -（4一環己基苯基）一 4一氧丁醯]苯甲醯 143 200401634 胺基} 一 2R—羥基丙酸乙基酯。 HPLC—MS(方法 D) : m/z=612(M+l) ; Rt=6.07 分鐘。步驟3 : 3-丨4 一「4 一（4—叔—丁基苯基）一 2-（4 一環己基苯基）- 4 -氧丁醯1苯甲醯胺基丨-2R-羥某丙酸於上述3 - {4 一 [4—(4 一叔—丁基苯基）一 2R—(4-環己基苯基）一 4一氧丁醯]苯甲醯胺基丨-2-羥基丙酸乙基酯中加入乙醇（10毫升），接著將NaOH(244毫克）溶於水（1毫升），及加入至此混合物中，攪拌混合物30分鐘，及以水稀釋 (15毫升），及以HC1(1N)水溶液調整pH値爲2，過濾分離出沈澱物，可得標題化合物，產量：430毫克（25%)。 ^HNMIKDMSO —d6) : δ1·08 — 1·42(14Η，m)，1·60—1.90(5H，m)， 2·42(1Η，m)，3·32—3·53(3Η，m)，3.95(1Η，t)，4·08(1Η，dd)，5·40(1Η，dd) ，7·15(2Η，d)，7·32(2Η，d)，7·52(2Η)，7·90(2Η，d)，7·95(2Η，d)，8·14(2Η ，d)，8·70(1Η，t) ; HPLC—MS(方法 D) ·· m/z=584(M+l) ; Rt=5.68 分鐘。實例94(一般程序（E)) 3 - {4 一 [4 一 —·苯基—4 一基一 2—(4 —環己基苯基）—4 -氧丁醯]苯甲醯胺基2R-羥基丙酸Step 1: 3- (4-formamidine benzamidine)-2R-methylammonium propionate in a 500 ml round bottom flask, place 4-formamidine benzoic acid (7.5 g, 50 mmol) Ear) was dissolved in DMF (80 ml), and 1 monohydroxybenzotriazole, hydrate (8.11 g, 60 mmol, 1.2 equivalents) and N5- (3-dimethylaminopropyl) -N- Ethylcarbodiimide hydrochloride (9.59 g, 50 mmol, 1 equivalent), then stir the solution under N2 for 3/4 hour, then add R-isoserine methyl ester hydrochloride (eg WO 02 / 00612, 11.67 g, 75 millimoles, 1.5 eq.) And DIPEA (13.6 ml, 80 millimoles, 1.6 eq.), And the mixture was stirred overnight. The reaction mixture was evaporated to 142 200401634 80 ml, and then separated with ethyl acetate (200 ml) and water (200 ml). The aqueous phase was extracted twice with ethyl acetate (100 ml and 80 ml), and the organic phases were combined with 0.2 N HCl (3 x 100 ml) and saturated sodium chloride: water (1: 1) (3 x 100 ml) were washed, dried (magnesium sulfate) and evaporated to dryness. The resulting compound was suspended in ethyl acetate (30 ml) and filtered. The resulting solid was washed, the individual filtrates were combined, and evaporated under vacuum. The residue was purified by column chromatography. The eluent was ethyl acetate: n-heptane (95: 5), and ethyl acetate: methanol (95 ·· 5). 3— (4 Monomethyl benzamidine) 2R-hydroxypropionic acid methyl ester (2.24 g, 10%). iHNMRCCDCy: δ 3.82 (3Η, s), 3.80-3.94 (1Η, m), 4.42-4.49 (1Η, m), 4.69 (1Η, br s), 6.78 (1Η , Br s), 7.92 (4Η, s). Step 2: 3— 丨 4— “4- (4-tert-butylphenyl) -2- (4-ring R-phenylphenyl) -4-oxobutane, 1 benzamidine, 2R-hydroxypropionic acid Ethyl ester in 1- (4-tert-butylphenyl) -3_ (4-cyclohexylphenyl) propenone (1.00 g, 2.91 mmol) is dissolved in absolute ethanol (99%, 10 Into a mixture of 3 ml, 3,4-dimethyl-5- (2-hydroxyethyl) _azole key iodide (165 mg, 0.58 mmol) and three were added as drops under a nitrogen atmosphere. Ethylamine (0.325 ml, 2.33 mmol), the mixture was heated at reflux for 1 hour, and the mixture was heated at reflux for 7 days, allowed to cool to room temperature, and the product was separated with DCM (50 ml) and aqueous HC1 (1N, 50 ml). . The aqueous phase was washed with DCM (50 ml), combined with the organic phases, and dried over Na 2 SO 4 and dried under vacuum. The residual oil was purified by silica gel column chromatography. The eluents were ethyl acetate and heptane ( 1: 1), can obtain pure 3 — {4-[4-((4-tert-butylphenyl) -2- (4-cyclohexylphenyl) -4-oxobutyridine] benzamidine 143 200401634 amino group }-2R-Ethyl hydroxypropionate. HPLC-MS (method D): m / z = 612 (M + 1); Rt = 6.07 minutes. Step 3: 3- 丨 4- 4- (4-tert-butylphenyl)-2- (4-cyclohexylphenyl) -4 -oxetane-1 benzamidine amine-2R-hydroxypropyl Acid in the above 3-{4- [4- (4-tert-butylphenyl)-2R- (4-cyclohexylphenyl) -4-oxobutyryl] benzamidine amino-2-hydroxypropyl To the ethyl acetate was added ethanol (10 ml), followed by dissolving NaOH (244 mg) in water (1 ml) and adding to the mixture, stirring the mixture for 30 minutes, and diluting with water (15 ml), and HC1 (1N) Aqueous solution was adjusted to pH 2 and the precipitate was separated by filtration to obtain the title compound. Yield: 430 mg (25%). ^ HNMIKDMSO —d6): δ1 · 08 — 1.42 (14 ·, m), 1 · 60—1.90 (5H, m), 2.42 (1Η, m), 3.32-3 · 53 (3Η, m), 3.95 (1Η, t), 4.08 (1Η, dd), 5 · 40 (1Η, dd), 7.15 (2Η, d), 7.32 (2Η, d), 7.52 (2Η), 7.90 (2Η, d), 7.95 (2Η, d), 8 · 14 (2Η, d), 8.70 (1Η, t); HPLC-MS (Method D) ·· m / z = 584 (M + 1); Rt = 5.68 minutes. Example 94 (General procedure (E )) 3-{4 a [4 a- · phenyl-4 a radical a 2— (4 — Cyclohexylphenyl) -4 -oxobutanyl] benzamidine 2R-hydroxypropionic acid

^NMIKDMSO — dJ選定：δ1·15 — 1·39(ηι，5H)，1.62—1.79(m，5H)， 2.38 —2.47(t，1Η)，3.40 — 3.51(m，2H)，3.84 —3·93(寬，1Η)，4.09—4.19(dd 200401634 ，lH)，5.38 — 5.45(dd，lH)，7.12 — 7.20(d，2H)，7.32—7.38(d，2H)，7.41 — 7.55(m，3H)，7.72—7.86(dd，4H)，7.89—7.97(d，2H)，8.08 —8.18(dd，4H) ，8.58 —8.65(t，1H) ; HPLC—MS(方法 C) : m/z=604(M+l) ; Rt=6.57 分鐘。實例95( —般程序（E)) 3 — {4 — [2 —二苯基一4—基一 4—氧一 4 一（4 一三氟化甲氧基苯基）丁醯]苯甲醯胺基} - 2R-羥基丙酸^ NMIKDMSO — dJ selection: δ1 · 15 — 1.39 (η, 5H), 1.62 — 1.79 (m, 5H), 2.38 — 2.47 (t, 1Η), 3.40 — 3.51 (m, 2H), 3.84 — 3. · 93 (width, 1Η), 4.09—4.19 (dd 200401634, 1H), 5.38—5.45 (dd, 1H), 7.12—7.20 (d, 2H), 7.32—7.38 (d, 2H), 7.41—7.55 (m, 3H), 7.72—7.86 (dd, 4H), 7.89—7.97 (d, 2H), 8.08—8.18 (dd, 4H), 8.58—8.65 (t, 1H); HPLC-MS (Method C): m / z = 604 (M + l); Rt = 6.57 minutes. Example 95 (General Procedure (E)) 3 — {4 — [2-diphenyl-4—yl-4—oxy-4— (4-trifluoromethoxyphenyl) butyrene] benzophenazine Amine}-2R-hydroxypropionic acid

啦 NMR(CDC13) : δ3.32(1Η，d)，3·89(2Η，bd)，4·23(1Η，dd)，4.44(1H ，bs)，5.33(1H，d)，7·06(1Η，bs)，7.3—7·7(11Η，m)，7·80(2Η，d)， 8.05(2H，d)，8.10(2H，d)。HPLC—MS(方法 A) : m/z=606(M+l) ; Rt=5O8 分鐘。實例96( —般程序（E)) 3 — {4 — [4 一（4 一環己基苯基）一 2—(4-異丙基苯基）一 4 —氧—丁醯]苯甲醯胺基} —2 — (R)-羥基丙酸NMR (CDC13): δ3.32 (1Η, d), 3.89 (2Η, bd), 4.23 (1Η, dd), 4.44 (1H, bs), 5.33 (1H, d), 7.06 (1Η, bs), 7.3-7 · 7 (11Η, m), 7.80 (2Η, d), 8.05 (2H, d), 8.10 (2H, d). HPLC-MS (Method A): m / z = 606 (M + 1); Rt = 5O8 minutes. Example 96 (General Procedure (E)) 3 — {4 — [4 mono (4 monocyclohexylphenyl) 2- (4-isopropylphenyl) 4- 4-oxo-butanyl] benzylamine } —2 — (R) -hydroxypropionic acid

145 200401634 怕 NMR(DMS〇 — d6)選定：31.13(d，6H)，1.10—1.50(m，5H)，1.65 — 1.90(m，5H)，2.57(m，1H)，2.80(m，1Η)，4_02-4.15(m，3H)，5.39(dd， 1H)，7.16(d，2H)，7.35(dd，4H)，7.93(d，4H)，8.13(d，2H)，8.63(brm， 1H)。一般程序（F) 溶液相合成式（I4)化合物的一般程序（F): 〇145 200401634 Afraid of NMR (DMS 0-d6) selection: 31.13 (d, 6H), 1.10-1.50 (m, 5H), 1.65-1.90 (m, 5H), 2.57 (m, 1H), 2.80 (m, 1Η) , 4_02-4.15 (m, 3H), 5.39 (dd, 1H), 7.16 (d, 2H), 7.35 (dd, 4H), 7.93 (d, 4H), 8.13 (d, 2H), 8.63 (brm, 1H ). General procedure (F) General procedure (F) for solution phase synthesis of compound of formula (I4): 〇

其中X，D，E，m，η和R4是如式（I)中所定義者，及 _ Pg是一標準羧酸保護基，像甲基，乙基，丙基，異丙基，叔一丁基或苯甲基。此程序在以下實例中說明。實例97( —般程序（F)) (Z) - 3 — {4 — [4 — (4 - 叔—丁基苯基）—2 — (4 - 環己基苯基）一 4 —氧丁 — 2—烯醯]苯甲醯胺基} — 2R-羥基丙酸 146 200401634Where X, D, E, m, η and R4 are as defined in formula (I), and _ Pg is a standard carboxylic acid protecting group, such as methyl, ethyl, propyl, isopropyl, tertiary Butyl or benzyl. This procedure is illustrated in the following example. Example 97 (General procedure (F)) (Z)-3 — {4 — [4 — (4-tert-butylphenyl) — 2 — (4-cyclohexylphenyl) — 4 —oxetane — 2 —Ene 醯] benzylamino} — 2R-hydroxypropionic acid 146 200401634

一 2 — (4 一環 ί^ι 知一基）—4 —氧丁酿1苯甲酿胺甚} — 9 R —頸基丙酸A 2 — (4 a ring 一 ^ know a radical) — 4 — oxetamine 1 benzylamine} — 9 R — neck propionic acid

此化合物依據一般程序（Ε)合成而得步驟4·This compound was synthesized according to the general procedure (E). Step 4 ·

環己某苯某J 丙酸丁 — 2—烯醯1苯甲醯胺黾丨-冰―羥某將3二ί4〜[4 一（4 一叔一丁基苯基）—2一（4 一環己基苯土) *氧丁酸]苯甲醯胺基} 一 2R —經基丙酸（350毫克， 0.599毫旲耳）溶於THF(5毫升），加入dbu(〇323毫升， 2·16笔旲耳）及結晶碘（183毫克，0.719毫莫耳），混合物在室溫下攪泮30分鐘，及倒入DCM(100毫升），和以亞硫酸水溶液（2% ’ 50毫升）洗滌，有機相以hC1(1N，50毫升）水溶液洗滌，乾燥（Na2S04)，及蒸發至乾，可得一 3- {4- [4 一（4 —叔一丁基苯基）一 2 — (4 —環己基苯基）—4 —氧丁一 2 一烯醯]苯甲醯胺基} 一 2R-羥基丙酸之E和Z混合物。 "HNMRCCDCy : δ1·28 和 1.32(9H，s，二個吸收峰），1.15 —1·40(5Η， m)，1.60—1·85(5Η，m)，2.36 和 2·50(1Η，m，二個吸收峰），4·38(1Η，q)， 6.88 和 7·62(1Η，s，二個吸收峰），7·〇1(1Η，d)，7.13—7·25(2Η，dd)，7.30 147 200401634 —7·40(2Η，m)，7·45(2Η，dd)，7.73 —8·00(6Η，m)0 步驟5 :製備(7) - 3-丨4 —「4 - (4 —叔一丁基苯基2R 一（4 —環己某一 4 一氧丁- 2-烯醯1苯甲醯胺基1 — 2R -羥某丙酸將3- {4 一 [4 一（4 一叔一丁基苯基）一 2-（4 一環己基苯基）一 4 一氧丁一2-烯醯]苯甲醯胺基} 一 2R-羥基丙酸之E 和Z混合物溶於甲苯（25毫升），加入濃HCU37%，900微升 )，及加熱混合物至迴流溫度持續1小時，蒸發溶劑，真空下乾燥過夜後可得（Z) - 3 - {4 一 [4 一（4 一叔一丁基苯基）一 2 一（4 一環己基苯基）一 4—氧丁— 2—烯醯]苯甲醯胺基} — 2R 一羥基丙酸。 ^NMIKCDCy : δ1·32(9Η，s)，1·15-1·42(5Η，m)，1·60—1·90(5Η， m)，2·50(1Η，m)，3·78(1Η，m)，3·88(1Η，m)，4.38(1Η，m)，7·22(2Η，d) ，7·46(2Η，d)，7·48(2Η，d)，7·61(1Η，s)，7·78(2Η，d)，7·88(2Η，d)， 7·98(2Η，d)，HPLC—MS(方法 D) : m/z=582(M+l)，Rt=5.40 分鐘。實例98( —般程序（F)) (Z) - 3 — {4 — [4 一（4一叔—丁基苯基）一 2 -（4一環己基苯基）一 4一氧丁一 2 —烯醯]苯甲醯胺基} — 2R-羥基丙酸Cyclohexane, Benzene, J, Butyl propionate, 2-benzidine, 1 benzamidine, 冰 -ice-hydroxyl, 3, 2 ~ 4, [4 ((t-tert-butylphenyl)), 2- (4, one-ring) Hexyl phenyl earth) * oxobutyric acid] benzamidine amine}-2R —Ethyl propionic acid (350 mg, 0.599 millitorr) was dissolved in THF (5 ml), and dbu (0323 ml, 2.16 pens) was added.旲) and crystalline iodine (183 mg, 0.719 mmol), the mixture was stirred at room temperature for 30 minutes, and poured into DCM (100 ml), and washed with an aqueous sulfurous acid solution (2% '50 ml), organic The phases were washed with an aqueous solution of hC1 (1N, 50 ml), dried (Na2S04), and evaporated to dryness to obtain a 3- {4- [4 ((4-tert-butylphenyl)) 2-(4-cyclo Hexylphenyl) -4-oxobutane-2 monoene fluorene] benzamidine amino}-2R-hydroxypropionic acid mixture of E and Z. " HNMRCCDCy: δ1 · 28 and 1.32 (9H, s, two absorption peaks), 1.15-1 · 40 (5Η, m), 1.60-1 · 85 (5Η, m), 2.36 and 2.50 (1Η, m, two absorption peaks), 4.38 (1Η, q), 6.88 and 7.62 (1Η, s, two absorption peaks), 7.01 (1Η, d), 7.13-7.25 (2Η , Dd), 7.30 147 200401634 — 7.40 (2Η, m), 7.45 (2Η, dd), 7.73 — 8.00 (6Η, m) 0 Step 5: Preparation (7)-3- 丨 4 — "4-(4-tert-butylphenyl 2R- (4-cyclohexyl-4 4-oxo-2-ene-1 benzamidine 1-2R-hydroxypropionic acid will be 3- {4- [4-mono (4-tert-butylphenyl) -2- (4-cyclohexylphenyl) -4-oxobut-2-enyl] benzylamino} E and Z of 2R-hydroxypropionic acid The mixture was dissolved in toluene (25 ml), concentrated HCU 37%, 900 μl) was added, and the mixture was heated to reflux temperature for 1 hour, the solvent was evaporated, and dried under vacuum overnight to obtain (Z)-3-{4 一 [4 Mono (4-tert-butylphenyl)-2 (4-cyclohexylphenyl) -4-oxobut-2-enyl] benzamidinyl} — 2R monohydroxypropionic acid. ^ NMIKCDCy: δ1 · 32 (9 , S), 1.15-1.42 (5Η, m), 1.60-1.90 (5Η, m), 2.50 (1Η, m), 3.78 (1Η, m), 3. · 88 (1Η, m), 4.38 (1Η, m), 7.22 (2Η, d), 7.46 (2Η, d), 7.48 (2Η, d), 7.61 (1Η, s), 7.78 (2Η, d), 7.88 (2Η, d), 7.98 (2Η, d), HPLC-MS (Method D): m / z = 582 (M + 1), Rt = 5.40 minutes Example 98 (General Procedure (F)) (Z)-3 — {4 — [4 mono (4-tert-butylphenyl) 2- 2- (4-cyclohexylphenyl) 4-oxobutane-2 —Ene 醯] benzylamido} — 2R-hydroxypropionic acid

148 200401634 ^NMRCCDCIJ : δ1·18 —1·41(5Η，m)，1.60—1·90(5Η，m)，2·47(1Η， m)，3.75(2H，m)，4.32(lH，m)，7.19(2H，d)，7.29—7.50(6H，m)，7.52— 7·67(4Η，m)，7·71(2Η，d)，7·92(2Η，d)，7·98(2Η，d)。實例99( 一般程序（F))實例42的化合物也可如下所述之依據一般程序（F)製備而得= (Z)—3 — {4 — [2 ——> 苯某—4 一某一 4 一氯一 4—(4 一二親化甲氧基苯基）丁-2-烯醯]苯甲醯胺基}-2R-羥基丙酸148 200401634 ^ NMRCCDCIJ: δ1 · 18 -1 · 41 (5Η, m), 1.60-1 · 90 (5Η, m), 2.47 (1Η, m), 3.75 (2H, m), 4.32 (lH, m ), 7.19 (2H, d), 7.29-7.50 (6H, m), 7.52-7.67 (4Η, m), 7.71 (2Η, d), 7.92 (2Η, d), 7.98 (2Η, d). Example 99 (General Procedure (F)) The compound of Example 42 can also be prepared according to General Procedure (F) as follows = (Z) —3 — {4 — [2 —> Benzene—4—A 4- (4-Chloro-4)-(4-dihydrophilic methoxyphenyl) but-2-enefluorenyl] benzamidinylamino} -2R-hydroxypropionic acid

HPLC—MS(方法 A) : m/z=604(M+l) ; Rt=4.98 分鐘。 ’ 實例1〇〇( —般程序（F)) (Z)—3 — {4一 [4 一（4 一環己基苯基）一 2 -（4 —異丙基苯基）一 4一氧丁一 2 -烯醯]苯甲醯胺基} 一 2R-羥基丙酸HPLC-MS (Method A): m / z = 604 (M + 1); Rt = 4.98 minutes. '' Example 100 (General Procedure (F)) (Z) — 3 — {4— [4— (4-Cyclohexylphenyl) —2— (4-Isopropylphenyl) —4—Oxidine— 2 -ene fluorene] benzamidine amino} 2R-hydroxypropionic acid

"FiNMI^CDCy : 51.18(d，6H)，1.10-1.50(m，5H)，1.60—1.93(m， 149 200401634 5H)，2.52(m，1H)，2.88(m，1H)，3.70(m，2H)，4.37(brs，1H)，7.23(dd， 4H)，7.44(d，2H)，7.58(s，1H)，7.70—8.00(m，6H)。HPLC—MS(方法 D): m/z=568(M+l) ; Rt=5.34 分鐘。實例101( —般程序(F)) s (Z) — 3 - {4一 [2 -（4一環己基苯基）一 4一（3，5 —二氯化苯基）一 4一氧丁-2-烯醯]苯甲醯胺基}丙酸" FiNMI ^ CDCy: 51.18 (d, 6H), 1.10-1.50 (m, 5H), 1.60—1.93 (m, 149 200401634 5H), 2.52 (m, 1H), 2.88 (m, 1H), 3.70 (m , 2H), 4.37 (brs, 1H), 7.23 (dd, 4H), 7.44 (d, 2H), 7.58 (s, 1H), 7.70-8.00 (m, 6H). HPLC-MS (method D): m / z = 568 (M + 1); Rt = 5.34 minutes. Example 101 (General Procedure (F)) s (Z) — 3-{4-[[2-(4-Cyclohexylphenyl)-4-(3, 5-Dichlorophenyl)-4-Oxidine- 2-enefluorene] benzylamido} propionic acid

iHNMI^CDCld : δ1·18—1·48(ιη，5H)，1.65 —1.94(m，5H)，2.50(m， 1H)，2.66(t，2H)，3.67(ci，2H)，6.94(brs，1Η)，7.15(d，2H)，7.22(d，2H) ，7.49(m，3H)，7.86(m，3H)，7.94(d，2H) ; HPLC—MS(方法 D): m/z=579(M+l) ; Rt=5.60 分鐘。一般程序（G) 溶液相合成式（I4)化合物的一般程序（G):iHNMI ^ CDCld: δ1 · 18-1 · 48 (ιη, 5H), 1.65-1.94 (m, 5H), 2.50 (m, 1H), 2.66 (t, 2H), 3.67 (ci, 2H), 6.94 (brs , 1Η), 7.15 (d, 2H), 7.22 (d, 2H), 7.49 (m, 3H), 7.86 (m, 3H), 7.94 (d, 2H); HPLC-MS (Method D): m / z = 579 (M + l); Rt = 5.60 minutes. General procedure (G) General procedure (G) for synthesis of compound of formula (I4) in solution phase:

EE

Pg 、又Pg, again

EE

步驟I 步驟2 150 200401634Step I Step 2 150 200401634

(丨 4) (E) + (Z) (l4) (Z) 其中X，D，E，m，η和R4是如式⑴中所定義者，及 Pg是一標準羧酸保護基，像甲基，乙基，丙基，異丙基，叔一丁基或苯甲基。實例102( —般程序（G))。實例65的化合物也可依據一般程序（G)的方法製得，說明如下： 3—Η - [2 — [4—(2, 2 —二甲基—丙基）_ 苯基]—4 一氧一 4 — (4一三氟化甲氧基苯基）一丁一 2一烯醯]苯甲醯胺基} 丙酸(丨 4) (E) + (Z) (l4) (Z) where X, D, E, m, η, and R4 are as defined in formula ⑴, and Pg is a standard carboxylic acid protecting group, such as formazan Group, ethyl, propyl, isopropyl, tert-butyl or benzyl. Example 102 (General Procedure (G)). The compound of Example 65 can also be prepared according to the method of General Procedure (G), which is illustrated as follows: 3—fluorene-[2 — [4— (2, 2-dimethyl-propyl) _phenyl] -4 monooxyl Mono 4- (4-trifluoromethoxyphenyl) monobutyr-2 monoene} benzamidine amino} propanoic acid

步驟1和步驟2 : 4 -「2 -『4一（2，2-二甲基丙基）苯某 1一 4一氧一 4一 (4 —三氟化甲氧某苯基）一丁醯1苯甲酸一混合物，包括3 - [4一（2, 2-二甲基丙基）苯基]一 1 一（4 一三氟化甲氧基苯基）丙烯酮（10.51克；29毫莫耳 )(Building Block 8)，3，4—二甲基一5—(2-經基乙基）噻哇 151 200401634 鑰碘化物（1.77克，6.2毫莫耳）及三乙胺（3.52毫升；25.27 毫莫耳），在一 100毫升無水乙醇中攪拌迴流加熱，接著以液滴的方式加入一含甲基4一甲醯苯甲酸酯（6.8克，41.4毫莫耳）溶於50毫升無水乙醇的溶液，持續攪拌和加熱16小時，冷卻混合物及以IN HC1(150毫升）和DCM(200毫升）分離混合物，分離出有機相，水溶液相再以DCM(200毫升）萃取，結合各個DCM萃取液，及以水洗滌，乾燥（Na2S〇4)，及澄淸（Norite A)，過濾和蒸發，可得14克（80%)的中間酯化合物。將此溶物溶於80毫升甲醇，加入一含氫氧化鈉 (2.68克，67.1毫莫耳）溶於10毫升水的溶液至此混合物中，持續攪拌直至酯起始物質消失爲止。PH値以稀氫氯酸調整爲2，過濾出沈澱物，及乾燥後可得10.3克的4一 [2 - [4 — (2, 2—二甲基丙基）苯基]一 4 一氧一（4 一三氟化甲氧基苯基）丁醯]苯甲酸。 iHNMIKCDCy : 38.12(d，2H)，8.09(d，2H)，8.02(d，2H)，7.28(d， 2H)，7.21(d，2H)，7.08(d，2H)，5.25(dd，1H)，4.20(m，1Η)，3.30(dd，1H) ，2.43(s，2H)，0.88(s，9H)。步馬聚 3 :製備(E，Z)—4 -「2 —「4—(2，2 —二甲基丙基) 苯基1 一 4 一氧一 4 一（4 一三氟化甲氣某苯基）丁一 2—烯醯1苯甲酸將4 — [2 — [4—(2，2 — 一甲基丙基）苯基]—4 —氧一 4 — (4一三氟化甲氧基苯基）丁醯]苯甲酸（9.3克；20.1毫莫耳）溶於丁1^(700毫升），攪拌混合物，同時加入碘（6.34克；24.1 毫莫耳）及DBU(11克；42.4毫莫耳）。攪拌混合物2小時及 152 200401634 在減壓下濃縮爲約100毫升的體積。加入2%亞硫酸鈉（150 毫升）溶液及1N氫氯酸（150毫升），混合物以DCM(2x300毫升）萃取，及以鹽水（400毫升）洗滌，分離出有機相，乾燥 (Na2S04)，及以Norite A澄淸溶液，過濾和蒸發後可得8.2 克（88%)的（E，Z)—4—[2 — [4 一（2，2— 二甲基丙基）苯基]一 4 一氧一 4 一（4 —三氟化甲氧基苯基）丁一 2 -烯醯]苯甲酸。 HPLC—MS(方法 A) : m/z=511(M + l) ; Rt=5.60 分鐘。步驟4和步驟5 :製備（Z) — 3 —丨4一「2 —「4 — (2，2 —二見基—丙基）一苯基1一 4 一氧一 4 — (4 —三氬化甲氬某一苯某 h 丁一 2 —烯醯1 —苯甲醯胺某丨丙酸攪拌一含有（E，Z) - 4 一 [2 - [4 一（2，2-二甲基丙基）苯基]一 4一氧一 4 一（4 一三氟化甲氧基苯基）丁一 2 —稀醯]苯甲酸（7.2克；14.1毫莫耳）溶於20毫升DMF的溶液，且同時加入1 一羥基苯並***水合物（2.29克；19.9毫莫耳），持續在室溫下攪拌混合物1小時，接著分別加入EDAC(3.24克 ;16.92毫莫耳），甲基3 —胺基丙酸酯氫氯化物（2.95克； 21.16毫莫耳）及DIPEA(7.37毫升；42.31毫莫耳），接著在溫度40°C下攪拌混合物2小時，及在減壓下蒸發混合物，殘留物以水和乙酸乙酯分離，分出有機相，及以鹽水洗滌 ’乾燥（Na2S04)和蒸發，殘留物溶於一含甲醇（80毫升）和 THF(20毫升）的混合物中，加入氫氧化鈉（1.69克；42.3毫莫耳）/10毫升水，在室溫下攪拌混合物1.5小時，及在減壓下濃縮混合物至約30毫升，加入40毫升的水，及加入1M 氫氯酸調整pH値爲1.5，過濾出沈澱物，乾燥後可得7.9 153 200401634 克的粗物質。此物質在甲苯（100毫升）和濃氫氯酸（2.7毫升) 的混合物中沸騰1小時，及冷卻混合物至室溫，過濾出沈澱物，可得5.6克（68%)的標題化合物。屯 NMR(CDC13) ·· δ8·02(ιη，很），7.80(d，2H)，7.60(s，1H)，7.48(d， 2H)，7.30(d，Η) ; 7.18(d，2H)，6.84(t，1Η)，3.63(q，2H)，2.72(t，2H)， 2.50(s，2H)，0.90(s，9H) ; HPLC -MS(方法 A) : m/z=583_) ; Rt=5.03 分鐘。實例103 3 - {4 一 [4 一（4 一叔一丁基苯基）—4 —氧—2 -（4 一三氟化甲氧基苯基）丁醯]苯甲醯胺基}丙酸Steps 1 and 2: 4-"2-" 4-((2,2-dimethylpropyl) benzene 1- 4 -oxy 4-(4 -trifluoromethoxy phenyl) monobutylene A mixture of 1 benzoic acid, including 3-[4-((2,2-dimethylpropyl) phenyl]]-1-(4-trifluoromethoxyphenyl) propenone (10.51 g; 29 mmol) (Ear) (Building Block 8), 3,4-Dimethyl-5 (2-Aminoethyl) thiawa 151 200401634 Key iodide (1.77 g, 6.2 mmol) and triethylamine (3.52 ml; 25.27 mmol), heated under stirring in 100 ml of absolute ethanol, and then added a methyl 4-methylammonium benzoate (6.8 g, 41.4 mmol) in 50 ml of water in the form of droplets The ethanol solution was continuously stirred and heated for 16 hours. The mixture was cooled and the mixture was separated with IN HC1 (150 ml) and DCM (200 ml). The organic phase was separated. The aqueous phase was extracted with DCM (200 ml) and combined with each DCM. Liquid, and washed with water, dried (Na2SO4), and clarified (Norite A), filtered and evaporated to obtain 14 g (80%) of the intermediate ester compound. This solution was dissolved in 80 ml Alcohol, add a solution containing sodium hydroxide (2.68 g, 67.1 mmol) in 10 ml of water to this mixture, and continue stirring until the ester starting material disappears. The pH is adjusted to 2 with dilute hydrochloric acid and filtered. Precipitate and 10.3 g of 4-[[2-[4- — (2, 2-dimethylpropyl) phenyl]]-4 -oxo- (4-trifluoromethoxyphenyl) ) Butyrate] benzoic acid. IHNMIKCDCy: 38.12 (d, 2H), 8.09 (d, 2H), 8.02 (d, 2H), 7.28 (d, 2H), 7.21 (d, 2H), 7.08 (d, 2H) , 5.25 (dd, 1H), 4.20 (m, 1Η), 3.30 (dd, 1H), 2.43 (s, 2H), 0.88 (s, 9H). Buma Poly 3: Preparation of (E, Z) -4- "2-" 4- (2,2-dimethylpropyl) phenyl 1-4-oxygen-4-(4-trifluoromethane, a phenyl) butan 2-ene, 1 benzoic acid, 4 — [2 — [4- (2,2-Methylpropyl) phenyl] -4—Oxy-4— (4-trifluoromethoxyphenyl) butyrene] benzoic acid (9.3 g; 20.1 Millimolar) was dissolved in 1ml (700ml), and the mixture was stirred while adding iodine (6.34g; 24.1mmol) and DBU (11g; 42.4mmol). It was concentrated for 2 hours and 152 200401634 under reduced pressure to a volume of about 100 ml. 2% sodium sulfite (150 ml) solution and 1N hydrochloric acid (150 ml) were added, and the mixture was extracted with DCM (2x300 ml) and brine ( (400 ml), washed, separated the organic phase, dried (Na2S04), and clarified with Norite A, filtered and evaporated to obtain 8.2 g (88%) of (E, Z) —4— [2 — [4 1 (2,2-Dimethylpropyl) phenyl] -4,4-oxy-1,4- (4-trifluoromethoxyphenyl) butan-2-enefluorene] benzoic acid. HPLC-MS (Method A): m / z = 511 (M + l); Rt = 5.60 minutes. Step 4 and Step 5: Preparation of (Z) — 3 — 丨 4— “2 —“ 4 — (2,2 —di-radyl-propyl) -phenyl 1—4—oxy-4— (4—triargonization Methyl argon, a benzene, a butan-2, ene-1, a benzamidine, a propionic acid, and a mixture containing (E, Z)-4 a [2-[4 a (2,2-dimethylpropyl) ) Phenyl] -4,4-oxy-4,4- (4-trifluoromethoxyphenyl) butan-2-dilute fluorene] benzoic acid (7.2 g; 14.1 mmol) in 20 ml of DMF, and At the same time, 1 monohydroxybenzotriazole hydrate (2.29 g; 19.9 mmol) was added, and the mixture was continuously stirred at room temperature for 1 hour, followed by EDAC (3.24 g; 16.92 mmol), methyl 3-amine, respectively. Propionate hydrochloride (2.95 g; 21.16 mmol) and DIPEA (7.37 ml; 42.31 mmol), followed by stirring the mixture at a temperature of 40 ° C for 2 hours, and evaporating the mixture under reduced pressure, the residue Separate with water and ethyl acetate, separate the organic phase, wash with brine, dry (Na2S04) and evaporate. The residue is dissolved in a mixture containing methanol (80 ml) and THF (20 ml), and hydrogen is added. Sodium (1.69 g; 42.3 mmol) / 10 ml of water, the mixture was stirred at room temperature for 1.5 hours, and the mixture was concentrated to about 30 ml under reduced pressure, 40 ml of water was added, and 1M hydrochloric acid was added to adjust the pH Is 1.5, the precipitate is filtered off, and 7.9 153 200401634 g of crude material is obtained after drying. This material is boiled in a mixture of toluene (100 ml) and concentrated hydrochloric acid (2.7 ml) for 1 hour, and the mixture is cooled to room temperature. The precipitate was filtered off to obtain 5.6 g (68%) of the title compound. NMR (CDC13) δ δ 8.02 (ιη, very), 7.80 (d, 2H), 7.60 (s, 1H), 7.48 (d, 2H), 7.30 (d, Η); 7.18 (d, 2H), 6.84 (t, 1Η), 3.63 (q, 2H), 2.72 (t, 2H), 2.50 (s, 2H), 0.90 ( s, 9H); HPLC-MS (method A): m / z = 583_); Rt = 5.03 minutes. Example 103 3-{4-[4-(4-tert-butylphenyl) -4 -oxo- 2-(4-trifluoromethoxyphenyl) butyridine] benzylamino} propionic acid

步驟 1 : 4~|~4—(4—叔—丁基苯）一4—氧—2—(4—三氟化甲氣基苯某）丁醯1茏甲酸甲基酯Step 1: 4 ~ | ~ 4— (4-tert-butylbenzene) —4-oxy-2— (4-trifluoromethanebenzene) —butyridine 1 acetic acid methyl ester

於一乾燥三頸50毫升的圓底燒瓶中，在氮氣氣氛之下放入1— (4 一叔一丁基苯基）一 3 -（4 一三氧化甲氧基苯基）丙烯酮（9.47克，27.18毫莫耳），3，4一二甲基一 5—（2-經基乙基）噻唑鑰碘化物（7.75克，27.18毫莫耳）及三乙胺（13.26 毫升，95.13毫莫耳）。將此混合物溶於一迴流乙醇（45毫升，99%)，接著以液滴的方式在大約2又1/2小時的時間內加 154 200401634 入一含3 —（4一甲醯苯甲醯胺基）丙酸甲基酯（6.97克，40.77 毫莫耳）溶於乙醇（50毫升，99%)，及在氮氣氣氛之下迴流混合物5小時，之後冷卻及蒸發至乾。殘留油狀物溶於 DCM(l〇〇毫升），及以IN HCU150毫升）萃取，水溶液相再以DCM(50毫升）萃取一次，收集各個不同有機相，以硫酸鎂乾燥，過濾和蒸發至乾，可得4一 [4一（4-叔一丁基苯基）一 4 一氧一 2 —（4 一三氟化甲氧基苯基）丁醯]苯甲酸甲基酯 (16.9 克）。 HPLC—MS(方法 C) : m/z=513(M+l) ; Rt=7.33 分鐘。步驟 2:4—「4 一（4 一叔—丁基苯基4 一氧一 2—(4 — Ξ氟化甲氢某苯某）丁醯1苯甲酸將4 — [4 — (4 —叔—丁基苯基）—4 一氧一 2 -（4 一三氟化甲氧基苯基）丁醯]苯甲酸甲基酯（13.9克，27.2毫莫耳）懸浮於乙醇（120毫升，96%)中，加入氫氧化鈉（4N，27.2毫升）。4又1/2小時後，蒸發反應物至乾，加入水（200毫升）和氫氯酸（4N，30毫升）至殘留物中，調整pH値爲1一 2，使其開始沈澱。攪拌混合物1/2小時，過瀘出沈澱物，及小心以水洗滌，及在溫度40°C及真空下乾燥過夜，殘留物由甲醇和水中結晶，可得4一 [4一（4一叔一丁基苯基）一4一氧一2 一（4一三氟化甲氧基苯基）丁醯]苯甲酸（10.4克）。 HPLC—MS(方法 D) ·· m/z=499(M+l) ; Rt=5.51 分鐘。 3 —丨4—「4—(4 一叔—丁基苯基）一 4 —氧—2—(4 —三氬化甲氧某苯基）丁醯1苯甲醯胺某丨丙酸甲基酯將4 —[4-(4—叔一丁基苯基)—4-氧—2-(4一三氟化甲氧基苯基)丁 200401634 醯]苯甲酸（10.4克，20.86毫莫耳）溶於DMF(150毫升），加入 EDAC(5.60 克，29.20 毫莫耳）及 H〇Bt(4.23 克，31.29 毫莫耳）。1/2小時後，加入一含β -丙氨酸甲基酯氫氯化物 (4.37克，31.29毫莫耳）和DIPEA(5.36毫升，31.29毫莫耳) 溶於DMF(20毫升）的溶液至此混合物中，及攪拌反應混合物過夜。濃縮反應混合物至約100毫升，加入水（200毫升) ，及以乙酸乙酯（200毫升）萃取。水溶液相另外以乙酸乙酯 (75毫升）萃取，結合各個有機相層，及以氫氯酸（0.2N， 3x150毫升），氯化鈉水溶液（50%飽和溶液，3x150毫升）洗滌，乾燥（硫酸鎂）。過濾乾燥後的有機相，及蒸發至乾，可得3 - {4 — [4 一（4—叔一丁基苯基）一 4 —氧一 2—(4 -三氟化甲氧基苯基）丁醯]苯甲醯胺基}丙酸甲基酯（12.76克）。 HPLC—MS(方法 D) : m/z=584(M+l) ; Rt=5.48 分鐘。步驟 4:3- ί4—「4—(4—叔一丁基苯基）—4一氧—2 — (4一三氟化甲氣基苯基）丁醯1苯甲醯胺基丨丙酸將 3— {4 一 [4 一（4 一叔一丁基苯基）—4 一氧一 2 — (4 —二氟化甲氧基苯基）丁醯]苯甲醯胺基}丙酸甲基酯（12克，21 毫莫耳）溶於乙醇96%(250毫升），加入4Ν Na〇H(31.2毫升，125毫莫耳），及攪拌2小時45分鐘。在真空下濃縮反應混合物，殘留物懸浮於水（150毫升），及加入氫氯酸（4N， 34毫升），使pH値爲1一 2。1小時後，過濾出沈澱物，及以水小心洗滌，及乾燥。殘留物以HPLC層析純化，洗提劑爲乙腈（梯度溶劑，從42%至97.5%)，水和TFA(2.5%)，可得4.7克的標題化合物。 156 200401634 iHNMIKDMSO-d6)選定的數據：δ8·68(ΐ，1Η)，8.15(d，2H)，7.93(m ，4H)，7.56(m，4H)，7.33(d，2H)，5.51(m，1H)，4.10(m，1H)，3.45(m， 4H)，1.31(s，9H) ; HPLC—MS(方法 A) : m/z=570(M+l) ; Rt=5.95 分鐘。實例104 3 — {4 — [4 -（4 一叔—丁基苯基）一 4 一氧—2 -（4 一三氟化甲氧基苯基）丁醯]苯甲醯胺基}一 2R-羥基丙酸In a dry three-necked 50 ml round-bottomed flask, put 1- (4-tert-butylphenyl) -3-(4-trimethoxymethoxyphenyl) propenone (9.47) under a nitrogen atmosphere. G, 27.18 mmoles), 3,4-dimethyl-5- (2-transylethyl) thiazole key iodide (7.75 g, 27.18 mmoles) and triethylamine (13.26 ml, 95.13 mmoles) ear). This mixture was dissolved in a refluxing ethanol (45 ml, 99%), and then 154 200401634 was added in a dropwise manner over a period of about 2 1/2 hours into a solution containing 3- (4-methylformyl benzamidine Methyl) propionate (6.97 g, 40.77 mmol) was dissolved in ethanol (50 ml, 99%), and the mixture was refluxed under a nitrogen atmosphere for 5 hours, then cooled and evaporated to dryness. The residual oil was dissolved in DCM (100 mL) and extracted with IN HCU 150 mL). The aqueous phase was extracted once more with DCM (50 mL). The different organic phases were collected, dried over magnesium sulfate, filtered and evaporated to dryness. , 4- [4- (4-tert-butylphenyl)-4 -oxo-2- (4-trifluoromethoxyphenyl) butyrene] benzoic acid methyl ester (16.9 g) can be obtained. HPLC-MS (method C): m / z = 513 (M + 1); Rt = 7.33 minutes. Step 2: 4— "4-mono (4-t-tert-butylphenyl 4-mono-oxo-2— (4--fluorinated methyl hydrogen fluoride, benzene, benzene) butanthine-1 benzoic acid will be 4-[4-(4-tertiary —Butylphenyl) —4-monooxy-2— (4-trifluoromethoxyphenyl) butyrene] benzoate methyl ester (13.9 g, 27.2 mmol) suspended in ethanol (120 ml, 96 %), Add sodium hydroxide (4N, 27.2 ml). After another 1/2 hour, evaporate the reaction to dryness, add water (200 ml) and hydrochloric acid (4N, 30 ml) to the residue, Adjust the pH to 1 to 2 to start precipitation. Stir the mixture for 1/2 hour, decanter the precipitate, and carefully wash with water, and dry at 40 ° C under vacuum overnight. The residue is made from methanol and water. Crystallization yielded 4- [4- (4-t-tert-butylphenyl) -4-oxo-2- (4-trifluoromethoxyphenyl) butyrene] benzoic acid (10.4 g). HPLC— MS (Method D) ·· m / z = 499 (M + 1); Rt = 5.51 minutes. 3 — 丨 4— “4— (4-tert-butylphenyl) —4-oxy-2— (4 —Triargonated methoxy, a phenyl) butanidine, 1 benzamidine, a methyl propionate, 4 — [4- (4-tert-Butylphenyl) -4-oxo-2- (4-trifluoromethoxyphenyl) butane 200401634 醯] benzoic acid (10.4 g, 20.86 mmol) was dissolved in DMF (150 ml), add EDAC (5.60 g, 29.20 mmol) and HOBt (4.23 g, 31.29 mmol). After 1/2 hour, add a β-alanine methyl ester hydrochloride (4.37 g, 31.29 mmol) and DIPEA (5.36 mL, 31.29 mmol) were dissolved in DMF (20 mL) to this mixture, and the reaction mixture was stirred overnight. The reaction mixture was concentrated to about 100 mL, and water ( 200 ml), and extracted with ethyl acetate (200 ml). The aqueous phase was additionally extracted with ethyl acetate (75 ml), combined the organic phase layers, and with hydrochloric acid (0.2 N, 3 x 150 ml), sodium chloride Aqueous solution (50% saturated solution, 3x150 ml) was washed and dried (magnesium sulfate). The dried organic phase was filtered and evaporated to dryness to obtain 3-{4-[4-(4-tert-butylphenyl)) 4-Oxy-2- (4-trifluoromethoxyphenyl) butylammonium] benzylidene} methyl propionate (12.76 g). HPLC-MS (Method D): m / z = 584 (M + l); Rt = 5.48 minutes. Step 4: 3- ί 4— “4— (4-tert-butylphenyl) —4—oxy-2 — (4-trifluoromethane Gasoyl phenyl) butyl hydrazone 1 benzamidine amine 丨 propionic acid will be 3- {4 a [4 a (4-t-t-butylphenyl)-4 a oxy 2-(4-difluorinated methoxy Phenyl) butyridine] benzylamino} methyl propionate (12 g, 21 mmol) was dissolved in 96% ethanol (250 ml) and 4N NaOH (31.2 ml, 125 mmol) was added ), And stir for 2 hours and 45 minutes. The reaction mixture was concentrated under vacuum, the residue was suspended in water (150 ml), and hydrochloric acid (4N, 34 ml) was added to a pH of 1 to 2. After 1 hour, the precipitate was filtered off and carefully washed with water Wash and dry. The residue was purified by HPLC chromatography using acetonitrile (gradient solvent, from 42% to 97.5%) as eluent, water and TFA (2.5%) to give 4.7 g of the title compound. 156 200401634 iHNMIKDMSO-d6) Selected data: δ8 · 68 (ΐ, 1Η), 8.15 (d, 2H), 7.93 (m, 4H), 7.56 (m, 4H), 7.33 (d, 2H), 5.51 (m , 1H), 4.10 (m, 1H), 3.45 (m, 4H), 1.31 (s, 9H); HPLC-MS (Method A): m / z = 570 (M + 1); Rt = 5.95 minutes. Example 104 3 — {4 — [4-(4-tert-butylphenyl)-4 monooxy-2-(4-trifluoromethoxyphenyl) butylammonium] benzamidineamino}-2R -Hydroxypropionic acid

3二」4-『4-(4-叔-丁某茏某）一4-氧-2-(4-=鬼化_里氧盖苯基）丁醯]苯甲醯胺某1 一 W —羥基丙酸甲某峰將4 [4 (4 一叔一丁基本基）一 4 —氧—2 -（4 一三氣化甲氧基苯基）丁醯]苯甲酸（〇·64克，1.28毫莫耳）溶於 DMF(10毫升），及加入EDAC(0.35克，1.8毫莫耳）和 H〇Bt(0.26克）。1/2小時後，加入一含R —異絲氣酸甲基酯氫氯化物（0.30克，1.92毫莫耳）及二異丙基乙基胺（0.31毫升，1.92毫莫耳）溶於DMF(6毫升）的溶液至上述混合物中 ’及在室溫下攪拌16小時。混合物以水（3〇毫升）稀釋，及以乙酸乙酯（30毫升）萃取，水溶液相再以乙酸乙酯（15毫升 )萃取一次，收集各個有機相及以氫氯酸（〇.2N，3x2〇毫升) 157 200401634 ，50%飽和氯化鈉水溶液（3x20毫升）洗滌，乾燥（硫酸鎂），過濾和蒸發至乾，可得0.79克的3- {4一 [4一（4一叔一丁基苯基）一 4一氧一 2—（4 一三氟化甲氧基苯基）丁醯]苯甲醯胺基}-2R-羥基丙酸甲基酯。 HPLC—MS(方法 D) : m/z=600(M+l) ; Rt=5.20 分鐘。將 3—{4—[4—(4—叔一丁基苯基）—4—氧—2—(4-三氟化甲氧基苯基）丁醯]苯甲醯胺基} - 2R—羥基丙酸甲基酯 (0.77克，1.28毫莫耳）溶於乙醇（96%，30毫升），加入氫氧化鈉（4N，1.93毫升），及攪拌2又1/2小時。反應混合物在真空下濃縮，殘留物懸浮於水（30毫升），及加入氫氯酸（4N ，2毫升），使pH爲1一 2。1/2小時後，過濾出沈澱物，小心以水洗滌，及在真空下乾燥，產物以HPLC純化，洗提劑爲乙腈（梯度溶劑，從55.5%至97.5%)，水和TFA(2.5%)，可得0,16克的標題化合物。 d6)選定的數據·· 38.66(t，1H)，8.15(d，2H)，7.93(m ，4H)，7_56(m，4H)，7.33(d，2H) ; 5.53(m，1Η)，4.07-4.20(m，2H)，3.48 —3.63(m，2H)，1.31(s，9H) ; HPLC—MS(方法 C) : m/z=586(M+l) ; Rt=5.42 分鐘。實例105 3— {4 一 [4 一（4 —叔—丁基苯基）—4 一氧一 2 — (4 —三氟化甲氧基苯基）丁-2-烯醯]苯甲醯胺基}-2R-羥基丙酸 158 2004016343 two "4-" 4- (4-tert-butyl amine) -4-oxo-2- (4- = ghosted_Lioxophenyl) butyl amine] benzamidine amine 1-W — A peak of methyl hydroxypropionate will be 4 [4 (4-tert-butylbenzyl) -4-oxo-2-(4-tri-gas-methoxymethoxyphenyl) butyrene] benzoic acid (0.64 g, 1.28 MM) was dissolved in DMF (10 mL), and EDAC (0.35 g, 1.8 mM) and HOBt (0.26 g) were added. After 1/2 hour, add R-isosinic acid methyl ester hydrochloride (0.30 g, 1.92 mmol) and diisopropylethylamine (0.31 ml, 1.92 mmol) to DMF. (6 ml) of the solution into the above mixture 'and stirred at room temperature for 16 hours. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL). The aqueous phase was extracted once more with ethyl acetate (15 mL). Each organic phase was collected and treated with hydrochloric acid (0.2N, 3x2 0 ml) 157 200401634, washed with 50% saturated sodium chloride aqueous solution (3x20 ml), dried (magnesium sulfate), filtered and evaporated to dryness, to obtain 0.79 g of 3- {4 一 [4 一 (4 一叔一丁Phenyl) -4,4-oxy-2— (4-trifluoromethoxyphenyl) butyrene] benzylamino} -2R-hydroxypropionic acid methyl ester. HPLC-MS (Method D): m / z = 600 (M + 1); Rt = 5.20 minutes. Add 3- {4— [4- (4-tert-butylphenyl) -4—oxy-2 -— (4-trifluoromethoxyphenyl) butylammonium] benzamidine}}-2R— Methyl hydroxypropionate (0.77 g, 1.28 mmol) was dissolved in ethanol (96%, 30 ml), sodium hydroxide (4N, 1.93 ml) was added, and stirred for 2 1/2 hours. The reaction mixture was concentrated under vacuum, the residue was suspended in water (30 ml), and hydrochloric acid (4 N, 2 ml) was added to a pH of 1 to 2. After 1/2 hour, the precipitate was filtered off, carefully using water After washing and drying under vacuum, the product was purified by HPLC using acetonitrile (gradient solvent from 55.5% to 97.5%), water and TFA (2.5%) to obtain 0,16 g of the title compound. d6) Selected data: 38.66 (t, 1H), 8.15 (d, 2H), 7.93 (m, 4H), 7_56 (m, 4H), 7.33 (d, 2H); 5.53 (m, 1Η), 4.07 -4.20 (m, 2H), 3.48—3.63 (m, 2H), 1.31 (s, 9H); HPLC-MS (Method C): m / z = 586 (M + 1); Rt = 5.42 minutes. Example 105 3— {4 mono [4 mono (4-tert-butylphenyl) -4 monooxy-2— (4-trifluoromethoxyphenyl) but-2-enefluorene] benzamide Yl} -2R-hydroxypropionic acid 158 200401634

氟化甲基苹基烯醯]苯甲醯胺基} 一基丙酸將得自貫例104的3、{4一[4_(4一叔一丁基苯基卜4 —氧一 2—（4一三氟化甲氧基苯基）丁醯]苯甲醯胺基}—2r_ 羥基丙酸（0·15克，0·24毫奠耳）溶於THF(3毫升），加入 DBU(0.13毫升’ 0.86毫莫耳），碘（〇11克，〇·44毫莫耳），及在室溫下攪拌。蒸發掉溶劑，殘留物溶於DCM(25毫升），及以亞硫酸鈉（2%，10毫升），氯化氫（1N，1〇毫升），水和飽和氯化鈉（2x1 : 1，10毫升）洗滌，乾燥（硫酸鎂），過濾和蒸發至乾，可得0.11克的E和Z異構物的混合物。殘留物溶於甲苯（5毫升），加入濃氫氯酸，及在溫度130°C下，於油浴中迴流加熱，接著冷卻反應混合物及蒸發至乾，然後以DCM(2x5毫升）重覆前述步驟2次。產物以HPLC純化，洗提劑爲乙腈（57.5%至97.5%)，水及TFA(2.5%)，蒸發至乾，可得0.04克的標題化合物。 ^NMIKDMSO—d6)選定的數據：δ8.63(ΐ，1H)，8.05(m，3H)，7.95(d ，2H)，7.91(d，2H)，7.80(d，2H) ; 7.58(d，2H)，7.48(d，2H)，5.48(寬， 1H)，4.15(m，1H)，3.54(m，1H)，1.31(s，9H) : HPLC—MS(方法 C): 159 200401634 m/z=585(M+l) ; Rt=5，78 分鐘。一般程序（Η) 分離式（1〇化合物對掌體的一般程序（Η) ·_ 〇Fluorinated methyl apinyl fluorene] benzamidine amino} monopropionic acid will be obtained from 3, {4— [4_ (4-t-tert-butylphenyl) 4-oxy-2— ( 4-trifluoromethoxyphenyl) butyrazine] benzylamido} -2r_hydroxypropionic acid (0.15 g, 0.24 mmol) was dissolved in THF (3 ml) and DBU (0.13 Ml '0.86 mmol), iodine (0.11 g, 0.44 mmol), and stirred at room temperature. The solvent was evaporated off, the residue was dissolved in DCM (25 ml), and sodium sulfite (2%, 10 ml), hydrogen chloride (1N, 10 ml), washed with water and saturated sodium chloride (2x1: 1,10 ml), dried (magnesium sulfate), filtered and evaporated to dryness, and 0.11 g of E and Z isomers were obtained. The residue was dissolved in toluene (5 ml), concentrated hydrochloric acid was added, and the mixture was heated at 130 ° C under reflux in an oil bath. The reaction mixture was then cooled and evaporated to dryness, then DCM (2x5 Ml) was repeated twice. The product was purified by HPLC using acetonitrile (57.5% to 97.5%) as eluent, water and TFA (2.5%), and evaporated to dryness to obtain 0.04 g of the title compound. d6) select Data: δ8.63 (ΐ, 1H), 8.05 (m, 3H), 7.95 (d, 2H), 7.91 (d, 2H), 7.80 (d, 2H); 7.58 (d, 2H), 7.48 (d , 2H), 5.48 (width, 1H), 4.15 (m, 1H), 3.54 (m, 1H), 1.31 (s, 9H): HPLC-MS (Method C): 159 200401634 m / z = 585 (M + l); Rt = 5, 78 minutes. General procedure (i) General procedure for isolating the palm of the compound of formula (10) (ii) · _

〇1) (R) + (S) 實例106( —般程序（Η))，如下所示，也可製得實例4的化合物，及依據一般程序（Η)分離不同的對掌體： ‘ 3— {4 — [4 一（3, 5 —雙一三氟化甲基苯基）一 2 — (4—環己基苯基）一 4一氧一丁醯]苯甲醯胺基} 一丙酸〇1) (R) + (S) Example 106 (general procedure (i)), as shown below, the compound of Example 4 can also be prepared, and different palms can be separated according to the general procedure (ii): '3 — {4 — [4 mono (3, 5 —bis-trifluoromethylphenyl) — 2 — (4-cyclohexylphenyl) — 4-oxo-butylammonium] benzamidineamino} monopropionic acid

步驟1 : 3—（4一甲醯苯甲醯胺基）丙酸甲某酯 160 200401634 3 —（4 -甲醯苯甲醯胺基）丙酸甲基酯可依據描述於 WO00/69810的步驟合成而得。舟琴3 — (4 —「4一（3，5—雙一三氬化甲基苯基）一 2 一（4—環己基苯基）- 4一氧一丁醯1苯甲醯胺某丨丙酸甲某酯於一含有1 —(3，5—雙—三氟化甲基苯基）一 3 -（4一環己基苯基）丙烯酮（6.12克，14.35毫莫耳）溶於無水乙醇（99% ’ 25毫升）的混合物中’在氣氣氣氛之下，加入3，4 — _^^甲基一 5 -（2 —羥基乙基）噻唑鑰碘化物（819毫克，2.87毫莫耳 )及三乙胺（1.60毫升，11.5毫莫耳），及迴流加熱混合物。將3-（4—甲醯苯甲醯胺基）丙酸甲基酯（4.39克，18.7毫莫耳）溶於無水乙醇（99%，15%)，且在2小時內以液滴的方式加入至前述迴流混合物中。持續迴流混合物30分鐘，讓其冷卻至室溫，然後過濾分離出3 — {4 - [4一（3，5 -雙一三氣化甲基本基）—2 - (4 一環己基一苯基）一 4 一氧一丁酸]一苯甲醯胺基}-丙酸甲基酯，接著以乙醇洗滌和在真空下乾燥，產量6.9克（73%)。步I 3 : 3—{生二「4—(3，5—雙—三氟化甲基苯基）一2 二14 -環己基苹基氣丁醯1苯甲醯胺基丨丙酸將3—{4 — [4一（3,5—雙—三氟化甲基苯基）一 2—（4一環己基-苯基）一 4 一氧一丁醯]一苯甲醯胺基} 一丙酸甲基酯 (6.20克’ 9.38毫莫耳）溶於raF(75毫升），加入HC1(6N，25 毫升），及迴流加熱此混合物，2小時後，關掉熱源，及在室溫下攪拌混合物16小時。蒸發混合物至乾，可得標題化合物，產量：定量。 200401634 ^NMI^DMSO—d6) : 38.72(t，1H)，8.60(s，2H)，8.42(s，1H)，8.14(d ，2H)，7.90(d，2H)，7.34(d，2H)，7.17(d，2H)，5.43(dd，1H)，4.29(dd， 1H)，3.64(dd，1H 和 t，2H)，3.42(t，2H)，2.42(m，1H)，1.78-1.64(m，5H) ，:1.38 —1.25(m，5H) : HPLC—MS(方法 D) : m/z=648(M+l) ; Rt=5.58 分鐘〇步驟4 :不對稱HPLC的解析將3—{4—[4 —（3, 5—雙一三氟化甲基苯基）一2 —（4 — 環己基苯基）一 4 一氧丁醯]苯甲醯胺基}丙酸（500毫克，0.77 毫莫耳）溶於異丙醇：庚烷60 : 40(20毫升），加入三氟乙酸 (0.02毫升）。接著在一 AD管，50x50毫米（得自DAICEL)分離此消旋混合物，流量：100毫升/分鐘。洗提液爲異丙醇 :庚烷混合物6 : 4，其中含0.01%的三氟乙酸。收集兩個含有化合物的洗出物。各別保存每一個洗出物，且以相同的方法處理。每一個洗出物的體櫝在真空下減爲約起始體積的1/8左右，接著以二氯甲烷（1升）和NaHC03水溶液 (10%，500毫升）分離，有機相以NaS〇4乾燥，及蒸發，可得一白色結晶體。將此結晶體迴流於乙腈中’接著冷卻至室溫，過濾及在真空下乾燥後可分離出純對掌體。實例107 3— (4 —「4 — (3，5—雙一三氟化甲某苯基）一2 —（4 一里· 己某苯某）- 4 -氧一丁醯1苯甲醯胺某丨丙酸最快洗出對掌體：Chiralpak AD，4.6x250毫米’庚院，異丙醇，三氟乙酸60 : 40 : 0.1，0.6毫升/分鐘的流量’ 遲滯時間=8.2分鐘。 162 200401634 實例108 3 —丨4 一「4 一（3，5 —雙一三氟化甲基苯基）—2 -（4 —環己某苯某）一 4一氧-丁醯1苯甲醯胺基丨丙酸最慢洗出對掌體：Chiralpak AD，4.6x250毫米，庚烷，異丙醇，三氟乙酸60 : 40 : 0.1，0.6毫升/分鐘的流量，遲滯時間=12.1分鐘。其它本發明較佳的化合物包括：Step 1: 3- (4-formamidine benzamidine) methyl propionate 160 200401634 3- (4-formamidine benzamidine) methyl propionate can be according to the procedure described in WO00 / 69810 Synthesized. Zhou Qin 3 — (4 — "4- (3,5-bis-triargonated methylphenyl)-2- (4-cyclohexylphenyl)-4-oxo-butyl hydrazone 1 benzylamine 丨Methyl propionate is dissolved in absolute ethanol in a solution containing 1- (3,5-bis-trifluoromethylphenyl) -3- (4-cyclohexylphenyl) propenone (6.12 g, 14.35 mmol). (99% '25 ml) of the mixture 'in a gas atmosphere, add 3,4- — ^^ methyl-5 (2-hydroxyethyl) thiazole key iodide (819 mg, 2.87 mmol) ) And triethylamine (1.60 ml, 11.5 mmol), and the mixture was heated at reflux. 3- (4-Toluenebenzylamino) propionic acid methyl ester (4.39 g, 18.7 mmol) was dissolved Anhydrous ethanol (99%, 15%), and added to the aforementioned reflux mixture in the form of droplets within 2 hours. Continue refluxing the mixture for 30 minutes, let it cool to room temperature, and then isolate 3 — {4-[ 4- (3,5 -bis-tri-gasified methylbenzyl) -2-(4-cyclohexyl-phenyl) -4 monooxobutanoic acid] -benzylamino} -propionic acid methyl ester, then Wash with ethanol and dry under vacuum Yield, 6.9 g (73%). Step I 3: 3— {raw di 4— (3,5—bis-trifluoromethylphenyl) —2 2 14-cyclohexyl pyrenyl butane 1 benzene Formamidine 丨 propanoic acid will be 3- {4 — [4-((3,5-bis-trifluoromethylphenyl) -2- (4-cyclohexyl-phenyl) -4-dioxo-butane] Monobenzylamino} methyl propionate (6.20 g '9.38 mmol) was dissolved in raF (75 ml), HC1 (6N, 25 ml) was added, and the mixture was heated under reflux. After 2 hours, turn off The heat source was removed, and the mixture was stirred at room temperature for 16 hours. The mixture was evaporated to dryness to obtain the title compound, yield: quantitative. 200401634 ^ NMI ^ DMSO-d6): 38.72 (t, 1H), 8.60 (s, 2H), 8.42 (s, 1H), 8.14 (d, 2H), 7.90 (d, 2H), 7.34 (d, 2H), 7.17 (d, 2H), 5.43 (dd, 1H), 4.29 (dd, 1H), 3.64 (dd, 1H and t, 2H), 3.42 (t, 2H), 2.42 (m, 1H), 1.78-1.64 (m, 5H) ,: 1.38-1.25 (m, 5H): HPLC-MS (Method D) : m / z = 648 (M + 1); Rt = 5.58 minutes. Step 4: Analysis of asymmetric HPLC will be 3- {4— [4 — (3, 5—bis-trifluoromethylphenyl) — 2 — (4 — ring yourself Phenyl) -4-oxobutyramine] benzamidine amino} propionic acid (500 mg, 0.77 mmol) dissolved in isopropanol: heptane 60:40 (20 ml), and trifluoroacetic acid (0.02 ml) ). The racemic mixture was then separated in an AD tube at 50x50 mm (from DAICEL) at a flow rate of 100 ml / min. The eluent was a mixture of isopropanol: heptane 6: 4, which contained 0.01% trifluoroacetic acid. Two eluates containing the compound were collected. Store each eluate separately and treat it in the same way. The volume of each eluate was reduced to about 1/8 of the initial volume under vacuum, and then separated with dichloromethane (1 liter) and NaHC03 aqueous solution (10%, 500 ml). Dry and evaporate to obtain a white crystal. This crystal was refluxed in acetonitrile and then cooled to room temperature, and the pure palm body was separated after filtering and drying under vacuum. Example 107 3— (4— “4— (3,5—bis-trifluoromethane, a phenyl group) —2— (4 mile, hexamethylene, a benzene) —4-oxobutane-1, benzamidine Propionic acid washes out the palm of the hand the fastest: Chiralpak AD, 4.6x250 mm 'Gengyuan, isopropanol, trifluoroacetic acid 60: 40: 0.1, 0.6 ml / min flow rate' Hysteresis time = 8.2 minutes. 162 200401634 Example 108 3— 丨 4— “4— (3,5-—Bistrifluoromethylphenyl) —2— (4-Cyclohexane, Benzene, etc.) — 4—Oxo-butylammonium 1 benzamidine丨 Propionate is the slowest to wash out palm body: Chiralpak AD, 4.6x250 mm, heptane, isopropanol, trifluoroacetic acid 60: 40: 0.1, 0.6 ml / min flow rate, lag time = 12.1 minutes. Others The present invention Preferred compounds include:

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179 200401634 〇 Pg'〇^x^° Η179 200401634 〇 Pg'〇 ^ x ^ ° Η

步驟1step 1

步驟3Step 3

Pg 步驟2Pg step 2

步驟4Step 4

步驟6 步驟5Step 6 step 5

(丨6)(丨 6)

其中Pg，E，X，D和R4是如上所定義者，步驟5所加入的Pg可不同於前述步驟的Pg。實例1〇9( —般程序（I)) 3 —丨4 —「2 — (4 —環己基苯基）—2 —（4 一三氟化甲氧基苯基氨基甲醯）乙某1-苯甲醯胺基丨丙酸Where Pg, E, X, D and R4 are as defined above, the Pg added in step 5 may be different from the Pg of the previous step. Example 10 (General Procedure (I)) 3-4-"2-(4-cyclohexylphenyl)-2-(4-trifluoromethoxyphenylaminomethane) Ethyl 1- Benzamidine

步驟 1:E，Z—4 -『2 —竣基—2—(4 —環己基苯基）乙烯某1苯甲酸甲某酯一混合物，含有甲基4 一甲醯苯甲酸酯（5.75克，35毫莫耳），4 —環己基苯基乙酸（10.93克，50.05毫莫耳）(Chem. 180 200401634Step 1: E, Z-4-"2-Endyl-2-(4-cyclohexylphenyl) ethylene, a benzoate, a certain ester mixture, containing methyl 4-formamidine benzoate (5.75 g , 35 mmol), 4-cyclohexylphenylacetic acid (10.93 g, 50.05 mmol) (Chem. 180 200401634

Ber.，76，（1943)，308)，乙酸酐（17.54 毫升，185.5 毫莫耳）及三乙胺（4.87毫升；35毫莫耳），在溫度155t下攪拌加熱 15分鐘。冷卻混合物至9(TC，及以液滴的方式加入水（18 毫升），加入速度爲可維持溫度在9(TC及100°C間的速度。冷卻混合物至室溫，加入一 50%乙酸水溶液（25毫升），過濾出沈澱物，及以25%乙酸水溶液（100毫升）洗滌，最後以水（125毫升）洗滌。乾燥粗產物，及由庚烷中再結晶，可得 10.89克（85%)的4 一 [2-羧基-2-(4-環己基苯基乙烯基）苯甲酸甲基酯。 ^NMI^DMSO—d6) : 512.88(brs，1H)，8.98—7.05(m，9H)，3.87 及 3.83(s，3H)，2.54(m，1H)，1.68-1.78(m，5H)，1.48 —1.20(m，5H)。步驟 2·· 4 — F2 —竣基—2—(4 —環己基苯基）乙基1—苯甲酸甲基酯一 E，Z—4 — [2 -羧基一 2 — (4-環己基苯基）乙烯基]苯甲酸甲基酯（10.85克，28.77毫莫耳）及鈀/活性碳（1.085克， 10%)溶於100毫升甲醇的混合物在56psi壓力下氫化7小時，過濾出觸媒，及蒸發濾液至乾，可得5.73克（53%)的4-[2 —羧基一 2 —（4—環己基苯基）乙基]苯甲酸甲基酯，其爲一固體。 iHNMI^CDCy : 57.90(d，2H)，7.23 — 7.13(m，6H)，3.88(s，3H)， 3.84(t ^ 1H) ^ 2.43(dd ^ 1H) ^ 3.07(dd ^ 1H) ^ 2.48(m ^ 1H) ^ 1.90-1.70(m ^ 5H) ，1.45 —1.18(m，5H)。 HPLC —MS(方法 D) ·· m/z=367(M+l) ; Rt=5.03 分鐘。步驟3 : 4— [2—氯化鑛基—2—(4-環己基苯基）乙基1 181 200401634 苯甲酸甲基酯攪拌一含4一 [2-羧基一2-（4一環己基苯基）乙基]—苯甲酸甲基酯（5·58克，15.2毫莫耳）溶於甲苯的溶液，及加入氯硫醯（2.79毫升，38.20毫莫耳），攪拌混合物及迴流15分鐘，接著在減壓下蒸發掉甲苯，殘留物以甲苯汽提二次，可得5.75克（95%)的4一[2-氯化羰基—2—(4-環己基苯基 )乙基]苯甲酸甲基酯。 iHNMRCCDCy : 57.79(d，2Η)，7.40-7.08(m，6Η)，4.11(m，1Η)， 3.85(s，3H)，3.30(m，1H)，3.03(m，1H)，2.45(m，1H)，1.83-1.65(m，5H) ，1·42—1.15(m，5H)。步驟4 : 4—「2—(4—環F,基苯某2—(4—三氟化甲氢某苯基氨基甲醯）乙基1苯甲酶在氮氣氣氛之下攪拌一含4-三氟化甲氧基苯胺（0.575 克，3.25毫莫耳）溶於無水甲苯（50毫升）的溶液，加入三乙胺（0.448毫升，3.25毫莫耳），接著加入一 4 — [2-氯化羰基一 2—（4一環己基苯基）乙基]—苯甲酸甲基酯（1.25克，3.25 毫莫耳）溶於無水甲苯（25毫升）的溶液，迴流混合物1小時，冷卻至室溫，及以水（2x100毫升）和飽和氯化鈉溶液 (2x100毫升）洗滌，收集有機相及在減壓下蒸發至乾，可得 1.43克的粗中間酯化合物。將此酯化合物溶於一甲醇（12.5 毫升）和THF(5毫升）的混合物中，加入4M氫氧化鈉水溶液 (2.43毫升，9.75毫莫耳），接著在室溫下攪拌混合物16小時，過濾混合物，及以濃氫氯酸使得pH値爲2。攪拌混合物1小時，過瀘出沈澱物，及以水洗滌，乾燥，可得1.32 182 200401634 克（80%)的4 一 [2 — (4 —環己基苯基）—2一（4_三氟化甲氧基苯基氨基甲醯）乙基]苯甲酸，其爲一固體。 ^NMiKDMSO—d6) : (H0.38(s，1H)，7.78(d，2H)，7.65(d，2H)， 7.28(m，2H) ’ 7.30(d，2H) ’ 7.18(d，2H) ’ 4.03(m，1H)，3.45(m，1H)， 2.42(m，1H)，1.85 —1.13(m，10H)。步驟5和步驟6 : 3 —丨4一 [2二二環己基苯某2_ (4 一三氟化甲氧基莖基氨基甲醯甲醯胺基丨丙酸攪拌一含4 一 [2—（4 一環己基苯基）一2_(4_三氟化甲氧基本基氣基甲酸）乙基]一苯甲酸（1· 44克；2·82毫莫耳）溶於DMF(45毫升）的溶液，同時加入1 —羥基一苯並三哇水合物（0.456克；3.38毫莫耳），在室溫下攪拌混合物丨小時 ’接著加入EDAC(0.648克；3.38毫莫耳），甲基3—胺基丙酸酯氫氯化物（0.589克’ 4.22毫莫耳）和£)ΙΡΕΑ(1·47毫升； 8.45毫莫耳）。在溫度40°C下攪拌混合物2小時，及在減壓下蒸發混合物’殘留物以水和乙酸乙酯分離，有機相以鹽水洗滌，乾燥（MgS04)，蒸發後可得2.11克的中間酯。接著將此酯（0.3克，0.5毫莫耳）溶於甲醇（11毫升）和THF(4.4毫升）的混合物中，加入4M氫氧化鈉溶液（0.37毫升；1.50毫莫耳），在室溫下攪拌混合物16小時，及在減壓下濃縮混合物至約1毫升，加入水（15毫升）。pH値以加入1M氫氯酸調整爲1.5，過濾出沈澱物，及以水洗滌，乾燥，可得 0.25克（85%)的標題化合物。 "HNMRCDMSO—d6) : (512.20(brs，1H)，l〇.25(s，1H)，8.43(t，1H)， 7.70(d，2H)，7.62(d，2H)，7.35(d，2H)，7.30(d，2H)，7.26(d，2H)，7.18(d 183 200401634 ，2H)，3.99(m，1H)，3.40(m，1H)，3.00(dd，1H)，2.48(m，3H)，1.85 — 1.13(m，1〇H)。以下化合物（實例110 - 117)是以類似上述的方法製備。實例11〇( —般程序⑴） 3 —丨4 —「2—(3，5—二氯苯基氨基甲醯）一 2—(4—三氟化甲氧基苯基）乙基1苯甲醯胺某）-丙酸Ber., 76, (1943), 308), acetic anhydride (17.54 ml, 185.5 mmol) and triethylamine (4.87 ml; 35 mmol), heated at 155 t with stirring for 15 minutes. Cool the mixture to 9 ° C and add water (18 ml) as a droplet at a rate that maintains the temperature between 9 ° C and 100 ° C. Cool the mixture to room temperature and add a 50% acetic acid solution (25 ml), the precipitate was filtered off, washed with 25% acetic acid aqueous solution (100 ml), and finally washed with water (125 ml). The crude product was dried and recrystallized from heptane to obtain 10.89 g (85%) ) Methyl 4-benzo [2-carboxy-2- (4-cyclohexylphenylvinyl) benzoate. ^ NMI ^ DMSO-d6): 512.88 (brs, 1H), 8.98-7.05 (m, 9H) , 3.87 and 3.83 (s, 3H), 2.54 (m, 1H), 1.68-1.78 (m, 5H), 1.48—1.20 (m, 5H). Step 2 ·· 4 — F2 — Junji—2— (4 —Cyclohexylphenyl) ethyl 1-benzoic acid methyl ester E, Z-4 — [2-carboxy-1— (4-cyclohexylphenyl) vinyl] benzoic acid methyl ester (10.85 g, 28.77 Millimolar) and palladium / activated carbon (1.085 g, 10%) dissolved in 100 ml of methanol were hydrogenated at 56 psi for 7 hours, the catalyst was filtered off, and the filtrate was evaporated to dryness to obtain 5.73 g (53%) 4- [2 —carboxyl-2 — 4-Cyclohexylphenyl) ethyl] benzoic acid methyl ester, which is a solid. IHNMI ^ CDCy: 57.90 (d, 2H), 7.23-7.13 (m, 6H), 3.88 (s, 3H), 3.84 ( t ^ 1H) ^ 2.43 (dd ^ 1H) ^ 3.07 (dd ^ 1H) ^ 2.48 (m ^ 1H) ^ 1.90-1.70 (m ^ 5H), 1.45-1.18 (m, 5H). HPLC -MS (Method D ) ·· m / z = 367 (M + l); Rt = 5.03 minutes. Step 3: 4— [2-Chlorinium—2— (4-cyclohexylphenyl) ethyl] 1 181 200401634 methyl benzoate Base ester stirred a solution containing 4-[[2-carboxy-2- (4-cyclohexylphenyl) ethyl] -benzoic acid methyl ester (5.58 g, 15.2 mmol) in toluene, and added chlorine Sulfur (2.79 ml, 38.20 mmol), stir the mixture and reflux for 15 minutes, then evaporate the toluene under reduced pressure, and strip the residue twice with toluene to obtain 5.75 g (95%) of 4-a [2 -Methyl chloride carbonyl-2- (4-cyclohexylphenyl) ethyl] benzoate. IHNMRCCDCy: 57.79 (d, 2Η), 7.40-7.08 (m, 6Η), 4.11 (m, 1Η), 3.85 (s, 3H), 3.30 (m, 1H), 3.03 (m, 1H), 2.45 (m, 1H), 1.83-1.65 (m, 5H), 1.42-1.15 (m, 5H). Step 4: 4-—2- (4-ring F, phenylbenzene, 2- (4-trifluoromethane, phenylaminoformamidine) ethyl-1, benzoyl, and a mixture containing 4- A solution of methoxyaniline trifluoride (0.575 g, 3.25 mmol) in anhydrous toluene (50 ml), triethylamine (0.448 ml, 3.25 mmol) was added, followed by 4-[2-chloro A solution of carbonyl 2- (4-cyclohexylphenyl) ethyl] -benzoate (1.25 g, 3.25 mmol) in anhydrous toluene (25 ml), the mixture was refluxed for 1 hour, and cooled to room temperature , And washed with water (2x100 ml) and saturated sodium chloride solution (2x100 ml), the organic phase was collected and evaporated to dryness under reduced pressure to obtain 1.43 g of a crude intermediate ester compound. This ester compound was dissolved in methanol To a mixture of (12.5 ml) and THF (5 ml), 4M aqueous sodium hydroxide solution (2.43 ml, 9.75 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The mixture was filtered and concentrated with hydrochloric acid to The pH was 2. The mixture was stirred for 1 hour, and the precipitate was decanted, washed with water, and dried to obtain 1.3. 2 182 200401634 g (80%) of 4-a [2- (4-cyclohexylphenyl) -2-a (4-trifluoromethoxyphenylaminocarbamidine) ethyl] benzoic acid, which is a solid ^ NMiKDMSO-d6): (H0.38 (s, 1H), 7.78 (d, 2H), 7.65 (d, 2H), 7.28 (m, 2H) '7.30 (d, 2H)' 7.18 (d, 2H ) '4.03 (m, 1H), 3.45 (m, 1H), 2.42 (m, 1H), 1.85 — 1.13 (m, 10H). Step 5 and Step 6: 3 — 4— [2 bisdicyclohexylbenzene Some 2_ (4-trifluoromethoxystemylaminocarbamidine formamidine 丨 propionic acid stirring-containing 4-[2- (4-cyclohexylphenyl)-2_ (4_trifluoromethoxybenzyl Gas-formic acid) ethyl] monobenzoic acid (1.44 g; 2.82 mmol) dissolved in DMF (45 ml) while adding 1-hydroxy-monobenzotriwa hydrate (0.456 g; 3.38 Mmol), the mixture was stirred at room temperature for 1 hour 'followed by EDAC (0.648 g; 3.38 mmol), methyl 3-aminopropionate hydrochloride (0.589 g' 4.22 mmol) and ) ΕΡΕΑ (1.47 ml; 8.45 mmol). The mixture was stirred at a temperature of 40 ° C for 2 hours and evaporated under reduced pressure. The 'residue' was separated with water and ethyl acetate, the organic phase was washed with brine, dried (MgS04) and evaporated to give 2.11 g of an intermediate ester. This ester (0.3 g, 0.5 mmol) was then dissolved in methanol To a mixture of (11 ml) and THF (4.4 ml), 4M sodium hydroxide solution (0.37 ml; 1.50 mmol) was added, the mixture was stirred at room temperature for 16 hours, and the mixture was concentrated to about 1 ml under reduced pressure. Add water (15 ml). The pH was adjusted to 1.5 by adding 1M hydrochloric acid, and the precipitate was filtered off, washed with water, and dried to obtain 0.25 g (85%) of the title compound. " HNMRCDMSO-d6): (512.20 (brs, 1H), 10.25 (s, 1H), 8.43 (t, 1H), 7.70 (d, 2H), 7.62 (d, 2H), 7.35 (d, 2H), 7.30 (d, 2H), 7.26 (d, 2H), 7.18 (d 183 200401634, 2H), 3.99 (m, 1H), 3.40 (m, 1H), 3.00 (dd, 1H), 2.48 (m , 3H), 1.85 — 1.13 (m, 10H). The following compounds (Examples 110-117) were prepared in a similar manner as described above. Example 11 (General procedure ⑴) 3-4-"2-(3 , 5-dichlorophenylcarbamidine)-2- (4-trifluoromethoxyphenyl) ethyl 1 benzamidine)-propionic acid

iHNMRQMSO—d6) : 512.30(brs，1H)，10.50(s，1H)，8.45(t，1H)， 7.88—7.20(m，11H)，4.08(m，1H)，3.42(m，3H)，3.05(dd，1Η)，2.48(m， 2H)。 HPLC—MS(方法 D) : m/z=569(M+l) ; Rt=4.83 分鐘。實例111(一般程序（1)) 3 — ί4—「2 -（3，5—二氯苯基氨基甲醯）一 2—(4—三氟化甲氧基苯基）乙基1苯甲醯胺基- 2R-羥基丙酸 ΛiHNMRQMSO-d6): 512.30 (brs, 1H), 10.50 (s, 1H), 8.45 (t, 1H), 7.88-7.20 (m, 11H), 4.08 (m, 1H), 3.42 (m, 3H), 3.05 (dd, 1Η), 2.48 (m, 2H). HPLC-MS (method D): m / z = 569 (M + 1); Rt = 4.83 minutes. Example 111 (General Procedure (1)) 3 — ί 4 — "2-(3,5-dichlorophenylcarbamidine)-2-(4-trifluoromethoxyphenyl) ethyl 1 benzamidine Amino-2R-hydroxypropionic acid Λ

Cl iHNMI^DMSO—cU : 512.55(brs，1H)，10.53(s，1H)，8.43(t，1H)， 184 200401634 7.7(d，2H)，7.62(s，2H) ; 7.55(d，2H) ; 7.35(d，2H)，7.30(d，2H)，7.28(s， 1H)，4.12(m，1H) ; 3.08(dd，1H)。 HPLC—MS(方法 D) : m/z=585(M+l) ; Rt=4.65 分鐘。實例112( —般程序（1)) 2R —羥基一 3 — ί4 一「2 — (4 —三氟化甲氧基苯基）—2 — (4一三氟化甲氧基苯某氨基甲醯）乙基1苯甲醯胺某）丙酸Cl iHNMI ^ DMSO-cU: 512.55 (brs, 1H), 10.53 (s, 1H), 8.43 (t, 1H), 184 200401634 7.7 (d, 2H), 7.62 (s, 2H); 7.55 (d, 2H) 7.35 (d, 2H), 7.30 (d, 2H), 7.28 (s, 1H), 4.12 (m, 1H); 3.08 (dd, 1H). HPLC-MS (method D): m / z = 585 (M + 1); Rt = 4.65 minutes. Example 112 (— General Procedure (1)) 2R —Hydroxy-3 — ί4 — “2 — (4-Trifluoromethoxyphenyl) — 2 — (4-trifluoromethoxybenzene ) Ethyl 1 benzamidine

^NMIKDMSO—cU ·· 5 8.40(t，1Η)，7.75(d，2Η)，7.62(s，2Η)， 7.55(d，2H)，7.30(m，6H)，4.10(m，2H)，3.08(dd，1H)。 HPLC—MS(方法 D) : m/z=601(M+l) ; Rt=4.42 分鐘。實例113( —般程序（1)) 3 — ί4一「2—（4一三氟化甲氧基苯基）一 2 -（4 —三氟化甲氧某苯基氨基甲醯）乙基1苯甲醯胺某丨丙酸^ NMIKDMSO-cU · 5. 8.40 (t, 1Η), 7.75 (d, 2Η), 7.62 (s, 2Η), 7.55 (d, 2H), 7.30 (m, 6H), 4.10 (m, 2H), 3.08 (dd, 1H). HPLC-MS (method D): m / z = 601 (M + 1); Rt = 4.42 minutes. Example 113 (— General Procedure (1)) 3 — ί 4 — "2-(4-trifluoromethoxyphenyl)-2-(4-trimethoxymethoxy, phenylaminocarbamate) ethyl 1 Benzamidine

185 200401634 iHNMRCDMSO —d6) : 510.40(s，1H)，8.47(t，1Η)，7.70(d，2H)， 7.65(d，2H) ; 7.55(d，2H)，7.30(m，6H)，4.10(m，1H)，3.05(dd，1H)， 2.47(t，2H)。 HPLC—MS(方法 D) : m/z=585(M+l) ; Rt=4.58 分鐘。實例114(一般程序（1)) 3 —丨4 —「2 — (4 —環己基苯基）一 2 — (3, 5-二氯化苯基氨基甲醯）乙某1 一苯甲醯胺基丨一丙酸185 200401634 iHNMRCDMSO-d6): 510.40 (s, 1H), 8.47 (t, 1Η), 7.70 (d, 2H), 7.65 (d, 2H); 7.55 (d, 2H), 7.30 (m, 6H), 4.10 (m, 1H), 3.05 (dd, 1H), 2.47 (t, 2H). HPLC-MS (method D): m / z = 585 (M + 1); Rt = 4.58 minutes. Example 114 (General Procedure (1)) 3 — 丨 4 — “2 — (4-cyclohexylphenyl) — 2 — (3, 5-dichlorophenylcarbamidine) Ethyl 1 – benzamidine P-propionic acid

^NMRCDMSO-d^ ： (512.22(brs 5 1H) ^ 10.40(s ^ 1H) ^ 8.42(t ^ 1H) ^^ NMRCDMSO-d ^: (512.22 (brs 5 1H) ^ 10.40 (s ^ 1H) ^ 8.42 (t ^ 1H) ^

7.70(d，2H)，7.60(s，2H)，7.35 —7.10(m，7H)，3.95(m，1Η)，3.42(m，2H) ，3.00(dd，1H)，2.48(m，3H)，1.85 —1.13(m，10H)。實例115( —般程序（1)) 3 —丨4 —「2—(4-環己基苯基）—2-（4—三氟化甲基苯基氨某甲醯）乙某1苯甲醯胺基丨一丙酸7.70 (d, 2H), 7.60 (s, 2H), 7.35—7.10 (m, 7H), 3.95 (m, 1Η), 3.42 (m, 2H), 3.00 (dd, 1H), 2.48 (m, 3H) , 1.85 —1.13 (m, 10H). Example 115 (General procedure (1)) 3-4-"2- (4-cyclohexylphenyl) -2- (4-trifluoromethylphenylaminomethane) Ethyl-1 benzamidine Amino acid

186 200401634 iHNMI^DMSO —d6) : 512.32(brs，1H)，10.40(s，1Η)，8.43(t，1H)， 7.72(d，2H)，7.69(d，2H)，7.35(d，2H)，7.30(d，2H)，7.28(d，2H)，7.18(d ，2H)，4.02(m，1H)，3.40(m，2H)，3.00(dd，1H)，2.46(m，3H)，1.85 — 1.13(m，10H)o 以下化合物（實例116和117)是依據一般程序（I)的步驟製得，但省略氫化步驟（步驟2)。實例116 3 — M —「2—(4—叔一丁基苯基氨基甲醯）一 2—（4—三氟化甲氧基苯基）乙烯基1苯甲醯胺基丨-丙酸186 200401634 iHNMI ^ DMSO —d6): 512.32 (brs, 1H), 10.40 (s, 1Η), 8.43 (t, 1H), 7.72 (d, 2H), 7.69 (d, 2H), 7.35 (d, 2H) , 7.30 (d, 2H), 7.28 (d, 2H), 7.18 (d, 2H), 4.02 (m, 1H), 3.40 (m, 2H), 3.00 (dd, 1H), 2.46 (m, 3H), 1.85 — 1.13 (m, 10H) o The following compounds (Examples 116 and 117) were prepared according to the procedure of General Procedure (I), but the hydrogenation step was omitted (Step 2). Example 116 3 — M — "2- (4-tert-butylbutylaminocarbamidine)-2- (4-trifluoromethoxyphenyl) vinyl-1 benzamidine amino-propionic acid

1HNMR(DMS〇一d6) : 512.22(brs，1H)，10.10(s，1H)，8.50(t，1H)， 7.69—7.10(m，13H)，3.43(q，2H)，2.47(t，2H)，1.29(s，9H)。實例117 3 —丨4 —「2 — (4 —叔—丁基苯基氨基甲醯）一 2—（4 —三氟化甲氧基苯基）乙烯基1苯甲醯胺基丨一 2R-羥基—丙酸1HNMR (DMS〇-d6): 512.22 (brs, 1H), 10.10 (s, 1H), 8.50 (t, 1H), 7.69-7.10 (m, 13H), 3.43 (q, 2H), 2.47 (t, 2H ), 1.29 (s, 9H). Example 117 3-4-"2-(4-tert-butylphenylaminocarbamate)-2-(4-trifluoromethoxyphenyl) vinyl 1 benzamidine amine-2R- Hydroxy-propionic acid

187 200401634 ^NMRCDMSO-dd : 510.10(s，1Η)，8.50(t，1H)，7.72—7.12(m， 13H)，4.12(t，1H)，3.55(m，1H)，1.28(s，9H)。以下較佳化合物在本發明的範圍之內，且可以此處所揭示的反應步驟反應製得：187 200401634 ^ NMRCDMSO-dd: 510.10 (s, 1Η), 8.50 (t, 1H), 7.72-7.12 (m, 13H), 4.12 (t, 1H), 3.55 (m, 1H), 1.28 (s, 9H) . The following preferred compounds are within the scope of the present invention and can be prepared by the reaction steps disclosed herein:

A 〇其中 200401634A 〇 of which 200401634

E D h3c ch3 ό ch3 0 1 、、(ΧΛ % 1 * 、α。龙 JCH3 ό 备含H3 I T ’、〇Λ xh3 0 ! T ·、'α欠 1 T 、、αΛ ch3 H3C--CH3 ό 1 T Cl 189 200401634 E D c H3C— c :h3 —ch3 , •、ax) h3c i •'ΟΛ c H3C— c :h3 -3ch3 c H3C— c 1 —ch3 ) ch3 h3c——ch3 ό 1 F * Lf c h3c— c ：H, -CH3 F 、aiF ( H3C— c :h3 一 ch3 ; 1 ch3 h3c4-ch3 ό 1 ’、於: 0 E D ( h3c— c :h3 一 ch3 ) 、、Ci A、 ( H3C— c »3 —ch3 ; 1 fXf •、i a。、 H古3 1 § *'a，F c h3c_ c 1 1 :h3 -ch3 ) 、prcl Cl § t § 1 * \^° _ 、、σκ> ch3 T 'ai< 0ED h3c ch3 ch3 0 1 、 (× Λ% 1 * 、 α. Dragon JCH3 contains H3 IT ', 〇Λ xh3 0! T ·,' α owe 1 T 、 α ch3 H3C--CH3 ό 1 T Cl 189 200401634 ED c H3C— c: h3 —ch3, •, ax) h3c i • 'ΟΛ c H3C— c: h3 -3ch3 c H3C— c 1 —ch3) ch3 h3c——ch3 ό 1 F * Lf c h3c — C: H, -CH3 F, aiF (H3C— c: h3-ch3; 1 ch3 h3c4-ch3) 1 ', in: 0 ED (h3c — c: h3-ch3),, Ci A, (H3C— c »3 —ch3; 1 fXf •, ia., H ancient 3 1 § * 'a, F c h3c_ c 1 1: h3 -ch3), prcl Cl § t § 1 * \ ^ ° _, σκ > ch3 T 'ai < 0

190 200401634 E D c h3c— c :h3 一 ch3 ·、€φ: 0 8 1 F^F c h3c— C 1 -CH3 1 v〇^N^cHa 二 0 § 1 、0^n^"ch3 0 c h3c- c 1 〕h3 一ch3 f 0 § "dy-〇 c H3C- c 1 ：Ha 一 ch3 1 Cl ( H3C— c :h3 —ch3 1 、co E D 8 1 * 、'(X;Ff 8 1 T * c h3c- 1 :h3 一 ch3 1 •、、a，F 8 * c h3c— c ! :h3 —ch3 ) r § | •、rY^: fj °'CH3 § 1 *、a，F § Br190 200401634 ED c h3c— c: h3 a ch3 ·, € φ: 0 8 1 F ^ F c h3c— C 1 -CH3 1 v〇 ^ N ^ cHa two 0 § 1, 0 ^ n ^ " ch3 0 c h3c- c 1] h3 a ch3 f 0 § " dy-〇c H3C- c 1: Ha a ch3 1 Cl (H3C — c: h3 — ch3 1, co ED 8 1 *, '(X; Ff 8 1 T * c h3c- 1: h3 a ch3 1 • ,, a, F 8 * c h3c— c!: H3 —ch3) r § | •, rY ^: fj ° 'CH3 § 1 *, a, F § Br

191 200401634191 200401634

192 200401634 E D t> Ff <TsJ^ o * h3c八〆 h^jQ Η3°Λη3 :2 ^ch3 ic 0 * N h3〇jO H3C^CH3 •、as f+f F H3〇wO h3c^Ch3192 200401634 E D t > Ff < TsJ ^ o * h3c eight 〆 h ^ jQ Η3 ° Λη3: 2 ^ ch3 ic 0 * N h3〇jO H3C ^ CH3 •, as f + f F H3〇wO h3c ^ Ch3

E D η3〇0^ H3C CH3 o^F 1 ★ H3cACH3 Cl F c I ★ h3c^xJ〇 h3c^〇0 o^F } * H3Cv^-s^O ci F P t •k h3C\/OO f+f F *O 〇丄0 ^CH3 廣’ 、as F——F F 193 200401634 E D 加’ I * w* Cl F P ★ ch3 h3c—ch3 0 1ED η3〇0 ^ H3C CH3 o ^ F 1 ★ H3cACH3 Cl F c I ★ h3c ^ xJ〇h3c ^ 〇0 o ^ F} * H3Cv ^ -s ^ O ci FP t • k h3C \ / OO f + f F * O 〇丄 0 ^ CH3 Guang ', as F——FF 193 200401634 ED plus' I * w * Cl FP ★ ch3 h3c—ch3 0 1

194 200401634 除此之外，以下化合物皆在本發明的範圍之內，且可依據此處所述的反應程序反應製得。未商業化的中間物可以類似描述於WO 00/69810的步驟反應製得：194 200401634 In addition, the following compounds are all within the scope of the present invention and can be prepared according to the reaction procedures described herein. Uncommercial intermediates can be prepared by reactions similar to those described in WO 00/69810:

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219 200401634 η 1^^γΝ^〇χΗ3 f+f ΗΟ^νχφ Η L^^N^^°'CH3 F士 F ΗΟ^-Ν Vi Υ Η ^ η ΗΟ^Ν Vi Υ Η F ηΊ〇Λ'^ F^F ΗΟ^,Χ^Ο Η hcA^^Q^ ;Η〇^η219 200401634 η 1 ^^ γN ^ 〇χΗ3 f + f ΗΟ ^ νχφ Η L ^^ N ^^ '' CH3 F 士 F ΗΟ ^ -Ν Vi Υ Η ^ η ΗΟ ^ Ν Vi Υ Η F ηΊ〇Λ '^ F ^ F Η〇 ^, χ ^ Ο Η hcA ^^ Q ^; Η〇 ^ η

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藥理方法在下段文中中揭述用以評估本發明化合物的功效之結合分析和功能分析。化合物結合至胰增血糖素受體係在使用克隆化（coined) 之人類胰增血糖素受體的競爭結合分析中測定。拮抗性測定爲化合物抑制在5 nM胰增血糖素存在下所形成的c AMP之量的能力。Pharmacological methods Combining analysis and functional analysis for assessing the efficacy of the compounds of the present invention are disclosed in the following paragraphs. Compound binding to the glucagon receptor system was determined in a competitive binding assay using cloned human glucagon receptors. Antagonism is determined as the ability of a compound to inhibit the amount of c AMP formed in the presence of 5 nM glucagon.

胰增血糖素結合分析（I ) 受體結合係使用克隆化之人類受體分析（Lok等人，基因 140 ，203-209 (1994))。插在使用 EcoRI/SStl 限制位置的 pLJ6’表現質體之受體（Lok等人）係表現於幼田鼠腎臟細胞株（A3 BHK 570-25)。克隆係選擇於0.5毫克/ 毫升G-418存在下且對於超過40次顯示是穩定。Kd顯示爲 0.1 nM。Glucagon binding assay (I) Receptor binding was performed using cloned human receptor analysis (Lok et al., Gene 140, 203-209 (1994)). The pLJ6 'plastid receptor (Lok et al.) Inserted at the restriction site using EcoRI / SStl was expressed in a young voles kidney cell line (A3 BHK 570-25). The clone line was selected in the presence of 0.5 mg / ml G-418 and was stable for more than 40 times. Kd is displayed as 0.1 nM.

胞漿膜藉由成長細胞到合流而製備，將其從表面分離和將該等細胞再懸浮於冷緩衝液（10mMTris/HCl)中，pH 227 200401634 7.4包含30 mM NaCl，1 mM二硫蘇糖醇，5毫克/升 leupeptin(Sigma)，5 毫克 / 升 pepstatin(Sigma)，100 毫克 / 升桿菌肽（Sigma)和1 5毫克/升重組子阿普羅鐵宁（ aprotinin)(Novo Nordisk))。藉由使用 Polytron PT10-35 勻合器（Kinematica)之二個10-s破裂均質化，和於41 w /v %蔗糖層於95.000 * g克離心75分鐘。位在二個層之間白色帶以緩衝液稀釋和在40.000* g離心45分鐘。包含胞漿膜之沈澱懸浮在緩衝液中且儲存於-80°C直到需要時。胰增血糖素依照氯胺T方法碘化（Hunter and Green-wood，自然194，495(1962))且使用陰離子交換色層分析法純化（J P gensen 等人，Hormone and Metab. Res. 4，223-224(1972)。比活性爲每天460 // Ci/ug之碘化作用。數分之示踪劑量儲存在 -18°C和在融解之後立刻使用。結合分析在過濾器微升盤（MADV N65微孔）進行三次。在此分析中所使用的緩衝液爲25 mM HEPES pH 7.4，包含0.1%人類血淸白蛋白（Sigma，等級V)。胰增血糖素溶解在0.05 M HC1，加入等量（w/w)之HSA且冷凍乾燥。在使用天數中，其溶解於水中且以緩衝液稀釋至所需要的濃度。測試化合物以D M S〇溶解和稀釋。1 4 0 # L緩衝液，2 5 # L胰增血糖素或緩衝液，及1 0 # L D M S〇或測試化合物加入至每一井中。示踪劑（50.000 cpm)以緩衝液稀釋且2 5 //加至每個井中。1 一 4 // g稀釋於緩衝液中的新鮮融解之胞漿膜蛋白質然後將其2 5 // L加到 228 200401634 每個井中。盤在3 0 °C培育2小時。非特定結合以10 一 6 Μ 胰增血糖素測定。結合和非結合的示踪劑然後藉由真空過濾（微孔真空歧管）分開。該盤以2 X 1 0 0 // L 緩衝液/井洗好一次。該等盤風乾數小時，然後過濾器使用Millpore Puncher從盤中分開。該等過濾器在τ計數器中計算。功能分析（I ) 功能分析在96井的微升盤（組織培養盤，Nunc)進行。在分析中所產生的緩衝液濃度爲50 mM Tris/HCl，1 Mm EGTA，1.5 mM MgS〇 4 ， 1·7 mM ATP，20 // M GTP， 2 mM IBMX (異丁基一甲基一黃嘌呤），0·02 % tween-20 和0.1% HSA 。 pH爲7.4 。胰增血糖素和所建議之拮抗劑以35// L加入稀釋之 50 mM Tris / HC1，1 mM EGTA，1.85 mM MgS〇 4 ， 0.0222% tween-20 和 0.111 % HSA，pH 7.4 。加入 20// L 之 50 mM Tris/HCl ， 1 mM EGTA，1.5 mM MgSO 4 ， 11.8 mM ATP ， 0.14 mM GTP，14mM IBMX 和 0.1% HSA，ρΗ7·4。GTP 在分析之前立刻溶解。加入50 // L包含5 // g胞漿膜蛋白質在Tris/HCl ’ EGTA ，MgS〇4 ，HSA緩衝液（實際濃度視在儲存漿膜中的蛋白質濃度而定）。總分析體積爲140// L。分析在37°C培育2小時同時連續搖動。反應藉由加入25 // L之0.5 N HC1結束。cAMP 藉使用閃爍接近套組（Amersham)測量。 229 200401634 胰增血糖素結合分析（i i ) ΒΗΚ(倉田鼠(hamster)的幼鼠的腎臟細胞線)細胞移殖人類胰增血糖素受體及製備細胞膜的製備物。小麥胚芽凝素 (wheat germ agglutinin)衍生的SPA珠狀物，含有閃爍劑 (WGA珠）(Amersham)結合至該細胞膜上。125I-胰增血糖素結合至該細胞膜上的人類胰增血糖素受體上，且以WGA珠狀物上的閃爍劑激發，使其發光。結合至該受體上的胰增血糖素或樣品和125I-胰增血糖素競爭。所有在細胞膜製備物中的操作步驟皆保持在冰中，或在4°C下進行。收集和離心BHK細胞，再將所得顆粒於均質化緩衝液（25 mM HEPES pH=7.4，2.5mM CaCl 2，1·〇 mM MgCl 2 ，250毫克/升枯草旱菌素），使用Polytron 10- 35均化器（Kinematica)均質化2個10秒，且加入相同量的均質化緩衝液，再懸浮用。離心後（15分鐘，2000xg)，將上層液移至冷離心管中，且再離心45分鐘（40.000 X g)。粒狀物再懸浮於均質化緩衝液中，均質化2個10秒（Polytron)，及再加入均質化緩衝液。離心懸浮液45分鐘（40.000 X g)，且再將粒狀物懸浮於再懸浮緩衝液中（25 mM HEPES pH=7.4 ，2.5mM CaCl2，1.0 mM MgCl2)且均質化 2 個 10 秒 (Polytron)。蛋白質的濃度一般是約1.75毫克/毫升。加入安定化緩衝液（25 mM HEPES ρΗ=7·4， 2.5mM CaCl 2 ，1.0 mM MgCl2，1% BSA，500毫克/升枯草旱菌素，2.5M蔗糖) ，且在-8(TC下保存細胞膜製備物。胰增血糖素結合分析是在一 opti盤上進行（聚苯乙烯微 230 200401634 滴定盤，Packard)，加入50// L分析緩衝液（25mM HEPES ρΗ=7·5， 2.5mM CaCl 2 5 1.0 mM MgCl 2 5 0.003% Tween- 20，0.005%枯草旱菌素，0.05%鈉疊氮化物）及5// L胰增血糖素或測試化合物（溶於DMSO中）至每一井。然後加入50 // L示踪劑（125I-豬胰增血糖素，70.000 cpm)及50// L含有人類胰增血糖素受體的細胞膜（12.5//g)至每一井中，最後將50// L含有1毫克珠狀物的WGA珠移轉至該井中。在一搖動器中培養分析物4小時，及靜置8-48小時。此opti盤在一 Topcounter中計數。非特定結合以500 nM的胰增血糖素測定。本發明大部份的化合物在胰增血糖素結合分析（Π)中顯示IC5G値低於ΙΟΟΟηΜ。 GIP結合分析 BHK(倉田鼠（hamster)的幼鼠的腎臟細胞線）細胞移殖人類胰增血糖素受體及製備細胞膜的製備物。小麥胚芽凝素 (wheat germ agglutinin)衍生的SPA珠狀物，含有閃爍劑 (WGA珠KAmersham)結合至該細胞膜上。125I-GIP結合至該細胞膜上的人體GIP受體上，且以WGA珠狀物上的閃爍劑激發，使其發光。結合至該受體上的GIP或樣品和125L· GIP競爭。The cytoplasmic membrane is prepared by growing cells to confluence, separating them from the surface and resuspending these cells in cold buffer (10 mM Tris / HCl), pH 227 200401634 7.4 contains 30 mM NaCl, 1 mM dithiothreose Alcohol, 5 mg / L leupeptin (Sigma), 5 mg / L pepstatin (Sigma), 100 mg / L bacitracin (Sigma), and 15 mg / L recombinant aprotinin (Novo Nordisk)). Homogenize by using two 10-s ruptures of a Polytron PT10-35 homogenizer (Kinematica), and centrifuge at 95.000 * g grams at 41 w / v% sucrose layer for 75 minutes. Between the two layers the white ribbon was diluted with buffer and centrifuged at 40.000 * g for 45 minutes. The pellet containing the cytosolic membrane is suspended in buffer and stored at -80 ° C until needed. Glucagon is iodinated according to the chloramine T method (Hunter and Green-wood, Nature 194, 495 (1962)) and purified using anion exchange chromatography (JP gensen et al., Hormone and Metab. Res. 4,223 -224 (1972). Specific activity is 460 // Ci / ug of iodination per day. Fractional tracer doses are stored at -18 ° C and used immediately after melting. Combined analysis in filter microliter disk (MADV N65 microwells) were performed three times. The buffer used in this analysis was 25 mM HEPES pH 7.4, containing 0.1% human serum albumin (Sigma, grade V). Glucagon was dissolved in 0.05 M HC1, added, etc. Amount (w / w) of HSA and freeze-dried. In the days of use, it was dissolved in water and diluted to the required concentration with buffer. The test compound was dissolved and diluted with DMS. 1 4 0 # L buffer, 2 5 # L glucagon or buffer, and 10 # LDMS〇 or test compound were added to each well. Tracer (50.000 cpm) was diluted with buffer and 2 5 // added to each well. 1 1 4 // g of freshly thawed cytoplasmic membrane protein diluted in buffer and then 2 5 // L Add to each well of 228 200401634. Incubate plates at 30 ° C for 2 hours. Unspecific binding is measured at 10-6 M glucagon. Bound and unbound tracers are then filtered by vacuum filtration (micropore vacuum manifold Tube). The plate was washed once with 2 X 1 0 0 // L buffer / well. The plates were air-dried for several hours, and then the filters were separated from the plate using Millpore Puncher. The filters were calculated in a τ counter Functional analysis (I) Functional analysis was performed in a 96-well microliter dish (tissue culture dish, Nunc). The buffer concentration generated during the analysis was 50 mM Tris / HCl, 1 Mm EGTA, 1.5 mM MgS04, 1.7 mM ATP, 20 // M GTP, 2 mM IBMX (isobutyl monomethyl-xanthine), 0.02% tween-20 and 0.1% HSA. PH is 7.4. Glucagon and recommended Antagonist was added at 50 / L diluted 50 mM Tris / HC1, 1 mM EGTA, 1.85 mM MgS04, 0.0222% tween-20 and 0.111% HSA, pH 7.4. 20 // L 50 mM Tris / HCl, 1 mM EGTA, 1.5 mM MgSO4, 11.8 mM ATP, 0.14 mM GTP, 14 mM IBMX and 0.1% HSA, ρΗ7.4. GTP dissolves immediately before analysis. Add 50 // L containing 5 // g of plasma membrane protein in Tris / HCl ’EGTA, MgS04, HSA buffer (the actual concentration depends on the protein concentration in the storage plasma membrane). The total analytical volume is 140 // L. The analysis was incubated at 37 ° C for 2 hours with continuous shaking. The reaction was completed by adding 25 // L of 0.5 N HC1. cAMP was measured using a blinking proximity kit (Amersham). 229 200401634 Glucagon binding assay (i i) ΒΗΚ (kidney cell line of hamster juvenile rat) cell transplantation of human glucagon receptor and preparation for preparing cell membrane. Wheat germ agglutinin-derived SPA beads containing a scintillator (WGA beads) (Amersham) bind to the cell membrane. 125I-glucagon binds to the human glucagon receptor on the cell membrane and is excited with a scintillator on the WGA beads to cause it to emit light. The glucagon or sample bound to this receptor competes with 125I-glucagon. All procedures in cell membrane preparations are kept in ice or performed at 4 ° C. BHK cells were collected and centrifuged, and the resulting particles were homogenized in a buffer (25 mM HEPES pH = 7.4, 2.5 mM CaCl 2, 1.0 mM MgCl 2, 250 mg / L subtilisin), using Polytron 10- 35 Homogenizer (Kinematica) homogenize for 2 10 seconds, add the same amount of homogenization buffer, and resuspend. After centrifugation (15 minutes, 2000xg), transfer the supernatant to a cold centrifuge tube and centrifuge for another 45 minutes (40.000 X g). The granules were resuspended in the homogenization buffer, homogenized for 2 seconds (Polytron), and the homogenization buffer was added again. Centrifuge the suspension for 45 minutes (40.000 X g), and resuspend the pellet in resuspension buffer (25 mM HEPES pH = 7.4, 2.5 mM CaCl2, 1.0 mM MgCl2) and homogenize for 2 10 seconds (Polytron) . The concentration of protein is generally about 1.75 mg / ml. Add stabilization buffer (25 mM HEPES ρΗ = 7.4, 2.5 mM CaCl 2, 1.0 mM MgCl 2, 1% BSA, 500 mg / L subtilisin, 2.5M sucrose), and store at -8 (TC Cell membrane preparation. Glucagon binding analysis was performed on an opti plate (polystyrene micro 230 200401634 titration plate, Packard), and 50 // L analysis buffer (25mM HEPES ρΗ = 7.5, 2.5mM CaCl) was added. 2 5 1.0 mM MgCl 2 5 0.003% Tween-20, 0.005% subtilisin, 0.05% sodium azide) and 5 / L glucagon or test compound (dissolved in DMSO) to each well. Then add 50 // L tracer (125I-pig glucagon, 70.000 cpm) and 50 // L cell membrane containing human glucagon receptor (12.5 // g) to each well, and finally 50 // L WGA beads containing 1 mg of beads are transferred to the well. The analytes are cultured in a shaker for 4 hours, and left to stand for 8-48 hours. This opti dish is counted in a Topcounter. Non-specific binding to Determination of glucagon at 500 nM. Most compounds of the present invention showed IC5G <100 nM in the glucagon binding assay (II). GIP binding analysis of BHK (kidney rat kidney cell line of hamster) cell transplantation of human glucagon receptor and preparation of cell membrane preparation. Wheat germ agglutinin-derived SPA beads The scintillant (WGA beads KAmersham) is bound to the cell membrane. 125I-GIP is bound to the human GIP receptor on the cell membrane and excited by the scintillator on the WGA beads to cause it to emit light. Binding to the receptor The body's GIP or sample competes with 125L · GIP.

所有在細胞膜製備物中的操作步驟皆保持在冰中，或在4°C下進行。收集和離心BHK細胞，再將所得顆粒於均質化緩衝液（25 mM HEPES pH=7.4， 2.5mM CaCl2，1·0 mMAll procedures in cell membrane preparations are kept in ice or performed at 4 ° C. BHK cells were collected and centrifuged, and the resulting particles were homogenized in a homogenization buffer (25 mM HEPES pH = 7.4, 2.5 mM CaCl2, 1.0 mM

MgCl2，250毫克/升枯草旱菌素），使用Polytron 10-35均化 231 200401634MgCl2, 250 mg / L subtilisin), homogenized with Polytron 10-35 231 200401634

器（Kinemadca)均質化2個10秒，且加入相同量的均質化緩衝液，再懸浮用。離心後（15分鐘，2000xg)，將上層液移至冷離心管中，且再離心45分鐘（40.000 X g)。粒狀物再懸浮於均質化緩衝液中，均質化2個10秒（Polytron)，及再加入均質化緩衝液。離心懸浮液45分鐘（40.000 X g)，且再將粒狀物懸浮於再懸浮緩衝液中（25 mM HEPES pH=7.4， 2.5mMHomogenizer (Kinemadca) homogenize for 2 10 seconds, add the same amount of homogenizing buffer, and resuspend. After centrifugation (15 minutes, 2000xg), transfer the supernatant to a cold centrifuge tube and centrifuge for another 45 minutes (40.000 X g). The granules were resuspended in the homogenization buffer, homogenized for two 10 seconds (Polytron), and the homogenization buffer was added again. Centrifuge the suspension for 45 minutes (40.000 X g) and resuspend the pellet in resuspension buffer (25 mM HEPES pH = 7.4, 2.5 mM

CaCl2，1.0 mM MgCl2)且均質化 2 個 10 秒（Polytron)。蛋白質的濃度一般是約1.75毫克/毫升。加入安定化緩衝液（25 mM HEPES ρΗ=7·4， 2.5mM CaCl 2 ，：L0 mM MgCl2，1% BSA，500毫克/升枯草旱菌素，2.5M蔗糖），且在-80°C下保存細胞膜製備物。 GIP結合分析是在一 opti盤上進行（聚苯乙烯微滴定盤，Packard)，加入 50//L 分析緩衝液（25mM HEPES pH=7.5 ，2.5mM CaCl 2 ，1·〇 mM MgCl 2 ，0.003% Tween-20， 0.005%枯草旱菌素，0.05%鈉疊氮化物）及5微升GIP或測試化合物（溶於DMS0中）至每一井。然後加入50微升的示踪劑（125I-豬GIP，50.000 cpm)及50// L含有人類GIP受體的細胞膜（12.5//g)至每一井中，最後將50/zL含有1毫克珠狀物的WGA珠移轉至該井中。在一搖動器中培養分析物 3.5時，及靜置8-48小時。此opti盤在一 Topcounter中計數。非特定結合以500 nM的GIP測定。一般而言，本發明的化合物顯示對胰增血糖素受體的高親核性（和GIP受體比較）。 232CaCl2, 1.0 mM MgCl2) and homogenize for 2 10 seconds (Polytron). The concentration of protein is generally about 1.75 mg / ml. Add stabilization buffer (25 mM HEPES ρΗ = 7.4, 2.5 mM CaCl 2: L0 mM MgCl 2, 1% BSA, 500 mg / L subtilisin, 2.5M sucrose), and at -80 ° C Save the cell membrane preparation. GIP binding analysis was performed on an opti plate (polystyrene microtiter plate, Packard), and 50 // L analysis buffer (25mM HEPES pH = 7.5, 2.5mM CaCl 2, 1.0mM MgCl 2, 0.003%) was added. Tween-20, 0.005% subtilisin, 0.05% sodium azide) and 5 μl GIP or test compound (dissolved in DMS0) to each well. Then add 50 μl of tracer (125I-pig GIP, 50.000 cpm) and 50 // L cell membrane containing human GIP receptor (12.5 // g) to each well, and finally 50 / zL contains 1 mg beads The WGA beads were transferred to the well. Incubate the analyte in a shaker for 3.5 and let stand for 8-48 hours. This opti disk is counted in a Topcounter. Non-specific binding was determined at 500 nM GIP. In general, the compounds of the invention exhibit high nucleophilicity (as compared to GIP receptors) to the glucagon receptor. 232

Claims

200401634 拾、申請專利範圍 1 · 一種式（I )化合物， F R1200401634 Patent application scope 1 · A compound of formula (I), F R1

其中 A是 HOWhere A is HO

m是〇或1， η 是 0，1，2 或 3，但其前提是m&n不能同時爲〇， R 4是氫，鹵素或一（C Η 2 )。一〇R 5，〇是0或1 ， R5是氮’ Cl — 6 -院基’ Ci_6 -院酸基’芳基或芳基—C卜6 —院基， R 1和R 2互不相關的分別是氫，鹵素或C 1 - 6 —烷基，或R 1和R 2—起形成一雙鍵， R3是氫，C 1_6 -烷基或鹵素，或R3及R2—起形成一鍵結至氧的雙鍵， X是芳撐或雜芳撐，其可選擇性的經一個或二個選自一 CN，一 CF3，一〇CF3，一〇CHF2，一 N〇 2 233 200401634 一〇r8，一 NR8R9及Ci-6—烷基之R6和R7群基所取代的， R 8和R 9互不相關的分別是氫或C i — 6 —烷基， Y 是一c(〇）一，一〇一，一 NR1 〇，一S-，一 S (〇）一， —S (〇）2 —或—CRilRi2 —， R 1 Q是氫或C 1 _ 6 -烷基， R 1 1和R 1 2互不相關的分別是氫，C 1 — 6 -烷基或羥基，或R 1 1和R 1結合形成一雙鍵，及R 1 2是氫，C工 —6 -院基或經基’ Z 是一c (〇）一（cr13r14) p —，一〇一（c R 1 3 R 1 4 ) p -，一 S- (CR"R1”P -，- S(〇）-(CR1 3 R 1 4 ) p -， —S (0) 2 — (CR13R14) p— 5— NR15 —( C R " R i 4 ) P —或 -(cr13r14)p-， p是0，1或2， R13和R14互不相關的分別選自氫，一 CF3，-〇 C F 3及Ci-6 -院基， R 1 5是氫或C 1 — 6 -烷基， D是芳基或雜芳基，其可是選擇性的經一個或多個取代基尺16，1^17，1^18，1^19，1^2()及1121所取代的，其中 234 200401634 R 1 6，R 1 7，R 1 8及r 1 9互不相關的分別是 •氫，鹵素，一CN，—CH2CN，—CHF2，—CF3，一〇chf2, 一〇ch2cf3，一〇cf2chf2， —S(〇）2CF3，一scf3，一n〇2,一〇r22，一NR22R23，-SR22，—NR22S (〇）2R23， —s (〇）2nr22r23，一s (〇）nr22r23， —S (〇）R22，一s (〇）2R22，m is 0 or 1, η is 0, 1, 2 or 3, but the premise is that m & n cannot be 0 at the same time, R 4 is hydrogen, halogen or one (C Η 2). 〇R 5, 〇 is 0 or 1, R5 is a nitrogen 'Cl-6-courtyard' Ci_6-courtyard acid 'aryl or aryl-C 6-courtyard, R 1 and R 2 are independent of each other Respectively hydrogen, halogen or C 1-6 -alkyl, or R 1 and R 2-form a double bond, R 3 is hydrogen, C 1-6 -alkyl or halogen, or R 3 and R 2-form a bond to Oxygen double bond, X is arylene or heteroarylene, which can be optionally selected from one or two selected from one CN, one CF3, one CF3, one CHF2, one NO2 233 200401634 one 10r8, NR8R9 and Ci-6-alkyl are substituted by the R6 and R7 group groups, and R 8 and R 9 are unrelated to each other hydrogen or Ci-6-alkyl, and Y is a c (〇) 一, a 〇 one, one NR1 〇, one S-, one S (〇) one, —S (〇) 2 — or —CRilRi2 —, R 1 Q is hydrogen or C 1_6-alkyl, R 1 1 and R 1 2 Not related to each other are hydrogen, C 1-6 -alkyl or hydroxy, or R 1 1 and R 1 combine to form a double bond, and R 1 2 is hydrogen, and C 6-6-or radical Z is a c (〇) 一 (cr13r14) p —, a 010 (c R 1 3 R 1 4) p-, a S- (CR " R1 ”P- , -S (〇)-(CR1 3 R 1 4) p-, —S (0) 2 — (CR13R14) p— 5— NR15 — (CR " R i 4) P —or-(cr13r14) p- , P is 0, 1, or 2, R13 and R14 are independently selected from hydrogen, a CF3, -〇CF3 and Ci-6-radical, R 1 5 is hydrogen or C 1-6-alkyl, D is aryl or heteroaryl, which may be optionally substituted by one or more substituents 16,1 ^ 17, 1 ^ 18, 1 ^ 19, 1 ^ 2 () and 1121, of which 234 200401634 R 1 6, R 1 7, R 1 8 and r 1 9 are unrelated to each other: hydrogen, halogen, -CN, -CH2CN, -CHF2, -CF3, 10chf2, 10ch2cf3, 10cf2chf2, -S (〇) 2CF3,-scf3, -no2, -0r22, -NR22R23, -SR22, -NR22S (〇) 2R23, -s (〇) 2nr22r23, -s (〇) nr22r23, --S (〇 ) R22, one s (〇) 2R22,

—C (〇）NR22R23，一〇C (〇）NR22R23， -nr22c (〇）R23，-ch2c (〇)nr22r23， —〇CH2C (〇）NR22R23, 一 CH2〇R23， —ch2nr22r23，一〇c (〇）r22，—c (〇）r22或 —C (〇）〇R22， c i _6 -院基，C 2 —6 -稀基或C 2 -6炔基其可選擇性的經一個或多個選自鹵素’一 C N ’一 C F -〇 C F 3，-C (〇) NR22R23, -0C (〇) NR22R23, -nr22c (〇) R23, -ch2c (〇) nr22r23, -〇CH2C (〇) NR22R23, -CH2〇R23, -ch2nr22r23, -0c (〇 ) R22, —c (〇) r22 or —C (〇) 〇R22, ci _6-courtyard, C 2-6-dilute or C 2 -6 alkynyl which can be optionally selected through one or more selected from Halogen '-CN'-CF-〇CF 3,

一〇CHF2，一 N〇2，一〇R22，— NR22R23 及 c 一烷基的取代基取代的， c3 —8-環烷基，C4 —8一環烯基，雜環基，C3 —8-環烷基-。―6-烷基，C3 —8—環烷基-烷氧基，C3-8-環烷氧基，C3 —8—環烷基—。卜6-烷硫基，C3-8-環烷基烷硫基’ C 3 _ 8 -環烷基—C 2 — 6 —烯基，。3 _ 8 -環烷基- C 2 - 6 -炔基’ C4 —8-環烯基-C! —6-烷基，。4 —8-環烯基-C2_6-烯基’ C 4 _ 8 -環烯基-C 2 _ 6 -炔基，雜環基—C 1 - 6 —錄，雜環基― C 2 —6 -臟，雜環基-C 2 —6 -賴，芳基，芳氧基’芳氧基簾基 235 200401634 ，芳醯基，芳基一 c卜6 -烷氧基，芳基—c卜6—烷基，芳基— c2 —6-烯基，芳基一 C2-6—炔基，雜芳基，雜芳基—Ch6—烷基，雜芳基—C 2_6—稀基或雜芳基一 C 2_6一炔基，其中芳香系及非-芳香系環系統可選擇性的經一個或多個選自鹵素，一C (〇）OR22，一CN，一 CF3，一〇 CF3 ’ 一 OCHFg ’ 一 N〇2 ，_〇R22 ，一 NR22 R 2 3及C 1 — 6 -烷基的取代基取代的， R 2 2和R 2 3互不相關的分別是氫，C i — 6 —烷基，芳基一 C 1 — 6 —烷基或芳基，或R 2 2及R 2 3—起鍵結至相同的氮原子上時，則其和氮原子形成一 3至8元雜環，且此雜環可選擇性的含有一個或二個其它選自氮，氧及硫的雜原子，及選擇性的含有一個或二個雙鍵，或R 1 6至R 1 9中的任二個群基是在相鄰位置時，其可一起形成一架橋基-(CR24R25) a —〇一（CR26R27) c —〇一， a是0，1或2， c是1或2， R 2 4，R 2 5，R 2 6和R 2 7互不相關的分別是氫，c 1 _ 6 一院基或氛’ R20和R21互不相關的分別是氫，Ci — 6 -院基，◦ 3-8 -環烷基或 C 3 一 8 —環院基-C i — 院基， E是 C 3 — 8 —環烷基或c 4 — 8 -環烯基，其可選擇性的經一個或二個取代基 236 200401634 R 2 8和R 2 9取代的，而此取代基是互不相關的分別選自：氫，鹵素，一CN，一 CF3，一〇CF3，一 OCHF 2，一〇R33，一 NR33R34，Ci_6_ 烷基，C3 — 8 一環院基，C 4 — 8—環烯基，雜芳基及芳基，其中該雜芳基及芳基是選擇性的經一個或多個選自鹵素，一cn，一cf3，一〇cf3，一〇chf2，一n 〇2，一〇R33，一 NR33R34及Cl — 6 —烷基取代的 R 33和R 3 4互不相關的分別是氫或C —烷基， · 或R 3 3及R 3 4—起鍵結至相同的氮原子上時，則其和該氮原子可形成一 3至8元雜環，且此雜環可選擇性的含有一個或二個其它選自氮，氧及硫的雜原子，及選擇性的含有一個或二個雙鍵，芳基，雜芳基，芳基一 C2 — 6烯基或芳基一 C2 — 6~ 炔基，其中該芳基及雜芳基可選擇性的經一個或多個取代基 R 2 8，r 2 9，r 3 0，r 3 1 及 R 3 2 取代的，其中R28和R29是如上所定義者，及R3Q，R31和 _ R 3 2互不相關的分別選自 •氫，鹵素，一chf2，一cf3，一〇cf3,一〇chf2，一〇ch2cf3，一〇cf2chf2，_scf3，一 OR35， —NR35R36，— SR35，_S (〇）R35，_s (〇）2R35， —c (〇）nr35r36，一〇c (〇）nr35r36， —NR35C (〇）R36，一〇CH2C (〇）NR35R36， —C (〇）R35及一C (〇）〇R35， 237 200401634 • Cu-烷基，c2 —6-烯基及C2 一 6-炔基，其可是選擇性的經一個或多個選自鹵素，一 c N，一 C F 3 ，一〇CF3 ，一〇CHF2 ，一 N〇2，一〇R35 ，一N R =3 5 R 3 6及c工-6 —烷基取代的， • C3_8-環烷基，c4一8-環烯基，雜環基，C3_8-環烷基-Ci—6 —院基，C 3 — 8—環院基一 C 2 —6 一烯基’ C 3-8—環院基—C 2-6 — 块基’ C4 — 8—環燦基—Ci — 6-院基’ C4 —8 - ί哀烯基—C2 —e—嫌基，C 4 _ 8 -環烯基-C 2 — 6 -炔基，雜環基-C ! _ 6 -烷基，雜環基 —C 2_6 -烯基，雜環基—C 2 —6 -炔基5芳基，芳氧基，芳醯基，芳基—C 1 — 6 —院氧基，芳基一 C 1 - 6 一丨兀基’芳基—C 2 — 6 —烯基，芳基—C 2_6-炔基，雜芳基，雜芳基一 c卜6-院基，雜芳基—C 2_6 —烯基及雜芳基—C 2_6-炔基，其中該芳香系及非-芳香系環系統選擇性的可經一個或多個選自鹵素，一CN，一CF、，一〇CF3，OCH F2，一 N〇2 ，一 OR35，一 N R 3 5 R 3 6及C 1 — 6 —烷基取代的，其中R 3 5和R 3 6互不相關的分別是氫，C 1 — 6 —烷基或芳基，或當R 3 5和R 3 6鍵結至相同的氮原子上時，則其和該氮原子一起形成一 3至8元雜環，且此雜環選擇性的包含一個或二個其它選自氮，氧及硫的雜環子，且選擇性的包含一個或二個雙鍵，或當取代基R 3 G，R 3 1和R 3 2中的二個鍵結至相同的碳原子或相鄰環之碳原子上時，則其可一起形成一架橋 238 200401634 基一〇一(CH2) t-CR37R38 — (CH2) i — O — ，—（CH2) t-CR37R38 - (CH2) i - 或- S-(CH2) t — CR37R38 - (CH2) i — s-， t和1互不相關的爲0，1，2，3，4或5， R37和R38互不相關的爲氫或C ι_6—烷基，以及任何其非對映異構物或對映異構物或互變型式異構物，包括這些異構物的混合物或其藥學上可接受的鹽。 2 ·如申請專利範圍第1項之化合物，其中A是10CHF2, No2, 10R22,-NR22R23 and c-alkyl substituted, c3- 8-cycloalkyl, C4- 8-cycloalkenyl, heterocyclyl, C3- 8-ring alkyl-. —6-Alkyl, C3-8-cycloalkyl-alkoxy, C3-8-cycloalkoxy, C3-8-cycloalkyl—. Bu 6-alkylthio, C3-8-cycloalkylalkylthio 'C 3-8 -cycloalkyl-C 2-6 -alkenyl. 3_8-cycloalkyl-C 2-6 -alkynyl 'C4- 8-cycloalkenyl-C! —6-alkyl. 4 —8-cycloalkenyl-C2_6-alkenyl 'C 4 _ 8 -cycloalkenyl-C 2 -6 -alkynyl, heterocyclyl —C 1-6 —, heterocyclyl — C 2 — 6 — Dirty, heterocyclyl-C 2-6-lysyl, aryl, aryloxy 'aryloxycuryl 235 200401634, arylfluorenyl, aryl-c 6 -alkoxy, aryl -c 6- Alkyl, aryl—c2-6-alkenyl, aryl—C2-6—alkynyl, heteroaryl, heteroaryl—Ch6—alkyl, heteroaryl—C 2-6—diluted or heteroaryl— C 2_6-alkynyl, wherein the aromatic and non-aromatic ring systems can be optionally selected via one or more halogens, -C (〇) OR22, -CN, -CF3, -CF3 '-OCHFg'- No 2, — 2 R 22, a NR 22 R 2 3 and a C 1 —6-alkyl substituent, R 2 2 and R 2 3 are unrelated to each other hydrogen, C i — 6-alkyl, When aryl-C 1-6 -alkyl or aryl, or R 2 2 and R 2 3-are bonded to the same nitrogen atom, then it forms a 3 to 8 membered heterocyclic ring with the nitrogen atom, and this The heterocyclic ring may optionally contain one or two other heteroatoms selected from nitrogen, oxygen and sulfur, and optionally one Or two double bonds, or when any of the two groups in R 1 6 to R 1 9 are in adjacent positions, they can form a bridge group together-(CR24R25) a -〇-(CR26R27) c -〇- , A is 0, 1 or 2, c is 1 or 2, R 2 4, R 2 5, R 2 6 and R 2 7 are unrelated to each other, respectively, hydrogen, c 1 _ 6 a radical or ambience 'R20 and R21 is irrelevant to each other, hydrogen, Ci-6-Cycloyl, ◦ 3-8-cycloalkyl or C3-8-Cycloyl-Ci-Cycloyl, E is C3-8-Cycloalkyl Or c 4 — 8-cycloalkenyl, which is optionally substituted with one or two substituents 236 200401634 R 2 8 and R 2 9, and this substituent is independently selected from: hydrogen, halogen , A CN, a CF3, a 10CF3, a OCHF 2, a 10R33, a NR33R34, a Ci_6_ alkyl group, a C3-8 a cycloalkyl group, a C 4-8 cycloalkenyl group, a heteroaryl group and an aryl group, of which The heteroaryl and aryl groups are optionally selected from one or more of halogen, one cn, one cf3, one 10cf3, one chf2, one n 〇2, 〇R33, NR33R34 and Cl — 6 — Alkyl-substituted R 33 and R 3 4 independently of one another are hydrogen or C — Group, or R 3 3 and R 3 4-are bonded to the same nitrogen atom, then it and the nitrogen atom may form a 3 to 8 membered heterocyclic ring, and the heterocyclic ring may optionally contain one or Two other heteroatoms selected from nitrogen, oxygen and sulfur, and optionally containing one or two double bonds, aryl, heteroaryl, aryl-C2-6 alkenyl or aryl-C2-6 ~ alkyne Group, wherein the aryl and heteroaryl groups are optionally substituted with one or more substituents R 2 8, r 2 9, r 3 0, r 3 1 and R 3 2, wherein R28 and R29 are as described above The definers, and R3Q, R31 and _R 3 2 are independently selected from hydrogen, halogen, chf2, cf3, 〇cf3, 〇chf2, 〇ch2cf3, 〇cf2chf2, _scf3, and OR35. — —NR35R36, — SR35, —S (〇) R35, —s (〇) 2R35, —c (〇) nr35r36, —c (〇) nr35r36, —NR35C (〇) R36, —CH2C (〇) NR35R36, — C (〇) R35 and one C (〇) OR35, 237 200401634 • Cu-alkyl, c2-6-alkenyl and C2-6-alkynyl, which may be optionally selected from one or more halogens, A c N, one CF 3, one 10 CF 3, one 10 CHF 2, one No 2, one O R35, one NR = 3 5 R 3 6 and c- 6-alkyl substituted, • C 3_8-cycloalkyl, c 4 An 8-cycloalkenyl, heterocyclyl, C3_8-cycloalkyl-Ci-6 —institutional base, C 3 — 8—cycloindenyl—C 2-6—alkenyl 'C 3-8—cycloindenyl — C 2-6 — block group 'C4 — 8 —cyclocanyl — Ci — 6-institutional base' C4 — 8-哀 alkenyl — C2 —e — alkyl, C 4 _ 8-cycloalkenyl-C 2 — 6-alkynyl, heterocyclyl-C! _6-alkyl, heterocyclyl-C 2-6-alkenyl, heterocyclyl-C 2-6-alkynyl 5aryl, aryloxy, arylfluorenyl , Aryl—C 1 — 6 —ethoxy, aryl—C 1-6 — alkoxy'aryl—C 2 — 6 —alkenyl, aryl—C 2_6-alkynyl, heteroaryl, hetero Aryl-C6-Chenyl, heteroaryl-C 2_6-alkenyl and heteroaryl-C 2_6-alkynyl, wherein the aromatic and non-aromatic ring systems can be selectively passed through one or more Selected from the group consisting of halogen, one CN, one CF, one 10CF3, OCH F2, one No2, one OR35, one NR 3 5 R 3 6 and C 1-6-alkyl substituted, wherein R 3 5 and R 3 6 each other The relevant ones are hydrogen, C 1-6 -alkyl or aryl, or when R 3 5 and R 3 6 are bonded to the same nitrogen atom, it will form a 3- to 8-membered hetero atom with the nitrogen atom. Ring, and the heterocyclic ring optionally includes one or two other heterocyclic rings selected from nitrogen, oxygen, and sulfur, and optionally includes one or two double bonds, or when substituted by R 3 G, R 3 1 When two of R 3 2 are bonded to the same carbon atom or a carbon atom of an adjacent ring, they can form a bridge together. 238 200401634 radical 010 (CH2) t-CR37R38 — (CH2) i — O —, — (CH2) t-CR37R38-(CH2) i-or-S- (CH2) t — CR37R38-(CH2) i — s-, where t and 1 are independent of each other, 0, 1, 2, 3 , 4 or 5, R37 and R38 are unrelated to each other hydrogen or C 1-6 alkyl, and any of its diastereomers or enantiomers or tautomeric isomers, including those of the isomers. A mixture or a pharmaceutically acceptable salt thereof. 2 · For the compound in the scope of application for item 1, wherein A is

其中m，η和R 1是如申請專利範圍第1項中所定義者。 3 ·如申請專利範圍第2項之化合物，其中Α是 /CH9—- 又Where m, η and R 1 are as defined in the first item of the patent application scope. 3 · If the compound in the scope of patent application No. 2 wherein A is / CH9—-

5 ·如申請專利範圍第1項之化合物，其中a是 1 ·如申請專利範圍第2項之化合物，其中A是 2004016345 · As for the compound in the scope of patent application, where a is 1 · As in the compound in the scope of patent application, where A is 200401634

6 ·如申請專利範圍第1，2，3，4或5項中任一項的化合物，其中X是單環芳撐或雜芳撐，其可選擇性的如申請專利範圍第1項所述所取代的。 7 ·如申請專利範圍第1，2，3，4，5或6項中任一項的化合物，其中X是6 · The compound according to any one of claims 1, 2, 3, 4 or 5 in which X is a monocyclic arylene or heteroarylene, which is optionally as described in the first patent application Replaced by. 7 · A compound according to any one of claims 1, 2, 3, 4, 5 or 6, wherein X is

其中R 6和R 7是如申請專利範圍第1項中所述者。 8 ·如申請專利範圍第7項之化合物，其中X是Wherein R 6 and R 7 are as described in item 1 of the scope of patent application. 8 · The compound as claimed in item 7 in which X is

其中R 6和R 7是如申請專利範圍第1項中所定義者。 9 ·如申請專利範圍第7或8項之化合物，其中R6和 R 7兩者皆爲氫。 1 0 ·如申請專利範圍第1，2，3，4，5，6， 7，8或9項中任一項之化合物，其中E是 200401634Wherein R 6 and R 7 are as defined in item 1 of the scope of patent application. 9) A compound as claimed in item 7 or 8 in which both R6 and R7 are hydrogen. 1 0 · A compound according to any one of claims 1, 2, 3, 4, 5, 6, 7, 8 or 9, wherein E is 200401634

利範圍第1項中所定義者。 1 1 ·如申請專利範圍第1 〇項之化合物，其中E是As defined in item 1. 1 1 · The compound according to item 10 of the scope of patent application, wherein E is

其中R28，R29，R3Q，R31和R32是如申請專利範圍第1項中所定義者。 1 2 ·如申請專利範圍第1 1項之化合物，其中E是 241 200401634Among them, R28, R29, R3Q, R31 and R32 are as defined in the first patent application scope. 1 2 · For the compound of item 11 in the scope of patent application, wherein E is 241 200401634

所定義者。 1 3 ·如申請專利範圍第1 2項之化合物，其中E是Defined by. 1 3 · The compound according to item 12 in the scope of patent application, wherein E is

其中R 3 Q，R 3 1和R 3 2是如申請專利範圍第1項中所定義者。 1 4 ·如申請專利範圍第1 1項之化合物，其中E是Among them, R 3 Q, R 3 1 and R 3 2 are as defined in item 1 of the scope of patent application. 1 4 · The compound under item 11 in the scope of patent application, wherein E is

利範圍第1項中所定義者。 1 5 ·如申請專利範圍第1 〇，1 1，1 2，1 3或 1 4項中任一項的化合物，其中R 3 0，R 3 1和R 3 2互不相關的分別爲· 氫鹵素，一〇CF3, 一 SCF 3或一 C F 3， 242 200401634 _ C 1 _ 6 —烷基，其是選擇性的經一個或多個選自下述之取代基取代的：氟，—CN，— CF3, 一〇CF3，— 〇R35 和一 NR35R36， C 3 — 8 -環烷基或C 4 - 8 -環烯基，其可選擇性的經一個或多個選自氟，一CN，一 CF3 ’ 一〇CF3，一〇 R 3 5，一 N R 3 5 R 3 6及C 1 — 6 -烷基的取代基取代的芳基，芳氧基或芳基一 Cl — 6 -烷氧基，其中該芳基可選擇性的經一個或多個選自鹵素，一 c N，一 C F 3，一〇CF3，一NOS ，一 R35 ，一NR35R36 及 C -烷基的取代基取代的， R 3 5和R 3 6互不相關的分別爲氫，C 1 _ 6 -烷基或芳基，或當R 3 5及R 3 6鍵結至相同的氮原子上時，則其和該氮原子可形成一 3至8元雜環，且此雜環選擇性的含有一個或二個其它選自氮，氧及硫的雜原子，且選擇性的含有一個或二個雙鍵。 1 6 ·如申請專利範圍第1 5項之化合物，其中R 3 0 ，R 3 1和R 3 2互不相關的分別是 _氫鹵素，〇CF3,或一SCF3， • c i — 6 —院基，其可選擇性的經一個或多個選自氟，一 CN，一CF3，一〇CF3，一 OR35 及一 N R 3 5 R 3 6取代的， 243 200401634 環己基或環己-1 -烯基，其可選擇性的經一個或多個選自氟，一CN，一 CF3，一〇CF3，一OR35，一 N R 3 5 R 3 6及C 1 _ 6 -烷基取代的，苯基，其可選擇性的經一個或多個選自鹵素，一 C N，一 C F 3 5 一 0 C F 3 5 一 N〇2 ，一〇R35 ，一 N R 3 5 R 3 6及c 1 — 6 -烷基取代的， •苯氧基或苯甲氧基，其中該苯基可選擇性的經一個或多個選自鹵素，一CN，一 CF3 ’ 一〇CF3 ’ 一 N〇2 5 一〇R 3 5，— N R 3 5 r 3 6及c 1 _ 6 —烷基取代的， R 3 5和R 3 6互不相關的分別爲氫或C 1 — 6 —烷基。 1 7 ·如申請專利範圍第1 0，1 1，1 2，1 3 ’ 1 4，1 5或1 6項之化合物，其中R30和R32兩者爲氫，及R 3 1不是氫。 1 8 ·如申請專利範圍第1 0項之化合物，其中E是As defined in item 1. 1 5 · The compound according to any one of the scope of the patent application No. 1 0, 1 1, 12, 1, 3 or 14 wherein R 3 0, R 3 1 and R 3 2 are unrelated to each other. · Hydrogen Halogen, 10CF3, SCF3 or CF3, 242 200401634_C1_6-alkyl, which is optionally substituted with one or more substituents selected from: fluorine, -CN, — CF3, —CF3, —ORR35 and —NR35R36, C 3 — 8-cycloalkyl or C 4-8-cycloalkenyl, which are optionally selected from one or more of fluorine, —CN, — CF3 '-10CF3, 10R 3 5, 1 NR 3 5 R 3 6 and C 1-6 -alkyl substituted aryl, aryloxy or aryl-Cl-6 -alkoxy, Wherein the aryl group may be optionally substituted with one or more substituents selected from halogen, -c N, -CF 3, 10 CF 3, -NOS,-R 35,-NR 35 R 36 and C-alkyl substituents, R 3 5 and R 3 6 are independently related to hydrogen, C 1 -6 -alkyl or aryl, or when R 3 5 and R 3 6 are bonded to the same nitrogen atom, they and the nitrogen atom may be Forms a 3 to 8 membered heterocyclic ring, and this heterocyclic ring is selective Containing one or two further hetero atoms selected from nitrogen, oxygen and sulfur, and optionally include one or two double bonds. 16 · If the compound in the 15th scope of the patent application, wherein R 3 0, R 3 1 and R 3 2 are irrelevant to each other _ hydrogen halogen, 〇CF3, or a SCF3, • ci — 6 — courtyard , Which is optionally substituted with one or more members selected from the group consisting of fluorine, -CN, -CF3, -0CF3, -OR35, and NR 3 5 R 3 6, 243 200401634 cyclohexyl or cyclohex-1-enyl Which is optionally substituted by one or more selected from fluorine, -CN, -CF3, -0CF3, -OR35, -NR 3 5 R 3 6 and C 1_6-alkyl, phenyl, which Optionally substituted by one or more selected from halogen, -CN, -CF 3 5 -0 CF 3 5 -N02, -R35, -NR 3 5 R 3 6 and c 1-6 -alkyl , Phenoxy or benzyloxy, wherein the phenyl group is optionally selected from one or more halogens, one CN, one CF3 ′, one CF3 ′, one NO2 5 and one 0R 3 5, — NR 3 5 r 3 6 and c 1 _ 6 —alkyl substituted, and R 3 5 and R 3 6 which are independent of each other are hydrogen or C 1 — 6 —alkyl. 17 · The compound according to the scope of application for a patent No. 10, 1 1, 12, 12, 3 '14, 14, 15 or 16 wherein R30 and R32 are both hydrogen and R 3 1 is not hydrogen. 1 8 · For the compound in item 10 of the scope of patent application, wherein E is

244 200401634 CH ‘244 200401634 CH ‘

2 0 ·如申請專利範圍第1 8項之化合物，其中E是2 0 · The compound under item 18 in the scope of patent application, wherein E is

245 200401634 2 1 ·如申請專利範圍第1 〇項之化合物，其中E是其中R 3 Q是如申請專利範圍第1項中所定義者。 2 2 ·如申請專利範圍第2 1項之化合物，其中R 3 〇是 •鹵素或 •雜芳基，其可選擇性經一個或多個選自鹵素，- C N ，一CF3 ，一NOS ，一〇R35，一 NR35R36 及 C 1 - 6 -烷基取代的， R 3 5和R 3 6互不相關的分別是氫或C 1 _ 6 一烷基，或當R 3 5及R 3 6鍵結至相同的氮原子上時，則其和該氮原子可形成一 3至8元雜環，此雜環選擇性的含有一個或二個其它選自氮，氧及硫的雑原子，及選擇性的含有一個或二個雙鍵。 2 3 ·如申請專利範圍第2 2項之化合物，其中R 3 〇是 •鹵素，或 •噻嗯基，其可選擇性經一個或多個選自鹵素，-C N ，一CF3 ，一NOS，一〇R35，一 NR35R36 及 c 1 — 6 -烷基取代的， R 35和R 3 6互不相關的分別是氫或C 1 — 6 —烷基，或當R 3 5及R 3 6鍵結至相同的氮原子上時，則其和該 246 200401634 氮原子可形成一 3至8元雜環，此雜環選擇性的含有一個或二個其它選自氮，氧及硫的雜原子，及選擇性的含有一個或二個雙鍵。 2 4 ·如申請專利範圍第2 3項之化合物，其中E是245 200401634 2 1 · A compound as claimed in item 10 of the scope of patent application, where E is where R 3 Q is as defined in item 1 of the scope of patent application. 2 2 · The compound according to item 21 of the scope of patent application, wherein R 3 0 is • halogen or • heteroaryl, which can be optionally selected from one or more of halogen, -CN, -CF3, -NOS,- 〇R35, NR35R36 and C 1-6 -alkyl substituted, R 3 5 and R 3 6 are unrelated to each other hydrogen or C 1 -6 alkyl, or when R 3 5 and R 3 6 are bonded When it is on the same nitrogen atom, it and the nitrogen atom can form a 3- to 8-membered heterocyclic ring. This heterocyclic ring optionally contains one or two other halogen atoms selected from nitrogen, oxygen, and sulfur, and the selectivity Contains one or two double bonds. 2 3 · The compound according to item 22 of the scope of patent application, wherein R 3 0 is a halogen, or a thionyl, which can be optionally selected from one or more of halogen, -CN, -CF3, -NOS, 〇R35, NR35R36 and c 1-6-alkyl substituted, R 35 and R 3 6 are unrelated to each other hydrogen or C 1-6-alkyl, or when R 3 5 and R 3 6 are bonded To the same nitrogen atom, it and the 246 200401634 nitrogen atom can form a 3 to 8 membered heterocyclic ring, which heterocyclic ring optionally contains one or two other heteroatoms selected from nitrogen, oxygen and sulfur, and Optionally contains one or two double bonds. 2 4 · If the compound in the scope of patent application No. 23, where E is

2 5 ·如前述申請專利範圍中任一項的化合物，其中 Y是一 C (〇）一，一〇一，一S (〇）2 —，一 NH—或 -C Η 2 -。 2 6 ·如申請專利範圍第1至2 4項中任一項的化合物，其中Υ是一 CHR11 —，其中R1 1是和R 1結合，形成一雙鍵。 2 7 ·如申請專利範圍第2 5項之化合物，其中Υ是 -C (〇）-。 2 8 ·如申請專利範圍第1至2 5項中任一項或第2 7項之化合物，其中R1和R 2兩者是氫。 2 9 ·如申請專利範圍第1至2 5項中任一項或第2 7項之化合物，其中R1和R 2結合形成一雙鍵。 3 0 ·如前述申請專利範圍中任一項的化合物，其中 R 3是氫。 3 1 ·如前述申請專利範圍中任一項的化合物，其中 200401634 Z 是一C (〇）-(CR13R14) p-，-〇_(CR13r14 )p-，一 NR15 一（CR13R14)p_s -S(〇）2- （CR13R14)P-，其中p，R 1 3，R 1 4和r 1 5是如申請專利範圍第1 項中所定義者。 3 2 ·如申請專利範圍第3 1項之化合物，其中z是 -NRi5 — (CRi3Ri4) p 一或一 c (〇）一（CRl . 3R14) p —，其中P是如申請專利葷δ圍第1項中所定義者，及R13和R14互不相關的分別選自氫，一 CF3，一〇 C F 3及C工一6 -烷基及R 1 5是氫。 3 3 ·如申請專利範圍第3 2項之化合物，其中Z是一 NH (CH2) p 或一 C (〇）一（CH2) p-，其中 p 是如申請專利範圍第1項中所定義者。 3 4 ·如申請專利範圍第3 3項之化合物，其中Z是 N Η 或一C (〇）一。25. A compound as claimed in any one of the foregoing patent applications, wherein Y is -C (0)-, 101, -S (0) 2-, -NH- or -CC2-. 26. The compound according to any one of claims 1 to 24, wherein 范围 is a CHR11 —, and R1 1 is combined with R 1 to form a double bond. 27. A compound as claimed in item 25, wherein Υ is -C (〇)-. 28. The compound according to any one of claims 1 to 25 or 27 in the scope of the patent application, wherein both R1 and R2 are hydrogen. 2 9 · The compound according to any one of items 1 to 25 or 27 in the scope of patent application, wherein R1 and R2 are combined to form a double bond. 30. A compound according to any one of the foregoing patent applications, wherein R3 is hydrogen. 3 1 · The compound according to any one of the aforementioned patent applications, wherein 200401634 Z is -C (〇)-(CR13R14) p-, -〇_ (CR13r14) p-, -NR15-(CR13R14) p_s -S ( 〇) 2- (CR13R14) P-, where p, R 1 3, R 1 4 and r 1 5 are as defined in the first item of the patent application scope. 3 2 · The compound of item 31 in the scope of patent application, wherein z is -NRi5 — (CRi3Ri4) p one or one c (〇) 一 (CRl. 3R14) p —, where P is as described in the patent application As defined in item 1, and R13 and R14 which are not related to each other are selected from hydrogen, -CF3, 10CF3, and C- 6-alkyl, and R15 is hydrogen. 3 3 · The compound according to item 32 of the scope of patent application, wherein Z is -NH (CH2) p or -C (〇)-(CH2) p-, where p is as defined in item 1 of the scope of patent application . 34. The compound according to item 33 in the scope of patent application, wherein Z is NΗ or -C (〇) 一.

3 5 ·如申請專利範圍第3 4項之化合物’其中Ζ是一 C (〇）—。 3 6 ·如前述申請專利範圍任一項中之化合物’其中 D是35. The compound according to item 34 of the patent application, wherein Z is -C (〇)-. 3 6 · The compound as described in any one of the aforementioned patent applications, wherein D is

248 200401634248 200401634

其中 R16，R17，R18，R19，R20 和 R21 是如申請專利範圍第1項中所定義者。 3 7 ·如申請專利範圍第3 6項之化合物，其中D是Among them, R16, R17, R18, R19, R20 and R21 are as defined in item 1 of the scope of patent application. 3 7 · If the compound in the scope of patent application No. 36, where D is

其中R 1 6，R 1 7和R 1 8是如申請專利範圍第1項中所定義者。 3 8 ·如申請專利範圍第3 7項之化合物，其中R 1 6 ，R 1 7和R 1 8分別是氫，鹵素，一CN，一CH2CN，一CHF2, 一 CF3，一〇chf2, 一〇ch2cf3, 一〇cf2chf2， —s (〇）2CF3，一SCF3, 一N〇2，一〇R22， —NR22R23，—SR22, 一NR22S (〇）2R23， —s (〇）2NR22R23，一s (〇）nr22r23， —S (〇）R22，一s (〇）2R22， —c (〇）nr22r23，一〇c (〇）nr22r23， —NR22C (〇）R23，一CH2C (〇）NR22R23， —〇CH2C (〇）nr22r23，一ch2〇r23， —CH2NR22R23，一〇C (〇）R22，一C (〇）R22或 249 200401634 一 C (〇）〇R22， _ C 1 - 6 -院基，其可選擇性的經一個或多個選自氟，一 CN，一 CF3，一〇CF3，一OR22 及一 N R 2 2 R 2 3的取代基取代的， • C 3-8 -環烷基，其可選擇性的經一個或多個選自氟， —c (〇）〇r24，_ CN，一 CF3，一〇CF3, —〇R22，—NR22R23&Ci_6 —烷基的取代基取代的， •芳基或芳氧基，其可選擇性的經一個或多個選自氟，一 C(〇）〇R24，一 CN，一CF3，一〇CF3，_ N〇2，一〇R22，— NR22R23 及 Cl — 6 —烷基的取代基取代的， R 2 2和R 2 3互不相關的分別是氫，C 1 _6 —烷基，芳基一 Ci — 6 -烷基或芳基，或當R22及R23鍵結至相同的氮原子上時，則其和該氮原子一起形成一 3至8元的雜環，且此雜環選擇性的含有一個或二個其它選自氮，氧及硫的雜原子，且選擇性的含有一個或二個雙鍵， -或當R 1 6至R 1 8中的二個位於相鄰位置時，則其可一起形成一架橋基 -(CR24R25) 3-0 - (CR26R27) c-O - 5 a是0，1或2， c是1或2， R 2 4，R 2 5，R 2 6及R 2 7互不相關的分別是氫，C 1 — 6 一烷基或氟。 250 200401634 3 9 ·如申請專利範圍第3 8項之化合物，R16，R 1 7和R 1 8互不相關的分別是 •氣’齒素’ 一CF3 ’ 一〇CFg ’ 一 SCF3 ’ Ci — 6 一烷基，Ci — 6 -烷氧基，苯基，環戊基，環己基或苯氧基， •或當R16至R18中的二個位於相鄰位置時，其可一起形成一架橋基 -0 - (CF2) 2-0 - 5 —CF 2 —〇一CF 2 — 〇一或一 0 — C Η 2 一〇一。 4 0 ·如申請專利範圍第3 6，3 7，3 8或3 9項中任一項之化合物，其中R16是氫，及R17和R18不是氫。 4 1 ·如申請專利範圍第3 6，3 7，3 8或3 9項中任一項之化合物，其中R16和R17是氫，及R18不是氫。 4 2 ·如申請專利範圍第1項之化合物，其爲式（I 4 )化合物，Wherein R 1 6, R 1 7 and R 1 8 are as defined in item 1 of the scope of patent application. 38. The compound according to item 37 of the scope of patent application, wherein R 1 6, R 1 7 and R 1 8 are hydrogen, halogen, one CN, one CH2CN, one CHF2, one CF3, one chf2, one. ch2cf3, -0cf2chf2, -s (〇) 2CF3, -SCF3, -No2, -0R22, -NR22R23, -SR22, -NR22S (〇) 2R23, -s (〇) 2NR22R23, -s (〇) nr22r23, —S (〇) R22, —s (〇) 2R22, —c (〇) nr22r23, —c (〇) nr22r23, —NR22C (〇) R23, —CH2C (〇) NR22R23, —〇CH2C (〇 ) Nr22r23, a ch2〇r23, —CH2NR22R23, a 〇C (〇) R22, a C (〇) R22 or 249 200401634 a C (〇) 〇R22, _C 1-6-courtyard, its optional Substituted by one or more substituents selected from fluorine, -CN, -CF3, -0CF3, -OR22, and -NR 2 2 R 2 3, C 3-8 -cycloalkyl, which is optionally Substituted by one or more substituents selected from the group consisting of fluorine, —c (〇) 〇r24, —CN, —CF3, —CF3, —ORR22, —NR22R23 & Ci-6 —alkyl, • aryl or aryloxy Base, which is optional Is substituted with one or more substituents selected from the group consisting of fluorine, -C (〇) 〇R24, -CN, -CF3, -0CF3, -N02, -OR22, -NR22R23 and Cl-6-alkyl. R 2 2 and R 2 3 are unrelated to each other, hydrogen, C 1_6-alkyl, aryl-Ci-6-alkyl or aryl, or when R22 and R23 are bonded to the same nitrogen atom , It forms a 3- to 8-membered heterocyclic ring with the nitrogen atom, and the heterocyclic ring optionally contains one or two other heteroatoms selected from nitrogen, oxygen, and sulfur, and optionally contains one or Two double bonds, or-when two of R 1 6 to R 1 8 are located adjacent to each other, they can form a bridge together-(CR24R25) 3-0-(CR26R27) cO-5 a is 0 , 1 or 2, c is 1 or 2, R 2 4, R 2 5, R 2 6 and R 2 7 are unrelated to each other, hydrogen, C 1-6 alkyl or fluorine. 250 200401634 3 9 · If the compound in the 38th scope of the patent application, R16, R 1 7 and R 1 8 are not related to each other: • gas' dentin '-CF3'-0CFg '-SCF3' Ci — 6 An alkyl group, Ci-6-alkoxy group, phenyl group, cyclopentyl group, cyclohexyl group, or phenoxy group, or when two of R16 to R18 are located adjacent to each other, they can form a bridge group together- 0-(CF2) 2-0-5-CF 2-0-CF 2-0 or-0-C Η 2 101. 40. The compound according to any one of claims 36, 37, 38 or 39, wherein R16 is hydrogen and R17 and R18 are not hydrogen. 4 1 · The compound according to any one of claims 36, 37, 38 or 39, wherein R16 and R17 are hydrogen, and R18 is not hydrogen. 4 2 · If the compound in the scope of application for item 1 is a compound of formula (I 4),

其中R6 ’ R7，Ε和D是如前述申請專利範圍第1， 1 0至2 2或3 6至4 1項中任一項所定義者，以及其任 251 200401634 何非對映或對映異構物或包括這些異構物混合物的互變異構物，或其藥學上可接受的鹽。 4 3 ·如申請專利範圍第1項之化合物，其爲式（I 5 )化合物，Where R6 'R7, E and D are as defined in any one of the aforementioned patent application scope Nos. 1, 10 to 2 2 or 36 to 41, and any of them 251 200401634 Structure or tautomers including a mixture of these isomers, or a pharmaceutically acceptable salt thereof. 4 3 · If the compound of the scope of application for item 1 is a compound of formula (I 5),

其中R 6，R 7，E和D是如前述申請專利範圍第1， 1 0至2 2或3 6至4 1項中任一項所定義者，以及其任何非對映或對映異構物或包括這些異構物混合物的互變異構物，或其藥學上可接受的鹽。 4 4 ·如申請專利範圍第4 3項之化合物，其爲下式的化合物，Where R 6, R 7, E and D are as defined in any one of the aforementioned patent application scopes 1, 10 to 22 or 36 to 41, and any diastereomers or enantiomers thereof Or a tautomer comprising a mixture of these isomers, or a pharmaceutically acceptable salt thereof. 4 4 · If the compound in the scope of patent application No. 43 is a compound of the following formula,

其中R 6，R 7，E和D是如前述申請專利範圍第1， 1 0至2 2或3 6至4 1項中任一項所定義者，以及其任何非對映或對映異構物或包括這些異構物混合物的互變異構物，或其藥學上可接受的鹽。 4 5 ·如申請專利範圍第4 3項之化合物，其爲下式的化合物， 200401634Where R 6, R 7, E and D are as defined in any one of the aforementioned patent application scopes 1, 10 to 22 or 36 to 41, and any diastereomers or enantiomers thereof Or a tautomer comprising a mixture of these isomers, or a pharmaceutically acceptable salt thereof. 4 5 · If the compound in the scope of patent application No. 43 is a compound of the following formula, 200401634

其中R 6，R 7，E和D是如前述申請專利範圍第1， 1 0至2 2或3 6至4 1項中任一項所定義者，以及其任何非對映或對映異構物或包括這些異構物混合物的互變異構物，或其藥學上可接受的鹽。 4 6 ·如申請專利範圍第1項之化合物，其爲式（I 6 )化合物，Where R 6, R 7, E and D are as defined in any one of the aforementioned patent application scopes 1, 10 to 22 or 36 to 41, and any diastereomers or enantiomers thereof Or a tautomer comprising a mixture of these isomers, or a pharmaceutically acceptable salt thereof. 4 6 · If the compound of the scope of application for item 1 is a compound of formula (I 6),

其中R 6，R 7，E和D是如前述申請專利範圍第1， 1 0至2 2或3 6至4 1項中任一項所定義者，以及其任何非對映或對映異構物或包括這些異構物混合物的互變異構物，或其藥學上可接受的鹽。 4 7 ·如前述申請專利範圍任一項之化合物，其具有 I C 5 〇値不超過5 // Μ (由在此所揭示之胰增血糖素結合試驗（I )或胰增血糖素結合試驗（I I )測定）。 4 8 ·如申請專利範圍第4 7項之化合物，其具有由在此所揭示之胰增血糖素結合試驗（I )或胰增血糖素結 253 200401634 合試驗（I I )測定値I c 5 Q少於1 // Μ ’較佳地，少於 5 0 0 η Μ，更佳地的少於1 0 0 η Μ。 4 9 ·如前述申請專利範圍任一項之化合物，可用作治療高血糖，IGT，第2型糖尿病，第1型糖尿病，脂肪代謝障礙及肥胖症的藥劑。 5 〇 ·如申請專利範圍第1至4 9項中任一項的化合物，其是用作藥物。 5 1 · —種藥學組成物，包括當作活性成份之如申請專利範圍第1至4 9項中任一項化合物，及一種或多種藥學上可接受的載體或輔助劑。 5 2 ·如申請專利範圍第5 1項之藥學組成物，其爲單位劑量型式，包括從約（λ〇5毫克至約1000毫克’較佳的從約0.1毫克至約500毫克，特別佳的從約0.5毫克至約 200毫克的如申請專利範圍第1至4 9項中任一項化合物。 5 3 ·如申請專利範圍第1至49項中任一項之化合物，其是用於製備可治療其中胰增血糖素拮抗作用是有利之疾病的藥物。 5 4 ·如申請專利範圍第1至49項中任一項之化合物，其是適用於製備治療任何胰增血糖素-調節的狀丨兄和疾病之藥物。 5 5 ·如申請專利範圍第1至4 9項中任一項β彳匕合物，其是適用於製備治療高血糖疾病之藥物。 5 6 ·如申請專利範圍第1至4 9項中任一項$彳七合物，其是適用於製備降低哺乳動動物血糖之藥物° 200401634 5 7 ·如申請專利範圍第1至4 9項中任一項之化合物，其是適用於製備治療I G T之藥物。 5 8 ·如申請專利範圍第1至4 9項中任一項之化合物，其是適用於製備治療第2型糖尿病之藥物。 5 9 ·如申請專利範圍第5 8項之化合物，其是適用於製備延緩或預防IGT發展爲第2型糖尿病之藥物。 6 〇 ·如申請專利範圍第5 8項之化合物，其是用於製造爲用於延緩或預防不需胰島素之第II型糖尿病惡化爲需胰島素之第II型糖尿病之藥物。 6 1 ·如申請專利範圍第1至4 9項中任一項之化合物，其是適用於製備治療第1型糖尿病之藥物。 6 2 ·如申請專利範圍第1至4 9項中任一項之化合物，其是適用於製備治療肥胖症之藥物。 6 3 ·如申請專利範圍第1至4 9項中任一項之化合物，其是適用於製備治療脂肪代謝障礙之藥物。 6 4 ·如申請專利範圍第5 3至6 1項中任一項之化合物，其包括施與其它抗糖尿病劑治療。 6 5 ·如申請專利範圍第5 3至6 2項中任一項之化合物，其包括施與其它抗肥胖劑治療。 6 6 ·如申請專利範圍第5 3至6 2項中任一項之化合物，其包括施與其它抗高血脂劑治療。 6 7 ·如申請專利範圍第5 3至6 3項中任一項之化合物，其包括施與其它抗高血壓劑治療。 6 8 · —種治療疾病的方法，其中胰增血糖素拮抗作 200401634 m 用是有利的，包括施與患者一有效量的如申請專利範圍第 # 1至4 9項中任一項之化合物，或一如申請專利範圍第5 1或5 2項之藥學組成物。 6 9 ·如申請專利範圍第6 8項之方法，其中該有效量的化合物是指每天從約0.05毫克至約2000毫克，較佳地從約0.1毫克至約1000毫克，尤其佳地是從約0.5毫克至約500毫克。 η 拾壹、圖式 Μ 〇Where R 6, R 7, E and D are as defined in any one of the aforementioned patent application scopes 1, 10 to 22 or 36 to 41, and any diastereomers or enantiomers thereof Or a tautomer comprising a mixture of these isomers, or a pharmaceutically acceptable salt thereof. 4 7 · The compound according to any one of the aforementioned patent applications, which has an IC 5 0 値 not exceeding 5 // M (by the glucagon binding test (I) or glucagon binding test disclosed herein ( II) determination). 48. The compound according to item 47 of the scope of patent application, which has a glucagon binding test (I) or a glucagon junction 253 200401634 combination test (II) disclosed herein. Less than 1 // M ′ is preferably less than 500 nM, and more preferably less than 100 nM. 49. The compound according to any one of the aforementioned patent applications can be used as a medicament for treating hyperglycemia, IGT, type 2 diabetes, type 1 diabetes, dyslipidemia and obesity. 50. The compound according to any one of claims 1 to 49, which is used as a medicine. 5 1-A pharmaceutical composition comprising, as an active ingredient, a compound according to any one of claims 1 to 49 of the scope of patent application, and one or more pharmaceutically acceptable carriers or adjuvants. 5 2 · The pharmaceutical composition according to item 51 of the scope of patent application, which is a unit dosage form, including from about (λ05 mg to about 1000 mg ') preferably from about 0.1 mg to about 500 mg, particularly preferably From about 0.5 mg to about 200 mg of a compound according to any one of claims 1 to 49. 5 3 · A compound according to any one of claims 1 to 49, which is used for preparing A drug for treating a disease in which glucagon antagonism is advantageous. 5 4 · The compound according to any one of claims 1 to 49, which is suitable for preparing the treatment of any glucagon-regulated condition 丨Medicine for brothers and diseases. 5 5 · If any of the β-dagger compounds in any one of the claims 1 to 49, it is suitable for the preparation of medicines for the treatment of hyperglycemic diseases. Any one of 49 to $ 7 is a compound which is suitable for preparing a drug for lowering blood glucose in mammals. 200401634 5 7 · If the compound of any one of claims 1 to 49 in the scope of patent application, which is Suitable for the preparation of medicines for treating IGT 5 8 · If applying for a patent The compound according to any one of the items 1 to 49, which is suitable for preparing a medicine for treating type 2 diabetes. 5 9 · If the compound applying for a patent, the item 58 is to be suitable for preparing the delay or prevention of IGT Developed as a drug for type 2 diabetes. 60. The compound as claimed in item 58 of the scope of patent application, which is used for the manufacture to delay or prevent the deterioration of type II diabetes that does not require insulin to type II that requires insulin. Drugs for diabetes. 6 1 · Compounds according to any one of claims 1 to 49, which are suitable for the preparation of drugs for treating type 1 diabetes. 6 2 · Items such as claims 1 to 49 The compound according to any one, which is suitable for preparing a medicine for treating obesity. 63. The compound according to any one of claims 1 to 49, which is suitable for preparing a medicine for treating fat metabolism disorder. 6 4 · The compound according to any one of the claims 53 to 61, which includes the administration of other anti-diabetic agents. 6 5 · The one according to any of the claims 5 3 to 62, Compounds, including administration to other Treatment of obesity. 6 6 · The compound according to any one of claims 53 to 62 in the scope of patent application, which includes the administration of other antihyperlipidemic agents. 6 7 · The scope of patent in claims 53 to 63 A compound according to any one, which comprises the administration of other antihypertensive agents. 6 8 · A method for treating a disease, wherein glucagon antagonist 200401634 m is advantageous, including administering to the patient an effective amount of For example, a compound in any one of the scope of patent application # 1 to 49, or a pharmaceutical composition in the scope of patent application scope 51 or 52. 69. The method of claim 68, wherein the effective amount of the compound is from about 0.05 mg to about 2000 mg per day, preferably from about 0.1 mg to about 1000 mg, particularly preferably from about 0.5 mg to about 500 mg. η Pick up, scheme Μ 〇

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