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TWI283240B - VLA-4 inhibitor compounds - Google Patents

VLA-4 inhibitor compounds Download PDF

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Publication number
TWI283240B
TWI283240B TW089112968A TW89112968A TWI283240B TW I283240 B TWI283240 B TW I283240B TW 089112968 A TW089112968 A TW 089112968A TW 89112968 A TW89112968 A TW 89112968A TW I283240 B TWI283240 B TW I283240B
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Taiwan
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group
mmol
ome
mixture
substituted
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TW089112968A
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Chinese (zh)
Inventor
Nobuo Machinaga
Atsushi Nakayama
Jun Chiba
Yoshiyuki Yoneda
Shin Iimura
Original Assignee
Daiichi Seiyaku Co
Pharmacopeia Drug Discovery
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    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
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    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
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Abstract

A compound represented by the following formula I, or a salt thereof.

Description

1283240 7、發明說明^ ' ~ -------- 本發明係關於選擇性地抑制配位子之結合至黏著受體， ^ /51整合素（integrin)，亦稱為vla 一 4之化合物。本發 1之化合物對治療及預防與由VLA-4所促成之細胞黏著^目 L的病症係有效的，諸如發炎及自體免疫疾病和腫瘤轉 發明之 諸如發炎及自體免疫疾病之病症的一主要特徵為活化白 血球=累積於受感染組織中。白血球在發炎部位自循環遷 移的程序涉及一連串的交互反應。其可分為四個主要步 驟·束缚及轉動、活化、穩固黏著、及遷移（Springer， τ· ’Ann· Rev· Physi〇1· ， 57:827 (1995))。 一開始，白 血球輕微地束缚至内皮並沿其表面轉動。接著為由可溶解 趨化〖生刺激所j足成的細胞活化，其引發在個別白血球與内 皮細胞之間產生更穩固的結合。此穩固的結合接著導致白 血球的成功黏著及遷移通過内皮細胞接面。此等步驟係連 、、’哀智生’且其各者對於遷移的發生皆是不可或缺。此亦意 謂可在各步驟調整遷移，因此而提供許多藥理抑制的可能 目標。 · 參與白血球遷移的受體有極大程度的特徵在於其係屬於 特殊的細胞黏著分子族（Cari〇s and Harlan，Bl〇〇d，84: 2 068 ( 1 994))。起始的附著及轉動步驟係由稱為選擇 (selections)巧一族黏著受體所促成。穩固的黏著係由白 血球表面整合素與表現於内皮表面上之免疫球.蛋白總科之1283240 7. Description of the Invention ^ ' ~ -------- The present invention relates to selectively inhibiting the binding of a ligand to an adhesion receptor, ^ /51 integrin, also known as vla-4 Compound. The compound of the present invention 1 is effective for the treatment and prevention of a condition associated with cell adhesion caused by VLA-4, such as an inflammatory and autoimmune disease and a tumor-transferred condition such as an inflammatory and autoimmune disease. The main feature is activated white blood cells = accumulated in infected tissues. The process of self-circulating migration of white blood cells at the site of inflammation involves a cascade of interactions. It can be divided into four main steps: restraint and rotation, activation, firm adhesion, and migration (Springer, τ·’Ann· Rev. Physi〇1·, 57:827 (1995)). At first, the white blood cells are slightly bound to the endothelium and rotate along their surface. This is followed by activation of cells that are soluble by chemotaxis, which triggers a more robust bond between individual white blood cells and endothelium. This robust binding then leads to successful adhesion of the white blood cells and migration through the endothelial cell junction. These steps are linked to, ‘ 智智生’ and each of them is indispensable for the occurrence of migration. This also means that migration can be adjusted at each step, thus providing many possible targets for pharmacological inhibition. · Receptors involved in leukocyte migration are characterized by a large degree of cell adhesion molecule family (Cari〇s and Harlan, Bl〇〇d, 84: 2 068 (1 994)). The initial attachment and rotation steps are facilitated by a selection of adhesion receptors called selections. The firm adhesion is caused by the integrin on the surface of the white blood cells and the immunoglobulins expressed on the surface of the endothelium.

89112968.ptd 第6頁 1283240 五、發明說明（2)89112968.ptd Page 6 1283240 V. Description of invention (2)

分子的交互作用所促成。整合素和免疫球蛋白型黏著八 兩者亦主要參與白血球的遷移。於遷移後，白血球依=敕 合素而橫越過細胞外基質，並停留於發炎部位上。 正整合素係一大族的雜二聚醣蛋白，其包括兩非共價結合 的次單元，α 及 y3(Hynes，R· ，Cell，69;1 1 ( 1 992 ))。口 共有至少1 6種不同的α次單元（α i a α, α, α, A、αΕ、aIIb、αν)及至少9種不同的冷（α —万ο次單元 。整合素根據方次單元而分成亞科。白血球表現許多不同 的整合素，包括α4 A、α5仏、％仏、&心、α 、 ^^召2、及 。 化仏整合素，亦稱為極遲抗原-wla-4; very iate ant igen-4)或CD4 9d/CD29，係表現於單核細胞、淋巴球、 嗜伊紅白血球、及嗜鹼性白血球上，其皆係在各種發炎病症中的關鍵效應物細胞（Helmer，M. ，Arm. Rev ^no1· ，8;36 5 ( 1 9 90 ))。/31 整血管細 胞黏著分子-1 (V CAM -1)，以及細胞外蛋白質纖維蜜素 (fibronectinKFN)之受體（El ices et al. ，Cel 1， 60,577 (1990))。於α4 /5〗/VCAM-1途徑之活體内的單株 抗體阻斷後展現抗發炎作用及延遲的疾病進展（L〇bb et al.，J· C1 in,_Invest.，94;1 722 - 28 ( 1 994)) 〇 於天竺 鼠的肺部發炎模型中’抗-&抑制由抗原所引起的支氣管 反應過敏及支氣管與肺胞灌流液中之白血球補充 (Pretolani et al. ’ J. Exp. Med.，180 ; 795 ( 1 9 94))。 Α或VC AM-1之抗體預防老鼠氣管之由抗原所引起的嗜伊The interaction of molecules is facilitated. Integrin and immunoglobulin adhesions are also involved in the migration of white blood cells. After migration, the white blood cells cross the extracellular matrix and remain on the inflamed site. A positive integrin is a large family of heterodimeric glycoproteins comprising two non-covalently bonded subunits, alpha and y3 (Hynes, R., Cell, 69; 1 1 (1 992 )). The mouth has at least 16 different alpha subunits (α ia α, α, α, A, αΕ, aIIb, αν) and at least 9 different cold (α-10,000 ο subunits. Integrin according to the square unit Divided into subfamilies. White blood cells exhibit many different integrins, including α4 A, α5仏, %仏, & heart, α, ^^召2, and 仏 仏 integrase, also known as very late antigen-wla-4 Very iate ant igen-4) or CD4 9d/CD29, expressed on monocytes, lymphocytes, eosinophils, and basophilic leukocytes, which are key effector cells in various inflammatory conditions ( Helmer, M., Arm. Rev ^no1· , 8; 36 5 ( 1 9 90 )). /31 Whole vascular cell adhesion molecule-1 (V CAM -1), and the receptor for extracellular protein fibronectin KFN (El ices et al., Cel 1, 60, 577 (1990)). Anti-inflammatory effects and delayed disease progression after blocking by monoclonal antibodies in the α4 /5/VCAM-1 pathway (L〇bb et al., J. C1 in, _Invest., 94; 1 722 - 28 (1 994)) In the lung inflammatory model of guinea pigs, 'anti-& inhibits bronchial allergy caused by antigen and white blood cell supplementation in bronchial and pulmonary perfusate (Pretolani et al. ' J. Exp. Med., 180; 795 (1 9 94)). Α or VC AM-1 antibody prevents the eosinophils caused by the antigen in the rat trachea

1283240 五、發明說明（3) 紅白血球浸潤（Naka j i ma et a 1. ，J. Exp· Med.， Π9;1 1 45 ( 1 994))。單株抗體療法亦可延遲 或預防老鼠及猴子的皮膚延遲過敏感性反應（Chisholm et a1·，iur. J· Immunol .，23 ; 682 ( 1 9 93 ) ; Silber et a1·，L Clin·· Invest. ，93 ; 1 554 ( 1 993 ));在老鼠體内 伴隨特定免疫抑制的心臟同種異體移植排斥（丨sobe e t a 1 · ，J. Immunol. ，153;5810 (1994));在老鼠體内於骨 髓移植後之移植物抗宿主疾病（Yang et al. ，Proc.1283240 V. INSTRUCTIONS (3) Red and white blood cell infiltration (Naka j i ma et a 1., J. Exp. Med., Π9; 1 1 45 (1 994)). Individual antibody therapy can also delay or prevent skin delayed hypersensitivity reactions in mice and monkeys (Chisholm et al., iur. J. Immunol., 23; 682 (1 9 93); Silber et al., L Clin·· Invest , 93; 1 554 (1 993 )); cardiac allograft rejection with specific immunosuppression in mice (丨sobe eta 1 · , J. Immunol. , 153; 5810 (1994)); in mice Graft-versus-host disease after bone marrow transplantation (Yang et al., Proc.

Natl- Acad. Sci, USA，90 ; 1 0494，（ 1 9 93 ));及在老鼠 體内之實驗自鉍免疫腦脊髓炎（Yednock et al.，Natl-Acad. Sci, USA, 90; 1 0494, (1 9 93 )); and experimental autoimmune encephalomyelitis in mice (Yednock et al.,

Mture，356;63 ( 1 992 ) ; Baron et al·，J· Exd·—Mture, 356; 63 (1 992); Baron et al., J. Exd.

Med.，177; 57 ( 1 993 ))。 合理的藥物設計研究已製造出含有兩人類VC AM-1之N-末 端領域融合至人類IgGl恆定區之可溶解的VCAM-Ig融合蛋 白質。融合蛋白質的活體給藥顯著地延遲壬糖糖尿病患鼠 之過繼性轉移自體免疫糖尿病的發病（Jakubowski et a 1. ’ L· I mmuno 1. ，155 ; 938 (1995))。另一種方式係使 用VCAM-1片斷的立體結晶結構於合成細密模仿在vc AM-1之 領域1中之α 4 ^合素結合圈的環月太拮抗劑。合成VCAM-1 月太CQIDSPC可抑制VLA-4-表現細胞之黏著至純化 VCAM-l(Wang et al. ，Proc· Nat 1 · Acad· Sc i · II^_A， 92:5714 (1995)) 〇 另一策略係阻斷a 4 /3 i之結合至其之其他的相反受體， 即含有連接片斷-l(CS-l)要素之纖維蜜素之選擇性的連接Med., 177; 57 (1 993 )). Reasonable drug design studies have produced soluble VCAM-Ig fusion proteins containing the N-terminal domain of two human VC AM-1 fused to the human IgGl constant region. In vivo administration of the fusion protein significantly delayed the onset of adoptive transfer autoimmune diabetes in diabetic mice with diabetes (Jakubowski et al 1. L' Immuno 1., 155; 938 (1995)). Another way is to use a stereoscopic crystal structure of the VCAM-1 fragment to synthesize a cyclosporin antagonist which closely mimics the α4^-binding ring in the field 1 of vc AM-1. Synthesis of VCAM-1 Months CQIDSPC inhibits adhesion of VLA-4-expressing cells to purified VCAM-1 (Wang et al., Proc. Nat 1 · Acad· Sc i · II^_A, 92:5714 (1995)) Another strategy is to block the binding of a 4 /3 i to its other opposite receptors, ie the selective linkage of cellophane containing the linker -1 (CS-1) element

1283240 五、發明說明（4) 區域（E·A· Wayner，J· Cell, Biol· ^ 116;489 (1992)) °合成CS-1四月太（苯乙酸-白胺酸-天冬胺酸-苯 丙胺酸—d〜脯胺酸-醯胺）抑制在試管内由VLA-4所促成的淋 巴球黏著及降低兔子心臟同種異體移植的加速冠狀動脈病 (Moloss^i et al.，』· Cl in· Invest·，9 5 ; 2 6 0 1 ( 1 9 9 5 )) 。各此等研究皆提供由A A /VCAM-1所促成之黏著的選 擇性抑制係用於治療自體免疫及過敏性發炎疾病之且 策略的證據。 、 此外，雖然 96/22966 、 W0 說明在試管内 但先前說明的 因此，儘管 具生物效力， 和黏著相關之 型、非肽的特 發明之 本發明之化 因此，其有用 黏著及與該黏 喘、關節炎、 廯、移植排斥 在一具體例中 或其鹽， 美國專利5, 821，231及公告PCT申請案W0 97/03094 、W0 98/04247及W0 98/04913 已 結合鑑定中展現VLA-4抑制活性之化合物， 化合物皆未於口服給藥中展現藥效。 有此專先鈾的成果，但仍有需要以口服方式 且適用於慢性發炎疾病及其他與白血球遷移 病症之長期治療之VLA-4相關細胞黏著之小 定抑制劑。 合物選擇性地抑制配位子之結合至α召 Ϊ預防及壓抑叫4所促“細胞 耆相關的病症，諸如，比方說，發炎 糖尿病自體免疫反應、多發 、及腫瘤轉移。 又化牛皮 ’本發明提供一種以化學式I表示之化合物 1283240 五、發明說明（5) W 1 其中： W係選自芳基、經取代芳基、雜芳基及經取代雜芳基；1283240 V. INSTRUCTIONS (4) Region (E·A· Wayner, J. Cell, Biol· 116; 489 (1992)) ° Synthesis of CS-1 April Tai (phenylacetic acid-leucine-aspartic acid -Phenylalanine-d~proline-decalamine inhibits lymphocyte adhesion caused by VLA-4 in vitro and accelerates coronary artery disease in rabbit heart allografts (Moloss^i et al., 』· Cl In· Invest·, 9 5 ; 2 6 0 1 (1 9 9 5 )). Each of these studies provides evidence for a strategy for the selective treatment of adhesions caused by A A /VCAM-1 for the treatment of autoimmune and allergic inflammatory diseases. In addition, although 96/22966 and W0 are described in the test tube, but previously described, in spite of the biological effectiveness, the adhesion-related type, the non-peptide specific invention of the invention, therefore, the useful adhesion and the adhesion , arthritis, sputum, transplant rejection in a specific case or a salt thereof, U.S. Patent No. 5,821,231 and the publication of PCT applications W0 97/03094, W0 98/04247 and W0 98/04913 have been combined to demonstrate VLA- 4 Compounds which inhibit activity, none of the compounds exhibit efficacy in oral administration. There are results of this prior uranium, but there are still small inhibitors of VLA-4-related cell adhesion that need to be administered orally and for chronic inflammatory diseases and other long-term treatments with leukocyte migration disorders. The compound selectively inhibits the binding of the ligand to the alpha-prophylaxis and suppresses the "cell-related disorders", such as, for example, inflammatory inflammation, autoimmune response, multiple tumors, and tumor metastasis. The present invention provides a compound 1283240 represented by the chemical formula I. 5. Description of the invention (5) W 1 wherein: W is selected from the group consisting of an aryl group, a substituted aryl group, a heteroaryl group and a substituted heteroaryl group;

Wi係選自伸芳基、經取代伸芳基、雜伸芳基及經取代雜 伸芳基；· A係選自=0、=S及=NH ; R係選自直接鍵、伸烯基及-（CH2)n-， 其中 η係選自0、1及2 ; X 係選自-C(0)-、-CH2 -及-S(0)2-； Μ係選自The Wi is selected from the group consisting of an extended aryl group, a substituted aryl group, a heteroaryl group, and a substituted heteroaryl group; · A is selected from the group consisting of =0, =S, and =NH; and the R system is selected from a direct bond and an extended alkenyl group. And -(CH2)n-, wherein η is selected from 0, 1 and 2; X is selected from -C(0)-, -CH2 - and -S(0)2-;

R3 R4 Υ——ζ- 0 R5R3 R4 Υ——ζ- 0 R5

QQ

γι ——ζ 1—A 2 〇 Λ R 8Γι ——ζ 1—A 2 〇 Λ R 8

X1——（CHRs)a-RX1——(CHRs)a-R

kL/NkL/N

Z2 及Z2 and

R 11 -Z 3-QR 11 -Z 3-Q

89112968.ptd 第10頁 1283240 五、發明說明（6)89112968.ptd Page 10 1283240 V. Description of invention (6)

為二價4-、5-、6_或7 -員雜環基團，其中該 氣原子係連接至X之點； ^ 以 比、R2及R3係分別選自-Η、~0H、-NH2、_原子、烧基、 經取代烧基、方基、經取代方基、烧氧基、經取代烧氧 基、單烷胺基、經取代單烷胺基、二烷胺基、經取代二烧 胺基、環烷胺基、經取代環烷胺基、烷磺醯胺基、經取代 烷磺醯胺基、芳磺醯胺基、經取代芳磺醯胺基、芳氧基、 經取代芳氧基、雜芳氧基、經取代雜芳氧基、爷氧基及經 取代苄氧基’或其中之兩個基根一起形成視需要可經分別 選自-0H、鹵原子、-NH2、烷基、烷氧基、芳基、芳氧 基、烷胺基、苄氧基及雜芳基之1至3個取代基取代之3 一、 4 -、5 -、6 -或7 -員碳環或雜環殘基； R4係選自_H及低碳烷基； Y係直接鍵或選自-C(0)-、-C(0)NH-、伸烯基、伸炔基 及-（CH2)kY2 -之二價基根，其中k係選自1、2及3 ;及γ2係直 接鍵或選自-0-、-S-、-S(0)-、-S(0)2-及-ΝΥ3 -之二價基 根，其中Y3係選自-Η及低碳烷基； Ζ係選自伸芳基、經取代伸芳基、伸雜環基、經取代伸 雜環基、伸環烷基及經取代伸環烷基； Α1係直接鍵或選自伸稀基’伸快基’ -(C H2 )t - ’其中t係 選自1、2及3，及-〇(CH2)v-，其中V係選自0、1、2及3之二 價基根；及Is a divalent 4-, 5-, 6- or 7-membered heterocyclic group wherein the gas atomic system is attached to the point of X; ^ is selected from the group consisting of -Η, ~0H, -NH2, respectively, R2 and R3 , _ atom, alkyl, substituted alkyl, aryl, substituted aryl, alkoxy, substituted alkoxy, monoalkylamino, substituted monoalkylamino, dialkylamino, substituted An amine group, a cycloalkylamino group, a substituted cycloalkylamino group, an alkanesulfonylamino group, a substituted alkanesulfonylamino group, an arylsulfonylamino group, a substituted arylsulfonylamino group, an aryloxy group, a substituted The aryloxy group, the heteroaryloxy group, the substituted heteroaryloxy group, the aryloxy group, and the substituted benzyloxy group or two of the base groups may be formed, if necessary, respectively, selected from -OH, a halogen atom, -NH2 3, 4 -, 5 -, 6 - or 7 - of the alkyl, alkoxy, aryl, aryloxy, alkylamino, benzyloxy and heteroaryl groups substituted by 1 to 3 substituents Carbocyclic or heterocyclic residue; R4 is selected from _H and lower alkyl; Y is a direct bond or is selected from -C(0)-, -C(0)NH-, an alkenyl group, an alkynyl group and -(CH2)kY2 - a divalent radical, wherein k is selected from 1, 2 and 3; and γ2 is a direct bond or is selected from -0, -S a divalent radical of -, -S(0)-, -S(0)2-, and -ΝΥ3 - wherein Y3 is selected from the group consisting of - and lower alkyl; the anthracene is selected from the group consisting of an exoaryl group and a substituted alkyl group. An aryl group, a heterocyclic group, a substituted heterocyclic group, a cycloalkyl group, and a substituted cycloalkyl group; Α1 is a direct bond or is selected from a dilute base 'extension base' -(C H2 )t - ' Wherein t is selected from 1, 2 and 3, and -〇(CH2)v-, wherein V is selected from the group consisting of divalent valencies of 0, 1, 2 and 3;

89112968.ptd 第11頁 1283240 ——— 五、發明說明（Ό R5係選自-〇 Η、低破烧氧基、-Ν Η 0 Η89112968.ptd Page 11 1283240 ——— V. INSTRUCTIONS (Ό R5 is selected from the group consisting of -〇 Η, low-breaking oxy, Ν Η 0 Η

其中，cy K 為二價4一、5-、6-或7-員雜環基團，其中 該氮原子係連接至χ之點； ^ R6及R7係分別選自-Η、-0Η、鹵原子、烷基及燒氧基； Y1 係選自-0-、-S_、-S(0)_、-S(0)2-及—NY4 -之二價基 根，其中Y4係選自-H及低碳烷基； ' > Z1係選自伸孝基、經取代伸芳基、伸雜環基、經取代伸 雜環基、伸環烷基及經取代伸環烷基之二價基根； A2係直接鍵或選自伸烯基、伸炔基及—（c ji2 )e -之二價基 根，其中e係選自1、2及3 ;及 6 'a R8係選自-OH、低碳烷氧基、- NH0H， Ν—Ν 及 n—n 7入 其中 L, ，其中 為二價4-、5-、6-、7-員 雜環基團上視需要可經分別選自烷基、烷氧基、羥烷、 基、〇Η、卞氧基、—龍2、鹵原子、芳基及雜芳基之丄至^ 個取代基取代’且此等雜環基團可融合至1Wherein cy K is a divalent 4,5-, 6- or 7-membered heterocyclic group, wherein the nitrogen atom is attached to the point of hydrazine; ^ R6 and R7 are respectively selected from -Η, -0Η, halogen Atom, alkyl and alkoxy; Y1 is selected from the group consisting of -0-, -S_, -S(0)_, -S(0)2- and -NY4-, wherein Y4 is selected from - H and lower alkyl; ' > Z1 is selected from the group consisting of a divalent group, a substituted aryl group, a heterocyclic group, a substituted heterocyclic group, a cycloalkyl group, and a substituted cycloalkyl group. A2 is a direct bond or a divalent radical selected from the group consisting of an alkenyl group, an alkynyl group, and —(c ji2 )e - wherein e is selected from 1, 2, and 3; and 6 'a R8 is selected from - OH, lower alkoxy, -NH0H, Ν-Ν and n-n 7 are in which L, wherein the divalent 4-, 5-, 6-, 7-membered heterocyclic group can be separately a substituent selected from the group consisting of an alkyl group, an alkoxy group, a hydroxyalkane group, a hydrazine group, a hydrazine group, a hydrazine group, a halogen atom, an aryl group and a heteroaryl group, to a substituent, and such a heterocyclic group Can be fused to 1

:分=自燒基、芳氧基、烧氧基、_、，、辛J 二从认1、自原子、芳基及雜芳基之1至3個取代基取代之 額外的奴環或雜環殘基；: sub = calcined, aryloxy, alkoxy, _,,, xin J 2 from the 1, additional atomic, aryl and heteroaryl substituted 1 to 3 substituents of the additional slave or miscellaneous Ring residue

第12頁 1283240 五、發明說明（8) · m及q係分別選自0、1、2及3 ; X1係選自-CH=及-N=; R9係選自-Η及低碳烷基； R1Q係選自-CQ2H、低碳烷氧羰基，Page 12 1283240 V. INSTRUCTIONS (8) · m and q are respectively selected from 0, 1, 2 and 3; X1 is selected from -CH= and -N=; R9 is selected from -Η and lower alkyl ; R1Q is selected from -CQ2H, lower alkoxycarbonyl,

其中 0 rT q R11 係選自-〇_，，KDH —-NR1: - Z2係選自-Η、- C 02 Η及低碳烧氧幾基； 其中R12係選自-Η、烷基、經取代烷基、環烷基、經取 代環烧基、芳基、經取代芳基、窄基、經取代窄基、低 碳烯基、經取代低碳烯基及低碳炔基 其中左手邊的鍵係連接至X之點，及右手邊的鍵係連接至 Ζ3之點； Ζ3係選自直接鍵及具有1至1 2個碳原子之二價脂族烴基 團，及其之一或多個碳原子可經-〇-或-NR13-取代 其中R13係選自-Η及低碳烷基；連接至脂族破原子之一 或多個氫原子可經低碳烧基取代； 及 X係選自0及1 ; y係選自1 .、2及3 ;及 R14係選自-Η、-0H及_原子，Wherein 0 rT q R11 is selected from the group consisting of -〇_, KDH - -NR1: - Z2 is selected from the group consisting of -Η, -C 02 Η and a low carbon alkoxy group; wherein R12 is selected from the group consisting of -Η, alkyl, and Substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, narrow, substituted narrow, lower alkenyl, substituted lower alkenyl and lower alkynyl wherein left hand The bond is connected to the point of X, and the bond on the right hand is connected to the point of Ζ3; Ζ3 is selected from the group consisting of a direct bond and a divalent aliphatic hydrocarbon group having 1 to 12 carbon atoms, and one or more thereof The carbon atom may be substituted by -〇- or -NR13- wherein R13 is selected from -anthracene and lower alkyl; one or more hydrogen atoms attached to the aliphatic breaking atom may be substituted by a lower carbon group; From 0 and 1; y is selected from 1, 2 and 3; and R14 is selected from -Η, -OH and _ atoms,

i 89112968.ptd 第13頁 |[283240 、發明說明（9) 其限制條杯為在Rii為—NR!2、丨/ 之限制情況中，Z4係選自以下三個以化學式表示的二 價基團，其中RHa係選自、一 〇H、低碳烷基及鹵原 子； 及j八/〇i 其中左手邊的鍵係連接至R11之點，及右手邊的鍵係連接至 <32之點； Q2係選自伸芳基、經取代伸芳基、伸雜環基、經取代伸 雜環基、伸環烷基、經取代伸環烷基之二價基根，i 89112968.ptd Page 13|[283240, invention description (9) The restriction strip is in the case where Rii is -NR!2, 丨/, and Z4 is selected from the following three divalent groups represented by chemical formula a group wherein RHa is selected from the group consisting of H, lower alkyl and halogen atoms; and j VIII/〇i wherein the bond on the left hand side is connected to the point of R11, and the bond on the right hand side is connected to <32 Q2 is selected from the group consisting of an extended aryl group, a substituted aryl group, a heterocyclic group, a substituted heterocyclic group, a cycloalkyl group, a substituted cycloalkyl group,

其中R15及R16係分別選自一Η、鹵原子及低碳烷基； 及 · Ιχί R17 R18 其中R17及R18係分別選自-Η、低碳烷基、經取代低碳烷 基及低碳烯基； 及 L1 係選自-C02’H 及-C02R19，Wherein R15 and R16 are each selected from the group consisting of a fluorene, a halogen atom and a lower alkyl group; and · Ιχί R17 R18 wherein R17 and R18 are respectively selected from the group consisting of -Η, lower alkyl, substituted lower alkyl and lower alkene And L1 are selected from -C02'H and -C02R19,

89112968.ptd 第 14 頁 1283240 五、發明說明（10) A為=〇，R為-(CHA-及X為-C(0)-。在以上的更佳具體 中，Y係選自伸稀基、伸快基、-(CH2)kYL、_CH S( 〜CH20_較佳，及γ為-CH20-更佳。89112968.ptd Page 14 1283240 V. INSTRUCTIONS (10) A is = 〇, R is - (CHA- and X are -C(0)-. In the above more specific, Y is selected from the group It is better to extend the radical, -(CH2)kYL, _CH S (~CH20_ is preferred, and γ is -CH20-.

，化學式！之較佳化合物中’W為未經取代的 鄰位具有選自佟碳烷基及函原子之一或兩個取代美之苯/、 f，及W1為未經取代的伸苯基或在其對—NH_之鄰ς且有 自甲氧基、低碳烷基及函原子之取代基的伸笨基較^圭。、 在彳匕學式〖，較佳化合物中，△為=0較佳，^為直接鍵 LU2)t-，及Α1為直接鍵及R5為—〇Η更佳。 下表I I覌化學式I之較佳化合物，其中11為 ” \丫-2—A « 二A，為:〇。關於冬的表示法，下方的鍵係連接至，一之 ·、、及上方的鍵係連接至-R-之點。標題為「―R —— R5 記示係描述在1匕學式Ϊ中以 ^的 之特殊化合物的該部分。卜&二—厶人5 义丁, chemical formula! In the preferred compound, 'W is an unsubstituted ortho position having one selected from the group consisting of a fluorenylalkyl group and a functional atom or two substituted benzenes/, f, and W1 is an unsubstituted stretched phenyl group or It is more suitable for the neighboring group of -NH_ and having a substituent derived from a methoxy group, a lower alkyl group and a functional atom. In the drop-off formula, the preferred compound, △ is =0 is preferable, ^ is the direct bond LU2)t-, and Α1 is a direct bond and R5 is preferably 〇Η. Table II below is a preferred compound of formula I, wherein 11 is "\丫-2-A « 二 A, is: 〇. Regarding the winter representation, the lower bond is connected to, the one, the , and the upper The key is connected to the point of -R-. The title is "-R —— R5 is the part of the special compound described in the 1 匕 Ϊ 。 ^ ^ & amp amp amp 。 。 。

ί 1283240ί 1283240

I 五、發明說明（11) 表1 質量光譜 (Ivr+l) W- -wr- -R - - ^ R5 486.7 -ό 508.7 0^ca〇〇2H 507.0 c,t5 501.6 : Φ χ^Η 486.6 Η3"ό Φ .co2h 553.6 ,~, 〇 ΗΝ-Ν (Τ^Λν;ν 486.6 丁 Η3Ό § 〇5^χχ^〇〇2η IHB111 j 89112968.ptd 第 16 頁 1283240 五、發明說明（12)I. Description of invention (11) Table 1 Mass spectrum (Ivr+l) W- -wr- -R - - ^ R5 486.7 -ό 508.7 0^ca〇〇2H 507.0 c,t5 501.6 : Φ χ^Η 486.6 Η3&quot ;ό Φ .co2h 553.6 ,~, 〇ΗΝ-Ν (Τ^Λν;ν 486.6 丁Η3Ό § 〇5^χχ^〇〇2η IHB111 j 89112968.ptd Page 16 1283240 V. Description of invention (12)

表1 質量光譜 (Μ"+3) W- -wr- 579.7 -δ 。^01¾ 552.7 H3Ci5 Φ 496.6 hsci5 °n 11 一 co2h 500.6 o5^d^c〇2H 512.6 H3Ci5 Φ 5^a。。， 527.7 H3Ci5 o^CXco, 484 、ja' C〇2H liiiilll 89112968.ptd 第 17 頁 1283240 五、發明說明（13) 表1 質量光譜 W-· -W1- -R——Rs 486 9v co2h 488 'ja、 ^^o^co2h 504 α〆 /0 ^^c>^-co2h 518 α〆 π /0 ^^-co2h 502 508 9ν CI 'JCT' /=\ O ° \_/ C02H 498 Oy /0 co2h 512 9ν /0 co2h 1·11 89112968.ptd 第18頁 ! 1283240 !ί :丨 五、發明說明（14) 表1 · 寶量光譜 (Ivf+l) W- -w1- -R - ^ - R5 526 /〇 co2h 532 9v 'JQ" 〇 CK^>-C02H ho2c 514 /〇 co2h 500 α〆 /〇 co2h 516 /〇 co2h 534 ^^sOTc〇2H 0 566 ^4crc〇2H 〇 ΗΙ11ΗΙ 89112968.ptd 第 19 頁 1283240 五、發明說明（15) 表1 W量光譜 (Nf+l) W- -W- ~R---R5 566 v^Hac〇2H 534 ^r^sxxc〇2H 550 9v 〇、 ^y^sX1c〇2H 517 /O ^^ο-〇-〇ο2η /0 〇-<7~\ 0~\〇2h 548 9v /0 \^N^-<KI)~C02H 0 H 562 /° 〇 (302H 552 /0 0 cr 586 9v /0 liHfi 89112968.ptd · 第 20 頁 1283240 五、發明說明（16) 表1 , Μ量光譜 (ΝΤ-Η> W- 尊 -R - - -R5 563 9ν /〇 ν^νΝ9 ° (〇-υλ xy^c〇2H ο2ν 533 9ν \^ύν9 0 °1>002η η2ν 516 /0 co2h 532 /0 ^^〇-p-CC2H 562 /Ο ho2c 542 9ν Me /0 °v CO 2h 561 /Ο vVp 〇^>c〇2h 11· 1. I 89_.Ptd 第 21 頁 1283240 五、發明說明（17) •表1 Μ量光譜 W- -Wr- - R——R5 536 /0 F 552 % /0 k〇 〇Me ^^co2h 519 π /〇 Χ"Ύ^ο^-οο2η 654 9v /0 OBn γ-νΡ 。 co2h 577 /〇 vV9 ° ^y〇〇2, N〇2 564 /0 ^〇-^yc〇2H 549 Me /0 PH 566 Ά' /Ο vV^八 〇 v〇H__/-co2h I·!· 89112968.ptd 第 22 頁 1283240 五、發明說明（18) ’表1 . 質量光譜 (Ivf-fl) W- -R-- .-R5 575 /° ^〇^>cc2h HN o卜 553 /0 523 /° 524 /〇 517 /° 535 /° 、A〇<h 521 /0 580 /° ο2νTable 1 Mass spectrum (Μ"+3) W- -wr- 579.7 -δ. ^013⁄4 552.7 H3Ci5 Φ 496.6 hsci5 °n 11 a co2h 500.6 o5^d^c〇2H 512.6 H3Ci5 Φ 5^a. . , 527.7 H3Ci5 o^CXco, 484, ja' C〇2H liiiilll 89112968.ptd Page 17 1283240 V. Description of invention (13) Table 1 Mass spectrum W-· -W1- -R——Rs 486 9v co2h 488 'ja , ^^o^co2h 504 α〆/0 ^^c>^-co2h 518 α〆π /0 ^^-co2h 502 508 9ν CI 'JCT' /=\ O ° \_/ C02H 498 Oy /0 co2h 512 9ν /0 co2h 1·11 89112968.ptd Page 18! 1283240 !ί :丨五、发明说明(14) Table 1 · Baoquan Spectrum (Ivf+l) W- -w1- -R - ^ - R5 526 / 〇co2h 532 9v 'JQ"〇CK^>-C02H ho2c 514 /〇co2h 500 α〆/〇co2h 516 /〇co2h 534 ^^sOTc〇2H 0 566 ^4crc〇2H 〇ΗΙ11ΗΙ 89112968.ptd Page 19 1283240 V. Description of invention (15) Table 1 W-spectrum spectrum (Nf+l) W- -W- ~R---R5 566 v^Hac〇2H 534 ^r^sxxc〇2H 550 9v 〇, ^y^sX1c〇 2H 517 /O ^^ο-〇-〇ο2η /0 〇-<7~\ 0~\〇2h 548 9v /0 \^N^-<KI)~C02H 0 H 562 /° 〇 (302H 552 /0 0 cr 586 9v /0 liHfi 89112968.ptd · Page 20 1283240 V. INSTRUCTIONS (16) Table 1, Μ-spectrum spectrum (ΝΤ-Η> W- 尊-R - - -R5 563 9ν /〇ν^νΝ9 ° (〇-υλ xy^c〇2H ο2ν 533 9ν \^ύν9 0 °1>002η η2ν 516 /0 co2h 532 /0 ^^〇-p -CC2H 562 /Ο ho2c 542 9ν Me /0 °v CO 2h 561 /Ο vVp 〇^>c〇2h 11· 1. I 89_.Ptd Page 21 1283240 V. Description of invention (17) • Table 1 Spectrum W- -Wr- - R - R5 536 /0 F 552 % /0 k〇〇Me ^^co2h 519 π /〇Χ"Ύ^ο^-οο2η 654 9v /0 OBn γ-νΡ . Co2h 577 /〇vV9 ° ^y〇〇2, N〇2 564 /0 ^〇-^yc〇2H 549 Me /0 PH 566 Ά' /Ο vV^八〇v〇H__/-co2h I·!· 89112968 .ptd Page 22 1283240 V. INSTRUCTIONS (18) 'Table 1. Mass spectrum (Ivf-fl) W- -R-- .-R5 575 /° ^〇^>cc2h HN o Bu 553 /0 523 / ° 524 /〇517 /° 535 /° , A〇<h 521 /0 580 /° ο2ν

IB 第23頁 ,89112968.ptd I 1283240 五、發明說明（19) 1 _ _ 表1 . 寶量光譜 1細） W- -W1- -R - - - R5 550 /0 η2ν 537 9v Cl /0 582 9v Br /〇 ,89112968.ptd 第24頁 1283240 五、發明說明（20) •表1 1 質量光譜 (M++l) 养 -R--R5 I 553 Pv Cl〆 OMe xY?〇jpr_ NH, 674 Ον Cl ^ v^V OMe -o 598 OMe CO,H 626 ?v OMe V Q V-OH 〇 599 ylpT ^ OMe v^N?ojprCOOH nh2 554 Cl ^ ^ OMe vr?〇jpr_ nh2 537 Cl ^ X^X OMe H ^ OH 582 9y Br r OMe H ^ OH 535 Py OMe nh2 639 Me OMe 9 P nh2 __1丨 89112968.ptd · 第 25 頁 1283240 五、發明說明（21) 表1 ............_ 11 ~Η η, »- rr r rn ——.--- 質量光譜！ w- -R …Rs 646 Qy Me〆 OMe 〇·ρ 629 Me ^ '炉 u OMe OBn Vyn9 ◦ kA^C〇2H 538 v^X ^ OMe \^〇^〇<jrCOOH 554 Me vQ^ ^ OMe Ί 々。~〇~co2h 583 / ^ OMe 536 Py Me r OMe Ί Io-Q-cc^h 556 OMe F 538 \^X OMe v^n^n-CV0 H ^ OH 518 Qy Me ^ OMe H ^ OH 601 OMe F ^〇-〇-c〇2H 516 Me ^ OMe Ί ?〇~〇-co2h 111111 I 89112968.ptd 第 26 頁 ! 1283240 五、發明說明（22)IB Page 23, 89112968.ptd I 1283240 V. INSTRUCTIONS (19) 1 _ _ Table 1. Treasure Spectrum 1 Fine) W- -W1- -R - - - R5 550 /0 η2ν 537 9v Cl /0 582 9v Br /〇,89112968.ptd Page 24 1283240 V. Description of invention (20) • Table 1 1 Mass spectrum (M++l) Raise-R--R5 I 553 Pv Cl〆OMe xY?〇jpr_ NH, 674 Ον Cl ^ v^V OMe -o 598 OMe CO,H 626 ?v OMe VQ V-OH 〇599 ylpT ^ OMe v^N?ojprCOOH nh2 554 Cl ^ ^ OMe vr?〇jpr_ nh2 537 Cl ^ X^X OMe H ^ OH 582 9y Br r OMe H ^ OH 535 Py OMe nh2 639 Me OMe 9 P nh2 __1 丨 89112968.ptd · Page 25 1283240 V. Description of invention (21) Table 1 .......... .._ 11 ~Η η, »- rr r rn ——.--- Mass spectrum! W- -R ...Rs 646 Qy Me〆OMe 〇·ρ 629 Me ^ 'furnace u O OBn Vyn9 ◦ kA^C〇2H 538 v^X ^ OMe \^〇^〇<jrCOOH 554 Me vQ^ ^ OMe Ί Hey. ~〇~co2h 583 / ^ OMe 536 Py Me r OMe Ί Io-Q-cc^h 556 OMe F 538 \^X OMe v^n^n-CV0 H ^ OH 518 Qy Me ^ OMe H ^ OH 601 OMe F ^〇-〇-c〇2H 516 Me ^ OMe Ί ?〇~〇-co2h 111111 I 89112968.ptd Page 26! 1283240 V. Description of invention (22)

| · 表1 質量光譜 οντ+ί) W- -R …Rs 534 Py Me ^ u OMe ^s^Nn^>0_/=v/ 554 χ^Χ u OMe Ά。^：。 OH 542 Me r ^ OMe F 〇 Ν^Ν_λ〇ο2η 561 Me r '矿 u OMe Me^Me V^^〇〇C〇〇H 536 A/ Me〆 '矿 u OMe vVN<0 分 COOH 556 9y χ^Χ u OMe γ-γΝΛ,〇Η〇κ〇ο〇Η 556 L OMe F 561 Me r u OMe Me j^e \-A〇〇C〇〇h λ o 572 X^X u OMe Cl νγ)◦分— 652 Qy Me r u OMe 。卩F \-ynY k.N^C〇2H 111111 89112968.ptd 第 27 頁 五、發明說明（23) 表1 | 質量光譜 (M" +1) -w1- - - - R5 I 555 u OMe ξ ^^^nhQ-cooh 672 '矿 u OMe k.N^C〇2H 487 Py Me r H ^ OH 600 2y I ^ OMe f 〜CO〇H X 〇 H 536 Py Me r '矿 u OMe 尸 X^N^〇-〇-〇〇2h 554 ^ OMe ,0H Ί 义 ~〇-co2h 534 Me r '矿 u OMe OH ^〇-〇-co2h 502 Py Me r i OMe 574 '矿 ^ OMe Ί 令。-〇-CQ2H 580 '矿 u OMe 〇 ν^ν~λ〇ο2η ΙΙΗΙΙΙΙΙ 89112968.ptd 第 28 頁 1283240 五、發明說明（24) | .表 1 | 質量光譜; ovr+i) W- 养 -n I 581 u OMe Me.^.Me Ά-〇"〇οη 1 0 533 Py Me ^ X^X w OMe nh2 、-A〇〇C〇〇H o 547 Me ^ I u OMe ΗΝ"Μβ 、-A〇〇C〇〇H ^ o 548 Me r u OMe OMe 552 9y F〆 X^X 1 OMe OMe ^N^〇-〇-〇〇2h 539 Qy Cl〆 χ^Χ u OMe 584 Qy Br〆 k OMe 523 Me r I u OMe \^^n〇cooh 568 Qy Cl〆 I u OMe OMe 613 9y Br〆 u OMe /〇Me 602 Qy Br〆 Λ: F Ί々◦分- 89112968.ptd 第29頁 111·· 1283240 五、發明說明（25)| Table 1 Mass Spectrum οντ+ί) W- -R ...Rs 534 Py Me ^ u OMe ^s^Nn^>0_/=v/ 554 χ^Χ u OMe Ά. ^:. OH 542 Me r ^ OMe F 〇Ν^Ν_λ〇ο2η 561 Me r 'mine u OMe Me^Me V^^〇〇C〇〇H 536 A/ Me〆' mine u OMe vVN<0 points COOH 556 9y χ^ Χ u OMe γ-γΝΛ,〇Η〇κ〇ο〇Η 556 L OMe F 561 Me ru OMe Me j^e \-A〇〇C〇〇h λ o 572 X^X u OMe Cl νγ)◦分— 652 Qy Me ru OMe.卩F \-ynY kN^C〇2H 111111 89112968.ptd Page 27 V. Description of invention (23) Table 1 | Mass spectrum (M" +1) -w1- - - - R5 I 555 u OMe ξ ^^^ nhQ-cooh 672 'mine u OMe kN^C〇2H 487 Py Me r H ^ OH 600 2y I ^ OMe f ~CO〇HX 〇H 536 Py Me r 'mine u OMe corpse X^N^〇-〇-〇 〇2h 554 ^ OMe ,0H Ί 义~〇-co2h 534 Me r 'mine u O OH ^〇-〇-co2h 502 Py Me ri OMe 574 'mine ^ OMe Ί Order. -〇-CQ2H 580 'mine u OMe 〇ν^ν~λ〇ο2η ΙΙΗΙΙΙΙΙ 89112968.ptd Page 28 1283240 V. Description of invention (24) | . Table 1 | Mass spectrum; ovr+i) W- 养-n I 581 u OMe Me.^.Me Ά-〇"〇οη 1 0 533 Py Me ^ X^X w OMe nh2 , -A〇〇C〇〇H o 547 Me ^ I u OMe ΗΝ"Μβ , -A〇 〇C〇〇H ^ o 548 Me ru OMe OMe 552 9y F〆X^X 1 OMe OMe ^N^〇-〇-〇〇2h 539 Qy Cl〆χ^Χ u OMe 584 Qy Br〆k OMe 523 Me r I u OMe \^^n〇cooh 568 Qy Cl〆I u OMe OMe 613 9y Br〆u OMe /〇Me 602 Qy Br〆Λ: F Ί々◦分- 89112968.ptd Page 29 111·· 1283240 V. Description of the invention (25)

表1 質量光譜 (M++l) W- -R …R5 572 Me〆 u OMe 592 χ^Χ u OMe 637 2y ^ OMe 717 I i OMe Ά k^N^COjH 651 Me ^ χ^Χ u OMe νχΝ?〇 kx^COjH 716 A ^ OMe k^v^COjH 671 χ^Χ ^ OMe v^rNY 0 O.C0, 524 Me r X^X ^ OMe 544 1 OMe \/^^^〇-^^-COOH (ill 89112968.ptd 第 30 頁 1283240 五、發明說明（26) 28Table 1 Mass spectrum (M++l) W- -R ...R5 572 Me〆u OMe 592 χ^Χ u OMe 637 2y ^ OMe 717 I i OMe Ά k^N^COjH 651 Me ^ χ^Χ u OMe νχΝ 〇kx^COjH 716 A ^ OMe k^v^COjH 671 χ^Χ ^ OMe v^rNY 0 O.C0, 524 Me r X^X ^ OMe 544 1 OMe \/^^^〇-^^-COOH (ill 89112968.ptd Page 30 1283240 V. INSTRUCTIONS (26) 28

1 表1 質量光譜 (M* +1> W- -wj. R - · · R $ 506 Me r 'XT、 ^^〇-〇-co2h 537 Me r u OMe 648 ?y X^X u OMe /=v 〇 ^°Λ_^γ"°〇2Η 581 u OMe Me.N.Me A。伊。H o 589 χ^Χ u OMe 537 Py Me ^ i OMe 557 '矿 t OMe 616 Me r u OMe pO ν^Ύ k^N^C〇2H 636 χ^Χ ^ OMe pO \Tr\ 、〇 S〇 ^N^CO,H 681 u OMe pO νΎΎ 、0 ^N^COjH 89112968.ptd 第31頁 1283240 五、發明說明（27)1 Table 1 Mass spectrum (M* +1 > W- -wj. R - · · R $ 506 Me r 'XT, ^^〇-〇-co2h 537 Me ru OMe 648 ?y X^X u OMe /=v 〇^°Λ_^γ"°〇2Η 581 u OMe Me.N.Me A.I.H o 589 χ^Χ u OMe 537 Py Me ^ i OMe 557 'mine t OMe 616 Me ru OMe pO ν^Ύ k ^N^C〇2H 636 χ^Χ ^ OMe pO \Tr\ , 〇S〇^N^CO, H 681 u OMe pO νΎΎ , 0 ^N^COjH 89112968.ptd Page 31 1283240 V. Description of invention (27 )

表1 質量光譜 (Μ*+ί) -R …Rs 522 χ^Χ u OMe 分— 590 9y Me ^ '矿 u OMe Ά:°·〇-〇2η 624 Qy Me r L OMe '4:分- 534 Me r ^ OMe Ύ?。分 c〇2h 494 Me r 'XT、 550 Qy Me r χ^Χ u OMe ^^ο^Ο-οο,η 570 Cl〆 '矿 u OMe OH ' 0 ^~o-^)-co2h 624 Me ^ 'XT、 ,o^〇-co^h 674 Cl〆 '矿 u OMe 又Ο-哪 '""T^^ohQ-c◦尸 661 Me r χ^Χ OMe Ύ。矿H liliill 89112968.ptd 第 32 頁 1283240 五、發明說明（28) 1 表1 1 質量光譜 (M^+l) W- -w1- -R - - R $ j 654 Py Me ^ OMe 670 Me u OMe νγ (η〇^οοη 680 Qy Cl ^ ^ OMe VY "LohQ^cooh 636 a/ Me 'XT、 ΓΛ Me vy(H〇^_ 666 Qy Me u OMe Μβτ A 520 Me '矿 ^ Me F VV^^Q-cooh 540 Cl ^ Me F VYNi^oHQ_COOH 598 Qy Cl r '矿 u OMe \^Pi0^yCOOH 643 Qy c〆 \矿 u OMe V^。分議 585 Qy B〆 u Me F Vy^Q^OOH 601 Qy Br尸 χ^Χ u OMe vyn^oh〇_cooh IRBill 89112968.ptd 第33頁 1283240 五、發明說明（29) 1 表 11 · · 質量光譜 IV- iBiiiiiiiiii “ R5 719 '矿 u OMe ^οΌ^οη vyQ。分 _ 594 '矿 u OMe 乂〇_〇~議 LohQ_cooh 686 Cl r '矿 u OMe ΓΛ Me V〇hQ_cooh 731 Qy Br r '矿 u OMe ΓΛ Me VYX^.COOH 573 χ^Χ u OMe 617 U OMe Cl νγ{。分 _ 492 a〆 'XT、 F ^^ohQ-cooh 725 Qy B〆 u OMe XO ^Y^ohQhcooh 552 χ^Χ u OMe F 743 Qy Cl ^ '矿 u OMe vCO ^-Y^o^Q^cooh 548 Me '矿 u OMe OMe 1_画 89112968.ptd 第34頁 I 1283240 五、發明說明（30) 1 表1 、 質量光譜 t (M^ +1) -WJ- -R - - - R ^ 568 Py '矿 u OMe OMe WXhQ.cooh 613 Py Br r u OMe OMe V^X^OHQ^COOH 506 Oy u Me F νγ 780 u OMe ^s)prMe ν^Ν~^-〇-〇-°°〇Η 831 Qy ,rrx ^OMe Λ _ 676 Py Br r I L OMe i.Me VY^-ohQ-cooh 524 Qy u Me F ^^ohQ-ccoh 644 Qy c〆 '矿 ^ OMe vV^cooh 689 Qy Cl r u OMe 594 Me Xxrx \〜ζ^,0Βη— \ 〇 '-o—COOH 681 9v ^ OMe o-CO \^nlohq^cooh 111·· 89112968.ptd 第 35 頁 ! 1283240 五、發明說明（31) • •表1 1 質量光譜 W- 726 u OMe p-OD 590 u OMe F ^^ohQ-cooh 594 Me ^ OMe % ΊG^_ 614 Qy c〆 i OMe % 659 Qy B〆 i OMe % νγ(分 _ 534 Qy Me I u OMe OH VY^O^^COOH 554 c〆 '矿 ^ OMe OH \^χνΓ^。分 COOH 599 Qy B〆 '矿 i OMe OH \^Ν^οη〇_οοοη 571 'XT、 F V^^ohQ-cooh 648 k OMe % VV U-^-cOOH 643 χ^Χ ^ Me VynTohq_cooh m ill 89112968.ptd 第 36 頁 1283240 五、發明說明（32)Table 1 Mass spectrum (Μ*+ί) -R ...Rs 522 χ^Χ u OMe min - 590 9y Me ^ 'mine u OMe Ά:°·〇-〇2η 624 Qy Me r L OMe '4:min - 534 Me r ^ OMe Ύ?. Sub-c〇2h 494 Me r 'XT, 550 Qy Me r χ^Χ u OMe ^^ο^Ο-οο,η 570 Cl〆'mine u OMe OH ' 0 ^~o-^)-co2h 624 Me ^ ' XT, ,o^〇-co^h 674 Cl〆'mine u OMe Ο-哪'""T^^ohQ-c corpse 661 Me r χ^Χ OMe Ύ. Mine H liliill 89112968.ptd Page 32 1283240 V. INSTRUCTIONS (28) 1 Table 1 1 Mass spectrum (M^+l) W- -w1- -R - - R $ j 654 Py Me ^ OMe 670 Me u OMe Γγ η 〇 680 680 680 Q-cooh 540 Cl ^ Me F VYNi^oHQ_COOH 598 Qy Cl r 'mine u OMe \^Pi0^yCOOH 643 Qy c〆\mine u OMe V^. Discussion 585 Qy B〆u Me F Vy^Q^OOH 601 Qy Br corpse ^Χ u OMe vyn^oh〇_cooh IRBill 89112968.ptd Page 33 1283240 V. Description of invention (29) 1 Table 11 · · Mass spectrum IV- iBiiiiiiiiii “R5 719 'mine u OMe ^οΌ^οη vyQ.分_ 594 '矿u OMe 乂〇_〇~ Discussion LohQ_cooh 686 Cl r 'mine u OMe ΓΛ Me V〇hQ_cooh 731 Qy Br r 'mine u OMe ΓΛ Me VYX^.COOH 573 χ^Χ u OMe 617 U OMe Cl νγ{.分_ 492 a〆'XT, F ^^ohQ-cooh 725 Qy B〆u OMe XO ^Y^ohQhcooh 552 χ^Χ u OMe F 743 Qy Cl ^ 'Mine u OMe vCO ^-Y^ o^Q^cooh 548 Me 'mine u OMe OMe 1_画89112968.ptd Page 34 I 1283240 V. Description (30) 1 Table 1, mass spectrum t (M^ +1) -WJ- -R - - - R ^ 568 Py 'mine u OMe OMe WXhQ.cooh 613 Py Br ru OMe OMe V^X^OHQ^COOH 506 y y y y y y y y y y y y y y y y y y 524 Qy u Me F ^^ohQ-ccoh 644 Qy c〆'mine^ OMe vV^cooh 689 Qy Cl ru OMe 594 Me Xxrx \~ζ^,0Βη— \ 〇'-o-COOH 681 9v ^ OMe o-CO \^nlohq^cooh 111·· 89112968.ptd Page 35! 1283240 V. Description of invention (31) • • Table 1 1 Mass spectrum W- 726 u OMe p-OD 590 u OMe F ^^ohQ-cooh 594 Me ^ OMe % ΊG^_ 614 Qy c〆i OMe % 659 Qy B〆i OMe % νγ (minute _ 534 Qy Me I u OMe OH VY^O^^COOH 554 c〆'mine ^ OMe OH \^χνΓ^. COOH 599 Qy B〆'mine i OMe OH \^Ν^οη〇_οοοη 571 'XT, FV^^ohQ-cooh 648 k OMe % VV U-^-cOOH 643 χ^Χ ^ Me VynTohq_cooh m ill 89112968. Ptd Page 36 1283240 V. Description of invention (32)

89112968.ptd 第37頁 II·! 1283240 五、發明說明（33) • 表1 質量光譜 1 (M^+l) W- -W1. -R - - * R. ^ 534 (X Me ^ '矿 L Me F νγΝί^〇^_ 520 (X： Me ^ 'XT、 F νγ^〇__ 536 X^X ^ Me νγΧ^,οοοπ 546 ^ Me F 540 Qy Me U Cl F νγ^ο^.^ 560 Qy X^X 1 Cl F VYn^0_q^C00H 605 Br ^ L Cl F 562 Qv Me L Me 582 Py χ^Χ i Me 627 Qy B〆 u Me V^^.〇_^_c〇〇H 508 Qy Me '矿 ~ Me vy?。分 _ • 111 1 1 89112968.ptd 第 38 頁 1283240 五、發明說明（34) 1- ... 表 1 ·. 質量光譜 I (Μ* +ί) W- -R …R5 558 L OMe Mev_^ 522 Qy Me L Me Me.^ W U^_COOH 522 Me u OMe Y^°-〇"COOH 526 Me L Me F 591 u Me F 513 9v Me F νγ4◦分酬 585 Pv Me L Br F W^__/=V 〇 ^·°~\ >~COOH 605 X^X F 650 X^X 1 Br F 617 9y L Me89112968.ptd Page 37 II·! 1283240 V. Description of invention (33) • Table 1 Mass spectrum 1 (M^+l) W- -W1. -R - - * R. ^ 534 (X Me ^ 'mine L Me F νγΝί^〇^_ 520 (X: Me ^ 'XT, F νγ^〇__ 536 X^X ^ Me νγΧ^, οοοπ 546 ^ Me F 540 Qy Me U Cl F νγ^ο^.^ 560 Qy X^X 1 Cl F VYn^0_q^C00H 605 Br ^ L Cl F 562 Qv Me L Me 582 Py χ^Χ i Me 627 Qy B〆u Me V^^.〇_^_c〇〇H 508 Qy Me ' Mine ~ Me vy?. _ • 111 1 1 89112968.ptd Page 38 1283240 V. INSTRUCTIONS (34) 1- ... Table 1 ·. Mass spectrum I (Μ* +ί) W- -R ...R5 558 L OMe Mev_^ 522 Qy Me L Me Me.^ WU^_COOH 522 Me u OMe Y^°-〇"COOH 526 Me L Me F 591 u Me F 513 9v Me F νγ4◦ 585 Pv Me L Br FW^__/=V 〇^·°~\ >~COOH 605 X^XF 650 X^X 1 Br F 617 9y L Me

89112968.ptd 第39頁89112968.ptd Page 39

五、發明說明（36)V. Description of invention (36)

表1 質量光譜 (M* +1) •R …R5 607 u F F 571 Oy '矿 ^ Br F 619 Cu r{ χν vV νΥ(Η〇Η_ 560 '矿 U Cl F 1283240 五、發明說明（37) 在化學式I之一較佳具體例中，Μ為 Α為=0，R為-（C'H2)n-及X為-C(0)-。在以上化合物之更佳具 體例中，Y1 係選自-0-、-S-、-S(〇)-、-S(〇) 及_Νγ4_/、 ，及Υ1為-0-更佳。 在化學式I之較佳化合物中，W為未經取代的苯基或在其 鄰位具有選自低碳烷基及鹵原子之一或兩個取代美之苯八 基，及wi為未經取代的伸苯基或在其對_ΝΗ—之鄰ς且 自：Ϊ ί ; 1低碳烧基及鹵原子之取代基的伸苯基較佳。 -(CH ):,及A，Hlb合物Α為=0較佳，Α2為直接鍵或 下表2呈現化·學式！之較佳化合 复 (f 及A為=0。關於— 的表 ，、中乂為K- 記不係描述在化學式I中以 · 為「— R---R8」的 表示之分。丫、一义Table 1 Mass spectrum (M* +1) • R ... R5 607 u FF 571 Oy 'mine ^ Br F 619 Cu r{ χν vV νΥ (Η〇Η_ 560 'mine U Cl F 1283240 V. Description of invention (37) In a preferred embodiment of the chemical formula I, Μ is Α = 0, R is -(C'H2)n- and X is -C(0)-. In a more specific example of the above compound, Y1 is selected From -0-, -S-, -S(〇)-, -S(〇) and _Νγ4_/, , and Υ1 are -0-. More preferably, in the preferred compound of formula I, W is unsubstituted. The phenyl group or in the ortho position thereof has one or two substituted benzene octayl groups selected from the group consisting of a lower alkyl group and a halogen atom, and wi is an unsubstituted phenyl group or an ortho quinone thereof And from: Ϊ ί; 1 low-carbon alkyl group and halogen atom substituents of the phenyl group is preferred. - (CH):, and A, Hlb compound Α is =0 is better, Α 2 is a direct bond or the following table 2 Presentation and learning! The better combination (f and A are = 0. For the table of -, the middle is K- not described in the chemical formula I as "- R---R8" The meaning of the points.

534 504 點：及上方的鍵係連接至—R—之點。標”係連接至— ΝΗ—之534 504 points: The upper key is connected to the point of -R-. "" is connected to - ΝΗ -

,0 1283240 五、發明說明（38) 及Μ為 在化學式I之二較佳具體例中，A為, 0 1283240 V. Inventive Note (38) and Μ In the preferred embodiment of Chemical Formula I bis, A is

k_/NK_/N

X1—(CHR9)q-l 在此具體例中.，較佳化合物為其中R1G為-C02H之化合物， 更佳化合物為其中R1G為-C02H及^為0或1之化合物。又更佳 的化合物為其中R1Q為- C02H，q為0或1及m為2之化合物，及 再更佳的化合物為其中R1G為-C02H，q為0或1及m為2之化合 物。 在一更佳具體例中，A為=0及L係選自X1 - (CHR9)q-l In this specific example, preferred compounds are those wherein R1G is -C02H, and more preferred are compounds wherein R1G is -C02H and ^ is 0 or 1. Still more preferred are compounds wherein R1Q is -C02H, q is 0 or 1 and m is 2, and even more preferred are compounds wherein R1G is -C02H, q is 0 or 1 and m is 2. In a more preferred embodiment, A is =0 and L is selected from

II

3 1 wm i 89112968.ptd 第43頁 1283240 五、發明說明（39)3 1 wm i 89112968.ptd Page 43 1283240 V. Description of invention (39)

ϊβϋ 89112968.ptd · 第 44 頁Ϊβϋ 89112968.ptd · page 44

1283240 五、發明說明（42) 化學式I之％佳化合物係其中尺為_c札一，χ為=〇及诼為未 經取代的苯基或在鄰接於連接至_NiJ—之點經選自低碳燒 基、鹵原子、硝基、—〇Η及烷氧基之取代基取代之苯基的 化合物。w1為未經取代的伸苯基或在鄰接於連接至—ΝΗ—之 點經低碳烷基或甲氧基取代之伸苯基較佳。 下表3呈現本發明 —(CHR9), 、’X為=0，及“ 。關於W1的表示1283240 V. INSTRUCTIONS (42) The best compound of formula I is that the ruler is _c, the χ is = 〇 and 诼 is unsubstituted phenyl or is adjacent to the point of attachment to _NiJ- A compound of a phenyl group substituted with a substituent of a halogen group, a halogen atom, a nitro group, a hydrazine, and an alkoxy group. It is preferred that w1 is an unsubstituted phenyl group or a phenyl group substituted by a lower alkyl group or a methoxy group adjacent to the point of attachment to ΝΗ. Table 3 below presents the present invention - (CHR9), , 'X is =0, and ". Representation of W1

ΐ點:方的鍵係連接至-NH-之點，及上方的鍵係連接至Rΐ Point: the bond of the square is connected to the point of -NH-, and the key above is connected to R

B9112968.ptdB9112968.ptd

第47頁 1283240 五、發明說明（43) | 表3 v 龍光譜 1 1>· w- 尊 議_議11鬆戀選懸S__BKl_ 540.6 ό H3C〇j5 丄 HO/, VSAA* 0 ^co2h 〔Ν〕 •ί1 523.7 Η3"ό Vy' 丄〇 co2h ό 1 555.7 Ο ^co2h 0 丄 583.8 ο^γ <c〇2h ό 1 524.7 Η3"ό Φ HQ, ζν 丄〇 广c〇2h 〔N〕 I 509.7 ό Η3〇〇-φ ηολ 9ν、 co2h ό 1 1111111 89112968.ptd 第 48 頁 1283240 五、發明說明（44)Page 47 1283240 V. INSTRUCTIONS (43) | Table 3 v Dragon Spectrum 1 1>· w- 尊议_议11松恋选悬S__BKl_ 540.6 ό H3C〇j5 丄HO/, VSAA* 0 ^co2h 〔Ν〕 • ί1 523.7 Η3"ό Vy' 丄〇co2h ό 1 555.7 Ο ^co2h 0 丄583.8 ο^γ <c〇2h ό 1 524.7 Η3"ό Φ HQ, ζν 丄〇广c〇2h [N] I 509.7 ό Η3〇〇-φ ηολ 9ν, co2h ό 1 1111111 89112968.ptd Page 48 1283240 V. Description of invention (44)

1 表3 質量光譜 |知4*1) W- 养 L_ Y+C^-z^ 538.7 Η3Ό HO' Vv 〇 广 co2h 0 V 554.7 Η3Ό Η3〇〇^φ HQ, ’w、 JL 〇 广 co2h ό V 569.7 : φ co2h 1 666.9 Η3"ό Φ «ΑΑ·Α^ ΟΫΤ、 °r\K^ N-N I 567.8 : — ?Y' co2h Α^οο2η 1 570.4 Η3^ό H3c〇4 HO OH 丄〇 广c〇2h 0 I 1 89112968.ptd 第 49 頁 1283240 五、發明說明（45) ·. :表 3 質量光譜 owr+i) w- 卷 ΐ縿灘縿繼1纖議擊 w。 552.7 Λ H3co*^y h2n 〇 ^co2h ό 丄 619.5 Βκό HO' 9v、 丄 〇 广 co2h ύ 575.1 °Ό ,οοψ HO' 丄〇 广 co2h ύ 553.6 Η3"ό Η3οο^φ V JL 〇 广 co2h 〔N〕 I 664.1 Η3"ό ,ρ-CIPh 丄〇 <c〇2h 0 1 629.7 Η3Ό Η3〇〇-φ PhO Vv" 丄〇 ^co2h 〔N〕 limn第50頁 89112968.ptd1 Table 3 Mass spectrum|Knowledge 4*1) W- Nursing L_ Y+C^-z^ 538.7 Η3Ό HO' Vv 〇广co2h 0 V 554.7 Η3Ό Η3〇〇^φ HQ, 'w, JL 〇广co2h ό V 569.7 : φ co2h 1 666.9 Η3"ό Φ «ΑΑ·Α^ ΟΫΤ, °r\K^ NN I 567.8 : — ?Y' co2h Α^οο2η 1 570.4 Η3^ό H3c〇4 HO OH 丄〇广c〇2h 0 I 1 89112968.ptd Page 49 1283240 V. INSTRUCTIONS (45) ·. : Table 3 Mass spectrum owr+i) w- ΐ縿 ΐ縿 縿 縿 Follow 1 fiber to negotiate w. 2.7 co co co 9.5 9.5 9.5 9.5 9.5 9.5 9.5 I 664.1 Η3"ό ,ρ-CIPh 丄〇<c〇2h 0 1 629.7 Η3Ό Η3〇〇-φ PhO Vv" 丄〇^co2h 〔N〕 limn Page 50 89112968.ptd

1283240 五、發明說明（46) 1 .表3 丨質量光譜 |分+1) · W- -w!-. -L- .C：r 555.6 Η3"ό Φ 9r、 %ΑΛΛ# 〇 ^co2h ό 1 613.7 Hs"0 Η300-φ Phv Vy、 ^co2h 0 ! 555.7 Η3Ό ςγ ^co2h 0 丄 585.7 Η3οο^φ 丄〇 ^co2h $ 591.7 Η3"ό 〇 ^co2h 6 1 660.7 Η3"ό p-MeOPh V 丄〇 .co2h 6 1 1B1 89112968.ptd · 第 51 頁 1283240 五、發明說明（47) 表3 寳量光譜 1) W- -W!- ΙΗ__ΙΙ_ΒΙ_ f。 555.6 Η2ί5 Λ h3co人γ Η〇' W1" 0 广 co2h 〔N〕 1 556.6 Η〇ιδ Η3〇〇-ψ HQ, 0 广 co2h ύ 1 570.7 ch3o^L u Η3〇〇-ψ ΗΟν Vy、 广 co2h ύ 570.7 Η3〇〇-φ HO〆, Ο ^co2h 〔N〕 1 673.8 Η3"ό Η# BnO Vy、 Ο co2h ^Χγ0Ο2Η I 600.7 Η3"ό Ο 广 co2h 〔N〕 N «ΑΛΑ# 1圓_11 89112968.ptd 第 52 頁 1283240 五、發明說明（48) 表3 質量光譜 •W- i^HR)r γ-Ν〇^-ΖΛ 552.7 Λ h3co 人γ ^r、 0 广 co2h ύ I 668.8 j5 h3co^Y BnO^^ Vy" 丄〇 cN〕 丄 583.7 Η3Ό Η3〇〇-φ H〇—N^H sv .co2h 6 丄 704.9 Η3Ό Λ h3co^Y -^-s* 〇 ^co2h 〔N〕 V 514.6 Η3"ό > /—N 丄 〇 .co2h 0 1 514.6 4 ’H N 丫S 丄 〇 xo2h ό 1 111111 89112968.ptd 第 53 頁 1283240 五、發明說明（49) [ 表3 |龍光譜 1) W- 赛 iBlIISlIlllill 562.6 h3cyS ’Η ^co2h Λί u Nws 丄1283240 V. INSTRUCTIONS (46) 1. Table 3 丨 Mass Spectrum | Minus +1) · W- -w!-. -L- .C:r 555.6 Η3"ό Φ 9r, %ΑΛΛ# 〇^co2h ό 1 613.7 Hs"0 Η300-φ Phv Vy, ^co2h 0 ! 555.7 Η3Ό ςγ ^co2h 0 丄585.7 Η3οο^φ 丄〇^co2h $ 591.7 Η3"ό 〇^co2h 6 1 660.7 Η3"ό p-MeOPh V 丄〇. Co2h 6 1 1B1 89112968.ptd · Page 51 1283240 V. INSTRUCTIONS (47) TABLE 3 Treasure Spectrum 1) W- -W!- ΙΗ__ΙΙ_ΒΙ_ f. 555.6 Η2ί5 Λ h3co human γ Η〇' W1" 0 wide co2h [N] 1 556.6 Η〇ιδ Η3〇〇-ψ HQ, 0 wide co2h ύ 1 570.7 ch3o^L u Η3〇〇-ψ ΗΟν Vy, wide co2h ύ 570.7 Η3〇〇-φ HO〆, Ο ^co2h 〔N〕 1 673.8 Η3"ό Η# BnO Vy, Ο co2h ^Χγ0Ο2Η I 600.7 Η3"ό 广 Guang co2h 〔N〕 N «ΑΛΑ# 1 circle_11 89112968. Ptd Page 52 1283240 V. Description of invention (48) Table 3 Mass spectrum • W- i^HR)r γ-Ν〇^-ΖΛ 552.7 Λ h3co Human γ ^r, 0 broad co2h ύ I 668.8 j5 h3co^Y BnO ^^ Vy" 丄〇cN] 丄583.7 Η3Ό Η3〇〇-φ H〇—N^H sv .co2h 6 丄704.9 Η3Ό Λ h3co^Y -^-s* 〇^co2h 〔N〕 V 514.6 Η3"ό &gt ; /—N 丄〇.co2h 0 1 514.6 4 'HN 丫S 丄〇xo2h ό 1 111111 89112968.ptd Page 53 1283240 V. Description of invention (49) [Table 3 | Dragon Spectrum 1) W-赛iBlIISlIlllill 562.6 h3cyS 'Η ^co2h Λί u Nws 丄

1RI1III 89112968.ptd 第 54 頁 12832401RI1III 89112968.ptd Page 54 1283240

五、發明說明（50) . 本發明之較佳化合物係其中八為=〇 Μ為丨m_Li，L丨為c〇2H，w為未經取代的笨基為二， 鄰接於連#至-NH-之點經選自低碳烷基、鹵原子^ 一斗〇1 及由烧*氧基之取代基取代之苯基的化合物。r為未經i、 苯基或在鄰接於連接至，-之點經低碳烷基或甲氧 二：代之：笨基較佳，為在其對，—之鄰位具有：自甲 2、低丨石厌丨烧基及鹵原子之取代基的伸苯基最佳。 人為1^”及23气二價脂族烴基團之化合物中，較佳化 =為J中Ru為Θ或，12，以.更佳之化合Π 低* 1 _Η、低碳烷基及經取代的低碳烷基，以二獅美 基為最佳。ζ3之較佳選擇為具有4、5及6個碳土 甲旨=基團：W1之較佳選擇為在其對，-之鄰位具 力m 1 1 1 ·、低奴烷基及豳原子之取代基的伸苯基。 Ζ Λ夺及23為之化合物中，ri1為-㈣2-括-H -nu此等化合物中’ X及7為1較佳。R14之較佳選擇包 選":/_F。：之較佳選擇為在其對*之鄰位具有 ^ Π2 ί :低碳烷基及_原子之取代基的伸苯基。 二Α'·及Ζ3為之化合物中，RH係選 及π8久& R11軼佳，其中R11係選自—Η及低碳烷基較佳。R17 R 較佳。W1之較佳選擇為在其對—ΝΗ-之鄰位具有 un、低碳烧基及_原子之取代基的伸苯基。 -NR11梦:么1'及^為卜Ο""1 之化合物中，R11為 勺；te ^ +D，其中RU為低碳燒基較佳。此具體例之化合物亦 ^ ’、 及1^18之至少一者為低碳烷基或經取代低碳烷基V. DESCRIPTION OF THE INVENTION (50). Preferred compounds of the present invention are those in which VIII is 丨m_Li, L丨 is c〇2H, and w is unsubstituted, and the singular group is two, adjacent to lian #至-NH. a compound selected from the group consisting of a lower alkyl group, a halogen atom, a hydrazine, and a phenyl group substituted with a substituent of a oxy-oxy group. r is not i, phenyl or adjacent to the point of attachment to -, via a lower alkyl or methoxy: instead: a stupid group is preferred, in its opposite, the ortho position has: from a 2 The phenyl group which is a substituent of a low-stone anodic pyridyl group and a halogen atom is most preferred. Among the compounds of the artificial 1 ^" and 23 gas divalent aliphatic hydrocarbon groups, it is preferred that R in the J is ruthenium or 12, and more preferably 化 * * * * 低 低 低 低 低 低 低 低 低 低The lower alkyl group is preferably the second schmaki group. The preferred choice of ζ3 is 4, 5 and 6 carbon clays. The preferred choice for W1 is in the pair, the ortho position of - Force m 1 1 1 ·, a lower phenyl group and a substituent of a ruthenium atom, a phenyl group. Ζ Λ 及 and 23 compounds, ri1 is - (tetra) 2----H-nu in these compounds 'X and 7 Preferably, R14 is preferably selected as ":/_F.: Preferably, it is a phenyl group having a substituent of a lower alkyl group and a _ atom in the ortho position to * Among the compounds of the two Α'· and Ζ3, RH is selected and π8 is & R11 is preferred, wherein R11 is preferably selected from the group consisting of fluorene and lower alkyl. R17 R is preferred. The preferred choice for W1 is In the ortho position of the ΝΗ-ΝΗ-, there is a phenyl group with a substituent of un, a low-carbon alkyl group and a _ atom. -NR11 Dream: What is 1' and ^ is a compound of dip" "1, R11 is a spoon ;te ^ +D, wherein RU is a low-carbon alkyl group. The compound of this specific example is also ^ , 18 ^ 1 and at least one of the substituted lower alkyl is lower alkyl or

11283240 五、發明說明（51) 之化合物較佳。 在Q2為丨Αΐ及Z3為 -NH-及Rn及…卷為刊較佳 N、} 之化合物中，R11為 粼办目*、西A wl之較佳選擇為在其對-NH-之 基，、有“甲氧基、低碳烷基及_原子之取代基的伸苯 在Q2係選自芳基及經取代芳基及 及選自苯基和在連接至Z3之點經取代之苯基 中，Z3為二價脂族烴基團較佳。 化5物 本發明之又另一具體例係以化學式丨丨表示之化合物，11283240 V. The compound of the invention (51) is preferred. In the case where Q2 is 丨Αΐ and Z3 is -NH- and Rn and ... is the preferred compound of N,}, R11 is 粼*, and West Awl is preferably selected as the base of -NH- , Benzene having a substituent of "methoxy, lower alkyl and _ atom" is selected from the group consisting of an aryl group and a substituted aryl group in Q2, and a benzene selected from the group consisting of a phenyl group and a point bonded to Z3. In the group, Z3 is preferably a divalent aliphatic hydrocarbon group. Another specific example of the present invention is a compound represented by a chemical formula,

II 及L3係選 其中取代基W、w1、R11及Z3係如化學式I所定義， 白 丨\。〆-”，^^· 及人 本發明之又另一具體例係以化學式111表示之化合物， 〇 〇 其中取代基W、W1及R11係如化學式I所定義，及d係、琴自 1，及f係選自1及2。 ’、^ 及 為-CH2 下表4顯示化學式I之較佳化合物，其中a為=q， 89112968.ptd 第56頁II and L3 are selected wherein the substituents W, w1, R11 and Z3 are as defined by the chemical formula I, white 丨. Further, another specific example of the present invention is a compound represented by Chemical Formula 111, wherein the substituents W, W1 and R11 are as defined in the chemical formula I, and the d-system, the piano is 1, And f is selected from 1 and 2. ', ^ and -CH2 Table 4 below shows preferred compounds of Formula I, wherein a is =q, 89112968.ptd第56页

1283240 五、發明說明（53) 質量光譜 廊確·、· "-w1- 輝心 ·、 504.1 ch3 及' och3 Hf|srCO^C〇2H 529.17 ς^ν ch3 π 〇ch3 H〇^H 501.16 Pv ch3 π 〇ch3 H〇^H S)T^^co2h 427.20 pv ch3 π och3 r^^CQH 441.22 pv ch3 〇ch3 468.1 pv ch3 och3 ^?^^c〇2h 532.2 pv ch3 〇ch3 丫 624.2 Qv ch3 0CH3 ft 2h 455.16 ch3 〇ch3 圓 Hill 89112968.ptd 第 58 頁 1283240 五、發明說明（54)1283240 V. INSTRUCTIONS (53) QUALITY SPECTRUM RANGE ·· · "-w1- 辉心·, 504.1 ch3 and ' och3 Hf|srCO^C〇2H 529.17 ς^ν ch3 π 〇ch3 H〇^H 501.16 Pv Ch3 π 〇ch3 H〇^HS)T^^co2h 427.20 pv ch3 π och3 r^^CQH 441.22 pv ch3 〇ch3 468.1 pv ch3 och3 ^?^^c〇2h 532.2 pv ch3 〇ch3 丫624.2 Qv ch3 0CH3 ft 2h 455.16 ch3 〇ch3 round Hill 89112968.ptd page 58 1283240 V. Description of invention (54)

質量光譜 i·. :· · • · ：w- ··：：：,,：· * ： * · * ::&:夢:. ·· · · · -.： ： ；：' ：： ；:. Γ：; -· ： · · · .·：：. -、： - 466.22 ch3 ,jax /~\ co2h 〇 496.22 ςχ ch3 och3 Hrr〇-C〇2H 〇 445.19 ch3 HriO0T^C〇2H 475.20 9v ch3 〇ch3 ΗΓ|Γ^^^〇〇2η 497.22 9v ch3 och3 ?Y〇-c〇2H 一〇 510.42 Qv ch3 0CH3 γγΟ^Η Ο 517.62 ch3 och3 \^Χ^Γχ°〇2Η 473.56 ςχ ch3 V"i0Ptc〇2HMass spectrum i·. :· · • · :w- ··:::,,:· * : * · * ::&:dream:. ·· · · · -.: : ;:' :: ; :. Γ:; -· : · · · .·::. -,: - 466.22 ch3 ,jax /~\ co2h 〇496.22 ςχ ch3 och3 Hrr〇-C〇2H 〇445.19 ch3 HriO0T^C〇2H 475.20 9v ch3 〇ch3 ΗΓ|Γ^^^〇〇2η 497.22 9v ch3 och3 ?Y〇-c〇2H 〇510.42 Qv ch3 0CH3 γγΟ^Η Ο 517.62 ch3 och3 \^Χ^Γχ°〇2Η 473.56 ςχ ch3 V"i0Ptc〇 2H

Hill 89112968.ptd 第 59 頁 1283240 五、發明說明（55) |; ... ： : «4 ：=； |質量光譜 丨就m ·. · ·· w1-·'；: * . · . · ... . if;·;:: • .· * · .·!.···：!；.··· · · i ·. * · ： - . ·. · · ： · ： · . · 483.70 Qv ch3 〇ch3 2h 459.54 ch3 Hr〇rrc〇2H 489.56 pv ch3 och3 Hr〇rrc〇2H 487.59 ch3 Nr〇rxc〇2H 469.24 Qv ch3 och3 489.56 Qv ch3 och3 TXJ^c〇2H 489.56 pv ch3 och3 xxx. ^^^co2h 459.54 Qv ch3 483.26 ch3 〇ch3Hill 89112968.ptd Page 59 1283240 V. INSTRUCTIONS (55) |; ... : : «4 :=; |Quality Spectrum 丨m ·. · ·· w1-·';: * . .. . if;·;:: • .· * · .·!.···:!;.····· i ·. * · : - . · · · : : : · · · · 483.70 Qv Ch3 〇ch3 2h 459.54 ch3 Hr〇rrc〇2H 489.56 pv ch3 och3 Hr〇rrc〇2H 487.59 ch3 Nr〇rxc〇2H 469.24 Qv ch3 och3 489.56 Qv ch3 och3 TXJ^c〇2H 489.56 pv ch3 och3 xxx. ^^^co2h 459.54 Qv ch3 483.26 ch3 〇ch3

Hi· 89112968.ptd 第 60 頁 1283240 五、發明說明（56) ..表4 · · 1;質量光譜: W- 441.23 ch3 och3 503.59 pv ch3 och3 0^"C〇2H 477.53 Qv ch3 \^P〇^^C〇2H 507.55 Pv ch3 π och3 \^P〇^^c〇2H 521.58 pv ch3 och3 Yxx^c〇2H pv ch3 〇ch3 Hf|j八C〇2H Qv ch3 〇ch3 h^^^co2h ch3 och3 l_l CO 2 H 441.22 Qv ch3 〇ch3Hi·89112968.ptd Page 60 1283240 V. Description of invention (56) .. Table 4 · · 1; Mass spectrum: W- 441.23 ch3 och3 503.59 pv ch3 och3 0^"C〇2H 477.53 Qv ch3 \^P〇 ^^C〇2H 507.55 Pv ch3 π och3 \^P〇^^c〇2H 521.58 pv ch3 och3 Yxx^c〇2H pv ch3 〇ch3 Hf|j八C〇2H Qv ch3 〇ch3 h^^^co2h ch3 och3 L_l CO 2 H 441.22 Qv ch3 〇ch3

HBIII 89112968.ptd 第 61 頁 1283240 五、發明說明（57)HBIII 89112968.ptd Page 61 1283240 V. INSTRUCTIONS (57)

· * 表....T 質量光譜G 轉讀‘ _ -w1- h：·. r^Q^U 1 511.47· Qv ch3 π och3 459.11 ch3 och3 ζΧ/ ch3 och3 vn^^^co2h 500.2 Qv ch3 V〇rA 530.2 ch3 och3 VcxA 516.4 a ch3 och3 V〇n& 486.2 ch3 V〇n& 544.2 Qv ch3 〇ch3 V〇ri 6 500.2 Qv ch3 VlX^0H· * Table ....T mass spectrum G read ' _ -w1- h:·. r^Q^U 1 511.47· Qv ch3 π och3 459.11 ch3 och3 ζΧ/ ch3 och3 vn^^^co2h 500.2 Qv ch3 V 〇rA 530.2 ch3 och3 VcxA 516.4 a ch3 och3 V〇n& 486.2 ch3 V〇n& 544.2 Qv ch3 〇ch3 V〇ri 6 500.2 Qv ch3 VlX^0H

TiSi 89112968.ptd - 第 62 頁 1283240 五、發明說明（58) =· .· .： ·. ^4 : ·· ·= · ·.；!·：' |質量光譜:: :…：w-、: --W1- 1 ... . Λ· ： ： . . · ··. . .. ·.: 506.2 pv ch3 〇ch3 〇 r^OH 乂 516.2 ch3 och3 ν〇τά 498.2 ςχ, ch3 xV 〇ch3 ^N^^VOH H。广 475.3 ch3 人ijT^Q^Y^OH 502.2 Qv ch3 H〇V 506.3 pv ch3 〇ch3 、飞厂τ^0Η 518.1 ςχ/ ch3 〇ch3 H〇V 、飞y 530.1 ch3 〇ch3 He// ΛΓ〇^ lllliii· 89112968.ptd 第 63 頁 1283240 五、發明說明（59)TiSi 89112968.ptd - Page 62 1283240 V. INSTRUCTIONS (58) =· .· .: ·. ^4 : ·· ·= · ·.;!·:' |Quality Spectrum:: :...:w-, : --W1- 1 ... . Λ· : : . . · ··· . . . ·.: 506.2 pv ch3 〇ch3 〇r^OH 乂516.2 ch3 och3 ν〇τά 498.2 ςχ, ch3 xV 〇ch3 ^ N^^VOH H. Wide 475.3 ch3 person ijT^Q^Y^OH 502.2 Qv ch3 H〇V 506.3 pv ch3 〇ch3, flying factory τ^0Η 518.1 ςχ/ ch3 〇ch3 H〇V, flying y 530.1 ch3 〇ch3 He// ΛΓ〇^ Llllij· 89112968.ptd Page 63 1283240 V. Description of invention (59)

表4 質量光譜. (M+ +1) W' ______ •RU-Z^Q2·!^ 526 Qv Me ^ OMe Me V ^-N^N-+Me co2h 602 Me 、OMe P VN1-N^e ^ co2h 573 Me P 謂 622 Qv Me 、OMe k^N^C〇2H 646 Qy Me r〇^ 518 Qy Cl 、OMe Me vN\ On.co2h 563 Qy Br 、OMe Me \rN\ s〇 k^N^C〇2H 543 Qy Cl y 638 Qy Br Ί一 639 Qy Br P ^N^COOH 画__ 89112968.ptd 第 64 頁 1283240 五、發明說明（60)Table 4 Mass spectrum. (M+ +1) W' ______ • RU-Z^Q2·!^ 526 Qv Me ^ OMe Me V ^-N^N-+Me co2h 602 Me , OMe P VN1-N^e ^ co2h 573 Me P 622 Qv Me , OMe k^N^C〇2H 646 Qy Me r〇^ 518 Qy Cl , OMe Me vN\ On.co2h 563 Qy Br , OMe Me \rN\ s〇k^N^C〇 2H 543 Qy Cl y 638 Qy Br Ί 639 Qy Br P ^N^COOH Painting __ 89112968.ptd Page 64 1283240 V. Description of invention (60)

1 . _ ·表4 - | 質量光譜 ovr+i) W· •W!- 594 Cl 、OMe P k^Ns^COOH 593 Py Cl 、OMe k^N^COOH 513 Me > OMe Me CX.C〇2H 638 Br ^ OMe r〇 k^Nv^COOH 593 Cl ^ OMe P ' k^Jv^COOH 624 Qy Br OMe P ^N^a.〇〇2H 515 Qy Me 、OMe Me γΝ kN"VF kA^C〇2H 595 Qy Me 、OMe ° NCLco2h 615 Cl 、OMe f^N^ss/Ns ° CLco2h 514 Qy Me r o 596 Qy Me 、OMe O^N^i k^N^C〇2H1 . _ · Table 4 - | Mass Spectrum ovr+i) W· •W!- 594 Cl , OMe P k^Ns^COOH 593 Py Cl , OMe k^N^COOH 513 Me > OMe Me CX.C〇 2H 638 Br ^ OMe r〇k^Nv^COOH 593 Cl ^ OMe P ' k^Jv^COOH 624 Qy Br OMe P ^N^a.〇〇2H 515 Qy Me ,OMe Me γΝ kN"VF kA^C〇 2H 595 Qy Me , OMe ° NCLco2h 615 Cl , OMe f^N^ss/Ns ° CLco2h 514 Qy Me ro 596 Qy Me , OMe O^N^ik^N^C〇2H

HI1IIII 89112968.ptd 第 65 頁 1283240 五、發明說明（61) 1 · 表4 質量光譜| +ί) w- 丨 616 Py Cl ^ OMe νΝΊ ° N〇N.co2h 516 1 Qy Me ^ OMe KL〇— 486 Me 'XT' kYjCT^hHI1IIII 89112968.ptd Page 65 1283240 V. INSTRUCTIONS (61) 1 · Table 4 Mass Spectrum | +ί) w- 丨616 Py Cl ^ OMe νΝΊ ° N〇N.co2h 516 1 Qy Me ^ OMe KL〇— 486 Me 'XT' kYjCT^h

Hill 89112968.ptd 第 66 頁Hill 89112968.ptd Page 66

1283240 五、發明說明（62) iHil 89112968.ptd 第67頁 1283240 五、發明說明（63) ·. ：· · -t-. A ： ·- ； · 表4 |質量光譜 1·:棚 _: . · ·· ·.: :·也 ··. ·： · .·-：.·：： ..：!· .：.··： · Y . · 620.69 Pv ch3 och3 och3 633.73 ζΧ/ ch3 och3 ch3 、» och3 590.67 Qv ch3 〇ch3 och3 495.5 F 〇ch3 529.94 ςν F 〇ch3 〇 9h3 iTY^h 491.54 Pv ch3 〇ch3 525.98 ch3 och3 9H3 Γτ OH 489.56 Pv ch3 〇ch3 461.51 Qv ch3 niinii 89112968.ptd 第 68 頁 1283240 五、發明說明（64) f質量光譜. [+1). -W1-. 495.95 Qv ch3 9h3 rV^oH Cl 491.54 Qv ch3 och3 Η ιΤγ^ΟΗ CH3 461.51 ch3 0Ηβ 495.95 ch3 η ry^〇H vV〇V 6η3 ci 525.98 Qv ch3 och3 Η rVOH 0Η3 Cl 534.6 ς>ν ch3 π 〇ch3 9η3 rV^H H3crNvCH3 538.57 a F och3 9η3 γτ'οη H3(TN、CH3 504.58 Qv ch3 9η3 rr^〇H h3ctn、ch3 552.59 F 〇ch3 9h3 r^r〇H vN^-〇iy h3c^h ch3 1·! 89112968.ptd · 第 69 頁 1283240 五、發明說明（65) 1麗_ W - • .-wr- '· .:: ::: ; . V i:，：〆·_ V 523.55 ςχ, F 〇ch3 529.94 Ρν F 〇ch3 η ΓΥ^οη 490.55 Qv ch3 〇ch3 H 543.97 ςν F 〇ch3 Η ΓΥ^ΟΗ 540.01 Pv ch3 〇ch3 548.63 ch3 och3 〇 9η3 ^VSdh H3CX/NH CH3 504.58 Qv ch3 π 〇ch3 9η3 Γί〇^ 〇η3 620.07 F π 〇ch3 562.66 a ch3 och3 9η3 ιΓΥ^οη v^0iy h3Cyn-ch3 ch3 1·· 89112968.ptd 第 70 頁 1283240 五、發明說明（66) 質量光譜 W- -#2^0-// · ： ·： :? . : ··.··:· . *···_. . ; 578.63 F och3 9h3 rv^oH 506.55 Qv ch3 och3 9h3 Γτ〇η nh2 574.67 ch3 〇ch3 CH3 fV^OH 0 510.51 ςν F och3 9Ha Γτ〇η nh2 506.55 ch3 och3 9H3 Γτ 〇h νΝ^〇Λ^ ch3 nh2 505.56 Qv ch3 〇ch3 Η H3G CH3 556.41 Br xV och3 H rVOH 0H3 596.67 Pv ch3 π 〇ch3 Η2Υί 9 Γτ^°Η VN^〇rv^ CH3 532.63 Qv ch3 och3 第71頁 \\312\2d-code\90-01\89112968.ptd 1 1283240 五、發明說明（67) :: .· _ ; ，. · · . . · · * * . ·. .. . ..-.·····:·__· ..·:: 丨胃量光譜^ ,·：*·； :：· ·：: · Γ.宴::v.: .· ·*.·.: . :. ··: . ·. ： ：；·/.；；.·. · ·. ·· - . _ . - . ·μ 691.53 Br 〇ch3 〇2ΝΡη^Η ch3 541.0 ςχ, Cl och3 Η Γΐ0^ H3dbH3 νη2 Ι_ϋΙ \\312\2d-code\90-01\89112968.ptd 第 72 頁 1283240 五、發明說明（68) t 表4 |質量光譜 W- -w1- -R^-Z^Q^L1 607 Qy Me ^ OMe 、 nh2 497 fpy Cl ^ OMe h nrCOOH ' H 525 Cl 、OMe ，nr· V Me 527 Cl ^ OMe Me f^YC00H VN^"〇 T 、 nh2 542 Qy Cl ^ OMe ?H 〆 ^.COOH 498 Cl ^ OMe h nrc〇2H 543 Br ^ OMe h nrc〇2H 611 Qy Cl ^οοη 、一 Nv^〇 人J 477 Py Me 、OMe h nrCOOH X H 512 Cl π OMe Λ^Ν^〇ζ}Α〇Η 518 Me 、OMe } ^yCOOH 569 Me 飞 OMe f^N 0 々nr% \\312\2d-code\90-01\89112968.ptd 第73頁 1283240 五、發明說明（69)1283240 V. INSTRUCTIONS (62) iHil 89112968.ptd Page 67 1283240 V. INSTRUCTIONS (63) ·. :· · -t-. A : ·- ; · Table 4 | Mass Spectrum 1·: Shed _: . · ·· ·.: :············:··::..:!· .:.··: · Y . · 620.69 Pv ch3 och3 och3 633.73 ζΧ/ ch3 och3 ch3 , » och3 590.67 Qv ch3 〇ch3 och3 495.5 F 〇ch3 529.94 ςν F 〇ch3 〇9h3 iTY^h 491.54 Pv ch3 〇ch3 525.98 ch3 och3 9H3 Γτ OH 489.56 Pv ch3 〇ch3 461.51 Qv ch3 niinii 89112968.ptd Page 68 1283240 Five , invention description (64) f mass spectrum. [+1). -W1-. 495.95 Qv ch3 9h3 rV^oH Cl 491.54 Qv ch3 och3 Η ιΤγ^ΟΗ CH3 461.51 ch3 0Ηβ 495.95 ch3 η ry^〇H vV〇V 6η3 Ci 525.98 Qv ch3 och3 Η rVOH 0Η3 Cl 534.6 ς>ν ch3 π 〇ch3 9η3 rV^H H3crNvCH3 538.57 a F och3 9η3 γτ'οη H3(TN, CH3 504.58 Qv ch3 9η3 rr^〇H h3ctn, ch3 552.59 F 〇ch3 9h3 r^r〇H vN^-〇iy h3c^h ch3 1·! 89112968.ptd · Page 69 1283240 V. Description of invention (65) 1 Li _ W - • .- Wr- '· .:: ::: ; . V i:,:〆·_ V 523.55 ςχ, F 〇ch3 529.94 Ρν F 〇ch3 η ΓΥ^οη 490.55 Qv ch3 〇ch3 H 543.97 ςν F 〇ch3 Η ΓΥ^ ΟΗ 540.01 Pv ch3 〇ch3 548.63 ch3 och3 〇9η3 ^VSdh H3CX/NH CH3 504.58 Qv ch3 π 〇ch3 9η3 Γί〇^ 〇η3 620.07 F π 〇ch3 562.66 a ch3 och3 9η3 ιΓΥ^οη v^0iy h3Cyn-ch3 ch3 1 · · 89112968.ptd Page 70 1283240 V. INSTRUCTIONS (66) Mass spectrum W- -#2^0-// · : ·: :? . : ·····:· . *···_. 578.63 F och3 9h3 rv^oH 506.55 Qv ch3 och3 9h3 Γτ〇η nh2 574.67 ch3 〇ch3 CH3 fV^OH 0 510.51 ςν F och3 9Ha Γτ〇η nh2 506.55 ch3 och3 9H3 Γτ 〇h νΝ^〇Λ^ ch3 nh2 505.56 Qv ch3 〇ch3 Η H3G CH3 556.41 Br xV och3 H rVOH 0H3 596.67 Pv ch3 π 〇ch3 Η2Υί 9 Γτ^°Η VN^〇rv^ CH3 532.63 Qv ch3 och3 Page 71\\312\2d-code\90- 01\89112968.ptd 1 1283240 V. INSTRUCTIONS (67) :: .. _ ; , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .·:: 丨 gastric mass spectrum ^ ,·:*·; :: · ·:: · Γ.宴::v.: .··*.·.: . :. ··: . ·. : :;··.;;.·. · ·. ·· - . - μ 691.53 Br 〇ch3 〇2ΝΡη^Η ch3 541.0 ςχ, Cl och3 Η Γΐ0^ H3dbH3 νη2 Ι_ϋΙ \\312\2d-code\90-01\89112968.ptd Page 72 1283240 V. Description of invention (68) t Table 4 | Mass spectrum W- -w1- -R^-Z^Q^L1 607 Qy Me ^ OMe , nh2 497 fpy Cl ^ OMe h nrCOOH ' H 525 Cl , OMe , nr · V Me 527 Cl ^ OMe Me f^YC00H VN^"〇T , nh2 542 Qy Cl ^ OMe ?H 〆^.COOH 498 Cl ^ OMe h nrc〇2H 543 Br ^ OMe h nrc〇2H 611 Qy Cl ^οοη , a Nv^〇人J 477 Py Me , OMe h nrCOOH XH 512 Cl π OMe Λ ^Ν^〇ζ}Α〇Η 518 Me , OMe } ^yCOOH 569 Me Fly OMe f^N 0 々nr% \\312\2d-code\90- 01\89112968.ptd Page 73 1283240 V. Description of invention (69)

1 表4 | 質量光譜 W-. ..-w1· · 569 Me 、OMe 592 Me Λ°γ/〇π 591 Py Me 、OMe 〇-> ^COOH 569 Py Cl 、OMe ^YCOOH 538 Cl 、OMe } ^COOH 乂 N 一 583 Qy Br } ^γ〇ΟΟΗ 561 Cl ^ OMe r^ci ^ycooh 549 Qy Me ^ OMe ^γΟΟΟΗ 604 Qy Me -nCn_ni ^cooh 589 Py C! 、OMe 506 Me 、OMe 1 fY^OH 111111 \\312\2d-code\90-01\89112968.ptd 第74頁 1283240 五、發明說明（70) 1 表4 1 : I t質量光譜I (M* +1) W-. • w1- •RU*Z3-Q2-Li 607 Me 、OMe ^yCOOH 589 Qy Me ^ OMe CN、 ^rCOOH 575 Me 、OMe CN、 ^yCOOH 619 Me 、OMe °^W〇r— 601 Py Me >^0jCtcooh 603 Qy Me CN、 nrCOOH 617 Qv Me t OMe Q ^ rvCOOH 625 Me 、OMe 〇 ^YCOOH 611 Qy Me 、OMe Q 尸' rrCOOH 522 Qy Me 、OMe HO--^ ^yCOOH 565 Py Me 、OMe MeQ 〇 593 Qy Me 、OMe ^γΟΟΟΗ \\312\2d-code\90-01\89112968.ptd 第75頁 III·! 1283240 五、發明說明（71) 表4 質量光譜 (Μ^+ί) W· -w1. 518 Py Me 、OMe γ rrc〇2H 538 Cl 、OMe Y rrc〇2H 627 Cl 、OMe ^YCOOH 585 Py Cl 、OMe MeO. 〇 尸、fV^OH 624 Cl ^v^COOH -L^NvX^q^^' 609 Qy Cl CN_V1 j^yCOOH 639 Py Cl 623 Qy Cl 、OMe 637 Py Cl π OMe Q 尸、i rrCOOH 595 Py Cl 飞 OMe CN-^, ^yCOOH 621 Cl 645 Cl 、OMe 〇Λ 581 Cl 、OMe K、 ^γΟΟΟΗ __麗_1 \\312\2d-code\90-01\89112968.ptd 第76頁 1283240 五、發明說明（72)1 Table 4 | Mass spectrum W-. ..-w1· · 569 Me , OMe 592 Me Λ°γ/〇π 591 Py Me , OMe 〇-> ^COOH 569 Py Cl , OMe ^YCOOH 538 Cl , OMe } ^COOH 乂N 583 Qy Br } ^γ〇ΟΟΗ 561 Cl ^ OMe r^ci ^ycooh 549 Qy Me ^ OMe ^γΟΟΟΗ 604 Qy Me -nCn_ni ^cooh 589 Py C! , OMe 506 Me , OMe 1 fY^OH 111111 \\312\2d-code\90-01\89112968.ptd Page 74 1283240 V. INSTRUCTIONS (70) 1 Table 4 1 : I t mass spectrum I (M* +1) W-. • w1- • RU*Z3-Q2-Li 607 Me, OMe ^yCOOH 589 Qy Me ^ OMe CN, ^rCOOH 575 Me, OMe CN, ^yCOOH 619 Me, OMe °^W〇r— 601 Py Me >^0jCtcooh 603 Qy Me CN, nrCOOH 617 Qv Me t OMe Q ^ rvCOOH 625 Me , OMe 〇 ^ YCOOH 611 Qy Me , OMe Q corpse ' rrCOOH 522 Qy Me , OMe HO--^ ^ yCOOH 565 Py Me , OMe MeQ 〇 593 Qy Me , OMe ^γΟΟΟΗ \\312\2d-code\90-01\89112968.ptd Page 75 III·! 1283240 V. Description of invention (71) Table 4 Mass spectrum (Μ^+ί) W· -w1. 518 Py Me, OMe γ rrc〇2H 538 Cl , OMe Y rrc〇2H 627 Cl , OMe ^YCOOH 585 Py Cl, OMe MeO. 〇 、, fV^OH 624 Cl ^v^COOH -L^NvX^q^^' 609 Qy Cl CN_V1 j^yCOOH 639 Py Cl 623 Qy Cl , OMe 637 Py Cl π OMe Q corpse, i rrCOOH 595 Py Cl Fly OMe CN-^, ^yCOOH 621 Cl 645 Cl , OMe 〇Λ 581 Cl , OMe K, ^γΟΟΟΗ __丽_1 \\312\2d-code\90-01\89112968.ptd Page 1283240 V. Description of invention (72)

\ 表4 質量光譜 f (MV+1) W- -R^.Z^Q^L1 637 Me MeO^v Me〇"^〇XT 611 Me ί OMe ^yCOOH 631 Cl 、OMe pTCn-Nj ^yCOOH 488 Qy Me 'XT、 ^ ^.COOH 504 Oy rr\ } ^γ〇ΟΟΗ 522 py F 、OMe } j^COOH 640 Br 、OMe CN-> ^COOH 676 Qy Br 、OMe FfX2^ ^γ^ΟΟΗ 548 Qy Me 、OMe 1 fl0H \ H人 613 Br 、OMe 1 fl0H 666 Py Br 、OMe N—s. ^^.COOH ^^0〇r 614 Py Br 、OMe N-^ ^γ〇〇〇Η 第77頁 \\312\2d-code\90-01\89112968.ptd 1283240 五、發明說明（73)\ Table 4 Mass spectrum f (MV+1) W- -R^.Z^Q^L1 637 Me MeO^v Me〇"^〇XT 611 Me ί OMe ^yCOOH 631 Cl ,OMe pTCn-Nj ^yCOOH 488 Qy Me 'XT, ^ ^.COOH 504 Oy rr\ } ^γ〇ΟΟΗ 522 py F , OMe } j^COOH 640 Br , OMe CN-> ^COOH 676 Qy Br , OMe FfX2^ ^γ^ΟΟΗ 548 Qy Me, OMe 1 fl0H \ H person 613 Br, OMe 1 fl0H 666 Py Br, OMe N-s. ^^.COOH ^^0〇r 614 Py Br , OMe N-^ ^γ〇〇〇Η Page 77\ \312\2d-code\90-01\89112968.ptd 1283240 V. Description of invention (73)

表4 質量光譜 W- -w1* υ3-(22-!/ 626 Qy Br 、OMe A HN O ΊοΧ/οη 630 Ο1/ Br 、OMe MeQ O 676 Br Q 尸-^ fyCOOH 506 Qv Me } ^γΟΟΟΗ 526 Qy Cl } ^γΟΟΟΗ ^^0K) 502 Py Me / } ^yCOOH 514 Me 飞 OMe 484 Me 'XT、 579 Br 、OMe KLo^H 585 Br 、OMe ^ ^yCOOH 512 Me 、OMe ^ ^yCOOH 482 Me 'XT、 / ^COOH 第78頁 \\312\2d-code\90-01\89112968.ptd 1283240 五、發明說明（74) ; •表4 | 質量光譜 (MH1) W爾 -w1- -R^-Z^Q^L1 532 Qy Cl 、OMe } ^γ〇ΟΟΗ 560 Me ^ OMe CP ^yCOOH ^^〇KJ 625 Br / 、OMe ^γΟΟΟΗ 583 Br 、OMe Y ^COOH ^N^〇KJ 568 Py Me 、OMe ^γΟΟΟΗ 534 Py Me OMe 574 Py Cl 、OMe Cp ^ryCOOH 536 Cl ^ OMe ^ ^COOH 乂 N/〇^J 581 Br 、OMe ^ ^γ〇Χ)Η 522 Me } ^yCOOH 520 Me ^ ^yCOOH 乂N 一 第79頁 \\312\2d-code\90-01\89112968.ptd 1283240 五、發明說明（75) 本發明之原理亦涵莒右 — 及其代表為化學式1之化合物予，^ JR,:R8内的藥物前體， 或R1G或R19為低碳烷氧羰基。八 或R為低碳燒氧基， 本發明之原理亦提供— 動物體内在“纠受體部位二=二著成，之尤严係在哺乳 ’ ί:此方法包括投給有效量之以化學式7?黏著之 合物。此處所使用之抑制細胞 =式1表不之化 及預防與由VLA_4所促成 /，耆係思指匕括抑制、壓抑 但不限於，發炎及Λ胞1胞黏著相關的症狀，其包括 應。 …田胞黏著相關的免疫或自體免疫反 因此 之細胞 種治療 物。此 應、糖 腸疾病 哺乳動 本發 抑制劑 劑量形 藥〇 ，本發 黏著相 之哺乳 種症狀 尿病、 、移植 物亦意 明之化 結合給 式給藥 明之原理亦提供一種治療與由VLA-4所促成 關之症狀的方法，其中該方法包括對需要此 動物投給有效量之以化學式I表示之化合 匕括例如但不限於，發炎及自體免疫反 哮喘、關節炎、牛皮癖、多發性硬化、炎性 排斥、及腫瘤轉移。此處所使用之「治療」 指包括預防。 合物可以單一療法給藥，或與抗發炎或免疫 藥。此種結合療法可包括將各種藥品以單一 ’或以多重劑量形式在同時間或不同時間給 可使用任何適當的給藥途徑於提供病患有效量的本發明 之化合物。適當的給藥途徑可包括，例如，口服、直腸、 鼻、含劑、非經腸道（諸如，靜脈内、鞘内、皮下、肌Table 4 Mass spectrum W- -w1* υ3-(22-!/ 626 Qy Br, OMe A HN O ΊοΧ/οη 630 Ο1/ Br, OMe MeQ O 676 Br Q corpse-^ fyCOOH 506 Qv Me } ^γΟΟΟΗ 526 Qy Cl } ^γΟΟΟΗ ^^0K) 502 Py Me / } ^yCOOH 514 Me Fly OMe 484 Me 'XT, 579 Br , OMe KLo^H 585 Br , OMe ^ ^yCOOH 512 Me , OMe ^ ^yCOOH 482 Me 'XT, / ^COOH Page 78 \\312\2d-code\90-01\89112968.ptd 1283240 V. Description of invention (74); • Table 4 | Mass spectrum (MH1) W-w1- -R^-Z^ Q^L1 532 Qy Cl , OMe } ^γ〇ΟΟΗ 560 Me ^ OMe CP ^yCOOH ^^〇KJ 625 Br / , OMe ^γΟΟΟΗ 583 Br , OMe Y ^COOH ^N^〇KJ 568 Py Me , OMe ^γΟΟΟΗ 534 Py Me OMe 574 Py Cl , OMe Cp ^ ryCOOH 536 Cl ^ OMe ^ ^COOH 乂N/〇^J 581 Br , OMe ^ ^γ〇Χ)Η 522 Me } ^yCOOH 520 Me ^ ^yCOOH 乂N 一79 pages \\312\2d-code\90-01\89112968.ptd 1283240 V. INSTRUCTIONS (75) The principle of the invention also encompasses the right--and its representative compound of the chemical formula 1, ^ JR, R8 The prodrug, or R1G or R19, is a lower alkoxycarbonyl group. Eight or R is a low-carbon alkoxy group, and the principles of the present invention are also provided - in the body of the animal, "the second part of the receptor is replaced by two, which is particularly strict in breastfeeding". ί: This method involves administering an effective amount of chemical formula. 7? Adhesive compound. The inhibitory cells used here = Formula 1 shows that the inhibition and prevention are caused by VLA_4, and the inhibition is suppressed, suppressed, but not limited to, inflammation and cell adhesion. Symptoms, including: should be ... field cell adhesion-related immune or autoimmune anti-cell therapy, this should be, sugar and intestinal disease, lactation, hair growth inhibitor, dose-shaped drug sputum, this hair adhesion phase of the mammal Symptoms of urinary tract disease, grafts, and the principle of administration of a given drug also provide a method of treating the symptoms associated with VLA-4, wherein the method comprises administering an effective amount of the chemical to the animal in need thereof. Compounds represented by I include, but are not limited to, inflammatory and autoimmune anti-asthma, arthritis, psoriasis, multiple sclerosis, inflammatory rejection, and tumor metastasis. As used herein, "treatment" is meant to include prevention. The compound can be administered as a monotherapy or with an anti-inflammatory or immunological drug. Such combination therapies can include providing a therapeutically effective amount of a compound of the invention in a single' or multiple doses at the same time or at different times, using any suitable route of administration. Suitable routes of administration may include, for example, oral, rectal, nasal, buccal, parenteral (such as intravenous, intrathecal, subcutaneous, intramuscular)

1283240 五、發明說明（76) 内、胸骨内、肝内、病灶内、顱内、關節内、及滑膜 内）、經皮（諸如，比方說，貼片）等等。由於其給藥的容 易度，因而口服劑量形式，諸如，片劑、錠劑、分散液、 懸浮液、溶液、膠囊、軟明膠膠囊等等，可能較佳。亦可 利用控制或緩釋及傳送裝置給藥。此等劑量形式之製備方 法係技藝中所熟知。 加入本發明之化合物的醫藥組成物除了其他的治療成份 之外，尚可包括賦形劑、藥學上可接受之載體。視給藥途 徑而定，賦形劑諸如澱粉、糖、微晶纖維素、稀釋劑、潤 滑劑、黏合劑、著色劑、矯味矯臭劑、製粒劑、崩解劑等 等，可為適當。片劑及膠囊由於其給藥的容易度，而為最 有利的口服劑量單位形式。若須要，可利用標準的水性或 非水性技術將片劑包覆。 本發明之化合物可以衍生自無機或有機驗之藥學上可接 受鹽的形式使用。適當的藥學上可接受之鹼加成鹽包括， 但不限於，銨鹽，驗金屬鹽，由铭、飼、链、鎭、鉀、納 及鋅製成的金屬鹽，由氯普魯卡因、膽鹼、N，Ν’ -二芊基 乙二胺、二環己胺、二乙醇胺、乙二胺、賴胺酸、Ν-曱基 葡萄胺、及普魯卡因製成的有機鹽，以及具有胺基酸，諸 如精胺酸、賴胺酸等等之鹽。 此外，如本發明之化合物具有鹼性基團，諸如胺基，則 本發明之化合物可以藥學上可接受之無毒性酸，包括無機 及有機酸的形式使用。此等酸包括乙酸、苯磺酸、苯甲 酸、樟腦磺酸、檸檬酸、乙磺酸、曱磺酸、反丁烯二酸、1283240 V. Description of the invention (76) internal, intrasternal, intrahepatic, intralesional, intracranial, intraarticular, and synovial), transdermal (such as, for example, patch), and the like. Oral dosage forms such as tablets, troches, dispersions, suspensions, solutions, capsules, soft gelatin capsules and the like may be preferred due to their ease of administration. It can also be administered by controlled or sustained release and delivery devices. Methods of preparing such dosage forms are well known in the art. The pharmaceutical composition to which the compound of the present invention is added may include, in addition to other therapeutic ingredients, an excipient, a pharmaceutically acceptable carrier. Depending on the route of administration, excipients such as starch, sugar, microcrystalline cellulose, diluents, lubricants, binders, colorants, flavoring agents, granulating agents, disintegrating agents and the like may be suitable. Tablets and capsules are the most advantageous oral dosage unit form due to their ease of administration. If desired, the tablets can be coated using standard aqueous or non-aqueous techniques. The compounds of the present invention can be used in the form of inorganic or organic pharmaceutically acceptable salts. Suitable pharmaceutically acceptable base addition salts include, but are not limited to, ammonium salts, metal salts, metal salts made from ing, feed, chain, bismuth, potassium, sodium and zinc, by chloroprocaine , choline, N, Ν'-dimercaptoethylenediamine, dicyclohexylamine, diethanolamine, ethylenediamine, lysine, ruthenium-mercaptoglucoine, and organic salts made from procaine, And salts having an amino acid such as arginine, lysine, and the like. Further, if the compound of the present invention has a basic group such as an amine group, the compound of the present invention can be used in the form of a pharmaceutically acceptable non-toxic acid, including inorganic and organic acids. Such acids include acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, sulfonic acid, fumaric acid,

\\312\2d-code\90-01\89112968.ptd 第81頁 1283240 五 發明說明（77) ___ 葡糖酸、胺基戊二酸、氫漠酸、氫氯酸了 酸、蘋果酸、扁桃酸、石肖酸、棕櫚酸：'順丁烯二 酸、硫酸、酒石酸、對甲笨磺酸等等。特=去，酸、琥珀 氫氯酸、順丁烯二酸、反丁烯二酸、磷酸、护=榉檬酸、 酸、及對甲苯磺酸。 H、酒石 本發明之此等化合物可形成水合物，且其亦 — 發明之詳細說明 、 π樂 簡寫及定義 以下的術語及簡寫在本揭示内容之各處 意義。 皆具有所指示的 293E HEK 細胞： :2 9 3 Ε人類胚胎腎細胞 Ac = :乙醯基 抗- ck4-PE共辆= =對抗整合素α 4次單元， 的單株抗體 藤紅蛋白共軛 抗-以-FITC共： :對抗整合素/3 1次單元， 螢光素共輕的 軛 早株抗體 ah β 1 = :整合素α5)51，纖維蜜素受體，VLA-5 αν β 3 = :整合素 αν/33，玻蜜素（vitronectin) 受體 αΛ β Ί = 1整合素α 4石7 Βη = =苄基 Boc = :第三丁氧羰基 BSA = :牛血清白蛋白 c 一 = % ~\\312\2d-code\90-01\89112968.ptd Page 81 1283240 Five inventions (77) ___ Gluconic acid, amino glutaric acid, hydrogen acid, hydrochloric acid, malic acid, almond Acid, tartaric acid, palmitic acid: 'maleic acid, sulfuric acid, tartaric acid, p-toluene sulfonic acid, and the like. Specifically, acid, amber, hydrochloric acid, maleic acid, fumaric acid, phosphoric acid, citric acid, acid, and p-toluenesulfonic acid. H. Liquor These compounds of the present invention form hydrates, and are also - detailed description of the invention, π music abbreviations and definitions The following terms and abbreviations are used throughout the disclosure. All have the indicated 293E HEK cells: : 2 9 3 Ε human embryonic kidney cells Ac = : acetylated anti- ck4-PE total = = anti-integrin α 4 subunit, conjugated ubiquitin antibody Anti-to-FITC total: : Against integrin / 3 1 unit, luciferin total light yoke early antibody ah β 1 = : integrin α5) 51, cellomycin receptor, VLA-5 αν β 3 = : integrin αν/33, vitronectin receptor αΛ β Ί = 1 integrin α 4 stone 7 Βη = = benzyl Boc = : third butoxycarbonyl BSA = : bovine serum albumin c = % ~

89112968.ptd 第82頁 128324089112968.ptd Page 82 1283240

五、發明說明（78) cDNA CH0細胞 p-CIPh CMV促進劑 m-CPBA DAST DCM DELFLA DIAD DIC DIEA MAP DMEM DMF DTPA EDC E t20 FACS Fmoc GPIIb/IIIa HEPES HMDS -中國鼠（Chinese Hamster)印巢細胞 =對氯苯基 =細胞巨大性病毒促進劑 =3-氯過氧苯甲酸 =三氟二乙胺基硫 =二氯甲烷= CH2C12 =解離增進鑭化物粉末免疫鑑定 =偶氮二羧酸二異丙酯 =二異丙氰胺 =N，N-二異丙基乙基胺 =4-N，N-二甲基胺基咄啶 =杜貝可改良伊格爾培養基（Dulbecco，sV. INSTRUCTIONS (78) cDNA CH0 cells p-CIPh CMV promoter m-CPBA DAST DCM DELFLA DIAD DIC DIEA MAP DMEM DMF DTPA EDC E t20 FACS Fmoc GPIIb/IIIa HEPES HMDS - Chinese Hamster Nesting cells = p-Chlorophenyl = cell giant virus promoter = 3-chloroperoxybenzoic acid = trifluorodiethylamine sulfide = dichloromethane = CH2C12 = dissociation promoted hydrazine powder immunoassay = diazo carboxylic acid diisopropyl Ester = diisopropyl cyanamide = N, N-diisopropylethylamine = 4-N, N-dimethylamino acridine = Dubeco modified Eagle medium (Dulbecco, s

Modified Eagles’s Medium) =N，N-二甲基甲醯胺 = 二伸乙三胺五乙酸 =1-乙基- 3- (3-二曱胺丙基）氰胺 = 乙醚 = 螢光細胞揀選 =9-苐甲氧羰基 =整合素aIIb/33，纖維蛋白原受體 =N-(2-羥乙基）六氫咄畊-N’-(2-乙磺 酸） =1，1，1，3，3，3-六曱基二碎胺烧Modified Eagles's Medium) =N,N-dimethylformamide = diethylenetriamine pentaacetic acid = 1 -ethyl-3-(3-diguanamine) cyanamide = ether = fluorescent cell sorting = 9-fluorenylmethoxycarbonyl=integrin aIIb/33, fibrinogen receptor=N-(2-hydroxyethyl)hexahydroindole-N'-(2-ethanesulfonic acid)=1,1,1, 3,3,3-hexamethylenediamine

89112968.ptd 第83頁 1283240 五、發明說明（79) -^---- HOAc = 乙酸 HOBt =1-羥基笨并三唑 人類IgGl =人類免疫球蛋白61 ICAM =細胞内黏著分子 LDV =白胺酸-天冬胺酸—纈胺酸 LFA-1 及Mac-1 =淋巴球功能相關抗原 LiHMDS - 1’ 1’ 1，3, 3, 3-六甲基二矽胺烧 Me =甲基 P~MeOPh =對甲氧笨基 nM =Φ微體積莫耳濃度 PBS =磷酸鹽緩衝鹽水 PEG = 聚乙二醇 Ph =苯基 PhOH = 紛 PyBroP 二六1礙酸漠-參-吼洛咬鱗 RPMI培養基 =羅素帕克紀念學會（Russell Park Memorial Institute)培養基 TFA =三氟乙酸 THF = 四氫咬喃 TLC =薄層層析術 TMS =三甲矽烷基 Ts =甲苯磺醯基 VCAM-1CD1D7) =血管細胞黏著分子（含有一至七個免疫 球蛋白領域）89112968.ptd Page 83 1283240 V. INSTRUCTIONS (79) -^---- HOAc = acetic acid HOBt =1-hydroxy benzotriazole human IgGl = human immunoglobulin 61 ICAM = intracellular adhesion molecule LDV = amine Acid-aspartic acid-proline sulphate LFA-1 and Mac-1 = lymphocyte function-associated antigen LiHMDS-1' 1' 1,3, 3, 3-hexamethyldiamine amide Me = methyl P~ MeOPh = p-methoxy stupid nM = Φ microvolume molar concentration PBS = phosphate buffered saline PEG = polyethylene glycol Ph = phenyl PhOH = PyBroP 260 sulphate desert - ginseng - 吼 咬 咬 RP RP RPMI medium = Russell Park Memorial Institute medium TFA = trifluoroacetic acid THF = tetrahydroanthracene TLC = thin layer chromatography TMS = trimethyl decyl Ts = toluene sulfonyl VCAM-1CD1D7) = vascular cell adhesion molecule (containing one to seven immunoglobulin fields)

89112968.ptd 第84頁 五、發明說明（80) VCAM_IgG融合=含有附加於IgG1*子之樞紐區域上方之 蛋白質 人類VCAM-1(D1D7)之一至七個免疫球蛋 白領域的VCAN IgG融合蛋白質 烧基j係思指包括直鏈或分支鏈烴基根，且其包含1 至2 0個妷原子。「低碳烷基」係指i至〗〇個碳原子之烷 基，以1至8個較佳，及！至6個更佳。此等基根之例子包括 甲基、乙基、正丙基、異丙基、正丁基、異丁基、第二 基、第三丁基、戊基、異戊基、己基、辛基等等。一 價基：烷基」係指經由自「烷基」移除氫原子而形成的二 「芳基」係指形成6至16個碳原子，以6至12個碳 佳，及6至10個碳原子更佳之芳族烴環的基根。 「伸芳基」係指經由自「芳基狡 # 價基根。 方土」移除虱原子而形成的二 二?芳芙烧气」Λ示包含連接至芳環之燒基的結構。其例子包 括·基、本乙基、4-氯苄基等等。 】于匕 「環烷基」係指3至12個碳原子，及 佳之飽和烴環基根。其例子包括環丙旯、产奴原子較 基、環己基、正端基、金剛烧基、二丁，、環戊 基」係指3至6個碳之環院基。 低碳環烧 「伸環烷基」係指經由自「環烷 的二價基根。 」移除風原子而形成 「二價C1至C20脂族烴基團」包括 伸稀基、伸炔基及其組合。其例申说基、伸環烷基、 匕括伸乙基、伸丙基、 1283240 五、發明說明（81) 伸丙炔基、伸2, 4—庚二烯基等等。 「雜環基」具有1至6個碳原子，以3至6個碳原子較佳， 及1至4個選自〇、N及3之雜原子的環基根。其例子包括： 比各基 比°定基、17比唾基、三嗤基、。密n定基、塔η井基 二今唑基、噻唑基、咪唑基、吲哚基、嘍嗯基、呋 玉辰氮丙烧基、四α企其 9 Μ M. Q 土 四嗤基、2-吼咯啉基、3-。比咯啉基、咄哈〇定 ‘五圜基、咪唑啉基、哞唑啶基、咄唑啉基 異S嗅基、異嗔唾基、1，2, 3- vg二唾基t j 1，3, 4 -噻二唾基、2H -哌喃基、4H —哌喃基、 1，4 -二噻嗯基、嗎福啉基、硫嗎福啉基、咄 基、1，3 -二 、咄唑咬基 2，3 -三σ坐基 六氫吼啶基 L嘴基、1，2, 5-三噻嗯基、苯 喳啉基等等。 雜環基」移除氫原子而形成 畊基、六氫°比嘴基、1，3,5- 并（b)硫苯基、笨并咪唑基 「伸雜環基」係指經由自 的基根。 「雜芳基」係指具#1至12個碳原子 佳，及1 $ 4徊、西A A ·" 土 0 1回奴原子較 至4個選自〇、N及S之雜原子的芳族環美 子句括：啐4 I ^々妖味丞根。其例 ’、土、〇比σ定基、σ弓丨噪基、°塞嗯美、键1 基、噻唑基、呋 „、，丄， 丞Μ基、本开哌喃 太~ 基、本开咪唑基、喳啉基、昱喳啉芙、 喑嗜琳基，基…井基、四唾 等：琳基 「伸雜芳基」係指經由自「雜婪A你&寺4。 的二價基根。 、土」移除氫原子而形成 「烷氧基」係指直鏈、分支鍵或 ^,20 ^ , ；8^；^ ^/； 接點的氧原子。適當的炫氧基包括甲氧基/乙氧基在正連丙89112968.ptd Page 84 V. INSTRUCTIONS (80) VCAM IgG fusion = VCAN IgG fusion protein base containing one of the proteins human VCAM-1 (D1D7) attached to the IgG1* sub-domain to seven immunoglobulin domains The j-system is intended to include a linear or branched hydrocarbon radical and which contains from 1 to 20 germanium atoms. "Lower alkyl" means an alkyl group of from 1 to 8 carbon atoms, preferably from 1 to 8, and! To 6 is better. Examples of such bases include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, second, t-butyl, pentyl, isopentyl, hexyl, octyl, etc. Wait. Monovalent group: alkyl" means that two "aryl" groups formed by the removal of a hydrogen atom from an "alkyl group" means 6 to 16 carbon atoms, preferably 6 to 12 carbons, and 6 to 10 The base of the aromatic hydrocarbon ring having a better carbon atom. "Stretching aryl" means a structure formed by removing a ruthenium atom from "aryl 狡 基 。 。 方 方 」 」 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 Examples thereof include a group, a ethyl group, a 4-chlorobenzyl group and the like. 】 "Cycloalkyl" means 3 to 12 carbon atoms, and preferably a saturated hydrocarbon ring root. Examples thereof include cyclopropene, alkaloid atom, cyclohexyl, n-terminal, adamantyl, dibutyl, and cyclopentyl which means a ring of 3 to 6 carbons. The low carbon ring-burning "cycloalkylene" refers to the removal of a wind atom from a "cycloalkane of a cycloalkane" to form a "divalent C1 to C20 aliphatic hydrocarbon group" including a dilute base, an alkyne group and Its combination. Examples thereof include a base group, a cycloalkyl group, an exoethyl group, a propyl group, 1283240, a description of the invention (81) a propynyl group, a 2,4-heptadienyl group, and the like. The "heterocyclic group" has 1 to 6 carbon atoms, preferably 3 to 6 carbon atoms, and 1 to 4 ring bases selected from hetero atoms of ruthenium, N and 3. Examples include: a specific base ratio, a 17-salt base, a tris-yl group, and a ratio.密定定基,塔η井基二今佐zolyl, thiazolyl, imidazolyl, anthracenyl, fluorenyl, furazan aziridine, four alpha qi 9 Μ M. Q soil tetradecyl, 2 - oxalyl group, 3-.比 啉 啉 咄, 咄 〇 ' ' 圜 圜 圜 圜 圜 圜 圜 圜 圜 圜 圜 圜 圜 圜 圜 圜 圜 圜 圜 圜 圜 圜 圜 圜 圜 圜 圜 圜 圜 圜 圜 圜 圜 圜 圜 圜 圜 圜 圜 圜 圜3,4-thiadiazolidinyl, 2H-piperidyl, 4H-piperidyl, 1,4-dithienyl, morpholinyl, thiophyllinyl, fluorenyl, 1,3-di, The carbazole bites a 2,3-tris-s-succinyl hexahydroacridinyl group, a 1,2,5-trithenyl group, a benzoinyl group, and the like. a heterocyclic group removes a hydrogen atom to form a terrarium group, a hexahydropyranyl group, a 1,3,5- and (b) thiophenyl group, a benzoyl imidazolyl group, and a heterocyclic group. root. "Heteroaryl" means a good one with #1 to 12 carbon atoms, and 1 $4徊, West AA ·" Earth 0 1 slave atom to 4 hetero atoms selected from 〇, N and S The family ring beauty sentence includes: 啐 4 I ^ 々 丞 丞 。 root. Examples thereof, soil, 〇 ratio σ base, σ bow 丨 noise base, ° 塞美, bond 1 base, thiazolyl, furyl, hydrazine, sulfhydryl, carbamide, benzyl, benzyl Base, porphyrin group, porphyrin, 喑 琳 ,, base... well base, four saliva, etc.: Linji "extended aryl" refers to the divalent through the "Chowder A You & Temple 4." "Alkoxy" refers to a straight chain, a branching bond or a ^,20 ^ , ;8^;^ ^/; oxygen atom of a junction. Suitable methoxy groups include methoxy/ethoxy groups in the continuous

麵IFace I

89112968.ptd 第86頁 1283240 五、發明說明（82) —— 一 異丙：基：正丁氧基、異丁氧基、第二丁氧基、第 氣基、ί衣丙氧基、環己氧基等等。Γ低碳烷氧基」係 才曰具有1至6個碳原子之烷氧基。 根。?基t ^指包含至少一個雙鍵之未經取代的無環煙基 乂 低碳烯基」係指含有2至丨〇個碳原子，以2至8個碳 ,p杈佳，及2至6個碳原子更佳之此種基根。適當烯基美 =之例子包括丙烯基、丁烯—卜基、異丁烯基、戊烯小 J烯2:甲/丁在烯―卜基、3-曱基丁烯+基、己烯-卜基、 庚烯—基、辛烯-1-基等等。 價基：烯基」係指經由自「烯基」移除氫原子而形成的二 快基」係指包含至少 根。其例子包括乙炔基、 伸快基」係指經由自 價基根。 一個參鍵之未經取代的無環烴義 丙炔基等等。 二土 「炔基」移除氫原子而形成的二 經取代烧基」係指其中至少一個連接至脂族碳之 子經取代基諸如烷基、胺基、烷氧基、羥基、芳美、^原 基、羧基、烧氧幾基，胺基、烧氧基、氰烧 基、烷硫基、烷亞磺醯基、烷磺醯基、芳硫基、羧烷其几 烷氧羰烷基、函烷基、醯胺基、二烷胺基、環胺基、=、 子及硝基取代之直鏈或分支鏈烷基。 &原 氣 氰 烷 「經取代伸烧基」係指其中至少一個連接至脂族碳 原子經取代基諸如烷基、胺基、烷氧基、輕基、芳基、 基、羧基、烷氧羰基、單烷胺基、烷氧基、氰烷基、枣89112968.ptd Page 86 1283240 V. INSTRUCTIONS (82) —— Isopropene: group: n-butoxy, isobutoxy, second butoxy, gas, propyl, cyclohexyl Oxyl and the like. The fluorene alkoxy group is an alkoxy group having 1 to 6 carbon atoms. root. The base t ^ refers to an unsubstituted acyclic nicotinyl group of a lower alkenyl group containing at least one double bond, which means 2 to 2 carbon atoms, 2 to 8 carbons, preferably p, and 2 to 2 A 6 carbon atom is better for such a base. Examples of suitable alkenyl groups include propenyl, butenyl-buyl, isobutenyl, pentene, and small Jene 2: methyl/butyl in the alkenyl group, 3-mercaptobutene + group, hexene-buyl group , heptene-based, octene-1-yl and the like. The valent group: alkenyl means a divalent radical formed by the removal of a hydrogen atom from an "alkenyl group" and means at least one radical. Examples thereof include an ethynyl group and a stretching group means via a self-valent base. A keyed unsubstituted acyclic alkyne-propynyl group and the like. A disubstituted alkyl group formed by removing a hydrogen atom from a "alkynyl group" means that at least one of them is bonded to an aliphatic carbon via a substituent such as an alkyl group, an amine group, an alkoxy group, a hydroxyl group, a aryl group, or a Base, carboxyl group, alkoxy group, amine group, alkoxy group, cyanomyl group, alkylthio group, alkylsulfinyl group, alkanesulfonyl group, arylthio group, carboxylic acid alkoxycarbonylalkyl group A linear or branched alkyl group substituted with an alkyl group, a decylamino group, a dialkylamino group, a cyclic amine group, a =, and a nitro group. &The original naphthenice "substituted substituted alkyl" means at least one of which is bonded to an aliphatic carbon atom via a substituent such as an alkyl group, an amine group, an alkoxy group, a light group, an aryl group, a group, a carboxyl group, an alkoxy group. Carbonyl, monoalkylamino, alkoxy, cyanoalkyl, jujube

\\312\2d-code\90-01\89112968.ptd 第87頁 1283240 五、發明說明（83) 基、烧硫基、烷亞磺醯基、烷磺醯基 烧氧戴烷基、鹵烷基、醯胺基、二烷 子及硝基取代之直鏈或分支鏈伸烷基 「經取代環烷基」係指其中至少一 氫原子經取代基諸如燒基、胺基、烧 氰基、羧基、烷氧羰基、單烷胺基、 烷基、烷硫基、烷亞磺醯基、烷磺醯 基、烧氧羰烷基、i(烷基、醯胺基、 鹵原子及硝基取代之環烷基。 「經取代伸環烷基」係指其中至少 之氫原子經取代基諸如烧基、胺基、 基、氰基、羧基、烷氧羰基、單烷胺 基、環基、烧硫基、烧亞績酸基、 羧烷基、烷氧羰烷基、齒烷基、醯胺 基、_原子及硝基取代之伸環烧基。 「經取代芳基」係指其中至少一個 子經取代基諸如烷基、胺基、烷氧基 基、羧基、烷氧羰基、單烷胺基、烷 基、烧硫基、烷亞磺醯基、烷磺醯基 烷氧羰烷基、_烷基、醯胺基、二烧 子及硝基取代之芳基。 「經取代伸芳基」係指其中至少一 原子經取代基諸如烷基、胺基、烷氧 基、羧基、烷氧羰基、單烷胺基、烷 、芳硫基、羧烷基、 胺基、環胺基、鹵原 〇 個連接至環碳原子之 氧基、羥基、芳基、 燒氧基、氰烷基、環 基、芳硫基、魏烧 二烷胺基、環胺基、 —個連接至環碳原子 烧氧基、經基、芳 基、烷氧基、氰烷 貌續酿基、芳硫基、 基、二烷胺基、環胺 連接至方族碳之氮原 、羥基、芳基、氰 氧基、氰烧基、環烷 、芳硫基、羧烷基、 胺基、環胺基、鹵原 個連接至芳族碳之氫 基、經基、芳基、氰 氧基、氰烷基、環烷\\312\2d-code\90-01\89112968.ptd Page 87 1283240 V. INSTRUCTIONS (83) Base, sulphur-based, alkylsulfinyl, alkanesulfonyloxyalkyl, halane A straight-chain or branched alkyl-substituted alkyl group substituted with a hydrazino group, a hydrazine group, a dialkyl group, and a nitro group means that at least one hydrogen atom is substituted with a substituent such as an alkyl group, an amine group, or a cyano group. Carboxyl, alkoxycarbonyl, monoalkylamino, alkyl, alkylthio, alkylsulfinyl, alkanesulfonyl, oxycarbonylalkyl, i (alkyl, decyl, halogen and nitro substituted "Substituted cycloalkylene" means at least one of the hydrogen atoms via a substituent such as an alkyl group, an amine group, a group, a cyano group, a carboxyl group, an alkoxycarbonyl group, a monoalkylamino group, a cyclic group, and a a thio group, a sulfonyl group, a carboxyalkyl group, an alkoxycarbonylalkyl group, a dentyl group, a decylamino group, a _ atom, and a nitro group-substituted exocyclic group. "Substituted aryl group" means at least one of them. Substituents such as alkyl, amine, alkoxy, carboxy, alkoxycarbonyl, monoalkylamino, alkyl, thiol, alkylsulfinyl, alkanesulfonyl alkoxycarbonyl, -alkyl, amidino, bis- and nitro substituted aryl. "Substituted aryl" means at least one of the atoms via a substituent such as alkyl, amine, alkoxy, carboxy, alkoxy a carbonyl group, a monoalkylamino group, an alkane group, an arylthio group, a carboxyalkyl group, an amine group, a cyclic amine group, a halogen atom, an oxy group bonded to a ring carbon atom, a hydroxyl group, an aryl group, an alkoxy group, a cyano group, a cyclic group, an arylthio group, a dialkylamino group, a cyclic amine group, an alkoxy group attached to a ring carbon atom, a carboxylic group, an aryl group, an alkoxy group, a cyanide group, an arylthio group, a dialkylamine group, a cyclic amine attached to a nitrogen of a cubic carbon, a hydroxyl group, an aryl group, a cyanooxy group, a cyanidyl group, a cycloalkane, an arylthio group, a carboxyalkyl group, an amine group, a cyclic amine group, a halogen Hydrogen group, trans group, aryl group, cyanooxy group, cyanoalkyl group, naphthenic ring originally attached to aromatic carbon

\\312\2d-code\90-01\89112968.ptd 第88頁 1283240 五、發明說明（84) ----- 基二烷硫基、烷亞磺醯基、烷磺醯基、芳硫基、羧烷基、 烷氧羰烷基、鹵烷基、醯胺基、二烷胺基、環胺▲二=眉 子及硝基取代之伸芳基。 京 「經取代雜芳基」或「經取代雜環基」係指其中至少一 個連接至其環之氫原子經取代基諸如烷基、胺^、烧^ ，、羥基、芳基、氰基、羧基、烷氧羰基、單烷胺=虱烷 氧基、氰烷基、環烷基、烷硫基、烷亞磺醯基、烷碏醯凡 基、芳硫基、羧烷基、烷氧羰烷基、！|烷基、醯胺基、m二 烷胺基、環胺基、鹵原子及硝基取代之雜芳基或雜^基。 「經取代伸雜芳基」或「經取代伸雜環基」係指其中至 少一個連接至其環之氫原子經取代基諸如烷基、胺^、烧 氧基、羥基、芳基、氰基、羧基、烷氧羰基、單烷胺基、 烷氧基、氰烷基、環烷基、烷硫基、烷亞磺醯基、烷磺醯 基、芳硫基、羧烷基、烷氧羰烷基、鹵烷基、醯胺基、二 烷胺基、環胺基、齒原子及硝基取代之伸雜芳基或伸雜 基。 ’ 「經取代芳烷基」係指具有一或多個取代基諸如烷基、 胺，、烷氧基、芳基、氰基、羧基、烷氧羰基、烷胺基、 烷氧基、氰烷基、烷硫基、烷磺醯基、羧烷基、烷氧羰烷 基、iS烷基、醯胺基、二烷胺基、鹵原子及硝基之芳烷 基。 「齒素」係意指包括，例如，F、c 1、Br及I。 本發明之化合物可利用在揭示於w 〇 9 5 / 3 〇 6 4 2之組合化 學中所使用的技術製傷得。此外，本發明之化合物亦可利\\312\2d-code\90-01\89112968.ptd Page 88 1283240 V. INSTRUCTIONS (84) ----- Dialkylthio, alkylsulfinyl, alkanesulfonyl, aromatic sulfur A aryl group, a carboxyalkyl group, an alkoxycarbonylalkyl group, a haloalkyl group, a decylamino group, a dialkylamino group, a cyclic amine ▲ two = a brow and a nitro group. "Substituted heteroaryl" or "substituted heterocyclic group" means that at least one of the hydrogen atoms attached to the ring thereof is substituted with a substituent such as an alkyl group, an amine group, a halogen group, a hydroxyl group, an aryl group or a cyano group. Carboxyl, alkoxycarbonyl, monoalkylamine=decaloxy, cyanoalkyl, cycloalkyl, alkylthio, alkylsulfinyl, alkynyl, arylthio, carboxyalkyl, alkoxycarbonyl alkyl,! An alkyl group, a decylamino group, a m-dialkylamino group, a cyclic amine group, a halogen atom, and a nitro-substituted heteroaryl group or a hetero group. "Substituted heteroaryl" or "substituted heterocyclic" means that at least one of the hydrogen atoms attached to the ring is substituted with a substituent such as an alkyl group, an amine group, an alkoxy group, a hydroxyl group, an aryl group or a cyano group. ,carboxy, alkoxycarbonyl, monoalkylamino, alkoxy, cyanoalkyl, cycloalkyl, alkylthio, alkylsulfinyl, alkanesulfonyl, arylthio, carboxyalkyl, alkoxycarbonyl An alkyl group, a haloalkyl group, a decylamino group, a dialkylamino group, a cyclic amine group, a tooth atom, and a nitro-substituted heteroaryl group or a hetero group. 'Substituted aralkyl" means having one or more substituents such as alkyl, amine, alkoxy, aryl, cyano, carboxy, alkoxycarbonyl, alkylamino, alkoxy, cyano An alkyl group, an alkylthio group, an alkanesulfonyl group, a carboxyalkyl group, an alkoxycarbonylalkyl group, an iS alkyl group, a decylamino group, a dialkylamino group, a halogen atom and an aralkyl group of a nitro group. "Tooth" means to include, for example, F, c 1, Br, and I. The compound of the present invention can be obtained by the technique used in the combination chemistry disclosed in w 〇 9 5 / 3 〇 6 4 2 . In addition, the compounds of the invention may also be advantageous

\\312\2d-code\90-01\89112968.ptd 第89頁 1283240 五、發明說明（85) 用通常的化學合成方法製備得。 術語「藥物前體」係指可在活體中經由代謝程序轉變成 活性藥劑之化學化合物。[參見，例如，N· B〇der&j· j.\\312\2d-code\90-01\89112968.ptd Page 89 1283240 V. INSTRUCTIONS (85) Prepared by the usual chemical synthesis method. The term "prodrug" refers to a chemical compound that can be converted into an active agent via a metabolic process in a living body. [See, for example, N·B〇der&j·j.

Kaminski ， Ann. Rep. Med. Chem· 22;303 (1987)及Η· Bundgarrd ， Adv. Drug Delivery Rev· ， 3;39 (1989)]。 可考慮在a兒明於文中之任何方法中使用本發明之化合物的 樂物别體别身’且其係在本發明之範圍内。 在本申請案之各處使用與「受保護」、「保護」及/或 「解保護」官能性相關的術語。熟悉技藝人士相當明瞭此 專術5吾’且其係在包括利用一系列試劑進行連續處理之方 法的情況中使用。在本文中，保護基係指在方法步驟中用 於掩蔽官能性，否則其將會反應，但並不希望此反應發生 之基團。保護基在該步驟防止反應，但接著可將其移除， 以使原來的官能性暴露。移除或「解保護」係於官能性會 造成干擾的一或多個反應完成後發生。因此，當在本發明 之方法中指明一序列的試劑時，熟悉技藝人士當可容易地 設想對所參與的官能性適合作為「保護基」的該等基團。 在本發明之情況中，必需被保護的官能性為胺。供該用途 用之適當基團論述於化學領域中的標準教科書中，諸如丁· W. Greene者之有機合成中之保護基（Protective Groups in Organic Synthesis)「.Tnhn Wiley & Sons，New York, 1 991 ]，將其併入本文為參考資料。特別注意標題 為「胺基之保護（Protection for the Amino Group)」的 章節（3 0 9-40 5頁）。較佳的保護基包括60(：及？111〇。。利用此Kaminski, Ann. Rep. Med. Chem. 22; 303 (1987) and Η Bundgarrd, Adv. Drug Delivery Rev., 3; 39 (1989)]. It is contemplated that the use of the compound of the present invention in any of the methods described herein is within the scope of the invention. Terms relating to the "protected", "protected" and/or "deprotected" functionality are used throughout this application. It is well known to those skilled in the art that this technique is used in the context of a method involving continuous treatment using a series of reagents. As used herein, a protecting group refers to a group that is used in a method step to mask functionality, which would otherwise react but would not be expected to occur. The protecting group prevents the reaction at this step, but can then be removed to expose the original functionality. Removal or "deprotection" occurs after one or more reactions in which the functionality causes interference. Thus, when a sequence of reagents is indicated in the methods of the present invention, those skilled in the art will readily recognize such groups as suitable for the "protecting group" of the participating functionality. In the context of the present invention, the functionality that must be protected is an amine. Suitable groups for this purpose are discussed in standard textbooks in the field of chemistry, such as Protective Groups in Organic Synthesis by T. W. Greene, "Tnhn Wiley & Sons, New York, 1 991 ], which is incorporated herein by reference. Pay particular attention to the section entitled "Protection for the Amino Group" (3 0 9-40 5 pages). Preferred protecting groups include 60 (: and ? 111 〇.

\\312\2d-code\90-01\89112968.ptd 第 90 頁 1283240 五、發明說明（86) 等基團保護及解保護之範例方法可見於Greene及…。 318 及3 27 頁。 將於其上進行說明於文中之合成的材料稱為固態擔體、 珠粒、及樹脂。此等術語包括：（a)珠粒、粒料、碟狀 物、f維、凝膠、或顆粒諸如纖維素珠粒、孔隙玻璃珠 粒、氧化矽凝膠、視需要利用二乙烯苯交聯及視需要利用 聚乙二醇接枝的聚笨乙烯珠粒、聚丙烯醯胺珠粒、乳豚 粒、視需要利用N，N’_雙-丙烯醯基乙二胺交聯之二曱基 烯醯=珠粒、經塗覆疏水性聚合物的玻璃顆粒等等，$具 有硬貝或半硬質表面之材料；及（b)可溶解擔體諸如聚乙 二醇或低分子*、非交聯的聚苯乙烯。固態擔體可具有， 且通常具有官能基’諸如胺基、經基、幾基、或函基 中胺基為最常見。 〃\\312\2d-code\90-01\89112968.ptd Page 90 1283240 V. INSTRUCTIONS (86) Example methods for group protection and deprotection can be found in Greene and... 318 and 3 27 pages. The materials on which the synthesis described herein will be referred to are referred to as solid supports, beads, and resins. These terms include: (a) beads, pellets, discs, f-dimensional, gels, or particles such as cellulose beads, porous glass beads, cerium oxide gel, cross-linking with divinylbenzene as needed And, if necessary, polyethylene glycol-grafted polystyrene beads, polypropylene amide beads, porpoise granules, and N,N'-bis-acryloylethylenediamine cross-linking di-mercapto group if necessary Alkene = beads, glass particles coated with a hydrophobic polymer, etc., $ material having a hard shell or semi-hard surface; and (b) a soluble carrier such as polyethylene glycol or low molecular weight*, non-crossing Combined polystyrene. The solid support can have, and typically has, a functional group such as an amine group, a thiol group, a aryl group, or an amine group in the functional group. 〃

Tentagel™ NH2(Rapp Po1ymere , Tubinge ^ Germany) 4 較佳的胺基官能化聚乙二醇接枝聚苯乙烯樹脂。 ht^geliS-PHB樹脂具有對經基(^基鏈結物，其可利用9 二亂乙酸的二氯甲烷溶液而裂解。技藝中熟知使固相之。 面官能化的技術。賴胺酸之連接至珠粒上的胺基（以增加、 有效α卩位的數目）及鏈結物的後續連接以及在典型缸合人 ^中的其他步驟說明在，例如，pCT申請案w〇 95/3〇64 2° 中，將其揭示内容併入本文為參考資料。在說明於w〇 9 5 / 3 0 6 4 2之口 f中’鏈結物為可以光解作用裂解的鍵結 物，但其充分說明鏈結物之使用的一般原理。 物一非-幾何異槿^TentagelTM NH2 (Rapp Po1ymere, Tubinge ^ Germany) 4 Preferred amine functionalized polyethylene glycol grafted polystyrene resin. The ht^geliS-PHB resin has a cleavage of a thiol-based chain, which can be cleaved in a methylene chloride solution of 9-disc acetic acid. It is well known in the art to make a solid phase. Surface functionalization. Lysine The attachment of amine groups to the beads (to increase the number of effective alpha sites) and subsequent linkages of the linkages and other steps in a typical cylinder is illustrated, for example, in the pCT application w〇95/3 In 〇64 2°, the disclosure is incorporated herein by reference. In the port f of the description of w〇9 5 / 3 0 6 4 2, the 'chain is a bond that can be photolyzed by cleavage, but It fully explains the general principle of the use of the chain.

1283240 五、發明說明（87) 且 說明於文中的一些化合物包含一或多個不對稱中心’二 其因此而可產生鏡像異構物、非鏡像異構物、及其他立體 異構形式’其對胺基酸可以絕對立體化學定義為（R ) 一或 (s )- ’或（D )-或（L )-。本發明係意圖包括所有此等町能的 非鏡像異構物以及其外消旋和光學上純化合物的形式。可 使用不對稱中心合成物或不對稱中心試劑，或使用習知之 技術分解而製備得旋光性（R)-&(S)_，或（]))—及（1)-異構 物。當說明於文中之化合物包含烯烴雙鍵或其他幾何不對 $中心時’除非特別指明，否則其係意圖包括（E)-及（Z)- 幾何異構物兩者。同樣意圖包括所有的互變異構形式。 出現於此之任何碳-碳雙鍵的組態僅係為方便而選取， 其並非要指示特殊的組態；因此，在文中任意描述為反式 的碳-碳雙鍵可為順式、反式，或兩者以任何比例的混合 物。 熟悉技藝人士鑑於以上之定義，當可容易明瞭在本申請 案之各處所使用的其他化學術語。術語可單獨使用或以其 任付、、且θ使用。基根之較佳及更佳的鏈長適用於所有此 組合。 、 效用 本毛月之化合物展現在V L A - 4受體作為選擇性抑制劑的 效用。在直接結合鏗定及與其他整合素受體諸如万 2CLFA-1 及Mac-1)、y53(GPIIb/IIIa&avy53)&/3l(a4 石7 \之競爭鑑定中測定試驗化合物使用試管中鑑定對a 4 石1受體的抑制濃度（IC^)和VLA-4選擇性。本發明之化合1283240 V. INSTRUCTIONS (87) and indicating that some of the compounds in the text contain one or more asymmetric centers', which in turn can produce mirror image isomers, non-image isomers, and other stereoisomeric forms. Amino acids can be defined by absolute stereochemistry as (R)- or (s)-' or (D)- or (L)-. The present invention is intended to include all such non-mirromeric isomers as well as the form of their racemic and optically pure compounds. The optically active (R)-&(S)_, or (]))- and (1)-isomers can be prepared using an asymmetric center composition or an asymmetric central reagent, or by decomposition using conventional techniques. When the compounds described herein contain an olefinic double bond or other geometrically incorrect center, unless otherwise specified, it is intended to include both (E)- and (Z)- geometric isomers. The same intention is intended to include all tautomeric forms. The configuration of any carbon-carbon double bonds appearing here is only for convenience, and it is not intended to indicate a particular configuration; therefore, any carbon-carbon double bond described as trans in the text may be cis, reverse a formula, or a mixture of the two in any ratio. Those skilled in the art will be able to readily appreciate other chemical terms used throughout the application in light of the above definitions. The term can be used alone or in any amount, and θ is used. The better and better chain length of the base is applicable to all of this combination. , Utility The compounds of this month show the utility of the V L A - 4 receptor as a selective inhibitor. Determination of test compounds in test tubes in direct binding assays and assays with other integrin receptors such as 2CLFA-1 and Mac-1), y53 (GPIIb/IIIa & avy53) &/3l (a4 Identification of inhibitory concentrations (IC^) and VLA-4 selectivity for the a 4 stone 1 receptor. Combination of the invention

Η ΜΗ Μ

第92頁 \\312\2d-code\90-01\89ll2968.ptd 1283240 五、發明說明（88) 物具有K i值< 1 // Μ。本發明之較佳化合物為具有K i值< 300 nM之化合物，< 100 nM更佳，< 50 nM又更佳，及< 12 nM最佳。 以下顯示具有Ki值< 50 nM之較佳化合物的例子。此等 例子僅係提供作為說明，本發明並不意圖受限於此。Page 92 \\312\2d-code\90-01\89ll2968.ptd 1283240 V. Description of invention (88) The object has a K i value < 1 // Μ. A preferred compound of the present invention is a compound having a K i value < 300 nM, more preferably < 100 nM, more preferably < 50 nM, and < 12 nM. An example of a preferred compound having a Ki value < 50 nM is shown below. These examples are provided by way of illustration only and the invention is not intended to be limited thereby.

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OH F 分-θ人^9^々〇分-OH F points - θ people ^ 9 ^ 々〇 points -

Me 〇Me c. H H k 汾^rr々c'H ί^ςτ^。众 _ C， 0Me Me H H iMeMe 〇Me c. H H k 汾^rr々c'H ί^ςτ^. Public _ C, 0Me Me H H iMe

化。H 9^'5^^。仏: H OMeChemical. H 9^'5^^.仏: H OMe

Br Η H 〇Me 祕5^视ex⑹ <分-Br Η H 〇Me Secret 5^视ex(6) <分分-

Cl Η H OMeCl Η H OMe

分，(>NAN^nNV〇-Q-c〇2HPoints, (>NAN^nNV〇-Q-c〇2H

Me OMe 〜u u 丄" N N Br Η H 〇MeMe OMe ~u u 丄" N N Br Η H 〇Me

caHcaH

cHp^F 巳r H H 〇MecHp^F 巳r H H 〇Me

Me H H Le kJ^CC 〇-〇-FW W F X0oH Cl Η H 〇MeMe H H Le kJ^CC 〇-〇-FW W F X0oH Cl Η H 〇Me

.C0oH.C0oH

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pAjPr^N 七。仆。。"pAjPr^N VII. servant. . "

Cl H H OMeCl H H OMe

Br H H Me ,°-〇-c〇^h liiiill \\312\2d-code\90-01\89112968.ptdBr H H Me ,°-〇-c〇^h liiiill \\312\2d-code\90-01\89112968.ptd

第102頁 1283240 五、發明說明（98)Page 102 1283240 V. Description of invention (98)

OMeOMe

Cl -Q^coohCl -Q^cooh

Cl Η H OMe 丫。〇·—Cl Η H OMe 丫. 〇·—

Br H H OMe ΗΝ· 〇Br H H OMe ΗΝ· 〇

H〇^c o .s^H〇^c o .s^

Br H H OMe JT ViiOBn h H H OMeBr H H OMe JT ViiOBn h H H OMe

Cl H H OMeCl H H OMe

-〇~c-〇~c

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Me H H OMe ν^〇Λ^ NH2Me H H OMe ν^〇Λ^ NH2

COOH 5iU0jpr nh2COOH 5iU0jpr nh2

jCT ,χ/0ΗjCT, χ/0Η

OHOH

COOHCOOH

n^nXTn^nXT

COOHCOOH

XTXT

COOHCOOH

Me H H OMe^AJT1Me H H OMe^AJT1

&CA&CA

iVOOHiVOOH

COOH £!x/c ^H^HNjp9^〇X)rCOOH £!x/c ^H^HNjp9^〇X)r

COOH PWP^N'COOH PWP^N'

XTXT

COOHCOOH

Br OMeBr OMe

COOHCOOH

Me-N N- )rrMe-N N- )rr

Me OMeMe OMe

COOH ΙΒΪ \\312\2d-code\90-01\89112968.ptd 第117頁 1283240 五、發明說明（113)COOH ΙΒΪ \\312\2d-code\90-01\89112968.ptd Page 117 1283240 V. Description of invention (113)

0 I rr^〇H g人汾、 Me H H L· ^S^COOH -〇XX Me H H iMe Me H H OMe Ό咖 Me H H OMe o) PA炉、 Me H H Le ^^COOH 八。XX s. Me H H OMe Q、 P^A^r?" Me H H Le ^ΓγΟΟΟΗ HO-^ αΐΝ^Γί- Me H H L· Me*0 Me H H OMe Me H H OMe xr^H Me H H XT"c〇iH Br H H Le xr"co" ΘΑ〆 Me H H OMe ^y-^C02H (^X^C Cl H H OMe Me H H L· ^^COOH 画_1丨 \\312\2d-code\90-01\89112968.ptd 第 118 頁 1283240 五、發明說明（114) q 又 Me H H OMe0 I rr^〇H g汾, Me H H L· ^S^COOH -〇XX Me H H iMe Me H H OMe Me Me Me H H OMe o) PA furnace, Me H H Le ^^COOH VIII. XX s. Me HH OMe Q, P^A^r?" Me HH Le ^ΓγΟΟΟΗ HO-^ αΐΝ^Γί- Me HHL· Me*0 Me HH OMe Me HH OMe xr^H Me HH XT"c〇iH Br HH Le xr"co" ΘΑ〆Me HH OMe ^y-^C02H (^X^C Cl HH OMe Me HHL· ^^COOH Painting_1丨\\312\2d-code\90-01\89112968.ptd Page 118 1283240 V. Description of invention (114) q Me HH OMe

LxrHLxrH

Lxr’MLxr’M

COOHCOOH

Me-0Me-0

Cl H H OMeCl H H OMe

j〇r^OH Λ~\ Me-N N--v λ Η ΗJ〇r^OH Λ~\ Me-N N--v λ Η Η

XTXT

COOH 0^1HNjpry、COOH 0^1HNjpry,

XrXr

COOHCOOH

frCOOHfrCOOH

XTXT

Cl Η Η OMeCl Η Η OMe

Fp>CN^ nr pi又 L H H LeFf>Cn、 fjc A亦N' Me H H OMe Ff"Cn、J^y OMeFp>CN^ nr pi and L H H LeFf>Cn, fjc A also N' Me H H OMe Ff"Cn, J^y OMe

COOHCOOH

COOHCOOH

OH 9^sahnV 1 H Λ〇OH 9^sahnV 1 H Λ〇

Me-〇 \Me-〇 \

Br OMe jCt^hBr OMe jCt^h

XTXT

COOHCOOH

PP

Me FMe F

XTXT

COOHCOOH

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\\312\2d-code\90-01\89112968.ptd 第120頁 1283240 五、發明說明（116) 試管内鑑定 使用直接結合鑑定於定量化合物之抑制活性。在此鑑定 中’將VLA-4表現細胞接種於96槽的微量滴定板 (111丨以0以41^1)1討〇上。使細胞成長2天單位融合。將不 同濃度的試驗化合物與2 nM經銪標示的VCAM—IgG融合蛋白 質一起加入。使細胞在室溫下在微量槽中培養至少3〇分 鐘。於培養後，將微量槽倒空清洗。利用時間分解螢光測 量測定經銪標示之VCAM-IgG融合蛋白質的結合量。經由 各不同濃度的試驗化合物以及不含試驗化合物的控制樣品 定量結合至板的螢光，而測定結合抑制。 7 0使用於此鑑定的VLA-4表現細胞為利用人類α 4及点工次 單το之cDNA穩定轉移感染的CH0細胞株。細胞株的構造及 =明於鑑定程序中。將含有附加於㈣分子之 人；VCAM_1(D1D7)之一至七個免疫球蛋白領域的 IgG融合蛋白質利用銪f合物作標示。融合蛋白質之 衣備及標示說明於鑑定程序中。 、\\312\2d-code\90-01\89112968.ptd Page 120 1283240 V. INSTRUCTIONS (116) In-tube identification The direct inhibitory assay was used to quantify the inhibitory activity of the compound. In this assay, VLA-4 expressing cells were seeded in 96-well microtiter plates (111 丨 at 0 to 41^1). The cells were allowed to grow for 2 days with unit fusion. Test compounds of different concentrations were added together with 2 nM of the labeled VCAM-IgG fusion protein. The cells were incubated in a microwell at room temperature for at least 3 minutes. After the cultivation, the microchannel is emptied and cleaned. The amount of binding of the labeled VCAM-IgG fusion protein by sputum was determined by time-resolved fluorescence measurement. Binding inhibition was determined by quantifying the fluorescence bound to the plate by various concentrations of test compound and control samples containing no test compound. The VLA-4 expressing cells used for this identification were CH0 cell lines stably infected with cDNAs of human α 4 and sub-single το. The structure of the cell line and = clearly in the identification procedure. An IgG fusion protein containing one of the molecules added to the (IV) molecule; one of VCAM_1 (D1D7) to seven immunoglobulin domains is labeled with a ruthenium compound. The clothing and labeling of the fusion protein are described in the identification procedure. ,

試驗化合物的細胞黏著抑制活性係經由阻斷捷卡 (jUrkat)細胞之連接至D1D7_VCAM IgG融合蛋白質而The cell adhesion inhibitory activity of the test compound is via blocking the ligation of the JUrkat cell to the D1D7_VCAM IgG fusion protein.

:株= = = =gG融合蛋…；= = = 試“ = = 素 加入。使細胞在里暗中在室、、…)> 不的捷卡細胞-同 、 在至，皿下黏者至經塗覆VCAM的槽1: strain = = = = gG fusion egg...; = = = try " = = prime addition. Make the cells in the dark, in the room, ...) > No Jieka cells - the same, in the, under the dish stick to VCAM coated slot 1

1283240 五、發明說明（117) 小時。於培養後，將板經由面向下地浸於裝有碗酸鹽緩衝 鹽水的容器中而洗滌。將槽於紙巾上吸乾。利用螢光測量 測定’而將黏著細胞定量。減小的螢光係指示細胞黏著受 試驗化合物的抑制。 檢測各試驗化合物在其他整合素受體，即冷2 ( LF A - 1及1283240 V. Description of invention (117) hours. After the cultivation, the plate was washed by immersing it face down in a container containing the citrate buffered saline. Drain the groove on the paper towel. Adhesive cells were quantified by fluorescence measurement. A reduced fluorescence indicates that cell adhesion is inhibited by the test compound. Detection of each test compound at other integrin receptors, ie cold 2 (LF A - 1 and

Mac — l) 、y5 3(GPIIb/IIIa 及 αν /53) 、/3 1( α5 /3 1)及万 7( α 4冷7)之中，對α 4冷1的特異性。LFA-1結合至The specificity of α 4 cold 1 among Mac — l) , y5 3 (GPIIb/IIIa and αν /53), /3 1 (α5 /3 1) and 10,000 (α 4 cold 7). LFA-1 binds to

IC A Μ -1 ’並促成白血球的遷移至發炎部位内。μ a c - 1結合 至§午多配位子，包括IC A Μ -1及纖維蛋白原，並於啥中性呑 嗟作用及氧自由基的產生中扮演重要的角色。在血小板表 面上的GPI Ib/I I la結合至血漿中之纖維蛋白原，並引起血 小板的凝聚作用。a v厶3結合至許多細胞外基質蛋白質， 包括玻蜜素’並促成細胞遷移及防止細胞凋零程序。α 4 召7與VLA-4共有相同的配位子（VCAM一1、MAdCAM-1、及纖 維蜜素），但其具有不同的偏好。此受體表現於淋巴樣細 胞上，並參與淋巴球的遷移至黏膜組織。IC A Μ -1 'and promotes the migration of white blood cells into the inflamed site. μ a c - 1 binds to the § no-multiple ligand, including IC A Μ -1 and fibrinogen, and plays an important role in the action of 啥 啥 呑 and oxygen free radicals. GPI Ib/I I la on the platelet surface binds to fibrinogen in plasma and causes agglomeration of platelets. a v厶3 binds to many extracellular matrix proteins, including cytosine' and contributes to cell migration and prevents cell dying. α 4 calls 7 share the same ligands as VLA-4 (VCAM-1, MAdCAM-1, and fibrin), but they have different preferences. This receptor is expressed on lymphoid cells and is involved in the migration of lymphocytes to the mucosal tissue.

m-l、Mac-l、GPIIb/IIIa& αν μ 的鑑定包括將純 $體塗覆於9 6槽的微量滴定板上。w用銪螯合物標示此 受體之特定配位子。在LFA—i及“卜工之鑑定 附加於IgG1分子之樞紐區域上方之人類VCAMq⑼^二 至五個免疫球蛋白領域的KAH IgG融合蛋白拼。 GPIIb/IIIaf αν々3之鑑定中，分別使用經銪：: 蛋白原及玻蜜素。使純化受體在槽中在經銪:不、、，. 的存在下’利用不同濃度的試驗化合物：：之配位 J增養。於培Identification of m-l, Mac-1, GPIIb/IIIa& αν μ involves the application of a pure body to a 96-well microtiter plate. w uses a chelating chelate to indicate the specific ligand of this receptor. In the identification of LFA-i and "Hugong's identification of human VCAMq(9)^ two to five immunoglobulin domains above the pivotal region of the IgG1 molecule. In the identification of GPIIb/IIIaf αν々3, respectively铕:: Proprotein and Bacillus. The purified receptor is allowed to grow in the tank in the presence of sputum: No,,,., using different concentrations of test compound:: Coordination J.

1283240 五、發明說明（118) 後’將槽倒空並清洗。利用時間分解螢光測量測定經銪標 不之配位子的結合量。α 4 /5 7之鑑定係與以上說明之 VLA-4的黏著抑制鑑定類似，並使用α 4冷7-表現細胞， RPMI-8 886。使用含有人類MAdCAMq之一及二個免疫球蛋 白領域的MAdCAM-1 igG融合蛋白質及似黏蛋白修復領域作 為α 4 /3 7之相關配位子。1283240 V. INSTRUCTIONS (118) After 'slot the tank and clean it. The amount of binding of the ligand without the sputum was determined by time-resolved fluorescence measurement. The identification of α 4 /5 7 was similar to the adhesion inhibition assay described above for VLA-4, and α 4 cold 7-expressing cells, RPMI-8 886, were used. The MAdCAM-1 igG fusion protein and the mucin-like repair domain containing one of human MAdCAMq and two immunoglobulin domains were used as α 4 /3 7 related ligands.

Eu3+-VCAM-1 IgG之結合至CH0/VLA-4細胞可測定如下。Binding of Eu3+-VCAM-1 IgG to CH0/VLA-4 cells can be determined as follows.

將4B4細胞（CHO/VLA-4細胞）以3 X 1 04 /槽分配至9 6槽微 量滴定板之各槽内。將板於37艺，5% c〇2下培養48小時， 然後以洗滌緩衝液洗滌兩次，再吸乾。將5 〇微升經鑑定緩 衝液（最終2% DMS0)稀釋之抑制劑溶液加至各槽，隨後再 加入50微升之在2 nM下之經鑑定緩衝液稀釋的Eu3+ —vcamm IgG °將板在室溫下培養至少3〇分鐘。然後將各槽以洗滌 緩衝液洗滌四次，並吸乾。將丨Q 〇微升之DELF丨A增進溶液 加至各槽’隨後使板在室溫下攪動5分鐘。接著測量各樣 品的螢光（例如，DELFIA螢光計1 234，Wallace， Inc., USA)。在此鑑定中，洗滌緩衝液包含25 _ HEPES(pH4B4 cells (CHO/VLA-4 cells) were dispensed at 3 X 1 04 /well into each well of a 96-well microtiter plate. The plates were incubated for 48 hours at 37 art, 5% c〇2, then washed twice with wash buffer and blotted dry. Add 5 〇 microliters of inhibitor solution diluted in assay buffer (final 2% DMS0) to each well, then add 50 μl of Eu3+-vcamm IgG ° diluted in 2 nM of the identified buffer. Incubate at room temperature for at least 3 minutes. The wells were then washed four times with wash buffer and blotted dry.丨Q 〇 microliters of DELF丨A enhancement solution was added to each tank. Then the plate was agitated for 5 minutes at room temperature. Fluorescence of each sample is then measured (e.g., DELFIA fluorometer 1 234, Wallace, Inc., USA). In this assay, the wash buffer contains 25 _ HEPES (pH

7· 5)、150 mM NaCl、1 mM CaCl2、1 mM MgCl2、及4 mM7· 5), 150 mM NaCl, 1 mM CaCl2, 1 mM MgCl2, and 4 mM

MnCl2;鑑定緩衝液包含25 禮 HEPES(pH 7·5)、l5〇 mMMnCl2; identification buffer containing 25 rits HEPES (pH 7.5), l5 〇 mM

NaCl、1 mM CaCl2、1 mM MgCl2、4 mM MnCl2、1% BSA、 及20 //M DTPA。 苈體内鑑定 可=活體内鑑定中將VLA —4抑制劑作進一步定性。一此 種鑑定係在老鼠（鼠科動物）模型中檢測抑制嗜伊紅白血球NaCl, 1 mM CaCl2, 1 mM MgCl2, 4 mM MnCl2, 1% BSA, and 20 //M DTPA. In vivo identification of sputum = VLA-4 inhibitors can be further characterized in in vivo identification. One such identification system detects inhibition of eosinophils in a mouse (murine) model

1283240 五、發明說明（119) 之浸潤至支氣管與肺胞灌流液内。在此鏗定中，在第〇天 將動物以癌得星（cyclophosphamide)進行治療。於第2及 1 4天，利用豬蛔蟲萃取物經腹膜内使動物免疫。七天後以 不同劑量的VLA-4抑制劑治療動物。於給藥後立即經由輸 入至氣管中而使動物接受豬蛔蟲萃取物。4 8小時後，經由 將鹽水輸入至肺内’而作為動物的支氣管與肺胞灌流液。 測定灌流液中之總細胞及嗜伊紅白血球數。 在由細蟲引起之支氣管發炎的鼠科動物模型中，其中一 ，代表性的化合物（實施例號32)以3〇毫克/公斤的口服劑 量抑制49%的嗜伊紅白血球浸潤。相對地，代表性的先前 技藝化合物-說明於W0 97/030 94中之4-(N，-2-曱基苯美 脲）笨基乙醯基-LDVP-0H -在5〇毫克/公斤之口服劑量^ 並未抑制嗜伊紅白血球浸潤（抑制百分比=—2%)。 表5顯示本發明之另一代表性化合物的抑制作用、給誠 途徑及劑量。經靜脈内（i.v·)每天兩次（在第〇及8小日I)7" I 口（P. 〇·)每天三次（在第〇、8及16小時）將試驗化合物投 給老氣。1283240 V. Infiltration of the invention (119) into the bronchial and pulmonary perfusion fluid. In this setting, animals were treated with cyclophosphamide on day 。. On days 2 and 14, the animals were immunized intraperitoneally using the swine mites extract. Animals were treated with different doses of VLA-4 inhibitor seven days later. The animals received the Ascaris suum extract after being administered to the trachea immediately after administration. After 4 hours, it was used as an animal's bronchi and lung perfusion solution by introducing saline into the lungs. The total cells in the perfusate and the number of eosinophils were determined. In a murine model of bronchial inflammation caused by fine insects, one of the representative compounds (Example No. 32) inhibited 49% of eosinophil infiltration in an oral dose of 3 mg/kg. In contrast, a representative prior art compound - described in WO 97/030 94, 4-(N,-2-mercaptobenzimide) phenyl acetoxy-LDVP-0H - at 5 mg/kg Oral doses did not inhibit eosinophil infiltration (% inhibition = -2%). Table 5 shows the inhibition, the route of administration and the dosage of another representative compound of the present invention. The test compound was administered to the old gas three times a day (at week 〇, 8 and 16 hours) intravenously (i.v.) twice a day (at week 〇 and 8 hours I) 7" I (P. 〇·).

1283240 五、發明說明（120) 實施例中之 化合物編號 劑量及次數/天 嗜伊紅白血球浸 潤的抑制百分比 79 30mg/kgx2x2 天 ι.ν. 35.9% 90 1 0mg/kgx3x2 天 p.O. 18.1% 30mg/kgx3x2 天 P.0,. 3 9.1% 50mg/kgx3x2 天 p.O. 45.9% 90 30mg/kgx2x2 天 i. v. 47.3% 3 14 50mg/kgx3x2 天 p.O. 18.9% 311 50mg/kgx3x2 天 S.C. 80.2% 3 11 50mg/kgx3x2 天 p.〇. 42.5% 33 1 L—-—----— 50mg/kgx3x2 天 s.c. 49.3% 表5 可於另一活體内鑑定中將VLA-4抑制劑作進一步定性。 其中一個例子為在老鼠體内的嗜伊紅白血球累積模型。將 5〇微克之化合物48 /80注射至公史布拉格道利（81)1^2116 Dawley )鼠的胸膜腔内。24小時後，以含〇· 2% EDTA之漢克 均衡鹽 /谷液（Hank s Balanced Salt Solution)將各腔洗 jit、兩a。測疋總細胞及嗜伊紅白血球數。經靜脈内 (i· ν·)、經口（ρ· 〇·)或經皮下（s· c·)將試驗化合物投給老 鼠，每天兩次（在第〇及8小時）。 表6顯示在此模型中之代表性化合物的抑制活性。1283240 V. INSTRUCTIONS (120) Compound number and number of times in the examples / Percentage inhibition of days eosinophilic leukocyte infiltration 79 30 mg / kg x 2 x 2 days ι. ν. 35.9% 90 1 0 mg / kg x 3 x 2 days pO 18.1% 30 mg / kg x 3 x 2 Day P.0,. 3 9.1% 50mg/kgx3x2 Day pO 45.9% 90 30mg/kgx2x2 Day iv 47.3% 3 14 50mg/kgx3x2 Day pO 18.9% 311 50mg/kgx3x2 Day SC 80.2% 3 11 50mg/kgx3x2 Day p.〇 42.5% 33 1 L—------ 50 mg/kg x 3 x 2 days sc 49.3% Table 5 VLA-4 inhibitors can be further characterized in another in vivo assay. An example of this is the accumulation model of eosinophils in mice. Five micrograms of compound 48/80 was injected into the pleural cavity of a public history Prague Dolly (81) 1^2116 Dawley rat. After 24 hours, each chamber was washed with jit and two a with Hank s Balanced Salt Solution containing 〇·2% EDTA. The total number of cells and eosinophils were measured. The test compound was administered to the rats intravenously (i·ν·), orally (ρ·〇·) or subcutaneously (s·c·) twice a day (at week 〇 and 8 hours). Table 6 shows the inhibitory activities of representative compounds in this model.

\\312\2d-code\90-01\89112968.ptd 第125頁 1283240 五、發明說明（121) 表6 實施例中之 劑量及次數/天 給藥途徑 嗜伊紅白血球浸 化合物編號 潤的抑制百分比 90 3mg/kgx2 i. v. 25.4% 1 0mg/kgx2 i. v. 46.7% 3 0mg/kgx2 i. v. 83.7% 90 5 0mg/kgx2 p.o. 5 0.5% 80 50mg/kgx2 s.c. 6 5.3% 92 50mg/kgx2 s.c. 43.1% 95 5 0mg/kgx2 s.c. 40.9% t鼠生物鑑定方法 利用適當的溶劑使化合物以丨毫克/毫升溶解或懸浮。 將化合物經口投給母的Baib/c鼠（7-9週大）。15分鐘後， 自經麻醉鼠的升腔靜脈收集血液樣本。於_2〇艽下製備及 儲存血清。使用VLA-4表現細胞及VCAM_IgG融合蛋白質經 由直接結合鑑定自稀釋血清的抑制活性測定化合物之血清 /辰度。利用此方法測得的血清濃度與利用LC/MS/MS方法測 得的濃度有相當良好的關聯性。表7顯示一些實施例之化 合物的結果。\\312\2d-code\90-01\89112968.ptd Page 125 1283240 V. INSTRUCTIONS (121) Table 6 Dose and number of times in the examples/day administration route inhibition of eosinophilic white blood cell immersion compound numbering Percentage 90 3 mg/kgx2 iv 25.4% 1 0 mg/kgx2 iv 46.7% 3 0 mg/kg x 2 iv 83.7% 90 5 0 mg/kg x 2 po 5 0.5% 80 50 mg/kg x 2 sc 6 5.3% 92 50 mg/kg x 2 sc 43.1% 95 5 0 mg/ Kgx2 sc 40.9% t murine bioassay method The compound is dissolved or suspended in mg/ml using a suitable solvent. Compounds were administered orally to the parental Baib/c mice (7-9 weeks old). After 15 minutes, blood samples were collected from the ascending vena cava of the anesthetized rats. Serum was prepared and stored at _2 〇艽. The serum/length of the compound was determined using VLA-4 expressing cells and VCAM_IgG fusion protein by direct binding to identify the inhibitory activity of the self-diluted serum. The serum concentration measured by this method has a fairly good correlation with the concentration measured by the LC/MS/MS method. Table 7 shows the results of the compounds of some of the examples.

\\312\2d-code\90-01\89ll2968.ptd 第126頁 1283240 五、發明說明（122) 表7 實施例中之 化合物編號 劑量/kg 給藥後的 時間 血淸濃度 (ng/ml) 58 50mg/kg 30分鐘 3614 68 1 0 mg/kg 15分鐘 261 78 1 0 mg/kg 15分鐘 368 79 1 0 mg/kg 15分鐘 618 80 ^ 10 mg/kg 15分鐘 693 90 10 mg/kg 15分鐘 3659 91 1 0 mg/kg 15分鐘 2523 92 10 mg/kg 1 5分鐘 2162 96 10 mg/kg 15分鐘 3514 97 10 mg/kg 1$分鐘 1733 98 10 mg/kg 15分鐘 2796 102 1 0 mg/kg 15分鐘 503 124 1 0 mg/kg 15分鐘 841 134 1 0 mg/kg 15分鐘 224 146 10 mg/kg 15分鐘 527 156 1 0 mg/kg 15分鐘 285 158 1 0 mg/kg 15分鐘 301 166 10 mg/kg 1 5分鐘 360 179 10 mg/kg 15分鐘 428 309 1 0 mg/kg 15分鐘 669 311 10 mg/kg 15分鐘 467 314 50 mg/kg 3 0分鐘 2309 3 18 50 mg/kg 3 0分鐘 2105 319 1 0 mg/kg 15分鐘’ 6 03 323 1 0 mg/kg 15分鐘 1423 liiiilll \\312\2d-code\90-01\89112968.ptd 第 127 頁 1283240 五、發明說明（123) 藥物動力評估 表8 (老鼠）、表9 (老鼠）及表1 0 (猴子）顯示本發明之一些 代表性化合物的藥物動力參數。 表8藥物動力參數（老鼠） 實施例 ^丨1之化 合物編 號 .劑量/kg A U C (n g · h / m 1) MRT (M CL (niL/miii/kg) 68 1 0mg/kg(i .v.) 15 9 5 0.2 104.5 159 5 0.2 104.5 20mg/kg(p.o.) 1307(0-6h) 1.6 637.6 ! 751(0-c〇) 4.1 476.0 90 1 0mg/kg(i. v.) 8995 0.5 18.5 3 9219 0.7 18.08 1 0mg/kg(p.o.) 2540(0-6h) 1.2 65.62 2950(0-〇〇) 2.5 56.50 80 1 0mg/kg(i. v.) 52 5 9 0.4 31.69 53 89 0.6 30.93 20mg/kg(p.o.) 2190(0-6h) 2.3 152.24 36 1 5(0-c〇) 6.5 92.2 1 藥物動力參數的簡寫如下：CL，視血漿廓清率；AUC，血 漿濃度對時間曲線下方的總面積，及濃度係利用LC/MS/MS 方法測量；MRT，平均滯留時間。\\312\2d-code\90-01\89ll2968.ptd Page 126 1283240 V. INSTRUCTIONS (122) Table 7 Compound number dose/kg in the examples Blood sputum concentration (ng/ml) after administration 58 50mg/kg 30 minutes 3614 68 1 0 mg/kg 15 minutes 261 78 1 0 mg/kg 15 minutes 368 79 1 0 mg/kg 15 minutes 618 80 ^ 10 mg/kg 15 minutes 693 90 10 mg/kg 15 minutes 3659 91 1 0 mg/kg 15 minutes 2523 92 10 mg/kg 1 5 minutes 2162 96 10 mg/kg 15 minutes 3514 97 10 mg/kg 1$ minutes 1733 98 10 mg/kg 15 minutes 2796 102 1 0 mg/kg 15 min 503 124 1 0 mg/kg 15 min 841 134 1 0 mg/kg 15 min 224 146 10 mg/kg 15 min 527 156 1 0 mg/kg 15 min 285 158 1 0 mg/kg 15 min 301 166 10 mg /kg 1 5 minutes 360 179 10 mg/kg 15 minutes 428 309 1 0 mg/kg 15 minutes 669 311 10 mg/kg 15 minutes 467 314 50 mg/kg 3 0 minutes 2309 3 18 50 mg/kg 3 0 minutes 2105 319 1 0 mg/kg 15 minutes' 6 03 323 1 0 mg/kg 15 minutes 1423 liiiilll \\312\2d-code\90-01\89112968.ptd Page 127 1283240 V. INSTRUCTIONS (123) DRESS DYNAMIC ASSESSMENT Table 8 (rats), Table 9 (rats) And Table 10 (monkey) pharmacokinetic parameters show some representative compounds of the present invention. Table 8 Pharmacokinetic parameters (rat) Example Compound number of 丨1. Dose/kg AUC (ng · h / m 1) MRT (M CL (niL/miii/kg) 68 1 0 mg/kg (i.v. 15 9 5 0.2 104.5 159 5 0.2 104.5 20mg/kg(po) 1307(0-6h) 1.6 637.6 ! 751(0-c〇) 4.1 476.0 90 1 0mg/kg(iv) 8995 0.5 18.5 3 9219 0.7 18.08 1 0mg/kg(po) 2540(0-6h) 1.2 65.62 2950(0-〇〇) 2.5 56.50 80 1 0mg/kg(iv) 52 5 9 0.4 31.69 53 89 0.6 30.93 20mg/kg(po) 2190(0- 6h) 2.3 152.24 36 1 5(0-c〇) 6.5 92.2 1 The shorthand for the pharmacokinetic parameters is as follows: CL, depending on the plasma clearance rate; AUC, the total area under the plasma concentration versus time curve, and the concentration using LC/MS/ MS method measurement; MRT, mean residence time.

\\312\2d-code\90-01\89112968.ptd 第128頁 1283240 五、發明說明（124) 力參數（老鼠） 實施例 編號 劑量/kg AUC(ngh/mi) MRT 00 CL (niL/inin/kg) 90 1 0mg/kg(i .v.) 3 19 15 0.8 5.23 33488 1.1 4.98 1 0mg/kg(p.o.) 11454(0-6h) 1.7 1 7.85 1 9968(0-〇d) 8.8 9.99 79 10mg/kg(i. v.) 52 59 0.4 31 .69 ~5389 0.6 30.93 1 0mg/kg(p.o.) 0.5 8.5 24867 (0-〇〇) 0.7 6.7 6 8 1 0mg/kg(i.v·) ^6341 0.63 26.45 Γ 6405 ~~ 卜0.67 26.20 20mg/kg(p.〇·) 1 867(〇T^^ 1.1 18 1.1 2086(0-00) 2.0 162.7 血 藥物動力參數的簡寫如下：CI ，相 毅濃度對時間曲線下方的總面 纟㈣清率，Auc:\\312\2d-code\90-01\89112968.ptd Page 128 1283240 V. INSTRUCTIONS (124) Force parameters (rat) Example number dose/kg AUC(ngh/mi) MRT 00 CL (niL/inin /kg) 90 1 0mg/kg(i .v.) 3 19 15 0.8 5.23 33488 1.1 4.98 1 0mg/kg(po) 11454(0-6h) 1.7 1 7.85 1 9968(0-〇d) 8.8 9.99 79 10mg /kg(iv) 52 59 0.4 31 .69 ~5389 0.6 30.93 1 0mg/kg(po) 0.5 8.5 24867 (0-〇〇) 0.7 6.7 6 8 1 0mg/kg(iv·) ^6341 0.63 26.45 Γ 6405 ~ ~ Bu 0.67 26.20 20mg/kg(p.〇·) 1 867(〇T^^ 1.1 18 1.1 2086(0-00) 2.0 162.7 The abbreviation of blood drug dynamic parameters is as follows: CI, the total concentration below the time curve Face 纟 (four) clearance rate, Auc:

方法測量；MRT，平均滞留時間積’及濃度係利用LC/MS/M 表1 0概述將代表性化合物及 劑量（2毫克/公斤）經靜脈内（i田諾羅（Atenojo1)以單· 度的時間過程（表1 1 )。 · V ·對猴子給藥之血清濃Method measurement; MRT, mean residence time product' and concentration using LC/MS/M Table 10 Overview of representative compounds and doses (2 mg/kg) intravenously (ienono (Atenojo1) in single degree Time course (Table 1 1) · V · Serum concentration for monkeys

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五、發明說明（125) 表1〇藥物動力參數（猴子 例號 劑量/kg AUC(ng*h/ml) C L t 〇 t (mL/min/kg) 195 2mg/kg(i.v.) 8405 4.0 (+/-)-ATENOLOL 2mg/kg(i.v.) 5020 6.7 藥物動力參數的簡寫如下：CLt()t，視血漿廓清率；AUC， 血漿濃度對時間曲線下方的總面積，及濃度係利用 LC/MS/MS方法測量。（ + /-)-ATENOLOL係抗高血壓及抗心律 失常藥劑。 表11於化合物之單次靜脈内劑量後之血清濃度的時間過糕 (猴子） 例號 劑量/kg 時間 5分鐘 3〇分鐘 1小時 2小時 4小時 8小時 195 2mg/kg (i.v·) 血清 65447 3900 2225 772 194 28 (+/-)- ATENOLOL 2mg/kg (iv.) 濃度 4057 1189 771 479 >148 h 137 濃度係利用LC/MS/MS方法測量。 VCAM-1對VLA-4表現細胞之結合鑑定 VCAM IgG融合蛋白質之製備 在此結合鑑定中使用含有結合至人類I gG 1之樞紐（Η)、 CH2及CH3區域之VCAM-1之一至七個免疫球蛋白領域（〇lD7) 的VCAM IgG融合蛋白質。 表現D1D7-VCAM IgG融合蛋白質之穩定細胞株的構逵 將以EB病毒（Epstein-Barr virus)為主，在CMV促進劑V. INSTRUCTIONS (125) Table 1 Pharmacokinetic parameters (monkey dose/kg AUC (ng*h/ml) CL t 〇t (mL/min/kg) 195 2mg/kg(iv) 8405 4.0 (+ /-)-ATENOLOL 2mg/kg(iv) 5020 6.7 Abbreviations for pharmacokinetic parameters are as follows: CLt()t, depending on plasma clearance rate; AUC, total area under plasma concentration vs. time curve, and concentration using LC/MS/ The MS method measures (+ /-)-ATENOLOL as an antihypertensive and antiarrhythmic agent. Table 11 Time of serum concentration after a single intravenous dose of the compound (monkey) Case No. / kg Time 5 minutes 3〇 min 1 hour 2 hours 4 hours 8 hours 195 2mg/kg (iv·) Serum 65447 3900 2225 772 194 28 (+/-)- ATENOLOL 2mg/kg (iv.) Concentration 4057 1189 771 479 >148 h 137 The concentration is measured by the LC/MS/MS method. The binding of VCAM-1 to VLA-4 expressing cells is identified. The preparation of VCAM IgG fusion protein uses the hub (Η), CH2 and the binding to human I gG 1 in this binding assay. VCAM IgG fusion protein from one of VCAM-1 in the CH3 region to seven immunoglobulin domains (〇1D7). Expression of D1D7-VCAM IgG fusion Stable cell lines of the protein structure will Kui EB virus (Epstein-Barr virus) mainly of the CMV promoter

\\312\2d-code\90-01\89112968.ptd 第130頁 1283240 五、發明說明（126) 之轉錄控制下之含有D1D7-VCAM IgG融合基因的游離基因 質體（episornal plasmid)轉移感染至2 93E人類胚胎腎細 胞。使用250微克/毫升潮黴素在具有1 〇%胎牛血清的DMEM 中選擇經穩定轉移感染的細胞。細胞將D1D7 VC AM I gG融 合蛋白質累積分泌至培養基直至9天。 D1D7-VCAM IgG融合蛋白質之純化 將細胞在具有1 0 %胎牛血清之D MEM中培養2天，然後更換 成CCM5培養基，並再多培養1〇天。將培養基離心，過濾， 然後利用蛋白質A瓊脂糖凝膠4(Pr〇tein A Sepharose 4) 培養隔夜。將蛋白質A瓊脂糖凝膠廣泛洗滌，及使用1 〇 〇 mM檸檬酸，pH 3，洗提結合的D1D7 VCAM IgG融合蛋白 質。 經銪標示之D 1 D7 VCAM I gG融合蛋白質之製備 使1毫克/毫升之D1D7-VCAM IgG融合蛋白質對50 mM NaHC03，0·9% NaCl，ρΗ 8.5，進行透析。將融合蛋白質 加至銪標示試劑（DELFIA標示套組，購自Wal lace， Gaithersberg. MD;目錄編號1244-302)的一個玻璃瓶 中，並在室溫下在黑暗中培養隔夜。使用瓊脂糖凝膠G 1 〇 管柱將經標示的蛋白質純化，並鑑定銪含量及蛋白質濃 度。在直至使用前將蛋白質儲存於-8 0 °C下。 表現VLA-4之細胞株（CH0/VLA-4)之構造 將經α4及1之cDNA穩定轉移感染的CH0細胞株使用於 結合鑑定中。人類α 4之基因係得自美國類型培養收集 (American Type Culture Collection)，並在哺乳動物表\\312\2d-code\90-01\89112968.ptd Page 130 1283240 V. Inventive Note (126) Transgenic control of the epigenal plasmid containing the D1D7-VCAM IgG fusion gene under transcriptional control 2 93E human embryonic kidney cells. Stably metastasized cells were selected in DMEM with 1% fetal bovine serum using 250 μg/ml hygromycin. The cells secreted the D1D7 VC AM I gG fusion protein to the medium until 9 days. Purification of D1D7-VCAM IgG fusion protein The cells were cultured in D MEM with 10% fetal bovine serum for 2 days, then replaced with CCM5 medium, and cultured for an additional 1 day. The medium was centrifuged, filtered, and then cultured overnight using Protein A Sepharose 4 (Pr〇tein A Sepharose 4). The Protein A Sepharose was extensively washed and the bound D1D7 VCAM IgG fusion protein was eluted using 1 〇 mM citric acid, pH 3. Preparation of D 1 D7 VCAM I gG fusion protein by hydrazine The D1D7-VCAM IgG fusion protein of 1 mg/ml was dialyzed against 50 mM NaHC03, 0.9% NaCl, pH 8.5. The fusion protein was added to a glass vial of a sputum labeling reagent (DELFIA label kit, available from Wall lace, Gaithersberg. MD; catalog number 1244-302) and incubated overnight at room temperature in the dark. The labeled protein was purified using an agarose gel G 1 column and the sputum content and protein concentration were identified. Store the protein at -80 °C until use. Structure of cell line expressing VLA-4 (CH0/VLA-4) A CH0 cell line stably infected with cDNA of α4 and 1 was used for binding identification. The human α 4 gene line was obtained from the American Type Culture Collection and in the Mammalian Table.

\\312\2d-code\90-01\89112968.ptd 第131頁 1283240 五、發明說明（127) 現向量 pCI - neo(Promega，Madison，wi)的 Xhol 及 Xba 位置 之間再次無性繁殖。冷1基因係利用PCr自人類的周邊白血 球cDNA放大，並經構造成將起始密碼子置於一致柯查克 (Kozak)序列的環境。將基因再次無性繁殖sCMv促進劑及 嵌合型插入序列的p C I - n e 〇下游。 利用將α4及/3 1基因編碼的質體將CH0 — K1細胞穩定地共 同轉移感染，及利用螢光細胞楝選（FACS)選擇表現VLA-4 之高階的單一細胞。使用於FACS分析中之抗體為反- α 4-PE 共軛（PharMingen，San Diego，CA)及反-/31-FITC 共 輛（Biosource ，Camari 1 1 ο ，CA)。將分別表現 α 4 及冷 1 次 單元之400, 0 00及3 00, 00 0位置/細胞的細胞株4Β4使闬於 結合鑑定中。次單元的數目係利用F ACS分析，使用量子簡 單細胞微珠（Quantium Simply Cellular microbeads) (Flow Cytometry Standards Corporation ， Puerto R i co )作為標準而測定。將細胞保存於含有1 〇%胎牛血清、 10mM HEPES pH 7.5、0.5 毫克 / 毫升 G418 之 F12 培養基 中，使用1 : 4 8程/週。 結合鑑定 將CH0/VLA-4細胞以30, 00 0細胞/槽種於96槽的微量滴 定板中，並在37 °C、5% C02下培養48小時，直至融合為 止。在鑑定當天，將槽排液，並以3 5 0微升之含有2 5mM HEPES pH 7· 5、150 mM NaGl、1 mM MgC12、1 mM CaCl2 、2 mM MnC 12的洗滌緩衝液洗滌兩次。然後使板排液並在 紙巾上吸乾，以將缓衝液移除。\\312\2d-code\90-01\89112968.ptd Page 131 1283240 V. INSTRUCTIONS (127) The current vector pCI - neo (Promega, Madison, wi) is reproducibly reproducible between the Xhol and Xba positions. The cold 1 gene line was amplified from human peripheral white blood cell cDNA using PCr and constructed to place the initiation codon in an environment consistent with the Kozak sequence. The gene was again clonally propagated downstream of the sCMv promoter and the chimeric insert of p C I - n e . CH0-K1 cells were stably co-transfected with the plastids encoding the α4 and /31 genes, and high-order single cells expressing VLA-4 were selected by fluorescence cell selection (FACS). The antibodies used in the FACS analysis were anti-α 4-PE conjugate (PharMingen, San Diego, CA) and anti-/31-FITC (Biosource, Camari 1 1 ο , CA). The cell lines 4, 4 and 4 of the 400, 0 00 and 3 00, 000 position/cells of the α 4 and cold 1 units, respectively, were identified in the binding assay. The number of subunits was determined by F ACS analysis using Quantum Simply Cellular microbeads (Flow Cytometry Standards Corporation, Puerto R i co ) as a standard. The cells were stored in F12 medium containing 1% fetal calf serum, 10 mM HEPES pH 7.5, 0.5 mg/ml G418, using 1:48 cycles/week. Binding Identification CH0/VLA-4 cells were seeded in 96-well microtiter plates at 30,00 cells/tank and incubated at 37 °C, 5% CO 2 for 48 hours until fusion. On the day of identification, the tank was drained and washed twice with 350 μl of a wash buffer containing 25 mM HEPES pH 7.5, 150 mM NaG1, 1 mM MgCl 2, 1 mM CaCl 2 , 2 mM MnC 12 . The plate is then drained and blotted dry on a paper towel to remove the buffer.

\\312\2d-code\90-01\89112968.ptd 第 132 頁 1283240 五、發明說明（128) 將試驗化合物在2 nM經銪標示之D1D7-VCAM IgG融合蛋 白質的存在下，連續稀釋於鑑定緩衝液（洗滌緩衝液以及 0.1%牛血清白蛋白、2〇 DTPA及1%二甲亞颯）中。所使 用的終濃度係自〇· 1 nM-1〇 # μ。將50微升等份的試驗化 合物混合物加至板中的兩個槽中。總結合的控制槽並未加 入任何的试驗化合物。非特異結合槽包含反—α 4單株抗體 (L25·3 ’ Becton Dickinson ， Bedfor ， ΜΑ)。\\312\2d-code\90-01\89112968.ptd Page 132 1283240 V. INSTRUCTIONS (128) The test compound was serially diluted in the presence of 2 nM of the D1D7-VCAM IgG fusion protein indicated by hydrazine. Buffer (wash buffer and 0.1% bovine serum albumin, 2 〇 DTPA and 1% dimethyl hydrazine). The final concentration used is from 1 nM-1〇 # μ. A 50 microliter aliquot of the test compound mixture was added to the two tanks in the plate. No test compound was added to the total combined control tank. The non-specific binding groove contains anti-α 4 monoclonal antibody (L25·3 'Becton Dickinson, Bedfor, ΜΑ).

使細胞與試驗化合物混合物在經銪標示之7 —A Μ I gG 合蛋白質的存在下在室溫下培養至少3 〇分鐘。然後 利用350微升之洗滌緩衝液，使用史迦重（Skatr〇n)洗板器 將細胞洗滌三次，並吸乾。將〗〇〇微升等份之DELFIA增進 溶液加至各槽’隨後在室溫下輕輕攪拌丨〇分鐘。利用時間 分解螢光測量（型式：VictorTM，Wallace Inc.，The cells are incubated with the test compound mixture for at least 3 minutes at room temperature in the presence of a sputum labeled 7-A Μ I gG protein. The cells were then washed three times with a 350 microliter wash buffer using a Skatr(R) plate washer and blotted dry. A microliter aliquot of the DELFIA booster solution was added to each well' followed by gentle agitation for a minute at room temperature. Use time to decompose fluorescence measurements (type: VictorTM, Wallace Inc.,

Gaithersberg· MD)測定經銪標示之VCAM IgG融合蛋白質 的結合量。 ' 將結合百分比計算為：[(Ft—Fns) —(F「Fns)]/(Ft—Fns) χ 1 00，其中FT及FNS分別為在不存在試驗化合物及含有反〜Q 4單株抗體下之結合至細胞之經銪標示之D1D7 —VCAM IgG融 合蛋白質的螢光信號。F!為在含有試驗化合物之槽中的螢 光。利用曲線迴歸常式，PRIZM(GraphPad s〇ftware，Gaithersberg MD) measures the amount of binding of the VCAM IgG fusion protein indicated by hydrazine. ' Calculate the percentage of binding as: [(Ft - Fns) - (F "Fns)] / (Ft - Fns) χ 1 00, where FT and FNS are in the absence of test compound and contain anti-Q 4 monoclonal antibodies The fluorescent signal of the D1D7-VCAM IgG fusion protein, which is bound to the cell by the 铕. F! is the fluorescence in the well containing the test compound. Using the curve regression routine, PRIZM (GraphPad s〇ftware,

Inc·，San Diego，CA)測定 IC5。（抑制劑抑制50% 之 VCAJUi 合至CHO/VLA-4細胞的濃度）。 VLA-4表現J田跑^黏著至vcAM-1 使用此第二功能鑑定於測定試驗化合物於抑制由VLA〜4Inc., San Diego, CA) Determination of IC5. (Inhibitor inhibits 50% of VCAJUi binding to CHO/VLA-4 cells). VLA-4 performance J field running ^ adhesion to vcAM-1 using this second function identified in the determination of test compounds in inhibition by VLA ~ 4

1283240 五、發明說明（129) 所促成之細胞黏著的效力。 鎏塗布VCAM之板的f借 將50微升等份之D1D7-VCAM IgG融合蛋白質（1 5微克/ 毫升於填酸鹽緩衝鹽水PBS中）加至96槽柯士達（c〇star)平 底板（Costar ’ Franklin Lakes，NJ，目錄編號258 〇)的各 槽。然後將板在4 C下培養隔夜。在鑑定當天，將槽排 液’並以3 5 0微升之PBS洗滌兩次。然後將板在室溫下利用 100微升之1%牛金清白蛋白（BSA，Sigma，cat# A9418)的 PBS溶液封住至少1小時。 細胞製備 自美國類型培養收集取得捷卡細胞（無性繁殖系E 6 _ 1 )， 並保存於RPMI培養基，10mM HEPES，PH 7· 5，1 mM丙酮酸 納’10% FCS中，使用1:64程/週。於進行鑑定之前立即 將捷卡細胞利用5 之秋水仙素-AM (Molecular Probe， Eugene，OR，目錄編號C 1 4 30 )於RPMI培養基中在室溫下 在黑暗中進行標示3 0分鐘。於標示後，將細胞以Rp M I培養 基洗滌兩次，並在1 X 1 〇6細胞/毫升下再懸浮。 細胞點荖鑑宗 於鑑定之前立即將BSA溶液自經塗布VCAM之板排液。然 後將板以RPMI培養基洗滌兩次。將1 00微升等份之經標示 的捷卡細胞加至各槽，隨後加入5 0微升之抑制劑溶液。最 終的抑制劑濃度係自1 nM至1 0 // Μ，且將各濃度重複測試 三次。使抑制劑及細胞在室溫下在黑暗中培養1小時。於 培養後，將板輕輕地浸入至盛裝有PBS之容器中，在PBS中1283240 V. INSTRUCTIONS (129) The effectiveness of the resulting cell adhesion.鎏 Apply a 50 μl aliquot of D1D7-VCAM IgG fusion protein (15 μg/ml in saline buffered saline PBS) to a 96-well csstar flat bottom plate (Costar) ' Franklin Lakes, NJ, catalog number 258 〇). The plates were then incubated overnight at 4 C. On the day of identification, the tank was drained' and washed twice with 305 microliters of PBS. The plates were then blocked with 100 microliters of 1% bovine albumin (BSA, Sigma, cat # A9418) in PBS for at least 1 hour at room temperature. Cell preparation Jaccar cells (clonal line E 6 _ 1 ) were collected from American type culture and stored in RPMI medium, 10 mM HEPES, pH 7.5, 1 mM sodium pyruvate '10% FCS, using 1: 64 steps / week. Immediately prior to identification, the Jaccarat cells were labeled with colchicine-AM (Molecular Probe, Eugene, OR, Cat. No. C1 4 30) in RPMI medium at room temperature for 30 minutes in the dark. After labeling, the cells were washed twice with Rp M I medium and resuspended at 1 X 1 〇 6 cells/ml. The cells were drained from the coated VCAM plate immediately prior to identification. The plates were then washed twice with RPMI medium. One hundred microliter aliquots of the labeled Jacca cells were added to each well followed by 50 microliters of inhibitor solution. The final inhibitor concentration ranged from 1 nM to 1 0 // Μ and the concentrations were repeated three times. The inhibitor and cells were incubated for 1 hour at room temperature in the dark. After culturing, the plate was gently immersed in a container containing PBS in PBS.

\\312\2d-code\90-01\89112968.ptd 第 134 頁 1283240 五、發明說明（130) 面轉向下。·將槽排液及在一層紙巾上吸乾。將5〇微升等份 之0· 1% Triton X- 100加至各槽。將板在黑暗中培養1〇分 鐘。在設於485 nM激發及53 0 nM發射下的MUlipore Cytofluor 2 300 System讀板器中將捷卡細胞的黏著定 量。利用曲線迴歸常式，PRIZM(GraphPad SQftwar^\\312\2d-code\90-01\89112968.ptd Page 134 1283240 V. INSTRUCTIONS (130) Turn down. • Drain the tank and blot it on a layer of paper towel. A 5 liter microliter aliquot of 0.1% Triton X-100 was added to each tank. The plate was incubated for 1 〇 in the dark. The adhesion of the Jaccar cells was quantified in a MUlipore Cytofluor 2 300 System plate reader set at 485 nM excitation and 53 0 nM emission. Using the curve regression routine, PRIZM (GraphPad SQftwar^

Inc. ，San Diego，CA)測定IC5Q(抑制劑抑制5〇%之捷卡細 胞黏著的濃度）。 ' 化合物1至1 8 7之合成實施例 經由以下實施例說明本發明之化合物的一般合成方法。 特定的具體例僅係呈現作為說明用，本發明並不受限於 此。熟悉技藝人士當可容易明瞭在任何給定材料或方法步 驟中的修改及變化。除非特別指示，否則在實施例中所使 用的固相擔體為Tent age Ith-S -PHB樹脂。此樹脂具有可利 用9 0 %之二IL乙酸的二氯甲烷溶液裂解之對羥基芊基鏈結 物。此樹脂之載入量係在〇· 27及〇. 30毫莫耳/克之間變" 化，且未雙倍負載。 實施例1Inc., San Diego, CA) Determination of IC5Q (inhibitor inhibits 5% of the concentration of Jacques adhesion). 'Synthesis Examples of Compounds 1 to 1 8 7 The general synthesis methods of the compounds of the present invention are illustrated by the following examples. The specific examples are merely presented for illustrative purposes, and the invention is not limited thereto. Modifications and variations in any given materials or method steps will be readily apparent to those skilled in the art. The solid phase support used in the examples was a Tent age Ith-S-PHB resin unless otherwise specified. This resin has a p-hydroxydecyl chain which can be cleaved by a solution of 90% diacetic acid in dichloromethane. The loading of this resin was changed between 〇·27 and 〇. 30 mmol/g and was not double loaded. Example 1

將500 cfe升的二頸圓底燒瓶裝入20Q毫升之thf及NaH(l. 5 克，72.9¾莫耳）。將1-乙稀基—2 -吼洛^定g同（6 g香，72 9 毫莫耳）及3-蛾苯甲酸甲醋（15.〇克，57.3毫(莫.耳^容於· THF(l〇〇毫升）之溶液於15分鐘内逐滴加至燒瓶中。於添加A 500 cfe liter two-necked round bottom flask was charged with 20 Q ml of thf and NaH (1.5 g, 72.93⁄4 mol). 1-Ethyl 2- 2 - 吼 ^ 定 同 g (6 g scent, 72 9 mmol) and 3- moth benzoic acid methyl vinegar (15. gram, 57.3 mA (Mo. Ear ^ Rong Yu· A solution of THF (10 mL) was added dropwise to the flask over 15 minutes.

1283240 五、發明說明（131) 完成後，使反應混合物迴流加熱1小時。使反應容器冷卻 至室溫，然後小心地加入6N HC1 (1 0 0毫升）。使反應於真 空中濃縮以將THF移除，然後再加入另一等份的6N H C1 ( 1 〇 〇毫升），及使反應迴流1 4小時。經由加入N a H C 03直 至pH 9而使反應停止，然後利用EtOAc將混合物萃取3次。 將結合的有機層於MgS04上乾燥，並於真空中濃縮，而得 黃色油。 然後將此油置於MeOH( 1 00毫升）中’並冷卻至-78 °C。接 著逐份加入NaBH4(3. 5克，96. 5毫莫耳），及使反應於2小 時内升溫至室溫。經由加入6N HC1直至成為酸性而使反應 停止，然後經由加入4 0 % N a 0 Η水溶液而成為驗性。利用 CH2C12將溶液萃取3次，將結合的有機層於篮2304上乾燥， 並於真空中濃縮，而得11.4克之黃色油。 然後經由將胺基置於50%二氧陸圜：H20( 1 0 0毫升）中， 並加入hCO3直至成為鹼性，而將以上的胺以Boc保護。於 此溶液中加入B 〇 c -酐（9 · 1克，4 1毫莫耳），然後使其在室 溫下攪拌14小時。經由加入IN HC1直至成為酸性而使反應 停止。將溶液利用EtOAc萃取3次，於MgS04上乾燥，並於 真空中濃縮，而得黃色黏性油。將油進行層析（25%1283240 V. INSTRUCTIONS (131) After completion, the reaction mixture was heated under reflux for 1 hour. The reaction vessel was allowed to cool to room temperature and then 6N HCl (1OmL) was carefully added. The reaction was concentrated in vacuo to remove THF, then another portion of 6N HCI (1 mL) was then charged and the reaction was refluxed for 14 hours. The reaction was stopped by the addition of NaH03 to pH 9 and then mixture was extracted three times with EtOAc. The combined organic layers were dried over MgSO4 and concentrated in vacuo to yield yellow oil. This oil was then placed in MeOH (100 mL) and cooled to -78 °C. Then, NaBH4 (3.5 g, 96.5 mmol) was added portionwise, and the reaction was allowed to warm to room temperature over 2 hours. The reaction was stopped by adding 6N HCl until it became acidic, and then it became an inspectability by adding a 40% aqueous solution of N a 0 hydrazine. The solution was extracted 3 times with CH.sub.2Cl.sub.sub.sub.sub.sub.sub. The above amine was then protected with Boc by placing the amine group in 50% dioxane:H20 (100 mL) and adding hCO3 until it became basic. To the solution was added B 〇 c-anhydride (9 · 1 g, 4 1 mmol), which was then stirred at room temperature for 14 hours. The reaction was stopped by adding IN HC1 until it became acidic. The solution was extracted 3 times with EtOAc, dried over EtOAc EtOAc EtOAc Chromatography of oil (25%

EtOAc:己烧），而得7.90克之A。EtOAc: hexanes) gave 7.90 g of A.

使氫氯酸（氣體）發泡通過15· 8克（73· 5毫莫耳）2 -漠笨乙Capturing hydrochloric acid (gas) through 15·8 g (73·5 mmol) 2 - Indifferent B

\\312\2d-code\90-01\89112968.ptd 第 136 頁 1283240 五、發明說明（132) 酸溶於1 0 0毫升甲醇之溶液1 〇分鐘。使所產生之溶液於1 〇 〇 毫升水與1 0 0毫升C Η 2 C1之間分配。將有機層於μ g s 〇4上乾 燥，及將溶劑於減壓下移除，而得1 6 · 8克（7 3 · 5毫莫耳）之 甲基-2 -溴苯乙酸酯，將其與9· 〇克（80· 8毫莫耳）之卜乙烯 基-2-吼咯啶酮及1 〇〇毫升之無水THF在氬氣下結合於25()毫 升的圓底燒瓶中。 於此燒瓶中加入3· 5克（147毫莫耳）氫化鈉（95%) -------X - - - y 汉便 溶液在室溫下攪拌1 0分鐘。加上迴流冷凝器，並使混合物 迴流加熱1小時。使溶液冷卻至室溫，及於減壓下將溶劑 移除。將30毫升水性氫氯酸及50毫升水之溶液加至所產生 之混合物中，並在沒有冷凝器的情況下迴流加熱，直至溶 液溫度達到9 6 °C為止，此時加上冷凝器，及使溶液再迴流 16小時。使溶液冷卻至室溫，利用15〇毫升之4〇%氫氧化： 的水溶液成為鹼性，以3 X 125毫升Cf^Cl2進行萃取，及將 結合的有機層以氯化鈉之飽和水溶液洗滌，於硫酸鎂上乾 燥，及將溶劑於減壓下移除而得1 5 · 〇克（6 3 · 〇毫莫耳， 8 6 %)之2 -（ 2 _漠爷基）-1 -。比嘻琳。 ' 於經冷卻至-78°C之15克（63毫莫耳）2_(2—溴节基）_丨…比 咯啉溶於80 : 20甲醇：醋酸水溶液之溶液中於丨5分鐘的 間内逐份加入5. 3克（140.0毫莫耳）硼氫化鈉。使混合物 拌1小時而升溫至室溫’此時在減壓下將溶劑移，σ i 150毫升水，及利用氫氧化鈉水溶液使溶液成鹼 其以1〇xlGG毫細仏萃取而產生乳劑1 將 以碳酸氫鈉之飽和水溶液洗滌，於硫酸 』名执層 文娱上乾燥，及將溶\\312\2d-code\90-01\89112968.ptd Page 136 1283240 V. INSTRUCTIONS (132) A solution of acid in 100 ml of methanol for 1 min. The resulting solution was partitioned between 1 〇 毫升 ml of water and 100 ml of C Η 2 C1. Drying the organic layer on μ gs 〇4, and removing the solvent under reduced pressure to give 1 6 · 8 g (7 3 · 5 mmol) of methyl-2-bromophenyl acetate. It was combined with 9· gram (80·8 mmol) of vinyl-2-pyrrolidone and 1 mL of anhydrous THF under argon in a 25 () mL round bottom flask. To the flask was added 3.5 gram (147 mmol) of sodium hydride (95%) -------X - - - y solution was stirred at room temperature for 10 minutes. A reflux condenser was added and the mixture was heated at reflux for 1 hour. The solution was allowed to cool to room temperature and the solvent was removed under reduced pressure. a solution of 30 ml of aqueous hydrochloric acid and 50 ml of water is added to the resulting mixture, and heated under reflux without a condenser until the temperature of the solution reaches 9 6 ° C, at which time a condenser is added, and The solution was refluxed for a further 16 hours. The solution was allowed to cool to room temperature, extracted with 15 ml of a 4% by weight aqueous solution of hydrogen peroxide: alkaline, extracted with 3 X 125 ml of Cf^Cl2, and the combined organic layer was washed with a saturated aqueous solution of sodium chloride. It was dried over magnesium sulfate, and the solvent was removed under reduced pressure to give 1 -5 g (6 3 · 〇m, 8 6 %) of 2 -( 2 _ _ _ _ _ _ Bi Lin. ' 15 g (63 mmol) cooled to -78 ° C 2_(2-bromo) 丨 比 比 比 咯 咯 溶于 溶于 80 80 80 80 80 80 80 80 80 80 80 80 80 80 80 80 80 80 80 80 80 80 80 80 80 丨 丨 丨 丨 丨 丨 丨5. 3 g (140.0 mmol) of sodium borohydride was added portionwise. The mixture was stirred for 1 hour and warmed to room temperature. At this time, the solvent was transferred under reduced pressure, σ i 150 ml of water, and the solution was made into a base using an aqueous sodium hydroxide solution, and the mixture was extracted with 1 〇 x GG 毫 而 而 to give an emulsion 1 It will be washed with a saturated aqueous solution of sodium bicarbonate, dried on the sulphuric acid, and dissolved.

W3l2\2d-code\90-01\89112968.ptd 第137頁 1283240 五、發明說明（133) 劑於真空中移除而得丨4· 6克（60· 8毫莫耳，97%)之苄基脯 胺酸。 於14. 6克（60· 8毫莫耳）苄基脯胺酸溶於70毫升碳酸氫鈉 飽和水溶液及70毫升二氧陸圜之溶液中加入15.1克（67.0 毫莫耳）之二碳酸-二—第三丁酯，及使混合物在室溫下攪 拌1 6小時。然後使溶液在2 〇 〇毫升氫氯酸水溶液與2 〇 〇毫升 乙酸乙酯之間分配。將乙酸乙酯層以2 〇 〇毫升之氯化鈉飽 和水溶液洗滌，於MgS04上乾燥，及將溶劑於減壓下移除 而得一殘留物，將其利用急速管柱層析（2 0 % -1 0 0 %乙酸乙 酯/己烷）純化而得11· 5克（33. 8莫耳，56%)之純的A’ 。W3l2\2d-code\90-01\89112968.ptd Page 137 1283240 V. INSTRUCTIONS (133) The agent was removed in vacuo to obtain 4.6 g (60·8 mmol, 97%) of benzyl Lysine. 14.6 g (60·8 mmol) of benzyl valine was dissolved in 70 ml of a saturated aqueous solution of sodium hydrogencarbonate and 70 ml of dioxanol solution to add 15.1 g (67.0 mmol) of dicarbonic acid - Di-tert-butyl ester, and the mixture was stirred at room temperature for 16 hours. The solution was then partitioned between 2 mL of aqueous hydrochloric acid and 2 mL of ethyl acetate. The ethyl acetate layer was washed with 2 ml of a saturated aqueous solution of sodium chloride, dried over MgSO4, and the solvent was removed under reduced pressure to give a residue which was subjected to flash column chromatography (20%) -1 0 0% ethyl acetate / hexane) was purified to give 11.5 g (33.8 m, 56%) of pure A'.

將Α(1·88克，5.0毫莫耳）置於1〇〇毫升的圓底燒瓶中， 並溶解於關卩（50毫升）中。於此溶液中加入卩(1(〇八(：）2(23毫 克，0· 3毫莫耳）、Ρ(ο-Το1)3(12毫克，0.3毫莫耳）、丙烯 酸甲酯（0.47克，5.5毫莫耳）、及NaOAc(〇· 5克，5· 5毫莫 耳）。然後將此混合物加熱至8 0 °C 1 4小時。接著將反應混 合物冷卻至室溫，並加入IN HC1(1 00毫升）。然後將溶液 以EtOAc萃取3次，於MgS04上乾燥，接著於真空中濃縮而 得一棕色油。將此油利用25% EtOAc :己烷進行層析’而 得1. 3 2克之烯酯的無色黏性油。 然後使此烯酯（1 · 3 2克，4 · 1毫莫耳）進行氫化。將此稀The hydrazine (1.88 g, 5.0 mmol) was placed in a 1 mL round bottom flask and dissolved in EtOAc (50 mL). To this solution were added hydrazine (1 (〇8 (:) 2 (23 mg, 0.3 mmol), Ρ (ο-Το1) 3 (12 mg, 0.3 mmol), methyl acrylate (0.47 g) , 5.5 mmol, and NaOAc (〇·5 g, 5·5 mmol). The mixture was then heated to 80 ° C for 14 hours. The reaction mixture was then cooled to room temperature and added to IN HC1. (3) </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> a colorless viscous oil of 2 g of the ester. The enester (1 · 32 2 g, 4 · 1 mmol) is then hydrogenated.

89112968.ptd 第138頁 1283240 五、發明說明（134) 置於帕爾（Parr)氫化瓶中，在惰性氣體環境下加入EtOAc (10毫升）及10% Pd/C(100毫克）。然後利用氫氣在45 psi 下將瓶子加壓，並在室溫下振搖4小時。接著將溶液過濾 通過矽藻土，並於真空中濃縮而得丨.2 9克之烷酯。 將此烷酯（1 · 29克，4· 0毫莫耳）溶解於THF( 30毫升）、 MeOH(20毫升）、及水（10毫升）中，並利用Li〇H(200毫克， 8· 0毫莫耳）皂化。使反應在室溫下攪拌3小時，然後倒入 IN HCL(50宅升）中。接著將此溶液以EtOAc萃取3次，於 MgS〇4上乾燥，然後於真空中濃縮而得丨.〇2克之烷酸的黃 色固體。 然後經由加入2 5 % T F A / C H2 C12溶液並在室溫下攪拌2小 時，而將此烷酸（1 · 02克，3· 3毫莫耳）解保護。接著將所 產生之混合物於真空中濃縮，並立即經由將經解保護的酸 溶解於50°/。二氧陸圜/水中，加入}(2(：〇3(1.2克）、及 Fmoc-Cl(l· 08克，4. 0毫莫耳）而進行保護。將此混合物在 室溫下攪拌14小時，接著倒入IN HC 1(1 〇〇毫升）中。然後 將溶液以EtOAc萃取3次，於MgS04上乾燥，接著於真空中 濃縮而得495毫克之1的白色結晶固體。89112968.ptd Page 138 1283240 V. INSTRUCTIONS (134) In a Parr hydrogenation flask, EtOAc (10 mL) and 10% Pd/C (100 mg) were added under an inert atmosphere. The bottle was then pressurized with hydrogen at 45 psi and shaken for 4 hours at room temperature. The solution was then filtered through celite and concentrated in vacuo to yield EtOAc. This alkyl ester (1 · 29 g, 4.0 mmol) was dissolved in THF (30 mL), MeOH (20 mL) and water (10 mL) 0 millimoles) saponification. The reaction was allowed to stir at room temperature for 3 hours and then poured into IN HCL (50 liters). This solution was then extracted three times with EtOAc, dried over EtOAc EtOAc EtOAc. This alkanoic acid (1. 02 g, 3.3 mmol) was then deprotected by the addition of a 25 % T F A / C H 2 C12 solution and stirring at room temperature for 2 hours. The resulting mixture was then concentrated in vacuo and immediately dissolved in 50 ° / via the deprotected acid. Dioxane in water/water, added with (2 (: 〇 3 (1.2 g), and Fmoc-Cl (1.08 g, 4.0 mmol). The mixture was stirred at room temperature. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt;

\\312\2d-code\90-01\89112968.ptd 第139頁 1283240 五、發明說明（135) DICU02毫克，0·84毫莫耳）、及DMAP(17毫克，〇· 14毫莫 耳）。接著將容器在室溫下振搖1 6小時。將内容物排出， 及將樹脂以DMF、MeOH、及CH2C12洗滌3次。然後經由將1 〇 毫升之50%六氫毗啶/DMF加至振搖容器，並在室溫下振搖 2小時，而將Fmoc基團移除。將所產生之胺樹脂aDMF、 MeOH、及CH2C12 洗條3 次。 於以上的樹脂中加入9毫升DMF、4 - [ N，-（鄰甲苯基 脲）]苯乙酸（132毫克，0.42毫莫耳）、pyBroP(196毫克， 0.42毫莫耳）、及DIEA (107毫克，0.84毫莫耳）。將内容物 在室溫下振搖14小時，然後排出，並以MF、MeOH、及 C H2 C 12洗滌3次。接著使化合物自樹脂分開，收集遽液，然 後於真空中濃縮。經由將油溶解於Me〇H，並緩慢加入Et20 中，直至形成沈澱物為止，而將所產生之油研製。收集此 沈澱物，並於真空中乾燥而得67毫克之1，的白色結晶固 體。 實施例2\\312\2d-code\90-01\89112968.ptd Page 139 1283240 V. Description of the invention (135) DICU02 mg, 0·84 mmol), and DMAP (17 mg, 〇·14 mmol) . The vessel was then shaken at room temperature for 16 hours. The contents were discharged, and the resin was washed 3 times with DMF, MeOH, and CH2C12. The Fmoc group was then removed by adding 1 mM of 50% hexahydropyridine/DMF to the shaker vessel and shaking at room temperature for 2 hours. The resulting amine resins aDMF, MeOH, and CH2C12 were washed three times. Add 9 ml of DMF, 4-[N,-(o-toluene)]phenylacetic acid (132 mg, 0.42 mmol), pyBroP (196 mg, 0.42 mmol), and DIEA (107) to the above resin. Mg, 0.84 millimoles). The contents were shaken at room temperature for 14 hours, then drained and washed 3 times with MF, MeOH, and C H 2 C 12 . The compound was then separated from the resin and the mash was collected and concentrated in vacuo. The oil produced was triturated by dissolving the oil in Me〇H and slowly adding it to Et20 until a precipitate formed. The precipitate was collected and dried in vacuo to give 67 mg of a white crystalline solid. Example 2

BocBoc

TMS 將Α(4·2克，11.3毫莫耳）置於100毫升的圓底燒瓶中， 並溶解於NEt3(50毫升）中。於此溶液中加入Pd(PPH3)2Cl2 (0.16克，0.23毫莫耳）、Cul(21毫克，0·12毫莫耳）、及 三甲矽烷基乙炔（1. 38克，13. 5毫莫耳）。將此混合物在室 溫下攪拌1 4小時。經由加入1 N HC 1 (1 0 0毫升）而使反應混TMS Α (4.2 g, 11.3 mmol) was placed in a 100 mL round bottom flask and dissolved in NEt3 (50 mL). To this solution were added Pd(PPH3)2Cl2 (0.16 g, 0.23 mmol), Cul (21 mg, 0·12 mmol), and trimethyldecyl acetylene (1.38 g, 13.5 mmol) ). The mixture was stirred at room temperature for 14 hours. Mixing the reaction by adding 1 N HC 1 (100 ml)

89112968.ptd 第140頁 1283240 五、發明說明（136) 合物停止。然後將溶液以EtOAc萃取3次，於MgS04上乾 燥，接著於真空中濃縮而得一黃色油。將此油利用1 5 % EtOAc :己烧進行層析，而得3· 8克之2的無色黏性油。89112968.ptd Page 140 1283240 V. INSTRUCTIONS (136) The compound is stopped. The solution was then extracted three times with EtOAc and dried over EtOAc EtOAc. This oil was chromatographed using 15% EtOAc: hexanes to give 3.8 g of EtOAc.

HO V〇 經由在0 C下將蝴院_THF(12.0毫升，12毫莫耳）加至環 己烯（2.3毫升）溶於6毫升無水THF之溶液中而產生二環己 基硼烷之溶液。將此溶液在〇 °C下再多攪拌1小時。然後將 乙快（2)(2.0克’ 5.84¾莫耳）在〇。〇下於15分鐘内逐滴加 入’接著使其於1小時内升溫至室溫。然後WMe〇H (2〇毫 升）稀釋反應混合物，接著再冷卻至〇艺。然後逐滴加入2N N a 0 Η (6耄升）及3 0 % I 〇2 (3 · 5毫升）之溶液。接著使反應混 合物在0 °C下攪拌1小時，然後升溫至4 〇它2. 5小時。接著 將混合物冷卻至室溫，並再加入6毫升之2N Na〇H。將有機 物質於真空中移除’及將殘留的水溶液以E ^ 〇萃取3次， 並將有機物質棄置。然後將水性萃取物以丨N HC丨酸化，並 以EtOAc萃取及於MgS〇4上乾燥，接著於真空中濃縮而得 1 · 7克之苯乙酸的黃褐色結晶固體。 然後經由加入25% TFA /CH2C12溶液並在室溫下攪拌2小 時、，而將此酸（1.7克，5·6毫莫耳）解保護。接著將所產生 之/把合物於真空中濃縮，並立即經由將經解保護 於⑽二氧陸&quot;水中，加入k2C〇3(15克）、AFm0C_c；^ 4克，5 · 5毫莫耳）而進行保護。將此混合物在室溫下攪拌HO V〇 A solution of dicyclohexylborane was produced by adding a solution of THF (12.0 ml, 12 mmol) to cyclohexene (2.3 ml) in 6 ml of anhydrous THF at 0 C. This solution was stirred for an additional hour at 〇 °C. Then B will be fast (2) (2.0 grams ' 5.843⁄4 moles). The underarm was added dropwise in 15 minutes and then allowed to warm to room temperature over 1 hour. The reaction mixture was then diluted with WMe 〇H (2 Torr) and then cooled to a scent. Then a solution of 2N N a 0 Η (6 liters) and 30% I 〇 2 (3 · 5 ml) was added dropwise. 5小时。 Then the reaction mixture was stirred at 0 ° C for 1 hour, and then heated to 4 〇 it 2. 5 hours. The mixture was then cooled to room temperature and 6 ml of 2N Na〇H was added. The organic material was removed in vacuo&apos; and the residual aqueous solution was extracted 3 times with E^, and the organic material was discarded. The aqueous extract was then acidified with EtOAc (EtOAc) eluting with EtOAc (EtOAc) This acid (1.7 g, 5.6 mmol) was then deprotected by the addition of 25% TFA / CH2C12 solution and stirred at room temperature for 2 h. The resulting/complex is then concentrated in vacuo and immediately added to the (10) dioxane &quot; water, k2C〇3 (15 g), AFm0C_c; ^ 4 g, 5 · 5 mmol Protected by the ear). Stir the mixture at room temperature

\\312\2d-code\90-0i\89i12968.ptd 第141頁 1283240 五、發明說明（137) 1 4小時，接著倒入1 N HC 1 ( 1 0 0毫升）中。然後將溶液以 EtOAc萃取3次，於MgS〇4上乾燥，接著於真空中濃縮而得 1 · 7克之3的白色結晶固體。\\312\2d-code\90-0i\89i12968.ptd Page 141 1283240 V. INSTRUCTIONS (137) 1 4 hours, then pour into 1 N HC 1 (100 ml). The solution was then extracted three times with EtOAc and dried over EtOAc EtOAc.

將乾燥樹脂（5 0 0毫克，〇 · 1 4毫莫耳）置於小的振搖容器 中。然後將容器裝入9毫升之DMF、3(180毫克，0.42毫莫 耳）、DIC(102 毫克，0.84 毫莫耳）、及DMAP(17 毫克，0.14 毫莫耳）。接著將容器在室溫下振搖1 6小時。將内容物排 出，及將樹脂以DMF、MeOH、及CH2C12洗滌3次。然後經由 將1 0毫升之5 0 %六氣吼°定/ D M F加至振搖容器，並在室溫下 振搖2小時，而將Fmoc基團移除。將所產生之胺樹脂以 DMF、MeOH、及CH2C12 洗滌3 次。 於以上的樹脂中加入9毫升DMF、4 - [N，-(鄰甲苯基 脲）]苯乙酸（132毫克，0.42毫莫耳）、pyBroP(196毫克， 〇·42毫莫耳）、及DIEAC107毫克，0.84毫莫耳）。將内容物 在室溫下振搖1 4小時，然後排出，並以DMF、MeOH、及CH 2 C丨2洗滌3次。接著使化合物自樹脂分開，收集濾液，然後 於真空中》辰縮。經由將油溶解於Me〇H，並緩慢加入Et20 中’直至形成沈殿物為止，而將所產生之油研製。收集此 沈殿物’並於真空中乾燥而得5 2毫克之3，的白色結晶物 質。The dry resin (500 mg, 〇 · 14 mmol) was placed in a small shaker vessel. The vessel was then filled with 9 ml of DMF, 3 (180 mg, 0.42 mmol), DIC (102 mg, 0.84 mmol), and DMAP (17 mg, 0.14 mmol). The vessel was then shaken at room temperature for 16 hours. The contents were discharged, and the resin was washed 3 times with DMF, MeOH, and CH2C12. The Fmoc group was then removed by adding 10 ml of 50% hexafluoropyrene / D M F to the shaker vessel and shaking at room temperature for 2 hours. The resulting amine resin was washed 3 times with DMF, MeOH, and CH2C12. Add 9 ml of DMF, 4-[N,-(o-toluene)]phenylacetic acid (132 mg, 0.42 mmol), pyBroP (196 mg, 〇·42 mmol), and DIEAC107 to the above resin. Mg, 0.84 millimoles). The contents were shaken at room temperature for 14 hours, then drained and washed 3 times with DMF, MeOH, and CH 2 C 2 . The compound is then separated from the resin and the filtrate is collected and then condensed in vacuo. The resulting oil was triturated by dissolving the oil in Me〇H and slowly adding it to Et20 until the formation of the sink. This shoal was collected and dried in vacuo to give a white crystalline material of 5 2 mg.

\\312\2d-code\90-01\89112968.ptd 第142頁 1283240 五、發明說明（138) 實施例3\\312\2d-code\90-01\89112968.ptd Page 142 1283240 V. Description of the Invention (138) Example 3

HOHO

Fmoc 經由將2(0· 75克’ 2. 1毫莫耳）置於Me〇H(25毫 此溶液中加入K〇H(1.4克），而將乙炔（2)解保護。將所產、 生之溶液在室溫下攪拌〗小時。接著將反應混合物於直空 =濃縮，並利用IN HC1酸化。將所產生之水溶液以趴〇Ac 萃取3次，將結合的有機層於MgS〇4上乾燥，接著於真空中 濃縮而得0 · 5 6克之經解保護乙炔的棕色油。 然後將經解保護的乙快（〇 . 5 6克，2. 0毫莫耳）置於 THFC50毫升）中，並冷卻至-78 °C。接著逐滴加入 Li HMDS (1M溶液，4.7毫升），並使反應授拌3〇分鐘。然後 使C02氣體發泡通過反應混合物1 5分鐘，接著將反應倒於 C02固體上。經由加入1 N HC1 (1 00毫升）使反應停止，及將 水溶液以EtOAc萃取3次，將結合的有機層於MgS04上乾 燥，接著於真空中濃縮而得丙酸（〇·71克）之白色固體。 然後經由加入25% TFA /CH2C12溶液並在室溫下攪拌2小 時，而將此烷酸（0 . 71克）解保護。接著將所產生之混合物 於真空中濃縮，並立即經由將經解保護的酸溶解於5 0%二 氧陸圜/水中，加入K2C03(15克）、及Fmoc - C1 (1·29克， 4. 9毫莫耳）而進行保護。將此混合物在室溫下攪拌1 4小 時，接著倒入IN HCK100毫升）中。然後將溶液以Et0Ac萃Fmoc deprotects acetylene (2) by placing 2 (0.75 g '2.1 mol) on Me〇H (25 ml of this solution is added K〇H (1.4 g). The resulting solution was stirred at room temperature for an hour. The reaction mixture was then concentrated in a straight space = acidified using IN HCl. The resulting aqueous solution was extracted three times with 趴〇Ac, and the combined organic layer was applied to MgS? Drying, followed by concentration in vacuo to give 5.6 g of EtOAc, EtOAc, EtOAc, EtOAc, EtOAc And cooled to -78 °C. Li HMDS (1 M solution, 4.7 mL) was then added dropwise and the reaction was stirred for 3 min. The CO 2 gas was then bubbled through the reaction mixture for 15 minutes, and then the reaction was poured onto a C02 solid. The reaction was quenched by the addition of 1 N EtOAc (1 mL) and EtOAc (EtOAc) EtOAc (EtOAc) solid. This alkanoic acid (0.77 g) was then deprotected by the addition of a 25% TFA / CH.sub.2 C.sub.2 solution and stirred at room temperature for 2 hours. The resulting mixture is then concentrated in vacuo and immediately dissolved in 50% dioxane/water by addition of the deprotected acid, K2C03 (15 g), and Fmoc-C1 (1·29 g, 4) 9 millimoles) for protection. The mixture was stirred at room temperature for 14 hours and then poured into 100 mL of IN HCK. Then extract the solution as Et0Ac

\\312\2d-code\90-01\89112968.ptd 第143頁 1283240 五、發明說明（139) 取3次，於MgS04上乾燥，接著於真空中濃縮而得4之棕色 油。然後利用5% Me0H /二氣甲烷將油進行層析，而得1〇〇 毫克之期望化合物。\\312\2d-code\90-01\89112968.ptd Page 143 1283240 V. INSTRUCTIONS (139) Take 3 times, dry on MgS04, and then concentrate in vacuo to give 4 brown oil. The oil was then chromatographed with 5% Me0H / di- methane to give 1 mg of the desired compound.

將乾燥樹脂（5 0 0毫克，0 · 1 4毫莫耳）置於小的振搖容器 中。然後將容器裝入9毫升之DMF、4(184毫克，〇·42毫莫 耳）、DIC(102 毫克，0.84 毫莫耳）、及 DMAPC17 毫克，0· 14 毫莫耳）。接著將容器在室溫下振搖1 6小時。將内容物排 出，及將樹脂以DMF、MeOH、及CH2C12洗滌3次。然後經由 將10毫升之50%六氫咄啶/DMF加至振搖容器，並在室溫下 振搖2小時，而將Fmoc基團移除。將所產生之胺樹脂以 DMF、MeOH、及CH2C12 洗滌3 次。 於以上的樹脂中加入9毫升DMF、4-[N，-(鄰甲苯基 脲）]苯乙酸（132毫克，〇·42毫莫耳）、PyBroP(l96毫克，The dry resin (500 mg, 0 · 14 mmol) was placed in a small shaker vessel. The vessel was then filled with 9 ml of DMF, 4 (184 mg, 〇·42 mmol), DIC (102 mg, 0.84 mmol), and DMAPC 17 mg, 0·14 mmol. The vessel was then shaken at room temperature for 16 hours. The contents were discharged, and the resin was washed 3 times with DMF, MeOH, and CH2C12. The Fmoc group was then removed by adding 10 ml of 50% hexahydroacridine/DMF to the shaker vessel and shaking at room temperature for 2 hours. The resulting amine resin was washed 3 times with DMF, MeOH, and CH2C12. To the above resin was added 9 ml of DMF, 4-[N,-(o-toluene)]phenylacetic acid (132 mg, 〇·42 mmol), PyBroP (1 96 mg,

〇· ΐ莫耳）、及DIEA(107毫克，〇· 82毫莫耳）。將内容物 在室溫下振搖14小時，然後排出，並以DMF、Me〇H、及 CHJl2洗滌3次。接著使化合物自樹脂分開，收集濾液，鈇 後於真空中濃縮。經由將油溶解於Me〇H，並緩慢加入厂 中，直至形成沈澱物為止，而將所產生之油研 π =澱物，並於真空中乾燥而得27毫克之4，的白色結晶^在〇·ΐ莫耳), and DIEA (107 mg, 〇·82 mmol). The contents were shaken at room temperature for 14 hours, then discharged, and washed 3 times with DMF, Me〇H, and CHJ12. The compound was then separated from the resin and the filtrate was collected, then concentrated in vacuo. By dissolving the oil in Me〇H and slowly adding it to the plant until a precipitate is formed, the resulting oil is ground to π = precipitate and dried in vacuo to give 27 mg of 4, white crystal

89112968.ptd 第144頁89112968.ptd Page 144

12832401283240

實施例4Example 4

Fmoc 5 將碘化物（Α)(〇· 5克，ι· 3毫莫耳）置於THF(20毫升）中， 並冷卻至-78 °C。逐滴加入丁基鋰（2· 21毫升，1 · 6M溶 液）’然後移除冷卻槽，並使氣態c〇2發泡通過丨〇分鐘。將 反應混合物倒於乾冰上，然後加入丨M HC丨（丨〇毫升）。將L 合物以EtOAc萃取3次，將結合的有機層於MgS〇4上乾燥，此 接著於真空中濃縮而得〇· 32克之苯曱酸的白色結晶固&quot;體。 然後經由加入2 5 % T F A / C % C12溶液並在室溫下攪拌2小 時，而將此苯甲酸（〇. 3 2克1 · 6 8毫莫耳）解保護。接著將所 產生之混合物於真空中濃縮，並立即經由將經解保護的酸 溶解於50%二氧陸圜/水中，加入K2C〇3(15克）、及又 欠Fmoc 5 Iodide (Α·5 g, ι·3 mmol) was placed in THF (20 mL) and cooled to -78 °C. Butyllithium (2.11 ml, 1.7 M solution) was added dropwise and then the cooling bath was removed and the gaseous c〇2 was foamed through for 丨〇min. The reaction mixture was poured onto dry ice and then 丨M HC((m). The L compound was extracted three times with EtOAc, and the combined organic layer was dried over <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; This benzoic acid (0.32 g of 1 · 6 8 mmol) was then deprotected by the addition of a 25 % T F A / C % C12 solution and stirring at room temperature for 2 hours. The resulting mixture is then concentrated in vacuo and immediately dissolved in 50% dioxane/water by addition of the deprotected acid, K2C〇3 (15 g), and owed

Fmoc-Cl (0·44克，1.67·毫莫耳）而進行保護。將此混合物 在室溫下攪拌1 4小時，接著倒入;i N hc 1 ( 1 〇 〇毫升）中。然 後將溶液以EtOAc萃取3次，於MgS〇4上乾燥，接著於真空、、 中濃縮而得0 . 3 8克之5的白色結晶固體。Protection was carried out with Fmoc-Cl (0.44 g, 1.67 mmol). The mixture was stirred at room temperature for 14 hours and then poured into i n hc 1 (1 〇 〇 ml). The solution was then extracted three times with EtOAc and dried over EtOAc EtOAc.

將乾燥樹脂（5 0 0耄克’ 〇. 1 4毫莫耳）置於小的振搖容器Place the dry resin (500 gram 〇. 1 4 millimoles) in a small shaker container

第145頁 1283240 五、發明說明（141) 中。然後將容器裝入9毫升之DMF、5(173毫克，〇· 42毫莫 耳）、DIC(102 毫克，〇·84 毫莫耳）、及DMAP(17 毫克，0.14 毫莫耳）。接著將容器在室溫下振搖1 6小時。將内容物排 出，及將樹脂以DMF、MeOH、及CH2C12洗滌3次。然後經由 將1 0毫升之5 0 %六氫σ比咬/ D M F加至振搖容器，並在室溫下 振搖2小時，而將Fmoc基團移除。將所產生之胺樹脂以 DMF、MeOH、及CH2C12 洗滌3 次。 於以上的樹脂中加入9毫升DMF、4 -[Ν’-(鄰曱苯基 脲）]苯乙酸（132毫克，0.42毫莫耳）、pyBroP(196毫克， 0.42毫莫耳）、及DIEA (107毫克，〇·8 4毫莫耳）。將内容物 在室溫下振搖14小時，然後排出，並以DMf、MeOH、及CH 2Cl2洗滌3次。接著使化合物自樹脂分開，收集濾液，然後 於真空中濃縮。經由將油溶解於Me〇H，並緩慢加入ΕΪ2〇 中，直至形成沈澱物為止，而將所產生之油研製。收集此 沈澱物，並於真空中乾燥而得51毫克之5，的白色結晶物 質。 實施例5 (Ε)-4 - [2-[I -[4-[Ν’_(2 -甲基苯基）脲基]苯基乙醯基一 2一 吼咯啶基]乙烯基]苯甲酸Page 145 1283240 V. Inventions (141). The container was then filled with 9 ml of DMF, 5 (173 mg, 〇·42 mmol), DIC (102 mg, 〇·84 mmol), and DMAP (17 mg, 0.14 mmol). The vessel was then shaken at room temperature for 16 hours. The contents were discharged, and the resin was washed 3 times with DMF, MeOH, and CH2C12. The Fmoc group was then removed by adding 10 ml of 50% hexahydro-sigma ratio / D M F to the shaker vessel and shaking at room temperature for 2 hours. The resulting amine resin was washed 3 times with DMF, MeOH, and CH2C12. To the above resin was added 9 ml of DMF, 4-[Ν'-(o-phenylphenylurea)]phenylacetic acid (132 mg, 0.42 mmol), pyBroP (196 mg, 0.42 mmol), and DIEA ( 107 mg, 〇·8 4 mmol). The contents were shaken at room temperature for 14 hours, then drained and washed 3 times with DMf, MeOH, and CH2Cl2. The compound was then separated from the resin and the filtrate was collected and concentrated in vacuo. The oil produced was prepared by dissolving the oil in Me〇H and slowly adding it to the 〇2〇 until a precipitate formed. The precipitate was collected and dried in vacuo to give 51 mg of white crystals. Example 5 (Ε)-4 - [2-[I -[4-[Ν'_(2-methylphenyl)ureido]phenylethenyl- 2 -pyridinyl]vinyl]benzene Formic acid

9人 於4-膦酸甲基苯曱酸三乙酯（9〇4毫克，3〇1毫莫耳）溶 於THF(20毫升）之冷的（-78。〇攪拌溶液中加入9 people were added to a cold (-78. 〇 stirred solution) of tetraethyl 4-phosphonomethylbenzoate (9 〇 4 mg, 3 〇 1 mmol) in THF (20 mL).

1283240 五、發明說明（142) UHMDS(1· 0M之THF溶液，3毫升，3· 00毫莫耳），並在相同 溫度下繼續攪拌1小時。將N_B〇c脯胺醛（ 50 0毫克，2. 5 1毫 莫耳）溶於THF( 1 0毫升）加至此混合物，並使混合物升溫至 室溫超過1小時。於攪拌2小時後，利用水使混合物停止反 應，並以E10 A c進行萃取。將萃取液以鹽水（2 〇 〇毫升）洗 條，於MgS04上乾燥，並蒸發。將殘留物於矽膠上利用正 己烧-EtOAc(8:l，v/v)作為洗提液進行層析，而得713毫 克（80%)之（E)-4-[2-[1-(第三丁氧羰基）—2 -吼咯啶基]乙 浠基]苯甲酸乙酯的無色結晶固體。 熔點 68 -70 °C ; IR (KBr) 1710、1 69 7、1681 / 公分；1 Η-NMR (CDC13) 6 1· 39 (12H，m 系列）、1. 77-1· 93 (3H， m)、2·11 (1H，m)、3·47 (2H，m)、4·34-4·54 (總計 3H， m)、6·22 (1Η，m)、6·43 (1Η，d，J = 14.2 Hz)、7·39 (2H，J = 8.3 Hz)、7·97 (2H，d，J = 8.3 Hz); MS(FAB) m/z 34 6 (MH1 ) ; C2GH27N04 之分析計算值：c，69. 54 ; H， 7· 88 ; N，4· 05。實測值：c，69. 52 ; H，8. 08 ; N， 4· 07 〇 於（£)-4-[2-[1_(第三丁氧羰基）-2-吼咯啶基]乙烯基] 苯曱酸乙酯（700毫克，2.03毫莫耳）溶於CH2C12 (3毫升）之 攪拌溶液中加入TF A(3毫升），並將所產生之混合物攪拌3 小時。將混合物濃縮，並經由加入飽和NaHC〇3而使殘留物 成為鹼性。將混合物以CHC 13 ( 2 X 1 〇 〇毫升）進行萃取。將 結合的萃取液於Nas〇3上乾燥，並於真空中濃縮而得4 34毫 克（87%)之（E)-4-[ 2-(2-吼咯啶基）乙烯基]苯甲酸乙酯之1283240 V. INSTRUCTIONS (142) UHMDS (1.0 M solution in THF, 3 mL, 3,000 mmol) and stirring was continued for 1 hour at the same temperature. N_B〇c-guanidine aldehyde (50 mg, 2.51 mmol) was dissolved in THF (10 mL), and the mixture was warmed to room temperature over 1 hr. After stirring for 2 hours, the mixture was quenched with water and extracted with E10 A c. The extract was washed with brine (2 mL), dried over MgSO 4 and evaporated. The residue was chromatographed on silica gel using hexane-EtOAc (8:1, v/v) as eluent to afford s. A colorless crystalline solid of ethyl 3-butoxycarbonyl)-2-chloropyridinyl]ethinyl]benzoate. Melting point 68 -70 °C; IR (KBr) 1710, 1 69 7 , 1681 / cm; 1 Η-NMR (CDC13) 6 1· 39 (12H, m series), 1. 77-1· 93 (3H, m ), 2·11 (1H, m), 3·47 (2H, m), 4·34-4·54 (total 3H, m), 6.22 (1Η, m), 6.43 (1Η, d , J = 14.2 Hz), 7·39 (2H, J = 8.3 Hz), 7·97 (2H, d, J = 8.3 Hz); MS(FAB) m/z 34 6 (MH1 ) ; C2GH27N04 Value: c, 69. 54 ; H, 7· 88 ; N, 4. 05. Found: c, 69. 52 ; H, 8. 08 ; N, 4 · 07 〇 (£)-4-[2-[1_(Tertidinoxycarbonyl)-2-pyrrolidinyl]vinyl To a stirred solution of ethyl benzoate (700 mg, 2.03 mmol) in CH.sub.2 C.sub.2 (3 mL), THF (3 mL). The mixture was concentrated and the residue was made basic by the addition of saturated NaHC. The mixture was extracted with CHC 13 ( 2 X 1 〇 〇 mL). The combined extracts were dried over Nas(R)3 and concentrated in vacuo to give 4 <RTI ID=0.0></RTI> </RTI> </RTI> <RTIgt; Ester

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棕色油。 M-NMR (CDC 13)(Η·39 (3H，t，J = 7.3 Hz)、1.52-2.06 (4H ’m 系、列）、2·93-2.99 (1H，m) υγ — g ig m)、3·74 (1H，q，J = 7.3 Hz)、4·37 (2H，q，J = 7 3Brown oil. M-NMR (CDC 13) (Η·39 (3H, t, J = 7.3 Hz), 1.52-2.06 (4H 'm system, column), 2.93-2.99 (1H, m) υγ — g ig m) , 3·74 (1H, q, J = 7.3 Hz), 4·37 (2H, q, J = 7 3

Hz)、6·34 (1H，dd，J=15.6，7·3 Hz)、6.54 (ih d J = 15.6 Hz)、7·41 (2H，d，J = 8.3 Hz)、7·97 ’ ’ J=8.3 Hz)。 ’ ’ 將（E)-4-[2-(2-吼哈咬基）乙烯基]苯甲酸乙酯（434 克毫莫、4-[N’ -（2-甲基苯基）脲基]笨基乙酸 五氟苯酯（797¾克，1·77毫莫耳）、Et3N(〇37毫升，2·66 宅莫耳）&gt;谷於D M F ( 1 5耄升）之混合物授拌1 $小時。以 EtOAc( 3 00毫升）稀釋混合物。將溶液以鹽水（2 χ 2〇〇毫升） 洗滌，於MgS〇4上乾燥，並於真空中蒸發掉。將殘留物於 石夕膠上利用CHCl3_EtOAc(4:l)作為洗提液進行層析，而得 906 毫克（q· y·)之（E)-4-[2-[1-[4-[N，一（2一甲基苯基）脲 基]苯基乙醯基]-2-咄咯啶基]乙烯基]苯甲酸乙酯的棕色 油。 ^-NMR (CDC13)^1.39 (3H, t, J = 7.3 Hz) ^1.83-2.20 (4H ，m 系列）、2·24 (3H， d， J=4.9 Hz) 、3·63 (4H， m)、4·36 (2H，q，J = 7.3 Hz)、4.63 及4.84 (總計 1H， m)、6·18-6·47 (2H，m)、7·〇3-8.02 (14H，m 系列）。 將（E)-4 - [2 - [1-[4-Ν’ -（2 -甲基苯基）脲基]苯基乙醯 基]-2 -吼咯啶基]乙烯基]笨甲酸乙酯（9〇6毫克，177毫莫 耳）溶於0· 2 5Ν NaOH(14毫升）及thf( 14毫升）之攪拌混合物Hz), 6.34 (1H, dd, J = 15.6, 7·3 Hz), 6.54 (ih d J = 15.6 Hz), 7·41 (2H, d, J = 8.3 Hz), 7.97 ' ' J = 8.3 Hz). ' '(E)-4-[2-(2-Hahabityl)vinyl]benzoic acid ethyl ester (434 g mM, 4-[N'-(2-methylphenyl)ureido] Pentaerythritol pentafluorophenyl ester (7973⁄4 g, 1.77 mmol), Et3N (〇37 ml, 2.66 house Moule) &gt; mixture of DMF (15 liters) in the mixture for 1 $ hour The mixture was diluted with EtOAc (3 mL) EtOAc (EtOAc (EtOAc) 4: l) Chromatography as an eluent to give 906 mg (q·y·) of (E)-4-[2-[1-[4-[N, mono(2-methylphenyl)) Brown oil of ureido]phenylethyl hydrazino]-2-oxaridinyl]vinyl]benzoate. ^-NMR (CDC13)^1.39 (3H, t, J = 7.3 Hz) ^1.83-2.20 (4H, m series), 2·24 (3H, d, J=4.9 Hz), 3·63 (4H, m), 4·36 (2H, q, J = 7.3 Hz), 4.63 and 4.84 (total 1H) , m), 6·18-6·47 (2H, m), 7·〇3-8.02 (14H, m series). (E)-4 - [2 - [1-[4-Ν' -( 2-methylphenyl)ureido]phenylethenyl]-2-pyridinyl]ethylene ] Ben-carboxylate (9〇6 mg, 177 mmol ear Mo) was dissolved in 0 · 2 5Ν NaOH (14 mL) and THF (14 ml) the mixture was stirred

1283240 五、發明說明（144) 迴流加熱3天。將此混合物倒入冰的1N HC 1 ( 2 0 0毫升）中， 並利用吸遽收集沈澱物。將固體由CHCl3—Me〇H一正己烷再 結晶而得453毫克（53%)之6的淡黃色結晶粉末。 熔點 165-168 °C; IR (KBr) 3282、2974、2663、2537、 1 7 00、1 685 / 公分；ιΗ一NMR (DMS〇 —d6) 5 ! · 74 —2· 12 (4H， m)、2·24 (3H，d，J = 4.9 Hz)、3·35-3·66 (4H，m)、 4·67 - 4.74 ( 1 H，m)、6·25 - 6·41 (1H，m)、6·53 (1H， s)、6·93 (1H， t， J = 7.3 Hz)、7·08 - 7·92 (12H, m 系 列）、9·00 (1H, m)、12·87 (1H，br s); MS(FAB) m/z 48 4 (MH1) ; C29H29N3 04 · 〇· 5H20 之分析計算值：C， 70. 71 ; H，6·14;Ν， 8.39。實測值：c， 70·46; H，6·07;Ν， 8. 39 ° 實施例6 [2- [卜[4 - [Ν’ - (2-甲基苯基）脲基]苯基乙醯基]2_吼咯 啶基]乙烯基]苯甲酸 7 使（E)-4 - [2 - [1 - [4 - [N，- (2-甲基苯基）脲基]笨基乙醯 基]_2-吼咯啶基]乙烯基；|苯甲酸酯（2〇〇毫克，〇·414毫莫 耳）及5% Pd/C( 2 0 0毫克）於Me〇H( 20毫升）中之混合物在1大 氣·壓下在劇烈擾摔下氫化1小時。將混合物過渡並將遽液 濃縮。將殘留物於矽膠上利用CHCl3_MeOH(4: 1)作為洗提 液進行層析，而得201毫克（q· y·)之7的無色結晶粉末。1283240 V. INSTRUCTIONS (144) Heating under reflux for 3 days. The mixture was poured into ice 1N HC 1 (200 mL) and the precipitate was collected by suction. The solid was recrystallized from CHCl3-Me-H-hexane to yield 453 mg (yield: 53%) of pale yellow crystalline powder. Mp 165-168 °C; IR (KBr) 3282, 2974, 2663, 2537, 1 7 00, 1 685 / cm; ιΗ NMR (DMS〇-d6) 5 ! · 74 —2· 12 (4H, m) , 2·24 (3H, d, J = 4.9 Hz), 3·35-3·66 (4H, m), 4.67 - 4.74 ( 1 H, m), 6·25 - 6·41 (1H, m), 6·53 (1H, s), 6.93 (1H, t, J = 7.3 Hz), 7·08 - 7·92 (12H, m series), 9·00 (1H, m), 12 · 87 (1H, br s); MS (FAB) m/z 48 4 (MH1); C29H29N3 04 · 〇· 5H20 Analysis calculated: C, 70. 71 ; H, 6·14; Ν, 8.39. Found: c, 70·46; H, 6·07; Ν, 8. 39 ° Example 6 [2- [Bu [4 - [Ν' - (2-methylphenyl) ureido]phenyl) Indenyl] 2_ oxaridinyl] vinyl]benzoic acid 7 (E)-4 - [2 - [1 - [4 - [N,-(2-methylphenyl)ureido]]醯基]_2-吼rrolidyl]vinyl;|benzoic acid ester (2〇〇 mg, 〇·414 mmol) and 5% Pd/C (200 mg) in Me〇H (20 ml) The mixture was hydrogenated at 1 atmosphere and under pressure for 1 hour under severe disturbance. The mixture was transferred and the mash was concentrated. The residue was chromatographed on silica gel eluting with CHCl3_MeOH (4:1) to afford 201 mg (q·y·) of 7 as colorless crystalline powder.

\\312\2d-code\90-01\89112968.ptd 第149頁 1283240 五、發明說明（145) 熔點 1 8 0- 1 9 0 °C ; IR (KBr) 3345、3124、3 0 6 0、30 27、 296 0、2927、28 75、1 70 6、1 672 / 公分；UMR (DMSO-d 6) 51 · 0 4 - 3 · 9 6 (總計 1 6 Η，m 系列）、6 · 9 1 - 7. 4 1 ( 9 Η， m) 、7·79-7·90 (3Η， m) 、8.23 (1Η， br s) 、9.31 (1Η， br s) ； MS (FAB) m/z 48 6 (MH 1 ) ； C29H31N3 04 · 2. 25 H20 之分析計算值：C，66. 21 ; H, 6· 80 ; N，7· 99。實測 值：C，65· 97 ; H，6· 20 ; N，7· 72。 實施例7 (S)-4-[2-[l -[4- [Ν’ - (2 -甲基苯基）脲基]苯基乙醯基]吼 咯啶基]曱氧基]苯甲酸 I Η Η (S)-4-[2-[l-[3-甲氧基-4-(Ν’-苯脲基）苯基乙醯基]0比咯 啶基]甲氧基]苯曱酸\\312\2d-code\90-01\89112968.ptd Page 149 1283240 V. INSTRUCTIONS (145) Melting point 1 8 0- 1 9 0 °C; IR (KBr) 3345, 3124, 3 0 6 0, 30 27, 296 0, 2927, 28 75, 1 70 6 , 1 672 / cm; UMR (DMSO-d 6) 51 · 0 4 - 3 · 9 6 (total 1 6 Η, m series), 6 · 9 1 - 7.4 (9 Η, m) (MH 1 ) ; C29H31N3 04 · 2. 25 H20 Analysis calculated: C, 66. 21 ; H, 6· 80 ; N, 7. 99. Found: C, 65 · 97 ; H, 6 · 20 ; N, 7. 72. Example 7 (S)-4-[2-[l -[4-[Ν' - (2-Methylphenyl)ureido]phenylethenyl]pyridinyl]nonyloxy]benzoic acid I Η Η (S)-4-[2-[l-[3-methoxy-4-(Ν'-phenylureido)phenylethenyl]0-pyridyl]methoxy]phenylhydrazine acid

、9及10在室溫下於Boc-脯胺醇（3〇〇克，14·9毫莫, 9 and 10 at room temperature in Boc-prolinol (3 gram, 14.9 mmol)

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耳）、對經基苯甲酸乙酯（2· 4〇克，14· 5毫莫耳）及三笨膦 (3. 91克’ 14· 9莫耳）溶於THF(8〇毫升）之攪拌混合物中逐 滴加入偶氛二羧酸二乙酯（2. 86克，ι6· 4毫莫耳）。於添加 完成後’將所產生之混合物迴流加熱2小時。於冷卻後， 將混合物於真空中濃縮。將殘留物溶解於Et〇Ac，並以1N Na0H、水、鹽水連續洗滌。將EtOAc層於MgS04上乾燥，並 於真空中蒸發。將殘留物經由於矽膠上利用EtOAc-正己燒 (1 · 4 ’ v / v)作為洗提液進行管柱層析，純化而得4 · w克 (93%)之（S)-4-（1-第三丁氧羰基—2-吼咯啶基）曱氧笨甲酸 乙醋的油。 於以上的（S)-4-(1-第三丁氧羰基—2-咄咯啶基）曱氧苯 甲酸乙酯中加入Me〇H(10〇毫升）及IN NaOH(50毫升）。將混 合物在室溫下攪拌1 5小時。於在減壓下移除Me〇H之後，將 水（50毫升）加至殘留溶液中。將水溶液以ΕΪ2〇(χ2)洗滌， 然後經由加入1 N H C1而酸化。將混合物利用£ t 〇 a c萃取， 以水、鹽水洗滌，於MgS〇4上乾燥，並於真空中蒸發而得 4·26克（95%)之（S)-4-(l -第三丁氧魏基—2 -吼洛淀基）曱氧 笨甲酸的結晶固體。 於以上的（S)-4-(1-第三丁氧羰基-2 - u比咯啶基）甲氧苯 甲酸中加入CHJl^lO毫升）及TFA(10毫升）。將混合物在室 溫下攪拌1小時，將Eta加至混合物，並收集所產生之固 體。將此固體溶解於水（100毫升）、二氧陸圜（5〇毫升）及 NaHC03(4· 4 克）中。將Fmoc-Cl(3· 34 克，12. 9 毫莫耳）加至 此溶液，並將所產生之混合物在室溫下攪拌2〇小時。將混Stir), stirring of ethyl benzoate (2.4 g, 14. 5 mmol) and triphenylphosphine (3.91 g '14·9 mol) in THF (8 mL) Diethyl aryl dicarboxylate (2.86 g, ι 6 · 4 mmol) was added dropwise to the mixture. After the addition was completed, the resulting mixture was heated under reflux for 2 hours. After cooling, the mixture was concentrated in vacuo. The residue was dissolved in Et 〇Ac and washed successively with 1N NaH, water, brine. The EtOAc layer was dried over MgSO4 and evaporated in vacuo. The residue was subjected to column chromatography using EtOAc-n-hexane (1·4' v / v) as an eluent to obtain 4 · w g (93%) of (S)-4-( An oil of 1-t-butoxycarbonyl-2-pyrrolidyl) oxime acetoacetate. Me(R) (10 mL) and IN NaOH (50 mL) were added to the above ethyl (S)-4-(1-tert-butoxycarbonyl-2-pyrrolidinyl) oxime benzoate. The mixture was stirred at room temperature for 15 hours. After removing Me〇H under reduced pressure, water (50 ml) was added to the residual solution. The aqueous solution was washed with ΕΪ2〇 (χ2) and then acidified by the addition of 1 N H C1. The mixture was extracted with £ t 〇ac, washed with water, brine, dried over MgSO 4 and evaporated in vacuo to give 4·26 g (95%) of (S) -4- A crystalline solid of oxime- 2 - fluorenyl hydrazine. To the above (S)-4-(1-tert-butoxycarbonyl-2-butyrrolidinyl)methoxybenzoic acid, CH.sub.1 (10 mL) and TFA (10 mL) were added. The mixture was stirred at room temperature for 1 hour, Eta was added to the mixture, and the resulting solid was collected. This solid was dissolved in water (100 ml), dioxane (5 ml) and NaHC03 (4.4 g). Fmoc-Cl (3·34 g, 12.9 mmol) was added to the solution, and the resulting mixture was stirred at room temperature for 2 hr. Will mix

\\312\2d-code\90-01\89112968.ptd 第151頁 1283240 五、發明說明（147) 合物以Et2〇(x2)洗滌，及將水層分離。經由加入in HC1而 使此層酸化。以EtOAc萃取混合物。將萃取物以水、鹽水 洗滌’於MgS04上乾燥，並於真空中蒸發而得5. 36克（910/〇) 之（S)-4 -（1 - Fmoc - 2-吡咯啶基）甲氧苯曱酸的黏性油，使 其靜置結晶。 使王氏樹脂（Wang resin) (0· 71毫莫耳/克，4 0 0毫克） 懸浮於（S) -4 -（1 - Fmoc -2 -吼咯啶基）曱氧苯曱酸（500毫 克，1.13 莫耳）、DMAP(35 毫克，0.29 毫莫耳）、HOBt(40 毫 克，0·30毫莫耳）及DIC(0.45毫升，2.9毫莫耳）溶於DMF(3 毫升）及CH2C12(7毫升）之混合物的溶液中。將混合物振搖 20 小時並排液。將樹脂以DMF(x3)、MeOH(x3)、CH2C 12(x3) 洗滌，並於減壓下乾燥而得522毫克之樹脂，使用其於製 備8、9及10。 8 於以上的樹脂（115毫克）中加入六氫π比啶-dmF之溶液 (5 0 % v / v ’ 4毫升），並將混合物振搖1小時。將樹脂以 DMF(x3)、MeOH(x3)、CH2C12(x3)洗滌。於樹脂中加入 DMF(4 毫升）、CH2C12(2 毫升）、4-[Ν’ -（2-曱基笨基） 脲基]苯乙酸（70毫克，〇·25毫莫耳）、PyBrop(l 15毫克， 〇·25毫莫耳）及DIEA(0.13毫升，〇·75毫莫耳）。將混合物 振搖21小時並排液。將樹脂以dmf(x3)、MeOH(x3)、CH2C1 “x3)洗滌。於樹脂中加入TFA溶於CH2C12之溶液（50% v/v，4毫升），並將混合物振搖2小時。將混合物過濾，並 將濾液於真空中濃縮。利用Sep-pak管柱將殘留物純化。 於移除浴劑後’將E i：2 0加至殘留物，並收集所產生之固體\\312\2d-code\90-01\89112968.ptd Page 151 1283240 V. INSTRUCTION DESCRIPTION (147) The compound was washed with Et2(x2) and the aqueous layer was separated. This layer was acidified by the addition of in HC1. The mixture was extracted with EtOAc. The extract was washed with water, brine, dried over MgS04, and evaporated in vacuo to give 5.36 g (910 / 〇) of (S)-4 -(1 - Fmoc-2-pyrrolidinyl) methoxy The viscous oil of benzoic acid is allowed to stand for crystallization. Wang resin (0·71 mmol/g, 400 mg) was suspended in (S) -4 -(1 - Fmoc -2 -pyridyl) oxobenzoic acid (500) Mg, 1.13 mol), DMAP (35 mg, 0.29 mmol), HOBt (40 mg, 0·30 mmol) and DIC (0.45 ml, 2.9 mmol) in DMF (3 mL) and CH2C12 (7 ml) of a mixture of solutions. The mixture was shaken for 20 hours and drained. The resin was washed with DMF (x3), MeOH (x3), CH.sub.2C (x3), and dried under reduced pressure to give 522 mg of resin, which was used for the preparation of 8, 9, and 10. 8 A solution of hexahydropyridinium-dmF (50% v / v '4 ml) was added to the above resin (115 mg), and the mixture was shaken for 1 hour. The resin was washed with DMF (x3), MeOH (x3), CH2C12 (x3). DMF (4 ml), CH2C12 (2 ml), 4-[Ν'-(2-mercapto) ureido]phenylacetic acid (70 mg, 〇25 mmol), PyBrop (l) were added to the resin. 15 mg, 〇·25 mmol) and DIEA (0.13 ml, 〇·75 mmol). The mixture was shaken for 21 hours and drained. The resin was washed with dmf (x3), MeOH (x3), CH.sub.2 &quot;&quot;&quot;&quot;&quot;&quot;&quot;&quot;&quot;&quot;&quot;&quot;&quot; Filtration and concentration of the filtrate in vacuo. The residue was purified using a sep-pak column. After the bath was removed, E i: 20 was added to the residue and the resulting solid was collected.

1283240 五、發明說明（148) 而得25毫克之8的淡黃色結晶物質。 9 於以上的樹脂（6 0毫克）中加入六氫吼σ定溶於D M F之溶 液（50% ν/ν，3毫升），並將混合物振搖2小時。將樹脂以 DMF(x3)、Me0H(x3)、CH2C12(x3)洗滌。於樹脂中加入 DMF(2毫升）、CH2C12(1毫升）、3 -甲氧基-4-(N’ -苯基脲 基）苯乙酸（40毫克，0·13毫莫耳）、PyBrop(60毫克，〇. 13 毫莫耳）及DIEA(0· 060毫升，0. 34毫莫耳）。將混合物振搖 40 小時並排液。將樹脂以DMF(x3)、MeOH(x3)、CH2C12(X3) 洗滌。於樹脂中加入TFA溶於CH2C12之溶液（30% v/v，3毫 升），並將混合物振搖5小時。將混合物過濾，並將濾液於 真空中濃縮。利用Sep-Pak管柱將殘留物純化。於移除溶 劑後，將EhO加至殘留物，並收集固體而得8毫克之9的結 晶固體。 10 於以上的樹脂（6 3 7毫克）中加入六氫咄咬溶於dmf之 溶液（5 0% v/v，20毫升），並將混合物振搖4小時。將樹脂 以DMF(x3)、MeOH(x3)、CH2C12(x3)洗滌。於樹脂中加入曰 DMF(12 毫升）、CH2C12(8 毫升）、4-(Fm〇C-胺基）笨乙酸（53〇 毫克，1.42毫莫耳）、PyBrop(660毫克，Γ·43毫莫耳）及 〇^八（0.62毫升，3.56毫莫耳）。將混合物振搖6〇小時並排 液。將樹脂以DMF(x3)、MeOH(x3)、CH2C12(x3)洗滌，並在 減壓下乾燥而得617毫克之樹脂。將57毫克之此樹脂加入 六氫咄啶溶於DMF之溶液（40% v/v，2毫升）。將混合物振 搖 1 小時。將樹脂以 D M F (X 3 )、M e Ο H ( X 3 )、c H2 C12 ( X 3)洗 滌。將異氰酸2 -氯苯酯（0 · 0 5 0毫升，〇 · 41毫莫耳）加至樹1283240 V. Inventive Note (148) gives 25 mg of 8 pale yellow crystalline material. 9 To the above resin (60 mg) was added a solution of hexahydropurine in D M F (50% ν/ν, 3 ml), and the mixture was shaken for 2 hr. The resin was washed with DMF (x3), Me0H (x3), and CH2C12 (x3). DMF (2 ml), CH2C12 (1 ml), 3-methoxy-4-(N'-phenylureido)phenylacetic acid (40 mg, 0·13 mmol), PyBrop (60) were added to the resin. Mg, 〇. 13 mM) and DIEA (0·060 ml, 0.334 mmol). The mixture was shaken for 40 hours and drained. The resin was washed with DMF (x3), MeOH (x3), CH2C12 (X3). A solution of TFA in CH2C12 (30% v/v, 3 ml) was added to the resin, and the mixture was shaken for 5 hours. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified using a Sep-Pak column. After removing the solvent, EhO was added to the residue, and the solid was collected to give 8 mg of 9 of crystalline solid. 10 To the above resin (6.37 mg) was added a solution of hexahydroguanidine in dmf (50% v/v, 20 ml), and the mixture was shaken for 4 hours. The resin was washed with DMF (x3), MeOH (x3), CH2C12 (x3).曰DMF (12 ml), CH2C12 (8 ml), 4-(Fm〇C-amino) stearic acid (53 mg, 1.42 mmol), PyBrop (660 mg, Γ·43 mmol) were added to the resin. Ear) and 〇^8 (0.62 ml, 3.56 mmol). The mixture was shaken for 6 hours and drained. The resin was washed with DMF (x3), MeOH (x3), CH2C12 (x3) and dried under reduced pressure to yield 617 mg of resin. 57 mg of this resin was added to a solution of hexahydroacridine dissolved in DMF (40% v/v, 2 ml). The mixture was shaken for 1 hour. The resin was washed with D M F (X 3 ), M e Ο H (X 3 ), and c H2 C12 (X 3). Add 2-chlorophenyl isocyanate (0 · 050 ml, 〇 · 41 mmol) to the tree

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第153頁 1283240 五、發明說明（149) '^ 脂於THF(1毫升）及CI^CIJI毫升）之懸浮液中。將混合物振 搖20小時並排液。將樹脂以DMF(x3)、Me〇H(x3)、CH9C1 己 2 (x3)洗滌。於樹脂中加入tf A溶於CH2C12之溶液（2 5% v/v， 2毫升），並將混合物振搖1 · 5小時。將混合物過濾，並將 濾液於真空中濃縮。利用S e p - P a k管柱將殘留物純化。於 移除溶劑後’將Et20加至殘留物，並收集固體而得2毫克 之10的結晶固體。 實施例8 (S)-3-[2-[1-[ 3-甲氧基-4-（Ν’ _苯基脲基）笨基乙醯基]口比 咯啶基]甲氧基]苯乙酸Page 153 1283240 V. INSTRUCTIONS INSTRUCTIONS (149) The suspension of '^ fat in THF (1 ml) and CI^CIJI ml). The mixture was shaken for 20 hours and drained. The resin was washed with DMF (x3), Me〇H (x3), CH9C1 hexane (x3). A solution of tf A in CH 2 C 12 (2 5% v/v, 2 ml) was added to the resin, and the mixture was shaken for 1.5 hours. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified using a SeP-P a k column. After removing the solvent, Et20 was added to the residue, and the solid was collected to give 2 mg of a crystalline solid. Example 8 (S)-3-[2-[1-[3-Methoxy-4-(Ν'_phenylureido)phenyl)-pyridyl]methoxy]benzene Acetic acid

(S)-3 - [2-[1 -[4-（Ν’（2-曱基苯基）脲基）笨基乙醯基]，比咯 σ定基]甲氧基]苯乙酸 11及12 在室溫下於Boc-脯胺醇（3· 51克，17· 5毫莫 耳）、間羥基苯基乙酸甲酯（2· 90克，17· 5毫莫耳）、三苯 膦（4· 60克，17· 6莫耳）.溶於THF( 50毫升）之攪拌混合物中 逐滴加入偶氮二綾酸二乙酯（3· 05克，17· 5毫莫耳）。於添 加完成後，將混合物迴流加熱3小時。於冷卻後，將混合 物於真空中濃縮。將殘留物溶解於Et〇Ac，並以in Na〇H、(S)-3 - [2-[1 -[4-(Ν'(2-Mercaptophenyl)ureido)]phenylidene],pyrrolidine]methoxy]phenylacetic acid 11 and 12 Boc-prolinol (3·51 g, 17.5 mmol), m-hydroxyphenylacetate (2·90 g, 7.5 mmol), triphenylphosphine (4) at room temperature · 60 g, 7.6 m.). Diethyl azodicarboxylate (3.05 g, 17.5 mmol) was added dropwise to a stirred mixture of THF (50 mL). After the addition was completed, the mixture was heated under reflux for 3 hours. After cooling, the mixture was concentrated in vacuo. The residue is dissolved in Et〇Ac and in Na〇H,

第154頁 1283240 五、發明說明（150) ' 水、鹽水連續洗滌，並於MgS04上乾燥。於移除溶劑後， ，殘留物，由於矽膠上利用EtOAc-己烷（1 : 4，v/v)作為洗 提液$行管柱層析，純化而得5.49克（90%)之（S)-3-(1〜第 三丁氧幾基-2-咄咯啶基）甲氧苯乙酸甲酯的油。 使以上之（S)-3-(1-第三丁氧羰基—2-咄咯啶基）甲氧笨 乙酸曱酿溶於MeOH(60毫升）及IN NaOH(20毫升）之混合物 在室溫下攪拌8小時。於在減壓下將溶劑移除後，將水（5 〇 毫升）加至殘留物中。將混合物以ΕΪ2〇(χ2)萃取，經由加 入1N H C1將水層酸化。將混合物以E t 〇 A c萃取。將萃取物 以水、鹽水洗滌’於“3〇4上乾燥，然後於真空中濃縮而 得4.43克（88%)之（S)-3 - 1-第三丁氧羰基-2 -咄咯啶基）甲 氧苯乙酸之黏性油。 使以上之（S)-3-(1-第三丁氧羰基-2 -咄咯啶基）曱氧苯 乙酸溶於CH2C12(10毫升）及TFA(l〇毫升）之混合物在室溫下 授拌1小時。將Et2〇加至混合物並使其靜置。經由傾析將 上層移除而得一油。將此油溶於水（1 〇 〇毫升）、二氧陸園 (30毫升）及NaHC03(6. 0克）之混合物加入Fmoc-C1 (2· 86 克’ 11 · 1毫莫耳），並將混合物在室溫下攪拌2 〇小時。將 混合物以Et2〇(x2)萃取，及經由加入in HC1而將水層酸 化。將混合物以E10 A c萃取。將萃取物以水、鹽水洗務， 於MgS〇4上乾燥，並於真空中濃縮而得5· 〇8克（81%)之 (S)-3 -（ 1 - Fmoc-2-吡咯啶基）甲氧苯乙酸之黏性油。 使王氏樹脂（0.71毫莫耳/克，400毫克）懸浮於（s)-4 -(l_Fmoc-2 -吼咯啶基）甲氧苯乙酸（5 20毫克，1. 14莫耳） _ U 11 _ m \\312\2d-code\90-01\89l 12968.ptd 第 155 頁 1283240 五、發明說明（151) 、DMAP(35毫克，0.29毫莫耳）、HOBt(40毫克，0.30毫莫 耳）及DIC((K45毫升，2.9毫莫耳）溶於DMF(3毫升）及CH2C12 (7毫升）之混合物的溶液中。將混合物振搖2 〇小時並排 液。將樹脂以 DMF ( x3 )、MeOH(x3 )、CH2C12 (x3 )洗滌，並於 減壓下乾燥而得59 3毫克之樹脂，使用其於製備11及丨2。 11將以上樹脂（70毫克）於六氫咄啶-DMF(40% v/v，3毫 升）中之混合物振搖1小時。將樹脂以DMF(x3)、Me0H(x3)Page 154 1283240 V. INSTRUCTIONS (150) 'Water, brine are washed continuously and dried on MgS04. After removing the solvent, the residue was purified by using EtOAc-hexane (1: 4, v/v) as eluent for column chromatography, yielding 5.49 g (90%). An oil of methyl 3-(1~3 -butoxymethyl-2-pyridinyl)methoxybenzoate. The above (S)-3-(1-tert-butoxycarbonyl-2-pyrrolidinyl)methoxybenzoic acid oxime was dissolved in a mixture of MeOH (60 ml) and IN NaOH (20 ml) at room temperature. Stir under 8 hours. After removing the solvent under reduced pressure, water (5 mL) was added to the residue. The mixture was extracted with ΕΪ 2 〇 (χ 2) and the aqueous layer was acidified by the addition of 1N H C1. The mixture was extracted with E t 〇 A c. The extract was washed with water, brine <RTI ID=0.0></RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> <RTI ID=0.0> a viscous oil of methoxybenzoic acid. The above (S)-3-(1-tert-butoxycarbonyl-2-pyridinyl) oxime acetic acid was dissolved in CH2C12 (10 ml) and TFA ( 1 〇 ml) mixture was stirred at room temperature for 1 hour. Et2 〇 was added to the mixture and allowed to stand. The upper layer was removed by decantation to obtain an oil. This oil was dissolved in water (1 〇〇 ml) A mixture of dioxane (30 ml) and NaHC03 (6.0 g) was added to Fmoc-C1 (2·86 g '11 · 1 mmol), and the mixture was stirred at room temperature for 2 hr. The mixture was extracted with Et 2 〇 (x 2 ), and the aqueous layer was acidified by the addition of in HCl. The mixture was extracted with E 10 A c. The extract was washed with water, brine, dried over MgS 4 and vacuum. Concentrated to obtain 5·(8%) of (S)-3-(1-Fmoc-2-pyrrolidinyl)methoxybenzoic acid viscous oil. Make Wang resin (0.71 mmol/g , 400 mg) suspended in (s)-4 - (l_Fmoc-2 - 吼Pyridyl)methoxybenzoic acid (5 20 mg, 1.14 mol) _ U 11 _ m \\312\2d-code\90-01\89l 12968.ptd Page 155 1283240 V. Description of invention (151) , DMAP (35 mg, 0.29 mmol), HOBt (40 mg, 0.30 mmol) and DIC ((K45 mL, 2.9 mmol) dissolved in a mixture of DMF (3 mL) and CH2C12 (7 mL) In the solution, the mixture was shaken for 2 hrs and drained. The resin was washed with DMF (x3), MeOH (x3), CH2C12 (x3) and dried under reduced pressure to give 59. 11 and 丨2. 11 The mixture of the above resin (70 mg) in hexahydroacridine-DMF (40% v/v, 3 ml) was shaken for 1 hour. The resin was DMF (x3), Me0H (x3)

、CH2C 12 (χ 3 )洗鲦。於樹脂中加入DMF (1 · 5毫升）、CH2C 12 (1·5毫升）、3-曱氧基-4-(Ν’ -苯基脲基）苯乙酸（42毫 克 ’〇.14cfe 莫耳）、PyBrop(70 毫克，0.15 毫莫耳）及 DIEA (0 · 0 6 5耄升’ 〇 · 3 7毫莫耳）。將混合物振搖1 5小時並排 液。將樹脂以DMF(x3)、MeOH(x3)、CH2C12(x3)洗滌。於樹 脂中加入TFA溶於CH2C 12之溶液（25% v/v，2毫升），並將混 合物振搖3小時。將混合物過濾，並將濾液於真空中濃 縮。利用Sep-Pak管柱將殘留物純化。於移除溶劑後，將 Et20加至殘留物，並收集固體而得8毫克之11的結晶固 體。 12將以上樹脂（7 0毫克）於六氫咄啶-DMF(4 0% v/v，3毫 升）中之混合物振搖1小時。將樹脂以DMF(x3)、MeOH(x3) 、CH2C12(x3)洗滌。於樹脂中加入DMF(1· 5毫升）、CH2C12 (1·5毫升）、4- [Ν’-（2_曱基苯基）脲基]苯乙酸（4〇毫克， 0.14毫莫耳）、PyBr op (70毫克，0.15毫莫耳）及 DIE A ( 0 · 0 6 5毫升，0 · 3 7毫莫耳）。將混合物振搖1 5小時並 排液。將樹脂以DMF(x3)、MeOH(x3)、CH2C12(x3)洗滌。將, CH2C 12 (χ 3 ) Wash. DMF (1.5 ml), CH2C12 (1.5 ml), 3-decyloxy-4-(Ν'-phenylureido)phenylacetic acid (42 mg '〇.14cfe Moer) were added to the resin. , PyBrop (70 mg, 0.15 mmol) and DIEA (0 · 0 6 5 liters ' 〇 · 3 7 mmol). The mixture was shaken for 15 hours and drained. The resin was washed with DMF (x3), MeOH (x3), CH2C12 (x3). A solution of TFA in CH2C12 (25% v/v, 2 mL) was added to the resin, and the mixture was shaken for 3 hours. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified using a Sep-Pak column. After removing the solvent, Et20 was added to the residue, and the solid was collected to give 8 mg of 11 of crystalline solid. 12 A mixture of the above resin (70 mg) in hexahydroacridine-DMF (40% v/v, 3 ml) was shaken for 1 hour. The resin was washed with DMF (x3), MeOH (x3), CH2C12 (x3). DMF (1.5 ml), CH2C12 (1.5 ml), 4-[Ν'-(2- mercaptophenyl)ureido]phenylacetic acid (4 mg, 0.14 mmol) were added to the resin. PyBr op (70 mg, 0.15 mmol) and DIE A (0 · 0 6 5 mL, 0 · 3 7 mmol). The mixture was shaken for 15 hours and drained. The resin was washed with DMF (x3), MeOH (x3), CH2C12 (x3). will

I \\312\2d-code\90-01\89112968.ptd 第 156 頁 1283240 五、發明說明（152) ' 一 ------- ^脂於TFA-CH2Cl2(25% v/v，2毫升）中之混合物振搖 時。f混合物過遽’並將據液於真空中濃縮。利用Sep -Pak官柱將殘留物純化。於移除溶劑後，將Et2〇加至殘留 物，並收集固體而得u毫克之12的結晶固體。 實施例9 4-[2-[卜[3-甲氧基—4-(N，-苯基脲基）苯基乙醯基]一2一咄 咯啶基]乙炔基]苯甲酸I \\312\2d-code\90-01\89112968.ptd Page 156 1283240 V. INSTRUCTIONS (152) 'ONE-------^Fat in TFA-CH2Cl2 (25% v/v, 2 When the mixture in milliliters is shaken. The mixture was passed through 遽 and the liquid was concentrated in vacuo. The residue was purified using a Sep-Pak column. After removing the solvent, Et 2 hydrazine was added to the residue, and the solid was collected to give a crystalline solid of &lt Example 9 4-[2-[Bu[3-methoxy-4-(N,-phenylureido)phenylethenyl]-2-indolyl]pyridyl]ethynyl]benzoic acid

於N-Boc-脯胺酸（5.98克，30毫莫耳）及Pph3(62.95克， 240毫莫耳）溶於CH2C 12 (200毫升）之冷（-5〇。〇的攪拌溶液 中緩慢加入CBr4 ( 3 9. 80克，120毫莫耳）溶於CH2cl2(50毫 升）之溶液，並在0 °C下繼續攪拌1小時。於此混合物中加 入飽和NaHC〇3，及以CHClg萃取混合物。將萃取液以h2〇洗 滌，於MgS〇4上乾燥，並蒸發。將殘留物於矽膠上利用 CHCI3及正己烷-EtOAc(4:l，v/v)作為洗提液進行層析， 而得7.84克（74%)之1-(第三丁氧羰基）-2-(2, 2 -二溴乙烯 基）吼咯啶的無色板狀物。 熔點 6 卜 63°C; IR (KBr) 1 6 93 /公分；1H — NMR (CDC13)&lt;5 1·46 (9H，s)、1·72-2·19 (4H, m)、3·35-3·45 (2H, m)、4·35 (1Η, br s)、6·36 (1Η，br s); MS(FAB) m/z 352、354、356、358，CuHnNOgBi^ 之分析計算值：C，N-Boc-proline (5.98 g, 30 mmol) and Pph3 (62.95 g, 240 mmol) dissolved in CH2C 12 (200 mL) in cold (-5 〇. 〇 stirred solution slowly added A solution of CBr4 (3 9.80 g, 120 mmol) in CH.sub.2Cl.sub.2 (50 mL) was then stirred for one hour at 0[deg.] C. To this mixture was added saturated NaHC.sub.3 and the mixture was extracted with CHClg. The extract was washed with h2 ,, dried over MgSO 4 and evaporated. The residue was chromatographed with CHCI3 and n-hexane-EtOAc (4:1, v/v) as eluent. 7.84 g (74%) of a colorless plate of 1-(t-butoxycarbonyl)-2-(2,2-dibromoethenyl)pyrrolidine. Melting point 6 b 63 ° C; IR (KBr) 1 6 93 / cm; 1H - NMR (CDC13) &lt;5 1·46 (9H, s), 1.72-2·19 (4H, m), 3·35-3·45 (2H, m), 4 ·35 (1Η, br s), 6.36 (1Η, br s); MS (FAB) m/z 352, 354, 356, 358, CuHnNOgBi^ Analysis calculated value: C,

89112968.ptd 第157頁 128324089112968.ptd Page 157 1283240

37.14； Η, 37· 21 ; Η, 4· 83 ; N，3. 94。實測值·· c 4·83，N， 4.00 〇 於匕（$二丁氧幾基）_2-(2’2-二演乙稀基）吼 克，22毫莫耳）溶於THF(200毫升）之冷（_78。〇的授^容液 中在10分鐘内加入n-BuLi(1.59 Μ之己烷溶液，28毫 44毫莫耳），ϋ在相同溫度下繼續授摔2 :=而使反應停止’並以Et〇Ac進行萃取。將由 鹽水洗務，於_04上乾燥，並蒸發。㈣留物㈣/上 利用正己烷-EtOAc(10:l，v/v)作為洗提液進行層析，而 :4.15克(97%)之卜（第三丁氧幾基)_2_乙炔基吡咯啶的淡 黃色油。 l-NMR (CDCl3)(n.48 (9H，s)、1·82-2·21 (4H，m)、 3. 3 0 - 3 · 4 5 ( 2 Η, m )、4 · 4 1 - 4 · 5 2 ( 1 Η，m )。 使4一碘苯曱酸乙酯（1·7毫升，10毫莫耳）、Pd(pph3)4 (578毫克，〇·5毫莫耳）、及CuI(190毫克，！毫莫耳）^ i-Pr2NH(20毫升）中之懸浮液在N2下攪拌〇· 5小時。於此混 合物中在超過10分鐘内加入卜（第三丁氧羰基）—2—乙炔基 吼洛唆（1· 95克，1〇毫莫耳）溶於i-Pr2NH(20毫升）中之溶 液。於在室溫下攪拌3小時後，將混合物倒入仏^中，並以 EtOAc萃取。將萃取液以鹽水洗滌，於MgS〇4上乾燥，並蒸 發❶將殘留物於矽膠上利用正己烷—以^以丨^^/”作 為洗提液進行層析，而得2·77克（81%)之1-(第三丁氧羰 基）-2-(2-(4-乙氧羰基苯基）乙炔基）咄咯啶的無色油。 1R~NMR (CDC13) 5 1. 3 7 (3H, t, J = 6. 8 Hz) ^1.49 (9H,37.14; Η, 37· 21 ; Η, 4· 83 ; N, 3.94. Found C······················································ ) cold (_78. 〇 授 授 容 在 在 在 在 在 n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n The reaction was stopped and extracted with Et 〇Ac. It was washed with brine, dried over _04, and evaporated. (4) Residue (4)/on with n-hexane-EtOAc (10:1, v/v) as eluent Chromatography, and: 4.15 g (97%) of bis(t-butoxymethyl)- 2 ethynylpyrrolidine as a pale yellow oil. l-NMR (CDCl3) (n.48 (9H, s), 1 · 82-2·21 (4H, m), 3. 3 0 - 3 · 4 5 ( 2 Η, m ), 4 · 4 1 - 4 · 5 2 ( 1 Η, m ). 4-Iodobenzoic acid Ethyl ester (1.7 ml, 10 mmol), Pd(pph3)4 (578 mg, 〇·5 mmol), and CuI (190 mg, ! mmol) ^ i-Pr2NH (20 ml) The suspension was stirred under N2 for 5 hours. In this mixture, more than 10 minutes was added to the (t-butoxycarbonyl)-2-ethynyl fluorene (1·95 g, 1 〇 mmol). The solution was dissolved in i-Pr2NH (20 mL). After stirring at room temperature for 3 hrs, the mixture was poured into EtOAc and extracted with EtOAc. Drying and evaporating, the residue was chromatographed on a silica gel using n-hexane - hexanes </ </ RTI> </ RTI> as an eluent to give 2.77 g (81%) of 1-(t-butoxycarbonyl) a colorless oil of 2-(2-(4-ethoxycarbonylphenyl)ethynyl)pyrrolidine. 1R~NMR (CDC13) 5 1. 3 7 (3H, t, J = 6. 8 Hz) ^ 1.49 (9H,

89112968.ptd 第158頁 1283240 發明說明（154) s)、1·85-2·12 (4H，m)、3·37-3·51 (2H，m)、4·37 (2H，q，J = 6.8 Hz)、4·54-4·77 (1H，m)、7·44 (2H，d J = 7· 8 Hz)、7· 96 (2H，d，J = 7· 8 Hz)。 ’ ’ 於1-(第三丁氧羰基）-2_[2-(4-乙氧羰基苯基）乙炔基] 吼咯啶（2· 75克，8毫莫耳）溶於CH'l2 (5毫升）之攪拌溶&quot;液 中加入TFA ( 5毫升），並將所產生之混合物攪拌隔夜。將混 合物於真空中濃縮，並利用飽和NaHC〇3使成鹼性及以CHC13 萃取。將萃取液以鹽水洗滌，於MgS〇4上乾燥，蒸發而得3 1· 95克（q· y·)之2-[2-（4 -乙氧羰基苯基）乙炔基]吡咯啶的 淡黃色油。 l-NMR (CDC13) (51.38 (3H，t，J = 6.8 Ηζ)、1·82-2·16 (4 Η，m )、3 · 01 - 3 · 4 8 (2 Η，m )、4 · 0 0 - 4. 11 (1 Η，m )、 4·37 (2H，q，J = 6.8 Hz)、4·54-4·77 (1H，m)、7.44-7 46 (2H， m) 、 7· 95-7·97 (2H， m)。 將3-莫耳） 克，0· 克，0· 物攪拌 體。將 劑後， 為洗提 氧基-4 笨曱酸 甲氧基-4-(N’-苯基脲基）苯乙酸（18〇毫克，〇·6毫 2 (2-(4 -乙氧幾基苯基）乙炔基）υ比略0定（146毫 6¾莫耳）、EDC(173毫克，0.9毫莫耳）、DMAP(73毫 6毫莫耳）、及催化劑hob t於DMF( 1 0毫升）中之混合 隔夜。將混合物倒入』HC1中，並利用吸濾收集固 殘留物溶解於CHC13，並於MgS〇4上乾燥。於移除溶 將殘/留物於矽膠上利用CHC13-MeOH (10:1，V/V)作 $進行;^析，而得192毫克（61%)之4-[2-[1- [3-甲 N 苯基脲基）苯乙醯基]-2 -咄咯啶基]乙炔基1 乙S曰的淡黃色非晶形固體。89112968.ptd Page 158 1283240 Description of invention (154) s), 1·85-2·12 (4H, m), 3·37-3·51 (2H, m), 4·37 (2H, q, J = 6.8 Hz), 4·54-4·77 (1H, m), 7.44 (2H, d J = 7·8 Hz), 7·96 (2H, d, J = 7.8 Hz). ' ' in 1-(t-butoxycarbonyl)-2_[2-(4-ethoxycarbonylphenyl)ethynyl]pyridinidine (2.75 g, 8 mmol) dissolved in CH'l2 (5 THF (5 ml) was added to the stirred solution of ML) and the resulting mixture was stirred overnight. The mixture was concentrated in vacuo and made basic with saturated NaHC.sub.3 and extracted with CH. The extract was washed with brine, dried over MgS 4 and evaporated to give 3 1·95 g (q·y·) of 2-[2-(4-ethoxycarbonylphenyl)ethynyl]pyrrolidine Yellow oil. l-NMR (CDC13) (51.38 (3H, t, J = 6.8 Ηζ), 1.82-2·16 (4 Η, m ), 3 · 01 - 3 · 4 8 (2 Η, m ), 4 · 0 0 - 4. 11 (1 Η,m ), 4·37 (2H,q,J = 6.8 Hz), 4·54-4·77 (1H,m), 7.44-7 46 (2H, m) , 7· 95-7·97 (2H, m). Mix 3-mole), 0·g, 0·. After the agent, it is eluted as oxy-4 methoxy-4-(N'-phenylureido)phenylacetic acid (18 〇 mg, 〇·6 2 2 (2-(4-ethoxy) Phenyl phenyl) ethynyl) oxime ratio 0 (146 gram 63⁄4 mol), EDC (173 mg, 0.9 mmol), DMAP (73 mM 6 mmol), and catalyst hob t in DMF (1 0 The mixture was mixed overnight. The mixture was poured into HCl1, and the solid residue was collected by suction filtration and dissolved in CHC13, and dried on MgS〇4. The residue/residue was removed on silica gel using CHC13- MeOH (10:1, V/V) was obtained as a mp mp mp (m.). A pale yellow amorphous solid of 2 - oxaridinyl] ethynyl 1 ethyl sulfonate.

\\3l2\2d-code\90-01\89112968 ptd 第159頁 1283240 五、發明說明（155) UMR (CDC13)51.38 (3H，t，J = 6,8 Ηζ)、1·98-2.24 (4H，m)、3·48-3·89 (2H，m)、3·53 (2H，s)、3·62 (3H，s)、4·33-4·40 (2H，m)、4·78_5·04 (1H，m)、 6·77-8·00 (14H， m)。 於4 - [2 - [l-[3 -甲氧基-4- (Ν’ _苯基脈基）苯乙酿基] -2-咄咯啶基]乙炔基]苯甲酸乙酯（1 84毫克，0. 35毫莫耳） 溶於THF(5毫升）之攪拌溶液中加入0.25 N NaOH(4毫升）。 將所產生之混合物攪拌隔夜。將混合物倒入112 0中，並經 由加入1 N H C1 (1毫升）而成為酸性。利用吸濾收集固體， 並將其溶解於CHC13。將溶液於MgS04上乾燥並蒸發。使殘 留物自CHC13 -正己烷再結晶而得65毫克（37%)之1 3的白色 結晶粉末。 熔點 154-157 °C; IR (KBr) 3346、2952、2615、1712、 1 693 /公分；1H-NMR (CDC13) 61.92-2·29 (4H，m)、 3·32-3·82 (2Η，m)、3·78 (2Η，s)、3·80 (3Η，s)、 4·87-5·11 (1Η，m)、6·77-9·26 (14Η，m)、13·1〇 (1Η， br s); MS(FAB) m/z 498(MH1) ο 實施例1 0 4 - [2-[1-[3_曱氧基-4-]Ν’-（2_甲基苯基）脲基]苯基乙酿 基]2 - ]吼咯啶基]乙炔基]苯曱酸\\3l2\2d-code\90-01\89112968 ptd Page 159 1283240 V. Description of invention (155) UMR (CDC13) 51.38 (3H, t, J = 6,8 Ηζ), 1.98-2.24 (4H , m), 3·48-3·89 (2H, m), 3·53 (2H, s), 3·62 (3H, s), 4·33-4·40 (2H, m), 4· 78_5·04 (1H, m), 6·77-8·00 (14H, m). 4-[2- [1-[l-[3-methoxy-4-(Ν'_phenylphenyl)phenylethyl]-2-oxaridinyl]ethynyl]benzoic acid ethyl ester (1 84 To a stirred solution of THF (5 mL) was added 0.25 N NaOH (4 mL). The resulting mixture was stirred overnight. The mixture was poured into 112 0 and made acidic by the addition of 1 N H C1 (1 mL). The solid was collected by suction filtration and dissolved in CHC13. The solution was dried over MgS04 and evaporated. The residue was recrystallized from CHC13-n-hexane to give 65 mg (37%) of white crystals. Mp 154-157 ° C; IR (KBr) 3346, 2952, 2615, 1712, 1 693 / cm; 1H-NMR (CDC13) 61.92-2·29 (4H, m), 3·32-3·82 (2Η , m), 3·78 (2Η, s), 3·80 (3Η, s), 4·87-5·11 (1Η, m), 6·77-9·26 (14Η, m), 13· 1〇(1Η, br s); MS(FAB) m/z 498(MH1) ο Example 1 0 4 - [2-[1-[3_曱oxy-4-]Ν'-(2_甲甲Phenyl)ureido]phenylethyl][2-]pyridinyl]ethynyl]benzoic acid

：\\312\2d-code\90-01\89112968.ptd 第 160 頁 1283240 五、發明說明（156) 將3-甲氧基-4- [Ν’ - (2 -曱基苯基）脲基Ί絮7 克，4· 6毫莫耳）、2-(2-(4-乙氧羰基苯基）乙蚯=— (1. 12克，4· 6毫莫耳）、EDC(1· 32克，6· 9毫莫耳°比哈0疋 DMAP(5 62毫克，4.6毫莫耳）於DMF(2 0毫升）、 » ^ ^ ifn 拌隔夜。將混合物倒入1 N HC 1中，並利用级、、念i /愿收^ 隼[Ϊ] 。 將固體溶解於CHCI3，並於MgS04上乾燥。於蔣…_ 不多除溶劑後， 將殘留物於矽膠上利用CHC13 - MeOH (100:1，w 、 0 ν / ν )作為：先 提液進行層析，而得2·20克（89%)之4-[2〜[i 「q:\\312\2d-code\90-01\89112968.ptd Page 160 1283240 V. INSTRUCTIONS (156) 3-methoxy-4-[Ν'-(2-mercaptophenyl)ureido 7 g, 4·6 mmol, 2-(2-(4-ethoxycarbonylphenyl)acetamidine = (1. 12 g, 4.6 mmol), EDC (1·32)克,6·9 mmoler than Haha 0疋DMAP (5 62 mg, 4.6 mmol) in DMF (20 mL), » ^ ^ ifn mixed overnight. Pour the mixture into 1 N HC 1 and Use the grade, read i / will accept ^ 隼 [Ϊ]. Dissolve the solid in CHCI3 and dry on MgS04. In Chiang... _ After removing the solvent, the residue is applied to the tannin using CHC13 - MeOH (100: 1,w 、 0 ν / ν ) as: first extract liquid for chromatography, and obtain 2·20 g (89%) of 4-[2~[i ”q

Lei -甲氧基Lei-methoxy

-4 一（Ν’ -曱基苯基）脲基]苯乙醢基]一2-口比定其 u 心丞」乙快基J 苯曱酸乙酯的白色非晶形固體。 4-NMR (CDC13) 6 1· 37-1· 41 (3Η，m)、1· 94- 2 2 2 ( 4Η m)、2·29 (3H，s)、3·4 卜 3.89 (2H，m)、3·62 (3H ’ s)、3·69 (2Η，s)、4·34-4·40 (2Η，m)、4·72-5 0’1 (1Η，m)、6·33 (1Η，br-s)、6·80-8·06 (12H m)。 於4-[2-[1-[ 3 -甲氧基-4 -（Ν’-(2-甲基笨基）脲基）苯乙 醯基]-2 -吼洛咬基]乙炔基]笨甲酸乙酯（2 · 1 β克，4毫莫 耳）溶於THF(30毫升）之攪拌溶液中加入〇· 25 ν NaOH^32毫 升）’並持續授拌隔夜。將混合物倒入H2 0中，並經由加入 1 N HC 1 (8毫升）而酸化。利用吸濾收集所產生之沈殿物， 並將其溶解於CHC1S。將溶液於MgS04上乾燥並蒸發。使殘 留物自CHCI3 -正己烧再結晶而得555毫克（27%)之14的白色 結晶粉末。 m-4 A (Ν'-nonylphenyl)ureido]phenidinyl]- 2-port ratio of a white amorphous solid of ethyl ketone ethyl benzoate. 4-NMR (CDC13) 6 1· 37-1· 41 (3Η,m), 1· 94-2 2 2 ( 4Η m), 2·29 (3H, s), 3·4 卜 3.89 (2H, m ), 3·62 (3H ' s), 3·69 (2Η, s), 4·34-4·40 (2Η, m), 4·72-5 0'1 (1Η, m), 6.33 (1Η, br-s), 6·80-8·06 (12H m). 4-[2-[1-[3-Methoxy-4 -(Ν'-(2-methylphenyl)ureido)phenidinyl]-2-indolyl]ethynyl] Ethyl formate (2 · 1 β g, 4 mmol) was dissolved in THF (30 mL). EtOAc··········· The mixture was poured into H2 0 and acidified with 1N EtOAc (EtOAc). The resulting sediment was collected by suction filtration and dissolved in CHC1S. The solution was dried over MgS04 and evaporated. The residue was recrystallized from CHCI3 - n-hexane to give 555 mg (27%) of 14 white crystalline powder. m

熔點 16 卜 164°C; IR (KBr) 3338、2954、2875、1707、 1691/ 公分；UMR (CDC13) (51·96-2·1〇 (4HMelting point 16 Bu 164 ° C; IR (KBr) 3338, 2954, 2875, 1707, 1691 / cm; UMR (CDC13) (51·96-2·1〇 (4H

W312\2d-code\90-01\89112968.ptd 第161頁 1283240 五、發明說明（157) 3· 62 (2H，s)、 6· 76-8· 58 ( 13Η， 2· 24 (3H，s)、3· 32-3. 81 (2H，m) 3· 81 (3H，s)、4· 87-5. 10 (1H，m) m) ; MS(FAB) m/z 512(MH1)。 實施例11W312\2d-code\90-01\89112968.ptd Page 161 1283240 V. Description of invention (157) 3· 62 (2H, s), 6· 76-8· 58 (13Η, 2· 24 (3H, s ), 3·32-3. 81 (2H, m) 3· 81 (3H, s), 4·87-5. 10 (1H, m) m); MS (FAB) m/z 512 (MH1). Example 11

COOH 15 將3-甲氧基-4 - [Ν，-（2 -甲基笨基）脲基]苯乙酸（141毫 克’0.45毫莫耳）、2-[2-(3 -乙氧羰基甲基苯基）乙炔基] 口比洛咬（116毫克，〇· 45毫莫耳）、EDC(130毫克，0· 68毫莫 耳）、DMAP(55毫克，0.45毫莫耳）、及催化劑H0Bt於 DMF(10毫升）中之混合物攪拌隔夜。將混合物倒入〇 HC1 中’並經由過濾收集固體。將固體溶解於CHC“，並於 MgS〇4上乾燥’及蒸發。將殘留物於矽膠上利用CHC1rMe〇H (100 : 1，v/v)作為洗提液進行層析，而得一油，將其溶解 於THF(5公升）=，將〇·25 N Na〇H($毫升）加至此溶液並攪 拌。於攪拌隔夜後，將混合物倒入i N HC丨（2 〇毫升）中。利 用吸濾收集所產生之沈殿物，並將其溶解於Cηc i3。將溶 液於MgS〇4上乾燥並蒸發。將殘留物於石夕膠 Η(5:1，ν/ν)作為洗提液進行層析，而上二】。毫HC克 13 (3 9 % )之1 5的白色非晶形固體。 HMR (CDC13) (51.96-2.18 (7H，m)、3. 5〇_3.88 (9H，COOH 15 3-methoxy-4 -[Ν,-(2-methylphenyl)ureido]phenylacetic acid (141 mg '0.45 mmol), 2-[2-(3-ethoxycarbonyl) Phenyl)ethynyl] piroxime (116 mg, 〇·45 mmol), EDC (130 mg, 0·68 mmol), DMAP (55 mg, 0.45 mmol), and catalyst H0Bt The mixture in DMF (10 mL) was stirred overnight. Pour the mixture into 〇 HC1' and collect the solids by filtration. The solid was dissolved in CHC ", and dried on MgS 4" and evaporated. The residue was chromatographed on a silica gel using CHC1rMe〇H (100:1, v/v) as an eluent to give an oil. This was dissolved in THF (5 liters) = 〇·25 N Na〇H ($ mL) was added to this solution and stirred. After stirring overnight, the mixture was poured into i N HC (2 mL). The resulting sediment was collected by suction filtration and dissolved in Cηc i3. The solution was dried on MgS 4 and evaporated. The residue was taken as an eluent on Shixia capsule (5:1, ν/ν). Chromatography, and the second two]. 1.5 g of a white amorphous solid of 15 g (3 9 %) of Hg (CDC13) (51.96-2.18 (7H, m), 3. 5〇_3.88 (9H,

\\312\2d-code\90-01\89112968.ptd\\312\2d-code\90-01\89112968.ptd

第162頁 1283240 (ΗΗ，m) ; MS(FAB) 乙酿基]~ 2 -吼洛σ定 m)、4·78_4·98 (2H，m)、6, 72-7.99 m/z 526(MH1) 〇 實施例1 2 4 - [1 - [4 - [Ν’ -（2 -甲基苯基）脲基]笨基 基甲氧基]異酞酸Page 162 1283240 (ΗΗ, m) ; MS(FAB) 乙酿基]~ 2 - 吼洛σ定m), 4·78_4·98 (2H, m), 6, 72-7.99 m/z 526 (MH1 〇Example 1 2 4 - [1 - [4 - [Ν' -(2-methylphenyl)ureido]] methoxy]isodecanoic acid

16 於4 - [Ν’-（2-甲基苯基）脲基]苯乙酸之五氟笨基酯（232 克，5·15毫莫耳）、（S)-4-(2 -吼咯啶基甲氧基）異酞酸二 甲酯（1. 51克，5· 15毫莫耳）溶於DMF (20毫升）之授摔溶液 中加入EtJU · 0毫升，6. 65毫莫耳），並將混合物攪拌隔 夜。將所產生之混合物以E10 A c稀釋。將溶液以鹽水洗 滌，於MgS〇4上乾燥，並於真空中蒸發掉。將殘留物經由 於矽膠上利用CHC13-MeOH(10 ·· 1，v/v)作為洗提液進行管 柱層析，純化而得1·58克（55%)之4-[1-[4-[1^’-(2-甲基苯 基）脲基]苯基乙醯基]-2-吼洛σ定基甲氧基]異酞酸二甲酉旨 的黃色結晶固體。 UMR (CDC13)(51.87-2·25 (m，總計7Η)、3·50-3·65 (m，4 Η)、3 · 8 5 (s，3 Η)、3 · 8 9 (s，3 Η)、4 · 1 8 - 4 · 3 1 (m， 2H)、4·44 (m，1H)、6·95-8·45 (m,總計 13H)。 於4-[1-[Ν’ _(2-甲基苯基）脲基]苯基乙醯基]-2 -咄咯啶 基曱氧基]異酞酸二甲酯（1·56克，2·79毫莫耳）溶於thf16 pentafluorophenyl ester of 4 - [Ν'-(2-methylphenyl)ureido]phenylacetic acid (232 g, 5·15 mmol), (S)-4-(2 -吼Dimethyl hexyl methoxy)isodecanoate (1.51 g, 5·15 mmol) was dissolved in DMF (20 ml) and added to EtJU · 0 ml, 6. 65 mmol. And the mixture was stirred overnight. The resulting mixture was diluted with E10 A c. The solution was washed with brine, dried over MgSO 4 and evaporated in vacuo. The residue was subjected to column chromatography using CHC13-MeOH (10··1, v/v) as an eluent, and purified to obtain 1.58 g (55%) of 4-[1-[4 - Yellow crystalline solid of [1^'-(2-methylphenyl)ureido]phenylethenyl]-2-indolyl sigma methoxy]isodecanoate. UMR (CDC13) (51.87-2·25 (m, total 7Η), 3·50-3·65 (m, 4 Η), 3 · 8 5 (s, 3 Η), 3 · 8 9 (s, 3 Η), 4 · 1 8 - 4 · 3 1 (m, 2H), 4·44 (m, 1H), 6·95-8·45 (m, total 13H). In 4-[1-[Ν' _(2-Methylphenyl)ureido]phenylethenyl]-2-pyrrolidinyloxy]isodecanoic acid dimethyl ester (1·56 g, 2.79 mmol) is soluble Thf

\\312\2d-code\90-01\89112968.ptd 第163頁 1283240 五、發明說明（159) (30毫升）之攪拌溶液中加入〇·25 N NaOH(20毫升），並將 反應混合物迴流加熱隔夜。將所產生之混合物倒入1 N HC1中，並收集固體。將粗製固體以Et20洗滌而得574毫克 (39%)之16的黃色非晶形固體。 IR (KBr) 1710/公分；NMR (DMSO-d6) 51.83-2 18 (m，4H)、2· 24 (s，3H)、3· 36-4· 28 (m，8H)、 · 6 · 9 1 -9 . 0 2 (m 系列，總計 1 3 Η)、1 2 · 8 9 (br s， 1 Η); MS(FAB) m/z 53 2 (MH1)。 ’ 實施例1 3 4-[ 2-[卜[3-曱氧基-4-[ Ν’ -(2-甲基苯基）脲基]笨基乙醯 基]- 2 -吼17各0定基]乙稀基]苯曱酸\\312\2d-code\90-01\89112968.ptd Page 163 1283240 V. Inventive Note (159) (30 ml) was added to a stirred solution of 〇·25 N NaOH (20 mL) and the reaction mixture was refluxed. Heat overnight. The resulting mixture was poured into 1 N HCl and a solid was collected. The crude solid was washed with EtOAc to afford 574 mg (39%). IR (KBr) 1710/cm; NMR (DMSO-d6) 51.83-2 18 (m, 4H), 2·24 (s, 3H), 3· 36-4· 28 (m, 8H), · 6 · 9 1 -9 . 0 2 (m series, total 1 3 Η), 1 2 · 8 9 (br s, 1 Η); MS (FAB) m/z 53 2 (MH1). 'Example 1 3 4-[2-[Bu[3-曱oxy-4-[Ν'-(2-methylphenyl)ureido]] phenylamino]- 2 -吼17 each 0 base Benzoic acid

ΌΟΗ 17 於4-[2-[2-[Ν’ -第三丁氧羰基]吼咯啶基乙烯基]苯甲腈 (2. 26克，7. 57毫莫耳）溶於⑶/丨“以毫升）之攪拌溶液中 在0 °C下於1 5分鐘内逐滴加入氫化二異丙鋁之丨.5Μ溶液（甲 苯溶液&gt;(6.06毫升，9.09毫莫耳）。將所產生之溶液在 下攪拌3小時。經由加入飽和肿/^吏溶液停止反應。將所 產生之混合物過滤通過矽藻土，並以以^〇萃取滤液。將 濾液以鹽水洗滌，於NazSO2上乾燥，並於真空中蒸發而 1. 89克（83%)之4-[2-[2-[N-第三丁氧羰基]n比咯 基]苯甲醛之黃色糖漿。 ~ 於NaOH(l. 00克，25, 1毫莫耳）溶於水（1〇毫升）之攪拌溶ΌΟΗ 17 is dissolved in (3) / 4- in 4-[2-[2-[Ν'-t-butoxycarbonyl]pyridinylvinyl]benzonitrile (2.26 g, 7.57 mmol) In a stirred solution of cc), a solution of diisopropylaluminum hydride (5 Torr) (toluene solution &gt; (6.06 ml, 9.09 mmol) was added dropwise at 0 ° C over 15 minutes. Stir for 3 hours. Stop the reaction by adding a saturated swollen solution. The resulting mixture was filtered through diatomaceous earth and the filtrate was extracted with hydrazine. The filtrate was washed with brine, dried over NazSO2, and evaporated. 1. 89 g (83%) of a yellow syrup of 4-[2-[2-[N-t-butoxycarbonyl]n-pyryl]benzaldehyde. ~ NaOH (1.0 g, 25, 1 millimolar) dissolved in water (1 ml)

1283240 五、發明說明（160) 液中在0 C下於0.5小時内加入AgN03(2.13克，12.5毫莫 耳）溶於C^CNCl 0毫升）之溶液。於以上的攪拌混合物中在 〇 C下於20分鐘内逐滴加入4-[2-[2-(N-第三丁氧羰基）吼 略啶基]乙烯基]苯甲醛（1·89克，6.27毫莫耳）溶於邙3 CN(1 〇毫升）之溶液。於將所產生之混合物在室溫下再多授 拌3小時後，利用吸濾將混合物過濾，然後以熱水洗滌。 於將濾'液以EtOAc洗滌後，經由小心加入1 ν HC 1而將水層 酸化，然後以CHCI3萃取。將萃取液於Na2S〇4上乾燥，並於 真空中蒸發而得〇· 700克（2步驟35°/〇)之4-[2 - [2-[(N-第三 丁氧羰基）咄咯啶基]乙烯基]苯曱酸之淡黃色結晶物質。 在室溫下於4-[ 2-[2-[Ν’ -第三丁氧羰基]咄咯啶基]乙烯 基]苯甲酸（0.700克，2.21毫莫耳）溶於Me〇H-苯（1 : 4 v/v，30毫升）之攪拌溶液中逐滴加入TMSCHN2(1· 32毫升， 2.65¾莫耳）之2M正己烧溶液。於將溶液在室溫下攪拌 小時後’將溶液於真空中蒸發。將所產生之唯一的殘留物 於矽膠上利用EtOAc -正己烷（1 : 6，v/v)作為洗提液進行層 析而得0· 64克（88%)之4-[2- [2-(N-第三丁氧羰基）。比咯咬曰 基]乙烯基]笨曱酸甲酯的淡黃色結晶物質。 在室溫下於4-[2-[2-(N-第三丁氧羰基')吡咯啶基]乙 基]苯曱酸曱酯（0.64克，1·93毫莫耳）溶於CH2Cl2(5毫 之攪拌溶液中加入TFA(5毫升）。於將混合物在室溫下 1小時後，將混合物於真空中蒸發。將殘留物以飽和 NaHC〇3進行處理，並以CHC13萃取。將萃取液於上 燥，並於真空中蒸發而得0.45克（100%)之4一[2一（2— ^\1283240 V. INSTRUCTIONS (160) A solution of AgN03 (2.13 g, 12.5 mmol) dissolved in C^CNCl 0 ml) was added to the solution at 0 C for 0.5 hour. To the above stirred mixture, 4-[2-[2-(N-Tertixocarbonylcarbonyl)-azulidine]vinyl]benzaldehyde (1·89 g, was added dropwise under 〇C over 20 min. 6.27 millimoles) A solution of 邙3 CN (1 〇 ml). After the resulting mixture was further mixed for 3 hours at room temperature, the mixture was filtered by suction filtration and then washed with hot water. After the filtrate was washed with EtOAc, the aqueous layer was acidified by careful addition of 1 EtOAc, and then extracted with CHCI3. The extract was dried over Na 2 S 〇 4 and evaporated in vacuo to give &lt;RTI ID=0.0&gt;&gt; Light yellow crystalline material of pyridyl]vinyl]benzoic acid. 4-[2-[2-[Ν'-T-Butoxycarbonyl]pyridinyl]vinyl]benzoic acid (0.700 g, 2.21 mmol) dissolved in Me〇H-benzene at room temperature ( A 2M positive hexane solution of TMSCHN2 (1·32 ml, 2.653⁄4 mol) was added dropwise to a stirred solution of 1 : 4 v/v, 30 ml). After the solution was stirred at room temperature for an hour, the solution was evaporated in vacuo. The only residue produced was chromatographed on silica gel using EtOAc-hexanes (1:6, v/v) as eluent to give &lt;RTI ID=0.0&gt; -(N-Tertidinoxycarbonyl). A light yellow crystalline material that is a bit of a vinyl ester. Ethyl 4-[2-[2-(N-tert-butoxycarbonyl')pyrrolidinyl]ethyl]benzoate (0.64 g, 1.93 mmol) was dissolved in CH 2 Cl 2 at room temperature ( To a stirred solution of EtOAc (5 mL), EtOAc (EtOAc) Dry on the air and evaporate in a vacuum to obtain 0.45 g (100%) of 4 [2 one (2 - ^\)

1283240 五、發明說明（161) --- •基）乙烯基]苯甲酸甲醋之黃色結晶物質。 在^溫下於3一甲氧基—4—[N，_(2一甲基苯基）脲基]笨乙酸 (285¾克，0.906毫莫耳）、4-[2-(2 -咄咯啶基）乙烯基]笨 甲酸甲酯（210毫克，〇· 9 06毫莫耳）溶於DMF(4毫升）之攪拌 混合物中加入1 -乙基一3一（3一二甲胺丙基）氰胺（EDC) (2〇9毫 克’ 1二09毫莫耳）、1-羥基苯并三唑（H〇Bt)(147毫克， 1二09毫莫耳）及4_二曱基胺基咄啶（DMAp)(11毫克，〇. 〇9〇6 毫莫耳）。於將所產生之混合物在室溫下授拌4 8小時後， 將混合物倒入冰的1 N HC 1中，並以ε t〇Ac萃取。將萃取液 於NaJO4上乾燥，並於真空中蒸發。將殘留物於矽膠上利 用丙酮-甲苯（1:4至1:1，v/v)作為洗提液進行層析而得〇· 47克（98%)之4- [2 - [1 - [3 -曱氧基一 4- [N，-(甲基苯基）脲基] 苯基乙醯基]-2-咄咯啶基]乙烯基]苯甲酸甲酯的白色結晶 物質。 於4 - [2-[1 -[3 -甲氧基-4-[N，-（甲基苯基）脲基]苯基乙 醯基]- 2 -咄咯啶基]乙烯基]苯甲酸甲酯（〇. 4 7克，〇 · 8 9毫 莫耳）溶於THF(5毫升）之攪拌溶液中加入〇· 25N NaOH (5 · 3 6毫升）。將所產生之混合物在室溫下攪拌2 〇小時。以 1N HC1將混合物酸化。以e 10Ac萃取混合物。將萃取液以 鹽水洗條’於N a? S 〇4上乾燦’並於真空中蒸發而得4 3 0毫克 (94%)之17的白色結晶物質。 W-NMR (4 0 0MHz, DMS0-d6) (51.78-2.13 (4H，m)、2·50 (3H，s)、3. 44-3.68 (4H，m)、3·75 及 3·82 (3H，s)、4· 71 (1H， m) 、 6· 26-8·59 (15H， m)。1283240 V. INSTRUCTIONS INSTRUCTIONS (161) --- • Phenyl] vinyl] benzoic acid methyl ketone yellow crystalline material. At a temperature of 3 -methoxy-4-[N,-(2-methylphenyl)ureido]dotic acid (2,853⁄4 g, 0.906 mmol), 4-[2-(2-pyrrole) Add 1-ethyl- 3-(3-dimethylaminopropyl) to a stirred mixture of DMF (4 ml) in a stirred solution of pyridine. Cyanamide (EDC) (2〇9 mg '1 2 09 mmol), 1-hydroxybenzotriazole (H〇Bt) (147 mg, 1 209 mmol) and 4-didecylamino Acridine (DMAp) (11 mg, 〇. 〇9〇6 mmol). After the resulting mixture was stirred at room temperature for 48 hours, the mixture was poured into ice 1 N HC 1 and extracted with ε t〇Ac. The extract was dried over NaJO4 and evaporated in vacuo. The residue was chromatographed on silica gel using acetone-toluene (1:4 to 1:1, v/v) as an eluent to give 47·47 g (98%) of 4-[2 - [1 - [ A white crystalline material of methyl 3-methoxy-[N,-(methylphenyl)ureido]phenyl(phenyl)]-2-oxaridinyl]vinyl]benzoate. 4-[2-[1 -[3-methoxy-4-[N,-(methylphenyl)ureido]phenylethenyl]-2-pyrrolidinyl]vinyl]benzoic acid To a stirred solution of MeOH (5 mL) was added EtOAc············ The resulting mixture was stirred at room temperature for 2 hrs. The mixture was acidified with 1 N HCl. The mixture was extracted with e 10Ac. The extract was washed with a brine <RTI ID=0.0></RTI> </ RTI> <RTI ID=0.0></RTI> </ RTI> <RTIgt; </ RTI> </ RTI> <RTIgt; W-NMR (400 MHz, DMS0-d6) (51.78-2.13 (4H, m), 2·50 (3H, s), 3. 44-3.68 (4H, m), 3.75 and 3.82 ( 3H, s), 4·71 (1H, m), 6·26-8·59 (15H, m).

I \\312\2d-code\90-01\89112968.ptd 第 166 頁 1283240 五、發明說明（162) 實施例1 4 4_[ 2-U - [3-甲氧基-4-(Ν’ -笨基脲基）苯基乙醯基]一2…比 咯啶基]乙烯基]苯甲酸I \\312\2d-code\90-01\89112968.ptd Page 166 1283240 V. INSTRUCTIONS (162) EXAMPLE 1 4 4_[ 2-U - [3-methoxy-4-(Ν' - Phenylureido)phenyl phenyl]] 2...pyrrolidyl]vinyl]benzoic acid

在室溫下於3-甲氧基_4-(Ν’ _苯基脲基）苯乙酸（3〇5毫 克，1· 03毫莫耳）、4- [2-（2-咄咯啶基）乙烯基]苯甲酸甲 酯（235毫克，1.01毫莫耳）溶於DMF( 4毫升）之攪拌溶液中 加入卜乙基-3-(3-二甲胺丙基）氰胺（232毫克，ι·2ΐ毫莫 耳）、1-經基苯并三11 坐（HOBt)(164毫克，1·21毫莫耳）及4一 二甲基胺基咄啶（ΜΑΡ)( 12毫克，0· 101毫莫耳）。於將混 合物攪拌48小時後，經由加入1 N HC 1將混合物酸化。以 EtOAc萃取混合物。將萃取液以鹽水洗滌，於Na2s〇4上乾 燥’並於真空中蒸發而得一油性殘留物。將殘留物於石夕膠 上利用丙酮··甲苯（1 : 4至1 : 1，v / v )作為洗提液進行層析 而得0· 43克（83%)之4 - [2 - [1-[3-甲氧基-4-(N’ -苯基脲基） 苯基乙醯基]-2 - σ比17各σ定基]乙稀基]苯曱酸曱酷的白色結晶 固體。 在室溫下於4-[2-[1-[ 3-曱氧基-4-(Ν，-笨基脲基）苯基 乙醯基]-2-咄咯啶基]乙烯基]苯曱酸甲酯（〇· 43克，0. 847 毫莫耳）溶於THF(5毫升）之攪拌溶液中加入Q.25N NaOH之 溶液（5· 04毫升）。於將所產生之混合物攪拌2〇小時後，經 由小心加入IN HC1將混合物酸化。以EtOAc萃取混合物。3-methoxy-4-(Ν'-phenylureido)phenylacetic acid (3〇5 mg, 1.03 mmol), 4-[2-(2-oxaridinyl) at room temperature To a stirred solution of methyl]benzoic acid methyl ester (235 mg, 1.01 mmol) in DMF (4 mL) was added ethyl b-ethyl-3-(3-dimethylaminopropyl) cyanamide (232 mg, ι·) 2 ΐ millimoles), 1-Phenylbenzotriene 11 (HOBt) (164 mg, 1.21 mmol) and 4 dimethylamino acridine (ΜΑΡ) (12 mg, 0·101 mil Moore). After the mixture was stirred for 48 hours, the mixture was acidified by the addition of 1 N HCl. The mixture was extracted with EtOAc. The extract was washed with brine, dried over Na.sub.4, and evaporated in vacuo to give an oily residue. The residue was chromatographed on acetone-toluene using acetone·· toluene (1:4 to 1:1, v / v) as an eluent to obtain 0·43 g (83%) of 4 - [2 - [ 1-[3-Methoxy-4-(N'-phenylureido)phenylphenyl]yl]-2 - σ ratio 17 sigma-based] ethylidene] benzoic acid 曱 cool white crystalline solid. 4-[2-[1-[3-曱-oxy-4-(indolyl)-phenylureido)phenylethenyl]-2-indolyl]vinyl]phenylhydrazine at room temperature A solution of Q.25N NaOH (5. 04 ml) was added to a stirred solution of EtOAc (5 mL, EtOAc). After the resulting mixture was stirred for 2 hours, the mixture was acidified by careful addition of IN HCl. The mixture was extracted with EtOAc.

W312\2d-code\90-01\89112968.ptd 第 167 頁 1283240W312\2d-code\90-01\89112968.ptd Page 167 1283240

五、發明說明（163) 將萃取液以鹽水洗條，於上乾燥 而得3 9 7毫克（9 5 %)之1 8的白色結晶物質 並於真空中蒸發 ^-NMR (4 00MHz, DMSO-d6) 5 1. ?8-2 13 (4H-3·68 (4H，m)、3·74、3·82 (3H，s)、4 716·27-9·28 (16Η， m) 。 ’ · 實施例1 5 m)、3· 17(1 H，m)、 4-[2-Π - [3_甲氧基-4-[Ν’-（2-甲基苯基）脲基]笨基乙 基]- 2 -吼洛σ定基]乙稀基]苯甲酸V. INSTRUCTIONS (163) The extract was washed with brine and dried to give 397 mg (yield: 975) of white crystals of white crystals and evaporated in vacuo. NMR (400 MHz, DMSO- D6) 5 1. ?8-2 13 (4H-3·68 (4H, m), 3.74, 3.82 (3H, s), 4 716·27-9·28 (16Η, m). · Example 1 5 m), 3 · 17 (1 H, m), 4-[2-Π-[3_methoxy-4-[Ν'-(2-methylphenyl)ureido] Benzyl]- 2 - fluorene succinyl] ethyl benzoic acid

ΟΟΗ 19 使4-[2-[1-[3_甲氧基-4-[Ν，-（2-甲基苯基）脲基]苯基 乙醯基]-2 -吼咯啶基]乙烯基]苯甲酸（184毫克，〇358毫 莫耳）及5% Pd-C(368宅克）於MeOH中之混合物在大氣壓力 中在室溫下氫化。於將混合物在室溫下攪拌21小時後，將 不溶解的催化劑過濾掉，及將濾液於真空中蒸發。將殘留 物於♦膠上利用M0H - CHC13(1:4至1:3，v/v)作為洗提液進 行層析而得1 2 3毫克（6 6 % )之1 9的白色結晶物質。 4-NMR (DMS0-d6) 51. 5 5-2. 03 (m，6H)、2. 24 (s，3H)、 2 · 6 0 (m，2 Η)、3 · 1 7 - 3. 5 9 (m，4 Η)、3 · 8 3 ( s，3 Η)、3 . 9 7 (m，1Η)、6· 61-8. 57 (m，13Η) ; MS(FAB) m/z ： 516(M HI)。 實施例1 6 3 - [1-[3-甲氧基-4 - [Ν’- (2-甲基苯基）脲基]笨基乙醯基]ΟΟΗ 19 4-[2-[1-[3_methoxy-4-[Ν,-(2-methylphenyl)ureido]phenylethenyl]-2-pyridinyl]ethene A mixture of benzoic acid (184 mg, 〇358 mM) and 5% Pd-C (368 oz) in MeOH was hydrogenated at room temperature under atmospheric pressure. After the mixture was stirred at room temperature for 21 hours, the insoluble catalyst was filtered off and the filtrate was evaporated in vacuo. The residue was chromatographed on EtOAc using EtOAc (EtOAc: EtOAc: EtOAc) 4-NMR (DMS0-d6) 51. 5 5-2. 03 (m, 6H), 2. 24 (s, 3H), 2 · 6 0 (m, 2 Η), 3 · 1 7 - 3. 5 9 (m, 4 Η), 3 · 8 3 ( s, 3 Η), 3. 9 7 (m, 1 Η), 6 · 61-8. 57 (m, 13 Η); MS (FAB) m/z : 516 (M HI). Example 1 6 3 - [1-[3-Methoxy-4 -[Ν'-(2-methylphenyl)ureido]]phenylamino]

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^ \\312\2d-code\90-01\89112968.ptd 第168頁 1283240 五、發明說明（164) - 2 -吡咯啶基]曱基硫苯甲酸^ \\312\2d-code\90-01\89112968.ptd Page 168 1283240 V. INSTRUCTIONS (164) - 2 - Pyrrolidinyl] Mercaptothiobenzoic acid

於間峨紛（20. 0克’ 90· 9毫莫耳）溶於DMF(2〇〇毫升）之溶 液中加入1，4-二4雙環[2,2, 2]辛烷（20.4克，181.8毫莫 耳）及二甲基硫胺甲酿氯（16.9克，136.4毫莫耳）。使所產 生之混濁溶液在35°C下攪拌〇·5小時，然後在75°c下加熱 0 · 5小時。於冷卻後，將3 0 0毫升水加至此混合物。收集固 體，以水洗滌，及於減壓下乾燥而得27· 63克（99%)之二甲 基硫胺基甲酸0 -間蛾笨s旨的淡黃色結晶粉末。 IR (KBr) 1 540、1 463、1 278、1193、1166、1124/公 分；1Η-NMR (400 MHz，CDC13) 6 3· 33 (s，3H)、3. 45 (s， 3H)、7.05-7.14 (m，2H)、7·43 (d，J = 1.9 Hz，1H)、 7.58 (dd, J = 1.0 &gt;7.8 Hz, 1H); MS(FAB) m/z 307(M+ + 1) ; C9H1QINOS 之分析計算值：c，35. 19 ; H，3. 28 ; N， 4.56。實測值：C，35.23; H，3.40; N，4.41。 使二甲基硫胺基甲酸0-間碘苯酯（1 〇 · 〇克，3 2 · 6毫莫耳） 溶於Ph2 0( 2 5宅升）之溶液在2 3 0 °C下加熱1 〇 \[、時。於冷卻 後’使反應混合物於矽膠上利用正己烧—E〇Ac(5 ·•丨，v/v) 作為洗提液進行層析而得9· 31克（93%)之二甲基硫胺基曱 酸S-間碘苯酯的淡黃色油。 !H-NMR (400 MHz, CDC13) ^3. 08 (br s, 6H) ' 7. 11 (t, J = 7.8 Hz，1H)、7·46 (d，J = 7.3 Hz，1H)、7·71 (d，Add 1,4-di 4bicyclo[2,2,2]octane (20.4 g, in a solution of 20.0 g of '90·9 mmol) dissolved in DMF (2 mL). 181.8 millimoles) and dimethyl thioamine-brewed chlorine (16.9 grams, 136.4 millimoles). The resulting turbid solution was stirred at 35 ° C for 5 hours and then heated at 75 ° C for 0.5 hours. After cooling, 300 ml of water was added to the mixture. The solid was collected, washed with water, and dried under reduced pressure to give 27.63 g (yield: 99%) of dimethyl thiocarbamic acid as a pale yellow crystalline powder. IR (KBr) 1 540, 1 463, 1 278, 1193, 1166, 1124 / cm; 1 Η-NMR (400 MHz, CDC13) 6 3· 33 (s, 3H), 3. 45 (s, 3H), 7.05 -7.14 (m, 2H), 7·43 (d, J = 1.9 Hz, 1H), 7.58 (dd, J = 1.0 &gt; 7.8 Hz, 1H); MS(FAB) m/z 307(M+ + 1) Analysis calculated for C9H1QINOS: c, 35. 19 ; H, 3. 28 ; N, 4.56. Found: C, 35.23; H, 3.40; N, 4.41. A solution of 0-m-iodophenyl dimethyl thiocarbamate (1 〇· gram, 3 2 · 6 mmol) dissolved in Ph 2 0 (25 liters) is heated at 2 30 ° C. 〇\[, hour. After cooling, the reaction mixture was chromatographed on a silica gel using hexane-E 〇Ac (5 ·•丨, v/v) as an eluent to give 9.31 g (93%) of dimethyl thiamine. A pale yellow oil based on S-m-phenyl iodide. !H-NMR (400 MHz, CDC13) ^3. 08 (br s, 6H) ' 7. 11 (t, J = 7.8 Hz, 1H), 7.46 (d, J = 7.3 Hz, 1H), 7 ·71 (d,

89l12968.ptd 第169頁 1283240 五、發明說明（165) J = 7.3 Hz，1H)、7·85 (s，1H); MS(FAB) m/z 307 (MH1)。 於二甲基硫胺基甲酸S -間碘苯酯（5 · 〇 1克，i 6 . 3 1毫莫 耳）溶於MeOH(20毫升）之溶液中加入28%-MeONa溶於MeOH (3.46¾升’ 17.94¾莫耳）。使所產生之混合物在室溫下 攪拌3 · 5小時，然後在7 〇 °c下加熱隔夜。於冷卻後，加入 1N HC1。將溶劑於減壓下移除，及以稀釋殘留物。 將溶液以4〇2、鹽水洗滌，及於Na2S〇4上乾燥。將有機層於 減壓下濃縮。將殘留物於矽膠上利用正己烷—Et〇Ac (10··1，v/v)作為洗提液進行層析而得3· 42克（89%)之間碘 φ 硫紛的油。 l-NMR (4 00 MHz，CDC13) 53.45 (s，lH)、6·95 (t， J = 7 · 8 Η z，1 Η)、7 · 2 3 ( d，J = 7 · 8 Η z，1 Η)、7 · 4 8 (d， J = 7.3 Hz，1H)、7·64 (t，J = 1.5 Hz，1H); El - MS m/z 236 (M+)。 於N-(第三丁氧羰基）-2-吡咯啶基甲醇（4· 30克，2〇· 〇毫 莫耳）溶於咄啶（40毫升）之攪拌溶液中加入p —Tsn(5. 72 克’ 3 0 · 0毫莫耳）。將所產生之混合物在室溫下攪拌3小 時。以tig 0使反應混合物停止反應，並將其蒸發掉。將殘 留物以EtOAc稀釋，及以iN HC1、鹽水洗滌’，並於Na2S〇4上鲁 乾燥。將溶劑於減壓下移除，及將殘留物於矽膠上利用正 己烷-EtOAc( 2 : 1，v/v)作為洗提液進行層析而得5. 76克 (81%)之N-(第二丁氧羰基）-2 -吡咯啶甲基對甲苯磺酸酯的 無色油。89l12968.ptd Page 169 1283240 V. INSTRUCTIONS (165) J = 7.3 Hz, 1H), 7.85 (s, 1H); MS (FAB) m/z 307 (MH1). Add 28%-MeONa in MeOH (3.46) to a solution of S-m-iodophenyl dimethyl sulfamate (5 · 〇1 g, i 6.3 1 mmol) in MeOH (20 mL). 3⁄4 liters ' 17.943⁄4 moles. The resulting mixture was stirred at room temperature for 3 · 5 hours and then heated at 7 ° C overnight. After cooling, 1N HCl was added. The solvent was removed under reduced pressure and the residue was diluted. The solution was washed with 4, 2, brine and dried over Na.sub.2.sub.4. The organic layer was concentrated under reduced pressure. The residue was chromatographed on a silica gel using n-hexane-Et?Ac (10··1, v/v) as an eluent to obtain 3.42 g (89%) of iodine φ sulphur oil. l-NMR (4 00 MHz, CDC13) 53.45 (s, lH), 6.95 (t, J = 7 · 8 Η z, 1 Η), 7 · 2 3 (d, J = 7 · 8 Η z, 1 Η), 7 · 4 8 (d, J = 7.3 Hz, 1H), 7·64 (t, J = 1.5 Hz, 1H); El - MS m/z 236 (M+). Add p-Tsn (5.) to a stirred solution of N-(t-butoxycarbonyl)-2-pyrrolidinylmethanol (4·30 g, 2 〇·〇 mmol) dissolved in acridine (40 ml). 72 grams '3 0 · 0 millimoles). The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with tig 0 and evaporated. The residue was diluted with EtOAc and washed with EtOAc EtOAc. The solvent was removed under reduced pressure, and the residue was purified eluted eluted eluted elut elut (Second butoxycarbonyl)-2-pyrrolidinylmethyl-p-toluenesulfonate as a colorless oil.

第170頁 1283240 五、發明說明（166) 4-NMR (400 MHz，CDC13) δ 1· 36 及1· 41 (各s，總計 9Η)、1·82 (br m，2Η)、1·96 (br m，2Η)、2·44 (s， 3H)、3·30 (br m，2H)、3·89 (br s, 1H)、3·96 (br s， 1H)、4.09 (br m，1H)、7.34 (br s，2H)、7.77 (d， J=8.3 Hz， 2H); MS(FAB) m/z 356(MH1)。 於間碘硫酚（2.66克，11.31毫莫耳）及N-(第三丁氧羰 基）-2 -咄咯啶甲基對甲苯磺酸酯（3· 34克，9. 43毫莫耳）溶 於咄啶（9. 4毫升）之攪拌混合物中加入8N KOH( 1 · 77毫 升）。將所產生之混合物在室溫下攪拌隔夜。以EtOAc稀釋 反應混合物。將溶液以H20、飽和NH4C1溶液、鹽水洗滌， 並於Na2S04上乾燥。將有機層於減壓下濃縮，及將殘留物 於石夕膠上利用正己烧_EtOAc(5 : 1，v/v)作為洗提液進行層 析而得1· 79克（45%)之[N-(第三丁氧羰基）—2 -咄咯啶基]甲 基]3 -碘苯硫的油。 ^-NMR (400 MHz, CDC13 )51.45 (s, 9H) -1.78-2.01 (br m，4H)、2·71 (dt，1H)、3·32-3·49 (br in，3H)、 3.90-4.02 (br m，1H)、7·12 (d，J = 7.8 Hz，1H)、7·18 (d，J = 7.8 Hz，1Η)、7·57 (dd，J:2.0、8.3 Hz，2H); MS(FAB) m/z 420(MH1)。 於[1-(第三丁氧羰基）-2 -吡咯啶基]甲基3 —碘苯硫（丨· 76 克，4· 20毫莫耳）溶於DMSO(20毫升）及MeOH(16毫升）之攪 拌溶液中加入Et3N(l. 28毫升，9· 24毫莫耳）、Pd(〇Ac)2 (47.1毫克’0·21毫莫耳）、及ι，3 -雙（二苯膦基）丙烷（86· 6毫克，0.21毫莫耳），然後使c〇氣體發泡5分鐘。使所產Page 170 1283240 V. INSTRUCTIONS (166) 4-NMR (400 MHz, CDC13) δ 1·36 and 1·41 (each s, total 9Η), 1.82 (br m, 2Η), 1.96 ( Br m,2Η), 2·44 (s, 3H), 3·30 (br m, 2H), 3·89 (br s, 1H), 3·96 (br s, 1H), 4.09 (br m, 1H), 7.34 (br s, 2H), 7.77 (d, J = 8.3 Hz, 2H); MS (FAB) m/z 356 (MH1). Isothiophenol (2.66 g, 11.31 mmol) and N-(t-butoxycarbonyl)-2-pyrrolidine methyl p-toluenesulfonate (3.33 g, 9.43 mmol) 8N KOH (1·77 ml) was added to a stirred mixture of acridine (9.4 ml). The resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted with EtOAc. The solution was washed with H.sub.2, sat. NH.sub.4Cl. The organic layer was concentrated under reduced pressure, and the residue was purified eluting with EtOAc (5:1, v/v) as the eluent to give 1.79 g (45%) An oil of [N-(t-butoxycarbonyl)-2-pyridinyl]methyl]3-iodobenzenesulfide. ^-NMR (400 MHz, CDC13) 51.45 (s, 9H) -1.78-2.01 (br m, 4H), 2·71 (dt, 1H), 3·32-3·49 (br in, 3H), 3.90 -4.02 (br m,1H), 7·12 (d, J = 7.8 Hz, 1H), 7·18 (d, J = 7.8 Hz, 1Η), 7·57 (dd, J: 2.0, 8.3 Hz, 2H); MS (FAB) m/z 420 (MH1). [1-(Tertidinoxycarbonyl)-2-pyrrolidinyl]methyl 3-iodobenzenesulfonate (丨· 76 g, 4·20 mmol) dissolved in DMSO (20 mL) and MeOH (16 mL) Et3N (1.88 ml, 9·24 mmol), Pd(〇Ac)2 (47.1 mg '0·21 mmol), and ι,3-bis(diphenylphosphino) were added to the stirred solution. Propane (86·6 mg, 0.21 mmol), and then c〇 gas was foamed for 5 minutes. Make

89112968.ptd 第171頁 128324089112968.ptd Page 171 1283240

生之混合物於70t下授拌隔夜。於冷卻後 縮。將殘留物以EtOAc稀釋，及以鹽水洗滌，/物^ 乾燥。將溶劑於減壓下移除，及將殘留物於碎膠;上‘ 4土 己烷-Et0Ac(5:l，v/v)作為洗提液進行層析而 (8 7%)之3-[1-(第三丁氧羰基）_2 -咄咯啶基]甲基硫苯甲酸 甲S旨的油。 UMR (4 0 0 MHz，CDC13) (H· 42 及1· 45 (各s，9H)、 1·79-2·05 (br m，4H)、2·83 (dt，J = l(K8、’3〇·3 Hz， 1H) 、3·34-3·54 (br m， 3H) 、3·92 (s， 3H) 、3·92及’ 4·05 (d，J一7·8 Hz，1H)、7·36 (t，J = 7·8Ηζ，1Η)、7· 63 (br d， J=14.7 Hz， 1H) 、7·83 (br d， J=12 7 Hz， 1H)、8.04 (s，1H); MS (FAB) m/z 352( M+ + 1)。 在0 C下於3-[1_(第二丁氧幾基）—2 -吼嘻。定基]甲基硫苯 甲酸曱酯（1· 46克，4· 16毫莫耳）溶於CH2Cl2(3〇毫升）之攪 拌溶液中加入TF A( 1 5公升）。使所產生之混合物於室溫下 擅:拌1小時。將溶劑於減壓下移除，及以1 N N a 0 Η處理殘留 物’並以C H C 13卒取。將卒取液以鹽水洗務，於ν a2 S 04上乾 燥，並於減壓下濃縮而得9 4 7毫克（9 1 % )之3 - ( 2 -吼17各咬基） 曱基硫苯曱酸曱酯的棕色油。 ^-NMR (4 0 0 MHz, CDC13) (5 1. 45- 1. 54 (m, 1H) ^ 1. 72-2. 00 (m，4H)、2·88-3.10 (m，4H)、3·30 (m，1H)、3.92 (s，3H)、7·34 (t，J = 7.8 Hz，1H)、7.52 (m，1H)、 7.84 (m，1H)、8·01 (t，J=2.0 Hz，1H); MS(FAB) m/z 252 (MH1)。The mixture was mixed overnight at 70t. After cooling, shrink. The residue was diluted with EtOAc and washed with brine and dried. The solvent was removed under reduced pressure, and the residue was applied to a mixture of EtOAc EtOAc EtOAc (EtOAc) An oil of [1-(t-butoxycarbonyl)-2-pyridridinyl]methylthiobenzoic acid methyl. UMR (4 0 0 MHz, CDC13) (H·42 and 1·45 (each s, 9H), 1·79-2·05 (br m, 4H), 2·83 (dt, J = l (K8, '3〇·3 Hz, 1H), 3·34-3·54 (br m, 3H), 3.92 (s, 3H), 3.92 and '4·05 (d, J-7·8 Hz , 1H), 7·36 (t, J = 7·8Ηζ, 1Η), 7·63 (br d, J=14.7 Hz, 1H), 7·83 (br d, J=12 7 Hz, 1H), 8.04 (s,1H); MS (FAB) m/z 352( M+ + 1). At 0 C, 3-[1_(2nd-butoxy-yl)-2-indol. Add TF A (15 liters) to a stirred solution of decyl formate (1·46 g, 4·16 mmol) in CH 2 Cl 2 (3 mL). Mix the resulting mixture at room temperature: Mix 1 The solvent was removed under reduced pressure, and the residue was treated with 1 NN a 0 并 and stroked with CHC 13. The stroke was washed with saline, dried on ν a2 S 04 and decompressed. Concentrated to give 9 4 7 mg (91%) of a brown oil of 3 - ( 2 - 吼 17 each) of decylthiobenzoic acid ester. ^-NMR (4 0 0 MHz, CDC13) (5 1. 45- 1. 54 (m, 1H) ^ 1. 72-2. 00 (m, 4H), 2·88-3.10 (m, 4H), 3·30 (m, 1H), 3.92 (s, 3 H), 7·34 (t, J = 7.8 Hz, 1H), 7.52 (m, 1H), 7.84 (m, 1H), 8·01 (t, J = 2.0 Hz, 1H); MS(FAB) m /z 252 (MH1).

\\312\2d-code\90-01\89112968.ptd 第 172 頁 1283240 五、發明說明（168) 使3—甲氧基一4 一 [Ν’-(2 一甲基笨基）脲基]苯乙酸（1. 18克 ，3· 77 毫，耳）、EDC(!· 〇8 克，5· 65 毫莫耳）、DMAP(23 毫 克，0.19¾莫耳）及H〇Bt(25毫克，〇·ΐ9毫莫耳）於DMF(5毫 升）中之混合物在室溫下攪拌i小時，將3一（2-咄咯啶基）甲 基硫苯甲酸甲酯（9 47毫克，3·77毫莫耳）加至混合物，及 ，所產生之此合物授拌隔夜。於加入dmap(460毫克，3.77 =莫耳）及HOBt( 83 5毫克，6. 18毫莫耳）後，再多攪拌5小 日守。以EtOAc稀釋反應混合物。將溶液以鹽水洗滌，並於 NaJO4上乾燥。將溶劑於減壓下移除。將殘留物於矽膠上 =用正^己烷-EtOAc(2:3，v/v)作為洗提液進行層析而得 毫克（14%)之3-[卜[3-[ Ψ氧基—4_[N，—（2一 ？基苯基） 脲基]笨基乙醯基]+。比略咬基]甲基硫苯甲 色非晶形物質。 IR (KBO 28 75、1724、1 62 0、1 284、1182/公分； 'H-NMR (4 00 MHz, CDC13) 5 l. 86^2. 〇5 (m, 4H) ^2.31 (s, 3H) ^2.84 (dd, 1=9.3 ^3.7 Hz, 1H) &gt;3.43-3.59 (m，5H)、3·73 (s’ 3H)、3·92 (s，3H)、4·33 (m，1H) 、6·16 (s，1H)、6·77一6·8〇 (m，2H)、7 〇4 (s，ih)、 7.16 (t，J = 8.3 Hz, 1H)、7·38 (t，J = 7 8 Hz，1H)、 7.49 (t，J = 7.8 Hz，1H)、7·73 (dt，J = 1〇、7·8 Hz， 1H)、7·79 (dd，J = 2.0、6·8 Hz, 1H) '8.01 (d，J = 2:0\\312\2d-code\90-01\89112968.ptd Page 172 1283240 V. INSTRUCTIONS (168) Making 3-methoxy-4-[['(2-(methylphenyl)))] Phenylacetic acid (1.18 g, 3.77 m, ear), EDC (!· 〇8 g, 5·65 mmol), DMAP (23 mg, 0.193⁄4 mol) and H〇Bt (25 mg, Mixture of 毫·ΐ 9 mmoles in DMF (5 mL) at room temperature for 1 hour, methyl 3-(2-pyridyl)methylthiobenzoate (9 47 mg, 3.77) Millions were added to the mixture and the resulting compound was mixed overnight. After adding dmap (460 mg, 3.77 = mol) and HOBt (83 5 mg, 6.18 mmol), stir for 5 more days. The reaction mixture was diluted with EtOAc. The solution was washed with brine and dried over NaJO4. The solvent was removed under reduced pressure. The residue was chromatographed on silica gel eluted with n-hexane-EtOAc (2:3, v/v). 4_[N,-(2-aminophenyl)ureido]]phenylamino]+. A little bit of a base] methyl thiobenzoate amorphous material. IR (KBO 28 75, 1724, 1 62 0, 1 284, 1182 / cm; 'H-NMR (4 00 MHz, CDC13) 5 l. 86^2. 〇5 (m, 4H) ^2.31 (s, 3H ) ^2.84 (dd, 1=9.3 ^3.7 Hz, 1H) &gt;3.43-3.59 (m,5H), 3·73 (s' 3H), 3.92 (s,3H), 4·33 (m, 1H), 6·16 (s, 1H), 6·77·6·8〇(m, 2H), 7 〇4 (s, ih), 7.16 (t, J = 8.3 Hz, 1H), 7.38 (t, J = 7 8 Hz, 1H), 7.49 (t, J = 7.8 Hz, 1H), 7.73 (dt, J = 1〇, 7·8 Hz, 1H), 7·79 (dd, J = 2.0, 6·8 Hz, 1H) '8.01 (d, J = 2:0

Hz, 1H) ^8.05 (dd, J = 2.4 ^7.8 Hz, 1H); MS(FAB) m/z 548(MH1)。 於3-[H3-[甲氧基-4-N’ -（2_甲基笨基）脲基]苯基乙醯Hz, 1H) ^ 8.05 (dd, J = 2.4 ^ 7.8 Hz, 1H); MS (FAB) m/z 548 (MH1). 3-[H3-[Methoxy-4-N'-(2-methylphenyl)ureido]phenylacetamidine

第173頁 1283240 五、發明說明（169) 基]-2-咬咯啶基]甲基硫苯甲酸甲酯（148· 2毫克，〇· 27ι毫 莫耳）溶於THF(7. 4毫升）及112〇(1· 8毫升）之攪拌溶液中加 入Li 0H( 19· 4毫克，0· 81 2毫莫耳），並使所產生之混合物 在室溫下攪拌9小時。將混合物以IN HC1處理，並以CHC13 萃取。將萃取液以鹽水洗滌，及於Na2S04上乾燥。將溶劑 於減壓下移除，及利用製備TLC以CHCl2-MeOH(l〇 : 1，v/v) 洗提，並自正己烷-EtOAc結晶將殘留物純化，而得89. 7毫 克（62%)之20的白色粉末。 IR (KBr) 29 60、1 708 / 公分；NMR ( 400 MHz，DMS0-d 6) 5 1· 82-2· 01 (m，4H)、2. 24 (s，3H)、2. 93 (dd， J = 9.3、12·7 Hz，1H)、3.4 0-3.54 (m，5H)、3·86 (s, 3H)、4· 13 (br m，1H)、6· 74 (d，J = 8· 3 Hz，1H)、6·87 (d，J=1.5 Hz，1H)、6·94 (t，J = 7.8 Hz, 1H)、7·10 - 7· 17 (m，2H)、7·42 (t，J = 7.8 Hz，1H)、7·70 (d，J = 7.8 Hz, 1H)、7.74 (d，J = 8.3 Hz，1H)、7·79 (d，J = 7.8 Hz，1H)、7·84 (s, 1H)、8·00 (d，J = 8.3 Hz，1H)、 8·48 (s，1H)、8.57 (s，1H); MS(FAB) m/z 5 34(M+ + l)〇 實施例1 7 3 - [1-[3-曱氧基-4 - [Ν’-（2-甲基苯基）脲基]苯基乙醯基]一 2-咄咯啶基]曱基磺醯基]苯甲酸Page 173, 1283240 V. INSTRUCTIONS (169) Methyl-2-pyrrolidyl]methylthiobenzoate (148·2 mg, 〇·27ιmmol) dissolved in THF (7.4 ml) To a stirred solution of 112 Torr (1.8 ml) was added Li 0H (1·4 mg, 0·81 2 mmol), and the resulting mixture was stirred at room temperature for 9 hours. The mixture was treated with IN HCl and extracted with CH.sub.3. The extract was washed with brine and dried over Na 2 SO 4 . The solvent was removed, and the residue was purified by EtOAc (EtOAc/EtOAc). %) of 20 white powder. IR (KBr) 29 60, 1 708 / cm; NMR (400 MHz, DMS0-d 6) 5 1· 82-2· 01 (m, 4H), 2. 24 (s, 3H), 2. 93 (dd , J = 9.3, 12·7 Hz, 1H), 3.4 0-3.54 (m, 5H), 3·86 (s, 3H), 4· 13 (br m, 1H), 6. 74 (d, J = 8· 3 Hz, 1H), 6·87 (d, J=1.5 Hz, 1H), 6.94 (t, J = 7.8 Hz, 1H), 7·10 - 7· 17 (m, 2H), 7 · 42 (t, J = 7.8 Hz, 1H), 7·70 (d, J = 7.8 Hz, 1H), 7.74 (d, J = 8.3 Hz, 1H), 7·79 (d, J = 7.8 Hz, 1H), 7·84 (s, 1H), 8·00 (d, J = 8.3 Hz, 1H), 8·48 (s, 1H), 8.57 (s, 1H); MS(FAB) m/z 5 34(M+ + l)〇Example 1 7 3 - [1-[3-曱oxy-4 -[Ν'-(2-methylphenyl)ureido]phenylethenyl]- 2-indole Pyridyl]nonylsulfonyl]benzoic acid

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在0 °C下於3-[l-[3-曱氧基-4 - [Ν’ -（2-甲基笨基）脲基] 苯基乙醯基]- 2 - η比咯啶基]曱基磺醯基]苯甲酸甲§旨（丨3 ^ 8 毫克，0.241毫莫耳）溶於^(：12(3毫升）之攪拌溶^中加入 m - CPBA( 130· 5毫克，0.5 29毫莫耳）。使反應混合物在室溫 下攪拌0 · 5小時。將混合物以CHC I3稀釋，並以飽和n七$ 〇 溶液使反應停止。將有機層分離，以飽和NaHC03溶液、2 ^ 水洗滌，及於NaJO4上乾燥。將溶劑於減壓下移除而得皿 3- [1 -[3-甲氧基-4- [Ν’ -(2-甲基苯基）脲基]苯基乙醯 基]-2-咄咯啶基]甲基磺醯基]苯甲酸曱酯之非晶形固體。 於此粗製化合物溶於THF(7· 4毫升）及4〇(1.8毫升）之擾拌 溶液中加入LiOH(17.3毫克，0·723毫莫耳），並繼續在室 溫下攪拌隔夜。將反應混合物以CHC 13稀釋，並先以丄Ν H C1，然後再以鹽水洗滌，及於N a2 S 04上乾燥。將溶劑於減 壓下移除，及利用製備TLC以CHCl3-MeOH (1 0 : 1 ，v/v)作 為洗提液，並使粗製固體自正己烷-EtOAc再結晶將殘留物 純化，而得6 9· 9毫克（51%)之21的白色結晶粉末。 熔點243-245。(：；11?(〇1〇 3354、2 974、1 533 /公分； 4- NMR ( 4 00 MHz, DMS0-d6) (51· 80-2· 0 0 (m，4H)、2· 2 4 (s，3H)、3·19 - 3·62 (m，6H)、3·82 (s，3H)、4·18 (m， 1H)、6·67 (d，J = 8.8 Hz，1H)、6·8〇 (d，J = l.〇 Hz, 1H)、6.93 (t，J = 7.3 Hz，1H)、7·10-7·17 (m，2H)、7· 66 (t， J = 7· 8 Hz， 1H)、7· 78 (d， J = 8· 3 Hz， 1H)、 7.9 卜 7.99 (m，2H)、8·20 (d，J = 7.3 Hz，1H)、8·34 (s，1H)、8·48 (s，1H)、8·56 (s，1H); MS(FAB) m/z3-[l-[3-曱oxy-4 -[Ν' -(2-methylphenyl)ureido]phenylphenyl]] 2 - ηpyrrolidyl] at 0 °C m-CPBA (130·5 mg, 0.5 29) was added to a stirred solution of ^(:12 (3 ml) in a solution of thiolsulfonyl]benzoic acid ( 丨3 ^ 8 mg, 0.241 mmol). The reaction mixture was stirred at room temperature for 0.5 hours. The mixture was diluted with CHC I3 and then quenched with sat. Washed and dried on NaJO4. The solvent was removed under reduced pressure to give 3-[1 -[3-methoxy-4-[Ν'-(2-methylphenyl)ureido]phenyl An amorphous solid of acetamido-2-pyrrolidyl]methylsulfonyl] benzoic acid benzoate. The crude compound was dissolved in THF (7.4 ml) and 4 〇 (1.8 ml). LiOH (17.3 mg, 0·723 mmol) was added to the solution and stirring was continued overnight at room temperature. The reaction mixture was diluted with CHC 13 and washed with 丄Ν H C1 then brine, and N Dry on a2 S 04. Remove the solvent under reduced pressure and use preparative TLC to CHCl3 - MeOH (1 0 : 1 , v/v) as eluent, and the crude solid was recrystallized from n-hexane-EtOAc to yield EtOAc (yield: Melting point 243-245. (:; 11? (〇1〇3354, 2 974, 1 533 / cm; 4- NMR ( 4 00 MHz, DMS0-d6) (51· 80-2· 0 0 (m, 4H ), 2· 2 4 (s, 3H), 3·19 - 3·62 (m, 6H), 3·82 (s, 3H), 4·18 (m, 1H), 6.67 (d, J = 8.8 Hz, 1H), 6·8〇 (d, J = l.〇Hz, 1H), 6.93 (t, J = 7.3 Hz, 1H), 7·10-7·17 (m, 2H), 7 · 66 (t, J = 7· 8 Hz, 1H), 7·78 (d, J = 8·3 Hz, 1H), 7.9, 7.99 (m, 2H), 8·20 (d, J = 7.3 Hz) , 1H), 8·34 (s, 1H), 8·48 (s, 1H), 8.56 (s, 1H); MS (FAB) m/z

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566 (MH1) ; C29H31N3 07 S · 1HC1 · lH2〇 之分析計瞀值· c 56· 17 ; H，5· 53 ; N，6· 78。實測值：c，55 了2 · h 5. 58 ; N， 6. 71 〇 5 ’ 實施例1 8 服:基]笨基乙醯基] 4-[1-[3_甲氧基-4-[1^’-(2-甲基笨基 -2-吼咯啶基]曱基磺醯基]苯甲酸566 (MH1) ; C29H31N3 07 S · 1HC1 · lH2〇 Analytical value · · c 56· 17 ; H, 5 · 53 ; N, 6. 78. Found: c, 55 2 · h 5. 58 ; N, 6. 71 〇 5 ' Example 1 8 Service: Base] Stupid Ethyl] 4-[1-[3_methoxy-4- [1^'-(2-methylphenyl-2-pyridinyl]nonylsulfonyl]benzoic acid

在0°C下於4 - [1 - [3-甲氧基-4-[N，-（2-甲基笨基）脲基] 苯基乙醯基]- 2 -吡咯啶基]甲基硫基]笨甲酸曱酯（3 〇 〇 ^ 克’0.548宅莫耳）溶於CH2C12(6毫升）之攪拌溶液中加入 111-0?84(297^：克’1.206耄莫耳），及使反應混合物在室溫 下攪拌1小時。將混合物以CHCI3稀釋，並以飽和％心％溶 液使反應停止。將分離的有機層以飽和NaHC03溶液、^水 洗滌，及於N S Ο*上乾燥。將溶劑於減壓下移除而得4 一 [ 1 - [3-甲氧基- 4- [Ν’-（2-甲基苯基）脲基]苯基乙醯基]一 2一 °比洛σ定基]甲基績醯基]苯甲酸甲酯之粗製黃色油。於此粗 製化合物溶於THF(4.4毫升）及1120(1.1毫升）之攪拌溶液中 加入Li 0 Η (39 · 4毫克，1.643毫莫耳），並繼續在室溫下攪 拌隔夜。將反應混合物以CHC13稀釋，並以IN HC1、鹽水 洗滌，及於N a2 S 04上乾燥。將溶劑於減壓下移除，及利用 製備TLC以CHCl3-MeOH(10 : 1，v/v)洗提，並自正己烷 -EtOAc結晶將殘留物純化，而得128. 0毫克（41%)之22的白4-[1-[3-methoxy-4-[N,-(2-methylphenyl)ureido]phenylphenyl]]-2-pyrrolidinyl]methyl at 0 °C Sulfuryl] benzoic acid decyl ester (3 〇〇 ^ gram '0.548 house Moule) dissolved in CH2C12 (6 ml) in a stirred solution of 111-0? 84 (297 ^: gram '1.206 耄 Mo ear), and The reaction mixture was stirred at room temperature for 1 hour. The mixture was diluted with CHCI3 and the reaction was stopped with a saturated % heart% solution. The separated organic layer was washed with a saturated NaHC03 solution, water, and dried over N? The solvent is removed under reduced pressure to give 4-[1-methoxy-3-[[4-methylphenyl]ureido]phenylethenyl]-one-to-one ratio A crude yellow oil of methyl benzoate. The crude compound was dissolved in THF (4.4 mL) and 1120 (1.1 mL). The reaction mixture was diluted with CH.sub.3 and washed with &lt The solvent was removed under reduced pressure, and the residue was purified eluting with EtOAc EtOAc (EtOAc) ) of the white of 22

\\312\2d-code\90-01\89112968.ptd 第 176 頁 1283240 五、發明說明（172) 色粉末。 IR (KBr) 3388、2974、1 537、1 2 9 8、1155 / 公分； UMR ( 40 0 MHz，DMS0-d6) (Π.80-1.98 (m，4H)、2.24 (s，3H)、2·54 (s，1H)、3·20-3.70 (m，5H)、3·82 (s， 3H) 、4·16 (br m， 1H) 、6.67 (dd， J=1.5 、8.3 Hz， 1H)、6·80 (d，J = 1.5 Hz，1H)、6·93 (d，J = 7.3 Hz, 1H)、7·10-7.16 (m，2H)、7·78 (d, J = 7.3 Hz，1H)、7. 95 (d，J = 8.3 Hz，2H)、7·98 (d，J = 8.3 Hz，1H)、8·14 (d，J = 8.3 Hz, 2H)、8.49 (s，1H)、8·57 (s，1H); MS(FAB) m/z 566 (MH1) ; C29H31N3 07 S · 3H20 之分析計算值： C，56· 21 ; H，6· 02 ; N，6· 78。實測值：C，56· 76 ; H， 5· 37 ; Ν，6· 70。 實施例1 9 4-[；1 - [3-曱氧基-4-[Ν’ -（2-曱基苯基）脲基]苯基乙醯基]一 2 - ϋ比咯啶基]甲基硫基]苯甲酸\\312\2d-code\90-01\89112968.ptd Page 176 1283240 V. INSTRUCTIONS (172) Color powder. IR (KBr) 3388, 2974, 1 537, 1 2 9 8 , 1155 / cm; UMR ( 40 0 MHz, DMS0-d6) (Π.80-1.98 (m, 4H), 2.24 (s, 3H), 2 · 54 (s, 1H), 3·20-3.70 (m, 5H), 3·82 (s, 3H), 4·16 (br m, 1H), 6.67 (dd, J=1.5, 8.3 Hz, 1H ), 6·80 (d, J = 1.5 Hz, 1H), 6.93 (d, J = 7.3 Hz, 1H), 7·10-7.16 (m, 2H), 7·78 (d, J = 7.3 Hz, 1H), 7.95 (d, J = 8.3 Hz, 2H), 7·98 (d, J = 8.3 Hz, 1H), 8·14 (d, J = 8.3 Hz, 2H), 8.49 (s ,1H),8·57 (s,1H); MS(FAB) m/z 566 (MH1) ; C29H31N3 07 S · 3H20 Analytical calculated value: C,56· 21 ; H,6· 02 ; N,6 · 78. Found: C, 56 · 76 ; H, 5 · 37 ; Ν, 6 · 70. Example 1 9 4-[;1 - [3-曱oxy-4-[Ν' -(2- Nonylphenyl)ureido]phenylethenyl]- 2 -indolepyridyl]methylthio]benzoic acid

COOH 23 於對峨驗（20.0克’90.9毫莫耳）溶於DMF( 2〇〇毫升）之攪拌 溶液中加入1，4-二叮雙環[2,2,2]辛烷（2〇·4克，1818毫 莫耳）及二甲基硫胺甲醯氣（16·9克，136.4毫莫耳）。使所 產生之溶液在7 5 C下攪拌3 · 5小時。於冷卻後，加入3 〇毫 升水。利用吸濾收集固體，並將其溶解於Et〇Ac中。將COOH 23 Add 1,4-dioxabicyclo[2,2,2]octane (2〇·4) to a stirred solution of 20.0 g of '90.9 mmoles dissolved in DMF (2 mL) Grams, 1818 millimoles) and dimethyl thiamine formazan (16.9 grams, 136.4 millimoles). The resulting solution was stirred at 75 C for 3 · 5 hours. After cooling, add 3 liters of water. The solid was collected by suction filtration and dissolved in Et EtOAc. will

_2968.ptd 第177頁 1283240 五、發明說明（173)_2968.ptd Page 177 1283240 V. Description of invention (173)

EtOAc層以水洗滌，於Na2S04上乾燥，並於減壓下蒸發。使 粗製固體自HgO再結晶而得26.75克（96%)之二甲基硫胺基 甲酸0-對破苯醋的淡黃色結晶粉末。 IR (KBr) 1479、1207、827/公分；UMR ( 40 0 MHz, CDC13) 53.37 (s，3Η)、3·45 (s，3H)、6.83 (d，J = 8.8 Hz， 2H) 、 7.69 (d， J=8.3 Hz， 2H); MS(FAB) m/z 307 (M+ + 1); C9H1QIN0S 之分析計算值：c，35.19; H，3.28; N， 4. 56。實測值：C，35· 17 ; H，3. 35 ; N，4. 44。 使二曱基硫胺基甲酸0-對蛾苯酯（1〇·〇克，32. 6毫莫耳） &gt;谷於P h 0 (2 5宅升）之撥摔溶液在2 3 0 °C下加熱5. 5小時。於 冷卻後，使反應混合物於矽膠上利用正己烧—E0Ac (3 : 1， v/v)作為洗提液進行層析而得2· 55克（26%)之二甲基硫胺 基甲酸S-對碘苯酯的白色結晶粉末。 IR (KBr) 3299、1651、1469、1371/公分；ih-NMR (400 MHz, CDC13) 6 3. 03(br s，3H)、3· 〇8(br s，3H)、 7.21(d，J = 8.3 Hz，2H)、7.70(d，J = 8.3 Hz, 2H); MS(FAB) m/z 308 (MH1); C9H1QIN0S 之分析計算值：c， 35. 19 ; H，3· 28 ; N，4· 56。實測值：C，35. 49 ; H， 3· 28 ; N， 4·43 。 於二甲基硫胺基甲酸S-對碘苯酯（2·55克，8.31毫莫耳） 溶於诞6〇11(10毫升）之溶液中加入丛6(^&amp;(495毫克，9.14毫 莫耳），及使所產生之混合物在7〇°C下攪拌隔夜。於冷卻 後，加入IN HC1，及將混合物於減壓下濃縮。將殘留物以 EtOAc稀釋，並以H20、鹽水洗滌，及於Na2S04上乾燥。將The EtOAc layer was washed with EtOAcq. The crude solid was recrystallized from HgO to give a pale yellow crystalline powder of &lt;RTIgt;&lt;/RTI&gt; IR (KBr) 1479, 1207, 827/cm; UMR (40 0 MHz, CDC13) 53.37 (s, 3Η), 3·45 (s, 3H), 6.83 (d, J = 8.8 Hz, 2H), 7.69 ( d, J = 8.3 Hz, 2H); MS (FAB) m/z 307 (M + + 1); C9H1QIN0S: C, 35.19; H, 3.28; N, 4. 56. Found: C, 35·17; H, 3.35; N, 4.44.曱 曱 硫 硫 硫 0 0 0 蛾 32 32 32 32 32 32 32 32 32 32 32 32 32 32 32 P P P P P P P P P P P P P P P P P P P P P P P P P P P 5小时。 Heating under C. 5. 5 hours. After cooling, the reaction mixture was chromatographed on a silica gel using hexane-E0Ac (3:1, v/v) as an eluent to obtain 2.55 g (26%) of dimethylthiocarbamic acid S. - White crystalline powder of p-iodophenyl ester. IR (KBr) 3299, 1651, 1469, 1371/cm; ih-NMR (400 MHz, CDC13) 6 3. 03(br s,3H), 3· 〇8(br s,3H), 7.21(d,J = 8.3 Hz, 2H), 7.70 (d, J = 8.3 Hz, 2H); MS(FAB) m/z 308 (MH1); Analytical calculated value of C9H1QIN0S: c, 35. 19 ; H,3· 28 ; , 4.56. Found: C, 35. 49; H, 3·28; N, 4·43. Add plexus 6 (^ &amp; (495 mg, 9.14) to a solution of S-p-iodophenyl dimethyl thiocarbamate (2. 55 g, 8.31 mmol) dissolved in 6 〇 11 (10 ml). The resulting mixture was stirred overnight at 7 ° C. After cooling, EtOAc was added and the mixture was evaporated. And dried on Na2S04.

89112968.ptd 第178頁 1283240 五、發明說明（174) 有機層於減壓下濃縮，及將殘留物於矽膠上利用正己烧 - Et0Ac(5:l，v/v)作為洗提液進行層析而得1.75克（89%) 之對碘硫酚的淡黃色結晶固體。 在室溫下於對碘硫酚（1.75克，7.43毫莫耳）及N-(第三 丁氧羰基）-2-咄咯啶甲基對甲苯磺酸酯（2. 39克，6. 75毫 莫耳）溶於咄啶（12. 7毫升）之攪拌混合物中加入8Ν Κ0Η 〇· 2 7毫升），並使所產生之混合物在相同溫度下攪拌4小 時。將反應混合物以EtOAc稀釋。將溶液以H2 02、飽和 NlCl、鹽水洗滌，並於Na2S04上乾燥。將有機層於減壓下 濃縮。將殘留物於矽膠上利用正己烷-Et0Ac(5 : 1，v/v)作 為洗提液進行層析而得1·49克（53%)之[N-(第三丁氧羰基） -2-吡咯啶基]甲基4-碘苯硫的淡黃色油。 IR (KBr) 2559、1097、1002、806/公分；NMR (400 MHz, CDC13) 53.43 (s, 1H) ^7.10 (d, J = 8.3 Hz, 2H)、7.53 (d，J = 8.3 Hz, 2H); MS(FAB) m/z 236( M+ + 1);C6H5 IS 之分析計算值：C，30.53; H，2.13。 實測值：C，30. 57 ; H，2. 15。 於[1-(第三丁氧羰基）-2 -吡咯啶基]甲基4_碘苯硫（1.49 克，3· 56毫莫耳）溶於DMS0(16毫升）及MeOH(13毫升）之攪 拌溶液中加入Et3N(1.09毫升，7.84毫莫耳）、Pd(〇Ac)2(40 毫克’0·178毫莫耳）、及1，3 -雙（二苯膦基）丙烷（73.4毫 克，0· 178毫莫耳）。於所產生之攪拌混合物中引入⑶氣體 5分鐘，及使混合物在7 0 °C下攪拌隔夜。於冷卻後，將混 合物濃縮至小的體積。將殘留物以Et〇Ac稀釋，以鹽水洗89112968.ptd Page 178 1283240 V. INSTRUCTIONS (174) The organic layer is concentrated under reduced pressure, and the residue is chromatographed on a silica gel using hexane - Et0Ac (5:1, v/v) as eluent The pale yellow crystalline solid of 1.75 g (89%) of thiophenol was obtained. At room temperature in p-iodothiophenol (1.75 g, 7.43 mmol) and N-(t-butoxycarbonyl)-2-pyrrolidine methyl p-toluenesulfonate (2. 39 g, 6.75 To a stirred mixture of acridine (12.7 ml) was added 8 Ν Η 0 Η 2 · 27 ml), and the resulting mixture was stirred at the same temperature for 4 hours. The reaction mixture was diluted with EtOAc. The solution was washed with H2O2, sat. NlCl, brine and dried over Na2SO. The organic layer was concentrated under reduced pressure. The residue was chromatographed on a silica gel using n-hexane-Et0Ac (5:1, v/v) as an eluent to give 1.49 g (53%) of [N-(T-butyloxycarbonyl)-2 -pyrrolidinyl]methyl 4-iodobenzenesulfonate as a pale yellow oil. IR (KBr) 2559, 1097, 1002, 806 / cm; NMR (400 MHz, CDC13) 53.43 (s, 1H) ^7.10 (d, J = 8.3 Hz, 2H), 7.53 (d, J = 8.3 Hz, 2H MS (FAB) m/z 236 (M+ + 1); calcd for C6H5 s: C, 30.53; H, 2.13. Found: C, 30. 57; H, 2.15. [1-(Tertidinoxycarbonyl)-2-pyrrolidinyl]methyl 4-iodobenzenesulfonate (1.49 g, 3.56 mmol) was dissolved in EtOAc (16 mL) To the stirred solution were added Et3N (1.09 mL, 7.84 mmol), Pd(〇Ac) 2 (40 mg '0·178 mmol), and 1,3 -bis(diphenylphosphino)propane (73.4 mg, 0· 178 millimoles). (3) Gas was introduced into the resulting stirred mixture for 5 minutes, and the mixture was stirred at 70 ° C overnight. After cooling, the mixture was concentrated to a small volume. The residue was diluted with Et〇Ac and washed with brine.

89112968.ptd 第179頁 丨 1283240 ____ 五、發明說明（175)~ '' 滌，並於NaJO4上乾燥。將溶劑於減壓下移除，及將殘留 物於石夕膠上利用正己烷—Et0Ac(5 : 1，v/v)作為洗提液進行 層析而得1· 16克（93%)之4_[ 1-(第三丁氧羰基）-2—吡咯啶 基]甲基硫苯甲酸甲醋的油。 ^H-NMR (4 00 MHz, CDC13) (5 1.45 (s, 9H) &gt; 78^2. 01 (br m，4H)、2.71 (dt，1H)、3·32-3·49 (br m，3H)、 3·90-4·02 (br m，1H)、7·12 (d，J = 7.8 HZ，ih)、7·18 (d，J:7. 8 Hz，1H)、7· 57 (dd，J = 2. 0、8· 3 Hz，2H); MS(FAB) m/z 42 0 (MH1)。 於4 - [1 -（第二丁氧裁基）一 2-吼洛唆基]曱基硫苯甲酸曱 酯（1· 16克，3· 32毫莫耳）溶於CH2C12(20毫升）之攪拌溶液 中加入TFA(4公升），及使混合物在室溫下攪拌丨.5小時。 將溶劑於減壓下移除，及以IN NaOH處理殘留物。以CHC1 3 萃取混合物。將萃取液以鹽水洗滌，於Koh上乾燥，並於 減壓下濃縮而得7 6 7毫克（9 2 %)之4 - ( 2 -吼洛咬基）甲基硫苯 甲酸甲酯的黃色油。 UMR (4 00 MHz，CDC13) 5 1· 51 及1· 47 (各s，9H)、 1·78-2·05 (br m，4H)、2·77 (dt，J = 10.8、37·1 Hz， 1H) 、3·34 - 3.58 (m， 3H) 、3·89 (s， 3H) 、4·03 (br d，J = 27.3 Hz，1H)、7·38 (d，J = 7.3 Hz，1H)、7·47 (d，J = 7.3 Hz，1H)、7·92 (br s，2H); MS(FAB) m/z 352 (M+ + 1)。 在0 °C下於3-甲氧基一4 一 [N，—（2-甲基苯基）脲基]苯乙酸 (1· 30 克，4· 136 毫莫耳）、Et3N(0. 63 毫升，4· 5 49 毫莫耳）89112968.ptd Page 179 丨 1283240 ____ V. INSTRUCTIONS (175)~ '' Diluted and dried on NaJO4. The solvent was removed under reduced pressure, and the residue was chromatographed with hexane-Et0Ac (5:1, v/v) as an eluent to obtain 16.16 g (93%). An oil of 4-[1-(t-butoxycarbonyl)-2-pyrrolidinyl]methylthiobenzoic acid methyl vinegar. ^H-NMR (4 00 MHz, CDC13) (5 1.45 (s, 9H) &gt; 78^2. 01 (br m, 4H), 2.71 (dt, 1H), 3·32-3·49 (br m , 3H), 3·90-4·02 (br m,1H), 7·12 (d, J = 7.8 HZ, ih), 7·18 (d, J: 7. 8 Hz, 1H), 7· 57 (dd, J = 2. 0, 8 · 3 Hz, 2H); MS (FAB) m/z 42 0 (MH1). 4 - [1 - (2nd butoxy) To a stirred solution of CH2C12 (20 ml) was added TFA (4 liters), and the mixture was stirred at room temperature 丨 丨 曱 曱 曱 曱 硫 硫 硫 ( 1 1 1 1 1 CH CH The solvent was removed under reduced pressure, and the residue was taken-up with EtOAc (EtOAc) eluting with CH.sub.3. The mixture was washed with brine, dried over Kohs and concentrated under reduced pressure. Mg (9 2 %) of a yellow oil of 4 - ( 2 - indole) methyl thiobenzoate. UMR (4 00 MHz, CDC13) 5 1· 51 and 1· 47 (each s, 9H) , 1·78-2·05 (br m, 4H), 2·77 (dt, J = 10.8, 37·1 Hz, 1H), 3·34 - 3.58 (m, 3H), 3·89 (s, 3H), 4·03 (br d, J = 27.3 Hz, 1H), 7·38 (d, J = 7.3 Hz, 1H), 7·47 (d, J = 7.3 Hz 1H), 7.92 (br s, 2H); MS (FAB) m/z 352 (M+ + 1). 3-methoxy- 4-[N,-(2-methyl) at 0 °C Phenyl)ureido]phenylacetic acid (1·30 g, 4·136 mmol), Et3N (0.63 ml, 4·5 49 mmol)

^ \\312\2d-code\90-01\89112968.ptd 第180頁 I 1283240 _ 五、發明說明（176) 溶於DMF( 20毫升）之攪拌混合物中加入三氟乙酸五氟苯 酯。使所產生之混合物在室溫下攪拌1小時。將混合物倒 入至水（60毫升）中，並利用吸濾收集沈澱物。將粗製固體 以0· IN HC1、H20、正己烷洗滌，及於40 °C下乾燥而得 1·91克（9 6%)之3-甲氧基-4 - [Ν’- (2-甲基苯基）脲基]苯基 乙酸五氟苯酯的淡棕色結晶粉末。 IR (KBr) 1785、1 224、1216 / 公分；iH-NMR (4 00 MHz, CDC13) 62.29 (s, 3H)、3·76 (s，3H)、3·90 (s，2H)、 6·49 (s，1Η)、6·81 (d，J = 1.5Hz，1Η)、6·91 (dd， J = 1.5、8·3 Ηζ，1Η)、7·15 (t，J = 7.3 Hz, 3Η)、7·24 (m，1H)、7·50 (d，J = 7.8 Hz，1H)、8·17 (d，J = 7.8 Hz, 1H) ; MS(FAB) m/z 481 (MH1 ) ; c3〇H33N3 05 S · 1/4H20 之 分析 §十鼻值·0，57.51，H， 3·57; N，5·83。實測值：C， 57. 40 ； Η, 3.75； Ν, 5.68° 使3-甲氧基-4-[Ν’-（2-甲基苯基）脲基]苯乙酸五氟苯酯 (1 · 4 7克’ 3 · 0 5毫莫耳）、4 - (2 -吡咯啶基）甲基硫笨曱酸甲 酯（767毫克，3.05毫莫耳）、Et3N(〇.51毫升，3.66毫莫 耳）溶於DMF (1 5毫升）之混合物在室溫下攪拌隔夜。將反應 混合物以EtOAc稀釋，以鹽水洗滌，並於Na2S〇4上乾燥。將 溶劑於減壓下移除，及將殘留物於石夕膠上利用正己烧 -EtOAc(l : 2，v/v)作為洗提液進行層析而得丨· 3 66克（82〇/〇) 之4-[1 -[3-甲氧基-4-[ Ν’ 2-甲基苯基）脲基]苯基乙醯 基]-2-吼洛咬基]甲基硫基]笨甲酸甲酯的白色結晶粉末。 IR (KBr) 1 7 85、1 224、121 6 / 公分；ιΗ一NMR (4〇〇 ΜΗζ，^ \\312\2d-code\90-01\89112968.ptd Page 180 I 1283240 _ V. INSTRUCTIONS (176) To a stirred mixture of DMF (20 ml) was added pentafluorophenyl trifluoroacetate. The resulting mixture was stirred at room temperature for 1 hour. The mixture was poured into water (60 ml), and the precipitate was collected by suction filtration. The crude solid was washed with 0·IN HC1, H20, n-hexane, and dried at 40 ° C to give 1.91 g (9 6%) of 3-methoxy-4 - [Ν'- (2- Light brown crystalline powder of phenylphenyl)ureido]phenylpentaacetate pentafluorophenyl ester. IR (KBr) 1785, 1 224, 1216 / cm; iH-NMR (4 00 MHz, CDC13) 62.29 (s, 3H), 3·76 (s, 3H), 3·90 (s, 2H), 6· 49 (s, 1Η), 6.81 (d, J = 1.5Hz, 1Η), 6.91 (dd, J = 1.5, 8·3 Ηζ, 1Η), 7·15 (t, J = 7.3 Hz, 3Η), 7·24 (m, 1H), 7·50 (d, J = 7.8 Hz, 1H), 8·17 (d, J = 7.8 Hz, 1H); MS(FAB) m/z 481 (MH1 ; c3〇H33N3 05 S · 1/4H20 analysis § ten nose value · 0,57.51, H, 3.57; N,5·83. Found: C, 57. 40 ; Η, 3.75; Ν, 5.68° 3-methoxy-4-[Ν'-(2-methylphenyl)ureido]phenylacetic acid pentafluorophenyl ester (1 · 4 7 g '3 · 0 5 mmol), 4 - (2-pyrrolidinyl)methyl thioanthronic acid methyl ester (767 mg, 3.05 mmol), Et3N (〇.51 ml, 3.66 mmol) The mixture was dissolved in DMF (15 mL) and stirred at room temperature overnight. The reaction mixture was diluted with EtOAc, washed with brine and dried over Na. The solvent was removed under reduced pressure, and the residue was applied to EtOAc (EtOAc: EtOAc (EtOAc) [) 4-[1-[3-methoxy-4-[Ν'2-methylphenyl]ureido]phenylethenyl]-2-indolyl]methylthio] A white crystalline powder of methyl formate. IR (KBr) 1 7 85, 1 224, 121 6 / cm; ιΗ NMR (4〇〇 ΜΗζ,

\\312\2d-code\90-01\89112968.ptd 第 181 頁 1283240 五、發明說明（177) CDC13) 5 1 · 88 -1 · 9 9 (m，4H)、2· 3 0 (s, 3Η)、2 · 75 (dd， J-9.8、13·2 Hz，1H)、3·43-3·55 (m，3H)、3.56 (s， 2H)、3·64 (dd，J = l.l、14·2 Hz, 1H)、3·73 (s，3H)、 3.88 (s，3H)、4·33 (m，1H)、6·29 (s，1H)、 6.78-6.81 (m，2H)、7·11-7·26 (m，5H)、7·50 (d， J = 8.3 Hz, 3H)、7·93 (d，J = 8.8 Hz，2H)、8-〇7 (d， J = 7.8 Hz，1H); MS(FAB) m/z 5 48(MH1) ; C30H33N3O5S · 1/4H20 之分析計算值：C，65· 26 ; H，6· 12 ; N, 7· 61。實 測值：C，65. 48 ； Η, 6· 20 ; Ν, 7.47° 於4 - [ 1 - [ 3 -甲氧基-4 - [ Ν’ -（2-曱基苯基）脲基]笨基乙醯 基]- 2-咄咯啶基]曱基硫基]苯曱酸甲酯（3〇〇毫克，Q.548 毫莫耳）溶於THF(5.5毫升）及Η20(1·1毫升）之攪拌溶液中 加入Li ΟΗ(39· 4毫克，1· 643毫莫耳），並使反應混合物在 室溫下攪拌隔夜，及在5 0 °C下攪拌9小時。將混合物以 CHCI3稀釋。將溶液以IN HC1、鹽水洗滌，及於Na2S04上乾 燥。將溶劑於減壓下移除，及使所得之粗製固體自正己烧 11:(^〇:-116〇11再結晶，而得218.6毫克（75%)之23的白色結 晶粉末。 IR (KBr) 3318、2 952、1596、1536、1299、115 5 /公 分；1H-NMR ( 40 0 MHz，DMSO-d6) 61·82-2·05 (m，4H)、 2.25 (s，3H)、2·91 (dd，J = 9.8、13·2 Hz，1H)、 3.47-3.52 (m，3H)、3·57 (s，2H)、3·87 (s，3H)、 4·14 (br m，1H)、6.76 (d，J=1.5、8.3 Hzd，1H)、 6.89 (d，J=1.5 Hz，1H)、6·94 (t，J = 7.3 Hz，1H)、7.\\312\2d-code\90-01\89112968.ptd Page 181 1283240 V. INSTRUCTIONS (177) CDC13) 5 1 · 88 -1 · 9 9 (m, 4H), 2· 3 0 (s, 3Η), 2 · 75 (dd, J-9.8, 13·2 Hz, 1H), 3·43-3·55 (m, 3H), 3.56 (s, 2H), 3·64 (dd, J = ll , 14·2 Hz, 1H), 3·73 (s, 3H), 3.88 (s, 3H), 4·33 (m, 1H), 6·29 (s, 1H), 6.78-6.81 (m, 2H ), 7·11-7·26 (m, 5H), 7·50 (d, J = 8.3 Hz, 3H), 7.93 (d, J = 8.8 Hz, 2H), 8-〇7 (d, J = 7.8 Hz, 1H); MS (FAB) m/z 5 48 (MH1); C30H33N3O5S · 1/4H20 Analysis calculated: C, 65 · 26 ; H, 6 · 12 ; N, 7. 61. Found: C, 65. 48; Η, 6·20 ; Ν, 7.47° in 4 - [ 1 - [ 3 -methoxy-4 - [ Ν ' - (2-nonylphenyl) ureido] Methyl ethyl 2-(2-pyridyl)] mercaptothio]benzoic acid methyl ester (3 mg, Q.548 mmol) dissolved in THF (5.5 ml) and hydrazine 20 (1·1 ml) Li ΟΗ (39·4 mg, 1.643 mmol) was added to the stirred solution, and the reaction mixture was stirred at room temperature overnight and stirred at 50 ° C for 9 hr. The mixture was diluted with CHCI3. The solution was washed with IN HCl, brine and dried over Na 2 SO 4 . The solvent was removed under reduced pressure, and the obtained crude solid was recrystallized from n-hexane: 21 (yield: -116) to give 218.6 mg (75%) of 23 white crystalline powder. IR (KBr) 3318, 2 952, 1596, 1536, 1299, 115 5 / cm; 1H-NMR (40 0 MHz, DMSO-d6) 61·82-2·05 (m, 4H), 2.25 (s, 3H), 2· 91 (dd, J = 9.8, 13·2 Hz, 1H), 3.47-3.52 (m, 3H), 3·57 (s, 2H), 3·87 (s, 3H), 4·14 (br m, 1H), 6.76 (d, J=1.5, 8.3 Hzd, 1H), 6.89 (d, J=1.5 Hz, 1H), 6.94 (t, J = 7.3 Hz, 1H), 7.

\\312\2d-code\90-01\89112968.ptd 第182頁 1283240 五、發明說明（178) U-7.19 (m，2H)、7·57 (d，J = 8.3 Hz, 2H)、7.80 (d， J = 8.3 Hz，1H)、7·83 (d，J = 8.3 Hz, 2H)、8·02 (d， J = 8.3 Hz，1H)、8·49 (s，1H)、8·58 (s，1H); MS(FAB) m/z 534(M+ + 1) ; C29H31N3 05 S ·5/4Η2〇 之分析計算值：C， 6 2 · 6 3 ’ Η ’ 6 · 0 7 ’ N ’ 7 · 3 6 ; S，5 · 7 7。實測值：c， 62·62;Η，5·74;Ν，7.36;S，5·67。 實施例20 4-[1 -[3-甲氧基-4-[Ν’ -（2-甲基笨基）脲基]笨基乙醯基] - 2 -吼洛咬基]曱基亞石黃醯基]苯曱酸 1 Η Η 乂 ^^COOH 24 在0 C下於4-[ 1- [3-甲氧基-4-[N，-（2-甲基笨基）脲基] 苯基乙醯基]- 2 -咄咯啶基]甲基硫基]苯曱酸曱酯（2 6 4毫 克，0· 482毫莫耳）溶於CH2C12(5· 2毫升）之攪拌溶液中加入 m - CPBAC118.8毫克，0.4 82毫莫耳），及使混合物在室溫下 授拌1小日ττ。將混合物以C H C 13稀釋，並以飽和n a ^ 使反 應停止。將分離的有機層以飽和NaHC〇3、鹽水洗&amp; 3，及於 NaJC»4上乾燥。將溶劑於減壓下移除而得4 —[丨—[3:甲y美 -4-[Ν’ -（2-甲基苯基）脲基]苯基乙醯基]—2- π比。各α定基^ $ 基石黃贐基苯甲酸甲酯之粗製非晶形固體。於此粗黎】化人 溶於THF(4毫升）及札0(1毫升）之攪拌溶液中加入 3 4 · 6毫克，1 · 4 5毫莫耳），並繼續在室溫下攪掉隔夜。將 混合物以CHC!3稀釋，以IN HC1、鹽水洗滌，及^N=s〇上\\312\2d-code\90-01\89112968.ptd Page 182 1283240 V. INSTRUCTIONS (178) U-7.19 (m, 2H), 7·57 (d, J = 8.3 Hz, 2H), 7.80 (d, J = 8.3 Hz, 1H), 7·83 (d, J = 8.3 Hz, 2H), 8·02 (d, J = 8.3 Hz, 1H), 8·49 (s, 1H), 8· 58 (s,1H); MS(FAB) m/z 534(M+ + 1) ; C29H31N3 05 S ·5/4Η2〇 Analysis calculated: C, 6 2 · 6 3 ' Η ' 6 · 0 7 ' N ' 7 · 3 6 ; S, 5 · 7 7. Found: c, 62·62; Η, 5.74; Ν, 7.36; S, 5.67. Example 20 4-[1-[3-Methoxy-4-[Ν'-(2-methylphenyl)ureido]]phenylamino]]-2-indolyl] sulfhydryl Astragaloside]benzoic acid 1 Η Η 乂^^COOH 24 at 0 C in 4-[ 1-[3-methoxy-4-[N,-(2-methylphenyl)ureido]phenylene醯 ] - - - - ] ] ] 2 2 2 2 2 2 2 2 2 2 2 2 2 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - CPBAC 118.8 mg, 0.4 82 mmol, and the mixture was allowed to mix for 1 hour ττ at room temperature. The mixture was diluted with CHC13 and the reaction was quenched with sat. The separated organic layer was washed with saturated NaHC.sub.3, brine and &lt;3&gt;, and dried over NaJC»4. The solvent is removed under reduced pressure to give 4-[丨-[3:甲yy-4-[Ν'-(2-methylphenyl)ureido]phenylethenyl]-2-π ratio . A crude amorphous solid of each of the α-based bases. In this stirred solution of THF (4 ml) and Zha 0 (1 ml), add 3 4 · 6 mg, 1/4 5 mmol, and continue to stir overnight at room temperature. . The mixture was diluted with CHC!3, washed with IN HCl, brine, and ^N=s〇

| \\312\2d.code\90-01\89112968.ptd 第 183 頁 ' ------- 1283240 五、發明說明（179) 乾燥。將溶劑於減壓下移除，及使所得之粗製固體自正己 烷-CHC13-MeOH再結晶，而得1 93. 2毫克（73%)之24的白色 結晶粉末。 IR (KBr) 33 38、2 956、1 70 8、1 529、1 299、1 2 07、1155 / 公分；NMR (400 MHz, DMS0-d6) 5 1.70- 2.0 6 (m， 4H)、2· 24 (s，3H)、2· 90 (dd，J = 8· 3、13· 2 Hz，1H)、 3.02-3.08 (m，1H)、3·16-3·25 (m，1H)、3·4 卜 3.60 (m， 3H) 、3·84 (s， 3H) 、4·40 (br s， 1H) 、6·74 (d， J = 7.8 Hz, 1H) &gt;6.87 (s, 1H) &gt;6.94 (d, J = 7.3 Hz, 1H)、7·η - 7·17 (m, 2H)、7·75 - 7、·81 (m，3H)、7·98 - 8. 05 (m，1Η)、8·10 (d，J = 8.3 Ηζ，2Η)、8·46 (s，1Η)、 8.56 (s，1H); MS(FAB) m/z 55 0 (MH1)、57 2(MHNa); C 29H31N3 06 S · 3/2H20 之分析計算值：c，60· 40 ; H，5· 94 ; N， 7. 29。實測值：C， 60. 1 5 ; H，5. 82 ; N，6. 90。 實施例21 (S)-4-[l-[ 3-曱氧基-4-[Ν’ - (2-曱基苯基）脲基]苯基乙醯 基]- 2 -咄咯啶甲氧基]苯甲酸| \\312\2d.code\90-01\89112968.ptd Page 183 ' ------- 1283240 V. INSTRUCTIONS (179) Drying. The solvent was removed under reduced pressure, and the obtained crude solid was recrystallized from n-hexane-CHC 13-MeOH to afford 19.2 mg (73%) of 24 white crystalline powder. IR (KBr) 33 38, 2 956, 1 70 8, 1 529, 1 299, 1 2 07, 1155 / cm; NMR (400 MHz, DMS0-d6) 5 1.70- 2.0 6 (m, 4H), 2· 24 (s, 3H), 2·90 (dd, J = 8·3, 13· 2 Hz, 1H), 3.02-3.08 (m, 1H), 3·16-3·25 (m, 1H), 3 ·4 卜 3.60 (m, 3H), 3.84 (s, 3H), 4·40 (br s, 1H), 6.74 (d, J = 7.8 Hz, 1H) &gt; 6.87 (s, 1H) &gt;6.94 (d, J = 7.3 Hz, 1H), 7·η - 7·17 (m, 2H), 7·75 - 7, 81 (m, 3H), 7·98 - 8. 05 (m , 1Η), 8·10 (d, J = 8.3 Ηζ, 2Η), 8.46 (s, 1Η), 8.56 (s, 1H); MS(FAB) m/z 55 0 (MH1), 57 2 ( Analytical calculated value for C 29H31N3 06 S · 3/2H20: c, 60·40 ; H, 5· 94 ; N, 7. 29. Found: C, 60. 1 5 ; H, 5. 82 ; N, 6.90. Example 21 (S)-4-[l-[ 3-decyloxy-4-[Ν'-(2-mercaptophenyl)ureido]phenylethenyl]-2-pyrrolidinemethoxy Benzoic acid

於4-羥基苯甲酸甲酯（1.96克，12.88毫莫耳）、N-Boc -脯胺醛（2.59克，12.87毫莫耳）及pph3( 4· 06克，15. 48毫 莫耳）溶於THF (4 0毫升）之攪拌溶液中加入di AD (3. 10毫 升，1 5 · 7 4毫莫耳）。使所產生之混合物迴流加熱1 4小時。Methyl 4-hydroxybenzoate (1.96 g, 12.88 mmol), N-Boc-prolinal (2.59 g, 12.87 mmol) and pph3 (4.66 g, 15.48 mmol) Di AD (3. 10 ml, 1 5 · 7 4 mmol) was added to a stirred solution of THF (40 mL). The resulting mixture was heated to reflux for 14 hours.

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五、發明說明（180) 將混合物於真空中蒸發掉’並將殘留物經由於矽膠上利用 正己烧-Et0Ac(6:l ’v/v)作為洗提液進行管柱層析，纯化 而得3. 34克（77%)之第三丁氧羰基）_2_咄嘻咬 甲氧基]苯甲酸.甲酯的油。V. Inventive Description (180) The mixture was evaporated in vacuo and the residue was purified by column chromatography using hexane-Et0Ac (6:l 'v/v) as an eluent. 3. An oil of 34 g (77%) of a third butoxycarbonyl)_2_咄嘻 methoxy]benzoic acid. Methyl ester.

UMR (CDC13) (5 1· 48 (s，9H)、1· 67 (d，J = 9 3 H 1H)、1·87-2·03 (m，3H)、3·36-3·43 (m，2H)、3·87-4· 09 (m，1H)、4·13-4·20 (m，2H)、6·94 (d，J = 8 3 Hz 2H)、7· 98 (d，J = 8· 3 Hz, 2H)。 ’ Z， 使（S) -4-[1-（第二丁氧羰基）一2-吡咯啶甲氧基]笨甲酸 甲醋（3.34克，9.96毫莫耳）溶於下1^(2〇毫升）及(：112(： 5 毫升）之混合物在室溫下攪拌15小時。將混合物於真空中 派縮，並利用飽和NaHC〇3使成為驗性。將混合物以cmι3萃 取，以鹽水洗滌，及於Na/O3上乾燥。將有機層蒸發而3寻&quot; 1. 70克（73%)之（S)-4-(2 -咄咯啶甲氧基）苯曱酸甲酯之黃 色油。 HR (CDC13) 5 1· 54-1· 61 (m，1H)、1· 77-1· 86 (m， 2 Η)、1 · 8 7 -1 · 9 7 (m，1 Η )、2 · 0 0 (b s，1 Η )、2 · 9 3 - 3 〇 6 (m，2H)、3·52-3·57 (m，1H)、3·88 (s，3H)、3·90 -3·99 (m，2H)、6·92 (d，J = 9.0 Hz, 2H)、7·98 (d， J = 9· 0 Hz，2H)。 ’ ’ 將3-曱氧基-4-[ Ν’ - (2 -甲基苯基）脲基]苯乙酸（428毫 克，1.36¾莫耳）、（S) - 4-[2_°比洛唆甲氧基]苯甲酸甲酯 (330毫克，1·40毫莫耳）、EDC (312毫克，1.63毫莫耳）、 HOBt(2 20毫克’1·63毫莫耳）、及催化量之DMAp於DMF(15UMR (CDC13) (5 1· 48 (s, 9H), 1·67 (d, J = 9 3 H 1H), 1·87-2·03 (m, 3H), 3·36-3·43 ( m, 2H), 3·87-4· 09 (m, 1H), 4·13-4·20 (m, 2H), 6.94 (d, J = 8 3 Hz 2H), 7· 98 (d , J = 8· 3 Hz, 2H). 'Z, (S) -4-[1-(2nd-butoxycarbonyl)- 2-pyrrolidinemethoxy]-formic acid methyl vinegar (3.34 g, 9.96 m Mol) was dissolved in a mixture of 1 ^ (2 mL) and (: 112 (: 5 mL) at room temperature for 15 hours. The mixture was transferred in vacuo and made saturated with saturated NaHC 3 The mixture was extracted with cm3, washed with brine, and dried over Na/O3. The organic layer was evaporated to yield &quot; 1. 70 g (73%) of (S)-4-(2-pyrrolidine) Yellow oil of methyl phenyl benzoate. HR (CDC13) 5 1· 54-1· 61 (m, 1H), 1·77-1· 86 (m, 2 Η), 1 · 8 7 -1 · 9 7 (m,1 Η ), 2 · 0 0 (bs,1 Η ), 2 · 9 3 - 3 〇6 (m, 2H), 3·52-3·57 (m, 1H), 3· 88 (s, 3H), 3·90 -3·99 (m, 2H), 6.92 (d, J = 9.0 Hz, 2H), 7·98 (d, J = 9. 0 Hz, 2H). ' ' will 3-曱oxy-4-[ Ν' - (2-methylphenyl)ureido]phenylacetic acid (428 mg, 1.363⁄4 mol), (S) - 4-[2_°piroximemethoxy]benzoic acid methyl ester (330 mg, 1.40 Millol), EDC (312 mg, 1.63 mmol), HOBt (2 20 mg '1·63 mmol), and catalytic amount of DMAp in DMF (15

\\312\2d-code\90-01\89112968.ptd 第185頁 1283240 五、發明說明（181) 中二合二授拌6小時。將所產生之現合物“Et0Ac 稀釋，以0.5N HC1、飽和NaHC〇3、鹽水 乾燥。將溶劑於真空中蒸發掉而得一油性殘J勿心經 由於矽膠上利用CHCh-MeOIK 5 〇 : i，v/v)作為洗提液進行 管柱層析，純化而得540毫克（75%)之（S)-“「〗_「3_甲氧某 -4-N’-(2-甲基苯基）脲基]苯乙醯基]_2_咣咯啶甲氧基]^ 甲酸甲酯的油。 UMR (CDC13) 5 1· 8卜2· 12 (m，4H)、2· 88 (bs，3H)、 3·48-3·61 (m，總計7H)、3·88 (s，3H)、4·ΐ〇-4·21 (m， 2H)、4· 42-4· 46 (m， 1H)、6· 75-8· 08 (m 系列，總計 13H)。 於（S)-4-[1-[3-曱氧基-4 - N，-(2-甲基笨基）脲基]苯基 乙醯基]- 2-σ比洛σ定甲氧基]笨甲酸甲酿（54〇毫克，；[·〇2毫 莫耳）溶於THF (10毫升）之攪拌溶液中加入0.25 N NaOH (1 0宅升）。使所產生之混合物迴流加熱1 6小時。將混合物 倒入至IN HC1中，並收集固體。將粗製固體以Ei：2〇洗滌而 得278毫克（53%)之25的白色非晶形固體。 IR (KBr) 1 7 08 / 公分；4-題R (DMS0-d6) (Π · 83-2· 14 (m，4H)、2·21 (s，3H)、2.46 (s，2H)、3·78 (s， 3Η) 、3·95-4·02 (m， 1Η) 、4·13-4·16 (m， 1Η) 、4·24 (bs， 1H)、6·5 卜 7.98(m 系列，12H)、8·43 (s， 1H)、 8. 53 (s， 1H)、12· 57 (bs， 1H) ; MS(FAB) m/z 51 7(M+ 實施例22\\312\2d-code\90-01\89112968.ptd Page 185 1283240 V. INSTRUCTIONS (181) Mix 2 hours for 6 hours. The resulting compound "Et0Ac was diluted, dried with 0.5N HCl, saturated NaHC 〇 3, and brine. The solvent was evaporated in vacuo to obtain an oily residue. The CHCH-MeOIK 5 was used on the silicone. , v/v) as a eluent for column chromatography, purification to obtain 540 mg (75%) of (S)-""__3_methoxy--4-N'-(2-methyl An oil of methyl phenyl) ureido]phenidinyl] 2 - fluorenyl methoxy] ^ methyl formate. UMR (CDC13) 5 1· 8 Bu 2· 12 (m, 4H), 2· 88 (bs , 3H), 3·48-3·61 (m, total 7H), 3·88 (s, 3H), 4·ΐ〇-4·21 (m, 2H), 4·42-4· 46 (m , 1H), 6·75-8· 08 (m series, total 13H). (S)-4-[1-[3-曱oxy-4 - N,-(2-methylphenyl)urea Add to the stirred solution of phenyl hydrazide]- 2-σ piroxime methoxy] benzoic acid formic acid (54 〇 mg,; [· 〇 2 mmol) in THF (10 ml) 0.25 N NaOH (10 liters). The resulting mixture was heated to reflux for 16 hours. The mixture was poured into IN HCl and solids were collected. The crude solid was washed with EtOAc: ) 25 of the white amorphous Solid. IR (KBr) 1 7 08 / cm; 4-question R (DMS0-d6) (Π · 83-2· 14 (m, 4H), 2·21 (s, 3H), 2.46 (s, 2H) , 3·78 (s, 3Η), 3·95-4·02 (m, 1Η), 4·13-4·16 (m, 1Η), 4·24 (bs, 1H), 6·5, 7.98 (m series, 12H), 8.43 (s, 1H), 8. 53 (s, 1H), 12·57 (bs, 1H); MS(FAB) m/z 51 7 (M+ Example 22

\\312\2d-code\90-01\89112968.ptd 第186頁 1283240 五、發明說明（182) 卜[卜[3-甲氧基-4- [Ν’ -(2-甲基苯基）脲基]笨甲醯基]一L-六氣11比唆乙酸\\312\2d-code\90-01\89112968.ptd Page 186 1283240 V. INSTRUCTIONS (182) BU [Bu [3-methoxy-4-[Ν' -(2-methylphenyl)) Urea-based] alkaloid]-L-six-gas 11-indole acetic acid

使3-甲氧基-4 -苯甲酸（229毫克，1·16毫莫耳）、4 -（1-脯胺醯基六氫咄啶基）乙酸第三丁酯（344毫克，1. 1 6毫莫 耳）、H0BU188 毫克，1.39 毫莫耳）、DMAP(14· 2 毫克， 0·116毫莫耳）、及EDC(267毫克，1.39毫莫耳）於DMF(7毫 升）中之混合物在室溫下攪拌22小時。將混合物以3-methoxy-4-benzoic acid (229 mg, 1.16 mmol), 4-(1-amidodecylhexahydroacridinyl)acetic acid tert-butyl ester (344 mg, 1.1) a mixture of 6 mM), H0BU 188 mg, 1.39 mM, DMAP (14.2 mg, 0·116 mmol), and EDC (267 mg, 1.39 mmol) in DMF (7 mL) Stir at room temperature for 22 hours. Mix the mixture

EtOAc(50毫升）稀釋，並以IN HC1、飽和NaHC03、及1120連 續洗滌。將有機層於NazS〇4上乾燥，並於真空中蒸發。將 殘留物於矽膠上利用MeOH ·· CHC13(1 ·· 30，v/v)作為洗提液 進行層析而得520毫克（94%)之第三丁基—（3-曱氧基—4-确 苯曱醯基）脯胺醯基-4 - (1 -六氫吼咬基）乙酸酯的白色結晶 物質。 4 - NMR (CDC13)(51.12-1.33 及 1·62-2·23 (各m，9H)、 1·44 (s，9H)、2·65、3·13、3·47、3·67、4·44、及4·61 (各m，8Η)、3·99 (s，3Η)、5·〇5 (m，1Η)、7·21 (d, J = 8- 3 Ηζ，1Η)、7·31 (s，1Η)、7·86 (d, J = 8.3 Ηζ， 1Η)。 使第三丁基-（3-曱氧基-4 -硝笨甲醯基）脯胺醯基一4 一（1 -六氫咄啶基）乙酸酯（〇· 52克，1· 〇9毫莫耳）及5% Pd-C ( 2·08克）於MeOH(10毫升）中之攪拌混合物在大氣壓力中在Diluted with EtOAc (50 mL) and washed with EtOAc EtOAc EtOAc The organic layer was dried over NazS 4 and evaporated in vacuo. The residue was chromatographed on silica gel using MeOH·· CHC13 (1··30, v/v) as eluent to give 520 mg (94%) of butyl-(3-methoxy- 4 - White phthalocyanine of benzoguanidino-4-indolyl-4-(1-hexahydroindenyl) acetate. 4 - NMR (CDC13) (51.12-1.33 and 1.62-2.23 (each m, 9H), 1.44 (s, 9H), 2·65, 3·13, 3.47, 3.67, 4·44, and 4·61 (each m, 8Η), 3·99 (s, 3Η), 5·〇5 (m, 1Η), 7·21 (d, J = 8- 3 Ηζ, 1Η), 7·31 (s,1Η), 7·86 (d, J = 8.3 Ηζ, 1Η). To make the third butyl-(3-oxixo-4-n-nitrophenyl) amidinoinyl group 4 a stirred mixture of mono(1-hexahydroacridinyl)acetate (〇·52 g, 1·〇9 mmol) and 5% Pd-C (2.08 g) in MeOH (10 mL) At atmospheric pressure

\\312\2d-code\90-01\89112968.ptd 第 187 頁 1283240 I、發明說明（183)------ iΓ，化9 4小日^&quot;。將不溶解的催化劑移除，及將遽液於 具工中蒸發。將殘留物於矽膠上利用Me〇H:cHci3 (丨：“至 1·6，v/v)作為洗提液進行層析而得279毫克（57%)之第三 丁基-（4 -胺基-3 -甲氧苯甲醯基）脯胺醯基一4一（1 一六氫咄啶 基）乙酸酯的白色結晶物質。 Η-NMR (CDC13)51.16-2.17、2·69、3·06、3·67、4·12、 及 4·59 (各m，ΐ7Η)、3·86 (s，3H)、51〇 (m，1Η)、 6.64(m， 1Η) 、 7·12 (各m， 2Η)。 在室溫下於第三丁基-（4-胺基-3-甲氧苯甲醯基&gt;-l-脯 胺醯基-4-(1-六氫咄啶基）乙酸酯（2 79毫克，〇· 627毫莫 耳）及Et3N(0· 08 76毫升，0· 62 7毫莫耳）溶於THF(4毫升）之 攪拌溶液中逐滴加入異三聚氰酸鄰甲苯酯（〇· 0777毫升， 〇 · 6 2 7毫莫耳），並使所產生之混合物再在室溫下多攪拌21 小時。將冰水加至混合物，並利用吸濾收集沈澱物。將粗 製固體經由利用丛6〇11吒11(：13(1:40，¥/¥)作為洗提液進行 矽膠管柱層析，純化而得25 4毫克（70%)之1-[ 1- [3-曱氧基 - 4-[N’-(2-曱基苯基）脲基]苯甲醯基-L-脯胺醯基]- 4-（1 -六氫咄啶基）乙酸第三丁酯的結晶固體。 LR (CDC13) (H· 43 (s，9H)、1· 13-1· 25 及1· 76-2· 14 (各m，9H)、2·60、3·18、3·71、4.06、及 4.57 (各 m， 8H)、3·67 (s，3H)、5·06 (m，1H)、6·63、及 6·90 (s，2Η)、6. 98-7· 23、及7· 64 (各m，5Η)、7· 56 (d， J = 7.8 Hz，1H)、8·21 (d，J = 8.8 Hz，1H)。 使卜[1-[3 -甲氧基-4 - [Ν’ -（2-甲基笨基）脲基]苯甲醯基\\312\2d-code\90-01\89112968.ptd Page 187 1283240 I. Description of invention (183)------ iΓ, 9 4 days ^&quot;. The insoluble catalyst is removed and the mash is evaporated in the work. The residue was chromatographed on a silica gel using Me〇H:cHci3 (丨: "to 1,6, v/v) as an eluent to give 279 mg (57%) of butyl-(4-amine a white crystalline material of benzyl-3-methoxybenzoinyl amidoxime-4-yl (1 hexahydroacridinyl) acetate. Η-NMR (CDC13) 51.16-2.17, 2·69, 3 ·06,3·67,4·12, and 4.59 (each m, ΐ7Η), 3·86 (s,3H), 51〇(m,1Η), 6.64(m, 1Η), 7·12 ( Each m, 2 Η). at room temperature in the third butyl-(4-amino-3-methoxybenzoindolide&gt;-l-amidoxime-4-(1-hexahydroacridinyl) ) Acetate (2 79 mg, 627 · 627 mmol) and Et3N (0· 08 76 ml, 0·62 7 mmol) in a stirred solution of THF (4 mL). O-cresyl cyanate (〇·7777 ml, 〇·6 2 7 mmol), and the resulting mixture was stirred for an additional 21 hours at room temperature. Ice water was added to the mixture and the precipitate was collected by suction filtration. The crude solid was purified by column chromatography using a cluster of 6〇11吒11 (:13 (1:40, ¥/¥) as an eluent to obtain 25 4 mg (70%). 1-[ 1- [3-曱-oxy-4-(N'-(2-mercaptophenyl)ureido]benzylidene-L-nonylamino]- 4-(1-hexahydroindole Crystalline solid of tributyl butyl pyridine) LR (CDC13) (H·43 (s, 9H), 1·13-1· 25 and 1·76-2· 14 (each m, 9H), 2· 60, 3·18, 3·71, 4.06, and 4.57 (each m, 8H), 3.67 (s, 3H), 5·06 (m, 1H), 6.63, and 6.90 (s, 2Η), 6. 98-7· 23, and 7·64 (each m, 5Η), 7.56 (d, J = 7.8 Hz, 1H), 8·21 (d, J = 8.8 Hz, 1H). [1-[3-Methoxy-4 -[Ν' -(2-methylphenyl))]benzimidyl

\\312\2d-code\90-01\89112968.ptd 第188頁 1283240 五、發明說明（184) -L-膽胺酿基]—4-( 1-六氫咄啶基）乙酸第三丁酯（ 25 4毫 克’ 0· 440毫莫耳）溶於CH2cl2(6毫升）及TFA(6毫升）之溶液 在室溫下授拌5小時。將混合物倒入至冰水中。利用吸濾 收集固體’將其以水洗滌，並風乾而得179毫克（78%)之26 的白色結晶固體。 U MR (DMS0-d6)枝47、1·〇5、1·44、及 1.62-1.99 (各 m，9Η)、2·49 (s，3Η)、2.15,2·30、2·35、2·56、 2· 78、3· 09、3· 04-3· 80、4· 05、4· 15、及4· 32 (各m， 8Η)、3.92(s，3Η)、4·92 (m，1Η)、6·82、6·95、7·11、 7· 77、8· 20、8· 57、及8· 75 (m，9Η) ; MS(FAB) m/z 523 (Μ+ + 1) ; C28H34N4 06 之分析計算值：c，64. 35 ; Η， 6· 56 ; N， 10· 72。實測值：c，5 5. 5 8 ; H，5. 89 ; N， 8· 75 〇 實施例23 (S)-3-甲氧基-4- [ 1- [3-甲氧基一4一 [N，一（ 2一甲基苯基）脲 基]苯基乙醯基]-2 -吼17各咬甲氧基]苯甲酸\\312\2d-code\90-01\89112968.ptd Page 188 1283240 V. INSTRUCTIONS (184) -L-Cholesteryl Alkyl] 4-(1-Hexahydroacridinyl)acetic acid Third A solution of the ester (25 4 mg '0· 440 mmol) in CH 2 Cl 2 (6 mL) and TFA (6 mL) was stirred at room temperature for 5 hours. Pour the mixture into ice water. The solid was collected by suction filtration, which was washed with water and air-dried to yield 179 mg (78%) of 26 white solid. U MR (DMS0-d6) branches 47, 1·〇5, 1.44, and 1.62-1.99 (each m, 9Η), 2·49 (s, 3Η), 2.15, 2·30, 2·35, 2 ·56, 2·78, 3· 09, 3· 04-3· 80, 4· 05, 4·15, and 4·32 (each m, 8Η), 3.92 (s, 3Η), 4.92 (m ,1Η),6·82,6·95,7·11,7·77,8·20,8·57, and 8·75 (m,9Η); MS(FAB) m/z 523 (Μ+ + 1) ; Analytical calculated value of C28H34N4 06: c, 64. 35 ; Η, 6· 56 ; N, 10· 72. Found: c, 5 5. 5 8 ; H, 5. 89 ; N, 8 · 75 〇 Example 23 (S)-3-methoxy-4- [ 1- [3-methoxy- 4- [N,-(2-methylphenyl)ureido]phenylethenyl]-2 -indolyl methoxy]benzoic acid

OOH 27 在0 °C下於4-經基-3 -甲氧苯甲酸乙酯（3· 〇〇克，J 5. 29毫 莫耳）、（S)_N-Boc-脯胺醇（3· 〇8 克，15· 3〇 毫莫耳）、ph3 Ρ(4· 81克，1 8· 34宅莫耳）溶於THF(5〇毫升）之攪拌溶液中 加入DI AD (3 · 61毫升’ 1 8 · 3 3毫莫耳）。使所產生之混合物OOH 27 at 0 ° C in 4-methyl 3-methoxybenzoic acid ethyl ester (3 · gram, J 5. 29 mmol), (S) _ N-Boc-decylamine (3 · 〇8 g, 15·3 mM millimolar), ph3 Ρ (4·81 g, 1 8·34 house Moer) dissolved in THF (5 〇 ml) in a stirred solution of DI AD (3 · 61 ml) 1 8 · 3 3 millimoles). Make the resulting mixture

\\312\2d-code\90-01\B9112968.ptd 第189頁 1283240 五、發明說明（185) 迴流加熱6 · 5小時。於冷卻至室溫後，將沪八 — 經由於矽膠上利用CHC13-MeOH(50 : 1，v/v^ :物瘵發，並 行管柱層析，純化而得（s)-3—曱氧基乍為洗提=進 基）-2-咄咯啶甲氧基]苯甲酸乙酯的膠。（f二^氧羰 甲氧基-4-[卜（第三丁氧羰基）一2-咄咯啶甲氧基之3〜 酯溶解於CH2C12(50毫升）及TFA(45毫升）中。土β人=乙 飽和NaHC〇3使成為鹼性。將混合物以CH2C12萃取，以醆水 洗滌，及於MgS〇4上乾燥。將溶劑蒸發，及殘留物經二^ 矽膠上利用CHCI3-MeOH(20 : 1，v/v)作為洗提液進行管柱 層析，純化而得3· 27克（2步驟77°/。）之（s)-3-甲氡美-4-Γ 9 吼洛咬甲氧基）苯甲酸乙醋的黃色油。） 乳基4 U- 1 -NMR (CDC13) 5 1.39 (t，3H，&gt;7.1 Hz)、1.52-1.59 (m，1H)、1·76-1.88 (m, 2H)、1·92〜2·01 (m，1H)、 2·92-3·06 (m，2H)、3·56- 3.63 (m，1H)、3·9〇 (s， 3H)、3.9Η·02 (m，2H)、4·35 (q，2H，J = 7] H幻、6 89 (d，1H，J = 8.3 Hz)、7·54 (d，1H，J = 2.0 Hz)、7 65 (dd，1H，J = 2. 0、8. 3Hz) 〇 · 於（S)-3-甲氧基-4-（2-咄咯啶甲氧基）苯甲酸乙酯（424 毫克，1· 52毫莫耳）溶於DMF(8毫升）之攪拌溶液中加入3一 甲氧基謂们基苯基）脲基]笨K酸：工二 (728毫克’ 1. 52毫莫耳）及Et3N(0. 26毫升，1. 87毫莫 耳）。使所，產生之混合物在室溫下攪拌隔夜。將混合物以 EtOc稀釋’以IN HC1、飽和NaHC03、鹽水洗滌，並於MgS〇4\\312\2d-code\90-01\B9112968.ptd Page 189 1283240 V. INSTRUCTIONS (185) Reflow heating for 6 · 5 hours. After cooling to room temperature, it was purified by using CHC13-MeOH (50:1, v/v^: material enthalpy, parallel column chromatography, and (s)-3-oxime The base is a gel of eluted=into the base of ethyl-2-pyrrolidinemethoxy]benzoate. (f bis oxycarbonylmethoxy-4-[b (t-butoxycarbonyl)- 2-pyrrolidine methoxy 3~ ester was dissolved in CH2C12 (50 ml) and TFA (45 ml). β human = ethyl acetate NaHC 〇 3 makes it alkaline. The mixture is extracted with CH 2 C 12 , washed with water and dried over Mg S 〇 4. The solvent is evaporated, and the residue is applied to CHCI3-MeOH (20). : 1, v / v) as a eluent for column chromatography, purification to obtain 3. 27 grams (2 steps 77 ° /.) of (s)-3-methodamine-4-Γ 9 吼Luo bite Yellow oil of methoxy) benzoic acid ethyl vinegar. ) Milk-based 4 U- 1 -NMR (CDC13) 5 1.39 (t, 3H, &gt; 7.1 Hz), 1.52-1.59 (m, 1H), 1.76-1.88 (m, 2H), 1.92~2 ·01 (m,1H), 2·92-3·06 (m,2H), 3·56- 3.63 (m,1H), 3·9〇(s, 3H), 3.9Η·02 (m, 2H ), 4·35 (q, 2H, J = 7) H illusion, 6 89 (d, 1H, J = 8.3 Hz), 7·54 (d, 1H, J = 2.0 Hz), 7 65 (dd, 1H , J = 2. 0, 8. 3 Hz) 〇 · (S)-3-methoxy-4-(2-indolyl methoxy)benzoic acid ethyl ester (424 mg, 1. 52 mmol) Add a solution of 3-methoxyl-phenylphenyl)urea] stupid K acid in the stirred solution of DMF (8 ml): work 2 (728 mg ' 1. 52 mmol) and Et 3 N (0. 26 ML, 1. 87 millimoles). The resulting mixture was stirred overnight at room temperature. The mixture was diluted with EtOc' washed with IN HCl, saturated NaHC03, brine, and at MgS 〇 4

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1283240 五、發明說明（186) 上乾燥。將溶劑於真空中蒸發掉， 上利用CHCl2-MeOH(50:l，v/v)作 摞物經^於矽膠 析，純化而得83〇毫克（95%〕之(^厂’ η打官柱層 ，基-4:[r-(2-甲基苯基)服二3基甲乙 氣基]苯甲酸乙酯的非晶形固體。 ^H-NMR (CDC13) ^1.38 (t, 3H, J = 7.3 Hz) ^.88-2.20 (m， 4H， m) 、2·24 (m， 3H) 、3·44—3·5〇 (m， 1H)、 3.53-3.58 (in, 7H) &gt;3.82 (s, 3H) ^4.09-4.17 (m, 1H) 、4·22-4.25 (m， 1H) 、4.35 (q， 2H， J=7.3 Hz) 、4· 38-4.49 (m，1H)、6·7卜6.78 (m，1H)、6·99 (d，1H， J = 8.3Hz) &gt; 7.04-7.07 (m, 1H) &gt;7. 16&gt;7.19 (m, 2H) 49-7.66 (m，3H)、8·06 (d，1H，J = 8.3 Hz)。 於（S)-3-甲氧基-4-[3-甲氧基一 4 一 [N，—（2一曱基苯基）脲 基]苯基乙醯基]-2 -咄咯啶甲氧基]苯甲酸乙酯（76〇毫克， 1· 32毫莫耳）溶於THF(l〇毫升）之攪拌溶液中加入〇. 25N NaOH (1 0毫升），及使所產生之混合物迴流加熱隔夜。於冷 卻至室溫後，將混合物倒入至1 N HC 1 (1 0 0毫升）中，並收 集固體。將粗製固體以Et20洗滌，而得429毫克（59%)之27 的黃色非晶形固體。 熔點 1 3 2-1 35 °C; IR (KBr) 1 70 7 /公分；HMR (DMS0 -d6) 5 1. 8 4-2. 18 (m, 4H) &gt; 2. 2 5 (s, 3H) ^ 2. 4 9-2 . 5 1 (m，2 H )、3 · 2 9 - 3 · 5 9 (m，4 H)、3 · 8 0 (s，3 H)、3 · 8 2 (s， 3H)、4·00 - 4.0 5 (m，1H)、6·53 - 8·01 (m，10H)、8.45 (s，1H)、8· 54 (s，1H)、12· 63 (bs，1H) ; MS(FAB) m/z1283240 V. Description of the invention (186) Drying. The solvent was evaporated in vacuo, and purified by CHCl2-MeOH (50:1, v/v) eluting with EtOAc (EtOAc: EtOAc) Layer, base-4: amorphous solid of [r-(2-methylphenyl) bis(3-3-ylmethyl)]benzoic acid ethyl ester. ^H-NMR (CDC13) </ RTI> 1.38 (t, 3H, J = 7.3 Hz) ^.88-2.20 (m, 4H, m), 2·24 (m, 3H), 3·44—3·5〇(m, 1H), 3.53-3.58 (in, 7H) &gt;3.82 (s, 3H) ^4.09-4.17 (m, 1H), 4·22-4.25 (m, 1H), 4.35 (q, 2H, J=7.3 Hz), 4·38-4.49 (m, 1H), 6 ·7b 6.78 (m,1H), 6.99 (d,1H, J = 8.3Hz) &gt; 7.04-7.07 (m, 1H) &gt;7. 16&gt;7.19 (m, 2H) 49-7.66 (m , 3H), 8·06 (d, 1H, J = 8.3 Hz). (S)-3-Methoxy-4-[3-methoxy-1,4-[N,-(2-mercaptobenzene) Addition of a solution of ureido]phenyl(indenyl)-2-phenylpyridinylmethoxy]benzoate (76 mg, 1.32 mmol) in THF (10 ml) 25 25 N NaOH (10 ml), and the resulting mixture was heated under reflux overnight. After cooling to room temperature, pour the mixture into 1 N HC 1 (1 0 0 ml), and the solid was collected. The crude solid was washed with Et20 to give 429 mg (59%) of yyy. /cm; HMR (DMS0 -d6) 5 1. 8 4-2. 18 (m, 4H) &gt; 2. 2 5 (s, 3H) ^ 2. 4 9-2 . 5 1 (m, 2 H ) , 3 · 2 9 - 3 · 5 9 (m, 4 H), 3 · 8 0 (s, 3 H), 3 · 8 2 (s, 3H), 4·00 - 4.0 5 (m, 1H), 6·53 - 8·01 (m, 10H), 8.45 (s, 1H), 8. 54 (s, 1H), 12· 63 (bs, 1H); MS (FAB) m/z

1283240 五、發明說明（187) 548(M+ + 1) 〇 實施例2 4 (S) - 4 - [1 - [3 -甲氧基- 4- [N’ -（2-曱基笨基）脲基]笨基乙酷 基]-2-吡咯啶甲氧基]酞酸1283240 V. INSTRUCTIONS (187) 548 (M+ + 1) 〇 Example 2 4 (S) - 4 - [1 - [3 -methoxy-4- [N'-(2-indolyl)]urea Base] stupid base]-2-pyrrolidine methoxy]decanoic acid

28 在0 °C下於4-羥基酞酸二曱酯（3. 00克，14· 27毫莫耳）、N-Boc_ 脯胺醇（2·87 克，14.26 毫莫耳）、Ph3P(4.49 克， 17· 12毫莫耳）溶於THFC50毫升）之攪拌溶液中加入DIAD(3. 40毫升’ 17· 27毫莫耳）。然後使所產生之混合物迴流加熱 隔夜。將所產生之混合物蒸發，並將殘留物經由於石夕膠上 利用正己烷-EtOAc(3 : 1，v/v)作為洗提液進行管柱層析， 純化而得5· 75克（Q. y·)之（S)-4-[l-[(第三丁氧幾基）一2一 咄咯啶甲氧基]酞酸二甲酯的油。 ^-NMR (CDC13) ^1.47 (s, X3 n j 'ΐ·ΰ〇-ζ.〇5 (m, 4Η) 36-3·40 (m，2Η)、3·87 (m，3Η)、3.91 (s，3Η)、3 96 -4·19 (m，3Η)、7·03-7·24 (m，2Η)、7·8〇 (m，1Η)·。 於（S)_4-[ 1-(第二丁氧羰基-2 -吡咯啶甲氧基）酞酸二 醋（5.75克，14.62毫莫耳）溶於〇1^12(25毫升）之溶液^加 入TFA(20毫升），及使所產生之混合物在室溫下攪拌5〇八 鐘。將所產生之混合物於真空中濃縮，並利用飽和NaH(；〇 使成為鹼性。將混合物以CH/〗2萃取，以鹽水洗滌，於328 Dicumyl 4-hydroxydecanoate (3.0 g, 14.27 mmol), N-Boc_prolinol (2·87 g, 14.26 mmol), Ph3P (4.49) at 0 °C DIA, 17·12 mmol (dissolved in THF (50 ml)) was added DIAD (3. 40 ml '17·27 mmol). The resulting mixture was then heated to reflux overnight. The resulting mixture was evaporated, and the residue was purified by column chromatography using hexane-EtOAc (3:1, v/v) as eluent. An oil of (S)-4-[l-[(t-butoxy-oxy)- 2 -pyridinylmethoxy] phthalate dimethyl ester. ^-NMR (CDC13) ^1.47 (s, X3 nj 'ΐ·ΰ〇-ζ.〇5 (m, 4Η) 36-3·40 (m, 2Η), 3·87 (m, 3Η), 3.91 ( s,3Η), 3 96 -4·19 (m,3Η), 7·03-7·24 (m,2Η), 7·8〇(m,1Η)·.(S)_4-[ 1- (Second butoxycarbonyl-2-pyrrolidine methoxy) decanoic acid diacetate (5.75 g, 14.62 mmol) in 〇1^12 (25 ml) solution ^Add TFA (20 ml), and The resulting mixture was stirred at room temperature for 5 h. The resulting mixture was concentrated in vacuo and taken to dryness using sat. NaH. 3

\\312\2d-code\90-01\89112968.ptd 第192頁 卩83240 五、發明說明（188)\\312\2d-code\90-01\89112968.ptd Page 192 卩83240 V. Description of invention (188)

MgS〇4上乾燥，並於真空中蒸發。將殘留物經由於矽膠上 利用CHCl-MeOH(50:l，v/v)作為洗提液進行管柱層析，純 化而付790毫克（18%)之（S)-4-(2 -吼洛17定曱氧基）酜酸二甲 酯的棕色油。 1-NMR (CDC13) 51· 48-1· 57 (m，1H)、1. 72- 1· 84 (m， 2H)、1·89 -1·98 (m，2H)、2·91 - 3·03 (m，2H)、3·48 - 3· 54 (m， 1Η)、3· 82-3· 97 (m，總計8Η)、6· 98 (dd， 1Η， J = 2.4、8·8Ηζ)、7·06 (d，1H，J = 2.4 Hz)、7·78 (d， 1H，J = 8. 8 Hz) 〇 於（S)-4-（2 -咄咯啶甲氧基）酞酸二甲酯（212毫克，〇. 72 毫莫耳）溶於DMF (8毫升）之攪拌溶液中加入3 -甲氧基 - 4-[N’-(2_甲基苯基）脲基]苯基乙酸之五氟苯酯（346毫 克，〇· 72毫莫耳）及Et2N(120毫升，〇· 86毫莫耳），及使混 合物攪拌隔夜。將所產生之混合物以EtOAc稀釋，以1N HC1、飽和NaHC03、鹽水洗滌，並於MgS04上乾燥。將溶劑 於真空中蒸發掉，而得413毫克（97%)之（S)-4-[ 1-[ 3-甲氧 基-4 - [Ν’ - (2-甲基苯基）脲基]苯基乙醯基]- 2-吼洛唆甲 氧基]苯甲酸二甲酯的油。 Μ-NMR (CDC13) 5 1· 92-2· 12 (m，4Η)、2· 29 (br s，3Η) 、3·5卜3·64 (m，7H)、3·87 (s，3H)、3·89 (s，3H)、 4· 10-4· 19 (m，2Η)、4· 44 (m，1Η)、6· 73-8· 02 (m 系列， 總計12H)。 在室溫下於（S) - 4-[卜[3-甲氧基-4-[Ν’ -（2-甲基苯基） 脈基]苯基乙醯基]- 2 -吼洛°定甲氧基]歐酸二甲g旨（413毫Dry on MgS〇4 and evaporate in vacuo. The residue was subjected to column chromatography using CHCl-MeOH (50:1, v/v) as an eluent, and 790 mg (18%) of (S)-4-(2 - Brown oil of dimethyl decyl phthalate. 1-NMR (CDC13) 51· 48-1· 57 (m, 1H), 1. 72- 1· 84 (m, 2H), 1·89 -1·98 (m, 2H), 2·91 - 3 ·03 (m, 2H), 3·48 - 3· 54 (m, 1Η), 3· 82-3· 97 (m, total 8Η), 6·98 (dd, 1Η, J = 2.4, 8·8Ηζ ), 7·06 (d, 1H, J = 2.4 Hz), 7·78 (d, 1H, J = 8. 8 Hz) 〇(S)-4-(2 -pyridinylmethoxy)酞Add dimethyl dimethyl ester (212 mg, 〇. 72 mmol) to a stirred solution of DMF (8 mL) and add 3-methoxy-4-[N'-(2-methylphenyl)ureido] Pentafluorophenyl acetate (346 mg, 〇 · 72 mmol) and Et 2 N (120 mL, 〇 86 mmol), and the mixture was stirred overnight. The resulting mixture was diluted with EtOAc, washed 1N EtOAc, sat. The solvent was evaporated in vacuo to give 413 mg (97%) of (S)-4-[1-[3-methoxy-4-[[s]-(2-methylphenyl)ureido] An oil of phenyl ethionyl]- 2-indolyl methoxy]benzoic acid dimethyl ester. Μ-NMR (CDC13) 5 1· 92-2· 12 (m, 4Η), 2· 29 (br s, 3Η), 3·5 Bu 3·64 (m, 7H), 3·87 (s, 3H ), 3·89 (s, 3H), 4· 10-4· 19 (m, 2Η), 4·44 (m, 1Η), 6·73-8· 02 (m series, total 12H). At room temperature in (S) - 4-[Bu [3-methoxy-4-[Ν' -(2-methylphenyl) fluorenyl]phenylethenyl]- 2 - fluorene Methoxy] oxalate dimethyl g (413 mM

\\312\2d-code\90-01\89112968.ptd 第193頁 1283240 五、發明說明（189) 克，0· 70毫莫耳）溶於THF(1 0毫升）之攪拌溶液中加入 0· 25N NaOH(1 0毫升），然後使所產生之混合物迴流加熱隔 夜。於冷卻至室溫後，將反應混合物倒入至1N HC1 (1 0 0毫 升）中.。收集固體，將其以水洗滌並風乾。將粗製固體以 E1：2 0洗滌，而得31 0毫克（7 9 % )之2 8的黃色非晶形固體。 IR (KBr) 1701 / 公分”H-NMR (DMS0-d6) 5 1. 87-2· 18 (m，4H)、2·25 (s，3H)、2·50 (s, 2H)、3·38-3·60 (m， 4Η)、3·83 (s，3Η)、4·00-4·14 (m，1Η)、6·74-8·02 (m 系列，10Η)、8· 46 (s，1Η)、8· 54 (s，1Η) ; MS(FAB) m/z 56 2 (M. + 1)。 實施例25 3-氯-4-[ 1-[3-甲氧基-4-[Ν’ -（2-甲基苯基）脲基]苯基乙 醯基]- 2-咄咯啶基]甲氧基]苯甲酸\\312\2d-code\90-01\89112968.ptd Page 193 1283240 V. Description of the invention (189) gram, 0·70 millimoles) Add 0% to the stirred solution of THF (10 ml) 25 N NaOH (10 mL) was then allowed to warm to reflux overnight. After cooling to room temperature, the reaction mixture was poured into 1N HCl (1 0 0 mL). The solid was collected, washed with water and air dried. The crude solid was washed with E1:20 to give 31 0 mg (79%) of y. IR (KBr) 1701 / cm "H-NMR (DMS0-d6) 5 1. 87-2· 18 (m, 4H), 2·25 (s, 3H), 2·50 (s, 2H), 3· 38-3·60 (m, 4Η), 3·83 (s, 3Η), 4·00-4·14 (m, 1Η), 6·74-8·02 (m series, 10Η), 8.46 (s, 1 Η), 8·54 (s, 1 Η); MS (FAB) m/z 56 2 (M. + 1). Example 25 3-chloro-4-[ 1-[3-methoxy- 4-[Ν'-(2-methylphenyl)ureido]phenylethenyl]-2-pyrrolidyl]methoxy]benzoic acid

在室溫下於3 -氯-4 -經基苯甲酸甲δ旨（600毫克，3 215毫莫 耳）、Ν-第三丁氧羰基脯胺醇（647.1毫克，3·215毫莫 耳）、及Ph3P(1.01克，3·858毫莫耳）溶於THF(1〇毫升）之 攪拌溶液中逐滴加入偶氮二羧酸二異丙酯（DIAD)(〇. 8毫 升，3· 8 90毫莫耳），使混合物每室溫下攪拌3天，及在7〇 °C下攪拌1 8小時。將反應混合物於真空中蒸發，並將殘留 物於矽膠上利用正己烷·· EtOAc(5: 1，v/v)作為洗提液進 行層析，而得1.147克（97%)之3-氣-[ι — (第三丁氧幾基）At room temperature in the form of 3-chloro-4-pyridylbenzoic acid (600 mg, 3 215 mmol), hydrazine-tert-butoxycarbonyl decylamine (647.1 mg, 3.215 mmol) And Ph3P (1.01 g, 3.858 mmol) dissolved in THF (1 mL), a solution of diisopropyl azodicarboxylate (DIAD) was added dropwise (〇. 8 ml, 3·8) 90 mmol, the mixture was stirred at room temperature for 3 days and at 7 ° C for 18 hours. The reaction mixture was evaporated in vacuo and EtOAc mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj -[ι — (third butoxy group)

第194頁 1283240 五、發明說明（190) - 2 -吼17各淀基]甲氧苯甲酸甲酯的油。 U-NMR (4 00 MHz，CDC13) (5 1· 46、1· 48 (各s，9H)、 1·59-1·63 (br，1H)、1·88 (br s，1H)、2·05 (s， 1H) &gt; 2. 05-2. 21 (m, 2H) &gt; 3.34-3.45 (br m, 1.5H) &gt;3. 89 (s， 3H) 、3.97 (br m， 0.5H) 、4·21 (br s， 2H) 、7· 05 (d，J = 8.8 Hz，1H)、7·90 (dd，J = 2.0、8·8 Hz, 1H) ^8.04 (d, J = 2.0 Hz, 1H)； MS(FAB) m/z 370 (M+ + 1) 〇 在0°C下於3_氣-[1-(第三丁氧羰基）-2-°比洛淀基]甲氧 苯甲酸甲酯（1.14克，3·10毫莫耳）溶於CH2C12(20毫升）之 攪拌溶液中加入TFA(5毫升），及使反應混合物在室溫下攪 拌2小時。將溶劑於減壓下移除，及以丨N Na〇H處理殘留 物。以CHCI3萃取混合物。將萃取液以鹽水洗滌，於k〇h上 乾燥，並於減壓下濃縮而得741毫克（89%)之3-氣-4-(2 -咄 咯啶基）曱氧苯曱酸甲酯的黃色油。 LR (4 00 MHz, CDC13) ά 1· 60-1· 6 7 (m，1H)、1· 78-2. 02 (m，3H)、2·93-2·98 (m，1H)、3·03-3.0 9 (m，1H)、 3·59 (dt，J = 2.0、9·3 Hz，1H)、3·89 (s，3H)、3·98 (dd，J = 6.3、8·8 Hz，1H)、4·〇5 (dd，j = 4 9、9·3 Hz， 1H) &gt;6. 93 (d, J = 8.8 Hz, 1H) v7.90 (dd, J = 2.0 '8.8 Hz， 1H) 、8·04 (d， J=2.0 Hz， 1H) ; MS(FAB) m/z 270 (MH1)。 ' 使3-甲氧基-4-[Ν’-(2-甲基笨基）脲基]苯基乙酸五氟苯 S旨（500毫克，1.04毫莫耳）、3一氯一4一（2一吼咯啶基）甲氧苯Page 194 1283240 V. INSTRUCTION DESCRIPTION (190) - 2 - 吼 17 each of the aryl groups] oil of methyl methoxybenzoate. U-NMR (4 00 MHz, CDC13) (5 1 · 46, 1 · 48 (each s, 9H), 1·59-1·63 (br, 1H), 1·88 (br s, 1H), 2 ·05 (s, 1H) &gt; 2. 05-2. 21 (m, 2H) &gt; 3.34-3.45 (br m, 1.5H) &gt;3. 89 (s, 3H) , 3.97 (br m, 0.5 H), 4·21 (br s, 2H), 7. 05 (d, J = 8.8 Hz, 1H), 7·90 (dd, J = 2.0, 8·8 Hz, 1H) ^8.04 (d, J = 2.0 Hz, 1H); MS(FAB) m/z 370 (M+ + 1) 〇 at 0 ° C in 3-gas-[1-(t-butoxycarbonyl)-2-° piroxicam] Methyl methoxybenzoate (1.14 g, 3·10 mmol) was dissolved in CH2C12 (20 mL). The residue was removed under reduced pressure and the residue was purified eluted eluted eluted eluted eluted eluted eluted eluted eluted eluted a yellow oil of methyl 3-(4-(pyridinyl)phosphonate. LR (4 00 MHz, CDC13) ά 1· 60-1· 6 7 (m, 1H), 1 · 78-2. 02 (m, 3H), 2·93-2·98 (m, 1H), 3·03-3.0 9 (m, 1H), 3·59 (dt, J = 2.0, 9·3 Hz 1H), 3·89 (s, 3H), 3·98 (dd, J = 6.3, 8·8 Hz, 1H), 4·〇5 (dd, j = 4 9 , 9·3 Hz, 1H) &gt ;6. 93 (d, J = 8.8 Hz, 1H) v7.90 (dd, J = 2.0 '8.8 Hz, 1H), 8·04 (d, J=2.0 Hz, 1H) ; MS(FAB) m/ z 270 (MH1). '3-methoxy-4-[Ν'-(2-methylphenyl)ureido]phenylacetic acid pentafluorobenzene (500 mg, 1.04 mmol), 3 Monochloro-4-iso(2-indolyl)methoxybenzene

\\312\2d-code\90-01\89112968.ptd 1283240 五、發明說明（191) ------- 甲酸甲酯（281毫克，1· 04毫莫耳）、Et3N(〇 17毫升， 1.25毫莫耳）溶於DMF(5毫升）之混合物在室溫下攪拌1小 時。將混合物以EtOAc稀釋，以鹽水洗滌，並於Na2S〇4上 燥。將溶劑於減壓下移除，及將殘留物於矽膠上利用正己乙 烷-Et0Ac(l:3，v/v)作為洗提液進行層析，而得3-氯一 &amp; -[卜[3-甲氧基-4-[Ν’ -（2-甲基苯基）脲基]苯基乙醯基] -2-吡咯啶基]甲氧基]笨甲酸甲酯（62〇毫克，l 〇4毫莫耳） 的白色結晶固體。於此化合物溶於THF(8毫升）及胪〇 (2毫 升）之攪拌溶液中加入Li0H(74.9毫克，3.126毫莫耳） 使混合物在室溫下攪拌2天。將混合物以CHC13稀釋，並以 1 N H C1處理。將溶液以鹽水洗條，於n a2 s 〇4上乾燥，並於 真空中蒸發。使粗製固體自正己烷一EtOAc-CHCl3再結晶， 而得56 1 · 2毫克（98%)之2 9的白色結晶物質。 IR (KBr) 1676、1599、1487、1267、758、754 /公分； ^-NMR (4 00 MHz, DMSO-d6) ^ 1. 82-2. 24 (m, 4H) ^2.25 (s，3H)、3·48-3·60 (m, 4H)、3·78 (s，3H)、4·18 (m， 2H) 、4·31 (m， 1H) 、6·74 (dd， J=1.5 、8·3 Hz， 1H)、 6.84 (d，J = 2.0 Hz，1H)、6·9 卜 6.95 (m，1H)、7·11—7· 17 (m，3H)、7· 79 (dd，J = 2· 0、8. 3 Hz, 2H)、7· 85 (d， J = 2.0 Hz，1H)、7·98 (d，J = 8.3 Hz，1H)、8·53 (s， 1H)、8·58 (s，1H); MS(FAB) m/z 552 (MH1)。 實施例26 3, 5-二氯-4-[[1 -[3-曱氧基-4-[N，-(2-甲基苯基）脲基]苯 基乙醯基]-2 -咄咯啶基]甲氧基]苯甲酸\\312\2d-code\90-01\89112968.ptd 1283240 V. Description of the invention (191) ------- Methyl formate (281 mg, 1.04 mmol), Et3N (〇17 ml) A mixture of 1.25 mmoles in DMF (5 mL) was stirred at room temperature for 1 hour. The mixture was diluted with EtOAc, washed with brine and dried over Na. The solvent was removed under reduced pressure, and the residue was chromatographed on a silica gel using n-hexane-Et0Ac (1:3, v/v) as an eluent to give 3-chloro- &amp; Methyl [3-methoxy-4-[Ν'-(2-methylphenyl)ureido]phenylethenyl]-2-pyrrolidinyl]methoxy]benzoate (62 mg, l 毫 4 millimoles) of white crystalline solid. To a stirred solution of THF (8 mL) and EtOAc (2 mL), EtOAc (EtOAc) The mixture was diluted with CHC13 and treated with 1 N H C1. The solution was washed with brine, dried over n a 2 s s 4 and evaporated in vacuo. The crude solid was recrystallized from n-hexane-EtOAc-EtOAc (EtOAc) (EtOAc) IR (KBr) 1676, 1599, 1487, 1267, 758, 754 / cm; ^-NMR (4 00 MHz, DMSO-d6) ^ 1. 82-2. 24 (m, 4H) ^ 2.25 (s, 3H) , 3·48-3·60 (m, 4H), 3·78 (s, 3H), 4·18 (m, 2H), 4·31 (m, 1H), 6.74 (dd, J=1.5 , 8·3 Hz, 1H), 6.84 (d, J = 2.0 Hz, 1H), 6·9 b 6.95 (m, 1H), 7·11—7· 17 (m, 3H), 7· 79 (dd , J = 2· 0, 8. 3 Hz, 2H), 7·85 (d, J = 2.0 Hz, 1H), 7·98 (d, J = 8.3 Hz, 1H), 8·53 (s, 1H ), 8·58 (s, 1H); MS (FAB) m/z 552 (MH1). Example 26 3,5-Dichloro-4-[[1 -[3-methoxy-4-[N,-(2-methylphenyl)ureido]phenylethenyl]-2-indole Pyridyl]methoxy]benzoic acid

\\312\2d-code\90-01\89112968.ptd 第 196 頁 1283240 五、發明說明（192)\\312\2d-code\90-01\89112968.ptd Page 196 1283240 V. Description of invention (192)

在室溫下於3, 5-二氯-4-羥基苯甲酸曱酯（6〇〇毫克， 2.714毫莫耳）、N-第三丁氧羰基脯胺醇（546毫克，2·714 毫莫耳）、及Ph3P(854毫克，3.257毫莫耳）溶於THF(10毫 升）之擾拌溶液中逐滴加入D IAD (0.68毫升，3.283毫莫 耳），使混合物在室溫下攪拌3天，及在7〇 t下攪拌18小 時。將反應混合物濃縮，並將殘留物於矽膠上利用正己烷 - EtOAc(6:l，v/v)作為洗提液進行層析，而得9 88·8毫克 (90%)之4- [ 1 -(第三丁氧羰基）一2 -吡咯啶基]τ氧基-3, 5一 二氯苯甲酸甲酯的淡黃色油。 ^-NMR (400 MHz, CDC13)51.44 (s, 9H) '1.88-2.15 (br m，3H)、2·34 (br s, 1H)、3·40-3·44 (m，2H)、3· 92 (s，3H)、3·92、4·14 (m，1H)、4·1δ (br s，2H)、 7.98 (s，2H) ; MS(FAB) m/z 40 4(MH1)。 在0 C下於4-[1-(第三丁氧羰基）—2 -吡咯啶基]甲氧基 -3,5-二氯苯曱酸甲酯（988毫克，3.248毫莫耳）溶於(：112(：12 (20毫升）之攪拌溶液中加入TFA( 5毫升），及使反應混合物 在室溫下攪拌2小時。將溶劑於減壓下移除，及以1N NaOH 處理殘留物。以CHC13萃取溶液。將萃取液以鹽水洗滌， 於NazS〇4上乾燥，並於減壓下濃縮而得672毫克（68%)之 3, 5-二氣-4-（2-咄咯唆基）甲氧苯曱酸甲酯的淡黃色油。 W-NMR (4 00 MHz，CDC13) 51· 62-1· 69 (m，1H)、1· 78-1·Ethyl 3,5-dichloro-4-hydroxybenzoate (6 mg, 2.714 mmol), N-tert-butoxycarbonylguanamine (546 mg, 2.714 mmol) at room temperature To the turbid solution of Ph3P (854 mg, 3.257 mmol) dissolved in THF (10 ml), D IAD (0.68 ml, 3.283 mmol) was added dropwise, and the mixture was stirred at room temperature for 3 days. And stirred at 7 °t for 18 hours. The reaction mixture was concentrated, and the residue was purified eluting eluting eluting eluting eluting eluting A pale yellow oil of methyl ((t-butoxycarbonyl)- 2 -pyrrolidinyl] τ oxy-3,5-dichlorobenzoate. ^-NMR (400 MHz, CDC13) 51.44 (s, 9H) '1.88-2.15 (br m,3H), 2·34 (br s, 1H), 3·40-3·44 (m, 2H), 3 · 92 (s, 3H), 3.92, 4·14 (m, 1H), 4·1δ (br s, 2H), 7.98 (s, 2H); MS (FAB) m/z 40 4 (MH1) . Methyl 4-[1-(t-butoxycarbonyl)-2-pyrrolidinyl]methoxy-3,5-dichlorobenzoate (988 mg, 3.248 mmol) dissolved at 0 C TFA (5 ml) was added to a stirred solution of &lt;RTI ID=0.0&gt;&gt;&gt;&gt; The solution was extracted with CH.sub.3, the extract was washed with brine, dried over Naz.sub.4, and concentrated under reduced pressure to afford 672 mg (68% a pale yellow oil of methyl methoxybenzoate. W-NMR (4 00 MHz, CDC13) 51· 62-1· 69 (m, 1H), 1·78-1·

\\312\2d-code\9〇.〇l\89112968.ptd 第197頁 1283240 五、發明說明（193) 86 (m， 2Η)、1·89-1.99 (m， 1Η)、2·92-2.98 (m， 1H)、 3.04-3-09 (m，lH)、3.55-3.60 (m，lH)、3.91(s， 3H)、4· 01 (dd，J = 6· 8、8· 8 Hz, 1H)、4· 08 (dd， J = 4.9、8·8 Hz，1H)、7·97 (s，2H); MS(FAB) m/z 3 04(M+ + 1) 〇 使3-甲氧基_4 - [Ν’- (2 -曱基笨基）脲基]苯基乙酸五氟苯 S 曰（385.8 毫克 ’ 0.803¾:莫耳）、3,5 -二氯-4-(2-吼洛 σ定 基）甲氧苯甲酸甲酯（244.3毫克，0.803莫耳）、Et3N(0. 13 毫升，0.964毫莫耳）溶於DMP (4毫升）之混合物在室溫下攪 拌1小時。將混合物以EtOAc稀釋，以鹽水洗滌，並於 NaJO4上乾燥。將溶劑於減壓下移除，及將殘留物於矽膠 上利用正己烷：EtOAc( 1 : 2，v/v)作為洗提液進行層析， 而得3, 5 -二氣-4 - [[1-[ 3 -甲氧基-4 - [N，- (2-曱基苯基）脲 基]|苯基乙醯基]-2 -咄咯啶基]甲氧基]苯甲酸甲酯的油。 於此化合物溶於THF(8毫升）及H20(2毫升）之攪拌溶液中加 入Li 0H( 57· 7毫克，2· 40 9毫莫耳），並使混合物在室溫下\\312\2d-code\9〇.〇l\89112968.ptd Page 197 1283240 V. Inventions (193) 86 (m, 2Η), 1.89-1.99 (m, 1Η), 2.92- 2.98 (m, 1H), 3.04-3-09 (m, lH), 3.55-3.60 (m, lH), 3.91 (s, 3H), 4· 01 (dd, J = 6.8, 8·8 Hz , 1H), 4· 08 (dd, J = 4.9, 8·8 Hz, 1H), 7·97 (s, 2H); MS(FAB) m/z 3 04(M+ + 1) 〇使3-甲Oxy_4 - [Ν'-(2-indolyl)ureido]phenylacetic acid pentafluorobenzene S 曰 (385.8 mg '0.8033⁄4: mole), 3,5-dichloro-4-(2 A mixture of methyl methoxybenzoate (244.3 mg, 0.803 mol), Et3N (0.13 ml, 0.964 mmol) in DMP (4 mL) was stirred at room temperature for 1 hour. The mixture was diluted with EtOAc, washed with brine and dried over Na. The solvent was removed under reduced pressure, and the residue was applied to silica gel eluting with hexane:EtOAc (1:2, v/v) as an eluent to give 3,5 - 2 gas-4 - [ [1-[ 3 -Methoxy-4 - [N,-(2-fluorenylphenyl)ureido]|phenylethyl]-2-pyridinyl]methoxy]benzoic acid methyl ester Oil. To a stirred solution of THF (8 mL) and H20 (2 mL), EtOAc (EtOAc, EtOAc, EtOAc

攪拌隔夜。將混合物於真空中濃縮，並將殘留物以CHC U 〇 稀釋。將溶液以IN HC1、鹽水洗滌，並於心2304上乾燥。 將溶劑於減壓下移除，並使所得之粗製固體自正己烷 -1^011-(：11(：13再結晶，而得4 28.2毫克（91%)之30的白色結 晶粉末。 IR (KBr) 1618、1 535、1 454、1 257、754 / 公分；NMR (400 MHz，DMS0-d6)心1· 83-2|· 24 (m，4H)、2· 24 (s， 3H)、3·50-3.58 (m，4H)、3·84 (s，3H)、3.98-4·05Stir overnight. The mixture was concentrated in vacuo and the residue was diluted with CHC EtOAc. The solution was washed with IN HCl, brine and dried on heart 2304. The solvent was removed under reduced pressure, and the obtained crude solid was recrystallized from n-hexane-1 - 011 - (: 11 (: 13) to give 4 28.2 mg (91%) of 30 white crystalline powder. KBr) 1618, 1 535, 1 454, 1 257, 754 / cm; NMR (400 MHz, DMS0-d6) heart 1 · 83-2|· 24 (m, 4H), 2 · 24 (s, 3H), 3·50-3.58 (m, 4H), 3.84 (s, 3H), 3.98-4·05

\\312\2d-code\90-01 \89112968.ptd 第 198 頁 1283240 五、發明說明（194) (m，111)、4 · 1 5 ( d d，J = 2 · 9、8 . 7 H z，1II)、4 · 2 9 ( b r m， 1Η)、6·74 (d，J = 8.3 H.z, III)、6·87 (s，111)、6·93 (t，J = 7.3 IIz，1H)、7·11 (d, J = 7.8 Hz, 111)、7·16 (d，ί = 8·3 Hz, 1H)、7··79 (d，J = 8.3 Hz，1Π)、7·86 (s，1H)、7·87 (d，&gt;9·8 [Iz，1H)、7·99 &quot;，J = 8 3 ilz, 111)^8.49 (s, 111) ^8.58 (s, 1II)；MS(FAB) m/z 586 (MH1)。 實施例27 4-[l-[3-甲氧基-4 -[Ν’ -(2-甲基苯基）脲基]苯乙醯基]一2-吼洛咬甲氧基]- 3 -硝基笨甲祕\\312\2d-code\90-01 \89112968.ptd Page 198 1283240 V. INSTRUCTIONS (194) (m, 111), 4 · 1 5 ( dd, J = 2 · 9, 8. 7 H z , 1II), 4 · 2 9 (brm, 1Η), 6.74 (d, J = 8.3 Hz, III), 6·87 (s, 111), 6.93 (t, J = 7.3 IIz, 1H) , 7·11 (d, J = 7.8 Hz, 111), 7·16 (d, ί = 8·3 Hz, 1H), 7··79 (d, J = 8.3 Hz, 1Π), 7·86 ( s,1H),7·87 (d,&gt;9·8 [Iz,1H),7·99 &quot;,J = 8 3 ilz, 111)^8.49 (s, 111) ^8.58 (s, 1II) ;MS(FAB) m/z 586 (MH1). Example 27 4-[l-[3-Methoxy-4 -[Ν' -(2-methylphenyl)ureido]phenethyl]- 2-indolyl methoxy]- 3 - Nitro stupid

在室溫下於4-經基-3-硝基苯甲酸（3· 〇〇克，〇· 〇1 64莫 耳）溶於Me ΟII-笨（1 : 4，ν/ν)之攪拌溶液中逐滴加入 TMSCHN2(8· 2毫升’ 0. 0164莫耳）之2, 0Μ正己烷溶液。於將 所產生之溶液在室溫下攪拌4小時後，將混合物於真空中 蒸發。將油性殘留物於矽膠上利用CIIC 13作為洗提液進行 層析而得4. 2 3克（7 9 %)之4-經基-3 -硝基苯甲酸甲的淡黃 色結晶物質。 在0 t下於N-第三丁氧羰基脯胺醇（1· 02克，5. 07莫耳） 、4 -羥基-3 -硝基苯曱酸甲酯（1· 〇〇克，5· 07毫莫耳）、及 Ph3P(l. 46克，5. 58毫莫耳）溶於THF(10毫升）之攪拌溶液 中逐滴加入偶氮二羧酸二異丙酯（DIAD)(95%)(1 · 1 6毫升，Dissolved in a stirred solution of Me ΟII-st (1:4, ν/ν) at room temperature in 4-pyridyl-3-nitrobenzoic acid (3·g, 〇· 641 64 mol) A solution of TMSCHN2 (8.2 mL '0.046 mol) in 2,0 hexanes was added dropwise. After the resulting solution was stirred at room temperature for 4 hours, the mixture was evaporated in vacuo. The oily residue was chromatographed on a silica gel using CIIC 13 as an eluent to give 4. 2 g (yield: 7%) of 4-ylidene-3-nitrobenzoic acid as a pale yellow crystalline material. At 0 t, N-tert-butoxycarbonyl decylamine (1. 02 g, 5.07 mol), methyl 4-hydroxy-3-nitrobenzoate (1· gram, 5· Addition of diazodicarboxylate (DIAD) (95%) to a stirred solution of THF (10 ml) was added dropwise to a stirred solution of Ph3P (1.46 g, 5.58 mmol). ) (1 · 16 ml,

\\3!2\2(i-c〇(ic\90-01\«9l 12968. pld 笫19?)頁 1283240 五、發明說明（195) 5 · 5 8毫莫耳）。將所產生之混合物迴流加熱4 6小時。於冷1 卻後’將混合物於真空中蒸發。將殘留物溶解於CH2Cl2 (10毫升），並加入TFA(10毫升）。於使溶液在室溫下攪拌 〇· 5小時後，將溶液於真空中蒸發。將水加至殘留物並以 EtOAc洗滌。將水層經由加入飽*NaHC〇3而中和，並以 EtOAc萃取。將萃取液於Na2S〇4上乾燥，並於真空中蒸發而 付0.698克（49%)之3-石肖基-4 -（2-°比口各唆曱氧基）苯曱酸曱 酯的膠。 使3-琐基-4-（2-吼咯啶甲氧基）苯甲酸甲酯（〇· 66 8克， 2.38毫莫耳）、3 -甲氧基-4 - [N，~(2-曱基苯基）脲基]笨乙 酸（1.12克’3.57毫莫耳）、卜羥基苯并三唑（H〇Bt)(〇.482 克’3.57毫莫耳）、4-二甲基胺基咄啶（DMAP) (4 3· 6毫克， 0.357¾莫耳）、及卜乙基-3-(3—二曱胺丙基）氰胺（EDC) (0· 684克’ 3 · 57毫莫耳）於DMF( 1 〇公升）中之混合物在室溫 下攪拌15小時。將EtOAc加至混合物中，並以in HC1、飽 和NaHC〇3、及鹽水連續洗滌。將有機層於上乾燥， 並於真空中蒸發。將殘留物於矽膠上利用Et〇H — CHC、 (1:20，v/v)作為洗提液進行層析而得〇·927克（68%)之 4-[1-[ 3-曱氧基-4 -[Ν’ -(2-曱基苯基）脲基]笨基乙醯 基]-2-吼洛咬甲氧基]一3一硝基苯甲酸甲酯的黃色結晶物 質。 使4-[1 -[3-甲氧基-4-[Ν，-(2-甲基苯基）脲基]笨基乙醯 基]-2-吼洛啶曱氧基]-3 -硝基苯甲酸甲酯（〇· 91 7克，j . 59 莫耳）於THF(10毫升）及in NaOH(2.38毫升，2.38毫莫耳）\\3!2\2(i-c〇(ic\90-01\«9l 12968. pld 笫19?) Page 1283240 V. Description of invention (195) 5 · 5 8 millimoles). The resulting mixture was heated under reflux for 4 6 hours. After cooling 1 but then the mixture was evaporated in vacuo. The residue was dissolved in CH.sub.2Cl.sub.2 (10 mL). After the solution was stirred at room temperature for 5 hours, the solution was evaporated in vacuo. Water was added to the residue and washed with EtOAc. The aqueous layer was neutralized by the addition of sat. NaHC.sub.3 and extracted with EtOAc. The extract was dried over Na 2 S 4 and evaporated in vacuo to give &lt;RTI ID=0.0&gt;&gt;&gt; Methyl 3-zolyl-4-(2-decalridinylmethoxy)benzoate (〇· 66 8 g, 2.38 mmol), 3-methoxy-4 - [N,~(2- Nonylphenyl)ureido] acetoacetic acid (1.12 g '3.57 mmol), hydroxybenzotriazole (H〇Bt) (〇.482 g '3.57 mmol), 4-dimethylamino group Acridine (DMAP) (4 3 · 6 mg, 0.3573⁄4 mol), and ethyl ethyl-3-(3-diaminopropyl) cyanamide (EDC) (0·684 g '3 · 57 mmol) The mixture in DMF (1 liter liter) was stirred at room temperature for 15 hours. EtOAc was added to the mixture and washed successively with in HCl, sat NaHC 3 and brine. The organic layer was dried over and evaporated in vacuo. The residue was chromatographed on a silica gel using Et〇H-CHC, (1:20, v/v) as an eluent to give 927·927 g (68%) of 4-[1-[3-oxo A yellow crystalline material of methyl-4-[Ν'-(2-mercaptophenyl)ureido]phenylidene]-2-indole methoxy]methyl 3-nitrobenzoate. 4-[1-[3-methoxy-4-[Ν,-(2-methylphenyl)ureido]]phenylamino]-2-indolyl]oxy]-3-nitrate Methyl benzoate (〇·91 7 g, j. 59 mol) in THF (10 mL) and in NaOH (2.38 mL, 2.38 mmol)

\\312\2d-code\90-01\89112968.ptd 第200頁 1283240 五、發明說明（196) 中之混合物迴流加熱2小時。於冷卻後，將混合物倒入至 冰水中’並以E10 A c萃取。將萃取液以鹽水洗條，於 NaJO4上乾燥，並於真空中蒸發而得〇· 826克（92%)之31的 黃色結晶固體。 〖H-NMR (400MHz，CDC13)(51.91、2.0 9 (1H，3H，各 m)、 2.28 (3H， s) 、3·54-3.62 (4H， m) 、3.64 (3H， s)、 4.15、4·59 (各 1H，各d，J = 7.8 Hz)、4·46 (1H，m)、 6.66、7.22 (各 1H，各s)、6·72 (lH，.d，J = 8.3 Hz)、 7.Π-7.28 (4H，m)、7·46 (1H，d，J二7·8 Hz)、7·74 (1H，d，J = 7.8 Hz)、7.85 (1H，s)、8·17 (1H，dd， J = 2.0、8.8 Hz)、8.48 (1H，d，J = 2.4 Hz)。 實施例2 8 3 -胺基-4 - [卜[3-甲氧基_4 - [Ν’ - (2 -甲基笨基）脲基]苯乙 醯基]-2-吼咯啶曱氧基]苯甲酸\\312\2d-code\90-01\89112968.ptd Page 200 1283240 V. The mixture in Invention (196) was heated under reflux for 2 hours. After cooling, the mixture was poured into ice water' and extracted with E10 A c. The extract was washed with brine, dried over Na.sub.4, and evaporated in vacuo. H-NMR (400MHz, CDC13) (51.91, 2.0 9 (1H, 3H, each m), 2.28 (3H, s), 3.54-3.62 (4H, m), 3.64 (3H, s), 4.15, 4·59 (each 1H, each d, J = 7.8 Hz), 4·46 (1H, m), 6.66, 7.22 (each 1H, each s), 6.72 (lH,.d, J = 8.3 Hz) , 7.Π-7.28 (4H,m), 7.46 (1H,d,J 27.8 Hz), 7.74 (1H,d,J = 7.8 Hz), 7.85 (1H, s), 8 · 17 (1H, dd, J = 2.0, 8.8 Hz), 8.48 (1H, d, J = 2.4 Hz). Example 2 8 3 -Amino-4 - [Bu [3-methoxy_4 - [ Ν'-(2-Methylphenyl)ureido]phenethyl]-2-indenylpyridiniumoxy]benzoic acid

使4 - [1-[3-曱氧基- 4 - [Ν’ -（2-甲基苯基）脲基]苯基乙醯 基]- 2-咄咯啶甲氧基]_3-硝基苯曱酸（ιοί毫克，0190毫 莫耳）及5% Pd-C(0· 247克）於甲醇中之攪拌混合物在1大氣 壓下氫化48小時。將不溶解的催化劑移除，及將濾液於真 空中蒸發。將殘留物於矽膠上利用EtOH-CHC13 (1 ·· 1， v/v)作為洗提液進行層析而得61· 〇毫克（6〇%)之32的結晶 物質。4-[1-[3-曱-Oxo- 4 -[Ν' -(2-methylphenyl)ureido]phenylethenyl]-2-pyrrolidinemethoxy]_3-nitro A stirred mixture of benzoic acid (ιοί mg, 0190 mmol) and 5% Pd-C (0·247 g) in methanol was hydrogenated at 1 atm for 48 hours. The insoluble catalyst was removed and the filtrate was evaporated in the vacuum. The residue was chromatographed on a silica gel using EtOH-CHC13 (1··1, v/v) as an eluent to obtain 61 g of a crystalline material of 32 mg (6 %).

89112968.ptd 第201頁 (197) ^ ~- 128324089112968.ptd Page 201 (197) ^ ~- 1283240

lH〜_ (40 0 MHz，DMS0-d6) (51· 95 (4H，m)、2· 23 (3H SJ、3·60、3·91、4·1〇、4·34 (5H,各 m)、3·81 (3Ii s)、4·88 (2H, m)、6·74 (1H, d，J = 8.3 Hz)、6·86’ 〜7·28 (5H，m)、7·78 (1H，d，J = 7.8 Hz)、7·99 (1η d’ J = 8· 3 Hz)、8. 30 (1H，s)、8. 45、8· 55 (各“ ’ 各s)。 ， -~~么—- 4 [2-[1 - [4 - [N -(2-氟苯基）脲基]-3—甲氧苯乙醯基]〜2 吼咯啶基]乙炔基]苯甲酸lH~_ (40 0 MHz, DMS0-d6) (51·95 (4H, m), 2·23 (3H SJ, 3·60, 3·91, 4·1〇, 4·34 (5H, each m ), 3·81 (3Ii s), 4·88 (2H, m), 6.74 (1H, d, J = 8.3 Hz), 6·86'~7·28 (5H, m), 7·78 (1H, d, J = 7.8 Hz), 7·99 (1η d' J = 8· 3 Hz), 8. 30 (1H, s), 8. 45, 8.55 (each ''each s). , -~~么—4 [2-[1 - [4 - [N -(2-Fluorophenyl)ureido]-3-methoxyphenethyl]~2 吼pyridinyl]ethynyl] benzoic acid

於4-胺基-3-甲氧苯基乙酸苄酯（1· 36克，5毫莫耳）溶於 THF(20毫升）之攪拌溶液中加入異氰酸2—氟苯酯（561微' 升’ 5毫莫耳）及催化量之E % N。使所產生之混合物授拌3 小時。經由加入Ηδ 0 (1 0毫升）使混合物停止反應，並以 EtOAc進行萃取。將萃取液以鹽水洗滌，於MgS〇4上乾燥， 並蒸發。將殘留物於矽膠上利用CHC13作為洗提液進行層 析而付2·06克（q.y.)之4 - [Ν’-（2_IL笨基）脲基]- 3 -甲氧苯 基乙酸笮S旨的綠色油。 M-NMR (CDC13 )53.63 (2H，s)、3·82 (3H, s)、5. 14 (2H, s) 、6·79-7·37 (12H, m) 、8·〇1 (iH， d, J:7.8To a stirred solution of 4-amino-3-methoxyphenylacetic acid benzyl ester (1·36 g, 5 mmol) in THF (20 mL) was added 2-fluorophenyl isocyanate (561 micro l '5 millimoles' and the catalytic amount of E % N. The resulting mixture was allowed to mix for 3 hours. The mixture was quenched by the addition of Ηδ 0 (10 mL) and extracted with EtOAc. The extract was washed with brine, dried over MgSO 4 and evaporated. The residue was chromatographed on a silica gel using CHC13 as an eluent to give 2·06 g (qy) of 4 - [Ν'-(2_IL phenyl)ureido]-3-methoxyphenylacetate 笮S Green oil. M-NMR (CDC13) 53.63 (2H, s), 3·82 (3H, s), 5. 14 (2H, s), 6.79-7·37 (12H, m), 8·〇1 (iH , d, J: 7.8

Hz) 、 8·09-8·14 (1H， m) 〇 於4-[1^’-（2-氟苯基）脲基]-3-甲氧笨基乙酸苄酯（2.〇4Hz) , 8·09-8·14 (1H, m) 苄 4-[1^'-(2-Fluorophenyl)ureido]-3-methoxyphenylacetate benzyl ester (2.〇4

89112968.ptd 第202頁 1283240 五、發明說明（198) &quot; ' 克，5毫莫耳）溶於THF(40毫升）之攪拌溶液中加入〇· 25n89112968.ptd Page 202 1283240 V. Inventive Note (198) &quot; 'g, 5 millimoles) Stirred in THF (40 ml) Add 〇·25n

NaOH(40毫升）。使所產生之混合物攪拌隔夜。將混合物倒 入至1 N HC1 (1 0毫升）中，並利用吸濾收集所產生之沈澱 物。使殘留物自CHC13-EtOH再結晶，而得丨· 〇4克（66%)之 4 (N -(2-氟笨基）脲基卜3-甲氧苯基乙酸的白色結晶粉 末。 熔點185-188它（〇1);11^關1?(0^^0-(16)5 3.50(211，3)、 3·82 (3H，s)、6·78 (1H，dd，J=1.4 及 8.3 Ηζ)、6·92 ⑴，d，J = 1.4 Hz)、6·95-7·01 (1Η，m)、7·10-7·14 (1H, m) ^ 7. 19-7. 24 (1H, m) ^ 8. 01 (1H, d, J = 8. 3NaOH (40 ml). The resulting mixture was stirred overnight. The mixture was poured into 1 N HCl (10 mL) and the resulting precipitate was collected by suction filtration. The residue was recrystallized from CHC13-EtOH to give 4 g (yield: 66%) of 4-(N-(2-fluorophenyl)ureido- 3-methoxyphenylacetic acid as a white crystalline powder. -188It(〇1);11^关1?(0^^0-(16)5 3.50(211,3), 3·82 (3H,s),6·78 (1H,dd,J=1.4 And 8.3 Ηζ), 6.92 (1), d, J = 1.4 Hz), 6.95-7·01 (1Η, m), 7·10-7·14 (1H, m) ^ 7. 19-7. 24 (1H, m) ^ 8. 01 (1H, d, J = 8. 3

Hz)、8.14-8.18 (1H，m)、8·72 (1H，s)、9·17 (1H， s) ; MS(FAB) m/z 319(MH1) ; C16H15N2 04 F 之分析計算值： c’ 60·37;Η，4·75;Ν，8.80。實測值：c，60.20; H， 4· 82 ; N，8· 67。 ’ 使4-[Ν’ -（2-氟苯基）脲基]-3-甲氧笨基乙酸（ 255毫克， 0.8¾莫耳）、2-[2-(4-乙氧魏苯基）乙快基]π比σ各σ定（195毫 克’ 0.8¾莫耳）、EDC (230毫克，1.2毫莫耳）、MAP (98毫 克’〇· 8毫莫耳）於DMF(2〇毫升）中之混合物攪拌隔夜。將 反應/%合物倒入至1 n H C 1中，利用吸濾收集所產生之沈殺 物’並將其溶解於CHCI3中。將溶液於MgS04上乾燥並蒸 發。將殘留物於矽膠上利用CHC13-Me〇H(1〇〇 : j，v/v)作為 洗提液進行層析而得期望化合物，將其溶解於THF ( 8毫升） 中。將0 · 2 5 N N a 0 Η ( 8毫升）加至此溶液，並使所產生之混 合物攪拌隔夜。將混合物倒入至1N HC1中，並以CHC13萃Hz), 8.14-8.18 (1H, m), 8.72 (1H, s), 9·17 (1H, s); MS(FAB) m/z 319(MH1) ; C16H15N2 04 F analytical calculation: c' 60·37; Η, 4·75; Ν, 8.80. Found: c, 60.20; H, 4·82; N, 8.67. ' 4-[Ν'-(2-Fluorophenyl)ureido]-3-methoxyphenylacetic acid (255 mg, 0.83⁄4 mol), 2-[2-(4-ethoxypropionyl)乙快基] π ratio σ σ (195 mg '0.83⁄4 mol), EDC (230 mg, 1.2 mmol), MAP (98 mg '〇 · 8 mmol) in DMF (2 ml) The mixture was stirred overnight. The reaction/% compound was poured into 1 n H C 1 , and the resulting precipitate was collected by suction filtration and dissolved in CHCI3. The solution was dried over MgS04 and evaporated. The residue was chromatographed on EtOAc (EtOAc:EtOAc) 0 · 2 5 N N a 0 Η (8 ml) was added to the solution, and the resulting mixture was stirred overnight. Pour the mixture into 1N HCl and extract with CHC13

89112968.ptd 第203頁 1283240 五、發明說明（199) 取。將萃取液以鹽水洗滌，於MgS〇4上乾燥，並蒸發。使 殘留物自CHC13-正己烷再結晶，而得144毫克（37%)之33的 淡黃色結晶粉末。 炼點 1 52- 1 55 °C (d);1}}-NMR (DMS0-d6)5 1.92-2.27 (4H， m)、2·50 (2H，s)、3·33-3.78 ( 2 H，m)、3·80 及 3.82 (總計 3Η，各 s)、4·88-5·12 (1Η，m)、6·77-7·24 及 7.99-8.20 (總計 7Η, m)、7·48 及 7.52 (各 2Η，d，J = 8.3 Hz)、7·91 (2H，d，J = 8.3 Hz)、8·72 (1H，s)、9·18 (1H, s) &gt;13.11 (1H, br~s) ； MS(FAB) m/z 516(M+ + 1)； C29 H26 N3 05 F · 2 H2 0 之分析計算值：c，6 3 · 1 5 ; H，5. 4 8 ; N， 7· 62。實測值·· C，63. 58 ; H，5. 1 5 ; N，7. 22。 實施例3 0 4-[ U - [3-甲氧基-4 - [Ν’ -（2-甲基苯基）脲基]苯乙醯基] -2-咄咯啶基]甲氧基]-3-甲基苯甲酸89112968.ptd Page 203 1283240 V. Description of invention (199) Take. The extract was washed with brine, dried over MgSO 4 and evaporated. The residue was recrystallized from CHC13-hexane to afford 144 mg (37%) of pale yellow crystals. Refining point 1 52- 1 55 °C (d); 1}}-NMR (DMS0-d6)5 1.92-2.27 (4H, m), 2·50 (2H, s), 3·33-3.78 ( 2 H , m), 3·80 and 3.82 (total 3 Η, each s), 4·88-5·12 (1Η, m), 6·77-7·24 and 7.99-8.20 (total 7Η, m), 7· 48 and 7.52 (2Η, d, J = 8.3 Hz), 7.91 (2H, d, J = 8.3 Hz), 8.72 (1H, s), 9·18 (1H, s) &gt;13.11 ( 1H, br~s); MS(FAB) m/z 516(M+ + 1); C29 H26 N3 05 F · 2 H2 0 Analysis calculated: c, 6 3 · 1 5 ; H, 5. 4 8 ; N, 7· 62. Found C·63.58; H,5. 1 5 ; N, 7.22. Example 3 0 4-[ U - [3-Methoxy-4 - [Ν' -(2-methylphenyl)ureido]phenethyl]-2-oxaridinyl]methoxy] -3-methylbenzoic acid

I Η H d) 、^C〇〇H 、 34 在室溫下於4 -蛾-2-甲基酚（465毫克，1.987毫莫耳）、 N -第三丁氧羰基脯胺醇（4〇〇毫克，1.987毫莫耳）、及php ( 625毫克’ 2. 384毫莫耳）溶於THF(7毫升）之攪拌溶液中3逐 滴加入0140(0.5毫升，2.404毫莫耳），並使混合物在7〇。〇 下授摔1 3小時。將反應混合物於真空中濃縮，並將殘留物 於石夕谬上利用正己烧-Et0Ac(9 : 1 ’ v/v)作為洗提液進行層 析而得645. 3毫克（78%)之4-[卜（第三丁氧羰基）_2_ π比二I Η H d) , ^C〇〇H , 34 at room temperature at 4 - moth-2-methylphenol (465 mg, 1.987 mmol), N - 3 -butoxycarbonyl decylamine (4 〇 〇mg, 1.987 mmol, and php (625 mg ' 2.384 mmol) in a stirred solution of THF (7 mL) 3 was added dropwise 0140 (0.5 mL, 2.404 mmol) and The mixture is at 7 〇. 〇 Give down 13 hours. The reaction mixture was concentrated in vacuo, and the residue was purified by chromatography eluting with EtOAc (EtOAc: EtOAc (EtOAc: EtOAc) -[Bu (t-butoxycarbonyl)_2_ π than two

1283240 五、發明說明（200) 基]曱氧基-1-碘-3-甲基笨的淡黃色油。 !Η-NMR (4〇0MHz，CDC13) 6147 (s，9H)、1·83-1·89 (m， 1H)、1·96-2·04 (m，3H)、2·16 (s，3H)、3·37-3.43 (br m， 2H) 、3·81 、3·94 (各br m， 1H) 、4·08-4·18 (m， 2H) &gt;6.62 (br s, 1H) &gt;7.42 (s, 2H)； MS(FAB) m/z 418(MH1)。 於4-[1-(第二丁氧羰基）—2 —。比咯啶基]曱氧基一 i -碘一 甲基苯（645.3毫克，1·546毫莫耳）溶於DMS0(7毫升）及1283240 V. INSTRUCTION DESCRIPTION (200) Alkyloxy-1-iodo-3-methyl stupid pale yellow oil. !Η-NMR (4〇0MHz, CDC13) 6147 (s, 9H), 1·83-1·89 (m, 1H), 1.96-2·04 (m, 3H), 2·16 (s, 3H), 3·37-3.43 (br m, 2H), 3·81, 3·94 (each br m, 1H), 4·08-4·18 (m, 2H) &gt; 6.62 (br s, 1H &gt; 7.42 (s, 2H); MS (FAB) m/z 418 (MH1). In 4-[1-(second butoxycarbonyl)-2. Pyrrolidinyl] methoxy-i-iodo-methylbenzene (645.3 mg, 1.546 mmol) dissolved in DMS0 (7 mL) and

MeOH(6t升）之攪拌溶液中加入Et3N(〇47毫升，3·4〇1毫 莫耳）、Pd(OAc)2(17.4毫克，〇·0 77毫莫耳）、及丨，3—雙 (二苯膦基）丙烷（31· 46毫克，〇· 0 7 7毫莫耳）。於此攪拌混 合物中引入CO氣體1 0分鐘。將混合物於了〇它下攪拌2天並 濃縮。將殘留物以EtOAc稀釋，以鹽水洗滌，並於上 乾餘。將溶劑於減壓下移除，及將殘留物於矽膠上利用正 己烷-EtOAc(5: 1，ν/ν)作為洗提液進行層析而得3〇1· 6毫 克（56%)之甲基-4-[1_(第三丁氧幾基）-2-17比洛。定基]甲氧 基-3-甲基苯甲酸g旨的油。To a stirred solution of MeOH (6 liters) was added Et3N (〇47 mL, 3.4 〇1 mmol), Pd(OAc)2 (17.4 mg, 〇·0 77 mmol), and 丨, 3-double (Diphenylphosphino)propane (31·46 mg, 〇·7 7 7 mmol). CO gas was introduced into the stirred mixture for 10 minutes. The mixture was stirred under mash for 2 days and concentrated. The residue was diluted with EtOAc, washed with brine and dried. The solvent was removed under reduced pressure, and the residue was purified eluting eluting eluting eluting eluting Methyl-4-[1_(t-butoxymethyl)-2-17 piroxime. A fixed oil of methoxy-3-methylbenzoic acid.

1-關R (400 MHz，CDC13) 61· 47 (s，9H)、1· 86-2· 1〇 (br m，4H)、2.33 (s，3H)、3.32-3.50 (br m，2H)、 3·88 (s，3H)、3·88、4·04 (各 br m，1H)、4·13、4 2〇 (m, 2H)、6.89 (br m，1H)、7·82 (s，1H)、7·85 (dd J = 2.0、8·8 Hz，lH); MS(FAB) m/z 3 5 0 (MU1)。 ’ 在0 C下於4-[l-(第三丁氧幾基）〜2 - σ比σ各咬基]甲氧其^ - 3-甲基苯甲酸甲酯（301.6毫克，0.863毫莫耳）溶於 11-off R (400 MHz, CDC13) 61· 47 (s, 9H), 1·86-2· 1〇 (br m, 4H), 2.33 (s, 3H), 3.32-3.50 (br m, 2H) , 3·88 (s, 3H), 3·88, 4·04 (each br m, 1H), 4·13, 4 2〇 (m, 2H), 6.89 (br m, 1H), 7·82 ( s, 1H), 7.85 (dd J = 2.0, 8·8 Hz, lH); MS (FAB) m/z 3 5 0 (MU1). ' at 4-C under 4-[l-(t-butoxy-oxyl)~2 - σ ratio σ each base] methoxy-methyl 3-methylbenzoate (301.6 mg, 0.863 mmol) ) dissolved in 1

12832401283240

CH2C12(6毫升）之攪拌溶液 物於室溫下攪拌1小時。 Π入17 A (1. 2毫升），並使混合 入IN NaOH而使殘留物成A =劑於減壓下移除，及經由加 萃取液以鹽水洗滌，於Na為^生。fCHC13萃取混合物。將 得192. 5毫克（90%)之3-甲美'乾燥，並於減壓下濃縮而 甲酯的油。 土 4-(2-吡咯啶基）曱氧苯曱酸 -NMR ( 40 0 MHz, CDC13) δΐ u 3〇i.58-1.65(m，lH)、178-2.00 (m，3H)、2·24 (s，3In、9 Q7 …τ ； 、，、2· 97 (dt，J = 6· 8、10· 2 Hz，1H)、3· 05 (dt，J = 5 9、H 1υΛ • y b· 8 Hz, 1H)、3· 54-3· 58 (m，1H)、3·87 (s，3H)、3·92 (dd，J = 6 3、9·3 Hz， 1H)、3·99 (dd，J = 4.9、9.3 Hz，1H)、6·81 (d，J = 8.3 Hz，1H)、7· 83 (s，1H)、7· 85 (dd，J = 2· 〇、8· 3 Hz， 1H) ; MS(FAB) m/z 250 (MH1)。 ’ 使3-甲氧基-4-[ Ν’ - (2-甲基笨基）脲基]笨基乙酸五氟笨 酉旨（211.3¾克’0.44宅莫耳）、3-曱基-4- (2 -吼洛咬基）甲 氧苯曱酸甲酯（109· 7毫克，0· 44毫莫耳）、Et3N(73· 6微 升，0.528毫莫耳）於DMF(2毫升）中之混合物在室溫下授掉 1 · 5小時。將反應混合物以EtOAc稀釋。將溶液以鹽水洗 滌，並於NS〇4上乾燥。將溶劑於減壓下移除，及將殘留 物於矽膠上利用正己烷_£1:0^(1 : 3，v/v)作為洗提液進行 層析，而得4 - [[1-[3-甲氧基-4-Ν’ - (2-曱基笨基）脲基] 苯乙醯基]- 2-吼咯啶基]甲氧基]-3 -曱基笨甲酸甲酯（ 241 · 6毫克，Q· y·)的油。於此化合物溶於THF(4· 4毫升）及 H20 (1· 1毫升）之攪拌溶液中加入Li〇H(32毫克，1· 32毫莫A stirred solution of CH2C12 (6 mL) was stirred at room temperature for one hour. 17 A (1.2 ml) was poured in, and the mixture was mixed with IN NaOH to remove the residue into A = the agent was removed under reduced pressure, and the mixture was washed with brine, and Na was formed. The mixture was extracted with fCHC13. 192.5 mg (90%) of 3-methyl-yield was dried and concentrated under reduced pressure to a methyl ester oil. Soil 4-(2-pyrrolidinyl)phosphonium oxyhydrazide-NMR ( 40 0 MHz, CDC13) δΐ u 3〇i.58-1.65 (m, lH), 178-2.00 (m, 3H), 2· 24 (s, 3In, 9 Q7 ... τ ; , , , 2· 97 (dt, J = 6.8, 10· 2 Hz, 1H), 3· 05 (dt, J = 5 9 , H 1υΛ • yb· 8 Hz, 1H), 3· 54-3· 58 (m, 1H), 3·87 (s, 3H), 3.92 (dd, J = 6 3, 9·3 Hz, 1H), 3·99 (dd, J = 4.9, 9.3 Hz, 1H), 6.81 (d, J = 8.3 Hz, 1H), 7·83 (s, 1H), 7·85 (dd, J = 2· 〇, 8· 3 Hz, 1H) ; MS(FAB) m/z 250 (MH1). 'M3-methoxy-4-[Ν'-(2-methylphenyl)ureido]pyroacetic acid pentafluoro alum Purpose (211.33⁄4 g '0.44 house Moer), 3-mercapto-4-(2-indolyl) methyl methoxybenzoate (109·7 mg, 0·44 mmol), Et3N ( The mixture was diluted with EtOAc at room temperature. The mixture was diluted with EtOAc. Drying. The solvent was removed under reduced pressure, and the residue was applied to the silica gel using n-hexane_£1:0^(1:3, v/v) as the eluent. Chromatography to give 4-[[1-[3-methoxy-4-Ν'-(2-amilyphenyl)ureido]phenethyl]-2-pyridinyl]methoxy An oil of methyl 3-methyl hydrazide methyl ester (241 · 6 mg, Q·y·). This compound is dissolved in a stirred solution of THF (4.4 ml) and H20 (1.1 ml). Li〇H (32 mg, 1.32 mmol)

89112968.ptd 第206頁 1283240 五、發明說明（202) 耳），並使反應混合物在室溫下攪拌隔夜。將混合物以 CHC13稀釋，並經由加入IN HC1而酸化。將溶液以鹽水洗 滌，並於Na2S04上乾燥。將溶劑於減壓下移除，並使所得 之粗製固體自正己烷-EtOAc-CHC13-MeOH再結晶，而得 12 6. 3毫克（54%)之34的白色結晶粉末。 IR (KBr) 1685、1606、1454、1257、752/公分；UMR ( 40 0 MHz, DMS0-d6) 51·8 7-2· 10 (m，4H)、2. 12 (s， 3Η) &gt;2.25 (s, 3H) &gt;3.51-3.71 (m, 4H) ^3.76 (s, 3H) 、4.08-4.18 (m， 2H) 、4.34 (m， 1H) 、6.74 (dd， J = 1.5、9·8 Hz，1H)、6.84 (d，J = 1.5 Hz，1H)、6·94 (t, J = 6.8 Hz, 1H)、7·06 (d，J = 8.8 Hz，1H)、7·12 (d，J = 7.8 Hz，1H)、7·16 (d，J = 7.8 Hz，1H)、7·72 (s， 1H) 、7·76 (dd， J=2.0 、8·3 Hz， 1H) 、7·79 (d， J = 7.8 Hz, 1H)、7.99 (d，J = 8.3 Hz, 1H)、8·46 (s， 1H)、8·54 (s，1H); MS(FAB) m/z 532(MH1); C3qH33N306 • 1/2H20 之分析計算值·· c，66. 65 ; H，6· 34 ; N，7. 77。 實測值·· C，66· 16 ; H，6. 37 ; N， 7. 50。 實施例3 1 (S) - 4-[l - [3-曱氧基一 4-[n’_(2-甲基苯基）脲基]苯乙醯 基]-2-咄咯啶曱氧基]異酞酸89112968.ptd Page 206 1283240 V. Inventive Note (202) Ears, and the reaction mixture was stirred overnight at room temperature. The mixture was diluted with CHC13 and acidified by the addition of IN HCl. The solution was washed with brine and dried over Na 2 SO 4 . The solvent was removed under reduced pressure, and the obtained crude solid was crystallised from hexane-EtOAc-CHC 13-MeOH to afford 12.6 mg (54%) of white crystals. IR (KBr) 1685, 1606, 1454, 1257, 752/cm; UMR (40 0 MHz, DMS0-d6) 51·8 7-2· 10 (m, 4H), 2. 12 (s, 3Η) &gt; 2.25 (s, 3H) &gt;3.51-3.71 (m, 4H) ^3.76 (s, 3H), 4.08-4.18 (m, 2H), 4.34 (m, 1H), 6.74 (dd, J = 1.5, 9· 8 Hz, 1H), 6.84 (d, J = 1.5 Hz, 1H), 6.94 (t, J = 6.8 Hz, 1H), 7·06 (d, J = 8.8 Hz, 1H), 7·12 ( d, J = 7.8 Hz, 1H), 7·16 (d, J = 7.8 Hz, 1H), 7·72 (s, 1H), 7·76 (dd, J=2.0, 8·3 Hz, 1H) , 7.79 (d, J = 7.8 Hz, 1H), 7.99 (d, J = 8.3 Hz, 1H), 8·46 (s, 1H), 8·54 (s, 1H); MS(FAB) m /z 532(MH1); C3qH33N306 • Analytical calculated value of 1/2H20·· c, 66. 65 ; H,6· 34 ; N, 7.77. Found C·66· 16 ; H, 6. 37 ; N, 7. 50. Example 3 1 (S) - 4-[l - [3-曱-oxy-4-[n'-(2-methylphenyl)ureido]phenidinyl]-2-pyrrolidinyloxy Isodecanoic acid

於4_乙醯氧異酞酸二甲酯（1· 52克，6· 03毫莫耳）溶於Dissolved in 4_ dimethyl oxonium isophthalate (1·52 g, 6·03 mmol)

1283240 五、發明說明（203) ' - = 011(70¾升）之溶液中加入飽和NaHC〇3，並使所產生之混 口物在至下攪拌3小時。將所產生之混合物倒入至丄N 、、C1中’並以EtOAc萃取。將萃取液以飽和NaHC〇3、鹽水洗 滌並於MgS〇4上乾燥。將溶劑蒸發而得丨· 27克^ )之 4 -羥基異酞酸二甲酯的白色結晶粉末。 ^-NMR (CDC13) ^3.91 (S, 3H) ^3.99 (s, 3H) ^7.01 (d, 1H, J = 8.8 Hz) &gt;8.11 (dd, 1H, 1 = 2.A ^8.8 Hz) &gt; 8.55 (d, 1H, J = 2.4 Hz)1283240 V. INSTRUCTIONS (203) A solution of - - 011 (703⁄4 liters) was added with saturated NaHC〇3, and the resulting mixture was stirred for 3 hours. The resulting mixture was poured into 丄N, C1] and extracted with EtOAc. The extract was washed with saturated NaHC 3, brine and dried over MgSO 4 . The solvent was evaporated to give a white crystalline powder of dimethylglycolic acid dimethyl ester. ^-NMR (CDC13) ^3.91 (S, 3H) ^3.99 (s, 3H) ^7.01 (d, 1H, J = 8.8 Hz) &gt;8.11 (dd, 1H, 1 = 2.A ^8.8 Hz) &gt ; 8.55 (d, 1H, J = 2.4 Hz)

在室溫下於4 -羥基異酞酸二甲酯（1.27克，6.04毫莫 耳）、（S)-N-Boc-脯胺醇（1. 22 克，6. 〇6 毫莫耳）、ρρ^、 (1. 90克，7, 24毫莫耳）溶於THF(3〇毫升）之攪拌溶液;加 入DIADC1. 43 *升，7. 26毫莫耳）。然後使所產生之攪拌沪 合物迴流加熱1 5小時。於冷卻至室溫後，使所產生之混: 物蒸發，及使殘留物經由於矽膠上利用正己烷—Et〇Ac ^ σ i，ν/ν)作為洗提液進行管柱層析，純化而得21〇克（88%j 之（S)-4-[l-(第三丁氧羰基）_2_„比咯啶甲氧基]異酞酸二 甲酯的黃色油。 ί-NMR (CDC13) 5 1. 26 (s, 9H) ^ 1. 85-2. 16 (m, 3H) &gt; 2 Η)、4 · 9 5 - 5 · 0 2 (m， Hz) 、8·11-8.14 (m， 使（S)-4-[l-(第三 甲酯（2 · 0 1克，5Dimethyl 4-hydroxyisophthalate (1.27 g, 6.04 mmol), (S)-N-Boc-decylamine (1. 22 g, 6. 〇6 mmol) at room temperature, 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。. The resulting stirred mixture was then heated to reflux for 15 hours. After cooling to room temperature, the resulting mixture is evaporated, and the residue is subjected to column chromatography by using n-hexane-Et〇Ac ^ σ i, ν/ν as an eluent on the tannin extract. Thus, 21 g of a yellow oil of 88% j of (S)-4-[l-(t-butoxycarbonyl)_2_„pyrrolidinemethoxy]isodecanoic acid dimethyl ester was obtained. ί-NMR (CDC13 5 1. 26 (s, 9H) ^ 1. 85-2. 16 (m, 3H) &gt; 2 Η), 4 · 9 5 - 5 · 0 2 (m, Hz), 8·11-8.14 ( m, make (S)-4-[l-(third methyl ester (2 · 0 1 gram, 5

• 36-3.46 (m，2H)、3·9〇 (s，6Η)、4 η—4·3; “， 2H)、7· 09 (dd，1H，J = 9· 3、24· 9 1H)、8· 46 (d，1H，J = 9· 3 Hz) 厂氧羰基）-2-咄咯啶甲氧基]異酞酸 宅莫耳）、TFA(20毫升）、及CHC1 (25毫升）之混合物在室溫下攪拌15小時。將所產生之^• 36-3.46 (m, 2H), 3·9〇(s, 6Η), 4 η—4·3; “, 2H), 7· 09 (dd, 1H, J = 9·3, 24· 9 1H ), 8· 46 (d, 1H, J = 9· 3 Hz) oxycarbonyl)-2-pyrrolidine methoxy]isodecanoic acid molybdenum), TFA (20 ml), and CHC1 (25 ml) The mixture was stirred at room temperature for 15 hours.

12832401283240

合物於真空中濃縮，並利用飽和NaHC〇3使成鹼性。將混合 物以CHJl2萃取，以鹽水洗滌，於μ/%上乾燥，並蒸發。 ，殘留物經由於矽膠上利用CHC13-Me〇H(9:丨，v/v)作為洗 提液進行管柱層析，純化而得〇 8〇克（53%)之（3)_4 — (2〜吡 洛唆曱氧基）異酞酸二甲酯的黃色油。 'H-NMR (CDCI3) 5 1.71 (m， 1H) 、 3·05-3.13 3H) 、 3·91 (s， 3H)、 J = 8·8 Hz)、8· 14 (dd 1H， J=2·4 Hz)。 (m，1H)、1·89 (m，2H)、2· 〇〇 (m， 2H) 、 3. 67 (m, ih) 、 3· 90 (s， 4· 05-4· 18 (m，2H)、7· 00 (d，1H， ，1H，J = 2· 4、8· 8 Hz)、8· 50 (d， 於（S)-4-(2-。比咯啶甲氧基）異酞酸二甲醋（6i6毫克， 2. 1 〇毫莫耳）溶於DMF(13毫升）之攪拌溶液中加入3_甲氧基 24〇Γ:ϋ甲t本基）脲基]苯基乙酸之五氟酯(1.〇°克， 2.〇8笔莫耳）及以0(425微升，312毫莫耳），並使所產生 =合Λ在室^下搜摔3.5小時。將所產生之混合物以 mi/ 、飽和NaHc〇3、鹽水洗務，並於 Γ而 Γ3二 、^ 匕J)脈基]“醯基]-2H定甲氧基]異醜酸二甲醋The compound was concentrated in vacuo and made basic with saturated NaHC. The mixture was extracted with CH.sub.2, washed with brine, dried over &lt The residue was purified by column chromatography on CHC13-Me〇H (9: 丨, v/v) as an eluent, and purified to obtain 8 g (53%) of (3)_4 — ( 2~Pylolyloxy) dimethyl phthalate is a yellow oil. 'H-NMR (CDCI3) 5 1.71 (m, 1H), 3·05-3.13 3H), 3·91 (s, 3H), J = 8·8 Hz), 8·14 (dd 1H, J=2 · 4 Hz). (m, 1H), 1.89 (m, 2H), 2· 〇〇 (m, 2H), 3. 67 (m, ih), 3· 90 (s, 4· 05-4· 18 (m, 2H), 7·00 (d, 1H, , 1H, J = 2·4, 8·8 Hz), 8·50 (d, (S)-4-(2-.pyrrolidinemethoxy) 3 methoxy 24 〇Γ: ϋ t ) ) 脲 ] ] 苯基 苯基 酞 酞 酞 酞 酞 酞 酞 酞 酞 酞 酞 酞 酞 酞 酞 酞 酞 酞 3 3 3 3 3 3 3 3 Pentafluoroacetate (1. 〇 ° grams, 2. 〇 8 moles) and 0 (425 μl, 312 millimoles), and the resulting = Λ 搜 搜 搜 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 The resulting mixture is washed with mi/, saturated NaHc〇3, brine, and Γ3Γ, ^ 匕J) 基 ] 醯 醯 醯 ] ] ] ] ] ] ] ] ] ] ] 二甲 二甲

1283240 五、發明說明（205) 4·42-4.47 (m， 1H)、6.44-8.46 (m 系列，12H)。 於（S) - 4 - [1-[3 -甲氧基-4 - [Ν’- (2-甲基苯基）脲基]苯乙 醯基]- 2-吼咯σ定甲氧基]異酞酸二曱酯（1.41克，2·39毫莫 耳）溶於THF(20毫升）之攪拌溶液中加入〇·25 N NaOH (20 毫升），然後使所產生之混合物迴流加熱隔夜。於冷卻至 室溫後，將混合物倒入至1 N HC1 (1 50毫升）中，並收集固 體。使粗製固體自CHCl3-MeOH再結晶而得140毫克（1〇%)之 35的白色結晶粉末。 NMR (CDC13) (51.83-2.18 (m，4H)、2·24 (s，3H)、 3 · 4 4 - 3 · 5 5 (m，4 Η)、3 · 5 9 ( s，2 Η )、3 · 8 0 ( s，3 Η )、 4.05-4.24 (m, 2H) ^ 4.28-4.32 (m, 1H) &gt; 6.73-8.55 (m 系列’總計12H) ; MS(FAB) m/z 562(MH1) ; C3QH31N3 08 · 4 H2 0 之分析计具值· C，5 6 · 8 7 ; H，6 · 2 0 ; N，6 · 6 3。實測 值·· C, 56· 73 ; H，5· 56 ; N，6. 52。 實施例3 2 3-曱氧基-4 - [2-[1 - [3 -甲氧基-4-[Ν’ - (2-甲基苯基）脲基] 苯基乙醯基]-2 -吡咯啶基]乙炔基]苯甲酸1283240 V. INSTRUCTIONS (205) 4·42-4.47 (m, 1H), 6.44-8.46 (m series, 12H). (S) - 4 - [1-[3 -Methoxy-4 - [Ν'- (2-methylphenyl) ureido] phenethyl] 2- 2-pyrrole 定 methoxy] To a stirred solution of di-decyl isodecanoate (1.41 g, 2.39 mmol) in THF (20 mL) was added EtOAc··········· After cooling to room temperature, the mixture was poured into 1 N HCl (1 50 mL) and solid was collected. The crude solid was recrystallized from CHCl3-MeOH to give 140 mg (1%) of white crystals of white crystals. NMR (CDC13) (51.83-2.18 (m, 4H), 2·24 (s, 3H), 3 · 4 4 - 3 · 5 5 (m, 4 Η), 3 · 5 9 ( s, 2 Η ), 3 · 8 0 ( s, 3 Η ), 4.05-4.24 (m, 2H) ^ 4.28-4.32 (m, 1H) &gt; 6.73-8.55 (m series 'total 12H); MS(FAB) m/z 562( MH1) ; C3QH31N3 08 · 4 H2 0 Analytical value · C,5 6 · 8 7 ; H,6 · 2 0 ; N,6 · 6 3. Measured value·· C, 56· 73 ; H,5 · 56 ; N, 6. 52. Example 3 2 3-decyloxy-4 - [2-[1 - [3-methoxy-4-[Ν-]-(2-methylphenyl)ureido Phenylethyl]-2-pyrrolidinyl]ethynyl]benzoic acid

使3-甲氧基-4 -硝基苯甲酸甲酯（1· 2〇克，5· 7毫莫耳）及 5% Pd-C(1.0克）於EtOH(30^升）及THF(20毫升）中之揽拌 混合物在1大氣壓下氫化隔夜。將混合物過濾並將濾液蒸Methyl 3-methoxy-4-nitrobenzoate (1.2 g, 5.7 mmol) and 5% Pd-C (1.0 g) in EtOH (30 L) and THF (20) The mixture in liters was hydrogenated overnight at 1 atmosphere. Filter the mixture and steam the filtrate

89112968.ptd 第210 1283240 五、發明說明（206) 發。將殘留物於矽膠上利用CHC13作為洗提液進行層析， 及使製得固體經由自CHC ls -正己烷再結晶而進一步純化得 805毫克（78%)之4 -胺基-3-甲氧苯甲酸甲酯的白色板狀 物。 熔點 1 26-1 28 °C ; IR (KBr) 3475、1 70 0 / 公分；ih-NMR (CDC13) 5 3. 86 (3H，s)、3. 89 (3H，s)、4· 21 (2H，br s) 、6·66 (1H， d， J=8.3 Hz) 、7·45 (1H， d， J=1.9 Hz) 、7·54 (1H， dd, 了=1.9 及8.3 Hz); MS(FAB) m/z 182(肘+ + 1)，〇9&amp;1叫3之分析計算值：〇，5966;|1， 6·12;Ν，7.73。實測值：c，59.65; H，6.15;n， 7.65。 在〇C下將4 -胺基-3-甲氧苯甲酸甲酯（725毫克，4毫莫 耳），於EtOH(10毫升）之攪拌溶液加至稀H2S〇4 (由iso* 〇/ 5耄升及H20 10毫升製備得）。將NaN〇2(331毫克，4· 8毫 莫耳）溶於之溶液（1〇毫升）加至此混合物。於在相同溫 度下攪拌0 · 5小時後，將混合物倒入至κ丨（丨· 8 3克，丨丨毫莫 耳）及催化劑Cu於40(100毫升）中之冷的（〇。〇攪拌懸浮溶 液中。，混合物在室溫下劇烈攪拌1小時，並以CHC13萃 取。將萃取液以鹽水洗滌，於MgS〇4上乾燥，並蒸發。將 殘留物於矽膠上利用正己烷—Et〇Ac (1〇:1，v/v)作為洗提 液進行層析，而得4-碘-3-甲氧苯甲酸甲酯及3—甲氧苯甲 酸甲_( 7 4 8毫克）之無色油的混合物。 於此油中加入Pd(PPh3)4 (150毫克，0.13毫莫耳）、 Cul(57笔克，〇· 3宅莫耳）及卜ρΓ2ΝΗ(1〇毫升）。使混合物89112968.ptd No. 210 1283240 V. Description of invention (206). The residue was chromatographed on silica gel using CHC13 as an eluent, and the solid was further purified by recrystallization from CHC ls - n-hexane to give 805 mg (78%) of 4-amino-3-methoxy A white plate of methyl benzoate. Melting point 1 26-1 28 °C; IR (KBr) 3475, 1 70 0 / cm; ih-NMR (CDC13) 5 3. 86 (3H, s), 3. 89 (3H, s), 4· 21 ( 2H, br s), 6.66 (1H, d, J = 8.3 Hz), 7.45 (1H, d, J = 1.9 Hz), 7.54 (1H, dd, = 1.9 and 8.3 Hz); MS (FAB) m/z 182 (elbow + + 1), 〇9 &amp; 1 called 3 analytical calculations: 〇, 5966; |1, 6·12; Ν, 7.73. Found: c, 59.65; H, 6.15; n, 7.65. Add a solution of methyl 4-amino-3-methoxybenzoate (725 mg, 4 mmol) in EtOH (10 mL) to dilute H.sub.2 (.sub.4). Soar and H20 10 ml prepared). A solution (1 mL) of NaN 2 (331 mg, 4.8 mmol) was added to the mixture. After stirring at the same temperature for 0.5 hours, the mixture was poured into κ丨 (丨·3 3 g, 丨丨 mmol) and the catalyst Cu was cooled in 40 (100 ml). The mixture was stirred vigorously for 1 hour at room temperature and extracted with CHC 13. The extract was washed with brine, dried over MgSO 4 and evaporated. (1〇:1,v/v) was chromatographed as an eluent to obtain a colorless oil of methyl 4-iodo-3-methoxybenzoate and methyl 3-benzoate (7 4 8 mg). A mixture of Pd(PPh3)4 (150 mg, 0.13 mmol), Cul (57 g, 〇·3 house Mo) and Bu Γ2ΝΗ (1 ml) were added to the oil.

第211頁 1283240 五、發明說明（207) 於K中攪袢1小時，並將卜（第三丁氧羰基）-2〜乙基，比略。定 (488毫克，2.5莫耳）溶於i-PhNHUO毫升）之溶液加至此 混合物。於攪拌2小時後，將混合物倒入至H2〇中，並以 EtOAc萃取。將萃取液以鹽水洗滌，於MgS〇4上乾燥，並蒸 發。將殘留物於矽膠上利用正己烷-Et0Ac(5 ·· 1，v/v)作為 洗提液進行層析，而得431毫克（48%)之卜（第三丁氧幾基） -2_[2-（2-甲氧基一4-甲氧羰基苯基）乙炔基]咄咯咬的黃&amp;色 油。 丨11 -NMR (CDC13) (Π. 49 (9H，s)、1· 77-2· 14 (4H，m)、 3.36-3.51 (2H，m)、3·90 (3H，s)、3·91 (3H，s)、 4·60-4·81 (1Η，m)、7·36-7·39 (1Η，m)、7·51 (1Η， s)、7· 55-7· 57 (1H, m)。 於1 -（第三丁氧羰基）-2-[2-（2-甲氧基一 4-甲氧羰基苯 基）乙炔基]咄咯啶（395毫克，1· 1毫莫耳）溶於CH2Cl2 (3毫 升）之攪拌溶液中加入TFA(3毫升）。使所產生之混合物攪 拌1小％。將混合物於真空中濃縮，經由加入飽*Ν&amp;(：〇3使 成為鹼性，並以CHC!3萃取。將萃取液以ΙΟ洗滌，於MgS〇4 上乾，並蒸發而得238毫克（84%)之2-[2-（2-甲氧基-4-甲氧羧基苯基）乙快基]吼嘻σ定的咅色油。 ^H-NMR (CDC13) (4H；m) ^.97-3.17 (2H, m)、3·91 (6H，s)、4.13一4·15 (1H，m)、7·41 (1H，d， J = 8.3 Hz) ^7.51 (1H, s) &gt;7.56 (1H, d, J = 8. 3 Hz) 〇 使2:[2-(2-曱氧基-4-甲氧羰基苯基）乙炔基]吼咯啶 (233¾克，〇.9耄莫耳）、3-甲氧基一 4 一 [N，—一曱基苯基） 1283240 五、發明說明（208) ★脲基]苯乙酸（314毫克，1毫莫耳）、EDC(268毫克，1.4毫 莫耳）、DMAP(1 1〇毫克，〇· 9毫莫耳）於DMF(1〇毫升）中之混 合物攪拌隔仪。將混合物倒入至丨N HC丨中，及利用吸濾收 集所產生之^固體。將所得固體溶解於CHC丨3，及將溶液於Page 211 1283240 V. INSTRUCTIONS (207) Stir in K for 1 hour, and put the (t-butoxycarbonyl)-2~ethyl group. A solution of (488 mg, 2.5 mol) dissolved in i-PhNHUO ml) was added to the mixture. After stirring for 2 hours, the mixture was poured into EtOAc and EtOAc. The extract was washed with brine, dried over MgSO 4 and evaporated. The residue was chromatographed on a silica gel using n-hexane-Et0Ac (5 ··1, v/v) as an eluent to give 431 mg (48%) of s. 2-(2-methoxy-4-methoxycarbonylphenyl)ethynyl]pyrene bite yellow &amp;丨11-NMR (CDC13) (Π. 49 (9H, s), 1. 77-2· 14 (4H, m), 3.36-3.51 (2H, m), 3.90 (3H, s), 3· 91 (3H, s), 4·60-4·81 (1Η, m), 7·36-7·39 (1Η, m), 7·51 (1Η, s), 7·55-7· 57 ( 1H, m). 1-(Tertidinoxycarbonyl)-2-[2-(2-methoxy-4-methoxycarbonylphenyl)ethynyl]pyrrolidine (395 mg, 1.1 mM To a stirred solution of CH2Cl2 (3 ml), EtOAc (3 mL) Alkaline and extracted with CHC! 3. The extract was washed with hydrazine, dried over MgSO 4 and evaporated to yield 238 mg (84%) of 2-[2-(2-methoxy-4- Oxy-carboxyphenyl)ethylidene]吼嘻σ定的咅色油.H-NMR (CDC13) (4H;m) ^.97-3.17 (2H, m), 3·91 (6H, s), 4.13 - 4·15 (1H, m), 7·41 (1H, d, J = 8.3 Hz) ^7.51 (1H, s) &gt; 7.56 (1H, d, J = 8. 3 Hz) 〇 2: [2-(2-decyloxy-4-methoxycarbonylphenyl)ethynyl]pyrrolidine (2333⁄4 g, 〇.9耄莫耳), 3-methoxy-1,4-[N,- Monodecylphenyl) 1283240 V. Description of the invention (208) ★ Urea-based phenylacetic acid (314 mg, 1 mmol), EDC (268 mg, 1.4 mmol), DMAP (1 1 mg, 〇· A mixture of 9 mmoles in DMF (1 mL) was stirred. The mixture was poured into 丨N HC丨, and the resulting solid was collected by suction filtration. The obtained solid was dissolved in CHC 丨3. And the solution

MfS〇4上，燥产春發。使殘留物於石夕膠上利用Et0Ac作為洗 提液進仃紐官柱層析而得一油。將油溶解於THF(5毫升） 中，及編攪拌邊將〇· 25N NaOH加至此溶液。將溶液倒入至 冰的1 N HC 1中而得_固體。收集此固體，將其以水洗條， 並風乾。使粗製固體自⑶^厂正己烷再結晶，而得215毫 克（4 4 %)之3 6的白色結晶粉末。 熔點 141 -145 C; IR (KBr) 3338、2956、2935、2875、 2593、1711/公分；1H_NMR (DMS〇 — d6) 5191一214 (4h， m) 2·24 (3H，s)、3·38-3·68 (4H，m)、4·88-5.08 (1Η, m) ^ 6.76-8.56 ( 1 2H, m) ; MS(FAB) m/z 542 (MH1)。 實施例3 3 卜Nj-二甲胺基4一Π-[3一曱氧基一4 — [N，一（2一曱基笨基）脲 基]苯乙醯基]-2 -吡咯啶曱氧基]苯曱酸On MfS〇4, dry spring is produced. The residue was subjected to chromatography on a mixture of Et0Ac as a washing liquid to obtain an oil. The oil was dissolved in THF (5 mL) and 〇·25N NaOH was added to this solution with stirring. The solution was poured into 1 N HCl 1 of ice to give a solid. This solid was collected, washed with water and air dried. The crude solid was recrystallized from (3) hexanes to give 215 g (4 4%) of s. Melting point 141 - 145 C; IR (KBr) 3338, 2956, 2935, 2875, 2593, 1711/cm; 1H_NMR (DMS〇-d6) 5191-214 (4h, m) 2·24 (3H, s), 3· 38-3·68 (4H, m), 4·88-5.08 (1Η, m) ^ 6.76-8.56 ( 1 2H, m) ; MS(FAB) m/z 542 (MH1). Example 3 3 Nj-dimethylamino 4-indole-[3-monooxy-4-[N, mono(2-indolyl)ureido]phenethyl]-2-pyrrolidinium Oxy]benzoic acid

使4-經基-3-硝基苯曱酸甲酯（3· 22克，〇· 〇163莫耳）及 5% Pd-C(12. 9克）於MeOH(30毫升）中之攪拌混合物在大氣 壓力中在室溫下氫化70小時。將不溶解的催化劑移除/、及Stirring mixture of 4-methyl-3-nitrobenzoic acid methyl ester (3.22 g, 〇·〇163 mol) and 5% Pd-C (12.9 g) in MeOH (30 ml) Hydrogenation was carried out at room temperature for 70 hours at atmospheric pressure. Remove insoluble catalyst / and

1283240 五、發明說明（209) 將遽液於真空中蒸發。將殘留物於矽膠上利用Et〇H —CHCls (1 : 20 ’ v/v)作為洗提液進行層析而得丨· 89克（69%)之3—胺 基-4-羥基苯曱酸曱酯的淡棕色糖漿。 使3 -胺基-4-羥基苯甲酸甲酯（1〇7克，6·4〇毫莫耳）及 5% Pd-C(2· 14克）於MeOH(20毫升）及37%甲醛水溶液（1. 〇8 毫升β’0·〇122莫耳）及IN HC1(6.1毫升）中之攪拌混合物在 大氣壓力中在室溫下氫化2 6小時。將不溶解的催化劑移 除’及將遽液於真空中蒸發。將殘留物於矽膠上利用 EtOAc-正己烧（1:1〇，v/v)作為洗提液進行層析而得 0.817克（70%)之3 -（N，N-二甲胺基）一4一羥基苯甲酸甲酯的 糖漿。 在〇 C下於3-(N，N-二甲胺基）一4-羥基苯甲酸甲酯（0.817 克，4.18毫莫耳）、N-第三丁氧羰基脯胺醇（〇·926克， 4.60¾ 莫耳）、Ph3P(1.21 克，4.60 毫莫耳）於 THF(20 毫升） 中之攪拌混合物中逐滴加入1)1八〇(95%)( 0.953毫升，4.60 宅莫耳）。使所產生之混合物迴流加熱4 1小時。於冷卻 後，將混合物於真空中蒸發掉。將殘留物於矽膠上利用 於使溶液在室溫下攪拌5小時，將溶液於真空中蒸發。將1283240 V. INSTRUCTIONS (209) Evaporate the mash in a vacuum. The residue was chromatographed on a silica gel using Et〇H-CHCls (1:20' v/v) as an eluent to give 89 g (69%) of 3-amino-4-hydroxybenzoic acid. Light brown syrup of oxime ester. Methyl 3-amino-4-hydroxybenzoate (1 〇 7 g, 6.4 mmol) and 5% Pd-C (2.6 g) in MeOH (20 mL) and 37% aqueous formaldehyde The stirred mixture in (1. 8 ml of β'0·〇122 mol) and IN HC1 (6.1 ml) was hydrogenated at room temperature for 6 hours at room temperature. The insoluble catalyst was removed&apos; and the mash was evaporated in vacuo. The residue was chromatographed on silica gel using EtOAc-hexanes (1:1, v/v) as eluent to give &lt;RTI ID=0.0&gt; 4-Methyl hydroxybenzoate syrup. Methyl 3-(N,N-dimethylamino)- 4-hydroxybenzoate (0.817 g, 4.18 mmol), N-tert-butoxycarbonylguanamine (〇·926 g) at 〇C To a stirred mixture of THF (20 mL) was added 1) 1 octa (95%) (0.953 ml, 4.60 house moles) in a stirred mixture of THF (20 mL). The resulting mixture was heated under reflux for 4 1 hour. After cooling, the mixture was evaporated in vacuo. The residue was applied to a silica gel and the solution was stirred at room temperature for 5 hours, and the solution was evaporated in vacuo. will

EtOAc-正己烷（1 : 1 〇至丨：6，v/v)作為洗提液進行層析而得 一糖漿，不經進一步的純化而將其使用於後續的反應中。 將此糖漿溶解於ch2ci2(io毫升）中，並加入TFA(1〇毫“升）。 水加至殘留物，並以CHC“洗滌。將水層經由加入飽和Ethyl acetate-n-hexane (1:1 Torr to hydrazine: 6, v/v) was used as an eluent to give a syrup which was used in the subsequent reaction without further purification. This syrup was dissolved in ch2ci2 (io ml) and TFA (1 Torr liter) was added. Water was added to the residue and washed with CHC. Saturation of the water layer by adding

NaHC〇3而中和，並以CHC13萃取。將萃取液於Ν^δ〇4上乾 燥，並於真空中蒸發而得1· 03克（89%)之3-(n，N—二甲胺NaHC〇3 was neutralized and extracted with CHC13. The extract was dried on Ν δ 〇 4 and evaporated in vacuo to give &lt;RTI ID=0.0&gt;&gt;

89112968.ptd 第214頁 1283240 五、發明說明（210) 基）- 4 - ( 2 -呲咯啶甲氧基）苯甲酸曱酯的膠。 使3 -（ N，N -二甲胺基）- 4 -（ 2 -咄咯啶甲氧基）苯甲酸甲酯 (0.529克，1·90毫莫耳）、3-甲氧基-4-[N’-（2-曱基笨基） 脲基]苯乙酸（0.597克，1.90毫莫耳）、HOBt((K 308克， 2· 28毫莫耳）、4-二甲基胺基咄啶（DM AP)( 23,2毫克， 0.190毫莫耳）、及1-乙基-3 -（3-二曱胺丙基）氰胺（EDC) (0· 437克，2· 28毫莫耳）於DMF(10毫升）中之混合物在室溫 下撥拌1 5小時。經由小心加入1 N HC1而將混合物中和， 並以EtOAc進行萃取。將萃取液於Na2S04上乾燥，並於真空 中蒸發而得0· 6 0 7克（56%)之3-N，N-二甲胺基-4-[1-[3-曱 氧基-4 - [Ν’ - (2-甲基苯基）脲基]苯乙醯基]一2-吼咯啶甲 氧基]苯甲酸曱酯的白色結晶物質。 使3-Ν，Ν-二曱胺基-4-[：1 - [3-甲氧基-4-[Ν’ -（2-甲基苯 基）脲基]苯乙醯基]- 2 -咄咯啶曱氧基]苯曱酸甲酯（0.600 克，1· 04毫莫耳）於THF(10毫升）及0· 25Ν NaOH(5毫升， 1· 25毫莫耳）中之混合物在室溫下攪拌21小時。將CHC1 3加 至混合物，並以水（100毫升）-lN NaOH(4毫升）之混合物萃 取。將萃取液以飽和NH4C1中和，並以CHC13萃取。將萃取 液於Na2S04上乾燥，並於真空中蒸發而得428毫克（70%)之 3 7的白色結晶固體。 1-NMR ( 40 0 MHz，DMS〇-d6) 51.88、1·99 及 2·11 (4H，各 m)、2·24 (3Η，s)、2·67 (6Η，s)、3.33 (2Η, m)、3·58 (2H, m) &gt;4.05-4.32 (3H, m) &gt;6.75 (1H, d, J = 7. 3 Hz)、6·92-6·95 (1H，m)、7·05 (1H，d, J = 8.3 Hz)、89112968.ptd Page 214 1283240 V. INSTRUCTIONS (210) Glues of 4-(2-pyrrolidinemethoxy)benzoate. Methyl 3-(N,N-dimethylamino)-4-(2-pyrrolidinemethoxy)benzoate (0.529 g, 1.90 mmol), 3-methoxy-4- [N'-(2-indolyl) ureido]phenylacetic acid (0.597 g, 1.90 mmol), HOBt ((K 308 g, 2.28 mmol), 4-dimethylamino hydrazine Pyridine (DM AP) (23,2 mg, 0.190 mmol), and 1-ethyl-3-(3-diamidinopropyl)cyanamide (EDC) (0·437 g, 2·28 mmol) The mixture was stirred at room temperature for 15 hours. The mixture was neutralized by careful addition of 1 N HCl and extracted with EtOAc. The extract was dried over Na 2 EtOAc and vacuum Evaporated to give 0.67 g (56%) of 3-N,N-dimethylamino-4-[1-[3-曱oxy-4 - [Ν' - (2-methylbenzene) a white crystalline material of ureido]phenidinyl]- 2-indolyl methoxy]benzoate oxime. 3-Ν,Ν-diaminomethyl-4-[:1 - [3- Methoxy-4-[Ν'-(2-methylphenyl)ureido]phenethyl]-2-pyrrolidiniumoxy]benzoic acid methyl ester (0.600 g, 1.04 mmol) Ear) in THF (10 ml) and 0. 25 NaOH (5 ml, 1.25 mM The mixture was stirred at room temperature for 21 hours. CHC1 3 was added to the mixture and extracted with a mixture of water (100 ml) - 1 N NaOH (4 ml). The extract was neutralized with saturated NH4C1 and The extract was dried over Na2SO4 and evaporated in vacuo to give 428 mg (yield: 70%) of white crystals as a white solid. 1-NMR (40 0 MHz, DMS 〇-d6) 51.88,1·99 And 2·11 (4H, each m), 2·24 (3Η, s), 2.67 (6Η, s), 3.33 (2Η, m), 3·58 (2H, m) &gt; 4.05-4.32 ( 3H, m) &gt; 6.75 (1H, d, J = 7. 3 Hz), 6.92-6·95 (1H, m), 7·05 (1H, d, J = 8.3 Hz),

89112968.ptd 第215頁 1283240 五、發明說明（211) 7·Η - 7·17 (2H，m)、7·42 (1H，s)、7·52 (1H，d，J = 7·8 Hz)、7·79 (1H，d，J = 7.8 Hz)、8·00 (1H，d，J = 7.8 Hz)、8·31 (1H，s)、8·46、8·55 (各 1H，各s); MS(FAB) m/z 533 (MH1)。 實施例3 4 3-氟-4-[[1 - [3-曱氧基-4- [Ν’-（2-曱基苯基）脲基]笨乙醯 基]- 2 -吼咯啶基]甲氧基]苯曱酸89112968.ptd Page 215 1283240 V. INSTRUCTIONS (211) 7·Η - 7·17 (2H, m), 7·42 (1H, s), 7·52 (1H, d, J = 7·8 Hz ), 7·79 (1H, d, J = 7.8 Hz), 8·00 (1H, d, J = 7.8 Hz), 8·31 (1H, s), 8.46, 8.55 (each 1H, Each s); MS (FAB) m/z 533 (MH1). Example 3 4 3-Fluoro-4-[[1 - [3-曱-oxy-4-[Ν'-(2-mercaptophenyl)ureido]]ethendyl]-2-pyrrolidinyl Methoxy]benzoic acid

在室溫下於4 -溴_2-氟酚（217微升，2.002毫莫耳）、ν-第三丁氧羰基脯胺醇（403毫克，2.002毫莫耳）、及 Ph3P( 630毫克，2· 403毫莫耳）溶於THF(7毫升）之攪拌溶液 中加入D IAD ( 4 7 7微升’ 2 · 4 2 3毫莫耳）。使所產生之混合物 在室溫下攪拌6小時，然後在7〇 下攪拌隔夜。將混合物 於真空中濃縮，及將殘留物於矽膠上利用正己烷— Et〇Ac (5 : 1 ’ v/v)作為洗提液進行層析而得549· 4毫克（73%)之1 - 漠-4-[1-(第三丁氧羰基）—2 — σ比咯啶基]曱氧基—3-氟苯的 油。 ^-NMR (400 MHz, CDC13) ^1.46 (s, 9H) Μ. 85 (br m, 1H)、1·90-2.10 (br s，3H)、3·30-3·47 (m，2H)、 3.85、4.04 (各br s，1H)、4·η-4·20 (m，2H)、6·82 -6.98 (m, 1H) 、7·13-7·26 (m， 2H); MS(FAB) m/z 374 (M+ +1) 〇4-bromo-2-fluorophenol (217 μl, 2.002 mmol), ν-t-butoxycarbonyl decylamine (403 mg, 2.002 mmol), and Ph3P (630 mg, at room temperature) 2· 403 mmoles) D IAD (47 7 μl '2 · 4 2 3 mmol) was added to a stirred solution of THF (7 mL). The resulting mixture was stirred at room temperature for 6 hours and then stirred at 7 Torr overnight. The mixture was concentrated in vacuo, and the residue was applied to silica gel eluting with hexane - EtOAc (5: 1 'v/v) as eluent to give 549. 4 mg (73%) of 1 - An oil of 4-(1-(t-butoxycarbonyl)-2 - σpyrrolidyl]nonyloxy-3-fluorobenzene. ^-NMR (400 MHz, CDC13) ^1.46 (s, 9H) Μ. 85 (br m, 1H), 1·90-2.10 (br s, 3H), 3·30-3·47 (m, 2H) , 3.85, 4.04 (each br s, 1H), 4·η-4·20 (m, 2H), 6.82 -6.98 (m, 1H), 7·13-7·26 (m, 2H); MS (FAB) m/z 374 (M+ +1) 〇

89112968.ptd 第216頁 1283240 五、發明說明（212) 於卜溴-4-U-(第三丁氧羰基）-2 -吡咯啶基]甲氧基— 氟苯（549.4毫克，1.468毫莫耳）溶於DMS0( 6毫升）及 Me0H(5毫升）之攪拌溶液中加入Et3N(448微升，3. 229毫莫 耳）、Pd(0Ac)2(36. 2 毫克，0.161 毫莫耳）、及1，3〜雙（二、 苯膦基）丙烷（66· 4毫克，0· 161毫莫耳）。於混合物中弓丨A CO氣體10分鐘。使所產生之混合物在70 °C下在CO之流_ τ 攪拌2天。於將混合物濃縮後，將殘留物以EtOAc稀釋。網^ 溶液以鹽水洗滌，並於NazSO4上乾燥。將溶劑於減壓下移 除，及將殘留物於矽膠上利用正己烷：EtOAc (5 : 1，v/v) 作為洗提液進行層析而得323. 0毫克（62%)之4-[ 1〜（第三丁 氧羰基）-2-咄咯啶基]曱氧基一3-氟苯甲酸甲酯的淡黃色 油。 M-NMR (40 0 MHz，CDC13) 5 1· 47 (s，9H)、1· 87 (br s 1 Η )、1 · 9 5 - 2 · 1 0 ( m，3 Η)、3 · 3 4 - 3 · 4 4 (b r m, 2 Η )、3 § 9 (3，31〇、3.94及4.11-4.26(各計111，31〇、7.03-7.11 (m， 1H) 、7·75-7·80 (m， 2H); MS(FAB) m/z 354 (MH1) 〇 在0 °C下於4-[ 1-(第三丁氧羰基）—2-咄咯啶基]甲氧基 - 3 -氟苯甲酸甲酯（323.0毫克，0.914毫莫耳）溶於CH2Cl2 (6· 5毫升）之攪拌溶液中加入TFA(1· 3毫升），及使混合物 在室溫下攪拌1 · 5小時。將溶劑於減壓下移除，及經由加 ^1N NaOH而使殘留物成為鹼性。以CHCl3萃取混合物。將 萃取液以^鹽水洗滌，於Na2S〇4上乾燥，並於減壓下濃縮而 得174.8毫克（76 %)之3 -氟〜4_(2 -11比咯啶基）甲氧苯甲酸曱89112968.ptd Page 216 1283240 V. INSTRUCTIONS (212) Ibbromo-4-U-(t-butoxycarbonyl)-2-pyrrolidinyl]methoxy-fluorobenzene (549.4 mg, 1.468 mmol) To a stirred solution of DMS0 (6 ml) and Me0H (5 ml), Et3N (448 μL, 3.229 mmol), Pd(0Ac) 2 (36.2 mg, 0.161 mmol), And 1,3~bis(diphenylphosphino)propane (66·4 mg, 0·161 mmol). A CO gas was trapped in the mixture for 10 minutes. The resulting mixture was stirred at 70 ° C for 2 days in a stream of CO _ τ. After the mixture was concentrated, the residue was diluted with EtOAc. The solution was washed with brine and dried over NazSO4. The solvent was removed under reduced pressure, and the residue was applied to silica gel eluting with hexane:EtOAc (5:1, v/v) as eluent to give 323. A pale yellow oil of [1~(t-butoxycarbonyl)-2-oxaridinyl]methoxy-methyl 3-fluorobenzoate. M-NMR (40 0 MHz, CDC13) 5 1· 47 (s, 9H), 1·87 (br s 1 Η ), 1 · 9 5 - 2 · 1 0 ( m, 3 Η), 3 · 3 4 - 3 · 4 4 (brm, 2 Η ), 3 § 9 (3, 31 〇, 3.94 and 4.11-4.26 (111, 31 〇, 7.03-7.11 (m, 1H), 7·75-7·80 (m, 2H); MS(FAB) m/z 354 (MH1) 〇 at 0 ° C under 4-[1-(t-butoxycarbonyl)-2-pyrrolidinyl]methoxy- 3 - To a stirred solution of methyl fluorobenzoate (323.0 mg, 0.914 mmol) in CH.sub.2Cl.sub.2 (5.sub.5 mL) was added TFA (1.3 mL), and the mixture was stirred at room temperature for 1.5 hours. The solvent was removed under reduced pressure, and the residue was made basic with EtOAc. EtOAc was evaporated. 174.8 mg (76%) of 3-fluoro-~4_(2 -11-pyridyl) methoxybenzoate

12832401283240

酉旨的標色油。 (400 MHz，CDC13)cH.54-1·63 (m，1H)、1·76 — 2.02 (m, 3Η) &gt; 2.93-3.07 (m, 2H) &gt;3.57 (ddd, J:4· 9 、 6· 9 、 14·3 Hz， 1H) 、 3·89 (s， 3H) 、 3· 97 (dd J = &quot;、9·3 Hz，1H)、4.〇4 (dd，J = 5.0、8·8 Hz，1H)’、 6.98 (t， J=17.6 Hz， 1H) 、7.73 (dd， J=2.〇 、11·7 Hz 1H)、7. 78 (dt，J = 2· 0、8· 8 Hz，1H) ; MS(FAB) m/z ’ 253(M++ 1)。 使3-甲氧基-4 - [Ν’ -（2-甲基苯基）脲基]笨乙酸五氟笨酯 (324.5¾克，0.676¾莫耳）、3-氟-4-(2-吼略唆基）甲氧 苯甲酸甲酯（171. 1毫克，〇· 676毫莫耳）、Et3N(U3微升， 〇· 811毫莫耳）於DMF(5毫升）中之混合物在室溫下攪拌2小 時。將混合物以EtOAc稀釋，以鹽水洗滌，並於Na2S〇4上乾 餘。將✓谷劑於減壓下移除，及將殘留物於石夕膠上利用正己 烷· EtOAc ( 1 ·· 2，v/v)作為洗提液進行層析而得3—氟—4一 [[卜3-甲氧基-4- [Ν’ - (2-甲基苯基）脲基]笨乙醯基]一2一 吡咯啶基]甲氧基]苯甲酸甲酯（365.1毫克，〇·664毫莫耳） 的油。於此化合物溶於THF(4.4毫升）及Η2〇(1·ΐ毫升）之攪 拌溶液中加入LiOH(46. 3毫克，1· 9 32毫莫耳），並使反應 混合物在室溫下攪拌隔夜。將混合物以CHC12稀釋，並經 由加入IN HC1而酸化。將分離的有機層以鹽水洗滌，並&amp;於 NaS〇4上乾燥。將溶劑於減壓下移除，並使所得之粗製固 體自正己烷-EtOAc-CHC13再結晶，而得1〇2毫克（3〇%)之38 的白色結晶粉末。The color oil of the purpose. (400 MHz, CDC13) cH.54-1·63 (m, 1H), 1.76 — 2.02 (m, 3Η) &gt; 2.93-3.07 (m, 2H) &gt;3.57 (ddd, J:4·9 , 6· 9 , 14·3 Hz, 1H), 3·89 (s, 3H), 3.97 (dd J = &quot;, 9·3 Hz, 1H), 4.〇4 (dd, J = 5.0 , 8·8 Hz, 1H)', 6.98 (t, J=17.6 Hz, 1H), 7.73 (dd, J=2.〇, 11·7 Hz 1H), 7.78 (dt, J = 2· 0 , 8·8 Hz, 1H); MS(FAB) m/z ' 253 (M++ 1). 3-methoxy-4-[[indol]-(2-methylphenyl)ureido]p-pentafluoroacetate (324.53⁄4 g, 0.6763⁄4 mol), 3-fluoro-4-(2- Mixture of methyl methoxybenzoate (171. 1 mg, 676 676 mmol), Et3N (U3 μL, 811·811 mmol) in DMF (5 mL) at room temperature Stir under 2 hours. The mixture was diluted with EtOAc, washed with brine and dried over Na. The ✓ granules were removed under reduced pressure, and the residue was chromatographed on a mixture of hexane, EtOAc (1··2, v/v) as an eluent to give 3-fluoro-4. [[Bu 3-methoxy-4-[Ν' - (2-methylphenyl)ureido]] oxaethyl]- 2 -pyrrolidinyl]methoxy]benzoic acid methyl ester (365.1 mg, 〇·664 millimoles) of oil. To a stirred solution of THF (4.4 mL) and EtOAc (1···················· . The mixture was diluted with CHC12 and acidified by the addition of IN HCl. The separated organic layer was washed with brine and dried over Na.sub.4. The solvent was removed under reduced pressure, and the obtained crude solid was recrystallised from n-hexane-EtOAc-CHC 13 to yield 1 2 2 (3 %) of 38 white crystalline powder.

1283240 五、發明說明（214) 熔點 1 23- 1 26 °C ; IR (KBr) 1616、1 537、1 282、756 / 公 分；1Η-NMR ( 4 0 0 MHz, DMS0-d6) (51.87-2·09 (m，4H)、 2·25 (s，3H)、3·48-3·57 (m，2H)、3·60 (s，2H)、 3·83 (s，3H)、4·η - 4·16 (m，1H)、4·24 (dd，J = 2.9、 9.8 Hz，1H)、4·28-4·34 (br s, 1H)、6·74 (dd， J = 1.5、8·3 Hz，1H)、6·87 (s，1H)、6.94 (t，J = 7.3 Hz， 1H)、7.12 (d，J = 7.8 Hz， 1H)、7.15 (t， J = 8.3 Hz, 1H)、7·34 (t，J = 8.8 Hz，1H)、7.66 (dd，J = 2.0、 12.2 Hz，1H)、7.73 (d，J = 9.3 Hz，1H)、7.79 (d， J = 8.3 Hz，1H)、7·99 (d，J:7.8 Hz，1H)、8·46 (s， 1H)、8.55 (s， 1H) ； MS(FAB) m/z 536 (MH1)； C29H30FN3O6 •0·5Η20 之分析計算值：c，63.96; H，5.74; N，7.72; F，3· 49。實測值：c，64· 11 ; H， 5. 80 ; N， 7. 39 ; F， 3.54。 實施例3 5 4 - [1-[4 - [Ν’ -（2-氟苯基）脲基]-3-甲氧苯基乙醯基]-2 - 口比咯啶基]甲氧基-3-曱氧笨甲酸1283240 V. Description of invention (214) Melting point 1 23- 1 26 °C; IR (KBr) 1616, 1 537, 1 282, 756 / cm; 1Η-NMR (400 MHz, DMS0-d6) (51.87-2 ·09 (m, 4H), 2·25 (s, 3H), 3·48-3·57 (m, 2H), 3·60 (s, 2H), 3·83 (s, 3H), 4· η - 4·16 (m, 1H), 4·24 (dd, J = 2.9, 9.8 Hz, 1H), 4·28-4·34 (br s, 1H), 6.74 (dd, J = 1.5 , 8·3 Hz, 1H), 6·87 (s, 1H), 6.94 (t, J = 7.3 Hz, 1H), 7.12 (d, J = 7.8 Hz, 1H), 7.15 (t, J = 8.3 Hz , 1H), 7·34 (t, J = 8.8 Hz, 1H), 7.66 (dd, J = 2.0, 12.2 Hz, 1H), 7.73 (d, J = 9.3 Hz, 1H), 7.79 (d, J = 8.3 Hz, 1H), 7·99 (d, J: 7.8 Hz, 1H), 8·46 (s, 1H), 8.55 (s, 1H); MS(FAB) m/z 536 (MH1); C29H30FN3O6 • Analysis calculated for 0·5Η20: c, 63.96; H, 5.74; N, 7.72; F, 3. 49. Found: c, 64·11; H, 5. 80; N, 7. 39 ; F, 3.54 Example 3 5 4 - [1-[4 - [Ν' -(2-Fluorophenyl)ureido]-3-methoxyphenylethenyl]-2 -cyclopyridyl]methoxy -3-oxooxybenzoic acid

使4 - [Ν’-（2-氟苯基）脲基]—3-甲氧苯乙酸（318毫克，1 毫莫耳）、2-（2-甲氧基-4-乙氧羰基）苯氧甲基吼咯啶（279 毫克，1毫莫耳）、EDC(288毫克，1.5毫莫耳）、及 DMAPU22毫克’ 1毫莫耳）於DMF(2〇毫升）中之混合物攪拌4-[Ν'-(2-Fluorophenyl)ureido]-3-methoxyphenylacetic acid (318 mg, 1 mmol), 2-(2-methoxy-4-ethoxycarbonyl)benzene Mixture of oxymethylpyrrolidine (279 mg, 1 mmol), EDC (288 mg, 1.5 mmol), and DMAPU 22 mg '1 mmol) in DMF (2 mL)

89112968.ptd 第219頁 1283240 五、發明說明（215) &quot; 隔夜。將混合物倒入至1N HC1中，並利用吸濾收集所產生 之固體。將固體溶解於CHCl3，並於MgS〇4上乾燥。於移除 溶劑後，將殘留物於矽膠上利用CHC13 : Me〇H (1 〇〇 : 1， V / V )作為洗提液進行層析而得一油，將其溶解於 THF-MeOH(4 ·· 1，v/v，毫升）中。將〇·25Ν Na〇H(8 毫升） 加至此溶液，並使所產生之攪拌混合物迴流加熱3小時。 將混合物倒入至1 N HC 1中。利用吸濾收集所產生之固體， 將其溶解於CHCI3中，於MgS〇4上乾燥，並蒸發。使殘留物 自CHC13-正己烷-乙醚再結晶，而得329毫克（6〇%)之39的 白色結晶粉末。 熔點 1 40-1 44 °C ; IR (KBr) 33 38、29 5 6、2875、260 7、 1 70 9 /公分；NMR (CDC13) (Η· 95-2· 25 (4H，m)、 3.45-4.50 ( 1 2Η, m) -6.66-8.15 (12H, m) ； MS(FAB) m/z 552(M+ + 1)。 實施例3 6 2-[[1-[3-甲氧基-4-[!^’-（2-曱基笨基）脲基]苯甲醯 基]- 2 - p比洛σ定基]甲氧基]吼σ定- 5 -羧酸89112968.ptd Page 219 1283240 V. Inventions (215) &quot; Overnight. The mixture was poured into 1 N HCl and the resulting solid was collected by suction filtration. The solid was dissolved in CHCl3 and dried over MgS〇4. After removing the solvent, the residue was chromatographed on a silica gel using CHC13 : Me 〇H (1 〇〇: 1, V / V ) as an eluent to obtain an oil which was dissolved in THF-MeOH (4 ·· 1, v/v, ml). 〇·25Ν Na〇H (8 ml) was added to the solution, and the resulting stirred mixture was heated under reflux for 3 hr. The mixture was poured into 1 N HC 1 . The resulting solid was collected by suction filtration, dissolved in CHCI3, dried over MgSO 4 and evaporated. The residue was recrystallized from CHC13-hexane-hexane to afford 329 mg (yield: Melting point 1 40-1 44 °C; IR (KBr) 33 38, 29 5 6 , 2875, 260 7, 1 70 9 /cm; NMR (CDC13) (Η· 95-2· 25 (4H, m), 3.45 -4.50 (1 2Η, m) -6.66-8.15 (12H, m); MS(FAB) m/z 552 (M+ + 1). Example 3 6 2-[[1-[3-methoxy-4 -[!^'-(2-indolyl)ureido]benzimidyl]- 2 - p-pyrrolidine]methoxy]吼σ定-5-carboxylic acid

40 在0°C下於6 -羥基菸鹼酸（500毫克，3.594毫莫耳）溶於 苯（8毫升）及MeOH(2毫升）之攪拌溶液中逐滴加入 TMSCHN2(1.97毫升，3·953毫莫耳），並使混合物在室溫下 攪拌隔夜。經由加入AcOH使反應混合物停止反應，及使所40 TMSCHN2 (1.97 ml, 3·953) was added dropwise to a stirred solution of 6-hydroxynicotinic acid (500 mg, 3.594 mmol) in benzene (8 mL) and MeOH (2 mL). Millions) and the mixture was stirred overnight at room temperature. Stop the reaction mixture by adding AcOH, and make the reaction

89112968.ptd 第220頁 1283240 五、發明說明（216) 產生之混合物於真空中濃縮。將殘留物於石夕膠上利用正己 院-£七(^(：(1:3，¥/¥)作為洗提液進行層析而得269.8毫克 (49%)之2-羥基吡啶-5-羧酸甲酯的白色結晶粉末。 IR (KBr) 3062 、1657 、1654 、1612 、1435 、1300 、1113 、775、642 / 公分；l-NMR (400 MHz, CDC13) (53.87 (s，3H)、6·58 (d，J = 9.8 Hz，1H)、7·99 (dd，J = 2.4、 9.8 Hz，1H)、8.19 (d，J = 2.4 Hz，1H); MS(FAB) m/z 154 (MH1) ; C7H7N03 · 1 / 4H20 之分析計算值：c，53. 33 ; H，4. 80 ; N， 8. 89。實測值：C，53· 58 ; H，4. 65 ; N， 8.87。 在室溫下於2 -羥基咄啶-5 -羧酸甲酯（ 2 69. 8毫克，1. 762 毫莫耳）、N-第三丁氧羰基脯胺醇（354. 6毫克，1.762毫莫 耳）、及Ph3P(554.6毫克，2.114毫莫耳）溶於THF(10毫升） 之攪拌溶液中緩慢加入DIAD(0· 42毫升，2. 114毫莫耳）， 及使所產生之混合物在70 °C下攪拌6小時。將反應混合物 濃縮，及將殘留物於矽膠上利用正己烷：EtOAc (5 : 1， v/v)作為洗提液進行層析而得262· 5毫克（44%)之2-[[ 1 -（第三丁氧獄基）-2 _ σ比嘻ϋ定基]甲氧基]吼唆- 5 -叛酸甲g旨 的油。 l-NMR (40 0 MHz, CDC13) (H· 47 (s，9H)、1. 85-1. 98 (m， 4H) 、3.37 (br s， 2H) 、3·92 (s， 3H) 、4·12-4.33 (br m， 2H) 、4·48 (brs， 1H) 、6·75 (m， 1H) 、8·15 (m， 1H) 、8.79 (m， 1H); MS(FAB) m/z 337 (MH1)。 在0 °C下於2-[[ ：l-(第三丁氧羰基）-2 -吼咯啶基]甲氧基]89112968.ptd Page 220 1283240 V. INSTRUCTIONS (216) The resulting mixture is concentrated in vacuo. The residue was chromatographed on the Shishi gum using Zhengjiyuan-£7 (^(::1,3/¥) as the eluent to obtain 269.8 mg (49%) of 2-hydroxypyridine-5- White crystalline powder of methyl carboxylate. IR (KBr) 3062, 1657, 1654, 1612, 1435, 1300, 1113, 775, 642 / cm; l-NMR (400 MHz, CDC13) (53.87 (s, 3H), 6·58 (d, J = 9.8 Hz, 1H), 7·99 (dd, J = 2.4, 9.8 Hz, 1H), 8.19 (d, J = 2.4 Hz, 1H); MS(FAB) m/z 154 (MH1); C7H7N03 · 1 / 4H20 calc.: C, 53.33; H, 4. 80; N, 8. 89. Found: C, 53 · 58 ; H, 4. 65 ; N, 8.87 Methyl 2-hydroxyacridin-5-carboxylate (2.69 mg, 1.762 mmol), N-tert-butoxycarbonylguanamine (354. 6 mg, 1.762) at room temperature To a stirred solution of Ph3P (554.6 mg, 2.114 mmol) dissolved in THF (10 mL), DIAD (0·42 mL, 2.114 mmol), and mixture Stir at 70 ° C for 6 hours. The reaction mixture was concentrated, and the residue was applied to silica gel using n-hexane:EtOAc (5:1 v/v) The solution was chromatographed to give 262. 5 mg (44%) of 2-[[ 1 -(T-butoxy-phenyl)-2 _ σ 嘻ϋ 基 ] ] ] ] 5 5 5 5 5 5 Oil for g. l-NMR (40 0 MHz, CDC13) (H. 47 (s, 9H), 1. 85-1. 98 (m, 4H), 3.37 (br s, 2H), 3.92 ( s, 3H), 4·12-4.33 (br m, 2H), 4·48 (brs, 1H), 6.75 (m, 1H), 8·15 (m, 1H), 8.79 (m, 1H) MS(FAB) m/z 337 (MH1). 2-[[l:(---------------------------

89112968.ptd 第221頁 1283240 五、發明說明（217)89112968.ptd Page 221 1283240 V. Description of invention (217)

酸工:;(262.5毫*，°.8 70毫莫耳)溶於CHA (5.3駕升）之撹拌溶液中加入17奴11毫升），及使 之混合物在室溫下授拌“、時。將溶劑於減壓下移除，及 經由加入IN NaOH而使殘留物成為鹼性’並以cHci3萃取。 將萃取液以鹽水洗滌’於牧叫上乾燥， 而得毫克（94%)之2_[(21〇各咬基）甲氧基]〇比咬辰^ 叛酸甲S旨的淡黃色油。 H-NMR ( 40 0 MHz, CDC13) 51.49^1.58 (ddt, J = 6 8 ^ 8 8 Hz, 1H) 72-1.87 (m, 2H) M. 90^1. 99 (m, 1H). 2.92-3.05 (m，2H)、3·50-3·57 (ddd, JM.4、7·3、 15·1 Hz， 1H) 、3.91 (s， 3H) 、4·23 (dd， J=7.8 、l〇 7 Hz，1H)、4·38 (dd，J一-4·4、1〇·7 Hz，1H)、6·78 (d: J = 8.8 Hz，1H)、8·15 (dd，J = 2.4、8.8 Hz, 1H)、8·80 (d，J = 2· 4 Hz，1H) ; MS(FAB) m/z 237 (MH1)。 · 使3-甲氧基-4-[Ν’-（2-甲基苯基）脲基]苯乙酸五氟笨酯 (351· 7毫克，0. 732毫莫耳）、2一 [ (2一咄咯啶基）甲氧基]咣 淀-5-羧酸曱酉旨（173.0毫克，0.732毫莫耳）、Et3N(122.4 微升，0.878¾莫耳）於DMF( 5· 2毫升）中之混合物在室溫下 攪拌1小時。將混合物以EtOAc稀釋，以鹽水洗滌，並於 NazSO4上乾燥。將溶劑於減壓下移除，及將殘留物於矽膠 上利用正己烷：EtOAc( 1 : 5，v/v)作為洗提液進行層析而 得2-[ Π - [3-甲氧基-4-[N，- (2-甲基苯基）脲基]笨乙醯 基]-2 -咄咯啶基]甲氧基]吡啶一5 —羧酸甲酯（ 338. 4毫克， 87%)的油。於此化合物溶於THF(5· 6毫升）及Η2〇(1· 4毫升）Acid worker: (262.5 mA, °. 8 70 mM) dissolved in a mixture of 17 (11 ml) of CHA (5.3 liters), and allowed the mixture to be mixed at room temperature. The solvent was removed under reduced pressure, and the residue was made basic with the addition of IN NaOH and extracted with cHci3. The extract was washed with brine and dried on a grazing machine to obtain milligrams (94%) of 2_[ (21 〇 each bite) methoxy] 〇 咬 ^ ^ 叛 叛 叛 叛 叛 叛 叛 叛 叛 H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H , 1H) 72-1.87 (m, 2H) M. 90^1. 99 (m, 1H). 2.92-3.05 (m, 2H), 3·50-3·57 (ddd, JM.4, 7. 3 , 15·1 Hz, 1H), 3.91 (s, 3H), 4·23 (dd, J=7.8, l〇7 Hz, 1H), 4·38 (dd, J-4-4, 4, 1〇· 7 Hz, 1H), 6·78 (d: J = 8.8 Hz, 1H), 8·15 (dd, J = 2.4, 8.8 Hz, 1H), 8·80 (d, J = 2· 4 Hz, 1H MS (FAB) m/z 237 (MH1). · 3-methoxy-4-[Ν'-(2-methylphenyl)ureido]phenylacetic acid pentafluoroester (351·7 mg) , 0. 732 millimoles), 2 -[(2-pyridinyl)methoxy]phosphonium-5-carboxylic acid hydrazine (173.0 mg, 0. The mixture was stirred at room temperature for 1 hour. The mixture was diluted with EtOAc, washed with brine and dried over NazSO4, EtOAc EtOAc. Drying. The solvent was removed under reduced pressure, and the residue was chromatographed with hexane:EtOAc (1:5, v/v) as the eluent to give 2-[ Π - [3- Oxy-4-[N,-(2-methylphenyl)ureido] phenylethyl]-2-pyridinyl]methoxy]pyridine-5-carboxylic acid methyl ester (338. 4 mg , 87%) oil. This compound is dissolved in THF (5.6 ml) and Η2〇 (1.4 ml)

1283240 五、發明說明（218) 之攪拌溶液中加入Li〇H(45· 7毫克，1· 91毫莫耳），並使反 應混合物在室溫下攪拌隔夜。將混合物以CHC込稀釋，並 以飽和NH4C1處理，以鹽水洗滌，於Na2S〇4上乾燥。將溶劑 於減壓下移除，並使所得之粗製固體自正己烷-Et2〇_ CHCl^MeOH再結晶，而得193. 8毫克（59%)之40的白色結晶 粉末。 熔點 1 25- 1 28 °C ; IR (KBr) 1716、1 6 0 0、1 53 3、1 2 5 5 / 公 *;1H-NMR(40 0 MHz，DMSO-d6)(5 1.6 7-2.03 (m，4H)、 2·50 (s，3H)、3·33-3·42 (m，1H)、3·52 (m，2H)、 3.58 (d, J = 4.4 Hz, 1H) &gt;3.83 (s, 3H) ^4.27-4.31 (m, 2H) ^ 4.42-4.47 (m, 1H) &gt;6.73 (d, J = 7. 8 Hz, 1H)、6·87-6·95 (m，3H)、7·1&quot;.17 (m，2H)、7·79 (d，J = 8.3 Hz，1H)、7·99 (d，J = 8.3 Hz, 1H)、8.14 (dd，】 = 2·0、8·8 Hz，1H)、8.46 (s，1H)、8·56 (s， 1H)、8·69 (d，J = 2.0 Hz，1H)、13.06 (br s，1H); MS(FAB) m/z 51 9(MH1) ; C28H3()N4 06 · 1 / 2H2〇 之分析計算 值：C，6 3. 75 ; H，5. 92 ; N，10. 62。實測值·· C， 6 3.61 ； H, 5. 94 ； N, 10.27。 實施例37 3-甲氧基-4_[ 2-[4-[Ν’-（2-甲基笨基）脲基]苄基]-4-噻唑 基]曱氧苯甲酸1283240 V. The stirred solution of Invention (218) was added with Li〇H (45·7 mg, 1.91 mmol), and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with CH.sub.2 s. The solvent was removed under reduced pressure, and the obtained crude solid was crystallised from n-hexane-EtOAc (EtOAc EtOAc) Melting point 1 25- 1 28 ° C; IR (KBr) 1716, 1 6 0 0, 1 53 3, 1 2 5 5 / male*; 1H-NMR (40 0 MHz, DMSO-d6) (5 1.6 7-2.03 (m, 4H), 2·50 (s, 3H), 3·33-3·42 (m, 1H), 3·52 (m, 2H), 3.58 (d, J = 4.4 Hz, 1H) &gt; 3.83 (s, 3H) ^ 4.27-4.31 (m, 2H) ^ 4.42-4.47 (m, 1H) &gt; 6.73 (d, J = 7. 8 Hz, 1H), 6·87-6·95 (m, 3H), 7·1&quot;.17 (m, 2H), 7.79 (d, J = 8.3 Hz, 1H), 7·99 (d, J = 8.3 Hz, 1H), 8.14 (dd,] = 2 ·0,8·8 Hz,1H), 8.46 (s,1H), 8·56 (s, 1H), 8·69 (d, J = 2.0 Hz, 1H), 13.06 (br s, 1H); MS (FAB) m/z 51 9(MH1); C28H3()N4 06 · 1 / 2H2〇 calc.: C, 6 3. 75 ; H, 5. 92 ; N, 10.62. C, 6 3.61; H, 5. 94; N, 10.27. Example 37 3-Methoxy-4_[2-[4-[Ν'-(2-methylphenyl)ureido]benzyl]- 4-thiazolyl]oxobenzoic acid

COOH 41COOH 41

89112968.ptd 第223頁 1283240 五、發明說明（219) &quot; 在室溫下於五硫化填（27.4克’ 1 23. 34毫莫耳）及新鮮製 備之無水Na2S(4.8克’61.67宅莫耳）溶於thf(200毫升）之 攪拌溶液中加入對硝基苯甲腈（2· 0克，12· 33毫莫耳）。使 所產生之混合物在室溫下攪拌17小時。將混合物以Et〇Ac 稀釋，並以10% K2P〇4洗滌。以CHgCl2萃取水層。將萃取液 於N az S Ο*上乾燥並於真空中漢縮。將殘留物於石夕膠上利用 正己烷：Et0Ac(5·· 1至2·· 1，v/v)作為洗提液進行層析而得 1 · 5 3克（6 4%)之4 -硝苄基羰硫醯胺的淡黃色結晶物質。89112968.ptd Page 223 1283240 V. INSTRUCTIONS (219) &quot; At room temperature in a five-vulcanized filling (27.4 g '1 23.34 mAh) and freshly prepared anhydrous Na2S (4.8 g '61.67 house Moule To a stirred solution of thf (200 ml) was added p-nitrobenzonitrile (2.0 g, 12.33 mmol). The resulting mixture was stirred at room temperature for 17 hours. The mixture was diluted with Et 〇Ac and washed with 10% K 2 EtOAc. The aqueous layer was extracted with CHgCl2. The extract was dried over N az S Ο* and hanked in vacuo. The residue was chromatographed on the Shiqi gum using n-hexane: Et0Ac (5··1 to 2··1, v/v) as an eluent to obtain 1 · 5 3 g (64%) of 4 - A pale yellow crystalline material of nitritol carbonyl sulfonamide.

IR (KBr) 1 529、1 446、1 326、1315、858 / 公分；ιΗ一NMR (400 MHz，CDC13) “·15 (s，2H)、7·51 (d，&gt;8·3 Hz， 2Η)、8·24 (d，J:8.8 Ηζ，2H); MS(FAB) m/z 197 (M+ +1 ) ; C8 H8 N2 02 S 之分析計算值：c，4 8. 9 7 ; Η，4 β 11 ; N， 14.28; S， 16.34。實測值：c，48.69; Η，4.06; N， 14· 07 ; S，16· 10。 ’ 於4 -硝苄基羰硫醯胺（5 〇 2 · 〇毫克，2 · 5 5 8毫莫耳）溶於 EtOH(5毫升）之攪拌溶液中加入1，3一二氯一2〜丙酮（649· 6毫 克’ 5 · 1 6宅莫耳），並使混合物迴流加熱1小時。將混合物 濃縮，並以CHCI3稀釋殘留物。將溶液以1N Na〇H、鹽水洗 滌，並於NaS〇4上乾燥。將溶劑於減壓下移除，及將殘留 物於石夕膠上利用正己烧：EtOAc(4:l，v/v)作為洗提液進 行層析而得495. 2毫克（72%)之4-[2-[(4_硝苄基）噻唑基] 甲基氯的淡黃色油。 l-NMR (400 MHz, CDC13) 54.43 (s，2H)、4·68 (s，IR (KBr) 1 529, 1 446, 1 326, 1315, 858 / cm; ιΗ NMR (400 MHz, CDC13) "·15 (s, 2H), 7·51 (d, &gt; 8·3 Hz, 2Η), 8·24 (d, J: 8.8 Ηζ, 2H); MS(FAB) m/z 197 (M+ +1); C8 H8 N2 02 S analytical calculation: c, 4 8. 9 7 ; , 4 β 11 ; N, 14.28; S, 16.34. Found: c, 48.69; Η, 4.06; N, 14· 07; S, 16·10. ' 4-N-benzyl carbamoylamine (5 〇 2 · 〇mg, 2 · 5 5 8 mM) in a stirred solution of EtOH (5 ml), add 1,3 - dichloro- 2 - acetone (649 · 6 mg ' 5 · 1 6 house Mo) And the mixture was heated to reflux for 1 h. The mixture was concentrated and the residue was diluted with CHCI 3. The solution was washed with 1N NaHH, brine and dried over Nas. The residue was chromatographed on EtOAc (4:1, v/v) eluted with EtOAc. Light yellow oil of methyl thiazolyl] methyl chloride. l-NMR (400 MHz, CDC13) 54.43 (s, 2H), 4.68 (s,

89112968.ptd 第224頁 1283240 五、發明說明（220) 2H)、7·23 (s，1H)、7.49 (d，J = 8.8 Hz，2H)、8·20 (d，J = 8.8 Ηζ，2H); MS(FAB) m/z 26 9 (ΜΗ1) ο 在0°C下於香草酸乙基酯（308.0毫克，1.570毫莫耳）及89112968.ptd Page 224 1283240 V. INSTRUCTIONS (220) 2H), 7·23 (s, 1H), 7.49 (d, J = 8.8 Hz, 2H), 8·20 (d, J = 8.8 Ηζ, 2H MS(FAB) m/z 26 9 (ΜΗ1) ο at 0 ° C in ethyl vanillate (308.0 mg, 1.570 mmol) and

MeONa(89毫克，1.570毫莫耳）溶於MeOH(6· 5毫升）之授拌 溶液中加入4-[2-(4 -硝苄基）噻唑基]甲基氣（211· 〇毫克， 0.785毫莫耳）溶於MeOH( 1 · 4毫升）之溶液。使所產生之混 合物在室溫下攪拌1 6小時，並迴流加熱1天。將溶劑於減 壓下移除，並以CHCI3萃取殘留物。將萃取液以to、魄水 洗條，並於Na2S04上乾燥。將溶劑於減壓下移除，二 久將錢· 留物於石夕膠上利用正己烧：EtOAc(2:l，v/v)作為、、先 進行層析而得201 · 7毫克（60%)之3-曱氧基-4 -[ 2〜、二液 基）-4-噻唑基]甲氧苯曱酸乙酯的淡黃色油。 硝卞 ^-NMR (400 MHz, CDC13) 51.39 (t, J = 7. 3 Hz, 3h 3·93 (s，3H)、4·36 (q，J = 7.3 Hz，2H)、4·44 (s 、 2H)、5.31 (s，2H)、6.97 (d，〗 = 8·3 Hz，1H)、/2 (s， 1H) 、7·48 (d， J = 8.8 Hz， 2H) 、7·57 (d， j:2 8 Hz， 1H) 、7.64 (dd， J=2.0 、8·3 Hz， 1H) 、8·2〇 (d〇 J = 8·8 Hz，2H) ; MS(FAB) m/z 429 (M+ + 1 )。 ’ 使3-甲氧基-4 - [2-（4 -胺苄基）-4-噻唑基甲氧笨甲&gt; 醋（201.7毫克，0.471毫莫耳）及5% Pd/C(40毫克）於§久乙 EtOH(8毫升）中之攪拌溶液在1大氣壓下氫化24小時'。 合物過濾並將濾液濃縮。將殘留物於矽膠上利用正 $混 EtOAc(l ·· 1，v/v)作為洗提液進行層析，而得8?. 8袁^ : (4 7°/〇之3-甲氧基-4-[2-(4-胺苄基）-4-噻唑基]甲=# τ乳米甲MeONa (89 mg, 1.570 mmol) dissolved in MeOH (6.5 mL) was added 4-[2-(4-nitrobenzyl)thiazolyl]methyl gas (211· 〇 mg, 0.785 Millol) A solution of MeOH (1.4 ml). The resulting mixture was stirred at room temperature for 16 hours and heated under reflux for 1 day. The solvent was removed under reduced pressure and the residue was extracted with CHCI3. The extract was washed with to, water and dried on Na2SO4. The solvent was removed under reduced pressure. For a long time, the residue was charged with hexane (2:1, v/v), and then subjected to chromatography to obtain 201·7 mg (60). %) A pale yellow oil of ethyl 3-methoxy-4-[2~,diyl)-4-thiazolyl]methoxybenzoate. Niobium ^-NMR (400 MHz, CDC13) 51.39 (t, J = 7. 3 Hz, 3h 3·93 (s, 3H), 4·36 (q, J = 7.3 Hz, 2H), 4·44 ( s , 2H), 5.31 (s, 2H), 6.97 (d, 〗 = 8·3 Hz, 1H), /2 (s, 1H), 7·48 (d, J = 8.8 Hz, 2H), 7· 57 (d, j: 2 8 Hz, 1H), 7.64 (dd, J=2.0, 8·3 Hz, 1H), 8·2〇 (d〇J = 8·8 Hz, 2H); MS(FAB) m/z 429 (M+ + 1 ). 'Methyl 3-methoxy-4 -[2-(4-aminobenzyl)-4-thiazolylmethoxybenzoate&gt; vinegar (201.7 mg, 0.471 mmol) And a stirred solution of 5% Pd/C (40 mg) in § EtOAc (8 mL) was hydrogenated at 1 atm for 24 s. The mixture was filtered and the filtrate was concentrated. Mixing EtOAc (l ·· 1, v/v) as an eluent for chromatography, and obtaining 8? 8 Yuan^ : (4 7 ° / 〇 3-methoxy-4-[2-(4- Amine benzyl)-4-thiazolyl]A=# τ乳米甲

12832401283240

玉'發明說明（221) 酸乙酯的淡黃色結晶粉末。 lH-NMR (400 MHz, CDC13) 51.38 (t, J = 7. 3 Hz, 3H) ^ 3.93 (s， 3H) 、4·21 (s, 2H) 、4,35 (q, J=7.3 Hz， 2H)、5·30 (s，2H)、6.66 (dd，J = 2.0、6·4 Hz，2H)、 6·97 (d， J=8.3 Hz， 1H) 、7·09 (d， J=8.3 Hz， 2H)、 7.18 (s，1H)、7·56 (d，J = 2.0 Hz, 1H)、7.64 (dd， J = 2.0、8·3 Hz，1H); MS(FAB) m/z 3 9 9 (MH1)。 於3-甲氧基-4 - [2 -（4 -胺苄基）- 4 -噻唑基]甲氧苯甲酸 乙酯（87.8毫克，0.220毫莫耳）溶於THF( 2· 0毫升）之溶液 中加入三乙胺（30. 5微升，0· 220毫莫耳）及異氰酸鄰甲苯 酯（3 0微升），並使反應混合物在室溫下攪拌21小時。將反 應混合物倒入至冰水中，並將所產生之沈澱物過濾掉。將 濾液以CHCI3萃取，以H2〇3及鹽水洗滌。將萃取液於Na2s〇4 上乾燥。將溶劑於減壓下移除而得11〇4毫克（94%)之3—甲 氧基一j 一 [2-[4-[N’_(2-甲基笨基）脲基]窄基]-4-嗔吐基] 甲氧笨甲酸乙酯的淡黃色結晶粉末。 JH-NMR (40 0 MHz, CDC13) dl.38 (t, J = 7 3 Hz 3H) ^ 2.28 (s，3H)、3.92 (s，3H)、4.28 (s，2H)、’4.35 (q， J = 7.3 Hz，2H)、5.29 (s，2H)、6.2〇 “，1H)、6 47 (s，1H)、6· 97 (d，J二8. 8 Hz， 7·24 (s， 2H) 、 7·27 (s， 2H) 2H)、7· 49 (d，J二7. 3 Hz, 1H) 1H)、7· 20 (s，1H)、 7. 33 (d， J=8. 3 Hz, 1H) 、 7·63 (dd， J=2· (MH1)。 、7. 56 (d， J=2· 0 Hz， • 3 Hz，1H) ; MS(FAB) m/z 532Jade 'Inventive Description (221) Light yellow crystalline powder of ethyl acetate. lH-NMR (400 MHz, CDC13) 51.38 (t, J = 7. 3 Hz, 3H) ^ 3.93 (s, 3H), 4·21 (s, 2H), 4,35 (q, J=7.3 Hz, 2H), 5·30 (s, 2H), 6.66 (dd, J = 2.0, 6.4 Hz, 2H), 6.97 (d, J=8.3 Hz, 1H), 7·09 (d, J= 8.3 Hz, 2H), 7.18 (s, 1H), 7·56 (d, J = 2.0 Hz, 1H), 7.64 (dd, J = 2.0, 8·3 Hz, 1H); MS(FAB) m/z 3 9 9 (MH1). Ethyl 3-methoxy-4-[2-(4-aminobenzyl)-4-thiazolyl]methoxybenzoate (87.8 mg, 0.220 mmol) was dissolved in THF (EtOAc) Triethylamine (30.5 microliters, 0.22 mmol) and o-cresyl isocyanate (30 μL) were added to the solution, and the reaction mixture was stirred at room temperature for 21 hr. The reaction mixture was poured into ice water and the resulting precipitate was filtered off. The filtrate was extracted with CHCI3 and washed with H.sub.3 and brine. The extract was dried over Na 2 s 4 . The solvent was removed under reduced pressure to give 11 〇4 mg (94%) of 3-methoxy-j-[2-[4-[N'-(2-methylphenyl)ureido]] ]-4-oxime] a pale yellow crystalline powder of ethyl methoxy benzoate. JH-NMR (40 0 MHz, CDC13) dl.38 (t, J = 7 3 Hz 3H) ^ 2.28 (s, 3H), 3.92 (s, 3H), 4.28 (s, 2H), '4.35 (q, J = 7.3 Hz, 2H), 5.29 (s, 2H), 6.2 〇 ", 1H), 6 47 (s, 1H), 6.97 (d, J 2.8 Hz, 7·24 (s, 2H) ), 7·27 (s, 2H) 2H), 7·49 (d, J 27.3 Hz, 1H) 1H), 7·20 (s, 1H), 7. 33 (d, J=8. 3 Hz, 1H), 7·63 (dd, J=2·(MH1)., 7.56 (d, J=2·0 Hz, • 3 Hz, 1H); MS(FAB) m/z 532

89112968.ptd 第226頁 1283240 五、發明說明（222) 於3-甲氧基-4 - [2-[4 - [N，- (2-曱基苯基）脲基]苄基] -4-噻唑基]甲氧苯甲酸乙酯溶於THF(1.6毫升）及1120(〇.4 毫升）之攪拌溶液中加入Li0H(6. 0毫克，〇· 249毫莫耳）， 使混合物在室溫下攪拌1小時，並迴流加熱8小時。將混合 物濃縮’並以C H C13稀釋。經由加入1 N N a 0 Η而使溶液成為 鹼性。經由加入1 N HC 1將水性萃取液酸化，並以CHC 13萃 取。將萃取液以鹽水洗滌，並於Na2S04上乾燥。將溶劑於 減壓下移除，並使所得之粗製固體自正己烷-Et0Ac-EtOH 再結晶，而得5 9 · 6毫克（5 7 %)之4 1的白色結晶粉末。 熔點 243-245°C ; IR (KBr) 3282、1 68 5、1 637、1 60 0、 1554、1516、1278、1234、763、748 /公分；NMR ( 40 0 MHz, DMS〇-d6) 62.27 (s，3H)、3.83 (s，3H)、 4·30 (s，2H)、5·21 (s，2H)、6·97 (t，J = 7.3 Hz， 1H)、7·15-7·24 (m，3H)、7.29 (d，J = 8.8 Hz，2H)、 7.47 (d，J = 8.3 Hz，2H)、7·50 (s，1H)、7·58 (d， J = 8.3 Hz，1H)、7·62 (s，1H)、7.86 (d，J = 7.8 Hz， 1H)、7·97 (s，1H)、9·09 (s，1H)、12·70 (br s， 1H) ; MS(FAB) m/z 50 4 (MH1) ; C27H25N3 05 S · 1/4H20 之分析 計算值·· C，63. 83 ; H，5· 06 ; N， 8. 27。實測值：C， 63. 74 ; H，4· 99 ; N，8· 10。 實施例3 8 4 - [[1 - [3-甲氧基-4 - [Ν’-（2-甲基笨基）脲基]苯基乙醯 基]-2-甲基-2 -吼咯啶基]曱氧基]-3-硝基苯曱酸89112968.ptd Page 226 1283240 V. INSTRUCTIONS (222) on 3-methoxy-4 - [2-[4- [N,-(2-mercaptophenyl)ureido]benzyl]-4- Ethyl thiazolyl] methoxybenzoate was dissolved in THF (1.6 ml) and 1120 (〇. 4 ml). A solution of EtOAc (. Stir for 1 hour and heat under reflux for 8 hours. The mixture was concentrated&apos; and diluted with CHC13. The solution was made alkaline by the addition of 1 N N a 0 Η. The aqueous extract was acidified by the addition of 1 N HCl 1 and extracted with CH. The extract was washed with brine and dried over Na 2 SO 4 . The solvent was removed under reduced pressure, and the obtained crude solid was recrystallized from n-hexane-Et0Ac-EtOH to give 5 6 · 6 mg (yield: 7%) of white crystalline powder. Mp 243-245 ° C; IR (KBr) 3282, 1 68 5, 1 637, 1 60 0, 1554, 1516, 1278, 1234, 763, 748 / cm; NMR ( 40 0 MHz, DMS 〇-d6) 62.27 (s, 3H), 3.83 (s, 3H), 4·30 (s, 2H), 5·21 (s, 2H), 6.97 (t, J = 7.3 Hz, 1H), 7·15-7 · 24 (m, 3H), 7.29 (d, J = 8.8 Hz, 2H), 7.47 (d, J = 8.3 Hz, 2H), 7·50 (s, 1H), 7·58 (d, J = 8.3 Hz, 1H), 7·62 (s, 1H), 7.86 (d, J = 7.8 Hz, 1H), 7·97 (s, 1H), 9·09 (s, 1H), 12·70 (br s , 1H) ; MS (FAB) m/z 50 4 (MH1) ; C27H25N3 05 S · 1/4H20 Analytical calculated value · · C, 63. 83 ; H, 5 · 06 ; N, 8. 27. Found: C, 63.74; H, 4·99; N, 8·10. Example 3 8 4 - [[1 - [3-Methoxy-4 -[Ν'-(2-methylphenyl)ureido]phenylethenyl]-2-methyl-2-pyrrole Pyridyl] methoxy]-3-nitrobenzoic acid

89112968.ptd 第 227 頁 1283240 五、發明說明（223) 在室溫下於N-第三丁氧羰基脯胺酸（6·00克，0.0279毫莫 耳）溶於M e Ο Η ··苯（1 : 4，ν / ν)之攪拌溶液中逐滴加入 TMSCHN2之2·0Μ正己烷溶液（16.7毫升，0.0334莫耳）。於 使所付溶液在室溫下攪拌1小時後，將混合物於真空中蒸 發，而得6· 39克（100%)之Ν-第三丁氧羰基脯胺酸甲基酯的 黃色糖漿。 1-NMR (CDC13) 51· 41 (s，9Η)、1· 85-1. 98 (m，4Η)、 2.21 -2.28 (m，2H)、3.72 (s, 3H)、4·29 (m，1H)。 在-78°C下於二異丙胺（2.02毫升，0·0144莫耳）溶於THF (30宅升）之祝拌溶液中於5分鐘内逐滴加入n — BuLi之1. 59M 正己烷溶液（9· 06毫升，〇· 0144莫耳）。使所產生之溶液在 - 78 C下授拌20分鐘。在-78 °C下於5分鐘内於此溶液中逐 滴加入N-第三丁氧羰基脯胺酸曱基酯（3 · 〇 〇克，〇 · 〇丨3丨毫 莫耳）溶於T H F ( 3 0 t升）之溶液。使所產生之溶液在—7 8 下攪拌10分鐘。在-78 °C下於此溶液中逐滴加入Me ΐ(〇β 900 毫升，0.0144莫耳）。使所產生之溶液在—π它下攪拌3〇分 鐘。經由加入NHJl而使溶液停止反應。以CHC13萃取所產 生之混合物。將萃取液以水洗滌，於N % § 〇4上乾燥，並於 真空中蒸發而得3.20克（q.y.)之N-第三丁氧羰基-2-曱基 膽胺酸曱基S旨的黃色糖漿。 !H-NMR (CDC13) 51.33 (s, 9H) n1.38 (s, 3H) ^1.72- 2·20 (m，4H)、3. 27-3.59 (m，2H)、3·63 (d, J = 6.389112968.ptd Page 227 1283240 V. INSTRUCTIONS (223) Dissolved in M- Ο Η ·· benzene at room temperature in N-tert-butoxycarbonyl decylamine (6·00 g, 0.0279 mmol) A stirred solution of 1 : 4, ν / ν) was added dropwise to a solution of TMSCHN 2 in hexane (16.7 mL, 0.0334 m). After the solution was stirred at room temperature for 1 hour, the mixture was evaporated in vacuo to give &lt;RTI ID=0.0&gt;&gt; 1-NMR (CDC13) 51· 41 (s, 9Η), 1.85-1. 98 (m, 4Η), 2.21 -2.28 (m, 2H), 3.72 (s, 3H), 4·29 (m, 1H). The solution of n-BuLi 1. 59M n-hexane solution was added dropwise to the mixture of diisopropylamine (2.02 ml, 0. 0144 m) in THF (30 liters) at -78 °C over 5 minutes. (9·06 ml, 〇·0144 m). The resulting solution was allowed to mix at -78 C for 20 minutes. N-tert-butoxycarbonyl decyl decyl citrate (3 · gram, 〇 · 〇丨 3 丨 millimolar) was dissolved in THF dropwise at -78 ° C for 5 minutes. (30 t liter) solution. The resulting solution was stirred at -78 for 10 minutes. Me ΐ (〇β 900 ml, 0.0144 mol) was added dropwise to this solution at -78 °C. The resulting solution was stirred under -π for 3 Torr. The solution was stopped by the addition of NHJ1. The resulting mixture was extracted with CHC13. The extract was washed with water, dried over N § 〇 4, and evaporated in vacuo to give 3.20 g (qy) of N-t-butoxycarbonyl-2-mercapto choline sulphate. syrup. !H-NMR (CDC13) 51.33 (s, 9H) n1.38 (s, 3H) ^1.72- 2·20 (m, 4H), 3.27-3.59 (m, 2H), 3·63 (d, J = 6.3

S m m % 89112968.ptd 第228頁 1283240 五、發明說明（224)S m m % 89112968.ptd Page 228 1283240 V. Description of invention (224)

Hz， 3H)。 在室溫下於N-第三丁氧羰基-2-甲基脯胺酸甲基酯（3. 20 克，0.0131莫耳）溶於THF( 20毫升）之攪拌溶液中加入1N NaOH( 15· 7毫升）。於使所產生之混合物攪拌24小時後，將 混合物以水稀釋，並以EtOAc洗滌。經由加入IN HC1而使 分離的水層酸化，並以EtOAc萃取。將萃取液於NaS04上乾 燥，並於真空中蒸發而得1. 71克（57%)之N-第三丁氧羰基 -2-甲基脯胺酸的黃色糖漿。 iH-NMR (CDC13) 51· 42 (s，9H)、1· 48 (s，3H)、1· 88-2.31 (m， 4H) 、3·34-3·57 (m， 2H) 、9·35 (br s， 1H)。 在室溫下於N-第三丁氧羰基-2-甲基脯胺酸（1. 10克， 4. 80毫莫耳）溶於THF( 20毫升）之攪拌溶液中逐滴加入 BH3-Sme2(0· 546毫升，5. 76毫莫耳）。於使所產生之混合物 在8 0 °C下攪拌6小時後，將混合物於真空中蒸發。將殘留 物以MeOH稀釋，以正己烷（3χ)洗滌，並於真空中蒸發而得 0.648克（60 %)之Ν-第三丁氧羰基一 2 -羥甲基-2-甲基咄咯啶 的黃色糖漿。 1-NMR (CDC13)51.47 (s，9Η)、1·76-2.05 (m，4Η)、 3 · 2 8 - 3 · 4 8 (m，2 Η)、3 · 6 6 (m，2 Η，d )。 在0 °C下於N-第三丁氧羰基一2-羥甲基一2-甲基咄咯啶（ 0.648克，3·01毫莫耳）、4-羥基-3 -硝基苯曱酸曱酯 (0.593 克，3·01 毫莫耳）、及ph3p(0· 868 克，331 毫莫耳） 溶於THF( 1 0毫升）之攪拌溶液中逐滴加aDIAD(95%)(〇· 686 毫升’ 3. 31毫莫耳）。於使所產生之混合物在8〇艺下攪拌Hz, 3H). Add 1N NaOH (15·) to a stirred solution of N-tert-butoxycarbonyl-2-methylproline methyl ester (3.20 g, 0.0131 mol) in THF (20 mL) at room temperature. 7 ml). After the resulting mixture was stirred for 24 hours, the mixture was diluted with water and washed with EtOAc. The separated aqueous layer was acidified via EtOAc (EtOAc). The extract was dried over Na.sub.4.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub. iH-NMR (CDC13) 51· 42 (s, 9H), 1·48 (s, 3H), 1·88-2.31 (m, 4H), 3·34-3·57 (m, 2H), 9· 35 (br s, 1H). BH3-Sme2 was added dropwise to a stirred solution of N-tert-butoxycarbonyl-2-methylproline (1.10 g, 4.80 mmol) in THF (20 mL) at room temperature. (0· 546 ml, 5.76 mmol). After the resulting mixture was stirred at 80 ° C for 6 hours, the mixture was evaporated in vacuo. The residue was diluted with MeOH, washed with EtOAc EtOAc (EtOAc) Yellow syrup. 1-NMR (CDC13) 51.47 (s, 9Η), 1.76-2.05 (m, 4Η), 3 · 2 8 - 3 · 4 8 (m, 2 Η), 3 · 6 6 (m, 2 Η, d). N-tert-butoxycarbonyl- 2-hydroxymethyl- 2-methyl-pyridinidine (0.648 g, 3.101 mmol), 4-hydroxy-3-nitrobenzoic acid at 0 °C Anthraquinone (0.593 g, 3·01 mmol), and ph3p (0·868 g, 331 mmol) dissolved in THF (10 ml), adiad (95%) was added dropwise (〇· 686 ml ' 3. 31 mAh). Stir the resulting mixture under 8 〇

89112968.ptd 第229頁 1283240 五、發明說明（225) 24小時後，將混合物於真空中蒸發。將殘留物以CHC i2 ( 5 毫升）稀釋，並加入TFA(5毫升）。於使所產生之混合物在 室溫下攪拌2小時後，將混合物於真空中蒸發。將殘留物 以0· 5N HC1稀釋，並以CHC13萃取。將水層利用飽和NaHC03 中和’並以CHC 13萃取。將萃取液於Na2S04上乾燥，並於真 空中蒸發而得0· 188克（21%)之3 -硝基-4-(2-曱基-2 -咄嘻 啶甲氧基）笨曱酸曱酯的黃色糖漿。 使3 -硝基- 4 -（ 2 -曱基-2 -咄咯啶甲氧基）苯甲酸曱酯89112968.ptd Page 229 1283240 V. INSTRUCTIONS (225) After 24 hours, the mixture was evaporated in vacuo. The residue was diluted with CH.sub.2 (5 mL) and TFA (5 mL). After the resulting mixture was stirred at room temperature for 2 hours, the mixture was evaporated in vacuo. The residue was diluted with 0.5 N HCl and extracted with CH.sub.3. The aqueous layer was neutralized with saturated NaHC03 and extracted with CHC13. The extract was dried over Na 2 SO 4 and evaporated in vacuo to give &lt;RTIgt;&lt;&quot;&gt;&gt;&gt; 188 g (21%) of 3-nitro-4-(2-mercapto-2 - acridine methoxy) Ester yellow syrup. Ethyl 3-nitro-4-(2-indolyl-2-pyridinylmethoxy)benzoate

(0.188克’0.920毫莫耳）、3-曱氧基-4- [Ν’ - (2-甲基笨 基）脲基]苯乙酸（ 0.289克，0·920毫莫耳）、HOBt(0.149 克，1.10宅莫耳）、DMAP(11.2毫克，0.0920毫莫耳）及EDC (0.211克，1·1〇毫莫耳）於DMF(5毫升）中之混合物在室溫 下攪拌14小時。將EtOAc加至混合物，並以〇· 5N HC1、飽 和NaHC〇3、及鹽水連續洗滌溶液。將有機層於上乾 燥，並於真空中蒸發而得〇· 489克（q· y·)之4-[ [ 1 一[3-曱氧 基-4-[Ν’-(2-曱基笨基）脲基]苯基乙醯基]—2一甲基一 2一咄 洛σ疋基]甲氧基]-3 -頌基笨甲酸甲酯的黃色結晶物質。 ^-NMR (CDC13) (51.26 (d, J = 5.9 Hz) ' 1.85-4.50 (m, 10H)、2·30 (s，3H)、3·67 (s, 2H)、3·92 (s，3H): 6.36 (s，2H)、6·75-7.52 (m，7H)、8. 02 (d，J = 7.8(0.188 g '0.920 mmol), 3-decyloxy-4-[Ν'-(2-methylphenyl)ureido]phenylacetic acid (0.289 g, 0·920 mmol), HOBt (0.149 A mixture of D.sub.1 (1.10 m.), DMAP (11.2 mg, 0.0920 mmol), and EDC (0.211 g, 1.1 mmol) in DMF (5 mL) was stirred at room temperature for 14 hours. EtOAc was added to the mixture, and the solution was washed successively with 〇·5N HCl, saturated NaHC 〇 3 and brine. The organic layer was dried on top and evaporated in vacuo to give 489· 489 g (q· y·) 4-[ [ 1 [[3-曱oxy-4-[Ν'-(2-曱-] A yellow crystalline material of methyl ureido]phenylethyl fluorenyl]-2-methyl phthalocyanine methyl methoxy]-3 fluorenyl benzoate. ^-NMR (CDC13) (51.26 (d, J = 5.9 Hz) ' 1.85-4.50 (m, 10H), 2·30 (s, 3H), 3·67 (s, 2H), 3.92 (s, 3H): 6.36 (s, 2H), 6.75-7.52 (m, 7H), 8. 02 (d, J = 7.8

Hz，1H)、8.15 (d，J = 8.8 Hz，1H)、8·47 (s，ih)。 使4-[[卜[3-甲氧基-4一 [N，一（2—甲基笨基）脲基]苯基乙 醯基]-2-甲基-2-咄咯啶基]甲氧基]一3〜硝基笨曱酸酯 ( 0.489 克，0.0828 毫莫耳）於 Me〇H(5 毫升）及 1Ν ν&amp;〇η 1283240 五、發明說明（226) 一~ (1 · 2 4毫升）中之攪拌混合物迴流加熱2小時。於冷卻後， 將混合物以水稀—釋，並以CHCh萃取。將水層以1N 1{〇酸 化，並以CHCI3卒取。將萃取液於上乾燥，並於真空 中蒸發而得0· 3 6 6克（99%)之42的黃色結晶物質。 實施例3 9 4 - [4_羥基-1-[3-甲氧基-4-[N’_(2 -甲基苯基）脲基]苯乙 醯基]-2-咄咯啶甲氧基]-3-甲氧笨甲酸Hz, 1H), 8.15 (d, J = 8.8 Hz, 1H), 8·47 (s, ih). 4-[[Bu [3-methoxy-4-[N,-(2-methylphenyl)ureido]phenylethenyl]-2-methyl-2-indenyl)] Oxy]- 3~nitro-indole (0.489 g, 0.0828 mmol) in Me〇H (5 ml) and 1Ν ν&amp;〇 1283240 V. Description of invention (226) one ~ (1 · 2 4 The stirred mixture in ML) was heated under reflux for 2 hours. After cooling, the mixture was diluted with water and extracted with CHCh. The aqueous layer was acidified with 1N 1 {〇 and was taken as CHCI3. The extract was dried over and evaporated in vacuo to give &lt;RTIgt;&lt;/RTI&gt; Example 3 9 4 - [4-Hydroxy-1-[3-methoxy-4-[N'-(2-methylphenyl)ureido]phenethyl]-2-indenylpyridine methoxy 3-methoxybenzoic acid

使4 - [4-苄氧基-1-[3-甲氧基-4 - [N，-（2-甲基苯基）脲 基]笨乙醯基]- 2 -咄咯啶甲氧基]-3 -甲氧苯甲酸酯（440毫 克，0.645 毫莫耳）及 5% Pd/C( 400 毫克）於 Ac0H:Et0H (1 : 1，v/v，10 0毫升）中之攪拌混合物在1大氣壓下氫化5 小時。將混合物過濾、以移除催化劑，並將遽液於真空中濃 縮。將殘留物於矽膠上利用CHC13 : EtOH(10 ·· 1，v/v)作為 洗提液進行層析，而得90毫克（24%)之4-[4 -經基-1-[3-曱 氧基-4-[Ν’ - (2-甲基苯基）脲基]苯乙醯基]-2 -吼咯啶甲 氧基]-3-甲氧苯甲酸乙酯的淡黃色油。（101) M-NMR (CDC13) 51· 39 (3Η，t，J = 7· 3 Hz)、2· 04-2· 37 (總計5H， m)、3· 44-4· 70 (16H， m 系列）、6. 63 (1H， s)、6·70-6·80 (2H，m)、6·84 (1H，d，J = 8.3 Hz)、 7.11 (1H，t，J二7.8 Hz)、7.20-7·24 (3H，m)、7.454-[4-Benzyloxy-1-[3-methoxy-4 - [N,-(2-methylphenyl)ureido]]ethidyl]-2-pyrrolidinylmethoxy Stirring mixture of 3-methoxybenzoate (440 mg, 0.645 mmol) and 5% Pd/C (400 mg) in Ac0H: Et0H (1:1, v/v, 100 mL) Hydrogenation was carried out for 5 hours at 1 atm. The mixture was filtered to remove the catalyst and the mash was concentrated in vacuo. The residue was chromatographed on a silica gel using CHC13: EtOH (10··1, v/v) as an eluent to give 90 mg (24%) of 4-[4-amino-l-[3- A pale yellow oil of ethyl methoxy-4-[Ν'-(2-methylphenyl)ureido]phenyridinyl]-2-pyridinylmethoxy]-3-methoxybenzoate. (101) M-NMR (CDC13) 51· 39 (3Η, t, J = 7· 3 Hz), 2·04-2· 37 (total 5H, m), 3· 44-4· 70 (16H, m Series), 6. 63 (1H, s), 6·70-6·80 (2H, m), 6.84 (1H, d, J = 8.3 Hz), 7.11 (1H, t, J 7.8 Hz) , 7.20-7·24 (3H, m), 7.45

89112968.ptd 第231頁 1283240 五、發明說明（227) (1H，d，J = 2.0 Ηζ)、7·59 (2H，dd，J = 8.3、2·0 Hz)、 8· 01 (1H， d， J=7·8 Hz)。 使4-[4 -羥基-1 - [3-曱氧基-4-[N’ -（2-甲基苯基）脲基] 笨乙醯基]-2 -吼咯啶曱氧基]-3-甲氧苯甲酸乙酯（90毫 克，0.152毫莫耳）於0.25N NaOH(5毫升，1.25毫莫耳）及 THF (5毫升）之攪拌混合物迴流加熱隔夜。將混合物倒入至 冰的1 N HC 1 ( 2 0 0毫升）中。利用吸濾收集沈澱物，並使其 自CHC13-MeOH-正己烧再結晶而得40毫克（47%)之43的無色 非晶形固體。 UMR (DMS0-d6) 6 1. 92-2· 1 1 (2H，m)、2· 24 (3H，s)、 3.3 卜 5·07 (14H，m 系列）、6·73 (1H，d， J = 8.3 Hz)、 6.84 (1H，s)、6·93 (1H，t，J = 7.8 Hz)、7·(Η-7·17 (3H, m)、7·44 (1H，s)、7.52 (1H，d, J = 8.8 Hz)、 7.79 (1H，d，J = 8.3 Hz)、7·99 (1H，d，J = 7.8 Hz)、 8.46 (1H，s)、8·55 (1H，s)、12.67 (1H, br s)。 實施例4 0 (2S，4R) -胺基-4-[4 -羥基-1 - [3-甲氧基-4- [Ν’-（2-甲基苯 基）脲基]笨基乙醯基]-2-吼咯啶基]甲氧苯曱酸89112968.ptd Page 231 1283240 V. INSTRUCTIONS (227) (1H, d, J = 2.0 Ηζ), 7·59 (2H, dd, J = 8.3, 2·0 Hz), 8· 01 (1H, d , J=7·8 Hz). 4-[4-Hydroxy-1 -[3-indolyl-4-[N'-(2-methylphenyl)ureido]]ethylidene]-2-pyridinyloxy]- Ethyl 3-methoxybenzoate (90 mg, 0.152 mmol) was stirred in EtOAc EtOAc EtOAc EtOAc EtOAc The mixture was poured into 1 N HC 1 (200 mL) of ice. The precipitate was collected by suction filtration and recrystallized from CHC13-MeOH-hexane to afford 40 mg (47%) of 43 as a colorless amorphous solid. UMR (DMS0-d6) 6 1. 92-2· 1 1 (2H, m), 2· 24 (3H, s), 3.3 Bu 5·07 (14H, m series), 6.73 (1H, d, J = 8.3 Hz), 6.84 (1H, s), 6.93 (1H, t, J = 7.8 Hz), 7·(Η-7·17 (3H, m), 7·44 (1H, s), 7.52 (1H,d, J = 8.8 Hz), 7.79 (1H,d,J = 8.3 Hz), 7·99 (1H,d,J = 7.8 Hz), 8.46 (1H, s), 8·55 (1H , s), 12.67 (1H, br s). Example 4 0 (2S,4R)-Amino-4-[4-hydroxy-1 -[3-methoxy-4-[Ν'-(2- Methylphenyl)ureido]pyridylethyl]-2-indolyl]methoxybenzoic acid

於（2S，4R)_4-爷氧基-1-(第三丁氧羰基）-2 -脯胺醇 (891毫克，2. 9毫莫耳）、4 -羥基-3 -硝基苯甲酸甲酯（572(2S,4R)_4-yloxy-1-(t-butoxycarbonyl)-2-indolamine (891 mg, 2.9 mmol), 4-hydroxy-3-nitrobenzoic acid Ester (572

89112968.ptd 第232頁 1283240 五、發明說明（228) ----- 毫克，2· 9毫莫耳）、及PPh3 ( 8 3 9毫克，3·2毫莫耳）溶於 THF(6毫升）之攪拌溶液中加入diaD(630毫升，3 2毫莫 耳），並使混合物迴流加熱隔夜。於移除溶劑後，使殘留 物於矽膠上利用正己烷：Et〇Ac(l:l)及甲笨：Et〇Ac (10 ·· 1，v/v)作為洗提液進行層析而得7〇〇毫克（5〇%)之 (^2S，4R)_4-[4-苄氧基一；[一（第三丁氧羰基）—2—σ比咯啶基]曱 氧基-3 -硝基苯曱酸曱酯的淡黃色油。 於（2^S，4R)-4-[4-爷氧基-1-(第三丁氧羰基）—2 —吡咯啶 基]甲氧基-3-硝基苯曱酸曱酯（681毫克，i 4毫莫耳）溶於 CH2C12(2毫升）之攪拌溶液中加入TFA(2毫升），並使所產生 之混合物攪拌2小時。於將反應混合物濃縮後，經由加入 飽和NaHC〇3使殘留物成為鹼性，並以CHCl3萃取。、將萃取液 以洗滌，於Mgs〇4上乾燥，並蒸發而得511毫克（95%)之 (2S，4R)-4-[4-爷氧基-2_吼咯啶基]甲氧基—3—硝基苯曱酸 甲酯的黃色油。 使3甲氧基4-[N -(2-甲基笨基）脲基]笨乙酸（4〇g毫 克，1.3¾莫耳）、（2S，4R) -4-（笮氧基-2_吼咯啶基）甲氧 基-3-硝基苯曱酸曱酯（5〇2毫克，13毫莫耳）、別以383毫 克，2毫莫耳）、及DMAP(159毫克，13毫莫耳）於㈣以“毫 升）中之心合物擾拌3天。將混合物倒入至1 n η C 1中，並利 用吸濾收集所產生之沈澱物。將殘留物溶解於CHC込中， 並於MgS〇4上乾燥。於移除溶劑後，將殘留物於矽膠上利 用CHC13 :Me〇H( 20 0:l，v/v)作為洗提液進行層析而得68〇 毫克（91%)之（2S，4R)-4-[4_ 窄氧基一1 一 [3一甲氧基一4—[N，一89112968.ptd Page 232 1283240 V. INSTRUCTIONS (228) ----- mg, 2·9 mmoles, and PPh3 (839%, 3. 2 mmol) dissolved in THF (6 ml) diaD (630 ml, 32 mmol) was added to the stirred solution and the mixture was reflux heated overnight. After removing the solvent, the residue was chromatographed on a silica gel using n-hexane: Et 〇Ac (l:l) and succinimide: Et 〇Ac (10 ··1, v/v) as an eluent. 7〇〇mg (5〇%) of (^2S,4R)_4-[4-benzyloxy-;[-(t-butoxycarbonyl)-2-pyrrolidyl]decyloxy-3 A pale yellow oil of decyl nitrobenzoate. Oxime (2^S,4R)-4-[4-yloxy-1-(t-butoxycarbonyl)-2-pyrrolidinyl]methoxy-3-nitrobenzoate (681 mg) To a stirred solution of CH.sub.2Cl.sub.2 (2 mL), EtOAc (2 mL). After concentrating the reaction mixture, the residue was made basic with saturated NaHC.sub.3 and extracted with CHCl3. The extract was washed, dried over Mgs 4 and evaporated to give 511 mg (95%) of (2S,4R)-4-[4-yloxy-2-oxazolidinyl]methoxy a yellow oil of methyl 3-nitrobenzoate. 3 methoxy 4-[N-(2-methylphenyl)ureido] acetoacetic acid (4 〇g mg, 1.33⁄4 mol), (2S,4R) -4-(decyloxy-2_ Ethyl pyridyl) methoxy-3-nitrobenzoate (5 〇 2 mg, 13 mmol), 383 mg, 2 mmol, and DMAP (159 mg, 13 mmol) The ear was spoiled for 3 days in (4) in a "ml". The mixture was poured into 1 n η C 1 and the resulting precipitate was collected by suction filtration. The residue was dissolved in CHC. And drying on MgS〇4. After removing the solvent, the residue was chromatographed on a silica gel using CHC13:Me〇H (20:1, v/v) as an eluent to give 68 mg (91). %)(2S,4R)-4-[4_Narrow oxy-l-[3-methoxy-4-[N, one

89112968.ptd 第233頁 1283240 五、發明說明（229) —- (2-甲基苯基）脲基]苯基乙醯基]一2 一吼咯啶基]甲氧基〜3一 硝基苯甲酸甲酯的白色非晶形固體。 使（2S，4R)-4-[4-芊氧基—1 一[3一曱氧基一4一[N，-(2—甲基 苯基）脲基]笨基乙醯基]—2 -π比咯啶基]甲氧基一 3 —硝基笨 甲酸甲酯（ 6 76毫克，〇·99毫莫耳）及5% Pd_C(l克）於Et0H: AcOH(l : 1，v/v，30毫升）中之溶液在！大氣壓下氫化6小 時。將混合物過濾，及將濾液蒸發而得一油，經由加入飽 和NaHC〇3而使其成為鹼性。以Et〇Ac萃取混合物。將萃取 液以鹽水洗滌，於MgS〇4上乾燥，並蒸發。使殘留物自作 為洗提液之CHClfEtOH -正己统再結晶，而得1 20毫克 (2 2%)之44的淡黃色結晶粉末。MS(FAB) m/z 549 (MH1)。 實施例41 4-[ [4-氟-1-[ 3-甲氧基一4-[N，—（2-甲基笨基）脲基]苯基乙 醯基]-2-吼咯啶基]甲氧基]一3一甲氧苯甲酸89112968.ptd Page 233 1283240 V. INSTRUCTIONS (229) —(2-Methylphenyl)ureido]phenylethenyl]-2-indolyl]methoxy~3-nitrobenzene A white amorphous solid of methyl formate. (2S,4R)-4-[4-decyloxy-1][3-monooxyl-4-yl[N,-(2-methylphenyl)ureido]]phenylamino]- 2 -πr-pyridinyl]methoxy-methyl 3-nitrobenzoate (6 76 mg, 〇·99 mmol) and 5% Pd_C (1 g) at Et0H: AcOH (l: 1, v/ The solution in v, 30 ml) is in! Hydrogenation at atmospheric pressure for 6 hours. The mixture was filtered, and the filtrate was evaporated to give an oil which was made basic by adding saturated NaHC. The mixture was extracted with Et〇Ac. The extract was washed with brine, dried over MgSO 4 and evaporated. The residue was recrystallized from CHClfEtOH-n-hexane as an eluent to give 1 20 mg (2 2%) of 44 pale yellow crystalline powder. MS (FAB) m/z 549 (MH1). Example 41 4-[[4-Fluoro-1-[3-methoxy-l4-[N,-(2-methylphenyl)ureido]phenylethenyl]-2-indenylpyridyl Methoxy]-1,3-methoxybenzoic acid

使4-[4-芊氧基-丨气第三丁氧羰基）-2—咄咯啶基]甲氧基 - 3-甲氧苯甲酸甲酯（1189克，2·449毫莫耳）及5°/〇 Pd-C ( 240毫克）於Et〇H( 1 〇毫升）中之攪拌混合物在室溫下氫化 隔夜。將混合物過濾以移除催化劑，及將濾液於真空中濃 縮而得4-[1-(第三丁氧羰基）_4-羥基-2 -咄咯啶基]曱氧基4-[4-Methoxy-helium tributoxycarbonyl)-2-pyridinyl]methoxy-3-methoxybenzoate (1189 g, 2.449 mmol) and The stirred mixture of 5 ° / 〇 Pd-C (240 mg) in EtOAc (1 mL) was hydrogenated overnight at room temperature. The mixture was filtered to remove the catalyst, and the filtrate was concentrated in vacuo to give 4-[1-(t-butoxycarbonyl)-4-hydroxy-2-pyridinyl]nonyloxy.

89112968.ptd 第234頁 128324089112968.ptd Page 234 1283240

五、發明說明（230) -3-甲氧苯甲酸乙酯（735· 3毫克，76%)的淡黃色油。於 DAST(0.491毫升，3·718毫莫耳）溶於Ch2C12(/7 4毫升）之冷 的（-78 t)攪拌溶液中逐滴加入此化合物溶於(2毫 升）之溶液，並使所產生之混合物攪拌隔夜。利2用2混 合物停止反應’並以CHC13萃取。將萃取液以鹽水 並於NaJO4上乾燥。將溶劑於減壓下移除，及將物於 矽膠上利用正己烷—Et0Ac(3:l，v/v) ^ ^ ^ τ ο π 一 + j 1卞馮洗提液進行層析 而付418.7耄克（57%)之4-[1-(第三丁氧羰基）_“ 吡 咯啶基]甲氧基-3-甲氧苯甲酸乙酯的油。 ％ iH-NMR ( 400 MHz’ CDC13) 51.39 (t，j = 7 3 Hz 3H)、 1.49 (s，9H)、2.16 (br m，1H)、2.58 (dd，； = 15 6、 19.0 Hz，1H)、3.60-3.75 (m，2H)、3.91 (s，3H)、 3.97 (t’ J = 9.3 Hz, 1H)、4.35 (q，j = 7 3 Hz，2H卜 4.33-4.53 (m，2H)、5. 25 (d，J = 52. 7Hz，1H)、7 04 (dd，J = 7.8、56·2 Hz，1H)、7.55 (s，1H)、7 65 (br s， 1H) ; MS(FAB) m/z 398 (MH1) 〇 在0 °C下於4-[ 1-(第三丁氧羰基）〜4—氟-2 —咄咯啶基]甲 氧基-3-甲氧苯甲酸乙酯（482· 2毫克，丨.2]^毫莫耳）溶於 Ci^Cl/lO· 0毫升）之攪拌溶液中加入τι?α(1· 9毫升），並使 混合物在室溫下搜拌2小時。將溶劑於減壓下移除，及經 由加入IN NaOH使殘留物成為鹼性，並以CHCI3萃取。將萃 取液以鹽水洗務，於NaJO4上乾燥，並於減壓下濃縮而^ 348.7毫克（97 %)之4 -（4-氟-2_吼咯啶基）甲氧基一3—甲氧笨 甲酸乙酯的棕色油。V. INSTRUCTIONS (230) Ethyl -3-methoxybenzoate (735·3 mg, 76%) of light yellow oil. A solution of this compound dissolved in (2 ml) was added dropwise to a cold (-78 t) stirred solution of D.sub.2 (0.491 ml, 3.718 mmol) dissolved in Ch2C12 (/7 4 ml). The resulting mixture was stirred overnight. The mixture was stopped with a mixture of 2 and extracted with CHC13. The extract was dried over NaH 4 with brine. The solvent was removed under reduced pressure, and the material was chromatographed on a silica gel using n-hexane-Et0Ac (3:1, v/v) ^^^ τ ο π +1 + j 1 卞 洗 extract to afford 418.7 An oil of 4-[1-(t-butoxycarbonyl)-"pyrrolidinyl]methoxy-3-methoxybenzoic acid ethyl ester of gram (57%). % iH-NMR (400 MHz' CDC13) 51.39 (t,j = 7 3 Hz 3H), 1.49 (s,9H), 2.16 (br m,1H), 2.58 (dd,; = 15 6 , 19.0 Hz, 1H), 3.60-3.75 (m, 2H) , 3.91 (s, 3H), 3.97 (t' J = 9.3 Hz, 1H), 4.35 (q, j = 7 3 Hz, 2H, 4.33-4.53 (m, 2H), 5. 25 (d, J = 52 7Hz, 1H), 7 04 (dd, J = 7.8, 56·2 Hz, 1H), 7.55 (s, 1H), 7 65 (br s, 1H); MS(FAB) m/z 398 (MH1) Ethyl 4-(1-(t-butoxycarbonyl)~4-fluoro-2-oxaridinyl]methoxy-3-methoxybenzoate (482·2 mg, 丨 at 0 °C .2]^mmol) dissolved in a stirred solution of Ci^Cl/lO·0 ml), add τι?α (1.9 ml), and mix the mixture for 2 hours at room temperature. Remove by pressing, and make the residue alkaline by adding IN NaOH and extract with CHCI3 The extract was washed with brine, dried over NaJO4 and concentrated under reduced pressure to give &lt;RTI ID=0.0&gt;&gt; A brown oil of ethyl oxyformate.

1283240 五、發明說明（231) ' -- UMR (400 MHz，CDCl3)(n.39 (t，J = 6.8 Hz，3H)、 1.97 (ddt， J:1.5 、5.4 、14·7 Hz, 1H) 、2·27 (dddd， J二5·9、8·8、14·7、32·7 Hz，1H)、3· 02 (ddd，J = 3· 9、 13.1 、35.2 Hz, 1H) 、3·36 (dd， J:12.7 、21·5 Hz，· 1H) 、3.65 (m， 1H) 、3·90 (s， 3H) 、4.〇9 (m， 1H)’、 4.35 (q， J=6.8 Hz， 2H) 、5·17 、5·31 (各br m， 1H)、 6.90 (d， J=8.3 Hz, 1H) 、7.75 (d， J=2.〇 Hz， 1H)、 7.65 (dd， J二2.0 、8·3 Hz，lH); MS(FAB) m/z 298 (MH1) 〇 使3-甲氧基-4-[N，-（2-甲基笨基）脲基]笨乙酸五氟苯 酯（404.0毫克，0.840毫莫耳）、4一（4—氟—2—吡咯啶基）甲 氧基-3-甲氧苯甲酸乙酯（25〇· 〇毫克，〇· 84〇毫莫耳^、1283240 V. INSTRUCTIONS (231) ' -- UMR (400 MHz, CDCl3) (n.39 (t, J = 6.8 Hz, 3H), 1.97 (ddt, J: 1.5, 5.4, 14·7 Hz, 1H) , 2·27 (dddd, J 2·5·9, 8·8, 14·7, 32·7 Hz, 1H), 3·02 (ddd, J = 3·9, 13.1, 35.2 Hz, 1H), 3 · 36 (dd, J: 12.7, 21·5 Hz, · 1H), 3.65 (m, 1H), 3·90 (s, 3H), 4.〇9 (m, 1H)', 4.35 (q, J =6.8 Hz, 2H), 5·17, 5.31 (each br m, 1H), 6.90 (d, J=8.3 Hz, 1H), 7.75 (d, J=2.〇Hz, 1H), 7.65 ( Dd, J 2 2.0, 8·3 Hz, lH); MS(FAB) m/z 298 (MH1) 〇 3-methoxy-4-[N,-(2-methylphenyl)ureido] Pentaacetic acid pentafluorophenyl ester (404.0 mg, 0.840 mmol), 4-(4-fluoro-2-pyrrolidinyl)methoxy-3-methoxybenzoic acid ethyl ester (25 〇·〇 mg, 〇· 84〇毫耳^,

Et3N (141微升，i· 0 0 9毫莫耳）於DMF(4· 〇毫升）中之混合 物在室溫y攪拌1小時。將混合物以Et〇Ac稀釋，以水\ 口鹽 水洗滌，並於NaJO4上乾燥。將溶劑於減壓下移除，將&quot; 殘留物於矽膠上利用正己烷·· Et〇Ac(1 :3，v/ =細毫克U.y.)之4-[[4_氣+[3_甲氧基+[;:(2析 ^ ^苯基）脲基]苯基乙醯基卜2 —咄咯啶基]甲氧基]一3 —甲 乳本甲酸乙酯的黃色油。於此化合物溶於丁 h Μ:毫升)之授拌溶液中加入⑽(6〇4毫*，=2)〇及 =莫耳），亚使混合物在室溫下攪拌隔夜，及在5〇它下攪 於將混合物以CHCl3稀釋。將萃取液以鹽水洗務，並 固上：t乾燥。將溶劑於減M下移除’並使所得之粗製 豆t Ac-chci3-正己烷再結晶，而得294· 8毫克（62%) 第236頁 89112968.ptd 1283240 五、發明說明（232) 之4 5的白色結晶粉末。 IR (KBr) 2958 、2937 、1687 、1601 、1531 、1454 、 1419、1267、1214、1029 /公分；iH-NMR (400 MHz, DMSO-d6) (51.86-2.09 (m，5H)、2.06 (s，3H)、2.25 (s， 3H) 、3·47-3·67 (m， 6H) 、3·76 (s， 3H)、 4·05-4.12 (m， 2H) 、4·30-4·31 (m， 1H) 、6·51 (s, 1H) 、6·55 (s， 1H) 、6.73-6.95 (m， 2H) 、7·11-7·17 (m，2Η)、7·64 (s，1Η)、7·79 (d，J二7.8 Hz, 1Η)、 7·99 (d，J = 7.8 Hz，1H)、8·47 (s，1H)、8·55 (s， 1H)·，MS(FAB) m/z 56 6 (MH1); C3GH32FN3 07 ·1/2Η20 之分析 計算值：C，62·71 ; H，5·79; F， 3·31 ; N，7.31。實測 值：C，63· 13 ; Η，6· 17 ; F，3· 12 ; Ν，7· 04。 、 實施例42 3-乙醯胺基-4-[1-[ 3-甲氧基-4 -[Ν，-（2-甲基笨基）脲基] 苯基乙醯基]-2 - °比略咬甲氧基]苯甲酸A mixture of Et3N (141 μl, i·0 0 9 mmol) in DMF (4 mL) was stirred at room temperature for 1 hour. The mixture was diluted with Et 〇Ac, washed with water / brine and dried over Na.sub.4. The solvent was removed under reduced pressure, and the residue was applied to the tannin using n-hexane·· Et〇Ac (1:3, v/ = fine milligrams of Uy) 4-[[4_气+[3_甲甲A yellow oil of ethyl oxy + [;: (2) phenyl) ureido] phenyl ethenyl 2 - oxaridinyl] methoxy] 3- methoxyethyl formate. Add (10) (6〇4m*, =2) 〇 and = mol) to the compounding solution of this compound in butyl hydrazine: ml), stir the mixture at room temperature overnight, and at 5 〇 it Stirring was carried out to dilute the mixture with CHCl3. The extract was washed with brine and fixed: t dry. The solvent was removed under minus M' and the resulting crude bean t Ac-chci 3-n-hexane was recrystallized to give 294. 8 mg (62%). 236 891 891 968. ptd 1283240 5. Invention (232) 4 5 white crystalline powder. IR (KBr) 2958, 2937, 1687, 1601, 1531, 1454, 1419, 1267, 1214, 1029 / cm; iH-NMR (400 MHz, DMSO-d6) (51.86-2.09 (m, 5H), 2.06 (s , 3H), 2.25 (s, 3H), 3·47-3·67 (m, 6H), 3·76 (s, 3H), 4·05-4.12 (m, 2H), 4·30-4· 31 (m, 1H), 6·51 (s, 1H), 6·55 (s, 1H), 6.73-6.95 (m, 2H), 7·11-7·17 (m, 2Η), 7·64 (s, 1Η), 7.79 (d, J two 7.8 Hz, 1Η), 7·99 (d, J = 7.8 Hz, 1H), 8·47 (s, 1H), 8·55 (s, 1H) )·, MS(FAB) m/z 56 6 (MH1); C3GH32FN3 07 · 1/2Η20 Analysis calculated: C, 62·71 ; H, 5·79; F, 3·31 ; N, 7.31. Value: C, 63·13; Η, 6·17; F, 3·12; Ν, 7·04., Example 42 3-Ethylamino-4-[1-[3-methoxy-4 -[Ν,-(2-methylphenyl)ureido]phenylphenyl]yl]-2 - ° ratio slightly methoxy]benzoic acid

-COOH 46 苯ί乙Γ 4，，—(2_甲基笨基)脲基] ί 甲氧基]苯甲酸（130毫H 244毫 莫耳）及DMAP(2.9毫克，0·0244毫莫耳）溶於吡 :醋酸肝(5毫升)之溶液在室溫下攪拌2小時。將混 一空中蒸發（過量的醋酸酐與甲苯共沸移除）。將 留物中’並以CHC13萃取。將萃取液於'叫上乾燥，〇並^-COOH 46 phenyl oxime 4,, -(2_methylphenyl)ureido] methoxy benzoic acid (130 mM H 244 mmol) and DMAP (2.9 mg, 0.0244 mmol) A solution of pyridinium acetate (5 ml) was stirred at room temperature for 2 hours. The mixture was evaporated in the air (excess acetic anhydride was removed azeotropically with toluene). The residue was taken and extracted with CHC13. Put the extract on the 'dry, 〇 and ^

1283240 五、發明說明（233) 真空中蒸發。將殘留物於矽膠上利用MeOH : CHC12 (1 : 15 至1 : 1，v/v)作為洗提液進行層析而得29毫克（21%)之46的 白色結晶物質。 UMR (DMSO-d6)(n.80-2.30 (m，4H)、2.04 (s，3H)、 2.26 (s， 3H) 、3·33 (s， 3H) 、3·4〇-4.80 (m， 7H)、 6.59 (s，1H)、6·74 (d，J = Hz，1H)、6·79 (d， J二8·8 Hz，1H)、7·07-7·57 (m，6H)、7·75 (d，J二8.8 Hz, 1H)、8·07 (d，J:8.3 Hz，1H)、8.41 及8·96 (各s， 各1H) ; MS(FAB) m/z 575 (MH1 )。 實施例43 3-氯-2-[ [1-[ 3-曱氧基-4-[Ν’ - (2-曱基苯基）脲基]苯乙醯 基]-2 -咄咯啶基]甲氧基]咄啶-5 -羧酸1283240 V. INSTRUCTIONS (233) Evaporation in a vacuum. The residue was chromatographed on silica gel using MeOH: CHC12 (1: 15 to 1:1, v/v) to afford 29 mg (21%) of white crystals. UMR (DMSO-d6) (n.80-2.30 (m, 4H), 2.04 (s, 3H), 2.26 (s, 3H), 3·33 (s, 3H), 3·4〇-4.80 (m, 7H), 6.59 (s, 1H), 6.74 (d, J = Hz, 1H), 6.79 (d, J 2·8 Hz, 1H), 7·07-7·57 (m, 6H) ), 7·75 (d, J 8.8 Hz, 1H), 8·07 (d, J: 8.3 Hz, 1H), 8.41 and 8.96 (each s, each 1H); MS (FAB) m/z 575 (MH1). Example 43 3-Chloro-2-[ [1-[ 3-methoxy-4-[Ν' - (2-mercaptophenyl)ureido]phenethyl]-2 Ethrolidinyl]methoxy]acridin-5-carboxylic acid

在0 °C下於3 -氯-2 -羥基咄啶-5 -羧酸（1克，5· 762毫莫 耳）溶於苯（16毫升）及Me0H(4毫升）之攪拌溶液中逐滴加入 丁皿8(]〇2(3.17毫升，6.338毫莫耳），並使所產生之混合物 在室溫下攪拌隔夜。經由加入AcOH使反應混合物停止反 應，及使混合物蒸發掉。使殘留物懸浮於水中，並收集沈 澱物。將粗製固體以Et20洗滌，並於減壓下乾燥而得 728· 1毫克（67%)之3 -氯-2-經基吼咬-5 -叛酸甲g旨的白色結 晶粉末。 IR (KBr) 1655、1282、1245、769/公分；NMR (400Distilled in a stirred solution of 3-chloro-2-hydroxyacridin-5-carboxylic acid (1 g, 5·762 mmol) in benzene (16 mL) and Me0H (4 mL) at 0 °C A dish 8 (] 〇 2 (3.17 ml, 6.338 mmol) was added, and the resulting mixture was stirred overnight at room temperature. The reaction mixture was quenched by the addition of AcOH and the mixture was evaporated. In the water, the precipitate was collected, and the crude solid was washed with Et20 and dried under reduced pressure to give 728·1 mg (67%) of 3-chloro-2-substrate-5- White crystalline powder. IR (KBr) 1655, 1282, 1245, 769 / cm; NMR (400

89112968.ptd 第238頁 1283240 五、發明說明（234) MHz，DMS0-d6) (53.79 (s，3H)、8·01 (s，1H)、8·〇6 (s, 1H); MS(FAB) m/z 188 (MH1); C7H6C1N03 之分析計算 值：C，44· 82 ; H，3· 22 ; Cl， 18. 90 ; N，7· 47。實測 值·· C, 44· 74 ; Η，3. 22 ; Cl，19· 00 ; Ν，7· 34。 在室溫下於3 -氯-2 -羥基吼啶-5 -羧酸曱酯（ 3 0 0毫克， 1.599毫莫耳）、Ν-第三丁氧羰基脯胺醇（321.9毫克， 1· 5 99毫莫耳）、及Ph3P( 5 0 3毫克，1· 919毫莫耳）溶於 丁1^(3毫升）之攪拌溶液中緩慢加入〇1八0( 3 78微升，1.919 毫莫耳），及使混合物在70 °C下攪拌1 3小時。將混合物濃 縮，及將殘留物於矽膠上利用正己烷-EtOAc (3 : 1，v/v) 作為洗提液進行層析而得235. 6毫克（40%)之3-氯-2-[ [ 1 -（弟二丁氧魏基）一 2 -吼洛咬基]甲氧基]吼α定一 5 -缓酸曱酉旨 的淡黃色油。 M-NMR ( 40 0 MHz, CDC13) 51 . 46 (s，9Η)、1· 87 (m， 1H) 、2·05 (br s， 3H) 、3·43 (br s， 2H) 、3·92 (s， 3H)、4·17、4·26 (各 br s，1H)、4·45-4·51 (m，1H)、 4.50 (s, 1H) ^8.21 (s, 1H) &gt;8.67 (d, J-2.0 Hz, 1H); MS(FAB) m/z 371 (MH1) o 在0 C下於3 -氣-2-[[l-(第三丁氧魏基）-2 -吼π各σ定基]甲 氧基]吼啶-5 -羧酸曱酯（ 23 5· 6毫克，0·. 6 3 5毫莫耳）溶於 CH2C12(5.0毫升）之攪拌溶液中加入TFA(1〇毫升），及使反 應混合物在室溫下攪拌2小時。將溶劑於減壓下移除。麵 由加入IN NaOH使殘留物成為鹼性，並以CHC“萃取。將^ 取液於NaJO4上乾燥，於減壓下濃縮而得172·3毫克89112968.ptd Page 238 1283240 V. INSTRUCTIONS (234) MHz, DMS0-d6) (53.79 (s, 3H), 8·01 (s, 1H), 8·〇6 (s, 1H); MS (FAB m/z 188 (MH1); Analytical calculated value for C7H6C1N03: C, 44· 82 ; H, 3 · 22 ; Cl, 18. 90 ; N, 7 · 47. Measured value · · C, 44· 74 ; , 3.22 ; Cl, 19· 00 ; Ν, 7· 34. at room temperature in 3-chloro-2-hydroxyacridin-5-carboxylate (300 mg, 1.599 mmol), Ν-T-butoxycarbonyl decylamine (321.9 mg, 1.999 mmol), and Ph3P (503 mg, 1.919 mmol) dissolved in butyl 1 (3 mL) 〇1 80 (3 78 μl, 1.919 mmol) was slowly added, and the mixture was stirred at 70 ° C for 13 hours. The mixture was concentrated, and the residue was applied to silica gel using n-hexane-EtOAc (3) :1, v/v) Chromatography as eluent to give 235. 6 mg (40%) of 3-chloro-2-[[1 -(di-di-butoxy-)- Methoxy] 吼α is a pale yellow oil of 5-acidic acid. M-NMR ( 40 0 MHz, CDC13) 51 . 46 (s, 9 Η), 1· 87 (m, 1H), 2 ·05 (br s, 3H), 3 43 (br s, 2H) , 3·92 (s, 3H), 4·17, 4·26 (each br s, 1H), 4·45-4·51 (m, 1H), 4.50 (s, 1H) ^8.21 (s, 1H) &gt;8.67 (d, J-2.0 Hz, 1H); MS(FAB) m/z 371 (MH1) o at 0 C at 3 - gas-2-[[l-( Third butyl oxy-yl)-2 - 吼 π σ determinate] methoxy] acridine-5-carboxylate oxime ester (23 5 · 6 mg, 0·. 6 3 5 mmol) dissolved in CH 2 C 12 ( To the stirred solution of 5.0 ml) was added TFA (1 mL), and the mixture was stirred at room temperature for 2 hr. The solvent was removed under reduced pressure, and the residue was made alkaline by the addition of IN NaOH. CHC "extraction. The liquid was dried on NaJO4 and concentrated under reduced pressure to give 172.

12832401283240

之3-氯-2-[ (2-吡咯啶基）甲氧基]吡啶羧酸甲醋的 色油。 、’貝 4-NMR (400 MHz, CDC14) 5 1.5 5- 1.6 3 (m，1I〇、l 76 — 1.99 (m， 3H) 、2·93-2·99 (m， 1H) 、3.〇2一Log (m 1H) 、3·57-3·62 (m， 1H) 、3.92 (s， 3H) 、4 33 (dd J = 7.3、10·? Hz, 1H)、4·44 (dd，J = 4.4、1〇·7 Hz， 1H) 、8·21 (d， J=2.0 Hz， 1H) 、8·67 (d， J=2 0 1H) ; MS(FAB) m/z 271(MH1)。 ’ · z’ 使3-甲氧基-4-[N，-（2-曱基苯基）脲基]苯乙酸五氟笨酽A color oil of 3-chloro-2-[(2-pyrrolidinyl)methoxy]pyridinecarboxylic acid methyl ketone. , 'Bei 4-NMR (400 MHz, CDC14) 5 1.5 5- 1.6 3 (m, 1I〇, l 76 — 1.99 (m, 3H), 2·93-2·99 (m, 1H), 3.〇 2-Log (m 1H), 3·57-3·62 (m, 1H), 3.92 (s, 3H), 4 33 (dd J = 7.3, 10·? Hz, 1H), 4·44 (dd, J = 4.4, 1〇·7 Hz, 1H), 8·21 (d, J=2.0 Hz, 1H), 8·67 (d, J=2 0 1H); MS(FAB) m/z 271(MH1 'z' makes 3-methoxy-4-[N,-(2-mercaptophenyl)ureido]phenylacetic acid pentafluoro alum

(317.0毫克，0.6 6 0毫莫耳）、3-氯-2-[(2—吡咯啶基）甲^ 基]°比啶-5 -羧酸甲酯（172.0毫克，0.635毫莫耳）、Et3N (105微升，〇· 75 6毫莫耳）於DMF( 2· 0毫升）中之混合物3在室 溫下攪拌1小時。將混合物以E10 A c稀釋，以鹽水洗條，並 於NaJO4上乾燥。將溶劑於減壓下移除而得3—氯—— [3-甲氧基-4 - [N -(2-曱基苯基）脲基]苯乙醯基]一2 一 π比0各 啶基]甲氧基]咄啶-5 -羧酸曱酯的棕色油。於此化合物溶 於THF(6. 0毫升）及Η20(2· 0毫升）之攪拌溶液中加入 Li0Η(45· 3毫克，1 · 89毫莫耳），並使反應混合物在室溫下 攪拌5小時。將混合物以正己烷稀釋，並以in-NaOH萃取。 將水層經由加入IN HC1而酸化，並以CHC13萃取。將萃取 液以鹽水洗滌，於Na2S04上乾燥。將溶劑於減壓下移除， 並使所得之粗製固體自正己烷-EtOAc-EtOH再結晶，而得 242. 2毫克（70%)之47的橙色結晶粉末。 熔點 1 22- 1 25 °C ; IR (KBr) 3354、1 70 9、1 5 93、1 535、(317.0 mg, 0.660 mmol), 3-chloro-2-[(2-pyrrolidinyl)methyl]]pyridyl-5-carboxylate (172.0 mg, 0.635 mmol), The mixture 3 of Et3N (105 μL, 〇·75 6 mmol) in DMF (2.0 mL) was stirred at room temperature for 1 hour. The mixture was diluted with E10 Ac, washed with brine and dried over Na.sub.4. The solvent is removed under reduced pressure to give 3-chloro-[3-methoxy-4-[N-(2-mercaptophenyl)ureido]phenethyl]- 2 - π ratio A brown oil of decyl]methoxy]acridin-5-carboxylate. To a stirred solution of this compound in THF (6.0 mL) and EtOAc (20 mL), EtOAc (45············ hour. The mixture was diluted with n-hexane and extracted with in-NaOH. The aqueous layer was acidified by the addition of IN HCl and extracted with CH. The extract was washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the obtained crude solid was crystallised from hexane-EtOAc-EtOAc (EtOAc) Melting point 1 22- 1 25 °C; IR (KBr) 3354, 1 70 9, 1 5 93, 1 535,

89112968.ptd 第240頁 128324089112968.ptd Page 240 1283240

1 4 54、1 2 5 7 / 公分；ih-NMR ( 4 0 0 MHz, DMSO-d6) 5 1.67-2.03 (m， 4H) 、2·50 (s, 3H) 、3.33-3.42 (m， 1H)、3·52 (m，2H)、3·58 (d，J = 4.4 Hz, 1H)、3·83 (s，3H)、4·27-4·31 (m，2H)、4·42-4·47 (m，1H)、 6·73 (d， J=7.8 Hz， 1H) 、6·87-6·95 (m， 3H) 、7.1i、 7.17 (m，2H)、7·79 (d，J = 8.3 Hz, 1H)、7.99 (d， J = 8.3 Hz，1H)、8·14 (dd，J二2·0、8·8 Hz，1H)、8.46 (s， 1H) 、8.56 (s， 1H) 、8.69 (d， J=2.0 Hz， 1H)、 13. 06 (br s, 1H) ； MS(FAB) m/z 553 (MH1) ； C28H29ClN 〇 之分析計算值：C，60· 81 ; H，5· 29 ; N，10. 31。實測 4 6 值：C，60· 98 ; H，5· 50 ; N，9· 46。 實施例44 2- [[1 - [4-[Ν’-(2-氟苯基）脲基]-3-曱氧苯乙醯基]-咯啶基]曱氧基]咣啶-5-羧酸 在0 °C下於6 -羥基菸鹼酸（2克，14· 38毫莫耳）溶於笨（32 毫升）及MeOH(8毫升）之攪拌溶液中逐滴加入TMSCHN2(i. 97 毫升，3· 953毫莫耳），並使所產生之混合物在室溫下授掉 2小時。經由加入AcOH使混合物停止反應，及使混合物於 真空中濃縮。使殘留物懸浮於水中，並收集固體。將粗製 固體以E10洗滌，並於真空中乾燥而得1 · 5 6 6克（7 1 %)之2 -羥基毗啶-5 -羧酸甲酯的淡棕色結晶粉末。1 4 54, 1 2 5 7 / cm; ih-NMR (400 MHz, DMSO-d6) 5 1.67-2.03 (m, 4H), 2·50 (s, 3H), 3.33-3.42 (m, 1H ), 3·52 (m, 2H), 3·58 (d, J = 4.4 Hz, 1H), 3·83 (s, 3H), 4·27-4·31 (m, 2H), 4.42 -4·47 (m,1H), 6.73 (d, J=7.8 Hz, 1H), 6.87-6·95 (m, 3H), 7.1i, 7.17 (m, 2H), 7.79 (d, J = 8.3 Hz, 1H), 7.99 (d, J = 8.3 Hz, 1H), 8·14 (dd, J 2·0, 8·8 Hz, 1H), 8.46 (s, 1H), 8.56 (s, 1H), 8.69 (d, J=2.0 Hz, 1H), 13. 06 (br s, 1H) ; MS(FAB) m/z 553 (MH1) ; C28H29ClN 〇 Analytical calculated value: C, 60· 81 ; H, 5· 29 ; N, 10. 31. Found 4 6 values: C, 60 · 98 ; H, 5 · 50 ; N, 9 · 46. Example 44 2- [[1 - [4-[Ν'-(2-Fluorophenyl)ureido]-3-indolylphenyridinyl]-pyridinyl]nonyloxy]acridin-5- The carboxylic acid was added dropwise to TMSCHN2 (i. 97) in a stirred solution of 6-hydroxynicotinic acid (2 g, 14.38 mmol) in EtOAc (32 mL) and MeOH (8 mL). ML, 3·953 mmoles, and the resulting mixture was allowed to stand at room temperature for 2 hours. The mixture was quenched by the addition of AcOH and the mixture was concentrated in vacuo. The residue was suspended in water and the solid was collected. The crude solid was washed with E10 and dried in vacuo to give a pale brown crystalline powder of &lt;RTIgt;&lt;/RTI&gt;

IIII

II

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1283240 五、發明說明（238) 發而得1 4 6 · 2毫克（9 0 % )之2 - ( 2 -咄咯啶基）甲氧基咄咬—5 一 鲮酸甲酯的油。 ^-NMR (40 0 MHz, CDC13) 5 1 . 49- 1. 58 (m, 1H)M.72-2 · 1 8 (m，3 H)、2 · 9 2 - 3 · 0 5 (m, 2 H )、3 · 5 0 - 3 · 5 7 ( m， 1H) 、3.91 (s， 3H) 、4.23 (dd， J:8.〇 、1〇·7 Hz, 1H)、 4.38 (dd， J=4.4 、10.3 Hz， 1H) 、6.78 (d， J=8.8 Hz, 1H)、8·15 (dd，J = 2.4、8.8 Hz, 1H)、8.80 (d，J二2.41283240 V. INSTRUCTIONS INSTRUCTION (238) An oil of 1 4 6 · 2 mg (90%) of 2 - ( 2 - oxaridinyl ) methoxy acetonate - 5 - methyl decanoate was obtained. ^-NMR (40 0 MHz, CDC13) 5 1 . 49- 1. 58 (m, 1H) M.72-2 · 1 8 (m, 3 H), 2 · 9 2 - 3 · 0 5 (m, 2 H ), 3 · 5 0 - 3 · 5 7 ( m, 1H), 3.91 (s, 3H), 4.23 (dd, J:8.〇, 1〇·7 Hz, 1H), 4.38 (dd, J =4.4, 10.3 Hz, 1H), 6.78 (d, J=8.8 Hz, 1H), 8·15 (dd, J = 2.4, 8.8 Hz, 1H), 8.80 (d, J 2.4)

Hz，1H); MS(FAB) m/z 237 (MH1)。 使4-[N -(2-氟苯基）脲基]—3—曱氧基苯乙酸五氟苯酯 (314.8毫克，0.650宅莫耳）、2-[(2-吼略π定基）曱氧基]σ比 咬-5-叛酸曱酯（146. 2毫克’ 〇· 619毫莫耳）、Et3N(103微 升，〇· 743毫莫耳）於DMFU. 5毫升）中之混合物在室溫下授 拌1小日^·'。將此合物以E t2 0稀釋，以鹽水洗務，並於n a2 s 〇4 上乾燥。將溶劑於減壓下移除而得2-[[卜[4-[N，-（2-氟笨 基）脲基]-3-甲氧苯乙醯基]—2-咄咯啶基]曱氧基]吡啶一5一 羧酸甲酯的粗製淡黃色油。 於此化合物溶於THF(6. 0毫升）及1120(2· 0毫升）之攪拌溶 液中加入LiOH(44· 5毫克，1· 85 7毫莫耳），並使反應混合 物在室溫下攪拌1 7小時。將混合物以正己烷稀釋，並經由 加入IN NaOH而成為鹼性。將水層藉由1N HC1酸化，並以 CHCI3萃取。將萃取液以鹽水洗滌，並於Na2S〇4上乾燥。將 溶劑於減壓下移除，並使所得之粗製固體自正己烷—Et〇Ac -E10 Η再結晶’而得2 〇 2 · 5毫克（6 3 % )之4 8的白色結晶粉 末0Hz, 1H); MS (FAB) m/z 237 (MH1). 4-[N-(2-Fluorophenyl)ureido]-3-methoxyphenylacetic acid pentafluorophenyl ester (314.8 mg, 0.650 house mole), 2-[(2-吼略π定基)曱a mixture of oxy] σ in the mixture of bismuth-5-restroxate (146. 2 mg '〇·619 mmol), Et3N (103 μl, 〇· 743 mmol) in DMFU. 5 ml) Mix at room temperature for 1 day ^·'. The mixture was diluted with Et20, washed with brine and dried over &lt;s&gt; The solvent was removed under reduced pressure to give 2-[[Bu[4-[N,-(2-fluorophenyl)ureido]-3-methoxyphenethyl]-2-pyridinyl] A crude pale yellow oil of decyloxy]pyridine-5-carboxylate. To a stirred solution of THF (6.0 mL) and 1120 (2.0 mL) was added LiOH (44·5 mg, 1.85 7 mmol), and the mixture was stirred at room temperature. 1 7 hours. The mixture was diluted with n-hexane and made basic via the addition of IN NaOH. The aqueous layer was acidified with 1N HCl and extracted with CHCI3. The extract was washed with brine and dried over Na.sub.2.sub.4. The solvent was removed under reduced pressure, and the obtained crude solid was recrystallized from n-hexane-Et 〇Ac-E10 ’ to give 2 〇 2 · 5 mg (63 % ) of 4 8 of white crystal powder.

89112968.ptd 第243頁 1283240 五、發明說明（239) IR (KBr) 1602、1537、1456、1265、752 /公分；l-NMR ( 40 0 MHz，DMS0-d6) (Π·67-2·03 (m，4H)、2.50 (s， 3Η) 、3·33-3·42 (m， 1Η) 、3·52 (m， 2Η) 、3·58 (d， J = 4.4 Hz，1H)、3.83 (s，3H)、4·27-4·31 (m，2H)、 4.42 - 4·47 (m，1H)、6.7 3(d，J = 7.8 Hz, 1H)、6.87 -6.95 (m，3H)、7·1 卜7.17 (m，2H)、7·79 (d，J = 8.3 Hz，1H)、7.99 (d，J = 8.3 Hz，1H)、8.14 (dd，J = 2.0、 8·8 Hz，1H)、8.46 (s，1H)、8.56 (s，1H)、8.69 (d， J=2.0 Hz, 1H) &gt;13.06 (br s, 1H)； MS(FAB) m/z 523 (M+ +1) ’ C27 H27 F N4 06 · 1 / 2 H2 0 之分析計算值：◦，6 1. 〇 1 ; H， 5· 31 ; N，10. 54。實測值：C，61. 52 ; H，5. 39 ; N，10. 01。 實施例45 ， 4 - ；l - [3-甲氧基-4 - [N，-（2-甲基苯基）脲基]苯基乙醯基] - 2 -吡咯啶甲基]-1 -六氫吡畊基乙酸89112968.ptd Page 243 1283240 V. INSTRUCTIONS (239) IR (KBr) 1602, 1537, 1456, 1265, 752 / cm; l-NMR (40 0 MHz, DMS0-d6) (Π·67-2·03 (m, 4H), 2.50 (s, 3Η), 3·33-3·42 (m, 1Η), 3·52 (m, 2Η), 3·58 (d, J = 4.4 Hz, 1H), 3.83 (s, 3H), 4·27-4·31 (m, 2H), 4.42 - 4·47 (m, 1H), 6.7 3 (d, J = 7.8 Hz, 1H), 6.87 - 6.95 (m, 3H ), 7·1 Bu 7.17 (m, 2H), 7.79 (d, J = 8.3 Hz, 1H), 7.99 (d, J = 8.3 Hz, 1H), 8.14 (dd, J = 2.0, 8·8 Hz, 1H), 8.46 (s, 1H), 8.56 (s, 1H), 8.69 (d, J = 2.0 Hz, 1H) &gt;13.06 (br s, 1H); MS(FAB) m/z 523 (M+ +1) 'C27 H27 F N4 06 · 1 / 2 H2 0 Analysis calculated: ◦,6 1. 〇1 ; H, 5· 31 ; N, 10. 54. Found: C, 61. 52 ; H , 5.39; N, 10. 01. Example 45, 4 - ; l - [3-methoxy-4 - [N,-(2-methylphenyl)ureido]phenylethyl] - 2 -pyrrolidinylmethyl]-1 -hexahydropyranyl acetic acid

在室溫下於卜苄基六氫咄畊（5克，28.4莫耳）&amp;k2c〇3 (5. 89克，42. 6毫莫耳）於DMF(30毫升）中之攪拌懸^ ^中 加入溴乙酸乙酯（4. 74克，28.4毫莫耳）。使所產生之混合 物再多攪拌3小時。將混合物以EtOAC( 3 0 0毫升）稀釋，以&quot; 鹽水洗滌（2 X 100毫升），於MgS〇4上乾燥並蒸發。將殘留 物於矽膠上利用CHC1^ EtOH(10:l，v/v)作為洗提液進行 層析而得7. 45克（q· y.)之4-苄基-1-六氫咄啡乙酸乙酯的Add to the stirring suspension of benzylidene hexahydroquinone (5 g, 28.4 mol) &amp; k2c〇3 (5. 89 g, 42.6 mmol) in DMF (30 ml) at room temperature. Ethyl bromoacetate (4. 74 g, 28.4 mmol). The resulting mixture was stirred for a further 3 hours. The mixture was diluted with EtOAc (300 mL), washed with &quot; brine (2 X 100 mL) The residue was chromatographed on a silica gel using CHC1^ EtOH (10:1, v/v) as an eluent to give 7.45 g (q·y.) of 4-benzyl-1-hexahydroindole. Ethyl acetate

89112968.ptd89112968.ptd

1283240 五、發明說明（240) 黃色油。 M-NMR (CDC13) 61.27 (3H，t，J:7.3 Ηζ)、2·,88-2. 96 (8H， m) 、3·20 (2H, s) 、3·52 (2H, s) 、4·18 (2H, q J = 7. 3 Hz)、7. 22-7. 32 ( 5H, m) 〇 ’ 使4-苄基-1-六氫咄畊乙酸乙酯（2. 00克，7· 62毫莫耳） 及5% Pd/C(2克）於AcOH:EtOH(l:l，40毫升）中之授拌溶液 在1大氣壓下氫化8小時。將混合物過濾並將濾液於真空中 濃縮。使殘留物經由加入飽和N a H C 03而成為驗性，並以 CHC h(2x 200毫升）萃取。將結合的萃取液於κ2 c〇3上乾 燥，並蒸發而得1 · 1 6克（8 8 %)之1 -六氫吡啡乙酸乙醋的普 色油。 ^-NMR (CDC13) 5 1. 2 6- 1. 3 0 ( 3H, m) Μ. 6 7 (1Η, br s) 、2·55 (4H, m) 、2·92-2·96 (4H, m) 、3·19-3·2〇 (2H，m)、4· 16-4· 22 (2H, m)。 在室溫下於N-Boc-L -脯胺醇（1·00克，5·〇2毫莫耳）及1 - 六氫吼啡乙酸乙酯（864毫克，5.02毫莫耳）溶於Me〇H:1283240 V. INSTRUCTIONS (240) Yellow oil. M-NMR (CDC13) 61.27 (3H, t, J: 7.3 Ηζ), 2·, 88-2. 96 (8H, m), 3·20 (2H, s), 3·52 (2H, s), 4·18 (2H, q J = 7. 3 Hz), 7. 22-7. 32 ( 5H, m) 〇' 4-ethyl-1-hexahydroindole acetate (2.00 g, The mixed solution of 7.2 Pm/C (2 g) in AcOH:EtOH (1:1, 40 mL) was hydrogenated at 1 atm for 8 hours. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was made passurized by the addition of saturated <RTI ID=0.0>N </ </RTI> <RTIgt; The combined extracts were dried on κ 2 c 〇 3 and evaporated to give 161 g (78%) of EtOAc. ^-NMR (CDC13) 5 1. 2 6- 1. 3 0 ( 3H, m) Μ. 6 7 (1Η, br s) , 2·55 (4H, m) , 2·92-2·96 (4H , m), 3·19-3·2〇(2H,m), 4·16-4· 22 (2H, m). N-Boc-L-prolinol (1·00 g, 5·〇2 mmol) and ethyl 1-hexahydrofurfurate (864 mg, 5.02 mmol) dissolved in Me at room temperature 〇H:

AcOH( 1 0 : 1，v/v，；[ J毫升）之攪拌溶液中加入NaBH3CN(664 毫克’ 1 0 · 0笔莫耳）。於攪拌隔夜後，將混合物倒入至冰 水（100宅升）中’並經由加入NaHC03而成為鹼性。以CHC13 (f X 20 0宅升）萃取混合物。將結合的萃取液於ν^〇3上乾 無’並洛發。將殘留物於矽膠上利用CHC 13 : EtOH( 1 0 : 1， v/v^)作為洗提液進行層析而得丨· 2〇克（67%)之4—[丨一（第三 丁氧幾基）—2—吨咯啶曱基]]-1-六氫咣畊乙酸乙酯的無色 油0To a stirred solution of AcOH (1 0 : 1, v/v,; [J ml) was added NaBH3CN (664 mg &apos; After stirring overnight, the mixture was poured into ice water (100 liters) and became basic via the addition of NaHC03. The mixture was extracted with CHC13 (f X 20 0 liter). The combined extract was dried on ν^〇3 without </ br>. The residue was chromatographed on a silica gel using CHC 13 : EtOH (1 0 : 1, v/v^) as an eluent to obtain 丨·2 gram (67%) of 4—[丨一(三丁Oxygen group) 2- torrolidinyl]]-1-hexahydrohydroquinone ethyl acetate colorless oil 0

89112968.ptd 第245頁 1283240 五、發明說明（241) ----- 1-NMR (CDC13) (Π· 27 (3H, t，J = 7· 3 Hz)、1. 4 6-1· 47 (9H， m)、1· 79-3. 9 6 (總計19H, m 系列）、4· 19 (2Η· J=7.3 Hz) 。 ’ q’ 使4_[1-(第三丁氧羰基）-2-吡咯啶曱基]]—丨-六氫吡啡 f酸乙酯（1· 20克，3· 38毫莫耳）於TFA(5毫升）及CH2c1j5 笔升）中之混合物攪拌隔夜。於移除溶劑後，經由加入飽 和NaHC〇3而使殘留物成為鹼性。以CHCl3 (2 χ 2〇〇毫升）萃 取混合物。將結合的萃取液於Na2C〇上乾燥，並蒗 毫克（⑽之4 -（2—比㈣甲基）+六氣口比喷^:二 的黃色油。 1 MS(FAB) 256(MH1)。 於4 - ( 2 -吼咯啶甲基）—1 _六氫吡啡乙酸乙酯（3 8 〇毫克， 1.49¾莫耳）及3-甲氧基一 4-[Ν’ - (2 -甲基苯基）脲基]苯乙 酸（468毫克，1.49毫莫耳）溶於DMF(10毫升）之攪拌溶液中 加入EDC-HCK428毫克，2· 24毫莫耳）、HOBt、及DMAP(催 化劑）。於攪拌隔夜後，將混合物以EtOAc(3〇〇毫升）稀 釋’以鹽水（2 X 2 0 0耄升）洗務，並於μ g s 〇4上乾燥。於移 除溶劑後，將殘留物於矽膠上利用CHC13 ·· EtOH (89:1， v/v)作為洗提液進行層析而得257毫克（31%)之4- [1-[3 -甲 氧基-4 - [Ν’ -（2 -甲基苯基）脲基]苯乙醯基]一2-吼洛啶甲 基]-1 -六氫吼σ井乙酸乙酯的黃色泡沐。 M-NMR (CDC13) (51· 2 4-1· 29 (3Η，m)、1· 69-4· 24 (總計 29H， m 系列）、6·41 (1H， m) 、6.81 (2H， m) 、7·13-7· 2 6 (4H，m)、7·52 (1H, d，J:7.3 Hz)、8·04 (1H，d，J =89112968.ptd Page 245 1283240 V. INSTRUCTIONS (241) ----- 1-NMR (CDC13) (Π· 27 (3H, t, J = 7· 3 Hz), 1. 4 6-1· 47 (9H, m), 1·79-3. 9 6 (total 19H, m series), 4·19 (2Η· J=7.3 Hz). 'q' makes 4_[1-(t-butoxycarbonyl)- A mixture of 2-pyrrolidinoyl]]-indole-hexahydropyridinium f-acid (1·20 g, 3·38 mmol) in TFA (5 mL) and CH.sub.2j. After the solvent was removed, the residue was made alkaline by the addition of saturated NaHC〇3. The mixture was extracted with CHCl3 (2 χ 2 mL). The combined extracts were dried over Na 2 C , and 蒗 mg ((4) 4 - (2 - (tetra) methyl) + 6-port ratio of yellow: 1 MS (FAB) 256 (MH1). 4 - (2-pyrrolidinylmethyl)- 1 _ hexahydropyridinylacetate (3 8 〇 mg, 1.493⁄4 mol) and 3-methoxy-4-[Ν' - (2-methyl Phenyl)ureido]phenylacetic acid (468 mg, 1.49 mmol) was dissolved in a stirred solution of DMF (10 mL), EDC-HCK 428 mg (2,24 mmol), HOBt, and DMAP (catalyst). After stirring overnight, the mixture was diluted with EtOAc (3 mL) and washed with brine (2.times. After removing the solvent, the residue was chromatographed on a silica gel using CHC13·· EtOH (89:1, v/v) as an eluent to give 257 mg (31%) of 4-[1-[3 - Methoxy-4 - [Ν'-(2-methylphenyl)ureido]phenylidene]- 2-indolylmethyl]-1 -hexahydropurine σ well ethyl acetate yellow foam . M-NMR (CDC13) (51· 2 4-1· 29 (3Η, m), 1· 69-4· 24 (total 29H, m series), 6.41 (1H, m), 6.81 (2H, m ), 7·13-7· 2 6 (4H, m), 7·52 (1H, d, J: 7.3 Hz), 8·04 (1H, d, J =

89112968.ptd 第246頁 1283240 五、發明說明（242) 8·3 Hz)。 於4-[1-[3-甲氧基-4-[Ν’ -（2〜甲基苯基）脲基]笨乙醯 基]-2-吼咯啶曱基]-1 -六氫咣畊乙酸乙酯（2 5 〇毫克， 0.453¾莫耳）溶於THF (4毫升）之攪拌溶液中加入〇· 2 5Ν NaOH (3 · 6毫升）。使所產生之混合物攪拌隔夜。將混合物 經由加入IN HC1而調整至pH 7.5，並以cHCl3:Me0H(4:l， 3 X 1 0 0毫升）卒取。將結合的萃取液於MgS〇4上乾燥並蒗 發。使粗製固體自CHClrMeOH-正己烷再結晶而得4〇毫克 (17%)之49的無色結晶粉末。 熔點 160-ntrc^H-NMR (DMS0-d6) 5 1.74-4.08 (總計 27H ’m 系列）、6·73 (1H， d， J = 7.8 Hz)、6·87 (1H， s)、6· 93 (1H，t，J = 7· 8 Hz)、7· u-7· 17 (2H，m)’、 7.79 (1H，d， J = 7.8 Hz)、8·00 (ih，dd， J = 7.8、2·4 Hz)、8·47 (1H，s)、8·56 (1H，s); MS(FAB) 524(M+ + 1)，C28H37N5 05 · HC1 · H20 之分析計算值：◦， 58.17，H，6.97，N， 12.11。實測值：c，58.26; H， 7·26 ; N， 11. 53 。 實施例4689112968.ptd Page 246 1283240 V. Description of invention (242) 8·3 Hz). 4-[1-[3-Methoxy-4-[Ν'-(2~methylphenyl)ureido]]ethendyl]-2-indenylpyridinyl]-1-hexahydroindole Ethyl acetate (25 mg, 0.4533 g) was dissolved in a stirred solution of THF (4 mL) and EtOAc (3·6 mL). The resulting mixture was stirred overnight. The mixture was adjusted to pH 7.5 via the addition of IN HCl and was taken in cHCl3:Me0H (4:1, 3 X 100 mL). The combined extracts were dried on MgS〇4 and coagulated. The crude solid was recrystallized from CHClrMeOH-hexane to afford 4 mg (17%) of 49 as colorless crystalline powder. Melting point 160-ntrc^H-NMR (DMS0-d6) 5 1.74-4.08 (total 27H 'm series), 6.73 (1H, d, J = 7.8 Hz), 6·87 (1H, s), 6· 93 (1H,t,J = 7· 8 Hz), 7· u-7· 17 (2H,m)', 7.79 (1H,d, J = 7.8 Hz), 8·00 (ih,dd, J = 7.8, 2·4 Hz), 8·47 (1H, s), 8.56 (1H, s); MS (FAB) 524 (M+ + 1), C28H37N5 05 · HC1 · H20 Analysis calculated value: ◦, 58.17, H, 6.97, N, 12.11. Found: c, 58.26; H, 7·26; N, 11. 53. Example 46

於4_胺基苯乙酸（10克，66毫莫耳）於1 ·· 1 CH2C12 :丙酮 (1 0 0毫升）之懸浮液中加入異氰酸鄰曱苯酯（8 · 8克，6 6毫 莫耳）。使混合物迴流加熱4小時’其間生成白色沈殿物。 將沈澱物過濾，並以1 : 1 CH2C 12 ··丙酮大量洗滌固體。將固Add o-p-phenylphenyl isocyanate (8 · 8 g, 6 6 ) to a suspension of 4 -aminophenylacetic acid (10 g, 66 mmol) in 1 ·· 1 CH 2 C 12 : acetone (100 ml) Millions of ears). The mixture was heated under reflux for 4 hours, during which time a white precipitate was formed. The precipitate was filtered and the solid was washed in a large portion with 1:1 CH.sub.2 C.sub.2. Will be solid

89112968.ptd 第247頁 1283240 五、發明說明（243) ' 體利用熱甲醇再結晶’並於真空中乾燥而得14. 1克（75%產 之期望的4一（鄰甲笨脲基）苯乙酸50。 貫施例4 789112968.ptd Page 247 1283240 V. INSTRUCTIONS (243) 'The body is recrystallized from hot methanol' and dried in vacuo to give 14.1 g (75% yield of the desired 4-iso-dosyl) benzene Acetic acid 50. Example 4 7

ΌΗ 51 於2_胺基_4_噻唑乙酸(4克，25毫莫耳）於1:1 CH2C12:丙 :。0 0笔升）之懸洋液中加入異氰酸鄰曱苯酯(3. 5克，2 6 毛莫耳）。使此合物迴流加熱8小時，其間生成黃色沈澱 物。將沈澱物過濾，並以1 : 1 CH2C12:丙酮大量洗滌固體。 1 固體利用熱甲醇再結晶，並於真空中乾燥而得4. 8克 (66/。產率）之期望的2弋鄰甲苯脲基）+嗔唾乙酸51。 實施例48 4-jU-[3-甲氧基-4-[N’ _(2一曱基苯基）脲基]苯基乙醯 基]-2-吡咯啶曱氧胺基]苯曱酸 使4一胺基苯甲酸曱酯（1. 52克，10. 04毫莫耳）及卜第三 丁氧羰基脯胺醛（3·〇〇克，ΐ5·〇6毫莫耳）於甲苯（μ毫升） 中之攪拌混合物迴流加熱3小時。於冷卻至室溫後，將溶 d於真空中蒸發。將固體溶解於Me〇jj(27毫升）及AcOH (3 毫升）中，然後將NaBH3CN(l· 33克，20· 08毫莫耳）加至混 3物’並使所產生之混合物在室溫下攪拌隔夜。利用水使ΌΗ 51 on 2_Amino-4-thiazoleacetic acid (4 g, 25 mmol) at 1:1 CH2C12: C:. 0 0 liters of the suspension of the o-p-phenylene isocyanate (3.5 g, 2 6 hair molars). The mixture was heated under reflux for 8 hours, during which time a yellow precipitate formed. The precipitate was filtered and the solid was washed with a large portion of 1:1 CH.sub.2 C.sub.2: acetone. 1 The solid was recrystallized from hot methanol and dried in vacuo to give 2.8 g (yield: 66%) of desired desired 2 s. Example 48 4-jU-[3-Methoxy-4-[N'-(2-mercaptophenyl)ureido]phenylethenyl]-2-pyrrolidinylamino]benzoic acid Ethyl 4-aminobenzoate (1.52 g, 10.04 mmol) and tributyloxycarbonylguanamine (3·〇〇g, ΐ5·〇6 mmol) in toluene ( The stirred mixture in μ ml) was heated under reflux for 3 hours. After cooling to room temperature, the solution was evaporated in vacuo. The solid was dissolved in Me〇jj (27 ml) and AcOH (3 ml), then NaBH3CN (1·33 g, 20·08 mmol) was added to the mixture 3 and the resulting mixture was allowed to react at room temperature Stir under night. Use water to make

89112968.ptd89112968.ptd

第248頁 1283240 五、發明說明（244) &quot; 一 反應混合物停止反應，及將溶劑於減壓下移除。將水加至 殘留物，並以EtOAc萃取。將萃取液以h2〇、鹽水洗滌，並 於NagSO4上乾無。將溶劑於減壓下移除，及將殘留物於矽 膠上利用正己烷-Et0Ac(3 : 1，v/v)作為洗提液進行層析而 得2. 17克（65%)之4-[1-(第三丁氧羰基）—2—吼咯啶曱胺基] 苯甲酸酯的淡黃色油。 4-NMR (400 MHz, CDC13)51,48 (s，9H)、1·51 一2.09 (m ’ 4 Η )、3 · G 5 - 3 · G 7 及 3 · 4 3 - 3 · 4 8 (b r m，1 Η )、3 · 1 8 (b r s， 1H) 、3.36 (br s， 2H) 、3·84 (s， 1H) 、4.06-4.08 、 4· 20-4. 24 (各br Hi，1H)、6· 49-6· 65 (m，2H)、7. 84 (d， J=8.3 Hz， 2H); MS(FAB)m/z 335(MH1)。 在0 °C下於4-[ 1-(第三丁氧羰基2一咄咯啶甲胺基]苯甲 酸甲酯（2· 17克，6· 49 0毫莫耳）溶於CH2Cl2 (44毫升）之攪拌 /谷液中加入TF A ( 8 · 7耄升）’並使所產生之混合物在室溫下 攪拌隔夜。將溶劑於減壓下移除，並以丨N Na〇H處理殘留 物。以CHgCl2卒取混合物。將萃取液以鹽水洗滌，於 上乾燥，及使溶劑於減壓下濃縮而得134克（88%)之4 —(2一4 吼嘻咬甲胺基）苯甲酸甲酯的棕色油，將其不經進一步的 純化而使用於後續的反應。 使以上之4 -（ 2 -吼咯啶甲胺基）苯甲酸甲酯（3 9 7. 8毫克， 1.69毫莫耳）、3-甲氧基-4-[『-（2-曱基苯基）脲基]苯乙 酸（587.1 毫克，1.87 毫莫耳）、EDC(HC 丨）（486 毫克，2.54 毫莫耳）、H0Bt(23毫克，〇· 17毫莫耳）、&amp;DMAP(2i毫克， 0 · 1 7耄莫耳）於DMF (4毫升）中之混合物在室溫下攪拌隔Page 248 1283240 V. INSTRUCTIONS (244) &quot; A reaction mixture stops the reaction and the solvent is removed under reduced pressure. Water was added to the residue and extracted with EtOAc. The extract was washed with h 2 〇, brine, and dried over NagSO4. The solvent is removed under reduced pressure, and the residue is chromatographed on the silica gel using n-hexane-Et0Ac (3:1, v/v) as the eluent to give 2.17 g (65%) of 4- A light yellow oil of [1-(t-butoxycarbonyl)-2-pyrrolidinium]benzoate. 4-NMR (400 MHz, CDC13) 51, 48 (s, 9H), 1·51 - 2.09 (m ' 4 Η ), 3 · G 5 - 3 · G 7 and 3 · 4 3 - 3 · 4 8 ( Brm,1 Η ),3 · 1 8 (brs, 1H), 3.36 (br s, 2H), 3·84 (s, 1H), 4.06-4.08, 4· 20-4. 24 (each br Hi, 1H ), 6·49-6· 65 (m, 2H), 7.84 (d, J = 8.3 Hz, 2H); MS (FAB) m/z 335 (MH1). Methyl 4-[1-(t-butoxycarbonyl-2-oxolidinemethylamino)benzoate (2·17 g, 6·49 0 mmol) dissolved in CH 2 Cl 2 (44 ml) at 0 °C TF A (8 · 7 liters) was added to the stirring/trough solution and the resulting mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure and the residue was treated with 丨N Na〇H. The mixture was taken up in CHgCl2, the extract was washed with brine, dried over EtOAc EtOAc EtOAc EtOAc EtOAc The brown oil of the methyl ester was used in the subsequent reaction without further purification. The above 4-(2-pyridinylmethylamino)benzoic acid methyl ester (3 9 7. 8 mg, 1.69 mmol) Ear), 3-methoxy-4-["-(2-mercaptophenyl)ureido]phenylacetic acid (587.1 mg, 1.87 mmol), EDC (HC 丨) (486 mg, 2.54 mmol) a mixture of H0Bt (23 mg, 〇17 mmol), &amp;DMAP (2i mg, 0 · 17 耄mol) in DMF (4 ml) at room temperature

89112968.ptd 第249頁 1283240 五、發明說明（245) ---— 仪。將混合物以EtOAc稀釋，以鹽水洗滌，並於N^s〇4上乾 燥。將溶劑於減壓下移除。將殘留物於矽膠上利用 CHCl3-MeOH(50:l，v/v)作為洗提液進行層析而得882毫克 (98%)之4-[1 -[3-甲氧基-4-N，-(2-甲基苯基）脲基]苯基乙 醯基]-2-咄咯啶甲胺基]苯甲酸甲酯的棕色非晶形固體， 將其不經進一步的純化而使用於後續的反應。 於以上之4-[1-[3-甲氧基-4 -Ν’-（2-曱基苯基）脲基]笨 基乙醯基]- 2 -咄咯啶甲胺基]苯曱酸甲酯（8 8 2毫克，i · 6 6 2 毫莫耳）溶於THF(18毫升）及Me0H(5. 〇毫升）之攪拌溶液中 加入IN NaOH(5.0毫升，5.0 0 0毫莫耳），並使混合物迴流 加熱3天。將混合物濃縮。將殘留物以1 n HC 1萃取，並以 CH2C12萃取。將萃取液以鹽水洗滌，於Na2s〇4上乾燥，並於 真空中蒸發。使固體自正己烷-二異丙醚-CHC13 -MeOH再結 晶而得180· 5毫克（21%)之52的淡黃色非晶形固體。 IR (KBr) 1604 、 1535 、 1511 、 1454 、 1255 、 1224 、 1174 / 公分；4-NMR ( 40 0 MHz，DMSO-d6) (Η. 79- 1. 9 9 (br m， 4H) 、2·25 (s， 3H) 、2·90-2·94 (m， 1H) 、3.35-3.62 (m，6H)、3·87 (s，3H)、4.12-4.15 (br s，1H)、 6·63-6.78 (m，4H)、6.89-6.95 及 7·11-7·17 (各m， 3H) 、7·65 (d， J=8.3 Hz， 2H) 、7.80 (d， J=8.3 Hz， 1H)、8·02 (d，J = 8.3 Hz，1H)、8.47 (s，1H)、8·57 (s，1H)、12· 0 (br s，1H) ; MS(FAB) m/z 517(MH1 ); ◦29Η32Ν4 05 · 1H20 之分析計算值：C，65· 15 ; H， 6· 41 ; N， 10. 48。實測值·· C， 6 5. 45 ; H，6. 33 ; N， 10· 02。89112968.ptd Page 249 1283240 V. INSTRUCTIONS (245) ---— Instrument. The mixture was diluted with EtOAc, washed with brine and dried over EtOAc. The solvent was removed under reduced pressure. The residue was chromatographed on silica gel using CHCl3-MeOH (50:1, v/v) to afford 882 mg (98%) of 4-[1 -[3-methoxy-4-N a brown amorphous solid of methyl (-(2-methylphenyl)ureido]phenylethenyl]-2-oxaridinylmethylamino]benzoate, which was used in the subsequent purification without further purification Reaction. 4-[1-[3-Methoxy-4-indol'-(2-mercaptophenyl)ureido]]indolyl]-2-pyrrolidinemethylamino]benzoic acid Methyl ester (8 8 2 mg, i · 6 6 2 mmol) was dissolved in THF (18 mL) and Me0H (5 mL). The mixture was heated under reflux for 3 days. The mixture was concentrated. The residue was extracted with 1 n HCl 1 and extracted with CH2C12. The extract was washed with brine, dried over Na.sub.2, and evaporated in vacuo. The solid was recrystallized from n-hexane-diisopropyl ether-CHC13-MeOH to give &lt;RTI ID=0.0&gt;&gt; IR (KBr) 1604, 1535, 1511, 1454, 1255, 1224, 1174 / cm; 4-NMR (40 0 MHz, DMSO-d6) (Η. 79- 1. 9 9 (br m, 4H), 2· 25 (s, 3H), 2·90-2·94 (m, 1H), 3.35-3.62 (m, 6H), 3·87 (s, 3H), 4.12-4.15 (br s, 1H), 6· 63-6.78 (m, 4H), 6.89-6.95 and 7·11-7·17 (each m, 3H), 7.65 (d, J=8.3 Hz, 2H), 7.80 (d, J=8.3 Hz, 1H), 8·02 (d, J = 8.3 Hz, 1H), 8.47 (s, 1H), 8·57 (s, 1H), 12·0 (br s, 1H); MS(FAB) m/z 517(MH1); ◦29Η32Ν4 05 · 1H20 Analysis calculated: C, 65· 15 ; H, 6· 41 ; N, 10. 48. Measured value · · C, 6 5. 45 ; H, 6. 33 ; N, 10· 02.

89112968.ptd 第250頁 1283240 五、發明說明（246) 實施例4 9 4-[N-[卜[3-甲氧基-4-[N，-(2-曱基苯基）脲基笨基乙醯 基]-2 -吡咯啶甲基]-N-甲胺基]笨曱酸89112968.ptd Page 250 1283240 V. INSTRUCTIONS (246) EXAMPLE 4 9 4-[N-[Bu[3-methoxy-4-[N,-(2-mercaptophenyl)ureido] Ethyl]-2-pyrrolidinylmethyl]-N-methylamino]cyanic acid

在4-[N-（2 -。比咯啶基）甲胺基]苯甲酸甲酯（6〇〇毫克， 1.794毫莫耳）、37%甲醛（1.79公升，23.32毫莫耳）、及 NaBH3CN( 368毫克，5. 561毫莫耳）於CH3CN(6. 0毫升）中之混 合物中逐滴加入AcOH( 0. 20 5毫升，3· 588毫莫耳），並使所 產生之混合物在室溫下攪拌2小時。經由加入飽和NaHC〇3 使反應混合物停止反應，並以E10 A c萃取。將萃取液以鹽 水洗務’並於Na2S04上乾燥。將溶劑於減壓下移除，及將 殘留物於矽膠上利用正己烷-Et0Ac(3:丨，v/v)作為洗提液 進行層析而得645毫克（100%)之4-[N-[l-(第三丁氧羰 基）-2-吼咯啶曱基]一N-甲胺基]苯甲酸曱酯的無色油。 lH-NMR ( 40 0 MHz, CDC13) 5 1. 5 0 (s, 9H) &gt; 1. 76-1. 91 (m， 4H) 、3·〇7 (s， 3H) 、3·15-3·43 (m, 3H)、 3.67-3.71 (m, 1H) -3.85 (s, 3H) ^4.11-4.17 (m, 1H) 、4·37 (s ，1H) 、6·75 (d， J:8.3 Hz， 2H) 、7.89 (d，J = 8.8 Hz，2H); MS(FAB)m/z 349 (MH1)。 在0 C下於4-[N-[l-(第三丁氧羰基）-2 -吼略。定曱基]-N-曱胺基]笨甲酸甲酯（ 645毫克，1· 794毫莫耳）溶於CH2C12 (6· 5毫升）之攪拌溶液中加入TFA(1 · 3毫升），並使混合物Methyl 4-[N-(2-pyrrolidyl)methylamino]benzoate (6 mg, 1.794 mmol), 37% formaldehyde (1.79 liters, 23.32 mmol), and NaBH3CN ( 368 mg, 5. 561 mmol), a mixture of CHOH (6.0 mL) was added dropwise AcOH (0.25 mL, 3. 588 mmol) and the mixture obtained was Stir for 2 hours at room temperature. The reaction mixture was quenched by the addition of saturated NaHC.sub.3 and extracted with EtOAc. The extract was washed with salt water and dried on Na2SO4. The solvent was removed under reduced pressure, and the residue was applied to silica gel eluted with n-hexane-EtOAc (3: hexane, v/v) as eluent to give 645 mg (100%) of 4-[N - a colorless oil of [l-(t-butoxycarbonyl)-2-oxaridinyl]-N-methylamino]benzoate. lH-NMR (40 0 MHz, CDC13) 5 1. 5 0 (s, 9H) &gt; 1. 76-1. 91 (m, 4H), 3·〇7 (s, 3H), 3·15-3 ·43 (m, 3H), 3.67-3.71 (m, 1H) -3.85 (s, 3H) ^4.11-4.17 (m, 1H), 4·37 (s, 1H), 6.75 (d, J: 8.3 Hz, 2H), 7.89 (d, J = 8.8 Hz, 2H); MS (FAB) m/z 349 (MH1). 4-[N-[l-(Tertidinoxycarbonyl)-2 - oxime at 0 C. To a stirred solution of CH2C12 (6.5 ml) was added TFA (1. 3 mL) in a stirred solution of methyl succinyl]-N-decylamine (645 mg, 1. 794 mmol). mixture

89112968.ptd 第251頁 1283240 五、發明說明（247)89112968.ptd Page 251 1283240 V. Description of invention (247)

在室溫下攪拌隔夜。將溶劑於減壓下移除，並以丨N Na〇H 溶液處理殘留物。以Cij2Cl2萃取混合物。將萃取液以鹽水 ，務，於NaJO4上乾燥，及使溶劑於減壓下濃縮而得3 63. 2 宅克（8 2%)之4- [N-( 2 -咄咯啶基）甲基-N-甲基]胺基苯甲酸 甲醋的淡黃色油，將其不經進一步的純化而使用於後續的 反應。 使4- [N-(2-吼咯啶基）甲基一N_甲基]胺基苯甲酸曱酯 (191.8毫克，〇·772毫莫耳）、3-甲氧基-4 -（N，- 2-甲基苯 基脈基）苯乙酸（258.1毫克，0.811毫莫耳）、EDC(氯化氫） (221.9毫克，ι·ι58毫莫耳）、H〇Bt(1〇〇毫克，〇〇77毫莫 耳）、及DMAP(9. 4毫克，〇·〇77毫莫耳）於DMF(2. 0毫升）中 之混合物在室溫下攪拌3小時。將反應混合物以E心〇稀 釋’以鹽水洗滌，並於Ν%3〇4上乾燥。將溶劑於減壓下移 除’而得482.5毫克之4-[N-[l-[3-甲氧基-4-[N，-（2-甲基 笨基）脲基]笨基乙醯基]—2 -吼咯啶甲基]—N-甲胺基]苯甲 酸曱S旨的白色非晶形粉末，將其不經進一步的純化而使用 於後續的反應。 於4 - [N - [1-[3-曱氧基-4-[N-(2-曱基苯基）脲基]苯基乙 驗基]-2-咄咯啶甲基]-N-曱胺基]苯甲酸甲酯溶於thF ( 5· 0毫升）之攪拌溶液中加入in Na0H(6· 2毫升，6. 2毫莫 耳）’並使混合物迴流加熱3天。將反應混合物於真空中濃 縮。將殘留物以1 N HC1中和，並以CH2C12萃取。將萃取液 以飽和NH4C1、鹽水洗滌，於Na2S04上乾燥，並於真空中蒸 發。使粗製固體自正己烷-CHC13-MeOH-異丙醚再結晶而得Stir overnight at room temperature. The solvent was removed under reduced pressure and the residue was taken up in EtOAc EtOAc. The mixture was extracted with Cij2Cl2. The extract was dried over NaJO4 in brine, and the solvent was concentrated under reduced pressure to give 3 63. 2 (2 2%) of 4-[N-(2-pyridinyl)methyl A light yellow oil of -N-methyl]aminobenzoic acid methyl acetal was used in the subsequent reaction without further purification. 4-[N-(2-Pyrrolidinyl)methyl-N-methyl]aminobenzoic acid oxime ester (191.8 mg, 〇 · 772 mmol), 3-methoxy-4 - (N) , - 2-methylphenyl phenyl) phenylacetic acid (258.1 mg, 0.811 mmol), EDC (hydrogen chloride) (221.9 mg, ι·ι 58 mmol), H〇Bt (1 〇〇 mg, 〇〇 A mixture of 77 mmoles, and DMAP (9.4 mg, 〇·〇 77 mmol) in DMF (2.0 mL) was stirred at room temperature for 3 hours. The reaction mixture was diluted with E-hearts, washed with brine and dried over EtOAc EtOAc. The solvent was removed under reduced pressure to give 482.5 mg of 4-[N-[l-[3-methoxy-4-[N,-(2-methylphenyl)ureido]] A white amorphous powder of the group of 2-(2-pyridylmethyl)-N-methylamino]benzoic acid sulfonate was used in the subsequent reaction without further purification. 4-[N-[1-[3-曱-oxy-4-[N-(2-indolylphenyl)ureido]phenylethyl]-2-indenylmethyl]-N- To a stirred solution of the threonyl]methyl benzoate in thF (0.5 mL) was added NaH.sub.2 (2. 2 mL, 6.2 mmol) and the mixture was heated under reflux for 3 days. The reaction mixture was concentrated in vacuo. The residue was neutralized with 1 N HCl and extracted with CH2C12. The extract was washed with saturated NH.sub.4Cl.sub.1, brine, dried over Na.sub. The crude solid was recrystallized from n-hexane-CHC13-MeOH-isopropyl ether.

89112968.ptd 第252頁 1283240 五、發明說明（248) 102. 8毫克（25%，2步驟）之53的淡黃色非晶形固體。 熔點 1 44-1 46 °C ; IR (KBr) 3325、1 6 0 0、1 52 9、1 454、 1 2 84、1 257、1184 / 公分；UMR ( 400 MHz， DMSO-d6)占 1.73-1·91 (m， 3H) 、2·03-2·11 (m， 1H) 、3.03 (s， 3H) 、3·16 (dd， J二9·3 、14·2 Hz, 1H) 、3.37-3.60 (m， 4H)、3·76-3.8 0 (m, 1H)、3·86 (s，3H)、4.25 (br s， 1H) 、6.75 (dd， J=1.5 、8·3 Hz, 1H) 、6·86 (d， J:1.5 Hz，1H)、6·90 (d，J = 8.8 Hz, 2H)、6·95-7.01 (m， 1H) &gt;7.12 (t, J-7.8 Hz, 1H) &gt; 7.20-7.25 (m, 1H)- 7·73 (d，J:8.8 Hz，2H)、8·〇1 (d，J = 7.8 Hz，1H)、 8·16-8·20 (m，1H)、8.73 (s, 1H)、9·19 (d，J:2.0 Hz，1H)、12.0 (br s，ih); MS(FAB) m/z 5 35 (MH1); C29H31FN4 05 · 1/2H20 之分析計算值：c，M. 〇8 ; H，5. 93 ; N， 10· 31 ; F，3· 49。實測值：C， 64. 17 ; H， 5. 84 ; N， 1 〇 · 0 6 ; F，3 · 2 6。 實施例5 0 4-[N-[1 -4-[N _(2〜氟苯基）脲基]一3-曱氧苯基乙醯基]一2_ 吼略淀甲基]- N-甲胺基]硝基苯甲酸89112968.ptd Page 252 1283240 V. INSTRUCTIONS (248) 102. 8 mg (25%, 2 steps) of 53 pale yellow amorphous solid. Melting point 1 44-1 46 °C; IR (KBr) 3325, 1 600, 1 52 9, 1 454, 1 2 84, 1 257, 1184 / cm; UMR (400 MHz, DMSO-d6) occupies 1.73 1·91 (m, 3H), 2·03-2·11 (m, 1H), 3.03 (s, 3H), 3·16 (dd, J 2:9, 14·2 Hz, 1H), 3.37 -3.60 (m, 4H), 3.76-3.8 0 (m, 1H), 3·86 (s, 3H), 4.25 (br s, 1H), 6.75 (dd, J=1.5, 8·3 Hz, 1H), 6·86 (d, J: 1.5 Hz, 1H), 6.90 (d, J = 8.8 Hz, 2H), 6.95-7.01 (m, 1H) &gt; 7.12 (t, J-7.8 Hz, 1H) &gt; 7.20-7.25 (m, 1H)- 7·73 (d, J: 8.8 Hz, 2H), 8·〇1 (d, J = 7.8 Hz, 1H), 8·16-8· 20 (m, 1H), 8.73 (s, 1H), 9·19 (d, J: 2.0 Hz, 1H), 12.0 (br s, ih); MS (FAB) m/z 5 35 (MH1); C29H31FN4 Analysis of calculated values for 05 · 1/2H20: c, M. 〇 8 ; H, 5.93 ; N, 10· 31 ; F, 3. 49. Found: C, 64. 17 ; H, 5. 84 ; N, 1 〇 · 0 6 ; F, 3 · 2 6. Example 5 0 4-[N-[1 -4-[N _(2~Fluorophenyl)ureido]-3-indolyloxyphenylethyl]- 2_ 吼 淀 methyl]-N-A Amino]nitrobenzoic acid

54 在登氣一 3一/肖基笨甲酸甲酿（1· 58克，4· 6 6 6毫莫耳）及 &gt; 二丁氧複基）—2 — u比咯啶基]甲基胺（ 5 50毫克，2· 333 笔莫耳）於DMF(8·0毫升）中之混合物中加入K2C03 ( 9 67毫54 In Dengqiyi 3-1/Xiaoji Bian formic acid brewing (1·58 g, 4·6 6 6 mmol) and &gt; dibutoxy complex) 2- 2 -u-pyridyl]methylamine (5 50 mg, 2·333 moules) K2C03 (9 67 m) in a mixture of DMF (8.0 ml)

第253頁 1283240Page 253 1283240

克，6· 99 9耄莫耳），並使所產生之混合物在室溫下攪拌3 小時。將反應混合物以EtOAC稀釋，以水洗滌，並於Na2S% 上乾燥。將溶劑於減壓下移除，並將殘留物於矽膠上利用4 ^己烷-Et0Ac(3: 1，v/v)作為洗提液進行層析而得834. g t克（91°/。）之4-[N- [；[-(第三丁氧羰基2一咄咯啶曱基卜N — 甲基]胺基-3-硝基苯甲酸曱酯的淡黃色油，將其不經進一 步的純化而使用於後續的反應。 於以上之油浴於CI^Cl2 (8· 3毫升）的冰冷溶液中加入τfa (1 · 7毫升），並使反應混合物在室溫下攪拌隔夜。將溶劑 於減壓下移除。以1 N NaOH處理殘留物，並以chc 13萃取。 將萃取液以鹽水洗滌，於NaJO4上乾燥，及於減壓下蒸發 而得553· 6毫克（90%)之4-[N -（2-吼洛咬甲基）一n-甲基]胺 基-3 -硝基苯甲酸甲酯的淡黃色油。 iH，R( 40 0 MHz，CDCl3)5 1.3H.40(m，iH)、1.74〜 2.05 (m, 4H) ^ 2.73-2.79 (m, 1H) ^2.81-2.99 (m, 1H)、2·94 (s, 3H)、3·29-3·55 (m, 2H)、3·89 (s， 3H)、7·14 (d，1 = 9.3 Hz，1H)、7·98 (dd，JIO、8·8Gram, 6·99 9 耄mol), and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with EtOAC, washed with water and dried over Na2S. The solvent was removed under reduced pressure and the residue was purified eluting eluting eluting eluting eluting a pale yellow oil of 4-[N-[;[-(t-butoxycarbonyl 2 -pyrrolidinyl)-N-methyl]amino-3-nitrobenzoate, which is not subjected to Further purification was used for the subsequent reaction. τfa (1·7 mL) was added to an ice-cooled solution of CI^Cl2 (3·3 mL), and the mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure. The residue was crystallised eluted with 1 N EtOAc EtOAc (EtOAc) a pale yellow oil of 4-[N-(2-indole methyl)-n-methyl]amino-3-nitrobenzoic acid methyl ester. iH, R (40 0 MHz, CDCl3) 5 1.3H .40(m,iH), 1.74~2.05 (m, 4H) ^ 2.73-2.79 (m, 1H) ^2.81-2.99 (m, 1H), 2·94 (s, 3H), 3·29-3· 55 (m, 2H), 3·89 (s, 3H), 7·14 (d, 1 = 9.3 Hz, 1H), 7·98 (dd, JIO, 8·8

Hz， 1H) 、8·42 (d， J=2.0 Hz， 1H); MS(FAB)m/z 294 (MH1) 〇 使3-甲氧基-4-[Ν’ -（2-氟笨基）脲基]苯乙酸（6 3 〇. 〇毫 克，1.979毫莫耳）、3 -硝基-4-N-(2-咄略。定基）曱基一 n-曱 胺基]苯甲酸甲酯（ 553· 0毫克，1. 885毫莫耳）、EDC(氯化 氫）（ 542.0 毫克，2.827 毫莫耳）、H0Bt(255 毫克，〇189 毫莫耳）、及DMAP(23· 1毫克，0.189毫莫耳）於DMF(5· 〇毫Hz, 1H), 8·42 (d, J=2.0 Hz, 1H); MS(FAB)m/z 294 (MH1) 3-3-methoxy-4-[Ν' -(2-fluorophenyl) Urea-based phenylacetic acid (6 3 〇. 〇mg, 1.979 mmol), 3-nitro-4-N-(2-咄 。. 定) thiol-n-nonylamino]benzoic acid methyl ester (553. 0 mg, 1.885 mmol), EDC (hydrogen chloride) (542.0 mg, 2.827 mmol), H0Bt (255 mg, 〇189 mmol), and DMAP (23. 1 mg, 0.189 m) Moer) in DMF (5· 〇 〇

89112968.ptd 第254頁 1283240 五、發明說明（250) 升）中之混合物在室溫下攪拌2小時。將混合物以Et2〇3稀 釋，以鹽水洗滌，並於NaJO4上乾燥。將溶劑於減壓下移 除，及將殘留物於矽膠上利用CHC13 - MeOH(30:l，v/v)作&quot; 為洗提液進行層析而得1·18克（100%)之4-[N-[l-[3-甲氧 基一 4 - [Ν’ - (2-氟苯基）脲基]-3-曱氧笨基乙醯基]—2 -吼。各 啶甲基]- Ν -甲胺基]-3 -硝基苯甲酸曱酯的黃色泡沫，將其 不經進一步的純化而使用於後續的反應。 於以上之4-[Ν-[1 - [3-甲氧基-4-[Ν’ -（2-氟笨基）脲基] -3-曱氧苯基乙醯基]-2 -咄咯啶曱基]-Ν-曱胺基]一3-硝基 苯甲酸甲酯（2·50毫克，0.421毫莫耳）溶於THF(3· 0毫升） 之攪拌溶液中加入IN NaOH(l· 5毫升，1.500毫莫耳），並 使混合物迴流加熱隔夜。於冷卻後，將混合物濃縮至小體 積。將殘留物以IN HC1處理，並以CHC13萃取。將萃取液 以鹽水洗滌，於Na2S04上乾燥，並於真空中蒸發。使粗製 固體自正己烷-乙醚-CHCl3_MeOH再結晶而得194. 9毫克 (8 0%)之54的黃色非晶形固體。 IR (KBr) 1685 、 1610 、 1529 、 1454 、 1284 、 1259 、 1228 / 公分；UMR ( 40 0 MHz，DMS0-d6) (51.63-1.91 (m， 3H)、2·04-2·07 (br s，1H)、2·60 (br s，1H)、2·80 (s， 1H)、2· 99 (s，2H)、3· 05-3· 10 (m，1H)、3. 32- 3·58 (m，3H)、3·76_3.81 (m，1H)、3.81 (s，3H)、 4.25 (br s，1H)、6.68 (t，J二3.9 Hz，1H)、6.71 (d， J 二 8 · 8 H z，1 H)、6 · 8 1 - 6 · 9 6 (m，1 H )、7 · 0 7 (t，J 二 7 · 3 Hz, 1H)、7·17 (dd，J = 7.8、9·8 Hz, 1H)、7·48 (t，89112968.ptd Page 254 1283240 V. Inventive Note (250) The mixture in liter was stirred at room temperature for 2 hours. The mixture was diluted with Et 2 〇 3, washed with brine and dried over Na.sub.4. The solvent was removed under reduced pressure, and the residue was applied to silica gel using CHC13-MeOH (30:1, v/v) as &quot; 4-[N-[l-[3-Methoxy- 4 -[Ν' - (2-fluorophenyl)ureido]-3-indoleoxy]indolyl]-2-anthracene. A yellow foam of each decylmethyl]-methyl-methylamino]-3-nitrobenzoate was used in the subsequent reaction without further purification. 4-[Ν-[1 - [3-methoxy-4-[Ν'-(2-fluorophenyl)ureido]-3-indolylphenylphenyl]-2-pyrrole To a stirred solution of methyl benzyl]-indole-nonylamino]methyl 3-nitrobenzoate (2·50 mg, 0.421 mmol) dissolved in THF (3.0 mL) 5 ml, 1.500 mmol, and the mixture was heated to reflux overnight. After cooling, the mixture was concentrated to a small volume. The residue was treated with IN HCl and extracted with CH.sub.3. The extract was washed with brine, dried over Na 2 EtOAc and evaporated. The crude solid was recrystallized from n-hexane-diethyl ether-EtOAc (MeOH) to yield 194. IR (KBr) 1685, 1610, 1529, 1454, 1284, 1259, 1228 / cm; UMR ( 40 0 MHz, DMS0-d6) (51.63-1.91 (m, 3H), 2·04-2·07 (br s , 1H), 2·60 (br s, 1H), 2·80 (s, 1H), 2·99 (s, 2H), 3· 05-3· 10 (m, 1H), 3. 32- 3 · 58 (m, 3H), 3.76_3.81 (m, 1H), 3.81 (s, 3H), 4.25 (br s, 1H), 6.68 (t, J 3.9 Hz, 1H), 6.71 (d, J 2 8 · 8 H z,1 H), 6 · 8 1 - 6 · 9 6 (m,1 H ), 7 · 0 7 (t, J 2 7 · 3 Hz, 1H), 7·17 (dd , J = 7.8, 9·8 Hz, 1H), 7·48 (t,

89112968.ptd 第255頁 128324089112968.ptd Page 255 1283240

五、發明說明（251) J = 7.8 Hz，1H)、7·85 (d，J = 8.8 Hz, 1H)、7·97 (t J = 8.8 Hz，1H)、8·：Π-8.20 (m，2H)、8·68 (s，1H)’、 9.14 (s，1H)、12.8 (br s，1H); MS(FAB) m/z 580 (MH1) ; C29H3()FN5 07 · 1/4H20 之分析計算值：r 59· 63 ; H，5· 26 ; N， 11. 99 ; F，3. 25。實測值：c 59· 68 ; H， 5· 34 ; N， 11· 80 ; F， 3. 21 。 ’ 實施例5 1 3 -胺基-4-N〜曱基-[卜4_[『-（2-氟笨基）脲基一甲一 苯基乙醯基]- 2 -吼咯啶甲基]- N -曱胺基]笨曱酸 氧 F H H OMe 55 使4-[N-[1-4-[Ν’-（2-氟苯基）脲基]-3-甲氧笨基乙醯 基]-2-咄咯啶甲基]—N一甲胺基]一3一硝基笨曱酸甲〇 毫克，1.518毫莫耳）溶於MeOH(18.〇毫升）之攪拌^液在5〇/V. INSTRUCTIONS (251) J = 7.8 Hz, 1H), 7.85 (d, J = 8.8 Hz, 1H), 7·97 (t J = 8.8 Hz, 1H), 8·: Π-8.20 (m) , 2H), 8.68 (s, 1H)', 9.14 (s, 1H), 12.8 (br s, 1H); MS (FAB) m/z 580 (MH1) ; C29H3()FN5 07 · 1/4H20 Analysis calculated: r 59· 63 ; H, 5 · 26 ; N, 11. 99 ; F, 3. 25. Found: c 59· 68 ; H, 5· 34 ; N, 11· 80 ; F, 3. 21 . 'Example 5 1 3 -Amino-4-N~indolyl-[Bu 4_[『-(2-Fluorophenyl)ureido-methyl-phenylethylidene]-2-pyrrolidinylmethyl] -N-ammonium] 曱 曱 氧 F F FHH OMe 55 makes 4-[N-[1-4-[Ν'-(2-fluorophenyl)ureido]-3-methoxyphenylethyl] -2- 咄 咄 甲基 甲基 甲基 甲基 甲基 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5

Pd—、C(1.35克）上在45 psi下氫化隔夜。將混合物過濾0 濾液於真空中濃縮。利用丨N Na〇H溶液使 1 、 性，並以CHCl3萃取。將萃取液以鹽水洗務，於^^上 燥，及將溶劑於減壓下移除。將殘留物於石夕膠上2 ‘乾 CHCl3-MeOH(24:1 ’v/v)作為洗提液進行層析，而得 宅克(48。之3-月，基-4-[N—&quot;_4_[N，_(2一氣笨基）· - 3-甲氧苯基乙a蓝基]-2 -口比嘻唆曱美〕 土」 酯的杵色非曰形固俨，脾：t , 土卜N一曱胺基]笨曱酸曱 酉曰的栋色非曰曰形U夺其不經進_ 續的反應。 κ叫便用於後Pd-, C (1.35 g) was hydrogenated overnight at 45 psi. The mixture was filtered and the filtrate was concentrated in vacuo. The solution was extracted with 丨N Na〇H solution and extracted with CHCl3. The extract was washed with brine, dried, and the solvent was removed under reduced pressure. The residue was chromatographed on a mixture of 2' dry CHCl3-MeOH (24:1 'v/v) as an eluent, and the house was obtained (48- of 3-month, base-4-[N- &quot;_4_[N,_(2一气笨基)·-3-methoxyphenylethylalanyl]-2 - 口比嘻唆曱美] soil" ester non-linear solid, spleen: t, Tubu N-Aminoamine] 曱 曱 曱酉曰 曱酉曰 栋 栋 栋 栋 栋 夺 夺 夺 U U U U U U U U _ _ _ _ _ _ _

12832401283240

於以上化合物溶於THF(3· 0毫升）之攪拌溶液中加入1N NaOH溶液（1·5毫升，1·500毫莫耳），並使混合物迴流隔 仪。將混合物濃縮，以1 N HC1處理，並以CHCΙ3萃取。將 萃取液以鹽水洗滌，於NaJC»4上乾燥，並於真空中蒸發'。 使固體自正己烷-乙醚-CHCI3-MeOH再結晶而得179.8毫克 (6 5%)之55的白色非晶形固體。 IR (KBr) 1614 、 1601 、 1537 、 1454 、 1228 、 1219 、 1184 /公分；NMR (400 MHz, DMSO -d6) (51.60-2.20 (m， 4H)、2.61-2.68 (πι，1H)、2·89 (s，3H)、3.13-3·18 (m， 1Η) 、 3·40-3· 61 (m， 4Η) 、 3·85 (s， 3Η) 、 4·01 (br m， 1H) 、4·93 (br s, 2H) 、6·50-7·31 (m， 8H)、 8.01 (dd, 1=2.9 ^8.3 Hz, 1H) ^8.18 (t, J=8.3 Hz, 1H)、8. 71 (s，1H)、9· 17 (d，J:l· 5 Hz，1H)、12· 3 (br s，1H); MS(FAB) m/z 550 (MH1); C29H32FN5〇5 ·1/4Η20 之分析計算值：C，6 2.86; H，5.91; N，12.64; F， 3. 43。實測值：C，62· 71 ; H，6. 00 ·，N， 12. 39 ; F， 3.16。 實施例5 2 4-[1 - [4-[Ν’-（2-甲基苯基）脲基]苯基乙醯基]一2一 α比咯啶 基]甲胺基]苯甲醅A 1 N NaOH solution (1.5 ml, 1.500 mmol) was added to a stirred solution of the above compound in THF (3.0 mL), and the mixture was refluxed. The mixture was concentrated, treated with 1 N EtOAc and extracted with CH.sub.3. The extract was washed with brine, dried over NaJC»4 and evaporated in vacuo. The solid was recrystallized from n-hexane-diethyl ether-CHCI3-MeOH to yield 179.8 mg (65%) IR (KBr) 1614, 1601, 1537, 1454, 1228, 1219, 1184 / cm; NMR (400 MHz, DMSO -d6) (51.60-2.20 (m, 4H), 2.61-2.68 (πι,1H), 2· 89 (s, 3H), 3.13-3·18 (m, 1Η), 3·40-3· 61 (m, 4Η), 3·85 (s, 3Η), 4·01 (br m, 1H), 4·93 (br s, 2H) , 6·50-7·31 (m, 8H), 8.01 (dd, 1=2.9 ^8.3 Hz, 1H) ^8.18 (t, J=8.3 Hz, 1H), 8 . 71 (s, 1H), 9· 17 (d, J: l· 5 Hz, 1H), 12· 3 (br s, 1H); MS (FAB) m/z 550 (MH1); C29H32FN5〇5 · Analysis calculated for 1/4Η20: C,6 2.86; H, 5.91; N, 12.64; F, 3. 43. Found: C, 62· 71 ; H, 6. 00 ·, N, 12. 39 ; F , 3.16. Example 5 2 4-[1 - [4-[Ν'-(2-methylphenyl)ureido]phenylethenyl]- 2 -α-pyridyl]methylamino]benzene Hyperthyroidism

在室溫下於4 - [( 2 -咄咯啶基）甲胺基]苯曱酸甲酯（2 2 0毫 克，0.94毫莫耳）、4-[N’-（2-甲基苯基）脲基]笨乙酸（285Methyl 4-[(2-pyrrolidyl)methylamino]benzoate (2 2 mg, 0.94 mmol), 4-[N'-(2-methylphenyl) at room temperature Urea-based] stupid acetic acid (285

89112968.ptd 第257頁 1283240 五、發明說明（253) &quot; -- 笔克，0.94«莫耳）、4~DMAP(140毫克，1.13毫莫耳）及催 化里之Η0ΒΤ於DMF(7毫升）中之攪拌混合物中加aEDC · 1^1^220¾克’1.13耄莫耳）。使所產生之混合物在室溫下 攪拌20小時。將混合物倒入至冰水中。收集固體，以水洗 條並風乾。將粗製固體經由利用CHC13 —Et〇Ac (3 : 1，v/v) 至CHCI3-EtOH(9:l ’v/v)作為洗提液進行矽膠（2〇毫升）管 柱層析，純化而得4-[l-[4-[N，-（2-曱基苯基）脲基]苯基 乙醯基]-2-吼咯啶基]曱胺基]苯甲酸甲酯（4〇〇.毫克，85%) 之膠。UMR (CDC13) (Π· 75-2. 05 (m 系列，4H)、2· 24 (s，3H)、3.18 及 3.27 (各m，各 1Η)、3·51 (m，2H)、 3.60 (s，2H)、3·83 (s，3H)、4.52 (m，1H)、6.52 (m 3H)、6· 81 (s， 1H)、7· U -7. 25 (m 系列，7H)、7· 53 1H) 、 7.81 (d， J=8.8 Hz， 2H)。 ’ 使4-[1 -[4-[Ν’ -（2-曱基苯基）脲基]苯基乙醯基]一2一 〇比 咯啶基]甲胺基]苯甲酸甲酯（ 280毫克，0· 56亳莫耳）於丁HF (3毫升）及〇· 2 5N NaOH(6· 8毫升，1·75毫莫耳）中之混合物 在6 0-7 0 °C下攪拌3小時。於冷卻後，將混合物倒入至^的 1 N H C1 (3毫升）中。收集固體，以水洗滌並風乾。使粗制 的結晶材料自CHCl3-EtOH-ΙΡΕ再結晶而得4〜[i^4^n， -甲基苯基）脲基]苯基乙醯基]- 2-吼咯啶基]甲胺基^笨^ 酸及56(180毫克，66%)的微細針狀物。IR (KBr) ν 3367 、3294、1712、1 6 0 6、1 539 / 公分； UMR (CDC13-DMSO-d6) (51· 8 0 -2. 0 5 (m 系列，4Η)、2 26 (s，3Η)、2· 94 (m， 1Η)、3· 38 及3· 56 (m 系列，3f〇、·89112968.ptd Page 257 1283240 V. INSTRUCTIONS (253) &quot; -- Pen, 0.94 «Mole, 4~DMAP (140 mg, 1.13 mmol) and 催化0 in DMF (7 ml) Add aEDC · 1^1^2203⁄4 g '1.13耄莫耳) to the stirred mixture. The resulting mixture was stirred at room temperature for 20 hours. Pour the mixture into ice water. The solid was collected, washed with water and air dried. The crude solid was purified by chromatography on silica gel (2 mL) using CHC13-Et〇Ac (3:1/v/v) to CHCI3-EtOH (9:1 'v/v) as eluent. 4-[l-[4-[N,-(2-Mercaptophenyl)ureido]phenylethenyl]-2-oxaridinyl]nonylamino]benzoic acid methyl ester (4〇〇) .mg, 85%) of the glue. UMR (CDC13) (Π· 75-2. 05 (m series, 4H), 2·24 (s, 3H), 3.18 and 3.27 (each m, each 1Η), 3·51 (m, 2H), 3.60 ( s, 2H), 3·83 (s, 3H), 4.52 (m, 1H), 6.52 (m 3H), 6.81 (s, 1H), 7· U -7. 25 (m series, 7H), 7· 53 1H), 7.81 (d, J=8.8 Hz, 2H). ' 4-[1-[4-[4-[Ν'-(2-Mercaptophenyl)ureido]phenylethenyl]- 2-indolylpyridinyl]methylamino]benzoic acid methyl ester (280 </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; . After cooling, the mixture was poured into 1 N H C1 (3 mL). The solid was collected, washed with water and air dried. The crude crystalline material is recrystallized from CHCl3-EtOH-oxime to give 4~[i^4^n,-methylphenyl)ureido]phenylethenyl]-2-pyrrolidyl]methylamine A fine needle with a base acid and 56 (180 mg, 66%). IR (KBr) ν 3367 , 3294 , 1712 , 1 6 0 6 , 1 539 / cm ; UMR (CDC13-DMSO-d6) (51· 8 0 -2. 0 5 (m series, 4Η), 2 26 (s , 3Η), 2· 94 (m, 1Η), 3·38, and 3.56 (m series, 3f〇, ·

89112968.ptd 第 258 頁 1283240 五、發明說明（254) 3.57 (s，2H)、4.23 (m，2H)、6.48 (br s，1H)、6.69 (d， J=8.8Hz， 2H) 、6·91 (t， J=7 Hz, 1H) 、6·91 (m， 4H)、7.39(d，J=8.3Hz，2H)、7.66(d，J=8.8Hz， 2H) 、7·80 (m， 2H) 、8.88 (s， 1H) 、11·76 (s， 1H); MS(FAB) m/z 487(MH1);C28H3()N404 . 0.7 5xH20 之分析計算 值：C，6 7. 24 ; H，6· 45 ; N，11· 20。實測值·· C, 7· 13 ; Η, 6. 32 ； Ν, 11.01。 實施例5 3 4-[1-[4-[Ν’ -（2-氯苯基）脲基]一3一甲氧苯基乙醯基]一（2S) -咄咯啶基]甲氧苯甲酸曱酯89112968.ptd Page 258 1283240 V. INSTRUCTIONS (254) 3.57 (s, 2H), 4.23 (m, 2H), 6.48 (br s, 1H), 6.69 (d, J = 8.8 Hz, 2H), 6· 91 (t, J=7 Hz, 1H), 6.91 (m, 4H), 7.39 (d, J=8.3Hz, 2H), 7.66 (d, J=8.8Hz, 2H), 7·80 (m , 2H), 8.88 (s, 1H), 11·76 (s, 1H); MS(FAB) m/z 487(MH1); C28H3()N404 . 0.7 5xH20 Analysis calculated: C,6 7. 24 ; H, 6 · 45 ; N, 11 · 20. Measured value·· C, 7· 13 ; Η, 6. 32 ; Ν, 11.01. Example 5 3 4-[1-[4-[Ν'-(2-Chlorophenyl)ureido]-3-methoxyphenylethyl]-(2S)-indenylpyridyl]methoxybenzene Ethyl formate

COOMe 57 及 4-[卜[4-[Ν’ -（2-氯笨基）脲基]一3一甲氧苯基乙醯基]— (2S) -咄咯唆基]甲氧笨曱酸COOMe 57 and 4-[Bu [4-[Ν' -(2-chlorophenyl)ureido]- 3-methoxyphenylethyl]-(2S)-indolyl]methoxy oxanoic acid

於μ-吼咯啶甲醇（15. i克，14958 5毫莫耳）溶於二氧陸園 (1〇〇耄升）之攪拌溶液中加入（Boc)20 ( 3 2. 6克，164. 4毫莫 耳）溶於二氧陸圜（1〇〇毫升）之溶液。使反應混合物於室溫 =授拌1 8小時，並於真空中濃縮。將殘留物經由 化而；τ π _笛=T t 作為洗k液進行管枉層析，純 于 一氧羰基—（2S)-咄咯啶基）曱醇（31. 6克，Add (Boc) 20 (3 2. 6 g, 164.) to a stirred solution of μ-pyrrolidinemethanol (15. i g, 14958 5 mmol) dissolved in dioxane (1 liter). 4 mmol of a solution dissolved in dioxane (1 mL). The reaction mixture was allowed to stir at room temperature for 18 h and concentrated in vacuo. The residue is hydrolyzed; τ π _ flute = T t is used as a washing liquid for tube chromatography, and is pure to monooxycarbonyl-(2S)-pyridinyl) decyl alcohol (31.6 g,

1283240 發明說明（255) 定量）的無色油。1H-NMR (CDC13) (Π· 47 (s， 9Η)、 1.60-2.00 (m， 3Η) 、3.25-3·70 (4Η， m) 、3·92-4·〇η (m， 1 Η) 〇 在〇°C下於（1-第三丁氧羰基-(2S)_吼咯啶基）甲醇（4 克，20·0毫莫耳）、4-羥基苯曱酸甲酯（3·04克，2〇.〇龙 耳）及Ph3P(6. 28克，24.0毫莫耳）溶於THF(50毫升）之^、 =液中加ADIAD(4.85克，24.0毫莫耳）。使反應混合^ 室溫下攪拌1 8小時。將混合物於真空中濃縮。將殘留物p 由於矽膠上利用正己烷-Et0Ac( 5 :丨，v/v)作為洗提液進^ 官桎層析，純化而得4-(1-第三丁氧羰基—（2S)—吡咯啶美I 甲氣本曱酸曱醋（5.4克’81%)的淡黃色油。hmr (CDC13) 51.47 (s，9H)、1·88-2·04 (m，4H)、3.41 (m 2H)、3·91 (s，3H)、3·90一3·92 (m，1H)、4.1卜4.16^ (m， 2H) 、6·94 (d， J二8·6 Hz, 2H) 、7·94 (d， J=8 31283240 Description of the invention (255) Quantitative) of a colorless oil. 1H-NMR (CDC13) (Π· 47 (s, 9Η), 1.60-2.00 (m, 3Η), 3.25-3·70 (4Η, m), 3·92-4·〇η (m, 1 Η) 1-(1-tert-butoxycarbonyl-(2S)-pyridinyl)methanol (4 g, 20·0 mmol), methyl 4-hydroxybenzoate (3·04) at 〇 °C克, 2〇.〇龙耳) and Ph3P (6. 28 g, 24.0 mmol) dissolved in THF (50 ml) ^, = solution plus ADIAD (4.85 g, 24.0 mmol). The mixture is stirred at room temperature for 18 hours. The mixture is concentrated in vacuo. The residue p is purified by using hexane-Et0Ac (5: 丨, v/v) as an eluent. 4-(1-tert-butoxycarbonyl-(2S)-pyrrolidinime I methyl phthalic acid bismuth vinegar (5.4 g '81%) light yellow oil. hmr (CDC13) 51.47 (s, 9H), 1·88-2·04 (m, 4H), 3.41 (m 2H), 3·91 (s, 3H), 3·90·3·92 (m, 1H), 4.1 4.16^ (m, 2H) ,6·94 (d, J 2·8 Hz, 2H), 7·94 (d, J=8 3

Hz, 2H) 。 ’ · 在0°C下於4-（1-第三丁氧羰基一2S—咣咯啶基）甲氧笨 ，甲酯（2·1克，6.27毫莫耳）溶於(：112(：12(9.〇毫升）之攪 溶液中加入TFA( 6.0毫升）。使反應混合物在室溫下攪拌〇 5小時。將混合物於真空中濃縮。將飽和NaHC〇3加至殘留· ，，並以CH2C12卒取。將萃取液以鹽水洗滌，於Na〗s〇4上乾 秌，並於真空中濃縮。將粗製產物不經進一步的純化而使 用於後續的反應中。在〇 t：下於此粗製產物（4 7 〇毫克，2 〇 毫莫耳）、4-[N -(2 -氣苯基）脲基]- 3-甲氧苯乙酸（669毫 克，2· 0毫莫耳）、HOBt( 40 5毫克，3.0毫莫耳）、及三乙胺Hz, 2H). ' · 4-(1-tert-butoxycarbonyl-2S-pyridinyl)methoxyx, methyl ester (2.11 g, 6.27 mmol) dissolved at 0 ° C (: 112 (: TFA (6.0 ml) was added to a stirred solution of 12 (9 mL). The mixture was stirred and stirred at room temperature for 5 hr. The mixture was concentrated in vacuo. The extract was washed with brine, dried over Na s 〇 4 and concentrated in vacuo. The crude product was used in the next reaction without further purification. Crude product (47 mg, 2 mmol), 4-[N-(2-(phenylphenyl)ureido]-3-methoxyphenylacetic acid (669 mg, 2.0 mmol), HOBt (40 5 mg, 3.0 mmol), and triethylamine

1283240 五、發明說明（256) --- ( 554毫升，4.0毫莫耳）溶於THF(1〇 〇毫升）及（1〇 〇 毫升）之攪拌溶液中加入EDC ·ΗΠ( 576毫克，3 〇毫莫 =)。使反應混合物在室溫下攪拌丨6小時，並於真空中濃 縮將水加至殘留物，並以EtOAc萃取。將萃取液以飽和 NaHC〇3洗滌，然後於^4〇4上乾燥，並於真空中濃縮。將 殘留物經由於矽膠上利用正己烷—Et〇Ac (1:4，v/v)作為 洗提液進行管柱層析，純化而得57(9〇〇毫克，82%)的無色 油。1Η-NMR (CDC13) (52.04-2.10 (m，4H)、3.51-3.70 (m，6 Η )、3 · 8 7 ( s，3 Η )、4 · 11 一 4 · 1 8 (in，2 Η )、6 · 7 7 -6·88 (m，4H)、7.23-7.34 (m，4H)、7·91-7·96 (m， 2H) 、 8·17-8·19 (m， 1H)。 於4-[1-[4-[N，-（2-氯苯基）脲基]-3一甲氧苯基乙醯基] -（2S)-咄咯啶基]甲氧苯曱酸甲酯（7〇〇毫克，127毫莫耳） 溶於THF(10· 0毫升）及Me〇H(5· 0毫升）之攪拌溶液中加入1N Na0H(2. 0毫升，2· 0毫莫耳）。使混合物在7〇。〇下攪拌24小 時。將混合物於真空中濃縮，加入水，並以丨N HC1中和。 收集所產生之固體，以水洗滌，並於真空中乾燥而得 5 8 ( 6 4 0毫克，9 4 %)的白色結晶固體。熔點1 2 6 - 1 3 0 °C ; IR(KBr) 3324 、2938 、2877 、1604 、1533 、1249 、1166 、 750 / 公分；UMR (DMSO-d6) (51· 93-2· 05 (m，4H)、 3·52-3·61 (m，5H)、3·82 (s，3H)、3·99-4.01 (m，2H) 、4 · 1 8 - 4. 2 0 (m，1 Η)、4 · 2 9 (m，1 Η )、6 · 7 4 - 6 · 7 6 ( d， 1H，J = 8.3 Hz)、6·87 (s，1H)、6·99-7.04 (m，3H)、 7·25-7·29 (m，1H)、7.4 卜 7.43 (d，1H，J 二8.1 Hz)、1283240 V. INSTRUCTIONS (256) --- (554 ml, 4.0 mmol) dissolved in THF (1 ml) and (1 ml) in EDC · ΗΠ (576 mg, 3 〇) Momo =). The reaction mixture was stirred at room temperature for 6 hr then EtOAc (EtOAc) The extract was washed with saturated NaHC.sub.3 then dried over EtOAc EtOAc. The residue was subjected to column chromatography using hexane-EtOAc (1:4, v/v) eluted to elute to afford 57 (9 mg, 82%) of colorless oil. 1Η-NMR (CDC13) (52.04-2.10 (m, 4H), 3.51-3.70 (m, 6 Η ), 3 · 8 7 ( s, 3 Η ), 4 · 11 - 4 · 1 8 (in, 2 Η ), 6 · 7 7 -6·88 (m, 4H), 7.23-7.34 (m, 4H), 7·91-7·96 (m, 2H), 8·17-8·19 (m, 1H) 4-[1-[4-[N,-(2-Chlorophenyl)ureido]-3-methoxyphenylethenyl]-(2S)-oxaridinyl]methoxybenzoic acid Methyl ester (7 mM, 127 mmol). In a stirred solution of THF (10.0 mL) and Me 〇H (5.0 mL), 1N NaH (2. The mixture was stirred at room temperature for 24 hours. The mixture was concentrated in vacuo, water was added, and then neutralized with 丨N HCl. The resulting solid was collected, washed with water and dried in vacuo. 5 8 ( 6 4 0 mg, 94%) of a white crystalline solid. m.p. 1 2 6 - 1 3 0 ° C; IR (KBr) 3324, 2938, 2877, 1604, 1533, 1249, 1166, 750 / cm; UMR (DMSO-d6) (51·93-2· 05 (m, 4H), 3·52-3·61 (m, 5H), 3·82 (s, 3H), 3.99-4.01 (m, 2H) , 4 · 1 8 - 4. 2 0 (m, 1 Η), 4 · 2 9 (m, 1 Η ), 6 · 7 4 - 6 · 7 6 ( d, 1H, J = 8.3 Hz), 6·87 (s, 1H), 6·99-7.04 (m, 3H), 7·25-7·29 (m, 1H), 7.4 7.4 7.43 (d , 1H, J two 8.1 Hz),

89112968.ptd 第261頁 1283240 五、發明說明（257) 7·86-7.91 (m， 2H) 、7·95-7.97 (m， 1H) 、8·09-8·11 (d， 1Η，】=8·3 Hz) 、8·87-8·92 (m， 1H); MS(FAB) m/z 5 3 8 (M+ +1)，C28 H28 N3 〇6 · 〇 · 5 h 2 0 之分析計算值：C，6 1 · 4 8 ;H，5· 34 ; N，7. 68 ; Cl, 6· 48。實測值：C，61· 46 ; H， 5. 36 ; N，7· 62 ; Cl，6· 50。 關於5 8之N a鹽· C28 H27 N3 〇6 · N a · 1. 5 H2 〇之分析計算值·· C， 5 7. 29 ; H，5· 15 ; N， 7· 16。實測值·· C， 57· 48 ; H， 5. 04 ； N, 6.99。 實施例54 4 - [1 - [4-[N’-(2 -溴笨基）脲基]一3 一甲氧苯基乙醯基]-(2S) -咄咯啶基]甲氧苯甲酸 在0°C下於4 -（2S-咄咯啶基）甲氧苯甲酸甲酯（470毫克， 2.0毫莫耳）、4-[Ν’-（2 -溴苯基）脲基]- 3-甲氧苯乙酸（758 毫克，2· 0毫莫耳）、HOBt(40 5毫克，3.0毫莫耳）、及三乙 胺（ 5 54毫升，3· 0毫莫耳）溶於THF(1〇· 〇毫升）&amp;MeCN(1(). 〇 毫升）之攪拌溶液中加入EDC · HC 1 ( 5 76毫克，3. 0毫莫 耳）。使反應混合物在室溫下攪拌丨6小時，並於真空中濃 縮。將水加至殘留物，並以Et0Ac萃取。將萃取液以飽$ NaHC〇3洗滌，然後於心2如4上乾燥，並於真空中濃縮。 殘留物經由於矽膠上利用正己烷_Et〇Ac (1:4，v/v)兔 洗提液進行管柱層析，純化而得4-[ι —[4-[N，-(2-溴笨美89112968.ptd Page 261 1283240 V. INSTRUCTIONS (257) 7·86-7.91 (m, 2H), 7.95-7.97 (m, 1H), 8·09-8·11 (d, 1Η,]= 8·3 Hz), 8·87-8·92 (m, 1H); MS(FAB) m/z 5 3 8 (M+ +1), C28 H28 N3 〇6 · 〇· 5 h 2 0 Value: C, 6 1 · 4 8 ; H, 5 · 34 ; N, 7. 68 ; Cl, 6. 48. Found: C, 61 · 46 ; H, 5. 36 ; N, 7· 62 ; Cl, 6. 50. About 5 8 N a salt · C28 H27 N3 〇 6 · N a · 1. 5 H2 〇 Analytical calculation value · · C, 5 7. 29 ; H, 5 · 15 ; N, 7· 16. Found C· 57· 48 ; H, 5. 04 ; N, 6.99. Example 54 4 - [1 - [4-[N'-(2-Butyl)ureido]- 3-methoxyphenylethyl]-(2S)-indolyl]methoxybenzoic acid Methyl 4-(2S-decalidyl)methoxybenzoate (470 mg, 2.0 mmol), 4-[Ν'-(2-bromophenyl)ureido]- 3 at 0 °C -Methoxybenzoic acid (758 mg, 2.0 mmol), HOBt (40 5 mg, 3.0 mmol), and triethylamine (5 54 mL, 3.0 mmol) dissolved in THF (1) EDC · HC 1 (5 76 mg, 3.0 mmol) was added to the stirred solution of 〇·〇ml) &amp;MeCN(1(). 〇ml). The reaction mixture was stirred at room temperature for 6 hours and concentrated in vacuo. Water was added to the residue and extracted with EtOAc. The extract was washed with sat NaCI 〇3, then dried on a heart 2 such as 4 and concentrated in vacuo. The residue was purified by column chromatography on a tannin extract using n-hexane_Et〇Ac (1:4, v/v) rabbit extract to obtain 4-[ι-[4-[N,-(2- Bromo stupid

12832401283240

)脲基]- 3-甲氧苯基乙驢基]-(2 S)-吼嘻17定基]曱氧笨甲酉分 甲酯（1· 0 克，84%)的無色油。1H-NMR (CDC13) 52.041 (m，4H)、3·52-3.54 (m，1H)、3·62 (s，2H)、3.70 :s 3H)、3·88 (s，3H)、4· 13-4· 19 (m，2H)、6· 79-6· 94 ’ (m，4Η)、7·20-7·31 (m，1Η)、7·91 -8·12 (m，2Η)、 8· 13-8. 15 (m，1Η)。 於4 - [1-[4-[Ν’-（2 -漠苯基）脲基]- 3 -甲氧笨基乙醯 基]-（2S) -咄咯啶基]曱氧苯甲酸曱酯（ 78 0毫克，；[· 31毫莫 耳）溶於THF(10· 0毫升）及Me0H(5. 0毫升）之攪拌溶液中加 入IN NaOH(2· 0毫升，2· 0毫莫耳）。使混合物在7〇。(：下擾 拌2 4小時。將混合物於真空中濃縮，加入水，並以1 n H C 1 中和。收集所產生之固體，以水洗條，並於真空中乾燥而 得5 9 ( 730毫克，96%)的白色結晶固體。熔點1 20- 1 25 °C ; IR(KBr) 3318、2938、1 6 04、1 5 2 9、1166、1025/公分； UMR (DMSO-d6) (51.92-1.96 (m，4H)、3.52-3.60 (m， 5H) 、3·82 (s， 3H) 、3·98-4·02 (m， 1H) 、4·16-4·19 (m， 1Η) 、4.29 (m， 1Η) 、6·75 (d, J=8.3 Ηζ， 1Η)、 6.87 (m, 1H) ^ 6.94-7.04 (m, 3H) ^7.29-7.33 (m, 1H) 、7.57-7.59 (m， 1H) 、7.85-7.96 (m， 4H) 、8.72 (s，1H)、8.91 (s，1H); MS(FAB) m/z 582 (MH1); C28H28N3 06 Br · 1. 0H2O 之分析計算值：C，56. 01 ; H，5. 04 ； N，7. 00 ； Br, 13. 3卜實測值：C, 56. 1 2 ; H，_ 4· 98 ; N， 6· 96 ; Br, 13· 57。 3 -胺基-4 - [1-[4 - [Ν’- (2-經苯基）脈基]- 3-甲氧苯基乙商脸Urea]-3-methoxyphenylethylidene]-(2S)-吼嘻17-decyl] anthracene oxime methyl ester (1.0 g, 84%) of a colorless oil. 1H-NMR (CDC13) 52.041 (m, 4H), 3·52-3.54 (m, 1H), 3.62 (s, 2H), 3.70: s 3H), 3·88 (s, 3H), 4· 13-4· 19 (m, 2H), 6·79-6· 94 ' (m, 4Η), 7·20-7·31 (m, 1Η), 7·91 -8·12 (m, 2Η) , 8· 13-8. 15 (m, 1Η). 4-[1-[4-[4-[Ν[-(2-Phenylphenyl)ureido]- 3 -methoxyphenylethyl]-(2S)-decalridinyl] decyloxybenzoate (78 0 mg,; [· 31 mmol] dissolved in THF (10.0 ml) and Me0H (5.0 ml) in a stirred solution of IN NaOH (2.0 mL, 2.0 mmol) . The mixture was allowed to stand at 7 Torr. (: Dissolve for 24 hours. Concentrate the mixture in vacuo, add water, neutralize with 1 n HC 1. Collect the resulting solid, wash the strip with water, and dry in vacuo to give 5 9 (730 mg) , 96%) of white crystalline solid. Melting point 1 20 - 1 25 ° C; IR (KBr) 3318, 2938, 1 6 04, 1 5 2 9 , 1166, 1025 / cm; UMR (DMSO-d6) (51.92- 1.96 (m, 4H), 3.52-3.60 (m, 5H), 3·82 (s, 3H), 3·98-4·02 (m, 1H), 4·16-4·19 (m, 1Η) , 4.29 (m, 1Η), 6.75 (d, J=8.3 Ηζ, 1Η), 6.87 (m, 1H) ^ 6.94-7.04 (m, 3H) ^7.29-7.33 (m, 1H), 7.57-7.59 (m, 1H), 7.85-7.96 (m, 4H), 8.72 (s, 1H), 8.91 (s, 1H); MS(FAB) m/z 582 (MH1); C28H28N3 06 Br · 1. Analysis of 0H2O Calculated: C, 56. 01 ; H, 5. 04 ; N, 7. 00 ; Br, 13. 3 measured values: C, 56. 1 2 ; H, _ 4 · 98 ; N, 6 · 96 ; Br, 13· 57. 3-Amino-4 - [1-[4 - [Ν'- (2-Phenyl))] 3-methoxyphenyl E

89112968.ptd 第 263 頁 1283240 五、發明說明（259) 胺基]- 2 -吼洛咬甲氧基]苯甲酸89112968.ptd Page 263 1283240 V. INSTRUCTIONS (259) Amino]- 2 - indole methoxy]benzoic acid

實施例5 5 2-窄氧硝基苯. OBn 在〇°C下於2 -石肖基S分（10.0克，72.0毫莫耳）及KC0 3 (9.96克，72·0毫莫耳）溶於DMF(1 50毫升）之攪拌溶液中逐 滴加入苯甲溴（9· 40毫升，79· 2毫莫耳）。於在室溫下攪拌 3小時後，將反應混合物以水稀釋，以Et2〇萃取。將萃取 液以鹽水洗務’於Nag SO#上乾燥，並濃縮至乾。利用己燒 jtOAc(j:l，v/v)作為洗提液將殘留物進行層析而得2—苄 氧硝基苯（14· 7 克，89%)的黃色油。1H_NMR (CDCl3) 5 5· 24 (s，2H)、7·04 (t，&gt;7·8 Hz, 1H)、7.12 (d，J = 7.8Example 5 5 2-Narrow nitrobenzene. OBn was dissolved in DMF at 2 ° Shishiji S (10.0 g, 72.0 mmol) and KCO 3 (9.96 g, 72.0 mmol) at 〇 °C. To a stirred solution of (1 50 ml) was added benzyl bromide (9·40 ml, 79·2 mmol). After stirring at room temperature for 3 hours, the reaction mixture was diluted with water and extracted with EtOAc. The extract was dried over Nag SO# with brine and concentrated to dryness. The residue was chromatographed using hexane (j:l, v/v) as eluent to give 2-benzyloxynitrobenzene (14.7 g, 89%) as a yellow oil. 1H_NMR (CDCl3) 5 5· 24 (s, 2H), 7·04 (t, &gt; 7·8 Hz, 1H), 7.12 (d, J = 7.8

Hz，1H)、7. 3&quot;· 50 (m，5H)、7· 51 (d，J = 1. 5 Hz， 1H)、7·86 (dd，J = 7.8、ι·5 hz，ih)。 2 一苄氧基苯胺 ^ΝΗ2 OBn 在〇C下於2-苄氧硝基苯（9·92克，43·3毫莫耳）及Hz, 1H), 7. 3&quot; 50 (m, 5H), 7· 51 (d, J = 1. 5 Hz, 1H), 7·86 (dd, J = 7.8, ι·5 hz, ih) . 2 monobenzyloxyaniline ^ΝΗ2 OBn in 〇C under 2-benzyloxynitrobenzene (9·92 g, 43·3 mmol) and

第264頁 1283240Page 264 1283240

五、發明說明（260) (20·3克，157毫莫耳）溶於Me〇H(35〇毫升） ° C利用TLC皿測）’將混合物蒸發掉。將黑色事 1Ν ΗΠ中，然後經由加入1N議將酸性=溶解於 卒取。將萃取液以鹽水洗蘇，於Na2S〇4上乾燥，並濃 、、、佰至乾。利用CHC13作為洗提液將殘留物進行層析而得2一 爷氧基笨胺（8· 60克，100%)的帶紅色油。lH — NeMR ) 占 3.71 (寬的 s，2H)、5·06 (s，2H)、6·6&quot;·86 (m，3 4Η)、7·32-7·44 (m，5Η) ; FAB-MS m/z 20 0 (ΜΗ1)’。 4一 [『-（2-芊氧苯基）脲基]-3-甲氧苯乙酸第三丁醋5. Description of the invention (260) (20·3 g, 157 mmol) dissolved in Me〇H (35 〇 ml) ° C using a TLC dish) The mixture was evaporated off. Put the black thing in 1 Ν, then dissolve the acid = dissolved in the stroke by adding 1N. The extract was washed with brine, dried over Na2S〇4, and concentrated to dryness. The residue was chromatographed using CHC13 as an eluent to give a reddish oil of bis- phenylamine (8·60 g, 100%). lH — NeMR ) accounts for 3.71 (width s, 2H), 5·06 (s, 2H), 6·6&quot; 86 (m, 3 4Η), 7·32-7·44 (m, 5Η); FAB -MS m/z 20 0 (ΜΗ1)'. 4-[[-(2-oxophenyl)ureido]-3-methoxyphenylacetic acid third vinegar

在〇C下於2-苄氧基苯胺（1·15克，5.77毫莫耳）溶於苯 (60毫升）之溶液中加入三光氣（1· 27克，6· 35毫莫耳）及 Eh2· 60毫升，1 7· 3毫莫耳）。並使反應混合物迴流加熱 2 〇小時。將所產生之混合物過濾並以己烧洗滌，及將濾液 濃縮留下殘留的油，將其利用己烷—Et〇Ac(4:丨，v/v)作為 洗夜進行層析而得4_[N -(2-苄氧苯基）脲基]-3-甲氧 苯乙酸第三丁酯（2.38克，89%)的黃色油。iH-NMR (CDC13) 51·44 (s， 9H)、3·44 (s， 2H)、3·78 (s， 3H)、5·07 (s，2Η)、6·73 (dd，j二8·0、1·7 Ηζ，1Η)、6·78 (d， J = 1·7 Ηζ，1Η)、6. 9 0 -6.98 (m，3Η)、7·07 (s，1Η)、 7·29 (s，1Η)、7·33-7·38 (m，5Η)、7·91 (d，J = 8.0Add tributary gas (1·27 g, 6.3 mmol) and Eh2 to a solution of 2-benzyloxyaniline (1·15 g, 5.77 mmol) dissolved in benzene (60 ml) at 〇C. · 60 ml, 1 7 · 3 mmol). The reaction mixture was heated at reflux for 2 hrs. The resulting mixture was filtered and washed with hexane, and the filtrate was concentrated to leave a residual oil, which was subjected to chromatography using hexane-Et〇Ac (4: 丨, v/v) as a wash night to obtain 4_[ Yellow oil of N-(2-benzyloxyphenyl)ureido]-3-methoxybenzoic acid tert-butyl ester (2.38 g, 89%). iH-NMR (CDC13) 51·44 (s, 9H), 3·44 (s, 2H), 3·78 (s, 3H), 5·07 (s, 2Η), 6.73 (dd, j 2 8·0,1·7 Ηζ,1Η),6·78 (d, J = 1·7 Ηζ, 1Η), 6. 9 0 -6.98 (m, 3Η), 7·07 (s, 1Η), 7 · 29 (s, 1Η), 7·33-7·38 (m, 5Η), 7·91 (d, J = 8.0

89112968.ptd 第265頁 1283240 五、發明說明（261)89112968.ptd Page 265 1283240 V. Description of invention (261)

Hz， 1H) 、 8·14 (m， 1H)。 4-[N’ -（2-苄氧苯基）脲基]—3-甲氧苯乙酸 在0 °C下於4-[Ν’ -（2-苄氧笨基）脲基]-3_曱氧苯乙酸第 三丁酯（2.35克，5·08毫莫耳）溶於CH2Cl2(25毫升）之溶液 中加入TFA(25宅升）。於在室溫下攪拌3小時後，將混合物 濃縮。將殘留物溶解於IN NaOH，並以Et20洗滌。將鹼性 水層倒入至冰的IN HC1中，並以CHCl3 — Me〇H (4: 1，v/v) 萃取所產生之混合物。將萃取液以鹽水洗滌，於Na2s〇4上 乾燥’並濃縮至乾。將殘留物溶解於異丙醚，並將己烷加 至此溶液直至完成結晶為止。收集固體而得4 — [ N，- ( 2 -苄 氧苯基）脲基]-3-甲氧笨乙酸的棕色固體。！H —NMr (DMS0-d6) 53·50 (s，2H)、3·85 (s，3H)、5·26 (s， 2Η)、6·76 (d，J = 8.3 Ηζ，1Η)、6·83-6·89 (m，2Η)、 6·91 (s， 1H) 、7·01 (dd， J=8.3 、2.3 Hz, 1H) 、7·31 (t，J = 7· 3 Hz, 1H)、7· 39 (t，J = 7· 3 Hz，2H)、7· 49 (d, J = 7.3 Hz, 2H) &gt;7.97 (d, J = 8. 3 Hz, 1H) ^8.04 (d，】 = 8·3 Hz，1H)、8.80 (s，1H)、8.86 (s，1H)、 12.24 (寬的s，1H) ; FAB-MS m/z 407 (MH1)。 4-[1 -[4-[Ν’ -（2 -辛氧苯基）脲基]—3一甲氧苯基乙醯胺基] -2-咄咯啶甲氧基]-3-硝基苯甲酸甲酯Hz, 1H), 8·14 (m, 1H). 4-[N'-(2-benzyloxyphenyl)ureido]-3-methoxyphenylacetic acid at 0 ° C in 4-[Ν' -(2-benzyloxyphenyl)ureido]-3_ TCA (25 liters) was added to a solution of tributyl phthalate (2.35 g, 5.08 mmol) in CH2Cl2 (25 mL). After stirring at room temperature for 3 hours, the mixture was concentrated. The residue was dissolved in IN NaOH and washed with EtOAc. The alkaline aqueous layer was poured into ice IN HCl, and the resulting mixture was extracted with CHCl 3 - Me 〇 H (4: 1, v/v). The extract was washed with brine, dried over Na.sub.4, and concentrated to dryness. The residue was dissolved in isopropyl ether, and hexane was added to the solution until crystallization was completed. The solid was collected to give 4-[N,-(2-benzyloxyphenyl)ureido]-3-methoxybenzoic acid as a brown solid. ! H—NMr (DMS0-d6) 53·50 (s, 2H), 3·85 (s, 3H), 5·26 (s, 2Η), 6·76 (d, J = 8.3 Ηζ, 1Η), 6 ·83-6·89 (m, 2Η), 6·91 (s, 1H), 7·01 (dd, J=8.3, 2.3 Hz, 1H), 7·31 (t, J = 7· 3 Hz, 1H), 7· 39 (t, J = 7· 3 Hz, 2H), 7·49 (d, J = 7.3 Hz, 2H) &gt; 7.97 (d, J = 8. 3 Hz, 1H) ^8.04 ( d,] = 8·3 Hz, 1H), 8.80 (s, 1H), 8.86 (s, 1H), 12.24 (wide s, 1H); FAB-MS m/z 407 (MH1). 4-[1 -[4-[Ν'-(2-octoxyphenyl)ureido]-3-methoxyphenylethylamino]-2-indenylpyridylmethoxy]-3-nitro Methyl benzoate

89112968.ptd 第266頁 1283240 五、發明說明（262) C〇2Me 於4 - [Ν’-（2-苄氧苯基）脲基]-3-甲氧苯乙酸（1.12克， 2.76毫莫耳）、4 -（2-吼洛咬甲氧基）-3-硝基苯甲酸甲酯 (890毫克，2.76毫莫耳）、HOBt(74.0毫克，〇·55毫莫 耳）、DMAP(67.〇 毫克，〇·55 毫莫耳）、及Et3N(0.58 毫升， 4.13宅莫耳）溶於THF(15毫升）之溶液中加入EDC ·Η(Μ(792 宅克，4 · 1 3 ^:莫耳）。於在室溫下授拌1 2小時後，將反應 混合物以水稀釋，並以EtOAc萃取。將萃取液以鹽水洗 滌，於NagSO4上乾燥，並濃縮至乾。利用Et〇Ac作為洗提液 將殘留物進行層析而得3 -胺基-4-[ l-[4-[N，-（2 -經苯基） 脲基]- 3 -甲氧苯基乙醯胺基]—2 -。比咯啶曱氧基]苯甲酸甲 酯（1· 52克，82%)的黃色非晶形固體。ιΗ一NMR (CDCl3)占 1 · 9 1 ( m，1 Η )、1 · 9 5 - 2 · 1 7 (m，3 Η )、3 · 4 7 - 3 · 5 3 ( m，2 Η ) 、3·56 (s， 2H) 、3·60 (m， 1H) 、3·68 (s， 3H) 、3·9〇 (s，3H)、4·11 (d，J = 7.3 Hz，1H)、4·45 (m，1H)、 5.08 (s，2H)、6.70 (dd，J=：8.3.、ι·9 Hz, 1H)、6.75 (d， J=1.9 Hz， 1H) 、6.91一6.99 (m, 3H) 、7·16 (s， 1H)、7·18 (d，〗 = 8·3 Hz，ih)、7.33-7.4G (m，6H)、 7·91 (d， J=8.3 Hz， 1H) 、8·ιι—8·ΐ6 (m， 2H) 、8·46 (s， 1H)。 3 -胺基-4 - [l-[ 4- [N -（2 -羥笨基）脲基]一3 一曱氧苯基乙醯 胺基]- 2 - 11比嘻°疋甲氧基]笨甲酸曱_89112968.ptd Page 266 1283240 V. INSTRUCTIONS (262) C〇2Me in 4 - [Ν'-(2-Benzyloxyphenyl)ureido]-3-methoxyphenylacetic acid (1.12 g, 2.76 mmol) ), 4-(2-indole methoxy)-3-nitrobenzoic acid methyl ester (890 mg, 2.76 mmol), HOBt (74.0 mg, 〇·55 mmol), DMAP (67. 〇mg, 〇·55 mM), and Et3N (0.58 ml, 4.13 house Moer) dissolved in THF (15 ml) to add EDC · Η (Μ (792 宅, 4 · 1 3 ^: Mo After the mixture was stirred at room temperature for 12 hours, the reaction mixture was diluted with water and evaporated with EtOAc. The mixture was washed with brine, dried over NagSO4 and concentrated to dry. The residue is subjected to chromatography to give 3-amino-4-[1-[4-[N,-(2-phenyl)ureido]-3-methoxyphenylacetamido]- 2--Pyrrolidinyloxy]benzoic acid methyl ester (1·52 g, 82%) of a yellow amorphous solid. ιΗ NMR (CDCl3) occupies 1 · 9 1 (m, 1 Η ), 1 · 9 5 - 2 · 1 7 (m, 3 Η ), 3 · 4 7 - 3 · 5 3 ( m, 2 Η ), 3·56 (s, 2H), 3·60 (m, 1H), 3 68 (s, 3H), 3·9〇(s,3H), 4·11 (d, J = 7.3 Hz, 1H), 4·45 (m, 1H), 5.08 (s, 2H), 6.70 (dd , J=: 8.3., ι·9 Hz, 1H), 6.75 (d, J=1.9 Hz, 1H), 6.91 to 6.99 (m, 3H), 7·16 (s, 1H), 7·18 (d , 〗 = 8·3 Hz, ih), 7.33-7.4G (m, 6H), 7·91 (d, J=8.3 Hz, 1H), 8·ιι—8·ΐ6 (m, 2H), 8· 46 (s, 1H). 3-Amino-4 - [l-[4-[N-(2-hydroxyphenyl)ureido]- 3-oxophenylphenylamino]- 2 - 11 ratio嘻°疋methoxy] 笨 曱 曱 _

89112968.ptd 弟267頁 1283240 五、發明說明（263)89112968.ptd 267 pages 1283240 V. Description of invention (263)

使4-[1-[4_[N’ -（2-苄氧笨基）脲基]- 3-曱氧苯基乙酿胺 基]-2-咄咯啶甲氧基]一3一硝基苯甲酸甲酯（1. 52克，2. 27 毫莫耳）溶於MeOH(20毫升）及THF(5毫升）之溶液在5% Pd-C (濕，52· 2% ; 1· 21克）上在氫氣中（4公斤/平方公分）在室 溫下氫化。於攪拌1 7小時後，將催化劑過濾掉並將濾液濃 縮至乾。利用EtOAc作為洗提液將殘留物進行層析得3-胺 基-4 - [1-[4-[Ν’ - (2-羥苯基）脲基]一3一曱氧苯基乙醯胺 基]-2-咄咯啶甲氧基]苯曱酸曱酯（12克，9〇%)的粽色非 晶形固體。1Η-NMR (CDC13)6：L97-2.10 (m，4Η)、3·44 (s， 3Η) 、3·52-3·63 (m， 2Η) 、3·85 (s， 3Η) 、4·1〇-4. 1 8 (m，2 Η )、4 · 5 3 (m，1 Η)、6 · 6 5 - 6 · 6 7 (m，4 Η )、 6·93-7.02 (m，3Η)、7.33 (d，J = 2.2 Ηζ，1Η)、7·36 (dd， J=8.3 、 2.2 Hz， 1H) 、 7.60 (s， 1H)、 7.69 (d， J = 8.3 Hz，1H)、8·08 (s，1H)、9·47 (寬的s， ih); FAB - MSm/z549(M+ + l)。 於3 -胺基-4 - [卜[4- [Ν’-（2-羥苯基）脲基]一3 一甲氧苯基 乙醯胺基]-2-吼咯啶甲氧基]苯甲酸甲酯（丨· 12克，2. 〇4毫 莫耳）溶於THF_MeOH(4:l，ν/ν; 20毫升）之溶液中加入in NaOH(4. 20毫升’4.20耄莫耳）。於在室溫下授拌μ小時 後’將反應混合物濃縮。將殘留物以水稀釋，並在〇 °C下4-[1-[4-[N'-(2-Benzyloxy)ureido]-3-oxophenylphenylamino]-2-indenylpyridylmethoxy]-3-nitro A solution of methyl benzoate (1.52 g, 2.27 mmol) dissolved in MeOH (20 mL) and THF (5 mL) in 5% Pd-C (wet, 52. 2%; 21. 21 g Hydrogenation at room temperature in hydrogen (4 kg/cm 2 ). After stirring for 17 hours, the catalyst was filtered off and the filtrate was concentrated to dryness. The residue was chromatographed using EtOAc as an eluent to give 3-amino-4-[1-[4-[Ν[-(2-hydroxyphenyl)ureido]- 3-oxooxyphenylacetamide A quinone amorphous solid of bismuth-2-pyrrolidine methoxy]benzoate (12 g, 9 %). 1Η-NMR (CDC13) 6: L97-2.10 (m, 4Η), 3·44 (s, 3Η), 3·52-3·63 (m, 2Η), 3·85 (s, 3Η), 4· 1〇-4. 1 8 (m,2 Η ), 4 · 5 3 (m,1 Η), 6 · 6 5 - 6 · 6 7 (m,4 Η ), 6·93-7.02 (m,3Η ), 7.33 (d, J = 2.2 Ηζ, 1 Η), 7.36 (dd, J = 8.3, 2.2 Hz, 1H), 7.60 (s, 1H), 7.69 (d, J = 8.3 Hz, 1H), 8 · 08 (s, 1H), 9·47 (wide s, ih); FAB - MSm/z549 (M+ + l). 3-Amino-4 - [Bu [4- [Ν'-(2-hydroxyphenyl)ureido]- 3-methoxyphenylethylamino]-2-pyrrolidine methoxy]benzene Methyl formate (丨·12 g, 2. 〇4 mmol) was dissolved in THF_MeOH (4:1, ν/ν; 20 mL). The reaction mixture was concentrated after stirring for 5 hours at room temperature. Dilute the residue with water and at 〇 °C

89112968.Ptd 第268頁 1283240 五、發明說明（264) 以IN HC1中和。將混合物以CHCl3-MeOH(4 : 1，v/v)萃取， 將其以鹽水洗滌，於Na2S〇4上乾燥，並濃縮至乾。利用 CHC13 :Me0H(5:l，v/v)作為洗提液將殘留物進行層析得 60 ( 352毫克，32°/。）的淡黃色非晶形固體。IR(KBi〇 3282、 3062 、 3025 、 2952 、 2865 、1629 ^ 1546 ^ 1509 &gt; 1454 、 1419 / 公分；UMR (DMSO-d6) 51.87-2.04 (m，4H)、3, 48-3.57 (m， 2H) 、3·60 (s， 2H) 、3·79 (s， 3H) 、3·94 (dd， J=9.5 、7·6 Ηζ， 1Η) 、4·12 (dd， J=9.5 、3·9 Hz) 、4·35 (m， 1H) 、4.87 (寬的s， 1H) 、6·70-6·91 (m， 6H) 、7·16 (dd， 1H， J=8.3 、2·〇 Hz, 1H) 、7·26 (d， J=2·0 Hz， 1H) 、 7·96 (d， J=8. 3 Hz, 1H) 、 7· 97 (d， &gt;8·3 Hz，1H)、8.80 (s，1H)、8·82 (s，1H); FAB-MS m/z 535 (MH1) ; C28H3QN4 07 · 4· 5H2〇 之分析計算值：C, 55. 63 ; Η, 6· 39 ; N，9· 10。實測值：C，55· 08 ; H， 5· 06 ; N，8.69。 實施例5 6 5 - [[卜[4 -[Ν’-（2-氯苯基）脲基]-3-甲氧苯基乙醯基]-2 -吼洛。定基]甲胺基]咄。定- 2 -羧酸89112968.Ptd Page 268 1283240 V. INSTRUCTIONS (264) Neutralize with IN HC1. The mixture was extracted with EtOAc (EtOAc (EtOAc) (EtOAc) The residue was chromatographed using CHC13:Me0H (5:1, v/v) as eluent to give a pale yellow amorphous solid of 60 (352 mg, 32 °). IR (KBi〇3282, 3062, 3025, 2952, 2865, 1629^1546^1509 &gt; 1454, 1419 / cm; UMR (DMSO-d6) 51.87-2.04 (m, 4H), 3, 48-3.57 (m, 2H), 3·60 (s, 2H), 3·79 (s, 3H), 3.94 (dd, J=9.5, 7·6 Ηζ, 1Η), 4·12 (dd, J=9.5, 3 · 9 Hz), 4·35 (m, 1H), 4.87 (wide s, 1H), 6.70-6·91 (m, 6H), 7·16 (dd, 1H, J=8.3, 2· 〇Hz, 1H), 7·26 (d, J=2·0 Hz, 1H), 7·96 (d, J=8. 3 Hz, 1H), 7·97 (d, &gt;8·3 Hz , 1H), 8.80 (s, 1H), 8·82 (s, 1H); FAB-MS m/z 535 (MH1) ; C28H3QN4 07 · 4· 5H2〇 Analytical calculated value: C, 55. 63 ; , 6· 39 ; N, 9· 10. Found: C, 55·08; H, 5· 06 ; N, 8.69. Example 5 6 5 - [[Bu [4 -[Ν'-(2-chloro) Phenyl)ureido]-3-methoxyphenylethenyl]-2-indolyl.]]]]]]]]]]

及 61 · · 5 - [[1-[3-甲氧基- 4 - [Ν’- (2-甲恭苯基）脈基]笨基乙酿 基]- 2 -吼π各咬基]甲胺基]吼π定- 2 -叛酸（D 91 - 4 7 1 0 )And 61 · · 5 - [[1-[3-methoxy- 4 - [Ν'- (2-methyl phenyl) phenyl]] phenyl group] - 2 - 吼 π each bite] Amino] 吼 定 定 - 2 - oxic acid (D 91 - 4 7 1 0 )

89112968.ptd 第269貢 1283240 五、發明說明（265^ 62 61及62在室溫下於5-(曱氧羰基）吡啶-2 -羧酸（2·5克， 13· 8毫莫耳）及4-DM ΑΡ( 340毫克，2·8亳莫耳）溶於第三 -Bu0H(15毫升）之攪拌溶液中加入Boc20(6克’ 27. 6毫莫 耳）。於在室溫下攪拌2小時後，將冰的〇. 2N HC 1 ( 2 0毫升） 加至混合物，並以CH2C12萃取。將萃取液以飽和NaHC03洗 滌，於Na2S04上乾燥，並蒸發。將殘留物於矽膠（50毫升） 上利用CH2C 12作為洗提液進行層析，而得6-第三丁氧羰基 菸鹼酸曱酯（2· 92克，89%)的針狀物。IR(KBr) 2729、 1 736、1 720、1 5 9 0、1 570 / 公分；MS(FAB) m/z 238 (MH1) ; C12H15N04 之分析計算值：c，60· 75 ; H，6· 37 ; N， 5· 90。實測值：c，60. 72 ; H，6. 46 ; N，5. 78。 使6-第三丁氧羰基菸鹼酸甲酯（12克，5〇6毫莫耳）於 THF(15毫升）及〇· 25N NaOH(40毫升，1〇莫耳）中之混合物 在室溫下0 · 5小時。將混合物倒入至冰的丨N hc 1 ( 1 〇毫升） 中。收集固體，以水洗滌並風乾。使粗製固體自CHC13 -EtOH-IPE再結晶而得6-第三丁氧羰基菸鹼酸（85〇毫克， 7 6%)的針狀物。IR (KBr) ζ； 30 95、1728、1705 / 公分； ^-NMR (DMS0~d6) 51.63 (Sj gH) ^8.09 (m, 1H) ^8.17 (m，1H)、8·42 (dt，《1 = 2.4 及 8·3 Hz，1H)、9·21 (ΐ， J = 2.4 及 8.8 Hz, 1H); MS(FAB) m/z 224 (MH1); C29H33N3 06 之分析計算值·· c，36. 18 ; H，1.18; M，3, 84。89112968.ptd 269 tribute 1283240 V. Description of the invention (265^ 62 61 and 62 at room temperature in 5-(oxacarbonyl)pyridine-2-carboxylic acid (2.5 g, 13.8 mmol) and 4-DM ΑΡ (340 mg, 2·8 亳mol) was dissolved in a stirred solution of the third-Bu0H (15 ml). Boc20 (6 g ' 27. 6 mmol) was added. Stir at room temperature 2 After </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Chromatography was carried out using CH 2 C 12 as an eluent to give a needle of 6-t-butoxycarbonyl nicotinic acid decyl ester (2.92 g, 89%). IR (KBr) 2729, 1 736, 1 720, 1 5 9 0, 1 570 / cm; MS (FAB) m / z 238 (MH1) ; C12H15N04 Analysis calculated: c, 60 · 75 ; H, 6 · 37 ; N, 5 · 90. :c,60.72 ; H,6. 46 ; N,5. 78. Methyl 6-t-butoxycarbonyl nicotinic acid (12 g, 5 〇 6 mmol) in THF (15 mL) 〇· 25N NaOH (40 ml, 1 Torr) mixture at room temperature for 0.5 hours. The product was poured into ice 丨N hc 1 (1 mL). The solid was collected, washed with water and air-dried. The crude solid was recrystallized from CHC13-EtOH-IPE to give 6-t-butoxycarbonylnicotinic acid ( 85 mg, 7 6%) of needles. IR (KBr) ζ; 30 95, 1728, 1705 / cm; ^-NMR (DMS0~d6) 51.63 (Sj gH) ^8.09 (m, 1H) ^8.17 (m, 1H), 8.42 (dt, "1 = 2.4 and 8·3 Hz, 1H), 9·21 (ΐ, J = 2.4 and 8.8 Hz, 1H); MS(FAB) m/z 224 ( MH1); Analytical calculated value of C29H33N3 06 · c, 36. 18 ; H, 1.18; M, 3, 84.

89112968.ptd89112968.ptd

第270頁 1283240 五、發明說明（266) 實測值：C, 36.85; H, 3.35； N, 3.79 ° 在室溫下於6 -第三丁氧羰基菸鹼酸（19克，8·51毫莫 耳）及三乙胺（1.17克，11. 49毫莫耳）於第三咄⑹以“毫 升）及甲苯（30毫升）中之攪拌混合物中加入叠氮二苯填醯 (2. 93克，10. 64毫莫耳）溶於甲苯（3毫升）之^液' 然&gt;後使 所產生之混合物迴流加熱5小時。於冷卻後，將冰的1 ν HC1 (5毫升）加至混合物，並以甲苯萃取。將萃取液以鹽 水洗；條’於N S 〇4上乾燥’並蒸發。將殘留物於石夕膠（&amp; 〇毫 升）上利用甲笨- E10 A c ( 5 : 1，v / v )作為洗提液進行層析， 而得5 -第二丁氧幾胺基-2 -吼唆敌酸第三丁 g旨（1 9克， 76%)的膠。NMR (CDC13) (Π· 53 (s，9H)、1· 63 (s， 9H) 、6·82 (br s， 1H) 、8·01 (d， J=8.8 Hz， 1H) 、8·17 (m，1H)、8. 46 (d，J = 2. 4 Hz, 1H)。 於5 -第二丁氧羰胺基-2 -咄啶羧酸第三丁酯（i · 9克， 6· 45耄莫耳）在CHgClJ 20毫升）中之攪拌混.合物中加入 TFA( 5毫升）。將混合物蒸發，並將殘留物溶解於Εΐ〇Η( 3〇 毫升）。將HC1氣體引入至溶液中，並在〇 —1〇下攪拌1〇分 姜里。然後使所產生之攪拌混合物迴流加熱1 Q小時。於冷卻 後’將N2氣體引入15分鐘，以移除大量過剩的HCi氣體。 將混合物蒸發。將殘留物經由加入飽和NaHC〇3而鹼化，並 以CH/l2萃取。將萃取液以鹽水洗滌，於上乾燥，並 蒸發。將殘留物於矽膠（3〇毫升）上利用CHC丨3_ EtOH (98:2，v/v)作為洗提液進行層析，而得5—胺基-2—π比啶羧 酸乙S旨（ 700毫克，65%)的結晶物質。IR (κβΓ) ^ 3423、Page 270 1283240 V. INSTRUCTIONS (266) Found: C, 36.85; H, 3.35; N, 3.79 ° at room temperature at 6-tert-butoxycarbonylnicotinic acid (19 g, 8.51 mmol) To a stirred mixture of the third oxime (6) in "ml" and toluene (30 ml) was added azide diphenyl ruthenium (2.93 g, 10. 64 mM) dissolved in toluene (3 ml) of the solution. The resulting mixture was heated under reflux for 5 hours. After cooling, 1 ν HCl (5 mL) of ice was added to the mixture. And extracted with toluene. The extract was washed with brine; the strip 'dried on NS 〇 4' and evaporated. The residue was applied to the lycopene (&amp; 〇 ml) using a stupid - E10 A c (5: 1, v / v ) Chromatography as an eluent to obtain a gel of 5 - 2 -butoxy-aminoamino-2 -propanoic acid tert-butylate (19 g, 76%). NMR (CDC13) (Π· 53 (s, 9H), 1· 63 (s, 9H), 6·82 (br s, 1H), 8·01 (d, J=8.8 Hz, 1H), 8·17 (m, 1H) ), 8. 46 (d, J = 2. 4 Hz, 1H). 5 - 2 - Butoxycarbonylamino-2-pyridinium carboxylic acid tert-butyl ester (i Tef (5 ml) was added to a stirred mixture of EtOAc (EtOAc) (EtOAc). The HC1 gas was introduced into the solution, and the mixture was stirred for 1 Torr in a 1 Torr. The resulting stirred mixture was then heated under reflux for 1 Q hours. After cooling, the N2 gas was introduced for 15 minutes to remove a large excess. The HCi gas was evaporated. The residue was basified by the addition of saturated NaHC[rho]3 and extracted with CH.sub.2. The extract was washed with brine, dried over and evaporated and evaporated. Chromatography using CHC丨3_ EtOH (98:2, v/v) as an eluent to give 5-amino-2-π-pyridylcarboxylic acid B (700 mg, 65%) Crystalline substance. IR (κβΓ) ^ 3423,

89112968.ptd 第271頁 1283240 五、發明說明（267) 3190、1708、1657、1587、3338、32 9 6、1:691、1.64i / 公 分； ^-NMR (CDC13) 51.42 (t, J = 7.0 Hz, 3H) ^4.11 (br s, 1H)、4·43 (q, J = 7.0 Hz, 2H)、6.99 (dd, J = 2、7 及 8.5 Hz，1H)、7·95 (d, J = 8.5 Hz, 1H)、8·16 (d，J = 2.7 Hz, 1H); MS(FAB) m/z 167 (M+); 之分析計算 值：C，5 7. 4 7 ; Η，6 · 6 3 ; N， 1 6 · 7 6。實測值：C， 5 7. 2 7 ；H，5.99； N, 16.72。 使5 -胺基-2-咄啶羧酸乙酯（660毫克，3·95毫莫耳）及l-第三丁氧羰基脯胺醛（1.1克，5.33毫莫耳）於甲笨（1〇毫 升）中之攪拌混合物迴流加熱1小時，其間利用狄恩-史塔 克水阱（Dean-Stark water-trap)將水共沸移除。於冷卻 後，將混合物於真空中蒸發。將殘留物溶解於Me〇H_Ac〇H (9 : 1，v/v，30毫升）中。在〇-5 °C下於此攪拌溶液中加入 NaBH3CN( 5 0 0毫克，7· 90毫莫耳）。使所產生之混合物再在 至溫下多授拌1 2小時。將混合物倒入至冰的飽和n a η C 03 (50毫升）中，並以CH2C12萃取。將萃取液以鹽水洗滌，於 NaJO4上乾燥，並蒸發。將殘留物於矽膠（5〇毫升）上利用 CHC13-EtOAc(98:2，v/v)作為洗提液進行層析，而得 5-[N-[2-(1-第三丁氧羰基）π比咯啶基]甲胺基]σ比啶-2 -羧 酸乙酯（1· 1 克，70%)之膠。ih-NMR (CDC13) (Η. 38 (s， 9H)、1.42 (s，6H)、3·93 (s，3H)、4·29 (s，2H)、 4.67 (br s，1Η)、7·15 (d，J = 8.8 Ηζ，1Η)、8·18 (dd， J = 1.7 及 8·8 Hz, 1H)、8.52 (d，J = 1.7 Hz，1H)。89112968.ptd Page 271 1283240 V. INSTRUCTIONS (267) 3190, 1708, 1657, 1587, 3338, 32 9 6 , 1:691, 1.64i / cm; ^-NMR (CDC13) 51.42 (t, J = 7.0 Hz, 3H) ^4.11 (br s, 1H), 4·43 (q, J = 7.0 Hz, 2H), 6.99 (dd, J = 2, 7 and 8.5 Hz, 1H), 7·95 (d, J = 8.5 Hz, 1H), 8·16 (d, J = 2.7 Hz, 1H); MS (FAB) m/z 167 (M+); Analytical calculated value: C, 5 7. 4 7 ; Η, 6 · 6 3 ; N, 1 6 · 7 6. Found: C, 5 7. 2 7 ; H, 5.99; N, 16.72. Ethyl 5-amino-2-acridonecarboxylate (660 mg, 3.95 mmol) and l-t-butoxycarbonylguanamine (1.1 g, 5.33 mmol) in a stupid (1) The stirred mixture in 〇 ml) was heated under reflux for 1 hour during which time the water was azeotropically removed using a Dean-Stark water-trap. After cooling, the mixture was evaporated in vacuo. The residue was dissolved in Me 〇H_Ac 〇H (9:1, v/v, 30 mL). NaBH3CN (500 mg, 7.90 mmol) was added to this stirred solution at 〇-5 °C. The resulting mixture was mixed for an additional 12 hours at ambient temperature. The mixture was poured into saturated EtOAc (50 mL) EtOAc. The extract was washed with brine, dried over Na.sub.4, and evaporated. The residue was chromatographed on silica gel (5 mL) using CHC13-EtOAc (98:2, v/v) as eluent to give 5-[N-[2-(1-tri-butoxycarbonyl) a π-pyridyl]methylamino] σ-pyridin-2-carboxylate (1·1 g, 70%) gum. ih-NMR (CDC13) (Η. 38 (s, 9H), 1.42 (s, 6H), 3·93 (s, 3H), 4·29 (s, 2H), 4.67 (br s, 1Η), 7 · 15 (d, J = 8.8 Ηζ, 1 Η), 8.18 (dd, J = 1.7 and 8·8 Hz, 1H), 8.52 (d, J = 1.7 Hz, 1H).

89112968.ptd 第272頁 1283240 五、發明說明（268) 使5-[ [2-(1-第三丁氧羰基）咄咯啶基]甲胺基比啶-2一 羧酸乙酯（800毫克’2·29毫莫耳）於ch2c12(17毫升）及 TFA(3毫升）中之混合物在室溫下攪拌3小時。將混合物蒸 發，並利用飽和NaHC〇3使殘留物成為驗性.。以Ch2C12萃取 混合物。將萃取液以鹽水洗滌，於Na2S〇4-Na2c〇3上乾燥， 並蒸發而得5-[ (2-吼咯啶基）甲胺基]σ比啶-2-羧酸乙酯 (46 0 毫克，81%)的膠。1-NMR (CDC13) (Η. 32 (t，J二7 Hz, 3H)、1· 58-2. 10 (m 系列，4H)、3· 12-3· 28 (m 系列， 3H) 、3·65 (m， 1H) 、4·3〇 (be q， j=7 Hz, 2H) 、6·27 (br， 1H) 、6·59 (dd， J=2.4 及8·5 Hz， 1H) 、7·65 (d， J=8·5 Hz， 1H) 、 7·94 (d， J=2.4 Hz， 1H)。 在室溫下於5-[ (2-吡咯啶基）甲胺基]呲啶-2—羧酸乙酯 (^220毫克，〇,88毫莫耳）、4—[N，一（2一氯苯基）脲基]一3一曱 氧苯乙酸（ 30 0毫克，0.88毫莫耳）、4-DMAPC1.35毫克， 1 · 1 0宅莫耳）於DMF(7毫升）中之攪拌混合物中加入Ej)c · ΗΠ21 5笔克’ 1 · 1 〇宅莫耳）。使所產生之混合物在室溫下 攪拌20小時。將混合物倒入至冰水中。收集固體，以水洗 滌並風乾。將粗製固體經由利用CHC13 —Et〇H(98:2，v/v) 作為洗提液進行矽膠（3 〇毫升）管柱層析，並利用E12 〇結 晶，純化而得5-[1-[4-[『-（2-氯苯基）脲基]-3一甲氧苯 基乙酿基]-2-咄咯啶基]甲胺基]咄啶—2—缓酸酯（42〇毫 克 ’84%)之微細針狀物。ir (κβΓ) 3319、，1 703、1628、 1 585、1 529 /公分；iH — NMr (CDCl3) 51.38 (ΐ，J = 7 Hz， 3H)、1· 73-2· 17 (m 系列，4H)、3. 19 及3. 54 (各m，各89112968.ptd Page 272 1283240 V. INSTRUCTIONS (268) Ethyl 5-[[2-(1-t-butoxycarbonyl)pyridinyl]methylaminopyridin-2-carboxylate (800 mg) A mixture of <2·29 mmol) in ch2c12 (17 ml) and TFA (3 ml) was stirred at room temperature for 3 hours. The mixture was evaporated and the residue was made purified using saturated NaHC. The mixture was extracted with Ch2C12. The extract was washed with brine, dried over Na.sub.2.sub.4-Na.sub.2.sub.3.sub.3. Mg, 81%) of the glue. 1-NMR (CDC13) (Η. 32 (t, J 2 7 Hz, 3H), 1.58-2. 10 (m series, 4H), 3·12-3· 28 (m series, 3H), 3 · 65 (m, 1H), 4·3〇 (be q, j=7 Hz, 2H), 6.27 (br, 1H), 6·59 (dd, J=2.4 and 8·5 Hz, 1H) , 7·65 (d, J=8·5 Hz, 1H), 7·94 (d, J=2.4 Hz, 1H) at room temperature in 5-[(2-pyrrolidyl)methylamino] Acridine-2-carboxylic acid ethyl ester (^220 mg, hydrazine, 88 mmol), 4-[N, mono(2-chlorophenyl)ureido]-3-oxooxyphenylacetic acid (30 mg, 0.88 millimolar), 4-DMAPC 1.35 mg, 1 · 1 0 house Moer) Add Ej)c in a stirred mixture of DMF (7 ml) · ΗΠ21 5 pg '1 · 1 〇家莫耳) . The resulting mixture was stirred at room temperature for 20 hours. Pour the mixture into ice water. The solid was collected, washed with water and air dried. The crude solid was subjected to column chromatography using CHC13-Et〇H (98:2, v/v) as an eluent, and purified by E12 crystallization to obtain 5-[1-[ 4-["-(2-Chlorophenyl)ureido]-3-methoxyphenylethyl]-2-oxaridinyl]methylamino]pyridinium-2-oxide (42 mg '84%) fine needles. Ir (κβΓ) 3319,, 1, 703, 1628, 1 585, 1 529 / cm; iH - NMr (CDCl3) 51.38 (ΐ, J = 7 Hz, 3H), 1·73-2· 17 (m series, 4H ), 3.19 and 3.54 (each m, each

89112968.ptd 第273頁. 1283240 五、發明說明（269) :H)、3·63 (S’ 2Η)、3·7〇 (s，3H)、4.39 (be q，J二7 广 I 、4·55 (m， 1H) 、6·〇2 (br s， 1H) 、6·78-6·84 s 及m 系列，3H)、6· 98 (dt，J = 2. 4 及8· 0 Hz，1H)、7· 16 s’ 1H 、7·21 - 7·26 (m 系列，3H)、7·34 (dd，1 = 2.4及 8·: HZ，1H)、7·90 (d，J = 8.3 Hz，1H)、7·98 (m， 60. 06 ； Η, 5. 76 ； N， 、、8.·16 (dd，J = 1·2 及 8·8 Hz，1H); MS(FAB) m/z 566 =+i ’（：29η32(：ιν5ο5 · h2〇 之分析·計算值：c，59· 63 ; H，5· 8 7，N， 1 2 · 3 7。實測值：c， 11.95。 ’ 使5 [N -（2-氯苯基）脲基卜3 一甲氧苯基乙醯 基t咄咯°疋基]曱胺基]咄啶—2 -羧酸乙酯（3 0 0毫克，89112968.ptd Page 273. 1283240 V. INSTRUCTIONS (269) : H), 3·63 (S' 2Η), 3·7〇(s, 3H), 4.39 (be q, J 2 7 Guang I, 4 · 55 (m, 1H), 6·〇2 (br s, 1H), 6·78-6·84 s and m series, 3H), 6· 98 (dt, J = 2. 4 and 8· 0 Hz , 1H), 7· 16 s' 1H , 7·21 - 7·26 (m series, 3H), 7·34 (dd, 1 = 2.4 and 8·: HZ, 1H), 7·90 (d, J = 8.3 Hz, 1H), 7·98 (m, 60. 06 ; Η, 5. 76 ; N, , , 8.16 (dd, J = 1·2 and 8·8 Hz, 1H); MS ( FAB) m/z 566 = +i '(:29η32(:ιν5ο5 · h2〇 analysis·calculated value: c, 59· 63 ; H, 5· 8 7, N, 1 2 · 3 7. Actual measured value: c , 11.95. 'Let 5 [N-(2-chlorophenyl)ureido3 methoxyphenylethyl fluorenyl] fluorenyl] guanidino] acridine-2-carboxylate (3 0 0 mg,

0.53 宅莫耳）於 THF.MeOH(l:l，v/v， 16 毫升）及 0.25N0.53 house Mo) in THF.MeOH (l:l, v/v, 16 ml) and 0.25 N

NaOH(ll毫升’ 2. 75毫莫耳）中之混合物在室溫下攪拌3小 時。將混合物倒入至冰的丨N HC丨（3毫升）中。收集固體， 以水洗滌並風乾。利用CH2Cl2-Et2〇收集粗製的結晶材料， 而得61 (180毫克，63%)的非晶形固體。IR (kBr) 3319、 Π01、1 6 2 0、1 585、1533 / 公分；I-NMR (CDC13) 5 1H-NMR (DMSO-d6) 61· 80-2· 0 5 (m 系列，4H)、2· 99 (m， 1Η) 、3·50-3·59 (m 系列，3Η) 、3.60 (s， 2Η) 、3·86 (s， 3Η) 、4·11 (m， 1Η) 、6.78 (d， J=8.5 Ηζ， 1Η) 、6·91 (s，1H)、6·94 (m，1H)、7.〇2 (m，1H)、7.14 (dd， J = 2.5 及 8.5 Hz, 1H)、7·28 (t，J = 7.0 Hz，1H)、7.45 (d，J = 8.0 Hz, 1H)、7·78 (d，J = 8.8 Hz，1H)、7.97 (d，J = 8.3 Hz，1H)、8·08 (br s，1H)、jll (m，1H)、The mixture in NaOH (ll ml ' 2.75 mmol) was stirred at room temperature for 3 hours. The mixture was poured into ice 丨N HCl (3 mL). The solid was collected, washed with water and air dried. The crude crystalline material was collected using CH.sub.2Cl.sub.2-.sub.2. IR (kBr) 3319, Π01, 1 6 2 0, 1 585, 1533 / cm; I-NMR (CDC13) 5 1H-NMR (DMSO-d6) 61· 80-2· 0 5 (m series, 4H), 2· 99 (m, 1Η), 3·50-3·59 (m series, 3Η), 3.60 (s, 2Η), 3·86 (s, 3Η), 4·11 (m, 1Η), 6.78 ( d, J=8.5 Ηζ, 1Η), 6.91 (s,1H), 6.94 (m,1H), 7.〇2 (m,1H), 7.14 (dd, J = 2.5 and 8.5 Hz, 1H ), 7·28 (t, J = 7.0 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7·78 (d, J = 8.8 Hz, 1H), 7.97 (d, J = 8.3 Hz) , 1H), 8·08 (br s, 1H), jll (m, 1H),

89112968.ptd 第274頁 1283240 五、發明說明（270) — 8.89 (s, 1H) &gt;8.94 (s, ih); MS(FAB) m/z 538 (MU1) ; C27H28C1N5 05 · 15xH2〇 之分析計算值：c，5739 ;H’ 5· 53 ; N， 12· 39。實測值：c， 57. 37 ; H， 5 54 ; N 11· 74 。 ’ 在室溫下於5-[(2-吼咯啶基）曱胺基]，比啶羧酸乙酯 (230¾克’0.923笔莫耳）、3-甲氧基一 4 一 [N，—（2—甲基苯 基）脈基]笨乙酸（ 2 9 0毫克，0.923毫莫耳）、4-DMAP (145毫克’1.15毫莫耳）於DMF( 7毫升）中之攪拌混合物中 加入EDC ·ΗΠ( 2 2 5毫克，hl5毫莫耳）。使所產生之混合 物在室溫下攪拌2 0小時。將混合物倒入至冰水中。收集固 體’以水洗滌並風乾。將粗製固體經由利用CHC“ —Et〇H (98 : 2，v/v)作為洗提液進行矽膠（3〇毫升）管柱層析，純 化而得5-[ [ 1-[3-甲氧基-4- [『- (2 -曱基苯基）脲基]苯基 乙龜基]-2 -吼咯啶基]甲胺基]咄啶—2—羧酸乙酯（4〇〇毫 克，80%)之微細針狀物。IR (KBr) ^ 3 3 2 5、17〇9、 1618、1 585、1531 / 公分；ih-NMR (CDC13) (5 NMR (CDC13) (51· 39 (t，J = 7 Hz, 3H)、1· 73-2· 0 7 (m 系列， 4H)、2· 28 (s, 3H)、3· 12 及 3· 49 (各m，各 1H)、3·60 (s， 2H) 、4·39 (br q， J=7 Hz， 2H) 、4·53 (m， 1H) 、6· 07 (br s， 1H) 、6·23 (br s， 1H) 、6·75—6.77 (s 及m 系 列，2H)、6·82 (dd，J = 3.0 及 8·5 Hz，1H)、7. 09-7.22 (m 系列，3H)、7.49 (d， J = 8.0 Hz, 1H)、7.90 (d， J = 8·5 Hz，1H)、7.98 (d，J = 2.6 Hz, 1H)、8.06 (d，J = 8.8 Hz, 1H) ； MS(FAB) m/z 546 (MH1)； C30H35N5O5 ·89112968.ptd Page 274 1283240 V. INSTRUCTIONS (270) — 8.89 (s, 1H) &gt; 8.94 (s, ih); MS(FAB) m/z 538 (MU1) ; C27H28C1N5 05 · 15xH2〇 Analytical calculation Value: c, 5739; H' 5· 53 ; N, 12· 39. Found: c, 57. 37 ; H, 5 54 ; N 11· 74 . ' 5-[(2-Pyrridinyl)guanidinyl] at room temperature, ethylpyridinium carboxylate (2303⁄4 g '0.923 moles), 3-methoxy-4 1 [N,- Add EDC to a stirred mixture of (2-methylphenyl) ruthenium acetate (290 mg, 0.923 mmol), 4-DMAP (145 mg '1.15 mmol) in DMF (7 mL) · ΗΠ (2 2 5 mg, hl 5 mmol). The resulting mixture was stirred at room temperature for 20 hours. Pour the mixture into ice water. The collected solids were washed with water and air dried. The crude solid was purified by a column chromatography using CHC "-Et〇H (98: 2, v/v) as an eluent to obtain 5-[[1-[3-methoxy] Ethyl 4-[『-(2-(phenylphenyl)ureido]phenylthioto]]-2-oxazolidinyl]methylamino]pyridin-2-carboxylate (4 mg , 80%) of fine needles. IR (KBr) ^ 3 3 2 5, 17〇9, 1618, 1 585, 1531 / cm; ih-NMR (CDC13) (5 NMR (CDC13) (51· 39 ( t, J = 7 Hz, 3H), 1·73-2· 0 7 (m series, 4H), 2·28 (s, 3H), 3·12 and 3· 49 (each m, each 1H), 3 ·60 (s, 2H), 4·39 (br q, J=7 Hz, 2H), 4·53 (m, 1H), 6· 07 (br s, 1H), 6·23 (br s, 1H ), 6·75—6.77 (s and m series, 2H), 6.82 (dd, J = 3.0 and 8·5 Hz, 1H), 7. 09-7.22 (m series, 3H), 7.49 (d, J = 8.0 Hz, 1H), 7.90 (d, J = 8·5 Hz, 1H), 7.98 (d, J = 2.6 Hz, 1H), 8.06 (d, J = 8.8 Hz, 1H); MS (FAB) m/z 546 (MH1); C30H35N5O5 ·

89112968.ptd 第275頁 1283240 五、發明說明（271) 1·5χΗ20 之分析計算值：C，52.9 2; H，6.69; N， 12.23。 實測值：C， 63. 11 ; H，6. 48 ; N， 11. 96。 使5-[Π-[3-甲氧基一4-[『- (2-甲基笨基）脲基]笨基乙 醯基]-2 -咄咯啶基]曱胺基]，比啶—2 -羧酸乙酯（D9 1 -45 9 5 ) ( 2 9 0 毫克，0.53 毫莫耳）於 THF*MeOH(l:l，v/v， 16 毫升） 及0· 25N NaOH(ll毫升，2· 75毫莫耳）中之混合物在室溫下 稅拌3小時。將混合物倒入至冰的1 n H C 1 ( 3毫升）中。收集 固體，以水洗滌並風乾。利用CH2C12-Et20收集粗製的結晶 材料，而得62 ( 1 70毫克，62%)的非晶形固體。IR (KBr) 3 283、1701、1618、1 5 2 9 / 公分；UMR (CDC13) ά UMR (DMS0-d6) (Η· 78-2· 0 4 (m 系列，4Η)、2· 25 (s， 3H) 、2·95-3·55 (m 系列，4H) 、 3.59 (s， 2H) 、3·87 (s， 3Η)、4·11 (m，1Η)、6·75-7·24 (m 系列，7H)、7.83 -7· 97 (m 系列，3H)、8· 01 (d， J二8· 3 Hz， 1H)、8· 13 (d， J = 2.6 Hz， 1H)、8·11 (m， 1H)、8·47 (s， 1H)、 8.57 (s, 1H) ； MS(FAB) m/z 518(MH1)； C28H31N5 05 · 2·5χΗ20 之分析計算值：C，60·50; Η, 6·39; N， 12.60。 實測值·· C，60. 31 ; H，6. 28 ; N， 12. 10。 實施例5 7 2 - [1-[[4 - [N，-(2-氯笨基）脲基]- 3 -甲氧苯基乙隨基]-2-吼咯啶基]甲氧基]吡啶-5-羧酸89112968.ptd Page 275 1283240 V. INSTRUCTIONS (271) Analysis of 1·5χΗ20: C, 52.9 2; H, 6.69; N, 12.23. Found: C, 63.11; H, 6. 48; N, 11. 96. 5-[Π-[3-methoxy-4-[">-(2-methylphenyl)ureido]]phenylamino]-2-pyridinyl]nonylamino] —2-carboxylate (D9 1 -45 9 5 ) ( 2 9 0 mg, 0.53 mmol) in THF*MeOH (1:1, v/v, 16 mL) and 0.25 N NaOH The mixture in 2, 75 millimoles was mixed at room temperature for 3 hours. The mixture was poured into 1 n H C 1 (3 mL) of ice. The solid was collected, washed with water and air dried. The crude crystalline material was collected using CH2C12-Et20 to afford 62 (1 70 mg, 62%) of amorphous solid. IR (KBr) 3 283, 1701, 1618, 1 5 2 9 / cm; UMR (CDC13) ά UMR (DMS0-d6) (Η·78-2· 0 4 (m series, 4Η), 2· 25 (s , 3H), 2·95-3·55 (m series, 4H), 3.59 (s, 2H), 3·87 (s, 3Η), 4·11 (m, 1Η), 6·75-7·24 (m series, 7H), 7.83 -7·97 (m series, 3H), 8· 01 (d, J 2·8 Hz, 1H), 8·13 (d, J = 2.6 Hz, 1H), 8 ·11 (m, 1H), 8·47 (s, 1H), 8.57 (s, 1H); MS(FAB) m/z 518(MH1); C28H31N5 05 · 2·5χΗ20 Analysis calculated: C, 60 · 50; Η, 6·39; N, 12.60. Measured value · · C, 60. 31 ; H, 6. 28 ; N, 12. 10. Example 5 7 2 - [1-[[4 - [N ,-(2-chlorophenyl)ureido]-3-methoxyphenylethyl]-2-indolyl]methoxy]pyridine-5-carboxylic acid

89112968.ptd 第276頁 1283240 五、發明說明（272) 在0-10 °C下於2-羥基-η比啶羧酸甲酯（2· 〇克，13· β毫 莫耳）、PPh3(4.2克，15.93¾莫耳）及1—第三丁氧羰基 -（L) -脯胺醇（2.63克’13.06毫莫耳）溶於thf( 25毫升）之 擾拌溶液中加入DIAD(3.3克，15.67毫莫耳）溶於THF (5毫 升）之溶液。然後使所產生之攪拌混合物迴流加熱3小時。 於冷卻後，將混合物於真空中蒸發。將殘留物於矽膠（丨2〇 耄升）上利用正己烧-Et0Ac(4 : 1，v/v)作為洗提液進行層 析，而得2- [2-(1-第三丁氧羰基）σ比咯啶基]曱氧咄啶—5_ 羧酸甲酯（3· 0 克，68%)的膠。ιΗ一NMR (CDCl3) 51· 46 (s， 9H) 、1.82-2.04 (m 系列，4H) 、3·45 (m， 2H) 、3.91 (s， 3H) 、 4.10-4.32 (m 系列，2H) 、4·48 (m, 1H) 、6·32 (br，1H)、6·75 (d，J = 8.8 Hz, 1H)、8·15 (dd，J = 2 及 8 · 8 H z，1H)、8 · 7 9 (d，J = 2 H z，1 H)。 使2 - [ 2 - (1 -第二丁氧羰基）π比略σ定基]甲氧p比唆—$ —魏酸 甲酯（2.9克’8.62毫莫耳）於CH2cl2(8〇毫升）及TFA(2〇毫 升）中之混合物在室溫下攪拌3小時。將混合物蒸發，並利 用飽和NaHC〇3將殘留物鹼化。以Μ/、萃取混合物。將萃 取液以鹽水洗務，於N S 04 - N a2 C 03上乾燥，並蒸發而得 2-(2-吡咯啶基）甲氧咄啶-5-羧酸甲酯（1· 2克，59%)的 膠。1Η - NMR (CDC13 )61.58-2.050 (m 系列，4H)、2.90-3.02 (m 系列，2H)、3·87 及 3.90 (各s，3H)、4.23 (m， 1H)、4.37 (m，1H)、6·33 (br，1H)、6.78 (d，J:8.5 Hz，1H)、8.15 (dd，J = 2.2 及 8·8 Hz, 1H)、8·79 (d， J二2·2 Hz， 1H)。89112968.ptd Page 276 1283240 V. INSTRUCTIONS (272) Methyl 2-hydroxy-n-pyridylcarboxylate (2·〇克, 13·β mmol), PPh3 (4.2) at 0-10 °C克, 15.933⁄4 mol) and 1-t-butoxycarbonyl-(L)-prolinol (2.63 g '13.06 mmol) dissolved in thf (25 ml) in a scrambled solution with DIAD (3.3 g, A solution of 15.67 mmoles in THF (5 mL). The resulting stirred mixture was then heated under reflux for 3 hours. After cooling, the mixture was evaporated in vacuo. The residue was chromatographed on a silica gel (丨 2 liter) using n-hexane-Et0Ac (4:1, v/v) as an eluent to give 2-[2-(1-tert-butoxycarbonyl) a gum of σpyrrolidyl]oxime acridine-5-carboxylate (3.0 g, 68%). ιΗ NMR (CDCl3) 51· 46 (s, 9H), 1.82-2.04 (m series, 4H), 3·45 (m, 2H), 3.91 (s, 3H), 4.10-4.32 (m series, 2H) , 4·48 (m, 1H), 6.32 (br, 1H), 6·75 (d, J = 8.8 Hz, 1H), 8·15 (dd, J = 2 and 8 · 8 H z, 1H ), 8 · 7 9 (d, J = 2 H z, 1 H). 2 - [ 2 - (1 - 2 -butoxycarbonyl) π is slightly sigma - methoxy pi - — - _ - methyl formate (2.9 g '8.62 mmol) in CH 2 Cl 2 (8 〇 ml) and The mixture in TFA (2 mL) was stirred at room temperature for 3 hours. The mixture was evaporated and the residue was basified using saturated NaHC. Extract the mixture with Μ/. The extract was washed with brine, dried over NS 04 - N a 2 C 03 and evaporated to give methyl 2-(2-pyrrolidinyl)methoxidine-5-carboxylate (1·2 g, 59 %) of the glue. 1Η - NMR (CDC13) 61.58-2.050 (m series, 4H), 2.90-3.02 (m series, 2H), 3·87 and 3.90 (each s, 3H), 4.23 (m, 1H), 4.37 (m, 1H) ),6·33 (br,1H), 6.78 (d, J: 8.5 Hz, 1H), 8.15 (dd, J = 2.2 and 8·8 Hz, 1H), 8.79 (d, J 2·2) Hz, 1H).

89112968.ptd 第 277 頁 1283240 ~7~---—_____ 五、發明說明（273) '&quot; 古，至溫下於2-（2-吨π各啶基）曱氧咄啶一5—羧酸曱酯（37〇 ，莫耳）、4 — [N’—（2-氣苯基）脲基]-3 -曱氧笨 s夂525笔克，J·57毫莫耳）、4—聞奵（23〇毫克，1· μ毫 ㈠耳 &gt;於DMF(10毫升）中之攪拌混合物中加入EDC · HC1 笔克’ 1 · 88宅莫耳）。使所產生之混合物在室溫下攪 、&quot;〇小枯。將混合物倒入至冰水中。收集固體，以水洗滌 並風乾。將粗製固體經由利用CHC13-Et〇H(98 : 2，v/v)作 為洗提液進行矽膠（30毫升）管柱層析，並利用以…結晶， 純化而得2-[1-[ 4-[N，-(2-氣苯基）脲基]_3-曱氧笨基乙醯 基]-2-咄咯啶曱氧基]咄啶一5—羧酸曱酯（6〇〇毫克，69%)之 非晶形固體。-NMR (CDC13) 5 1· 21 及2· 01 (各m，4H) 、3· 45-4· 50 (s及m系列，1 3H ’其包含醯胺異構物）、 6. 58-8· 83 (s及m系列，12H，其包含醯胺異構物）。 使2-[1-[4 - [Ν’ -（2-氯苯基）脲基]一 3-甲氧苯基乙醯 基]-2 -吼咯啶甲氧基]吡啶一5 —羧酸甲酯（23◦毫克，〇. 41 5 毫莫耳）於THF(1毫升）及0.25Ν NaOH(4毫升，1毫莫耳）中 之混合物在室溫下攪拌14小時及在60 °C下攪拌3小時。於 冷卻後’將混合物倒入至冰的1 N HC1 ( 2毫升）中。收集固 體’以水洗滌並風乾。利用製備T L C板以C H C 13 - E t Ο Η ( 9 : 1， ν / ν)作為洗提液將粗製結晶材料純化，並利用ε q結晶而 得63 (150毫克，67%)的非晶形固體。IR (KBr) 332 9、 1 70 9、1601、1 533 / 公分；l-NMR (DMSO-d6) 31.85-2. 05 (m 系列，4H)、3. 50-3. 60 (m 系列，2H)、3· 82 (s， 3H)、 3.86 (s，2H)、4.29 (m，1H)、4.42 (m，1H)、6.7289112968.ptd Page 277 1283240 ~7~----_____ V. Description of invention (273) '&quot; Ancient, to 2-(2-ton π-pyridyl) anthraquinone 5-carboxy Acid oxime ester (37 〇, Mohr), 4 — [N'-(2- phenylphenyl) ureido]-3 - 曱 笨 夂 夂 夂 525 gram, J · 57 millimoles), 4 - smell奵 (23 〇 mg, 1 μm (1) ear&gt; EDC · HC1 pen gram '1 · 88 house Moules) was added to the stirred mixture in DMF (10 ml). The resulting mixture is stirred at room temperature and &quot;small. Pour the mixture into ice water. The solid was collected, washed with water and air dried. The crude solid was subjected to column chromatography using CHC13-Et〇H (98:2, v/v) as an eluent, and was purified by crystallization to obtain 2-[1-[ 4 -[N,-(2-Phenylphenyl)ureido]_3-曱oxyphenylamino]-2-indenylpyridiniumoxy]acridine-5-carboxylic acid oxime ester (6 mg, 69%) amorphous solid. -NMR (CDC13) 5 1· 21 and 2· 01 (each m, 4H), 3·45-4· 50 (s and m series, 1 3H 'which contains indole isomers), 6. 58-8 · 83 (s and m series, 12H, which contains a guanamine isomer). 2-[1-[4 - [Ν' -(2-Chlorophenyl)ureido] 3-methoxyphenylethenyl]-2-pyrrolidinyloxy]pyridine-5-carboxylic acid Mixture of methyl ester (23 mg, 〇. 41 5 mmol) in THF (1 mL) and 0.25 EtOAc (4 mL, 1 mmol) at room temperature for 14 hours and at 60 ° C Stir for 3 hours. After cooling, the mixture was poured into 1 N HCl (2 mL) of ice. The collected solids were washed with water and air dried. The crude crystalline material was purified by preparative TLC plate with CHC 13 - E t Ο Η (9: 1, ν / ν) as the eluent, and crystallized by ε q to obtain 63 (150 mg, 67%) of amorphous solid. . IR (KBr) 332 9, 1 70 9, 1601, 1 533 / cm; l-NMR (DMSO-d6) 31.85-2. 05 (m series, 4H), 3. 50-3. 60 (m series, 2H ), 3· 82 (s, 3H), 3.86 (s, 2H), 4.29 (m, 1H), 4.42 (m, 1H), 6.72

89112968.ptd 第278頁 1283240 五、發明說明（274) 一7·05 (m 系列，4H)、7.28 (m， 1H)、7·43 (d， J二8 Hz， 2H) 、7·95 (d， J=8.3 Hz, 1H) 、8·09 (d， J=8.3 Hz， 2H)、8·64 (m，1H)、8·89 (s，1H)、8·93 (s，1H); MS(FAB) m/z 3xH20 之分析計算 值：C，5 7· 55 ; H，5· 47 ; N, 9· 94。實測值：C，57· 94 ; Η, 5. 00 ； Ν， 9· 45 〇 實施例5 8 5 - [1-[4 - [Ν’ -（2 -溴笨基）脲基]-3-甲氧苯基乙醯基]一 2 -咄咯啶甲氧基]咄啶一 2 -羧酸 64 在室溫下於5 -（ 2 -咣咯啶基）甲氧咄啶一 2 —羧酸曱酯（3 7 0 毫克’1.57毫莫耳）、4-[N，-（2 -溴笨基）脲基]- 3-曱氧苯 乙酸（595毫克，1.57毫莫耳）、4-D MAP (230毫克，1.88毫 莫耳）於DMF(10毫升）中之攪拌混合物中加、EDC · HC1 (3 6 0毫克’ 1 · 8 8毫莫耳）。使所產生之混合物在室溫下攪 掉2 0小時。將混合物倒入至冰水中。收集固體，以水洗滌 並風乾。將粗製固體經由利用CHC丨厂Εΐ〇Η(98 : 2，v/v)作 為洗提液進行矽膠（3 〇毫升）管柱層析，並利用e t2 〇結晶， 1化而得5 —[卜[4 —[『-（2 -溴苯基）脲基]-3-甲氧苯基乙 酉避基]-2 -吼咯啶曱氧基]0比啶—2 —羧酸甲酯（65〇毫克，69%) 之非晶形固體。IR (KBr) u 3323、1720、1624、1601 、 1 527 /公分；NMR (CDC13) (5 1.22 及2.00 (各m，4H)、89112968.ptd Page 278 1283240 V. INSTRUCTIONS (274) A 7.05 (m series, 4H), 7.28 (m, 1H), 7·43 (d, J 2 8 Hz, 2H), 7.95 ( d, J=8.3 Hz, 1H), 8·09 (d, J=8.3 Hz, 2H), 8·64 (m, 1H), 8·89 (s, 1H), 8·93 (s, 1H) MS (FAB) m/z 3xH20: C, 5 7 · 55 ; H, 5 · 47 ; N, 9. 94. Found: C, 57·94 ; Η, 5. 00 ; Ν, 9· 45 〇 Example 5 8 5 - [1-[4 - [Ν' -(2-bromo)]ureido]-3- Methoxyphenylethylidene]-2-oxazolidinylmethoxy]acridine-2-carboxylic acid 64 at room temperature in 5-(2-pyrrolidinyl)methoxyoxidine-2-carboxylic acid Oxime ester (3 70 mg '1.57 mmol), 4-[N,-(2-bromophenyl)ureido]-3-oxophenylacetic acid (595 mg, 1.57 mmol), 4-D MAP (230 mg, 1.88 mmol) was added to a stirred mixture of DMF (10 mL), EDC · HCl (3. The resulting mixture was stirred at room temperature for 20 hours. Pour the mixture into ice water. The solid was collected, washed with water and air dried. The crude solid was subjected to column chromatography using a CHC crucible (98: 2, v/v) as an eluent, and was crystallized by e t2 ,, and 1 was obtained.卜 [4 —[『-(2-Bromophenyl)ureido]-3-methoxyphenylacetamidine]-2-pyridinium oxy]0-pyridyl-2-carboxylate (65 〇mg, 69%) amorphous solid. IR (KBr) u 3323, 1720, 1624, 1601, 1 527 / cm; NMR (CDC13) (5 1.22 and 2.00 (each m, 4H),

1283240 五、發明說明（275) 3.48-4.5 5 (3及111系列，13}1，其包含醯胺異構物）、6.93 -8. 82 (s及m系列，12H，其包含醯胺異構物）；ms (FAB) m/Z 5 97 (M+- 1)及 5 9 9 (MH1) ; C28H3()BrN4 06 · 1· 〇χΗ20 之分析 計算值：C, 54· 55 ; Η, 5· 23 ; N， 9· 09。實測值：C, 54.13; Η，5·03;Ν，9.33。 使5 [1-[4 - [Ν -(2 - &gt;臭本基）脈基]- 3-曱氧苯基乙酸 基]-2 -呲咯啶甲氧基]咄啶一2 -羧酸甲酯（ 3 0 0毫克，〇. 5毫 莫耳）於 THF:MeOH(l:l，ν/ν，2 毫升）及 0.25Ν NaOH(4 毫1283240 V. INSTRUCTIONS (275) 3.48-4.5 5 (3 and 111 series, 13}1, which contain amidine isomers), 6.93 -8. 82 (s and m series, 12H, which contain indoleamine isomers MS); ms (FAB) m/Z 5 97 (M+- 1) and 5 9 9 (MH1) ; C28H3()BrN4 06 · 1· 〇χΗ20 Analysis calculated: C, 54· 55 ; Η, 5· 23 ; N, 9· 09. Found: C, 54.13; Η, 5·03; Ν, 9.33. 5 [1-[4 - [Ν -(2 - &gt; 臭本基基基)] 3-曱 oxyphenylacetate]-2-pyrrolidinyl methoxy] acridine-2-carboxylic acid Methyl ester (300 mg, 〇. 5 mmol) in THF:MeOH (1:1, ν/ν, 2 mL) and 0.25 NaOH (4 mM)

升，1毫莫耳）中之混合物在室溫下攪拌3小時及在6 0 °C下 攪拌5小時。於冷卻後，將混合物倒入至冰的1 N hc 1 ( 2毫 升）中。收集固體，以水洗滌並風乾。利用製備TLC板以 CHCI3-EtOH(9: 1，v/v)作為洗提液將粗製結晶材料純化， 並利用Et20結晶而得64 ( 1 80毫克，62%)的非晶形固體。IR (KBr) y 3319、1705、1685、1601、1529 /公分；iH-NMR (DMSO-d6) (51. 82 - 2.05 (m 系列，4H)、3.48 — 3.58 (m 系 列，2H)、3·82 (s，3H)、3·86 (s，2H)、4·42-4·55 (m 系列，3Η)、6. 72-6· 98 (m 系列，4Η)、7. 32 (t， J = 8 Ηζ， 1H) 、7·60 (d， J=8 Hz, 1H) 、7.95 (m， 2H) 、8·08 (m， 1H)、8·63 (m，1H)、8.64 (m，1H)、8.89 (s，1H)、 8. 93 (s, 1H) ； MS(FAB) m/z 583 (M+) ； C27H28BrN4 06 · 2·0χΗ2Ο 之分析計算值：C，52.2 6; H，5.20; N， 9.03。 實測值：C，52. 72 ; H，4. 63 ; N， 8. 50。 實施例5 9 4 - [1-[3- [Ν’ -（2 -溴苯基）脲基]- 2-甲氧基-6-吼11定乙酷基The mixture in liter, 1 mmol was stirred at room temperature for 3 hours and at 60 ° C for 5 hours. After cooling, the mixture was poured into 1 N hc 1 (2 mL) of ice. The solid was collected, washed with water and air dried. The crude crystalline material was purified by preparative TLC using CHCI3-EtOH (9:1, v/v) as eluent, and crystallised from Et20 to give 64 (1 80 mg, 62%) of amorphous solid. IR (KBr) y 3319, 1705, 1685, 1601, 1529 / cm; iH-NMR (DMSO-d6) (51. 82 - 2.05 (m series, 4H), 3.48 - 3.58 (m series, 2H), 3· 82 (s, 3H), 3·86 (s, 2H), 4·42-4·55 (m series, 3Η), 6. 72-6. 98 (m series, 4Η), 7. 32 (t, J = 8 Ηζ, 1H), 7·60 (d, J=8 Hz, 1H), 7.95 (m, 2H), 8·08 (m, 1H), 8·63 (m, 1H), 8.64 (m , 1H), 8.89 (s, 1H), 8. 93 (s, 1H); MS (FAB) m/z 583 (M+); C27H28BrN4 06 · 2·0χΗ2Ο Analytical calculated value: C, 52.2 6; H, 5.20; N, 9.03. Found: C, 52.72; H, 4. 63; N, 8. 50. Example 5 9 4 - [1-[3-[Ν' -(2 -bromophenyl) Ureido]- 2-methoxy-6-indole 11

89112968.ptd 第280頁 1283240 五、發明說明（276) ]_(4S) -氟-（2S)-吼咯啶曱氧基]苯甲酸89112968.ptd Page 280 1283240 V. INSTRUCTIONS (276) ]_(4S)-Fluoro-(2S)-吼rrolidineoxy]benzoic acid

Br Η H 〇Me 65 3-[Ν’ -（2 -漠苯基）脲基]-2-甲氧基—6〜σ比啶乙酸Br Η H 〇Me 65 3-[Ν' -(2-indolyl)ureido]-2-methoxy-6~σ-pyridinic acid

co2h ^於3-胺基-2-甲氧基-6-咄啶乙酸乙酯（1· 61克，7· 66毫 莫耳）洛於THF( 1 0耄升）之攪拌溶液中加入異氰酸2_溴苯酯 ( 948微升，7.66毫莫耳）及Et3N(l〇7微升，〇·776毫莫 耳）。於撥拌隔仪後，將混合物倒入至Q ( 1 〇 〇毫升）中， 並以CHC1S-Me0H(4:l, 2x200毫升）萃取。將結合的萃取液 於MgS〇4上乾燥並蒸發。使殘留物自CHC13_Me〇H_己烷再結 曰曰而得3 - [ N - ( 2 _溴笨基）脲基]—2 —甲氧基_ 6 _咄啶乙酸乙 S曰（2 · 9 1克’ 9 3 %)的無色結晶粉末。熔點1 6 〇 _丨6 3艺； !H-NMR (DMSO-d6)(51.19 (dt, J-7.1 ^0.7 Hz, 3H) &gt; 3.69 (s, 2H) ^3.95 (s, 3H) &gt;4.07-4.13 (m, 2H) &gt; 6·90 (d，J:7.8 Hz, 1H)、6.99 (t, J = 7.8 Hz，1H)、 7.33 (t，J = 7.8 Hz, 1H)、7·6ΐ (d，J = 7.8 Hz，1H)、 7.96 (dd， J=7.8 、1·5 Hz， 1H) 、8.31 (d， J=7.8 Hz， 1H) 、8·82 (s， 1H) 、9·12 (s， 1H); MS(FAB) m/z 4〇8(M+)、410 (MH2) ; C17H18BrN3 04 · 0. 25H20 之分析計算 值：C，4 9 · 4 7 ; Η，4 · 5 2 ; N，9 · 9 6。實測值·· C，4 9 · 3 4 ; Ι·ϋΙ 89112968.ptd 第281頁 1283240 五、發明說明（277) H, 4.48; N, 9.96。 於3-[Ν’ -（2 -溴笨基）脲基]-2-甲氧基—6—,比啶乙酸乙酯 (2.90 克 ’7.10毫莫耳）、〇·25Ν Na0H(56.8 毫升，14.2 毫 莫耳）、及THF(50毫升）之混合物攪拌5小時。將混合物以 1 N HC1中和，並利用過濾收集所產生之沈澱物。使殘留物 自CHC13-MeOH-己烧再結晶而得3 — [ν’-（2 -溴苯基）脲基] -2-甲氧基-6-吼唆乙酸（2· 40克，89%)的無色結晶粉末。 熔點195-197。(：；1}1-關1?(0%50-4)53.59(5，2[〇、3.95 (s，3Η)、6.88 (d，J:8.1 Ηζ，1Η)、6·97-7.01 (m， 1Η) 、7·33 (t， J=7.3 Hz, 1Η) 、7·61 (d， J=8.1 Ηζ， 1H)、7·9 5-7.97 (m，1H)、8·29 (d，HI Hz，1H)、 8. 81 (s，1H)、9· 10 (s，ih)、12· 35 (br s，1H); C15H14BrN3 04 之分析計算值：c，47. 39 ; h，3. 71 ; n， 11· 05。實測值：C，47. 27 ; H，3. 59 ,· N， 10. 86。’ 於3 [N (2-溴本基）脲基]-2-甲氧基-6 - σ比咬乙酸（751 宅克，1.97宅莫耳）及（4S) -氟-（2S)-吼嘻嗓甲氧基苯甲酸 甲酯（500毫克，1.97毫莫耳）溶於DMF(10毫升）之攪拌溶液 中加入EDC ·Η(： 1(566毫克，2.96毫莫耳）、DMAP(催化 劑）、/H0Bt(催化劑）。於攪拌隔夜後，使混合物在Εί〇Αε (2 0 0笔升）與鹽水（2 〇 〇毫升）之間分配。使相分離。將有機 相以鹽水（100毫升）洗滌，於MgS〇4上乾燥，並蒸發。使所 產生之殘留物於矽膠上利用CHC13—Me〇H (2〇 ··丨）作為洗提 液進行層析，而得4 - [1-[3-[N，-（2-溴苯基）脲基]—2-甲$氧 基-6_咣啶乙醯基]一（4S)-氟一（2S) 一吼咯啶甲氧基]苯甲酸 1283240 五、發明說明（278) ~ 曱酯（1.16克，96%)之黃色黏性固體。 使4 - [1-[3-[Ν -(2-溴苯基）脲基]一2—曱氧基一6 —。比咬乙 醯基]-（4S)_氟-(2S)-吼咯啶曱氧基]笨曱酸曱酯（1. 16 克’1.88毫莫耳）、0·25Ν Na0H(15毫升，3.75毫莫耳）、 及T H F (1 5耄升）之混合物搜拌隔夜。將混合物以1 n η C 1中 和，並利用(：11(：13-诞6〇11(4:1，2又2 0 0毫升）萃取。使結合的 萃取液於MgS〇4上乾燥，並蒸發。使所產生之殘留物於石夕 膠上利用CHClg-MeOH (40 ·· 1至1 〇 ·· 1)作為洗提液進行層 析’而得65之淡黃色非晶形固體。iH-NMR (DMS0_d6) 5 2. 27 - 2 · 3 9 (m, 2H) 、3. 33 - •4. 84 (m 系 列 10H) 、5· 33 - 5. 53 (m, 1H)、 6. 87 -6· 90 (ir 1, 1H) \ 6. 99 (t, 1H, J 二 7. 6 Hz)、 7.08 (d, 2H, J 二 :9. 0 Hz) 、 7. 34 (t, 1H, J = 7. 6 Hz)、 7. 61 (d， 1H, J = 7. 8 Hz) 7. 88 (d, 2H, J = 9. 0 Hz)、 7. 97 (d, 1H, J = 8. 3 Hz) 、 8. 28 -8.32 (m j 1H) 、8· 81 -8. 82 (m, 1H)、 9. 10 - 9. 12 ( m, 1H) 、12 .66 (br s，1H) ; MS(FAB) m/z 601(M+)、6 0 3 (MH2); C27H26BrFN4 06 之分析計算值：c，53. 92 ; H，4. 36 ; N， 9· 32。實測值：C，52. 37 ; H，4. 62 ; N，8. 38。 實施例6 0 4 - [(4S)-氟-1-[4 -[Ν’ -（2-甲基苯基）脲基]苯基乙醯基] -（2S) -吡咯啶甲氧基]苯甲酸Co2h ^ Addition of isocyanide to a stirred solution of 3-amino-2-methoxy-6-acridine ethyl acetate (1·61 g, 7.66 mmol) in THF (10 mL) Acid 2-bromophenyl ester (948 μl, 7.66 mmol) and Et3N (10 μL, 776 776 mmol). After dialing the stirrer, the mixture was poured into Q (1 〇 〇 ml) and extracted with CHC1S-Me0H (4:1, 2×200 mL). The combined extracts were dried over MgS 4 and evaporated. Residue the residue from CHC13_Me〇H_hexane to give 3-[N-(2-bromophenyl)ureido]-2-methoxy- 6-acridineacetic acid ethyl s(2) 1 g '93%) of a colorless crystalline powder. Melting point 1 6 〇 _ 丨 6 3 art; !H-NMR (DMSO-d6) (51.19 (dt, J-7.1 ^0.7 Hz, 3H) &gt; 3.69 (s, 2H) ^3.95 (s, 3H) &gt; 4.07-4.13 (m, 2H) &gt; 6·90 (d, J: 7.8 Hz, 1H), 6.99 (t, J = 7.8 Hz, 1H), 7.33 (t, J = 7.8 Hz, 1H), 7· 6ΐ (d, J = 7.8 Hz, 1H), 7.96 (dd, J=7.8, 1. 5 Hz, 1H), 8.31 (d, J=7.8 Hz, 1H), 8·82 (s, 1H), 9 · 12 (s, 1H); MS (FAB) m / z 4 〇 8 (M +), 410 (MH2); C17H18BrN3 04 · 0. 25H20 Analysis calculated value: C, 4 9 · 4 7 ; Η, 4 · 5 2 ; N,9 · 9 6. Measured value·· C,4 9 · 3 4 ; Ι·ϋΙ 89112968.ptd Page 281 1283240 V. Description of invention (277) H, 4.48; N, 9.96. [Ν'-(2-Bromophenyl)ureido]-2-methoxy-6-, ethylpyridinium ethyl acetate (2.90 g '7.10 mmol), 〇·25Ν Na0H (56.8 ml, 14.2 mmol) The mixture was stirred for 5 hours with THF (50 mL). The mixture was neutralized with 1 N HCl and the resulting residue was collected by filtration. The residue was recrystallized from CHC13-MeOH-hexane to give 3 [ν'-(2-bromophenyl)ureido]-2-methoxy-6-indoleacetic acid (2·40 g, 89%) colorless crystalline powder. Melting point 195-197. (:;1}1-off 1?(0%50-4)53.59 (5,2[〇,3.95 (s,3Η) , 6.88 (d, J: 8.1 Ηζ, 1 Η), 6.97-7.01 (m, 1 Η), 7·33 (t, J = 7.3 Hz, 1 Η), 7·61 (d, J=8.1 Ηζ, 1H ), 7·9 5-7.97 (m, 1H), 8·29 (d, HI Hz, 1H), 8. 81 (s, 1H), 9· 10 (s, ih), 12·35 (br s , 1H); Analysis of C15H14BrN3 04: c, 47. 39 ; h, 3. 71 ; n, 11· 05. Found: C, 47. 27 ; H, 3. 59 , · N, 10. 86 . '3' [N (2-bromo-based) ureido]-2-methoxy-6 - σ ratio bite acetic acid (751 house, 1.97 house mole) and (4S) - fluorine-(2S)-吼Methyl methoxy benzoate (500 mg, 1.97 mmol) was dissolved in a stirred solution of DMF (10 mL). EDC · Η (: 1 (566 mg, 2.96 mmol), DMAP (catalyst) /H0Bt (catalyst). After stirring overnight, the mixture was partitioned between Εί〇Αε (200 liters) and brine (2 liters). The phases were separated. The organic phase was brine (100 mL). Washing, drying on MgS〇4, and evaporating. The resulting residue was chromatographed on a silica gel using CHC13-Me〇H (2〇··丨) as an eluent to obtain 4 - [1-[ 3-[N,-(2-bromophenyl)ureido]-2-methyl oxy-6-acridinyl]-(4S)-fluoro-(2S)-indolyl methoxy] Benzoic acid 1283240 V. Description of the invention (278) ~ oxime ester (1.16 g, 96%) of yellow viscous solid. 4 - [1-[3-[3-[Ν-(2-bromophenyl)ureido]] 2 - 曱 一 一 6 -. 比 醯 ] ]] - (4S) _ fluoro - (2S) - 吼 曱 曱 曱 ] ] ] ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( A mixture of millimolar, 0.25 Ν Na0H (15 ml, 3.75 mmol), and THF (15 liters) was mixed overnight. The mixture was neutralized with 1 n η C 1 and utilized (: 11 ( :13-86 〇11 (4:1, 2 and 200 ml) extraction. The combined extract was dried on MgS〇4 and evaporated, and the residue was applied to the gelatin using CHClg- MeOH (40 ··1 to 1 〇·· 1) was chromatographed as an eluent to give a pale yellow amorphous solid of 65. iH-NMR (DMS0_d6) 5 2. 27 - 2 · 3 9 (m, 2H ), 3. 33 - • 4.84 (m series 10H), 5.33 - 5. 53 (m, 1H), 6. 87 -6· 90 (ir 1, 1H) \ 6. 99 (t, 1H , J 27.6 Hz), 7.08 (d, 2H, J 2: 9. 0 Hz), 7. 34 (t, 1H, J = 7. 6 Hz), 7. 61 (d, 1H, J = 7. 8 Hz) 7. 88 (d, 2H, J = 9. 0 Hz), 7. 97 (d, 1H, J = 8. 3 Hz), 8. 28 -8.32 (mj 1H), 8.81 -8. 82 (m, 1H), 9. 10 - 9. 12 ( m, 1H) , 12.66 (br s, 1H) ; MS (FAB) m/z 601 (M+), 6 0 3 (MH2 Analysis calculated for C27H26BrFN4 06: c, 53. 92 ; H, 4. 36 ; N, 9·32. Found: C, 52. 37; H, 4. 62; N, 8. 38. Example 6 0 4 - [(4S)-Fluoro-1-[4-][Ν'-(2-methylphenyl)ureido]phenylethenyl]-(2S)-pyrrolidinemethoxy] benzoic acid

FF

89112968.ptd 第283頁 1283240 五、發明說明（279) &quot; ----- ▲於4-[N -(2-甲基苯基）脲基]笨乙酸（337毫克，主 ，耳）及4- [(jS) -氟-（2S)-咄咯啶曱氧基]苯甲酸甲酯（= 笔克，1.18*莫耳）溶於DMF(1〇毫升）之攪拌溶液中加 EDC · HC1C 339毫克，：[· 77毫莫耳）、H〇Bt(催化劑）及 DMAP(催化劑）。使反應混合物攪拌隔夜。使混合物在 EtOAc( 2 0 0毫升）與H2〇(2〇〇毫升）之間分配，及將有機相八 離。將有機相以鹽水（ 20 0毫升）洗滌，於MgS04上乾燥，二 蒸發。使殘留物於矽膠上利用CHC^一Me〇H (5〇:1)進行層^ 析:而得4-[(43)-氟一1-[4-[『-（2-曱基苯基）脲基]笨^ 乙酿基]-（2S)-吼咯啶甲氧基]苯甲酸甲酯（613毫克，定 量）之黃色黏性油。：1H-NMr (CDCl3) 5 2· 〇3一2· Μ (m 系 列，總计 5 Η )、3 · 4 7 - 4 · 2 1 ( m 系列，總計 7 Η)、4 · 4 4 - 4 · 6 0 (m，3Η)、5·21 及 5.34 (各m，總計 1Η)、6·87-7.16 (m， 8H)、7·52-7·55 (m，3H)、7·93 (d，J = 8.8 Hz, 2H)、 7.99 (d，J = 8，8 Hz，1H)。 於4-[(43)-氟一1-[4-[『—（2—曱基苯基）脲基]苯基乙醯89112968.ptd Page 283 1283240 V. INSTRUCTIONS (279) &quot; ----- ▲ in 4-[N-(2-methylphenyl)ureido] stearic acid (337 mg, main, ear) and 4-[(jS)-Fluoro-(2S)-decalidinyloxy]benzoic acid methyl ester (= pen gram, 1.18* mol) dissolved in DMF (1 〇 ml) in a stirred solution plus EDC · HC1C 339 mg, [· 77 mmol], H〇Bt (catalyst) and DMAP (catalyst). The reaction mixture was stirred overnight. The mixture was partitioned between EtOAc (EtOAc) (EtOAc) The organic phase was washed with brine (20 mL) dried over EtOAc EtOAc. The residue was subjected to layer chromatography on silica gel using CHC^-Me〇H (5〇:1) to give 4-[(43)-fluoro-l-[4-[『-(2-mercaptophenyl) A yellow viscous oil of urea-based (2-(2S)-fluorenyl methoxy]benzoic acid methyl ester (613 mg, quantitative). :1H-NMr (CDCl3) 5 2· 〇3一2· Μ (m series, total 5 Η), 3 · 4 7 - 4 · 2 1 (m series, total 7 Η), 4 · 4 4 - 4 · 6 0 (m, 3 Η), 5·21 and 5.34 (each m, total 1 Η), 6·87-7.16 (m, 8H), 7·52-7·55 (m, 3H), 7.93 ( d, J = 8.8 Hz, 2H), 7.99 (d, J = 8,8 Hz, 1H). 4-[(43)-Fluoro-1-[4-[『-(2-mercaptophenyl)ureido]phenyl acetamidine

基]一（2S)- 17比咯啶曱氧基]笨甲酸曱酯（613毫克，ι· 18毫莫 耳）溶於THF(l〇毫升）之攪拌溶液中加入〇. 25N Na〇H (9 · 4宅升’ 2 · 3 6宅莫耳）。使混合物迴流1天。於冷卻至室 溫後’將混合物倒入至1N HC1 (50毫升）中，並利用CHC13 -MeOH(5:l，2x200毫升）萃取。使結合的萃取液於^§〇4上 乾紐並条發。使殘留物於矽膠上利用CHC13-MeOH( 1 0 : 1)進 行層析’而得6 6 ( 378毫克，63%)之無色非晶形固體。 HMR (DMSO-d6) 6 2. 0 8-2. 3 0 (m，總計5H)、3· 47-4. 6325(NasH) (a) 9 · 4 home rise ' 2 · 3 6 house Moer). The mixture was refluxed for 1 day. After cooling to room temperature, the mixture was poured into 1N EtOAc (50 mL) and extracted with CHC13-MeOH (5:1, The combined extract is applied to the ^ 〇 4 and dried. The residue was chromatographed on EtOAc EtOAc (EtOAc) (EtOAc) HMR (DMSO-d6) 6 2. 0 8-2. 3 0 (m, total 5H), 3·47-4. 63

89112968.ptd I IIHil 第284頁 1283240 五、發明說明（280) (in 系列，7H)、5. 30-5· 50 (m，1H)、6. 94 (t，J = 7. 3 Hz， 1H)、7·02-7·17 (m，6H)、7·37-7·41 (m，2H)、7·82- 7.96 (m, 4H) &gt;9.05 (s, 1H)； MS(FAB) m/z 5 0 6 (MUl );C28H28FN3 05 · 1 · 75H20 之分析計算值：C，6 2.6 2； H, 5· 91 ; N， 7, 82。實測值：c， 6 2. 2 3 ; H， 5. 63 ; N，7. 18。 實施例6 1 4-[(4S)_氟-1 - [3-甲氧基一 4-[n，-(2-甲基苯基）脲基]笨基 乙醯基]-（2 S)-吼洛啶甲氧基]苯甲酸89112968.ptd I IIHil Page 284 1283240 V. INSTRUCTIONS (280) (in series, 7H), 5. 30-5· 50 (m, 1H), 6.94 (t, J = 7. 3 Hz, 1H ), 7·02-7·17 (m, 6H), 7·37-7·41 (m, 2H), 7.82- 7.96 (m, 4H) &gt; 9.05 (s, 1H); MS (FAB m/z 5 0 6 (MUl); C28H28FN3 05 · 1 · 75H20 Analytical calculated value: C, 6 2.6 2; H, 5· 91 ; N, 7, 82. Found: c, 6 2. 2 3 ; H, 5. 63 ; N, 7.18. Example 6 1 4-[(4S)-Fluoro-1 -[3-methoxy-4-[n,-(2-methylphenyl)ureido]]phenylamino]-(2S) -lopodidine methoxy]benzoic acid

-Q-c〇2h 67 在室溫下於卜（第三丁氧羰基）—（4S) —氟—（2S) -脯胺酸 (1.85克’ 7.93¾莫耳）溶於THF(15毫升）之攪拌溶液中加 入BH3 · DMS( 0· 75耄升’ 7. 93毫莫耳）。於邊授拌邊迴流加 熱5小時後，使混合物冷卻至室溫，並於真空中濃縮。經 由加入4 0 (1 0 0毫升）使所產生之殘留物停止反應，並以 CHCI3 ( 2x2 0 0毫升）萃取。將結合的萃取液以鹽水（1⑽毫 升）洗滌’於MgS〇4上乾燥，並蒸發。使殘留物於矽膠上利 用CHCI3-EtOAc(4:l)作為洗提液進行層析，而得ι_(第三 丁氧羰基）-（4S)-氟-(2S)_吼咯啶甲醇（ι·76克，定量）之 無色油。1H-NMR (CDC13) 6 1. 48 (s，9Η)、1· 64 (m， 1H)、1·97-2·28 (m， 2H)、3·53〜3.87 (m 系列，4H)、 4.0 9-4.25 (m，1H)、5. 09 及 5.22 (各 m，總計 1H)。 在室溫下於卜（第三丁氧羰基）〜（4S) —氟—（2S) -。比咯啶曱-Qc〇2h 67 Stir at room temperature in di(t-butoxycarbonyl)-(4S)-fluoro-(2S)-proline (1.85 g ' 7.933⁄4 mol) in THF (15 ml) BH3 · DMS (0.77 liters ' 7. 93 mmol) was added to the solution. After heating at reflux for 5 hours while stirring, the mixture was cooled to room temperature and concentrated in vacuo. The resulting residue was quenched by the addition of 40 (10 mL) and extracted with CHCI3 (2×200 mL). The combined extracts were washed with brine (1 (10) mL) and dried over MgS 4 and evaporated. The residue was chromatographed on silica gel using CHCI3-EtOAc (4:1) eluting · 76 grams, quantitative) of colorless oil. 1H-NMR (CDC13) 6 1. 48 (s, 9Η), 1·64 (m, 1H), 1.97-2·28 (m, 2H), 3·53~3.87 (m series, 4H), 4.0 9-4.25 (m, 1H), 5. 09 and 5.22 (each m, total 1H). At room temperature, di(t-butoxycarbonyl)~(4S)-fluoro-(2S)-. Bipyridinium

89112968.ptd 第285頁 1283240 五、發明說明（281) 醇（500毫克，2.28毫莫耳）、4 -羥基苯甲酸甲s旨（416ΐ 克，2.74 毫莫耳）、Ph3P(719 毫克，2.74 毫莫耳）μΤη^(1〇 毫升）中之攪拌混合物中加入DI AD(0_ 54毫升，2· 74毫莫 耳）。使混合物邊攪：拌邊迴流加熱5小時。於冷卻至室溫 後，將混合物於真空中濃縮。使殘留物於石夕膠上利用 CHCl3__EtOAc作為洗提液（10:1至4:1)進行層析，而得4一 [1-(第三丁氧幾基）-（4S) - H-（28)-吼洛°定曱氧基]苯曱酸 甲酯（ 5 97 毫克，74%)之無 g*°1H-NMR(CDCl3)(Jl.49-1· 59 (m，9H)、2· 0 5-2· 21 (m，1H)、3· 56-4· 43 (in 系列， 8H)、5·19 及 5.32 (各m，總計 1H)、6·97 (m，2H) 、7·98 (d, J=8· 5 Hz， 2H)。 使4 - [1 -（第三丁氧羰基）-（4S) -氟-（2S) - π略咬甲氧基] 苯甲酸甲酯（590毫克，1.67毫莫耳）及TFA(5毫升）於CH2C12 (5毫升）中之混合物攪拌3小時。於將混合物於真空中濃縮 後，利用飽和NaHC03使殘留物成為鹼性，並以CHC13(2x200 毫升）萃取。將結合萃取液於K2 C 03上乾燥，並蒸發而得 4 - [(4S) -氟-（2S) -咄咯啶甲氧基]苯甲酸甲酯（414毫克， 98%)的黃色固體。ιΗ一NMR (CDC13) 51. 89-2· 02 (m， 1Η)、 2·16-2.31 (m， 1H) 、2·98 (m， 1H) 、3·35 (m， 1H)、 3.46-3·68 (m，1Η)、3·86 (s，3Η)、4·0 0 -4.0 8 (m， 2H)、5·16 及 5·29 (各t，J = 4.7 Hz，總計 1H)、6·91 (d， J = 8.8 Hz，2H)、7· 96 (d，J = 8. 8 Hz，2H)。 使4-[ (4S)-氟-(2S)-咄咯啶甲氧基]苯甲酸曱酯（2 0 5毫 克，0·810毫莫耳）、3-甲氧基-4 - [N，-（2-曱基苯基）脲89112968.ptd Page 285 1283240 V. INSTRUCTIONS (281) Alcohol (500 mg, 2.28 mmol), 4-hydroxybenzoic acid methyls (416 g, 2.74 mmol), Ph3P (719 mg, 2.74 m) DI AD (0-54 ml, 2.74 mmol) was added to the stirred mixture of MeOH (1 mL). The mixture was stirred while being heated under reflux for 5 hours. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was chromatographed on silica gel using CHCl3__EtOAc as eluent (10:1 to 4:1) to give 4-[1-(t-butoxy- yl)-(4S)-H- ( 28)- 吼 ° 曱 曱 曱 ] ] 甲酯 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 * * * * * * * * * * · 0 5-2· 21 (m, 1H), 3· 56-4· 43 (in series, 8H), 5·19 and 5.32 (each m, total 1H), 6.97 (m, 2H), 7 ·98 (d, J=8·5 Hz, 2H). 4-[1-(Tertidinoxycarbonyl)-(4S)-fluoro-(2S)-π slightly methoxyl]methyl benzoate (590 mg, 1.67 mmol) and a mixture of TFA (5 mL) in CH2C12 (5 mL). (2x200 ml) extraction. The combined extracts were dried over K2C03 and evaporated to give 4-[(4S)-fluoro-(2S)--------------- %) of yellow solid. ιΗ NMR (CDC13) 51. 89-2· 02 (m, 1Η), 2·16-2.31 (m, 1H), 2·98 (m, 1H), 3·35 (m , 1H), 3.46-3·68 (m, 1Η), 3·86 ( s, 3Η), 4·0 0 -4.0 8 (m, 2H), 5·16 and 5·29 (each t, J = 4.7 Hz, total 1H), 6.91 (d, J = 8.8 Hz, 2H ), 7·96 (d, J = 8. 8 Hz, 2H). 4-[(4S)-Fluoro-(2S)-indolyl methoxy]benzoate oxime (2, 5 mg, 0) · 810 millimoles), 3-methoxy-4 - [N,-(2-mercaptophenyl)urea

89112968.ptd 第286頁 1283240 五、發明說明（282) 基]苯乙酸（254毫克，0·810毫莫耳）、EDC*HC 1(233毫 克，1. 22毫莫耳）、HOBt(催化劑）及DMAP(催化劑）於DMF (1 0毫升）中之混合物攪拌隔夜。將混合物以E t 〇 A c ( 2 〇 〇毫 升）稀釋，以鹽水（2x1 00毫升）洗滌，於MgS04上乾燥，並 蒸發。使殘留物於矽膠上利用CHC13-MeOH (20:1)進行層 析，而得4 - [(4S)-氟-1 - [3-甲氧基-4 - [N，-(2-曱基苯基） 脲基]苯基乙醯基]-（2S) -咄咯啶曱氧基]苯曱酸曱酯（445 毫克，定量）之淡棕色黏性。1H-NMR (CDC13) 3 2.05-2.55 (m，總計6H)、3.55-4.13 (m，11H)、4.48-4.60 (m， 2H)、5·20 及 5·33 (各m，總計1H)、6·29 (s, 1H)、6·79 (m， 2H) 、 6· 96 (d， J=8·8 Hz, 2H) 、 7·1卜7· 25 (m， 3H) 、7·48 (d， J=7.6 Hz, 1H) 、7·93-8.09 (m， 4H)。 使4-[(4S)-氟-l-[ 3-曱氧基-4--（2-曱基苯基）脲基] 苯基乙酷基]-(2S) -吼咯啶甲氧基]苯甲酸曱酯（445毫克，89112968.ptd Page 286 1283240 V. INSTRUCTIONS (282) Base] phenylacetic acid (254 mg, 0·810 mmol), EDC*HC 1 (233 mg, 1.22 mmol), HOBt (catalyst) The mixture of DMAP (catalyst) in DMF (10 mL) was stirred overnight. The mixture was diluted with EtOAc (2 mL), washed with brine (2×1 00 mL), dried over EtOAc and evaporated. The residue was chromatographed on silica gel using CHC13-MeOH (20:1) to give 4-[(4S)-fluoro-1 -[3-methoxy-4 - [N,-(2-mercapto) Phenyl) ureido]phenylethyl fluorenyl]-(2S)-decalidinyloxy] benzoic acid oxime ester (445 mg, quantitative) of light brown viscous. 1H-NMR (CDC13) 3 2.05-2.55 (m, total 6H), 3.55-4.13 (m, 11H), 4.48-4.60 (m, 2H), 5·20 and 5·33 (each m, total 1H), 6·29 (s, 1H), 6.79 (m, 2H), 6.96 (d, J=8·8 Hz, 2H), 7·1 b 7· 25 (m, 3H), 7·48 (d, J=7.6 Hz, 1H), 7.93-8.09 (m, 4H). 4-[(4S)-Fluoro-l-[3-methoxy-4-(2-mercaptophenyl)ureido]phenylethyl]-(2S)-pyrrolidinemethoxy Ethyl benzoate (445 mg,

1·62φ莫耳）及0.25N NaOH(15毫升，3.75毫莫耳）於THF (1 5毫升）中之混合物在室溫下攪拌隔夜，然後再在迴流下 2小時。將混合物以in HC1酸化，並利用CHC13-MeOH(4 : 1， 2x200毫升）萃取。使結合的萃取液於MgS〇4上乾燥並蒸 發。使殘留物於'石夕膠上利用CHCl3—Me〇H(1〇:1)作為洗提液 進行層析，而得67 ( 26 0毫克，30%)之淡黃色非晶形固體。 丨!1-NMR (DMS0-d6) (5 2· 25-2· 51 (m，5H)、3· 33-4. 41 (m 系 列，10H)、5.3〇-5.50 (m，1H)、6.75-7.17(m，71〇、 7·79 (d，J = 8.1 Hz，1H)、7·87-8·04 (m，3H)、8·48 (m，1H)、8·58 (m，ih); MS(FAB) m/z 53 6 (MH1);The mixture was stirred at room temperature overnight and then refluxed for 2 h. EtOAc (EtOAc m. The mixture was acidified with in HCl and extracted with CH.sub.3-MeOH (4:1, 2 x 200 mL). The combined extracts were dried over MgS 4 and evaporated. The residue was chromatographed on <RTI ID=0.0></RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt;丨! 1-NMR (DMS0-d6) (5 2· 25-2· 51 (m, 5H), 3· 33-4. 41 (m series, 10H), 5.3〇-5.50 (m, 1H), 6.75 -7.17 (m, 71 〇, 7.79 (d, J = 8.1 Hz, 1H), 7·87-8·04 (m, 3H), 8·48 (m, 1H), 8·58 (m, Ih); MS(FAB) m/z 53 6 (MH1);

1283240 五、發明說明（283) -----1283240 V. Description of invention (283) -----

C29H3()FN3 06 · H20 之分析計算值：c，62. 92 ; H，5. 83 ; N 7·59。實測值：C，62.40; Η，5.82; N，6.93。 實施例6 2 4-[：1-[4-[Ν -（2-溴笨基）脲基]-3一甲氧苯基乙醯基]—(4s) -氟-（2 S ) -咣略啶曱氧基]苯甲酸For C29H3()FN3 06 · H20: C, 62. 92; H, 5. 83; N 7.59. Found: C, 62.40; Η, 5.82; N, 6.93. Example 6 2 4-[:1-[4-[Ν-(2-Bromophenyl)ureido]-3-methoxyphenylethenyl]-(4s)-fluoro-(2S)-咣Acridineoxy]benzoic acid

〇^〇~C02H H OMe 使4 - [(4S)-氟-（2S)-咄咯啶曱氧基]苯甲酸甲酯（5〇1毫 克，1·98毫莫耳）、4-[N，-（2-溴苯基）脲基]一3 一曱氧苯乙 酸（750毫克，1· 98毫莫耳）、EDC · HC 1 ( 5 6 9毫克，2· 97毫 莫耳）、Η 0 B t (催化劑）及d M A Ρ (催化劑）於D M F (1 0毫升）中 之混合物攪拌隔夜。將混合物以Et〇Ac( 3 0 0毫升）稀釋，以 鹽水（100毫升）洗滌，於MgS04上乾燥，並蒸發。使殘留物 於矽膠上利用CHC13-EtOAc(4: 1)至CHC13-MeOH(10: 1)作為 洗提液進行層析，而得4-[1-[4-[Ν，-（2 -溴苯基）脲基]-3 -甲氧苯基乙醯基]-(4S) -氟-（2S) -咣咯啶甲氧基]苯甲酸曱 酯（1· 29克，定量）之棕色黏性油。ih-NMR (CDC13) 5 2·0 5-2.58 (m，2H)、3·49 - 4.17 (m 系列，12H)、4·52 -4· 65 (m， 2Η) 、6· 82-7· 33 (m 系列，8Η) 、7· 52 (dd， J = 8·1 、1·5 Hz， 1H) 、7·95-8·02 (m， 4H) 、8·14 (dd， J=8·3 、 1·7 Hz， 1H)。 使4-[1-[4 - [Ν’ -（2-溴苯基）脲基]-3-甲氧苯基乙醯基 ]-(4S) -氟-（2S) -咄咯啶甲氧基]苯甲酸甲酯（1. 29克，〇^〇~C02H H OMe Methyl 4-((4S)-fluoro-(2S)-fluorenyl hydrazideoxy]benzoate (5〇1 mg, 1.98 mmol), 4-[N ,-(2-bromophenyl)ureido]-3-oxooxyphenylacetic acid (750 mg, 1. 98 mmol), EDC · HC 1 (5 6 9 mg, 2.97 mmol), Η A mixture of 0 B t (catalyst) and d MA Ρ (catalyst) in DMF (10 mL) was stirred overnight. The mixture was diluted with EtOAc (3 mL) and brine (100 mL). The residue was chromatographed on a silica gel using CHC13-EtOAc (4:1) to CHC13-MeOH (10:1) as eluent to give 4-[1-[4-[Ν,-(2-bromo) Phenyl)ureido]-3-methoxyphenylethenyl]-(4S)-fluoro-(2S)-indolyl methoxy]benzoic acid oxime ester (1·29 g, quantitative) of brown sticky Sex oil. Ih-NMR (CDC13) 5 2·0 5-2.58 (m, 2H), 3.49 - 4.17 (m series, 12H), 4·52 -4· 65 (m, 2Η), 6·82-7· 33 (m series, 8Η), 7.52 (dd, J = 8·1, 1·5 Hz, 1H), 7·95-8·02 (m, 4H), 8·14 (dd, J=8 · 3, 1·7 Hz, 1H). 4-[1-[4 - [Ν' -(2-Bromophenyl)ureido]-3-methoxyphenylethenyl]-(4S)-fluoro-(2S)-pyrrolidine methoxy Methyl benzoate (1. 29 g,

89112968.ptd 第288頁 128324089112968.ptd Page 288 1283240

五、發明說明（284) 2·10毫莫耳）及0.25N Na0H(17毫升，4.20毫莫耳）於 THF ( 2 0毫升）中之混合物邊攪拌邊迴流5小時。將混合物倒 入至冰冷的IN HC1(100毫升）中，並利用CHCl3-MeOH (4·· 1，2x20 0毫升）萃取。使結合的萃取液於MgS04上乾燥 並蒸發。使殘留物於矽膠上利用CHCI3-MeOH( 1 0 : 1)作為洗 提液進行層析，而得6 8 ( 8 6 0毫克，6 8 %)之無色非晶形固 體。1Η-NMR (DMS0-d6)52.24-2.31 (m，2H)、3·21-4 63 (m 系列，10Η)、5·31 - 5.51 (m， 1Η) 、6.74 —7·1〇 (m， 5H)、7·32 (t， J = 7.8 Hz， 1H)、7·60 (d， J = 7.8 Hz， 2H)、7·87-7.99 (m，4H)、8·74-8.75 (m，1H)、8·92- 8.94 (m, 1H) ； MS(FAB) m/z 60 1 ( MH 1) ； C28H27BrFN3〇6 · 2H20 之分析計算值：C，52.84;H，4·91;Ν，6·60。3^ 測 值·· C，52· 38 ; H，4· 62 ; N，5· 99。 、 關於6 8 之Na 鹽：熔點180-182 °C ; C28H27BrFN3Na06 · 〇. 75Η20 之分析計算值·· C，52· 88 ; Η，4· 36 ; Ν，6· 61。實測值% C，52· 97 ; Η，4· 36 ; Ν，6. 61。 貫施例fi 3 4 - [1- [4-[Ν’ -（2-氣笨基）脲基]-3-曱氧笨基乙醯基]一（4S) -氟-（2S) -咄咯啶甲氧基]苯甲酸5. Inventive Note (284) 2·10 mmoles and 0.25 N NaHH (17 mL, 4.20 mmol) in THF (20 mL). The mixture was poured into ice cold <RTI ID=0.0># </RTI> </RTI> <RTI ID=0.0> The combined extracts were dried over MgS04 and evaporated. The residue was chromatographed on silica gel eluting with CHCI3-MeOH (1O:1) to afford 6 8 ( 680 mg, 68%) of colorless amorphous solid. 1Η-NMR (DMS0-d6) 52.24-2.31 (m, 2H), 3·21-4 63 (m series, 10Η), 5.31 - 5.51 (m, 1Η), 6.74 —7·1〇 (m, 5H), 7·32 (t, J = 7.8 Hz, 1H), 7·60 (d, J = 7.8 Hz, 2H), 7·87-7.99 (m, 4H), 8.74-8.75 (m, 1H), 8.92- 8.94 (m, 1H); MS (FAB) m/z 60 1 (MH 1); C28H27BrFN3〇6 · 2H20 calc.: C, 52.84; H, 4·91; 6·60. 3^ measured value · · C, 52 · 38 ; H, 4 · 62 ; N, 5. 99. , about 6 8 Na salt: melting point 180-182 ° C; C28H27BrFN3Na06 · 〇. 75Η20 analytical calculation · · C, 52 · 88 ; Η, 4 · 36 ; Ν, 6 · 61. Founded values % C, 52 · 97 ; Η, 4 · 36 ; Ν, 6. 61. Example fi 3 4 - [1- [4-[4-[Ν' -(2-Azyl))]]]]]]]]]]]]]]]]] Pyridylmethoxy]benzoic acid

使4-[(4S) -氟-（2S) -吼咯啶甲氧基]苯曱酸甲酯（2〇5毫Methyl 4-[(4S)-fluoro-(2S)-indolyl methoxy]benzoate (2〇5 毫

11

«I 1Γ 11 _ 89112968.ptd 第289頁 1283240 五、發明說明（285)«I 1Γ 11 _ 89112968.ptd Page 289 1283240 V. Description of invention (285)

克，0.810毫莫耳）、3-甲氧基-4-[Ν’ - (2-甲基笨基）脲 基]苯乙酸（254毫克，0.810毫莫耳）、EDC*HC 1(233毫 克’ 1 · 2 2毫莫耳）、Η Ο B t (催化劑）及D M A P (催化劑）於d M F (10毫升）中之混合物攪拌隔夜。將混合物以EtOAc( 200毫 升）稀釋，以鹽水（2x1 00毫升）洗滌，於MgS04上乾燥，並 蒸發。使殘留物於矽膠上利用CHC13-MeOH(20 : 1 )作為洗提 液進行層析，而得4-[1-[4 - [Ν’-（2 -氯笨基）脲基]一 3-曱氧 苯基乙Si基]-（4S)_氟-（2S) -咄略咬曱氧基]苯曱酸曱酯g, 0.810 mmol, 3-methoxy-4-[Ν'-(2-methylphenyl)ureido]phenylacetic acid (254 mg, 0.810 mmol), EDC*HC 1 (233 mg) A mixture of '1 · 2 2 mmoles), Η Ο B t (catalyst) and DMAP (catalyst) in d MF (10 ml) was stirred overnight. The mixture was diluted with EtOAc (EtOAc (EtOAc)EtOAc. The residue was chromatographed on silica gel using CHC13-MeOH (20:1) as an eluent to give 4-[1-[4-[[-[(-)]]曱Phenyl phenyl Ethyl]-(4S)-fluoro-(2S)-咄 slightly bite oxy] benzoic acid decyl phthalate

( 376 毫克，81°/〇)之黃色泡沫。1H-NMR (CDC13) 6 2. 07-2·56(πι， 2H)、3.57-4.14 (m 糸列，11H)、4.50 - 4.61 (m， 2H)、5. 22 及5· 35 (m 系列，總計1H)、6· 80-7· 33 (m 系歹L 9H) 、7·93-8.00 (m, 3H) 、8.16 (d， J=8.1 Hz， 1H)。 ’ 使4-[1-[4 - [N’_(2_氯苯基）脲基]—3-曱氧苯基乙醯 基]-(4S)-氟-（2S)-咄咯啶甲氧基]苯甲酸甲酯（3 76毫克，(376 mg, 81 ° / 〇) yellow foam. 1H-NMR (CDC13) 6 2. 07-2·56 (πι, 2H), 3.57-4.14 (m 糸, 11H), 4.50 - 4.61 (m, 2H), 5. 22 and 5· 35 (m series) , total 1H), 6·80-7· 33 (m system 歹L 9H), 7.93-8.00 (m, 3H), 8.16 (d, J=8.1 Hz, 1H). ' 4-[1-[4 - [N'_(2_Chlorophenyl)ureido]-3-methoxyphenylethyl]-(4S)-fluoro-(2S)-pyrrolidine Methyl oxy]benzoate (3 76 mg,

0_6 6 0毫莫耳）及〇·25Ν NaOH(15毫升，3.75毫莫耳）於THF (1 5宅升）中之混合物在室溫下授拌隔夜，然後迴流2小 時。將混合物以IN HC1酸化，並利用CHC13-MeOH (4 : 1， 2x20 0 t升）卒取。使結合的萃取液於MgS〇4上乾燥並蒸 發。使殘留物於矽膠上利用CHCl3 —Me〇H(2〇:1)作為洗提液 進行層析’而得6 9 ( 2 6 0毫克，3 0 % )之淡黃色非晶形固體。 M-NMR (DMS0-d6) (5 2· 24-2. 5 0 1 (m，2H)、3· 4 8-4· 65 (m 系列，10H)、5·3 0-5.50 (m，1H)、6.75-7.0 8 (m，510、 7.29 (t，J = 7.3 Hz, 1H)、7·43-7·45 (m, 1H)、7·89-7.98 (m，2H)、7·99 (d，J = 8.3 Hz，1H)、8·〇9 (d，A mixture of NaOH (15 ml, 3.75 mmol) in THF (15 liters) was stirred at room temperature overnight and then refluxed for 2 hours. The mixture was acidified with IN HCl and was taken from CHC13-MeOH (4:1, 2 x 20 0 liter). The combined extracts were dried over MgS 4 and evaporated. The residue was chromatographed on silica gel using CHCl 3 -Me </RTI> (2::1) as eluent to give 6 9 (260 mg, 30%) of pale yellow amorphous solid. M-NMR (DMS0-d6) (5 2· 24-2. 5 0 1 (m, 2H), 3· 4 8-4· 65 (m series, 10H), 5·3 0-5.50 (m, 1H ), 6.75-7.0 8 (m, 510, 7.29 (t, J = 7.3 Hz, 1H), 7·43-7·45 (m, 1H), 7·89-7.98 (m, 2H), 7.99 (d, J = 8.3 Hz, 1H), 8·〇9 (d,

1283240 五、發明說明（286) J二7·1 Hz， 1H) η η ^ 90~8. 96 (m, 2Η) ； MS(FAB) m/z 60.00; Η, 4.95 5. 08 ； Ν, 7.10 實施例64 5 5 6 (MU 1 ) ； C28 Η27 C I F Μ η ί / a η ρπ Λη · ττ ^ 8一27 UN3〇6 · 1/4Η2〇 之分析計算值：C， Ν，7· 50。實測值：C, 5 9.6 7； Η, 4-[1-[4 一 [Ν’ 一（2〜淳笼 、丰基）脲基]苯基乙醯基]-(4S)-氟 一（2S)一吼略〇疋甲氧基]笨甲酸1283240 V. Description of invention (286) J 2 7.1 Hz, 1H) η η ^ 90~8. 96 (m, 2Η) ; MS(FAB) m/z 60.00; Η, 4.95 5. 08 ; Ν, 7.10 Example 64 5 5 6 (MU 1 ) ; C28 Η 27 CIF Μ η ί / a η ρπ Λη · ττ ^ 8 - 27 UN3 〇 6 · 1/4 Η 2 〇 Analysis calculated values: C, Ν, 7·50. Found: C, 5 9.6 7; Η, 4-[1-[4 一[Ν'一(2~淳笼,丰基)U allyl]phenylethenyl]-(4S)-fluoro-(2S a slightly methoxy] benzoic acid

)HC)-c〇2h 4 - [1-(4-胺苯基乙柄其、7 甲酸甲醋 基）-(4S)—氟-(2S)-咄咯啶甲氧基]苯)HC)-c〇2h 4 - [1-(4-Aminophenyl acetonate, 7-methyl formate)-(4S)-fluoro-(2S)-indenyl methoxy]benzene

H2N 咯!J4甲%1 —卞乳碳胺基苯基乙醯基)_(4S)-氟-(2S)-咄H2N !! J4甲%1 - 卞乳碳carbophenyl phenyl fluorenyl) _(4S)-fluoro-(2S)-咄

Γ甲Λ甲醋（3〇0毫克’ 〇· 576毫莫耳）加人 (3⑽古升彳t / 〇笔升），並使溶液邊攪拌邊在5% Pd/C 咸〔下浪鈿。將殘留物於矽膠上利用CHC1 _ =以作，，提液進行層析，心;基乙 克%0Π的龙氣（2S) D比咯啶曱氧基]笨甲酸甲酯（2 0 0毫 克 T 的彡色油。1H_NMR (CDC13)d2 01_2 56 (m系列， 2H) 、3.50-4.14 (m 系列，5H) 、4.45_462 (m， 2H)、Armored vinegar (3 〇 0 mg ' 〇 · 576 mmol) plus people (3 (10) Gu Sheng 彳 t / 〇 pen liter), and the solution is stirred at 5% Pd / C salty [low waves. The residue was applied to silica gel using CHC1 _ =, and the solution was subjected to chromatography, and the heart; methyl ethyl ketone %0 Π long gas (2S) D than pyridinium oxy] methyl benzoate methyl ester (200 mg T 彡 color oil. 1H_NMR (CDC13)d2 01_2 56 (m series, 2H), 3.50-4.14 (m series, 5H), 4.45_462 (m, 2H),

第291頁 1283240 五、發明說明（287) 5.21 及5.34 (各出，總、計 1H)、6.6〇_6 65 (m，2H)、6 88 (d， J=8·8 Hz， 〇·5H) 、 6·99—7·〇5 (m， 3· 5H)、 7.95-8.00 (m， 2H) 〇 4-[1-[4-[Ν’ -（2-溴苯基）脲基]苯基乙醯基]—(4S)一氟 -（2S)-吡咯啶甲氧基]笨曱酸甲酯Page 291 1283240 V. INSTRUCTIONS (287) 5.21 and 5.34 (each out, total, 1H), 6.6〇_6 65 (m, 2H), 6 88 (d, J=8·8 Hz, 〇·5H ), 6·99—7·〇5 (m, 3· 5H), 7.95-8.00 (m, 2H) 〇4-[1-[4-[Ν' -(2-bromophenyl)ureido]benzene Ethyl thiol]-(4S)-fluoro-(2S)-pyrrolidinemethoxy]methyl benzoate

e 將4-[1-（4-胺笨基乙醯基）-(4S)-氟—（2S)—吼咯啶甲氧 基]苯甲馱甲酉曰（200毫克，〇·518毫莫耳）溶解於THF( j 〇毫 升）。將Et3N(108微升’ 776毫莫耳）及異氰酸2 —溴苯酯 (96微升，0.776毫莫耳）加至溶液中。將混合物攪拌隔 仪’並以E10Ac ( 2 0 0毫升）稀釋。將溶液以鹽水（丨〇 〇毫升） 洗滌’於MgS〇4上乾燥，及將溶劑於減壓下移除。使殘留 物於矽膠上利用CHC13 - EtOAc(4: 1)至CHC13 - MeOH (10:1)作 為洗提液進行層析，而得4-[l-[4-[N，-（2 -溴苯基）脲基] 笨基乙醯基]-（4S) -氟- (2S)-咄咯啶甲氧基]苯曱酸甲酯 ( 30 3 毫克，定量）的黃色油。iH-NMR (CDC13) 5 2. 08-2. 60 (m 系列，2H)、3· 56-4· 69 (m 系列，1 0H)、5· 28 及5· 40 (各m，總計1H)、6. 84-6. 92 (m，3H)、7· 0 3-7· 1 0 (m, 3H) 、7·14 (d， J:8.1 Hz， 1H) 、7.23 (t， J=8.1 Hz， 1H)、7·39-7·44 (m，2H)、7.89 (d，J = 8.1 Hz，1H)、 7.98-8.0 3 (m，2H)、8.09(d，J = 8.1Hz，lH)。 將4-[l-[ 4-[Ν’ -（2-溴苯基）脲基]苯基乙醯基]-(4S)-氟e 4-[1-(4-Amino-p-ethyl)-(4S)-fluoro-(2S)-pyrrolidinemethoxy]benzamide (200 mg, 〇·518 mmol) Ear) dissolved in THF (j 〇 ml). Et3N (108 microliters '776 millimoles) and 2-bromophenyl isocyanate (96 microliters, 0.776 millimoles) were added to the solution. The mixture was stirred and replaced with E10Ac (200 mL). The solution was washed with brine (丨〇 〇 mL) and dried over MgSO 4 and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel using CHC13 - EtOAc (4: 1) to CHC13 - MeOH (10:1) as eluent to give 4-[l-[4-[N,-(2-bromo) Phenyl)ureido] phenylamino]-(4S)-fluoro-(2S)-decalyl methoxy]benzoic acid methyl ester (30 3 mg, quantitative) of a yellow oil. iH-NMR (CDC13) 5 2. 08-2. 60 (m series, 2H), 3· 56-4· 69 (m series, 1 0H), 5·28 and 5·40 (each m, total 1H) 6. 84-6. 92 (m, 3H), 7· 0 3-7· 1 0 (m, 3H), 7·14 (d, J: 8.1 Hz, 1H), 7.23 (t, J=8.1 Hz, 1H), 7·39-7·44 (m, 2H), 7.89 (d, J = 8.1 Hz, 1H), 7.98-8.0 3 (m, 2H), 8.09 (d, J = 8.1Hz, lH ). 4-[l-[4-[Ν'-(2-Bromophenyl)ureido]phenylethenyl]-(4S)-fluoro

89112968.ptd 第292頁 1283240 五、發明說明（288) -（2S )-吼略啶曱氧基]苯甲酸曱酯（3 〇 〇毫克，〇 · 5 i 3毫莫 耳）溶解於THF(5毫升）中，及將0·25Ν Na〇H(4· 0毫升， 1 · 〇 〇毫莫耳）加至此溶液。於攪拌3天後，將混合物倒入至 IN HC1(100 毫升）中，並利用 CHCl3—Me〇H(5:1，2x2〇〇 毫 升）萃取。將結合的萃取液於MgS〇4上乾燥，及將溶劑於減 壓下移除。使殘留物於矽膠上利用CHCl3 —Me〇H(丨〇 :丨）進行 層析，而得70 ( 209毫克，71%)的無色非晶形固體。ih-NMR (DMSO-d6) (5 2· 24-2· 51 (m，2H)、3· 36-4. 64 (m 系列， 7H)、5·3 卜 5·50 (m, 1H)、6·97 (t，J:7.8 Hz, 1H)、 7.04 (d，J = 8.5 Hz，1H)、7.09 (d，J = 8.8 Hz, 1H)、 7.14-7.20 (m，2H)、7.34 (t，J二 7·8 Hz，1H)、7·38 -7·43 (m，2H)、7·61 (d，J二8·1 Hz，1H)、7·87-7·92 (m， 2Η) 、8·08 (d， J=8.1 Ηζ， 1Η) 、8.15 (s， 1Η)、 9.45-9.47 (m， 1H) 、 12.66 (br s， 1H); MS(FAB) m/z 572 (MH2)、570(M+) ; C27H25BrFN3 05 · 1·5Η20 之分析計算 值·· C，54. 28 ; H，4· 72 ; N，7· 03。實測值：c，54. 6 7 ; Η，4·51; N，6.61。 實施例6 5 4-[1 - [4 - [Ν’ -（2 -碘苯基）脲基]- 3-曱氧苯基乙醯基]一（4S) -氟-（2 S)-吼略咬甲氧基]苯甲酸 h〇hco2h I Η H 〇Me 71 4 - [Ν’ -（2 -碘苯基）脲基]—3一甲氧基笨乙酸89112968.ptd Page 292 1283240 V. INSTRUCTIONS (288) -(2S )-吼 曱 曱 曱 曱 ] ] ( ( ( (3 〇〇 mg, 〇 · 5 i 3 mmol) dissolved in THF (5 In ml), add 0.25 Ν Na〇H (4.0 ml, 1 · 〇〇 millimol) to this solution. After stirring for 3 days, the mixture was poured into IN HCl (100 mL) and extracted with CHCl 3 -Me 〇H (5:1, 2 x 2 毫m). The combined extracts were dried on MgS 4 and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel eluting EtOAc (EtOAc:EtOAc) ih-NMR (DMSO-d6) (5 2· 24-2· 51 (m, 2H), 3· 36-4. 64 (m series, 7H), 5·3 b 5·50 (m, 1H), 6.97 (t, J: 7.8 Hz, 1H), 7.04 (d, J = 8.5 Hz, 1H), 7.09 (d, J = 8.8 Hz, 1H), 7.14-7.20 (m, 2H), 7.34 (t , J 2·7 Hz, 1H), 7·38 -7·43 (m, 2H), 7.61 (d, J 2·1 Hz, 1H), 7·87-7·92 (m, 2Η), 8·08 (d, J=8.1 Ηζ, 1Η), 8.15 (s, 1Η), 9.45-9.47 (m, 1H), 12.66 (br s, 1H); MS(FAB) m/z 572 ( MH2), 570(M+); C27H25BrFN3 05 · 1·5Η20 Analysis calculated value ····································· 4·51; N, 6.61. Example 6 5 4-[1 - [4 - [Ν' -(2-Iodophenyl)ureido]-3-oxophenylphenyl]](4S) - Fluorine-(2S)-吼 slightly methoxy]benzoic acid h〇hco2h I Η H 〇Me 71 4 - [Ν'-(2-Iodophenyl)ureido]-3 methoxy acetoacetic acid

89112968.ptd 第293頁 1283240 五、發明說明（289) 於4-胺基-3-甲氧苯乙酸第三丁酯（1·94克，816毫莫 耳）溶於THF( 20亳升）之攪拌溶液中加入異氰酸2_碘苯酯 (2· &lt;0克’ 8. 1 6耄莫耳）及Et3N( 1 1 4微升，〇· 81 6毫莫耳）。 於攪拌隔夜後，將混合物倒入至1N HC1(2〇〇毫升）中。經 由過濾收集所產生之沈澱物，並將其溶解KCHC13(2〇()毫 =)中。將溶液於MgS〇4上乾燥，並蒸發而得4 —[N，_(2一碘 j基）脲基]-3-甲氧苯乙酸第三丁酯（3· 93克，定量）的淡 育色非晶形固體。iH — NMR (CDC13) 5144 (s，9Η)、3·49 s，2Η)、3·85 (s，3Η)、6.78-6·88 (m，4Η)、7 G7 (s， Η)、7·3 卜 7·35 (m，1Η)、7·76 (dd，J = 7.8、1·5 Ηζ， Η) ^7.95 (d, j,8.3 Hz, lH) ^7.99 (dd, J = 8. 3 M.5 Hz，1H)。MS(ESI)，m/z 483(M+H)。 3使4 [N〜（2 —碘苯基）脲基]曱氧苯乙酸第三丁酯（ 声93 士丄8· 16毫莫耳）及TFA(5毫升）於CH22C12(5毫升）中之 掉r t物迴流3小時。於冷卻至室溫後，將混合物於真 =中濃縮’並將10(50毫升）加至此殘留物。經由過濾收 =所^生之沈澱物，並於矽膠上利用CHCl3-MeOH (9:1)作 8 3()1提，，行管柱層析，純化而得標題化合物（2. 8 9克， %)之淡黃色結晶粉末。UMR (DMSO-d6) 53· 62 (s， Η) 、3·88 (s， 3H) 、6·78 (d， J:8.3 Hz， 1H) 、6·83一 ·87 (m，1H)、6·94 (s，1H)、7·32-7.36 (m，1H)、 • 69 (dd，J = 8· 3、1· 5 Hz，1H)、7· 84 (dd，J = 8· 3、1. 589112968.ptd Page 293 1283240 V. INSTRUCTIONS (289) Dissolved in tert-butyl 4-amino-3-methoxybenzoate (1·94 g, 816 mmol) in THF (20 liters) To the stirred solution were added 2-iodophenyl isocyanate (2· &lt; 0 g ' 8.16 mol) and Et3N (1 1 4 μL, 〇·81 6 mmol). After stirring overnight, the mixture was poured into 1N HCl (2 mL). The resulting precipitate was collected by filtration and dissolved in KCHC13 (2 〇 () mA =). The solution was dried over MgS 4 and evaporated to give 4-[N,-(2-Iodojyl)ureido]-3-methoxyphenylacetic acid tert-butyl ester (3·93 g, quantitative) Coloring an amorphous solid. iH — NMR (CDC13) 5144 (s, 9Η), 3·49 s, 2Η), 3.85 (s, 3Η), 6.78-6·88 (m, 4Η), 7 G7 (s, Η), 7 ·3 卜7·35 (m,1Η), 7.76 (dd, J = 7.8,1·5 Ηζ, Η) ^7.95 (d, j,8.3 Hz, lH) ^7.99 (dd, J = 8. 3 M.5 Hz, 1H). MS (ESI), m/z 483 (M+H). 3 4 [N~(2-Iodophenyl)ureido]nonoxyphenylacetic acid tert-butyl ester (sound 93 丄8·16 mmol) and TFA (5 ml) in CH22C12 (5 ml) The rt was refluxed for 3 hours. After cooling to room temperature, the mixture was concentrated in <RTI ID=0.0># </ RTI> and 10 (50 mL) was added to the residue. The title compound (2.89 g, the title compound was obtained from EtOAc EtOAc (EtOAc) , %) of light yellow crystalline powder. UMR (DMSO-d6) 53· 62 (s, Η), 3·88 (s, 3H), 6.78 (d, J: 8.3 Hz, 1H), 6.83-87 (m, 1H), 6·94 (s, 1H), 7·32-7.36 (m, 1H), • 69 (dd, J = 8·3, 1·5 Hz, 1H), 7·84 (dd, J = 8·3 , 1. 5

89112968.ptd 第294頁 128324089112968.ptd Page 294 1283240

Hz， 1H) 、7.97-8.00 (m， 1H) 、8.55 (m， 1H) 、8·82 (m 1H) 、 12·26 (br s， 1H)。 ’ 使4-[Ν’ -（2-碘苯基）脲基]- 3-甲氧苯乙酸（505毫克， 1. 18毫莫耳）、4- [ (4S) -氟-（2S)-吼咯啶曱氧基]笨甲酸曱 醋（300毫克，1.18毫莫耳）、EDC.HC 1(339毫克，1.77毫 莫耳）、DMAP(催化量）及HOBt(催化量）於DMF (10毫升）中 之混合物攪拌隔夜。將混合物以E10Ac ( 3 0 0毫升）稀釋，並 以鹽水（.2x2 0 0毫升）洗滌。將溶液於MgS04上乾燥並蒸發。 五、發明說明（290)Hz, 1H), 7.97-8.00 (m, 1H), 8.55 (m, 1H), 8.82 (m 1H), 12·26 (br s, 1H). ' 4-[Ν'-(2-iodophenyl)ureido]-3-methoxyphenylacetic acid (505 mg, 1. 18 mmol), 4-[(4S)-fluoro-(2S)-吼 曱 曱 曱 ] ] ] 300 300 300 300 300 (300 mg, 1.18 mmol), EDC.HC 1 (339 mg, 1.77 mmol), DMAP (catalytic amount) and HOBt (catalytic amount) in DMF (10 The mixture in ml) was stirred overnight. The mixture was diluted with E10Ac (300 mL) and washed with brine (.2×200 mL). The solution was dried over MgS04 and evaporated. V. Description of the invention (290)

使所產生之殘留物於矽膠上利用CHC13-EtOAc(4 : 1 )作為洗 提液進行層析，而得4-[1-[4 - [N，-（2-碘苯基）脲基]- 曱 氧苯基乙醯基]-（4S) -氟-（2S) -吼咯啶甲氧基]苯甲酸曱@旨 ( 50 0毫克，64%)之無色黏性油。iH-NMR (CDC13) 5 2.07-2.58 (m， 2H) 、3·59-4·20 (m， 11H) 、4·5卜4.64 (m，2Η)、5·24 及 5.37 (各m，總計 1Η)、6·80-6.91 (m， 5Η) 、6·98 (d， J:8.8 Ηζ， 2Η) 、7·34 (t， J=7.8 Ηζ， 1H) 、7·78 (dd， J=7.8 、1·2 Hz， 1H) 、7·95-8.02 (m， 4H)。 於4 - [l-[4-[Ν’-（2 -碘苯基）脲基]—3—甲氧苯基乙醯 基]_(4S) -氟-（2S)-吼咯啶甲氧基]苯甲酸甲酯（5〇〇毫克， 〇· 75 6毫莫耳）溶於THF(6毫升）之攪拌溶液中加入25N NaOH( 6毫升）。繼續在室溫下攪拌隔夜，然後迴流5小時。 於冷卻至室溫後，將溶液倒入至1N hc 1 (1 〇 〇毫升）中，並 利用CHCl3-MeOH(4 : 1，2x20 0毫升）萃取。使結合的萃取液 於MgS04上乾燥並蒸發。使殘留物於矽膠上利用chc13_The resulting residue was chromatographed on silica gel using CHC13-EtOAc (4:1) eluting - Hydroxyphenyl ethyl fluorenyl]-(4S)-fluoro-(2S)-decalyl methoxy]benzoic acid hydrazine @ (50 0 mg, 64%) of a colorless viscous oil. iH-NMR (CDC13) 5 2.07-2.58 (m, 2H), 3·59-4·20 (m, 11H), 4·5 b 4.64 (m, 2Η), 5·24 and 5.37 (each m, total 1Η),6·80-6.91 (m, 5Η), 6.98 (d, J:8.8 Ηζ, 2Η), 7·34 (t, J=7.8 Ηζ, 1H), 7·78 (dd, J= 7.8, 1·2 Hz, 1H), 7.95-8.02 (m, 4H). 4-[l-[4-[Ν[-(2-Iodophenyl)ureido]-3-methoxyphenylethenyl]-(4S)-fluoro-(2S)-purine methoxy A solution of methyl benzoate (5 mg, 〇·75 6 mmol) in THF (6 mL) was added 25N NaOH (6 mL). Stirring was continued overnight at room temperature and then refluxed for 5 hours. After cooling to room temperature, the solution was poured into 1 N hc 1 (1 mL) and extracted with CHCl3-MeOH (4:1, 2×20 mL). The combined extracts were dried over MgS04 and evaporated. Make the residue on the tannin using chc13_

89112968.ptd 第295頁 1283240 五、發明說明（291) M:〇二10非1曰乍為洗提液進行層析’而得7 1 ( 2 95毫克，_ 之無色非日日形固體。1H_NMR (DMS0_d6) d 2 0 9_2 31 (m (“ 列，i〇h)、5·30-5.5。（m，⑻、， 6. 77-6. 92 (m, 3H) ^ 7. 03-7. 09 (m, 2H) &gt; 7. 34 (t J = 8.1 Hz’ 1H)、7.69 (dd, J = 8.3 m.5 Hz, 1H) '， 7.83-7.99 (m，4H)、8.54 (m, 1H)、8·82 ⑶，ih); MS(FAB) m/z 648 (MH1) ; C28H27FIN3〇4 之分析計算值：c， 51·94，Η，4·20;Ν，6.49。實測值：◦，5i 17;h 4.53， N， 5.76 。 « 實施例6 6 4 - [(4S)-氟-1-[4-(『 -苯基脲基）笨基乙醯基]一（2幻一咄 咯啶甲氧基]苯甲酸 72 4-（Ν’ -苯基脲基）苯乙酸 α又声Η Η Η _ 於4 -胺基苯乙酸乙酯（6· 43克，35· 9毫莫耳）及Et3N ( 5·50毫升，39.5毫莫耳）溶於THF(70毫升）之攪拌溶液中加 入異氰酸苯酯（3· 90毫升，35. 9毫莫耳），並使反應混合物 在室溫下攪拌4天。在減壓下收集所產生之沈殿物，並以 正己烷洗滌濾液而得4-(Ν’ -苯基脲基）苯乙酸乙酯（9. 64 克，90%)的白色結晶粉末。熔點1 5 3- 1 5 5。(：；111_關1^89112968.ptd Page 295 1283240 V. INSTRUCTIONS (291) M: 〇二10非一曰乍 is used for chromatography of the eluent' to obtain 7 1 ( 2 95 mg, _ colorless non-Japanese solid. 1H_NMR (DMS0_d6) d 2 0 9_2 31 (m ("column, i〇h), 5·30-5.5. (m, (8),, 6. 77-6. 92 (m, 3H) ^ 7. 03-7. 09 (m, 2H) &gt; 7. 34 (t J = 8.1 Hz' 1H), 7.69 (dd, J = 8.3 m.5 Hz, 1H) ', 7.83-7.99 (m, 4H), 8.54 (m, 1H), 8·82 (3), ih); MS (FAB) m/z 648 (MH1); C28H27FIN3〇4 Analysis calculated: c, 51·94, Η, 4·20; Ν, 6.49. Found: ◦, 5i 17; h 4.53, N, 5.76. « Example 6 6 4 - [(4S)-Fluoro-1-[4-("-phenylureido)] phenylamino] one (2 phantom Ethrolidine methoxy]benzoic acid 72 4-(Ν'-phenylureido)phenylacetic acid α Η Η Η _ _ ethyl 4-aminophenyl phenylacetate (6·43 g, 35·9 mmol) To the stirred solution of Et3N (5·50 ml, 39.5 mmol) dissolved in THF (70 mL), phenyl isocyanate (3·90 ml, 35.9 mmol) and the reaction mixture Stir at room temperature for 4 days. Collected under reduced pressure. The precipitate was washed with n-hexane to give a white crystalline powder of ethyl 4-(p-[rho]-phenylureido)phenylacetate (9. 64 g, 90%). :;111_关1^

89112968.ptd 第296頁 1283240 五、發明說明（292) (CDC13) (51.26 (t，J = 7.1 Hz， 3H)、3·52 (s， 2H)、 4.15 (q， J=7.1 Hz， 2H) 、 6.98-7.04 (m， 1H) 、7·〇7— 7.11 (m，4H)、7.18-7.25 (m，5H)、7.42 (s，1H); MS(FAB) m/z 2 9 9 (MH1); C17H18N2 03 之分析計算值：c， 68· 44 ; H， 6· 08 ; N，9· 39。實測值·· C，68. 2 2 ; H， 6.10； N, 9.36°89112968.ptd Page 296 1283240 V. INSTRUCTIONS (292) (CDC13) (51.26 (t, J = 7.1 Hz, 3H), 3·52 (s, 2H), 4.15 (q, J=7.1 Hz, 2H) , 6.98-7.04 (m, 1H), 7·〇7— 7.11 (m, 4H), 7.18-7.25 (m, 5H), 7.42 (s, 1H); MS (FAB) m/z 2 9 9 (MH1 ); Analysis of C17H18N2 03: c, 68· 44 ; H, 6· 08 ; N, 9· 39. Measured value · · C, 68. 2 2 ; H, 6.10; N, 9.36°

於4-(N’ -苯基脲基）苯乙酸乙酯（9.64克，32.3毫莫耳） 溶於THF(80毫升）之攪拌溶液中加入〇·5Ν NaOH(80毫升）， 並使反應混合物迴流加熱5小時。於冷卻至室溫後，將混 合物倒入至冰的1 N H C1中。在減壓下收集所產生之沈殿 物，並使粗製固體自MeOH-CHC13再結晶而得4_(Ν，~苯基脲 基）苯乙酸（8· 14克，93%)之白色結晶粉末。MS (FAB) m/z 2 71 (M+ + 1)，C15 H14 N2 03 之分析計算值：C，6 6. 6 6 ; Η， 5· 22 ; Ν, 10· 36。實測值·· C， 6 6. 45 ; Η，5. 22 ; Ν， 10.30。 ’ 使4-( Ν’ -苯基脲基）苯乙酸（310毫克，1· 15毫莫耳）、 4-[(4S) -氟-（2S)-吼咯啶甲氧基]苯甲酸甲酯（287毫克， 1.13¾:莫耳）、EDC*HC1(260 毫克，1.36 毫莫耳）、To a stirred solution of 4-(N'-phenylureido)phenylacetate (9.64 g, 32.3 mmol) in THF (80 mL) EtOAc······· Heated under reflux for 5 hours. After cooling to room temperature, the mixture was poured into 1 N H C1 of ice. The resulting precipitate was collected under reduced pressure, and the crude solid was recrystallized from MeOH-CHC 13 to yield white crystals of 4-(?,~~~~~~~~~~~~~~~~~~~ MS (FAB) m/z 2 71 (M+ + 1), C15 H14 N2 03: C, 6 6. 6 6 ; Η, 5· 22 ; Ν, 10· 36. Measured value ·· C, 6 6. 45 ; Η, 5. 22 ; Ν, 10.30. ' 4-( Ν'-Phenylureido)phenylacetic acid (310 mg, 1.15 mmol), 4-[(4S)-fluoro-(2S)-decalylmethoxy]benzoic acid Ester (287 mg, 1.133⁄4: mole), EDC*HC1 (260 mg, 1.36 mmol),

H0Bt(185毫克，1· 37毫莫耳）、及Et3N(190微升，i 36毫 莫耳）於DMF(5毫升）中之混合物在室溫下攪拌隔夜;^將^ 合物以札0稀釋，並以EtOAc萃取。將萃取液以鹽水洗滌此 於Na2S04上乾燥，並蒸發。使殘留物經由於矽膠 = CHC13-MeOH(l〇〇·· 1 至5 0: 1，v/v)作為洗提液進行 析，純化而得4-[(4S)-氟-1-[4-(Ν，-苯基脲基）苯基乙曰醯a mixture of H0Bt (185 mg, 1.37 mmol) and Et3N (190 μl, i 36 mmol) in DMF (5 mL) was stirred overnight at room temperature; Dilute and extract with EtOAc. The extract was washed with brine, dried over Na 2 SO 4 and evaporated. The residue was subjected to precipitation as an eluent by silica gel = CHC13-MeOH (1 〇〇··1 to 50:1, v/v), and purified to give 4-[(4S)-fluoro-1-[4 -(Ν,-phenylureido)phenyl acetamidine

1283240 五、發明說明（293) 基]-（2S) -吼咯啶曱氧基]笨曱酸曱酯（ 570毫克，99%)之淡 黃色泡沫。1Η- NMR (CDC13) 6 2.07-2.58 (m，2H)、 3· 55-3· 5 6 (m， 1H)、3· 69-3· 98 (s 及m 系列，總計6H)、 4.01-4.08 及 4.21-4.25 (各m，1H)、4.46-4.65 (m，2H) 、5. 23-5.25 及 5.38 (各m，1H)、6·88-7·07 (m，7H)、 7 · 1 5 - 7 · 2 0 (m，2 H )、7 · 2 8 - 7 · 3 0 ( m，2 H )、7 · 3 4 及 7 · 4 0 (各s，1Η)、7·71 及 7·81 (各s, 1Η)、7·91-7·95 及 7·99-8·01 (各m，2H); MS(ESI) m/z 5 0 6 (ΜΗ1)。 於4-[(4S)-亂-1-[4-(Ν’ -苯基脲基）苯基乙酿基] -（2S)-咄咯啶甲氧基]苯曱酸甲酯（570毫克，1.13毫莫耳） 溶於THF(5毫升）之攪拌溶液中加入0.5N NaOH(5毫升）。並 使反應混合物迴流加熱5小時。於冷卻至室溫後，將混合 物倒入至冰的1 N HC 1中，並在減壓下收集所產生之沈澱 物。使粗製固體自MeOH-CHC13-IPE再結晶而得4-[ (4S)-氟 -1-[4-(Ν’ _苯基脲基）苯基乙醯基]-(2S)_吼咯啶甲氧基] 苯甲酸72 ( 348毫克，63%)之白色結晶粉末。熔點169-171 °C ; UMR (DMS0-d6) (52.24-2.36 (m，2H)、3·47-4·08 (m， 5H) 、4·20-4.64 (m， 2H) 、5·31-5·50 (m， 1H)、 6·94 - 7.46 (m 系列，總計 11H)、7·87-7·92 (m， 2H)、 8· 64-8· 67 (m，2Η)、12. 63 (br s，1Η) ; MS(FAB) m/z 492 (MH1 ) ; C27H26FN3 06 · 1/4H20 之分析計算值·· C，6 5.38； H，5· 38 ; N，8· 47 ; F，3· 83。實測值：C，65. 13 ; Η, 5· 38 ; N， 8. 25 ; F， 3· 78 。 實施例6 71283240 V. INSTRUCTIONS (293) A light yellowish foam of the base [-](2S)-indolyloxyl] decyl decanoate (570 mg, 99%). 1Η- NMR (CDC13) 6 2.07-2.58 (m, 2H), 3· 55-3· 5 6 (m, 1H), 3· 69-3· 98 (s and m series, total 6H), 4.01-4.08 And 4.21-4.25 (each m, 1H), 4.46-4.65 (m, 2H), 5. 23-5.25 and 5.38 (each m, 1H), 6·88-7·07 (m, 7H), 7 · 1 5 - 7 · 2 0 (m, 2 H ), 7 · 2 8 - 7 · 3 0 ( m, 2 H ), 7 · 3 4 and 7 · 4 0 (each s, 1 Η), 7·71 and 7 · 81 (each s, 1 Η), 7·91-7·95 and 7·99-8·01 (each m, 2H); MS (ESI) m/z 5 0 6 (ΜΗ1). 4-[(4S)-disorder-1-[4-(Ν'-phenylureido)phenylethyl]-(2S)-indolyl methoxy]benzoic acid methyl ester (570 mg To a stirred solution of THF (5 mL) was added 0.5N NaOH (5 mL). The reaction mixture was heated under reflux for 5 hours. After cooling to room temperature, the mixture was poured into 1 N HCl 1 of ice, and the resulting precipitate was collected under reduced pressure. The crude solid was recrystallized from MeOH-CHC13-IPE to give 4-[(4S)-fluoro-1-[4-(Ν' _phenylureido)phenylethenyl]-(2S)-pyrrolidine A white crystalline powder of methoxy]benzoic acid 72 (348 mg, 63%). Mp 169-171 °C; UMR (DMS0-d6) (52.24-2.36 (m, 2H), 3·47-4·08 (m, 5H), 4·20-4.64 (m, 2H), 5.31 -5·50 (m, 1H), 6.94 - 7.46 (m series, total 11H), 7·87-7·92 (m, 2H), 8·64-8· 67 (m, 2Η), 12 63 (br s,1Η) ; MS(FAB) m/z 492 (MH1 ) ; C27H26FN3 06 · 1/4H20 analytical calculation ···················· F, 3· 83. Found: C, 65. 13 ; Η, 5· 38 ; N, 8. 25 ; F, 3· 78. Example 6 7

89112968.ptd 第298頁 1283240 五、發明說明（294) 4^S)_氣ΙΑ—甲基—苯基脲基）苯基乙醯基] (2 S) -咄咯。疋甲氧基]苯甲酸 ' - 'O^c〇2h 73 酸 3-甲基-4-(N’ -苯基脲基）苯乙 〇/ΗΝγΤΗ 於4胺基3甲基本乙酸第三丁酯（1.20克，542毫莫 耳）及£13以830微升，5.95毫莫耳）溶於丁111^1〇毫升）之攪 拌溶液中加入異氰酸苯酯（65〇微升，5·98毫莫耳），並使 反應混合物在室溫下攪拌隔夜。將反應混合物濃縮至一小 的體積，並以正己烷稀釋。在減壓下收集所產生之沈澱 物，並以正己烷洗滌濾液而得3-甲基—4 — (Ν，—苯基脲基）苯 乙酸第三丁酯（1 · 1 2克，6 1 %)的白色結晶粉末。熔點丨43 -145 C’iH-NMR CCDClg) 61.47 (s，9Η)、2.09 (s 3H)、3·47 (s，2H)、6·44 (s，1H)、7·(Π-7.07 (m， 4Η)、7·16-7.27(in，2H)、7.30-7.33 (m，2H)、7.45- 7· 47 (m，1Η)。 _ 於3-甲基- 4 -（Ν’ -苯基脲基）苯乙酸第三丁 I旨克， 3. 29毫莫耳）洛於Cf^ClJlO毫升）之授掉溶液中加入tfa (1 0毫升），並使反應混合物在室溫下授拌4小時。將反應 混合物濃縮至一小的體積，並倒入至冰的H2 〇中。在減壓 下收集所產生之沈殿物，並使粗製固體自Me〇H-CHCl3再結89112968.ptd Page 298 1283240 V. INSTRUCTIONS (294) 4^S)_Air-methyl-phenylureido)phenylethenyl] (2S)-fluorene.疋Methoxy]benzoic acid ' - 'O^c〇2h 73 acid 3-methyl-4-(N'-phenylureido)phenidinium / ΗΝγΤΗ in 4-amino 3 methyl benzoic acid tert-butyl ester Add phenylisocyanate (65 〇 microliter, 5.98) to a stirred solution of (1.20 g, 542 mmol) and £13 in 830 μl, 5.95 mmol (dissolved in butyl 111^1 ml). Millions) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated to a small volume and diluted with n-hexane. The resulting precipitate was collected under reduced pressure, and the filtrate was washed with n-hexane to give &lt;RTI ID=0.0&gt;&gt; %) of white crystalline powder. Melting point 丨43 -145 C'iH-NMR CCDClg) 61.47 (s,9Η), 2.09 (s 3H), 3·47 (s,2H), 6.44 (s,1H), 7·(Π-7.07 ( m, 4Η), 7·16-7.27(in, 2H), 7.30-7.33 (m, 2H), 7.45-74.7 (m, 1Η). _ 3-methyl- 4 -(Ν'-benzene Add the tfa (10 ml) to the solution of the phenylacetic acid phenylacetate, the third butyl ketone, 3. 29 mM, and the reaction mixture at room temperature. 4 hours. The reaction mixture was concentrated to a small volume and poured into ice H2. The resulting sediment was collected under reduced pressure, and the crude solid was re-knotted from Me〇H-CHCl3.

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五、發明說明（295) 晶而得3一甲基一4_(N’ _苯基脲基）苯乙酸（68〇毫克， 白色針狀物。iH-NMR (DMS0-d6) (s，3H)、3 4fi〇 (s, 2H) ' 6.93-7.05 (m, 3H) ' 7.25-7.29 (m 7.43-7.46 (m，2H)、7· 72-7· 74 (m，1H)、7 9〇 (:、 1H) 、 8.98 (s， 1H) 、 12.26 (br s 1H)· Γ η μλ ,,^ ^ . 〇 , S， ’ L16HuN2〇3 之分析 。十，值· C， 67· 59 ; H，5. 67 ; N， 9· 85。實測值：c 67· 47 ; H，5· 68 ; N，9. 73。 ’ 使3-甲基-4-(N，-苯基脲基）苯乙酸（301毫克，κ 〇6毫 耳）、4-[(4S)-氟-（2S)-咄咯啶甲氧基]笨曱酸甲酯（2β 克，1· 06毫莫耳）、EDC · HC1 ( 243毫克，1· 27毫莫耳）、毛 HOBt(172毫克，1. 27毫莫耳）、及Et3N(180微升，l 29毫 莫耳）於DMF ( 5毫升）中之混合物在室溫下攪拌隔夜。將混 合物以10稀釋，並以Ε ΐ 0 A c萃取。將萃取液以鹽水洗條， 於N az S 〇4上乾燥，並蒸發。使殘留物經由於石夕膠上利用 CHC13-MeOH(100:l至60:1，v/v)作為洗提液進行管柱層 析’純化而得4 - [(4S)-氟-1 - [3-甲基- 4-（Ν’ -苯基脲基）苯 基乙酿基]-(2S) - 1:7比洛σ定曱氧基]苯曱酸曱g旨（550毫克，q. y·)之白色泡沐。4-NMR (CDC13) 5 1.79及 1.87 (各s， 3H) 、2·04-2·61 (m， 2Η)、3·52-3.54(m，lH)、373-4. 2 7 (s 及 m 系列，總計 7 Η)、4 · 4 7 - 4 · 6 7 (m， 2 Η)、 5.26-5.27&amp;5.40(gm，lH)、6.7 9-6.99 (m，6H)、 7.14-7.18 (m，2H)、7·27-7.31 (m，2H)、7·40-7·44 (m，1Η)、7·89-8·01 (m，3H); MS(ESI) m/z 520 (Μ+ + 1)。V. INSTRUCTIONS (295) Crystallized 3-methyl-4-(N'-phenylureido)phenylacetic acid (68 mg, white needle. iH-NMR (DMS0-d6) (s, 3H) , 3 4fi〇(s, 2H) ' 6.93-7.05 (m, 3H) ' 7.25-7.29 (m 7.43-7.46 (m, 2H), 7·72-7· 74 (m, 1H), 7 9〇 ( :, 1H), 8.98 (s, 1H), 12.26 (br s 1H)· Γ η μλ ,, ^ ^ . 〇, S, 'L16HuN2〇3 analysis. Ten, value · C, 67· 59 ; H, 5. 67 ; N, 9· 85. Found: c 67· 47 ; H, 5 · 68 ; N, 9. 73. 'Methyl 3-methyl-4-(N,-phenylureido)phenylacetic acid (301 mg, κ 〇 6 mil), 4-[(4S)-fluoro-(2S)-decalidine methoxy] methyl benzoate (2β g, 1.00 mmol), EDC a mixture of HC1 (243 mg, 1.27 mmol), hairy HOBt (172 mg, 1.27 mmol), and Et3N (180 μl, l 29 mmol) in DMF (5 mL) Stir at room temperature overnight. The mixture was diluted with 10 and extracted with Ε ΐ 0 A c. The extract was washed with brine, dried over Naz S 〇 4 and evaporated. Utilize CHC13-MeOH (100:1 to 6) 0:1, v/v) as a eluent for column chromatography 'purification to give 4-[(4S)-fluoro-1 -[3-methyl-4-(indolyl)-phenyl)benzene乙乙基基]-(2S) - 1:7 洛 σ 曱 曱 ] ] ] 550 550 550 550 (550 mg, q. y·) white foam. 4-NMR (CDC13) 5 1.79 and 1.87 (each s, 3H), 2·04-2·61 (m, 2Η), 3·52-3.54 (m, lH), 373-4. 2 7 (s and m series, total 7 Η), 4 · 4 7 - 4 · 6 7 (m, 2 Η), 5.26-5.27 &amp; 5.40 (gm, lH), 6.7 9-6.99 (m, 6H), 7.14-7.18 (m, 2H), 7·27- 7.31 (m, 2H), 7·40-7·44 (m, 1Η), 7·89-8·01 (m, 3H); MS (ESI) m/z 520 (Μ + + 1).

89112968.ptd 第300頁 1283240 五、發明說明（296) 於4-[(4S) -氟-1-[ 3-甲基-4-( Ν’ -笨基脲基）苯基乙醯 基]-（2S) -吼洛σ定甲氧基]苯甲酸甲酯（550毫克，1·06毫莫 耳）溶於THF(5毫升）之攪拌溶液中加入0· 5Ν NaOH(5毫 升），並使反應混合物迴流加熱2小時。於冷卻至室溫後， 將混合物倒入至冰的1 N HC 1中，並在減壓下收集所產生之 沈殿物。使粗製固體自M e 0 Η - C H C 13 - I P E再結晶而得4 -[(4S) -氟-1-[3-甲基-4-(Ν’ -苯基脲基）苯基乙醯基]-(2S) -咄咯啶甲氧基]苯甲酸73 (2 26毫克，42%)之白色結晶 粉末。熔點1 30-135 °C ; UMR (DMSO-d6) 62.18-2.30 (s 及m系列，總計5H)、3· 47 - 3· 92 (m系列，總計5H)、 4.03-4.63 (m, 2H) &gt;5.31-5.50 (m, 1H) ^6.94-7.10 (m，5H)、7·26-7·30 (m，2H)、7·4 5-7.47 (m，2H)、 7.70 - 7.75 (m，1H)、7·87 - 7.92 (m，3H)、8·96-8·98 (m, 1H) &gt;12.63 (br s, 1H) ； MS (ESI) m/z 5 0 6 (MH1)； C28H28FN3 05 · 1/2H20 之分析計算值·· C， 65· 36 ; H， 5· 68 ; N，8· 1 7 ; F， 3. 69。實測值·· C， 65· 61 ; H， 5. 71 ; N， 7· 84 ； F, 3. 60 〇 實施例6 8 4 - [(4S)-氟-l-[4-[N，-（2-氟苯基）脲基]_3-甲基苯基乙 S盘基]-定甲氧基]本甲酸（D01-1506)89112968.ptd Page 300 1283240 V. INSTRUCTIONS (296) on 4-[(4S)-fluoro-1-[3-methyl-4-(indolyl-phenyl)phenylethenyl]- (2S) - a solution of methyl benzoate methoxy] benzoate (550 mg, 1.06 mmol) dissolved in THF (5 mL), EtOAc (5 mL) The reaction mixture was heated under reflux for 2 hours. After cooling to room temperature, the mixture was poured into 1 N HCl 1 of ice, and the resulting precipitate was collected under reduced pressure. The crude solid was recrystallized from Me 0 Η - CHC 13 - IPE to give 4-[(4S)-fluoro-1-[3-methyl-4-(Ν'-phenylureido)phenylethenyl ]-(2S)-Ethrolidine methoxy]benzoic acid 73 (2 26 mg, 42%) of white crystalline powder. Melting point 1 30-135 °C; UMR (DMSO-d6) 62.18-2.30 (s and m series, total 5H), 3·47 - 3· 92 (m series, total 5H), 4.03-4.63 (m, 2H) &gt;5.31-5.50 (m, 1H) ^6.94-7.10 (m, 5H), 7·26-7·30 (m, 2H), 7·4 5-7.47 (m, 2H), 7.70 - 7.75 (m ,1H),7·87 - 7.92 (m,3H),8·96-8·98 (m, 1H) &gt;12.63 (br s, 1H) ; MS (ESI) m/z 5 0 6 (MH1) ; C28H28FN3 05 · 1/2H20 analytical calculations · · C, 65 · 36 ; H, 5 · 68 ; N, 8 · 1 7 ; F, 3. 69. Found C· 65· 61 ; H, 5. 71 ; N, 7· 84 ; F, 3. 60 〇 Example 6 8 4 - [(4S)-Fluoro-l-[4-[N,- (2-fluorophenyl)ureido]_3-methylphenylethyl S-group]-butoxy] Benzoic acid (D01-1506)

FF

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4 - [N -(2-氟本基）脲基]—3-甲基苯乙酸 方；4- fe基-3-甲基苯乙酸第三丁酯（1〇9克，4.93毫莫 耳）及Et3N( 75 5微升，5· 42毫莫耳）溶於THF(1 0毫升）之攪 拌溶液中加入異氰酸2-氟苯酯（610微升，5· 44毫莫耳）， 並使反應混合物在室溫下攪拌隔夜。將反應混合物濃縮至 一小的體積，並以正己烷稀釋。在減壓下收集所產生之沈 澱物，並以正己烷洗滌濾液而得4—[N，—（ 2—氟笨基）脲仏 基]-3-甲基苯乙酸第三丁酯（1· 3i克，74%)的白色結晶粉 末。溶點89-91 °C ; NMR (CDC13) 6 1.47 (s，9Η)Ί.刀〇6 (s，3Η)、3·49 (s，2Η)、6·62 (s，1Η)、6·92〜7·〇9 (m， 5H)、7·21 (br s，1H)、7·49-7·51 (ni，1H)、8·1〇 —8·15 (m，1 Η )，C2Q H23 F N2 〇3 之分析計算值：c，6 7. 0 2 ; Η，6 4 7 · N，7.82;F， 5.3〇。實測值：C， 66.74;H，6·35;ν 7 85 ; F， 5· 69 。 ’ ’ · 於4-[Ν’-（2-氟苯基）脲基]-3-甲基笨乙酸第三丁酷 (1· 25克，3· 49毫莫耳）溶於毫升）之攪拌溶^夜中 加入TF A (1 0毫升）’並使反應混合物在室溫下攪拌隔夜。 將反應混合物濃縮至一小的體積，並倒入至冰的&amp; 〇中。 在減壓下收集所產生之沈澱物，並使粗製固體自Me〇H — CHC13-IPE再結晶而得4 - [Ν’-（2-氟笨基）脲基]一3 一甲基苯 乙酸（830毫克’79%)之白色針狀物。—NMR (DMSO-d6) 54-[N-(2-Fluorobenzyl)ureido]-3-methylphenylacetic acid; 4-butyl-3-methylphenylacetic acid tert-butyl ester (1〇9 g, 4.93 mmol) And Et3N (75 5 μl, 5.42 mmol) in a stirred solution of THF (10 mL) was added 2-fluorophenyl isocyanate (610 μl, 5.44 mmol), and The reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was concentrated to a small volume and diluted with n-hexane. The resulting precipitate was collected under reduced pressure, and the filtrate was washed with n-hexane to give 4-(N-(2-fluorophenyl)ureido]-3-methylphenylacetic acid tert-butyl ester (1· 3i gram, 74%) of white crystalline powder. Melting point 89-91 °C; NMR (CDC13) 6 1.47 (s, 9Η)Ί. Knife 6 (s, 3Η), 3·49 (s, 2Η), 6.62 (s, 1Η), 6· 92~7·〇9 (m, 5H), 7·21 (br s, 1H), 7·49-7·51 (ni, 1H), 8·1〇—8·15 (m, 1 Η ), Analysis calculated for C2Q H23 F N2 〇3: c,6 7. 0 2 ; Η, 6 4 7 · N, 7.82; F, 5.3 〇. Found: C, 66.74; H, 6.35; ν 7 85 ; F, 5· 69. ' ' · Stirring of 4-[Ν'-(2-fluorophenyl)ureido]-3-methyl acetoacetic acid, third butyl (1·25 g, 3. 49 mmol) dissolved in ml) TF A (10 mL) was added in vacuo and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated to a small volume and poured into ice &amp; The resulting precipitate was collected under reduced pressure, and the crude solid was recrystallized from Me〇H-CHC13-IPE to give 4-[[rho]-(2-fluorophenyl)ureido]- 3-methylphenylacetic acid. (830 mg '79%) of white needles. —NMR (DMSO-d6) 5

\\312\2d-code\90-01\89112968.ptd 第302頁 1283240 五、發明說明（298) 2.23 (s，3H)、3.47 (s，2H)、6·96-7·30 (m，5H)、 7·74-7.76 (m，1H)、8·17-8·20 (m，1H)、8·33 (s， 1H)、8.94 (s，1H)、12.27 (br s，1H); C16Hi5FN203 之分析計算值：C，63· 57 ; H，5. 00 ; N，9 · 27 ; F，6.28。實測值：C，63.28; H， 5.00; N，9.14; F， 6.43。 ’ 使4 - [Ν’ -（2-敗苯基）脲基]- 3-甲基笨乙酸（321毫克， 1· 06愛：莫耳）、4-[(4S)~氟-（28)-°比p各唆曱氧基]苯曱酸曱 酯（ 269毫克，1· 06毫莫耳）、EDC · HCr(244毫克，1· 27毫 莫耳）、HOBt(172毫克，1.27毫莫耳）、及Et3N(177微升， 1 · 27毫莫耳）於DMF ( 5毫升）中之混合物在室溫下授拌隔 仪。將混合物以％ 0稀釋，並以E10 A c萃取。將萃取液以鹽 水洗滌，於NazS〇4上乾燥，並蒸發。使殘留物經由於矽膠 上利用CHCI3-MeOH( 1 00 : 1，v/v)作為洗提液進行管柱層 析’純化而得4-[(4S) -氟-1-[4-[Ν’-（2-氟笨基）脲基] 一3-曱基苯基乙醯基]— (2S)-咄咯啶曱氧基]笨甲酸曱酯 (560 毫克，98%)之白色泡沫。UMR (CDC13) 6 1. 78 及 1·86 (各s，3H)、2·16-2.65 (m，2H)、3·58-3·61 (m， 1Η)、3· 7 4-4· 15 (s 及m 系列，總計7Η)、4· 29-4· 34 及 4.46-4.49 (各m，1Η)、4·64-4·73 (m，1Η)、5.29-5.34 &amp;5.43-5.47 (&amp;m，iH)、6.84-6.97 (m，6H)、7.04_ 7·〇7 (m，1Η)、7.21 (br s，1Η)、7·55-7·59 (m，1Η)、 7.85-8.02 (m, 3H) &gt;8.18-8.22 (m, 1H)； MS(ESI) m/z 538 (MH1)。\\312\2d-code\90-01\89112968.ptd Page 302 1283240 V. Description of invention (298) 2.23 (s, 3H), 3.47 (s, 2H), 6.96-7·30 (m, 5H), 7·74-7.76 (m, 1H), 8·17-8·20 (m, 1H), 8·33 (s, 1H), 8.94 (s, 1H), 12.27 (br s, 1H) Analysis calculated for C16Hi5FN203: C, 63· 57 ; H, 5. 00 ; N, 9 · 27 ; F, 6.28. Found: C, 63.28; H, 5.00; N, 9.14; F, 6.43. 'Make 4 - [Ν' -(2-phenylphenyl)ureido]-3-methyl stearic acid (321 mg, 1.00 love: Moer), 4-[(4S)~fluoro-(28) -° ratio p 唆曱 ] ] 曱 曱 ( ( 269 269 269 269 269 269 269 269 269 269 269 269 269 269 269 269 269 269 269 269 269 269 269 269 269 269 269 269 269 269 269 269 269 269 269 269 269 269 269 269 269 269 269 269 269 A mixture of Et3N (177 μl, 1 · 27 mmol) in DMF (5 mL) was incubated at room temperature. The mixture was diluted at % 0 and extracted with E10 A c. The extract was washed with brine, dried over NazS 4 and evaporated. The residue was purified by column chromatography using CHCI3-MeOH (1 00:1, v/v) as an eluent to obtain 4-[(4S)-fluoro-1-[4-[Ν '-(2-Fluorophenyl)ureido]-3-(indolylphenylethyl)](2S)-indolyl hydrazinyloxy] decyl carbazate (560 mg, 98%) as a white foam. UMR (CDC13) 6 1. 78 and 1·86 (each s, 3H), 2.16-2.65 (m, 2H), 3·58-3·61 (m, 1Η), 3· 7 4-4· 15 (s and m series, total 7Η), 4·29-4· 34 and 4.46-4.49 (each m, 1Η), 4·64-4·73 (m, 1Η), 5.29-5.34 &amp;5.43-5.47 (&amp;m,iH), 6.84-6.97 (m,6H), 7.04_ 7·〇7 (m,1Η), 7.21 (br s,1Η), 7·55-7·59 (m,1Η), 7.85-8.02 (m, 3H) &gt; 8.18-8.22 (m, 1H); MS (ESI) m/z 538 (MH1).

89112968.ptd 第303頁 1283240 五、發明說明（299) 於4-[(4S)-氟-1 - [4 - [Ν’-（2-氟笨基）脲基]一 3 -甲基笨基 乙醯基]-(2S) -吡咯啶甲氧基]苯曱酸甲酯（560毫克，1.04 毫莫耳）溶於THF(5毫升）之攪拌溶液中加入0.5Ν NaOH (5 毫升），並使反應混合物迴流加熱5小時。於冷卻至室溫 後，將混合物倒入至冰的1 N HC1中，並在減壓下收集所產 生之沈澱物。使粗製固體自MeOH_CHCl3-IPE再結晶而得 4-[(4S) -氟-1-[4-[Ν’ -（2-氟苯基）脲基]-3-甲基苯基乙醯 基]-(2S) -咄咯啶甲氧基]苯甲酸74(297毫克，42%)之白色 結晶粉末。熔點 1 3 7- 1 43 °&lt;：;111-1^0(0^180-(16)(52.20 - 2 · 3 1 ( s及m系列，總計5 Η)、3 · 5 6 - 3 · 9 2 (m系列，總計 5H)、4·0 3-4.63 (m，2H)、5·31-5.50 (m，1H)、6·96-7· 26 (m 系列，總計 7H)、7·72-7·77 (m，1H)、7·87 - 7.92 (m，2H)、8·17 - 8·22 (m，1H)、8·3 2 - 8.3 6 (m，1H)、 8.94-8.95 (m，1H)、12·66 (br s，1H); MS(ESI) m/z 5 24 (MU1) ; C28H27F2N3 05 之分析計算值：C， 64. 24 ； H, 5.20; N，8.03; F，7.26。實測值：C，64.44; H， 5.75 ;N， 7. 40 ; F， 6· 73 。 實施例6 9 4 - [(4S) -氟-1_[4-[Ν’ -（2-三氟甲基苯基）脈基]苯基乙酿 基]-(2 S)-吼咯啶甲氧基]苯甲酸 74 4-[Ν’-（2-三氟甲基笨基）脲基]笨乙酸89112968.ptd Page 303 1283240 V. INSTRUCTIONS (299) On 4-[(4S)-fluoro-1 -[4 - [Ν'-(2-fluorophenyl)ureido]- 3-methylphenyl Add a 0.5 NaOH solution (5 ml) to a stirred solution of methyl ethionyl-(2S)-pyrrolidine methoxy]benzoate (560 mg, 1.04 mmol) in THF (5 mL). The reaction mixture was heated at reflux for 5 hours. After cooling to room temperature, the mixture was poured into ice 1 N HCl, and the resulting precipitate was collected under reduced pressure. The crude solid was recrystallized from MeOH_CHCl3-IP to give 4-[(4S)-fluoro-1-[4-[Ν'-(2-fluorophenyl)ureido]-3-methylphenylethyl] -(2S)-Ethrolidine methoxy]benzoic acid 74 (297 mg, 42%) as a white crystalline powder. Melting point 1 3 7- 1 43 °&lt;:;111-1^0 (0^180-(16)(52.20 - 2 · 3 1 (s and m series, total 5 Η), 3 · 5 6 - 3 · 9 2 (m series, total 5H), 4·0 3-4.63 (m, 2H), 5·31-5.50 (m, 1H), 6·96-7· 26 (m series, total 7H), 7· 72-7·77 (m, 1H), 7.87 - 7.92 (m, 2H), 8·17 - 8·22 (m, 1H), 8·3 2 - 8.3 6 (m, 1H), 8.94- </ RTI> <RTIgt; ; F, 7.26. Found: C, 64.44; H, 5.75; N, 7. 40; F, 6· 73. Example 6 9 4 - [(4S) -Fluor-1_[4-[Ν' -( 2-trifluoromethylphenyl)-yl]phenylethyl]-(2S)-indolyl methoxy]benzoic acid 74 4-[Ν'-(2-trifluoromethylphenyl) Urea-based

\\312\2d-code\90-01\89112968.ptd 第304頁 1283240 五、發明說明（300) 於4 -胺基苯乙酸乙酯（113克，631毫莫耳）及 ( 965微升，6. 92毫莫耳）溶於THF(1〇毫升）之攪拌溶3液中加 入異氰酸2-三氟甲基苯酯（9 5 3微升，6· 31毫莫耳），並使 反應混合物在室溫下攪拌2天。在減壓下收集所產生之沈 殿物，並以正己烧洗滌濾液而得4 - [ n ’〜（2 —三氟甲基苯基） 脲基]苯乙酸乙酯（1· 93克，84%)的白色針狀物。溶點 1 37- 1 3 9 t ; iH-NMR (CDC13) 5 1.25- 1.29 (m，3H) : 3.59 (s, 2H)、4·15-4·20 (m, 2H)、7·05 (br s，1H)、 7.13-7.23 (m, 6H)、7·47-7·51 (m，1H)、7. 54-7.56 (m，1H)、8. 01-8· 03 (m，1H)。 於4-[N -(2 -三氟甲基笨基）脲基]苯乙酸乙酯（1.93克， 5. 27毫莫耳）溶於THF(10毫升）之攪拌溶液中加入1N N a Ο Η (1 0毫升），並使反應混合物迴流加熱5小時。於冷卻 至室溫後，將混合物倒入至冰的1 N HC 1中。在減壓下收集 所產生之沈澱物，並使粗製固體自MeOH-CHCl3-IPE再結晶 而得4-[Ν’ - (2 -三氟甲基苯基）脲基]苯乙酸（910毫克， 51%)之白色結晶粉末。熔點224- 225 °C ; NMR (DMSO-d6) 53·50 (s，2H)、7·18 (d，J:8.3 Hz, 2H)、7. 25-7.29 (m，1H)、7·40 (d，J二8·3 Hz，2H)、7.62-7.6 9 (m， 2H) 、7.95-7.97 (m， 1H) 、8.06 (s， 1H) 、9·37 (s, 1H)、1 2· 27 (br s，1H) ; C16H13F3N2 03 之分析計算值·· C，\\312\2d-code\90-01\89112968.ptd Page 304 1283240 V. INSTRUCTIONS (300) Ethyl 4-aminophenylacetate (113 g, 631 mmol) and (965 μl, 6. 92 mmoles of 2-trifluoromethylphenyl isocyanate (9.53 μL, 6.31 mmol) dissolved in a stirred solution of THF (1 mL). The reaction mixture was stirred at room temperature for 2 days. The resulting sediment was collected under reduced pressure, and the filtrate was washed with n-hexane to give ethyl 4-[n'~(2-trifluoromethylphenyl)ureido]phenylacetate (1·93 g, 84%). ) white needles. Melting point 1 37- 1 3 9 t ; iH-NMR (CDC13) 5 1.25- 1.29 (m, 3H) : 3.59 (s, 2H), 4·15-4·20 (m, 2H), 7·05 ( Br s,1H), 7.13-7.23 (m, 6H), 7·47-7·51 (m,1H), 7. 54-7.56 (m,1H), 8. 01-8· 03 (m,1H ). Add 1N N a Ο to a stirred solution of 4-[N-(2-trifluoromethylphenyl)ureido]phenylacetate (1.93 g, 5.27 mmol) in THF (10 mL). Η (10 ml) and the reaction mixture was heated at reflux for 5 h. After cooling to room temperature, the mixture was poured into 1 N HCl 1 of ice. The resulting precipitate was collected under reduced pressure and the crude solid was recrystallized from MeOH-CHCl3-IPE to give 4-[[Lambda]-(2-trifluoromethylphenyl)ureido]phenylacetic acid (910 mg, 51%) of white crystalline powder. Mp 224- 225 ° C; NMR (DMSO-d6) 53·50 (s, 2H), 7.18 (d, J: 8.3 Hz, 2H), 7. 25-7.29 (m, 1H), 7.40 (d, J 2·8 Hz, 2H), 7.62-7.6 9 (m, 2H), 7.95-7.97 (m, 1H), 8.06 (s, 1H), 9·37 (s, 1H), 1 2 · 27 (br s,1H) ; C16H13F3N2 03 analytical calculation ···C,

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ς56·81.;Η’ 3.87;N’ 8.28;F， 16.85。實測值：c， 56· 68，Η，3· 87 , Ν，8· 16 ; F，16 89。 ， 使4-[r-(2_三氟甲基苯基）脲基 U9毫莫耳LHUS)-氟_(2s)m各（^克 莫耳）、_t(145宅克，107毫莫耳）、及（15〇微 !· 08毫莫耳）於MF(5毫升）中之混合物在室溫下授拌3天。 將混合物以HJ稀釋，並以Et0Ac萃取。將萃取液以鹽水洗 滌，於NazS〇4上乾燥，並蒸發。使殘留物經由於矽膠上利 用CHCl3-MeOH(l 00 : 1至60 : 1，v/v)作為洗提液進行管柱層 析，純化而得4-[(4S) -氟-1-[4-[n，-(2 -三氟甲基苯基） 脲基]笨基乙醯基]-（2S) -咄咯啶甲氧基]苯甲酸甲酯（463 毫克 ’90%)之淡黃色泡沫。NMR (CDC13)(5 2.09-2.60 (m， 2H)、3· 56-4· 12 (s 及m 系列，總計8H)、4· 26-4· 65 (m，2Η)、5·26-5·29 及 5.39-5.42 (各m，總計 1Η)、 6.87-6.93 (m，2H)、6. 99-7.13 (m，5H)、7·30-7·33 (m，1H)、7·44-7·53 (m，2H)、7·8 8-7.92 (m，1H)、 7·99-8·04 (m， 2H) 、8.09-8.15 (m， 1H); MS(ESI) m/z 574 (MH1)。 於4-[(4S)-氟-l-[4-[N’-（2-三氟甲基苯基）脲基]苯基 乙SI*基]- (2S)-u比洛σ定甲氧基]苯曱酸甲醋（460毫克，0·80 毫莫耳）溶於THF(5毫升）之攪拌溶液中加入0·5Ν NaOH (5 毫升），並使反應混合物迴流加熱5小時。於冷卻至室溫 後，將混合物倒入至冰的1 N HC 1中，並在減壓下收集所產Σ56·81.;Η’ 3.87; N’ 8.28; F, 16.85. Found: c, 56·68, Η, 3·87, Ν, 8·16; F, 16 89. , 4-[r-(2-trifluoromethylphenyl)ureido-based U9 millimolar LHUS)-fluoro-(2s)m each (^ gram), _t (145 house grams, 107 millimoles A mixture of (15 μm!· 08 mmol) in MF (5 ml) was stirred at room temperature for 3 days. The mixture was diluted with HJ and extracted with EtOAc. The extract was washed with brine, dried over NazS 4 and evaporated. The residue was subjected to column chromatography using CHCl3-MeOH (100:1 to 60:1, v/v) as an eluent to obtain 4-[(4S)-fluoro-1-[ 4-[n,-(2-trifluoromethylphenyl)ureido]]phenylamino]-(2S)-indolyl methoxy]benzoic acid methyl ester (463 mg '90%) Yellow foam. NMR (CDC13) (5 2.09-2.60 (m, 2H), 3· 56-4· 12 (s and m series, total 8H), 4·26-4· 65 (m, 2Η), 5·26-5 ·29 and 5.39-5.42 (each m, total 1Η), 6.87-6.93 (m, 2H), 6.99-7.13 (m, 5H), 7·30-7·33 (m, 1H), 7.44 -7·53 (m, 2H), 7·8 8-7.92 (m, 1H), 7·99-8·04 (m, 2H), 8.09-8.15 (m, 1H); MS (ESI) m/ z 574 (MH1). 4-[(4S)-Fluoro-l-[4-[N'-(2-trifluoromethylphenyl)ureido]phenylethyl SI*yl]-(2S)- u, a solution of piroxicam methoxy]benzoic acid methyl vinegar (460 mg, 0. 80 mmol) dissolved in THF (5 ml) was added 0. 5 NaOH (5 mL) and the reaction mixture was allowed. Heated under reflux for 5 hours. After cooling to room temperature, the mixture was poured into ice 1 N HC 1 and collected under reduced pressure.

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\\312\2d-code\90-01\89112968.ptcl 第306頁 1283240 五、發明說明（302) 生之沈殿物。使粗製固體自MeOH-CHCl3*~IPE再結晶而得4一 [(4S)-就- 1-[4 - [Ν’-（2-三氟甲基苯基）脈基]本基乙酿 基]-(2S) -咄咯啶甲氧基]苯曱酸75 ( 1 69毫克，38%)之白色 結晶粉末。熔點 1 3 0- 1 35 °C ; M-NMR (DMSO-d6) (5 2. 24 -2· 3 0 (m， 2H)、3· 5卜4· 24 (m 系列，總計5H)、4· 38-4· 40 及4. 61 (各m，總計 2H)、5· 3 卜 5· 50 (m，1 Η)、 7.03-7.42 (m 系列，總計 7Η)、7·62 - 7.69 (m， 2Η)、 7·87-8·07 (m， 4H) 、9·36-9·37 (m， 1H) 、12·64 (br s， 1H) ; MS(ESI ) m/z 56 0 (MH1) ; C28H25F4N3 05 之分析計算 值：C， 60.11； Η, 4. 50 ； N, 7. 51 ； F, 13· 58。實測值： C, 60.10; Η, 4.85； N, 7.01 ； F, 12.90° 實施例7 0 4-[(4S)-氟-1-[3-甲氧基-4-[N’ - (2 -三氟甲基苯基）脲基] 苯基乙醯基]-（2 S)-吼咯啶甲氧基]苯曱酸 C^N AN ^o-^-co2h CF, H H OMe 76 3-甲氧基-4 - [Ν’ -（2 -三氟曱基苯基）脲基]苯乙酸\\312\2d-code\90-01\89112968.ptcl Page 306 1283240 V. Description of invention (302) The hall of life. The crude solid was recrystallized from MeOH-CHCl3*~IPE to give 4-[(4S)--- 1-[4 - [Ν'-(2-trifluoromethylphenyl)] yl] A white crystalline powder of -(2S)-indolyl methoxy]benzoic acid 75 (1 69 mg, 38%). Melting point 1 3 0- 1 35 °C; M-NMR (DMSO-d6) (5 2. 24 -2· 3 0 (m, 2H), 3·5 Bu 4· 24 (m series, total 5H), 4 · 38-4· 40 and 4.61 (each m, total 2H), 5·3 Bu 5· 50 (m, 1 Η), 7.03-7.42 (m series, total 7Η), 7.62 - 7.69 (m , 2Η), 7·87-8·07 (m, 4H), 9·36-9·37 (m, 1H), 12·64 (br s, 1H) ; MS(ESI ) m/z 56 0 ( MH1) ; C28H25F4N3 05 analytical calculated value: C, 60.11; Η, 4. 50 ; N, 7. 51 ; F, 13· 58. Found: C, 60.10; Η, 4.85; N, 7.01 ; F, 12.90 ° Example 7 0 4-[(4S)-Fluoro-1-[3-methoxy-4-[N'-(2-trifluoromethylphenyl)ureido]phenylphenyl]]-( 2 S)-Ethrolidine methoxy]benzoic acid C^N AN ^o-^-co2h CF, HH OMe 76 3-methoxy-4 - [Ν' -(2-trifluorodecylphenyl) Urea-based phenylacetic acid

4 -胺基-3-甲氧苯基乙酸第三丁酯（i u克，4.68毫莫 耳）及Et3N(720微升，5.17毫莫耳）溶於THF(1 0毫升）之攪 拌溶液中加入異氰酸2 -三氟甲基苯酯（707微升，4.68毫莫 耳），並使反應混合物在室溫下攪拌2天。將反應混合物濃4-Amino-3-methoxyphenylacetic acid tert-butyl ester (iu g, 4.68 mmol) and Et3N (720 μL, 5.17 mmol) dissolved in THF (10 mL) in a stirred solution 2-Trifluoromethylphenyl isocyanate (707 μL, 4.68 mmol), and the reaction mixture was stirred at room temperature for 2 days. Concentrate the reaction mixture

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縮至一小體積，並以正己烷稀釋。在減壓下收集所產生之 沈澱物，並以正己烷洗滌而得3一甲氧基一4〜[N，2—三氟曱 基苯基）脲基]苯乙酸第三丁酯（1·11克，56%)的白色結晶 粉末。熔點 131-133°C ; NMR (CDC13) 51.44 (s，^曰、 3·49 (s’ 2Η)、3·85 (s，3Η)、6·83-6·88 (m，別）、 6·98 (br s，1Η)、7·17-7·21 (m，1Η)、7·52:7·59 (m， 2H) 、7·89-7.91 (m， ih) 、8·〇4-8.06 (m， iH)。 於3-曱氧基-4-[N，-（2-三氟曱基苯基）脲基]苯乙酸第三 丁酯（1.11克，2.62毫莫耳）溶於(^2(：12(10毫升）之攪拌溶 液中加入TF A (1 0耄升），並使反應混合物在室溫下攪拌4小 時。將反應混合物濃縮至一小體積，並倒入至冰的&amp; 〇 中。在減壓下收集所產生之沈澱物，並使粒製固體自Reduce to a small volume and dilute with n-hexane. The resulting precipitate was collected under reduced pressure and washed with n-hexane to give &lt;RTI ID=0.0&gt; 11 g, 56%) of a white crystalline powder. Melting point 131-133°C; NMR (CDC13) 51.44 (s, ^曰, 3·49 (s' 2Η), 3·85 (s, 3Η), 6·83-6·88 (m, 别), 6 ·98 (br s,1Η),7·17-7·21 (m,1Η),7·52:7·59 (m, 2H), 7·89-7.91 (m, ih), 8·〇4 -8.06 (m, iH). Dissolved in 3-butoxy-4-[N,-(2-trifluoromethylphenyl)ureido]phenylacetic acid tert-butyl ester (1.11 g, 2.62 mmol) TF A (10 mL) was added to a stirred solution of (2:2 (10 mL), and the reaction mixture was stirred at room temperature for 4 hr. The reaction mixture was concentrated to a small volume and poured. Ice &amp; 〇. Collect the resulting precipitate under reduced pressure and make the pellet solid

MeOH - CHC13 - IPE再結晶而得3—甲氧基—4 - [N，-（2 —三氟甲基 苯基）脲基]苯乙酸（ 839毫克，87%)之白色結晶粉末。溶點 218-22 0 °C ; Μ-NMR (DMS0-d6) 53.51 (s，2H)、3·87 (s， 3Η)、6·76-6.79 (m，1Η)、6·93-6.94 (m, 1Η)、7 27-7 30 (m，1H)、7·6 卜 7·69 (m，2H)、7·82 - 7·84 (m，1H)、 7·97-7·99 (m，1H)、8·71 (s，1H)、8·89 (s，1H)、12· 3 0 (br s，1 H) ; C17H15F3N2 04 之分析計算值：c，55. 44 ; h， 4·11;Ν，7.61; F， 15.47。實測值：c，55.30; H， 4·08，N， 7.63，F, 15.13 〇 使3-甲氧基-4-[『-（2 -三氟曱基苯基）脲基]苯乙酸（353 毫克，〇· 96 t莫耳）、4-[(4S)-氟-（2S)-咄咯啶曱氧基]苯 甲酸甲_( 24 3毫克，〇· 96毫莫耳）、EDC · hC1(221毫克，MeOH-CHC13-IPE was recrystallized to give white crystal powder of 3-methoxy-4-[N,-(2-trifluoromethylphenyl)ureido]phenylacetic acid ( 839 mg, 87%). Melting point 218-22 0 °C; Μ-NMR (DMS0-d6) 53.51 (s, 2H), 3·87 (s, 3Η), 6.76-6.79 (m, 1Η), 6.93-6.94 ( m, 1Η), 7 27-7 30 (m, 1H), 7·6 Bu 7·69 (m, 2H), 7·82 - 7·84 (m, 1H), 7·97-7·99 ( m,1H),8·71 (s,1H),8·89 (s,1H), 12·3 0 (br s,1 H) ; C17H15F3N2 04 analytical calculation: c, 55. 44 ; h, 4·11; Ν, 7.61; F, 15.47. Found: c, 55.30; H, 4·08, N, 7.63, F, 15.13 3- 3-methoxy-4-["-(2-trifluoromethylphenyl)ureido]phenylacetic acid (353 Mg, 〇· 96 tmol), 4-[(4S)-fluoro-(2S)- 咄 曱 曱 曱 曱 曱 曱 曱 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 24 (221 mg,

1283240 五、發明說明（304) 1·15毫莫耳）、HOB t(156毫克，1.15毫莫耳）、及以^(16〇 微升，1· 15毫莫耳）於DMF(5毫升）中之混合物在室^下撥 拌隔夜。將混合物以稀釋，並以EtOAc萃取。將萃取液 以鹽水洗滌，於NaJO4上乾燥，並蒸發。使殘留物經由於 石夕膠上利用CHCl3-MeOH(100:l至60:1，v/v)作為洗提液進 行管柱層析，純化而得4-[(4S) -氟-1-[3-甲氧基一 4 一 [n， -（2 -三氟曱基苯基）脲基]苯基乙醯基]-（2S) -吼。各0定甲氧 基]苯曱酸曱酯（ 57 0毫克，98%)之白色泡沫。 列，總計 11H)、4·05 - 4·64 (m, 2H)、5·23-5·25 及 5.36 -5·37 (各m，總計 1Η)、6. 7 9-6.82 (m，2Η)、6·89-7·00 (m，2H)、7·16 - 7.20 (m，2H)、7. 3 9-7.43 (m，1H)、 7.51-7.59 (m, 2H) &gt; 7.93- 8.0 2 (m, 4H) ； MS(ESI) m/z 6 04 (MH1)。 於4 - [(4S)-氟-1 - [3-甲氧基-4-[Ν’ -（2-三氟曱基苯基） 脲基]苯基乙醯基]-(2S)_吼咯啶甲氧基]苯甲酸甲酯（5 70 毫克，〇· 94毫莫耳）溶於THF (5毫升）之攪拌溶液中加入 0 · 5 N N a 0 Η ( 5毫升），並使反應混合物迴流加熱2小時。於 冷卻至室溫後，將混合物倒入至冰的1 N HC 1中，並在減壓 下收集所產生之沈澱物。使粗製固體自MeOH-CHCl3-ΙΡΕ再 結晶而得76 ( 234毫克，42%)之白色結晶粉末。熔點 1 29- 1 3 2 °C ; !Η-NMR (DMSO-d6) (5 2.23-2.2 9 (m，2H)、 3·54-4·38 (s 及m 系列，總計 8H)、4·40 - 4.61 (m， 2H)、 5·30-5·36 及 5·43-5·49 (各m，總計 1H)、6·72-6·91 (m，1283240 V. Description of invention (304) 1.15 millimoles), HOB t (156 mg, 1.15 mmol), and ^ (16 μL, 1.25 mmol) in DMF (5 mL) Mix the mixture in the room and mix it overnight. The mixture was diluted and extracted with EtOAc. The extract was washed with brine, dried over Na.sub.4, and evaporated. The residue was subjected to column chromatography using CHCl3-MeOH (100:1 to 60:1, v/v) as an eluent, and purified to give 4-[(4S)-fluoro-1- [3-Methoxy-4-iso[n,-(2-trifluoromethylphenyl)ureido]phenylethenyl]-(2S)-indole. Each of 0 methoxy] benzoic acid decyl ester (57 0 mg, 98%) of white foam. Column, total 11H), 4·05 - 4·64 (m, 2H), 5·23-5·25 and 5.36 -5·37 (each m, total 1Η), 6. 7 9-6.82 (m, 2Η ), 6·89-7·00 (m, 2H), 7.16 - 7.20 (m, 2H), 7. 3 9-7.43 (m, 1H), 7.51-7.59 (m, 2H) &gt; 7.93- 8.0 2 (m, 4H); MS (ESI) m/z 6 04 (MH1). 4-[(4S)-Fluoro-1 -[3-methoxy-4-[Ν'-(2-Trifluoromethylphenyl)ureido]phenylethenyl]-(2S)_吼To a stirred solution of methyl bromo methoxy]benzoate (5 70 mg, 〇·94 mmol) in THF (5 mL) was added EtOAc EtOAc (5 mL) Heated under reflux for 2 hours. After cooling to room temperature, the mixture was poured into 1 N HCl 1 of ice, and the resulting precipitate was collected under reduced pressure. The crude solid was recrystallized from MeOH-CHCl3-hexane to yield 76 ( 234 mg, 42%) of white crystalline powder. Melting point 1 29- 1 3 2 ° C ; !Η-NMR (DMSO-d6) (5 2.23-2.2 9 (m, 2H), 3·54-4·38 (s and m series, total 8H), 4· 40 - 4.61 (m, 2H), 5·30-5·36 and 5·43-5·49 (each m, total 1H), 6.72-6·91 (m,

\\312\2d-code\90-01\89112968.ptd 第309頁 1283240 五、發明說明（305) ---- 2H) ^ 7.02-7.08 (m, 2H) &gt; 7. 25 -7. 29 (m, 1H) ^7.59-7. 67 (m, 2H) ^7.81-7.99 (m, 4H) ^ 8.69-8.70 (m, 1H) ^ 8.87-8.90 (ffl) 1H) &gt;12.67 (br s, 1H); MS(ESI) ,/z 58 9(M+ + 1 )，C29H27F4N3 06 之分析計算值：c，μ. 〇8 ; h， 4. 62，N，7. 13。實測值：c，59. 22 ; h，L 10 ; N， 6· 58。 實施例7 1 4-[(43)-氟-1-[3-甲基-4 —[『一（2—三氟曱基苯基）脲基] 苯基乙酿基]-（2S)-吡咯啶甲氧基]苯甲酸 -〇-c〇2h % 77 3-曱基-4-[ Ν’ 2-三氟甲基苯基）脲基]苯乙酸 於4-胺基-3-甲基苯基乙酸第三丁酯（927毫克，4·丨9毫 莫耳）及Et3N(645微升，4·63毫莫耳）溶於THF(1〇毫升）之 授拌溶液中加入異氰酸2 -三氟甲基苯酯（6 3 3微升，4 · 1 9毫 莫耳），並使反應混合物在室溫下攪拌2天。將反應混合物 濃縮至一小體積，並以正己烷稀釋。在減壓下收集所產生 之沈澱物，並以正己烷洗滌濾液而得3—曱氧基— 4—[N，—（2-一氣甲基本基）服基]本乙酸第三丁 g旨（1〇6克，62%)的白 色結晶粉末。熔點 1 78-1 80 °C ; UMR (CDC13) 6 1· 44 (s， 9H)、2·25 (s，3H)、3·51 (s，2H)、6·38 (br s，1H)、\\312\2d-code\90-01\89112968.ptd Page 309 1283240 V. Inventions (305) ---- 2H) ^ 7.02-7.08 (m, 2H) &gt; 7. 25 -7. 29 (m, 1H) ^7.59-7. 67 (m, 2H) ^7.81-7.99 (m, 4H) ^ 8.69-8.70 (m, 1H) ^ 8.87-8.90 (ffl) 1H) &gt;12.67 (br s, 1H); MS (ESI), /z 58 9 (M+ + 1), C29H27F4N3 06: Calculated: C, μ. 〇8; h, 4. 62, N, 7.13. Found: c, 59. 22; h, L 10 ; N, 6.58. Example 7 1 4-[(43)-Fluoro-1-[3-methyl-4-["mono(2-trifluoromethylphenyl)ureido]phenylphenyl]]-(2S)- Pyrrrolidine methoxy]benzoic acid-〇-c〇2h % 77 3-mercapto-4-[ Ν' 2-trifluoromethylphenyl)ureido]phenylacetic acid in 4-amino-3-methyl Addition of isocyanic acid to a solution of tert-butyl phenylacetate (927 mg, 4·9 9 mmol) and Et3N (645 μl, 4.63 mmol) dissolved in THF (1 mL) 2-Trifluoromethylphenyl ester (6 3 3 μL, 4 · 19 mmol), and the reaction mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated to a small volume and diluted with n-hexane. The resulting precipitate was collected under reduced pressure, and the filtrate was washed with n-hexane to give 3-methoxy- 4-[N,-(2-monomethylmethyl)-based] 1 〇 6 g, 62%) of a white crystalline powder. Melting point 1 78-1 80 °C; UMR (CDC13) 6 1· 44 (s, 9H), 2·25 (s, 3H), 3·51 (s, 2H), 6·38 (br s, 1H) ,

W312\2d-code\90-01\89112968.ptdW312\2d-code\90-01\89112968.ptd

第310頁 1283240 五、發明說明（306) 7 · 1 2 - 7 · 1 8 ( m，3 Η )、7 · 3 6 - 7 · 3 7 (m，1 Η)、7 · 4 9 - 7 · 5 3 (m， 2Η) 、8·13-8·16 (m， 1Η)。 於3-甲基-4 - [Ν’ - (2 -三氟甲基笨基）脲基]笨乙酸第三丁 酉旨（1· 06克’ 2· 60毫莫耳）溶於CH2Cl2(i〇毫升）之授摔溶液 中加入T F A ( 1 0毫升），並使反應混合物在室溫下攪拌4小 時。將反應混合物濃縮至一小體積，並倒入至冰的H2 〇 中。在減壓下收集所產生之沈澱物，並使粗製固體自 MeOH-CHC13 - IPE再結晶而得3-甲基-4 - [Ν’ -（2-三氟i曱基苯 基）脲基]苯乙酸（7 02毫克，77%)之白色結晶粉末。熔點 262-2 63 °C； ^-NMR (DMS0-d6) 52.24 (s, 3H) -3.48 (s, 2H)、7·03 (d，J = 8.3 Hz, 1H)、7·〇8 (s，1H)、7·26 - 7· 30 (m，1H)、7·61 -7·69 (m，3H)、7.88 (d，J = 8.3 Hz， 1H)、8·39 (s，1H)、8·55 (s，1H)、12.28 (br s，1H) ;C17H15F3N2 03 之分析計算值：C，57. 9 6 ; H，4. 29 ; N， 7. 95 ; F， 16· 18。實測值：C，57. 73 ; H，4. 23 ; N， 7· 92 ; F，16· 05。 &gt; 使3-甲基-4 - [Ν’ - (2-三氟曱基苯基）脲基]苯乙酸（359毫 克’ 1· 02毫莫耳）、4-[(4S) -氟- (2S)~°比略σ定甲氧基]苯甲 酸甲酯（ 258毫克，1· 02毫莫耳）、EDC · HC1 (234毫克， 1· 22 毫莫耳）、HOBU165 毫克，1· 22 毫莫耳）、&amp;Et3N(17〇 微升，1. 22毫莫耳）於DMF(5毫升）中之混合物在室溫下攪 拌隔夜。將混合物以&amp;0稀釋，並以E10Ac萃取。將萃取液 以鹽水洗滌，於NaJO4上乾燥，並蒸發。使殘留物妳由於 石夕膠上利用(：1^13-^^〇11(100:1至60:11/〇作為洗^液進Page 310 1283240 V. INSTRUCTIONS (306) 7 · 1 2 - 7 · 1 8 ( m, 3 Η ), 7 · 3 6 - 7 · 3 7 (m, 1 Η), 7 · 4 9 - 7 · 5 3 (m, 2Η), 8·13-8·16 (m, 1Η). In the 3-methyl-4 -[Ν' - (2-trifluoromethylphenyl)ureido] benzoic acid tributyl hydrazine (1 · 06 g ' 2 · 60 mmol) dissolved in CH 2 Cl 2 (i 〇 TFA (10 ml) was added to the drop solution of ML), and the reaction mixture was stirred at room temperature for 4 hr. The reaction mixture was concentrated to a small volume and poured into ice H2. The resulting precipitate was collected under reduced pressure, and the crude solid was recrystallized from MeOH-CHC13-IPE to give 3-methyl-4-[[rho]-(2-trifluoroimethylphenyl)ureido] A white crystalline powder of phenylacetic acid (72 mg, 77%). Mp 262-2 63 °C; ^-NMR (DMS0-d6) 52.24 (s, 3H) -3.48 (s, 2H), 7·03 (d, J = 8.3 Hz, 1H), 7·〇8 (s , 1H), 7·26 - 7· 30 (m, 1H), 7·61 -7·69 (m, 3H), 7.88 (d, J = 8.3 Hz, 1H), 8·39 (s, 1H) , 8·55 (s, 1H), 12.28 (br s, 1H); C17H15F3N2 03 analytical calculations: C, 57. 9 6 ; H, 4. 29 ; N, 7. 95 ; F, 16· 18. Found: C, 57. 73; H, 4. 23; N, 7· 92 ; F, 16.05. &gt; 3-methyl-4 -[Ν' - (2-trifluoromethylphenyl)ureido]phenylacetic acid (359 mg '1.22 mmol), 4-[(4S)-fluoro- (2S)~° ratio sigma methoxy] benzoic acid methyl ester (258 mg, 1.02 mmol), EDC · HC1 (234 mg, 12.22 mmol), HOBU 165 mg, 1·22 A mixture of mM, &lt;RTI ID=0.0&gt;&gt; The mixture was diluted with &amp; 0 and extracted with E10Ac. The extract was washed with brine, dried over Na.sub.4, and evaporated. Let the residue 妳 be used on Shishijiao (:1^13-^^〇11 (100:1 to 60:11/〇 as a washing liquid)

\\312\2d-code\90-01\89112968.ptd 第311頁 1283240 五、發明說明（307) 行管柱層析，純化而得4 - [(4S)-氟-1-[3-甲基-4-[N，-（2-三氟曱基苯基）脲基]苯基乙醯基]-（2S) -吼咯啶曱氧基]苯 甲酸曱酉旨（61 2毫克，q· y.)之白色泡床。ih_NMr (CDC13) 5 1· 92 及 2· 00 (各3，總計 3H)、2· 09-2· 61 (m，2H)、3· 56 -4.29 (m 系列，總計81〇、4.45-4.48及4.59-4.64 (各111， 總 a十 2H)、5·24-5.30 及 5.38-5.44 (各m，總計 1H)、6·90 -7·14 (m，5Η)、7·22-7·53 (m，5Η)、7.90-7·92 (m, 1H) 、8·00-8·06 (m, 2H); MS(ESI) m/z 588(MH1)。 於4-[(4S)-氟-1-[ 3-甲基-4-[N，-（2-三氟甲基苯基） 脲基]苯基乙醯基]-(2S)-咄咯啶甲氧基]苯甲酸甲酯（6 1 0 毫克'1.04毫莫耳）溶於THF(5毫升）之攪;摔溶液中加入 0·5Ν NaOH(5毫升），並使反應混合物迴流加熱2 實施例72 4-[(4S)-氟-1-[3 -甲基-4-[Ν’ -（2-甲基苯基）脲基]苯基乙 醯基]-（2 S)-咄咯啶基]甲氧苯甲酸\\312\2d-code\90-01\89112968.ptd Page 311 1283240 V. Description of the invention (307) Column chromatography, purification to obtain 4 - [(4S)-fluoro-1-[3- 4-[N,-(2-Trifluoromethylphenyl)ureido]phenylethenyl]-(2S)-indolyloxyl]benzoic acid (61 2 mg, q · y.) White bubble bed. ih_NMr (CDC13) 5 1· 92 and 2· 00 (each 3, total 3H), 2· 09-2· 61 (m, 2H), 3· 56 - 4.29 (m series, total 81〇, 4.45-4.48 and 4.59-4.64 (each 111, total a ten 2H), 5·24-5.30 and 5.38-5.44 (each m, total 1H), 6.90 -7·14 (m, 5Η), 7·22-7·53 (m, 5Η), 7.90-7·92 (m, 1H), 8·00-8·06 (m, 2H); MS (ESI) m/z 588 (MH1). 4-[(4S)- Fluor-1-[3-methyl-4-[N,-(2-trifluoromethylphenyl)ureido]phenylethenyl]-(2S)-indolyl methoxy]benzoic acid The ester (6 1 0 mg '1.04 mmol) was dissolved in THF (5 mL); 0. 5 NaOH (5 mL) was added to the solution and the reaction mixture was heated under reflux 2 Example 72 4-[(4S -Fluoro-1-[3-methyl-4-[Ν'-(2-methylphenyl)ureido]phenylethenyl]-(2S)-indenylpyridyl]methoxybenzoic acid

78 使3 -曱基-4-[Ν’-（2-甲基苯基）脲基]苯乙酸（250毫克， 0.84毫莫耳）、4-[(4S) -氟-（2S)-吼咯啶基]曱氧苯甲酸甲 酯（400 毫克，1.06 毫莫耳）、EDC ·Η(：1(242 毫克，1.26 毫 莫耳）及DMAP(154毫克，1. 26毫莫耳）於DMF(5毫升）中之混 合物在室溫下攪拌2 1小時。將混合物倒入至冰水中，並以 E10 A c卒取。將結合的萃取液以冰水及鹽水洗條。於在n a78 3-Mercapto-4-[Ν'-(2-methylphenyl)ureido]phenylacetic acid (250 mg, 0.84 mmol), 4-[(4S)-fluoro-(2S)-吼Methyl pyridyl] oxime benzoate (400 mg, 1.06 mmol), EDC Η (: 1 (242 mg, 1.26 mmol) and DMAP (154 mg, 1.26 mmol) in DMF The mixture in (5 ml) was stirred at room temperature for 2 hours. The mixture was poured into ice water and was taken as E10 A c. The combined extracts were washed with ice water and brine.

W312\2d-code\90-01\89112968. ptd 第312頁 1283240 五、發明說明（308) 2S04上乾燥後，將萃取液於真空中濃縮。將殘留物於矽膠 [50克，CHCl3/MeOH(50/l)]上進行層析，然後於TLC [CHC13/丙酮（10/1)]上純化而得4 - [(4S) -氟-1-[3-甲基 -4 - [Ν’ -（2-甲基苯基）脲基]苯基乙醯基]-（2S) -吼咯啶基] 甲氧苯曱酸甲酯（3 42毫克，76%)之無色非晶形固體。IR (KBr) 3356、2951、1716、1651、1604、1537、1252 / 公 分；1H-NMR (CDC13)(5 2·07 (d，J = 6.6 Hz, 2H)、2·12 (s， 3H) 、2·27 (m， 1H) 、2·24 (s， 3H) 、2·30-2.59 (m， lH)、3.60(d，J=5.3Hz，lH)、3.65-4.23(m，3H)、3· 87 (s， 3H) 、4· 50-4.62 (m， 1H) 、5.31 (d， J=52.4 Hz, 1H) 、6·23 (d， J=11.2 Hz, 1H) 、6·26 (d, J=11.9 Hz， 1H) 、6·87-7.27 (m， 8H) 、7·54-7·65 (m， 3H) 、7.94-8· 01 (m，2H) ; MS(FAB) m/z 534 (MH1) ; C30H32FN3O5 · 0·7Η20 之分析計算值：C，65.97; H，6.16; F，3.48 ;N，7.69。實測值：C， 66.04; H，6.07; F， 3.55; N， 7.64。 於4-[(4S)-氟-1-[3 -曱基-4 - [Ν’ -（2-曱基苯基）脲基]苯 基乙醯基]-(2S) -咄咯啶基]曱氧苯曱酸曱酯（227毫克，0· 425毫莫耳）溶於THF(3.4毫升）之攪拌溶液中加入〇. 25Ν NaOH(3· 4毫升）。於在室溫下攪拌4天後，將混合物以in HC1酸化’並以CHCl3-MeOH(10/l)萃取。將結合的萃取液 於NazS〇4上乾燥，並於真空中濃縮。使殘留物於製備 TLC[CHCl3/MeOH(10/l)]上純化而得78(190 毫克，86%)的 無色非晶形固體。IR (KBr) 3356、2974、1604、1537、W312\2d-code\90-01\89112968. ptd Page 312 1283240 V. INSTRUCTIONS (308) After drying on 2S04, the extract was concentrated in vacuo. The residue was chromatographed on silica gel [50 g, CHCl3 / MeOH (50/l)] and then purified on TLC [CHC13/Acetone (10/1)] to give 4-[(4S)-fluoro-1 -[3-methyl-4 -[Ν' -(2-methylphenyl)ureido]phenylethenyl]-(2S)-oxaridinyl]methyl methoxybenzoate (3 42 Mg, 76%) of a colorless amorphous solid. IR (KBr) 3356, 2951, 1716, 1651, 1604, 1537, 1252 / cm; 1H-NMR (CDC13) (5 2·07 (d, J = 6.6 Hz, 2H), 2·12 (s, 3H) , 2·27 (m, 1H), 2·24 (s, 3H), 2·30-2.59 (m, lH), 3.60 (d, J=5.3Hz, lH), 3.65-4.23 (m, 3H) , 3· 87 (s, 3H), 4· 50-4.62 (m, 1H), 5.31 (d, J=52.4 Hz, 1H), 6.23 (d, J=11.2 Hz, 1H), 6.26 (d, J=11.9 Hz, 1H), 6.87-7.27 (m, 8H), 7·54-7·65 (m, 3H), 7.94-8· 01 (m, 2H); MS (FAB) m/z 534 (MH1); calcd for C30H32FN3O5 · 0·7 Η 20: C, 65.97; H, 6.16; F, 3.48; N, 7.69. Found: C, 66.04; H, 6.07; F, 3.55; , 7.64. 4-[(4S)-Fluoro-1-[3-indolyl-4 -[Ν'-(2-mercaptophenyl)ureido]phenylethenyl]-(2S)-咄搅拌. 25Ν NaOH (3.4 ml) was added to a stirred solution of hydrazinyl]nonyl benzoate (227 mg, 0. 425 mmol) in THF (3.4 mL). After stirring for 4 days, the mixture was acidified with in HC1 and extracted with CHCl3-MeOH (10/1). The combined extracts were dried over NazS 4 and vacuum Concentration in EtOAc (EtOAc/MeOH (EtOAc) (EtOAc)

\\312\2d-code\90-01\89112968.ptd 第 313 頁 1283240 五、發明說明（309) 1 454、1 252 / 公分；I-NMR (DMS0-d6) 3 2· 24 (s，3H) 、2·26 (s，3H)、3·60 (d，J = 3.7 Hz，2H)、3·65-4·65 (m, 8H)、5·3 卜 5·50 (m, ih)、6·92 - 7.18 (平，7H)、 7·67-7·92 (m，4Η)、8· 22-8· 32 (m, 2Η) ; ks(FAB) m/z 520 (MH1) ; C29H3QFN3 07 · 1· ih2〇 之分析計算值：C，64· 58 ; 11，6.02;?，3.52;17.79。實測值：（：，64.71;11，5· 90 ; F， 3· 24 ; N， 7· 51 。 實施例73 4 - [1 - [4 - [Ν’ -（2 -氣笨基）脲基]-3-曱基苯基乙醯基]-(4S) -氟-（2 S) -吼洛唆基]甲氧苯曱酸\\312\2d-code\90-01\89112968.ptd Page 313 1283240 V. INSTRUCTIONS (309) 1 454, 1 252 / cm; I-NMR (DMS0-d6) 3 2· 24 (s, 3H ), 2·26 (s, 3H), 3·60 (d, J = 3.7 Hz, 2H), 3·65-4·65 (m, 8H), 5·3 Bu 5·50 (m, ih) , 6.92 - 7.18 (flat, 7H), 7·67-7·92 (m, 4Η), 8·22-8· 32 (m, 2Η); ks(FAB) m/z 520 (MH1); Analysis calculated for C29H3QFN3 07 · 1· ih2〇: C, 64· 58 ; 11, 6.02; ?, 3.52; 17.79. Found: (:, 64.71; 11,5·90; F, 3·24; N, 7· 51. Example 73 4 - [1 - [4 - [Ν - - (2 - oxa)] ]-3-mercaptophenylethyl]-(4S)-fluoro-(2S)-indolyl]methoxybenzoic acid

4 - [Ν’ -（2 -氣苯基）脲基]-3-曱基苯乙酸4 - [Ν' -(2-Phenylphenyl)ureido]-3-indolylphenylacetic acid

在室溫下於4-胺基-3-甲基苯基乙酸第三丁酯（1·〇〇克， 4·52毫莫耳）、異氰酸2 -氯苯酯（0.55毫升，4.52毫莫耳） 於THF (1〇毫升）中之攪拌混合物中加入Et3N(0· 13毫升， 0· 90毫莫耳）。於攪拌6小時後，將反應混合物於真空中濃 縮。經由加入正己烷將殘留物研製而得4_[N，-(2 -氯苯基） 脲基]-3-甲基苯乙酸第三丁酯（I 57克，93%)的淡黃色粉 末。熔點 1 04- 1 0 6 °C (分解）；NMR (CDC13) 6 1. 45 (s，T-butyl 4-amino-3-methylphenylacetate (1·〇〇g, 4.52 mmol), 2-chlorophenyl isocyanate (0.55 ml, 4.52 m) at room temperature To a stirred mixture of THF (1 mL) was added Et3N (0········· After stirring for 6 hours, the reaction mixture was concentrated in vacuo. The residue was triturated by the addition of n-hexane to give the pale yellow powder of 4-[N,-(2-chlorophenyl)ureido]-3-methylphenylacetic acid tert-butyl ester (I 57 g, 93%). Melting point 1 04- 1 0 6 °C (decomposition); NMR (CDC13) 6 1. 45 (s,

89112968.ptd 第314頁 1283240 五、發明說明（310) 9H)、2·28 (s，3H)、3·51 (s，2H)、6·33 (br，1H)、6· 96 (t，J二7.6 Hz, 1H)、7·〇8 (br, 1H)、7·16-7.30 (m， 4H)、7·42 (m，1H)、8·2 (d，J = 8.1 Hz，1H)。 在室溫下於4-[N’ -（2-氣苯基）脈基]-3-曱基苯乙酸第三 丁酯（1 · 57克，4· 1 9毫莫耳）溶於CH，l2(l〇毫升）之攪拌溶 液中加入TF A ( 6毫升）。於攪拌4小時後，將混合物於真空 中濃縮。經由加入水將殘留物研製而得4-1 Ν’ 2-氣笨基） 脲基]-3-曱基苯乙酸（1.33克，100%)之黃色粉末。熔點 243-24 5 °C (分解）；UMR (CDC13) δ2· 24 (s，3Η)、3· 47 (s, 2Η)、6·99- 7.08 (m，3Η)、7·28 (t J = 7.6 Ηζ，ιΗ) 、7·44 (dt，J:8.0、2·4 Ηζ，1Η)、7·66 (dd，J = 8.3、 1·9 Ηζ， 1Η) 、8·13 (dd， J=6.1 、1·7 Hz, 1Η) 、8·61 (d， J:6.3 Hz， 2H); MS(ESI) m/z 319(MH1) 、321 (MH3) ; C16H15C1N2 03 · 〇· 7TFA 之分析計算值·· C，5 9. 33 ; H，4· 65 ; Cl， 1 0· 85 ; N，8· 57。實測值：C，59· 23 ; H， 4· 64 ; Cl， 10· 90 ; N， 8·40 。 使4 - [Ν’-（2 -氯苯基）脲基]-3-甲基苯乙酸（ 252毫克， 〇· 79毫莫耳）、4-[ (4S) -氟-(2S)-吼咯啶基]甲氧苯甲酸甲 酯（200 毫克，0.79 毫莫耳）、EDC ·Η(：1(227 毫克，1·2〇 毫 莫耳）及DMAP(147毫克，1· 20毫莫耳）於DMF(5毫升）中之現 合物在室溫下攪拌1 7小時。將混合物倒入至冰水中，並^ EtOAc萃取。將結合的萃取液以冰水及鹽水洗滌。於在 Na2S04上乾燥後，將萃取液於真空中濃縮。使殘留物於 TLC[CHC13/丙酮（10/1 )]上純化而得4-[卜[4-[N，- (2〜氣笨89112968.ptd Page 314 1283240 V. INSTRUCTIONS (310) 9H), 2·28 (s, 3H), 3·51 (s, 2H), 6.33 (br, 1H), 6.96 (t, J 7.6 Hz, 1H), 7·〇8 (br, 1H), 7·16-7.30 (m, 4H), 7·42 (m, 1H), 8·2 (d, J = 8.1 Hz, 1H ). Dissolved in the residue of 4-[N'-(2-phenylphenyl)] benzyl-3-mercaptophenylacetate (1 · 57 g, 4·19 mmol) at room temperature. To the stirred solution of l2 (10 mL) was added TF A (6 mL). After stirring for 4 hours, the mixture was concentrated in vacuo. The residue was triturated by the addition of water to give a white powder of </RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; Melting point 243-24 5 °C (decomposition); UMR (CDC13) δ2· 24 (s, 3Η), 3· 47 (s, 2Η), 6·99- 7.08 (m, 3Η), 7·28 (t J = 7.6 Ηζ, ιΗ), 7.44 (dt, J: 8.0, 2·4 Ηζ, 1Η), 7.66 (dd, J = 8.3, 1·9 Ηζ, 1Η), 8·13 (dd, J =6.1, 1·7 Hz, 1Η), 8.61 (d, J: 6.3 Hz, 2H); MS(ESI) m/z 319(MH1), 321 (MH3) ; C16H15C1N2 03 · 〇· 7TFA analysis Calculated value ·· C,5 9. 33 ; H,4· 65 ; Cl, 1 0· 85 ; N,8· 57. Found: C, 59· 23 ; H, 4· 64 ; Cl, 10· 90 ; N, 8·40. 4-[Ν'-(2-Chlorophenyl)ureido]-3-methylphenylacetic acid (252 mg, 〇·79 mmol), 4-[(4S)-fluoro-(2S)-吼Methyl pyridyl]methoxybenzoate (200 mg, 0.79 mmol), EDC · Η (: 1 (227 mg, 1.2 mmol) and DMAP (147 mg, 1 · 20 mmol) The mixture was stirred at room temperature for 1 hour. The mixture was poured into ice water and extracted with EtOAc. The combined extracts were washed with ice water and brine over Na2S04 After drying, the extract was concentrated in vacuo, and the residue was purified on TLC [CHC13 / acetone (10/1)] to give 4-[Bu[4-[N,- (2~

1283240 五、發明說明（311) 基）脲基]-3 -甲基苯基乙醯基]-(4S) -氟-(2S) -吼咯啶基] 甲氧苯甲酸甲酯（390毫克，89 %)之無色非晶形固體。ir (KBr) 3340、2951、1712、1624、1604、1533、1438 / 公 分；1H-NMR (CDC13)之 1· 92-2· 05 (m，3H)、2· 07-2· 63 (m，2H)、3·61 (d，2H, J = 8.8 Hz)、3·70-4·15 (m， 5H) ^ 4.25-4.67 (m, 2H) ^ 5.26 -5.44 (m, 1H) &gt;6.84-8. 19 (m，13H) ; MS(FAB) m/z 554(MH1)、556(MH3) o 於4 - [1-[4-[N’-（2 -氯笨基）脲基]- 3-曱基苯基乙醯 基]-(4S) -氟-（2S)-吼咯啶基]甲氧苯甲酸甲酯（268毫克， 0.484毫莫耳）溶於THF(3.8毫升）之攪拌溶液中加入〇.25N NaOH(3· 8毫升）。於在室溫下攪拌1天後，將混合物以1N HC1酸化，並以CHC 13-MeOH( 1 0/1 )萃取。將結合的萃取液 於Na2S04上乾燥，並於真空中濃縮。使殘留物於tlc[chC13 /诞6〇1!(10/1)]上純化而得79 ( 1 24毫克，47%)的無色非晶形 固體。IR (KBr) 3346、2976、1709、1685、1604、1533 、1 439 / 公分；1H-NMR (DMSO-d6) 6 2.20(s, 3H，其中 一個異構物）、2.24(s， 3H，其中一個異構物）、2.30 (m， 1H) 、3.60 (s， 2H) 、3·7卜4.62 (m， 6H) 、5.30-5'50 (m, 1H)、7·01-7·09 (m，5H)、7·28 (t，J 二7.81283240 V. INSTRUCTIONS (311) yl) ureido]-3-methylphenylethyl hydrazide]-(4S)-fluoro-(2S)- oxaridinyl] methyl methoxybenzoate (390 mg, 89%) of a colorless amorphous solid. Ir (KBr) 3340, 2951, 1712, 1624, 1604, 1533, 1438 / cm; 1H-NMR (CDC13) 1· 92-2· 05 (m, 3H), 2· 07-2· 63 (m, 2H), 3·61 (d, 2H, J = 8.8 Hz), 3·70-4·15 (m, 5H) ^ 4.25-4.67 (m, 2H) ^ 5.26 -5.44 (m, 1H) &gt; 6.84 -8. 19 (m,13H) ; MS(FAB) m/z 554(MH1), 556(MH3) o 4 - [1-[4-[N'-(2-chlorophenyl)ureido] - 3-decylphenylethylidene]-(4S)-fluoro-(2S)-decalidyl]methyl methoxybenzoate (268 mg, 0.484 mmol) dissolved in THF (3.8 mL) To the stirred solution was added 〇.25N NaOH (3.8 mL). After stirring at room temperature for 1 day, the mixture was acidified with 1N EtOAc, and extracted with CHCI 13-MeOH (1 0/1). The combined extracts were dried over Na2SO4 and concentrated in vacuo. The residue was purified on EtOAc EtOAc EtOAc (EtOAc). IR (KBr) 3346, 2976, 1709, 1685, 1604, 1533, 1 439 / cm; 1H-NMR (DMSO-d6) 6 2.20 (s, 3H, one of the isomers), 2.24 (s, 3H, An isomer), 2.30 (m, 1H), 3.60 (s, 2H), 3·7, 4.62 (m, 6H), 5.30-5'50 (m, 1H), 7·01-7·09 ( m, 5H), 7·28 (t, J two 7.8

Hz，1H)、7·44 (d, J二8·1 Hz, 1H)、7·66 (t，J = 8.1 Hz, 1H) 、7·87 (d， J:7.1 Hz， 2H) 、8·13 (d， J:7.9 Hz, 1H) 、 8. 62 (d， J=6.1 Hz， 2H) ; MS(FAB) m/z 540 (MH1)、5 42 (MH3)。 關於Na 鹽：C28H27C1FN3 07 · Na · 0· 5EtOH · 1· 5H20 之分析Hz, 1H), 7·44 (d, J 2·8 Hz, 1H), 7·66 (t, J = 8.1 Hz, 1H), 7·87 (d, J: 7.1 Hz, 2H), 8 · 13 (d, J: 7.9 Hz, 1H), 8. 62 (d, J = 6.1 Hz, 2H); MS (FAB) m/z 540 (MH1), 5 42 (MH3). About Na Salt: Analysis of C28H27C1FN3 07 · Na · 0· 5EtOH · 1· 5H20

\\312\2d-code\90-01\89112968.ptd 第316頁 1283240 五、發明說明（312) 計算值：C，56.91 ； Η, 5.27； Cl, 5.79; F，3.10； N, 6. 87 ° 實測值·· C，5 6.6 0； H, 4.98； Cl, 5.88； F, 3.08； N, 6. 52 。 實施例74 4-[卜[4-[ Ν’ -(2-溴苯基）脲基]-3-曱基苯基乙醯基]-(4S) -氟-（2 S )-吼咯啶基]曱氧苯甲酸 4 - [Ν’-（2 -溴苯基）脲基]-3-曱基苯乙酸\\312\2d-code\90-01\89112968.ptd Page 316 1283240 V. INSTRUCTIONS (312) Calculated values: C, 56.91; Η, 5.27; Cl, 5.79; F, 3.10; N, 6. 87 ° Measured value · · C, 5 6.6 0; H, 4.98; Cl, 5.88; F, 3.08; N, 6. 52 . Example 74 4-[Bu[4-[ Ν'-(2-bromophenyl)ureido]-3-mercaptophenylethyl]-(4S)-fluoro-(2S)-anthrolidine 4-oxobenzoic acid 4-[Ν'-(2-bromophenyl)ureido]-3-indolylphenylacetic acid

在室溫下於4-胺基-3-曱基苯基乙酸第三丁酯（780毫 克，3. 30毫莫耳）、異氰酸2 -溴苯酯（0· 41毫升，3. 30毫莫 耳）於THF(7毫升）中之攪拌混合物中加入Et3N(0· 0 92毫 升，0. 6 6毫莫耳）。於攪拌3小時後，將反應混合物於真空 中濃縮。經由加入正己烧將殘留物研製而得4 - [ N ’ - ( 2 -演 苯基）脲基]-3-曱基苯乙酸第三丁酯（1.57克，93%)的淡黃 色粉末。熔點 1 3 8- 1 45 °C (分解）；NMR (CDC13) 6 1 · 44 (s， 9H) 、2.33 (s， 3H) 、3·51 (s， 2H) 、6·90 (dt， J = 9.0、1·4 Hz, 1H) &gt;6. 98 (br, 1H)、7 · 18-7. 3 1 (m， 4H)、7.39 (dd, J 二 8.1、2.9 Hz, 1H)、7. 44 (d, J = 8. 0 Hz, 1H)、8· 22 (d，J = 8. 3 Hz, 2H) ； C20H22BrN2O3 · 0. 2H20 之分析計算值：C，56· 80 ; H，5. 58 ; N，6. 62。實測值··T-butyl 4-amino-3-mercaptophenylacetate (780 mg, 3.30 mmol), 2-bromophenyl isocyanate (0.41 ml, 3.30) at room temperature To a stirred mixture of THF (7 mL) was added Et.sub.3 (0. After stirring for 3 hours, the reaction mixture was concentrated in vacuo. The residue was triturated by the addition of hexane to give a pale yellow powder of &lt;RTIgt;&quot;&quot;&quot;&quot;&quot;&quot;&quot;&quot;&quot; Melting point 1 3 8- 1 45 °C (decomposition); NMR (CDC13) 6 1 · 44 (s, 9H), 2.33 (s, 3H), 3·51 (s, 2H), 6.90 (dt, J = 9.0, 1·4 Hz, 1H) &gt;6. 98 (br, 1H), 7 · 18-7. 3 1 (m, 4H), 7.39 (dd, J 8.1, 2.9 Hz, 1H), 7 44 (d, J = 8. 0 Hz, 1H), 8·22 (d, J = 8. 3 Hz, 2H) ; C20H22BrN2O3 · 0. 2H20 Analysis calculated: C, 56· 80 ; H, 5 58 ; N, 6. 62. Measured value··

\\312\2d-code\90-01\89112968.ptd 第317頁 1283240 --------- 五、發明說明（313) C，56· 85 ; H，5· 42 ; N，6· 62。 在室溫下於4-[N’-（2-溴苯基）脲基]—3_曱基苯乙酸第三 丁酿（1· 27克，3· 03毫莫耳）溶於CH2Cl2(1〇毫升）之攪拌溶 液中加入TF A ( 5毫升）。於攪拌1小時後，將混合物於真空 中濃縮。經由加入水將殘留物研製而得4—[N，-(2 -溴苯基） 脲基]-3-甲基苯乙酸（1· 〇5克，95%)之淡黃色粉末。熔點 245-248 °C (分解）；NMR (CDC13) 52. 24 (s，3H)、3· 48 (s，2H)、6·96 (dt，J = 7.3、1·5 Hz, 1H)、7·02 (d， J=8.3 Hz， 1H) 、7·〇7 (s， 1H) 、7·32 (t， J=8.1 Hz， 1H)、7·59-7·66 (m，2H)、8·44 (s，1H)、8.62 (s， 1H); MS(ESI)，m/z 36 3 (MH1)、365 (MH3); C16H15BrN203 • 〇· 7H20 之分析計算值：c，51. 13 ; H，4. 40 ; Br， 21·26;Ν， 7.45。實測值：（：，50.84;11，4.62;8]：，21· 72 ; N，7· 18。 使4-[Ν’ - (2 -溴苯基）脲基]- 3-甲基苯乙酸（287毫克，〇· 79毫莫耳）、4 - [(4S) -氟-（2S)-咄咯啶基]甲氧苯曱酸曱_ (200毫克，〇·79毫莫耳）、EDC*HC 1(228毫克，1·2〇毫莫 耳）、HOBT(160毫克，1.19毫莫耳）及Et3N(0.55毫升’ 3· 95毫莫耳）於DMF (5毫升）中之混合物在室溫下攪拌4天。 將混合物倒入至冰水中，並以EtOAc萃取。將結合的萃取 液以冰水及鹽水洗滌。於在Na2S04上乾燥後，將萃取液於 真空中濃縮。使殘留物於TLC[CHC13/丙酮（10Λ)]上純化 而得4-[ (2S，4S)-：l-[4-[N，-（2-氯苯基）脲基]- 3-曱基苯 基乙醯基]-4 -氟-2 -u比洛咬基]甲氧苯曱酸甲酉旨（440宅克\\312\2d-code\90-01\89112968.ptd Page 317 1283240 --------- V. Description of invention (313) C, 56· 85 ; H, 5· 42 ; N, 6 · 62. In the room of 4-[N'-(2-bromophenyl)ureido]-3-indolyl phenylacetic acid, the third butyl (1·27 g, 3·03 mmol) was dissolved in CH2Cl2 (1). TF (5 ml) was added to the stirred solution of 〇ml). After stirring for 1 hour, the mixture was concentrated in vacuo. The residue was triturated with water to give 4-[N,-(2-bromophenyl)ureido]-3-methylphenylacetic acid (1·5 g, 95%) as pale yellow powder. Melting point 245-248 °C (decomposition); NMR (CDC13) 52. 24 (s, 3H), 3·48 (s, 2H), 6.96 (dt, J = 7.3, 1.5 Hz, 1H), 7·02 (d, J=8.3 Hz, 1H), 7·〇7 (s, 1H), 7·32 (t, J=8.1 Hz, 1H), 7·59-7·66 (m, 2H) , 8·44 (s, 1H), 8.62 (s, 1H); MS (ESI), m/z 36 3 (MH1), 365 (MH3); C16H15BrN203 • 〇· 7H20 Analysis calculated: c, 51. 13 ; H, 4. 40 ; Br, 21·26; Ν, 7.45. Found: (:, 50.84; 11, 4.62; 8]:, 21·72; N,7·18. 4-[Ν'-(2-bromophenyl)ureido]-3-methylphenylacetic acid (287 mg, 〇·79 mmol), 4 - [(4S)-fluoro-(2S)-decalidyl] methoxybenzoate 曱 (200 mg, 〇·79 mmol), EDC *HC 1 (228 mg, 1.2 mmol), HOBT (160 mg, 1.19 mmol) and Et3N (0.55 ml '3.95 mmol) in DMF (5 mL) in a mixture The mixture was stirred for 4 days. The mixture was poured into ice water and extracted with EtOAc. The combined extracts were washed with ice water and brine. After drying over Na2S04, the extract was concentrated in vacuo. Purification on TLC [CHC13/acetone (10 Λ)] gave 4-[(2S,4S)-:l-[4-[N,-(2-chlorophenyl)ureido]-3-mercaptophenyl醯基]-4 -Fluoro-2 -u 洛洛基基]methoxybenzoate 甲 酉 (440 克

\\312\2d-code\90-01\89112968.ptd 第 318 頁 1283240 五、發明說明（314) 93%)之無色非晶形固體。1H 一 NMR (CDCl3)(5 190*^97 (各 3H ’ 醯胺異構物）、2·〇5-2·62 (m，2H)、3·58 (d， J = 8.1 Hz，1H)、3·77 (m，1H)、3·86 及 3·89 (各 3H，醯 胺異構物）、3·9 2- 4.64 (m, 5H)、5·24-5·42 (m，1H)、 6·83-7.23 (m，6H)、7·4卜7·62 (m，4H)、7·86-8.09 (m，3H); MS(ESI) m/z 598 (ΜΗ1)、6 0 0 (ΜΗ3)。 於4 - [1-[4 - [Ν’ -（2 -溴苯基）脲基]一3 一甲基苯基乙醯 基]-(4S) -氟-（2S)-吼咯啶基]甲氧苯甲酸曱酯（440毫克， 〇· 74毫莫耳）溶於THF(6· 0毫升）之攪拌溶液中加入〇· 25N NaOH(6· 0毫升）。於在室溫下攪拌！天後，將混合物以1N HC1酸化，並以CHCl3-MeOH(10/l)萃取。將結合的萃取液 於Na2S04上乾燥，並於真空中濃縮。使殘留物於Tlc [CHCl3/MeOH(10/l)]上純化而得80(229毫克，53%)的無色 非晶形固體。IR (KBr) 3325 、 2972 、 1709 、 1604 、 1 529、1 252 / 公分；l-NMR (DMSO-d6) 5 2· 25 (s，3H)、 2·31 (m, 1H)、3·17 (s，1H)、3·60 (d，J = 4.7 Hz, 2H) 、3.83-4.67 (m， 5H) 、5·31-5·51 (m， 1H) 、6.97 (t，J = 7.3 Hz, 1H)、7·02- 7.0 9 (m，5H)、7·33 (t， J = 8.0 Hz, 1H)、7·61 (d, J二7.8 Hz, 1H)、7.64 (d， J二8·3 Hz，1H)、7.87 (d，J = 8.3 Hz，2H)、7·90 (d， J二8.8 Hz, 1H) 、8·44-8·65 (m， 2H); MS(ESI) ，m/z 584 (MH1)、5 86 (MH3) ; C28H27BrFN3 07 · 〇. 4H20 之分析計算 值：C，56·84;Η，4.74;Br, 13.51;F，3·21;Ν， 7·10。實測值：C， 56·91;Η，4.93;Br， 13.23;F，\\312\2d-code\90-01\89112968.ptd Page 318 1283240 V. INSTRUCTIONS (314) 93%) colorless amorphous solid. 1H-NMR (CDCl3) (5 190*^97 (each 3H 'decylamine isomer), 2·〇5-2·62 (m, 2H), 3·58 (d, J = 8.1 Hz, 1H) , 3·77 (m, 1H), 3·86, and 3.89 (each 3H, amidoxime isomer), 3·9 2- 4.64 (m, 5H), 5·24-5·42 (m, 1H), 6·83-7.23 (m, 6H), 7·4 b 7·62 (m, 4H), 7·86-8.09 (m, 3H); MS (ESI) m/z 598 (ΜΗ1), 6 0 0 (ΜΗ3). 4 - [1-[4 - [Ν' -(2 -Bromophenyl)ureido]-3 3-methylphenylethenyl]-(4S)-fluoro-(2S吼· 25N NaOH (6.0 ml) was added to a stirred solution of decylpyridyl methoxybenzoate (440 mg, 〇·74 mmol) in THF (6.0 mL). After stirring at room temperature, the mixture was acidified with 1N EtOAc (EtOAc) (EtOAc) elute Purification on CHCl3 / MeOH (10 / 1) afforded (yield: 80 (229 mg, 53%) as colorless amorphous solid. IR (KBr) 3325, 2972, 1709, 1604, 1 529, 1 252 / cm; l-NMR (DMSO-d6) 5 2· 25 (s, 3H), 2·31 (m, 1H), 3·17 (s, 1H), 3·60 (d, J = 4.7 Hz, 2H), 3.83-4.67 (m, 5H), 5·31-5·51 (m, 1H), 6.97 (t, J = 7.3 Hz, 1H), 7·02- 7.0 9 (m, 5H), 7·33 (t, J = 8.0 Hz, 1H), 7.61 (d, J two 7.8 Hz, 1H), 7.64 (d, J 2·8 Hz, 1H), 7.87 (d, J = 8.3 Hz, 2H), 7·90 (d, J 8.8 Hz, 1H), 8·44-8·65 (m, 2H); MS (ESI), m/z 584 (MH1), 5 86 ( MH3) ; C28H27BrFN3 07 · 〇. 4H20 Analysis calculated: C, 56·84; Η, 4.74; Br, 13.51; F, 3·21; Ν, 7·10. Found: C, 56·91; , 4.93; Br, 13.23; F,

\\312\2d-code\90-01\89112968.ptd 第 319 頁 1283240 五、發明說明（315) 3. 1 5 ; N， 6· 88。關於80 之Na 鹽：C28H27BrFN3 07 · Na · 1 · 8H 2〇 之分析計算值：C，52·64; Η, 4.67; Br，12.51; F, 2·97;Ν， 6.58。實測值：c，53.04; H，4.67; Br, 12.95； F, 3.28； N, 6」1 〇 實施例7 5 4-[l-[4_[N’ - (2 -氯苯基）脲基]一 3一曱基苯基乙醯基]-（2S) -吡咯啶基]甲氧苯曱酸 分 cooh 。丨 H H &amp; 81 4 - ( 2 S-咄洛咬基）甲氧苯甲酸甲酯i鹽 HC, K~^〇-^^-c〇〇Me 在0°C下於4-(1-第三丁氧羰基比咯啶基）甲氧苯 甲酸甲酉旨（2· 0克，5· 9毫莫耳）溶於EtOH(10· 〇毫升）之攪拌 溶液中加入濃HC 1 ( 3 · 0毫升）。使反應混合物在室溫下攪拌 4· 0小時。將混合物於真空中濃縮。收集所產生之固體， 並以£1;01141；2〇洗滌而得4-(28-吼咯啶基）曱氧苯曱酸甲酉旨 HC1鹽（1· 4克，87%)的白色結晶固體。1H_NMR (CDCl3)占j 90-2.2 5 (m，4Η)、3·2 5 -3.45 (m，2Η)、3·88 (s，3Η)、 3.90-4.00 (m, 1H) ^4.25-4.45 (m, 2H) &gt;6.96 (d, J:8.5 Hz， 2H) 、7.95 (d， J=8.5 Hz, 2H)。 4-[1-[4 - [Ν’ -（2 -氯苯基）脲基]一3_甲基苯基乙醯基]—2\\312\2d-code\90-01\89112968.ptd Page 319 1283240 V. Description of invention (315) 3. 1 5 ; N, 6. 88. For the Na salt of 80: C28H27BrFN3 07 · Na · 1 · 8H 2 〇 Analysis calculated: C, 52·64; Η, 4.67; Br, 12.51; F, 2·97; Ν, 6.58. Found: c, 53.04; H, 4.67; Br, 12.95; F, 3.28; N, 6"1 〇 Example 7 5 4-[l-[4_[N' - (2-Chlorophenyl)ureido] A 3-monodecylphenylethyl]-(2S)-pyrrolidinyl]methoxybenzoic acid is a cooh.丨HH &amp; 81 4 - ( 2 S-咄 咬 ) ) methyl methoxybenzoate i salt HC, K~^〇-^^-c〇〇Me at 0 ° C in 4-(1- Tributoxycarbonylpyrrolidyl)methobenzoic acid formazan (2.0 g, 5.9 mmol) dissolved in EtOH (10·ml) in a stirred solution of concentrated HC 1 (3 · 0) ML). The reaction mixture was stirred at room temperature for 4.0 hours. The mixture was concentrated in vacuo. The resulting solid was collected and washed with £1;01141;2 而 to give white crystals of 4-(28-oxaridinyl)phosphonium sulfonate as a HCl salt (1.4 g, 87%). solid. 1H_NMR (CDCl3) accounts for j 90-2.2 5 (m, 4Η), 3·2 5 -3.45 (m, 2Η), 3.88 (s, 3Η), 3.90-4.00 (m, 1H) ^ 4.25-4.45 ( m, 2H) &gt; 6.96 (d, J: 8.5 Hz, 2H), 7.95 (d, J = 8.5 Hz, 2H). 4-[1-[4 - [Ν' -(2-chlorophenyl)ureido]-3-methylphenylethylidene]-2

\\312\2d-code\90-01\89112968.ptd 第320頁 1283240 五、發明說明（316) -吼咯啶基]曱氧苯曱酸甲酯\\312\2d-code\90-01\89112968.ptd Page 320 1283240 V. INSTRUCTIONS (316) - Ethrolidinyl] oxobenzoate

COOMe 在0 C下於4-[(2S)-吡咯啶基]甲氧苯曱酸曱酯HC1鹽 (13j毫克，0.5¾莫耳）、4—[N，—（2-氯苯基）脲基]—3一甲 基苯乙酸_(159耄克’〇·5毫莫耳）、H〇BT(68毫克，〇·5毫莫 耳）、及二乙^胺（27 8毫升’ 2· 〇毫莫耳）溶於THF(5· 0毫升） 及MeC^5· 〇 *升）之攪拌溶液中加入EDC · ΗΠ (1 44毫克， 〇 · 7 5毫莫耳）。使反應混合物在室溫下攪拌丨6小時，並於 i真空中濃縮。將水加至殘留物，並以Et〇Ac萃取。將萃取 以飽和NaHC〇3洗滌，然後於Na2S〇4上乾燥，並於真空中 浪lis °將殘留物經由於矽膠上利用正己院—Et〇Ac (丨：2， v/v)作為洗提液進行管柱層析，純化而得々-[i — H—LN，-(2-氯苯基）脲基]〜3一曱基苯基乙醯基]一2一吼咯啶基]曱氧 苯甲酸甲酯（ 220毫克，82%)之無色油。ih-NMR (CDC13) 5 1.91 及 1.97 (各s，總計 3H)、2·〇〇-2·20 (m，4H)、3.55 - 3.65 (m，4H)、3·87 及 3·89 (各s，總計 3H)、4·10-4.20 (m，2Η)、4·51 (m，ΐΗ)、6·86-7·〇4 (m，6Η)、 7·20-7.53 (m，4Η)、7·89-8·01 (m, 2Η)、8·22 (d， J二8· 3 Ηζ，1Η)。 ’ 於4 - [l-[4-[N’〜（2 -氯苯基）脲基]—3-甲基苯基乙醯 基]-2S -吼咯啶基]曱氧苯曱酸甲酯（220毫克，0· 41毫莫 耳）溶於THF( 8· 0毫升）及MeOΗ(4· 0毫升）之攪拌溶液中加入 IN NaOH(0· 8毫升，〇· 8毫莫耳）。將混合物在70 °C下授祥COOMe at 0 C in 4-[(2S)-pyrrolidinyl]methoxybenzoic acid oxime ester HC1 salt (13j mg, 0.53⁄4 mol), 4-[N,-(2-chlorophenyl)urea Base]-3 monomethylphenylacetic acid _ (159 gram '〇·5 mmol), H〇BT (68 mg, 〇·5 mmol), and diethylamine (27 8 ml ' 2 · Ethyl alcohol (1 44 mg, 〇·7 5 mmol) was added to a stirred solution of THF (5.0 ml) and MeC^5· 〇* liter. The reaction mixture was stirred at room temperature for 6 h and concentrated in vacuo. Water was added to the residue and extracted with EtOAc. The extract was washed with saturated NaHC〇3, then dried on Na2S〇4, and the residue was applied to the silica gel in a vacuum using hexanes-Et〇Ac (丨:2, v/v) as a stripping solution. The column is subjected to column chromatography and purified to obtain 々-[i-H-LN,-(2-chlorophenyl)ureido]~3-mercaptophenylethyl]- 2 - fluorenyl] anthracene A colorless oil of methyl benzoate (220 mg, 82%). Ih-NMR (CDC13) 5 1.91 and 1.97 (each s, total 3H), 2·〇〇-2·20 (m, 4H), 3.55 - 3.65 (m, 4H), 3·87 and 3.89 (each s, total 3H), 4·10-4.20 (m, 2Η), 4·51 (m, ΐΗ), 6·86-7·〇4 (m, 6Η), 7·20-7.53 (m, 4Η) , 7·89-8·01 (m, 2Η), 8.22 (d, J 2·8 3, 1Η). '4-[l-[4-[N'~(2-Chlorophenyl)ureido]-3-methylphenylethenyl]-2S-indolyl]oxobenzoate (220 mg, 0.41 mmol) was added to a stirred solution of THF (8.0 mL) and EtOAc (4.0 mL). Mix the mixture at 70 °C

\\312\2d-code\90-01\89112968.ptd 第321頁 1283240 五、發明說明（317) 24小時。將混合物於真空中濃縮，加入水，並以1 N HC 1中 和。收集所產生之固體，以水洗滌，並於真空中乾燥而得 8 1 ( 22 0毫克，定量）的白色結晶固體。熔點1 22- 1 24 °C ; IR (KBr) 3340 、 1710 、 1685 、 1604 、 1533 、 1511 、 1438/ 公 分；1H-NMR (DMSO-d6) (5 1·81-2·11 (m，4H)、2·18 及 2.20 (各s，總計3Η)、3·45-3.80 (m, 4Η)、3·95-4·05 (m，1H)、4.12 - 4.20 (m，1H)、4·2 卜 4·31 (m, 1H)、 6.99-7·06 (m，5H)、7·26-7·30 (m, 1H)、7·44 (d， J = Hz，1H)、7·62-7.64 (m，1H)、7.85-7.90 (m， 2H) &gt;8.13 (d, J = 6.8 Hz, 1H) &gt; 8.60-8.62 (m, 2H)； MS(FAB)m/z 522 (MH1); C28H28N3 05 C1 ·0·2Η2Ο 之分析計算 值：C， 63· 99 ; H， 5· 45 ; N，7· 99。實測值：C，6 3. 9 0 ; Η, 5· 40 ; Ν，7· 72。 實施例7 6 4 - [1-[4-[Ν’ _(2 -溴苯基）脲基]一 3一曱基苯基乙醯基]一（2S) -咄咯啶基]曱氧苯曱酸\\312\2d-code\90-01\89112968.ptd Page 321 1283240 V. Description of invention (317) 24 hours. The mixture was concentrated in vacuo, water was added and neutralized with 1 N EtOAc. The resulting solid was collected, washed with water and dried in vacuo to give EtOAc (EtOAc) Melting point 1 22- 1 24 °C; IR (KBr) 3340, 1710, 1685, 1604, 1533, 1511, 1438/cm; 1H-NMR (DMSO-d6) (5 1·81-2·11 (m, 4H ), 2·18 and 2.20 (each s, total 3Η), 3·45-3.80 (m, 4Η), 3.95-4·05 (m, 1H), 4.12 - 4.20 (m, 1H), 4· 2 Bu 4·31 (m, 1H), 6.99-7·06 (m, 5H), 7·26-7·30 (m, 1H), 7·44 (d, J = Hz, 1H), 7· 62-7.64 (m,1H), 7.85-7.90 (m, 2H) &gt;8.13 (d, J = 6.8 Hz, 1H) &gt; 8.60-8.62 (m, 2H); MS(FAB)m/z 522 ( MH1); C28H28N3 05 C1 ·0·2Η2Ο Analysis calculated: C, 63· 99 ; H, 5· 45 ; N, 7. 99. Found: C, 6 3. 9 0 ; Η, 5· 40 ; Ν,7·72. Example 7 6 4 - [1-[4-[Ν' _(2-Bromophenyl)ureido]- 3-indolylphenylethyl]-(2S)-fluorene Pyridyl] oxobenzoic acid

4-[1 -[4-[Ν’ _( 2 -演苯基）脲基]一 3一甲基苯基乙醯基]-(2S) -吼洛σ定基]曱氧苯甲酸甲酉旨4-[1 -[4-[Ν' _( 2 -phenyl)ureido]- 3 -methylphenylethyl fluorenyl]-(2S)-indolyl succinyl]

COOMeCOOMe

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第322頁 1283240 五、發明說明（318) 在0°C下於[(2S)-吼咯啶基]曱氧苯甲酸曱酯HC1鹽（135 毫克，0.5毫莫耳）、4-[N’-(2-溴苯基）脲基]一 3-曱基苯 乙酉夂（181¾克’〇·5晕莫耳）、jj〇Bt(68毫克，0.5毫莫 耳）、及三乙胺（278毫升，2·0毫莫耳）溶於THF(5. 0毫升） 及MeCN(5· 0毫升）之攪拌溶液中加入EDC · HC1(144毫克， 0.75¾莫耳）。使反應；合物在室溫下授掉1 6小時，並於 真空中濃縮。將水加至殘留物，並以EtOAc萃取。將萃取 液以飽和N a H C 〇3洗滌，然後於n a2 S 04上乾燥，並於真空中 濃縮。將殘留物經由於矽膠上利用正己烷— EtOAc (1 /2， v / v )作為洗提液進行管柱層析，純化而得4 —[丨-[4 — [ n，— (2-演本基）脈基]-3-甲基苯基乙醯基]-(2S) -吼洛。定基]甲 氧苯曱酸甲酯（290毫克，定量）之無色油。iH — NMR (CDCl3) 占 1.95 及 2·01 (各s，總計 3H)、2·00 - 2.20 (m，4H)、3· 50-3.65 (m，4Η)、3·87 及 3·89 (各s，總計 3Η)、4.10-4· 20 (m， 2Η) 、4·50 (m， 1Η) 、6·85-7.06 (m， 6Η)、 7.24-7·28 (m，1Η)、7·40-7.44 (m，3Η)、7·89-8·16 (m，2 Η )、8 · 1 7 - 8 · 1 8 (m，1 Η)。 於4-[1-[4 - [Ν’ -（2-溴苯基）脲基]-3-曱基苯基乙醯基]Page 322 1283240 V. INSTRUCTIONS (318) In the [(2S)-hydrazinyl] oxabenzoic acid oxime ester HC1 salt (135 mg, 0.5 mmol), 4-[N' at 0 °C -(2-bromophenyl)ureido]- 3-mercaptophenidin (1813⁄4 g '〇·5 halo), jj〇Bt (68 mg, 0.5 mmol), and triethylamine (278 ML, 0.02 mmol, dissolved in THF (5.0 mL) and MeCN (5.0 mL The reaction was allowed to proceed; the mixture was taken at room temperature for 16 hours and concentrated in vacuo. Water was added to the residue and extracted with EtOAc. The extract was washed with saturated NaH.sub.3.sub.3, then dried over EtOAc EtOAc. The residue was subjected to column chromatography using n-hexane- EtOAc (1 /2, v / v) as an eluent, and purified to give 4 -[丨-[4 - [ n, - (2- Benzo)]-3-methylphenylethenyl]-(2S)-吼洛. A colorless oil of methyl methoxybenzoate (290 mg, quantitative). iH — NMR (CDCl3) accounted for 1.95 and 2·01 (each s, total 3H), 2·00 - 2.20 (m, 4H), 3·50-3.65 (m, 4Η), 3·87 and 3.89 ( Each s, total 3Η), 4.10-4· 20 (m, 2Η), 4·50 (m, 1Η), 6.85-7.06 (m, 6Η), 7.24-7·28 (m, 1Η), 7 ·40-7.44 (m, 3 Η), 7·89-8·16 (m, 2 Η ), 8 · 1 7 - 8 · 1 8 (m, 1 Η). 4-[1-[4 - [Ν' -(2-Bromophenyl)ureido]-3-indolylphenylethyl]

-2S-吼咯啶基]曱氧苯甲酸曱酯（2 90毫克，〇· 5毫莫耳）溶 於THF(8. 0毫升）及Me〇H(4· 0毫升）之攪拌溶液中加入ιΝ NaOH( 1 · 0毫升，1 · 〇毫莫耳）。將混合物在7〇 i下攪拌24小 時。將混合物於真空中濃縮，加入水，並以i N HC1中和。 收集所產生之固體，以水洗滌，並於真空中乾燥而得 82(240毫克，85%)的白色結晶固體。熔點！ 25- 1 30 °C ; IR-2S-Pyrridinyl] decyloxybenzoate (2 90 mg, 〇·5 mmol) was dissolved in a stirred solution of THF (8.0 mL) and Me〇H (4.0 mL) Ν NaOH (1 · 0 ml, 1 · 〇 millimol). The mixture was stirred at 7 ° i for 24 hours. The mixture was concentrated in vacuo, water was added and neutralized with EtOAc. The resulting solid was collected, washed with water and dried in vacuo tolululululululu Melting point! 25- 1 30 °C; IR

\\312\2d-code\90-01\89112968.ptd 第323頁 1283240 五、發明說明（319) (KBr) 3340、1604、1529、1 434 /公分；I-NMR (DMS0-d6) (5 1· 80-2· 10 (m，4H)、2· 18 及2· 20 (各3，總計3H) 、3·45-3.80 (m, 4H)、3·95-4·05 (m，1H)、4.15-4.20 (m, 1Η) 、4·25-4·30 (m， 1Η) 、6·94-7·〇6 (m， 5Η)、 7·30-7·34 (m，1H)、7·59-7·62 (m，2H)、7·85-7·9〇 (m，2H)、8·01 (d，J = 8.1 Hz，1H)、8·44 (s，1H)、 8. 62 (s，1H) ; MS(FAB)m/z 566 (M+) ; C28H28N3 05 Br · 0.5H2O 之分析計算值：C，58·44; Η, 5·〇8; N, 7.30。實 測值：C，58. 57 ; H，4· 99 ; N，7· 18。 實施例7 7 4 - [1 - [3-曱基-4-[ Ν’-(2-甲基苯基）脲基]苯基乙醯基] -（2S)-吼咯啶甲氧基]苯甲酸\\312\2d-code\90-01\89112968.ptd Page 323 1283240 V. Description of invention (319) (KBr) 3340, 1604, 1529, 1 434 / cm; I-NMR (DMS0-d6) (5 1· 80-2· 10 (m, 4H), 2· 18 and 2· 20 (each 3, total 3H), 3·45-3.80 (m, 4H), 3·95-4·05 (m, 1H) ), 4.15-4.20 (m, 1Η), 4·25-4·30 (m, 1Η), 6·94-7·〇6 (m, 5Η), 7·30-7·34 (m, 1H) , 7·59-7·62 (m, 2H), 7·85-7·9〇(m, 2H), 8·01 (d, J = 8.1 Hz, 1H), 8.44 (s, 1H) 8. 62 (s, 1H); MS (FAB) m/z 566 (M+); C28H28N3 05 Br · 0.5H2O Analysis calculated: C, 58·44; Η, 5·〇8; N, 7.30. Found: C, 58.57; H, 4·99; N, 7.18. Example 7 7 4 - [1 - [3-indolyl-4-[ Ν'-(2-methylphenyl) Ureido]phenylethenyl]-(2S)-indolyl methoxy]benzoic acid

83 使3 -甲基-4 - [Ν -(2-曱基苯基）脲基]苯乙酸（438毫克， 1· 47毫莫=)、4-[(2S)-咄咯啶甲氧基]苯甲酸甲酯（42〇毫 克，1.79¾ 莫耳）、EDC«HC1(410 毫克，2.14 毫莫耳）、 HOBU 228毫克，1·69毫莫耳）及Et3N(24〇毫升，毫莫 耳）於DMF(5毫升）中之混合物在室溫下攪拌隔夜。將混合 物以40稀釋，並以Et0Ac萃取。將萃取液以鹽水洗滌，於83 3-3-Methyl-4 -[indolyl-(2-mercaptophenyl)ureido]phenylacetic acid (438 mg, 1.47 mmol), 4-[(2S)-indenyl methoxy Methyl benzoate (42 mg, 1.793⁄4 mol), EDC «HC1 (410 mg, 2.14 mmol), HOBU 228 mg, 1.69 mmol) and Et3N (24 ml, millimolar) The mixture in DMF (5 mL) was stirred at room temperature overnight. The mixture was diluted 40 and extracted with EtOAc. Wash the extract with salt water,

NaJO4上乾燥，並蒸發。將殘留物經由於矽膠上 - MeOH(50:l 至 25:1，v/v)作為哚描汸、隹&quot;μ 4 a 3 ， v ’忭局/无徒液進仃官柱層析，純化 而得4-[卜[3-甲基-4-[N，-(2_甲基苯基）脲基]苯基乙醯Dry on NaJO4 and evaporate. The residue was passed through a gelatin-MeOH (50:1 to 25:1, v/v) as a sputum, 隹&quot;μ 4 a 3 , v '忭局/无徒液仃, column chromatography, Purification to give 4-[Bu[3-methyl-4-[N,-(2-methylphenyl)ureido]phenyl hydrazine

89112968.ptd 第324頁 1283240 五、發明說明（320) 基]-(2S) -咄咯啶甲氧基]苯曱酸甲酯（760毫克，定量）之 白色泡沫。111一麗1^(00〇13)(5 1.89(3，311)、1.94一2.14 (m，4H)、2.16 (s，3H)、3·50-3·69 (m，4H)、3·87 (s， 3Η)、4·09-4·17 (m，2Η)、4·42-4·45 (m，1Η)、6·85-7· 02 (m， 6H) 、7·10-7·16 (m， 3H) 、7·5卜7.53 (m， 1H)、 7.62-7.64 (m, 1H) '7.91-7.94 (m, 2H) ； MS (FAB) m/z 516 (MH1)。 於4 - [1 - [3-甲基-4 - [Ν’-(2-甲基苯基）脲基]苯基乙醯 基]-（2S) -吡咯啶甲氧基]苯甲酸曱酯（420毫克，〇· 71毫莫 耳）溶於THF(7毫升）之攪拌溶液中加入〇· 5Ν NaOH(7毫 升），並使反應混合物迴流加熱2小時。於冷卻至室溫後， 將混合物倒入至冰的1 N 1中’並在減壓下收集所產生之 沈澱物。將粗製固體經由自CHC13 —IPE再結晶，純化而得 83 ( 526毫克，69%)的白色結晶粉末。熔點191-193 °C ; l-NMR (DMSO-d6) 6 1·87-2·10 (m，4H)、2·20 (s， 3H)、2· 26 (s，3H)、3· 44-3· 79 (m 系列，總計4H)、 3. 99-4. 4 5 (m 系列，總計3Η)、6· 91 一7. 17 (m 系列，總計 7 Η)、7 · 6 6 - 7 · 6 8 (m，1Η)、7 · 8 0 - 7 · 9 0 (m，3 Η)、8 · 1 9 - 8 · 21 (in, 2H) ^12.62 (br s, 1H)； MS (FAB) m/z 502 (MH1) ; C29H31N3 05 · 1/4H20 之分析計算值：C，68·83 ; H， 6·27; N，8.30。實測值：c，68·81;Η，6.17; Ν，8·23。 實施例7 8 4__[(4S)—氟一卜[4-[Ν’ -（2-甲氧苯基）脲基]-3-曱基苯基乙 醯基]-（2S)-吼咯啶甲氧基]苯曱酸（D〇 1 - 1 437)89112968.ptd Page 324 1283240 V. INSTRUCTION DESCRIPTION (320) A white foam of methyl [-](2S)-indolyl methoxy]benzoate (760 mg, quantitative). 111一丽1^(00〇13)(5 1.89(3,311), 1.94-2.14 (m,4H), 2.16 (s,3H), 3·50-3·69 (m,4H), 3· 87 (s, 3Η), 4·09-4·17 (m, 2Η), 4·42-4·45 (m, 1Η), 6.85-7· 02 (m, 6H), 7·10- 7·16 (m, 3H), 7·5, 7.53 (m, 1H), 7.62-7.64 (m, 1H) '7.91-7.94 (m, 2H); MS (FAB) m/z 516 (MH1). 4-[1-[3-Methyl-4 -[Ν'-(2-methylphenyl)ureido]phenylethenyl]-(2S)-pyrrolidinemethoxy]benzoate decyl ester (420 mg, 〇 71 mmol), a stirred solution of THF (7 mL), EtOAc·············· Pour into 1 N 1 of ice and collect the resulting precipitate under reduced pressure. The crude solid was recrystallized from CHC13-IPE to afford 83 ( 526 mg, 69%) of white crystalline powder. 191-193 °C; l-NMR (DMSO-d6) 6 1·87-2·10 (m, 4H), 2·20 (s, 3H), 2·26 (s, 3H), 3· 44- 3· 79 (m series, total 4H), 3. 99-4. 4 5 (m series, total 3Η), 6·91 a 7.17 (m series, 7 Η), 7 · 6 6 - 7 · 6 8 (m, 1 Η), 7 · 8 0 - 7 · 9 0 (m, 3 Η), 8 · 1 9 - 8 · 21 (in, 2H) ^ 12.62 (br s, 1H); MS (FAB) m/z 502 (MH1); C29H31N3 05 · 1/4H20 Analysis calculated: C, 68·83; H, 6·27; N, 8.30. Found: c,68·81;Η,6.17; Ν,8·23. Example 7 8 4__[(4S)-Fluoro-[4-[Ν'-(2-methoxyphenyl)ureido]-3- Nonylphenylethyl fluorenyl]-(2S)-indolyl methoxy]benzoic acid (D〇1 - 1 437)

89112968.ptd 第325頁 1283240 五、發明說明（321)89112968.ptd Page 325 1283240 V. Description of invention (321)

84 4-[Ν’-（2-甲氧苯基）脲基]- 3-曱基苯基乙酸 於4-胺基-3-曱氧苯基乙酸第三丁酯（1.36克，6. 15毫莫 耳）及三乙胺（170毫升，1.23毫莫耳）溶於THF(3 0毫升）之 攪拌溶液中加入異氰酸2_曱氧苯酯（ 820毫升，6. 15毫莫 耳），並使所產生之混合物攪拌2 7小時。將混合物於真空 中〉農縮至一小體積’並將己烧加至殘留物中而得沈殿物， 利用過濾收集而得4-[ Ν’ - (2 -甲氧苯基）脲基]-3-曱基苯基 乙酸第三丁酯（1 · 74克，76%)的白色結晶物質。熔點 1 57- 1 5 8 °C ; 1-NMR (CDC13) (5 1· 46 (s, 9Η)、2· 30 (s， 3H)、3·50 (s，2H)、3·76 (s，3H)、6·43 (s，1H)、 6.83 (br d, J = 8.4 Hz, 1H) ^6.95 (br d, J-8. 0 Hz, 1H) 、6·98-6·99 (m， 2H) 、7.13 (brs， 1H) 、7·23 (br s，1H)、7·48 (d，J = 8.8 Hz，1H)、8.14 (d，J = 8.4 Hz， 1H); MS (ESI) m/z 371 (MHH)。 •於4 [N -(2-甲氧苯基）脲基]—3—甲基苯基乙酸第三丁酯 (1·32克’3.56耄莫耳）溶於CH2Cl2(15毫升）之攪拌溶液中 加入三氟乙酸（1 0毫升），並使所產生之混合物迴流加執3〇 分鐘。將混合物於真空中濃縮，並加入水以產生沈澱物， 經由過濾將其收集。使粗製固體自E t〇H /己烷再結晶而得84 4-[Ν'-(2-Methoxyphenyl)ureido]-3-mercaptophenylacetic acid in tert-butyl 4-amino-3-indolylphenylacetate (1.36 g, 6.15 To a stirred solution of triethylamine (170 ml, 1.23 mmol) dissolved in THF (30 mL) was added &lt;RTI ID=0.0&gt; And the resulting mixture was stirred for 27 hours. The mixture was condensed to a small volume in a vacuum and added to the residue to obtain a sediment, which was collected by filtration to give 4-[Ν'-(2-methoxyphenyl)ureido]- White crystalline material of tert-butyl 3-mercaptophenylacetate (1 · 74 g, 76%). Melting point 1 57- 1 5 8 ° C ; 1-NMR (CDC13) (5 1 · 46 (s, 9Η), 2· 30 (s, 3H), 3·50 (s, 2H), 3·76 (s , 3H), 6·43 (s, 1H), 6.83 (br d, J = 8.4 Hz, 1H) ^6.95 (br d, J-8. 0 Hz, 1H), 6·98-6·99 (m , 2H), 7.13 (brs, 1H), 7·23 (br s, 1H), 7·48 (d, J = 8.8 Hz, 1H), 8.14 (d, J = 8.4 Hz, 1H); MS (ESI m/z 371 (MHH). • soluble in 4 [N-(2-methoxyphenyl)ureido]-3-methylphenylacetic acid tert-butyl ester (1·32 g '3.56 耄mol) Trifluoroacetic acid (10 ml) was added to a stirred solution of CH.sub.2Cl.sub.2 (15 mL), and the resulting mixture was refluxed for 3 min. The mixture was concentrated in vacuo and water was added to give a precipitate. Collect it. Recrystallize the crude solid from E t〇H / hexane.

\\312\2d-code\90-01\89112968.ptd 第326頁 1283240 五、發明說明（322) 4-[Ν’-（2-曱氧苯基）脲基]-3-曱基苯乙酸（932毫克，83%) 之白色粉末。熔點260-264 °C ; l-NMR (CD30D) (5 2. 30 (s， 3H)、3·55 (s，2H)、4·87 (s，3H)、6·87-6·92 (m，2H) 、6·97-6·99 (m， 2Η) 、7·10-7·24 (m， 2Η) 、7·53-7·58 (m， 1Η) 、8·04 (d， J=7.2 Ηζ， 1H); MS(ESI) m/z 314(Μ+)。 在室溫下於4 - [Ν’-（2-甲氧苯基）脲基]-3-甲基苯乙酸 (336毫克，1.07毫莫耳）、4-[(4S) -氟-（2S)-吡咯啶甲氧 基]苯曱酸甲酯（271毫克，1·〇7毫莫耳）及N，N-二曱胺基吡 啶（130毫克，1·〇7毫莫耳）溶於DMF (10毫升）之攪拌溶液中 加入EDC ·Η01(226：δ克’1.18毫莫耳），並使所產生之混 合物攪拌20小時。將混合物倒入至1 ν HC1水溶液中，並以 EtOAc萃取。將有機層以鹽水洗滌，於無水Na2S〇4上乾燥， 然後於真空中濃縮。使殘留物於矽膠上利用CHCl3-MeOH (10:1)作為洗提液，進行層析而得4-[(4S) -氟-1_[4-[N’-(2-甲氧苯基）脲基]- 3-甲基苯基乙醯基]— (2S)_吼咯 啶甲氧基]苯曱酸甲酯（ 583毫克，99%)之無色非晶形固 體。1H-NMR (CDC13)消旋異構物之混合物，3 2. 05及2. 12 (s，總 a十3H)、2·05-2·61 (in， 2H)、3·55 — 4.73 (in 系列， 13H)、4·51-4·66 (m，2H)、5·26-5·40 (m，1H)、 6. 72-7· 01 (m 系列，8H)、7· 38-8· 13 (m 系列，3H); MS(ESI) m/z 55 0 (MHH)。 在室溫下於4-[ (4S)-氟-1~[4 -[Ν’ -（2-甲氧苯基）脲基] - 3-曱基苯基乙醯基]-（2S) -咄咯啶甲氧基]苯甲酸曱酯\\312\2d-code\90-01\89112968.ptd Page 326 1283240 V. INSTRUCTIONS (322) 4-[Ν'-(2-Phenoxyphenyl)ureido]-3-indolylphenylacetic acid (932 mg, 83%) of a white powder. Melting point 260-264 °C; l-NMR (CD30D) (5 2. 30 (s, 3H), 3·55 (s, 2H), 4·87 (s, 3H), 6.87-6·92 ( m, 2H), 6.97-6·99 (m, 2Η), 7·10-7·24 (m, 2Η), 7·53-7·58 (m, 1Η), 8·04 (d, J=7.2 Ηζ, 1H); MS (ESI) m/z 314 (Μ+). 4 - [Ν'-(2-methoxyphenyl)ureido]-3-methylphenylacetic acid at room temperature (336 mg, 1.07 mmol), methyl 4-[(4S)-fluoro-(2S)-pyrrolidinemethoxy]benzoate (271 mg, 1·〇7 mmol) and N,N - a solution of diammonium pyridine (130 mg, 1 〇 7 mmol) dissolved in DMF (10 ml), EDC · Η01 (226: δ g '1.18 mmol), and produced The mixture was stirred for 20 hours. The mixture was poured with EtOAc EtOAc EtOAc (EtOAc m. -MeOH (10:1) as an eluent and chromatography to give 4-[(4S)-fluoro-1_[4-[N'-(2-methoxyphenyl)ureido]-3-methyl Phenylethyl hydrazide] — (2S) 吼 吼 pyridyl methoxy] benzoic acid methyl ester ( 583克, 99%) of a colorless amorphous solid. 1H-NMR (CDC13) mixture of racemic isomers, 3 2. 05 and 2. 12 (s, total a ten 3H), 2·05-2·61 ( In, 2H), 3·55 — 4.73 (in series, 13H), 4·51-4·66 (m, 2H), 5·26-5·40 (m, 1H), 6. 72-7· 01 (m series, 8H), 7·38-8· 13 (m series, 3H); MS (ESI) m/z 55 0 (MHH). 4-[(4S)-fluoro-1~ at room temperature [4-][Ν--(2-Methoxyphenyl)ureido]-3-nonylphenylethanyl]-(2S)-indolyl methoxy]benzoate oxime ester

89112968.ptd 第327頁 1283240 五、發明說明（323) (557毫克，ι·01毫莫耳）溶於Me〇H_THF(1 ··丨，1〇毫升）之檀 拌溶液中加入1· ON NaOH水溶液（4· 05毫升，4· 05毫莫 耳）’並使所產生之混合物在60 °c下加熱2小時。將混合物 倒入至IN HC1水溶液中，並以EtOAc萃取。將有機層以鹽 水洗務，於無水Na2S〇4上乾燥，然後於真空中濃縮。使殘 留物於矽膠上利用CHC13-MeOH(10:l)作為洗提液，進行層 析而得4 - [(4S)-氟-i-[4-[N，-(2 -曱氧苯基）脲基]-3-甲 基本基乙醯基]-（2S) -吼洛唆甲氧基]苯曱酸84 (492毫 克’ 91%)之無色非晶形固體。1H-NMR (CD3〇D)消旋異構物 之混合物，5 2.96 (s，3H)、2·11-2·45 (m，2H)、 3.64-4.15 (111系列，5H)、3·91 (s， 3H)、4·41-4·45 (m， 1Η)、4·52 - 4·61 (m，1Η)、5·25 - 5·38 (m，1Η)、6·84-7· 10 (m 系列，7H) 、7·54 - 7.5 8 (m， 1H)、7·93 (d， J = 8.8 Hz, 2H) &gt; 8. 02 (d, J=8.8 Hz, 2H) ； MS(ESI) m/z 53 6 (MHH)、5 38 (MHNa+)。 實施例7 9 4 - [(4S) -氟-1-[4 一 [ν’ -（2-甲氧苯基）脲基]苯基乙醯基] -（2S)-咄咯啶甲氧基]苯甲酸（DO 1 -1 438)89112968.ptd Page 327 1283240 V. INSTRUCTIONS (323) (557 mg, ι·01 mmol) dissolved in Me〇H_THF (1 ··丨, 1 〇 ml) in sandalwood solution Add 1·ON NaOH Aqueous solution (4·05 mL, 4·5 mmol) was then allowed to warm at 60 °C for 2 hours. The mixture was poured into aqueous 1N HCl and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na.sub.2, and then concentrated in vacuo. The residue was chromatographed on CHC13-MeOH (10:1) eluted to give 4-[(4S)-fluoro-i-[4-[N,-(2- oxyphenyl) Urea]-3-methylbenzylindenyl]-(2S)-indolyl methoxy]benzoic acid 84 (492 mg '91%) as a colorless amorphous solid. 1H-NMR (CD3〇D) a mixture of racemic isomers, 5 2.96 (s, 3H), 2·11-2·45 (m, 2H), 3.64-4.15 (111 series, 5H), 3.91 (s, 3H), 4·41-4·45 (m, 1Η), 4·52 - 4·61 (m, 1Η), 5·25 - 5·38 (m, 1Η), 6·84-7 · 10 (m series, 7H), 7.54 - 7.5 8 (m, 1H), 7·93 (d, J = 8.8 Hz, 2H) &gt; 8. 02 (d, J = 8.8 Hz, 2H); MS (ESI) m/z 53 6 (MHH), 5 38 (MHNa+). Example 7 9 4 - [(4S)-Fluoro-1-[4-[ν'-(2-methoxyphenyl)ureido]phenylethenyl]-(2S)-indenylpyridylmethoxy Benzoic acid (DO 1 -1 438)

4-[Ν’ -（2-甲氧苯基）脲基]苯基乙酸4-[Ν' -(2-methoxyphenyl)ureido]phenylacetic acid

\\312\2d-code\90-01\89112968.ptd 第328頁 1283240 五、發明說明（324) 於4 -胺基-3-甲氧苯基乙酸乙酯（132克，7.37毫莫耳） 及三乙胺（205毫升，1.47毫莫耳）溶於THF( 20毫升）之攪拌 溶液中加入異氰酸2-曱氧苯酯（980毫升，7.37毫莫耳）， 並使所產生之混合物攪拌2 3小時。將混合物於真空中濃縮 至一小體積’並將己烧加至殘留物中而得沈澱物，將其收 集而得4-[Ν’ - (2 -甲氧苯基）脲基]苯基乙酸乙酯（2. 44克， 定量）的白色結晶物質。熔點1〇7-1〇9。(：；111-關1^(00(：13) 占 1.26 (t， J二7·1 Ηζ， 3Η) 、3·56 (s, 3Η)、3·79 (s， 3Η)、4·15 (q, J = 7.1 Hz, 2Η)、6·82-6·85 (m，1Η)、6· 91-7·00 (m，2H)、7·08 (s，1H)、7·17 (d，J = 8.5 Hz， 2H)、7.27 (d，J = 8.6 Hz, 2H)、7.33 (s，1H)、8·07-8· 10 (m，1H); MS (ESI) m/z 329 (MHH)。 於4-[Ν’-(2-甲氧苯基）脲基]苯基乙酸乙酯（2.22克，6. 78毫莫耳）溶於MeOH(30毫升）之攪拌溶液中加入ι.ομ NaOH 水溶液（1 0 · 2毫升，1 0 · 2毫莫耳），並使所產生之混合物攪 拌隔夜。加入1 N H C1 (水溶液），並將混合物於真空中濃 縮。將水加至殘留物以產生沈殿物，經由過濾將其收集。 使粗製固體自EtOH /己烷再結晶而得4-[Ν’-（2-曱氧苯基） 脲基]苯乙酸之白色粉末（1.87克，92%)。熔點165-168 °C ; UMR (CD30D) 6 2· 30 (s，3Η)、3. 55 (s, 2Η)、 4.87 (s, 3H)、6.87-6.92 (m, 2H)、6·97-6·99 (m, 2Η)、7·10-7·24 (in, 2Η)、7·53 - 7.58 (m，1Η)、8·04 (d，J = 7.2 Hz，1H); MS(ESI) m/z 300 (M+)。 在室溫下於4-[Ν’-（2-甲氧苯基）脲基]苯乙酸（353毫\\312\2d-code\90-01\89112968.ptd Page 328 1283240 V. INSTRUCTIONS (324) Ethyl 4-amino-3-methoxyphenylacetate (132 g, 7.37 mmol) And a solution of triethylamine (205 ml, 1.47 mmol) dissolved in THF (20 ml) was added 2- phenoxyphenyl isocyanate (980 ml, 7.37 mmol) and the resulting mixture Stir for 2 3 hours. The mixture was concentrated to a small volume in vacuo and the residue was added to a residue to give a precipitate which was collected to give 4-[[rho]-(2-methoxyphenyl)ureido]phenylacetic acid. Ethyl ester (2.44 g, quantitative) of white crystalline material. Melting point 1〇7-1〇9. (:; 111- Guan 1^(00(:13) accounted for 1.26 (t, J 2:7 1, 3Η), 3·56 (s, 3Η), 3·79 (s, 3Η), 4·15 (q, J = 7.1 Hz, 2Η), 6·82-6·85 (m, 1Η), 6·91-7·00 (m, 2H), 7·08 (s, 1H), 7·17 ( d, J = 8.5 Hz, 2H), 7.27 (d, J = 8.6 Hz, 2H), 7.33 (s, 1H), 8·07-8· 10 (m, 1H); MS (ESI) m/z 329 (MHH). Add to a stirred solution of ethyl 4-[Ν'-(2-methoxyphenyl)ureido]phenylacetate (2.22 g, 6.78 mmol) in MeOH (30 mL) Ι.ομ NaOH aq. (1 0 · 2 mL, 1 0 2 2 mmol), and the mixture was stirred overnight. 1 EtOAc (aq) was then weighed and the mixture was concentrated in vacuo. Residues were taken to produce a smatter, which was collected by filtration. The crude solid was recrystallized from EtOH / hexane to give white powder of 4-[Ν'-(2-indoxyphenyl)ureido]phenylacetic acid (1.87 g). , 92%). Melting point 165-168 °C; UMR (CD30D) 6 2· 30 (s, 3Η), 3. 55 (s, 2Η), 4.87 (s, 3H), 6.87-6.92 (m, 2H) , 6.97-6·99 (m, 2Η), 7·10-7·24 (in, 2Η), 7·53 - 7.58 (m, 1Η) 8·04 (d, J = 7.2 Hz, 1H); MS (ESI) m/z 300 (M+). 4-[Ν'-(2-methoxyphenyl)ureido]phenylacetic acid at room temperature (353 millimeters

\\312\2d-code\90-01\89112968.ptd 第329頁 1283240 五、發明說明（325) 克，1.18毫莫耳）、4- [(4S) -氟-（2S)-咄咯啶曱氧基]苯甲 酸曱酯（298毫克，1·18毫莫耳）及N，N-二甲胺基吡啶（144 毫克，1.18毫莫耳）溶於DMF( 10毫升）之攪拌溶液中加入 EDC · HC 1 ( 22 6毫克，1. 1 8毫莫耳），並使所產生之混合物 攪拌22小時。將混合物倒入至1 n HC 1水溶液中，並以 EtOAc萃取。將有機層以鹽水洗滌，於無水Na2S04上乾燥， 然後於真空中濃縮。使殘留物於矽膠上利用CHC13-MeOH (10:1)進行層析’而得4-[(4S)-氣-1-[4 - [Ν’ -（2-曱氧苯 基）脲基]苯基乙醯基]-(2S) -吼洛唆甲氧基]苯甲酸甲酯 ( 5 94毫克，94%)之無色非晶形固體。ih-NMR (CDC13)消旋 異構物之混合物，5 2· 05-2· 58 (m系列，2H)、3. 55-4.25 (m 系列，5H)、3·77 (s，3H)、3.87 - 3.9 0 (m，3H) 、4·50 -4.63 (m，2H)、5. 23-5.37 (m，1H)、6·81-6.84 (m，1H)、6·91-6·99 (m，4H)、7·09-7·12 (m，2H)、 7.18-7.26 (m, 2H) ^7.45-7.53 (m, 2H) ^7.91-8.03 (m，2H)、8·10-8.12 (m，1H); MS(ESI) m/z 5 36 (M+ + H)° 在室溫下於4-[(4S)-氟-1-[ 4-[Ν’ -（2-曱氧苯基）脲基] 苯基乙醯基]-(2S) -咄咯啶曱氧基]苯甲酸甲酯（568毫克， 1. 06毫莫耳）溶於MeOH-THF(l:l，10毫升）之攪拌溶液中加 入1.01^仏011水溶液（4.24毫升，4.24毫莫耳），並使所產 生之混合物在6 0 °C下加熱1小時。將混合物倒入至1 N HC 1 水溶液中，並以EtOAc萃取。將有機層以鹽水洗滌，於無 水Na2S04上乾燥，然後於真空中濃縮。使殘留物於矽膠上\\312\2d-code\90-01\89112968.ptd Page 329 1283240 V. INSTRUCTIONS (325) gram, 1.18 millimoles), 4-[(4S)-fluoro-(2S)-pyrrolidine曱 ] ] 298 298 298 298 298 298 298 298 298 298 298 298 298 298 298 298 298 298 298 298 298 298 298 298 298 298 298 298 298 298 298 298 298 298 298 298 298 298 298 298 298 298 298 298 298 298 298 298 EDC · HC 1 (22 6 mg, 1.18 mmol) and the resulting mixture was stirred for 22 hours. The mixture was poured into 1 n aqueous HCl solution and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na. The residue was chromatographed on silica gel using CHC13-MeOH (10:1) to give 4-[(4S)- gas-1-[4 - [Ν'-(2-indolylphenyl)ureido] A colorless amorphous solid of phenyl ethionyl]-(2S)-indolyl methoxy]benzoic acid methyl ester (5 94 mg, 94%). Ih-NMR (CDC13) mixture of racemic isomers, 5 2· 05-2· 58 (m series, 2H), 3. 55-4.25 (m series, 5H), 3·77 (s, 3H), 3.87 - 3.9 0 (m, 3H), 4·50 - 4.63 (m, 2H), 5. 23-5.37 (m, 1H), 6.81-6.84 (m, 1H), 6·91-6·99 (m, 4H), 7·09-7·12 (m, 2H), 7.18-7.26 (m, 2H) ^7.45-7.53 (m, 2H) ^7.91-8.03 (m, 2H), 8·10- 8.12 (m,1H); MS (ESI) m/z 5 36 (M+ + H) ° 4-[(4S)-fluoro-1-[4-[Ν[ Phenyl)ureido] phenylacetamido]-(2S)-indolyloxyl]methyl benzoate (568 mg, 1.06 mmol) dissolved in MeOH-THF (1:1, 10) To a stirred solution of MgSO.sub.1, EtOAc (EtOAc, EtOAc, EtOAc, The mixture was poured into 1 N aqueous HCl solution and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na. Make the residue on the silicone

\\312\2d-code\90-01\89112968.ptd 第 330 頁 1283240 五、發明說明（326) 利用CHCI3 - MeOH(10:l)作為洗提液，進行層析而得85(516 毫克，93%)之無色非晶形固體。iH —NMR (CD3〇D)消旋異構 物之混合物，5 2·12-2.46 (m， 2H)、3·65_4·19 (^系 列，5Η)、3·88 (s，3Η)、4·42-4·45 (m，1Η)、4·52 -4·62 (m，1Η)、5·24-5·39 (m，1Η)、6·85-6·91 (m， 1Η)、6·94-7·03 (m 系列，4Η)、7·14 - 7.19 (m， 2Η)、 7.35-7.40 (m， 2Η)、7·92-7·96 (m，2Η)、8·02 — 8·〇4 (m，1H); MS(ESI) m/z 52l(MHH)、544(MHNa+)。 實施例8 0 4 - [(4S)-氟-l-[4-[Ν’-（2-曱氧苯基）脲基]一3 一曱氧苯基乙 醯基]-（2S)-咄咯啶曱氧基]苯曱酸\\312\2d-code\90-01\89112968.ptd Page 330 1283240 V. INSTRUCTIONS (326) Using CHCI3 - MeOH (10:1) as an eluent, chromatography was carried out to give 85 (516 mg, 93%) of a colorless amorphous solid. iH-NMR (CD3〇D) mixture of racemic isomers, 5 2·12-2.46 (m, 2H), 3·65_4·19 (^ series, 5Η), 3·88 (s, 3Η), 4 ·42-4·45 (m,1Η), 4·52 -4·62 (m,1Η), 5·24-5·39 (m,1Η),6·85-6·91 (m, 1Η) , 6.94-7·03 (m series, 4Η), 7.14 - 7.19 (m, 2Η), 7.35-7.40 (m, 2Η), 7.92-7·96 (m, 2Η), 8· 02 — 8·〇4 (m, 1H); MS (ESI) m/z 52l (MHH), 544 (MHNa+). Example 8 0 4 - [(4S)-Fluoro-l-[4-[Ν'-(2-曱-oxyphenyl)ureido]- 3 methoxyphenylphenyl]-(2S)-咄Pyridyloxy]benzoic acid

4-[Ν’-（2-曱氧苯基）脲基]—3-甲氧苯基乙酸4-[Ν'-(2-曱-oxyphenyl)ureido]-3-methoxyphenylacetic acid

於4 -胺基-3-甲氧苯基乙酸第三丁酯（ι·4ΐ克，5· 94毫莫 耳）及三乙胺（165毫升，1.19毫莫耳）溶於thf (20毫升）之 祝拌浴液中加入異氰酸2 -曱氧苯g旨（790毫升，5.94毫莫 耳）’並使所產生之混合物攪拌4天。將混合物於真空中濃 縮至一小體積，並將己烷加至殘留物中而得沈澱物，將其 收集而得4-[Ν’ -（2~甲氧苯基）脲基]—3-甲氧苯基乙酸第 二丁醋（2 · 0 6克，9 0 %)的白色結晶物質。溶點1 3 2 — 1 3 4 °C ;Tetrabutyl 4-amino-3-methoxyphenylacetate (1·4 g, 5.94 mmol) and triethylamine (165 ml, 1.19 mmol) dissolved in thf (20 ml) To the mixture was added 2-isoxylbenzene isocyanate (790 ml, 5.94 mmol) and the resulting mixture was stirred for 4 days. The mixture was concentrated to a small volume in vacuo, and hexane was added to the residue to give a precipitate which was collected to give 4-[Ν'-(2-methoxyphenyl)ureido]3- A white crystalline material of methoxyacetic acid second butyl vinegar (2 · 0.6 g, 90%). Melting point 1 3 2 - 1 3 4 °C ;

\\312\2d-code\90-01\89112968.ptd 第331頁 1283240 五、發明說明（327) l-NMR (CDC13) 3 1· 46 (s，9H)、3· 50 (s, 2H)、3· 87 (s, 3H)、3·88 (s, 3H)、6·84 (s，ΐΗ)、6·87-6·90 (m，2 Η)、6 · 9 8 - 7 · 0 3 (m，2 Η)、7 · 1 2 (s，1 Η )、7 · 1 6 (s，1H)、8·06 (d，J = 8.4 Hz，1H)、8·13 (dd，J = 、 2.0 Hz, 1H); MS (ESI) m/z 387 (MHH)。 於4-[Ν’-(2-曱氧苯基）脲基]- 3-甲氧苯基乙酸第三丁酯 (2·01克，5.20毫莫耳）溶於CH2C 12( 1 5毫升）之攪拌溶液中 加入三氟乙酸（1 〇毫升），並使所產生之混合物迴流加熱3〇 分鐘。將混合物於真空中濃縮。將水加至殘留物以產生沈 澱物，經由過濾將其收集。使粗製固體自/己烷再結 晶而得4 - [Ν’ -（2-曱氧苯基）脲基]一 3-甲氧苯乙酸之白色粉 末（1· 40 克，82%)。熔點 1 82-1 85 °C ; U-NMR (CD3OD)占 3.55 (s，2H)、3·88 (s，3H)、3·89 (s，3H)、6·80-6·99 (m，5Η)、7·94 (d，J = 8.4 Ηζ，1Η)、8·00 (d， 1 = 7.2 Hz，1H) ; MS(ESI) m/z 300(M+)。 4 - [(4S)-氟-1 - [4-[Ν’ -（2-甲氧笨基）脲基]一3 一甲氧苯基乙 醯基]-(2 S)-吡咯啶甲氧基]苯甲酸甲酯\\312\2d-code\90-01\89112968.ptd Page 331 1283240 V. INSTRUCTIONS (327) l-NMR (CDC13) 3 1· 46 (s, 9H), 3· 50 (s, 2H) , 3· 87 (s, 3H), 3·88 (s, 3H), 6.84 (s, ΐΗ), 6·87-6·90 (m, 2 Η), 6 · 9 8 - 7 · 0 3 (m, 2 Η), 7 · 1 2 (s, 1 Η ), 7 · 1 6 (s, 1H), 8·06 (d, J = 8.4 Hz, 1H), 8·13 (dd, J = , 2.0 Hz, 1H); MS (ESI) m/z 387 (MHH). Tetrabutyl 4-[Ν'-(2-decyloxyphenyl)ureido]-3-methoxyphenylacetate (2.01 g, 5.20 mmol) dissolved in CH2C 12 (15 mL) Trifluoroacetic acid (1 ml) was added to the stirred solution, and the resulting mixture was heated under reflux for 3 min. The mixture was concentrated in vacuo. Water was added to the residue to produce a precipitate which was collected by filtration. The crude solid was recrystallized from /hexane to give white powder (1·40 g, 82%) of 4-[[upsilon]-(2-indoleoxyphenyl)ureido] 3-methoxyphenylacetic acid. Melting point 1 82-1 85 °C; U-NMR (CD3OD) accounts for 3.55 (s, 2H), 3.88 (s, 3H), 3·89 (s, 3H), 6·80-6·99 (m , 5Η), 7·94 (d, J = 8.4 Ηζ, 1Η), 8·00 (d, 1 = 7.2 Hz, 1H); MS (ESI) m/z 300 (M+). 4-([4S)-fluoro-1 - [4-[Ν'-(2-methoxyphenyl)ureido]- 3-methoxyphenylethyl]-(2S)-pyrrolidine methoxy Methyl benzoate

Or C〇2Me 在至溫下於4 - [N -(2-甲氧苯基）脈基]一 3-曱氧苯乙酸 (353毫克’ 1· 07 :莫耳）、4 - [(4S) -氟-（2S)-吼洛淀曱氧 基]苯甲酸甲酯（271毫克，1· 〇7毫莫耳）及N，N-二甲胺基咄 啶（1 31毫克，1 · 07毫莫耳）溶於DMF (1 0毫升）之攪拌溶液中Or C〇2Me at 4 to [N-(2-methoxyphenyl) fluorenyl] 3-oxooxyphenylacetic acid (353 mg '1·07: molar), 4 - [(4S) -Fluoro-(2S)-吼洛盐曱oxy]methyl benzoate (271 mg, 1·〇7 mmol) and N,N-dimethylaminoacridine (1 31 mg, 1 · 07 m Molar) is dissolved in a stirred solution of DMF (10 ml)

89112968.ptd 第332頁 1283240 五、發明說明（328) 加入EDC · HC 1 ( 2 24 毫香，。^ —、 ^ 宅見us毫莫耳），並使所產生之混 δ物稅拌14小時。將混合物倒人·们水溶液中，並以89112968.ptd Page 332 1283240 V. INSTRUCTIONS (328) Add EDC · HC 1 ( 2 24 mil, .^ —, ^ house see us millimolar), and mix the resulting δ substance tax for 14 hours. Pour the mixture into the aqueous solution and

EtOAc萃取。將有機屏u丄 ^ ^ ^ 、_成層以鹽水洗滌，於無水Na2S04上乾燥， 於…工中’辰縮。使殘留物於矽膠上利用CHC13-MeOH (1〇:1)作為^洗提液進行層析，而得4-[(4S)-說-卜[4-[N -(2-甲氧苯基）脲基卜3—甲氧苯基乙醯基]— (2s)—p比咯 淀甲氧基]苯甲酸甲酿（372毫克，61%)之無色非晶形固 體。1H-NMR (CDC13)，消旋異構物之混合物，$ 2 〇4一 2. 57 (m 系列，2H)、3. 58-4· 18 (m 系列，5H)、3· 79 及 3.83 (s，總計3H)、3.86 (s，3H)、3·87 (s，31〇、 4.51 -4·63 (m，2Η)、5·22- 5.3 6 (m，1Η)、6·80-6.89 (m, 3Η)、6·94-7.03 (m，4Η)、7·15-7·25 (m，2Η)、 7.94-8.01 (m， 2Η) 、8·04-8.11 (m， 2H); MS(ESI) m/z 5 6 6 (MHH)。 在室溫下於4-[(4S)-氟-1_[4-[N，—（2—甲氧苯基）脲基;j - 3-甲氧苯基乙醯基]- (2S) -吡咯啶甲氧基]苯曱酸甲酯 (356毫克，0.63毫莫耳）溶於Me〇H-THF(1 : 1，10毫升）之擾 拌溶液中加入1. ON NaOH水溶液（1. 88毫升，1· 88毫莫 耳），並使所產生之混合物在60 °C下加熱2小時。將混合物 倒入至1 N HC 1水溶液中，並以E10Ac萃取。將有機層以鹽 水洗滌，於無水NagSO4上乾燥，然後於真空中濃縮。使殘 留物於矽膠上利用CHCI3-MeOH(10:l)作為洗提液，進行層 析而得標題化合物（D0 1 - 1 444 ) ( 3 35毫克，97%)之無色非晶 形固體。1H-NMR (CD30D)，消旋異構物之混合物，占Extracted with EtOAc. The organic screen u 丄 ^ ^ ^, _ layer was washed with brine, dried on anhydrous Na 2 S04, and condensed in the work. The residue was chromatographed on silica gel using CHC13-MeOH (1::1) as the eluent to give 4-[(4S)-say-b[4-[N-(2-methoxyphenyl) Urea-based 3-methoxyphenylethenyl]-(2s)-p-pyroxymethyloxybenzoic acid (372 mg, 61%) as a colorless amorphous solid. 1H-NMR (CDC13), a mixture of racemic isomers, $ 2 〇 4 - 2. 57 (m series, 2H), 3. 58-4 · 18 (m series, 5H), 3.79 and 3.83 ( s, total 3H), 3.86 (s, 3H), 3·87 (s, 31〇, 4.51 -4·63 (m, 2Η), 5.22- 5.3 6 (m, 1Η), 6·80-6.89 (m, 3Η), 6.94-7.03 (m, 4Η), 7·15-7·25 (m, 2Η), 7.94-8.01 (m, 2Η), 8·04-8.11 (m, 2H); MS (ESI) m/z 5 6 6 (MHH). 4-[(4S)-fluoro-1_[4-[N,-(2-methoxyphenyl)ureido; j - 3 at room temperature Methyl 3-methoxyphenylethylidene]-(2S)-pyrrolidinemethoxy]benzoate (356 mg, 0.63 mmol) dissolved in Me 〇H-THF (1:1,10 mL) 1. Aqueous NaOH aqueous solution (1.88 ml, 1. 88 mmol) was added to the scrambled solution, and the resulting mixture was heated at 60 ° C for 2 hours. The mixture was poured into 1 N HCl 1 aqueous solution. And the extract was extracted with E10Ac. The organic layer was washed with brine, dried over anhydrous NagSO4, and then concentrated in vacuo. The residue was applied to silica gel using CHCI3-MeOH (10:1) as eluent. Title compound (D0 1 - 1 444 ) ( 3 35 mg, 97%) of a colorless amorphous solid. 1H-NMR (CD30D), a mixture of racemic isomers,

W312\2d-code\90-01\89112968.ptd 第333頁 1283240 五、發明說明（329) 2.14-2.48 (m， 2H) 、3·69-4.20 (m 系列，5H) 、3.88 (s， 3H)、3·89 (s，3H)、4·46-4·57 (m，2H)、5·27-5·41 (m, 1Η)、6·79 - 7.04 (m，7Η)、7·90 - 8·02 (m，4H); MS(ESI ) m/z 5 5 2 (M+ + H)。 ’ 實施例8 1 4 - [1-[4- [Ν’ -（2, 6-二氯苯基）脲基]苯基乙醯基i — —惫 -（2S)-吼咯啶基]甲氧苯甲酸W312\2d-code\90-01\89112968.ptd Page 333 1283240 V. INSTRUCTIONS (329) 2.14-2.48 (m, 2H), 3.69-4.20 (m series, 5H), 3.88 (s, 3H) ), 3·89 (s, 3H), 4·46-4·57 (m, 2H), 5·27-5·41 (m, 1Η), 6.79 - 7.04 (m, 7Η), 7· 90 - 8·02 (m, 4H); MS (ESI) m/z 5 5 2 (M+ + H). 'Example 8 1 4 - [1-[4-[Ν' -(2, 6-Dichlorophenyl)ureido]phenylethenyl i - 惫-(2S)-吼 啶 pyridyl] A Oxybenzoic acid

4-[Ν’ -（2, 6 -二氯苯基）脲基]苯基乙酸乙酯4-[Ν' -(2,6-dichlorophenyl)ureido]phenylacetate

在室溫下於4 -胺基苯乙酸乙S旨（1.62克，9.04毫莫耳）及 異氰酸2,6 -二氯苯酯（1·7〇克，9.04毫莫耳）在THF (40毫 升）中之混合物中加入Ε1：3Ν(0·25毫升，1·81毫莫耳）。於 攪拌2小時後，將反應混合物於真空中濃縮。經由加入正 己烷將殘留物研製而得4_[Ν’-（2,6 -二氯苯基）脲基]苯乙 酸乙酯（3. 19克，96%)的無色粉末。熔點1 68- 1 7 0 °C (分 解）；NMR (CDC13) (Π. 25 (t，J = 7. 1 Hz，3H)、3. 56 (s，2H)、4.14(q，J=7.1Hz，2H)、6.50(br，lH)、6· 67 (br， 1H) 、 7·12-7· 52 (m， 7H)。 4-[N’-（2，6 -二氣苯基）脈基]本乙酸4-(Aminophenyl)acetate (1.62 g, 9.04 mmol) and 2,6-dichlorophenyl isocyanate (1·7 g, 9.04 mmol) in THF (at room temperature) Ε1:3Ν (0·25 ml, 1.81 mmol) was added to the mixture in 40 ml). After stirring for 2 hours, the reaction mixture was concentrated in vacuo. The residue was triturated with n-hexane to afford ethyl 4-[[delta]&apos;-(2,6-dichlorophenyl)ureido] phenylacetate (3.19 g, 96%). Melting point 1 68- 1 70 °C (decomposition); NMR (CDC13) (Π. 25 (t, J = 7. 1 Hz, 3H), 3. 56 (s, 2H), 4.14 (q, J = 7.1 Hz, 2H), 6.50 (br, lH), 6·67 (br, 1H), 7·12-7· 52 (m, 7H). 4-[N'-(2,6-di-phenyl) Benzoic acid

\\312\2d-code\90-01\89112968.ptd 第334頁 1283240 五、發明說明（330) 於4-[N -(2，6-二氯苯基）脲基]苯乙酸乙酯（3.19克，8. 69毫莫耳）溶於THF(70毫升）之攪拌溶液中加入〇·25Ν NaOH(70毫升）。於在室溫下攪拌17小時後，將溶劑於真空 中濃縮。經由加入水將殘留物研製而得4—[N，一（ 2, 6 -二氣 苯基）脲基]苯乙酸（2· 44克，82%)之無色粉末。Γ點 2 62-26 3 °C (分解）；W-NMR (DMSO-d6) (5 3· 48 (s，2H)、7. 14 (d，J = 8.3 Hz, 2H)、7·31 (t，&gt;8.3 Hz，1H)、7·37 (d，J = 8.3 Hz，2H)、7·52 (d，J = 8.0 Hz, 2H)、8·18 (s，1H)、8.90 (s，1H)、12·22 (br，1H); MS(ESI) m/z 339 (MH1)、341(MH3)、34 3 (MH5)。 4 - [1-[4-[Ν’-（2, 6 -二氯苯基）脲基]苯基乙醯基]— (4S)-氟 -（2 S)-吡咯啶基]曱氧苯甲酸甲酯\\312\2d-code\90-01\89112968.ptd Page 334 1283240 V. INSTRUCTIONS (330) Ethyl 4-[N-(2,6-dichlorophenyl)ureido]phenylacetate 3.19 g, 8.69 mmoles) of a stirred solution of THF (70 mL) was added 〇·25Ν NaOH (70 mL). After stirring at room temperature for 17 hours, the solvent was concentrated in vacuo. The residue was triturated by the addition of water to give 4-[N,-(2,6-diphenylphenyl)ureido]phenylacetic acid (2.4 g, 82%) as a colorless powder. 2 2 62-26 3 °C (decomposition); W-NMR (DMSO-d6) (5 3· 48 (s, 2H), 7. 14 (d, J = 8.3 Hz, 2H), 7·31 ( t, &gt;8.3 Hz, 1H), 7·37 (d, J = 8.3 Hz, 2H), 7·52 (d, J = 8.0 Hz, 2H), 8·18 (s, 1H), 8.90 (s , 1H), 12·22 (br, 1H); MS (ESI) m/z 339 (MH1), 341 (MH3), 34 3 (MH5). 4 - [1-[4-[Ν'-(2 , 6-dichlorophenyl)ureido]phenylethenyl]-(4S)-fluoro-(2S)-pyrrolidyl]methyloxybenzoate

使4 [N -(2，6-^一氣本基）服基]苯乙酸（268毫克，0.79 毫莫耳）、4-[(2S，4S)-4-氟-2 -咄咯啶基]甲氧苯曱酸甲酯 (200毫克，0·79毫莫耳）、EDC*HC 1(227毫克，1.19毫莫 耳）、HOBT(161毫克，1·19毫莫耳）及Et3N(0.55毫升， 3· 95毫莫耳）於DMF (4毫升）中之混合物在室溫下攪拌1 8小 時。將混合物倒入至冰水中，並以EtOAc萃取。將結合的 萃取液以冰水及鹽水洗滌。於在N a2 S 04上乾燥後，將萃取 液於真空中濃縮。使殘留物於TLC[CHC13 /MeOH (10/1)]4 [N - (2,6-^ a gas base) base] phenylacetic acid (268 mg, 0.79 mmol), 4-[(2S,4S)-4-fluoro-2-pyridridinyl] Methyl methoxybenzoate (200 mg, 0. 79 mmol), EDC*HC 1 (227 mg, 1.19 mmol), HOBT (161 mg, 1.19 mmol) and Et3N (0.55 ml) The mixture in DM (4 mL) was stirred at room temperature for 18 h. The mixture was poured into ice water and extracted with EtOAc. The combined extracts were washed with ice water and brine. After drying on Na 2 S 04, the extract was concentrated in vacuo. Leave the residue in TLC [CHC13 / MeOH (10/1)]

\\312\2d-code\90-01\89112968.ptd 第335頁 1283240 五、發明說明（331) 上純化而得4-[1-[4-[Ν，-（2,6 -二氯苯基）脲基]苯基乙醯 基]-(4S) -氟-（2S)-吼17各啶基]曱氧苯曱酸曱酯（465毫克， 100%)之無色非晶形固體。NMR (CDC13) 5 2· 05-2. 57 (m，2H)、3·60 (d, 2H，J = 3.4 Hz)、3.64-3.8 4 (m， 2H)、3.88 及 3·89 (各s，3H,醯胺異構物）、3·92-4·63 (m, 3Η)、5· 22-5· 38 (m, 1Η)、6· 87 及6. 89 (名 d,各 J 二 7·9 Hz, 2H,醯胺異構物）、7·01-7·17 (m, 6H)、7.28 (m, 2H)、7·36 (br，1H)、7·92 (d, J = 8.8 Hz, 1H)、7· 79 (d，J = 8.8 Hz, 1H); MS(ESI) m/z 574 (MH1)、576 (MH3)、5 78 (MH5)。 於4-[(23,48)-1-[4-[『-（2,6-二氣苯基）脲基]苯基乙 醯基]-4-氟-2 -咄咯啶基]曱氧苯甲酸甲酯（465毫克， 0.809毫莫耳）溶於THF(4 0毫升）之溶液中加入〇. 25N NaOH (40毫升）。於在室溫下攪拌11小時後，將混合物以in HC1 酸化’並以CHCl3-MeOH(10/l)萃取。將結合的萃取液於Na 2S04上乾燥，並於真空中濃縮。使殘留物於TLC[CHC13 / MeOH (10/1)]上純化而得期望化合物（ 340毫克，75%)之無 色非晶形固體。經由加入CHC13、EtOH及乙醚，使無色非 晶形化合物再結晶而得87之無色粉末（128毫克）。熔點 168-172 °C (分解）；IR (KBr) 3340、1711、1685、1604、 1 240、773 / 公分；NMR (DMSO-d6) 5 2· 22-2· 30 (m， 2H)、3·61 (d，J二7.4 Hz，2H)、3·70-4.75 (m，6H)、5· 3 0 - 5.4 9 (m，1H)、7·02-7·18 (m，5H)、7·28 - 7·41 (m， 4Η)、7·52 (dd，J = 8.0、2·9 Ηζ，2Η)、7.86 (m，2Η)、\\312\2d-code\90-01\89112968.ptd Page 335 1283240 V. INSTRUCTIONS (331) Purification of 4-[1-[4-[Ν,-(2,6-dichlorobenzene) A chromoxy amorphous solid of ureido]phenylethyl fluorenyl]-(4S)-fluoro-(2S)-hydrazine 17-pyridyl]phosphonium oxybenzoate (465 mg, 100%). NMR (CDC13) 5 2· 05-2. 57 (m, 2H), 3·60 (d, 2H, J = 3.4 Hz), 3.64-3.8 4 (m, 2H), 3.88 and 3.89 (each s , 3H, guanamine isomers), 3·92-4·63 (m, 3Η), 5·22-5· 38 (m, 1Η), 6·87 and 6.89 (name d, each J II 7·9 Hz, 2H, guanamine isomer), 7·01-7·17 (m, 6H), 7.28 (m, 2H), 7·36 (br, 1H), 7.92 (d, J = 8.8 Hz, 1H), 7·79 (d, J = 8.8 Hz, 1H); MS (ESI) m/z 574 (MH1), 576 (MH3), 5 78 (MH5). 4-[(23,48)-1-[4-[『-(2,6-Diphenylphenyl)ureido]phenylethenyl]-4-fluoro-2-pyridinyl]曱Methyl benzoate (465 mg, 0.809 mmol) was dissolved in THF (40 mL) EtOAc. After stirring at room temperature for 11 hours, the mixture was acidified with &lt;RTI ID=0.0&gt;&gt; The combined extracts were dried over Na2SO4 and concentrated in vacuo. The residue was purified with EtOAc EtOAc EtOAcjHHHHH The colorless amorphous compound was recrystallized by the addition of CHC13, EtOH and diethyl ether to give 87 as a colorless powder (128 mg). Melting point 168-172 °C (decomposition); IR (KBr) 3340, 1711, 1685, 1604, 1 240, 773 / cm; NMR (DMSO-d6) 5 2· 22-2· 30 (m, 2H), 3 ·61 (d, J two 7.4 Hz, 2H), 3.70-4.75 (m, 6H), 5·3 0 - 5.4 9 (m, 1H), 7·02-7·18 (m, 5H), 7·28 - 7·41 (m, 4Η), 7.52 (dd, J = 8.0, 2·9 Ηζ, 2Η), 7.86 (m, 2Η),

\\312\2d-code\90-01\89i12968.ptd 第 336 頁 1283240 五、發明說明（332) 8.29 (br，1H)、9·01 (br，1H)、12·66 (br，1H); MS(ESI) m/z 56 0 (ΜΗ1)、562 (ΜΗ3)、564 (MH5); C27H24 C12FN3 05 · 0· 5H20 之分析計算值：C，56. 95 ； H, 4. 43 ； Cl, 12.45; F，3·34; N，7.38。實測值：C，57.04; H, 4. 34 ； Cl, 12.98； F, 3.27； N, 7.21 〇 實施例8 2 4 - [1-[4 -[Ν’ -（2, 6-二氯苯基）脲基]- 3-甲氧苯基乙醯基] -（4S)-氟-（2S)-啦咯啶基]曱氧苯甲酸\\312\2d-code\90-01\89i12968.ptd Page 336 1283240 V. INSTRUCTIONS (332) 8.29 (br, 1H), 9·01 (br, 1H), 12·66 (br, 1H) ; MS (ESI) m/z 56 0 (ΜΗ1), 562 (ΜΗ3), 564 (MH5); C27H24 C12FN3 05 · 0· 5H20 Analysis calculated: C, 56. 95 ; H, 4. 43 ; Cl, 12.45; F, 3·34; N, 7.38. Found: C, 57.04; H, 4. 34; Cl, 12.98; F, 3.27; N, 7.21 〇 Example 8 2 4 - [1-[4 -[Ν' -(2, 6-dichlorophenyl) Urea]- 3-methoxyphenylethenyl]-(4S)-fluoro-(2S)-lahydropyridyl]nonyloxybenzoic acid

co2h N N 〜 H Η Cl OMe 4-[Ν’-（2, 6 -二氯苯基）脲基]-3-曱氧苯基乙酸第三丁酯Co2h N N ～ H Η Cl OMe 4-[Ν'-(2,6-Dichlorophenyl)ureido]-3-indolyloxyphenylacetic acid tert-butyl ester

OtBu 在室溫下於4 -胺基-3-曱氧苯乙酸第三丁酯（2.15克，9. 04毫莫耳）、異氰酸2 ,6 -二氯苯酯（1.70克，9.04毫莫耳） 在THF(40毫升）中之混合物中加入Et3N(0.25毫升，9.04毫; 莫耳）。於攪拌1 8小時後，將反應混合物於真空中濃縮。 經由加入正己烷將殘留物研製而得4-[『-（2, 6 -二氯笨基） 脲基]-3-甲氧苯乙酸第三丁酯（2. 27克，59%)的無色粉 末。熔點177-181 °C (分解）；UMR (CDC13) (51· 43 (s， 9H)、3·74 (s，2H)、3·83 (s，3H)、6·34 (s，1H) 、6·81 (s， 1H) 、6·84 (d， J:8.3 Hz， 1H) 、7·〇6 (br， 1H)、7·27 (t，J = 8.1 Hz, 1H)、7.39 (d，J = 8.1 Hz,OtBu at room temperature in tert-butyl 4-amino-3-indoxyphenylacetate (2.15 g, 9.04 mmol), 2,6-dichlorophenyl isocyanate (1.70 g, 9.04 m) To a mixture of THF (40 ml) was added Et3N (0.25 mL, 9. After stirring for 18 hours, the reaction mixture was concentrated in vacuo. The residue was triturated by the addition of n-hexane to give the colorlessness of 4-[(-(2,6-dichlorophenyl)ureido]-3-methoxyphenylacetic acid tert-butyl ester (2.77 g, 59%) powder. Melting point 177-181 °C (decomposition); UMR (CDC13) (51·43 (s, 9H), 3.74 (s, 2H), 3·83 (s, 3H), 6·34 (s, 1H) , 6·81 (s, 1H), 6.84 (d, J: 8.3 Hz, 1H), 7·〇6 (br, 1H), 7·27 (t, J = 8.1 Hz, 1H), 7.39 ( d, J = 8.1 Hz,

\\312\2d-code\90-01\89112968.ptd 第337頁 1283240 五、發明說明（333) 2H) 、 8·04 (d， J=8·3 Hz, 1H)。 4 - [N -（2，6-二氣苯基）脲基]一3-甲氧苯乙酸\\312\2d-code\90-01\89112968.ptd Page 337 1283240 V. Description of invention (333) 2H), 8·04 (d, J=8·3 Hz, 1H). 4-[N-(2,6-diphenyl)ureido]-3-methoxyphenylacetic acid

在室溫下於4-[Ν’-（2, 6 -二氯苯基）脲基]—3-甲氧苯乙酸 第二丁酯（2·27克’5.34毫莫耳）溶於cH2Cl2(50e升）之攪 拌溶液中加入TF A ( 2 0毫升）。於攪拌2小時後，將混合物於 真空中濃縮。經由加入水將殘留物研製而得4 — [ N，-(2，6 -二氯苯基）脲基]-3-甲氧苯乙酸u. 5〇克，76%)之無 色粉末。熔點 24 6- 249。〇(分解）；4-麗1^(0頁30-(16)(53.49 (s，2H)、3.88 (s，3H)、6·75 (d，J = 8.3 Hz，1H)、 6·93 (s，1H)、7·30 (t，J = 7.8 Hz, 1H)、7·52 (d， J:8.0 Hz, 2H)、7.97 (d，J = 8.〇 Hz, 1H)、8·40 (s， 1H)、8·86 (s，1H)、12.23 (br，1H); MS(ESI) m/z 369 (MH1)、371 (MH3)、37 3 (MH5)。 4- [1 - [4 - [Ν’ -（2, 6 -二氯苯基）脲基]一3 一甲氧苯基乙醯 基]-(4S) -氟-（2S)-咄咯啶基]甲氧苯甲酸甲酯Dibutyl 2-[Ν'-(2,6-dichlorophenyl)ureido]-3-methoxybenzoate (2·27 g '5.34 mmol) dissolved in cH 2 Cl 2 at room temperature ( To a stirred solution of 50 liters) was added TF A (20 mL). After stirring for 2 hours, the mixture was concentrated in vacuo. The residue was triturated with water to give 4-[N,-(2,6-dichlorophenyl)ureido]-3-methoxyphenylacetic acid (5 g, 76%) as a colorless powder. Melting point 24 6-249. 〇(decomposition); 4-Li 1^(0 pages 30-(16)(53.49 (s, 2H), 3.88 (s, 3H), 6.75 (d, J = 8.3 Hz, 1H), 6.93 (s, 1H), 7·30 (t, J = 7.8 Hz, 1H), 7·52 (d, J: 8.0 Hz, 2H), 7.97 (d, J = 8.〇Hz, 1H), 8· 40 (s, 1H), 8·86 (s, 1H), 12.23 (br, 1H); MS (ESI) m/z 369 (MH1), 371 (MH3), 37 3 (MH5). 4- [1 - [4 - [Ν' -(2,6-Dichlorophenyl)ureido]- 3-methoxyphenylethyl]-(4S)-fluoro-(2S)-indenylpyridyl]methoxy Methyl benzoate

使4-[Ν’ -（2, 6 -二氯苯基）脲基]一3-甲氧苯乙酸（288毫 克’0.78毫莫耳）、4-[(2S，4S) - 4-氟-2 -咄咯啶基]曱氧苯 甲酸甲酯（200毫克，0.79毫莫耳）、EDC*HC 1(227毫克， 1.19 毫莫耳）、HOBT(161 毫克，1.19 毫莫耳）及Et3N(0.554-[Ν' -(2,6-Dichlorophenyl)ureido]-3-methoxyphenylacetic acid (288 mg '0.78 mmol), 4-[(2S,4S)-4-fluoro- 2-Chloropyryl]methyl benzoate (200 mg, 0.79 mmol), EDC*HC 1 (227 mg, 1.19 mmol), HOBT (161 mg, 1.19 mmol) and Et3N ( 0.55

\\312\2d-code\90-01\89112968.ptd 第338頁 1283240 五、發明說明（334) 宅升’3.95毫莫耳）於])μ f (4毫升）中之混合物在室溫下授 拌1 8小時。將混合物倒入至冰水中，並以Et〇Ac萃取。將 結合的萃取液以冰水及鹽水洗滌。於在Na2s〇4上乾燥後， 將萃取液於真空中濃縮。使殘留物於矽膠[5〇克，CHCl3 /\\312\2d-code\90-01\89112968.ptd Page 338 1283240 V. INSTRUCTIONS (334) ZF's '3.95 mM' in a mixture of μ) (4 ml) at room temperature Mix for 18 hours. The mixture was poured into ice water and extracted with Et EtOAc. The combined extracts were washed with ice water and brine. After drying over Na2s(R)4, the extract was concentrated in vacuo. Make the residue in silicone [5 gram, CHCl3 /

MeOH (40/1)]上進行層析，而得 4—[卜[4 - [N，-（2,6-二氯 苯基）脲基]-3-曱氧苯基乙醯基]_(4S) -氟-(2S) -吼咯啶 基]甲氧苯曱酸甲酯（ 530毫克，100%)之無色非晶形固體。 'H-NMR (CDC13) (5 2.03-2.62 (m, 2H) ^3.61 (d, 2H, J = 4.7 Hz)、3·62-3·66 (m, 2H)、3·73 及 3·77 (各s，3H， 酿胺異構物）、3·78-3.85 (m，1H)、3·87 及 3·88 (各s， 3H，醯胺異構物）、3·95-4·63 (m，4H)、5·22-5·36 (m， 1H)、6·82 (s，1H)、6·88 (d，J = 8.8 Hz，1H)、6·95 (d，J = 8.8Hz，2H)、7·14-7·25 (m，1H)、7·38 (d，J = 8· 1 Hz, 2H)、7.94-8.10 (m, 3H); MS(ESI) m/z 604 (MH1)、60 6 (MH3)、608 (MH5)。 於4-[1-[4 - [Ν’-（2, 6 -二氯苯基）脲基]- 3-甲氧苯基乙 醯基]-（4S) -氟-（2S) -咄咯啶基]甲氧苯甲酸甲酯（ 530毫 克，0.78毫莫耳）溶於THF(40毫升）之溶液中加入〇.25Ν NaOH(40毫升）。於在室溫下攪拌11小時後，將混合物以u 11(：1酸化，並以(：11(：13-^^011(10/1)萃取。將結合的萃取液 於Na2S04上乾燥，並於真空中濃縮。使殘留物於Tlc [CHCl3/MeOH (10/1)]上純化而得 88 (420 毫克，75%)之無 色非晶形固體。熔點1 62- 1 68 °〇(分解）；11{(〇1') 3346、 2974、1709、1604、1533、1254 /公分；ih-NMR (DMS0-Chromatography on MeOH (40/1)] gave 4-[Bu[4-[N,-(2,6-dichlorophenyl)ureido]-3-oxophenylphenyl]] (4S)-Fluoro-(2S)-decalidyl]methyl methoxybenzoate (530 mg, 100%) as a colorless amorphous solid. 'H-NMR (CDC13) (5 2.03-2.62 (m, 2H) ^3.61 (d, 2H, J = 4.7 Hz), 3·62-3·66 (m, 2H), 3.73 and 3.77 (each s, 3H, amine-isomers), 3.78-3.85 (m, 1H), 3·87 and 3.88 (each s, 3H, guanamine isomer), 3·95-4· 63 (m, 4H), 5·22-5·36 (m, 1H), 6·82 (s, 1H), 6.88 (d, J = 8.8 Hz, 1H), 6.95 (d, J = 8.8 Hz, 2H), 7·14-7·25 (m, 1H), 7·38 (d, J = 8·1 Hz, 2H), 7.94-8.10 (m, 3H); MS(ESI) m /z 604 (MH1), 60 6 (MH3), 608 (MH5). 4-[1-[4 - [Ν'-(2, 6-Dichlorophenyl)ureido]-3-methoxybenzene Methyl hydrazide]-(4S)-fluoro-(2S)-decalidyl]methyl methoxybenzoate (530 mg, 0.78 mmol) dissolved in THF (40 mL) NaOH (40 ml). After stirring at room temperature for 11 hours, the mixture was acidified with u 11 (: 1) and extracted with (: 11 (: 13-^^ 011 (10/1). The residue was dried over EtOAc (EtOAc)EtOAc. °〇(decomposition) 11 {(〇1 ') 3346, 2974,1709,1604,1533,1254 / cm; ih-NMR (DMS0-

89112968.ptd 第339頁 1283240 五、發明說明（335) d6) 5 1.98-2·36 (m，2H)、3.58 (s，2H)、3.78-3.95 (m， 6H) 、4·02-4.68 (m， 2H) 、5·31-5·50 (m， 1H)、 6·7 卜 7·09 (m，4Η)、7·31 (t，J=：7.8 Ηζ，1Η)、7·53 (d，J = 8.1 Hz，2H)、7·87 (d，J = 8.1 Hz，2H)、7.88-8· 00 (m，1H)、8.30-8.40 (m，1H)、8·89 (s，1H); MS(ESI) m/z 590 (M+ + 1)、592(MH3)、594(MH5); C28H26C13FN4 06 · 1. 5H20 之分析計算值：C，54. 47 ； H, 4.73； F, 3. 08 ； N, 6.81 0 實測值：C，54.53; H， 4. 49 ； F，2. 93 ； N, 6.65° 實施例83 4-[(23,43)-卜[4-[^-（2,6-二氣苯基）脲基]-3-甲基苯基 乙醯基]-4-氟-2 -毗咯啶基]甲氧苯甲酸89112968.ptd Page 339 1283240 V. INSTRUCTIONS (335) d6) 5 1.98-2·36 (m, 2H), 3.58 (s, 2H), 3.78-3.95 (m, 6H), 4·02-4.68 ( m, 2H), 5·31-5·50 (m, 1H), 6·7 Bu 7·09 (m, 4Η), 7·31 (t, J=: 7.8 Ηζ, 1Η), 7·53 ( d, J = 8.1 Hz, 2H), 7·87 (d, J = 8.1 Hz, 2H), 7.88-8· 00 (m, 1H), 8.30-8.40 (m, 1H), 8·89 (s, 1H); MS (ESI) m/z 590 (M+ + 1), 592 (MH3), 594 (MH5); C28H26C13FN4 06 · 1. 5H20 Analysis calculated: C, 54.47; H, 4.73; F, 3. 08 ; N, 6.81 0 Measured value: C, 54.53; H, 4. 49 ; F, 2.93 ; N, 6.65° Example 83 4-[(23,43)-卜[4-[^- (2,6-diphenyl)ureido]-3-methylphenylethenyl]-4-fluoro-2-pyridinyl]methoxybenzoic acid

4-[N，-（2, 6-二氣苯基）脲基]-3-曱基苯基乙酸第三丁酉旨4-[N,-(2,6-diphenylphenyl)ureido]-3-indolylphenylacetic acid tert-butyl

在室溫下於4 -胺基-3-甲基苯乙酸第三丁酯（1·88克’8· 51毫莫耳）、異氰酸2, 6 -二氯苯酯（1. 60克，8· 51毫莫耳） 在THF(40毫升）中之混合物中加入Et3N(0. 24毫升，1· 70毫 莫耳）。於攪拌3小時後，將反應混合物於真空中濃縮。經 由加入正己烷將殘留物研製而得4_[N，- (2, 6_二氯苯基）脲 基]-3-甲基苯乙酸第三丁酯（2.58克，74%)的無色粉末。T-butyl 4-amino-3-methylphenylacetate (1·88 g '8·51 mmol), 2,6-dichlorophenyl isocyanate (1. 60 g) at room temperature Et3N (0.24 ml, 1.70 mmol) was added to a mixture of THF (40 mL). After stirring for 3 hours, the reaction mixture was concentrated in vacuo. The residue was triturated with n-hexane to afford 4-[N,-(2,6-dichlorophenyl)ureido]-3-methylphenylacetic acid tert-butyl ester (2.58 g, 74%).

89112968.ptd 第340頁 1283240 五、發明說明（336) 熔點24 3-244 °C (分解）；〗Η-NMR (CDC13) (5 1. 45 (s，9H) 2· 30 (s，3H)、3· 49 (s，2H)、6· 2 4 (s，2H)、7·’ 12-7·16 (m，3H)、7·35 (d，J = 8.3 Hz，2H)、7·5ΐ (d J=7.8 Hz, 1H) ° ' 4-[Ν’ -（2，6-二氯笨基）脲基]- 3-甲基苯乙酸89112968.ptd Page 340 1283240 V. INSTRUCTIONS (336) Melting point 24 3-244 °C (decomposition); Η-NMR (CDC13) (5 1. 45 (s, 9H) 2· 30 (s, 3H) , 3· 49 (s, 2H), 6· 2 4 (s, 2H), 7·' 12-7·16 (m, 3H), 7·35 (d, J = 8.3 Hz, 2H), 7· 5ΐ (d J=7.8 Hz, 1H) ° ' 4-[Ν' -(2,6-Dichlorophenyl)ureido]-3-methylphenylacetic acid

在室溫下於4-[Ν’ - (2, 6-二氣苯基）脲基]—3—甲基苯乙酸 第三丁酯（2. 58克，6· 30毫莫耳）溶於CH2C12 (50毫升）之攪 拌溶液中加入TFA( 20毫升）。於攪拌2小時後，將混合物於 真空中濃縮。經由加入水將殘留物研製而得4-[N，-(2, 6-二氯苯基）脲基]-3 -曱基苯乙酸（2. 12克，95%)之無 色粉末。熔點 274- 283 1(分解）；11!-麗1^(0河30-(16)6 2.24 (s， 3H) 、3·46 (s， 2H) 、7·00 (d， J=8.6 Hz, 1H)、 7.06 (s，1H)、7·30 (t，J=7.8 Hz，1H)、7·52 (d， J = 8.3 Hz, 2H)、7·65 (d，J二8·2 Hz，1H)、8·12 (s， 1H)、8.50 (s，1H)、12·22 (br，1H); MS(ESI) m/z 353 (MH1)、3 55 (MH3)、3 57(MH5)。 4 - [1 - [4 - [Ν’ -（2，6 -二氯苯基）脲基]- 3-甲基苯基乙醯 基]-（4 S )-氟-(28)-吼咯啶基]曱氧苯曱酸曱酯Dissolved in tert-butyl 4-[Ν' - (2,6-diphenylphenyl)ureido]-3-methylphenylacetate (2. 58 g, 6.3 mmol) at room temperature TCA (20 ml) was added to a stirred solution of CH2C12 (50 mL). After stirring for 2 hours, the mixture was concentrated in vacuo. The residue was triturated with water to give 4-[N,-(2,6-dichlorophenyl)ureido]-3 -mercaptophenylacetic acid (2.22 g, 95%) as a coloured powder. Melting point 274- 283 1 (decomposition); 11!-丽1^(0河30-(16)6 2.24 (s, 3H), 3·46 (s, 2H), 7·00 (d, J=8.6 Hz , 1H), 7.06 (s, 1H), 7·30 (t, J = 7.8 Hz, 1H), 7·52 (d, J = 8.3 Hz, 2H), 7·65 (d, J 2:8) Hz, 1H), 8·12 (s, 1H), 8.50 (s, 1H), 12·22 (br, 1H); MS (ESI) m/z 353 (MH1), 3 55 (MH3), 3 57 (MH5) 4 - [1 - [4 - [Ν' -(2,6-Dichlorophenyl)ureido]-3-methylphenylethenyl]-(4 S )-fluoro-(28 )--pyridinyl]nonyl benzoate

使4-[Ν’ -（2, 6 -二氯笨基）脲基]—3一曱基苯乙酸（181毫4-[Ν' -(2,6-Dichlorophenyl)ureido]-3-mercaptophenylacetic acid (181 mM)

\\312\2d-code\90-01\89112968.ptd 第341頁 1283240 五、發明說明（337) 克’0.51毫莫耳）、4 - [(2S，4S) - 4-氟-2 -吼洛咬基]甲氧苯 甲酸曱酯（130毫克，〇· 51毫莫耳）、EDC · HC1(147毫克， 0.77¾ 莫耳）、h〇BT(104 毫克，0.77 毫莫耳）及 Et3N(0.35 毫升’ 2.55¾莫耳）於DMF (4毫升）中之混合物在室溫下揽 拌1 8小時。將混合物倒入至冰水中，並以Et〇Ac萃取。將 結合的萃取液以冰水及鹽水洗滌。於在Na2s〇4上乾燥後， 將萃取液於真空中濃縮。使殘留物於TLC[CHC13 /MeOH (2 0/1)]上純化而得4-[i-[4-[N，-（2, 6-二氯苯基）脲 基]-3-曱基苯基乙醯基]-(4S) -氟-(2S) -啦咯啶基]甲氧苯 曱酸甲酯（ 28 3毫克，94%)之無色非晶形固體。iH-NMR (CDC13) 5 1· 95-2· 61 (m，3H)、3. 55 (br, 2H)、3. 67 -3.81 (m， 2H) 、3·87 (s， 6H) 、3.89-4.68 (m, 2H) 、5· 23-5.4 3 (m, 1Η) &gt;6.81-7.10 (m, 6H) ^7.13-7.43 (m, 3H)、7· 56 (br， 1H，其中一個異構物）、7· 73 (br，1H， 其中一個異構物）、7· 89 -8. 0 0 (m，2H) ; MS(ESI) m/z 588 (MH1)、590 (MH3)、592 (MH5)。 於4 - [l-[4 - [Ν’ -（2, 6-二氣苯基）脲基]-3-甲基苯基乙醯 基]-(4S) -氟-（2S)-吼咯啶基]甲氧苯甲酸曱酯（283毫克， 〇· 48毫莫耳）溶於THF(20毫升）之溶液中加入〇· 25Ν NaOH (20毫升）。於在室溫下攪拌丨丨小時後，將混合物以Et〇Ac 萃取。將其餘的水層以IN HC1酸化，並以EtOAc萃取。將 結合的萃取液於Na2S04上乾燥，並於真空中濃縮。使殘留 物於几(：[(：11(：13//^6〇11(20/1)]上得89 (450 毫克，67%)之淡 棕色非晶形固體。熔點1 74- 1 8 0 °C (分解）；IR (KBr)\\312\2d-code\90-01\89112968.ptd Page 341 1283240 V. Description of invention (337) gram '0.51 millimolar), 4 - [(2S, 4S) - 4-fluoro-2 - 吼Ethyl methoxybenzoate (130 mg, 〇·51 mmol), EDC · HC1 (147 mg, 0.773⁄4 mol), h〇BT (104 mg, 0.77 mmol) and Et3N ( A mixture of 0.35 ml of ' 2.553⁄4 mol) in DMF (4 ml) was stirred at room temperature for 18 hours. The mixture was poured into ice water and extracted with Et EtOAc. The combined extracts were washed with ice water and brine. After drying over Na2s(R)4, the extract was concentrated in vacuo. The residue was purified on TLC [CHC13 /MeOH (2 0/1)] to give 4-[i-[4-[N,-(2,6-dichlorophenyl)ureido]-3-indolyl A colorless amorphous solid of methyl phenyl ethionyl]-(4S)-fluoro-(2S)-lahydropyridinyl]methoxybenzoate (28 3 mg, 94%). iH-NMR (CDC13) 5 1· 95-2· 61 (m, 3H), 3. 55 (br, 2H), 3. 67 -3.81 (m, 2H), 3·87 (s, 6H), 3.89 -4.68 (m, 2H), 5· 23-5.4 3 (m, 1Η) &gt;6.81-7.10 (m, 6H) ^7.13-7.43 (m, 3H), 7· 56 (br, 1H, one of which is different Structure), 7·73 (br, 1H, one of the isomers), 7·89 -8. 0 0 (m, 2H); MS (ESI) m/z 588 (MH1), 590 (MH3), 592 (MH5). 4-[l-[4 - [Ν' -(2, 6-Diphenyl)ureido]-3-methylphenylethenyl]-(4S)-fluoro-(2S)-fluorene To a solution of hydrazinyl methoxybenzoate (283 mg, 〇·48 mmol) in THF (20 mL) was added EtOAc EtOAc (20 mL). After stirring at room temperature for a few hours, the mixture was extracted with Et 〇Ac. The remaining aqueous layer was acidified with EtOAc and extracted with EtOAc. The combined extracts were dried over Na2SO4 and concentrated in vacuo. The residue was obtained as a light brown amorphous solid of 89 (450 mg, 67%). °C (decomposition); IR (KBr)

\\312\2d-code\90-01\89112968.ptd 第342頁 1283240 五、發明說明（338) 3330、3288、1711、1685、1604、1512、1242 / 公分；1 H-NMR (DMS〇-d6) δ 2.24 (m, 3H) -3.61 (d, 2H, J-6.1 H z )、3 · 7 2 - 4 · 6 8 ( m，7 H )、5 · 3 0 - 5 · 5 0 ( m，1 H )、6 · 9 7 - 7 · 20 (m，4H)、7·29 - 7.68 (m, 5H)、7·87 (m，2H)、 8.10-8.95 (m，1H)、12·65 (br，1H); MS(ESI) m/z 574(MH1)、5 76 (MH3)、578(MH5) ; C28H26C12FN3 05 · 0· 5H20 之分析計算值：C，57.6 4; H，4.66; Cl，12.15; F， 3. 26 ; N， 7. 20。實測值：C，57. 37 ; H，4. 44 ; Cl， 12. 64 ; F, 3. 23 ; N, 7· 25 。 實施例8 4 4-[1 - [3 -氯-4- [Ν’ -（2-甲基苯基）脲基]苯基乙醯基]一（4s) -氟-（2 S)-吼咯啶基]曱氧苯甲酸\\312\2d-code\90-01\89112968.ptd Page 342 1283240 V. Description of invention (338) 3330, 3288, 1711, 1685, 1604, 1512, 1242 / cm; 1 H-NMR (DMS〇- D6) δ 2.24 (m, 3H) -3.61 (d, 2H, J-6.1 H z ), 3 · 7 2 - 4 · 6 8 ( m,7 H ), 5 · 3 0 - 5 · 5 0 ( m , 1 H ), 6 · 9 7 - 7 · 20 (m, 4H), 7.29 - 7.68 (m, 5H), 7·87 (m, 2H), 8.10-8.95 (m, 1H), 12· </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; Cl, 12.15; F, 3. 26 ; N, 7. 20. Found: C, 57. 37; H, 4. 44; Cl, 12. 64; F, 3. 23 ; N, 7· 25 . Example 8 4 4-[1-[3-Chloro-4-[Ν'-(2-methylphenyl)ureido]phenylethenyl]-(4s)-fluoro-(2S)-吼Pyridyl]oxobenzoic acid

FF

Me H H CI 90 3-氯苯乙酸甲酉旨Me H H CI 90 3-chlorophenylacetate

在室溫下於3-氯苯乙酸（21.76克，127.6毫莫耳）溶於二 氯乙烧（100毫升）之撥拌溶液中加入MeOH(15.6毫升，383 毫莫耳）及IS 04 ( 1毫升）。於攪:拌2 0分鐘後，將混合物在§ 〇 C下加熱2小時。將反應混合物倒入至冰水中，並以c {{C 1 3 萃取，。將結合的萃取液以NaHC〇3水溶液及鹽水洗滌。於在 N S 〇4上乾燥後，將萃取液於真空中濃縮，而得3 —氯苯乙MeOH (15.6 ml, 383 mmol) and IS 04 (1) were added to a stirred solution of 3-chlorophenylacetic acid (21.76 g, 127.6 mmol) dissolved in dichloroethane (100 mL) at room temperature. ML). After stirring: After mixing for 20 minutes, the mixture was heated at § 〇 C for 2 hours. The reaction mixture was poured into ice water and extracted with c{{C13. The combined extracts were washed with a NaHC 3 aqueous solution and brine. After drying on N S 〇 4, the extract is concentrated in vacuo to give 3-chlorobenzene.

\\312\2d-code\90-01\89112968.ptd 第343頁 1283240 五、發明說明（339) 酸曱酯（25· 4 克，1 〇〇%)的無色油。1H — NMR (CDCl3) 5 3· 6〇 (s， 2H) 、3.70 (s， 3H) 、7.15〜7.26 (m， 4H)。 3 -氯-4 -硝基苯乙酸甲酉旨 o2n\\312\2d-code\90-01\89112968.ptd Page 343 1283240 V. INSTRUCTIONS (339) A colorless oil of bismuth ester (25·4 g, 1 〇〇%). 1H - NMR (CDCl3) 5 3· 6〇 (s, 2H), 3.70 (s, 3H), 7.15 to 7.26 (m, 4H). 3-chloro-4-nitrophenylacetic acid formazan o2n

在0°C下於3 -氯苯乙酸甲酯（25·4克，128毫莫耳）在11230 J44毫升）中之攪拌混合物中加入ΗΝ〇3(5· 5毫升，138毫莫 耳）。使反應混合物於4小時内逐漸升溫至室溫。將反應混 合物倒入至冰水中，並以Et OAc萃取。將結合的萃取液以 NaHC〇3水溶液及鹽水洗滌。於在Na2S〇4上乾燥後，將萃取 液於真空中濃縮。使殘留物於矽膠[1公斤，正己烧/ EtOAc(40/l)]上進行層析，而得3 —氯_4_硝基苯乙酸曱酯 (11· 4 克，36%)之黃色油。NMR (CDC13) 33· 69 (s， 2H)、3·74 (s，3H)、7·33 (dd，J = 8.3、1.5 Hz，1H)、 7.49 (d，J=1.5 Hz，1H)、7·87 (d，J = 8.3 Hz，1H)。 4-胺基-3-氯苯乙酸甲酯To a stirred mixture of methyl 3-chlorophenylacetate (25. 4 g, 128 mmol) in 11230 J 44 ml) was added EtOAc (5·5 mL, 138 mM). The reaction mixture was gradually warmed to room temperature over 4 hours. The reaction mixture was poured into ice water and extracted with EtOAc. The combined extracts were washed with a NaHC 3 aqueous solution and brine. After drying over Na 2 S 〇 4, the extract was concentrated in vacuo. The residue was chromatographed on silica gel (1 kg, hexanes / EtOAc (40/l)) to give the crude oil of 3-chloro- 4- nitrophenylacetate (11·4 g, 36%) . NMR (CDC13) 33· 69 (s, 2H), 3·74 (s, 3H), 7·33 (dd, J = 8.3, 1.5 Hz, 1H), 7.49 (d, J = 1.5 Hz, 1H), 7·87 (d, J = 8.3 Hz, 1H). Methyl 4-amino-3-chlorophenylacetate

使3-氯-4-硝基苯乙酸甲酯（ι〇·9克，47· 5毫莫耳）、還Methyl 3-chloro-4-nitrophenylacetate (ι〇·9 g, 47·5 mmol),

原鐵粉（8. 58 克，1 53· 6 毫莫耳）、Ac0Na · 3Η20(6· 05 克， 44.5 毫莫耳）及AcOH(17.6 毫升）於 Me〇H/H20(l 0 0/ 40 0 毫升） 中之混合物在11 〇 °C下加熱1小時。於冷卻至室溫後，使反 應混合物過濾通過矽藻土，並以Me〇H洗滌濾餅。將結合的Raw iron powder (8. 58 g, 1 53·6 mmol), Ac0Na · 3Η20 (6·05 g, 44.5 mmol) and AcOH (17.6 ml) on Me〇H/H20 (l 0 0/ 40) The mixture in 0 ml) was heated at 11 ° C for 1 hour. After cooling to room temperature, the reaction mixture was filtered through celite and the cake was washed with Me. Combined

\\312\2d-code\90-01\89112968.ptd 第344頁 1283240 五、發明說明（340) 濾液蒸發，並以EtOAc萃取。將結合的萃取液以鹽水洗 滌，於Na2S04上乾燥，並於真空中濃縮。使殘留物於矽膠 [150克，CHCl3/EtOAc(10/l)]上進行層析，而得4-胺基 -3-氣苯乙酸曱酯（4.58克，48%)之紅色油。ijj-NMR (CDC1 3)6 3.49 (s，2Η)、3·68 (s，3Η)、4·〇ΐ (br，2H)、6 70 (d，J = 7.4 Hz, 1H)、6·96 (dd，j：=8.i、2 0 Hz, 1H)、7· 17 (d，J = 2· 0 Hz, 1H)。 3-氣-4- [N’-(2-曱基苯基）服基]笨乙酸曱酉旨\\312\2d-code\90-01\89112968.ptd Page 344 1283240 V. INSTRUCTIONS (340) The filtrate was evaporated and extracted with EtOAc. The combined extracts were washed with brine, dried over Na.sub.2SO.sub. The residue was chromatographed on EtOAc (EtOAc:EtOAc:EtOAc: Ijj-NMR (CDC1 3)6 3.49 (s, 2Η), 3·68 (s, 3Η), 4·〇ΐ (br, 2H), 6 70 (d, J = 7.4 Hz, 1H), 6.96 (dd, j:=8.i, 2 0 Hz, 1H), 7·17 (d, J = 2·0 Hz, 1H). 3-ox-4-[N'-(2-mercaptophenyl)-based group]

在室溫下在4 -胺基-3-氯本乙酸甲|旨（1〇〇克，5 〇1毫莫 耳）及異氰酸2-甲基苯酯（0.60毫升，5·〇1毫莫耳）於7111?、 (20毫升）中之混合物中加入Et3N(0.l4毫升，1 〇〇毫莫 耳）。於攪拌1天後，將異氰酸2-曱基笨自旨（0·6〇毫升: 5.01毫莫耳）加至反應混合物’並攪拌17小時。^反應混 合物於真空中濃縮。經由加入正己烷將殘留物研製而得3一 氯-4-[Ν’-（2 -甲基苯基）脲基]苯乙酸甲醋（ι·23克，74%) 之無色粉末。UMR (CDC13) 5 2· 34 (s， 3Η)、3· 54 (s， 2H)、3·68 (s，3H)、6·24 (br，1H)、6·99 (br，1H)、 7.15 (dd，J = 8.3、2·0 Hz，1H)、7·2 卜 7.31 (m，5H)、 7.44 (d，J = 7.6 Hz, 1H)、8·20 (d, J = 8.5 Hz，1H); MS(ESI) m/z 33 3 (MH1)、33 5 (MH3)。 3 -氯-4 - [Ν’ - (2-甲基苯基）脈基]苯乙酸4-Amino-3-chlorobenzate acetate at room temperature (1 gram, 5 〇 1 mmol) and 2-methylphenyl isocyanate (0.60 ml, 5·〇1 毫Et3N (0.14 ml, 1 Torr millimolar) was added to a mixture of 7111 Å (20 mL). After stirring for 1 day, 2-nonyl isocyanate was added to the reaction mixture, and stirred for 17 hours. The reaction mixture was concentrated in vacuo. The residue was triturated by the addition of n-hexane to give a colorless powder of &lt;RTI ID=0.0&gt;&gt;&gt; UMR (CDC13) 5 2· 34 (s, 3Η), 3· 54 (s, 2H), 3·68 (s, 3H), 6·24 (br, 1H), 6·99 (br, 1H), 7.15 (dd, J = 8.3, 2·0 Hz, 1H), 7·2, 7.31 (m, 5H), 7.44 (d, J = 7.6 Hz, 1H), 8·20 (d, J = 8.5 Hz, 1H); MS (ESI) m/z 33 3 (MH1), 33 5 (MH3). 3-chloro-4 - [Ν' - (2-methylphenyl) fluorenyl] phenylacetic acid

\\312\2d-code\90-01\89112968.ptd 第345頁 1283240 五、發明說明（341) 於3-氣-4-[Ν’ -（2-甲基苯基）脲基]苯乙酸曱酯（1· 23 克，3.70毫莫耳）溶於THF(30毫升）之攪拌溶液中加入 〇· 25N NaOH(30毫升）。於在室溫下攪拌14小時後，將溶劑 於真空中濃縮。經由加入1 N HC1將殘留物研製，並在6 0 °C 下在減壓下乾燥2天，而得3 -氯-4-[Ν’ - (2-甲基苯基）脲 基]苯乙酸（1 · 22克，100%)之無色粉末。iH-NMR (DMS0-d6) δ 2.26 (s, 3H) ^3.40 (s, 2H) ^6.95 (t, J = 7.3 Hz, 1H)、7·11 (d，J = 7.6 Hz，2H)、7·16 (d，J = 7.3 Hz, 1H) 、7.32 (s, 1H) 、7·76 (d， J=8.0 Hz， 1H) 、7·94 (dd， J=9.3 、1·0 Hz， 1H) 、8·72 (s， 2H); MS(ESI) m/z 319(MH1)、321(MH3)、341(MHNa)。 4 - [1 - [3-氯-4-[Ν’ - (2-曱基苯基）脲基]苯基乙醯基]— (4S) -氟-（2S) -吼哈唆基]甲氧苯甲酸甲酯\\312\2d-code\90-01\89112968.ptd Page 345 1283240 V. INSTRUCTIONS (341) In 3-Gas-4-[Ν'-(2-methylphenyl)ureido]phenylacetic acid To a stirred solution of THF (30 mL) was added EtOAc (30 mL). After stirring at room temperature for 14 hours, the solvent was concentrated in vacuo. The residue was triturated by the addition of 1 N HCl, and dried under reduced pressure at 60 ° C for 2 days to give 3-chloro-4-[?-(2-methylphenyl)ureido]phenylacetic acid (1 · 22 g, 100%) of a colorless powder. iH-NMR (DMS0-d6) δ 2.26 (s, 3H) ^3.40 (s, 2H) ^6.95 (t, J = 7.3 Hz, 1H), 7·11 (d, J = 7.6 Hz, 2H), 7 ·16 (d, J = 7.3 Hz, 1H), 7.32 (s, 1H), 7·76 (d, J=8.0 Hz, 1H), 7·94 (dd, J=9.3, 1·0 Hz, 1H , 8·72 (s, 2H); MS (ESI) m/z 319 (MH1), 321 (MH3), 341 (MHNa). 4-[1-Chloro[4-chloro-4-[Ν'-(2-mercaptophenyl)ureido]phenylethenyl]-(4S)-fluoro-(2S)-吼哈唆基]甲Methyl benzoate

C〇2Me 使3-氯-4-[N’-(2-甲基苯基）脲基]苯乙酸（319毫克，I 00毫莫耳）、4-[ (4S) -氟-（2S)-吼咯啶基]甲氧苯曱酸甲酯 (253毫克，1·〇〇毫莫耳）、edc.hc 1(288毫克，1·50毫莫 耳）、ΗΟΒΤ( 2 0 3毫克，1·50毫莫耳）及Et3N(0.70毫升， 5· 00毫莫耳）於DMF (4毫升）中之混合物在室溫下攪拌15小 時。將混合物倒入至冰水中，並以Et〇Ac萃取。將結合的 萃取液以冰水及鹽水洗滌。於在NAS%上乾燥後，將萃取C〇2Me makes 3-chloro-4-[N'-(2-methylphenyl)ureido]phenylacetic acid (319 mg, I 00 mmol), 4-[(4S)-fluoro-(2S) - 吼pyridyl]methyl methoxybenzoate (253 mg, 1·〇〇 mmol), edc.hc 1 (288 mg, 1.50 mmol), ΗΟΒΤ (203 mg, 1 The mixture was stirred at room temperature for 15 hours at rt. The mixture was poured into ice water and extracted with Et EtOAc. The combined extracts were washed with ice water and brine. After drying on NAS%, it will be extracted

1283240 五、發明說明（342) 液於真空中濃縮。使殘留物於TLC[CHC13 /丙酮（5Λ )]上 1化而得4- [1 -[3-氯一4- [『-（2-甲基苯基）脲基]苯基乙 酿基]-（4S)-氟-（2S)-咄咯啶基]甲氧苯甲酸曱酯（4 80毫 克’ 87%)之無色非晶形固體。UMR (CDC13) 5 2· 1 〇 -2.60 (m，2H)、2·29 (s, 3H)、3·56 (d，J = 6.8 Hz， 1H)、3·71-3.84 (m, 1H)、3·87 及 3·89 (各s，3H，醯胺 異構物）、3·91-4.20 (m，3H)、4·49-4·60 (m，2H)、 5·32 (dt，J = 53.〇、4·2 Ηζ，1Η)、6·80 (br，1Η)、6·89 及6· 95 (各d，J = 8· 8 Hz，2H，醯胺異構物）、7· 09-7· 26 (m， 6H) 、7.50 (d， J=7.3 Hz， 1H) 、7·94 及8.00 (各d， J = Hz, 2H，醯胺異構物）、8·10 及815 (各d，J = 831283240 V. INSTRUCTIONS (342) The liquid is concentrated in vacuo. The residue was chromatographed on TLC [CHC13 / acetone (5 Λ)] to give 4-[1 -[3-chloro-l[4-[2-(2-methylphenyl)ureido]phenyl]] -(4S)-Fluoro-(2S)-decalidyl] methoxybenzoate (4 80 mg '87%) as a colorless amorphous solid. UMR (CDC13) 5 2· 1 〇-2.60 (m, 2H), 2·29 (s, 3H), 3·56 (d, J = 6.8 Hz, 1H), 3·71-3.84 (m, 1H) , 3·87 and 3.89 (each s, 3H, guanamine isomer), 3·91-4.20 (m, 3H), 4·49-4·60 (m, 2H), 5·32 (dt , J = 53. 〇, 4·2 Ηζ, 1Η), 6·80 (br, 1Η), 6.89 and 6.95 (each d, J = 8·8 Hz, 2H, guanamine isomer) , 7· 09-7· 26 (m, 6H), 7.50 (d, J=7.3 Hz, 1H), 7.94 and 8.00 (each d, J = Hz, 2H, guanamine isomer), 8· 10 and 815 (each d, J = 83

Hz，1H，酿胺異構物）；ms(FAB) m/z 554 (MH1)、556 (MH3) 〇 於4 - [,1-[3-氯-4 - [Ν’-（2-曱基苯基）脲基]苯基乙醯 基]-（4S) -氟-（2S)-吼咯啶基]曱氧苯甲酸曱酯（480毫克， 0· 866毫莫耳）溶於THF(30毫升）之溶液中加入〇. 25Ν NaOH(30毫升）。於在室溫下攪拌2天後，將混合物於減壓 下浪縮’並以1N H C1酸化。收集沈澱物，以水洗滌，並於 減壓下乾燥而得90(374毫克，80%)之無色粉末。ir (KBr) 3354、3060、2976、1709、1604、1244 /公分；NMR (DMSO-d6) 5 2· 27 (s，3Η)、2· 31 (s，2Η)、3· 66 (d， J=7.2 Hz, 2H) ^3.71-4.67 (m, 5H) ^5.32-5.53 (m, 1H)、6.97 (t， J = 7.3 Hz, 1H)、7·04-7·22 (m，5H)、7· 32 及 7.35 (各d，J = 1.7 Hz, 1H，醯胺異構物）、7·77Hz, 1H, amine amide isomer; ms (FAB) m/z 554 (MH1), 556 (MH3) 〇 4 - [, 1-[3-chloro-4 - [Ν'-(2-曱Ethylphenyl)ureido]phenylethenyl]-(4S)-fluoro-(2S)-decalidyl]nonyloxybenzoate (480 mg, 0·866 mmol) dissolved in THF ( Add 30 ml of NaOH (30 ml) to the solution of 30 ml). After stirring at room temperature for 2 days, the mixture was boiled under reduced pressure and acidified with 1N H C1. The precipitate was collected, washed with water and dried under reduced pressure toield (yield: 90, 374 g, 80%). Ir (KBr) 3354, 3060, 2976, 1709, 1604, 1244 / cm; NMR (DMSO-d6) 5 2· 27 (s, 3Η), 2· 31 (s, 2Η), 3· 66 (d, J =7.2 Hz, 2H) ^3.71-4.67 (m, 5H) ^5.32-5.53 (m, 1H), 6.97 (t, J = 7.3 Hz, 1H), 7·04-7·22 (m, 5H), 7·32 and 7.35 (each d, J = 1.7 Hz, 1H, guanamine isomer), 7.77

\\312\2d-code\90-01\89112968.ptd 第347頁 1283240 _ 五、發明說明（343) (d，J = 7.6 Hz, 1H)、7.87 及 7.90 (各d，&gt;9.0 Hz，2H, 醯胺異構物）、8· 01及8· 03 (各d, J=8· 5 Hz, 1H, 醯胺異 構物）、8· 57及8· 59 (各s， 1H, 醯胺異構物）、8·63及 8.65(各s， 1Η，醯胺異構物）、12.63(s，ih);MS(ESI) m/z 54 0 (MH1 )、542 (MH3) 〇 實施例8 5 4 - [1-[3 -氣-4 - [Ν’ -（2_氣苯基）脈基]本基乙酸基]-(4S)-氟-（2S)-吼咯啶基]甲氧苯曱酸\\312\2d-code\90-01\89112968.ptd Page 347 1283240 _ V. Description of invention (343) (d, J = 7.6 Hz, 1H), 7.87 and 7.90 (each d, &gt; 9.0 Hz, 2H, guanamine isomers), 8. 01 and 8. 03 (each d, J=8·5 Hz, 1H, guanamine isomer), 8.57 and 8.59 (each s, 1H, 醯Amine isomers), 8.63 and 8.65 (each s, 1 oxime, guanamine isomer), 12.63 (s, ih); MS (ESI) m/z 54 0 (MH1), 542 (MH3) 〇 Example 8 5 4 - [1-[3 -Gas-4 - [Ν' -(2_ phenyl)) thiol] benzyl acetate]-(4S)-fluoro-(2S)-pyridinyl] Methoxybenzoic acid

3-氣-4 - [N，-（2-氯苯基）脲基]苯乙酸曱酯3-ox-4 -[N,-(2-chlorophenyl)ureido]phenyl phthalate

在室溫下在4 -胺基-3-氯苯乙酸甲酯（1.00克，5.01毫莫 耳）及異氰酸2-氯苯酯（0.60毫升，5·〇1毫莫耳）於THF (20 毫升）中之混合物中加入Et3N(0. 14毫升，I 〇〇毫莫耳）。 於攪拌1天後，將異氰酸2 -氯苯酯（〇· 60毫升’ 5· 01毫莫 耳）加至反應混合物，並攪拌1 7小時。將反應混合物於真 空中濃縮。經由加入正己烷將殘留物研製而得3 -氯 -4 - [Ν’ - (2 -氣苯基）脈基]苯乙酸甲S旨（1.35克’ 76%)之無 色粉末。1H-NMR (CDC13) 5 3· 58 (s，3Η)、3· 71 (s， 2H)、7·04 (m，3H)、7·18 (dd，&gt;8·5、2·0 Hz，1H)、 7.27-7.39 (m, 3Η) 、 8· 07 (m, 2Η) ； MS(ESI) m/zMethyl 4-amino-3-chlorophenylacetate (1.00 g, 5.01 mmol) and 2-chlorophenyl isocyanate (0.60 mL, 5·〇1 mmol) in THF at room temperature Et3N (0.14 ml, I 〇〇 millimolar) was added to the mixture in 20 ml). After stirring for 1 day, 2-chlorophenyl isocyanate (〇·60 ml '5·01 mmol) was added to the reaction mixture, and stirred for 17 hours. The reaction mixture was concentrated in vacuo. The residue was triturated by the addition of n-hexane to give 3-chloro-[delta]-[[upsilon]-(2-phenylphenyl) yl]phenylacetic acid as a succinic acid (1.35 g &apos; 76%). 1H-NMR (CDC13) 5 3· 58 (s, 3Η), 3·71 (s, 2H), 7·04 (m, 3H), 7·18 (dd, &gt;8·5, 2·0 Hz , 1H), 7.27-7.39 (m, 3Η), 8· 07 (m, 2Η); MS(ESI) m/z

\\312\2d-code\90-01\89112968.ptd 第348頁 1283240 五、發明說明（344) 353 (MH1)、3 55 (MH3)、35 7 (MH5)。 3 -氯-4- [Ν’ -（2-氯苯基）脲基]苯乙酸\\312\2d-code\90-01\89112968.ptd Page 348 1283240 V. Inventions (344) 353 (MH1), 3 55 (MH3), 35 7 (MH5). 3-chloro-4-[Ν'-(2-chlorophenyl)ureido]phenylacetic acid

OH 於3-氯-4 - [Ν’ -（2-氣苯基）脲基]苯乙酸曱酯（ι·35克， 3· 82毫莫耳）溶於THF(30毫升）之攪拌溶液中加入〇. 25Ν NaOH ( 3 0毫升）。於在室溫下攪拌1 4小時後，將溶劑於真空 中濃縮。經由加入1 N HC 1將殘留物研製，並在6 〇 °c下在減 壓下乾燥2天，而得3-氯-4-[N，-（2-氯苯基）脲基]苯乙酸 (1· 12 克，86%)之無色粉末。I-NMR (DMS0-d6) 5 3· 52 (s，2H)、7·05 (m，1H)、7.17 (d，J = 8.5 Hz, 1H)、 7.30 (d，J:7.6 Hz, 1H)、7·37 (s，1H)、7·46 (dd， J=8.0 、1·5 Hz， 1H) 、7·95 (dd， J=8.3 、1·2 Hz， 1H)、 8.07 (d，J = 8.3 Hz，1H)、9.00 (d，J = 8.0 Hz, 2H); MS(FAB) m/z 33 9 (MH1)、341(MH3)、343 (MH5)。 4 - [1-[3-氯-4-[N’ _(2 -氣苯基）脲基]苯基乙醯基]—(4S) — 氟-（2S)-咄咯啶基]甲氧苯甲酸甲酯OH is dissolved in a stirred solution of 3-chloro-4-[[rho]-(2-phenylphenyl)ureido]phenylacetate (1·3 g, 3.82 mmol) in THF (30 mL) Add 〇. 25Ν NaOH (30 ml). After stirring at room temperature for 14 hours, the solvent was concentrated in vacuo. The residue was triturated by the addition of 1 N HCl 1 and dried under reduced pressure at 6 ° C for 2 days to give 3-chloro-4-[N,-(2-chlorophenyl)ureido]phenylacetic acid. (1·12 g, 86%) of a colorless powder. I-NMR (DMS0-d6) 5 3· 52 (s, 2H), 7·05 (m, 1H), 7.17 (d, J = 8.5 Hz, 1H), 7.30 (d, J: 7.6 Hz, 1H) , 7·37 (s, 1H), 7.46 (dd, J=8.0, 1. 5 Hz, 1H), 7.95 (dd, J=8.3, 1·2 Hz, 1H), 8.07 (d, J = 8.3 Hz, 1H), 9.00 (d, J = 8.0 Hz, 2H); MS (FAB) m/z 33 9 (MH1), 341 (MH3), 343 (MH5). 4-[1-[3-Chloro-4-[N' _(2-phenylphenyl)ureido]phenylethenyl]-(4S)-fluoro-(2S)-decalridinyl]methoxy Methyl benzoate

使3-氯-4-[Ν’-（2 -氣苯基）脲基]苯乙酸（339毫克，1〇〇 毫莫耳）、4-[(2S，4S)- 4 -氟-2 -咄咯啶基]曱氧苯甲酸甲酉旨 (253毫克，1.00毫莫耳）、EDC*HC 1(288毫克，1.50毫莫3-Chloro-4-[Ν'-(2-(phenylphenyl)ureido]phenylacetic acid (339 mg, 1 〇〇 mmol), 4-[(2S,4S)-4-fluoro-2-咄 啶 啶 曱 曱 253 253 253 (253 mg, 1.00 mmol), EDC*HC 1 (288 mg, 1.50 mmol)

\\312\2d-code\90-01\89112968.ptd 第349頁 1283240 五、發明說明（345) 耳）、HOBT( 2 0 3毫克，1.50毫莫耳）及Et3N(0.70毫升， 5.00毫莫耳）於DMF(4毫升）中之混合物在室溫下攪拌15小 時。將混合物倒入至冰水中，並以Et〇Ac萃取。將結合的 萃取液以冰水及鹽水洗滌。於在Na2S〇4上乾燥後，將萃取 液於真空中濃縮。使殘留物於矽膠[5〇克，CHC13 /丙酮 (10/1)]上進行層析，而得4-[1-[3-氣-4-[N，-（2-氯苯基） 脲基]本基乙醯基]-(4S) -敦-（2S)-p比洛咬基]甲氧苯甲酸 曱酯（5 5 0毫克，96%)之無色非晶形固體。111-題1^(〇〇(：13) 占 2· 14-2· 64 (m，2H)、3· 59 (d, J:ll. 2 Hz, 2H)、 3·78_3·82 (m， 1H)、3·86 及 3·89 (各s, 3H，醯胺異構 物）、3·91-4·28 (m，2H)、4·50-4·79 (m，2H)、5·34 及 5.39 (各 dt， J = 52.5、4·4 Hz, 1Η，酿胺異構物）、 6.8 9-6.98 (m，3H)、7·09-7·13 (m，2H)、7·22 (dt， J=7.3 、2·2 Hz, 1H) 、7·29 (dd， J=8.1 、2·0 Hz, 1H)、 7· 79 及7. 86 (各s， 1H，醯胺異構物）、7. 86-8· 03 (m， 4H)、8· 11 (dd，J = 8· 3、1. 0 Hz, 1H) ; MS(FAB) m/z 5 74 (M++1)、5 76 (MH3)、578 (MH5)。 於4-[ l-[3 -氯-4-[N，- (2-氯苯基）脲基]苯基乙醯基] -（4S)-氟-（2S) -吡咯啶基]曱氧苯甲酸甲酯（550毫克， 〇· 957毫莫耳）溶於THF(30毫升）之溶液中加入〇· 25N NaOH (3 0毫升）。於在室溫下攪拌2天後，將混合物於減壓下濃 縮，並以1N HC1酸化。收集沈澱物，以水洗滌，並於減壓 下乾燥而得9 1 (437毫克，82%)之無色粉末。IR (KBr) 3348、3072、2954、1703、1604、1529、1439 / 公分；\\312\2d-code\90-01\89112968.ptd Page 349 1283240 V. Description of invention (345) Ear), HOBT (203 mg, 1.50 mmol) and Et3N (0.70 ml, 5.00 mmol) The mixture in the DMF (4 mL) was stirred at room temperature for 15 h. The mixture was poured into ice water and extracted with Et EtOAc. The combined extracts were washed with ice water and brine. After drying over Na 2 S 〇 4, the extract was concentrated in vacuo. The residue was chromatographed on silica gel [5 g, CHC13 / acetone (10/1)] to give 4-[1-[3-[sup. A chromophoric amorphous solid of benzyl thiol]-(4S)-Dan-(2S)-p piroxime] methoxy methoxybenzoate (550 mg, 96%). 111-question 1^(〇〇(:13) 占2·14-2· 64 (m,2H), 3·59 (d, J:ll. 2 Hz, 2H), 3·78_3·82 (m, 1H), 3·86 and 3.89 (each s, 3H, guanamine isomer), 3·91-4·28 (m, 2H), 4·50-4·79 (m, 2H), 5 · 34 and 5.39 (each dt, J = 52.5, 4·4 Hz, 1 Η, amine-isomers), 6.8 9-6.98 (m, 3H), 7·09-7·13 (m, 2H), 7 · 22 (dt, J=7.3, 2·2 Hz, 1H), 7·29 (dd, J=8.1, 2·0 Hz, 1H), 7·79 and 7.86 (each s, 1H, guanamine Isomers), 7. 86-8· 03 (m, 4H), 8·11 (dd, J = 8·3, 1.0 Hz, 1H); MS(FAB) m/z 5 74 (M+ +1), 5 76 (MH3), 578 (MH5). 4-[ l-[3-chloro-4-[N,-(2-chlorophenyl)ureido]phenylethenyl]-( 4S)-Fluoro-(2S)-pyrrolidinyl]methyloxybenzoate (550 mg, 957·957 mM) dissolved in THF (30 mL) was added 〇·25N NaOH (30 mL) After stirring at room temperature for 2 days, the mixture was concentrated under reduced pressure and acidified with &lt;RTI ID=0.0&gt;&gt; Colorless powder. IR (KBr) 3348, 3072 2954,1703,1604,1529,1439 / cm;

\\312\2d-code\90-01\89112968.ptd 第 350 頁 1283240 五、發明說明（346) W-NMR (DMS0-d6) 5 2.25-2.42 (m，2H)、3.67 (d，J二8· 3 Hz, 2H) 、3·81-4.68 (m， 5H) 、5·39及5·46 (各d, J= 54.4 Hz, 1H，醯胺異構物）、7·〇4 — 71〇 (m，3H)、718 (d，J-8.3 Hz， 1H)、7·31 (t，J = 8.3 Hz, 1H)、7.33 及 7.37 (各s， 1H，醯胺異構物）、7· 47 (d，J = 8. 1 Hz, 1H) 、7.88 (dd，J 二 9.0、3.2 Hz, 2H)、7·98 (dd，J = 8.5、 3.0 Hz，1H) m，1H)、8.〇9 (d，J = 8.3 Hz, 1H)、8·99 (d，J = 2.9 Hz, 1H)、9·02 (s，1H)、12.64 (s，1H); MS(ESI) m/z 56 0 (M+ + 1)、562 (MH3)、564 (MH5); C27H24 C12FN3 05 ·0·2Η20 之分析計算值：c， 57.50; H，4.36; N， 7.45; Cl， 12.57; F，3.37。實測值：c，57.72; H， 4· 47 ; N，7· 14 ; Cl，12· 44 ; F，3. 44。 實施例8 6 4-[l-[4-[Ν’ -（2 -溴苯基）脲基]-3 -氯苯基乙醯基]-（4S)-氟-（2S) -吼咯啶基]曱氧苯曱酸\\312\2d-code\90-01\89112968.ptd Page 350 1283240 V. INSTRUCTIONS (346) W-NMR (DMS0-d6) 5 2.25-2.42 (m, 2H), 3.67 (d, J 2 8· 3 Hz, 2H), 3·81-4.68 (m, 5H), 5.39 and 5.46 (each d, J= 54.4 Hz, 1H, guanamine isomer), 7·〇4 — 71 〇(m,3H), 718 (d,J-8.3 Hz, 1H), 7·31 (t, J = 8.3 Hz, 1H), 7.33 and 7.37 (each s, 1H, guanamine isomer), 7 · 47 (d, J = 8. 1 Hz, 1H), 7.88 (dd, J 9.0, 3.2 Hz, 2H), 7·98 (dd, J = 8.5, 3.0 Hz, 1H) m, 1H), 8 .〇9 (d, J = 8.3 Hz, 1H), 8·99 (d, J = 2.9 Hz, 1H), 9·02 (s, 1H), 12.64 (s, 1H); MS(ESI) m/ z 56 0 (M+ + 1), 562 (MH3), 564 (MH5); C27H24 C12FN3 05 ·0·2Η20 Analysis calculated: c, 57.50; H, 4.36; N, 7.45; Cl, 12.57; F, 3.37 . Found: c, 57.72; H, 4·47; N, 7·14; Cl, 12·44; F, 3.44. Example 8 6 4-[l-[4-[Ν'-(2-Bromophenyl)ureido]-3-chlorophenylethenyl]-(4S)-fluoro-(2S)-indenylpyridine Hydroxybenzoic acid

日Γ Η H CI I u w JL. 4- [Ν’ - (2-溴苯基）脲基]- 3-氯苯乙酸甲酯 92 在室溫下在4 耳）及異氰酸2-毫升）中之混合 苯中 溴物Γ Γ H CI I uw JL. 4- [Ν' - (2-Bromophenyl)ureido]- 3-chlorophenylacetate methyl ester 92 at room temperature at 4 ears) and isocyanate 2-ml) Mixed benzene in benzene

莫 毫C 。 1 Fo ο Η 耳 • Ε—_ 5 於莫 ，} 毫 克耳 ο 00莫1.0 L毫Τ 酯 2Mo Mo C. 1 Fo ο 耳 ear • Ε—_ 5 于莫 , } 毫克 ο 00 莫 1.0 L Τ Τ ester 2

\\312\2d-code\90-01\89112968.ptd 第351頁 1283240 五、發明說明（347) 於攪拌1天後，將異氰酸2 -溴苯酯（0 · 6 0毫升，5 · 0 1毫莫 耳）加至反應混合物，並攪拌2 4小時。將反應混合物於真 空中濃縮。經由加入正己烧將殘留物研製而得4 - [ N，-（ 2 -漠苯基）脲基]-3 -氯苯乙酸曱醋（1.34克，67%)之無色粉 末。1H-NMR (CDC13) 6 3. 58 (s，3H)、3. 70 (s，2H)、6. 98 (m，3H)、7·19 (dd，J:8.3、1·9 Hz, 1H)、7·32 (m, 1H) 、7·51 (m, 2H) 、 8.05 (m， 1H); MS(ESI) m/z 398 (ΜΗ 1 )、4 0 0 ( M+ + 3 )、4 0 2 (MH 5 )。 4 - [N -(2 -漠苯基）脈基]-3-氯苯乙酸\\312\2d-code\90-01\89112968.ptd Page 351 1283240 V. INSTRUCTIONS (347) After stirring for 1 day, 2-bromophenyl isocyanate (0 · 60 ml, 5 · 0 1 mmol) was added to the reaction mixture and stirred for 24 hours. The reaction mixture was concentrated in vacuo. The residue was triturated by adding hexane to give 4-[N,-(2-diphenyl)ureido]-3-chlorophenylacetic acid vinegar (1.34 g, 67%) as a colorless powder. 1H-NMR (CDC13) 6 3. 58 (s, 3H), 3.70 (s, 2H), 6. 98 (m, 3H), 7·19 (dd, J: 8.3, 1·9 Hz, 1H ), 7·32 (m, 1H), 7·51 (m, 2H), 8.05 (m, 1H); MS (ESI) m/z 398 (ΜΗ 1 ), 4 0 0 ( M+ + 3 ), 4 0 2 (MH 5 ). 4-[N-(2-Phenylphenyl)-based]-3-chlorophenylacetic acid

於4-[N’-(2-溴苯基）脲基]-3-氯苯乙酸曱酯（1.34克， 3. 37毫莫耳）溶於THF(30毫升）之攪拌溶液中加入〇· 25N NaOH(30毫升）。於在室溫下攪拌14小時後，將溶劑於真空 中濃縮。經由加入1 N HC 1將殘留物研製，並在6 0 °C下在減 壓下乾燥2天，而得4-[Ν’-（2-溴苯基）脲基]-3-氯苯乙酸 (1· 03 克，80%)之無色粉末。iH-NMR (DMSO-d6) 5 3· 56 (s，2H)、7.00 (m，1H)、7·17 (dd，J二9·0、1·7 Hz, 1H) 、 7.32-7.40 (m， 2H) 、 7.62 (dd， J=8.0 、1·2 Hz, lH)、7.95(m，2H)、8.83(s，lH)、9.01(s,lH)、12. 41 (br，1H) ; MS(FAB) m/z 385 (MH2)、386 (MH4)、 388 (MH6)。 4 - [1-[4-[Ν’ - (2 -溴苯基）脲基]一3 —氯苯基乙醯基]-(4S)-氟-（2S )-咣咯啶基]甲氧苯甲酸甲酉旨Add hydrazine to a stirred solution of 4-[N'-(2-bromophenyl)ureido]-3-chlorophenylacetate (1.34 g, 3.37 mmol) in THF (30 mL) 25N NaOH (30 mL). After stirring at room temperature for 14 hours, the solvent was concentrated in vacuo. The residue was triturated by the addition of 1 N HCl 1 and dried under reduced pressure at 60 ° C for 2 days to give 4-[Ν'-(2-bromophenyl)ureido]-3-chlorophenylacetic acid (1·03 g, 80%) of a colorless powder. iH-NMR (DMSO-d6) 5 3· 56 (s, 2H), 7.00 (m, 1H), 7·17 (dd, J 2 9.0, 1·7 Hz, 1H), 7.32-7.40 (m , 2H), 7.62 (dd, J=8.0, 1. 2 Hz, lH), 7.95 (m, 2H), 8.83 (s, lH), 9.01 (s, lH), 12.41 (br, 1H); MS (FAB) m/z 385 (MH2), 386 (MH4), 388 (MH6). 4-[1-[4-[Ν' - (2-Bromophenyl)ureido]-3-chlorophenylethyl]-(4S)-fluoro-(2S)-indenylpyridyl]methoxy Benzoic acid

\\312\2d-code\90-01\89112968.ptd 第352頁 1283240\\312\2d-code\90-01\89112968.ptd Page 352 1283240

使4-[Ν’-（2~溴苯基）脲基]—3—氯苯乙酸（384毫克， 1:00¾，耳）、4-[(4S)~氟-（2S) -吡咯啶基]曱氧苯甲酸 酯（ 25 3毫克，1· 00毫莫耳）、EDC · HC 1 ( 288毫克，1 · 5〇古 莫耳）、HOBT( 20 3毫克，1.50毫莫耳）及Et3N(0.70毫升笔 5^00晕莫耳）於DMF (4毫升）中之混合物在室溫下攪拌Η小 時。將混合物倒入至冰水中，並以E t〇Ac萃取。將結合的 萃取液以冰水及鹽水洗滌。於在上乾燥後，^ ^取 液於真空中濃縮。使殘留物於矽膠[50克，CHC13 /丙酮 (10/1)]上進行層析，而得4-[1 — [4-[N，-（2 -溴苯基） 服基]3氣本基乙醯基]-(4S)- I-(2S) -。比0各σ定基]曱氧 笨曱酸曱酯（53 0毫克，8 6%)之無色非晶形固體。1 h-NMR (CDC13)5 2.14-2.63 (m, 2H)-3.58 (d, J = l〇.〇 Hz, 1H)、3·73-3.83 (m，1H)、3·86 及3.89 (各s，3H，醯胺 異構物）、3.90-4.29 (m，3H)、4.50-4.69 (m， 2H)、 5.33 及 5·37 (各 m， 1H，醯胺異構物）、6·88-6.93 (m， 3Η)、7·1 卜7.14 (m，2Η)、7·26 (m，1Η)、7·46 (d， J 二 8.1 Hz, 1H)、7·62-7.78 (m，2H)、7·89 及 7.93 (各m， 2H，醯胺異構物）、8· 01 (dd，J = 8. 8、1· 7 Hz, 2H); MS(FAB) m/z 618 (M+)、620 (MH2)、622 (MH4)。 於4 [1 [4-[N -(2 -漠本基）脈基]-3 -氯苯基乙酉篮 基]-(4S) -氟-（2S)-吼咯啶基]甲氧苯甲酸甲酯（53〇毫克，4-[Ν'-(2~Bromophenyl)ureido]-3-chlorophenylacetic acid (384 mg, 1:003⁄4, ear), 4-[(4S)~fluoro-(2S)-pyrrolidinyl曱Phenyl benzoate (25 3 mg, 1.00 mmol), EDC · HC 1 (288 mg, 1.25 gram of Gu Mo), HOBT (20 3 mg, 1.50 mmol) and Et3N (0.70 ml pen 5^00 vaole) The mixture in DMF (4 ml) was stirred at room temperature for a few hours. The mixture was poured into ice water and extracted with EtOAc. The combined extracts were washed with ice water and brine. After drying on top, the solution was concentrated in vacuo. The residue was chromatographed on silica gel [50 g, CHC13 / acetone (10/1)] to give 4-[1 -[4-[N,-(2-bromophenyl))yl] Ethyl thiol]-(4S)-I-(2S)-. a colorless amorphous solid of 曱 定 曱 曱 曱 曱 53 53 53 53 53 53 53 53 53 53 53 53 53 53 53 53 1 h-NMR (CDC13) 5 2.14 - 2.63 (m, 2H) - 3.58 (d, J = l〇.〇Hz, 1H), 3.73-3.83 (m, 1H), 3·86 and 3.89 (each s, 3H, guanamine isomers), 3.90-4.29 (m, 3H), 4.50-4.69 (m, 2H), 5.33 and 5.37 (each m, 1H, decylamine isomer), 6.88 -6.93 (m, 3Η), 7·1 Bu 7.14 (m, 2Η), 7·26 (m, 1Η), 7·46 (d, J 2 8.1 Hz, 1H), 7·62-7.78 (m, 2H), 7·89 and 7.93 (each m, 2H, guanamine isomer), 8. 01 (dd, J = 8. 8 , 1.7 Hz, 2H); MS (FAB) m/z 618 ( M+), 620 (MH2), 622 (MH4). On 4 [1 [4-[N -(2 -Moline)-based]-3-chlorophenylacetamidine]-(4S)-fluoro-(2S)-decalidyl]methoxybenzoic acid Methyl ester (53 mg,

\\312\2d-code\90-01\89112968.ptd 第353頁 1283240 五、發明說明（349) 0· 856毫莫耳）溶於THF(30毫升）之溶液中加入〇· 25N NaOH (3 0毫升）。於在室溫下攪拌2天後，將混合物於減壓下濃 縮，並以IN HC1酸化。以CHC13 /MeOH(10/l)萃取混合 物。將結合的萃取液以冰水及鹽水洗滌。於在Na2S04上乾 燥後，將萃取液於真空中濃縮。使殘留物於矽膠[2 0克， CHC13/ 丙酮（10/l)-CHCl3/MeOH(10/l)]上進行層析，而 得9 2 ( 5 9毫克，1 1%)之無色非晶形固體。ir (KBr) 332 9、 3 0 6 0、2 9 76、1712、1 52 6、1 435 / 公分；NMR (DMS0-d6 )5 2.31 (m，Η)、3.48 - 4.68 (m，7H)、5. 32-5.53 (m， 1H) 、6·99-7.19 (m， 4H) 、7·36 (s, 1H) 、7·63 (dd， J二6·7、1·2 Hz, 1H)、7·86-8·18 (m, 4H)、8·83 (s, 1H)、9·02 (s，1H)、12·67 (br，1H); MS(ESI) m/z 604 (MH1)、6 0 6 (MH3)、60 8 (MU5) ; C27H24BrClFN3 05 · 0.5H2O 之分析計算值：C，52.83; H，4.10; N，6.85; C1， 5·78;ρ， 3·〇9。實測值：C，53·24;Η， 4.32; N， 6.43; Cl, 6.01;F，3.07。 實施例8 7 4-[1-[3-氣-4-（Ν’ -苯基脲基）笨基乙醯基]—氟—（2S) -咄咯啶基]甲氧苯甲酸\\312\2d-code\90-01\89112968.ptd Page 353 1283240 V. Description of the invention (349) 0·856 mmol) In solution of THF (30 ml), 〇·25N NaOH (3) 0 ml). After stirring at room temperature for 2 days, the mixture was concentrated under reduced pressure and acidified with IN HCl. The mixture was extracted with CHC13 / MeOH (10 / 1). The combined extracts were washed with ice water and brine. After drying on Na2S04, the extract was concentrated in vacuo. The residue was chromatographed on silica gel [20 g, EtOAc (EtOAc) (EtOAc) solid. Ir (KBr) 332 9, 3 0 6 0, 2 9 76, 1712, 1 52 6, 1 435 / cm; NMR (DMS0-d6) 5 2.31 (m, Η), 3.48 - 4.68 (m, 7H), 5. 32-5.53 (m, 1H), 6.99-7.19 (m, 4H), 7·36 (s, 1H), 7·63 (dd, J 2:6, 1·2 Hz, 1H) , 7·86-8·18 (m, 4H), 8·83 (s, 1H), 9·02 (s, 1H), 12·67 (br, 1H); MS (ESI) m/z 604 ( MH1), 6 0 6 (MH3), 60 8 (MU5) ; C27H24BrClFN3 05 · 0.5H2O: C, 52.83; H, 4.10; N, 6.85; C1, 5·78; ρ, 3·〇9 . Found: C, 53·24; Η, 4.32; N, 6.43; Cl, 6.01; F, 3.07. Example 8 7 4-[1-[3-Ga-4-(Ν'-phenylureido)phenylidenyl]-fluoro-(2S)-indolyl]methoxybenzoic acid

93 3-氣-4-(Ν’-苯基脲基）苯乙酸甲酯93 3-Ox-4-(Ν'-phenylureido)phenylacetate

\\312\2d-code\90-01\89112968.ptd 第354頁 1283240 五、發明說明（350) 在室溫下在4 -胺基-3-氯苯乙酸曱酯（ι·3ΐ克，6.56毫莫 耳）及異氰酸苯S旨（0.71¾升，6.56毫莫耳）於THF(20毫升） 中之混合物中加入Et3N(0· 19毫升，1.33毫莫耳）。於擾拌 1 5小時後’將反應混合物於真空中濃縮。經由加入正己烷 將殘留物研製而得3-氣-4-(Ν’ -苯基脲基）苯乙酸曱酯 (1. 79 克，86%)之淡棕色固體。I-NMR (CDC13) 6 3. 56 (s，2H)、3·70 (s，3H)、6·70 (m，1Η)、7·06 (s，1H) 、7·14-7·18 (m，2H)、7·26 (dd，J = 7.8、1·9 Hz, 1H) 、7·33 -7.38 (m，4H)、8·14 (dd，J = 8.3、3·0 Hz, 1H); MS(ESI) m/z 319(MH1)、321(MH3)。 3-氯-4-(Ν’ _苯基脈基）苯乙酸\\312\2d-code\90-01\89112968.ptd Page 354 1283240 V. INSTRUCTIONS (350) Ethyl 4-amino-3-chlorophenylacetate at room temperature (ι·3ΐ克, 6.56 Et3N (0.19 ml, 1.33 mmol) was added to a mixture of EtOAc (m.p.). After stirring for 15 hours, the reaction mixture was concentrated in vacuo. The residue was triturated with n-hexane to afford EtOAc (EtOAc: EtOAc (EtOAc) I-NMR (CDC13) 6 3. 56 (s, 2H), 3·70 (s, 3H), 6·70 (m, 1Η), 7·06 (s, 1H), 7·14-7·18 (m, 2H), 7.26 (dd, J = 7.8, 1·9 Hz, 1H), 7.33 - 7.38 (m, 4H), 8·14 (dd, J = 8.3, 3·0 Hz, 1H); MS (ESI) m/z 319 (MH1), 321 (MH3). 3-chloro-4-(Ν' _phenyl-phenyl)phenylacetic acid

於3-氣-4-(Ν’ -苯基脲基）苯乙酸甲酯（ι·79克，5.62毫 莫耳）溶於THF(3 0毫升）之攪拌溶液中加入〇.25Ν NaOH (3 0毫升）。於在室溫下攪拌2 0小時後，將溶劑於真空中濃 縮。經由加入IN HC1將殘留物研製，並在60 °C下在減壓下 乾燥2天，而得3_氣-4-(Ν’-苯基脲基）苯乙酸（1.58克， 92%)之淡棕色固體。1H-NMR (DMS0-d6) 6 3· 55 (s，2Η)、 6·99 (t，J = 7.3 Hz, 1H)、7·17 (d，J = 8.3 Hz，1H)、7· 29 (t，J = 7.6 Hz, 2H)、7·36 (s, 1H)、7·46 (d，J = 8.0 Hz, 2H) 、8.07 (d， J=8.3 Hz, 1H) 、8·28 (s， 1H)、 9. 37 (s， 1H)、12· 37 (br， 1H)。Add 〇.25Ν NaOH (3) to a stirred solution of methyl 3-oxo-4-(indolyl-phenylureido)phenylacetate (ι·79 g, 5.62 mmol) in THF (30 mL). 0 ml). After stirring at room temperature for 20 hours, the solvent was concentrated in vacuo. The residue was triturated by the addition of IN HCl and dried under reduced pressure at 60 ° C for 2 d to give 3- s- 4-(p-[p.s.]-phenyl phenyl) phenylacetic acid (1.58 g, 92%) Light brown solid. 1H-NMR (DMS0-d6) 6 3· 55 (s, 2Η), 6·99 (t, J = 7.3 Hz, 1H), 7·17 (d, J = 8.3 Hz, 1H), 7· 29 ( t, J = 7.6 Hz, 2H), 7·36 (s, 1H), 7·46 (d, J = 8.0 Hz, 2H), 8.07 (d, J=8.3 Hz, 1H), 8·28 (s , 1H), 9. 37 (s, 1H), 12·37 (br, 1H).

\\312\2d-code\90-01\89112968.ptd 第 355 頁 1283240 五、發明說明（351) 4-[卜[3-氯-4-(N’ -苯基脲基）苯基乙醯基]一（4S) —氟一（2S) -吼咯啶基]甲氧苯甲酸曱酯\\312\2d-code\90-01\89112968.ptd Page 355 1283240 V. INSTRUCTIONS (351) 4-[Bu [3-chloro-4-(N'-phenylureido)phenyl) ]](4S)-fluoro-(2S)-decalridinyl] methoxybenzoate

使3-氯-4-(Ν’ -苯基脲基）苯乙酸（3〇5毫克，1〇〇毫莫 耳）、4-[(2S，4S)-4-氟-2 -吡咯啶基]甲氧苯曱酸曱酯（253 毫克，1· 00毫莫耳）、EDC · HC 1 ( 288毫克，i 50毫莫耳）、 HOBT( 2 0 3毫克，1.50毫莫耳）及Et3N(〇7〇毫升，5〇〇毫莫 耳）於DMF ( 4笔升）中之混合物在室溫下攪拌丨7小時。將混 合物倒入至冰水中，並以Et0Ac萃取。將結合的萃取液以 冰水及鹽水洗滌。於在Na2s〇4上乾燥後，將萃取液於真空 中濃縮。使殘留物於矽膠[30克，CHC13 /丙酮（20/1)]上 進行層析’而得4-[1-[3-氣-4-(N，-苯基脲基）苯基乙醯 基]-(4S)-|L-(2S)-吼咯啶基]甲氧苯甲酸甲酯（72〇毫克， 10 0%)之無色非晶形固體。ms(FAB) m/z 540 (MH1) 、542 (MH3)。 於4-[1-[3 -氯-4-(N，-苯基脲基）苯基乙醯基]—(4S) —氟 -（2S) -吼嘻唆基]甲氧苯甲酸曱酯（72〇毫克，l 〇〇毫莫耳） 溶於THF/MeOH( 3 0/ 30毫升）之溶液中加入0.25N NaOH (30 毫升）°於在室溫下攪拌2小時後，將反應混合物於5〇 〇c下 加熱2 2小時。於移除溶劑後，以丨N hc 1將所得之殘留物酸 化。收集沈激物’將其以水洗滌，並於減壓下乾燥而得期 望化合物（41 2毫克，78%(2步驟））之無色粉末。ir (KBr)3-Chloro-4-(indolyl-phenylureido)phenylacetic acid (3〇5 mg, 1 〇〇 mmol), 4-[(2S,4S)-4-fluoro-2-pyrrolidinyl Ammonium methoxybenzoate (253 mg, 1.00 mmol), EDC · HC 1 (288 mg, i 50 mmol), HOBT (203 mg, 1.50 mmol) and Et3N ( A mixture of 〇7 〇ml, 5 〇〇mol) in DMF (4 liters) was stirred at room temperature for 7 hours. The mixture was poured into ice water and extracted with EtOAc. The combined extracts were washed with ice water and brine. After drying over Na2s(R)4, the extract was concentrated in vacuo. The residue was chromatographed on silica gel [30 g, CHC13 / acetone (20/1)] to give 4-[1-[3- gas-4-(N,-phenylureido)phenyl hydrazide. A colorless amorphous solid of methyl]-(4S)-|L-(2S)-decalidyl]methyl methoxybenzoate (72 mg, 100%). Ms(FAB) m/z 540 (MH1), 542 (MH3). 4-[1-[3-Chloro-4-(N,-phenylureido)phenylethenyl]-(4S)-fluoro-(2S)-indolyl] methoxybenzoate (72 mg, 1 mmol) Add 0.25 N NaOH (30 ml) to a solution of THF / MeOH (30 / 30 mL). After stirring at room temperature for 2 h, the reaction mixture was Heat at 2 〇〇c for 2 2 hours. After removing the solvent, the resulting residue was acidified with 丨N hc 1 . The sinker was collected, washed with water, and dried under reduced pressure to give a colorless powder of compound (41 2 mg, 78% (2)). Ir (KBr)

第356頁 \\312\2d-code\90-01\89112968.ptd 1283240 五、發明說明（352)Page 356 \\312\2d-code\90-01\89112968.ptd 1283240 V. Description of invention (352)

3346、3302、2976、1712、1604、1240 /公分；NMR (DMSO-d6) (5 2.25-2.31 (m, 2H) &gt;3.66 (d, J-7.8 Hz, 2H) 、3·71-4·67 (m， 5H) 、5·31-5·52 (m， 1H) 、6·99 (t，J = 7.3 Hz， 1H)、7. 04 及 7. 07 (各d，J = 8· 7 Hz，2H， 醯胺異構物）、7·14-7.18 (m，1H)、7·29 (t，J = 7.3 Hz， 2H) 、7·35 (d， J:1.7 Hz, 1H) 、7·46 (d， J=7.8 Hz， 2H)、7.87 及 7.90 (各d, J = 9.0 Hz，2H，醯胺異構物）、 8.04 及 8·06 (各d，J = 8.5 Hz，1H，醯胺異構物）、8·26 及 8· 28 (各s， 1Η，醯胺異構物）、9. 36 (s，1Η)、12. 63 (s，1H); MS(ESI) m/z 526 (MH1)、528 (MH3); C27H25C1FN3 05 ·0·5Η20 之分析計算值：C，60.6 2; H， 4· 90 ; N，7· 85 ; Cl, 6. 63 ; F，3. 55。實測值：C， 61· 〇〇 ; H，5· 19 ; N，7. 40 ; Cl，6· 66 ; F，3· 39。 實施例8 8 4 - [1 - [3 -溴-4-[Ν’ -（2-甲基苯基）脲基]苯基乙醯基]— (4S) -氟-（2 S )-咄咯啶基]曱氧苯甲酸3346, 3302, 2976, 1712, 1604, 1240 / cm; NMR (DMSO-d6) (5 2.25-2.31 (m, 2H) &gt; 3.66 (d, J-7.8 Hz, 2H), 3·71-4· 67 (m, 5H), 5·31-5·52 (m, 1H), 6.99 (t, J = 7.3 Hz, 1H), 7. 04 and 7. 07 (each d, J = 8· 7 Hz, 2H, guanamine isomers), 7·14-7.18 (m, 1H), 7·29 (t, J = 7.3 Hz, 2H), 7.35 (d, J: 1.7 Hz, 1H), 7·46 (d, J=7.8 Hz, 2H), 7.87 and 7.90 (each d, J = 9.0 Hz, 2H, guanamine isomer), 8.04 and 8·06 (each d, J = 8.5 Hz, 1H , guanamine isomers), 8.26 and 8·28 (each s, 1 Η, guanamine isomer), 9.36 (s, 1 Η), 12.63 (s, 1H); MS (ESI) Analysis calculated for m/z 526 (MH1), 528 (MH3); C27H25C1FN3 05 ·0·5Η20: C,60.6 2; H, 4· 90 ; N,7· 85 ; Cl, 6. 63 ; F,3 55. Found: C, 61·〇〇; H,5·19; N, 7.40; Cl,6·66; F,3·39. Example 8 8 4 - [1 - [3 - bromine -4-[Ν' -(2-methylphenyl)ureido]phenylethenyl]-(4S)-fluoro-(2S)-decalidyl]oxobenzoic acid

Me Η Η 3 -漠苯乙酸甲酉旨 ςττMe Η Η 3 - Desert phenylacetate

Br 在室溫下於3-溴苯乙酸（1 〇· 2克，47· 4毫莫耳）溶於二氯 乙烧（50¾升）之攪拌溶液中加入Me〇H(5.8毫升，142毫莫Br Add Me〇H (5.8 ml, 142 mmol) to a stirred solution of 3-bromophenylacetic acid (1 〇·2 g, 47·4 mmol) in dichloroethane (503⁄4 liter) at room temperature.

\\312\2d-code\90-01\89112968.ptd 第357頁 1283240 五、發明說明（353) 耳）&amp;H2S04(0.5毫升）。於攪拌20分鐘後，將混合物在8〇°c 下加熱7小時。將反應混合物倒入至冰水中，並以CHC 13萃 取。將結合的萃取液以N a H C 03水溶液及鹽水洗滌。於在n a 2 S 04上乾燥後’將举取液於真空中濃縮，而得3 -漠苯乙酸 甲酯（1 0· 8 克，99%)的無色油。1H-NMR (CDC13) (5 3. 60 (s， 2H)、3·71 (d，J = 1.0 Hz, 3H)、7. 18-7.44 (m，4H)。 3 —演一 4 -石肖基苯乙酸曱酉旨\\312\2d-code\90-01\89112968.ptd Page 357 1283240 V. Inventive Note (353) Ear) &amp; H2S04 (0.5 ml). After stirring for 20 minutes, the mixture was heated at 8 ° C for 7 hours. The reaction mixture was poured into ice water and extracted with CHC13. The combined extracts were washed with aq. NaH03 aqueous solution and brine. After drying on n a 2 S 04, the extract was concentrated in vacuo to give a colorless oil of &lt;RTI ID=0.0&gt;&gt; 1H-NMR (CDC13) (5 3. 60 (s, 2H), 3.71 (d, J = 1.0 Hz, 3H), 7. 18-7.44 (m, 4H). 3 - Acting a 4 - Shi Xiaoji benzene Acetic acid

在0°C下於3 -氣苯乙酸甲酯（1〇·8克，47.1毫莫耳）在112 SOJ 15· 1毫升）中之攪拌混合物中加入ην〇3(2· 8毫升，70. 7 毫莫耳）。使反應混合物於5 · 5小時内逐漸升溫至室溫。將 反應混合物倒入至冰水中，並以CHC 13萃取。將結合的萃 取液以NaHC〇3水溶液及鹽水洗滌。於在Na2S〇4上乾燥後， 將萃取液於真空中濃縮。使殘留物於矽膠[5 〇 〇克，正己烷 /EtOAc(10/l)]上進行層析，而得3 -漠、-4-石肖基苯乙酸甲 酯（3. 69 克，29%)之黃色油。π-NMR (CDC13) 53· 68 (s, 2H)、3·73 (s, 3H)、7·38 (dd, J = 8.3、1·2 Hz’ 1H)、 7.67 (d，J=1.3 Hz, 1H)、7·83 (d, J = 8.3 Hz, 1H)。 4 -胺基-3 -漠苯乙酸甲g旨Ην〇3 (2·8 ml, 70.) was added to the stirred mixture of 3-methylphenoxyacetate (1 〇·8 g, 47.1 mmol) in 112 SOJ 15·1 ml) at 0 °C. 7 millimoles). The reaction mixture was gradually warmed to room temperature over 5 hours. The reaction mixture was poured into ice water and extracted with CHC 13. The combined extracts were washed with a NaHC 3 aqueous solution and brine. After drying over Na 2 S 〇 4, the extract was concentrated in vacuo. The residue was chromatographed on EtOAc (EtOAc (EtOAc:EtOAc) Yellow oil. π-NMR (CDC13) 53· 68 (s, 2H), 3·73 (s, 3H), 7·38 (dd, J = 8.3, 1·2 Hz' 1H), 7.67 (d, J=1.3 Hz) , 1H), 7·83 (d, J = 8.3 Hz, 1H). 4-amino-3-indiprofenacetate

使3 -溴-4 -硝基苯乙酸甲酯（14. 8克，53. 8毫莫耳）、還Methyl 3-bromo-4-nitrophenylacetate (14. 8 g, 53.8 mM),

\\312\2d-code\90-01\B9112968.ptd 第358頁 1283240 五、發明說明（354) 原鐵粉（9·62 克，172 毫莫耳）、Ac0Na*3H20(7.32 克，53· 8毫莫耳）及八〇011(20.0毫升）於^011/1120( 1 5 0/ 60 0毫升）中 之混合物在9 0 °C下加熱1小時。於冷卻至室溫後，使反應 混合物過濾通過矽藻土，並以Me〇H洗滌濾餅。將結合的濾 液蒸發，並以Et OAc萃取。將萃取液以鹽水洗滌，於Na2S04 上乾燥，並於真空中濃縮。使殘留物於矽膠[4 〇 0克， CHCl3/EtOAc(20/l)]上進行層析，而得4-胺基-3-溴苯乙 酸甲酯（9· 01 克，69%)之棕色油。iH-NMR (CDC13) 5 3· 48 (s， 2H) 、3·68 (s， 3H) 、4·05 (br， 2H) 、6·69 (d， J = 8.3 Hz，1H)、7·00 (dd，J = 8.1、2·0 Hz，1H)、7·32 (d, J = 2· 0 Hz, 1H)。 3-溴-4 - [Ν’ _(2-曱基苯基）脲基]苯乙酸曱酯\\312\2d-code\90-01\B9112968.ptd Page 358 1283240 V. INSTRUCTIONS (354) Original iron powder (9·62 grams, 172 millimoles), Ac0Na*3H20 (7.32 grams, 53·) A mixture of 8 mmol (8 mmol) and gossip 011 (20.0 ml) in ^011/1120 (1 50 / 60 0 mL) was heated at 90 ° C for 1 hour. After cooling to room temperature, the reaction mixture was filtered through celite, and the cake was washed with Me. The combined filtrate was evaporated and extracted with EtOAc. The extract was washed with brine, dried over Na2 EtOAc and evaporated. The residue was chromatographed on EtOAc (EtOAc (EtOAc:EtOAc) oil. iH-NMR (CDC13) 5 3· 48 (s, 2H), 3·68 (s, 3H), 4·05 (br, 2H), 6.69 (d, J = 8.3 Hz, 1H), 7· 00 (dd, J = 8.1, 2·0 Hz, 1H), 7·32 (d, J = 2·0 Hz, 1H). 3-bromo-4 -[Ν' _(2-mercaptophenyl)ureido]phenyl phthalate

在室溫下在4 -胺基-3-溴苯乙酸甲酯（587毫克，2.40毫 莫耳）及異氰酸2 -甲基苯酯（〇·287毫升，2.40毫莫耳）於 THF(2毫升）中之混合物中加入ΕΪ3ν(33毫升，〇· 24毫莫 耳）。於攪拌2 1小時後，將反應混合物於真空中濃縮。經 由加入正己烷將殘留物研製而得3 -溴-4-[Ν，-（2 -甲基苯 基）脲基]苯乙酸甲酯（ 6 5 0毫克，72%)之淡棕色粉末。 NMR (CDC13) (5 2· 34 (s，3Η)、3· 53 (s，2Η)、3· 68 (s，3H)、6·18 (br，1H)、6·96 (br，1H)、7·18-7·33 (m，4Η)、7·29 (d，J=：4.4 Hz, 1Η)、7·30 (d，J = 7.3 Hz, 1H) &gt; 8.19 (d, J-8.3 Hz, 1H) ； MS(ESI) m/zMethyl 4-amino-3-bromophenylacetate (587 mg, 2.40 mmol) and 2-methylphenyl isocyanate (〇·287 mL, 2.40 mmol) in THF at room temperature ΕΪ3ν (33 ml, 〇·24 mmol) was added to the mixture in 2 ml). After stirring for 21 hours, the reaction mixture was concentrated in vacuo. The residue was triturated by the addition of n-hexane to give a pale brown powder of &lt;RTIgt;&lt;/RTI&gt;&gt; 3-bromo-4-[p-,-(2-methylphenyl)ureido]phenylacetate (650 mg, 72%). NMR (CDC13) (5 2· 34 (s, 3Η), 3· 53 (s, 2Η), 3·68 (s, 3H), 6.18 (br, 1H), 6.96 (br, 1H) , 7·18-7·33 (m, 4Η), 7·29 (d, J=: 4.4 Hz, 1Η), 7·30 (d, J = 7.3 Hz, 1H) &gt; 8.19 (d, J- 8.3 Hz, 1H) ; MS(ESI) m/z

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第359頁 1283240 五、發明說明（355) 377 (M+)、379 (MH2)。 3-溴-4 一 [N，一（2 -甲基苯基）脲基]苯乙酸Page 359 1283240 V. Description of invention (355) 377 (M+), 379 (MH2). 3-bromo-4-[N,mono(2-methylphenyl)ureido]phenylacetic acid

於3-溴-4 - [Ν’ - (2-甲基苯基）脲基]苯乙酸曱酯（650毫 克，1· 72毫莫耳）溶於THF(10毫升）之攪拌溶液中加入 0 · 2 5 N N a Ο Η ( 1 0毫升）。於在室溫下授拌1 4小時後，將溶劑 於真空中濃縮。經由加入1 N HC1將殘留物研製，並在6 〇 下在減壓下乾燥2天，而得3 -溴-4-[Ν’-（2-甲基苯基）脲 基]苯乙酸（1.22克，100%)之無色粉末。iH-NMR (DMS0-d6) 占 2·26 (s，3H)、3·32 (s, 2H)、6·93 (m, 2H)、 7.10-7·17 (m， 4Η) 、7·76 (d, J=8.1 Hz, 2Η) 、8·52 (s，1H); MS(ESI) m/z 385 (MHNa)、387(MH2 + Na)。 4 - [1 - [3 -溴-4-[Ν’-（2-甲基苯基）脲基]苯基乙醯基]— (4S) -氟-（2 S)-咄咯啶基]甲氧苯甲酸甲酯Add 0 to a stirred solution of 3-bromo-4 -[2-(2-methylphenyl)ureido]phenylacetate (650 mg, 1.72 mmol) in THF (10 mL) · 2 5 NN a Ο Η (10 ml). After stirring for 14 hours at room temperature, the solvent was concentrated in vacuo. The residue was triturated by the addition of 1 N HCl and dried under reduced pressure at 6 Torr for 2 days to give 3-bromo-4-[[s]-(2-methylphenyl)ureido]phenylacetic acid (1.22). Gram, 100%) of a colorless powder. iH-NMR (DMS0-d6) accounts for 2.26 (s, 3H), 3·32 (s, 2H), 6.93 (m, 2H), 7.10-7·17 (m, 4Η), 7.76 (d, J = 8.1 Hz, 2 Η), 8.52 (s, 1H); MS (ESI) m/z 385 (MHNa), 387 (MH2 + Na). 4-[1 - [3 -Bromo-4-[Ν'-(2-methylphenyl)ureido]phenylethenyl]-(4S)-fluoro-(2S)-indenylpyridyl] Methyl methoxybenzoate

使3-漠-4-[Ν’ -（2-甲基苯基）脲基；]苯乙酸（8〇毫克， 3.22宅莫耳）、4-[(4S)-氟-（2S) -吼咯啶基]曱氧苯曱酸曱 醋（56毫克，〇· 22毫莫耳）、EDC · HCi(63毫克，〇· 33毫莫 =)/11031'(45毫克，〇.33毫莫耳）及£1：31^(0.15毫升，1.10 宅莫耳）於DMF(1毫升）中之混合物在室溫下攪拌18小時。 將此合物倒入至冰水中，並以Et 〇Ac萃取。將結合的萃取3-3--4-(Ν'-(2-methylphenyl)ureido;]phenylacetic acid (8〇mg, 3.22 houser), 4-[(4S)-fluoro-(2S)-吼咯 基 曱 56 56 56 56 56 (56 mg, 〇 · 22 mmol), EDC · HCi (63 mg, 〇 · 33 mM =) / 11031 ' (45 mg, 〇. And a mixture of £1:31 (0.15 ml, 1.10 m.) in DMF (1 mL) was stirred at room temperature for 18 hours. The mixture was poured into ice water and extracted with Et 〇Ac. Combined extraction

\\312\2d-code\90-0l\89112968.ptd 第360頁 1283240 五、發明說明（356) 液以冰水及鹽水洗滌。於在Na2S04上乾燥後，將萃取液於 真空中濃縮。使殘留物於TLC[CHC13 /丙酮（5/1)]上純化 而得4-[1 - [3臭-4 - [Ν’ - (2-甲基苯基）脈基]苯基乙醢 基]-（4S) -氟- (2S) -吼咯啶基]曱氧苯曱酸曱酯（140毫克， 10 0%)之黃色油。1H-NMR (CDC13) δ 2· 30 (s， 3Η)、2· 55 (m，1Η)、3.56 (d，J = 6.4 Hz, 2Η)、3·70-3·84 (m， 3H)、3·87 (s，3H)、3·99 - 4.59 (m，3H)、5·23 - 5·38 (m，1Η)、6·83-6·94 (m，2Η)、6·95 (d, J = 8.8 Ηζ， 1H) ^7.07-7.26 (m, 5H) &gt;7.36-7.63 (m, 2H) &gt;7.94-8. 15 (m，3H); MS(ESI) m/z 598 (MH1)、6 0 0 (MH3)。 於4 - [1 - [3-漠-4 - [Ν’ - (2-曱基苯基）脈基]苯基乙酿 基]-(4S) -氟-（2S) -吼咯啶基]曱氧苯曱酸甲酯（140毫克， 0· 22毫莫耳）溶於THF(10毫升）之溶液中加入〇· 25N NaOH (1 0毫升）。於在室溫下攪拌1 4小時後，將混合物於減壓下 濃縮，並以1 N HC1酸化。收集沈澱物，以水洗滌，並於減 壓下乾燥而得94 ( 1 0 9毫克，85%)之無色粉末。IR (KBr) 3313、3060、2976、1687、1604、1525、1244 / 公分；1 H-NMR (DMS0-d6) 5 2.27 (s, 3H)、2·29 (m，2H)、3·66 (d，J:8.1 Hz, 2H)、3·72-4·68 (m, 5H)、5·31 -5·53 (m，1Η)、6·92-6·99 (m，1Η)、7·04 及 7·07 (各d，J = 8.3 Hz, 2H,醯胺異構物）、7. 1 卜7· 21 (m, 3H)、7. 48 及7. 51 (s, 1H,醯胺異構物）、7· 75 及7· 79 (各d, J = 8· 1 Hz, 1H,醯胺異構物）、7·86 -7.9 2 (m, 3H)、8.45 及 8.47 (各 s, 1H,醯胺異構物）、8, 59 (s，1H)、12· 64 (s，1H);\\312\2d-code\90-0l\89112968.ptd Page 360 1283240 V. INSTRUCTIONS (356) The liquid is washed with ice water and brine. After drying over Na 2 SO 4 , the extract was concentrated in vacuo. The residue was purified on TLC [CHC13 / acetone (5 / 1)] to give 4-[1 - [3 odor-4 - [Ν' - (2-methylphenyl) fluorenyl] phenyl ethane A yellow oil of -(4S)-fluoro-(2S)-indolyl]phosphonium oxyhydrazide (140 mg, 100%). 1H-NMR (CDC13) δ 2· 30 (s, 3Η), 2· 55 (m, 1Η), 3.56 (d, J = 6.4 Hz, 2Η), 3·70-3·84 (m, 3H), 3·87 (s,3H),3·99 - 4.59 (m,3H),5·23 - 5·38 (m,1Η),6·83-6·94 (m,2Η),6·95 ( d, J = 8.8 Ηζ, 1H) ^7.07-7.26 (m, 5H) &gt;7.36-7.63 (m, 2H) &gt;7.94-8. 15 (m,3H); MS(ESI) m/z 598 ( MH1), 600 (MH3). 4 - [1 - [3-Moist-4 - [Ν' - (2-Mercaptophenyl))]phenylethyl]-(4S)-fluoro-(2S)-oxaridinyl] Methyl phenoxybenzoate (140 mg, 0.22 mmol) was dissolved in THF (10 mL) and EtOAc········ After stirring at room temperature for 14 hours, the mixture was concentrated under reduced pressure and acidified with 1 N EtOAc. The precipitate was collected, washed with water and dried under reduced pressure to give 94 (1,9,,,, IR (KBr) 3313, 3060, 2976, 1687, 1604, 1525, 1244 / cm; 1 H-NMR (DMS0-d6) 5 2.27 (s, 3H), 2·29 (m, 2H), 3·66 ( d, J: 8.1 Hz, 2H), 3·72-4·68 (m, 5H), 5·31 -5·53 (m, 1Η), 6.92-6·99 (m, 1Η), 7 · 04 and 7·07 (each d, J = 8.3 Hz, 2H, guanamine isomer), 7. 1 卜 7· 21 (m, 3H), 7.48 and 7. 51 (s, 1H, 醯Amine isomers), 7·75 and 7·79 (each d, J = 8·1 Hz, 1H, guanamine isomer), 7·86 -7.9 2 (m, 3H), 8.45 and 8.47 (each s, 1H, guanamine isomer), 8, 59 (s, 1H), 12·64 (s, 1H);

\\312\2d-code\90-01\89112968.ptd 第361頁 1283240 五、發明說明（357) MS(FAB) m/z 584(MH1)、586 (MH3); C28H27BrFN3〇5 之分析 計算值：C, 57.54 ; H，4.66; N，7·19; Br，13·67; f， 3.25° 實測值· C, 57.9 3； H, 4.97； N, 7.04； Br, 13· 35 ; F， 2. 89 。 實施例8 9 4 - [l-[3 -漠-4 - [Ν’ -（2 -氣苯基）脲基]苯基乙酿基]-(4S) -氟-(2S)-吼咯啶基]甲氧苯曱酸\\312\2d-code\90-01\89112968.ptd Page 361 1283240 V. INSTRUCTIONS (357) MS (FAB) m/z 584 (MH1), 586 (MH3); C28H27BrFN3〇5 analytical calculation :C, 57.54; H,4.66; N,7·19; Br,13·67; f, 3.25° Found C · 57.9 3; H, 4.97; N, 7.04; Br, 13· 35 ; F, 2 89. Example 8 9 4 - [l-[3 - Desert-4 - [Ν' -(2-Phenylphenyl)ureido]phenylethyl]-(4S)-Fluoro-(2S)-Ethrolidine Methotrexate

Cl Η H 4r 95 3-漠-4-[N’ _(2-氣苯基）脈基]苯乙酸甲S旨Cl Η H 4r 95 3- Desert-4-[N' _(2-Phenylphenyl)-yl]phenylacetate A

在室溫下在4_胺基-3-溴苯乙酸曱酯（587毫克，2.40毫 莫耳）及異氰酸2 -氣苯酯（0.29毫升，2.40毫莫耳）於THF (2毫升）中之混合物中加入E t3 N ( 3 3毫升，〇 . 2 4毫莫耳）。 於攪拌2 1小時後，將反應混合物於真空中濃縮。經由加入 正己烷將殘留物研製而得3-溴-4-[Ν’ _(2 -氯苯基）脲基] 苯乙酸甲酯（710毫克，74%)之淡棕色粉末。1H-NMR (CDC1 3) (5 3· 57 (s， 2H)、3· 7 0 (s， 3H)、7· 02-7· 28 (m， 2H)、7·36 (d，J 二 6·8 Hz，1H)、7·48 (s，1H)、8·00-8· 11 (m, 2H); MS(ESI) m/z 397(M+) 、399 (MH2)、401 (MH4) 〇 3-溴-4-[Ν’-（2-氯苯基）脲基]苯乙酸Ethyl 4-amino-3-bromophenylacetate (587 mg, 2.40 mmol) and 2-phenylphenyl isocyanate (0.29 mL, 2.40 mmol) in THF (2 mL) E t3 N (3 3 ml, 〇. 2 4 mmol) was added to the mixture. After stirring for 21 hours, the reaction mixture was concentrated in vacuo. The residue was triturated by the addition of n-hexane to give a pale brown powder of methyl 3-bromo-4-[?? 1H-NMR (CDC1 3) (5 3· 57 (s, 2H), 3· 7 0 (s, 3H), 7· 02-7· 28 (m, 2H), 7·36 (d, J 2 6 · 8 Hz, 1H), 7·48 (s, 1H), 8·00-8· 11 (m, 2H); MS (ESI) m/z 397 (M+), 399 (MH2), 401 (MH4) 〇3-bromo-4-[Ν'-(2-chlorophenyl)ureido]phenylacetic acid

\\312\2d-code\90-01\89112968.ptd 第362頁 1283240 五、發明說明（358)\\312\2d-code\90-01\89112968.ptd Page 362 1283240 V. Description of invention (358)

於3-溴-4-[N’ -（2-氣苯基）脲基]笨乙酸曱酯（71〇毫克， 1· 79毫莫耳）溶於THF(10毫升）之攪拌溶液中加入〇. 25N NaOH(10毫升）。於在室溫下攪拌14小時後，將溶劑於真空 中濃縮。經由加入IN HC1將殘留物研製，並在6〇下在減 壓下乾無2天’而得3 - &gt;臭-4-[Ν’-（2~氯苯基）脲基]苯乙酸（ 643 毫克，94%)之無色粉末。NMR (DMS0-d6)(5 3.56 (s，2H)、7·05 (m，1H)、7·21 (dd，J = 8.6、1·7 Hz, 1H)、7·29 (t，J一7·8 Hz，1H)、7·46 (d，J = 8.1 Hz, 1H)、7·46 (d, J = 8.1 Hz，1H)、7·53 (d，J:1.7 Hz, 1H)、7.83 (d，J = 8.3 Hz, 1H)、8·〇6 (d，J = 7.6 Hz, 1H)、8.86 (s，1H)、8.89 (s，1H)、12,40 (s，1H); MS(ESI) m/z 38 2 (MH1)、384 (MH3)。 4 - [1-[3 -溴-4-[Ν’ -（2 -氯苯基）脲基]苯基乙醯基卜（4S) — 氟-（2S)-咄咯啶基]曱氧苯甲酸曱酯Add hydrazine to a stirred solution of 3-bromo-4-[N'-(2-phenylphenyl)ureido] acetoacetate (71 mg, 1.79 mmol) in THF (10 mL) . 25N NaOH (10 ml). After stirring at room temperature for 14 hours, the solvent was concentrated in vacuo. The residue was triturated by the addition of IN HC1 and dried under reduced pressure at 6 Torr for 2 days to give 3 -&gt; odor-4-[Ν'-(2~chlorophenyl)ureido]phenylacetic acid ( 643 mg, 94%) of a colorless powder. NMR (DMS0-d6) (5 3.56 (s, 2H), 7·05 (m, 1H), 7·21 (dd, J = 8.6, 1. 7 Hz, 1H), 7·29 (t, J 7·8 Hz, 1H), 7·46 (d, J = 8.1 Hz, 1H), 7.46 (d, J = 8.1 Hz, 1H), 7·53 (d, J: 1.7 Hz, 1H), 7.83 (d, J = 8.3 Hz, 1H), 8·〇6 (d, J = 7.6 Hz, 1H), 8.86 (s, 1H), 8.89 (s, 1H), 12, 40 (s, 1H); MS (ESI) m/z 38 2 (MH1), 384 (MH3). 4 - [1-[3 -bromo-4-[Ν' -(2-chlorophenyl)ureido]phenylethenyl (4S) — fluoro-(2S)-decalidyl] decyloxybenzoate

C〇2Me 使3-溴-4-[N’-(2 -氯苯基）脲基]苯乙酸（384毫克，1〇〇 毫莫耳）、4-[(4S) -氟-（2S) -吼咯啶基]甲氧苯曱酸曱酯 (253毫克，1.00毫莫耳）、EDC*HC 1(288毫克，1.50毫莫 耳）、HOBT( 2 0 3毫克，1·50毫莫耳）及Et3N(0.70毫升， 5.00¾莫耳）於DMF(4毫升）中之混合物在室溫下攪拌Η小C〇2Me makes 3-bromo-4-[N'-(2-chlorophenyl)ureido]phenylacetic acid (384 mg, 1 〇〇 mmol), 4-[(4S)-fluoro-(2S) - 吼pyridyl] methoxybenzoate (253 mg, 1.00 mmol), EDC*HC 1 (288 mg, 1.50 mmol), HOBT (203 mg, 1.50 mmol) And a mixture of Et3N (0.70 ml, 5.003⁄4 mol) in DMF (4 ml) was stirred at room temperature.

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第363頁 1283240 五、發明說明（359) 時。將混合物倒入至冰水中，並以Et〇Ac萃取。將結合的 萃取液以冰水及鹽水洗滌。於在Na2S〇4上乾燥後，將萃取 液於真空中》辰縮。使殘留物於矽膠[3〇克，CHCh /丙酮 (10/1)]上進行層析，而得4-[1 —[3_溴-4—[N，—（2-氣苯基） 脲基]苯基乙醯基]- (4S) -氟〜（2S) -吼咯啶基]甲氧苯曱酸 曱6旨（6 40毫克，100°/〇之無色非晶形固體。111一麗1?((：1)(：13) 5 2.0 7-2.4 6 (m，2H)、2·59 (t，J:18.4 Hz, 1H)、 3.57 (d，J=10.5 Hz, 2H)、3.6 3-4.67 (m, 7H)、5·26 -5·44 (m，1H)、6·89-6.96 (m，3H)、7·13 (d，J = 7.6 Hz, 1H)、7·1 (t，J = 7.3 Hz, 1H)、7.26-7.2 9 (m， 2H) 、7.52-7.94 (m， 4H) 、8·〇1 (d， J=8·5Ηζ，1Η)、8· 09 (d，J = 8.5 Hz, 1H); MS(FAB) m/z 618 (M+)、6 20 (M H3)、622 (MH5)。 於4_[1-[3-溴- 4- [N’-(2-氣苯基）脲基]苯基乙醯 基]-（4S) -氟-（2S)-毗咯啶基]甲氧苯甲酸曱酯（640毫克， 1· 00毫莫耳）溶於THF(40毫升）之溶液中加入0· 25N NaOH (4 0毫升）。於在室溫下攪拌1 4小時後，將混合物於減壓下 濃縮，並以1 N H C 1酸化。收集沈澱物，以水洗滌，並於減 壓下乾燥而得95 ( 5 22毫克，86%)之淡黃色粉末。IR UBr) 3317、3072、1709、1685、1604、1529、1290 / 公分；1 H-NMR (DMS0-d6) (5 2.24 -2.5 0 (m, 2H) ^ 3. 67 (d, J = 8. 3 Hz，2H)、3·73-4·68 (m，5H)、5·3 卜 5.52 (m，1H)、 7.03-7.09 (m，3H)、7.22(dt，J==8.3、1.7Hz，lH)、 7.30 (d， J = 7.3 Hz， 1Η)、7·46 (dd，J = 8.0、1.4 Hz,Page 363 1283240 V. Inventions (359). The mixture was poured into ice water and extracted with Et EtOAc. The combined extracts were washed with ice water and brine. After drying on Na2S〇4, the extract was condensed in a vacuum. The residue was chromatographed on silica gel [3 g, CHCh / acetone (10/1)] to give 4-[1 -[3_bromo-4-[N,-(2-phenylphenyl)urea Phenylethyl fluorenyl]-(4S)-fluoro-(2S)-pyridinyl]methoxybenzoic acid hydrazine 6 (6 40 mg, 100 ° / 〇 colorless amorphous solid. 111 a Li 1?((:1)(:13) 5 2.0 7-2.4 6 (m,2H), 2·59 (t, J:18.4 Hz, 1H), 3.57 (d, J=10.5 Hz, 2H), 3.6 3-4.67 (m, 7H), 5·26 -5·44 (m, 1H), 6·89-6.96 (m, 3H), 7·13 (d, J = 7.6 Hz, 1H), 7·1 (t, J = 7.3 Hz, 1H), 7.26-7.2 9 (m, 2H), 7.52-7.94 (m, 4H), 8·〇1 (d, J=8·5Ηζ, 1Η), 8· 09 ( d, J = 8.5 Hz, 1H); MS(FAB) m/z 618 (M+), 6 20 (M H3), 622 (MH5). 4_[1-[3-Bromo- 4- [N'- (2-Phenylphenyl)ureido]phenylethenyl]-(4S)-fluoro-(2S)-azirolidyl]methoxybenzoate (640 mg, 1.00 mmol) 0. 25N NaOH (40 ml) was added to a solution of THF (40 ml). After stirring at room temperature for 14 hours, the mixture was concentrated under reduced pressure and acidified with 1 NH. Washed with water and Dry to 95 (5 22 mg, 86%) of pale yellow powder. IR UBr) 3317, 3072, 1709, 1685, 1604, 1529, 1290 / cm; 1 H-NMR (DMS0-d6) (5 2.24 -2.5 0 (m, 2H) ^ 3. 67 (d, J = 8. 3 Hz, 2H), 3·73-4·68 (m, 5H), 5·3 Bu 5.52 (m, 1H), 7.03 -7.09 (m, 3H), 7.22 (dt, J==8.3, 1.7 Hz, lH), 7.30 (d, J = 7.3 Hz, 1Η), 7.46 (dd, J = 8.0, 1.4 Hz,

\\312\2d-code\90-01\89112968.ptd 第 364 頁 1283240 五、發明說明（360) 1H)、7·49 及 7·52 (各d，J = 2.0 Hz，1H，醯胺異構物）、 7·80-7·91 (m，3H)、8·07 (dd，J = 8.3、1·2 Hz, 1H)、 8·85及8·86 (各s，1H，醯胺異構物）、8·96及8·97 (各s， 1H，醯胺異構物）、12· 62 (s，1H) ; MS(FAB) m/z 605 (MH1)、607(MH3)、60 9 (MH3)、626 (MH1+Na); C27H24BrClFN3 05 · 〇· 8H20 之分析計算值：C，52. 37 ; H， 4·17;Ν，6.79;F，3.07。實測值：C，52.63; H， 4.12； N, 6.62; F, 2.97° 實施例9 0 4 - [1_[3-漠-4-[Ν’ -（2 -漠苯基）脲基]苯基乙醯基]-(4S)_ 氟-（2S)-吼咯啶基]甲氧苯甲酸\\312\2d-code\90-01\89112968.ptd Page 364 1283240 V. INSTRUCTIONS (360) 1H), 7·49 and 7·52 (each d, J = 2.0 Hz, 1H, indoleamine Structure), 7·80-7·91 (m, 3H), 8·07 (dd, J = 8.3, 1·2 Hz, 1H), 8·85 and 8·86 (each s, 1H, guanamine Isomers), 8.96 and 8.97 (each s, 1H, guanamine isomer), 12.62 (s, 1H); MS (FAB) m/z 605 (MH1), 607 (MH3) , 60 9 (MH3), 626 (MH1 + Na); C27H24BrClFN3 05 · 〇· 8H20 Analysis calculated: C, 52. 37; H, 4·17; Ν, 6.79; F, 3.07. Found: C, 52.63; H, 4.12; N, 6.62; F, 2.97° Example 9 0 4 - [1_[3-Mo -4-[Ν' -(2 - 苯基 phenyl) ureido]phenyl Ethyl]-(4S)_fluoro-(2S)-indolyl]methoxybenzoic acid

3 -溴-4-[Ν’ -（2-溴苯基）脲基]苯乙酸甲酯Methyl 3-bromo-4-[Ν'-(2-bromophenyl)ureido]phenylacetate

在室溫下在4-胺基-3 -溴苯乙酸甲酯（587毫克，2. 40毫 莫耳）及異氰酸2 -溴苯酯（0.30毫升，2.40毫莫耳）於THF (2毫升）中之混合物中加入Et3N(33毫升’0.24毫莫耳）。 於攪拌4小時後，將反應混合物於真空中濃縮。經由加入 正己烷將殘留物研製而得3 —溴-4 - [ N ’ -（ 2 -溴苯基）脲基] 苯乙酸甲酯（770毫克，73%)之淡棕色粉末。1H-NMR (CDC13) 5 3· 55 (s，2H)、3. 70 (s，3H)、6· 97 (dd，Methyl 4-amino-3-bromophenylacetate (587 mg, 2.40 mmol) and 2-bromophenyl isocyanate (0.30 mL, 2.40 mmol) in THF (2) Et3N (33 ml '0.24 mmol) was added to the mixture in ML). After stirring for 4 hours, the reaction mixture was concentrated in vacuo. The residue was triturated by the addition of n-hexane to give &lt;RTI ID=0.0&gt;&gt;&gt; 1H-NMR (CDC13) 5 3· 55 (s, 2H), 3. 70 (s, 3H), 6.97 (dd,

89112968.ptd 第365頁 1283240 五、發明說明（361) J = 7.3、1·5 Hz，1H)、7·22 (dd, J = 8.5、2·2 Hz, 1H)、 7.29-7.33 (m，2H)、7·48 (d, J = l.〇、2·2 Hz，1H)、7· 54 (dd，J = 8.0、1·2 Hz，1H)、8·01 (m，2H); MSUSI) m/z 443(MH1)、445 (MH3)、447(MH5)。 3-溴- 4- [N’-（2 -溴笨基）脲基]苯乙酸89112968.ptd Page 365 1283240 V. INSTRUCTIONS (361) J = 7.3, 1·5 Hz, 1H), 7·22 (dd, J = 8.5, 2·2 Hz, 1H), 7.29-7.33 (m, 2H), 7·48 (d, J = l.〇, 2·2 Hz, 1H), 7·54 (dd, J = 8.0, 1·2 Hz, 1H), 8·01 (m, 2H); MSUSI) m/z 443 (MH1), 445 (MH3), 447 (MH5). 3-bromo-4-[N'-(2-bromophenyl)ureido]phenylacetic acid

於3-溴-4-[Ν’ 2-溴苯基）脲基]苯乙酸甲酯（ 770毫克， 1. 74毫莫耳）溶於THF( 1 0毫升）之攪拌溶液中加入〇. 25Ν NaOH(1 0毫升）。於在室溫下攪拌1 4小時後，將溶劑於真空 中濃縮。經由加入1 N HC1將殘留物研製，並在6〇 °C下在減 壓下乾燥2天，而得3-溴-4-[N’-(2-溴苯基）脲基]苯乙酸 (702 毫克，94%)之無色粉末。iH-NMR (DMS0-d6) 5 3· 56 (s，2H)、6·99 (dt，】 = 7·8、1·5 Hz，1H)、7·21 (dd， J = 8.3、1·7 Ηζ，1Η)、7·33 (dt，J = 7.1、1·5 Hz, 1Η)、 7.53 (d，J = 1.7 Hz, 1H)、7·62 (dd，J = 8.1、1·5 Hz， 1H)、7·82 (d，J = 8.3 Hz， 1H)、7·93 (dd，J = 8.1、1·5 Hz，1H)、8·82 (s，1H)、8·86 (s，1H)、12.39 (s， 1H); MS(ESI) m/z 428 (MH1)、430 (MH3)。 4 - [l-[3 -溴-4 - [Ν’- (2 -溴苯基）脲基]苯基乙醯基]— (4S) 一 氟-（2S)-吡咯啶基]甲氧苯甲酸甲酯Add hydrazine to a stirred solution of methyl 3-bromo-4-[Ν'2-bromophenyl)ureido]phenylacetate (770 mg, 1.74 mmol) in THF (10 mL). NaOH (10 ml). After stirring at room temperature for 14 hours, the solvent was concentrated in vacuo. The residue was triturated by the addition of 1 N HCl and dried under reduced pressure at 6 ° C for 2 days to give 3-bromo-4-[N'-(2-bromophenyl)ureido]phenylacetic acid ( 702 mg, 94%) of a colorless powder. iH-NMR (DMS0-d6) 5 3· 56 (s, 2H), 6·99 (dt, ) = 7·8, 1·5 Hz, 1H), 7·21 (dd, J = 8.3, 1· 7 Ηζ, 1Η), 7·33 (dt, J = 7.1, 1·5 Hz, 1Η), 7.53 (d, J = 1.7 Hz, 1H), 7.62 (dd, J = 8.1, 1. 5 Hz , 1H), 7·82 (d, J = 8.3 Hz, 1H), 7.93 (dd, J = 8.1, 1. 5 Hz, 1H), 8·82 (s, 1H), 8·86 (s , 1H), 12.39 (s, 1H); MS (ESI) m/z 428 (MH1), 430 (MH3). 4-[1-[3-Bromo-4 -[Ν'-(2-bromophenyl)ureido]phenylethenyl]-(4S)-fluoro-(2S)-pyrrolidinyl]methoxybenzene Methyl formate

89112968.ptd 第366頁 1283240 五、發明說明（362) &quot;~ 使3-漠-4-[N’ -(2-氣笨基）脲基]苯乙酸（428毫克，L 〇〇 毫莫耳）、4 - [(2S，4S)-4 -氟-2 -咄咯啶基]曱氧苯甲酸甲酯 (253宅克’1.00耄莫耳）、EDC*HC1(288毫克，1.50毫莫 耳）、HOBT( 2 03毫克，1.50毫莫耳）及Et3N(0.70毫升， 5· 00毫莫耳）於DMF (4毫升）中之混合物在室溫下攪拌丨8小 時。將混合物倒入至冰水中，並以E t〇Ac萃取。將結合的 萃取液以冰水及鹽水洗滌。於在Na2S04上乾燥後，將萃取 液於真空中濃縮。使殘留物於矽膠[3〇克，CHC13 /丙酮 (10/1)]上進行層析而得4-[1-[3 -溴-4-[N，-（2-溴苯基） 脲基]苯基乙醯基]- (4S) - (2S) - ϋ比洛咬基]曱氧苯曱酸 曱酯（ 7 20毫克，100%)之無色非晶形固體。iH — NMR (CDCl3) 5 2.0 7-2.4 5 (m，2H)、2·58 (m，1H)、3·58 (d，J:9.0 H z，2 H )、3. 6 3 - 4 · 6 9 (m，9 H )、5 · 2 6 - 5 · 4 3 (m，1 H )、 6.88-6.99 (m，3H)、7.16(d，J = 8.3Hz，lH)、7.23-7· 32 (m, 2H) 、7·46 (dd， J=8.1 、1·5 Hz, 1H) 、7·51 -8.20 (m，5H); MS(FAB) m/z 6 64 (M+)、6 6 6 (MH3)、 668 (MH5)。 於4-[l-[3 -臭- 4- [N’ - (2-漠苯基）脲基]苯基乙醯基 ]-(4S) -氟-(2S)-吼咯啶基]甲氧苯甲酸曱酯（720毫克，1. 00毫莫耳）溶於THF (40毫升）之溶液中加入0· 25N NaOH (4 0毫升）。於在室溫下授拌1 4小時後，將混合物於真空中 濃縮，並以IN HC1酸化。以CHC13 /MeOH(10/l)萃取混合 物。將結合的萃取液以冰水及鹽水洗滌。於在Na2S04上乾 燥後，將萃取液於真空中濃縮。使殘留物於矽膠[2 0克，89112968.ptd Page 366 1283240 V. INSTRUCTIONS (362) &quot;~ 3-3--4-(N'-(2-Aceto)-ureido]phenylacetic acid (428 mg, L 〇〇 millimol , 4 - [(2S,4S)-4 -Fluoro-2-pyridinyl]oxobenzoic acid methyl ester (253 home grams '1.00 耄 Mo ear), EDC*HC1 (288 mg, 1.50 millimoles) The mixture of HOBT (2 03 mg, 1.50 mmol) and Et3N (0.70 ml, 5.00 mmol) in DMF (4 ml) was stirred at room temperature for 8 hours. The mixture was poured into ice water and extracted with EtOAc. The combined extracts were washed with ice water and brine. After drying over Na 2 SO 4 , the extract was concentrated in vacuo. The residue was chromatographed on silica gel [3 g, CHC13 / acetone (10/1)] to give 4-[1-[3-bromo-4-[N,-(2-bromophenyl)ureido Phenylethyl fluorenyl]-(4S) - (2S) - indole thiophene phthalate (7 20 mg, 100%) as a colorless amorphous solid. iH — NMR (CDCl3) 5 2.0 7-2.4 5 (m, 2H), 2·58 (m, 1H), 3·58 (d, J: 9.0 H z, 2 H ), 3. 6 3 - 4 · 6 9 (m, 9 H ), 5 · 2 6 - 5 · 4 3 (m, 1 H ), 6.88-6.99 (m, 3H), 7.16 (d, J = 8.3 Hz, lH), 7.23-7· 32 (m, 2H), 7.46 (dd, J=8.1, 1. 5 Hz, 1H), 7·51 - 8.20 (m, 5H); MS(FAB) m/z 6 64 (M+), 6 6 6 (MH3), 668 (MH5). 4-[l-[3-odor 4-[N'-(2-indolyl)ureido]phenylethenyl]-(4S)-fluoro-(2S)-indolyl]A To a solution of decyl oxybenzoate (720 mg, 1.00 mmol) in THF (40 mL) was added EtOAc (EtOAc). After stirring for 14 hours at room temperature, the mixture was concentrated in vacuo and acidified with IN EtOAc. The mixture was extracted with CHC13 / MeOH (10 / 1). The combined extracts were washed with ice water and brine. After drying on Na2S04, the extract was concentrated in vacuo. Make the residue in silicone [20 grams,

\\312\2d-code\90-01\89112968.ptd 第 367 頁 1283240 五、發明說明（363) CHC13/ 丙酮（10/1) - CHCl3/MeOH(20/l)]上進行層析，並 經由加入乙醚研製而得9 6 ( 4 8 9毫克，75%)的無色非晶形固 體。IR (KBr) 3450、3313、3070、1709、1684、1525、 1435 / 公分；l-NMR (DM SO-d6) 6 2.25-2.50 (m，2H)、 3. 67 (d, J = 8. 3 Hz, 2H)、3.73 - 4.68 (m, 5H)、5.3 卜 5. 53 (m，1H)、6·98 -7.08 (m, 3H)、7.21 (d，&gt;8.2 Hz, 1H)、7.34 (t, J = 8. 8 Hz, 1H)、7.50 及 7.53 (各s, 1H， 醯胺異構物）、7.62 (d, J = 8.0 Hz, 1H)、7·80-7·96 (m， 4H)、8·82 (s，1H); 8.85 及 8·86 (各s，1H，醯胺異構 物）、12·63 (br，1H); MS(FAB) m/z 650 (MH1)、652 (MH3)、6 54 (MH3)、672 (MHNa); C27H24Br2FN3 05 ·0·9Η20 之分析計算值：C，48· 73 ; H，3. 91 ; N，6. 31 ; F，2. 85 。實測值：C, 4 8. 96 ； H, 3.98； N, 5. 92 ； F, 2.77 ° 實施例9 1 4-[l-[4-[N’ - (2 -曱基苯基）脈基]- 2，3-二氟苯基乙醢基] -(4S) -氟-（2 S)-吼咯啶曱氧基]苯甲酸\\312\2d-code\90-01\89112968.ptd Page 367 1283240 V. INSTRUCTIONS (363) CHC13/ Acetone (10/1) - CHCl3/MeOH (20/l)] was chromatographed and Trituration via the addition of diethyl ether gave 9 6 ( 498 mg, 75%) of colourless amorphous solid. IR (KBr) 3450, 3313, 3070, 1709, 1684, 1525, 1435 / cm; l-NMR (DM SO-d6) 6 2.25-2.50 (m, 2H), 3. 67 (d, J = 8. 3 Hz, 2H), 3.73 - 4.68 (m, 5H), 5.3 Bu 5. 53 (m, 1H), 6.98 -7.08 (m, 3H), 7.21 (d, &gt; 8.2 Hz, 1H), 7.34 ( t, J = 8. 8 Hz, 1H), 7.50 and 7.53 (each s, 1H, guanamine isomer), 7.62 (d, J = 8.0 Hz, 1H), 7·80-7·96 (m, 4H), 8.82 (s, 1H); 8.85 and 8.86 (each s, 1H, guanamine isomer), 12·63 (br, 1H); MS (FAB) m/z 650 (MH1) 652 (MH3), 6 54 (MH3), 672 (MHNa); C27H24Br2FN3 05 ·0·9Η20 Analysis calculated: C, 48· 73 ; H, 3. 91 ; N, 6. 31 ; F, 2. 85. Found: C, 4 8. 96 ; H, 3.98; N, 5. 92 ; F, 2.77 ° Example 9 1 4-[l-[4-[N' - (2-nonylphenyl)) ]- 2,3-Difluorophenylethenyl]-(4S)-fluoro-(2S)-indolyloxyl]benzoic acid

2，3 -二IL-4 -石肖基苯乙酸乙酉旨2,3 -di-IL-4 - schiffyl phenylacetate

在室溫下於乙基丙二酸第三丁酯（5.35毫升，28.2毫莫 耳）溶於DMF( 150毫升）之攪拌溶液中加入NaH(60%溶於油NaH (60% soluble in oil) was added to a stirred solution of tert-butyl ethylmalonate (5.35 mL, 28.2 mmol) in DMF (150 mL) at room temperature.

\\312\2d-code\90-01\89112968.ptd 第368頁 1283240 五、發明說明（364) 3· 38克，84· 7毫莫耳）。於20分鐘後，將2, 3-二氟硝基苯 (5克，28.2毫莫耳）溶於DMF( 50毫升）經由滴漏斗逐滴加 入。於添加後，使混合物在室溫下攪拌3小時。將混合物 倒入至冰水及飽和NH4C1(100毫升）中。以EtOAc萃取混合 物，並將結合的有機層以1M HC1及鹽水洗滌，於MgS04上 乾燥，過濾及濃縮。將殘留物溶解於二氯甲烷（20毫升）， 並在室溫下加入T F A ( 2 0毫升）。使混合物迴流1 8小時。使 混合物於真空中蒸發，與甲苯（20毫升x2)共同蒸發。使殘 留物於矽膠（中壓層析系統：YAMAZENYFLC-540 4-FC，線 性梯度己烷-EtOAc 10:0至1:1，¢)50毫米X 300毫米，15 毫升/分鐘）上進行層析，而得2, 3_二氟-4 -硝基苯乙酸乙 酯（5· 85 克，85%)之黃色油。iH-NMR (CDC13) 6 1 · 30 (m, 3H)、3·78 (s, 2H)、4·22 (m，2H)、7·22 (m, 1H)、 7·84 (m，1H); MS(FAB) m/z 24 6(MH1)。 4-胺基-2, 3-二氟苯乙酸乙酯\\312\2d-code\90-01\89112968.ptd Page 368 1283240 V. Inventions (364) 3·38 grams, 84·7 millimoles). After 20 minutes, 2,3-difluoronitrobenzene (5 g, 28.2 mmol) was dissolved in DMF (50 mL). After the addition, the mixture was stirred at room temperature for 3 hours. The mixture was poured into ice water and saturated aqueous NH4CI (100 mL). The mixture was extracted with EtOAc. EtOAc m. The residue was dissolved in dichloromethane (20 mL) and EtOAc (EtOAc) The mixture was refluxed for 18 hours. The mixture was evaporated in vacuo and evaporated with EtOAc (20 mL). The residue was chromatographed on silica gel (medium pressure chromatography system: YAMAZENYFLC-540 4-FC, linear gradient hexane-EtOAc 10:0 to 1:1, hydrazine) 50 mm X 300 mm, 15 ml/min) A yellow oil of 2,3-difluoro-4-nitrophenylacetate (5·85 g, 85%) was obtained. iH-NMR (CDC13) 6 1 · 30 (m, 3H), 3·78 (s, 2H), 4·22 (m, 2H), 7·22 (m, 1H), 7·84 (m, 1H) MS (FAB) m/z 24 6 (MH1). Ethyl 4-amino-2, 3-difluorophenylacetate

OEt 在室溫下於2, 3-二氟-4 -硝基苯乙酸乙酯（5.85克，23·9 莫耳）溶於EtOH( 1 0 0毫升）之攪拌溶液中加入SnC i2 (j 1 克，7 1 · 6毫莫耳）。在迴流下持續攪拌1 8小時。於移卜々 劑後，將殘留物溶解於CHCl〆1〇〇毫升），並倒入至^牙、落 -4M NaOH(40毫升之4M NaOH溶於30 0毫升之冰水）中’，水 CHC13(100毫升x2)萃取，於無水MgS04上乾燥，並於 、残壓下OEt Add SnC i2 (j 1) to a stirred solution of ethyl 2, 3-difluoro-4-nitrophenylacetate (5.85 g, 2·9 mol) in EtOH (100 mL) at room temperature. Gram, 7 1 · 6 millimoles). Stirring was continued for 18 hours under reflux. After the transfer of the herbicide, the residue was dissolved in CHCl (1 ml) and poured into a tooth, 4 M NaOH (40 ml of 4 M NaOH dissolved in 30 ml of ice water), water Extracted by CHC13 (100 ml x 2), dried on anhydrous MgS04, and under residual pressure

1283240 五、發明說明（365) 濃縮。使殘留物於矽膠（中壓層析系統YAMAZEN YFLC-5404，己烷-EtOAc自9:1至7:3之線性梯度，050毫米X 500毫米，15毫升/分鐘）上進行層析，而得4—胺基— 2,3-二氟苯乙酸乙酯（1.94克，38%)之無色油。iH —(Cj)ci3) 5 1.25 (t， J=7.3 Hz, 3H) 、3·55 (d, J二1·〇 Hz, 2H)、3· 78 (brs，2H)、4· 15 (dd，&gt;7· 2 Hz、14 2 Hz 2H)、6. 49 (dt，J = l· 8、8· 2 Hz，1H)、6· 78 (m，ih); MS(FAB) m/z 216 (MH1) o 4-[(2-甲基苯基）脲基]-2, 3-二氟苯乙酸1283240 V. Description of invention (365) Concentration. The residue was chromatographed on silica gel (medium pressure chromatography system YAMAZEN YFLC-5404, hexane-EtOAc from a linear gradient from 9:1 to 7:3, 050 mm X 500 mm, 15 ml/min). 4-Amino-2,3-difluorophenylacetate (1.94 g, 38%) as a colorless oil. iH —(Cj)ci3) 5 1.25 (t, J=7.3 Hz, 3H), 3·55 (d, J 2·〇Hz, 2H), 3·78 (brs, 2H), 4·15 (dd , &gt;7· 2 Hz, 14 2 Hz 2H), 6.49 (dt, J = l·8, 8· 2 Hz, 1H), 6·78 (m, ih); MS(FAB) m/z 216 (MH1) o 4-[(2-Methylphenyl)ureido]-2, 3-difluorophenylacetic acid

一 ^室溫下於4-胺基-2, 3-二氟笨乙酸乙酯（323毫克，丨· 5 ”耳)，DMF(8·升)之搜拌溶液中加入三乙胺(〇 2〇9 ，1.5毫莫耳）及異氰酸2_甲基苯酯（〇 372毫升，3 〇 3 ΐ):在8?下持續攪拌48小時。將反應混合物於真 工中瘵發，及使固體懸浮於正己栌 π丄、、 體。將固體溶解於THF-MeOHU · 1元/。坐過濾收集固 溫下加入4MNa〇H(10毫升）1在20毫升），並在室 物。利用CHCl3-正己燒使固二過f收集所產生之沈澱 基）服基]-π二氣笨乙、[(2_甲基苯 'H-NMR (CDC13) (52. 30 (s 3ίΠ ^ 2%)的白色固體。 1H) ^7.04 (m, 1H ：7 ；：·3： 2H)'6·98 ;18 (d， &gt;7· 3 Hz， 2H)、Add triethylamine (〇2) to a solution of 4-amino-2,3-difluoroacetic acid ethyl ester (323 mg, 丨· 5 ” ear) and DMF (8 liter) at room temperature. 〇9, 1.5 mmol) and 2-methylphenyl isocyanate (〇372 ml, 3 〇3 ΐ): stirring was continued for 48 hours at 8 °. The reaction mixture was spun in real work and made The solid was suspended in n-hexane 栌 丄 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , - Precipitated base produced by the collection of solids by the addition of n), the base of the precipitated base, the base of the solution, and the base of the precipitated base. White solid. 1H) ^7.04 (m, 1H :7 ;:·3: 2H) '6·98 ;18 (d, &gt;7· 3 Hz, 2H),

1283240 五、發明說明（366) 7.69 (d, J=8.1 Hz, 1H) &gt;7.90 (m, 1H)； MS (FAB) m/z 321 (MH1 )。 於4 -（4- S-4-氟-2 -吡咯啶基）曱氧苯曱酸甲酯（63毫克， 0· 25毫莫耳）及4-[N，-（2 -甲基苯基）脲基]一2, 3一二氟苯乙 酸（82毫克，〇· 25毫莫耳）溶於DMF(5毫升）之攪拌溶液中加 入 EDC-HC1(72 毫克，0.38 毫莫耳）、H0Bt(69 毫克，〇·48 毫 莫耳）、及DMAP(催化劑），並在室溫不持續攪拌隔夜。將 混合物以EtOAc(50毫升）稀釋，以NaOH、1M HC1、及鹽 水洗滌，於無水MgS〇4上乾燥，並於減壓下濃縮。將殘留 物溶解於THF-MeOH-H2 0(21 毫升，1:1:1，v/v/v),並在室 下持績撥掉6小時。將混合物倒入至1 M H C1中，並以 CHCI3-MeOH(9 : 1，ν/ν)萃取。將結合的有機相於無水MgS〇4 上乾燥，並於減壓下濃縮。將殘留物利用TLC( What man， PLK-5F，CHCl3/MeOH，20:1，v/v)純化得97(69 毫克， 51%)的白色粉末。IR (KBr) 3340 、 1604 、 1540 、 1251 、 1168、754/&amp;*;1H-NMR(DMS0-d6)(5 2.25(s，3H)、 2.32 (m，2H)、3·68-4·40 (m，7H)、5·32-5.55 (m， 1H)、6·98 (m，2H)、7·05 (d，J = 8.8 Hz，2H)、7·83 (d，J = 8.8 Hz, 2H)、7· 8 2- 7.92 (in，2H)、8.40 (s，1283240 V. INSTRUCTIONS (366) 7.69 (d, J=8.1 Hz, 1H) &gt; 7.90 (m, 1H); MS (FAB) m/z 321 (MH1). Methyl 4-(4-S-4-fluoro-2-pyrrolidinyl)phosphonium benzoate (63 mg, 0.25 mmol) and 4-[N,-(2-methylphenyl) Ethyl] 2,3 difluorophenylacetic acid (82 mg, 〇 25 mmol) dissolved in DMF (5 ml) in a stirred solution of EDC-HC1 (72 mg, 0.38 mmol), H0Bt (69 mg, 〇·48 mmol), and DMAP (catalyst), and did not continue to stir overnight at room temperature. The mixture was diluted with EtOAc (EtOAc)EtOAc. The residue was dissolved in THF-MeOH-H.sub.2 (21 mL, 1:1:1, v/v/v). The mixture was poured into 1 M H C1 and extracted with CHCI3-MeOH (9:1, v/v). The combined organic phases were dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified with EtOAc (EtOAc/EtOAc/EtOAc/EtOAc. IR (KBr) 3340, 1604, 1540, 1251, 1168, 754/&amp;*; 1H-NMR (DMS0-d6) (5 2.25(s,3H), 2.32 (m,2H), 3.68-4· 40 (m, 7H), 5·32-5.55 (m, 1H), 6·98 (m, 2H), 7·05 (d, J = 8.8 Hz, 2H), 7·83 (d, J = 8.8 Hz, 2H), 7· 8 2- 7.92 (in, 2H), 8.40 (s,

1H) &gt; 9. 14 (s, 1H) ； MS(ESI) m/z 564 (MHNa) ； C28H26F 3N3 05 · 2· 0H2O 之分析計算值：C，58· 23 ; H，5. 24 ; N， 7. 28。實測值：C， 58. 0 7 ; H，4· 84 ; N，7· 03。 實施例9 2 4-[1-[4 - [Ν’ -（2 -甲基苯基）脲基]_2, 5 -二氟苯基乙醯1H) &gt; 9. 14 (s, 1H); MS (ESI) m/z 564 (MHNa); C28H26F 3N3 05 · 2 · 0H2O Analysis calculated: C, 58 · 23 ; H, 5. 24 ; , 7. 28. Found: C, 58. 0 7 ; H, 4· 84 ; N, 7· 03. Example 9 2 4-[1-[4 - [Ν' -(2-methylphenyl)ureido]_2,5-difluorophenylacetamidine

\\312\2d-code\90-01\89112968.ptd 第 371 頁 1283240 五、發明說明（367) 基]-（4S) -氟_(2S)-吼咯啶曱氧基]苯曱酸\\312\2d-code\90-01\89112968.ptd Page 371 1283240 V. INSTRUCTIONS (367) BASE]-(4S)-Fluorine((2S)-吼rrolidineoxy]benzoic acid

2，5 -二I-4 -石肖基苯乙酸乙西旨2,5-di-I-4 - schiffyl phenylacetate

F jfS^Y°Me o2h^Y οF jfS^Y°Me o2h^Y ο

F 在室溫下於乙基丙二酸二-第三丁酯（6.32毫升，28·2毫 莫耳）溶於DMF(1 50毫升）之攪拌溶液中加入NaH(6〇%溶於 油，3. 38克，84· 7毫莫耳）。於2〇分鐘後，將2, 5 -二氟硝 基本（5克’28.2毫莫耳）溶於DMF(50毫升）經由滴漏斗逐滴 加入。於添加後，使混合物在室溫下攪拌3小時。將混合 物倒入至冰水及飽和NH4C 1 ( 1 〇 〇毫升）中。以E tOA c萃取混 合物，並將結合的有機層以1M HC1及鹽水洗滌，於MgS04 上乾燥，過濾及濃縮。將殘留物溶解於二氯甲烷（2 0毫 升），並在室溫下加入TF A ( 2 0毫升）。使混合物迴流1 8小 時。使混合物於真空中蒸發，與曱苯（20毫升x2)共同蒸 發。使殘留物溶解於MeOH(l 50毫升），並加入濃112804(5毫 升）。使混合物迴流1 8小時。將混合物以EtOAc( 30 0毫升） 稀釋，以水、1M HC1、及鹽水洗滌，於無水MgS04上乾 燥，並於減壓下濃縮。將殘留物於矽膠（中壓層析系統： YAMAZEN YFLC-5 40 4-FC，線性梯度己烷-EtOAc 10:0 至 1 : 1，0 5 0毫米X 3 0 0毫米，1 5毫升/分鐘）上進行層析， 而得2, 5 -二氟-4 -硝基苯乙酸乙酯（6.53克，90%)之黃色To a stirred solution of di-tert-butyl ethylmalonate (6.32 ml, 28.2 mmol) in DMF (1 50 mL) at room temperature, add NaH (6 〇% in oil, 3. 38 grams, 84·7 millimoles). After 2 minutes, 2,5-difluoronitrate basic (5 g &apos;28.2 mmol) was dissolved in DMF (50 mL) and added dropwise via a dropping funnel. After the addition, the mixture was stirred at room temperature for 3 hours. Pour the mixture into ice water and saturated NH4C1 (1 〇 〇 ml). The mixture was extracted with EtOAc (br.) and EtOAc (EtOAc) The residue was dissolved in dichloromethane (20 mL) and TFA (20 mL). The mixture was refluxed for 18 hours. The mixture was evaporated in vacuo and evaporated with EtOAc (20 mL). The residue was dissolved in MeOH (1 mL) and EtOAc (EtOAc) The mixture was refluxed for 18 hours. The mixture was diluted with EtOAc (EtOAc)EtOAc. The residue was applied to a silica gel (medium pressure chromatography system: YAMAZEN YFLC-5 40 4-FC, linear gradient hexane-EtOAc 10:0 to 1: 1,500 mm X 3 0 0 mm, 15 ml/min Chromatography to give 2,5-difluoro-4-nitrophenylacetate (6.53 g, 90%) of yellow

\\312\2d-code\90-01\89112968.ptd 第 372 頁 1283240 五、發明說明（368) 油。1Η-NMR (CDC13) δ 3.75 (s，2H)、3.76 (s，3H)、7· 29 (dd, J=5.8 Hz, 10.5 Hz, 1H) ^7.81 (dd, J=6.0 Hz， 8.4 Hz, 1H); MS(ESI) m/z 232(MH1)。 4-胺基-2，5-二氟苯乙酸乙酉旨 ^Υ^ΎΌΕ{ Η2Ν^ν °\\312\2d-code\90-01\89112968.ptd Page 372 1283240 V. INSTRUCTIONS (368) OIL. 1Η-NMR (CDC13) δ 3.75 (s, 2H), 3.76 (s, 3H), 7·29 (dd, J=5.8 Hz, 10.5 Hz, 1H) ^7.81 (dd, J=6.0 Hz, 8.4 Hz, 1H); MS (ESI) m/z 232 (MH1). 4-Amino-2,5-difluorophenylacetic acid ethyl ester Υ^ΎΌΕ^ ΎΌΕ2Ν^ν °

F 在室溫下於2, 5-二氟-4 -硝基苯乙酸乙酯（5.88克，25.4 莫耳）溶於EtOH(100毫升）之攪拌溶液中加入SnCi2(17. 2 克，7 6 · 3毫莫耳）。在迴流下持續攪拌1 8小時。於移除溶 劑後，將殘留物溶解於CHCl3(l〇〇毫升），並倒入至冰水 - 4M NaOH(40毫升之4M NaOH溶於3 0 0毫升之冰水）中，以 CHCl/lOOcfe升x2)萃取，於無水MgS04上乾燥，並於減壓下 濃縮。使殘留物於石夕膠（中壓層析系統γAMAZEN YFLC-To a stirred solution of ethyl 2,5-difluoro-4-nitrophenylacetate (5.88 g, 25.4 mol) in EtOH (100 mL), EtOAc (12.7 g, 7 6 · 3 millimoles). Stirring was continued for 18 hours under reflux. After removing the solvent, the residue was dissolved in CHCl3 (10 mL) and poured into ice water - 4M NaOH (40 mL of 4M NaOH in 300 ml of ice water) to CHCl/lOOcfe The mixture was extracted with MgSO.sub.4, dried over anhydrous EtOAc. Make the residue in Shixia (medium pressure chromatography system γAMAZEN YFLC-

5404 ’己烧- EtOAc自9:1至7:3之線性梯度，050毫米X 500¾米’ 15¾升/分鐘）上進行層析，而得4_胺基—2, 5-一氟苯乙酸乙酯（2.85克，52%)之無色油。ijj — nMR (CDC13) 5 1.28 (t， J = 7.3 Hz, 3H)、3·51 (s, 2H)、3·78 (brs，2H)、4·15 (dd, J = 7.2 Hz、14·2 Hz, 2H)、6·47 (dd, J=7·5 、 10.4 Hz, 1H) 、 6. 88 (dd, J=6·7 、 11·05404 'Heat- EtOAc was chromatographed from a linear gradient of 9:1 to 7:3, 050 mm X 5003⁄4 m ' 152⁄4 L/min) to give 4-amino-2,5-fluorophenylacetate Ester (2.85 g, 52%) of a colorless oil. Ijj — nMR (CDC13) 5 1.28 (t, J = 7.3 Hz, 3H), 3·51 (s, 2H), 3·78 (brs, 2H), 4·15 (dd, J = 7.2 Hz, 14· 2 Hz, 2H), 6·47 (dd, J=7·5, 10.4 Hz, 1H), 6. 88 (dd, J=6·7, 11·0

Hz, 1H) ; MS(FAB) m/z 216 (MH1)。 4 - [(2-曱基苯基）脲基]—2, 5-二氟苯乙酸Hz, 1H) ; MS(FAB) m/z 216 (MH1). 4-[(2-Mercaptophenyl)ureido]-2, 5-difluorophenylacetic acid

FF

\\312\2d-code\90-01\89112968.ptd 第373頁 1283240 五、發明說明（369) &quot;--- 毫^耳）溶=DMF(8毫升）之攪拌溶液中加入三乙胺（〇·2〇9 宅=，1· 5耄莫耳）及異氰酸2一甲基苯酯（〇· 3?2毫升，3· 〇 在㈣下持續攪拌48小時。將反應混合物於真 二中洛發，幻吏固體懸浮於正己烷中 體。將固體溶解於THF-Me0H(1:1，ν/ν，2〇毫、/)，並在室 溫下加入4Μ NaOH(l〇毫升）。在室溫下持續擾掉18小時。 將反應倒入至1M HCM中，並經由過濾、收集所產生之沈澱 物。利用CHCI3-正己烷使固體再結晶而得4—[(2一曱基苯 基）脲基]-2,5-二氟苯乙酸（214毫克，46%)的白色ς體。 1-NMR (CDC13) (5 2. 30 (s，3Η)、3· 35 (m，2Η)、7. 〇2 (m， 2H) 、7.18 (d， J=7.3 Hz， 2H) 、7·69 (d J=7 8\\312\2d-code\90-01\89112968.ptd Page 373 1283240 V. INSTRUCTIONS (369) &quot;--- ^^ ear) dissolved = DMF (8 ml) in a stirred solution of triethylamine (〇·2〇9 house=,1·5耄莫耳) and 2-methylphenyl isocyanate (〇·3?2 ml, 3·〇 stirring under (4) for 48 hours. The reaction mixture is true. The second solid is suspended in n-hexane medium. The solid is dissolved in THF-Me0H (1:1, ν / ν, 2 〇, /), and 4 Μ NaOH (l 〇 ml) is added at room temperature. The mixture was continuously disturbed for 18 hours at room temperature. The reaction was poured into 1 M HCM, and the resulting precipitate was collected by filtration. The solid was recrystallized from CHCI 3-n-hexane to give 4-[(2) Phenylphenyl)ureido]-2,5-difluorophenylacetic acid (214 mg, 46%) as a white steroid. 1-NMR (CDC13) (5 2. 30 (s, 3 Η), 3 · 35 (m , 2Η), 7. 〇2 (m, 2H), 7.18 (d, J=7.3 Hz, 2H), 7·69 (d J=7 8

Hz，1H)、8· 03 (m，1H) ; MS (FAB) m/z 321 U+H)·。 於4- [(4S)-氟-（2S) -吡咯啶基]甲氧苯甲酸甲酯（63毫 克，〇·25毫莫耳）及2,5-二氟-4-[N，-（2-甲基苯基）脲基] 苯乙酸（82毫克，0· 25毫莫耳）溶於DMF(5毫升）之攪拌溶液 中加入EDC-HC1(72毫克，〇· 38毫莫耳）、HOBt(69毫克，〇·Hz, 1H), 8· 03 (m, 1H); MS (FAB) m/z 321 U+H)·. Methyl 4-[(4S)-fluoro-(2S)-pyrrolidinyl]methoxybenzoate (63 mg, 〇25 mmol) and 2,5-difluoro-4-[N,-( 2-Methylphenyl)ureido] phenylacetic acid (82 mg, 0. 25 mmol) was dissolved in DMF (5 mL) in a stirred solution. EDC-HC1 (72 mg, 〇·38 mmol), HOBt (69 mg, 〇·

48耄莫耳）、及DMAP(催化劑），並在室溫下持續授摔隔 夜。將混合物以EtOAc(5 0毫升）稀釋，以1M Na〇H、1M H C1、及鹽水洗條，於無水μ g s O4上乾燥，並於減壓下濃 縮。將殘留物溶解於THF-MeOH-H20(21毫升，1 ·· 1 :；[， v/v/v)，並在室溫下持續攪拌6小時。將混合物倒入至lM HC1中’並以CHC13-MeOH(9:l，v/v)萃取。將結合的有機 相於無水MgS〇4上乾燥，並於減壓下濃縮。將殘留物利用 TLC( What man ’ PLK-5F，CHCl3/MeOH，20:1，v/v)純化得48 耄 Mo ear), and DMAP (catalyst), and continued to drop at room temperature overnight. The mixture was diluted with EtOAc (EtOAc) (EtOAc)EtOAc. The residue was dissolved in THF-MeOH-H.sub.2 (21 mL, 1·1:;;, v/v/v), and stirring was continued at room temperature for 6 hours. The mixture was poured into 1 M HCl 1 and extracted with CHC13-MeOH (9:1, v/v). The combined organic phases were dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified by TLC (What man s PLK-5F, CHCl3/MeOH, 20:1, v/v)

1283240 五、發明說明（370) 98 ( 6 9 毫克，51%)的白色粉末。IR-ATR : 335 1、1 6 04、 1 537、1167、75 4( 1 / 公分）；iH-NMR (DMSO) 6 2. 25 (s, 3H) 、2.32 (m, 2H) 、 3. 68-4·70 (m, 7H) 、5·32-5.55 (m，1Η)、6·97 (t，J = 7.6 Hz, 1Η)、7·06 (d，JU Hz, 2H)、7·20 (m，3H)、7·87 (d，J = 8.8 Hz, 2H)、 7.83-8.04 (m，2H)、8·45 (s，1H)、9.18 (s，1H); MS(ESI) m/z 56 4 (MHNa); C28H26F3N3 05 . 1.7 5H20 之分析計 算值：C，58· 69 ; H，5· 19 ; N， 7· 33。實測值：C， 58. 54 ； Η, 4. 85 ； Ν, 6· 98。 實施例9 3 4 - [1-[4-[Ν’ -（2 -氯苯基）脲基]- 3-甲氧苯基乙醯基]一4-氟 - 2 -咄咯啶基]甲基胺基苯甲酸1283240 V. Inventive Note (370) 98 (69 mg, 51%) of white powder. IR-ATR : 335 1,1 6 04, 1 537, 1167, 75 4 (1 / cm); iH-NMR (DMSO) 6 2. 25 (s, 3H), 2.32 (m, 2H), 3. 68 -4·70 (m, 7H), 5·32-5.55 (m, 1Η), 6.97 (t, J = 7.6 Hz, 1Η), 7·06 (d, JU Hz, 2H), 7·20 (m, 3H), 7·87 (d, J = 8.8 Hz, 2H), 7.83-8.04 (m, 2H), 8.45 (s, 1H), 9.18 (s, 1H); MS (ESI) m /z 56 4 (MHNa); C28H26F3N3 05 . 1.7 Analysis of 5H20: C, 58 · 69 ; H, 5 · 19 ; N, 7. 33. Found: C, 58. 54 ; Η, 4. 85 ; Ν, 6· 98. Example 9 3 4 - [1-[4-[4-[Ν' -(2-Chlorophenyl)ureido]-3-methoxyphenylethenyl]-4-fluoro-2-pyridinyl]A Aminobenzoic acid

COOH 99 及 4 - [1 - [4- [Ν’ -（2 -溴苯基）脲基]- 3-曱氧苯基乙醯基]一4 一氣 - 2 -吡咯啶基]甲基胺基苯甲酸COOH 99 and 4 - [1 - [4- [Ν[-(2-bromophenyl)ureido]-3-oxophenylphenyl]]-4-one- 2 -pyrrolidinyl]methylamino benzoic acid

COOH 100 99及100於丨―第三丁氧羰基-4-氟吡咯啶—2-叛酸甲酿d 2克，4·85毫莫耳）溶於MeOH(5毫升）之攪拌溶液中加二1Ν· NaOH(5毫升），並使混合物在室溫下攪拌1小時。將混合物COOH 100 99 and 100 in a solution of 丨-t-butoxycarbonyl-4-fluoropyrrolidine-2-repulsively brewed d 2 g, 4.85 mmoles dissolved in MeOH (5 ml) plus two 1 Ν NaOH (5 ml), and the mixture was stirred at room temperature for 1 hour. Mixture

1283240 五、發明說明（371) 於真空中濃縮，加入水，並以IN HC1中和。以EtOAc萃取 混合物。將萃取液以水洗滌，然後於Na2S04上乾燥，並於 真空中濃縮而得卜第三丁氧羰基-4-氟吡咯啶-2 -羧酸（1. 1 克，定量）之無色油。1H-NMR (CDC13)(5 1.47 (br s， 9H) 、2·78-2·83 (br s， 3H) 、4·37 (s， 2H) 、6·73-6·76 (m， 3Η) 、 7·17 (m， 1Η)。 在〇°C下於1-第三丁氧羰基-4-氟吡咯啶-2 -羧酸（i.i 克，4· 7毫莫耳）溶於THF(10· 0毫升）之攪拌溶液中加入bh3 • THF(1. 〇 Μ之THF溶液，10. 〇毫升，10· 0毫莫耳）。在室 溫下攪拌1 · 0小時。於冷卻後，將混合物於真空中濃縮。1283240 V. INSTRUCTIONS (371) Concentrate in vacuo, add water, and neutralize with IN HC1. The mixture was extracted with EtOAc. The extract was washed with water, dried over Na2SO4, and concentrated in vacuo to give EtOAc (EtOAc, EtOAc, EtOAc, 1H-NMR (CDC13) (5 1.47 (br s, 9H), 2·78-2·83 (br s, 3H), 4·37 (s, 2H), 6.73-6·76 (m, 3Η) , 7·17 (m, 1Η). Dissolved in 1-THF at 1-°C in 1-t-butoxycarbonyl-4-fluoropyrrolidine-2-carboxylic acid (ii g, 4.7 mmol) To a stirred solution of 10·0 ml), add bh3 • THF (1. 〇Μ THF solution, 10. 〇 ml, 10·0 mmol). Stir at room temperature for 1 hour. After cooling, The mixture was concentrated in vacuo.

在0 °C下加入水，並以EtOAc萃取。將萃取液以水洗條，然 後於NaJO4上乾燥，並於真空中濃縮而得卜第三丁氧魏基 - 4-氟-2 -叫：洛咬曱醇（1·〇克，定量）之無色油。ljj-NMR (CDC13) (5 1· 48 (s, 9Η)、2· 29- 2· 39 (m，1Η)、3· 38- 3· 59 (m， 2H) 、3·74-3·88 (m， 2H) 、4·09-4·14 (m， 2H)、 4.85 (m，1Η)、5·03 (br s，1Η) '5.16 (br s，1Η)。 在-7 8 °C下於草醯氯（〇· 28毫升，2. 3毫莫耳）溶於CH2Cl2 (20.0毫升）之攪拌溶液中加入DMS〇(〇39毫升）。於5分鐘 後，在混合物中加入卜第三丁氧羰基—4—氟一2—吡咯啶甲醇 ( 50 0毫克，2.28毫莫耳）溶於毫升）。將混合物 在-78 C下攪拌30分鐘，並加入三乙胺（16毫升）。使混合 物在-78 °C下攪拌30分鐘，及在室溫下攪拌3 〇分鐘。將水 加至混合物，並以CHJl2萃取。將有機層於Na2s〇4上乾燥， 並於真空中濃縮。將粗製產物不經進一步的純化而使用於Water was added at 0 ° C and extracted with EtOAc. The extract was washed with water, then dried on NaJO4, and concentrated in vacuo to obtain a third color of butyl sulphate- 4-fluoro-2 - called: sterol (1 gram, quantitative) oil. ljj-NMR (CDC13) (5 1· 48 (s, 9Η), 2· 29- 2· 39 (m, 1Η), 3· 38- 3· 59 (m, 2H), 3·74-3·88 (m, 2H), 4·09-4·14 (m, 2H), 4.85 (m, 1Η), 5·03 (br s, 1Η) '5.16 (br s, 1Η). At -7 8 °C DMS(〇39 ml) was added to a stirred solution of chloroform (〇·28 ml, 2.3 mmol) dissolved in CH2Cl2 (20.0 ml). After 5 minutes, the mixture was added to the mixture. Butoxycarbonyl-4-furo-2-pyrrolidinemethanol (50 mg, 2.28 mmol) is dissolved in ml). The mixture was stirred at -78 C for 30 min and triethylamine (16 mL) was added. The mixture was stirred at -78 °C for 30 minutes and at room temperature for 3 minutes. Water was added to the mixture and extracted with CHJ12. The organic layer was dried over Na 2 s s 4 and concentrated in vacuo. The crude product was used without further purification

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後續的反應中。在〇 t：下於此粗製產物、4一胺基苯曱酸甲 酉旨（302毫克，2·0毫莫耳）、及Ac〇H (〇· 13毫升）溶於 DCE(10毫升）之攪拌溶液中加入NaM(〇Ac)3 (656毫克， 3 · 0 9耄莫耳）。使反應混合物在室溫下攪拌丨8小時。將混 合物於真空中濃縮。將飽和NaHC03加至殘留物，並以Ch2 C 12 f取。將萃取液以鹽水洗滌，於n g 上乾燥，並於真 空中濃縮。使殘留物經由於矽膠上利用Et〇Ac_正己烧 (1 : 3 ’ v/v)作為洗提液進行管柱層析，純化而得4—(丨一第 三丁氧羰基-4-氟-2_吡咯啶基）曱基胺基苯甲酸甲酯（541 毫克，77%)之淡黃色油。iH —NMR (CDCl3) s l 55 —h 59 (m，1H)、2·16 - 2.27 (m，1H)、2·89-3·03 (m, 2H)、 3·19-3.28 (m，2H)、3·6 9- 3.73 (m, 1H)、3·84 (s， 3H)、5· 15 及 5· 29 (各s，總計 1 Η )、6· 55-6· 58 (m，2H )、 7· 84-7· 86 (m，2Η)。 99 在0 C下於4-(1_第三丁氧羰基-4-氟-2 -吼咯啶基）甲胺 基苯甲酸甲酯（541毫克，1·53毫莫耳）溶於CH2C12 (8· 0毫 升）之攪拌溶液中加入TF A ( 4 · 0毫升）。使反應混合物在室 溫下授拌〇 · 5小時。將混合物於真空中濃縮。將飽和 NaHC〇3加至殘留物，並以ch2C 12萃取。將萃取液以鹽水洗 條，於Ν&amp;β〇4上乾燥，並於真空中濃縮。將粗製產物不經 進一步的純化而使用於後續的反應中◦在0 °C下於此粗製 產物（151毫克，〇·6毫莫耳）、4-[N，-（2-氯苯基）脲 基]-3-甲氧苯乙酸（2〇1毫克，0.6毫莫耳）、HOB t( 94毫Subsequent reactions. The crude product, 4-aminobenzoic acid formazan (302 mg, 2.0 mmol), and Ac〇H (〇·13 ml) were dissolved in DCE (10 mL) under 〇t: NaM (〇Ac) 3 (656 mg, 3 · 0 9 mol) was added to the stirred solution. The reaction mixture was stirred at room temperature for 8 hours. The mixture was concentrated in vacuo. Saturated NaHC03 was added to the residue and taken in Ch 2 C 12 f. The extract was washed with brine, dried over n g and concentrated in vacuo. The residue was subjected to column chromatography using Et〇Ac_n-hexane (1:3 'v/v) as an eluent on a silica gel, and purified to obtain 4-(丨-third butoxycarbonyl-4-fluoro -2_Pyrrolidinyl)methyl decylaminobenzoate (541 mg, 77%) as a pale yellow oil. iH-NMR (CDCl3) sl 55 —h 59 (m,1H), 2·16 - 2.27 (m,1H), 2·89-3·03 (m, 2H), 3·19-3.28 (m, 2H ), 3·6 9- 3.73 (m, 1H), 3·84 (s, 3H), 5·15 and 5· 29 (each s, total 1 Η), 6·55-6· 58 (m, 2H ), 7· 84-7· 86 (m, 2Η). Methyl 4-(1_t-butoxycarbonyl-4-fluoro-2-pyridinyl)methylaminobenzoate (541 mg, 1.53 mmol) dissolved in CH2C12 TF A (4.0 ml) was added to the stirred solution of 8.0 ml. The reaction mixture was allowed to stir at room temperature for 5 hours. The mixture was concentrated in vacuo. Saturated NaHC〇3 was added to the residue and extracted with CH2C12. The extract was washed with brine, dried over EtOAc &amp; The crude product was used in the subsequent reaction without further purification. The crude product (151 mg, 〇·6 mmol), 4-[N,-(2-chlorophenyl) at 0 °C. Urea]-3-methoxyphenylacetic acid (2〇1 mg, 0.6 mmol), HOB t (94 m

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克，〇·7毫莫耳）、及三乙胺（167微升，1.2毫莫耳）溶於 THF(10· 0毫升）及MeCN(l 0· 0毫升）之攪拌溶液中加入EDC · HC 1 (1 73毫克，〇· 9毫莫耳）。使反應混合物在室溫下攪拌 16小時，並於真空中濃縮。將水加至殘留物，並以Et〇Ac 萃取。將萃取液以飽和NaHC03、2M擰檬酸、及飽和NaHCO 3 洗滌，然後於NagSO〗上乾燥，並於真空中濃縮。使殘留物 經由於矽膠上利用正己烷-EtOAc(l : 2，v/v)作為洗提液進 行管柱層析，純化而得4-[1-[4-[N，-（2-氣苯基）脲基卜 甲氧苯基乙醯基]- 4-氟-2 -咄咯啶基]曱基胺基笨曱酸甲酉旨 ( 32 0 毫克，94%)之非晶形固體。ιή-NMR (CDC13) (5 1 . 80 -1.95 (m, 1H) &gt;2.42-2.58 (m, 1H) ^3.20-3.51 (m, 3H) 、3·5卜3·76 (m， 5H) 、3·84 (s， 3H) 、3·85-3·98 (m，1H)、4· 67-4· 70 (m，1H)、5· 10 及 5· 23 (各 s,總計 1H) 、5·50 (br s， 1H) 、6·49-6·52 (m， 2H) 、6·78-6·81 (m, 2H)、6·97 - 7.01 (m，1H)、7·14-7·18 (m，2H)、 7.24-7.36 (m, 2H) &gt;7.80-7.82 (m, 2H) ^7.99-8.01 (m，1H)、8. 15 - 8· 18 (m，1H)。 於4 - [1-[4 - [Ν’ - (2 -氯苯基）脲基]- 3-甲氧苯基乙醯基] - 4-氟-2 -咣咯啶基]曱基胺基苯甲酸曱酯（320毫克，〇.56 毫莫耳）溶於THF(5. 0毫升）及Me〇H(3· 0毫升）之攪拌溶液中 加入IN NaOH(0. 8毫升，〇· 8毫莫耳）。使混合物在70 °c下 攪拌2 4小時。將混合物於真空中濃縮，加入水，並以j n HC 1中和。收集所產生之固體，以水洗滌，並於真空中乾 燥而得9 9 ( 2 8 0毫克，9 0 % )之白色結晶固體。熔點1 3 2〜克,〇·7 mmol, and triethylamine (167 μl, 1.2 mmol) dissolved in THF (10 mL) and MeCN (10 mL) were added EDC · HC 1 (1 73 mg, 〇·9 mmol). The reaction mixture was stirred at room temperature for 16 h and concentrated in vacuo. Water was added to the residue and extracted with Et 〇Ac. The extract was washed with saturated NaHC03, 2M EtOAc, and sat. NaHCO3, then dried over NagSO and concentrated in vacuo. The residue was subjected to column chromatography using n-hexane-EtOAc (1:2, v/v) as an eluent to obtain 4-[1-[4-[N,-(2- Amorphous solids of phenyl)ureido-methoxyphenylethylidene]- 4-fluoro-2-pyridinyl]nonylamino alumic acid methyl ester (32 0 mg, 94%). ιή-NMR (CDC13) (5 1 . 80 -1.95 (m, 1H) &gt;2.42-2.58 (m, 1H) ^3.20-3.51 (m, 3H), 3·5 Bu 3·76 (m, 5H) , 3·84 (s, 3H), 3·85-3·98 (m, 1H), 4·67-4· 70 (m, 1H), 5·10, and 5· 23 (each s, total 1H) , 5·50 (br s, 1H), 6·49-6·52 (m, 2H), 6.78-6·81 (m, 2H), 6.97 - 7.01 (m, 1H), 7· 14-7·18 (m, 2H), 7.24-7.36 (m, 2H) &gt; 7.80-7.82 (m, 2H) ^7.99-8.01 (m, 1H), 8. 15 - 8· 18 (m, 1H 4-(1-[4 - [Ν' - (2-Chlorophenyl)ureido]-3-methoxyphenylethyl] 4-fluoro-2-pyridinyl] fluorenyl To a stirred solution of THF (0.5 ml) and Me 〇H (3.0 mL) was added IN NaOH (0 mL, EtOAc) · 8 mM. The mixture was stirred at 70 ° C for 24 hours. The mixture was concentrated in vacuo, water was added and neutralized with jn HC 1. The resulting solid was collected, washed with water and vacuum Drying to obtain 9 9 (280 mg, 90%) of white crystalline solid. Melting point 1 3 2~

1283240 五、發明說明（374) 136〇C; IR (KBr) 3332、2937、1602、1531、1174、752 / 公分；M-NMR (DMSO-d6) δ 2.0 0-2.40 (m，2H)、 3·50-3.90 (m，4H)、3. 75-3.85 (m, 5H)、4·27 (m, 1H)、5.23 及 5.37 (各s，總計 1H)、6.5 卜 7.03 (m，5H)、 7.25-7.29 (m，1H)、7·4卜7·44 (m，1H)、7·64-7.68 (m, 2H)、7· 92-8. 10 (m，2H)、8.8 7-8.94 (m，2H); C28 H28N4 05 FC1*0.6H20 之分析計算值：C，59.44; H，5.20; N，9.90。實測值：C，59.41;H，5.19;N，9.72。 100 在0°C下於4-(1-第三丁氧魏基-4-氟—2 -吼洛咬基）甲胺 基苯曱酸曱酯（541毫克，1.53毫莫耳）溶於CH2C12( 8. 0毫 升）之攪拌溶液中加入TF A ( 4 · 0毫升）。使反應混合物在室 溫下攪拌〇· 5小時。將混合物於真空中濃縮。將飽和 NaHC〇3加至殘留物，並以CH2C12萃取。將萃取液以鹽水洗 滌’於NaJO4上乾燥，並於真空中濃縮。將粗製產物不經 進一步的純化而使用於後續的反應中。在〇 t下於此粗製 產物（151毫克，0.6毫莫耳）、4-[N，-(2-溴苯基）脲基]-3 -甲氧苯乙酸（227毫克，0.6毫莫耳）、HOB t( 94毫克，0. 7毫 莫耳）、及三乙胺（167微升，1.2毫莫耳）溶於THF( 10. 0毫 升）及MeCN(10.0毫升）之攪拌溶液中加入EDC · hci (173毫 克’ 0 · 9毫莫耳）。使反應混合物在室溫下攪拌丨6小時，並 於真空中濃縮。將水加至殘留物，並以Et〇Ac萃取。將萃 取液以飽和NaHC〇3、2M檸檬酸、及飽和NaHC〇3洗滌，然後 於WSO4上乾燥，並於真空中濃縮。使殘留物經由於矽膠1283240 V. INSTRUCTIONS (374) 136〇C; IR (KBr) 3332, 2937, 1602, 1531, 1174, 752 / cm; M-NMR (DMSO-d6) δ 2.0 0-2.40 (m, 2H), 3 · 50-3.90 (m, 4H), 3.75-3.85 (m, 5H), 4·27 (m, 1H), 5.23 and 5.37 (each s, total 1H), 6.5 b 7.03 (m, 5H), 7.25-7.29 (m, 1H), 7·4 Bu 7·44 (m, 1H), 7·64-7.68 (m, 2H), 7· 92-8. 10 (m, 2H), 8.8 7-8.94 Analysis calculated for C28 H28N4 05 FC1*0.6H20: C, 59.44; H, 5.20; N, 9.90. Found: C, 59.41; H, 5.19; N, 9.72. 100 at 4 ° C in 4-(1-tert-butoxy-Wiki-4-fluoro-2-indolyl) methyl methacrylate (541 mg, 1.53 mmol) dissolved in CH2C12 TF A (4.0 ml) was added to the stirred solution of (8.0 ml). The reaction mixture was stirred at room temperature for 5 hours. The mixture was concentrated in vacuo. Saturated NaHC〇3 was added to the residue and extracted with CH2C12. The extract was washed with brine and dried over Na.sub.4 and concentrated in vacuo. The crude product was used in the subsequent reaction without further purification. This crude product (151 mg, 0.6 mmol), 4-[N,-(2-bromophenyl)ureido]-3-methoxyphenylacetic acid (227 mg, 0.6 mmol). Add EDC to a stirred solution of HOB t (94 mg, 0.7 mmol) and triethylamine (167 μl, 1.2 mmol) in THF (10 mL) and MeCN (10.0 mL) · hci (173 mg ' 0 · 9 mmol). The reaction mixture was stirred at room temperature for 6 h and concentrated in vacuo. Water was added to the residue and extracted with EtOAc. The extract was washed with saturated NaHC(R) 3, 2M EtOAc, sat. NaH.sub.3, and then dried on WSO4 and concentrated in vacuo. Passing the residue through the silicone

\\312\2d-code\90-01\89112968.ptd 第379頁 1283240 五、發明說明（375) 上利用正己烷-EtOAc(2:3，v/v)作為洗提液進行管柱層 析’純化而得4-[1-[4- [Ν’-（2-漠苯基）脲基]一 3—曱氧苯 基乙醯基]- 4-敗-2 -11比哈°定基]曱基胺基苯甲酸曱酉旨（280毫 克，76%)之無色油，。1-NMR (CDC13) 6 1· 80-1· 98 (m， 1H) 、1·42-1.58 (m, 1H) 、3·20-3·52 (m， 3H) 、3·67-3 79 (m, 5H)、3·84 (s，3H)、3·94 - 3·97 (m，1H)、 4.68-4.71 (m， 1H)、5.10 及 5·23 (各s，總計 ih)、5·51 (br s， 1H) 、6·50-6·52 (m， 2H) 、6·79-7.07 (m， 5H)、 7 · 2 5 - 7 · 3 3 ( m，1 Η )、7 · 5 1 - 7 · 5 3 ( m，1 Η)、7 · 8 0 - 7 · 8 3 (m，2Η)、7.98 - 8·00 (m，1Η)、8.11-8.14 (m，1Η)。 於4-[1-[4-[ Ν’ -（2-溴苯基）脲基]-3-甲氧苯基乙醯 基]-4-氟-2-吡咯啶基]曱基胺基苯甲酸甲酯（280毫克，0. 46毫莫耳）溶於THF (8. 0毫升）及MeOH(8. 0毫升）之攪拌溶液 中加入IN NaOH(2.8毫升，2.8毫莫耳）。使混合物在70°C 下攪拌1 8小時。將混合物於真空中濃縮，加入水，並以1 N HC 1中和。收集所產生之固體，以水洗滌，並於真空中乾 燥而得1 0 0 ( 2 6 0毫克，9 5 %)之白色結晶固體。熔點1 3 1 - 1 3 5 °C ; IR (KBr) 3 33 2、29 35、1 60 2、1 529、1174 / 公分； ^-NMR (DMSO-d6) 5 1.95-2.01 (m, 1 Η) ^ 2 . 2 0 - 2. 3 5 (m， 1H) 、3·10-3.20 (m， 1H) 、3·50-3.70 (m， 3H) 、3· 80-3. 8 5 (m，5H)、4· 27 (m, 1H)、5· 24 及5· 37 (各s，總 計 1H)、6·54-6·99 (m，5H)、7·30- 7.33 (m，1H)、 7·58-7.94 (m，3H)、7·94-7·98 (m，2H)、8·73 (m， 1H)、8. 93 (m，1 H ) ; C28H28N4 05 BrF · 0 · 7H20 之分析計算\\312\2d-code\90-01\89112968.ptd Page 379 1283240 V. INSTRUCTIONS (375) Pipe chromatography using n-hexane-EtOAc (2:3, v/v) as eluent 'Purification to obtain 4-[1-[4-[Ν'-(2-Molyphenyl)ureido]-3-methoxyphenylethyl]- 4-a-2-2-11 than the base] A colorless oil of decylaminobenzoic acid (280 mg, 76%). 1-NMR (CDC13) 6 1· 80-1· 98 (m, 1H), 1·42-1.58 (m, 1H), 3·20-3·52 (m, 3H), 3·67-3 79 (m, 5H), 3.84 (s, 3H), 3·94 - 3·97 (m, 1H), 4.68-4.71 (m, 1H), 5.10, and 5.23 (each s, total ih), 5·51 (br s, 1H) , 6·50-6·52 (m, 2H), 6.79-7.07 (m, 5H), 7 · 2 5 - 7 · 3 3 ( m,1 Η ), 7 · 5 1 - 7 · 5 3 ( m,1 Η), 7 · 8 0 - 7 · 8 3 (m, 2 Η), 7.98 - 8·00 (m, 1 Η), 8.11-8.14 (m, 1 Η) . 4-[1-[4-[4-[ 溴'-(2-Bromophenyl)ureido]-3-methoxyphenylethenyl]-4-fluoro-2-pyrrolidinyl]decylaminobenzene Methyl formate (280 mg, 0.44 mmol) was dissolved in THF (EtOAc) (EtOAc) (EtOAc) The mixture was stirred at 70 ° C for 18 hours. The mixture was concentrated in vacuo, water was added and neutralized with 1 N EtOAc. The resulting solid was collected, washed with water and dried in vacuo to give a white crystallite. Melting point 1 3 1 - 1 3 5 °C; IR (KBr) 3 33 2, 29 35, 1 60 2, 1 529, 1174 / cm; ^-NMR (DMSO-d6) 5 1.95-2.01 (m, 1 Η ) ^ 2 . 2 0 - 2. 3 5 (m, 1H), 3·10-3.20 (m, 1H), 3·50-3.70 (m, 3H), 3·80-3. 8 5 (m, 5H), 4· 27 (m, 1H), 5· 24 and 5· 37 (each s, total 1H), 6·54-6·99 (m, 5H), 7·30- 7.33 (m, 1H) , 7·58-7.94 (m, 3H), 7·94-7·98 (m, 2H), 8.73 (m, 1H), 8.93 (m, 1 H ); C28H28N4 05 BrF · 0 · Analysis and calculation of 7H20

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Η, 4.81； Ν, 8. 93 〇 實施例9 4 4-[1 -[3-甲氧基-4 -[Ν’ -（2-曱基苯基）脲基]笨基乙醯基] -（4R)-氟-（2S) -吼咯啶曱氧基]苯曱酸Η, 4.81; Ν, 8. 93 〇Example 9 4 4-[1 -[3-Methoxy-4 -[Ν'-(2-mercaptophenyl)ureido]]phenylamino]] (4R)-fluoro-(2S)-indolyloxyl]benzoic acid

FF

Me Η H 〇Me 101 使4-[(4R) -氟-（2S)-咄咯啶甲氧基]苯曱酸甲酯（ 634毫 克，2·50毫莫耳）、3-甲氧基-4-[N，-（2-甲基苯基）脲基] 苯乙酸（787毫克，2.50毫莫耳）、EDC ·Η(： 1(718毫克， 3.75毫莫耳）、11061:(催化劑）、〇肘八？（催化劑）及〇1^(1〇毫 升）之混合物攪拌隔夜。以EtOAc( 30 0毫升）稀釋混合物。 將溶液以鹽水（2x1 00毫升）洗滌，於MgS〇4上乾燥，並於真 空中濃縮。使殘留物於矽膠上利用CHCI3-EtOAc(4: 1 )作^ 洗提液進行層析，而得4-[1-[3-甲氧基-4 - [Ν’-（2~甲式^ 基）脲基]苯基乙醯基]-(4R) -氟-（2S) -吼咯啶甲氧基]Me Η H 〇Me 101 methyl 4-[(4R)-fluoro-(2S)-decalylmethoxy]benzoate (634 mg, 2·50 mmol), 3-methoxy- 4-[N,-(2-methylphenyl)ureido]phenylacetic acid (787 mg, 2.50 mmol), EDC · Η (: 1 (718 mg, 3.75 mmol), 11061: (catalyst) The mixture was stirred overnight with EtOAc (30 mL). The mixture was washed with brine (2×1 00 mL) and dried over MgSO. And concentrated in vacuo. The residue was chromatographed eluting with CHCI3-EtOAc (4:1) eluting to give 4-[1-[3-methoxy-4 - [Ν'- (2~Formula) Ureido]Phenylethenyl]-(4R)-Fluoro-(2S)-Pyrrolidinylmethoxy]

甲酸曱酯（1. 37克，定量）之淡黃色黏性固體。HMR (CDC13)(J 2.24 (S, 3H)、2·26 - 2.47 (m，2H)、3.46 (s，3H)、3· 49-3· 64 (m, 4H)、3· 8 7 (s，3H)、4· 〇6 (dd，J = 9.5、2·〇 Ηζ，1Η)、4·5 卜 4.62 (m，2Η)、5·2〇 及 5.33 (各 br s，總計 1H)、6· 63 (s，1H)、6· 72 (d，J==8 3 Hz， 1H)、6·77 (d，J = 9.0 Hz，2H)、7·〇5 (t， J” 6· Hz, 1H)、7·16 - 7·20 (m，3H)、7.53 (s，1H)、7·63 (dA pale yellow viscous solid of decylformate (1.37 g, quantitative). HMR (CDC13) (J 2.24 (S, 3H), 2.26 - 2.47 (m, 2H), 3.46 (s, 3H), 3· 49-3· 64 (m, 4H), 3· 8 7 (s , 3H), 4· 〇6 (dd, J = 9.5, 2·〇Ηζ, 1Η), 4·5 卜 4.62 (m, 2Η), 5.2 〇 and 5.33 (each br s, total 1H), 6 · 63 (s, 1H), 6.72 (d, J==8 3 Hz, 1H), 6·77 (d, J = 9.0 Hz, 2H), 7·〇5 (t, J” 6· Hz , 1H), 7·16 - 7·20 (m, 3H), 7.53 (s, 1H), 7·63 (d

1283240 五、發明說明（377) J=7.8 Hz, 1H) &gt;7.91 (d, J=9. 0 Hz, 2H) . 8. 07 (d, J= 8·1 Hz, 1H)。 使4-[1 - [3-曱氧基-4-[Ν’ -（2-甲基苯基）脲基]笨基乙醯 基]-(4R) -氟-（2S)-吼咯啶甲氧基]苯甲酸甲醋（l 37克， 2·49毫莫耳）、〇·2 5Ν NaOH(20毫升，5·〇〇毫莫耳）、及 T H F ( 2 0毫升）之混合物攪拌3天。將混合物倒入至丨n H C 1 (100毫升）中，並利用CHC13-MeOH(5:l, 2x200毫升）萃1283240 V. INSTRUCTIONS (377) J=7.8 Hz, 1H) &gt; 7.91 (d, J=9. 0 Hz, 2H) . 8. 07 (d, J= 8·1 Hz, 1H). 4-[1-[3-Methoxy-4-[Ν'-(2-methylphenyl)ureido]]phenylamino]-(4R)-fluoro-(2S)-pyrrolidine Mixture of methoxy]benzoic acid methyl vinegar (37 g, 2.49 mmol), 〇·5 5 NaOH (20 ml, 5·〇〇 mmol), and THF (20 ml) 3 day. The mixture was poured into 丨n H C 1 (100 mL) and extracted with CHC13-MeOH (5:1, 2×200 mL)

取。使結合的萃取液於MgS〇4上乾燥，並於真空中濃縮。 使殘留物於石夕膠上利用CHC13-MeOH (20:1至4:1)進行層 析’而得101(930毫克，70%)之淡黃色非晶形固體。 NMR (DMSO-d6)(52.24-2.41 (m，總計5H)、3.42-4.66 (m 系列，1 0 Η )、5. 3 1 及 5 · 4 4 (各 b r s，總計 1 η )、6 · 71 - 7 · 16 (m 系列，7Η)、7·79 (d， J = 8.1 Ηζ， 1Η)、7·85 - 7.89 (m, 2Η)、7·98-8·00 (m，1Η)、8·47 (s，1Η)、8·55 (s， 1H) ; MS(FAB) m/z 53 6 (MH1)。 實施例9 5 4 - [(4S) -氣-1 - [3 -曱氧基一 4-（2 -氣笨基）脲基]苯基乙 醯基]-(2S) -咄咯啶基]甲氧苯曱酸 αtake. The combined extracts were dried over MgS 4 and concentrated in vacuo. The residue was subjected to chromatography on CH.sub.3-MeOH (20:1 to 4:1) to afford 101 (930 mg, 70%) of pale yellow amorphous solid. NMR (DMSO-d6) (52.24-2.41 (m, total 5H), 3.42-4.66 (m series, 10 Η ), 5. 3 1 and 5 · 4 4 (each brs, total 1 η ), 6 · 71 - 7 · 16 (m series, 7Η), 7.79 (d, J = 8.1 Ηζ, 1Η), 7.85 - 7.89 (m, 2Η), 7·98-8·00 (m, 1Η), 8 · 47 (s, 1 Η), 8·55 (s, 1H); MS (FAB) m/z 53 6 (MH1). Example 9 5 4 - [(4S) - gas-1 - [3 - 曱 oxygen 4-(2-indolyl)ureido]phenylethenyl]-(2S)-indolyl]methoxybenzoate

P^NANJp^^°-〇-co〇HP^NANJp^^°-〇-co〇H

Cl H H OMe 102 在室溫下於4-(反-1-第三丁氧羰基-4 -羥基-（2S) -咣咯 啶基）甲氧苯甲酸甲酯（3 51毫克，1. 0毫莫耳）及Ph3P( 393 毫克’ 1· 5毫莫耳）溶於CHC13 (5· 0毫升）之攪拌溶液中加入 CC14 (5. 0毫升）。使反應混合物在50 °C下攪拌24小時。將Cl HH OMe 102 methyl 4-(trans-1-t-butoxycarbonyl-4-hydroxy-(2S)-inertyryl)methoxybenzoate (3 51 mg, 1.0 mM at room temperature) To a stirred solution of CHC13 (5.0 ml) was added CC14 (5.0 mL). The reaction mixture was stirred at 50 ° C for 24 hours. will

\\312\2d-code\90-01\89112968.ptd 1283240 五、發明說明（378) ---\\312\2d-code\90-01\89112968.ptd 1283240 V. Description of invention (378) ---

反應混合物於真空中濃縮。將殘留物經由於石夕膠上利用正 己烧至正己烧-EtOAc(4: 1，v/v)作為洗提液進行管柱層 析，純化而得4-(順-1-第三丁氧羰基-4-氣〜（2S)_吡咯啶 基）甲氧苯甲酸甲酯（ 340毫克，92%)之淡黃色油。1H-NMR (CDC13) 5 1· 48 (s，9H)、2· 38- 2· 65 (m，2H)、3· 50-3.60 (m，1H)、3·88 (s，3H)、3·8 9-4.0 5 (m，1Η·)、 4·26 - 4·41 (m，4Η)、6·95 - 6·97 (m，2Η)、7.’98 (d， J-8.5 Hz, 2Η)° •’ 在0°C下於4-(1-第三丁氧羰基-（4S)-氯-（2S)-吼咯啶 基）曱氧苯甲酸曱酯（369毫克，1.0毫莫耳）溶於Cjj2ci2 (3. 0毫升）之攪拌溶液中加入T F A ( 3 · 0毫升）。使反應混合物在 室溫下攪拌0 · 5小時。將混合物於真空中濃縮。將飽和 N a H C 〇3加至殘留物’並以C H2 C 12萃取。將萃取液以鹽水洗 條’於N a2 S 04上乾無’並於真空中濃縮。將粗製產物不經 進一步的純化而使用於後續的反應中。在〇 °C下於此粗製 產物（185毫克，〇·5毫莫耳）、4-[N，-（2-氣苯基）脲基] -3-甲氧苯乙酸（167毫克，0.5毫莫耳）、HOBt (68毫克， 0.5毫莫耳）、及三乙胺（208毫升，1.5毫莫耳）溶於THF (8. 〇毫升）及MeCN(8· 0毫升）之攪拌溶液中加入EDC · HC 1 (144 毫克，0 · 7 5毫莫耳）。使反應混合物在室溫下攪拌1 6小時 ’並於真空中濃縮。將水加至殘留物，並以EtOAc萃取。 將萃取液以飽和NaHC03、2M檸檬酸、及飽和NaHC03洗滌， 然後於Na2S04上乾燥，並於真空中濃縮。使殘留物經由於 矽膠上利用正己烷-EtOAc(l : 2，v/v)作為洗提液進行管柱The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography on a mixture of hexane and hexane (4:1, v/v) as an eluent to obtain 4-(cis-1-t-butoxy). A light yellow oil of methyl carbonyl-4-oxo-(2S)-pyrrolidinyl)methoxybenzoate (340 mg, 92%). 1H-NMR (CDC13) 5 1· 48 (s, 9H), 2· 38- 2· 65 (m, 2H), 3· 50-3.60 (m, 1H), 3·88 (s, 3H), 3 ·8 9-4.0 5 (m,1Η·), 4·26 - 4·41 (m,4Η), 6.95 - 6·97 (m,2Η), 7.'98 (d, J-8.5 Hz , 2Η)° •' 4-(1-tert-butoxycarbonyl-(4S)-chloro-(2S)-pyridinyl) decyloxybenzoate (0 mg, 1.0 mM at 0 °C) To a stirred solution of Cjj2ci2 (3.0 ml) was added TFA (3.0 mL). The reaction mixture was stirred at room temperature for 0.5 hours. The mixture was concentrated in vacuo. Saturated N a H C 〇3 was added to the residue' and extracted with CH 2 C 12 . The extract was washed with brine <RTI ID=0.0></RTI> <RTI ID=0.0> The crude product was used in the subsequent reaction without further purification. The crude product (185 mg, 〇·5 mmol), 4-[N,-(2-phenylphenyl)ureido]-3-methoxyphenylacetic acid (167 mg, 0.5 mM) at 〇 ° C Add the mixture of THF (8. EDC · HC 1 (144 mg, 0 · 7 5 mmol). The reaction mixture was stirred at room temperature for 16 h then concentrated in vacuo. Water was added to the residue and extracted with EtOAc. The extract was washed with saturated NaHC03, 2M EtOAc and sat. NaHC.sub.3, and then evaporated. The residue was passed through a ruthenium gel using n-hexane-EtOAc (1:2, v/v) as an eluent.

W312\2d-code\90-01\89112968.ptd 第 383 頁 1283240 五、發明說明（379) 層析’純化而得4 - [(4S)-氣-1-[3 -曱氧基- 4 - [Ν’ -（2 -氣苯 基）脲基]苯基乙醯基]一（2S) -吼洛咬基]甲氧苯甲酸曱酯 (210 毫克，72%)之無色油。iH-NMR (CDC13) 5 3. 35- 3· 50 (m，1H)、3·55-3·65 (m，1H)、3·6 卜 3.66 (m，3H)、 3·75 (s，3H)、3·88 (s，3H)、3·99-4·04 (m，1H)、 4.35-4.40 (m, 3H) ^ 4.48-4.53 (m, 1H) &gt;6.77-7.10 (m，7H)、7·2 5 - 7.3 6 (m，2H)、7.9 3-8.0 0 (m，2H)、 8. 18 (d，J = 8· 0 Hz，1H)。 於4-[ (4S)-氯-1-[3-甲氧基-4-[N，-（2-氣苯基）脲基]苯 基乙酿基]-(2S) -吡咯啶基]甲氧苯甲酸曱酯（21 0毫克，0. 35毫莫耳）溶於THF(6. 0毫升）及MeOH(3. 0毫升）之攪拌溶液 中加入IN NaOH(0. 7毫升，0· 7毫莫耳）。使混合物在70 t： 下攪拌1 8小時。將混合物於真空中濃縮，加入水，並以1 n HC1中和。收集所產生之固體，以水洗滌，並於真空中乾 燥而得1 0 2 ( 2 0 0毫克，9 8 %)之白色結晶固體。熔點1 2 6 -131 °C; IR (KBr) 3330、1685、1604、1533、1438 / 公 分；1Η-NMR (DMSO-d6) 6 2.15-2.25 (m，1H)、2·58-2·63 (m， 1Η) 、3·58-3·78 (m， 3Η) 、3·83 (s， 3Η) 、4·13 -4.42 (m，4H)、4·73 (m，1H)、6· 75-7.45 (m，7H)、7· 86-8.10 (m，4H)、8·90 (s，1H)、8·95 (s，1H); MS (FAB) m/z 5 72(MH1 ) ; C28H27N3 06 C1 之分析計算值：C，58. 75; H, 4.75; N， 7·34。實測值：C，58.9 3; H，4.85; N，7.15。 實施例9 6W312\2d-code\90-01\89112968.ptd Page 383 1283240 V. INSTRUCTIONS (379) Chromatography 'purification to give 4 - [(4S)-gas-1-[3 -decyloxy- 4 - [Ν'-(2-Phenylphenyl)ureido]phenylethenyl]-(2S)-indolyl] methoxy methoxybenzoate (210 mg, 72%) as a colorless oil. iH-NMR (CDC13) 5 3. 35- 3· 50 (m, 1H), 3·55-3·65 (m, 1H), 3·6, 3.66 (m, 3H), 3·75 (s, 3H), 3·88 (s, 3H), 3·99-4·04 (m, 1H), 4.35-4.40 (m, 3H) ^ 4.48-4.53 (m, 1H) &gt; 6.77-7.10 (m, 7H), 7·2 5 - 7.3 6 (m, 2H), 7.9 3-8.0 0 (m, 2H), 8. 18 (d, J = 8·0 Hz, 1H). 4-[(4S)-Chloro-1-[3-methoxy-4-[N,-(2-phenylphenyl)ureido]phenylethyl]-(2S)-pyrrolidinyl] To a stirred solution of THF (6.0 ml) and MeOH (3.0 ml) was added IN NaOH (0.7 mL, 0·············· 7 millimoles). The mixture was stirred at 70 t: for 18 hours. The mixture was concentrated in vacuo, water was added and neutralized with 1 n EtOAc. The resulting solid was collected, washed with water and dried in vacuo to give a white crystallite. Melting point 1 2 6 -131 ° C; IR (KBr) 3330, 1685, 1604, 1533, 1438 / cm; 1Η-NMR (DMSO-d6) 6 2.15-2.25 (m, 1H), 2·58-2·63 (m, 1Η), 3·58-3·78 (m, 3Η), 3·83 (s, 3Η), 4·13 -4.42 (m, 4H), 4·73 (m, 1H), 6· 75-7.45 (m,7H),7·86-8.10 (m,4H),8·90 (s,1H),8·95 (s,1H); MS (FAB) m/z 5 72(MH1 ) ; C28H27N3 06 C1 Analysis calculated: C, 58. 75; H, 4.75; N, 7.34. Found: C, 58.9 3; H, 4.85; N, 7.15. Example 9 6

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-氯-(2s)—°比咬:]本甲基氧)ίΐ]酸氧苯 基乙醯基]-(4S)-Chloro-(2s)-° ratio bite:]Methyloxy) ΐ 酸 酸 酸 酸 ] ] ]]] (4S)

3&quot;^)~C〇〇h 在〇 °C下於4 - [ 1 —第：丁 g至山A ^ ? 某1甲氧芨甲舻田弟一 基-s)-氯-(2S)-吡咯啶 基一j曱乳本甲酸甲酯（369毫克，10毫莫耳 , 〇毫升）之攪拌溶液中加入TFA(3 〇 ' ' ' 2 2 (3·3&quot;^)~C〇〇h at 〇°C at 4 - [ 1 -第:丁格至山 A ^ ?一一methoxy 甲甲舻田一基-s)-Chloro-(2S)- Add a TFA (3 〇' ' ' 2 2 (3·) to a stirred solution of pyrrolidinyl-methyl hydrazine methyl ester (369 mg, 10 mmol, 〇ml).

乾燥，並於… 進Υ的，、、屯化而使用於後續的反應中。在〇 t -ρ ^ =5”，〇.5毫莫耳)、心漠苯^ Ϊ，_ 一 酸（190毫克，〇.5毫莫耳）、瞻（68毫 克0.5笔莫耳）、及三乙胺（2 08毫升，15 THFU.0毫升）及MeCN(8.〇毫升）之撥拌溶液中加 HC1 (144毫克，〇· 75毫莫耳）。使反應混合物在室溫下 拌1 6小時，並於真空中濃縮。將水加至殘留物，並以It is dried and used in subsequent reactions in the enthalpy, and enthalpy. In 〇t -ρ ^ =5", 〇.5 millimoles), heart benzene Ϊ, _ acid (190 mg, 〇.5 millimoles), prospect (68 mg 0.5 moles), and Add HCl (144 mg, 〇 · 75 mmol) to a mixture of triethylamine (2 08 mL, 15 THFU.0 mL) and MeCN (8. mM). Mix the reaction mixture at room temperature. 6 hours and concentrated in vacuo. Add water to the residue and

EtOAc萃取。將萃取液以飽和NaHC〇3、2M檸檬酸、及飽和Extracted with EtOAc. The extract was saturated with NaHC 3, 2 M citric acid, and saturated.

NaHC〇3洗務，然後於NajO4上乾燥，並於真空中濃縮。使 殘留物經由於矽膠上利用正己烷—Et〇Ac(1:2，v/v)作為铁 提液進行管柱層析，純化而得4 — [ 1 — [4-[N，-(2-溴苯基）/ 脲基]-3-甲氧苯基乙醯基]—(4S) -氯-（2S) - u比咯啶基]甲氧 苯甲酸甲酯（ 260毫克，83%)之無色油。ιΗ一NMR (CDCl3)占NaHC(R) 3 was washed, then dried over NajO4 and concentrated in vacuo. The residue was subjected to column chromatography using n-hexane-Et〇Ac (1:2, v/v) as an iron extract on silica gel, and purified to obtain 4 — [ 1 — [4-[N,-(2 -Bromophenyl)/ureido]-3-methoxyphenylethenyl]-(4S)-chloro-(2S)-u-pyridyl]methyl methoxybenzoate (260 mg, 83%) Colorless oil. Η Η NMR (CDCl3) accounted for

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1283240 五、發明說明（381) 2.32-2.5 0 (m，1H)、2·53-2·65 (m，1H)、3.6卜3.67 (m，3H)、3·75 (s，3H)、3·88 (s，3H)、3·99-4·03 (m, 1Η)、4·35-4·40 (m，3Η)、4·45-4·55 (m，1Η)、6·78-7· 10 (m，7Η)、7·28-7·33 (m，1Η)、7·52 (d，J = 8.0 Hz, 1H)、7·94-7·99 (m，3H)、8.14 (d，J = 8.3 Hz, 1H)。 於4-[l-[ 4-[Ν’ -（2-溴苯基）脲基]-3-甲氧苯基乙醯基]-(4S) -氣-（2S)-毗咯啶基]甲氧苯曱酸曱酯（260毫克，0. 4 毫莫耳）溶於THF(6· 0毫升）及MeOH(3· 0毫升）之攪拌溶液中 加入IN NaOH(0. 8毫升，〇. 8毫莫耳）。使混合物在70 t：下 攪拌24小時。將混合物於真空中濃縮，加入水，並以1 N HC 1中和。收集所產生之固體，以水洗滌，並於真空中乾 燥而得103(210毫克，83%)之白色結晶固體。熔點127-132 °C ; IR (KBr) 3330、1 685、1 604、1 529、1 434 / 公分； 'H-NMR (DMSO-d6) ά 2.18-2.28 (m, 1Η) &gt; 2.60-2. 70 (m, 1H)、3·55-3·75 (m，3H)、3·83 (s，3H)、4·12-4·42 (m，4H)、4·60-4.75 (m, 1H)、6·75-7·06 (m，5H)、 7·30-7.34 (m，1H)、7·60 (d，J = 7.3 Hz，1H)、7·86-7· 94 (m，5H)、8·75 (s，1H)、8·94 (s，1H); MS(FAB) m/z 616(M+)、618(MH2) ; C28H27N3 06 ClBr 之分析計算值·· C， 54. 52 ; H，4· 41 ; N，6· 81。實測值·· C，54· 98 ; H，4. 54 ；N，6. 66 ° 實施例9 7 4-[(4R)-氯-1 - [3-甲氧基-4 - [Ν’-（2-甲基苯基）脲基]苯基 乙醯基]-（2S)-吼咯啶曱氧基]苯曱酸1283240 V. INSTRUCTIONS (381) 2.32-2.5 0 (m, 1H), 2·53-2·65 (m, 1H), 3.6 3.67 (m, 3H), 3·75 (s, 3H), 3 ·88 (s, 3H), 3·99-4·03 (m, 1Η), 4·35-4·40 (m, 3Η), 4·45-4·55 (m, 1Η), 6.78 -7· 10 (m, 7Η), 7·28-7·33 (m, 1Η), 7·52 (d, J = 8.0 Hz, 1H), 7·94-7·99 (m, 3H), 8.14 (d, J = 8.3 Hz, 1H). 4-[l-[4-[Ν'-(2-Bromophenyl)ureido]-3-methoxyphenylethenyl]-(4S)-gas-(2S)-pyrrolidinyl] To a stirred solution of THF (0.6 mL, 0.45 mL) in THF (6.0 mL) and MeOH (3.0 mL). 8 millimoles). The mixture was stirred at 70 t: for 24 hours. The mixture was concentrated in vacuo, water was added and neutralized with 1 N EtOAc. The resulting solid was collected, washed with water and dried mjjjjjjj Melting point 127-132 °C; IR (KBr) 3330, 1 685, 1 604, 1 529, 1 434 / cm; 'H-NMR (DMSO-d6) ά 2.18-2.28 (m, 1Η) &gt; 2.60-2 70 (m, 1H), 3·55-3·75 (m, 3H), 3·83 (s, 3H), 4·12-4·42 (m, 4H), 4·60-4.75 (m , 1H), 6·75-7·06 (m, 5H), 7·30-7.34 (m, 1H), 7·60 (d, J = 7.3 Hz, 1H), 7·86-7· 94 ( m,5H),8·75 (s,1H),8·94 (s,1H); MS(FAB) m/z 616(M+), 618(MH2); C28H27N3 06 ClBr analytical value·· C , 54. 52 ; H, 4· 41 ; N, 6. 81. Found C·54·98 ; H, 4. 54 ; N, 6. 66 ° Example 9 7 4-[(4R)-Chloro-1 - [3-methoxy-4 - [Ν'- (2-methylphenyl)ureido]phenylethenyl]-(2S)-indenylpyridiniumoxy]benzoic acid

89112968.ptd 第386頁 1283240 五、發明說明（382) Μβ Η H 〇Me 104 及 4 - [(4R)-氯-1-[4-[Ν，-（2-氯苯基）脲基]-3-曱氧苯基乙醢 基]-(2S) -吼咯啶甲氧基]苯曱酸89112968.ptd Page 386 1283240 V. INSTRUCTIONS (382) Μβ Η H 〇Me 104 and 4 - [(4R)-chloro-1-[4-[Ν,-(2-chlorophenyl)ureido]- 3-oxophenylphenylmercapto]-(2S)-indolyl methoxy]benzoic acid

104及105 於卜（第三丁氧羰基）-（4S) -羥基-（2S)-吡ρ各咬 基羧酸甲酯（1·81克，7·34毫莫耳）溶於CC14-CH2C12 (20毫 升，1:1，v/v)之攪拌溶液中加入Ph3P(3.87毫莫耳， 14· 75毫莫耳），並使反應混合物在室溫下攪拌2小時。於 混合物中加入E t OH ( 5毫升），並使反應混合物在室溫下授 拌隔夜。於移除溶劑後，將殘留物經由於矽膠上利用正己 烷-EtOAc(3:l，v/v)作為洗提液進行管柱層析，純化而得 1 -（第三丁氧魏基）-（4R) -氯- (2S) -吼略ϋ定叛酸甲酯之合成 物（1· 36 克，70%)之無色油。iH-NMR (CDC13) (5 1· 42 (s, 9H) &gt; 2.32-2.39 (m, 1H) &gt; 2.49-2.54 (m, 1H) &gt;3.66-3. 92 (s 及m 系列，總計5H)、4. 44-4. 55 (m，2H) ; MS(FAB) m/z 264(M+ + 1)。 於1-(第三丁氧羰基氯—（2S)一吡咯啶羧酸甲酯 (1· 35克，5· 12毫莫耳）溶於THF(1〇毫升）之攪拌溶液中加104 and 105 Ib (t-butoxycarbonyl)-(4S)-hydroxy-(2S)-pyridinyl carboxylic acid methyl ester (1.81 g, 7.34 mmol) dissolved in CC14-CH2C12 Ph3P (3.87 mmol, 14.75 mmol) was added to a stirred solution of (20 mL, 1:1, v/v), and the mixture was stirred at room temperature for 2 hr. Et OH (5 mL) was added to the mixture and the mixture was stirred overnight at room temperature. After the solvent was removed, the residue was purified by column chromatography using n-hexane-EtOAc (3:1, v/v) as eluent to obtain 1-(t-butoxy-Wiki). -(4R)-Chloro-(2S) - a colorless oil of a combination of tartrate methyl ester (1·36 g, 70%). iH-NMR (CDC13) (5 1·42 (s, 9H) &gt; 2.32-2.39 (m, 1H) &gt; 2.49-2.54 (m, 1H) &gt;3.66-3. 92 (s and m series, total 5H), 4. 44-4. 55 (m, 2H); MS (FAB) m/z 264 (M+ + 1). 1-(T-butoxycarbonyl chloride-(2S)-pyrrolidinecarboxylic acid A The ester (1·35 g, 5·12 mmol) was dissolved in a stirred solution of THF (1 mL).

89112968.ptd 第387頁 1283240 五、發明說明（383) 入0·5Ν NaOH(10毫升），並使反應混合物迴流加熱；ι·5小 時。於冷卻至室溫後，將混合物倒入至冰的丨N HC 1中，並 以CHCl3_Me0H(9:l，ν/ν)萃取混合物。將萃取液以鹽水洗 &gt;條’於Na2S04上乾燥，並蒸發而得卜（第三丁氧羰基） -（4R)-氣-（2S)-吡咯啶羧酸（1.28克，定量）之無色油。 4-NMR (CDC13) 5 1·44 (s，9H)、2·37-2·54 (m, 2H)、 3.68-3·88 (m，2H)、4·42-4.45 (m，2H)。 經由注射針於1-(第三丁氧羰基）—（4R)-氯—（2S) -吼咯啶 羧酸（1·28克，5·13毫莫耳）溶於THF(20毫升）之攪拌溶液 中逐滴加入別3 4^13(0.60毫升，6.33毫莫耳），並使反應 混合物在室溫下攪拌1小時。於移除溶劑後，將殘留物溶 解於CH2C12中。將溶液以η2〇、鹽水洗滌，於Na2S04上乾 燥，並蒸發。將殘留物經由於矽膠上利用CHCl3_MeOH(50 : 1，v/v)作為洗提液進行管柱層析，純化而得卜（第三丁氧 羰基）-（4R)-氯脯胺醇（〇·88克，73%)之無色油。1H-NMR (CDC13)6 1.48 (s，9Η)、1·98 (m，1Η)、2·26-2·32 (m， 1Η) 、3·56-3·65 (m， 2Η) 、3·77 (m， 2Η) 、4·24 (m， 1H)、4·4 卜 4.46 (m，2H) ; MS(FAB) m/z 236 (MH1)。 於4-羥基苯甲酸甲酯（560毫克，3.68毫莫耳）、：l -（第三 丁氧羰基）-（41〇_氣脯胺醇（870毫克，3.69毫莫耳）、？4? (1.16克，4.42毫莫耳）溶於THF( 15毫升）之冷的（〇°C)攪拌 溶液中加入DIAD ( 870毫升，4· 42毫莫耳），並使反應混合 物迴流加熱1 0小時。於冷卻至室溫後，將混合物蒸發。將 殘留物經由於矽膠上利用正己烷-EtOAc(5: 1, v/v)作為洗89112968.ptd Page 387 1283240 V. INSTRUCTIONS (383) Into 0. 5 NaOH (10 mL), and the reaction mixture was heated under reflux; ι·5 hr. After cooling to room temperature, the mixture was poured into ice 丨N HCl 1 and mixture was extracted with CHCl3_Me0H (9:1, ν / ν). The extract was washed with brine and dried on Na2SO4, and evaporated to give a colorless product of (t-butyloxycarbonyl)-(4R)-gas-(2S)-pyrrolidinecarboxylic acid (1.28 g, quantitative). oil. 4-NMR (CDC13) 5 1·44 (s, 9H), 2·37-2·54 (m, 2H), 3.68-3·88 (m, 2H), 4·42-4.45 (m, 2H) . It was dissolved in THF (20 ml) via an injection needle to 1-(t-butoxycarbonyl)-(4R)-chloro-(2S)-pyrrolidinecarboxylic acid (1·28 g, 5·13 mmol). Additional 3 4^13 (0.60 ml, 6.33 mmol) was added dropwise to the stirred solution and the mixture was stirred at room temperature for 1 hour. After the solvent was removed, the residue was dissolved in CH2C12. The solution was washed with η 2 〇, brine, dried over Na 2 EtOAc and evaporated. The residue was subjected to column chromatography using CHCl3_MeOH (50:1, v/v) as an eluent, and purified to obtain (t-butoxycarbonyl)-(4R)-chloroguanamine (〇). · 88 grams, 73%) of colorless oil. 1H-NMR (CDC13)6 1.48 (s,9Η), 1.98 (m,1Η), 2·26-2·32 (m, 1Η), 3·56-3·65 (m, 2Η), 3 · 77 (m, 2Η), 4·24 (m, 1H), 4·4 卜 4.46 (m, 2H); MS(FAB) m/z 236 (MH1). Methyl 4-hydroxybenzoate (560 mg, 3.68 mmol), l-(t-butoxycarbonyl)-(41〇_gas glutamine (870 mg, 3.69 mmol), ?4? (1.16 g, 4.42 mmol) in a cold (〇 ° C) stirred solution of THF (15 mL) was added DIAD ( 870 mL, 4.42 mmol), and the reaction mixture was heated at reflux for 10 hours. After cooling to room temperature, the mixture was evaporated. The residue was taken on a silica gel using n-hexane-EtOAc (5:1 v/v).

89112968.ptd 第388頁 1283240 五、發明說明（384) 提液進行管柱層析，純化而得4-[1-(第三丁氧羰基）—（4R) -氣-（2S)-咄咯啶甲氧基]苯甲酸曱酯（ 890毫克，65%)之白 色固體。熔點116-120 °C ; 1-NMR (CDC13) 5 1· 47 (s， 9Η)、2·39-2·53(ιη，2Η)、3·69-3·70&amp;4.13 -4.17 (m，總計3Η)、3·88 (s，3Η)、4·30-4.41 (m， 2Η)、4·50-4·55 (m，1Η)、6·90-6·92 (m，2Η)、7.96-7 98 (m，2H); MS(FAB) m/z 370 (MH1); C18H24C1N05 之分析 計算值：C，58·46;Η，6.54;C1，9·59;Ν，3.79。實測 值：C，58·35;Η，6.56;C1, 9·75;Ν，3.77。 於4-[1-(第三丁氧羰基）-(4R) -氣-(2S) -吼咯啶曱氧基;j 苯曱酸曱酯（840毫克，2· 27毫莫耳）溶於CH2Cl2(l〇毫升f之 攪拌溶液中加入TFA( 1 0毫升），並使反應混合物在室溫下 攪拌隔夜。將混合物於真空中濃縮，並利用飽和NaHC〇3使 其成為鹼性。將混合物以CHC 13萃取，以鹽水洗滌，於 N a2 S Ο*上乾燥，並蒸發而得4 - [ (4 R) -氯-（2 S) -吼洛咬甲氧 基]苯曱酸甲酯（ 580毫克，95%)的白色固體。溶點61一64 t 1-NMR (CDC13) (5 1· 85 (br s，1H)、2· 03-2· 10 (m， 1H)、2·29-2·35 (m，1H)、3·19-3.31 (m，2H)、3·88 (s，3 Η )、3 · 9 2 - 4 · 0 6 (m，3 Η)、4 · 5 3 - 4 · 5 6 (m，1 Η)、 6·91 (d，J = 8.8 Hz，2H)、7·98 (d，J = 8.8 Hz, 2H); MS(FAB) m/z 270(MH1)。 104 使3 -曱氧基-4 - [Ν’ -（2-甲基苯基）脲基]苯乙酸（gw毫 克，1·22毫莫耳）、4 - [(4R) -氣-（2S)-吼略咬甲氧基]苯甲89112968.ptd Page 388 1283240 V. INSTRUCTIONS (384) The liquid is subjected to column chromatography and purified to give 4-[1-(t-butoxycarbonyl)-(4R)-gas-(2S)-pyro Pyridylmethoxy]benzoate benzoate (890 mg, 65%) as a white solid. Melting point 116-120 °C; 1-NMR (CDC13) 5 1· 47 (s, 9Η), 2·39-2·53 (ιη, 2Η), 3·69-3·70&amp;4.13 -4.17 (m, 3Η), 3·88 (s, 3Η), 4·30-4.41 (m, 2Η), 4·50-4·55 (m, 1Η), 6.90-6·92 (m, 2Η), 7.96-7 98 (m, 2H); MS (FAB) m/z 370 (MH1); C18H24C1N05 analytical value: C, 58·46; Η, 6.54; C1,9·59; Ν, 3.79. Found: C, 58·35; Η, 6.56; C1, 9·75; Ν, 3.77. 4-[1-(Tertidinoxycarbonyl)-(4R)-gas-(2S)-indolyloxyl;j benzoyl benzoate (840 mg, 2·27 mmol) To a stirred solution of CH.sub.2Cl.sub.sub.sub.sub.sub.sub. Extracted with CHC 13 , washed with brine, dried over Na 2 S Ο*, and evaporated to give 4-[(4R)-chloro-(2S)-indole methoxy]benzoic acid methyl ester ( 580 mg, 95%) of white solid. Melting point 61-64 t 1-NMR (CDC13) (5 1 · 85 (br s, 1H), 2· 03-2· 10 (m, 1H), 2·29 -2·35 (m, 1H), 3·19-3.31 (m, 2H), 3·88 (s, 3 Η ), 3 · 9 2 - 4 · 0 6 (m, 3 Η), 4 · 5 3 - 4 · 5 6 (m,1 Η), 6.91 (d, J = 8.8 Hz, 2H), 7·98 (d, J = 8.8 Hz, 2H); MS(FAB) m/z 270( MH1). 104 3 -Methoxy-4 -[Ν' -(2-methylphenyl)ureido]phenylacetic acid (gw mg, 12.22 mmol), 4 - [(4R) - gas -(2S)-吼 slightly bite methoxy]benzol

89112968.ptd 第389頁 1283240 五、發明說明（385) 酸甲酯（330毫克，1·22毫莫耳）、EDC· HC 1(281毫克， 1.47毫莫耳）、HOBt(200毫克，1.48毫莫耳）及Et3N(205毫 升’ 1 · 47耄莫耳）於THF ( 1 0毫升）中之混合物在室溫下授拌 隔仪。將混合物以H2 〇稀釋，並以e 10 A c萃取。將萃取液以 鹽水洗務’於Na2S04上乾燥’並蒸發。將殘留物經由於石夕 膠上利用CHCl3-MeOH(100:l至50:1, v/v)作為洗提液進行 管柱層析，純化而得4 - [(4R)-氯-1 - [3 -甲氧基-4-[N，-(2 -甲基苯基）脲基]苯基乙酿基]一（2S) -吼洛咬甲氧基]苯甲 酸甲酯（ 670毫克，97%)的白色泡沫。UMR (CDCl3) 5 2· 28 (s， 3H) 、2·33-2.57 (m， 2H) 、3·50 (s, 3H)、 3.59-3·60 (m，2H)、3·75- 3.82 (m，2H)、3·88 (s， 3Η) 、4·06-4·09 (m， 1Η) 、4·51-4· 63 (m， 3Η) '6.65-6. 80 (m, 5H)、7·09 - 7.13 (m, 1H)、7.20 - 7.27 (m，3H)、 7.56-7.58 (m， 1H) 、7·91-7·93 (m, 2H) 、8·05-8.07 (m, 1H) ; MS(FAB) m/z 5 6 6 (MH1)。 於4 - [(4R)-氯-1 - [3-曱氧基-4 - [N，-（2-甲基苯基）脲基] 苯基乙醯基]-（2S) -咄咯啶曱氧基]苯甲酸甲酯（480毫克， 0· 85毫莫耳）溶於THF(5毫升）之攪拌溶液中加入〇. 5N NaOH( 5毫升），並使反應混合物迴流加熱2小時。於冷卻至 室溫後’將混合物倒入至冰的1 N H C 1中，並於減壓下收集 所產生之沈澱物。將粗製固體溶解於CHCl3-MeOH中，並蒸 發。將殘留物以Et20洗滌而得1 04 ( 355毫克，76%)之白色 非晶形固體。熔點 1 28- 1 3 2 °C ; 1-NMR (DMSO-d6) 3 2. 25 (s，3H)、2·29-2.46 (m，2H)、3·57-3·73 (m，2H)、89112968.ptd Page 389 1283240 V. INSTRUCTIONS (385) Methyl ester (330 mg, 12.22 mmol), EDC· HC 1 (281 mg, 1.47 mmol), HOBt (200 mg, 1.48 m) Mixture of Et3 and Et3N (205 ml '1 · 47 Torr) in THF (10 mL) was stirred at room temperature. The mixture was diluted with H 2 〇 and extracted with e 10 A c. The extract was washed with brine to dry on Na 2 SO 4 and evaporated. The residue was subjected to column chromatography using CHCl3-MeOH (100:1 to 50:1, v/v) as an eluent, and purified to give 4-[(4R)-chloro-1 - [3-methoxy-4-[N,-(2-methylphenyl)ureido]phenylethyl]](2S)-indolyl methoxy]benzoic acid methyl ester (670 mg, 97%) white foam. UMR (CDCl3) 5 2· 28 (s, 3H), 2·33-2.57 (m, 2H), 3·50 (s, 3H), 3.59-3·60 (m, 2H), 3.75- 3.82 (m, 2H), 3·88 (s, 3Η), 4·06-4·09 (m, 1Η), 4·51-4· 63 (m, 3Η) '6.65-6. 80 (m, 5H ), 7·09 - 7.13 (m, 1H), 7.20 - 7.27 (m, 3H), 7.56-7.58 (m, 1H), 7.91-7·93 (m, 2H), 8.05-8.07 ( m, 1H); MS (FAB) m/z 5 6 6 (MH1). 4-[(4R)-Chloro-1 -[3-indolyl-4-[N,-(2-methylphenyl)ureido]phenylphenyl]](2S)-indolyl To a stirred solution of methyl benzo]methyl benzoate (480 mg, EtOAc) (EtOAc) (EtOAc) After cooling to room temperature, the mixture was poured into 1 N H C 1 of ice, and the resulting precipitate was collected under reduced pressure. The crude solid was dissolved in CHCl3-MeOH and evaporated. The residue was washed with EtOAc (EtOAc EtOAc). Melting point 1 28- 1 3 2 ° C ; 1-NMR (DMSO-d6) 3 2. 25 (s, 3H), 2·29-2.46 (m, 2H), 3·57-3·73 (m, 2H ),

\\312\2d-code\90-01\89112968.ptd 第390頁 1283240 五、發明說明（386) 3.78 (s, 3H) ^3.81-3.99 (m, 2H) &gt;4.11-4.31 (m, 2H) 、4·43-4·45 及 4·64-4·67 (各m，總計 m)、4·83-4·85 (m，1Η)、6·7 卜 7·17 (m, 7Η)、7·78 - 7·80 (m, 1Η)、 7·87-7·91 (m，2H)、7·99-8·01 (m，ih)、8·47 (s，1H) 、8·56 (s，1H)、12·66 (br s，1H); MS(FAB) m/z 552 (M+ + 1 )，C29H3QC1N3 06 · 3/4H2〇 之分析計算值·· c，61 . 59 ’ H’ 5· 61 ’ C1’ 6· 27 ; N，7. 43。實測值：C，61. 56 ; H， 5· 51 ; Cl, 6· 68 ; N， 7· 26 。 105 ，4-[N -(2-氣苯基）脲基]一 3—甲氧笨乙酸（4〇〇毫克，l 19耄莫耳）、4-[ (4R)-氯-(2 S)-吼咯啶甲氧基]苯曱酸 (320毫克，Κ19毫莫耳）、εκ·ηπ(275毫克，i 甲®曰 耳）、H〇Bt(195毫克，1&gt;44毫莫耳μΕμ(2〇〇毫升，巧毫，耳）於THFU0毫升）中之混合物在室溫下授拌隔夜“二 混δ物以稀釋，並以Et0Ac萃取。將萃取液以鹽將 滌，於NaJO4上乾燥，並蒸發。將殘留物經由於:用CHC13-Me〇H(1〇0:1，v/v)作為洗提液進行管柱上利 化而得4-[(4R)-氯-1-[4-[Ν，_(2_氣苯基）脲基] 苯基乙醯基]-(2S)-吡咯啶甲氧基]苯甲酸甲酯（6甲虱 9 8%)的淡黃色泡沫。ih-NMR (CDC13) 5 2 35-2 41 ⑻、2.49-2·59 (m，1Η)、3·55 (s，3Η·)、3·5(m，2Η)、3·73 - 3·86 (m，2Η)、3·88 (s，3Η)、· 純 毫克 ’m， 09 (m，1H)、4·54-4·66 (m，3H)、6·67-6·81 〇6〜4m， 4H) 6.9 5-6.9 9 (m，1H)、7·23-7·25 (m，1H)、7·2&quot; '· O 〇\\312\2d-code\90-01\89112968.ptd Page 390 1283240 V. Description of invention (386) 3.78 (s, 3H) ^3.81-3.99 (m, 2H) &gt;4.11-4.31 (m, 2H ), 4·43-4·45 and 4·64-4·67 (each m, total m), 4·83-4·85 (m, 1Η), 6·7 Bu 7·17 (m, 7Η) , 7·78 - 7·80 (m, 1Η), 7·87-7·91 (m, 2H), 7·99-8·01 (m, ih), 8·47 (s, 1H), 8 ·56 (s,1H),12·66 (br s,1H); MS(FAB) m/z 552 (M+ + 1 ), C29H3QC1N3 06 · 3/4H2〇 Analytical calculations·· c,61 . 59 ' H' 5· 61 ' C1' 6· 27 ; N, 7. 43. Found: C, 61.56; H, 5· 51; Cl, 6·68; N, 7·26. 105,4-[N-(2-Phenylphenyl)ureido]3-methoxybenzoic acid (4〇〇mg, l 19耄莫耳), 4-[(4R)-chloro-(2 S) - 吼 啶 甲 methoxy] benzoic acid (320 mg, Κ 19 mmol), εκ·ηπ (275 mg, i 甲® )), H〇Bt (195 mg, 1 &gt; 44 mM μμμμ ( 2 〇〇 ml, 巧, ear) mixture in THF (0 ml) was mixed overnight at room temperature "diluted δ substance to dilute, and extracted with Et0Ac. The extract was washed with salt and dried on NaJO4. And evaporating. The residue is passed through: using CHC13-Me〇H (1〇0:1, v/v) as an eluent to carry out the column to obtain 4-[(4R)-chloro-1-[ A pale yellow foam of 4-[indole, _(2-phenylphenyl)ureido]phenylphenyl]](2S)-pyrrolidinemethoxy]benzoic acid methyl ester (6-carbamidine 9 8%). ih-NMR (CDC13) 5 2 35-2 41 (8), 2.49-2·59 (m, 1Η), 3·55 (s, 3Η·), 3·5 (m, 2Η), 3·73 - 3· 86 (m, 2Η), 3·88 (s, 3Η), · pure milligrams 'm, 09 (m, 1H), 4·54-4·66 (m, 3H), 6·67-6·81 〇 6~4m, 4H) 6.9 5-6.9 9 (m,1H), 7·23-7·25 (m,1H), 7·2&quot; '· O 〇

1283240 五、發明說明（387) (m, 1H)、7. 47-7.49 (m，2H)、7·9 0-7.99 (m，3H)、 8·18-8·21 (m，1H); MS(FAB) m/z 586(M+ + 1)。 於4-[(4R)-氣-卜[4-[Ν’ -（2 -氣苯基）脲基]-3-曱氧苯基 乙醯基]-（2S) -吼咯啶甲氧基]苯甲酸曱酯（410毫克，〇·7〇 毫莫耳）溶於THF(5毫升）之攪拌溶液中加入0.5N NaOH (5 毫升），並使反應混合物迴流加熱5小時。於冷卻至室溫 後，將混合物倒入至冰的1 N HC1中，並於減壓下收集所產 生之沈澱物。將粗製固體溶解於CHC13-MeOH中，並蒸發。 將殘留物以Et20洗滌而得1 0 5 ( 282毫克，70%)之非晶形固 體。熔點131-13 6°(：;111-關1?(^%30-(16)5 2.2 9-2.3 5 (m，1H)、2·44-2·47 (m，1H)、3·5 8-3.74 (m，2H)、 3·78 (s, 3H)、3·8 卜 3.99 (m, 2H)、4·10 - 4·32 (m，2H) 、4· 44-4· 46 及4· 66 (各m，總計 1 Η)、4· 84 (m， 1 Η )、 6·74-7·04 (m，5Η)、7·26-7·30 (m，1Η)、7·43-7.45 (m，1Η)、7·87 - 7·91 (m，2Η)、7·96 (d，J = 8.3 Ηζ， 1H)、8·09 (d，J = 8.3 Hz, 1H)、8·90 (s，1H)、8·94 (s， 1H) ; C28H27C12N3 06 · 3/4H20 之分析計算值·· c， 57. 39 ; H，4· 90 ; Cl，1 1· 66 ; N，7· 17。實測值：c， 57 57 ; H，4. 94 ; Cl，11· 66 ; N，6· 89。 * 實施例9 8 4-[(4S) -羥基-1-[4 - [Ν’ - (2 -甲基苯基）脲基]苯基乙醯基] -(2S)…比咯啶基]甲氧苯甲酸 &amp;1283240 V. INSTRUCTIONS (387) (m, 1H), 7. 47-7.49 (m, 2H), 7·9 0-7.99 (m, 3H), 8·18-8·21 (m, 1H); MS (FAB) m/z 586 (M + + 1). 4-[(4R)-Gas-Bu[4-[Ν'-(2-(phenylphenyl))]]]]]]]]]]]] To a stirred solution of decyl benzoate (410 mg, EtOAc EtOAc) (EtOAc) (EtOAc) After cooling to room temperature, the mixture was poured into ice 1 N HCl, and the resulting precipitate was collected under reduced pressure. The crude solid was dissolved in CHC13-MeOH and evaporated. The residue was washed with Et20 to give 10.5 (yield: 282 mg, 70%) of amorphous solid. Melting point 131-13 6°(:;111-off 1?(^%30-(16)5 2.2 9-2.3 5 (m,1H), 2·44-2·47 (m,1H), 3·5 8-3.74 (m, 2H), 3·78 (s, 3H), 3·8 卜 3.99 (m, 2H), 4·10 - 4·32 (m, 2H), 4· 44-4· 46 and 4· 66 (each m, total 1 Η), 4·84 (m, 1 Η), 6·74-7·04 (m, 5Η), 7·26-7·30 (m, 1Η), 7· 43-7.45 (m,1Η), 7.87 - 7·91 (m, 2Η), 7.96 (d, J = 8.3 Ηζ, 1H), 8·09 (d, J = 8.3 Hz, 1H), 8.90 (s, 1H), 8·94 (s, 1H); C28H27C12N3 06 · 3/4H20 analytical calculations ·· c, 57. 39 ; H,4· 90 ; Cl,1 1· 66 ; N , 7.17. Found: c, 57 57 ; H, 4. 94 ; Cl, 11 · 66 ; N, 6 · 89. * Example 9 8 4-[(4S) -hydroxy-1-[4 - [Ν' - (2-Methylphenyl)ureido]phenylethenyl]-(2S)...pyrrolidyl]methoxybenzoic acid &amp;

1283240 五、發明說明（388) 4-[ (4S)-乙醯氧基—（2S)-吼咯啶基]甲氧苯曱酸甲酉旨 在室溫下於4-[(4S) -乙醯氧基-1-第三丁氧艘基〜（2S)-吼咯啶基]甲氧苯曱酸曱酯（2· 31克，5. 87毫莫耳）溶於CH 2C12(46毫升）之攪拌溶液中加入TFA(10毫升）。於攪拌3. 5 小時後，將混合物於真空中濃縮。將由加入CH2C 12及1 n NaOH將殘留物稀釋，將其以CH2Cl2萃取。將結合的萃取液 以鹽水洗滌，於Na2S04上乾燥，並將其於真空中濃縮。將 殘留物於矽膠[1〇〇克，CHCl3/MeOH(20/l)]上進行層析而 付4 [(4S)-乙醯氧基一（2S) -吼洛。定基]甲氧苯甲酸甲醋（1 89 毫克，100%)的淡紫色固體。1H —NMR (CDCl3) 6 2. Η (s， 3Η) 、2.14 (m， ΐΗ) 、2·65 (m， 1Η) 、3·52-3·63 (m， H) &gt;3.89 (s, 3H) &gt;4.18 (m, 1H) &gt;4.28 (d, J-5.9 Hz, 2H) 、5·38 (m， 1H) 、6·93 (d， J:8.8 Hz, 2H) 、7·99 (d, J = 8· 8 Hz，2H)。 4-[(4S) -乙酷氧基一一曱氧基一4—[N，一（2一甲基苯基）脲 基]苯基乙醯基]-(2 S)-吼咯啶基]甲氧苯甲酸曱酯1283240 V. INSTRUCTIONS (388) 4-[(4S)-Ethyloxy-(2S)-oxaridinyl]methoxybenzoic acid formazan is intended for 4-[(4S)-B at room temperature醯oxy-1-tert-butoxycarbonyl~(2S)-decalidyl] methoxybenzoate (2·31 g, 5.87 mmol) dissolved in CH 2 C12 (46 mL) To the stirred solution was added TFA (10 mL). After stirring for 3.5 hours, the mixture was concentrated in vacuo. The residue was diluted with CH 2 C 12 and 1 n NaOH and extracted with CH 2 Cl 2 . The combined extracts were washed with brine, dried over Na2ss The residue was chromatographed on silica gel [1 g, CHCl3 / MeOH (20/l)] to afford 4 [(4S)-ethyloxy-(2S)-indole. A lavender solid of methyl methoxybenzoic acid (1 89 mg, 100%). 1H-NMR (CDCl3) 6 2. Η (s, 3Η), 2.14 (m, ΐΗ), 2·65 (m, 1Η), 3·52-3·63 (m, H) &gt;3.89 (s, 3H) &gt;4.18 (m, 1H) &gt;4.28 (d, J-5.9 Hz, 2H), 5·38 (m, 1H), 6.93 (d, J: 8.8 Hz, 2H), 7·99 (d, J = 8·8 Hz, 2H). 4-[(4S)-Ethyloxyl-methoxy-4-[N,mono(2-methylphenyl)ureido]phenylethenyl]-(2S)-indolyl Ethyl methoxybenzoate

使3-曱氧基-4- [N，-（2 -甲基苯基）脲基]苯乙酸（ 3 43毫 克’1.09毫莫耳）、4-[(4S) -乙醯氧基-（2S)-咄咯啶基]甲3-methoxy-4-[N,-(2-methylphenyl)ureido]phenylacetic acid (3 43 mg '1.09 mmol), 4-[(4S)-acetoxy-( 2S)-咄 啶 啶 ] ]

\\312\2d-code\90-01\89112968.ptd 第393頁 1283240 五、發明說明（389) 氧苯曱酸曱酯（320毫克，ι·〇9毫莫耳）、edc*HC1(313毫 克’1·64宅莫耳）、H0BT(222毫克，1.64毫莫耳）及Et3N (0.76¾升’ 5.45¾莫耳）於DMF( 7毫升）中之混合物在室溫 下攪:拌1 6小時。將混合物倒入至冰水中，並以E t 〇 a c萃 取。將結合的萃取液以冰水及鹽水洗滌。於在N % s 上乾 燥後，將萃取液於真空中濃縮。將殘留物於矽膠[5 〇克， CHCl〆丙酮（5/1 )]上進行層析而得標題化合物（52〇毫克， 81%)的棕色非晶形固體。ih-NMR (CDC13) 5 2· 00 (s，3H ，其中一個異構物）、2 · 〇 3 (s， 3 Η，其中一個異構物）、 2.28 (m，5Η)、3.54 (s，1Η)、3·58 (s，2Η)、3.64 (s， 1Η)、3·67 及 3.69 (各s，3Η，醯胺異構物）、3.85(d， J = 5.4 Hz, 1H)、3·88 (s，3H)、4·04 (t，J = 9.3 Hz, 1H)、5.27-5.34 (m，1H)、6·51 (m，1H)、6·76-6·89 (m， 2H) 、6·94 (d， J=8.1 Hz， 1H) 、7·14 (m, 1H)、 7.25 (m, 4H)、7.53 (d，J = 8.3 Hz, 1H)、7·96 (d， J=8.0 Hz， 1H) 、8·00-8.10 (m, 2H); MS(ESI) m/z 5 9 0 (MH1)。 於4-[(4S) -乙醯氧基-1 —[4-[N，-（2-曱基苯基）脲基]苯 基乙醯基]-(2S) -吡咯啶基]曱氧苯甲酸曱酯（520毫克，0· 882毫莫耳）溶於THF(30毫升）之溶液中加入0· 25N NaOH(30 毫升）。於在室溫下攪拌2天後，以EtOAc萃取混合物。將 水層以IN HC1酸化，並以CHC13-MeOH(10/l)萃取。將結合 的萃取液以鹽水洗滌.。於在Na2S04上乾燥後，將萃取液於 真空中濃縮。經由加入CHC13、EtOH及乙醚使殘留物結晶\\312\2d-code\90-01\89112968.ptd Page 393 1283240 V. INSTRUCTIONS (389) Oxime benzoate (320 mg, ι·〇9 mmol), edc*HC1 (313 Mixture of mg '1·64 house Moules), H0BT (222 mg, 1.64 mmol) and Et3N (0.763⁄4 liters ' 5.453⁄4 mol) in DMF (7 ml) at room temperature: mix 1 6 hour. The mixture was poured into ice water and extracted with E t 〇 a c. The combined extracts were washed with ice water and brine. After drying on N % s, the extract was concentrated in vacuo. The residue was chromatographed on EtOAc EtOAc (EtOAc:EtOAc Ih-NMR (CDC13) 5 2· 00 (s, 3H, one of the isomers), 2 · 〇3 (s, 3 Η, one of the isomers), 2.28 (m, 5 Η), 3.54 (s, 1Η), 3·58 (s, 2Η), 3.64 (s, 1Η), 3.67 and 3.69 (each s, 3Η, guanamine isomer), 3.85 (d, J = 5.4 Hz, 1H), 3 ·88 (s, 3H), 4·04 (t, J = 9.3 Hz, 1H), 5.27-5.34 (m, 1H), 6·51 (m, 1H), 6·76-6·89 (m, 2H), 6.94 (d, J=8.1 Hz, 1H), 7·14 (m, 1H), 7.25 (m, 4H), 7.53 (d, J = 8.3 Hz, 1H), 7·96 (d , J = 8.0 Hz, 1H), 8·00-8.10 (m, 2H); MS (ESI) m/z 5 9 0 (MH1). 4-[(4S)-Ethyloxy-1 -[4-[N,-(2-mercaptophenyl)ureido]phenylethenyl]-(2S)-pyrrolidinyl]oxime To a solution of decyl benzoate (520 mg, 0· 882 mmol) in THF (30 mL) was added EtOAc (30 mL). After stirring at room temperature for 2 days, the mixture was extracted with EtOAc. The aqueous layer was acidified with 1N HCl and extracted with CH.sub.3-MeOH (10/l). The combined extracts were washed with brine. After drying over Na 2 SO 4 , the extract was concentrated in vacuo. Crystallization of the residue by addition of CHC13, EtOH and diethyl ether

\\312\2d-code\90-01\89112968.ptd 第394頁 1283240 五、發明說明（390) 而得106(68毫克，14%)的無色粉末。熔點148-152 °C (分 解）；IR (KBr) 3356、2939、1687、1604、1533、1454、 1255 / 公分；NMR (DMSO-d6) (5 1. 95-2· 09 (m，2H)、 2·25 (s，3H)、3·59 (d，J = 5.9 Hz, 2H)、3.71 (m， 1H)、3·81 及 3.85 (各s，3H，醯胺異構物）、4·ΐ3 — 4·47 (m，4Η)、5·19 (br, 1Η)、6·70 - 7·21 (m，7Η)、7·79 (d，J:7.9 Hz, 1H)、7·86 (d，J = 8.8 Hz，2H)、8·01 (d，J = 8.3 Hz, 1H)、8·47 (s，1H)、8·57 (s，1H); MS(ESI ) m/z 53 3 (MH1) ; C29H31N3 07 · 1H20 之分析計算值： C， 63·15;Η, 6·03;Ν， 7.62。實測值：c，63·29;Η， 5. 76 ； N, 7.46° 實施例9 9 4 - [1 - [4 - [Ν’ -（2 -氯苯基）脲基]- 3-甲氧苯基乙醯基]-(4S) -羥基-（2S) -咄咯啶基]甲氧苯曱酸\\312\2d-code\90-01\89112968.ptd Page 394 1283240 V. Inventive Note (390) gave 106 (68 mg, 14%) of a colorless powder. Melting point 148-152 ° C (decomposition); IR (KBr) 3356, 2939, 1687, 1604, 1533, 1454, 1255 / cm; NMR (DMSO-d6) (5 1. 95-2· 09 (m, 2H) , 2·25 (s, 3H), 3·59 (d, J = 5.9 Hz, 2H), 3.71 (m, 1H), 3.81 and 3.85 (each s, 3H, guanamine isomer), 4 ·ΐ3 — 4·47 (m, 4Η), 5·19 (br, 1Η), 6·70 - 7·21 (m, 7Η), 7·79 (d, J: 7.9 Hz, 1H), 7· 86 (d, J = 8.8 Hz, 2H), 8·01 (d, J = 8.3 Hz, 1H), 8·47 (s, 1H), 8·57 (s, 1H); MS(ESI) m/ Analysis of calculated values for C 53H31N3 07 · 1H20: C, 63·15; Η, 6·03; Ν, 7.62. Found: c, 63·29; Η, 5. 76 ; N, 7.46 ° Example 9 9 4 - [1 - [4 - [Ν' -(2-Chlorophenyl)ureido]-3-methoxyphenylethenyl]-(4S)-hydroxy-(2S)-咄Pyridyl]methoxybenzoic acid

4 -[(4S)-乙醯氧基-1 -[4-[N’-（2 -氯苯基）脲基]一3-甲氧苯 基乙醯基]-(2S) -吡咯啶基]曱氧苯曱酸甲酯4-[(4S)-Ethyloxy-1 -[4-[N'-(2-chlorophenyl)ureido]3-methoxyphenylethenyl]-(2S)-pyrrolidinyl Methyl benzoate

使4-[N’ - (2 -氯苯基）脲基]- 3-曱氧笨乙酸（342毫克，1. 02毫莫耳）、4_[(2S，4S)-4-乙醯氧基〜2 -吼洛啶基]甲氧苯4-[N'-(2-Chlorophenyl)ureido]-3-oxooxyacetic acid (342 mg, 1.02 mmol), 4_[(2S,4S)-4-ethenyloxy 〜2-吼 啶 ridyl]methoxybenzene

\\312\2d-code\90-01\89112968.ptd 第395頁 1283240 五、發明說明（391) 曱酸甲酯（300¾克，1.02毫莫耳）、EDC*HC1(293毫克， 1·53 毫莫耳）、HOBT( 2 07 毫克，1.53 毫莫耳）及Et3N(0.71 耄升’ 5. 10毫莫耳）於DMF(6毫升）中之混合物在室溫下攪 拌1 5小時。將混合物倒入至冰水中，並以Et〇Ac萃取。將 結合的萃取液以冰水及鹽水洗滌。於在Na2s〇4上乾燥後， 將萃取液於真空中濃縮。將殘留物於矽膠[5 〇克，C HC 13 / 丙酮（5/1)]上進行層析，而得4-[(4S) -乙醯氧基 -：1 - [4-[Ν’ -（2-氣苯基）脲基]- 3 -曱氧苯基乙醯基] -（2S) -咄咯啶基]曱氧苯曱酸曱酯（51〇毫克，82〇/〇)的淡棕 色非晶形固體。1H-NMR (CDC13) 6 2.01 及2.04 (各s，3Η， 醯胺異構物）、2.17 (m，2H)、3·56 -3.66 (m，3H)、3·61 (s， 3Η) 、3·88 (s， 3Η) 、3·89 (m， 1Η) 、4·07 (t， J=9. 6 Hz， 1H)、4·45 (dd， J = 9.2、3·4 Hz, 1H)、4·56 (m， 1 H)、5 · 3 1 - 5 · 3 9 ( m，1 H )、6 · 8 0 - 7 · 0 1 ( m，4 H )、7 · 2 3 (d， J:8.1 Hz， 4H) 、7·34 (d， J=8.1 Hz, 1H) 、7·95 (d，J = 8.5 Hz，1H)、8·00 (m，1H)、8·18 (d，J:8.3 Hz, 1H); MS(ESI) m/z 610(MH1)、612(MH3)。 於4-[(4S)-乙醯氧基-1-[4 - [N，-（2 -氯苯基）脲基]-3-甲 氧苯基乙酿基]-（2S) - 17比洛σ定基]甲氧笨甲酸曱酯（510毫 克’0.836毫莫耳）溶於THF( 30毫升）之攪拌溶液中加入 0.25N NaOH(30毫升）。於在室溫下攪拌2天後，以Et〇Ac萃 取混合物。將水層以IN HC1酸化，並以CHC1Q-MeOH (1 0/ 1)萃取。將結合的萃取液以鹽水洗滌。於在Na2s〇4上 乾煉後’將萃取液於真空中濃縮。經由加入E t 〇 Η及乙鱗使\\312\2d-code\90-01\89112968.ptd Page 395 1283240 V. INSTRUCTIONS (391) Methyl decanoate (3003⁄4 g, 1.02 mmol), EDC*HC1 (293 mg, 1.53 A mixture of HOBT (2,07 mg, 1.53 mmol) and Et3N (0.71 liters &lt;RTI ID=0.0&gt;0&gt; The mixture was poured into ice water and extracted with Et EtOAc. The combined extracts were washed with ice water and brine. After drying over Na2s(R)4, the extract was concentrated in vacuo. The residue was chromatographed on silica gel [5 g, C HC 13 / acetone (5/1)] to give 4-[(4S)-acetoxy-:1 - [4-[Ν' - (2-Phenylphenyl)ureido]-(3-oxophenylphenyl)]-(2S)-decalidyl]nonyl phthalate (51 mg, 82 〇/〇) Brown amorphous solid. 1H-NMR (CDC13) 6 2.01 and 2.04 (each s, 3 Η, guanamine isomer), 2.17 (m, 2H), 3·56 - 3.66 (m, 3H), 3·61 (s, 3Η), 3·88 (s, 3Η), 3·89 (m, 1Η), 4·07 (t, J=9. 6 Hz, 1H), 4·45 (dd, J = 9.2, 3·4 Hz, 1H ), 4·56 (m, 1 H), 5 · 3 1 - 5 · 3 9 ( m, 1 H ), 6 · 8 0 - 7 · 0 1 ( m, 4 H ), 7 · 2 3 (d , J: 8.1 Hz, 4H), 7·34 (d, J=8.1 Hz, 1H), 7.95 (d, J = 8.5 Hz, 1H), 8·00 (m, 1H), 8·18 ( d, J: 8.3 Hz, 1H); MS (ESI) m/z 610 (MH1), 612 (MH3). 4-[(4S)-Ethyloxy-1-[4-[N,-(2-chlorophenyl)ureido]-3-methoxyphenylethyl]-(2S) - 17 ratio To a stirred solution of decyl methoxybenzoate (510 mg '0.836 mmol) in THF (30 mL) was added 0.25 N NaOH (30 mL). After stirring at room temperature for 2 days, the mixture was extracted with Et 〇Ac. The aqueous layer was acidified with 1N HCl and extracted with CHC1Q-MeOH (1 0 / 1). The combined extracts were washed with brine. After drying on Na2s〇4, the extract was concentrated in vacuo. By adding E t 〇 Η and B scale

\\312\2d-code\90-01\89112968.ptd 第396頁 1283240 五、發明說明（392) 殘留物結晶而得1 0 7 (22毫克，5%)的無色粉末。熔點 138-14 2 X：(分解）；IR (KBr) 33 34、2939、1685、1 60 4、 1 533、1 439、1248 / 公分；HMR (DMSO-d6) 5 1· 93-2.14 (m, 2H) ^3.60 (d, J = 5.7 Hz, 2H) &gt;3.71 (m, 1H)、3·81 及 3·85 (各s，3H，醯胺異構物）、4.14-4.50 (m，4H)、5·19 (br，1H)、6·72 及6.76 (各m， 1H，醯胺 異構物）、6·85及6·90 (各s，1H，醯胺異構物）、7.00-7· 08 (m, 3H) ^7.28 (t, J = 7.3 Hz, 1H) &gt;7.43 (dd, J = 8. 1、1.2 Hz, 1H)、7·86 - 7.9 5 (m，2H)、7.97 (d，J = 8.1 Hz，1H)、8.10 (dd，J = 8.3、1·5 Hz，1H)、8.90 (s， 1H)、8·94 (s，1H)、12.64 (br，1H); MS(ESI) m/z 5 54 (MH1)、5 5 6 (MH3) ; C28H28C1N3 07 之分析計算值：C， 60· 71 ; Η, 5· 05 ; Cl，6. 40 ; N, 7· 58。實測值：C， 60. 47 ; H，5· 37 ; Cl, 6·31 ; N，7· 19。 實施例1 0 0 4-[(4S) -乙醯氧基-1-[4_[N’ -（2 -漠苯基）脈基]苯基乙醯 基]-(2 S)-吼咯啶基]甲氧苯甲酸\\312\2d-code\90-01\89112968.ptd Page 396 1283240 V. INSTRUCTIONS (392) The residue crystallized to give 1 0 7 (22 mg, 5%) of a colorless powder. Melting point 138-14 2 X: (decomposition); IR (KBr) 33 34, 2939, 1685, 1 60 4, 1 533, 1 439, 1248 / cm; HMR (DMSO-d6) 5 1 · 93-2.14 (m , 2H) ^3.60 (d, J = 5.7 Hz, 2H) &gt;3.71 (m, 1H), 3.81 and 3.85 (each s, 3H, guanamine isomer), 4.14 - 4.50 (m, 4H), 5·19 (br, 1H), 6.72 and 6.76 (each m, 1H, guanamine isomer), 6.85 and 6.90 (each s, 1H, guanamine isomer), 7.00-7· 08 (m, 3H) ^7.28 (t, J = 7.3 Hz, 1H) &gt;7.43 (dd, J = 8. 1, 1.2 Hz, 1H), 7·86 - 7.9 5 (m, 2H ), 7.97 (d, J = 8.1 Hz, 1H), 8.10 (dd, J = 8.3, 1. 5 Hz, 1H), 8.90 (s, 1H), 8.94 (s, 1H), 12.64 (br, 1H); MS (ESI) m/z 5 54 (MH1), 5 5 6 (MH3); C28H28C1N3 07 Analysis calculated: C, 60·71; Η, 5· 05 ; Cl, 6.40; N, 7.58. Found: C, 60.47; H, 5·37; Cl, 6.31; N, 7.19. Example 1 0 0 4-[(4S)-Ethyloxy-1-[4_[N'-(2-indolyl))]phenylethenyl]-(2S)-indenylpyridine Methoxybenzoic acid

4 - [(4S) -乙醯氧基-i-[4-[N’ - (2 -漠苯基）脈基]苯基乙醯 基]-（2 S)-吼咯啶基]甲氧苯甲酸曱酯4-[(4S)-Ethyloxy-i-[4-[N'-(2-indolyl))]phenylethenyl]-(2S)-indolyl]methoxy Ethyl benzoate

\\312\2d-code\90-01\89112968.ptd 第397頁 1283240 五、發明說明（393) 使4 - [Ν’ -（2 -溴苯基）脲基]一 3-曱氧苯乙酸（387毫克，1. 02宅莫耳）、4 [(4S) -乙醯氧基一（2S) -吼洛咬基]甲氧苯甲 酸甲酯（300毫克’1.02毫莫耳）、EDC*HC 1(293毫克， 1.53 毫莫耳）、HOBT(207 毫克，1.53 毫莫耳）及Et3N(0.71 毫升’ 5· 1 0毫莫耳）於DMF( 6毫升）中之混合物在室溫下攪 拌1 5小時。將混合物倒入至冰水中，並以Et〇Ac萃取。將 結合的萃取液以冰水及鹽水洗滌。於在Na2S〇4上乾燥後， 將萃取液於真空中濃縮。將殘留物於矽膠[克，CHC13 / 丙酮（5/1)]上進行層析，而得4-[(4S)-乙醯氧基-1-[4-[N -(2 - &gt;臭本基）脈基]笨基乙酿基]_(2S) -吼洛σ定基]甲氧 苯甲酸甲酯（510毫克，76%)的黃色油。ih-NMR (CDC13)占 2. 01 及2· 04 (各s，3H,醯胺異構物）、2· 31 (m, 2H)、3. 54-3·68 (m，3H)、3·76 (s, 2H)、3·88 (s，3H)、 3.89-4.58 (m, 4Η) ^5.31-5.36 (m, 1Η) ^6.81-6.96 (m，5H)、7·19-7.32 (m，3H)、7·51 (d，J = 8.0 Hz, 1H)、7·93-8·00 (m，3H)、8.13 (d，J = 8.3 Hz, 1H); MS(ESI) m/z 65 4 (MH1)、65 6 (MH3)。 於4-[(4S) -乙醯氧基-i — [4-[n，-（2 -溴苯基）脲基]苯基 乙醯基]-(2S )-吡咯啶基]曱氧苯甲酸甲酯（5 ! 〇毫克， 〇· 779毫莫耳）溶於THF(30毫升）之溶液中加入〇· 25N NaOH(30毫升）。於在室溫下攪拌2天後，以EtOAc萃取混合 物。將殘留的水層以IN HC1酸化，並以CHCl3-MeOH (10/1)萃取。將結合的萃取液以鹽水洗滌。於在Na2S04上\\312\2d-code\90-01\89112968.ptd Page 397 1283240 V. INSTRUCTIONS (393) Making 4-[Ν'-(2-bromophenyl)ureido]-3-oxophenylacetic acid (387 mg, 1. 02 house Mo), 4 [(4S)-acetoxy-(2S)-吼 咬] methyl methoxybenzoate (300 mg '1.02 mmol), EDC* A mixture of HC 1 (293 mg, 1.53 mmol), HOBT (207 mg, 1.53 mmol) and Et3N (0.71 mL '5·10 mmol) in DMF (6 mL) was stirred at room temperature 1 5 hours. The mixture was poured into ice water and extracted with Et EtOAc. The combined extracts were washed with ice water and brine. After drying over Na 2 S 〇 4, the extract was concentrated in vacuo. The residue was chromatographed on silica gel [g, CHC13 / acetone (5/1)] to give 4-[(4S)-ethyloxy-1-[4-[N -(2 - &gt; This base) is a yellow oil of methyl methoxybenzoate (510 mg, 76%). Ih-NMR (CDC13) accounts for 2. 01 and 2·04 (each s, 3H, guanamine isomer), 2·31 (m, 2H), 3. 54-3·68 (m, 3H), 3 ·76 (s, 2H), 3·88 (s, 3H), 3.89-4.58 (m, 4Η) ^5.31-5.36 (m, 1Η) ^6.81-6.96 (m, 5H), 7·19-7.32 ( m, 3H), 7·51 (d, J = 8.0 Hz, 1H), 7·93-8·00 (m, 3H), 8.13 (d, J = 8.3 Hz, 1H); MS(ESI) m/ z 65 4 (MH1), 65 6 (MH3). 4-[(4S)-Ethyloxy-i-[4-[n,-(2-bromophenyl)ureido]phenylethenyl]-(2S)-pyrrolidinyl]anthoxybenzene Methyl formate (5 mg ,, 779 mmol) was dissolved in THF (30 mL). After stirring at room temperature for 2 days, the mixture was extracted with EtOAc. The residual aqueous layer was acidified with 1N HCl and extracted with CHCl3-MeOH (10/1). The combined extracts were washed with brine. On Na2S04

\\312\2d-code\90-01\89112968.ptd 第398頁 1283240 五、發明說明（394) 乾燥後，將萃取液於真空中濃縮。經由加入EtOH及乙醚使 殘留物結晶而得1 〇 8 (8 7毫克，1 9 %)的淡棕色粉末。熔點 143-151 °C (分解）；IR (KBr) 3332、2937、1 685、1604、 1 529、1 52 9、1 4 35 / 公分；1-NMR (DMSO-d6) 5 1· 92 -2.14 (m，2H)、3·60 (d, J二5.9 Hz, 2H)、3·72 (m， 1Η)、3·81 及 3·85 (各s，3Η，醯胺異構物）、4.14-4·49 (m，4Η)、5·19 (br，1Η)、6·72 及6·75 (各m， 1Η，醯胺 異構物）、6·85及6.90 (各m，1H，醯胺異構物）、6·97 (t，J = 6.1 Hz, 1Η)、7·06 (d，J二8·8 Ηζ，2Η)、7·32 (t, J = 7.1 Hz, 1Η)、7·60 (dd，J 二 7.8、1·2 Hz, 1Η)、 7.86 (d，J二8·8 Hz，2H)、7.87 -7.97 (m，3H)、8·74 (s, 1H)、8·93 (s，1H)、12·60 (br，1H); MS(ESI) m/z 5 5 9 (MH1)、561 (MH3) ; C28H28BrN3 07 · 0· 1H20 之分析計算 值：C， 5 6. 0 3 ; H， 4· 74 ; Br， 1 3· 31 ; N，7· 00。實測 值·· C， 55. 80 ; Η，4· 84 ; Br，13· 64 ; Ν，6· 66。 實施例1 0 1 4-[1-[4- [Ν’-（2 -氯苯基）脲基]-3-甲氧苯基乙醯基]-(4R) -經基-（2S)-u比略σ定甲氧基]苯曱酸\\312\2d-code\90-01\89112968.ptd Page 398 1283240 V. INSTRUCTIONS (394) After drying, the extract is concentrated in vacuo. The residue was crystallized from EtOAc (EtOAc) eluted elute Melting point 143-151 °C (decomposition); IR (KBr) 3332, 2937, 1 685, 1604, 1 529, 1 52 9 , 1 4 35 / cm; 1-NMR (DMSO-d6) 5 1· 92 -2.14 (m, 2H), 3·60 (d, J 5.9 Hz, 2H), 3·72 (m, 1Η), 3.81 and 3.85 (each s, 3Η, guanamine isomer), 4.14 -4·49 (m, 4Η), 5·19 (br, 1Η), 6.72 and 6.75 (each m, 1Η, guanamine isomer), 6.85 and 6.90 (each m, 1H, Indole isomers), 6.97 (t, J = 6.1 Hz, 1 Η), 7·06 (d, J 2.8 Ηζ, 2 Η), 7·32 (t, J = 7.1 Hz, 1 Η) , 7·60 (dd, J 2 7.8, 1·2 Hz, 1Η), 7.86 (d, J 2·8 Hz, 2H), 7.87 -7.97 (m, 3H), 8·74 (s, 1H) ,········· , 5 6. 0 3 ; H, 4· 74 ; Br, 1 3· 31 ; N, 7· 00. Measured value·· C, 55. 80 ; Η, 4· 84 ; Br, 13· 64 ; Ν, 6· 66. Example 1 0 1 4-[1-[4-[Ν'-(2-Chlorophenyl)ureido]-3-methoxyphenylethenyl]-(4R)-radio-(2S)- U ratio slightly sigma methoxy] benzoic acid

pH 109 於4-[(4R) -乙醯氧基―卜（第三丁氧羰基）_(2S)_吼咯啶 曱氧基]苯甲酸甲酯（835毫克，2.12毫莫耳）溶於CH2C12 (5 毫升）之攪拌溶液中加入TFA(5毫升），並使反應混合物於pH 109 is soluble in methyl 4-[(4R)-acetoxy-b (t-butoxycarbonyl)-(2S)- oxazolidinyloxy]benzoate (835 mg, 2.12 mmol) TFA (5 ml) was added to a stirred solution of CH2C12 (5 mL).

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1283240 五、發明說明（395) 室溫下攪拌1小時。將混合物於真空中濃縮，並利用飽和 NaHC〇3使成為鹼性。將混合物以CHCI3萃取，以鹽水洗條， 於Kg C 〇3上乾燥’並蒸發而得4 - [ ( 4 R )-乙酿氧基—（2 s )-吼洛 啶甲氧基]苯曱酸甲酯（ 5 80毫克，95%)的棕色油。1H — NMR (CDC13) 5 1· 86 -1. 93 (m， 1H)、2. 0 0 —2· 12 (S 及m 系列， 總計5H)、3·〇3-3.29 (m，1H)、3·73-3·80 (m，1H)、 3.88 (s，3H)、3·93-4.01 (m，2H)、5·27-5·30 (m, 1H) &gt;6.91 (d, J-9.0 Hz, 2H) ^7.98 (d, J=9.0 Hz, 2H) ;MS(FAB) m/z 294(MH1) 〇 使4 - [N -（2-氣苯基）脲基]—3一甲氧苯乙酸（365毫克，l 09宅莫耳）、4-[(4R)_乙酿氧基一（2s)-吼。各。定甲氧基]苯甲 酸甲酉曰（320毫克，1.09¾莫耳）、edC*HC1(250毫克， 1.30¾ 莫耳）、HOBt(180 毫克，133 毫莫耳）及Et3N(182* 升，1·31毫莫耳）於THF(5毫升）中之混合物在室溫下攪拌2 天。將混合物以H20稀釋，並以Εΐ〇Α(：萃取。萃 機’於Na2s〇4上乾燥，並蒸發。將殘留：：由取以 上利用CHC13-Me〇H(5〇:1，v/v)作為洗提液進行管柱層 析，純化而得4-U4R)-乙酸氧基—卜[4-[N,—(2—氯苯基） 脲基]- 3:甲氧苯基乙醯基卜（2S)—吡咯啶甲氧基]苯甲酸甲 酯（ 50 0 耄克，75%)的白色泡沫。1Η —Ν〇 (CDC13) $ 2 · 〇1 (s，3H)、2.03- 2.05 (m，1H)、2 2〇一2·26 (m，1H)、 2·37-2·43 (m，1H)、3·59 (s，2Η)、3·62 (s，3H)、 3.66-3.87 (m，2H)、3.89(s，3H)、4 〇7 —4 〇9 (m， 1H)、4·48-4·51 (m，1H)、4·59 (m，1H)、6·7〇 —6·821283240 V. INSTRUCTIONS (395) Stir at room temperature for 1 hour. The mixture was concentrated in vacuo and made basic with saturated NaHC. The mixture was extracted with CHCI3, washed with brine, dried over Kg C 〇3 and evaporated to give 4-[(4R)-ethyl-ethoxy-(2 s)-indolyl methoxy]phenylhydrazine. Methyl ester (5 80 mg, 95%) in brown oil. 1H — NMR (CDC13) 5 1· 86 -1. 93 (m, 1H), 2. 0 0 —2· 12 (S and m series, total 5H), 3·〇3-3.29 (m, 1H), 3·73-3·80 (m,1H), 3.88 (s,3H),3·93-4.01 (m,2H), 5·27-5·30 (m, 1H) &gt;6.91 (d, J -9.0 Hz, 2H) ^7.98 (d, J=9.0 Hz, 2H); MS(FAB) m/z 294(MH1) 〇4 - [N -(2-Phenylphenyl)ureido]-3 Methoxyphenylacetic acid (365 mg, l 09 house mole), 4-[(4R)_ethyloxy-(2s)-indole. each. Methyl methoxy]benzoate (320 mg, 1.093⁄4 mol), edC*HC1 (250 mg, 1.303⁄4 mol), HOBt (180 mg, 133 mmol) and Et3N (182* liter, The mixture in THF (5 mL) was stirred at room temperature for 2 days. The mixture was diluted with H20 and dried with hydrazine (: extraction, extraction machine) on Na2s 〇4, and evaporated. Residue:: From above, use CHC13-Me〇H (5 〇:1, v/v Purified by column chromatography as an eluent to give 4-U4R)-acetoxy--[4-[N,-(2-chlorophenyl)ureido]- 3:methoxyphenylacetamidine A white foam of methyl (2S)-pyrrolidine methoxy]benzoate (50 gram, 75%). 1Η—Ν〇(CDC13) $ 2 · 〇1 (s,3H), 2.03- 2.05 (m,1H), 2 2〇1·26 (m,1H), 2·37-2·43 (m, 1H), 3·59 (s, 2Η), 3.62 (s, 3H), 3.66-3.87 (m, 2H), 3.89 (s, 3H), 4 〇 7 — 4 〇 9 (m, 1H), 4·48-4·51 (m, 1H), 4·59 (m, 1H), 6·7〇—6·82

\\312\2d-code\90-01\89112968.ptd 1283240 五、發明說明（396) (m，4H)、6·97-7.01 (m，1H)、7.24-7·35 (m，4H)、 7·92-7·98 (m，3H)、8·12-8·21 (m，1H); MS(FAB) m/z 610(M+ + 1)。 於4 - [(4R)-乙醯氧基-1-[4 - [Ν’ -（2 -氣苯基）脈基]- 3-曱 氧苯基乙醯基]-(2 S)-咄咯啶甲氧基]苯甲酸甲酯（5 0 0毫 克，〇· 82毫莫耳）溶於THF(5毫升）之攪拌溶液中加入0· 5N Na0H(5毫升），並使反應混合物迴流加熱隔夜。於冷卻至 室溫後，將混合物倒入至冰的1 N HC 1中，並於減壓下收集 所產生之沈澱物。將粗製固體經由自CHC13 - IPE再結晶， 純化而得1 0 9 ( 22 3毫克，49%)的白色結晶粉末。熔點137 -142〇C；1H~NMR (DMS0-d6)5 1.95-2.09 (m, 2H) ^3.41 -3.43 (m，1H)、3·57 (m，3H)、3·78 (s，3H)、4·07-4. 40 (m 系列，總計 4H)、5·〇7 (m， 1H)、6·72-6.74 (m， 1H)、6·85 (m，1H)、6·99 - 7.03 (m，3H)、7.25-7.29 (m, 1H)、7·42-7·43 (m，1H)、7·8 5-7.87 (m，2H)、 7.93 - 7.95 (m，1H)、8·07 - 8.09 (m，1H)、8·88 (s，1H) 、8·92 (s，1H)、12·65 (br s，1H); MS(FAB) m/z 554 (M+ + 1) ; C28H28C1N3 07 · 1/2H20 之分析計算值：C，59. 73 ; H，5.19; Cl, 6.30; N, 7.46。實測值：C，59.58; H， 5. 32 ; Cl， 6· 99 ; N， 7. 21 。 實施例1 0 2 .4 - [(4R) -經基-1 - [3-甲氧基-4-[Ν’ - (2-曱基苯基）脲基]苯 基乙醯基]-(2S) -吼咯啶甲氧基]苯甲酸\\312\2d-code\90-01\89112968.ptd 1283240 V. Description of invention (396) (m, 4H), 6.97-7.01 (m, 1H), 7.24-7.35 (m, 4H) , 7.92-7·98 (m, 3H), 8·12-8·21 (m, 1H); MS (FAB) m/z 610 (M+ + 1). 4-[(4R)-Ethyloxy-1-[4 - [Ν'-(2-(phenylphenyl))]-3-oxophenylphenyl]-(2S)-咄To a stirred solution of methyl bromo methoxy]benzoate (500 mg, 〇· 82 mmol) in THF (5 mL), EtOAc (EtOAc) Overnight. After cooling to room temperature, the mixture was poured into 1 N HCl 1 of ice, and the resulting precipitate was collected under reduced pressure. The crude solid was recrystallized from CHC13-IPE to afford 1O9 (22. Melting point 137 -142〇C; 1H~NMR (DMS0-d6)5 1.95-2.09 (m, 2H) ^3.41 -3.43 (m,1H),3·57 (m,3H),3·78 (s,3H ), 4·07-4. 40 (m series, total 4H), 5·〇7 (m, 1H), 6.72-6.74 (m, 1H), 6·85 (m, 1H), 6.99 - 7.03 (m, 3H), 7.25-7.29 (m, 1H), 7·42-7·43 (m, 1H), 7·8 5-7.87 (m, 2H), 7.93 - 7.95 (m, 1H) , 8.07 - 8.09 (m, 1H), 8·88 (s, 1H), 8.92 (s, 1H), 12·65 (br s, 1H); MS (FAB) m/z 554 (M+ + 1) ; C28H28C1N3 07 · 1/2H20 Analysis calculated: C, 59. 73 ; H, 5.19; Cl, 6.30; N, 7.46. Found: C, 59.58; H, 5. 32; Cl, 6·99; N, 7. 21 . Example 1 0 2 .4 - [(4R)-Phenyl-1 -[3-methoxy-4-[Ν' - (2-mercaptophenyl)ureido]phenylethenyl]-( 2S) -Ethrolidine methoxy]benzoic acid

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Me H H OMeMe H H OMe

使3-曱氧基-4- [Ν’ -（2 -甲基苯基）脲基]苯乙酸（32〇毫 克，1·〇2毫莫耳）、4—[(4R)—乙醯氧基一（2S)一吡咯啶甲氧 基]苯甲酸甲酯（300¾克，1·〇2毫莫耳）、EDC.HC 1(235毫 克，1.23¾莫耳）、HOBt(166毫克，ι·23毫莫耳）及Et3N (171毫升，1.23毫莫耳）於THF(5毫升）中之混合物在室溫 下撥拌2天。將混合物以0稀釋，並以£ ^ 〇 a c萃取。將萃 取液以鹽水洗滌，於υ〇4上乾燥，並蒸發。將殘留物經 由於矽膠上利用CHCl3-MeOH(50:l，ν/ν)作為洗提液進行 管柱層析，純化而得4-[(4R) -乙醯氧基—1 —[3—甲氧基 -4 - [Ν’-（2-甲基苯基）脲基]苯基乙醯基]— (2s) —吼咯啶曱 氧基]苯曱酸甲酯（420毫克，70%)的白色泡沫。ih-NMR (CDC13)3 1.99 (s，3Η)、2·02 - 2.05 (m，1Η)、2·15 - 2· 41 (s 及 m 系列，總計 5H)、3· 55 (s，3H)、3· 57 (s，2H) 、3.63-3·73 (m, 2Η) 、3·89 (s， 3Η) 、4·07-4·1〇 (m， 1Η)、4·45-4·48 (m，1Η)、4·57 (m，1Η)、6·56 (s， 1H)、6·66 (m，1H)、6·75-6·82 (m，3H)、7.1卜7.24 (m，4H)、7·54-7·56 (m, 1H)、7·92-7·94 (m，2H)、 8.0 5-8.07 (m，1H); MS(FAB) m/z 5 9 0 (MH1)。 於4 - [(4R)-乙醯氧基-l-[3-甲氧基-4-[N，-（2 -甲基苯 基）脲基]苯基乙酸基]-（2S)-wb洛咬甲氧基]苯甲酸甲酯 (420毫克，0.71毫莫耳）溶於THF(5毫升）之攪拌溶液中加 入0 · 5 N N a 0 Η ( 5毫升），並使反應混合物迴流加熱隔夜。於3-methoxy-4-[Ν'-(2-methylphenyl)ureido]phenylacetic acid (32〇 mg, 1·〇2 mmol), 4-[(4R)-acetamidine Methyl (2S)-pyrrolidinemethoxy]benzoate (3003⁄4 g, 1·〇2 mmol), EDC.HC 1 (235 mg, 1.233⁄4 mol), HOBt (166 mg, ι·) A mixture of 23 mmoles and Et3N (171 mL, 1.23 mmol) in THF (5 mL) was stirred at room temperature for 2 days. The mixture was diluted at 0 and extracted with £^ 〇 a c. The extract was washed with brine, dried over EtOAc 4 and evaporated. The residue was subjected to column chromatography using CHCl3-MeOH (50:1, ν/ν) as an eluent to obtain 4-[(4R)-acetoxyl-1-[3- Methoxy-4 -[Ν'-(2-methylphenyl)ureido]phenylethenyl]-(2s)-fluorenylpyridiniumoxy]benzoic acid methyl ester (420 mg, 70% ) white foam. ih-NMR (CDC13)3 1.99 (s,3Η), 2·02 - 2.05 (m,1Η), 2·15 - 2· 41 (s and m series, total 5H), 3·55 (s,3H) , 3· 57 (s, 2H), 3.63-3·73 (m, 2Η), 3·89 (s, 3Η), 4·07-4·1〇 (m, 1Η), 4·45-4· 48 (m, 1Η), 4·57 (m, 1Η), 6.56 (s, 1H), 6.66 (m, 1H), 6·75-6·82 (m, 3H), 7.1 7.24 (m, 4H), 7·54-7·56 (m, 1H), 7.92-7·94 (m, 2H), 8.0 5-8.07 (m, 1H); MS(FAB) m/z 5 9 0 (MH1). 4-[(4R)-Ethyloxy-l-[3-methoxy-4-[N,-(2-methylphenyl)ureido]phenylacetic acid]-(2S)-wb Add a solution of methyl methoxy]benzoic acid methyl ester (420 mg, 0.71 mmol) in THF (5 mL), EtOAc (5 mL). . to

\\312\2d-code\90-01\89112968.ptd 第402頁 1283240 五、發明說明（398) 冷卻至室溫後，將混合物倒入至冰的1 N HC 1中，並於減壓 下收集所產生之沈澱物。將粗製固體經由自CHC13 - IPE再 結晶，純化而得11 0(1 82毫克，489%)的白色結晶粉末。熔 點 1 78-1 82 X： ; Μ-NMR (DMS0-d6) (5 1.92-2.10 (m，2H)、 2.23 (s，3H)、3.40-3.44 (m，1H)、3·56-3·67 (m， 3H)、3· 78 (s， 3H)、4· 05-4· 39 (m 系列，總計4H)、5· 06 (m，1Η)、6·71-7.01 (m，5Η)、7·10-7·16 (m, 2Η)、 7.77-7.79 (m，1H)、7·85-7·89 (m，2H)、7·98-8·00 (m，1 H)、8 · 4 5 (s，1 H)、8 · 5 4 (s，1 H)、1 2 · 5 9 (b r s， 1H) ; MS(FAB) m/z 53 4 (MH1) ; C29H31N3 07 · 1/2H20 之分析計 算值：C，64· 20 ; Η, 5· 94 ; N，7· 74。實測值：C，64· 35 ；Η, 5. 83 ； Ν, 7.68° 實施例1 0 3 4-[(4S)-氟-1 - [3-曱氧基-4-[Ν’-（2-甲基苯基）脲基]苯基 乙醯基]-2 -咄咯啶甲基]-；1-六氫吡啡乙酸\\312\2d-code\90-01\89112968.ptd Page 402 1283240 V. INSTRUCTIONS (398) After cooling to room temperature, the mixture was poured into 1 N HC 1 of ice and decompressed under reduced pressure. The resulting precipitate was collected. The crude solid was recrystallized from CHC13-IPH to afford to afford of &lt;1&gt; Melting point 1 78-1 82 X: ; Μ-NMR (DMS0-d6) (5 1.92-2.10 (m, 2H), 2.23 (s, 3H), 3.40-3.44 (m, 1H), 3·56-3· 67 (m, 3H), 3·78 (s, 3H), 4· 05-4· 39 (m series, total 4H), 5·06 (m, 1Η), 6.71-7.01 (m, 5Η) , 7·10-7·16 (m, 2Η), 7.77-7.79 (m, 1H), 7·85-7·89 (m, 2H), 7·98-8·00 (m, 1 H), 8 · 4 5 (s, 1 H), 8 · 5 4 (s, 1 H), 1 2 · 5 9 (brs, 1H); MS (FAB) m/z 53 4 (MH1) ; C29H31N3 07 · 1 Analytical calculated value of /2H20: C, 64·20; Η, 5· 94 ; N, 7· 74. Found: C, 64·35 ; Η, 5. 83 ; Ν, 7.68° Example 1 0 3 4 -[(4S)-fluoro-1 -[3-decyloxy-4-[Ν'-(2-methylphenyl)ureido]phenylethenyl]-2-pyrrolidinylmethyl]- ; 1-hexahydropyridinone acetate

QLNiNJPriQLNiNJPri

Me Η H OMe 於Ν-(第三丁氧羰基）（4S) -氟脯胺醇（1· 26克，5· 75毫莫 耳）、Et3N(4毫升，28.5毫莫耳）及DMS0(4.1毫升，57.5毫 莫耳）溶於CH2C12(20毫升）之攪拌溶液中加入S03 ·吡啶（Me Η H OMe in Ν-(t-butoxycarbonyl)(4S)-fluorohamamine (1.66 g, 5.75 mmol), Et3N (4 ml, 28.5 mmol) and DMS0 (4.1 ML, 57.5 mmol, dissolved in CH2C12 (20 mL) in a stirred solution of S03·pyridine (

2. 74克，17. 2毫莫耳）。於攪拌5小時後，將混合物蒸發以 移除CH2C12，並以Et20( 20 0毫升）稀釋。將溶液以1N2. 74 grams, 17. 2 millimoles). After stirring for 5 hours, the mixture was evaporated to remove CH.sub.2 C.sub.2 and diluted with Et. Put the solution at 1N

89112968.ptd 第403頁 128324089112968.ptd Page 403 1283240

HCl( 20 0 t升）及鹽水（ 20 0毫升）洗滌，於MgS〇4上乾燥，並 蒸發。使所產生之殘留物於矽膠上利用己烷一Et〇Ac(4 :工） 進行層析，而得N-(第三丁氧羰基）（4S)-氟脯胺醛（628毫 克，50%)的黃色油。ιΗ一NMR (CDCl3) 3 i· 41 — κ 47 (m， 9H)、2·02-2.48 (m，2H)、3·47-3.94 (m，2H)、4·16 及 4.29 (各d，各 J = 9· 8 Hz，總計 1H)、5· 13 及 5· 26 (各s 總計1 Η )。 ’ 於N-(第二丁氧羰基）（4S) -氟脯胺醛（ι·44克，6·63毫莫 耳）、1-六氫吼畊乙酸乙酯（1· 71克，9· 94毫莫耳）及Ac〇h、 (759微升，13·3毫莫耳）溶於MeOH(20毫升）之攪拌溶液中 加入N a B &amp; C N ( 8 8 0毫克’ 1 3 · 3毫莫耳）。使反應混合物攪拌 隔夜並蒸發。利用飽和NaHCO〆1〇〇毫升）使殘留物停止反 應並與CHC 13 ( 2x 2 0 0毫升）蒸發。將結合的萃取液於MgS〇4i 乾燥並蒸發。將油性殘留物於矽膠上利用CHC1r Me〇H(2(): 1)進行層析，而得4-[1-(第三丁氧羰基）_(4幻-氟—2—吼略 鳴曱基]-1-六氫吼畊乙酸乙酯（2· 38克，95%)的黃色油。 使4-[1-（弟二丁乳幾基）-（4S) -氟-2 - σ比口各〇定甲基]一卜丄 氫吼畊乙酸乙酯（2· 38克，6· 37毫莫耳）、TFA(5毫升）及/' CH2 C丨2 ( 5毫升）之混合物攪拌3小時。將混合物蒸發，並利 用飽和NaHC〇3(l 00毫升）使殘留物成為鹼性。將混合物以 CHC13-MeOH(4:l，2x150毫升）萃取，及將結合的萃2取液於 IC 〇3上乾無’並祭發而付4 - [ ( 4 S )-說- 2 - 口比π各咬甲芙]一 1 一 六氫吡啡乙酸乙酯（1· 44克，83%)的棕色油。iH—nmr (CDC13) 5 1· 27 (dt，J = 7· 1、2· 0 Hz, 3H)、1· 66_3· 35Wash with HCl (20 0 liter) and brine (20 mL), dry over MgSO 4 and evaporated. The resulting residue was chromatographed on cerium gel using hexane-EtOAc (4: EtOAc) to afford N-(t-butoxycarbonyl) (4S)- fluorodealamine (628 mg, 50%) ) yellow oil. Η NMR (CDCl3) 3 i· 41 — κ 47 (m, 9H), 2·02-2.48 (m, 2H), 3·47-3.94 (m, 2H), 4·16 and 4.29 (each d, Each J = 9· 8 Hz, totaling 1H), 5·13, and 5·26 (each s total 1 Η). 'N-(2nd butoxycarbonyl)(4S)-fluoroamidaldehyde (Ig 44 g, 6.63 mmol), 1-hexahydroindole ethyl acetate (1·71 g, 9· </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> </ RTI> <RTIgt; Millions of ears). The reaction mixture was stirred overnight and evaporated. The residue was quenched with saturated NaHCO (1 mL) and evaporated with CH.sub.3 (2×250). The combined extracts were dried over MgS 4i and evaporated. The oily residue was chromatographed on silica gel using CHC1r Me〇H(2(): 1) to give 4-[1-(t-butoxycarbonyl)-(4-phanyl-fluoro-2-pyrene) a yellow oil of ethyl acetate (2·38 g, 95%). 4-[1-(di-dibutyl)-(4S)-fluoro-2 - σ ratio a mixture of ethyl hydrazide and ethyl hydrazine (2·38 g, 6.3 mmol), TFA (5 ml) and /' CH2 C丨2 (5 ml) were stirred. The mixture was evaporated, and the residue was made basic with saturated NaHC EtOAc (l 00 mL). The mixture was extracted with CHC13-MeOH (4:1, 2×150 mL) and the combined extracts were taken from IC 〇3 on the dry no 'and the sacrifice and pay 4 - [( 4 S ) - say - 2 - mouth ratio π each bite a buff] 1 hexahydropyridin ethyl acetate (1 · 44 grams, 83%) Brown oil. iH-nmr (CDC13) 5 1· 27 (dt, J = 7·1, 2· 0 Hz, 3H), 1·66_3· 35

1283240 五、發明說明（400) (m 系列，17H)、4· 18 (dq， J = 7· 1、2· 0 Hz， 2H)、5· 09 及 5· 22 (各m，總計1 Η)。 使4-[(4S) -氟-2-咄咯啶甲基]-卜六氫咄啡乙酸乙酯（i. 44克’5.27毫莫耳）、3-甲氧基-4-[N，- (2-甲基苯基） 服基]苯乙酸（1.66克，5.27毫莫耳）、EDC · HC1 (1. 52克， 7.91毫莫耳）、11〇]&amp;1：(催化劑）及麗人{)(催化劑）於1)肝（1〇毫 升）中之混合物攪拌隔夜。將混合物以Et〇Ac —Me〇H (1〇 : h 22〇毫升）稀釋。將溶液以鹽水（2〇〇毫升）洗滌，於MgS〇4上 乾燥’並蒸發。將殘留物於矽膠上利用CHC丨3_Me〇H( 2〇 : 1) 作為洗提液進行層析，而得標題化合物（2· 47克，82%)的 黃色黏性固體。iH-NMR (CDC13) 6 1· 24」· 29 (m，3H)、 1·92-4·36 (m 系列，7H)、5.16 及 5·29 (各m，總計 1H)、 6·43 (s，1H)、6·76-6·81 (m，2H)、7·12-7·29 (m， 4Η)、7.50(d，J = 7.8 Ηζ，1Η)、8·(Π-8·07 (m，1Η)。 111 ’’ 一 [(4S)-氟-卜[3-甲氧基一 4—[n，-(2-甲基苯基） 服基]苯基乙醯基]-2 -咄咯啶曱基]—卜六氫咄畊乙酸乙酯 (1·〇克’1·76毫莫耳）及〇·25Ν NaOH(14毫升，3· 50毫莫 耳）於THF(1 5毫升）中之混合物攪拌隔夜。將混合物以1N HC1中和並蒸發。利用離子交換樹脂（DIAION，HP2〇)以H20 至MeOH作為洗提液將殘留物純化而得丨丨丨（4〇〇毫克，4〇%) 之淡頁色非晶形固體。iH-NMR (CD3〇D) 5 2· 00-3· 95 (m系 列，24H)、4.34 - 4.40 (m，1H)、5·23 及 5.36 (各m，總計 1H) 、6·78-6.82 (m， 1H) 、6.92 (m， 1H) 、7·00-7.04 (m，1Η)、7.09-7· 23 (m，4Η)、7.59 (d，J = 7.1 Ηζ，1283240 V. INSTRUCTIONS (400) (m series, 17H), 4·18 (dq, J = 7·1, 2·0 Hz, 2H), 5·09 and 5·22 (each m, total 1 Η) . 4-[(4S)-Fluoro-2-indenylmethyl]- hexahydrofurfuryl ethyl acetate (i. 44 g '5.27 mmol), 3-methoxy-4-[N, - (2-methylphenyl)-based phenylacetic acid (1.66 g, 5.27 mmol), EDC · HC1 (1.52 g, 7.91 mmol), 11 〇] &amp; 1: (catalyst) and The mixture of 丽人{) (catalyst) in 1) liver (1 〇 ml) was stirred overnight. The mixture was diluted with Et 〇Ac - Me 〇 H (1 〇 : h 22 〇 mL). The solution was washed with brine (2 mL), dried over <RTIgt; The residue was chromatographed on EtOAc EtOAc (EtOAc:EtOAc) iH-NMR (CDC13) 6 1· 24"· 29 (m, 3H), 1·92-4·36 (m series, 7H), 5.16 and 5.29 (each m, total 1H), 6.43 ( s,1H),6·76-6·81 (m,2H), 7·12-7·29 (m, 4Η), 7.50 (d, J = 7.8 Ηζ, 1Η), 8·(Π-8· 07 (m,1Η). 111 ''-[(4S)-Fluoro-bu [3-methoxy-4-[n,-(2-methylphenyl)-yl]phenylethenyl]- 2- 咄 曱 曱 ] ] ] ] 乙酸乙酯 乙酸乙酯 乙酸乙酯 乙酸乙酯 乙酸乙酯 乙酸乙酯 乙酸乙酯 乙酸乙酯 乙酸乙酯 乙酸乙酯 乙酸乙酯 乙酸乙酯 乙酸乙酯 乙酸乙酯 乙酸乙酯 乙酸乙酯 (1·〇克 '1·76 mmol) and 〇·25Ν NaOH (14 ml, 3 · 50 mmol) in THF (1 The mixture was stirred overnight. The mixture was neutralized with 1N HCl and evaporated. The residue was purified using EtOAc (EtOAc, EtOAc) Mg, 4〇%) pale-page amorphous solid. iH-NMR (CD3〇D) 5 2· 00-3· 95 (m series, 24H), 4.34 - 4.40 (m, 1H), 5·23 and 5.36 (each m, total 1H), 6.78-6.82 (m, 1H), 6.92 (m, 1H), 7·00-7.04 (m, 1Η), 7.09-7· 23 (m, 4Η), 7.59 (d, J = 7.1 Ηζ,

\\312\2d-code\90-01\89l12968.ptd 第405頁 1283240 五、發明說明（401) 1H)、7·99_8·02 (m，1H) ; MS(FAB) m/z 542 (MH1)。 實施例1 0 4 4 - [1 - [4 - [Ν’ -（2 -氯苯基）脲基]- 3-甲氧苯基乙醯基]-4，4-二氟-2 -咄咯啶甲基]-1-六氫吡啡乙酸酯\\312\2d-code\90-01\89l12968.ptd Page 405 1283240 V. Invention description (401) 1H), 7·99_8·02 (m, 1H); MS(FAB) m/z 542 (MH1 ). Example 1 0 4 4 - [1 - [4 - [Ν' -(2-Chlorophenyl)ureido]-3-methoxyphenylethenyl]-4,4-difluoro-2-pyrrole Pyridylmethyl]-1-hexahydropyridin acetate

Cl η H OMe 112 1 -（弟二丁氧幾基）—4，4 -二氣-2 -比嘻唆缓酸Cl η H OMe 112 1 - (di-dioxyoxy) - 4,4 - digas-2 - than sulphuric acid

於1-（第三丁氧羰基）一4, 4 -二氟-2 -吡咯啶甲醇（2. 11 克，8.89毫莫耳）、Et3N(6.2毫升，44.5毫莫耳）、DMS0 (6.3毫升，88·9毫莫耳）於CH2C12(20毫升）中之攪拌混合物 中加入S03 ·咄啶（4. 25克，26. 7毫莫耳）。於攪拌3小時 後，將混合物於真空中濃縮，並以Et20( 20 0毫升）稀釋。 將所產生之混合物以IN HC1( 100毫升）及鹽水（1〇〇毫升）洗 條’於MgS〇4上乾燥’並於真空中濃縮。使殘留物於石夕膠 上利用己烷-EtOAc(4 : 1 )作為洗提液進行層析，而得卜（第 三丁氧羰棊）-4,4 -二氟-2-咄咯啶羧醛（1·40克，67%)的黃 色油。UMR (CDC13) (5 1· 45-1· 52 (m，9Η)、2· 49 (m， 2H)、3·75 - 3·88 (m，2H)、4·29 - 4·42 (m，1H)、9·54 及 9· 60 (各s，總計 1H)。 4- [l-(第三丁氧羰基）-4, 4 -二氟-2 -吼咯啶曱基]—i_六氫 吡哜乙酸乙酯In 1-(t-butoxycarbonyl)- 4,4-difluoro-2-pyrrolidinemethanol (2.11 g, 8.89 mmol), Et3N (6.2 ml, 44.5 mmol), DMS0 (6.3 ml) </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; After stirring for 3 hours, the mixture was concentrated in vacuo and diluted with Et20 (EtOAc). The resulting mixture was washed with <RTI ID=0.0># </RTI> </RTI> <RTIgt; The residue was chromatographed on celite using hexane-EtOAc (4:1) as eluent, and decod (t-butoxycarbonyl hydrazide)-4,4-difluoro-2-pyrrolidine Carboxylic (1·40 g, 67%) yellow oil. UMR (CDC13) (5 1· 45-1· 52 (m, 9Η), 2· 49 (m, 2H), 3·75 - 3·88 (m, 2H), 4·29 - 4·42 (m , 1H), 9·54 and 9·60 (each s, total 1H). 4- [l-(Tertidinoxycarbonyl)-4,4-difluoro-2-pyridinyl]-i_ Hexahydropyridinium ethyl acetate

89112968.ptd 第406頁 1283240 五、發明說明（402) •C〇2Et ter89112968.ptd Page 406 1283240 V. Description of invention (402) • C〇2Et ter

Boc 在0 C下於1-(第二丁乳幾基）-4，4 -二氟- 定緩駿 (1·40克’ 5.95¾莫耳）及1-六氫吡畊乙酸乙酯（1〇2克， 5· 95毫莫耳）溶於MeOH-AcOH(12: 1， 13毫升）之攪拌溶液中 加入NaBH3CN(787t克，11.9毫莫耳）。於攪拌3天後，經 由加入飽和NaHCO/lOO毫升）使混合物停止反痒，並 “woo毫升）萃取。將結合的萃V;止4應s〇4上並乾乂燥並 於真空中，濃縮。將殘留物於矽膠上利用CHC13_Me〇H(2〇: 〇 作為洗提液進行層析，而得4-[ 1 —(第三丁氧羰基）—4, 4—二 氟-2 _咄咯。疋甲基]—丨—六氫咄畊乙酸乙酯（8 2 2毫克，3 5 %)Boc at 0 C in 1-(second butyl-based)-4,4-difluoro-preservative (1·40 g ' 5.953⁄4 mol) and 1-hexahydropyrrole ethyl acetate (1 To a stirred solution of MeOH-AcOH (12:1, 13 mL) was added NaBH3CN (787t, After stirring for 3 days, the mixture was stopped by adding saturated NaHCO/100 ml) and extracted with "woo ml". The combined extract V; the end 4 should be s〇4 and dried and vacuumed and concentrated. The residue was chromatographed on CHM using CHC13_Me〇H (2:: hydrazine as the eluent to give 4-[1-(t-butoxycarbonyl)-4,4-difluoro-2 _ 咄疋Methyl]-丨-hexahydro hydrazine ethyl acetate (8 2 2 mg, 3 5 %)

的畀色 /由。1H-NMR (CDC13)&lt;5 1.27 (t J = 7 1 Hz 3H)、 1.46 (, (m, 2H)^ 2.3 9-2.64 V 19 (s，2H)、3·42 -4.0 5 (m 系列，3h)、4 18 (q J = 7 jTwilight / by. 1H-NMR (CDC13) &lt;5 1.27 (t J = 7 1 Hz 3H), 1.46 (, (m, 2H)^ 2.3 9-2.64 V 19 (s, 2H), 3·42 - 4.0 5 (m series , 3h), 4 18 (q J = 7 j

Hz， 2H) 。 · ， · 氫咄啡乙酸乙酯 4 -（4, 4 -二氟-2 -吡咯啶甲基）一 i —六 ,C〇2Et 0^X0^° QI Η H OMe 使4 - [1-（第三丁氧羰基）一4, 4—二氟—2 —吡咯啶甲美]—卜 ^ Sl(82° ^ ^ ' 2· 09 ^ ^ ^TFA(5 ☆於CH2Cl2(5毫升）之溶液攪拌1小時。將混合物於直空中 濃縮，並利用飽和NaHC03使殘留物成為鹼性。將所產生之Hz, 2H). · · · Hydroquinone ethyl acetate 4 -(4,4-difluoro-2-pyrrolidinylmethyl)-i-6, C〇2Et 0^X0^° QI Η H OMe makes 4 - [1-( Third butoxycarbonyl)-4,4-difluoro-2-pyrrolidine-methyl]-b^ Sl (82° ^ ^ ' 2· 09 ^ ^ ^TFA (5 ☆ solution in CH2Cl2 (5 ml)) 1 hour. The mixture was concentrated in the air and the residue was made alkaline with saturated NaHC03.

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第407頁 1283240 五、發明說明（403) 混合物以CHCI3-Me0H(5:l，2x 20 0毫升）萃取。使結合的萃 取液於K2C03上乾燥’並於真空中濃縮而得4-(4,4 -二敦〜 吡咯啶甲基）-1 -六氫吡畊乙酸乙酯（4 9 3毫克，8 1 %)的棕色 油。1H-NMR (CDC13) 5 1· 27 (t，J = 7. 1 Hz, 3H)、1· 91 (m， 2H) 、2·27-2.60 (m， 1〇H) 、3·〇9-3·34 (m， 4H)、 3.46-3.53 (m，1H)、4·19 (q, J = 7.1 Hz, 2H)。 4 - [1-[4-[N -(2 -氣苯基）脈基]-3-甲氧苯基乙醯基]— 4，4 -二氟-2 -咄洛淀曱基]-1 -六氫咄啡乙酸乙酯Page 407 1283240 V. INSTRUCTIONS (403) The mixture was extracted with CHCI3-Me0H (5:1, 2×20 mL). The combined extracts were dried on K2C03 and concentrated in vacuo to give 4-(4,4-di-n-pyrrolidinemethyl)-1 -hexahydropyrazine ethyl acetate (4,93 mg, 8 1 %) of brown oil. 1H-NMR (CDC13) 5 1· 27 (t, J = 7. 1 Hz, 3H), 1.91 (m, 2H), 2·27-2.60 (m, 1〇H), 3·〇9- 3·34 (m, 4H), 3.46-3.53 (m, 1H), 4·19 (q, J = 7.1 Hz, 2H). 4-[1-[4-[N-(2-(Phenylphenyl))]-3-methoxyphenylethenyl]-4,4-difluoro-2-indolyl]-1 - hexahydrofurfuryl ethyl acetate

113 使4-(4, 4 -二氟-2 -咄咯啶甲基）-1-六氫吡畊乙酸乙酯 ( 49 0毫克，1.69毫莫耳）、4 —[N，-(2-氣苯基）脲基]—3-甲 氧苯乙酸（567毫克，1.69毫莫耳）、EDC*HC 1(486毫克， 2.54毫莫耳）、11081:(催化劑）及〇%4?(催化劑）於0肘？（1〇毫 升）中之混合物攪拌隔夜。將混合物以Et0Ac( 2 5 0毫升）稀 釋，以鹽水（ 2x2 0 0毫升）洗滌，於MgS〇4上乾燥，並於真空 中濃縮。將殘留物於矽膠上利用CHC13-EtOAc (4 : 1)至 CHC13-MeOH(10:l)作為洗提液進行層析，而得4-[1-[4-[ Ν’-（2-氯苯基）脲基]—3 —甲氧苯基乙醯基]一4, 4 -二氟-2 -吼咯啶曱基]-1-六氫吡畊乙酸乙酯（973毫克，95%)的黃 色黏性油。1H-NMR (CDC13) 6 1· 25 (t，J = 7· 1 Hz, 3Η)、 2.3 卜 2.68 (m，12Η·)、3·17-3·20 (m，2H)、3·52-3·91 (m，4Η)、4·10-4·48 (111系列，3Η)、6·75-6.84 (m，2Η)113 4-(4,4-difluoro-2-pyridinylmethyl)-1-hexahydropyrrole ethyl acetate (49 0 mg, 1.69 mmol), 4 —[N,-(2- Phenyl)ureido]-3-methoxyphenylacetic acid (567 mg, 1.69 mmol), EDC*HC 1 (486 mg, 2.54 mmol), 11081: (catalyst) and 〇%4? (catalyst ) at 0 cubits? The mixture in (1 Torr) was stirred overnight. The mixture was diluted with EtOAc (EtOAc) (EtOAc)EtOAc. The residue was chromatographed on silica gel using CHC13-EtOAc (4:1) to CHC13-MeOH (10:1) as eluent to give 4-[1-[4-[ Phenyl)ureido]-3-methoxyphenylethenyl]- 4,4-difluoro-2-oxazolidinyl]-1-hexahydropyridinium ethyl acetate (973 mg, 95%) Yellow sticky oil. 1H-NMR (CDC13) 6 1· 25 (t, J = 7· 1 Hz, 3Η), 2.3 2.68 (m, 12Η·), 3·17-3·20 (m, 2H), 3·52- 3·91 (m, 4Η), 4·10-4·48 (111 series, 3Η), 6.75-6.84 (m, 2Η)

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五、發明說明（404) &gt;7.00(dt, J = 7.8 ^1.5 Hz, 1H) &gt;7.16-7.29 (m, 3Ηλ , 7.35 (dd，J=8.3、1·5 Hz, 1H)、8 〇〇 (d, J = 8·; 1H)、8· 18 (dd，J = 8. 3、1· 5 Hz，1H)。 · ’ 於4-[W4 - [N，-（2—氯苯基）脲基]一3一甲氧苯基乙醯基 —古4, 4—二氟_2—吡咯啶甲基]—卜六氫吡啡乙酸乙醋（2 92 ^ 克，0. 480耄莫耳）溶於THF(4毫升）之攪拌溶液中加入 0.25N NaOH(3.8毫升，0.96 0毫莫耳）。於攪拌2天後 混合物以IN HC1中和，並以CHCl3_Me〇H(4:1，2χ2〇〇毫升 萃取。將結合的萃取液於MgS〇4上乾燥，並於真空中濃 縮。將殘留物於矽膠上利用CHCl3-Me〇H(5:1)經由錫層管 柱層析純化，而得1 i 2 ( 8 1 · 7毫克，2 9% )之淡黃色非晶形固 體。1H-NMR (DMSO-d6) (5 2. 24-2· 50 (m 系列，12H)、 3·40 - 4·47 (m 系列，10H)、6·76 (d， J = 8.1 Hz， 1H)、 6.88 (s，1H)、7·〇2 (t，J = 8.1 Hz，1H)、7·28 (t， J = 8.1 Hz, 1H)、7.44 (d，J = 8.1 Hz, 1H)、7·97 (d， J = 8.1 Hz，1H)、8·〇8 (d，J = 8.1 Hz，1H)、8·96 - 8.99 (m，2H) °MS(FAB) m/z 580 (MH1)。 實施例1 0 5 4 - [1-[3-甲氧基-4-[Ν’-（2-甲基苯基）脲基]苯基乙醯基 ]-(4 S)-苯氧基-（2 S)-吼咯啶基]甲基-1 -六氫吼畊乙酸V. INSTRUCTIONS (404) &gt; 7.00 (dt, J = 7.8 ^1.5 Hz, 1H) &gt;7.16-7.29 (m, 3Ηλ, 7.35 (dd, J=8.3, 1.5 Hz, 1H), 8 〇 〇(d, J = 8·; 1H), 8·18 (dd, J = 8. 3, 1.5 Hz, 1H) · ' at 4-[W4 - [N,-(2-chlorophenyl) Urea]]3-methoxyphenylethylidene-ancient 4,4-difluoro-2-pyrrolidinylmethyl]-hexahydropyridinone acetate (2 92 ^ g, 0. 480 耄 Mo To a stirred solution of THF (4 mL) was added 0.25N NaOH (3.8 mL, EtOAc, EtOAc). After stirring for 2 days, the mixture was neutralized with &lt;RTI ID=0.0&gt; 2 χ 2 ml extraction. The combined extracts were dried over MgS 〇 4 and concentrated in vacuo. The residue was purified on a silica gel using CHCl3-Me〇H (5:1). 1 i 2 (8 1 · 7 mg, 2 9%) of pale yellow amorphous solid. 1H-NMR (DMSO-d6) (5 2. 24-2 · 50 (m series, 12H), 3·40 - 4·47 (m series, 10H), 6.76 (d, J = 8.1 Hz, 1H), 6.88 (s, 1H), 7·〇2 (t, J = 8.1 Hz, 1H), 7.28 (t, J = 8.1 Hz, 1H), 7.44 (d, J = 8.1 Hz, 1H), 7 ·97 (d, J = 8.1 Hz, 1H), 8·〇8 (d, J = 8.1 Hz, 1H), 8.96 - 8.99 (m, 2H) °MS(FAB) m/z 580 (MH1) Example 1 0 5 4 - [1-[3-Methoxy-4-[Ν'-(2-methylphenyl)ureido]phenylethenyl]-(4 S)-phenoxy -(2 S)-decalridinyl]methyl-1 -hexahydroindole

\\312\2d-code\90-01\89112968.ptd 第409頁 1283240 五、發明說明（405) (2S，4S)-1-第二丁氧数基-4-苯氧基—2 -吼σ各cr定叛酸甲醋 在室溫下在氮氣環境中，於（2S，4R)-1-第三丁氧羰基 -4 -經基-2 -吼洛σ定叛酸甲酯（4.69克，19.1毫莫耳）、紛 (1· 98克，21· 0毫莫耳）及PPh3 (5· 51克，21.0毫莫耳）於 THFC80毫升）中之攪拌混合物中加入DIAD(4· 13毫升，21. 0 毫莫耳）。使混合物攪拌隔夜。於將溶劑移除後，使所產 生之殘留物於矽膠[ 700克，CHCl3/EtOAc(l〇/l)]上進行層 析’而付（2S，4S)-1~第二丁氧幾基—4-苯氧基-2-吼p各σ定魏 酸甲酯（5. 31 克，86%)之無色油。iH-NMR (CDC13) 5 1. 43 (br， 9H ’其中一個異構物）、ΐ·48 (br， 9H，其中一個異 構物）、2.48 (m，1H)、3.75 (br，3H)、4·42-4·96 (m， 2H) 、 6·88-7·35 (m， 5H)。 ’ (2S，4S)-1-第三丁氧羰基-4 -苯氧基-2 -吡洛啶缓酸\\312\2d-code\90-01\89112968.ptd Page 409 1283240 V. INSTRUCTIONS (405) (2S,4S)-1-Second butoxymethyl-4-phenoxy-2-ene σ each cr to determine the methyl vinegar at room temperature in a nitrogen atmosphere at (2S,4R)-1-tert-butoxycarbonyl-4-trans-yl-2-pyrrolidine methyl ester (4.69 g Add DIAD (4·13 ml) to a stirred mixture of 19.1 mmol, 1 (98 g, 21.0 mmol) and PPh3 (5·51 g, 21.0 mmol) in THF (80 ml) , 21. 0 millimoles). The mixture was stirred overnight. After the solvent was removed, the resulting residue was chromatographed on silica gel [700 g, CHCl3 / EtOAc (l/l)] to afford (2S, 4S)-1~2. 4-4-phenoxy-2-indole p-methyl sulphate (5. 31 g, 86%) as a colorless oil. iH-NMR (CDC13) 5 1. 43 (br, 9H 'one of the isomers), ΐ·48 (br, 9H, one of the isomers), 2.48 (m, 1H), 3.75 (br, 3H) , 4·42-4·96 (m, 2H), 6·88-7·35 (m, 5H). '(2S,4S)-1-tert-butoxycarbonyl-4-phenoxy-2-pyrrolidine acid

在室溫下於（2S，4S)-1-第三丁氧羰基-4-苯氧基-2-吡咯 啶羧酸甲酯（5. 31克，16· 5毫莫耳）溶於THF (132毫升）之攪 拌溶液中加入0.25N NaOH(132毫升，33.0毫莫耳）。使所 產生之混合物攪拌隔夜。於移除溶劑後，將混合物經由加 入IN HC1酸化，並以CHC 13萃取。將結合的萃取液以鹽水Methyl (2S,4S)-1-tert-butoxycarbonyl-4-phenoxy-2-pyrrolidinecarboxylate (5. 31 g, 16.5 mmol) was dissolved in THF at room temperature. To a stirred solution of 132 ml) was added 0.25 N NaOH (132 mL, 33.0 mmol). The resulting mixture was stirred overnight. After removing the solvent, the mixture was acidified by addition of IN HCl and extracted with CHC 13. Combine the extract with saline

\\312\2d-code\90-01\89112968.ptd 第410頁 1283240 五、發明說明（406) 洗滌，於Na2S04上乾燥，並蒸發。使殘留物自正己烷 -CHCI3再結晶而得（2S，4S)-1-第三丁氧羰基-4-苯氧基-2-咄咯啶羧酸（2.96克，58%)之白色粉末。1H-NMR (DMS0 - d 6)(5 1.36 (s， 9H)、2.16 (d， J = 13.2 Hz， 1H) 、2.56 (m，1H)、3·46 (m，1H)、3·71 (dt，J = 12.0、5· 4 Hz, 1H)、4·26 (dt，J = 9.5、7·1 Hz, 1H)、4·99 (m， 1H)、6.85 (m，2H)、6.94 (t，J = 7.3 Hz，1H)、7.28 (t, 1 = 1. 3 Hz, 1H)。 (2S，4S)-1-第三丁氧幾基-4 -苯氧基- 2-nbp各咬甲醇 °v boc 在0°C下於（2S，4S)-1-第三丁氧羰基-4-苯氧基—2 -吡洛 啶羧酸（2· 39克，7· 76毫莫耳）溶於THF( 50毫升）之擾拌溶 液中加入BH3 · DMS(1. 55毫升，15. 5毫莫耳）。於在相同溫 度下攪拌1 0分鐘後’使混合物達到室溫，然後在5 〇 下加 熱2小時。於冷卻至室溫後，將混合物於真空中濃縮，並 經由在0 C下加入水而停止反應。以E10 A c萃取混合物。將 結合的萃取液以鹽水洗滌，於NaJO4上乾燥，並蒸發。使 殘留物於矽膠[60克，CHCl3/MeOH(50/l)]上進行層析，而 得（2S，4S)-1-第三丁氧魏基-4-苯氧基-2 -吼嘻咬曱醇 (2· 83 克，10 0%)之無色油。1H-NMR (CDC13) 5 1. 47 (s 9H) 、1·95 (br， 1H) 、2·36 (m， 1H) 、3·56-3.74 (m，’ 3Η) 、 3.89-4.52 (m， 3Η) 、4·85 (br， 1Η) 、6·84 (dd\\312\2d-code\90-01\89112968.ptd Page 410 1283240 V. INSTRUCTIONS (406) Wash, dry on Na2S04, and evaporate. The residue was recrystallized from n-hexane-CHCI to afford (2S,4S)-1-t-butoxycarbonyl-4-phenoxy-2-indole carboxylic acid (2.96 g, 58%) as white powder. 1H-NMR (DMS0 - d 6) (5 1.36 (s, 9H), 2.16 (d, J = 13.2 Hz, 1H), 2.56 (m, 1H), 3·46 (m, 1H), 3·71 ( Dt, J = 12.0, 5·4 Hz, 1H), 4·26 (dt, J = 9.5, 7·1 Hz, 1H), 4·99 (m, 1H), 6.85 (m, 2H), 6.94 ( t, J = 7.3 Hz, 1H), 7.28 (t, 1 = 1. 3 Hz, 1H). (2S, 4S)-1-tert-butoxymethyl-4-phenoxy-2-nbp Methanol °v boc at (0S,4S)-1-tert-butoxycarbonyl-4-phenoxy-2-pyrrolidinecarboxylic acid (2·39 g, 7.76 mmol) at 0 °C BH3 · DMS (1.55 ml, 15.5 mmol) was added to the stirrer solution in THF (50 ml). After stirring at the same temperature for 10 minutes, 'the mixture was allowed to reach room temperature, then at 5 The mixture was heated for 2 hours under the aft. After cooling to room temperature, the mixture was concentrated in vacuo and quenched by adding water at 0 C. The mixture was extracted with E10 A c. The combined extracts were washed with brine at NaJO4 Drying and evaporation. The residue was chromatographed on silica gel [60 g, CHCl3 / MeOH (50 /l) to give (2S,4S)-1-t-butoxy- yl Base-2 - bite sterol (2·83克, 10 0%) of a colorless oil. 1H-NMR (CDC13) 5 1. 47 (s 9H), 1·95 (br, 1H), 2·36 (m, 1H), 3·56-3.74 (m , '3Η), 3.89-4.52 (m, 3Η), 4·85 (br, 1Η), 6.84 (dd

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第411頁 1283240Page 411 1283240

J = 8.8、1.2 Hz，2H)、6.97 (t，J = 7.2 Hz，1H)、7 29 (t, 2H, J=7·8 Hz) 。 · (2S，4S)-：l -第三丁氧羰基-4-苯氧基—2—吡咯啶叛酸 °^VcH〇 boc 在0 C下於（2S，4S)-卜第三丁氧羰基_4-笨氧基—2 —吡洛 啶甲醇（2.75克，9.37毫莫耳）、Et3N(7.84毫升，56.2毫 莫耳）、0诞30(6.66毫升，9.37毫莫耳）於(：112(：12(3()毫升）中 之攪拌混合物中加入S 〇3 · 口比咬（4 · 4 7克，2 8 · 1毫莫耳）， 然後使所產生之混合物提升至室溫。於授拌2 · 5小時後， 將混合物於真空中濃縮。於所產生之混合物中加入水，並 以EtgO萃取。將結合的萃取液以鹽水洗滌，於Na2S〇4上乾 燥，並於真空中濃縮。使殘留物於矽膠[丨〇〇克，CHCl3/丙 酮（5/1)]上進行層析，而得（2S，4S)-1-第三丁氧羰基-4-苯氧基-2 -咄咯啶羧醛（2· 54克，93%)之黃色油。1H-NMR (CDC13) 6 1·45 (s， 9H，其中一個異構物）、ι·49 (s， 9Η，其中一個異構物）、2·17 (br, 2Η)、3·65 - 4.31 (m， 3H)、4·91 (br，1H)、6·79 (d, J:7.8 Hz，1H)、6·77 (m，1H)、7· 28 (m，2H)、9· 66 (m，1H)。 4-[1-第三丁氧幾基-(4S) -苯氧基_(2S) -吼哈*7定基]甲基 - 1 -六氫吡畊乙酸乙酯J = 8.8, 1.2 Hz, 2H), 6.97 (t, J = 7.2 Hz, 1H), 7 29 (t, 2H, J = 7·8 Hz). · (2S,4S)-:l-Tertidinoxycarbonyl-4-phenoxy-2-pyrrolidine tracing °^VcH〇boc at 0 C in (2S,4S)-b-butoxycarbonyl _4-Phenoxy-2 pyrrolidine methanol (2.75 g, 9.37 mmol), Et3N (7.84 mL, 56.2 mmol), 0 3030 (6.66 mL, 9.37 mmol) at (:112 Add S 〇3 to the stirred mixture in (12 (3 ml)). The mouth bite (4 · 47 g, 2 8 · 1 mmol), then raise the resulting mixture to room temperature. After 2 hours of mixing, the mixture was concentrated in vacuo. Water was added and the mixture was extracted with EtgO. The combined extracts were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was chromatographed on silica gel, CHCl3/acetone (5/1) to give (2S,4S)-1-t-butoxycarbonyl-4-phenoxy-2. Acridine carboxaldehyde (2·54 g, 93%) of yellow oil. 1H-NMR (CDC13) 6 1·45 (s, 9H, one of the isomers), ι·49 (s, 9 Η, one of them Isomers), 2·17 (br, 2Η), 3.65 - 4.31 (m, 3H), 4·91 (br, 1H), 6.79 (d, J: 7.8 Hz, 1H), 6.77 (m, 1H), 7·28 (m, 2H), 9·66 (m, 1H). 4-[1-Tertioxyl-based- (4S)-phenoxy-(2S)-haha*7-based]methyl- 1 -hexahydropyrrolic acid ethyl acetate

\\312\2d-code\90-01\89112968.ptd 第412頁 1283240 五、發明說明（408) 在室溫下於1-第三丁氧羰基—（4S) -笨氧基-(2s)_吼咯啶 羧醛（1.36克，4.67毫莫耳）、1-六氫咄畊乙酸乙酯（1.61 克，9· 37毫莫耳）於THF( 30毫升）中之攪拌混合物中加入\\312\2d-code\90-01\89112968.ptd Page 412 1283240 V. INSTRUCTIONS (408) At room temperature in 1-tert-butoxycarbonyl-(4S)-stupyloxy-(2s) _ 吼 吼 羧 carboxy aldehyde (1.36 g, 4.67 mmol), 1-hexahydroindole acetonitrile (1.61 g, 9.37 mmol) in a stirred mixture of THF (30 mL)

NaBH(OAc)3(1.98克，9.34毫莫耳）。於攪拌3小時後，經 由加入水使混合物停止反應，並以E 萃取。將結合的 卒取液以N a H C 〇3水溶液及鹽水洗條。將有機層於n七g 上 乾燥’並於真空中濃縮。使殘留物於矽膠[5 〇克，C HC 13 / MeOH(10/l)]上進行層析，而得4-[l-第三丁氧羰基-(4S) - 苯氧基-（2 S)-吼洛咬基]甲基-1 -六氫吼p井乙酸乙酯（1 · 〇 5 克，50%)之無色油。iH-NMR (CDC13) 5 1· 27 (t，J = 7· 3 Hz, 3H) 、1·57 (s， 9H) 、2·18 (m， 1H) 、2·33-2·74 (m， 9H)、3·17 (s，2H)、3·52-4.10 (m，5H)、4.17 (q， J = 7.3 Hz，2H)、4·89 (br，1H)、6·84 (d，J:6.8 Hz, 2H) 、 6· 95 (m, 1H) 、 7· 26 (m， 3H)。 4-[(4S) -苯氧基-（2S) -吼洛咬基]甲基-1 -六氫p比喷乙酸乙 酯 在室溫下於4-[1-第三丁氧羰基-（4S) -苯氧基-（2S) -吡 咯啶基]甲基-1-六氫吡畊乙酸乙酯（1.05克，2. 35毫莫耳） 浴於ΟΗ2Οΐ2(20：ί：升）之撲摔溶液中加入TFA(20毫升）。於授 拌3小時後，將混合物於真空中濃縮，將其以CHCl3-MeOH (1 0/1 )稀釋，並經由加入IN NaOH使其成為鹼性。將結合NaBH(OAc) 3 (1.98 g, 9.34 mmol). After stirring for 3 hours, the mixture was quenched by the addition of water and extracted with E. The combined strokes were washed with an aqueous solution of NaH??3 and brine. The organic layer was dried on n 7 g and concentrated in vacuo. The residue was chromatographed on silica gel [5 g, C HC 13 / MeOH (10/l)] to give 4-[l-t-butoxycarbonyl-(4S)-phenoxy-(2 S ) - 吼 咬 ]] methyl 1- hexahydropyrene p well ethyl acetate (1 · 〇 5 g, 50%) of colorless oil. iH-NMR (CDC13) 5 1· 27 (t, J = 7· 3 Hz, 3H), 1.57 (s, 9H), 2·18 (m, 1H), 2·33-2·74 (m , 9H), 3·17 (s, 2H), 3·52-4.10 (m, 5H), 4.17 (q, J = 7.3 Hz, 2H), 4·89 (br, 1H), 6.84 (d , J: 6.8 Hz, 2H), 6·95 (m, 1H), 7·26 (m, 3H). 4-[(4S)-phenoxy-(2S)-indolyl]methyl-1 -hexahydro-p is sprayed with ethyl acetate at room temperature in 4-[1-tert-butoxycarbonyl-( 4S) -Phenoxy-(2S)-pyrrolidinyl]methyl-1-hexahydropyrrolic acid ethyl acetate (1.05 g, 2.35 mmol) Bath in ΟΗ2Οΐ2 (20:ί: liter) TFA (20 ml) was added to the drop solution. After 3 hours of incubation, the mixture was concentrated in vacuo, diluted with CHCI <RTI ID=0.0># </RTI> MeOH (1 0/1) and made basic with the addition of IN NaOH. Will combine

\\312\2d-code\90-01\89112968.ptd 第413頁 1283240 五、發明說明（409) 的反應混合物以CHCI3-MeOH(l 0/1 )萃取。將有機層以鹽水 洗滌，於NaS〇4上乾燥並濃縮，而得4-[(4S)-苯氧基—（2S) -吡咯啶基]甲基-1 -六氫咄啡乙酸乙酯（丨·丨2克，定量）的 棕色油，將其不經進一步的純化而使用。1 Η — n M R ( c D C 1 ) 5 1. 2 5 (11，J = 7 · 1、7 · 1 Η ζ，3 Η)、1 · 9 1 (d，J = 1 2 0\\312\2d-code\90-01\89112968.ptd Page 413 1283240 V. Inventive Note (409) The reaction mixture was extracted with CHCI3-MeOH (l 0/1). The organic layer was washed with brine, dried over Nassssssssssssssssssssssssssssssss棕色·丨 2 g, quantitative) of a brown oil which was used without further purification. 1 Η — n M R ( c D C 1 ) 5 1. 2 5 (11, J = 7 · 1, 7 · 1 Η ζ, 3 Η), 1 · 9 1 (d, J = 1 2 0

Hz， 1H) 、2·42-2.85 (m， 10H) 、3·22 (s， 2H) 、3·5〇 (s，2H)、3·54- 3.82 (m，2H)、4·15 (q，】 = 7·ι Hz, 2H)、4·98 (br，1H)、6·84 (d，J = 8.1 Hz，2H)、6·76 (t，J = 7.1 Hz，1H)、7·26-7·31 (m，3H)、7·4〇 (br， 1H)。 ’ 4-[1-[3-甲氧基-4-[Ν’ -（2-甲基苯基）脲基]苯基乙醯 基]-(4S) -苯氧基-（2S) -咄咯啶基]甲基—丨―六氫吡畊乙酸 乙酯Hz, 1H), 2·42-2.85 (m, 10H), 3·22 (s, 2H), 3·5〇(s, 2H), 3·54- 3.82 (m, 2H), 4·15 ( q,] = 7·ι Hz, 2H), 4·98 (br, 1H), 6.84 (d, J = 8.1 Hz, 2H), 6·76 (t, J = 7.1 Hz, 1H), 7 · 26-7·31 (m, 3H), 7·4〇 (br, 1H). '4-[1-[3-Methoxy-4-[Ν'-(2-methylphenyl)ureido]phenylethenyl]-(4S)-phenoxy-(2S)-咄Pyridyl]methyl-hydrazine-hexahydropyrrole ethyl acetate

使4 - [Ν -(2-甲基苯基）脲基]—3-曱氧苯乙酸（337毫克， 1· 07毫莫耳）、4 - [(4S) -苯氧基一（28)-口比洛咬基]甲基—1-六氫17比啡乙酸乙酯（373毫克，ΐ·〇7毫莫耳）、EDC*HC1 ( 308¾克’1.61耄莫耳）及DMAP(197毫克，1·61毫莫耳）於 DMF( 6毫升）中之混合物在室溫下攪拌18小時。將混合物倒 入至冰水中’並以EtOAc萃取。將結合的萃取液以冰水及 鹽水洗滌。於在Nag SO*上乾燥後，將萃取液於真空中濃 縮。使殘留物於矽膠[50克，CHCl3/MeOH(50/l)]上進行層4-[Ν-(2-methylphenyl)ureido]-3-oxophenylacetic acid (337 mg, 1.07 mmol), 4-[(4S)-phenoxy-(28) - mouth piroxime] methyl 1- hexahydro 17 morphine ethyl acetate (373 mg, ΐ·〇 7 mmol), EDC*HC1 (3083⁄4 g '1.61 耄 Moel) and DMAP (197 mg A mixture of 1.61 mmoles in DMF (6 mL) was stirred at room temperature for 18 h. The mixture was poured into ice water' and extracted with EtOAc. The combined extracts were washed with ice water and brine. After drying on Nag SO*, the extract was concentrated in vacuo. The residue was layered on silica gel [50 g, CHCl3 / MeOH (50 / l)]

\\312\2d-code\90-01\89112968.ptd 第414頁 1283240 五、發明說明（410) -- 析，而付4-[1 - [3 -曱氧基— 4-[N，-(2-甲基苯基）脲基]苯 基乙醯基]-(4S)-苯氧基—（2S)-吼咯啶基]曱基-丨―六氫吼 。井乙酸乙醋（ 4 3 0毫克，62%)的無色非晶形固體。 ^-NMR (CDC13)(5 1.25 (t, J = 7.8 Hz, 3H) &gt;1.98-2.17 (m，2H)、2·26 (s，3H)、2·36-2·82 (m，11H)、3·13 (s，1H)、3.17 (s，1H)、3·55 (d，U.4 Hz，1H)、 3.66 (d，J = 0.9 Hz，3H)、3.67 -3.84 (m，2H)、3.98-4. 35 (m，3H)、4·85-4·95 (m，ih)、6·27-6·89 (m，6H)、 7.08 (t，J = 7.3 Hz，1H)、7·19 (d，J = 6.8 Hz, 1H)、7· 28 (m，2H)、7·41 (d，J = 4.9 Hz，1H)、7·55 (d，J = 7.8\\312\2d-code\90-01\89112968.ptd Page 414 1283240 V. Description of invention (410) - Analysis, and pay 4-[1 - [3 - 曱 oxy - 4-[N,- (2-Methylphenyl)ureido]phenylethenyl]-(4S)-phenoxy-(2S)-decalridinyl]fluorenyl-hydrazine-hexahydroindole. Well, ethyl acetate (430 mg, 62%) of a colorless amorphous solid. ^-NMR (CDC13) (5 1.25 (t, J = 7.8 Hz, 3H) &gt; 1.98-2.17 (m, 2H), 2·26 (s, 3H), 2·36-2·82 (m, 11H) ), 3·13 (s, 1H), 3.17 (s, 1H), 3·55 (d, U.4 Hz, 1H), 3.66 (d, J = 0.9 Hz, 3H), 3.67 - 3.84 (m, 2H), 3.98-4. 35 (m, 3H), 4·85-4·95 (m, ih), 6.27-6·89 (m, 6H), 7.08 (t, J = 7.3 Hz, 1H ), 7·19 (d, J = 6.8 Hz, 1H), 7·28 (m, 2H), 7·41 (d, J = 4.9 Hz, 1H), 7·55 (d, J = 7.8

Hz，1H)、8.05 (dd，J = 7.3、2·2 Hz, 1H)。 關於HC1鹽：淡棕色非晶形固體。IR (KBr) 3265、3〇59、 1 747、1 5 3 3、1 2 25 / 公分；ms(FAB) m/z 644(MH1) ; C36H 45N5 06 ·Η(：1 ·2·1Η20 之分析計算值：c，60.22; H， 7.05; N，9.75。實測值：c，59.97;Η，6.72;N，9.54。 於4 - [1 - [3 -甲氧基-4—[『—（2-曱基苯基）脲基]苯基乙醯 基]-(4S) -苯氧基-（2S) - π比咯啶基]曱基_丨—六氫吼畊乙酸 乙酉旨（ 2 40毫克’〇· 373毫莫耳）溶於THF( 3. 0毫升）之溶液中 加入0· 2 5N NaOH(3. 〇毫升）。於在室溫下攪拌2〇小時後， 將混合物以〇11(：1中和，並以(^(：13一^011(10/1)萃取。將 結合的卒取液於Na2S04上乾燥，並於真空中濃縮。經由加 入乙_將殘留物研製而得丨丨3(143毫克，62%)之白色粉 末。IR (KBr) 3346、2949、1633、1533、1227/公分； LR (DMSO-d6) (5 1· 76 (m, 1H)、2· 18 (br，2H)、Hz, 1H), 8.05 (dd, J = 7.3, 2·2 Hz, 1H). Regarding the HCl salt: a light brown amorphous solid. IR (KBr) 3265, 3〇59, 1 747, 1 5 3 3, 1 2 25 / cm; ms(FAB) m/z 644(MH1) ; C36H 45N5 06 ·Η(:1 ·2·1Η20 analysis Calculated: c, 60.22; H, 7.05; N, 9.75. Found: c, 59.97; Η, 6.72; N, 9.54. 4 - [1 - [3 - methoxy-4-[『-(2 -mercaptophenyl)ureido]phenylethenyl]-(4S)-phenoxy-(2S)-πpyrrolidyl]fluorenyl-hydrazine-hexahydroindole acetic acid ethyl acetate (2 40 mg Add a solution of 0·2 5N NaOH (3. 〇ml) to a solution of THF (3.0 ml). After stirring at room temperature for 2 hrs, the mixture was 〇11 ( :1 neutralized, and extracted with (^(:13~^011(10/1). The combined stroke liquid was dried on Na2S04 and concentrated in vacuo. The residue was prepared by adding B.丨3 (143 mg, 62%) of white powder. IR (KBr) 3346, 2949, 1633, 1533, 1227 / cm; LR (DMSO-d6) (5 1 · 76 (m, 1H), 2 · 18 ( Br, 2H),

\\312\2d-code\90-01\89112968.ptd 第415頁 1283240 五、發明說明（411) 2.25 (s，3H)、2·42-2·83 (in, 9H)、3.17 (s，1H)、 3. 20 (s，1Η)、3. 38 (m, 1H) &gt;3.70 (s, 2H)、3· 72 -3· 78 (m， 2Η)、3· 85 (s, 3Η，其中一個異構物）、3· 87 (s, 3Η，其中一個異構物）、3· 95 (m，1Η)、4· 27 (br， 1H) 、5·08 (m， 1H) 、6·75 (d， J=8.3 Hz， 1H) 、6·93 (m， 5H) 、7.14 (m， 2H) 、7·30 (d, J:7.6 Hz， 1H)、 7.79 (d，、J 二 9.0 Hz, 1H)、8·02 (m，1H)、8·50 (s, 1H)、8·58 (s，1H); MS(FAB) m/z 616(MH1); C34H41N506 • 0. lEtOH · 2H20 之分析計算值·· C，62. 58 ; H，7. 00 ; N， 10. 67 ° 實測值：C，62. 73 ； H, 6.58； N, 10.24° 實施例1 0 6 4-[1-[4- [Ν’ - (2 -氣苯基）脈基]-3-甲氧笨基乙酿基]- (4S) -苯氧基-(2S) -咄咯啶基]曱基-1 -六氫咄畊乙酸\\312\2d-code\90-01\89112968.ptd Page 415 1283240 V. Description of invention (411) 2.25 (s, 3H), 2·42-2·83 (in, 9H), 3.17 (s, 1H), 3. 20 (s, 1Η), 3. 38 (m, 1H) &gt; 3.70 (s, 2H), 3·72 -3· 78 (m, 2Η), 3·85 (s, 3Η, One of the isomers), 3·87 (s, 3Η, one of the isomers), 3·95 (m, 1Η), 4·27 (br, 1H), 5·08 (m, 1H), 6 ·75 (d, J=8.3 Hz, 1H), 6.93 (m, 5H), 7.14 (m, 2H), 7·30 (d, J: 7.6 Hz, 1H), 7.79 (d, J 9.0 Hz, 1H), 8·02 (m, 1H), 8·50 (s, 1H), 8·58 (s, 1H); MS(FAB) m/z 616(MH1); C34H41N506 • 0. lEtOH · Analytical calculation of 2H20 · · C, 62. 58 ; H, 7. 00 ; N, 10. 67 ° Found: C, 62. 73 ; H, 6.58; N, 10.24° Example 1 0 6 4- [1-[4-[Ν[-(2-phenylphenyl))]]]]]]]]]]]]]] Base-1 - hexahydroindole

114 4-[1-[4-[『-(2-氣苯基）脲基]-3-曱氧苯基乙醯基]-(43) -苯氧基-(2S )-吼咯啶基]甲基-1 -六氫吼啡乙酸乙酯 r〇114 4-[1-[4-[『-(2-Phenylphenyl)ureido]-3-indolylphenylphenyl]-(43)-phenoxy-(2S)-indenylpyridyl ]methyl-1 -hexahydrofurfuryl ethyl acetate r〇

使4-[Ν’ -(2 -氯苯基）脲基]-3-曱氧苯乙酸（358毫克， 1.07毫莫耳）、4-[(43)-苯氧基-(23)-吼咯啶甲基]-1-六4-[Ν'-(2-Chlorophenyl)ureido]-3-indolyl phenylacetic acid (358 mg, 1.07 mmol), 4-[(43)-phenoxy-(23)-oxime Pyridylmethyl]-1-hexa

\\312\2d-code\90-01\89112968.ptd 第416頁 1283240 五、發明說明（412) 氫吼讲乙酸乙酯（ 3 73毫克，1 · 07毫莫耳）、EDC · HC 1 ( 308 耄克，1.61¾莫耳）及])map(197毫克，1.61毫莫耳）於 DMF ( 6毫升）中之混合物在室溫下攪拌丨8小時。將混合物倒 入至冰水中’並以Et〇Ac萃取。將結合的萃取液以冰水及 鹽水洗滌。於在Na2S04上乾燥後，將萃取液於真空中濃 縮。使殘留物於矽膠[5〇克，CHCl3/MeOH(50/l)]上進行層 析，而得4 - [1-[4 - [N，-(2-氣苯基）脲基]-3-曱氧苯基乙 醯基]-(4S)-笨氧基—（2S) -咄咯啶基]甲基—1—六氫吼畊乙 酸乙酉旨（320毫克，45%)的無色非晶形固體。ih-NMR (CDC1 3)5 1·25 (qq， 】=7·3、7·3 Hz, 3Η)、2·05-2·20 (m， 2H)、2.35-2.8 0 (m，ih)、3·12 及 3.18 (各s， 1H，醯胺 異構物）、3·57 (d，J-5.4 Hz, 1H)、3·66 及 3·38 (各 s, 3H，醯胺異構物）、3·70 -3.9 0 (m，2H)、4·02 -4.43 (m， 3H) 、4·88-4.97 (m， 1H) 、6·83-6·99 (m， 6H) 、7·18-7.32(m，3H)、7.68(d，J=8.3Hz，lH)、7. 74 (s， 1H) 、8·16 (dd， J=8.3 、1·4 Hz, 1H)。 關於HC1鹽：淡棕色非晶形固體。ir (KBr) 33〇〇、2978、 1 745、1533、1 2 25 / 公分；MS(FAB) m/z 664 (MH1)、 6 66 (MH3) ; C35H42C1N5 06 · HC1 · 2. 4H20 之分析計算值：C， 56· 51 ; H，6· 48 ; N，9· 41。實測值：C，56· 51 ; H， 6.18； N, 9. 28 〇 於4- [l-[4-[N，-（2~氯苯基）脲基]一 3一曱氧苯基乙醯基]一 (4S)-苯氧基-(2 S)-吡咯啶基]曱基-1 -六氫咄畊乙酸乙酯 (181毫克’0.273毫莫耳）溶於THF( 2. 2毫升）之溶液中加入\\312\2d-code\90-01\89112968.ptd Page 416 1283240 V. INSTRUCTIONS (412) Hydroquinone speaks ethyl acetate (3 73 mg, 1 · 07 mmol), EDC · HC 1 ( A mixture of 308 g, 1.613⁄4 mol) and ]) map (197 mg, 1.61 mmol) in DMF (6 mL) was stirred at room temperature for 8 hours. The mixture was poured into ice water' and extracted with Et 〇Ac. The combined extracts were washed with ice water and brine. After drying on Na2S04, the extract was concentrated in vacuo. The residue was chromatographed on silica gel [5 g, CHCl3 / MeOH (50 / l)] to give 4-[1-[4-[N,-(2-phenylphenyl)ureido]-3 - oxime phenylethyl fluorenyl]-(4S)-p-oxy-(2S)- oxazolidinyl]methyl-1 hexahydro hydrazine acetate (320 mg, 45%) colorless amorphous solid. ih-NMR (CDC1 3)5 1·25 (qq, 】=7·3, 7·3 Hz, 3Η), 2·05-2·20 (m, 2H), 2.35-2.8 0 (m, ih) , 3·12 and 3.18 (each s, 1H, guanamine isomer), 3·57 (d, J-5.4 Hz, 1H), 3.66 and 3.38 (each s, 3H, guanamine isomerism (), 3·70 -3.9 0 (m, 2H), 4·02 - 4.43 (m, 3H), 4·88-4.97 (m, 1H), 6·83-6·99 (m, 6H), 7·18-7.32(m,3H), 7.68 (d, J=8.3Hz, lH), 7.74 (s, 1H), 8.16 (dd, J=8.3, 1. 4 Hz, 1H). Regarding the HCl salt: a light brown amorphous solid. Ir (KBr) 33〇〇, 2978, 1 745, 1533, 1 2 25 / cm; MS(FAB) m/z 664 (MH1), 6 66 (MH3) ; C35H42C1N5 06 · HC1 · 2. 4H20 Analytical calculation Value: C, 56· 51 ; H, 6· 48 ; N, 9· 41. Found: C, 56· 51 ; H, 6.18; N, 9. 28 〇 4- [l-[4-[N,-(2~Chlorophenyl)ureido]- 3-indolyl phenyl b Indole]-(4S)-phenoxy-(2S)-pyrrolidinyl]nonyl-1 -hexahydroindoleic acid ethyl acetate (181 mg '0.273 mmol) dissolved in THF (2.2 ml ) added to the solution

\\312\2d-code\90-01\89112968.ptd 第417頁 1283240 五、發明說明（413) 0· 25N NaOH( 2. 2毫升）。於在室溫下攪拌20小時後，將混 合物以IN HC1中和，並以CHC13-MeOH(10/l)萃取。將結合 的萃取液於N a2 S 04上乾燥，並於真空中濃縮。經由加入乙 醚將殘留物研製而得114 (133毫克，77%)之白色粉末。IR (KBr) 3317、2949、1701、1631、1595、1225 / 公分；1 Η - NMR (DMSO-d6) (5 2.13-3.05 (m，11H)、3.22 及 3.36 (各s，2H，醯胺異構物）、3·38 (m， 1H)、3·60 (s， 2Η) 、3·71 (m， 1Η) 、3·85 (s， 3Η) 、3·95 (m， 1Η)、 4.28 (br，1H)、5·06 (m，1H)、6·76 (d，J = 8.3 Hz， 1H)、6·91-7.03 (m, 5H)、7·29 (m，3H)、7.44 (d， J = 7.9 Hz, 1H)、7.97 (dd，J = 8.1、4.1 Hz，1H)、8·08 (d，J = 7.0 Hz, 1H)、8·91 (s，1H)、8.95 (s，1H); MS(FAB) m/z 63 6 (MH1)、6 38 (M+ + 3); C33H38C1N5 06 · 0· 2EtOH · 1. 3H20 之分析計算值：C，59· 98 ; H，6· 30 ; N， 10· 47。實測值：C，60. 25 ; H，6. 12 ; N，10. 1 1。 實施例1 0 7 4 - [1-[4 - [N -(2 - &gt;臭苯基）脈基]- 3-甲氧苯基乙酿基]-(4S) -苯氧基-（2S )-咄咯啶基]甲基-1 -六氫吼畊乙酸\\312\2d-code\90-01\89112968.ptd Page 417 1283240 V. INSTRUCTIONS (413) 0·25N NaOH (2.2 ml). After stirring at room temperature for 20 hours, the mixture was neutralized with 1N HCl and extracted with CH.sub.3-MeOH (10/l). The combined extracts were dried over Na 2 S 04 and concentrated in vacuo. The residue was triturated with EtOAc (EtOAc)EtOAc. IR (KBr) 3317, 2949, 1701, 1631, 1595, 1225 / cm; 1 Η - NMR (DMSO-d6) (5 2.13-3.05 (m, 11H), 3.22 and 3.36 (each s, 2H, decylamine Structure), 3·38 (m, 1H), 3·60 (s, 2Η), 3·71 (m, 1Η), 3·85 (s, 3Η), 3·95 (m, 1Η), 4.28 (br,1H),5·06 (m,1H),6·76 (d,J = 8.3 Hz, 1H), 6.91-7.03 (m, 5H), 7·29 (m, 3H), 7.44 (d, J = 7.9 Hz, 1H), 7.97 (dd, J = 8.1, 4.1 Hz, 1H), 8·08 (d, J = 7.0 Hz, 1H), 8.91 (s, 1H), 8.95 ( s,1H); MS(FAB) m/z 63 6 (MH1), 6 38 (M+ + 3); C33H38C1N5 06 · 0· 2EtOH · 1. Analysis of 3H20: C, 59· 98 ; H, 6 · 30 ; N, 10 · 47. Found: C, 60. 25 ; H, 6. 12 ; N, 10. 1 1. Example 1 0 7 4 - [1-[4 - [N -(2 - &gt;Smelly phenyl)-yl]- 3-methoxyphenylethyl]-(4S)-phenoxy-(2S)-decalridinyl]methyl-1 -hexahydroindole

4-[1-[4-|^’-(2-溴苯基）脲基]-3-甲氧苯基乙醯基]-（43) -苯氧基-（2S )-吡咯啶基]甲基_ 1 -六氫吼啡乙酸乙酯4-[1-[4-|^'-(2-Bromophenyl)ureido]-3-methoxyphenylethenyl]-(43)-phenoxy-(2S)-pyrrolidinyl] Methyl _ 1 - hexahydropyrone ethyl acetate

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使4-[Ν’-（2-溴苯基）脲基]一3一甲氧苯乙酸（4〇6毫克， 1.07毫莫耳）、4-[(48)-笨氧基一（28)一咄咯啶基]甲基一1一 六氫咄畊乙酸乙酯（ 373毫克，1· 〇7毫莫耳）、EDC · K1 ( 308毫克，1· 61毫莫耳）及DMAP(197毫克，161毫莫耳）於 DMF( 6毫升）中之混合物在室溫下攪拌18小時。將混合物倒 入至冰水中，並以EtOAc萃取。將結合的萃取液以冰水及 鹽水洗滌。於在NaJO4上乾燥後，將萃取液於真空中濃 縮。使殘留物於矽膠[50克，CHCl3/MeOH(50/l)]上進行層 析’而得標題化合物（5 6 0毫克，7 4 % )的無色非晶形固體。 1 -NMR (CDC13) 5 1·25 (tt，J = 7.1、7·1 Hz，3H)、 2.04-2.84 (m， 13H) 、3·12 及3.18 (各s, 1H ，醯胺異構 物）、3·57 (d，JM.4 Hz， 1H)、3·66 及 3.68 (各 s，3H， 醯胺異構物）、3·6 8-3.8 7 (m，3H)、4·05-4.41 (m，2H) 、4·87-4·96 (m， 1Η) 、6·76-6·98 (m， 6Η) 、7·20-7·33 (m， 3Η) 、7·46 (d, J=8.1 Hz, 1Η) 、7·67及7.71 (各s, 1H，醯胺異構物）、7·78及7.81 (各s，1H，醯胺異構 物）、7·95 (d，J = 8.3 Hz，1H)、8·09 (d，J = 8.1 Hz, 1H)。 關於HC1鹽：淡棕色非晶形固體。ir (KBr) 338 4、297 8、 1745、1 340、1120 / 公分；MS(FAB) m/z 708 (MH1)、 710(MH3) ; C35H42BrN5〇6 · HC1 · 2· 5H20 之分析計算值：C,4-[Ν'-(2-Bromophenyl)ureido]- 3-methoxybenzoic acid (4〇6 mg, 1.07 mmol), 4-[(48)-phenyloxy-(28) Ethyl pyridyl]methyl-1,6-hydroquinone ethyl acetate (373 mg, 1·7 mM), EDC · K1 (308 mg, 1.61 mmol) and DMAP (197 mg) The mixture in DM (6 mL) was stirred at room temperature for 18 h. The mixture was poured into ice water and extracted with EtOAc. The combined extracts were washed with ice water and brine. After drying on NaJO4, the extract was concentrated in vacuo. The residue was crystallized from EtOAc (EtOAc:EtOAc:EtOAc: 1 -NMR (CDC13) 5 1·25 (tt, J = 7.1, 7·1 Hz, 3H), 2.04-2.84 (m, 13H), 3·12 and 3.18 (each s, 1H, guanamine isomer ), 3·57 (d, JM.4 Hz, 1H), 3.66 and 3.68 (each s, 3H, guanamine isomer), 3·6 8-3.8 7 (m, 3H), 4·05 -4.41 (m, 2H), 4·87-4·96 (m, 1Η), 6·76-6·98 (m, 6Η), 7·20-7·33 (m, 3Η), 7.46 (d, J=8.1 Hz, 1Η), 7.67 and 7.71 (each s, 1H, guanamine isomer), 7.78 and 7.81 (each s, 1H, guanamine isomer), 7.95 (d, J = 8.3 Hz, 1H), 8·09 (d, J = 8.1 Hz, 1H). Regarding the HCl salt: a light brown amorphous solid. Ir (KBr) 338 4,297 8,1745,1 340,1120 / cm; MS(FAB) m/z 708 (MH1), 710(MH3) ; C35H42BrN5〇6 · HC1 · 2· 5H20 Analytical calculations: C,

\\312\2d-code\90-01\89112968.ptd 第419頁 1283240 五、發明說明（415) 5 3 · 2 0 ; Η，6 · 1 2 ; N，8. 8 6。實測值：C，5 2 · 9 8 ; Η， 5. 79 ; Ν，8. 66 ° 於4 - [1-[4 -[Ν’-（2-溴苯基）脲基]-3-甲氧苯基乙醯基] -(4S) -本氧基- (28)-%13各π定基]甲基-1-六氯υ比υ井乙酸乙酉旨 (330毫克，0.466毫莫耳）溶於THF (3· 7毫升）之溶液中加入 0· 25N NaOH( 3· 7毫升）。於在室溫下攪拌2〇小時後，將混 合物以IN HC1中和，並以CHC13-MeOH(10/l )萃取。將結合 的萃取液於N a2 S 04上乾燥，並於真空中濃縮。經由加入乙 醚將殘留物研製而得11 5 (217毫克，68%)之白色粉末。IR (KBr) 3315、30 95、2 94 1、1631、1 529、1 435 / 公分；1 Η-NMR (DMSO-d6) 5 1· 75 (m，1H)、2· 18 及2· 23 (各s, 2H，醯胺異構物）、2· 30-2· 78 (m，9H).、3· 15 (2，2H)、 3·47 (m，1H)、3·58 (s，2H)、3·60-3·82 (m，3H)、 3·84 (m，3Η)、3·93 (m，1Η)、4·26 (br，1Η)、5·08 (m， 1Η) 、6·75 (d， J=7.8 Ηζ， 1Η) 、6·98 (m， 5Η)、 7·30 (m，3Η)、7·60 (dd，J = 8.1、2.2 Hz, 1Η)、7·94 (m，2Η)、8·75 (s，1Η)、8·93 (s，1H); MS(FAB) m/z 680 (ΜΗ1)、6 82 (ΜΗ3) ; C33H38BrN5 06 · 0. 2EtOH · 2Η20 之分 析計算值：C，5 5. 27 ; Η，6· 00 ; Ν， 9· 65。實測值：C， 55. 32 ； Η, 5.56； N, 9· 25 ο 實施例1 0 8 4-[(4S)-（4-羧笨氧基甲氧基-4-[N’ -（2 -甲基苯 基）脲基]笨基乙醯基]-(2S)_吼咯啶甲氧基]苯甲酸\\312\2d-code\90-01\89112968.ptd Page 419 1283240 V. Description of invention (415) 5 3 · 2 0 ; Η, 6 · 1 2 ; N, 8. 8 6. Found: C, 5 2 · 9 8 ; Η, 5. 79 ; Ν, 8. 66 ° at 4 - [1-[4 -[Ν'-(2-bromophenyl)ureido]-3-A Oxyphenyl phenyl fluorenyl] - (4S) - benzyloxy - (28) - % 13 π decyl group] methyl-1-hexachloropyrene is more soluble than υ 乙酸 acetic acid acetonitrile (330 mg, 0.466 mmol) To a solution of THF (3.7 ml) was added 0. 25 N NaOH (3.7 mL). After stirring at room temperature for 2 hours, the mixture was neutralized with IN HCl and extracted with CH.sub.3-MeOH (10/l). The combined extracts were dried over Na 2 S 04 and concentrated in vacuo. The residue was triturated with EtOAc (EtOAc EtOAc). IR (KBr) 3315, 30 95, 2 94 1, 1631, 1 529, 1 435 / cm; 1 Η-NMR (DMSO-d6) 5 1· 75 (m, 1H), 2·18 and 2· 23 ( Each s, 2H, guanamine isomer), 2·30-2·78 (m, 9H), 3·15 (2, 2H), 3·47 (m, 1H), 3·58 (s, 2H), 3·60-3·82 (m, 3H), 3·84 (m, 3Η), 3·93 (m, 1Η), 4·26 (br, 1Η), 5·08 (m, 1Η) ), 6.75 (d, J=7.8 Ηζ, 1Η), 6.98 (m, 5Η), 7·30 (m, 3Η), 7·60 (dd, J = 8.1, 2.2 Hz, 1Η), 7·94 (m, 2Η), 8·75 (s, 1Η), 8.93 (s, 1H); MS(FAB) m/z 680 (ΜΗ1), 6 82 (ΜΗ3); C33H38BrN5 06 · 0. Analytical calculated value of 2EtOH · 2Η20: C, 5 5. 27 ; Η, 6· 00 ; Ν, 9· 65. Found: C, 55.32; Η, 5.56; N, 9· 25 ο Example 1 0 8 4-[(4S)-(4-Carboxyoxymethoxy-4-[N'-(2) -methylphenyl)ureido]pyridylethyl]-(2S)-decalylmethoxy]benzoic acid

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116 卜（第三丁氧羰基）—（4R)-(第三丁基二曱基矽燒氧基） (2 S )-咄咯啶羧酸甲酯116 (tributoxycarbonyl)-(4R)-(t-butyldiindenyloxyloxy) (2S)-indenylpyridinecarboxylic acid methyl ester

於1-(第二丁氧羰基）-(4R) -羥基- (2S) - π比^各。定叛酸甲, (10.4克’0.04莫耳）及味唾（8.66克，0.13莫耳）溶於 DMFC40毫升）之攪拌溶液中加入TBS-C1(7· 03克，〇· 05莫 耳），並使反應混合物在6 0 C下授摔3小時。於冷卻至室、、w 後，將混合物以鹽水稀釋，並以Et20萃取。將萃取液以： 水洗務’於N a? S Ο*上乾燦’並療發。使殘留物經由於; 上利用正己烧- EtOAc(5:l，v/v)作為洗提液進行管柱層 析，純化而得1-(第三丁氧羰基）-(4R)-(第三丁基二甲基 矽烷氧基）-(2S) -咄咯啶羧酸曱酯（15. 0克，98%)之無色 油。1H-NMR (CDC13) 5 0· 06 (s， 6H)、0· 87 (s， 9H)、1· 41 及 1.46 (各s，9H)、1·99 -2.0 3 (m，1H)、2·16-2.18 (m，1Η)、3·3 卜 3.42 (m，1Η)、3·56 - 3·63 (m，1Η)、 3.73及3. 74 (各s，3H) ^ 4. 31-4.42 (m，2H) ； MS(ESI) m/z 36 0 (MH1)。 1 -（第三丁氧魏基）-(4R)-(第三丁基二甲基石夕烧氧基）-(2 S)-咄洛σ定羧酸In the 1-(second butoxycarbonyl)-(4R)-hydroxy-(2S)-π ratio. Add TBS-C1 (7·03 g, 〇· 05 Mo) to a stirred solution of Toxic Acid, (10.4 g '0.04 mol) and taste saliva (8.66 g, 0.13 mol) dissolved in DMFC 40 ml). The reaction mixture was allowed to fall for 3 hours at 60 °C. After cooling to the chamber, w, the mixture was diluted with brine and extracted with Et20. The extract is treated with: water washing 'on N a? S Ο*' and dried. The residue was subjected to column chromatography using n-hexane- EtOAc (5:1, v/v) as an eluent to give 1-(t-butoxycarbonyl)-(4R)- Tributyl dimethyl decyloxy)-(2S)-indenyl carboxylic acid oxime ester (15.0 g, 98%) as a colorless oil. 1H-NMR (CDC13) 5 0· 06 (s, 6H), 0·87 (s, 9H), 1.41 and 1.46 (each s, 9H), 1·99 -2.0 3 (m, 1H), 2 ·16-2.18 (m,1Η),3·3 Bu 3.42 (m,1Η),3·56 - 3·63 (m,1Η), 3.73 and 3.74 (each s,3H) ^ 4. 31- 4.42 (m, 2H); MS (ESI) m/z 36 (MH). 1-(t-butoxypropenyl)-(4R)-(t-butyldimethyl oxalate alkoxy)-(2 S)-indolyl sigmacarboxylic acid

\\312V2d-code\90-01\89112968.ptd 第421頁 1283240 五、發明說明（417) 於1-(第三丁氧戴基）-(4R)-(第三丁基二甲基石夕烧氧基） -(2S)-咄咯啶羧酸甲酯（15.0克，0.04莫耳）溶於THF (60 毫升）之攪拌溶液中加入IN NaOH(60毫升），並使反應混合 物在6 0 °C下攪拌2小時。於冷卻至室溫後，將混合物濃縮 至一小體積，以1 N H C 1酸化，並以E 10 A c萃取。將萃取液 以鹽水洗鲦’於N a2 S 04上乾燥，並蒸發而得1 -(第三丁氧幾 基）-(4R)-(第三丁基二甲基矽烷氧基）—（2S) -吼咯啶羧酸 (12· 8 克，89%)之無色油。iH-NMR (CDC13) δ 0· 07 及0· 08 (各s, 6Η)、〇·87 (s，9Η)、1·49 (s, 9Η)、2.06-2.11 (m， 1Η) 、 2.4卜2.44 (m， 1Η) 、 3· 4〇-3· 59 (m， 2Η) 、 4. 36-4.5 0 (m, 2H); ESI，m/z 3 46 (MH1)。 1一（弟二丁氧幾基）-（4R)-(第三丁基二甲基石夕；)：完氧基）— (2S)-脯胺醇 TBsa〜\\312V2d-code\90-01\89112968.ptd Page 421 1283240 V. INSTRUCTIONS (417) On 1-(Terti-butoxy-based)-(4R)-(Third butyl dimethyl Shi Xi To a stirred solution of methyl (2S)-pyrrolidinecarboxylate (15.0 g, 0.04 mol) in THF (60 mL) was added IN NaOH (60 mL). Stir at ° C for 2 hours. After cooling to room temperature, the mixture was concentrated to a small volume, acidified with 1 N H C 1 and extracted with E 10 A c. The extract was washed with brine to dryness on Na 2 S 04 and evaporated to give 1-(t-butoxy-yl)-(4R)-(t-butyldimethyl-decyloxy)-(2S ) - Equirogincarboxylic acid (12. 8 g, 89%) of a colorless oil. iH-NMR (CDC13) δ 0· 07 and 0· 08 (each s, 6Η), 〇·87 (s, 9Η), 1·49 (s, 9Η), 2.06-2.11 (m, 1Η), 2.4 2.44 (m, 1Η), 3·4〇-3· 59 (m, 2Η), 4. 36-4.5 0 (m, 2H); ESI, m/z 3 46 (MH1). 1 (di-dibutoxymethyl)-(4R)-(t-butyldimethyl sulphate;): oxy)-(2S)-prolinol TBsa~

Boc 於1-(第二丁氧羰基）-(4R)_(第三丁基二甲基石夕烧氧基） -(2S) -吼咯啶羧酸（12· 8克，〇· 〇4莫耳）溶於THF(150毫升） 之冷卻（〇 °c)攪拌溶液中逐滴加入BH3 · DMS(5· 30毫升，〇. 06莫耳），並使反應混合物在室溫下攪拌隔夜。利用飽和 ΝΗ/ 1使反應混合物停止反應，並以Et〇Ac進行萃取。將萃 取液以鹽水洗滌，於NaJO4上乾燥，並蒸發。使殘留物經 由於矽膠上利用曱苯-丙酮（5 :丨，v/ v)作為洗提液進行管Boc in 1-(second butoxycarbonyl)-(4R)_(t-butyldimethyl oxalate alkoxy)-(2S)-indolyl carboxylic acid (12·8 g, 〇·〇4 To a cooled (〇°c) stirred solution of THF (150 mL), BH3·DMS (5·30 ml, 〇.06 Mo) was added dropwise and the mixture was stirred overnight at room temperature. The reaction mixture was quenched with saturated ΝΗ / 1 and extracted with Et EtOAc. The extract was washed with brine, dried over Na.sub.4, and evaporated. The residue was passed through a tube of tantalum-acetone (5: 丨, v/v) as an eluent

1283240 發明說明（418) 柱層析，純化而得1-(第三丁氧羰基）-(4R)-(第三丁基二 甲基矽烷氧基）-（2S) -脯胺醇（10.5克，85 %)之無色油。1 H-NMR (CDC13) (5 0· 06 (s，6H)、0. 87 (s，9H)、1 · 47 (s，9H)、1·58-1·63 (m，1H)、1·93-1·98 (m，1H)、 3.32-3.44 (m， 2Η)、3·51-3·57 (m， 1H) 、3·67-3·71 (m，1H)、4·13-4.15 (m，1H)、4·27 (m，1H)、4·87 —4· 89 (m， 1H)。 4 - [1-(第三丁氧羰基）—（4R) —(第三丁基二甲基矽烷氧基） -（2S)-咄咯啶甲氧基]苯甲酸曱酯 TBSO^ C02Me 於4-羥基笨曱酸甲酯（4.81克，0·03莫耳）、1-（第三丁 氧羰基）-(4R)-(第三丁基二甲基矽烷氧基）-(2S) -脯胺醇 (10·5克’0.03莫耳）、及ph3P(9.96克，0·04莫耳）溶於 THF(160毫升）之冷的（〇它）攪拌溶液中逐滴加入DIaD (7. 48毫升，0· 04莫耳），並使反應混合物迴流加熱7小 時。於冷卻至室溫後，將混合物蒸發。將殘留物經由於石夕 膠上利用正己烧-E tOAc( 6 : 1，v/v)進行管柱層析，純化而 得4-[1-(第三丁氧羰基）-(4R)-(第三丁基二甲基矽烷氧 基）-C2S)_吼咯啶曱氧基]苯甲酸甲酯（9· 58克，65%)之白 色固體。熔點 86 -8 8 °C ; NMR (CDC13) 5 〇· 〇8 (s， 6H) 、0.88 (s，9H)、1·46 (s，9H)、2·04-2·15 (m，2H)、 3.29-3.48 (m，2H)、3·88 (s, 3H)、4·06-4·30 (m，3H)1283240 Description of the invention (418) Column chromatography, purification to give 1-(t-butoxycarbonyl)-(4R)-(t-butyldimethylsilyloxy)-(2S)-decaline alcohol (10.5 g , 85%) of colorless oil. 1 H-NMR (CDC13) (5 0· 06 (s, 6H), 0. 87 (s, 9H), 1 · 47 (s, 9H), 1.58-1·63 (m, 1H), 1 ·93-1·98 (m, 1H), 3.32-3.44 (m, 2Η), 3·51-3·57 (m, 1H), 3·67-3·71 (m, 1H), 4·13 -4.15 (m,1H), 4·27 (m,1H), 4·87 —4· 89 (m, 1H). 4 - [1-(Tertidinyloxycarbonyl)-(4R)—(third Butyl dimethyl decyloxy) - (2S)-decalyl methoxy] benzoic acid oxime ester TBSO ^ C02Me in 4-hydroxy acyl methyl ester (4.81 g, 0·03 mol), 1- (Third butoxycarbonyl)-(4R)-(t-butyldimethylmethylalkoxy)-(2S)-prolinol (10·5 g '0.03 mol), and ph3P (9.96 g, 0 · 04 mol) DIAD (7. 48 ml, 0. 04 mol) was added dropwise to a cold (〇) stirring solution of THF (160 mL), and the reaction mixture was heated under reflux for 7 hours. After the reaction to room temperature, the mixture was evaporated. The residue was purified by column chromatography using hexane-EtOAc (6:1, v/v) to obtain 4-[1-(third Butoxycarbonyl)-(4R)-(t-butyldimethylmethylalkoxy)-C2S)-indolyloxyl]benzene Acid methyl ester (9. 58 g, 65%) of a white solid. Melting point 86 -8 8 °C; NMR (CDC13) 5 〇· 〇8 (s, 6H), 0.88 (s, 9H), 1.46 (s, 9H), 2·04-2·15 (m, 2H ), 3.29-3.48 (m, 2H), 3·88 (s, 3H), 4·06-4·30 (m, 3H)

\\312\2d-code\90-01\89112968.ptd 第423頁 1283240 五、發明說明（419) 、4·46 - 4.51 (m，1H)、6·9 卜 6.93 (m，2H)、7.96-7.98 (m，2H) ; ESI，m/z 46 6 (M+ + 1)。 4-[1-(第三丁氧魏基）—（4R)_經基-（2S)~n比嘻。定甲氧基]苯 曱酸甲酯\\312\2d-code\90-01\89112968.ptd Page 423 1283240 V. Description of invention (419), 4.46 - 4.51 (m, 1H), 6·9 Bu 6.93 (m, 2H), 7.96 -7.98 (m, 2H); ESI, m/z 46 6 (M+ + 1). 4-[1-(Third-butoxy-Weiyl)-(4R)_trans-base-(2S)~n is 嘻. Methyl methoxy] benzoate

C02Me 於4-[l-(第二丁氧羰基）-(4R)-(第三丁基二甲基石夕炫氧 基）-（2S) -吡咯啶甲氧基]苯甲酸甲酯（ι·49克，3 2〇毫莫 耳）溶於THF(15毫升）之冷卻（〇。〇攪拌溶液中加入tbaf (6.40毫升，6.40毫莫耳，1M之THF溶液），並使反應混合 物在室溫下攪拌2小時。將混合物以Et〇Ac稀釋，^ 鹽水洗滌，於NaJO4上乾燥，並菽發。使殘留 2 #上利用甲策&amp; 1 / 、、 夕戈@物經由於矽 胗上利用甲本-丙酮（5: 1，ν/ν)作為洗提液進 吼 熔點 析，純化而得4-[1-(第三丁氧羰基）_(4R)—羥^官柱層 洛°定甲氧基]笨甲酸甲酯（1·〇5克，93%)之白a Μ) 103-io^cmh-nmr (CDc^r^e ；3 (m，2H) ' 3.49-3.60 (m’ 2H)、3.88 (s，3H) 4U_2. 28 -4.34 (m， 3H) 、4.53-4.57 (m， 1H) 、6.91 、4·15C02Me is 4-[l-(2,4-butoxycarbonyl)-(4R)-(t-butyldimethyl oxaxoethoxy)-(2S)-pyrrolidinemethoxy]benzoic acid methyl ester ( · 49 g, 3 2 mmol of mil.) Cooled in THF (15 mL). EtOAc was added to tbaf (6.40 mL, 6.40 mmol, 1M in THF) and the reaction mixture was Stir at room temperature for 2 hours. Dilute the mixture with Et〇Ac, wash with brine, dry on NaJO4, and swell. Make the residue 2 #上用甲策&amp; 1 / , 夕戈@物上上上上Using abenz-acetone (5: 1, ν / ν) as an eluent into the oxime melting point, purified to give 4-[1-(t-butoxycarbonyl)_(4R)-hydroxyl column Methyl methoxy] benzoic acid methyl ester (1·〇5 g, 93%) white a Μ) 103-io^cmh-nmr (CDc^r^e ;3 (m,2H) ' 3.49-3.60 (m ' 2H), 3.88 (s, 3H) 4U_2. 28 -4.34 (m, 3H), 4.53-4.57 (m, 1H), 6.91, 4.15

Hz，2H)、7.97 (d，J = 8.6 Hz, 2H) ; ESI，m/’ J〇 = U + 1) 〇 m/2 3 52 (M+ 羰基笨氧基）—（2S) 4 - [1-(苐二丁氧魏基）-(4S)-(4〜甲氧 咄咯啶甲氧基]苯甲酸甲酯Hz, 2H), 7.97 (d, J = 8.6 Hz, 2H); ESI,m/' J〇= U + 1) 〇m/2 3 52 (M+ carbonyl phenyloxy)—(2S) 4 - [1 -(苐二丁氧魏基)-(4S)-(4~methoxyxoridine methoxy)benzoic acid methyl ester

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五、發明說明（420) 於4-羥基苯甲酸甲酯（〇·56克，3·68毫莫耳）、4一[;1 —(第 三丁氧羰基）-(4R)-羥基—（2S)一咄咯啶甲氧基]笨曱酸甲酯 (1.3克，3.70毫莫耳）、及Ph3p(1· 16克，4·42毫莫耳）溶曰 於THF(20宅升）之冷的（〇。〇攪拌溶液中逐滴加入DI (0· 87毫升，4· 42毫莫耳），並使反應混合物在室溫下 合1物洛發，及將殘留物經由於石夕膠上利用正 得4_[卜（第三丁氧v)作為洗提液進行管柱層析，純化而 -吼洛。定甲氧基]苯甲=(4〜（4_甲氧幾基苯氧基）—（⑻ H-NMR (CDa3)(5 i 4^1醋（1.80 克，Q.y.)之無色油。1 U5-2.49 (m，⑴ 9/;; 9H)、2.3&quot;.38 (m，⑻、 nw ⑴ fi 0C U)、4.33-4. 44 (m，2H)、4. 95-5. 01 (m， 1Η)、6·85 Γη t 、 , J = 8. 8 Hz, 2H) &gt; 6. 94 (br s, 2H) 、 7·97 (d， J=8 R u 、 5 / “ 田— 8 Hz， 4H) ; ESI ， m/z 48 6 (MH1) 〇 4-[(4S)_(4-甲M基笨氧 s)l定 酸甲酯 丁 6H)、4.07-4.15 ( “Η.77 (m，2H)、3.88 “，V. Description of the invention (420) Methyl 4-hydroxybenzoate (〇·56 g, 3.68 mmol), 4-[;1—(Tertidinoxycarbonyl)-(4R)-hydroxy-( 2S) monopyridyl methoxy] methyl benzoate (1.3 g, 3.70 mmol), and Ph3p (1·16 g, 4.42 mmol) dissolved in THF (20 liters) Cold (〇. 〇 stirring solution was added DI (0·87 ml, 4.42 mmol) dropwise, and the reaction mixture was combined at room temperature, and the residue was passed through Shishijiao The column was subjected to column chromatography using the obtained 4_[Bu (3rd butoxide v) as an eluent, and purified - 吼 。. methoxy] benzene = (4~(4_methoxy phenoxy) Base)—((8) H-NMR (CDa3) (5 i 4^1 vinegar (1.80 g, Qy) as a colorless oil. 1 U5-2.49 (m,(1) 9/;; 9H), 2.3&quot;.38 (m , (8), nw (1) fi 0C U), 4.33-4. 44 (m, 2H), 4. 95-5. 01 (m, 1Η), 6.85 Γη t , , J = 8. 8 Hz, 2H) &gt; 6. 94 (br s, 2H) , 7·97 (d, J=8 R u , 5 / “field — 8 Hz, 4H) ; ESI , m/z 48 6 (MH1) 〇4-[( 4S) _ (4-methyl M-based oxy) s-acid methyl ester butyl 6H), 4.07-4.15 ("Η.77 (m, 2 H), 3.88 ",

於4_[1-(第三丁氧如* /nn、 m K故基）-（4S) -（4 -甲氧羰基苯氧基） -（2 S)-吼洛咬曱氧其1 w 乳暴]4甲酸甲酯（1· 80克，3· 71毫莫耳）In 4_[1-(Third butoxide such as * /nn, m K)-(4S)-(4-methoxycarbonylphenoxy)-(2S)-吼洛 bite 曱 oxygen 1 w milk Storm] Methyl 4-carboxylate (1·80 g, 3.71 mmol)

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第425頁 1283240Page 425 1283240

/谷於CHzCl/lSt升）之攪拌溶液中加入TFA(15毫升），並使 ^應混合物於室溫下攪拌丨· 5小時。將混合物於真空中濃 細，並利用飽和NaHC〇3使成為鹼性，及以CH(：i3萃取。將萃 取液以鹽水洗滌，於K2C〇3上乾燥，並蒸發而得4- [ (4S) 一（4-甲氧羰基苯氧基）—（2s) -吼咯啶甲氧基]苯甲酸甲酯 (1· 50 克，q· y·)之淡黃色油。1H —NMR (CDCl3) 5 l 87一 1·92 (m，1H)、2·4卜2.48 (m，1Η)、3·18-3·23 (m， 1H) 、3·34-3.37 (m, 1H) 、3·60-3·66 (m， 1H) 、3·88 (s， 3H) 、3·89 (s， 3H) 、4·〇4-4.13 (m， 2H) 、4·94-5·00 (m，1H)、6·87-6·93 (m，4H)、7·96-8·00 (m， 4Η) ; ESI，m/z 3 86 (MU 1)。 4-[1- [3-甲氧基-4-[Ν’ -(2-曱基苯基）脲基]苯基乙醯 基]-（4S)-（4 -甲氧羰基苯氧基）—（2S) -吼咯啶甲氧基]苯甲 酸甲S旨TFA (15 ml) was added to a stirred solution of EtOAc / EtOAc (EtOAc). The mixture was concentrated in vacuo and made basic with saturated NaHC 〇3, and extracted with CH (:i3. The extract was washed with brine, dried over K2C 〇3, and evaporated to give 4-[ (4S a light yellow oil of methyl (4-methoxycarbonylphenoxy)-(2s)-indolyl methoxy]benzoate (1·50 g, q·y·). 1H-NMR (CDCl3) 5 l 87 -1·92 (m, 1H), 2·4, 2.48 (m, 1Η), 3·18-3·23 (m, 1H), 3·34-3.37 (m, 1H), 3· 60-3·66 (m, 1H), 3·88 (s, 3H), 3·89 (s, 3H), 4·〇4-4.13 (m, 2H), 4·94-5·00 (m , 1H), 6·87-6·93 (m, 4H), 7·96-8·00 (m, 4Η); ESI, m/z 3 86 (MU 1). 4-[1- [3- Methoxy-4-[Ν'-(2-mercaptophenyl)ureido]phenylethenyl]-(4S)-(4-methoxycarbonylphenoxy)-(2S)-indenylpyridine Methoxy]benzoic acid

使3-甲氧基-4 - [Ν’ -（2 -甲基苯基）脲基]苯乙酸（4〇〇毫3-methoxy-4 -[Ν' -(2-methylphenyl)ureido]phenylacetic acid (4 〇〇

克，1.27毫莫耳）、4-[(4S) -（4-甲氧羰基苯氧基）一（2S) — 吼洛啶甲氧基]笨甲酸甲酯（491毫克，1.27毫莫耳）、EDC •HC 1(293 毫克，1.53 毫莫耳）、HOB t(207 毫克，ι·53 毫莫 耳）、及Et3N(215微升，1.54毫莫耳）於THF(l〇毫升）中之 混合物在室溫下攪拌隔夜。將混合物以&amp; 〇稀釋，並以g, 1.27 mmol, 4-[(4S)-(4-methoxycarbonylphenoxy)-(2S)-indolyl methoxy] methyl methane (491 mg, 1.27 mmol) , EDC • HC 1 (293 mg, 1.53 mmol), HOB t (207 mg, ι·53 mmol), and Et3N (215 μL, 1.54 mmol) in THF (1 mL) The mixture was stirred overnight at room temperature. Dilute the mixture with &amp; , and

EtOAc萃取。將萃取液以鹽水洗滌，於Na2S〇4上乾 -1s%\\Extracted with EtOAc. Wash the extract with brine and dry on Na2S〇4 -1s%\\

\\312\2d-code\90-01\89112968.ptd 第426頁 1283240 五、發明說明（422) ' &quot; — -- 發。將殘留物經由於矽膠上利用CHC13—Me〇H(6〇 : 1至5〇 :工 v/v)作為洗提液進行管柱層析，純化而得4—[丨―[3—甲氧基 - (2_曱基笨基）脲基]苯基乙醯基]一（4S) 一（4一甲氧羰 基苯氧基）-(2S) -吼咯啶甲氧基]苯甲酸甲酯（532毫克，Λ 61%)的白色泡沫。ιΗ 一 NMR (CDCl3)(5 226一2 49 (^及^ 系 列，總計 5H)、3.5 6-3.9 3 (s 及 m 系列，總計 13H)、4·〇7 - 4·59 (m 系列，總計 3H)、5〇1 (m， a)、6 69 一6 94 (m， 7H)、7. 09-7.13 (m，1Η)、7·20-7·31 (m，3H)、7·52-7· 57 (m， 1Η) 、 7.92-8.00 (m, 4Η) 、8·06-8·09 (m， 1H); ESI，m/z 6 82 (MH1)。 於4-[l-[ 3 -曱氧基-4-[N，-（2-甲基苯基）脲基]笨基乙醯 基]-（4S)-(4-甲氧羰基苯氧基）_(2S) -吼咯啶甲氧基]苯甲 酸甲酯（ 532毫克，0· 78毫莫耳）溶於THF( 5毫升）之攪拌溶 液中加入0· 5N NaOH(5毫升），並使反應混合物迴流加熱5 小時。於冷卻至室溫後，將混合物倒入至冰的1 N H C 1中， 並收集所產生之沈澱物。使粗製固體自MeOH-CHC13-Et20再 結晶，而得1 1 6 (1 2 5毫克，2 5 %)之淡黃色結晶粉末。溶點 1 54- 1 5 9 °C ； JH-NMR (DMS0~d6) 5 2.2 4 (s, 3Η) &gt;2.38 -2.49 (m，2H)、3·63 (s， 2H)、3.67-3.88 (s 及m 系列， 總計 4H)、4·(Π-4.06 及 4·15-4·19 (各m，總計 2H)、 4.27-4.31 及 4·38-4·42 (各m，總計 2H)、5·18-5.25 (m， 1H)、6·72-6·77 (m，1H)、6·85 - 7.16 (m 系列，總計 8H)、7·78 - 7.89 (m，5H)、7·99 - 8.02 (m，1H)、8·46 (s， 1H) 、8·57 (s， 1H) 、12.65(br s， 2H); ESI ， m/z\\312\2d-code\90-01\89112968.ptd Page 426 1283240 V. Description of invention (422) ' &quot; — -- Send. The residue was subjected to column chromatography using CHC13-Me〇H (6〇: 1 to 5〇: work v/v) as an eluent, and purified to obtain 4-[丨-[3-methoxy Methyl-(2-mercapto-yl)ureido]phenylethenyl]-(4S)-(4-methoxycarbonylphenoxy)-(2S)-indolyl methoxy]benzoic acid methyl ester (532 mg, Λ 61%) of white foam. ιΗ NMR (CDCl3) (5 226 to 2 49 (^ and ^ series, total 5H), 3.5 6-3.9 3 (s and m series, total 13H), 4·〇7 - 4·59 (m series, total 3H), 5〇1 (m, a), 6 69 - 6 94 (m, 7H), 7. 09-7.13 (m, 1Η), 7·20-7·31 (m, 3H), 7.52 -7· 57 (m, 1Η), 7.92-8.00 (m, 4Η), 8·06-8·09 (m, 1H); ESI, m/z 6 82 (MH1). 4-[l-[ 3-methoxy-4-(N,-(2-methylphenyl)ureido]phenylamino]-(4S)-(4-methoxycarbonylphenoxy)-(2S)-吼To a stirred solution of methyl bromo methoxy]benzoate (532 mg, 0·78 mmol) in THF (5 mL) was added EtOAc (5 mL). After cooling to room temperature, the mixture was poured into 1 NHC 1 of ice, and the resulting precipitate was collected. The crude solid was recrystallized from MeOH-CHC13-Et20 to give 1 16 (1 25 mg) , 2 5 %) of pale yellow crystalline powder. Melting point 1 54- 1 5 9 ° C; JH-NMR (DMS0~d6) 5 2.2 4 (s, 3Η) &gt;2.38 -2.49 (m, 2H), 3 ·63 (s, 2H), 3.67-3.88 (s and m series, total 4H), 4·(Π-4.06 4·15-4·19 (each m, total 2H), 4.27-4.31 and 4.38-4.42 (each m, total 2H), 5.18-5.25 (m, 1H), 6.72-6 · 77 (m, 1H), 6.85 - 7.16 (m series, total 8H), 7.78 - 7.89 (m, 5H), 7·99 - 8.02 (m, 1H), 8·46 (s, 1H ), 8·57 (s, 1H), 12.65 (br s, 2H); ESI , m/z

\\312\2d-code\90-01\89112968.ptd 第427頁 1283240 五、發明說明（423) 6 5 4 (M+ +1) ; C36 Η35 Ν3 09 · 1 / 2 H2 〇 之分析計算值：◦， 6 5 . 2 5 ; Η，5·48;Ν，6.34。實測值：c, 65.29; H，5.54; N， 6.20。 ’ 實施例1 0 9 4 - [(4S)-(4-羧苯氧基）-l-[4-[N，-(2 -氣苯基）脲基]-3-曱 氧苯基乙醯基]-（2S) -吼咯啶甲氧基]笨甲酸\\312\2d-code\90-01\89112968.ptd Page 427 1283240 V. Description of invention (423) 6 5 4 (M+ +1) ; C36 Η35 Ν3 09 · 1 / 2 H2 分析 Analysis calculated value: ◦, 6 5 . 2 5 ; Η, 5·48; Ν, 6.34. Found: c, 65.29; H, 5.54; N, 6.20. 'Example 1 0 9 4 - [(4S)-(4-carboxyphenoxy)-l-[4-[N,-(2-phenylphenyl)ureido]-3-indoleoxyphenylacetamidine] Base]-(2S)-pyridinylmethoxy]benzoic acid

4—[1-[4；[N’ 一（2-氯苯基）脲基]-3-甲氧苯基乙醯基]-（4S) -（4-曱氧羰基苯氧基）—（2S) -吡咯啶甲氧基]苯曱酸曱酯4-[1-[4;[N'-(2-chlorophenyl)ureido]-3-methoxyphenylethenyl]-(4S)-(4-oxacarbonylphenoxy)-( 2S)-pyrrolidinomethoxy]benzoate

使4j[^i -(2 -氯苯基）脲基]—3—甲氧苯乙酸（42〇毫克， 1丄25,莫耳）、4-[(4S)-(4-曱氧羰基苯氧基（2S) -吡咯 啶甲，基]苯甲酸甲酯（483毫克，L 25毫莫耳）、edc · ΗΠ ( 288耄克，ι· 50毫莫耳）、η〇μ(2〇3毫克，毫莫耳）、 =t3N(210微升，！· 51毫莫耳）於THF(1〇毫升）中之混人物 取,C夜。將混合物以M稀釋，並以Et〇心 將卒取液以鹽水洗滌，於Na2S04上乾燥，並基路 殘留物經由於矽膠上利C Me f:將 提=行管柱層析，純化而得34_[卜 脲d甲乳笨基乙酿基]-(4S)_(4-甲氧幾基^氧本爲基)）4j[^i-(2-chlorophenyl)ureido]-3-methoxyphenylacetic acid (42〇mg, 1丄25, mole), 4-[(4S)-(4-曱-oxycarbonylbenzene Oxy (2S)-pyrrolidinylmethyl, benzoic acid methyl ester (483 mg, L 25 mmol), edc · ΗΠ (288 耄, ι· 50 mmol), η〇μ (2〇3) Mg, millimolar), =t3N (210 μl, !· 51 mmol) in a blend of THF (1 mL), C night. Dilute the mixture in M and smear with Et The liquid was washed with brine, dried on Na2SO4, and the residue of the base was passed through a gelatin gel to extract C Me f: the column was subjected to column chromatography and purified to obtain 34_[i urea d-milk base] -(4S)_(4-methoxyloxy^oxygen as a base))

1283240 五、發明說明（424) (2S) -吡咯啶甲氧基]苯甲酸甲酯（488毫克，55°/〇)的白色泡 沫。1H-NMR (CDC13) (5 2.28-2.51 (m，2H)、3.62-3.94 (s及m系列，總計1 3H)、4· 0 7-4· 62 (m系列，總計3H)、4· 9 9-5.0 3 (m, 1H) &gt; 6.78 -6.99 (m, 7H) ^ 7.23- 7.3 4 (m, 2H) 、7.42-7.52 (m， 2H) 、7·92_8·01 (m, 5H) 、8.17-8· 20 (m，1H) ; ESI，m/z 70 2 (MH1 )。 於4-[1-[4-[Ν’-（2-氯苯基）脲基]-3-曱氧苯基乙醯基] -（4S)-(4-甲氧羰基苯氧基）-(2S)-吼咯啶甲氧基]苯甲酸 甲酯（488毫克，0.70毫莫耳）溶於THF(5毫升）之攪拌溶液 中加入0· 5N NaOH(5毫升），並使反應混合物迴流加熱3小 時。於冷卻至室溫後，將混合物倒入至冰的1 N HC 1中，並 收集所產生之沈澱物。使粗製固體自MeOH-CHC13-Et20再結 晶’而得117(137毫克，29%)之白色結晶粉末。炼點150 -153 °C ； 'H-NMR (DMS0-d6) 5 2.21-2.27 (m, 1H) &gt;2.40- 2. 48 (m， 1H)、3· 66 (s， 2H)、3· 7 0-3. 91 (s 及m 系列， 總計 4H)、4. 03-4· 09 及 4. 17-4. 21 (各m,總計 2H)、4·30 -4.34及4.40 -4.45 (各111，總計2}〇、5.2 0 -5.27 (111，11〇 、6·77-6·81 (m， 1Η) 、6·89-6.92 (m， 1Η) 、7·01-7·08 (m，5Η)、7·27-7·31 (m，1Η)、7.4 3-7.46 (m，1Η)、 7·86-7.92 (m，4H)、7·97-8·00 (m，1H)、8·10-8.12 (m， 1H) 、8·91 (s， 1H) 、8·96 (s， 1H) 、12·65 (br s， 2H) ; ESI， m/z 6 74(MH1 ) ; C35H32C1 N3 09 · 1/4H20 之分析 計算值：C， 61· 95 ; H，4· 83 ; N，6· 19 ; Cl，5. 22。實測 值：C， 61.77； Η, 4. 86 ； N, 6.13； Cl, 5.49。1283240 V. INSTRUCTIONS (424) (2S)-Pyrrolidine methoxy]benzoic acid methyl ester (488 mg, 55 ° / 〇) white foam. 1H-NMR (CDC13) (5 2.28-2.51 (m, 2H), 3.62-3.94 (s and m series, total 1 3H), 4·0 7-4· 62 (m series, total 3H), 4·9 9-5.0 3 (m, 1H) &gt; 6.78 -6.99 (m, 7H) ^ 7.23- 7.3 4 (m, 2H), 7.42-7.52 (m, 2H), 7.92_8·01 (m, 5H), 8.17-8· 20 (m,1H) ; ESI, m/z 70 2 (MH1 ). 4-[1-[4-[Ν'-(2-chlorophenyl)ureido]-3-oxo Phenylethyl hydrazide]-(4S)-(4-methoxycarbonylphenoxy)-(2S)-decalyl methoxy]benzoic acid methyl ester (488 mg, 0.70 mmol) dissolved in THF ( 0 ml) of NaOH (5 ml) was added to the stirred solution, and the reaction mixture was heated under reflux for 3 hours. After cooling to room temperature, the mixture was poured into ice 1 N HCl 1 and collected. Precipitate. The crude solid was recrystallized from MeOH-CHC13-Et.sub.2 to give 117 (137 mg, 29%) of white crystalline powder. </ RTI> </ RTI> 150-153 ° C; 'H-NMR (DMS0-d6) 5 2.21 -2.27 (m, 1H) &gt;2.40- 2. 48 (m, 1H), 3· 66 (s, 2H), 3· 7 0-3. 91 (s and m series, total 4H), 4. 03 -4· 09 and 4. 17-4. 21 (each m, total 2H), 4·30 -4.34 and 4.40 -4.45 (each 111, Total 2}〇, 5.2 0 -5.27 (111,11〇,6·77-6·81 (m, 1Η), 6.89-6.92 (m, 1Η), 7·01-7·08 (m,5Η) ), 7·27-7·31 (m, 1Η), 7.4 3-7.46 (m, 1Η), 7·86-7.92 (m, 4H), 7·97-8·00 (m, 1H), 8 ·10-8.12 (m, 1H), 8.91 (s, 1H), 8.96 (s, 1H), 12·65 (br s, 2H); ESI, m/z 6 74(MH1 ) ; C35H32C1 Analysis calculated for N3 09 · 1/4H20: C, 61· 95 ; H, 4· 83 ; N, 6 · 19 ; Cl, 5. 22. Found: C, 61.77; Η, 4. 86 ; 6.13; Cl, 5.49.

\\312\2d-code\90-01\89112968.ptd 第429頁 1283240 五、發明說明（425) 實施例1 1 0 4-[ 1-[ 4-[N’ -（2-溴苯基）脲基， ο。、 丞」3—甲氧苯基乙醯基]_(4S) 羧本巩基）-（2S)-咄咯啶甲氧基]笨曱酸\\312\2d-code\90-01\89112968.ptd Page 429 1283240 V. INSTRUCTIONS (425) EXAMPLE 1 1 0 4-[ 1-[ 4-[N' -(2-Bromophenyl) Urea group, ο. , 丞"3-methoxyphenylethylidene]_(4S) carboxybenzol)-(2S)-咄-rhodium methoxy]cracked acid

Br Λ^' 0 Me CO.Me ，'^3~C〇2Me 基&gt; 脲基]I甲氧笨乙酸（464毫克，1· ，、μ、4 (4S)_(4—甲氧羰基笨氧基）-（2S)_咄咯啶 甲氧基]苯甲酸甲酯（472毫克，；[· 22毫莫耳）、EDC · K1 ( 282毫克，1·47毫莫耳）、HOBt(2〇〇毫克，148毫莫耳）、 及Et：3N( 20 5微升，1· 47毫莫耳）於THF(l〇毫升）中之混合物 在室溫下攪拌隔夜。將混合物以Η2 〇稀釋，並以E t 〇 a c萃 取。將萃取液以鹽水洗滌，於NajO〗上乾燥，並蒸發。將 殘留物經由於矽膠上利用CHC13-MeOH(60:l至50: 1， v/v) 作為洗提液進行管柱層析，純化而得4-[ 1-[4-[N，-（2〜填 苯基）脲基]- 3-甲氧苯基乙醯基]-（4S)-(4-甲氧羰基笨氧 基）-（2S)-咄咯啶甲氧基]苯甲酸甲酯（ 379毫克，41%)的白 色泡沫。1H-NMR (CDC13) 3 2. 28-2· 51 (m， 2H)、3· 59〜3 95 (s及in系列，總計13H)、4. 0 7-4· 6 2 (m系列，總計 ·Br Λ^' 0 Me CO.Me , '^3~C〇2Me base> Urea-based]I methoxy acetoacetic acid (464 mg, 1·, μ, 4 (4S)_(4-methoxycarbonyl stupid) Methyl oxy)-(2S)-decalyl methoxy]benzoate (472 mg,; 22 mil), EDC · K1 (282 mg, 1.47 mmol), HOBt (2) A mixture of 〇〇mg, 148 mmol, and Et: 3N (20 5 μl, 147 mmol) in THF (1 mL) was stirred overnight at room temperature. And extracted with E t 〇 ac. The extract was washed with brine, dried over NajO, and evaporated. The residue was applied to silica gel using CHC13-MeOH (60:1 to 50:1, v/v) The eluent is subjected to column chromatography and purified to give 4-[1-[4-[N,-(2~phenyl)ureido]-3-methoxyphenylethenyl]-(4S)- Methyl (4-methoxycarbonyloxy)-(2S)-indolyl methoxy]benzoate (379 mg, 41%) as a white foam. 1H-NMR (CDC13) 3 2. 28-2. 51 (m, 2H), 3·59~3 95 (s and in series, total 13H), 4. 0 7-4· 6 2 (m series, total ·

1283240 五、發明說明（426) 3H)、4·99 - 5·03 (m，1H) ^ 6. 79 -6. 95 (m, 7H) &gt;7.27-7 3 6 (m，3 Η)、7 · 4 9 - 7 · 51 (m，1 Η)、7 · 9 3 - 8 · 0 1 (m，5 Η )、 8·1 卜8·14 (m，1H); ESI，m/z 74 7 (ΜΗ1)。 於4-[l-[4-[N’-（2-漠苯基）脲基]-3-甲氧苯基乙酷 基]-（4S)-(4-甲氧羰基苯氧基）-（2S) -吼洛咬甲氧基]笨甲 酸甲酯（379毫克，0.51毫莫耳）溶於THF(5毫升）之攪拌溶 液中加入0· 5N Na0H(5毫升），並使反應混合物迴流加熱5 小時。於冷卻至室溫後，將混合物倒入至冰的丨N H C 1中， 並收集所產生之沈澱物。使粗製固體經由製備丁!^純化， 而得11 8(51毫克，14°/。）之淡黃色非晶形固體。ih — nmr (DMS0-d6) 5 2· 20 -2. 40 (m， 2H) 、3· 6 5-3. 8 9 (m 系列， 總計6H)、4· 0 2- 4. 63 (m 系列，總計4H)、5· 19-5· 26 (m， 1H) 、6·74-7·06 (m， 7H) 、7·30-7.34 (m， 1H) 、7·59-7 61 (m， 1H) 、7·83-7·96 (m， 6H) 、8·74 (s， 1H) 、8·93 (s，1 H )，C35 H32 B r N3 09 · 2 H2 0 之分析計算值：c，5 5 . 7 i ; h 4.81; N，5.57。實測值：c，55.92; H，4.80; N， ’ 5.30。 ’ 實施例1111283240 V. INSTRUCTIONS (426) 3H), 4·99 - 5·03 (m, 1H) ^ 6. 79 -6. 95 (m, 7H) &gt;7.27-7 3 6 (m, 3 Η), 7 · 4 9 - 7 · 51 (m,1 Η), 7 · 9 3 - 8 · 0 1 (m,5 Η ), 8·1 卜8·14 (m,1H); ESI,m/z 74 7 (ΜΗ1). 4-[l-[4-[N'-(2-Molyphenyl)ureido]-3-methoxyphenylethyl]-(4S)-(4-methoxycarbonylphenoxy)- (2S) - 吼 methoxy methoxy] methyl benzoate (379 mg, 0.51 mmol) dissolved in THF (5 mL), EtOAc (5 mL) Heat for 5 hours. After cooling to room temperature, the mixture was poured into ice 丨N H C 1 and the resulting precipitate was collected. The crude solid was purified by preparative EtOAc (EtOAc:EtOAc) Ih — nmr (DMS0-d6) 5 2· 20 -2. 40 (m, 2H), 3· 6 5-3. 8 9 (m series, total 6H), 4· 0 2- 4. 63 (m series , total 4H), 5· 19-5· 26 (m, 1H), 6·74-7·06 (m, 7H), 7·30-7.34 (m, 1H), 7·59-7 61 (m , 1H), 7·83-7·96 (m, 6H), 8.74 (s, 1H), 8.93 (s, 1 H ), C35 H32 B r N3 09 · 2 H2 0 analytical calculation :c,5 5 . 7 i ; h 4.81; N, 5.57. Found: c, 55.92; H, 4.80; N, </ 5.30. </ br />

4 - [(4S)-(4-羧苯氧基）- l —[4-[N，一（2—曱基笨基）脲基]笨 基乙醯基]_( 2 S)-咄嘻啶曱氧基]苯甲酸 4 - [(4S)-(4-甲氧羰基苯氧基）一卜^ 一 [N，_(2—甲基笨基)119 脲基]苯基乙醯基]-（2 S)-吼咯啶甲氧基]苯甲酸甲酯4-[(4S)-(4-Carboxyphenoxy)-l-[4-[N,-(2-indolyl)ureido]]-(yl)indolyl]-( 2 S)-咄嘻4-pyridyloxy]benzoic acid 4-[(4S)-(4-methoxycarbonylphenoxy)-bromo-[N,-(2-methylphenyl)119-ureido]phenylethenyl] -(2 S)-fluorenidine methoxy]methyl benzoate

12832401283240

*使“[Ν’ -（2-甲基苯基）脲基]苯乙酸（328毫克，1.15毫 莫耳）、4-[ (4S) -（4-甲氧羰基苯氧基）—（2S) -吼咯啶曱氧 基]笨曱酸甲酯（444毫克，1·15毫莫耳）、EDC · HC1 (265 毫克’1.38毫莫耳）、H0Bt(187毫克，1.38毫莫耳）、及 Et；3N(195微升，1. 40毫莫耳）於THF(l〇毫升）中之混合物在 室溫下攪拌隔夜。將混合物以H20稀釋，並以EtOAc萃取。 將萃取液以鹽水洗務’於N az S Ο#上乾燥，並蒸發。將殘留 物經由於碎膠上利用CHC13-MeOH(60:l至50:1，v/v)作為 洗提液進行管柱層析，純化而得4 - [(4 S) - ( 4 -甲氧羰基笨 氧基）-1-[4-[Ν’ -（2-甲基苯基）脲基]笨基乙醯基]一（2s)〜 吼咯啶曱氧基]苯曱酸甲酯（ 332毫克，44%)的白色泡沐。 ^-NMR (CDC13)5 2.13 (s, 3H) ^2.24-2.48 (m, 2H) 3· 52-3· 90 (s 及m 系列，總計10H)、4· 05-4· 58 (m 系列， 總計3Η)、5· 01 (m， 1Η)、6· 78- 6. 9 0 (m，4Η)、6· 98 ’ - 7 · 2 0 (m，8 Η)、7 . 5 1 - 7 · 5 6 (m，2 Η )、7 · 9 0 - 8 · 0 0 (m， 4H); ESI，m/z 652(MH1)。 於4-[(4S)-(4-甲氧羰基苯氧基）-l-[4- [ν’ - (2-甲基笨 基）脲基]苯基乙醯基]-(2S) -吼咯啶甲氧基]苯甲酸甲酉旨 (332毫克，0.51毫莫耳）溶於THF (5毫升）之攪拌溶液中加 入0· 5N NaOH(5毫升），並使反應混合物迴流加熱3小時。 於冷卻至室溫後’將混合物倒入至冰的1 N H C1中，並收負*""[Ν'-(2-methylphenyl)ureido]phenylacetic acid (328 mg, 1.15 mmol), 4-[(4S)-(4-methoxycarbonylphenoxy)-(2S - 吼 曱 曱 曱 ] ] 444 444 444 444 444 444 444 444 444 444 444 444 444 444 444 444 444 444 444 444 444 444 444 444 444 444 444 444 444 444 444 444 444 444 444 444 444 444 444 444 444 444 444 444 444 444 444 444 444 The mixture was stirred with EtOAc (1 mL) (EtOAc) Drying on a Naz S Ο#, and evaporating. The residue was purified by column chromatography using CHC13-MeOH (60:1 to 50:1, v/v) as an eluent. And 4 - [(4 S) - ( 4 - methoxycarbonyl phenyloxy)-1-[4-[Ν' -(2-methylphenyl) ureido]] phenylamino] 1 (2s ) ~ 吼 曱 曱 曱 ] ] ] 332 332 332 332 332 332 332 332 332 332 332 ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ 52-3· 90 (s and m series, total 10H), 4· 05-4· 58 (m series, total 3Η), 5· 01 (m, 1Η), 6·78- 6. 9 0 (m, 4Η), 6· 98 ' - 7 2 0 (m, 8 Η), 7. 5 1 - 7 · 5 6 (m, 2 Η ), 7 · 9 0 - 8 · 0 0 (m, 4H); ESI, m/z 652 (MH1). 4-[(4S)-(4-Methoxycarbonylphenoxy)-l-[4-[ν'-(2-methylphenyl)ureido]phenylethenyl]-(2S)- To a stirred solution of hydrazide methoxy]benzoic acid methyl hydrazide (332 mg, 0.51 mmol) in THF (5 mL) was added EtOAc (5 mL). After cooling to room temperature, 'pour the mixture into 1 NH C1 of ice and collect it.

1283240 五、發明說明（428) 所產生之沈澱物。使粗製固體自MeOH-CHCl3-Et20再結晶， 而得1 1 9 ( 11 8毫克，3 7%)之白色結晶粉末。熔點1 5 7 -1 6 0 C ; 1 Η - N M R ( D M S 0 - d6 ) δ 2 · 2 0 - 2 · 2 5 ( s 及 m 系列，總計 4H)、2·39-2·47 (m，1H)、3·64 (s，2H)、3·68-3·89 (m，1Η)、4·02-4·08 及 4·16-4·20 (各m，總計 2Η)、 4· 29 - 4· 33 及 4. 3 9 - 4. 43 (各m，總計 2H) ^ 5. 2 0- 5. 2 6 (m, 1Η)、6·92_6.96(πι，1Η)、7·02-7·08(πι，4Η)、7·12-7· 18 (m， 4Η) 、 7· 39-7.41 (m， 2Η) 、 7·84-7. 92 (m， 6Η)、 9·01 (s， 1Η) 、12·65 (br s， 2H); ESI ， m/z 624 (MH1) ; C35H33N3 08 · 1H20 之分析計算值：C，65. 51 ; H， 5. 50 ； N, 6. 55 ° 實測值：C，65. 4 8 ； H, 5.36； N, 6.52° 實施例11 2 4-[4-（2,4-二氟苯氧基）-1-[3-甲氧基-4-[『-（2-甲基苯 基）脲基]苯基乙醯基]-2 -吼咯啶甲氧基苯甲酸1283240 V. Description of invention (428) Precipitate produced. The crude solid was recrystallized from MeOH-CHCl3-EtOAc (yield: EtOAc (EtOAc) Melting point 1 5 7 -1 6 0 C ; 1 Η - NMR ( DMS 0 - d6 ) δ 2 · 2 0 - 2 · 2 5 (s and m series, total 4H), 2·39-2·47 (m, 1H), 3·64 (s, 2H), 3·68-3·89 (m, 1Η), 4·02-4·08, and 4·16-4·20 (each m, total 2Η), 4· 29 - 4· 33 and 4. 3 9 - 4. 43 (each m, total 2H) ^ 5. 2 0- 5. 2 6 (m, 1Η), 6.92_6.96 (πι, 1Η), 7· 02-7·08(πι,4Η), 7·12-7· 18 (m, 4Η), 7·39-7.41 (m, 2Η), 7·84-7. 92 (m, 6Η), 9· 01 (s, 1Η), 12·65 (br s, 2H); ESI , m/z 624 (MH1) ; C35H33N3 08 · 1H20 Analysis calculated: C, 65. 51 ; H, 5. 50 ; N, 6. 55 ° Found: C, 65. 4 8 ; H, 5.36; N, 6.52 ° Example 11 2 4-[4-(2,4-difluorophenoxy)-1-[3-methoxy 4-["-(2-methylphenyl)ureido]phenylethenyl]-2-pyrrolidinemethoxybenzoic acid

120 1 -（第三丁氧羰基）-4-(2, 4-二氟苯氧基）咄咯啶-2 -羧酸甲 酯 0^〇〇2Me120 1 -(Tertidinoxycarbonyl)-4-(2,4-difluorophenoxy)pyrrolidine-2 -carboxylic acid methyl ester 0^〇〇2Me

Boc 於1-(第三丁氧羰基）-4-羥基脯胺酸（4.0克，16·3毫莫Boc in 1-(t-butoxycarbonyl)-4-hydroxyproline (4.0 g, 16.3 mmol)

\\312\2d-code\90-01\89112968.ptd 第433頁 1283240 五、發明說明（429) 耳）、Ph3P(5.14 克 ’19.6 宅莫耳）、及2,4 -二就 g分（2 55 克，19· 6毫莫耳）溶於THF(50毫升）之攪拌溶液中加入 DIAD ( 3 · 9笔升，1 9 · 6毫莫耳），並使混合物迴流加熱3小 時。於冷卻至室溫後，將混合物於真空中濃縮，並使殘留 物於矽膠上利用CHCI3-EtOAc(4:l)進行層析，而得卜（第 三丁氧羰基）-4-(2, 4-二氟苯氧基）咄咯啶—2—羧酸曱酯（5· 82克，定量）之黃色油。 1-(第三丁氧羰基）-4-(2，4-二氟笨氧基）吼咯啶_2_羧酸\\312\2d-code\90-01\89112968.ptd Page 433 1283240 V. Invention description (429) Ear), Ph3P (5.14 g '19.6 house Moh), and 2, 4 - 2 g points ( 2 55 g, 19·6 mmol), a solution of THF (50 ml) was added DIAD (3.99 liters, 19.6 mmol), and the mixture was heated under reflux for 3 hours. After cooling to room temperature, the mixture was concentrated in vacuo and EtOAc mjjjjjjjjj Yellow oil of 4-difluorophenoxy)indole pyridine-2-carboxylate (5·82 g, quantitative). 1-(Tertidinoxycarbonyl)-4-(2,4-difluoro-p-oxy)pyrrolidine-2-carboxylic acid

XrF N C〇2H Boc 於1-(第三丁氧幾基）-4-(2,4—二氟苯氧基）吼咯啶—2—羧 酸甲酯（5. 82克，16· 3毫莫耳）溶於THF(13〇毫升）之攪拌溶 液中加入0.25N NaOH(130毫升，32.6毫莫耳）。使所產生 之混合物攪拌隔夜。將混合物倒入至丨N HC丨彳 毫 :，並㈣cl3(2x2〇〇毫升）萃取。將萃取液㈣g0sH)乾 燥，並瘵發。使殘留物於矽膠上利用CHC1rEt〇Ac(4 : i) 為洗提液進行層析，而得1〜（第三丁氧羰基）_4_(2, 4—二 苯氧基）吼洛唆-2-缓酸（2.55克，46%)之無色泡沫。i Η-NMR (CDC13) 5 1.42-1·47 (m，9H)、2· 29-2· 74 (m 系 列，2H)、3·66-3·71 (m，2H)、4·4 6 —4 5 1 (m，1H) /、 4·83 (m， 1H) 、 6· 73-6. 95 (m， 3H)。 1 -（第三丁氧羰基）-4-(2, 4- —氟苯氧基）- 2 -吼洛唆曱醇XrF NC〇2H Boc in methyl 1-(t-butoxy-oxy)-4-(2,4-difluorophenoxy)oxaridin-2-carboxylate (5. 82 g, 16·3 m To a stirred solution of THF (13 mL) was added 0.25 N NaOH (130 mL, 32.6 mmol). The resulting mixture was stirred overnight. The mixture was poured into 丨N HC丨彳: and (iv) cl3 (2 x 2 mL) was extracted. The extract (4) g0sH) was dried and spun. The residue was chromatographed on silica gel using CHC1rEt〇Ac (4: i) as an eluent to give 1~(t-butoxycarbonyl)_4_(2,4-diphenoxy)indole-2 - Colorless foam (2.55 g, 46%). i Η-NMR (CDC13) 5 1.42-1·47 (m, 9H), 2· 29-2· 74 (m series, 2H), 3·66-3·71 (m, 2H), 4·4 6 —4 5 1 (m,1H) /, 4·83 (m, 1H), 6·73-6. 95 (m, 3H). 1-(Tertidinoxycarbonyl)-4-(2,4-fluorophenoxy)-2-indolenol

12832401283240

Boc 於卜（第三丁氧幾基）-4-(2, 4-二氟笨氧基）吼咯啶 酸（2· 55克，7· 43毫莫耳）溶於THF(50毫升）之攪拌溶液 加入BH 3 · DM S ( 4 5 2微升’ 7 · 4 3毫莫耳）。使混合物迴流加 熱隔夜。於冷卻至室溫後，將混合物於真空中濃縮，1 ^ 由加入10 (1 0 0毫升）使反應停止。將混合物以CHc丨 ί ( 2x200毫升）萃取，於MgS〇4上乾燥，並蒸發。使殘3留物於 石夕勝上利用C H C 13 - E10 A c ( 4 : 1)作為洗提液進行層析，而^ 卜（第三丁氧羰基）-4-(2，4-二氟苯氧基）—2—吼咯咬甲醇传 (1. 76 克，72%)之無色油。1H-NMR (CDC13) (5 1· 45 (s 9H)、2.28 - 2·36 (in, 2H)、3·58 - 4.99 (m 系列，8H)、 6· 74-6· 90 (m， 3H)。 4-[1-（第三丁氧羰基）-4-（2, 4-二氟笨氧基）—2 一咄略。定甲 氧基]苯甲酸甲酯Boc (dibutoxyxyl)-4-(2,4-difluorophenyloxy)pyrrolic acid (2.55 g, 7.43 mmol) dissolved in THF (50 mL) The solution was stirred to add BH 3 · DM S ( 4 5 2 μl '7 · 4 3 mmol). The mixture was refluxed and heated overnight. After cooling to room temperature, the mixture was concentrated in vacuo and 1 &lt;RTI ID=0.0&gt;&gt; The mixture was extracted with CH.sub.2 (2.times.sup.2 mL), dried over <RTIgt; Residue 3 residue was applied to Shi Xisheng using CHC 13 - E10 A c ( 4 : 1) as eluent for chromatography, and ^b (t-butoxycarbonyl)-4-(2,4-difluoro Phenoxy)-2-ythracene bite methanol (1. 76 g, 72%) of a colorless oil. 1H-NMR (CDC13) (5 1· 45 (s 9H), 2.28 - 2·36 (in, 2H), 3.58 - 4.99 (m series, 8H), 6·74-6· 90 (m, 3H 4-[1-(Tertidinoxycarbonyl)-4-(2,4-difluorophenyloxy)- 2 oxime. Methyl methoxy]benzoate

C02Me 於卜（第三丁氧羰基）-4-(2, 4-二氟苯氧基）—2 —吼嘻σ定甲 醇（500毫克，1.52毫莫耳）、4-羥基苯曱酸曱酯（277毫 克，1. 82毫莫耳）、及Ph3P(47 7毫克，1.82毫莫耳）溶於 THF(10毫升）之攪拌溶液中加入DIAD(358微升，1· 82毫莫 耳），並使混合物迴流加熱5小時。於冷卻至室溫後，將混 合物於真空中濃縮，及使殘留物於矽膠上利用CHC1 - 3C02Me Ib (t-butoxycarbonyl)-4-(2,4-difluorophenoxy)-2-pyrenequinone methanol (500 mg, 1.52 mmol), 4-hydroxybenzoic acid decyl ester (277 mg, 1.82 mmol), and Ph3P (47 7 mg, 1.82 mmol) dissolved in THF (10 mL) was added DIAD (358 μL, 1. 82 mmol). The mixture was heated under reflux for 5 hours. After cooling to room temperature, the mixture was concentrated in vacuo and the residue was applied to silica gel using CHC1 - 3

\\312\2d-code\90-01\89112968.ptd 第435頁 1283240 五、發明說明（431)\\312\2d-code\90-01\89112968.ptd Page 435 1283240 V. Description of invention (431)

EtOAc(20:l)作為洗提液進行層析，而得4-[i-(第三丁氧 幾基）-4-(2, 4-二氟苯氧基）-2-吼咯啶曱氧基]笨甲酸甲 ( 529 毫克，75%)之無色油。iH-NMR (CDC13) δ 1· 46 (s， 9Η)、2·20-2·47 (m, 2Η)、3·64 (m，2Η)、3·86 (s， 3Η)、4·07-4·43 (m，3Η)、4·86 (m，1Η)、6·74-6·87 (m，3Η)、6·94 (d, 2Η，J:8.5 Hz)、7·95 (d，2Η，J=8 5 Hz) 。 ’ · 4-[4-（ 2, 4-二氟苯氧基）-2-吼咯啶曱氧基]苯甲酸曱酉旨Ethyl acetate (20:1) was used as an eluent to give 4-[i-(t-butoxy-oxy)-4-(2,4-difluorophenoxy)-2-pyrrolidine A colorless oil of oxy] benzoic acid ( 529 mg, 75%). iH-NMR (CDC13) δ 1· 46 (s, 9Η), 2·20-2·47 (m, 2Η), 3·64 (m, 2Η), 3·86 (s, 3Η), 4·07 -4·43 (m, 3Η), 4·86 (m, 1Η), 6.74-6·87 (m, 3Η), 6.94 (d, 2Η, J: 8.5 Hz), 7.95 ( d, 2Η, J=8 5 Hz). ' 4- 4-(4-( 2, 4-Difluorophenoxy)-2-pyrrolidinyloxy]benzoic acid

C〇2Me 於4-[1_(第三丁氧羰基）—4-(2，4-二氟苯氧基）—2—吼咯 啶甲氧基]苯甲酸甲酯（529毫克，1.15毫莫耳）溶於CH2Cl2 (5毫升）之攪拌溶液中加入TFA(5毫升）。使混合物搜拌隔 夜。將混合物於真空中濃縮，並經由加入飽和N a H C 03使殘 留物成為鹼性。以CHCIJ 2x1 00毫升）萃取混合物。將萃取 液於C 〇3上乾燥’並蒸發而得4 - [ 4 - ( 2，4 -二氟苯氧基）一 2 -吼咯啶曱氧基]苯曱酸甲酯（ 385毫克，92°/〇)的黃色油。 1-NMR (CDC13) (51· 8 9 - 1. 9 5 (m，1H)、2· 28-2· 3 5 (m， 1H)、3·09 (dd, J = 12.5、4·9 Hz，1H)、3·33 (d，J:12. 5 Hz，1H)、3.60 (m，1H)、3.86 (s，3H)、4·10 (d， J = 5.6 Hz，2H)、4.84 (m，1H)、6.73-6·89 (m，3H)、6· 91 (d， J:8.5 Hz， 2H) 、7.96 (d， J=8.5 Hz, 2H)。 4 - [4 -（2，4 -二氟本氧基）-1-[3-甲氧基-4-[Ν’ - (2-甲基苯C〇2Me is methyl 4-[1_(t-butoxycarbonyl)-4-(2,4-difluorophenoxy)-2-pyrrolidinemethoxy]benzoate (529 mg, 1.15 mmol) To the stirred solution of CH.sub.2Cl.sub.2 (5 mL) was added TFA (5 mL). Mix the mixture overnight. The mixture was concentrated in vacuo and the residue was made basic with saturated NaCI. The mixture was extracted with CHCIJ 2 x 1 00 mL). The extract was dried on C 〇 3 and evaporated to give 4-[4-(2,4-difluorophenoxy)-2-oxazolidinyloxy]benzoic acid methyl ester (385 mg, 92 °/〇) yellow oil. 1-NMR (CDC13) (51· 8 9 - 1. 9 5 (m, 1H), 2· 28-2· 3 5 (m, 1H), 3·09 (dd, J = 12.5, 4·9 Hz , 1H), 3·33 (d, J: 12. 5 Hz, 1H), 3.60 (m, 1H), 3.86 (s, 3H), 4·10 (d, J = 5.6 Hz, 2H), 4.84 ( m,1H), 6.73-6·89 (m,3H), 6.91 (d, J: 8.5 Hz, 2H), 7.96 (d, J=8.5 Hz, 2H). 4 - [4 -(2, 4-difluoro-p-oxy)-1-[3-methoxy-4-[Ν' - (2-methylbenzene

\\312\2d-code\90-01\89112968.ptd 第436頁 1283240 五、發明說明（432) 基）脈基]本基乙酿基]- 2-吼洛咬甲氧基苯甲酸甲醋\\312\2d-code\90-01\89112968.ptd Page 436 1283240 V. Inventive Note (432) Base) 基基] Benyl Erythryl]- 2-吼 咬 methoxybenzoic acid methyl vinegar

使4 - [4 -（2, 4-二氟苯氧基）- 2 -咄咯啶曱氧基]苯曱酸甲 酯（380毫克，ΐ·〇5毫莫耳）、3-曱氧基-4 - [N，-（2 -曱基苯 基）脲基]苯乙酸（ 32 9毫克，1· 05毫莫耳）、EDC · HC 1(302 毫克，1·58毫莫耳）、及催化量之HOBt及DMAP於DMF (1 0毫 升）中之混合物攪拌3天。將混合物以EtOAc( 20 0毫升）稀 釋’並以鹽水（2 X 2 0 0毫升）洗務。於移除溶劑後，使殘留 物於矽膠上利用CHC13-EtOAc(4: 1 )至CHC13-MeOH(10: 1)作 為洗提液進行層析，而得4_[4_(2,4 -二氟苯氧基）—1 — [3-甲氧基-4 - [Ν’-（2-甲基苯基）脲基]苯基乙醯基]—2 - π比π各n定 曱氧基苯甲酸甲酯（693毫克，定量）。UMR (CDC13) (5 2.16-2.53 (m， 5H)、3.61 - 4.93 (m 系列，14H)、6.48 - 8· 12 (m 系列，16Η)。 於4 - [4 -（2, 4-二氟苯氧基）-卜[3-曱氧基-4-[N，-（2-曱 基苯基）脲基]苯基乙醯基]一2-吼咯啶甲氧基苯甲酸甲酉旨 ( 6 93毫克’ 1· 〇5毫莫耳）溶於THF (8毫升）之攪拌溶液中加 入〇· 25N NaOH(8· 4毫升，2· 10毫莫耳）。使混合物攪拌隔 夜。將混合物倒入至1N HC 1 ( 20 0毫升）中，並利用吸據收 集所產生之沈澱物。使固體於矽膠上利用CHCl3 — Me〇H(5〇 : 1至10:1)作為洗提液進行層析，而得1 20 ( 323毫克，48%) 之無色非晶形固體。iH-NMR (DMS0-d6) 62.25 (s， 3H)、Methyl 4-[4-(2,4-difluorophenoxy)-2-pyrrolidinyloxy]benzoate (380 mg, ΐ·〇 5 mmol), 3-methoxyl -4 - [N,-(2-mercaptophenyl)ureido]phenylacetic acid (32 9 mg, 1.00 mmol), EDC · HC 1 (302 mg, 1.58 mmol), and The catalytic amount of HOBt and the mixture of DMAP in DMF (10 mL) were stirred for 3 days. The mixture was diluted with EtOAc (20 mL) and washed with brine (2×250). After removing the solvent, the residue was chromatographed on a silica gel using CHC13-EtOAc (4:1) to CHC13-MeOH (10:1) as an eluent to give 4-[4_(2,4-difluoro) Phenoxy)-1 -[3-methoxy-4 -[Ν'-(2-methylphenyl)ureido]phenylethenyl]-2 - π ratio π each n-doped oxybenzene Methyl formate (693 mg, quantitative). UMR (CDC13) (5 2.16-2.53 (m, 5H), 3.61 - 4.93 (m series, 14H), 6.48 - 8· 12 (m series, 16Η). 4 - [4 - (2, 4-difluoro) Phenoxy)-bromo[3-decyloxy-4-[N,-(2-mercaptophenyl)ureido]phenylethenyl]- 2-indolyl methoxybenzoate (6 93 mg '1· 〇 5 mmol) 搅拌·25N NaOH (8.4 ml, 2·10 mmol) was added to a stirred solution of THF (8 mL). The mixture was stirred overnight. Pour into 1N HC 1 (200 ml) and collect the resulting precipitate by suction. The solid was applied to the silicone using CHCl3-Me〇H (5〇: 1 to 10:1) as the eluent. Chromatography gave 1 20 ( 323 mg, 48%) of colorless amorphous solid. iH-NMR (DMS0-d6) 62.25 (s, 3H),

\\312\2d-code\90-01\89112968.ptd 第437頁 1283240 五、發明說明（433) 2.35 (m， 2H) 、3·33 — 5·18 (m 系列，11H)、6·75 (dd， 1H，J = 8· 3、1· 7 Hz)、6·87-7· 30 (m 系列，8H)、7· 7 9 (d，1H，J = 8.3 Hz)、7·85-7·9〇 (m，3H)、8·01 (d，1H， J = 8.3 Hz)、8·49 (s，1H)、8.57 (s，1H); MS(FAB) m/z 646 (MH1)。 實施例11 3 4 - [1 - [4 - [Ν’ -（2-氣笨基）脲基]- 3-甲氧苯基乙醯 基]-4-（6 -喳啉氧基-2S-咣咯啶基]甲氧苯甲酸\\312\2d-code\90-01\89112968.ptd Page 437 1283240 V. Description of invention (433) 2.35 (m, 2H), 3·33 — 5·18 (m series, 11H), 6.75 (dd, 1H, J = 8·3, 1·7 Hz), 6·87-7· 30 (m series, 8H), 7· 7 9 (d, 1H, J = 8.3 Hz), 7.85- 7·9〇(m,3H),8·01 (d,1H, J=8.3 Hz), 8·49 (s,1H), 8.57 (s,1H); MS(FAB) m/z 646 (MH1 ). Example 11 3 4 - [1 - [4 - [Ν--(2-Acetyl)ureido]-3-methoxyphenylethenyl]-4-(6-carbolineoxy-2S- Ethrolidine]methoxybenzoic acid

Cl H H OMeCl H H OMe

COOH 121COOH 121

SI 4 - [(4S)-[(6-喳啉氧基一（2S)-咄咯啶基）]曱氧苯甲酸甲 〇J〇5 Η&quot;^〇-(Ι^*ΟΟΟΜβ 在0 °C下於（反-1-第三丁氧羰基-4_羥基-2 -咄咯啶基）甲 氧苯曱酸甲酯（1. 〇克，3· 0毫莫耳）、6 -羥基喳啉（435毫 克，3. 0毫莫耳）、及Ph3P( 943毫克，3.6毫莫耳）溶於 THF(10毫升）之攪拌溶液中加入DiAD( 727毫克，3· 6毫莫 耳）。使反應混合物在室溫下攪拌1 8小時。將混合物於真 空中濃縮。使殘留物經由於矽膠上利用正己燒—Et〇Ac (^ · 2, v/v)進行管柱層析而純化。在下於產物溶於c · (6.0毫升）之授拌溶液中加入TFA(6.〇毫升）。使反 入SI 4 - [(4S)-[(6-Phenyloxyl-(2S)- oxazolidinyl)] oxobenzoic acid formazan J〇5 Η&quot;^〇-(Ι^*ΟΟΟΜβ at 0 °C Methyl (methoxy-1-butoxycarbonyl-4-hydroxy-2-pyridinyl)methoxybenzoate (1. gram, 3.0 mmol), 6-hydroxyporphyrin (435 mg, 3.0 mmol), and a solution of Ph3P (943 mg, 3.6 mmol) dissolved in THF (10 mL) was added with DiAD (727 mg, 3.6 mmol). The mixture was stirred at room temperature for 18 hours. The mixture was concentrated in vacuo. EtOAc m. The product was dissolved in c · (6.0 ml) of the mixing solution and TFA (6. 〇 ml) was added.

12832401283240

物在至’JHL下稅拌〇 · 5小時。將混合物於真空。 和NaHC0q加至碡囟輪 .ινΓυ Γ1 T /辰滩將飽 冰仪^ 亚2C12卒取。將萃取液以鹽水 洗滌，於Na2S〇4上乾燥，並於真空中濃縮。使殘留物辦乂 於矽膠上利用Me0H — cH2Cl2(l%至10%, v/v)作為洗提液二由一 官柱層析，純化而得4—[(4S) —[(6_喳啉氧基—（2S)—呪咯二 基）]甲氧苯甲酸甲酯（9 0 0毫克，82%)之淡黃色油。！ 疋 (CDCl3)5 i.92-2.1〇(m，lH)、2.45-2.55 (m，lH)、3 20-3.3 0 (m, in) ^ 3.38 -3.5 0 (m, 1H) &gt; 3.6 0- 3.7 0 (/ 1H)、3·88 (s，3H)、4·05-4·18 (m，2H)、5.03 (m，’ 1H)、6·91 (d，J = 8.5 Hz, 1H)、7·02 (d，J = 2.7 H: 4 [1 [4-[N -(2 -氣苯基）脲基]-3-甲氧苯基乙醯基]—4 -（6 -噇啉氧基一（2S)-吡咯啶基]甲氧苯甲酸甲酷 1H)、7·35-7.38 (m，2H)、7·96 (d，JU Hz: 1H)’、8 00-8·05 (m， 2H) 、 8·76 (d， J=3.2 Hz， 1H) 。 ’ ·The goods are mixed under the tax of 'JHL. · 5 hours. The mixture was placed under vacuum. And NaHC0q added to the 碡囟 wheel.ινΓυ Γ1 T / 辰 beach will be full of ice ^ ^ 2C12 stroke. The extract was washed with brine, dried over Na.sub.2.sub.4, and concentrated in vacuo. The residue was applied to the tannin extract using Me0H-cH2Cl2 (1% to 10%, v/v) as the eluent. The column was chromatographed and purified to obtain 4-[(4S)-[(6_喳Phenyloxy-(2S)-fluorenyldiyl)methyl methoxybenzoate (90 mg, 82%) as a pale yellow oil. !疋(CDCl3)5 i.92-2.1〇(m,lH), 2.45-2.55 (m,lH),3 20-3.3 0 (m, in) ^ 3.38 -3.5 0 (m, 1H) &gt; 3.6 0 - 3.7 0 (/ 1H), 3·88 (s, 3H), 4·05-4·18 (m, 2H), 5.03 (m, ' 1H), 6.91 (d, J = 8.5 Hz, 1H ), 7·02 (d, J = 2.7 H: 4 [1 [4-[N -(2- gasphenyl)ureido]-3-methoxyphenylethinyl]-4-(6-噇) Oxyloxy-(2S)-pyrrolidinyl]methoxybenzoic acid methyl 1H), 7·35-7.38 (m, 2H), 7.96 (d, JU Hz: 1H)', 8 00-8· 05 (m, 2H), 8·76 (d, J=3.2 Hz, 1H).

COOMe 在〇 C下於4-[4S-(6 -嗜琳氧基-23-ϋ比洛。定基）曱氧苯甲 酸曱醋（ 3 0 0毫克，〇·79毫莫耳）、4一 [Ν，—（2一氯苯基）脲 基]-3-甲氧苯乙酸（264毫克，〇· 79毫莫耳）、H〇Bt(1(n毫 克，0.79毫莫耳）、及三乙胺（330毫升，2·37毫莫耳）溶於 THF(10· 〇毫升）及MeCN(10· 〇毫升）之攪拌溶液中加入ED(： · H C1 ( 2 2 8宅克，1 · 2宅莫耳）。使反應混合物在室溫下授拌 16小時，並於真空中濃縮。將水加至殘留物，並以Et〇AcCOOMe in 〇C under 4-[4S-(6-isolinyl-23-indolobi. fixed) oxabenzoic acid vinegar (300 mg, 〇·79 mmol), 4 [ Ν,-(2-chlorophenyl)ureido]-3-methoxyphenylacetic acid (264 mg, 〇·79 mmol), H〇Bt (1 (n mg, 0.79 mmol), and triethyl Amine (330 ml, 2.37 mmol) dissolved in THF (10·ml) and MeCN (10·ml) were added to ED (: · H C1 ( 2 2 8 house, 1 · 2) The reaction mixture was allowed to stir at room temperature for 16 hours and concentrated in vacuo. Water was added to residue and Et.

\\312\2d-code\90-01\89112968.ptd 第439頁 1283240 五、發明說明（435) 萃取。將萃取液以飽和NaHC〇3洗滌，然後於Na2S〇4上乾 燥，並於真空中濃縮。使殘留物經由於矽膠上利用Ac 至EtOH-EtOAc(l〇%，v/v)作為洗提液進行管柱層析，純化 而得4-[1-[4-[Ν’ -（2_氯苯基）脲基]—3—曱氧笨基乙醯 基]- 4 -（6 -噎啉氧基-（2S) -咄咯啶基）曱氧苯甲酸甲酯（52〇 毫克，95%)之無色油。iH-NMR (CDC13) 5 2. 30-2· 60 (m， 3H)、3·64 (s，2H)、3·73 (s，3H)、3·8〇-3·95 (m，1H) 、3 · 8 7 (s，3 Η)、4 · 1 5 - 4 · 3 0 (m，1 Η)、4 · 5 〇 一 4 · 7 〇 (m， 2Η) 、5·11 (br s， 1Η) 、6·81-7·〇1 (m， 6Η)、 7·26-7·39 (m，6H)、7·93-8.03 (m，5H)、8·19 (d，J = 8. 3 Hz, 1H)、8· 80 (s，1H)。 於4 - [1-[4 - [Ν’-（2-氯苯基）脲基]-3-甲氧苯基乙醯 基]-4 -（6 -喳啉氧基-2S-咄咯啶基）甲氧苯甲酸甲酯（520毫 克，0.75毫莫耳）溶於THF (10.0毫升）及Me 0Η (5.0毫升）之 攪拌溶液中加入IN NaOH(l. 5毫升，1. 5毫莫耳）。使混合 物在60 °C下攪拌18小時。將混合物於真空中濃縮，加入 水，並以1N HC1中和。收集所產生之固體，以水洗滌，並 於真空中乾燥而得121(450毫克，88%)之白色結晶固體。 熔點 1 29- 1 33 °C ; IR (KBr) 3332、1 704、1 604、1531、 141 9、1 222、11 66 / 公分；UMR (DMSO-d6) ά2·25-2.55 (m， 2H) 、3·67 (s， 2H) 、3·82 (s， 3H) 、3·81-3.92 (m， 1H)、4·02-4·15 (m，2H)、4·40_4·50 (m，2H)、5·25-5· 40 (m，1Η)、5·33-7·07 (m，5Η)、7·26-7·49 (m，5Η)、 7·83-8·23 (m，6H)、8·73-8.74 (m，1H)、8·90 (s,\\312\2d-code\90-01\89112968.ptd Page 439 1283240 V. INSTRUCTIONS (435) Extraction. The extract was washed with saturated aHC.sub.3, then dried over Na.sub.2.sub.4, and concentrated in vacuo. The residue was subjected to column chromatography using Ac to EtOH-EtOAc (10%, v/v) as an eluent to obtain 4-[1-[4-[Ν' - (2_ Chlorophenyl)ureido]-3-inoxyloxyindolyl]- 4 -(6-oxalinyloxy-(2S)-indolyl)methyl oxabenzoate (52 mg, 95 %) of colorless oil. iH-NMR (CDC13) 5 2. 30-2· 60 (m, 3H), 3·64 (s, 2H), 3·73 (s, 3H), 3·8〇-3·95 (m, 1H) ), 3 · 8 7 (s, 3 Η), 4 · 1 5 - 4 · 3 0 (m, 1 Η), 4 · 5 〇 1 4 · 7 〇 (m, 2 Η), 5·11 (br s , 1Η), 6·81-7·〇1 (m, 6Η), 7·26-7·39 (m, 6H), 7.93-8.03 (m, 5H), 8·19 (d, J = 8. 3 Hz, 1H), 8·80 (s, 1H). 4-[1-[4 - [Ν'-(2-Chlorophenyl)ureido]-3-methoxyphenylethenyl]-4 -(6-nonanyloxy-2S-indolyl) Methyl methoxybenzoate (520 mg, 0.75 mmol) dissolved in THF (10.0 mL) and EtOAc (5 mL). ). The mixture was stirred at 60 ° C for 18 hours. The mixture was concentrated in vacuo, water was added and neutralized with 1N EtOAc. The resulting solid was collected, washed with water and dried in vacuo to afford white crystals of 127 (450 mg, 88%). Melting point 1 29- 1 33 °C; IR (KBr) 3332, 1 704, 1 604, 1531, 141 9, 1 222, 11 66 / cm; UMR (DMSO-d6) ά2·25-2.55 (m, 2H) , 3·67 (s, 2H), 3·82 (s, 3H), 3.81-3.92 (m, 1H), 4·02-4·15 (m, 2H), 4·40_4·50 (m , 2H), 5·25-5· 40 (m, 1Η), 5·33-7·07 (m, 5Η), 7·26-7·49 (m, 5Η), 7·83-8·23 (m, 6H), 8.73-8.74 (m, 1H), 8·90 (s,

89112968.ptd 第440頁 1283240 五、發明說明（436) 1H)、8.94 (s，1H) ； MS(FAB) m/z 681(MH1)； C37H33N407 Cl · 0· 5H20 之分析計算值 _· c， 64. 39 ; H，4· 97 ; N， 8· 12。實測值·· c， 64. 2 2 ; H，4. 90 ; N， 7. 96。 實施例11 4 4 [1 [4 [N -(2 -漠求基）脲基]一3—甲氧苯基乙醯基]一（4s) -（6 -喳啉氧基-（2S) -咄咯啶基）甲氧苯甲酸89112968.ptd Page 440 1283240 V. INSTRUCTIONS (436) 1H), 8.94 (s, 1H); MS(FAB) m/z 681(MH1); C37H33N407 Cl · 0· 5H20 Analytical calculated value _· c, 64. 39 ; H, 4· 97 ; N, 8· 12. Found C· 64. 2 2 ; H, 4. 90 ; N, 7. 96. Example 11 4 4 [1 [4 [N -(2-)-carbamoyl]-3-methoxyphenylethenyl]-(4s)-(6-carbolineoxy-(2S)- Ethrolidinyl methoxybenzoic acid

COOH 122 4-[卜[4-[Ν’ -(2-溴苯基）脲基]一3_甲氧苯基乙醯基]_(4S) -(6-嗜琳氧基-(2S)-吼咯啶基）甲氧苯甲酸甲酯COOH 122 4-[Bu [4-[Ν' -(2-bromophenyl)ureido]-3-methoxyphenylethenyl]-(4S)-(6-terinyloxy-(2S) - oxaridinyl) methyl methoxybenzoate

在〇°C下於4-(4S-(6-喳啉氧基-2S_^咯啶基）甲氧苯甲 酸甲酯（300毫克，〇. 79毫莫耳）、4_[n，_(2_溴苯基）脲 基]-3-甲氧苯乙酸（ 29 9毫克，0.79毫莫耳）、11〇肘（1〇7毫 克，0.79毫莫耳）、及二乙胺（33〇毫升，2.37毫莫耳）溶於 THFUU毫升）及MeW10.0毫升）之授拌溶液中力口入飢·' HC1C 22 8窀克’ 1. 2 *莫耳）。使反應混合物在室溫下攪拌 16小時’並於真&quot;濃縮。將水加至殘留物，並以 萃取。將萃取液以飽和NaHC〇3洗條，然後於Na2S〇4上乾 燥，並於真空中濃縮。使殘留物經由於矽膠上利用射〇八。Methyl 4-(4S-(6-oxalinyloxy-2S-bromopyridyl)methoxybenzoate (300 mg, 〇. 79 mmol), 4_[n, _(2) at 〇 °C _Bromophenyl)ureido]-3-methoxyphenylacetic acid (29 9 mg, 0.79 mmol), 11 〇 elbow (1〇7 mg, 0.79 mmol), and diethylamine (33 mL, 2.37 millimoles) dissolved in THFUU) and MeW (10.0 ml) in a mixing solution to force hunger · 'HC1C 22 8 gram ' 1. 2 * Moel). The reaction mixture was stirred at room temperature for 16 hours and concentrated. Water was added to the residue and extracted. The extract was washed with saturated NaHC.sub.3 then dried over Na.sub.2.sub.4 and concentrated in vacuo. The residue was applied to the tannin via a tantalum.

\\312\2d-code\90-01\89112968.ptd 第441頁 1283240 五、發明說明（437) 至EtOH-EtOAc(10%，v/v)作為洗提液進行管柱層析，純化 而得4-[1-[4 - [Ν’-（2 -溴笨基）脲基]一3一甲氧苯基乙醯 基]-（4S)-（6 - 4琳氧基—（2S)一吼咯啶基）甲氧苯甲酸甲酯 (530 毫克，91%)之無色油。1H-NMr (CDCl3)(5 2·3〇_2·62 (m， 3Η) 、3·65 (s， 2Η) 、3·75 (s， 3Η) 、3·80-3·95 (m， 1Η) 、3·93 (s， 3Η) 、4.10—4.30 (m， 1Η) 、4·50-4.70 (m，2H)、5·11 (br s，1H)、6·82- 6.98 (m，6H)、7·15 -7.39 (m，5H)、7·52 (d，J = 8.0 Hz，1H)、7·93-8·03 (m，5H)、8·14 (d，J = 8.3 Hz，1H)、8·80 (s，1H)。 於4-[l-[4 - [Ν’-（2-溴苯基）脲基]- 3-甲氧苯基乙醯基] -4-（ 6 -喳啉氧基-2S-咄咯啶基）甲氧苯甲酸曱酯（ 53 0毫 克，〇· 72毫莫耳）溶於THF(10. 0毫升）及MeOH(5. 0毫升）之 攪拌溶液中加入IN NaOH(l. 4毫升，1. 4毫莫耳）。使混合 物在70 °C下攪拌24小時。將混合物於真空中濃縮，加入 水，並以1 N H C1中和。收集所產生之固體，以水洗務，並 於真空中乾燥而得1 22 ( 4 6 0毫克，88%)之白色結晶固體。 熔點 1 4 9- 1 53 °C ; IR (KBr) 3332、1 704、1 6 04、1 5 27、 1 222、1164 / 公分；NMR (DMSO-d6) 62·28-2.58 (m， 2H)、3·67 (s，2H)、3·82 (s，3H)、3·85-3·90 (m， 1Η)、4·05-4·15(ιη，2Η)、4·40-4·50(ιη，2Η)、5·20-5· 32 (m，1H)、6·77-7.07 (m，5H)、7·31 -7·61 (m, 5H)、 7.83-7.97 (m, 5H) ^8.21-8.22 (m, 1H) ^8.73-8.74 (m，2H)、8· 92 (s，1H) ; MS(FAB) m/z 725 (M+)、727 (MH2) ; C37H33N4 06 Br · 0. 5H20 之分析計算值：C，60· 50 ;\\312\2d-code\90-01\89112968.ptd Page 441 1283240 V. Description of the invention (437) to EtOH-EtOAc (10%, v/v) as an eluent for column chromatography, purification 4-[1-[4 - [Ν'-(2-Bromophenyl)ureido]-3-methoxyphenylethyl]-(4S)-(6 - 4 aryloxy-(2S) A colorless oil of methyl pyridyl) methoxybenzoate (530 mg, 91%). 1H-NMr (CDCl3) (5 2·3〇_2·62 (m, 3Η), 3·65 (s, 2Η), 3·75 (s, 3Η), 3·80-3·95 (m, 1Η), 3·93 (s, 3Η), 4.10-4.30 (m, 1Η), 4·50-4.70 (m, 2H), 5·11 (br s, 1H), 6.82- 6.98 (m, 6H), 7·15 -7.39 (m, 5H), 7·52 (d, J = 8.0 Hz, 1H), 7·93-8·03 (m, 5H), 8·14 (d, J = 8.3 Hz, 1H), 8·80 (s, 1H). 4-[l-[4 - [Ν'-(2-Bromophenyl)ureido]-3-methoxyphenylethenyl]-4 -( 6 -Phenanyloxy-2S-oxaridinyl) methoxy benzoate (53 0 mg, 〇 · 72 mmol) dissolved in THF (10.0 mL) and MeOH (5.0 mL) Into the stirred solution was added IN NaOH (1.4 ml, 1.4 mmol). The mixture was stirred at 70 ° C for 24 hours. The mixture was concentrated in vacuo, water was added, and neutralized with 1 NH C1 The resulting solid was collected, washed with water and dried in vacuo to give a white crystals of 1 22 (460 mg, 88%) mp. 1 704, 1 6 04, 1 5 27, 1 222, 1164 / cm; NMR (DMSO-d6) 62·28-2.58 (m, 2H), 3.67 (s, 2 H), 3·82 (s, 3H), 3·85-3·90 (m, 1Η), 4·05-4·15 (ιη, 2Η), 4·40-4·50 (ιη, 2Η) ,5·20-5· 32 (m,1H),6·77-7.07 (m,5H),7·31 -7·61 (m, 5H), 7.83-7.97 (m, 5H) ^8.21-8.22 (m, 1H) ^8.73-8.74 (m, 2H), 8. 92 (s, 1H); MS (FAB) m/z 725 (M+), 727 (MH2); C37H33N4 06 Br · 0. 5H20 Calculated value: C, 60 · 50;

\\312\2d-code\90-01\89112968.ptd 第442頁 1283240 五、發明說明（438) 4.67; N’ 7.63; Br，1〇. 88。實測值 4.60; N，7.52; Br，11〇6。 b(J.51，H， 實施例11 5 4-[(2S，4SH-[3-甲氧基—4_[N’_(2_ f 基笨基）脲 乙醯基]-4-(2-萘氧基）一2 ”比洛咬基]甲氧苯曱酸土 土\\312\2d-code\90-01\89112968.ptd Page 442 1283240 V. Description of invention (438) 4.67; N’ 7.63; Br, 1〇. 88. Found 4.60; N, 7.52; Br, 11〇6. b(J.51,H, Example 11 5 4-[(2S,4SH-[3-methoxy-4_[N'_(2_f-phenyl)]indolyl]-4-(2- Naphthyloxy)- 2"bilocene]methoxybenzoic acid soil

123 吼咯啶羧酸甲 (2S，4S)- 1 一第：丁葡避f | 々—丁乳板基&lt;4-(2-萘氧基）-2- 酯 hoc 在至 下在鼠氣環境中，於（2s，4R) 一卜第三丁氧羰基 \4 一羥基一 2—咄咯啶基羧酸甲醋（4· 22克，17.2毫莫耳）、2-秦紛（2· 73克’ 18· 9毫莫耳）及PPh3(4· 96克，18· 9毫莫耳） 於THF^0宅升）中之攪拌混合物中加入DIAD(3. 72毫升， 1 8 · 9宅莫耳）。於攪拌隔夜後，將混合物於真空中濃縮。 將殘留物於矽膠[ 6 0 0克，CHCl3/EtOAc(10/l)]上進行層析 而付（2S，4S)-1-第三丁氧幾基_4-(2 -寨氧基）-2 -吼洛°定魏 酸曱酯（5 · 37克），將其不經進一步的純化而使用。 (2S，4S)-1-第三丁氧羰基—4-(2 -萘氧基）-各咬魏酸123 吼 啶 羧酸 carboxylic acid A (2S, 4S) - 1 A: Ding shun f | 々 丁 丁 基 & &&lt; 4-(2-naphthalenyloxy)-2- ester hoc in the next in the rat In the environment, in (2s, 4R), a third butoxycarbonyl group, a 4-hydroxy-2-pyridinylcarboxylic acid, methyl vinegar (4·22 g, 17.2 mmol), 2-Qin (2· Add DIAD (3. 72 ml, 1 8 · 9 house) to a stirred mixture of 73 g '18·9 mmol) and PPh3 (4·96 g, 18·9 mmol) in THF^0 house liter) Moore). After stirring overnight, the mixture was concentrated in vacuo. The residue was chromatographed on silica gel [600 g, CHCl3/EtOAc (10/l)] to afford (2S,4S)-1-tert-butoxy-yl- 4-(2-zyloxy) -2 - 吼 ° 定 魏 魏 ( (5 · 37 g), which was used without further purification. (2S,4S)-1-tert-butoxycarbonyl-4-(2-naphthyloxy)-each biting

1283240 五、發明說明（439) S/&quot;C〇^ boc 在室溫於（2S，4S)-1-第三丁氧羰基-4-(2 -萘氧基）—2- 口比 咯啶羧酸甲酯（5. 37克）溶於THF( 116毫升）之攪拌溶液中加 入0· 25N NaOH(l 16毫升，29· 0毫莫耳）。使所產生之混合 物攪拌隔夜。於移除溶劑後，將混合物經由加入1 N HC 1酸 化，並以CHC 13萃取。將結合的萃取液以鹽水洗滌，於ν&amp;2 SO4上乾燥，並蒸發。使殘留物自正己烷-CHC 13再結晶而得 (2S，4S)-1-第三丁氧戴基-4-(2-萘氧基）-2 -吼洛。定魏酸 [4· 44 克，85°/〇(2 步驟）]之白色粉末。ιΗ一NMR (DMS〇 — d6)占 1.37 及 1·41 (s，9H，醯胺異構物）、2·26 (d， J = 13.9 Hz，1H)、2·65 (m，1H)、3·47 (d，&gt;11·5 Hz, 1H)、3· 8 1 ( m，1 H )、4. 3 0 ( m，1 H )、5 · 4 1 ( m，1 H )、7 · 0 2 - 7 · 8 6 (m， 7H) 。 ’ * (2S，4S)-1-第二丁氧羰基一 4 — (2 —萘氧基）一2一吼咯啶甲醇 °v boc 在(TC下於（2S，4S)-卜第三丁氧羰基_4_(2_萘氧基）_2_ 吼洛咬，酸克，3_13毫莫耳）溶於TH 〇 拌溶液中加入MrMS(0.63毫升，63毫莫耳）。使混合 物立即^升至室溫’然後在5〇 t下加熱h1283240 V. INSTRUCTIONS (439) S/&quot;C〇^ boc at (2S,4S)-1-tert-butoxycarbonyl-4-(2-naphthyloxy)-2-pyrrolidine at room temperature Methyl carboxylate (5.37 g) was dissolved in THF (116 mL). EtOAc (l········ The resulting mixture was stirred overnight. After removing the solvent, the mixture was acidified by the addition of 1 N HCl and extracted with CH. The combined extracts were washed with brine, dried over EtOAc & EtOAc &lt The residue was recrystallized from n-hexane-CHC 13 to give (2S,4S)-1-t-butoxy-diyl-4-(2-naphthalenyloxy)-2-indole. A white powder of ferulic acid [4·44 g, 85°/〇 (2 steps)]. Η NMR (DMS〇-d6) accounts for 1.37 and 1.41 (s, 9H, guanamine isomers), 2·26 (d, J = 13.9 Hz, 1H), 2·65 (m, 1H), 3·47 (d, &gt;11·5 Hz, 1H), 3· 8 1 ( m,1 H ), 4. 3 0 ( m,1 H ), 5 · 4 1 ( m,1 H ), 7 · 0 2 - 7 · 8 6 (m, 7H). ' * (2S,4S)-1-Secondoxycarbonyl- 4 - (2-naphthyloxy)- 2 -pyrrolidine methanol °v boc ((2S,4S)-b third in (TC) Oxycarbonyl _4_(2_naphthyloxy)_2_ 吼 咬, acid gram, 3_13 mmoles was dissolved in TH 〇 solution and added with MrMS (0.63 ml, 63 mmol). Allow the mixture to immediately rise to room temperature' and then heat at 5 ° t

至室溫後，經由在0 r下加入★品处 A r A A — 入水而使混合物停止反應，並 以EtOAc卒取。將結合的萃&amp;、方 ]卒取液以鹽水洗滌，於Na2S04上乾After standing to room temperature, the mixture was quenched by the addition of water at 0 r, A r A A - water, and the mixture was taken with EtOAc. The combined extract &amp;, square] draw solution was washed with saline and dried on Na2S04

第444頁 1283240 五、發明說明（440)Page 444 1283240 V. Description of invention (440)

燥’並蒸發。使殘留物於矽膠[5〇克，CHCl3/MeOH (50 /1)]上進行層析’而得（214s) — ；!-第三丁氧羰基一 4 —(2-萘 氧基）-2-吼嘻唉曱醇1〇克，1 〇〇%)之淡黃色油。1H — NMR (CDC13) 5 1.48 (s，9H)、2.45 (m，1H)、3.58-4.80 (m，4H)、5·01 (br, 1H)、7.〇4 一 7.99 (m，7H)。 4-[(2S，4S)-1-第三丁氧羰基—4—(2-萘氧基）_2—咄咯啶基] 甲氧苯甲酸甲酯Dry and evaporate. The residue was chromatographed on silica gel [5 g, CHCl3 / MeOH (50 /1)] to give (214s) -; ---tri-butoxycarbonyl- 4-(2-naphthyloxy)-2 - sterol 1 gram, 1 〇〇%) light yellow oil. 1H — NMR (CDC13) 5 1.48 (s, 9H), 2.45 (m, 1H), 3.58-4.80 (m, 4H), 5·01 (br, 1H), 7.〇4 a 7.99 (m, 7H) . 4-[(2S,4S)-1-Tertidinoxycarbonyl-4-(2-naphthyloxy)_2-oxaridinyl]methyl methoxybenzoate

在室溫下在氮氣環境中，於（2s，4S)-l_第三丁氧羰基 -4-（2-萘氧基）- 2 - π比咯啶甲醇（640毫克，1.86毫莫耳）、 4-經基苯甲酸甲酯（283毫克，l 86毫莫耳）及pph3 ( 4 88毫 克’ 1 · 86毫莫耳）於thF( 1 8毫升）中之攪拌混合物中加入 D IAD ( 0 · 3 7毫升，1 · 8 6毫莫耳）。使混合物攪拌隔夜。於移 除溶劑後，使所產生之殘留物於矽膠[丨0 〇克，正己烷 /EtOAc(2/l)]上進行層析，而得4-[(2S，4S)-卜第三丁氧 羰基-4 -（2 -萘氧基）一2 -吼咯啶基]甲氧苯甲酸甲酯（830毫 克，93%)之無色油。UMR (CDC13) 5 1· 50 (d， J二8. 3(2s, 4S)-l-t-butoxycarbonyl-4-(2-naphthyloxy)-2-pyrrolidine methanol (640 mg, 1.86 mmol) at room temperature under nitrogen. Add D IAD ( 0 ) to a stirred mixture of methyl 4-benzoic acid (283 mg, l 86 mmol) and pph3 ( 4 88 mg '1 · 86 mmol) in thF (18 mL) · 3 7 ml, 1 · 8 6 mmol). The mixture was stirred overnight. After removing the solvent, the resulting residue was chromatographed on silica gel [丨0 〇g, n-hexane/EtOAc (2/l)] to give 4-[(2S,4S)-b. A colorless oil of methyl oxycarbonyl-4 -(2-naphthyloxy)-2-oxazolidinyl]methoxybenzoate (830 mg, 93%). UMR (CDC13) 5 1· 50 (d, J 2 8. 3

Hz, 9H) 、2·34 (m， 1H) 、2·53 (d， J=14.2 Hz， 1H) 、3· 72 - 3·85 (m， 1H)、3·86 及 3.87 (s，3H，醯胺異構物）、 4.17 (m，1H)、4.26-4·52 (m, 2H)、5·06 (br，1H)、6· 87 (d， J=8.8 Hz， 1H) 、6·94 (d， J=8.8 Hz， 2H) 、7·〇4 (br，2H)、7·33 (t，J二7.3 Hz，1H)、7·42 (t，J = 7.3Hz, 9H), 2·34 (m, 1H), 2·53 (d, J=14.2 Hz, 1H), 3·72 - 3·85 (m, 1H), 3·86 and 3.87 (s, 3H , guanamine isomers), 4.17 (m, 1H), 4.26-4·52 (m, 2H), 5·06 (br, 1H), 6· 87 (d, J=8.8 Hz, 1H), 6 ·94 (d, J=8.8 Hz, 2H), 7·〇4 (br, 2H), 7·33 (t, J two 7.3 Hz, 1H), 7·42 (t, J = 7.3

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Hz， 1H) 、 7. 64-8. 02 (m， 5H)。 4-[(2S，4S)- 4-（2 -萘氧基）-2 -吼咯啶基]甲氧苯曱酸曱酯Hz, 1H), 7. 64-8. 02 (m, 5H). 4-[(2S,4S)- 4-(2-Naphthyloxy)-2-pyridinyl]methoxybenzoate

CX)2Me 在室溫下於4-[(2S，4S)-1-第三丁氧羰基-4-(2 -萘氧基 )-2-咄咯啶基]甲氧苯甲酸甲酯（870毫克，1. 74毫莫耳）溶 於CH2C12(24毫升）之攪拌溶液中加入TFA(6毫升）。使混合 物攪拌隔夜，將其於真空中濃縮。將殘留物以CH2C12稀 釋，並經由加入IN NaOH使成為鹼性，將其以CH2C12萃取。 將有機層以鹽水洗滌，於NaS04上乾燥，並濃縮。使殘留 物於石夕膠[100克，正己烧/ EtOAc(2/l)]上進行層析，而得 4-[ (2S，4S)-4-（2 -萘氧基）-2-吼咯啶基]曱氧苯甲酸曱酯 ( 7 5 0 毫克，1 00%)之黑色油。1H-NMR (CDC13) (5 1 · 99 (dd， J-14. 2、5.6 Hz, 1H)、2·48 (m, 1H)、3. 22 (dd, 1=12. 2 、4·6 Hz， 1H) 、3.43 (d， J=12.5Hz， 1H) 、3·67 (m， 1H)、3·86 及 3.87 (s，3H，醯胺異構物）、4·11 (m，2H) 、5·04 (m，1Η)、6·83 (d，J = 8.8 Ηζ，1Η)、6·89 (d， J二8.8 Hz，2H)、7·07 (d，J = 2.0 Hz，1H)、7·12 (d, J = 9. 0 Hz，1H)、7. 33 (dt，J = 8. 1、1. 2 Hz，1H)、7· 44 (dt，J = 6.8、1.2 Hz, 1H)、7.70 (d，J = 8.1 Hz, 1H)、 7. 75 (dd, J = 9.0、5.1 Hz, 2H)、7.90 (d，J = 8. 5 Hz, 1H) 、 7. 96 (dd， J=6.8 、 2. 0 Hz， 2H) ° 4 - [(2S，4S) - ：l - [3-甲氧基-4-[N’-（2 -甲基苯基）脲基]苯CX) 2Me at room temperature in methyl 4-[(2S,4S)-1-tert-butoxycarbonyl-4-(2-naphthyloxy)-2-oxaridinyl]methoxybenzoate (870 Tm (6 ml) was added to a stirred solution of CH2C12 (24 mL). The mixture was stirred overnight and concentrated in vacuo. The residue was diluted with CH.sub.2Cl.sub.sub.sub.sub.sub.sub.sub. The organic layer was washed with brine, dried over Nasss The residue was chromatographed on EtOAc (100 g, hexanes / EtOAc (2/l)) to give 4-[(2S,4S)-4-(2-naphthyloxy)-2-indole. Black oil of pyridyl] decyloxybenzoate (750 mg, 100%). 1H-NMR (CDC13) (5 1 · 99 (dd, J-14. 2, 5.6 Hz, 1H), 2·48 (m, 1H), 3. 22 (dd, 1=12. 2, 4·6 Hz, 1H), 3.43 (d, J = 12.5 Hz, 1H), 3·67 (m, 1H), 3·86 and 3.87 (s, 3H, guanamine isomer), 4·11 (m, 2H) ), 5·04 (m, 1Η), 6.83 (d, J = 8.8 Ηζ, 1Η), 6.89 (d, J 8.8 Hz, 2H), 7·07 (d, J = 2.0 Hz, 1H), 7·12 (d, J = 9. 0 Hz, 1H), 7.33 (dt, J = 8. 1, 1. 2 Hz, 1H), 7·44 (dt, J = 6.8, 1.2 Hz, 1H), 7.70 (d, J = 8.1 Hz, 1H), 7. 75 (dd, J = 9.0, 5.1 Hz, 2H), 7.90 (d, J = 8. 5 Hz, 1H), 7. 96 (dd, J=6.8, 2. 0 Hz, 2H) ° 4 - [(2S,4S) - :l - [3-methoxy-4-[N'-(2-methylphenyl)ureido) ]benzene

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基乙醯基]-4 -（2 -萘氧基）- 2-吼咯啶基]甲氧苯曱酸曱酯Ethyl decyl]-4 -(2-naphthyloxy)-2-pyrrolidyl] methoxybenzoate

使3-甲氧基-4-[Ν’-（2 -甲基苯基）脲基]苯乙酸（333毫 克，0.106毫莫耳）、4-[(2S，4S)-4-(2-萘氧基）—2-咄咯啶 基]甲氧本甲酸曱S旨（400毫克，1·〇6毫莫耳）、EDC.HC1 (305毫克，1.59毫莫耳）及DMAP (194毫克，[59毫莫耳）於 DMFO0毫升）中之混合物在室溫下攪拌3天。將混合物倒入 至冰水中’並以E t 0 A c萃取。將結合的萃取液以冰水及鹽 水洗務。於在Naz S〇4上乾無後’將卒取液於真空中濃縮。 使殘留物於石夕膠[100克，正己烧/EtOAc(l/l)〜CHC13/ MeOH(50/l)]上進行層析，而得4-[(28,48)-1-[3-甲氧基 -4- [Ν’-（2-曱基苯基）脲基]苯基乙醯基]一4-(2 -萘氧基） - 2 -咄咯文基]甲氧苯曱酸甲酯（5 2 0毫克，7 3 %)的淡棕色非 晶形。NMR (CDC13) 5 2·28 (s，3Η)、2.29 (m，1Η)、 2·55 (d，J=14.2 Hz, 1H)、3·60 (d，J = 3.4 Hz，2H)、 3 · 6 6 ( d，J = 3 · 7 H z，3 H )、3 · 6 8 - 4 · 0 0 (m，5 H )、4 · 0 5 - 4 · 67 (m，3H)、5·09 (br，1H)、6·61 (s，1H)、6·77 (m， 2H)、6·87 (d，J二8.8 Hz, 1H) &gt; 6. 94-7. 54 (m, 8H)、7· 68-8.0 9 (m，8H); MS(ESI) m/z 674(MH1)。 1 23 4-[(2S，4S)-卜[3-甲氧基-4-[Ν’-（2-曱基苯基）脲 基]苯基乙龜基]-4-(2 -萘氧基）-2-°比洛°定基]曱氧苯甲酸 於4-[(25,45)-：1-[3-甲氧基-4-[『-(2_甲基笨基）脲基]苯3-methoxy-4-[Ν'-(2-methylphenyl)ureido]phenylacetic acid (333 mg, 0.106 mmol), 4-[(2S,4S)-4-(2- Naphthyloxy)-2-pyrrolidyl]methoxypropionate 曱S (400 mg, 1·〇6 mmol), EDC.HC1 (305 mg, 1.59 mmol) and DMAP (194 mg, The mixture [59 mmol) in DMFO (0 mL) was stirred at room temperature for 3 days. Pour the mixture into ice water' and extract with Et0Ac. The combined extracts were washed with ice water and salt water. The stem solution was concentrated in vacuo after drying on Naz S〇4. The residue was chromatographed on EtOAc (100 g, hexanes / EtOAc (l/l)~CHC13 / MeOH (50/l)) to give 4-[(28,48)-1-[3 -methoxy-4-[Ν'-(2-mercaptophenyl)ureido]phenylethenyl]-4-(2-naphthyloxy)-2-pyranyl]methoxybenzoquinone Methyl ester (5 2 0 mg, 73%) is light brown amorphous. NMR (CDC13) 5 2·28 (s, 3Η), 2.29 (m, 1Η), 2·55 (d, J=14.2 Hz, 1H), 3·60 (d, J = 3.4 Hz, 2H), 3 · 6 6 ( d, J = 3 · 7 H z, 3 H ), 3 · 6 8 - 4 · 0 0 (m, 5 H ), 4 · 0 5 - 4 · 67 (m, 3H), 5· 09 (br,1H),6·61 (s,1H),6·77 (m, 2H), 6·87 (d,J 2 8.8 Hz, 1H) &gt; 6. 94-7. 54 (m, 8H), 7·68-8.0 9 (m, 8H); MS (ESI) m/z 674 (MH1). 1 23 4-[(2S,4S)-Bu [3-methoxy-4-[Ν'-(2-mercaptophenyl)ureido]phenylthioto]]-4-(2-naphthyloxy ))-2-°Bilo °] 曱 曱 benzoic acid in 4-[(25,45)-:1-[3-methoxy-4-[『-(2-methylphenyl)ureido ]benzene

\\312\2d-code\90-01\89112968.ptd 第447頁 1283240 五、發明說明（443) 基乙醯基]-4 -（2 -萘氧基）—2 -咄咯啶基]甲氧苯甲酸曱酯 (415毫克，0.616毫莫耳）溶於THF (4. 9毫升）之溶液中加入 0· 25N NaOH(4· 9毫升）。於在室溫下攪拌3天後，將混合物 以IN HC1酸化，並以CHC13 - MeOH(10/l)萃取。將結合的萃 取液於Na2S04上乾燥，並於真空中濃縮。將殘留物於 1^(：[(：}1(：13/诞6〇11(10/1)]上純化而得1 23 ( 1 80 毫克，44°/〇之 無色非晶形。IR (KBr) 3354 、 2937 、 1685 、 1601 、 1533 、1 255 / 公分；UMR (DMS0-d6) 5 2.24 (s，3H)、 2.25-2·43 (m，2H)、3·65 (s，2H)、3·81 (s，3H)、 3.83 (m，1H)、4·05-4.70 (m，4H)、5·2 卜 5.33 (br， lH)、6.76(d，J = 7.3Hz，lH)、6.86-7.35 (m，9H)、7· 44 (t，J = 7,3 Hz，1H)、7·76-7·89 (m，6H)、8·01 (d， J = 8.3 Hz, 1H)、8·48 (s，1H)、8·56 (s，1H); MS(FAB) m/z 66 0 (MH1 )。 實施例11 6 4-[(2S，4S)-1 - [4-[N’ -（2-氣笨基）脈基]-3-曱氧苯基乙醯 基]-4-(2 -萘氧基）- 2 -吼咯啶基]甲氧苯甲酸\\312\2d-code\90-01\89112968.ptd Page 447 1283240 V. INSTRUCTIONS (443) Ethyl fluorenyl]-4 -(2-naphthyloxy)-2-pyrrolidinyl] To a solution of hydrazine oxalate (415 mg, 0.616 mmol) in THF (4.9 mL) was added &lt;RTIgt; After stirring at room temperature for 3 days, the mixture was acidified with EtOAc (EtOAc) (EtOAc) The combined extracts were dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified on 1^(:[(:}1(:13/6 〇11(10/1)) to give 1 23 (1 80 mg, 44 ° / 无 colorless amorphous. IR (KBr 3354, 2937, 1685, 1601, 1533, 1 255 / cm; UMR (DMS0-d6) 5 2.24 (s, 3H), 2.25-2·43 (m, 2H), 3·65 (s, 2H), 3·81 (s, 3H), 3.83 (m, 1H), 4·05-4.70 (m, 4H), 5·2 卜 5.33 (br, lH), 6.76 (d, J = 7.3 Hz, lH), 6.86-7.35 (m, 9H), 7.44 (t, J = 7, 3 Hz, 1H), 7·76-7·89 (m, 6H), 8·01 (d, J = 8.3 Hz, 1H ), 8·48 (s, 1H), 8.56 (s, 1H); MS (FAB) m/z 66 0 (MH1 ). Example 11 6 4-[(2S,4S)-1 - [4 -[N'-(2-indolyl)yl]-3-indolylphenylethyl]-4-(2-naphthyloxy)-2-pyridinyl]methoxybenzoic acid

4 - [(2S，4S) - l-[4-[N’ - (2-氣笨基）脲基]-3-甲氧苯基乙醮 基]-4-(2 -萘氧基）-2-咄咯啶基]甲氧苯甲酸甲酯4-[(2S,4S) - l-[4-[N' - (2-Acetyl)ureido]-3-methoxyphenylethenyl]-4-(2-naphthyloxy)- 2-oxaridinyl]methyl methoxybenzoate

\\312\2d-code\90-01\89112968.ptd 第448頁 1283240 五、發明說明（444)\\312\2d-code\90-01\89112968.ptd Page 448 1283240 V. Description of invention (444)

使4 - [N -(2 -氯苯基）脲基]—3-甲氧苯乙酸（31〇毫克，〇· 93¾莫耳）、4- [(2S，4S)-4-（2 -萘氧基）— 2-π比咯啶基]曱氧 苯曱酸甲醋（350毫克，0.93毫莫耳）、EDc · HC 1 ( 26 7毫 克’1.40毫莫耳）及DMAP(171毫克，ι·4〇毫莫耳）於DMF (1 0毫升）中之混合物在室溫下攪拌3天。將混合物倒入至 冰水中，並以E10 A c萃取。將結合的萃取液以冰水及鹽水 洗滌。於在NaJO4上乾燥後，將萃取液於真空中濃縮。使 殘留物於矽膠[100克，正己烷/Et〇Ac(l/l)〜CHCl3/MeOH (50/1)]上進行層析，而得4-[(2S，4S)-1-[4 - [N，-（2-氣苯 基）祕基]-3_曱氧苯基乙醯基]-4-(2 -萘氧基）-2 -吼咯啶 基]甲氧苯甲酸甲酯（ 450毫克，68%)的淡棕色非晶形。1 H-NMR (CDC13)(5 2.32 (m, 1H) ^2.58 (d, J = 14.5 Hz, 1H)、3.63 (d，J = 2.7 Hz，1H)、3·70 (s，3H)、3·86 (s，3H)、3·84-3·95 (m，2H)、4·15-4·64 (m，4H)、 5.11 (br, 1H) &gt; 6.79-7.0 6 (m, 7H) &gt;7.21-7.46 (m, 7H)、7.66-7.77 (m，3H)、7.92(d，J = 8.8Hz，lH)、7. 97 (m，1H)、8·17 (d，J = 8.4 Hz, 1H); MS(ESI) m/z 694 (MH1)、6 9 6 (MH3) 〇 於4-[(2S，4S) - 1-[4-[N，-（2-氯苯基）脲基]-3-甲氧笨基 乙醯基]- 4-(2 -萘氧基）-2 - σ比洛σ定基]甲氧苯甲酸曱酯（381 毫克，0.535毫莫耳）溶於THF(4.3毫升）之溶液中加入 0· 25N NaOH(4· 3毫升）。於在室溫下攪拌3天後，將混合物 以IN HC1酸化，並以CHC13-MeOH(10/l)萃取。將結合的萃4-[N-(2-Chlorophenyl)ureido]-3-methoxyphenylacetic acid (31 mg, 〇·933⁄4 mol), 4-[(2S,4S)-4-(2-naphthalene) Oxy)) 2-πpyrrolidyl]oxobenzoic acid methyl vinegar (350 mg, 0.93 mmol), EDC · HC 1 (26 7 mg '1.40 mmol) and DMAP (171 mg, ι - 4 mM of a mixture of DMF (10 ml) was stirred at room temperature for 3 days. The mixture was poured into ice water and extracted with E10 A c. The combined extracts were washed with ice water and brine. After drying on NaJO4, the extract was concentrated in vacuo. The residue was chromatographed on silica gel [100 g, n-hexane / EtOAc / EtOAc (50/1)] to give 4-[(2S,4S)-1-[4 - [N,-(2-Phenylphenyl)-based]-3_曱Oxophenyl Ethyl]-4-(2-naphthyloxy)-2-pyridinyl]methyl methoxybenzoate (450 mg, 68%) of light brown amorphous. 1 H-NMR (CDC13) (5 2.32 (m, 1H) ^2.58 (d, J = 14.5 Hz, 1H), 3.63 (d, J = 2.7 Hz, 1H), 3·70 (s, 3H), 3 · 86 (s, 3H), 3·84-3·95 (m, 2H), 4·15-4·64 (m, 4H), 5.11 (br, 1H) &gt; 6.79-7.0 6 (m, 7H &gt;7.21-7.46 (m, 7H), 7.66-7.77 (m, 3H), 7.92 (d, J = 8.8Hz, lH), 7. 97 (m, 1H), 8·17 (d, J = 8.4 Hz, 1H); MS (ESI) m/z 694 (MH1), 6 9 6 (MH3) 〇 4-[(2S,4S) - 1-[4-[N,-(2-chlorophenyl) ) ureido]-3-methoxyphenylethyl] 4-(2-naphthyloxy)-2 - σ pyrrolidine] methoxy methoxybenzoate (381 mg, 0.535 mmol) To a solution of THF (4.3 mL) was added EtOAc (EtOAc) (EtOAc). Combined extract

\\312\2d-code\90-01\89112968.ptd 第449頁 1283240 五、發明說明（445) 取液於Na2S04上乾燥，並於真空中濃縮。將殘留物於TLC [CHCl3/MeOH( 10/1)]上純化而得1 24( 1 40 毫克，39%)之無 色非晶形。IR (KBr) 3323、2935、1 704、1601、1529、 1 529、1 508 / 公分；UMR (DMSO-d6) 6 2· 27-2· 49 (m， 2H)、3·65 (s，2H)、3.81 (s，3H)、3·83 (m，1H)、 4 · 0 5 - 4 · 71 (m， 4 H)、5 · 3 0 (b r， 1 H)、6 · 7 7 ( d， J = 7 · 8 Hz，1H)、6.87-7.16 (m，4H)、7.14 (dd，J = 8.8、2·2\\312\2d-code\90-01\89112968.ptd Page 449 1283240 V. INSTRUCTIONS (445) The liquid was dried over Na2S04 and concentrated in vacuo. The residue was purified with EtOAc EtOAc EtOAc (EtOAc) IR (KBr) 3323, 2935, 1 704, 1601, 1529, 1 529, 1 508 / cm; UMR (DMSO-d6) 6 2· 27-2· 49 (m, 2H), 3·65 (s, 2H ), 3.81 (s, 3H), 3·83 (m, 1H), 4 · 0 5 - 4 · 71 (m, 4 H), 5 · 3 0 (br, 1 H), 6 · 7 7 (d , J = 7 · 8 Hz, 1H), 6.87-7.16 (m, 4H), 7.14 (dd, J = 8.8, 2·2

Hz, 1H) &gt;7.27 (t, J = 7.3 Hz, 1H) &gt; 7.29-7.46 (m, 4H)、7.76-7.86(m，5H)、7.96(d，J = 8.3Hz，lH)、8. 08 (dd，J = 8.3、1·2 Hz, 1H)、8.90 (s，1H)、8.93 (s， 1H) ; MS(FAB) m/z 680 (M+ + 1)、682 (MH3) ； C38H34C1N3 07 · 1H2 0 之分析計算值·· C, 6 5 · 3 7 ; H，5 · 2 0 ; N，6 · 0 2。實測 值：C, 65. 43 ； Η, 5.11； N, 5. 93 〇 實施例11 7 4 - [(2S,4S)-1-[3-甲氧基-4 - [Ν’ -（2-甲基苯基）脲基]苯基 乙醢基]-4 - (2 -萘氧基）_ 2 -吼洛σ定基]曱氧基-5 ~。比。定叛酸Hz, 1H) &gt;7.27 (t, J = 7.3 Hz, 1H) &gt; 7.29-7.46 (m, 4H), 7.76-7.86 (m, 5H), 7.96 (d, J = 8.3Hz, lH), 8 . 08 (dd, J = 8.3, 1·2 Hz, 1H), 8.90 (s, 1H), 8.93 (s, 1H); MS (FAB) m/z 680 (M+ + 1), 682 (MH3); C38H34C1N3 07 · 1H2 0 Analytical calculations·· C, 6 5 · 3 7 ; H,5 · 2 0 ; N,6 · 0 2 . Found: C, 65.43; Η, 5.11; N, 5. 93 〇 Example 11 7 4 - [(2S,4S)-1-[3-methoxy-4 - [Ν' -(2- Methylphenyl)ureido]phenylethenyl]-4 -(2-naphthyloxy)_ 2 -fluorene sigma] oxime-5 ~. ratio. Detergent acid

(2S，4S)-1-第三丁氧幾基-4_(2_秦氧基）-比洛π定敌酸曱 酯(2S,4S)-1-tert-butoxymethyl-4_(2_hhenyloxy)-bipro π-dead acid ester

89112968.ptd 第 450 頁 1283240 五、發明說明（446) 在室溫下在氮氣環境中，於（2S，4R)-1-第三丁氧羰基 -4-羥基-2 -咄咯啶羧酸甲酯（4.22克，17.2毫莫耳）、2-萘 酚（2.73克，18·9毫莫耳）及pph3(4· 96克，18.9毫莫耳）於 THF(80毫升）中之攪拌混合物中加入DIAD(3. 72毫升，18. 9 毫莫耳）。於攪拌隔夜後，將混合物於真空中濃縮。將殘 留物於矽膠[6 0 0克，CHCl3/EtOAc(10/l)]上進行層析而得 (2S，4S)-1-第三丁氧羰基-4_(2_萘氧基）-2 -咄咯啶羧酸甲 S旨（5 · 3 7克），將其不經進一步的純化而使用於後續的反 應。 (23,43)_1-第三丁氧羰基-4-(2-萘氧基）-2-吼咯啶羧酸89112968.ptd Page 450 1283240 V. INSTRUCTIONS (446) (2S,4R)-1-Tertidoxycarbonyl-4-hydroxy-2-pyridinylcarboxylic acid A in a nitrogen atmosphere at room temperature Ester (4.22 g, 17.2 mmol), 2-naphthol (2.73 g, 18.9 mmol) and pph3 (4.69 g, 18.9 mmol) in THF (80 mL). Add DIAD (3. 72 ml, 18.9 mmol). After stirring overnight, the mixture was concentrated in vacuo. The residue was chromatographed on silica gel [60 g, CHCl3 /EtOAc (10 /l)] to afford (2S,4S)-1-t-butoxycarbonyl-4-(2-naphthyloxy)-2 - hydrazine carboxylic acid methyl S (5 · 37 g) was used in the subsequent reaction without further purification. (23,43)_1-Tertidinoxycarbonyl-4-(2-naphthyloxy)-2-indoleidinecarboxylic acid

在室溫於（2S，4S)-1-第三丁氧羰基-4-(2 -萘氧基）-2-吼 咯啶羧酸曱酯（5. 37克）溶於THF(11 6毫升）之攪拌溶液中加 入0.25N NaOH(116毫升，29.0毫莫耳）。使所產生之混合 物攪拌隔夜。於移除溶劑後，將混合物經由加入1 N HC1酸 化，並以CHC13萃取。將結合的萃取液以鹽水洗滌，於 Na2S04上乾燥，並蒸發。利用正己烷-CHC13使殘留物再結 晶而得（2S，4S)-1-第三丁氧羰基-4-(2 -萘氧基）-2-吼咯啶 羧酸[4· 44克，85%(2步驟）]之白色粉末。l-NMR (DMSO-d6) 5 1· 37 及 1· 41 (s, 9H，醯胺異構物）、2· 26 (d， J = 13.9 Hz，1H)、2·65 (m，1H)、3·47 (d，J = 11.5 Hz， 1H)、3·81 (m，1H)、4·30 (m，1H)、5·14 (m，1H)、Ethyl tert-butyl (2S,4S)-1-tert-butoxycarbonyl-4-(2-naphthyloxy)-2-indrolidinecarboxylate (5. 37 g) was dissolved in THF (11 6 ml) at room temperature To the stirred solution was added 0.25 N NaOH (116 mL, 29.0 mmol). The resulting mixture was stirred overnight. After removing the solvent, the mixture was acidified by addition of 1 N HCl and extracted with CH. The combined extracts were washed with brine, dried over Na 2 SO 4 and evaporated. The residue was recrystallized from n-hexane-CHC13 to give (2S,4S)-1-tert-butoxycarbonyl-4-(2-naphthyloxy)-2-indoleidinecarboxylic acid [4·44 g, 85 % (2 steps)] white powder. l-NMR (DMSO-d6) 5 1·37 and 1·41 (s, 9H, decylamine isomer), 2·26 (d, J = 13.9 Hz, 1H), 2·65 (m, 1H) , 3·47 (d, J = 11.5 Hz, 1H), 3·81 (m, 1H), 4·30 (m, 1H), 5·14 (m, 1H),

89112968.ptd 第451頁 1283240 五、發明說明（447) 7.02-7.86 (m, 7H) ° (2S，4S) -1-第二丁氧幾基-4 -（2 -萘氧基）- 2_σΛσ各唆甲醇89112968.ptd Page 451 1283240 V. INSTRUCTIONS (447) 7.02-7.86 (m, 7H) ° (2S, 4S) -1-Secondoxybutoxy-4 -(2-naphthyloxy)- 2_σΛσ Methanol

在0°(：下於（25,48)-1-第三丁氧羰基-4-(2-萘氧基）-2-咄咯啶羧酸（1· 12克，3· 13毫莫耳）溶於THF (30毫升）之攪 拌溶液中加入M3 · DMS( 0· 63毫升，6. 3毫莫耳）。使混合 物立即提昇至室溫，然後在5 0 °C下加熱1. 5小時。於冷卻 至室溫後’經由在0 °C下加入水而使混合物停止反應，並 以EtOAc萃取。將結合的萃取液以鹽水洗滌，於Na2S04上乾 燥，並蒸發。使殘留物於矽膠[50克，CHCl3/MeOH (50/1)At 0° (: under (25,48)-1-tert-butoxycarbonyl-4-(2-naphthalenyloxy)-2-indolyl carboxylic acid (1·12 g, 3·13 mmol) 5小时。 Heating in a mixture of THF (30 ml) was added to M3 · DMS (0 · 63 ml, 6.3 mM). The mixture was immediately raised to room temperature, then heated at 50 ° C for 1.5 hours After cooling to room temperature, the mixture was quenched by the addition of water at 0 ° C, and extracted with EtOAc. The combined extracts were washed with brine, dried over Na 2 SO 4 and evaporated. 50 g, CHCl3/MeOH (50/1)

]上進行層析，而得（2S，4S)-1-第三丁氧羰基-4-(2-萘氧 基）-2-咣咯啶甲醇（1. 1〇克，1〇〇%)之淡黃色油。iH-NMR (CDC13) (5 1· 48 (s，9H)、2· 45 (m，1H)、3· 58-4· 80 (m，4H)、5·01 (br，1H)、7·04-7·99 (m，7H)。 曱基-2 - [(2S，4S)-1-第三丁氧幾基-4 -（2 -萘氧基）-2-。比口各 啶基]甲氧咄啶- 5 -羧酸酯Chromatography was carried out to give (2S,4S)-1-tert-butoxycarbonyl-4-(2-naphthyloxy)-2-indoleidinemethanol (1.1 g, 1%) Light yellow oil. iH-NMR (CDC13) (5 1· 48 (s, 9H), 2·45 (m, 1H), 3· 58-4· 80 (m, 4H), 5·01 (br, 1H), 7· 04-7·99 (m,7H). Mercapto-2 - [(2S,4S)-1-tert-butoxymethyl-4 -(2-naphthyloxy)-2-. Methio acridine-5-carboxylate

C02Me 在室溫下在氮氣環境中，於（2S，4S)_1-第三丁氧魏基 -4-(2 -萘氧基2-吼咯啶甲醇（484毫克，1·41毫莫耳）、 2 -羥基-5 -咄啶羧酸甲酯（21 6毫克’ 1 · 41毫莫耳）及pph3C02Me at room temperature in a nitrogen atmosphere at (2S,4S)_1-t-butoxypropionyl-4-(2-naphthyloxy 2-indoleridinyl methanol (484 mg, 1.41 mmol) , 2-hydroxy-5-azetidinecarboxylic acid methyl ester (21 6 mg '1 · 41 mmol) and pph3

\\312\2d-code\90-01\89112968.ptd 第452頁 1283240 五、發明說明（448) &quot; &quot; ( 370毫克，1·41毫莫耳）於THF(15毫升）中之攪拌混合物中 加入DIAD(0.28毫升，141毫莫耳）。使混合物攪拌隔夜。 於移除/谷劑後，使所產生之殘留物於矽膠[5 〇克，正己烧 /Et0Ac(2/l)]上進行層析，而得甲基—2-[(2S，4s)-；l 一第三 丁氧羰基-4-( 2-萘氧基）-2—咄咯啶基]甲氧咄啶—5_羧酸酯 (170¾ 克，25%)之無色油。ir — nmr (CDC13)(5 1.47 (s， 9H)、2·37 (m，1H)、2·46 (d，J=14.2 Hz，1H)、 3.7H.00 (m，2H)、3·89 (s，3H)、4·30-4·56 (m， 2H)、4·74 (dd，J = 9.8、4·6 Hz，1H)、5.06 (br, 1H)、6·70 (d，J = 8.8 Hz，2H)、7·0 5-7.09 (m，2H)、7· 33 (t，J = 6.9 Hz，1H)、7·42 (t，J = 6.9 Hz，1H)、 7.67-7·75 (m，3H)、8·〇9 (d，J = 8.8 Hz，1H)、8·77 (d， J=2· 2 Hz， 1H)。 2 - [(2S，4S)-4 -（2-萘氧基）一2 - π比π各ϋ定基]甲氧。比。定一5_羧酸 甲酯\\312\2d-code\90-01\89112968.ptd Page 452 1283240 V. Inventive Note (448) &quot;&quot; (370 mg, 1.41 mmol) in THF (15 mL) DIAD (0.28 ml, 141 mmol) was added to the mixture. The mixture was stirred overnight. After the removal/treasure, the resulting residue was chromatographed on silica gel [5 gram, Zhengjia/Et0Ac (2/l)] to give methyl-2-([2S,4s)- 1 a third butoxycarbonyl-4-(2-naphthyloxy)-2-bromopyridinyl]methoxyoxidine-5-carboxylate (1703⁄4 g, 25%) as a colorless oil. Ir — nmr (CDC13) (5 1.47 (s, 9H), 2·37 (m, 1H), 2·46 (d, J=14.2 Hz, 1H), 3.7H.00 (m, 2H), 3· 89 (s, 3H), 4·30-4·56 (m, 2H), 4·74 (dd, J = 9.8, 4·6 Hz, 1H), 5.06 (br, 1H), 6.70 (d , J = 8.8 Hz, 2H), 7·0 5-7.09 (m, 2H), 7· 33 (t, J = 6.9 Hz, 1H), 7·42 (t, J = 6.9 Hz, 1H), 7.67 -7·75 (m, 3H), 8·〇9 (d, J = 8.8 Hz, 1H), 8.77 (d, J=2· 2 Hz, 1H). 2 - [(2S, 4S)- 4-(2-naphthyloxy)- 2 - π ratio π ϋ ] ] methoxy] methyl.

在室溫下於5-羧甲基-2-[(2S，4S)-1-第三丁氧羰基-4-(2 -萘氧基）-2 -吼咯啶基]甲氧吼啶（170毫克，0.36毫莫 耳）溶於CH2C12(5毫升）之攪拌溶液中加入TFA(2毫升）。於 攪拌2小時後，將混合物於真空中濃縮，將其以CH2C 12稀 釋，並經由加入IN NaOH而鹼化。以(：112(：12萃取結合的反應 混合物。將有機層以鹽水洗滌，將其於NaS04上乾燥並濃5-carboxymethyl-2-[(2S,4S)-1-t-butoxycarbonyl-4-(2-naphthyloxy)-2-pyridinyl]methoxyoxidine at room temperature ( To a stirred solution of CH2C12 (5 mL) was added EtOAc (2 mL). After stirring for 2 hours, the mixture was concentrated in vacuo, diluted with CH.sub.2 C.sub.2, and basified with &lt The reaction mixture was extracted with (:112 (:12). The organic layer was washed with brine, dried over NaS04 and concentrated.

89112968.ptd 第453頁 1283240 五、發明說明（449) 縮。使殘留物於几(：[(：11(：13/^^011(10/1)]上純化而得 2_[(2S，4S)-4-(2-萘氧基）-2-吼咯啶基]曱氧咄啶-5 -羧酸 曱酯（107 毫克，80%)之無色油。1H_NMR (CDC13) 5 1. 95 (m，1H)、2·27 (br，1H)、2·46 (m，1H)、3·19 (dd，J = 12·2、4.9Hz，1H)、3·41 (d, J = 12.2Hz, 1H)、3·65 (m， 1H)、3.89 (s，3H)、4·58 (m，2H)、5·00 (br，1H) 、6·77 (d，J = 8.8 Hz, 1H)、7.06 (br，1H)、7·11 (dd， J = 8.8、2.7 Hz，1H)、7.3卜7.45 (m，2H)、7·69-7.76 (m，3H)、8·13 (dd，J = 8.8、2·4 Hz，1H)、8·78 (d，J = 2·2 Hz, 1H)。 2-[(2S，4S)-1-[3-甲氧基-4 - [Ν’ -（2-甲基苯基）脲基]苯基 乙醯基]- 4- (2 -萘氧基）-2 - σ比σ各唆基]甲氧基-5-nba定叛酸 甲基酯 使3-甲氧基-4 - [Ν’ - (2-甲基苯基）脲基]苯乙酸（89毫 克 ’0.283 毫莫耳）、曱基-2-[(2S,4S)-4-(2-萘氧基）-2 -咄咯啶基]甲氧吡啶-5 -羧酸酯（107毫克，〇· 78毫莫耳）、 EDC · HC1(81 毫克，〇· 425 毫莫耳）及DMAPC52 毫克，0· 425 毫莫耳）於DMF(3毫升）中之混合物在室溫下攪拌1 8小時。 將混合物倒入至冰水中，並以E10 A c萃取。將結合的萃取 液以冰水及鹽水洗務。於在N a2 s 〇4上乾燥後，將萃取液於 真空中濃縮。使殘留物於几(：[(：11(：13/籠6〇11(1〇/1)]上純化89112968.ptd Page 453 1283240 V. Description of invention (449) Contraction. The residue was purified on several (:[(:13/^^011 (10/1)]) to give 2-[(2S,4S)-4-(2-naphthyloxy)-2-pyrrole a colorless oil of pyridyl-5-carboxylic acid oxime ester (107 mg, 80%). 1H_NMR (CDC13) 5 1. 95 (m, 1H), 2·27 (br, 1H), 2· 46 (m, 1H), 3·19 (dd, J = 12·2, 4.9 Hz, 1H), 3.41 (d, J = 12.2 Hz, 1H), 3·65 (m, 1H), 3.89 ( s, 3H), 4·58 (m, 2H), 5·00 (br, 1H), 6.77 (d, J = 8.8 Hz, 1H), 7.06 (br, 1H), 7·11 (dd, J = 8.8, 2.7 Hz, 1H), 7.3, 7.45 (m, 2H), 7·69-7.76 (m, 3H), 8·13 (dd, J = 8.8, 2·4 Hz, 1H), 8· 78 (d, J = 2·2 Hz, 1H) 2-[(2S,4S)-1-[3-methoxy-4 -[Ν' -(2-methylphenyl)ureido]benzene醯 醯 ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] ] 3- 3- 3- 3- - (2-methylphenyl)ureido]phenylacetic acid (89 mg '0.283 mmol), mercapto-2-[(2S,4S)-4-(2-naphthyloxy)-2-pyrrole Pyridyl] methoxypyridine-5-carboxylate (107 mg, 〇 · 78 mmol), EDC · HC1 (81 mg, 〇 · 425 mmol) A mixture of DMAPC (50 mg, 0. 425 mmol) in DMF (3 mL) was stirred at room temperature for 18 hr. The mixture was poured into ice water and extracted with E10 A c. Washing with water and brine. After drying on Na 2 s 〇 4, concentrate the extract in vacuo to make the residue a few (:[(:11(:13/cage 6〇11(1〇/1)) Upper purification

89112968.ptd89112968.ptd

第454頁 1283240 五、發明說明（450)Page 454 1283240 V. Description of invention (450)

而得2- [(2S，4S) -1-[3-甲氧基-4 - [N，-（2-甲基苯基）脲基] 苯基乙醯基]-4-(2 -萘氧基）-2 -吼咯啶基]甲氧基—5 —。比啶 羧酸甲基酯（193毫克，1〇〇%)的無色非晶形。ljj-NMR (CDC13) 5 2· 2 7 (d，J = 3· 2 Ηζ，3Η)、2· 30 (m，1Η)、2. 49 (dd，J二 14·2、2·0 Hz, 1Η)、3·60 (d，J:3.9 Ηζ， 1H) 、3·67 (d， J=5.9 Hz， 3H) 、3.81 (s， 1H) 、3·8 (s， 1H)、3·88 及3·91 (s，3H，醯胺異構物）、3·95 (m，ih) 、4·02 - 5.0 9 (m，4H)、6·67 (d，J = 8.8 Hz，1H)、6·73 -7·13 (m，3H)、7·20-7·45 (m，7H)、7·53 (t，J=7.8 Hz，1H)、7·67-7.77 (m，3H)、8·02-8·84 (m，3H)。 關於HC1鹽：淡棕色非晶形。ir (KBr) 3346、2 9 5 1、1 720 、1601、1533、1281/公分；MS(FAB) m/z 675 (M+ + 1)。 於2-[(2S，4S)-1 -[3-甲氧基-4-[N，-（2-甲基苯基）脲基] 苯基乙醯基]-4-(2 -萘氧基）-2 -吼咯啶基]曱氧基-5 -吼啶 羧酸曱基酯（158毫克，0.23毫莫耳）溶於THF(1. 8毫升）之 溶液中加入0. 25N NaOH( 1. 8毫升）。於在室溫下攪拌22小 時後，將混合物以11^11(：1中和，並以(：11(：1316〇}1(10/1)萃 取。將結合的萃取液於N a2 S 04上乾燥，並於真空中濃縮。 將殘留物於几(：[(：11(：13/心011(5/1)]上純化而得125(51毫 克，34%)之無色非晶形固體。IR (KBr) 3354、2 9 5 6、 1601、1 5 33、1 2 55、1 0 2 2 / 公分；1-NMR (DMSO-d6) (5 2. 24 (s，3H)、3. 30 - 5· 32 (m，1 3H )、6· 72 - 8· 82 (m， 19H) ； MS (FAB) m/z 661 (MH1 ) ； C38H36N4 07 · 0. 5EtOH · 1H 20 之分析計算值：C，6 6. 75 ; H， 5. 89 ; N，7· 98。實測And 2-[(2S,4S)-1-[3-methoxy-4 -[N,-(2-methylphenyl)ureido]phenylphenyl]-4-(2-naphthalene) Oxy)-2-pyridridinyl]methoxy-5-. A colorless amorphous form of a pyridine carboxylic acid methyl ester (193 mg, 1%). ljj-NMR (CDC13) 5 2· 2 7 (d, J = 3· 2 Ηζ, 3Η), 2·30 (m, 1Η), 2. 49 (dd, J 2, 14.2, 2·0 Hz, 1Η), 3·60 (d, J: 3.9 Ηζ, 1H), 3.67 (d, J=5.9 Hz, 3H), 3.81 (s, 1H), 3·8 (s, 1H), 3.88 And 3.91 (s, 3H, guanamine isomers), 3·95 (m, ih), 4·02 - 5.0 9 (m, 4H), 6·67 (d, J = 8.8 Hz, 1H) , 6.73 -7·13 (m, 3H), 7·20-7·45 (m, 7H), 7·53 (t, J=7.8 Hz, 1H), 7·67-7.77 (m, 3H ), 8·02-8·84 (m, 3H). Regarding the HCl salt: light brown amorphous. Ir (KBr) 3346, 2 9 5 1, 1 720, 1601, 1533, 1281/cm; MS (FAB) m/z 675 (M+ + 1). 2-[(2S,4S)-1 -[3-methoxy-4-[N,-(2-methylphenyl)ureido]phenylphenyl]-4-(2-naphthyloxy) 25N NaOH((2) 吼 吼 吼 ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( 1. 8 ml). After stirring at room temperature for 22 hours, the mixture was neutralized at 11^11 (:1) and extracted with (:11 (:1316 〇}1 (10/1). The combined extract was applied to Na 2 S 04 It was dried and concentrated in vacuo. EtOAc (EtOAc:EtOAc. IR (KBr) 3354, 2 9 5 6 , 1601, 1 5 33, 1 2 55, 1 0 2 2 / cm; 1-NMR (DMSO-d6) (5 2. 24 (s, 3H), 3. 30 - 5· 32 (m,1 3H ),6·72 - 8· 82 (m, 19H) ; MS (FAB) m/z 661 (MH1 ) ; C38H36N4 07 · 0. 5EtOH · 1H 20 Analysis calculated: C,6 6. 75 ; H, 5. 89 ; N,7· 98. Measured

W312\2d-code\90-01\89112968.ptd 第 455 頁 1283240 五、發明說明（451) 值：C，6 6.3 9； H, 5. 55 ； N, 7.66° 實施例11 8 4 - [5 -（R) -芊氧甲基-1-[4 - [Ν’ -(2-甲基苯基）脲基]苯基乙 醯基]-2 -（ S ) -吼咯啶甲氧基]苯曱酸W312\2d-code\90-01\89112968.ptd Page 455 1283240 V. INSTRUCTIONS (451) Value: C,6 6.3 9; H, 5. 55 ; N, 7.66° Example 11 8 4 - [5 -(R)-芊Oxymethyl-1-[4- [Ν'-(2-methylphenyl)ureido]phenylethenyl]-2 -(S)-pyrrolidinemethoxy] Benzoic acid

卜苄氧基-2-(R)-羥基-5-己烯Bubenzyloxy-2-(R)-hydroxy-5-hexene

在-78 °C下於苄基-（S) -環氧丙醚（5.0克，30.5毫莫耳） 溶於THF( 100毫升）之攪拌溶液中加入氯化烯丙鎂（1 · 0 Μ於 Et20，30. 5毫升，30. 5毫莫耳），並在攪拌下使所產生之 混合物逐漸升溫至室溫。將混合物倒入至水中並於真空中 濃縮，然後以CHC13萃取。將有機層於無水Na2S04上乾燥， 並於真空中濃縮。使殘留物於矽膠上利用己烷-EtOAc (5:1)作為洗提液進行層析，而得1-苄氧基-2-(R) -經基 - 5-己烯（2.18 克，35%)之無色油。1H-NMR (CDC13) (5 1. 52 -1.60 (m，2H)、2.1卜2.25 (m，2H)、2·34 (d，J 二3·2 Ηζ，1Η)、3·35 (dd，J = 9.6、8·0 Hz, 1Η)、3·52 (dd， J = 9.6、3·2 Hz，1H)、3·84_3·86 (m，1H)、4·57 (s， 2H)、4·96 - 5.0 7 (m 系列，2H)、5·78-5·88 (m， 1H) 、7.29 -7.38 (m，5H); MS(ESI) m/z，224 (MHNH4+)。 1 -苄氧基-2-(S) -酞醯亞胺基-5-己烯Add allylmethylene chloride (1 · 0 Μ) to a stirred solution of benzyl-(S)-glycidyl ether (5.0 g, 30.5 mmol) in THF (100 mL) at -78 °C Et20, 30. 5 ml, 30.5 mmol), and the resulting mixture was gradually warmed to room temperature with stirring. The mixture was poured into water and concentrated in vacuo, then extracted with CHCI. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane-EtOAc (5:1) to afford 1-benzyloxy-2-(R)- yl- 5-hexene (2.18 g, 35 %) of colorless oil. 1H-NMR (CDC13) (5 1. 52 -1.60 (m, 2H), 2.1 b 2.25 (m, 2H), 2·34 (d, J 2·3 Ηζ, 1Η), 3·35 (dd, J = 9.6, 8·0 Hz, 1Η), 3·52 (dd, J = 9.6, 3·2 Hz, 1H), 3·84_3·86 (m, 1H), 4·57 (s, 2H), 4·96 - 5.0 7 (m series, 2H), 5·78-5·88 (m, 1H), 7.29 - 7.38 (m, 5H); MS (ESI) m/z, 224 (MHNH4+). Benzyloxy-2-(S)-indenido-5-hexene

\\312\2d-code\90-01\89112968.ptd 第456頁 1283240 五、發明說明（452)\\312\2d-code\90-01\89112968.ptd Page 456 1283240 V. Description of invention (452)

在室溫下於卜苄氧 10· 5毫莫耳）、三笨鱗土〜—（R)—羥基-5-己烯（2· 18克， d.86克，12·7毫莫耳、·32克，I2.7毫莫耳）及酞醯亞胺 丙酯（2 · 6 2毫升，1 2 7 a之攪拌溶液中加入偶氮二羧酸二異 溫下攪拌隔夜。將混4/Λ) ’並使所產生之混合物在室 取。將有機層以水洗；物：ί空中濃縮’並以叫萃 細。使殘留物於石夕膠上利用己烧_Et〇Ac(5:l)作為 =進行層#，而得卜爷氧基―2—⑻—酜醯亞…-己 、•5克’83%)之無色油。111-關1?(〇0(：13)(5 1.76-1.84 m’ 2H)、2·06 (dd，J=i4.4、6·8 Ηζ)、2Η、2·12 - 2.22 (m’ 1H)、3·69 (dd，j = i〇.0、5·6 Hz，1H)、4 〇〇 (t， J:9.6 Hz，1H)、4·46 (d，J = 12.0 Hz, 1H)、4.53 (d，At room temperature in benzyloxy 10·5 mmol, three stupids ~-(R)-hydroxy-5-hexene (2·18 g, d.86 g, 12·7 mmol, · 32 grams, I2.7 millimolar) and imipenem propyl ester (2 · 6 2 ml, 1 2 7 a stirred solution was added to the azodicarboxylic acid at diiso warm temperature and stirred overnight. Λ) 'And take the resulting mixture in the chamber. The organic layer is washed with water; the material: ί is concentrated in the air and is called finely extracted. The residue was made on the Shishi gum by using _Et〇Ac (5:1) as the layer =, and the sulphate oxy-2-(8)-酜醯亚...-hex, • 5 g '83% ) colorless oil. 111-OFF 1?(〇0(:13)(5 1.76-1.84 m' 2H), 2·06 (dd, J=i4.4, 6·8 Ηζ), 2Η, 2·12 - 2.22 (m' 1H), 3·69 (dd, j = i〇.0, 5·6 Hz, 1H), 4 〇〇 (t, J: 9.6 Hz, 1H), 4·46 (d, J = 12.0 Hz, 1H ), 4.53 (d,

Hz， 1H)、4.5 卜 4.58 (m，1H)、4.9 卜 4·99 (m 系 列，2H)、5·72 - 5·79 (m，1H)、7·2 卜 7.26 (m，5H)、 7.71 -7.83 (m 系列，2H); MS(ESI) m/z， 336(M+ + H)。 2-(S) -胺基—i —辛氧基—5_己烯Hz, 1H), 4.5 Bu 4.58 (m, 1H), 4.9 Bu 4·99 (m series, 2H), 5·72 - 5·79 (m, 1H), 7·2 Bu 7.26 (m, 5H), 7.71 - 7.83 (m series, 2H); MS (ESI) m/z, 336 (M+ + H). 2-(S)-Amino-i-octyloxy-5-hexene

在室溫下於1-苄氧基—2-(S) -酞醯亞胺基-5-己烯（2· 95 克’ 8. 80毫莫耳）溶於Et0H( 30毫升）之攪拌溶液中加入水Stirred solution of 1-benzyloxy-2-(S)-indolyl-5-hexene (2.95 g ' 8. 80 mmol) in Et0H (30 mL) at room temperature Add water

\\312\2d-code\90-01\89112968.ptd 第457頁 1283240 發明說明（453) 合肼（80%溶於水，460毫升，Π·4毫莫耳），並使所產生之 混合物在授摔下迴流加熱7· 5小時。將溶液過濾，並將濾 液於真空中濃縮。將殘留物倒入至NaHC〇3水溶液中，並以 CHCI3萃取。將有機層於無水心2如4上乾燥，然後於真空中 濃縮而得2-(S)-胺基-1-爷氧基—5—己烯（19〇毫克，定量） 之無色油。iH - NMR (CDCl3)5 化系列，4H)、 2·08-2·19 (m，2H)、2·9&quot;·03 (m，1Η)、3·25 ⑷， J = 9.2、7.6 Hz，1H)、3·45 (dd, J = 9 2、4 〇 Hz，1H)、 4·53 (s，2H)、4·94-5·06 (m 系列，2H)、5.76 -5.85 (m， 1H) 、7·27-7·37 (m， 5H); MS(ESI) m/z ， 206 (MHH)、247(M. + H + CH3CN)。 N-[2-（S)-（1-窄氧基）一5一己烯基]苯甲醯胺\\312\2d-code\90-01\89112968.ptd Page 457 1283240 Description of invention (453) Combined (80% soluble in water, 460 ml, Π·4 mmol) and the resulting mixture The heating was carried out under reflux for 7 hours. The solution was filtered and the filtrate was concentrated in vacuo. The residue was poured into an aqueous solution of NaHC〇3 and extracted with CHCI3. The organic layer was dried over anhydrous EtOAc (EtOAc) (EtOAc m. iH - NMR (CDCl3) 5 series, 4H), 2·08-2·19 (m, 2H), 2·9&quot;·03 (m, 1Η), 3·25 (4), J = 9.2, 7.6 Hz, 1H), 3·45 (dd, J = 9 2, 4 〇 Hz, 1H), 4·53 (s, 2H), 4·94-5·06 (m series, 2H), 5.76 - 5.85 (m, 1H), 7·27-7·37 (m, 5H); MS (ESI) m/z, 206 (MHH), 247 (M. + H + CH3CN). N-[2-(S)-(1-Nativeoxy)-5-hexenyl]benzamide

在^溫下於2-(S) -胺基苄氧基一5_己烯（1·89克， 9· 21毫莫^)及三乙胺（1· 28毫升，9· 21毫莫耳）溶於 毫升）之攪拌溶液中加入苯甲醯氯（丨· 〇7毫升， 从21笔莫耳），並使所產生之混合物攪拌23小時。將混合 倒入至水中，並以eld2萃取。將有機層以水洗滌，於 …、水NaJO4上乾燥，然後於真空中漠縮。使殘留物於矽膠 用己Ht0Ac(5:1)作為洗提液進行層析，而得 — (1—卞氧基）一5一己烯基]苯甲醯胺（2.67克，94%)之 …、針狀物。熔點78-79 °C ; ih-NMR (CDC13) 5 1· 76-1· 822-(S)-Aminobenzyloxy-5-hexene (1·89 g, 9·21 mmol) and triethylamine (1·28 ml, 9·21 mmol) at a temperature To a stirred solution of ML), benzamidine chloride (7 ml, from 21 moles) was added, and the resulting mixture was stirred for 23 hours. The mixture was poured into water and extracted with eld2. The organic layer was washed with water, dried on water NaJO4, and then dried in vacuo. The residue was chromatographed on silica gel with Ht0Ac (5:1) as eluent to give -(1-methoxy)-5-hexenyl]benzamide (2.67 g, 94%). , needles. Melting point 78-79 °C; ih-NMR (CDC13) 5 1· 76-1· 82

第458頁 1283240 五、發明說明（454) (m，2H)、2·11-2·17 (m，2H)、3·59 (brs，2H)、4·29 -4·35 (m, 1Η)、4·54 (dd，J = 19.2、12·0 Ηζ，2Η)、 4·9 6 - 5.0 5 (m 系列，2H) 、5·78 - 5.89 (m， 1H)、6·39 (d， JU Hz, 1H)、7·27-7·51 (m，8H)、7·74 (d，J = 7.2Page 458 1283240 V. INSTRUCTIONS (454) (m, 2H), 2·11-2·17 (m, 2H), 3·59 (brs, 2H), 4·29 -4·35 (m, 1Η) ), 4·54 (dd, J = 19.2, 12·0 Ηζ, 2Η), 4·9 6 - 5.0 5 (m series, 2H), 5.78 - 5.89 (m, 1H), 6.39 (d , JU Hz, 1H), 7·27-7·51 (m, 8H), 7·74 (d, J = 7.2

Hz，2H) ; MS(ESI) m/z，310(M+ + H)。 N-Boc - 2 -（S) -苯甲醯氧甲基-5 -（S)_爷氧甲基吼嘻σ定Hz, 2H); MS (ESI) m/z, 310 (M+ + H). N-Boc - 2 -(S)-benzhydryloxymethyl-5 -(S)_ methoxymethyl吼嘻 定

於N-[2-(S)-(1-窄氧基）-5-己烯基]苯甲醯胺（2·41克， 7· 79毫莫耳）溶於CH3CN-H2〇(3: 1，40毫升）之攪拌溶液中將 碘（2· 97克，23. 4毫莫耳）一次加入，並使所產生之混合物 攪拌20小時。將混合物倒入至NazS2〇3水溶液中，並於真空 中濃縮，然後以CHC13萃取。將有機層以鹽水洗條，於無 水NagSO4上乾燥，然後於真空中濃縮。將殘留物溶解於CH 2C12( 30毫升）中，並加入二碳酸二-第三丁酯（2· 55克，11. 7毫莫耳）、Et3N(1.63毫升，11.7毫莫耳）及N，N-二曱胺基 吡啶（180毫克，1. 47毫莫耳），並使所產生之混合物在室 溫下攪拌隔夜。將混合物倒入至水中，並以CH2C 12萃取。 將有機層以水洗滌，於Na2S04上乾燥，並於真空中濃縮。 使殘留物於矽膠上利用己烷-EtOAc(5:l)進行層析，而得 N-Boc-2-（S) -苯甲醯氧甲基-5-（S)-窄氧甲基^比略唆（1. 27 克，38%)之無色油。iH-NMR (CDC13) δ 1· 41 及1· 49 (s， 總計91〇、1.85- 2.00 (111系列，41〇、3.3 3-4.5 9 (111系列，N-[2-(S)-(1-Nativeoxy)-5-hexenyl]benzamide (2.41 g, 7.79 mmol) dissolved in CH3CN-H2 (3: Iodine (2.97 g, 23.4 mmol) was added in one portion of a stirred solution of 1,40 ml), and the resulting mixture was stirred for 20 hours. The mixture was poured into a NazS 2 2 aqueous solution and concentrated in vacuo then extracted with CH. The organic layer was washed with brine, dried over anhydrous NagSO4 and then concentrated in vacuo. The residue was dissolved in CH 2 C 12 (30 mL), and di-t-butyl dicarbonate (2.55 g, 11.7 mmol), Et3N (1.63 mL, 11.7 mmol) and N. N-Diaminoguanidine pyridine (180 mg, 1.47 mmol) and the resulting mixture was stirred at room temperature overnight. The mixture was poured into water and extracted with CH2C12. The organic layer was washed with water, dried over Na2ss The residue was chromatographed on silica gel eluting with hexane-EtOAc (5:1) to give N-Boc-2-(S)-benzylideneoxymethyl-5-(S)-n-n-oxymethyl A slightly colorless oil (1. 27 grams, 38%). iH-NMR (CDC13) δ 1· 41 and 1·49 (s, total 91〇, 1.85- 2.00 (111 series, 41〇, 3.3 3-4.5 9 (111 series,

\\312\2d-code\90-01\89112968.ptd 第 459 頁 1283240 五、發明說明（455) 8H)、7. 26-7.32 (m，5H)、7·41—7.46 (m，2H)、7·54-7· 57 (m，1Η)、8·02 (d，Ρ7·6 Ηζ，2H); MS(ESI) m/z， 426(M++ H)、448(MHNa + )。 N-Boc-5-(S)-羥甲基-2-（S) -爷氧甲基。比咯啶 在室溫下於N-Boc-2-（S)-苯甲醯氧甲基-5-(S)_窄氧甲 基咄咯啶（1. 23克，2. 89毫莫耳）溶於MeOH( 30毫升）之攪拌 溶液中加入NaOH(l . 0 Μ溶於水，3. 47毫升，3. 47毫莫 耳），並使所產生之混合物攪拌4小時。將混合物以1 N HC 1 水溶液中和並於真空中濃縮’然後以CHC 13萃取。將有機 層以鹽水洗滌，於無水Na2S04上乾燥，然後於真空中濃 縮。使殘留物於矽膠上利用己烷-Et0Ac(3 : 1)作為洗提液 進行層析，而得N-Boc-5 -（S)-羥曱基-2-(S) -爷氧甲基咄 咯啶（847 毫克，91%)之無色油。111-關1?(00(：13)(51.41 (s，9H)、1·57 (brs，1H)、1.9 5- 1.9 7 (m，2H)、2.05 -2.18 (m，1H)、3.36 (t，J = 8.4 Hz，1H)、3·56-3·62 (m，2Η)、3·67 - 3·72 (m，2Η)、3·95 (brs，1Η)、4·03 (brs，1H)、4·51 (s，1H)、7. 2 8-7.37 (m，5H); MS(FAB) m/z，32 2 (M+ + H)。 4- [2-(S)-(N-Boc-5-(S)- f氧甲基）吼洛唆甲氧基]苯甲酸 甲酯\\312\2d-code\90-01\89112968.ptd Page 459 1283240 V. Description of invention (455) 8H), 7. 26-7.32 (m, 5H), 7·41—7.46 (m, 2H) , 7·54-7· 57 (m, 1Η), 8·02 (d, Ρ7·6 Ηζ, 2H); MS (ESI) m/z, 426 (M++ H), 448 (MHNa + ). N-Boc-5-(S)-hydroxymethyl-2-(S)-yloxymethyl. Bilidine at room temperature in N-Boc-2-(S)-benzylideneoxymethyl-5-(S)-narrow oxymethylpyrrolidine (1. 23 g, 2.89 mmol) To a stirred solution of MeOH (30 mL) was added EtOAc (l············· The mixture was neutralized with 1 N aqueous HCl solution and concentrated in vacuo then extracted with CH. The organic layer was washed with brine, dried over anhydrous Na.sub.2SO.sub. The residue was chromatographed on silica gel using hexane-Et0Ac (3:1) as eluent to give N-Boc-5-(S)-hydroxymethyl-2-(S)-yloxymethyl A colorless oil of cockrole (847 mg, 91%). 111-OFF 1?(00(:13)(51.41 (s,9H), 1.57 (brs,1H), 1.9 5- 1.9 7 (m,2H), 2.05 -2.18 (m,1H), 3.36 ( t, J = 8.4 Hz, 1H), 3·56-3·62 (m, 2Η), 3·67 - 3·72 (m, 2Η), 3·95 (brs, 1Η), 4·03 (brs , 1H), 4·51 (s, 1H), 7. 2 8-7.37 (m, 5H); MS (FAB) m/z, 32 2 (M+ + H). 4- [2-(S)- (N-Boc-5-(S)-f oxymethyl) 吼 唆 methoxy] methyl benzoate

\\312\2d-code\90-01\89112968.ptd 第 460 頁 1283240 五、發明說明（456) 在室溫下於N-Boc-2-(S) -羥甲基-5-(S) -爷氧甲基吼，各 啶（ 388毫克，1· 21毫莫耳）、三苯膦（ 380毫克，1· 45毫莫 耳）及4 -羥基苯甲酸甲酯（220毫克，1.45毫莫耳）之授拌溶 液中加入偶氮二羧酸二異丙酯（200毫升，ι·45毫莫耳）， 並使所產生之混合物攪拌隔夜。將混合物於真空中濃縮， 並以EtOAc萃取。將有機層以水洗滌，於無水Na2S〇4上乾 燥，然後於真空中濃縮。使殘留物於矽膠上利用己烧 - EtOAc(3:l)作為洗提液進行層析，而得4—[2-(S)- (N_Boc-5-(S)-窄氧甲基）吼咯啶甲氧基]苯曱酸甲酯（462 毫克，84%)之無色油：iH-NMR (CDC13) δ 1.40 及 1.48 (s， 總計 9Η)、1·98-2.13 (m，4Η)、3·83 及 3.85 (s，3Η)、3 33-4.25 (m 系列，4Η)、4·47-4·59 (m， 2Η)、6.91 - 6·96 (m，2Η)、7·26-7·34 (m，5Η)、7. 9 5-7.98 (m，2H); MS(FAB) m/z，45 6 (MHH)、4 78 (MHNa+)。 4-[2-(S) -（5 -（S) -笮氧甲基）咄咯啶甲氧基]苯曱酸曱酯\\312\2d-code\90-01\89112968.ptd Page 460 1283240 V. INSTRUCTIONS (456) At room temperature in N-Boc-2-(S)-hydroxymethyl-5-(S) - oxymethyl hydrazine, each pyridine (388 mg, 1. 21 mmol), triphenylphosphine (380 mg, 145 mmol) and methyl 4-hydroxybenzoate (220 mg, 1.45 mmol) To the mixing solution of the ear), diisopropyl azodicarboxylate (200 ml, ι·45 mmol) was added, and the resulting mixture was stirred overnight. The mixture was concentrated in vacuo and extracted with EtOAc. The organic layer was washed with water, dried over anhydrous Na? The residue was chromatographed on silica gel using hexane-EtOAc (3:1) eluted to afford 4-[2-(S)-(N-Boc-5-(S)-N-N-methyl) Colorless oil of methyl pyridyl methoxy]benzoate (462 mg, 84%): iH-NMR (CDC13) δ 1.40 and 1.48 (s, total 9 Η), 1.98-2.13 (m, 4 Η), 3·83 and 3.85 (s, 3Η), 3 33-4.25 (m series, 4Η), 4·47-4·59 (m, 2Η), 6.91 - 6·96 (m, 2Η), 7·26- 7·34 (m, 5Η), 7. 9 5-7.98 (m, 2H); MS (FAB) m/z, 45 6 (MHH), 4 78 (MHNa+). 4-[2-(S) -(5 -(S)-indolylmethyl)oxaridinylmethoxy]phenyl decanoate

在室溫下於4-[2-(S) -（N-Boc-5-(S) -爷氧甲基）π比略咬 甲氧基]苯甲酸甲酯（446毫克，0.98毫莫耳）溶於CH2C12 (10毫升）之攪拌溶液中加入三氟乙酸（10毫升），並使所產 生之混合物攪拌1小時。將混合物於真空中濃縮，並倒入Methyl 4-(2-(S)-(N-Boc-5-(S)-yloxymethyl) π ratio slightly methoxy]benzoic acid at room temperature (446 mg, 0.98 mmol) Trifluoroacetic acid (10 ml) was added to a stirred solution of CH2C12 (10 ml), and the mixture was stirred for one hour. Concentrate the mixture in vacuo and pour

\\312\2d-code\90-01\89112968.ptd 第461頁 1283240 五、發明說明（457) 至NaHC〇3水溶液中，然後以CHCI3萃取。將有機層以水洗 滌，於無水NaJO4上乾燥，然後於真空中濃縮而胃得4—[2 -（S)-(5-（S)-辛氧曱基）吼咯啶甲氧基]笨曱酸曱酯（363毫 克’定量）之淡黃色油。將產物不經進一步的純化而使用 於後續的反應。1H-NMR (CDC13) (5 1. 43- 1. 6 5 (m, 2H)、 1·93-2.07 (m， 3H) 、3·36-3.68 (m 系列，4H) 、3·89 (s 3Η)、3·86 — 3·93 (重疊，2Η)、4.55 (s， 2Η)、6.90 (d， J = 8.4 Hz，2H)、7·26-7·37 (m, 5H)、7,97 (d，J = 8.4’ Hz，2H) ; MS(FAB) m/z，356(MHH)。 4-[5-(R)-笮氧·曱基—卜[4_[N，—（2-甲基苯基）脲基]苯基乙 醯胺基]- 2 -（ S) -咄咯啶曱氧基]笨曱酸曱酯\\312\2d-code\90-01\89112968.ptd Page 461 1283240 V. Inventive Note (457) Into an aqueous NaHC〇3 solution, then extract with CHCI3. The organic layer was washed with water, dried over anhydrous NaJO4, and then concentrated in vacuo to give 4-[2-(S)-(5-(S)-octyloxy)pyridinylmethoxy] Ethyl decanoate (363 mg 'quantitative) of pale yellow oil. The product was used in the subsequent reaction without further purification. 1H-NMR (CDC13) (5 1. 43- 1. 6 5 (m, 2H), 1.93-2.07 (m, 3H), 3·36-3.68 (m series, 4H), 3·89 (s 3Η), 3·86 — 3·93 (overlap, 2Η), 4.55 (s, 2Η), 6.90 (d, J = 8.4 Hz, 2H), 7·26-7·37 (m, 5H), 7, 97 (d, J = 8.4' Hz, 2H); MS (FAB) m/z, 356 (MHH). 4-[5-(R)-笮氧·曱基-卜[4_[N,—(2 -Methylphenyl)ureido]phenylethylamino]- 2 -(S)-indolyloxyl] decyl decanoate

在室溫下於4-[2-(S)-(5-(S)-苄氧甲基）吼咯啶曱氧基] 笨甲酸曱酯（115毫克，〇.32毫莫耳）、4-[^}，-(2_曱基笨 基）脲基]苯乙酸（92.〇毫克，0.32毫莫耳）及心卜二甲胺基 吨啶（52. 0亳克，〇. 42毫莫耳）溶於1)訂（1〇毫升）之攪拌溶1 液中力二入EDC ·Η(：1(81.〇毫克，〇 42毫莫耳），並使所 之混合物攪拌隔夜。將反應混合物倒入至水中，並以生 萃古取。將有機層以鹽杏洗滌，於無水㈣讥上乾燥， 空中濃縮。使殘留物於石夕膠上利用CHC13 一 作為洗提液進行層析，而得4_[5_(R)_笮氧曱 土 N ~(2-甲基苯基）脲基]苯基乙醯胺基]_2_(s)、4-[2-(S)-(5-(S)-Benzyloxymethyl)-pyridinium oxy] benzoic acid oxime ester (115 mg, 〇.32 mmol) at room temperature, 4 -[^},-(2_曱基笨基)U allyl]phenylacetic acid (92. 〇mg, 0.32 mmol) and dimethylamino oxapyridine (52.0 g, 〇. 42 毫Mol) dissolved in 1) (1 〇 ml) of stirring solution 1 medium into EDC · Η (: 1 (81. 〇 mg, 〇 42 mmol), and the mixture was stirred overnight. The reaction mixture was poured into water and extracted with a green extract. The organic layer was washed with dried apricots, dried over anhydrous (tetra), and concentrated in the air. The residue was chromatographed on CH. And 4_[5_(R)_笮 曱 N N ~ (2-methylphenyl) ureido] phenyl acetamido] 2 _ (s),

第462頁 1283240Page 462 1283240

lb ί °定甲氧基]苯甲酸甲169毫克，84%)的無色非晶形 H NMR (CDC13)，消旋異構物之混合物，δ 192 —218 (m’ 3H)、2·24 及 2.25 (s，總計 3H)、2·20-2·31 (重聶， 1Η)、3· 39-3· 70 (m 系列，4Η)、3· 87 及3· 89 (s，總計 3H)、4,17 及 4.18 (s，總計 2H)、43〇一4.45 (m 系列， 2H)、4· 53 (s，2H)、6· 43-7· 13 (m 系、列，9H)、7. 20’ 一7· 36 (m 系列，7Η)、7· 58一7· 99 (m 系列，3H) ; M a m/z 62 2 (MHH)。 在室溫下於4一[5 一（R)-苄氧甲基-1 - [4-[N，- (2 -甲基苯 基）脲基]苯基乙醯基]一2一（S)一吼咯啶曱氧基]苯甲酸甲酯 (156毫克，〇·24毫莫耳）溶於Me0H-THF(1:5，12毫升）之攪 拌溶液中加入1· 〇M Na〇H(l. 2毫升，1· 20毫莫耳），並使所 產生之混合物在8 0 °C下加熱攪拌7小時，將混合物倒入至 IN HC1中’然後以CHCI3萃取。將有機層以鹽水洗條，於 無水NagSO4上乾燥，然後於真空中濃縮。將殘留物於矽膠 上利用CHCI3-MeOH(5:l)作為洗提液進行層析，而得4一[5 - -苄氧曱基-1 - [4 - [N，-（2-曱基苯基）脲基]苯基乙醯 基]-2-（S)-吼咯啶甲氧基]苯甲酸1 2 6 ( 94· 0毫克，65%)的 無色非晶形固體。1 Η - N M R (C D3 0 D)，消旋異構物之混合 物，5 1· 85-2· 35 (m 系列，4H) 、2· 43-2. 92 (m 系列， 5H)、2.28 (s， 3H)、3.55 - 4.55 (m 系列，10H)、6.85 - 7. 95 (m 系列，17H); MS(ESI) m/z 630(MHNa+)。 實施例11 9Lb ί ° methoxy] benzoic acid methyl 169 mg, 84%) colorless amorphous H NMR (CDC13), mixture of racemic isomers, δ 192 - 218 (m' 3H), 2 · 24 and 2.25 (s, total 3H), 2·20-2·31 (Heavy Nie, 1Η), 3·39-3· 70 (m series, 4Η), 3·87 and 3·89 (s, total 3H), 4 , 17 and 4.18 (s, total 2H), 43〇4.45 (m series, 2H), 4·53 (s, 2H), 6·43-7· 13 (m system, column, 9H), 7. 20 'A 7.36 (m series, 7Η), 7·58-7. 99 (m series, 3H); M am/z 62 2 (MHH). At room temperature in 4-[5-(R)-benzyloxymethyl-1 -[4-[N,-(2-methylphenyl)ureido]phenylethenyl]-2-one (S Add a solution of 1 〇M Na〇H to a stirred solution of MeHH-THF (1:5, 12 mL) in a solution of methyl pyridinium oxy]benzoate (156 mg, 〇 24 mmol). l. 2 ml, 1·20 mmol), and the resulting mixture was heated and stirred at 80 ° C for 7 hours, and the mixture was poured into IN HC1' and then extracted with CHCI3. The organic layer was washed with brine, dried over anhydrous NagSO4 and then evaporated. The residue was chromatographed on silica gel using CHCI3-MeOH (5:1) as eluent to give 4-[5--benzyloxyindolyl-1 - [4- [N,-(2-fluorenyl). Phenyl)ureido]phenylethenyl]-2-(S)-decalylmethoxy]benzoic acid 1 2 6 (9.4 mg, 65%) as a colorless amorphous solid. 1 Η - NMR (C D3 0 D), a mixture of racemic isomers, 5 1· 85-2· 35 (m series, 4H), 2·43-2. 92 (m series, 5H), 2.28 ( s, 3H), 3.55 - 4.55 (m series, 10H), 6.85 - 7. 95 (m series, 17H); MS (ESI) m/z 630 (MHNa+). Example 11 9

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1283240 五、發明說明（460) 晶形固體。1 H-NMR (CDC13)，消旋異構物之混合物占 1·91 - 2·30 (m 糸列，4H)、3.39 - 3.74(m 系列，3H)、3 73 (s，2H)、4·15-4.02 (m，2H)、4.32-4.44 (m，1H)、 4·54 (s，2H)、6·7；1 - 7.02 (m 系列，5H)、7·06 (s， 1Η)、7·17 (s， 1Η)、7·24-7.40 (m 系列，7Η)、7·89-8· 22 (m 系列，4Η) ; MS(FAB) m/z 672 (ΜΗΗ)。 在室溫下於4-[5-(R) -辛氧曱基-1 一 [4-[n，-（2-氯笨基） 脲基]- 3-曱氧苯基乙醯基]-2-(S)_wb咯啶甲氧基]苯甲酸 甲酯（169毫克，〇·25毫莫耳）溶於MeOH-THF(2:5，7毫升） 之攪拌溶液中加入1.0M NaOH(750毫升，0.75毫莫耳），並 使所產生之混合物在80 t下加熱攪拌2小時。將混合物倒 入至IN HC1中，然後以CHC13萃取。將有機層以鹽水洗 條，於無水NaJO4上乾燥，然後.於真空中濃縮。將殘留物 於石夕膠上利用CHCI3-MeOH(15:l)作為洗提液進行層析，而 知4 - [5-(R) —苄氧甲基-1 一 [4-[n’-(2-氯苯基）脲基]-3-曱 氧笨基乙醯胺基]- 2 -（S) -咄略啶甲氧基]苯曱酸127(114毫 克’ 69%)的無色非晶形固體。iH-NMR (CD3〇D)，消j旋異構 物之混合物，6 ι· 88-2· 37 (m 系列，4H)、3. 51 -4. 49 (m 系列，8H)、3· 64 及3· 73 (s，總計3H)、4· 86 (s， 2H)、 6.85-7.95 (m 系列，16H); MS(ESI) m/z 658 (MHH)、680 (M+ + Na+) ; C36H36C1N3 07 · H20 之分析計算值·· c，63· 95 ; Η, 5· 66 ; N， 6· 21。實測值：C， 63· 65 ; Η, 5. 40 ; N， 5.95。 實施例1 2 01283240 V. INSTRUCTIONS (460) Crystal solid. 1 H-NMR (CDC13), a mixture of racemic isomers of 1.91 - 2·30 (m 糸, 4H), 3.39 - 3.74 (m series, 3H), 3 73 (s, 2H), 4 ·15-4.02 (m, 2H), 4.32-4.44 (m, 1H), 4·54 (s, 2H), 6·7; 1 - 7.02 (m series, 5H), 7·06 (s, 1Η) , 7·17 (s, 1Η), 7·24-7.40 (m series, 7Η), 7·89-8· 22 (m series, 4Η); MS(FAB) m/z 672 (ΜΗΗ). 4-[5-(R)-octyloxyindolyl-1-[4-[n,-(2-chlorophenyl)ureido]-3-oxophenylphenyl]]- at room temperature Methyl 2-(S)-wb-robromomethoxy]benzoate (169 mg, 〇25 mmol) was dissolved in MeOH-THF (2:5, 7 mL). Millimeter, 0.75 mmol, and the resulting mixture was heated and stirred at 80 t for 2 hours. The mixture was poured into IN HC1 and then extracted with CHC13. The organic layer was washed with brine, dried over anhydrous Na.sub.4, and then concentrated. The residue was chromatographed on CHisha gum using CHCI3-MeOH (15:1) as the eluent, and 4-[5-(R)-benzyloxymethyl-1-[4-[n'- (2-Chlorophenyl)ureido]-3-indoleoxyphenylaminoamino]- 2 -(S)-indolyl methoxy]benzoic acid 127 (114 mg '69%) of colorless Crystal form solid. iH-NMR (CD3〇D), a mixture of isomers, 6 ι· 88-2· 37 (m series, 4H), 3. 51 -4. 49 (m series, 8H), 3·64 And 3·73 (s, total 3H), 4·86 (s, 2H), 6.85-7.95 (m series, 16H); MS (ESI) m/z 658 (MHH), 680 (M+ + Na+); C36H36C1N3 07 · H20 analysis and calculation value · · c, 63 · 95 ; Η, 5 · 66 ; N, 6 · 21. Found: C, 63·65; Η, 5. 40 ; N, 5.95. Example 1 2 0

89112968.ptd 128324089112968.ptd 1283240

1283240 五、發明說明（462) 2.31 (m 系列，4Η)、3·39-3·73 (m 系列，3H)、3.65 (s, 2H) 、4·15-4·02 (m, 2H) 、4·32-4·44 (m, 1H) 、4·54 (s, 2Η)、6.71-6.99 (m 系列，5Η)、7.04 (s， 1Η)、7.11 (s， 1Η)、7· 22-7· 3 9 (m 系列，7Η)、7· 5 卜8· 17 (m 系列， 4H); MS(FAB) m/z 716(M+)、718(MH2)。 在室溫下於4-[5 -（R) -笮氧甲基-l - [4-[n’ -（2~漠苯基） 脲基]-3-甲氧苯基乙醯基]-2-（S)-°比洛。定甲氧基]苯甲酸 甲酯（178毫克，0.25毫莫耳）溶於MeOH - THF(2:5，7毫升） 之攪拌溶液中加入1.0M NaOH(750毫升，0.75毫莫耳），並 使所產生之混合物在80 °C下加熱攪拌1 · 5小時。將反應混 合物倒入至IN HC1中，然後以CHC13萃取。將有機層以鹽 水洗滌，於無水NazS〇4上乾燥，然後於真空中濃縮。將殘 留物於石夕膠上利用CHCI3-MeOH(15:l)作為洗提液進行層 析’而得4 - [5 -（R)-苄氧甲基-1-[4-[Ν’ -（2-溴苯基）脲基] -3-甲氧苯基乙醯基]- 2-(s)-咄咯啶曱氧基]苯甲酸128 (159毫克，91%)的無色非晶形固體。iH — NMr (CD3〇d)，消 旋異構物之混合物，δ 1· 8 8-2. 3 5 (m系列，4H)、3· 51-4·49 (m 系列，8H)、3·64 及 3.72 (s，總計 3H)、4·87 (s， 2Η) 、6·65-8·05 (m 系列，16H); MS(ESI) m/z 702(Μ+)、 704 (MH2) ; C36H36BrN3〇7 ·η20 之分析計算值·· C，60.0 0 ; H，5· 32 ; N， 5· 83。實測值：c， 59· 66 ; Η, 5· 04 ; N， 5· 65。 例 1 2 1 3 - [5-(R) -爷氧甲基-1-[4 - [Ν，-(2-甲基苯基）脲基]- 3-甲1283240 V. INSTRUCTIONS (462) 2.31 (m series, 4Η), 3·39-3·73 (m series, 3H), 3.65 (s, 2H), 4·15-4·02 (m, 2H), 4·32-4·44 (m, 1H), 4·54 (s, 2Η), 6.71-6.99 (m series, 5Η), 7.04 (s, 1Η), 7.11 (s, 1Η), 7· 22- 7· 3 9 (m series, 7Η), 7·5 b 8·17 (m series, 4H); MS (FAB) m/z 716 (M+), 718 (MH2). 4-[5-(R)-笮-oxymethyl-l-[4-[n'-(2~-diphenyl)ureido]-3-methoxyphenylethenyl]- at room temperature 2-(S)-°Bilo. Methyl methoxy]benzoate (178 mg, 0.25 mmol) was dissolved in MeOH - THF (2:5, 7 mL). The resulting mixture was heated and stirred at 80 ° C for 1 · 5 hours. The reaction mixture was poured into IN HC1 and then extracted with CHC13. The organic layer was washed with brine, dried over anhydrous Naz. The residue was chromatographed on CHisha gum using CHCI3-MeOH (15:1) as the eluent to give 4-[5-(R)-benzyloxymethyl-1-[4-[Ν'- Colorless amorphous solid of (2-bromophenyl)ureido]-3-methoxyphenylethenyl]-2-(s)-indenylpyridiniumoxy]benzoic acid 128 (159 mg, 91%) . iH — NMr (CD3〇d), a mixture of racemic isomers, δ 1· 8 8-2. 3 5 (m series, 4H), 3· 51-4·49 (m series, 8H), 3· 64 and 3.72 (s, total 3H), 4·87 (s, 2Η), 6·65-8·05 (m series, 16H); MS (ESI) m/z 702 (Μ+), 704 (MH2) ; C36H36BrN3〇7 · η20 analytical calculations · · C, 60.0 0 ; H, 5 · 32 ; N, 5 · 83. Found: c, 59· 66 ; Η, 5· 04 ; N, 5· 65. Example 1 2 1 3 - [5-(R)-Y-Oxomethyl-1-[4 - [Ν,-(2-methylphenyl)ureido]- 3-

\\312\2d-code\90-01\89112968.ptd 第 467 頁 1283240 五、發明說明（463) 氧苯基乙醯基]-2-（S)-吡咯啶甲氧基]苯甲酸\\312\2d-code\90-01\89112968.ptd Page 467 1283240 V. INSTRUCTIONS (463) Oxyphenylphenylmercapto]-2-(S)-pyrrolidinemethoxy]benzoic acid

3-[2-（5)-（1^-6〇(：-5-（5)一卞氧甲基）1[7比17各0定甲氧基]苯甲酸 甲酯3-[2-(5)-(1^-6〇(:-5-(5)-indolyloxymethyl) 1[7 to 17 each 0 methoxy]benzoic acid methyl ester

在室溫下於N-Boc_2-（S)-羥甲基-5-(S) -窄氧甲基咄，各 啶（415毫克，1·29毫莫耳）、三苯膦（410毫克，L55毫莫 耳）及3-經基苯甲酸甲酯（240毫克，1·55毫莫耳）之授拌溶 液中加入偶氮二羧酸二異丙酯（320毫升，1·55毫莫耳）， 並使所產生之混合物授拌隔夜。將混合物於真空中濃縮， 然後使殘留物於矽膠上利用己烷-EtOAc(3 : 1)作為洗提液 進行層析，而得3-[2-(S)-(N-Boc-5 -（S)-苄氧甲基）吼口各 啶甲氧基]苯甲酸甲酯（5 13毫克，87%)之無色油。1H-NMR (CDC13) 5 1· 40 及1· 46 (s，總計 9H)、1· 95- 2. 2 0 (m 系 列，4H)、3. 33-3· 72 (m 系列，2H)、3·82-4· 00 (m， 1H) 、3·90 及 3·91 (s，總計 3H)、4·09-4·21 (m，3H)、4.21 -4.57 (m，2H)、7·1 卜7」5 (m，1H)、7·26-7·37 (m， 6Η)、7·53-7.65 (m，2H); MS(ESI) m/z，456 (ΜΗΗ)。 卜[2-(S)-（4-（S)-苄氧曱基）吡咯啶曱氧基]-3-笨甲酸甲At room temperature in N-Boc_2-(S)-hydroxymethyl-5-(S)-n-oxymethylhydrazine, each pyridine (415 mg, 1.29 mmol), triphenylphosphine (410 mg, Add isopropyl azodicarboxylate (320 ml, 1.55 mmol) to a solution of L55 mM and 3-methylbenzoic acid methyl ester (240 mg, 1.55 mmol). ), and the resulting mixture was mixed overnight. The mixture was concentrated in vacuo and the residue was crystallised eluted eluted elut elut elut (S)-Benzyloxymethyl) A colorless oil of methylene chloride benzoate (5 13 mg, 87%). 1H-NMR (CDC13) 5 1·40 and 1·46 (s, total 9H), 1.95- 2. 2 0 (m series, 4H), 3. 33-3· 72 (m series, 2H), 3·82-4· 00 (m, 1H), 3.90 and 3.91 (s, total 3H), 4·09-4·21 (m, 3H), 4.21 -4.57 (m, 2H), 7 · 1 Bu 7"5 (m, 1H), 7·26-7·37 (m, 6Η), 7·53-7.65 (m, 2H); MS (ESI) m/z, 456 (ΜΗΗ). [2-(S)-(4-(S)-Benzyloxyindenyl)pyrrolidinyloxy]-3-inertic acid A

\\312\2d-code\90-01\89112968.ptd 第 468 頁 1283240 五、發明說明（464) 酯\\312\2d-code\90-01\89112968.ptd Page 468 1283240 V. INSTRUCTIONS (464) Ester

在室溫下於3-[2-（3)-（^1-6(^-5-(3)-辛氧甲基）咄咯啶 甲氧基]苯甲酸曱酯（501毫克，1 · 10毫莫耳）溶於CH2C12 (1 0毫升）之攪拌溶液中加入三氟乙酸（1 0毫升），並使所產 生之混合物攪拌1小時。將混合物於真空中濃縮，並倒入 至NaHC03水溶液中，以CHC13萃取。將有機層以水洗滌，於 無水Na2S04上乾燥，並於真空中濃縮而得3-[2-(S)-(5-(S) -苄氧甲基）吼咯啶甲氧基]苯甲酸甲酯（387毫克，定量）之 淡黃色油。將產物不經進一步的純化而使用於後續的反 應。1H — NMR (CDC13) 5 1· 26- 1 · 65 (m， 2H ) 、1 · 9 4一2 · 04 (m， 3H) 、3·37-3.52 (m， 2H) 、3·63-3·66 (m， 1H)、 3.85-3. 93 (m, 1H) 、3.91 (s, 3H) 、4.55 (s, 2H)、 7. 09-7. 11 (m, 1H )、7· 27 - 7 · 54 (m，6H)、7· 54 - 7 · 55 (m，1H)、7·61-7·63 (m，2H); MS(ESI) m/z，35(M+ + H)。 3 - [5 -（R)-^氧甲基-1-[4 - [Ν’-（2-甲基苯基）脲基]- 3-甲 氧苯基乙醯基]-2-(S)-吼咯啶甲氧基]苯甲酸甲酯Ethyl 3-[2-(3)-(^1-6(^-5-(3)-octyloxymethyl)oxaridinylmethoxy]benzoate at room temperature (501 mg, 1 · Trifluoroacetic acid (10 ml) was added to a stirred solution of CH2C12 (10 mL), and the resulting mixture was stirred for 1 hour. The mixture was concentrated in vacuo and poured into NaHC03 aqueous solution. The organic layer was washed with water, dried over anhydrous Na 2 SO 4 and concentrated in vacuo to give 3-[2-(S)-(5-(S)-benzyloxymethyl)pyrrolidine. A pale yellow oil of methyl methoxy]benzoate (387 mg, EtOAc). The product was used in the next reaction without further purification. 1H - NMR (CDC13) 5 1 · 26 - 1 · 65 (m, 2H ) , 1 · 9 4 - 2 · 04 (m, 3H), 3·37-3.52 (m, 2H), 3·63-3·66 (m, 1H), 3.85-3. 93 (m, 1H ), 3.91 (s, 3H), 4.55 (s, 2H), 7. 09-7. 11 (m, 1H), 7·27 - 7 · 54 (m, 6H), 7· 54 - 7 · 55 ( m,1H),7·61-7·63 (m,2H); MS (ESI) m/z, 35 (M+ + H) 3 - [5 -(R)-^oxymethyl-1-[ 4-[Ν'-(2-Methylphenyl)ureido]-3-methoxyphenylethenyl]-2- (S)-Ethrolidine methoxy]methyl benzoate

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在室溫下於 3 - [2 -1 ^ ® ^ W 1 , η ) (5 (S)卞軋甲基）咄咯啶甲氧基] 本曱酉夂甲S曰（140毫克，〇·39毫莫耳）、4_[n, _甲基苯 基）脲基]-3 -甲氧笨乙酸古 η τ虱本乙1(125笔克，〇· 39毫莫耳）及Ν，Ν一二 曱月女基口比口疋（58.0臺券，η垃了喜曾甘、、〜 、·υ笔見0.47笔莫耳）溶於THF(15毫升）之 攪拌〉谷液中加入EDC ·Η(： 1(90.0毫克，〇·47毫莫耳），並使 所產生之―混合物攪拌隔夜。將反應混合物倒入至水中，並 ?CHC13萃取。將有機層以鹽水洗滌，於無水上乾 燥，然後於真空中濃縮。使殘留物於矽膠上利用CHC 1一 MeOH(10:l)作為洗提液進行層析，而得3 一 [5 — (r)_笮氧曱 基-1 - [4-[N，-（2_甲基苯基）脲基]一 3〜甲氧苯基乙醯基] -2-(S)-吡咯啶甲氧基]苯曱酸甲酯（25 6毫克，定量）的無 色非晶形固體。iH-NMR (CDCI3)，消旋異構物之混合物了 占 1.67 (s， 3H)、1.97 - 2.4 0 (m 系列，4H)、3.42 - 3.85 (m 系列 ’ 5H)、3· 60 (s， 3H)、3. 95 及3. 97 (s，總計 3H)、4·15-4·26 (m, 2H)、4·36 - 4·49 (m，1H)、4·59 (s， 2H)、6· 32 及6. 36 (s，總計 1H)、6· 75-6. 8 7 (m 系列 2H)、7. 20 (brs，2H)、7. 16-7. 72 (m 系、列，10H)、8、〇3’ -8· 09 (m，1Η) ; MS(ESI) m/z 6 52 (MUH)。 · 在室溫下於3 - [5 -（R) -爷氧甲基-l-[ 4-[N，-(2 -甲基笨 基）脲基]- 3-曱氧苯基乙隨基]-2-(S)-吼嘻咬曱氧基]笨 酸甲酯（185毫克，0·28毫莫耳）溶於MeOH - THF(2 ·· 5，7毫 升）之攪拌溶液中加入1· 0M NaOH( 86 0毫升，0· 86毫莫耳） ，並使所產生之混合物在6 0 °C下加熱攪拌1小時。將反Λ 混合物倒入至IN HC1中，然後以CHCI3萃取。將有機層以&quot;At room temperature at 3 - [2 -1 ^ ® ^ W 1 , η ) (5 (S) 甲基 methyl) 咄 咄 甲 methoxy] 曱酉夂 曰 曰 曰 (140 mg, 〇 · 39 Millol), 4_[n, _methylphenyl)ureido]-3-methoxybenzoic acid, ancient η τ虱ben B 1 (125 gram, 〇 · 39 millimoles) and Ν, Ν一二The female base of the month of the month is more than the mouth (58.0 coupons, η拉了喜曾甘,,~,·υ see 0.47 pens). Stir in the THF (15 ml), add EDC · Η ( : 1 (90.0 mg, 〇·47 mmol), and the resulting mixture was stirred overnight. The reaction mixture was poured into water and extracted with CHC 13. The organic layer was washed with brine and dried over anhydrous Concentration in vacuo. The residue was chromatographed on a silica gel using CHC 1 - MeOH (10:1) as eluent to give 3-[5 - (r)- oxalyl-1 - [4- [N,-(2-methylphenyl)ureido]-3~methoxyphenylethenyl]-2-(S)-pyrrolidinemethoxy]benzoic acid methyl ester (25 6 mg, quantitative a colorless amorphous solid. iH-NMR (CDCI3), a mixture of racemic isomers of 1.67 (s, 3H), 1.97 - 2.4 0 (m) Series, 4H), 3.42 - 3.85 (m series '5H), 3·60 (s, 3H), 3.95 and 3.97 (s, total 3H), 4·15-4·26 (m, 2H) , 4·36 - 4·49 (m, 1H), 4·59 (s, 2H), 6·32, and 6.36 (s, total 1H), 6·75-6. 8 7 (m series 2H) , 7. 20 (brs, 2H), 7. 16-7. 72 (m series, column, 10H), 8, 〇3' -8· 09 (m, 1Η); MS(ESI) m/z 6 52 (MUH) · 3 - [5 -(R)-Y-oxymethyl-l-[ 4-[N,-(2-methylphenyl)ureido]-3-oxobenzene at room temperature Styrene methyl ketone (185 mg, 0·28 mmol) dissolved in MeOH - THF (2 · · 5, 7 mL) 1.0 M NaOH (86 0 ml, 0·86 mmol) was added to the solution, and the resulting mixture was heated and stirred at 60 ° C for 1 hour. The ruthenium mixture was poured into IN HC1, and then CHCI3 extraction. The organic layer is &quot;

\\312\2d-code\90-01\89112968.ptd 第470頁 1283240 五、發明說明（466) 鹽水洗務，於無水NaJO4上乾燥，然後於真空中濃縮。將 殘留物於矽膠上利用CHC 13-MeOH( 5 : 1)作為洗提液進行層 析，而得3 - [5-(R)-^氧甲基—1 — [4 - [N，-（2-甲基苯基）脲 基]-3-甲氧苯基乙醯基]-2-(S)-吼略咬甲氧基]苯甲酸 129(171毫克，94%)的無色非晶形固體。iH — NMR (Cd3〇D)， 消旋異構物之混合物，6 1 · 89-2· 37 (m系列，4H)、2· 29 (s， 3Η)、3. 5 2-4· 53 (m 系列，8Η)、3· 66 及3· 74 (s，總 計 3H)、4·85 (s， 2H)、6·66 - 7.98 (m 系列，16H); MS (ESI) m/z 6 38 (MHH)、6 60 (MHNa+); C37H39N3 07 ·Η20 之分 析什鼻值· C，6 7 · 7 7 ’ Η，6 · 3 0 ’· N，6. 41。實測值：C 67. 40 ; H，5. 95 ; N，6. 14 ° ? 實施例1 2 2\\312\2d-code\90-01\89112968.ptd Page 470 1283240 V. INSTRUCTIONS (466) Brine washing, drying on anhydrous NaJO4, and then concentrating in vacuo. The residue was chromatographed on a silica gel using CHC 13-MeOH (5:1) as an eluent to give 3-[5-(R)-^-oxymethyl-l-[4-[N,-( 2-methylphenyl)ureido]-3-methoxyphenylethenyl]-2-(S)-fluorenyl methoxy]benzoic acid 129 (171 mg, 94%) as a colorless amorphous solid . iH — NMR (Cd3〇D), a mixture of racemic isomers, 6 1 · 89-2· 37 (m series, 4H), 2· 29 (s, 3Η), 3. 5 2-4· 53 ( m series, 8Η), 3·66 and 3.74 (s, total 3H), 4·85 (s, 2H), 6.66 - 7.98 (m series, 16H); MS (ESI) m/z 6 38 (MHH), 6 60 (MHNa+); C37H39N3 07 · Η20 analysis of the nose value · C, 6 7 · 7 7 ' Η, 6 · 3 0 '· N, 6. 41. Found: C 67. 40 ; H, 5. 95 ; N, 6. 14 ° ? Example 1 2 2

3 - [5 -（R) -窄氧甲基-：1 - [4-[Ν’-（2-氯苯基）脲基]一3 一甲氧 苯基乙醯基]-2-(S) -吼咯啶甲氧基]笨甲酸 3- [5-(R) -爷氧甲基-1 - [4 - [Ν’ -（2 -氯笨基）脲基]一3 苯基乙醯基]- 2 -（ S )-吼σ各咬甲氧基]苯甲酸甲酉旨3-[5-(R)-Narrow oxymethyl-:1 - [4-[Ν'-(2-chlorophenyl)ureido]-3 methoxyphenylethenyl]-2-(S - 吼 吼 啶 methoxy] 笨 甲酸 3- [5-(R)-Y-oxymethyl-1 - [4 - [Ν' -(2-chlorophenyl))]] 3-phenyl phenyl hydrazine ]]- 2 -( S )-吼σ each bite methoxy]benzoic acid formazan

曱氧 在室溫下於3-[2 -（S)-( 5-(S)-苄氧曱基）吡咯啶Oxygen at room temperature in 3-[2-(S)-(5-(S)-benzyloxyindenyl)pyrrolidine

苯甲酸甲酯（118毫克，0· 33毫莫耳）、4—「n，一〇 &amp; *乳暴J L1N l z —氣笨基）Methyl benzoate (118 mg, 0·33 mmol), 4-"n, one 〇 &amp; *milk violence J L1N l z - gas base)

12832401283240

脲基]- 3-甲氧苯乙酸（U2毫杳，n L ΛΑ 兄0.33笔莫耳）及Ν，Ν 一二甲 私基吼欠（50.0毫克，0.40毫莫耳）溶於 拌溶液：加入m.HC1(8。.。毫克，0 40毫莫耳，升)並使所 產生之/吧合物攪拌隔夜。將反應混合物倒入至水中，並以 chh3萃#。將有機層以鹽水洗滌’於無水叫上乾燥， 然後於真空中濃縮。使殘留物於矽膠上利用CHC13_Me0H (10:1)作為洗提液進行層析，而得3_[5_(R)_苄氧甲基 -1-[4-[Ν’-(2-氯笨基）脲基卜3—甲氧苯基乙醯胺基]_2 -(s)-咄咯啶甲氧基]苯甲酸甲酯（22 6毫克，定量）的無色 (CDCI3)，消旋異構物之混合物，占 4H)、3· 43- 3. 9 2 (m 系列，5H)、3· 67Ureido]- 3-methoxyphenylacetic acid (U2 杳, n L ΛΑ brother 0.33 mp) and Ν, Ν 二甲 私 ( ( (50.0 mg, 0.40 mmol) dissolved in the solution: add m.HC1 (8..mg, 0 40 mmol, liter) and the resulting bar was stirred overnight. The reaction mixture was poured into water and extracted with chh3. The organic layer was washed with brine, dried over anhydrous water and then concentrated in vacuo. The residue was chromatographed on a silica gel using CHC13_Me0H (10:1) as an eluent to give 3-[5_(R)-benzyloxymethyl-1-[4-[Ν'-(2-chlorophenyl) Urea-based 3-methoxyphenylethylamino] 2 -(s)-decalyl methoxy]benzoic acid methyl ester (22 6 mg, quantitative) of colorless (CDCI3), racemic isomer Mixture, 4H), 3·43- 3. 9 2 (m series, 5H), 3.67

非晶形固體。l-NMR 1 · 9 9 - 2 · 4 0 ( m 系列， (s，3H)、3.98 及 4·02 (s,總計 3H)、4·18-4.29 (m，2H) 、4·36 - 4.51 (m，1H)、4·60 (s，2H)、6·75-6·92 (m 系列，2H)、7· 01 -7· 22 (m 系列，4H)、7· 29-7· 5 3 (m 系列，9Η)、7· 6 2-8· 2 6 (m 系列，3Η) ; MS(ESI) m/z 672 (MHH)。 在室溫下於3-[5 -（R) -苄氧曱基一 i-[4 一 [N，—（2 -氯苯基） 脈基]3-甲氧本基乙酸基]一 2 -（S)-n比u各。定甲氧基]苯甲酸 甲_(169毫克，0.25毫莫耳）溶於MeOH-THF(2:5，7毫升） 之攪拌溶液中加入1.0M NaOH( 76 0毫升，0.76毫莫耳），並 使所產生之混合物在6 0 °C下加熱攪拌1. 5小時。將反應混 合物倒入至1 N HC1中，然後以CHC13萃取。將有機層以鹽 水洗滌，於無水NagSO4上乾燥，然後於真空中濃縮。將殘 留物於矽膠上利用CHC13-Me〇H(5 : 1)作為洗提液進行層析Amorphous solid. l-NMR 1 · 9 9 - 2 · 4 0 (m series, (s, 3H), 3.98 and 4·02 (s, total 3H), 4·18-4.29 (m, 2H), 4.36 - 4.51 (m, 1H), 4·60 (s, 2H), 6·75-6·92 (m series, 2H), 7· 01 -7· 22 (m series, 4H), 7· 29-7· 5 3 (m series, 9Η), 7· 6 2-8· 2 6 (m series, 3Η); MS(ESI) m/z 672 (MHH). at room temperature at 3-[5 -(R) - Benzyloxyindenyl-i-[4-[N,-(2-chlorophenyl)-yl]3-methoxycarbonylacetic acid]- 2 -(S)-n ratio u. A solution of methyl benzoate (169 mg, 0.25 mmol) dissolved in MeOH-THF (2:5, 7 mL) was added 1.0 M NaOH (76 mL, 0.76 mmol) and The mixture was heated and stirred at 60 ° C for 1.5 hours. The reaction mixture was poured into 1 N EtOAc, and then extracted with CHCI 13. The organic layer was washed with brine, dried over anhydrous NagSO4 and then concentrated in vacuo. The residue was chromatographed on silica gel using CHC13-Me〇H (5:1) as the eluent.

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1283240 五、發明說明（469) 胺基咄啶（48. 0毫克，〇· 39毫莫耳）溶於THF(15毫升）之攪 拌溶液中加入EDC · HC1(75. 0毫克，39毫莫耳），並使所 產生之混合物攪拌隔夜。將反應混合物倒入至水中，並以 CHCI3萃取。將有機層以鹽水洗滌，於無水Na2S〇4上乾燥， 然後於真空中濃縮。使殘留物於矽膠上利用CHCl3-MeOH (1〇 : 1 )作為洗提液進行層析，而得3-[ 5-(R)-苄氧甲基-卜 [4 - [Ν’-（2-溴笨基）脲基]一3-甲氧苯基乙醯基]-2-(S)-口比 17各啶甲氧基]苯甲酸甲酯（2 0 9毫克，8 9 %)的無色非晶形固 體。4-題1^(00(：13)，消旋異構物之混合物61.99-2.37 (m 系列，4Η)、3· 43-3. 91 (m 系列，5Η)、3· 70 (s， 3Η)、 3·93 及 3·96 (s,總計 3Η)、4· 19-4. 28 (m，2Η)、4· 37-4· 51 (πι，1H)、4· 60 (s，2H)、6· 77-7· 11 (m 系列，6H)、 了· 28 —7· 74 (m 系列，10H)、7· 91 -7. 95 (m 系列，1H)、 8· 20 —8· 23 (m 系列，1H) ; MS(ESI) m/z 716(M+) 、718 (MU 2) 〇 在室溫下於3-[5 -（R) -苄氧甲基-l-[ 4-[N，-（2-溴苯基） 脲基]-3-甲氧苯基乙醯基]-2-(S)-n比洛咬甲氧基]苯甲酸 甲酯（176毫克，0·25毫莫耳）溶於MeOH - THF(2:5，7毫升） 之攪拌溶液中加入1. 〇M NaOH( 76 0毫升，〇· 76毫莫耳），並 使所產生之混合物在6 0 °C下加熱攪拌1 · 5小時。將反應混 合物倒入至1 N HC1中，然後以CHC13萃取。將有機層以鹽 水洗滌，於無水NagSO4上乾燥，然後於真空中濃縮。將殘 留物於矽膠上利用CHClg -MeOH (5 ·· 1 )作為洗提液進行層 析，而得3-[5 -（R)-午氧甲基-1-[4-[Ν’ -（2 -溴苯基）脲1283240 V. Inventive Note (469) Acryl acridine (48. 0 mg, 〇 39 mmol) dissolved in THF (15 mL) was added EDC · HC1 (75. 0 mg, 39 mmol) ) and the resulting mixture was stirred overnight. The reaction mixture was poured into water and extracted with CHCI3. The organic layer was washed with brine, dried over anhydrous Na. The residue was chromatographed on silica gel using CHCl3-MeOH (1::1) as eluent to give 3-[ 5-(R)-benzyloxymethyl-b[4 - [Ν'-(2 -bromophenyl)ureido]3-methoxyphenylethenyl]-2-(S)-port ratio of 17 hexyl methoxy]benzoic acid methyl ester (209 mg, 89%) Colorless amorphous solid. 4-question 1^(00(:13), a mixture of racemic isomers 61.99-2.37 (m series, 4Η), 3·43-3. 91 (m series, 5Η), 3·70 (s, 3Η) ), 3·93 and 3·96 (s, total 3Η), 4·19-4. 28 (m, 2Η), 4· 37-4· 51 (πι, 1H), 4· 60 (s, 2H) , 6· 77-7· 11 (m series, 6H), · 28 —7· 74 (m series, 10H), 7·91 -7. 95 (m series, 1H), 8· 20 —8· 23 (m series, 1H); MS (ESI) m/z 716 (M+), 718 (MU 2) 〇 at room temperature in 3-[5 -(R)-benzyloxymethyl-l-[4-[ N,-(2-Bromophenyl)ureido]-3-methoxyphenylethenyl]-2-(S)-n, butyl methoxy]benzoic acid methyl ester (176 mg, 0·25 To a stirred solution of MeOH-THF (2:5, 7 mL) was added 1. 〇M NaOH (76 0 mL, 〇· 76 mmol), and the resulting mixture was at 60 ° C. The mixture was heated and stirred for 1.5 hours. The reaction mixture was poured into 1 N EtOAc, and then extracted with CHCI 13. The organic layer was washed with brine, dried over anhydrous NagSO4 and then concentrated in vacuo. Chromatography using CHClg-MeOH (5 ··1) as an eluent, To give 3- [5 - (R) - oxymethyl afternoon -1- [4- [Ν '- (2 - bromophenyl) urea

^312\2d.c〇de\90-01\89112968.ptd 第 474 頁 1283240 五、發明說明（470) 基]-3-甲氧苯基乙醯基]一2-（S)-吼咯啶甲氧基]笨曱酸 (156毫克，88%)的無色非晶形固體。UMR (CD30D)，消 旋異構物之混合物6 1 · 89-2. 37 (m系列，4H)、2. 29 (s，3H)、3·52-4·53 (m 系列，8H)、3·68 及3.75 (s，總 計31〇、4.85(5，21〇、6.6 7-7.9 5 (111系列，161〇; MS(ESI) m/z 702CMHH) ^ 704 (MHNa+) ； C36H36BrN3 07 · H20 之分析計算值·· C，60· 〇〇 ; η, 5· 32 ; N，5· 83。實測值： C， 59.65 ;Η， 5.02; Ν， 5·65。 實施例124 4-[(2S，4S) - 4-甲氧基一 ι 一 [3 一甲氧基一 4—[Ν，- (2-甲基苯基） 脲基]苯基乙醯基]一 2 - π比咯啶基]曱氧苯曱酸 OMe^312\2d.c〇de\90-01\89112968.ptd Page 474 1283240 V. INSTRUCTIONS (470) BASE]-3-Methoxyphenylethylidene]- 2-(S)-indenylpyridine Methoxy] citric acid (156 mg, 88%) as a colorless amorphous solid. UMR (CD30D), a mixture of racemic isomers 6 1 · 89-2. 37 (m series, 4H), 2. 29 (s, 3H), 3·52-4·53 (m series, 8H), 3·68 and 3.75 (s, total 31〇, 4.85 (5, 21〇, 6.6 7-7.9 5 (111 series, 161〇; MS(ESI) m/z 702CMHH) ^ 704 (MHNa+) ; C36H36BrN3 07 · H20 Analysis of calculated values·· C, 60· 〇〇; η, 5· 32 ; N, 5· 83. Found: C, 59.65; Η, 5.02; Ν, 5·65. Example 124 4-[(2S ,4S) - 4-methoxy-1 -[3 -methoxy- 4-[Ν,-(2-methylphenyl)ureido]phenylethenyl]- 2 - π-pyridyl Oxybenzoquinone OMe

. 132 (，）-4—乙醯氧基-1-第三丁氧羰基-2-第三丁基二苯基 石夕院氧甲基°比Π各σ定 2在/-溫7/氮氣環境中，於（2S，4R)_卜第三丁氧羰基 47 一—本基矽烷氧甲基-4-羥基吡咯啶（21.7克， 克，酸(3.°毫升，52.4毫莫耳)及pph3(i2.5 酬UK 7TTf升)中之謙合物中加^ • 6笔莫耳）。於在相同溫度下攪拌2小時132 (,)-4-Ethyloxy-1-t-butoxycarbonyl-2-t-butyldiphenyl sylvestre oxymethyl ° Π Π 在 在 在 在 在 在 在 在 在 在 在 在 在 在Wherein, (2S, 4R) - tributyloxycarbonyl 47 - benzyl decyloxymethyl-4-hydroxypyrrolidine (21.7 g, gram, acid (3. ° ml, 52.4 mmol) and pph3 (i2.5 reward UK 7TTf rise) in the modest compound plus ^ • 6 moles). Stir at the same temperature for 2 hours

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第475頁 1283240Page 475 1283240

後，將混合物於50 °C下加熱2小時。於冷卻至室溫後，將 反應混合物於真空中？辰縮。將所產生之殘留物於矽膠[丨公 斤，正己烷/EtOAc(5/l)]上進行層析而得（2S，4S) —4—乙醯 氧基-1-第二丁氧羰基-2-第三丁基二苯基矽烷氧甲基吼咯 啶（23. 3 克，99%)之無色油。4卜NMR (CDC13) 5 1· 06 (s， 9H)、1·35 及 1.43 (s，9H，醯胺異構物）、192 (br，3H) ' 2,20-2.45 (m, 2H) ^3.31-4.07 (m, 5H) -5.17-5.30 (m，1H)、7·36-7.44 (m，6H)、7. 65-7. 71 (m，4H)。 (2S，4S)-4_乙醯氧基-1-第三丁氧羰基—2-吡咯啶甲醇Thereafter, the mixture was heated at 50 ° C for 2 hours. After cooling to room temperature, the reaction mixture was placed under vacuum. Cum. The resulting residue was chromatographed on silica gel [丨 kg, n-hexane/EtOAc (5/l)] to give (2S,4S)-4-ethoxycarbonyl-1- 2 butyloxycarbonyl-2 a colorless oil of tert-butyldiphenyldecaneoxymethylpyrrolidine (23. 3 g, 99%). 4 NMR (CDC13) 5 1· 06 (s, 9H), 1.35 and 1.43 (s, 9H, guanamine isomer), 192 (br, 3H) ' 2,20-2.45 (m, 2H) ^3.31-4.07 (m, 5H) -5.17-5.30 (m, 1H), 7.36-7.44 (m, 6H), 7. 65-7. 71 (m, 4H). (2S,4S)-4_Ethyloxy-1-tert-butoxycarbonyl-2-pyrrolidinemethanol

在0°C下於（2S，4S)-4-乙醯氧基—1-第三丁氧羰基—2-第 三丁基二苯基矽烷氧甲基咄咯啶（23.3克，46.9毫莫耳）及 乙酸（6·0毫升，104.8毫莫耳）於THF( 4 70毫升）中之攪拌混 合物中加入TBAF( 93. 8毫升，93. 8毫莫耳）。於攪拌24小時 後，將混合物於真空中濃縮。將所得之殘留物以EtOAc及 Ν Η* C1水溶液稀釋’並以E10 A c萃取。將結合的萃取液以鹽 水洗滌，將其於Na2S04上乾燥，並於真空中濃縮。使殘留 物於矽膠[ 700克，CHCl3/EtOAc(4/l)]上進行層析，而得 (2S，4S) - 4-乙醯氧基-1-第三丁氧羰基一 2 -咄咯啶甲醇 (9· 70 克，8%)之無色油。1H-NMR (CDC13) 3 1· 47 (s， 9H)、ΐ· 63 (πι，1H)、1· 81 (m，1H)、2· 07 (s，3H)、 2·34 (m，1H)、3·42 (dd，J-12.7、0·9 Hz，1H)、(2S,4S)-4-Ethyloxy-1-1-tert-butoxycarbonyl-2-tert-butyldiphenyldecaneoxymethylpyrrolidine (23.3 g, 46.9 mmol) at 0 °C TBAF (93. 8 ml, 93.8 mmol) was added to a stirred mixture of EtOAc (EtOAc). After stirring for 24 hours, the mixture was concentrated in vacuo. The residue obtained was diluted with EtOAc and EtOAc (EtOAc) and evaporated. The combined extracts were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was chromatographed on silica gel [700 g, CHCl3 /EtOAc (4/l) to give (2S,4S)-4-ethyloxy-1-l-butoxycarbonyl-2-pyrene A colorless oil of pyridine methanol (9·70 g, 8%). 1H-NMR (CDC13) 3 1· 47 (s, 9H), ΐ· 63 (πι, 1H), 1·81 (m, 1H), 2· 07 (s, 3H), 2·34 (m, 1H) ), 3·42 (dd, J-12.7, 0·9 Hz, 1H),

89112968.ptd 第476頁 1283240 五、發明說明（472) 3·62-3·85 (m，3H)、4.48 (br，1H)、5.20 (br，1H)。 4 - [(2S，4S) - 4-乙醯氧基_1—第三丁氧羰基—2 -咄咯啶基]甲 氧苯甲酸甲酯 hoc 在室溫下於（2S，4S)-4-乙醯氧基-1-第三丁氧羰基-2-吼 咯啶曱醇（9.70克，37.4毫莫耳）、對羥基苯曱酸曱基酯 (5.69克，37.4毫莫耳）及pph3(10.8克，41.1毫莫耳）於 THF( 200毫升）中之攪拌混合物中加入DIAD(8. 10毫升，41· 1毫莫耳）。於攪拌1 · 5小時後，將混合物於真空中濃縮。 使所產生之殘留物於矽膠[70 0克，CHCl3/EtOAc( 1 0/1 )]上 進行層析，而得4-[(2S，4S)-4-乙醯氧基-1-第三丁氧魏基 - 2 -咄咯啶基]甲氧苯曱酸甲酯（11 · 8克，8 1 %)之淡黃色 油。1H-NMR (CDC13) δ 1· 48 (s，9H)、2· 03 (s，3H)、2. 27 (m，2Η)、3·46 (m, 1Η)、3·72 (m，1Η)、3·88 (s， 3H)、3·98 (t，J = 9.0 Hz，1H)、4·2 卜 4·47 (m，2H)、5· 31 (br， 1H) 、6·96 (br， 2H) 、7·98 (d， J=8.8 Hz， 2H)。 4-[(2S，4S)-1-第三丁氧羰基_4_羥基-2-吼咯啶基]曱氧笨 曱酸甲酯89112968.ptd Page 476 1283240 V. INSTRUCTIONS (472) 3·62-3·85 (m, 3H), 4.48 (br, 1H), 5.20 (br, 1H). 4-((2S,4S)-4-Ethyloxyl-1-t-butoxycarbonyl-2-cyanoazinyl]methyl methoxybenzoate hoc at room temperature at (2S,4S)-4 - ethoxylated-1-t-butoxycarbonyl-2-oxaridinyl sterol (9.70 g, 37.4 mmol), decyl p-hydroxybenzoate (5.69 g, 37.4 mmol) and pph3 (10.8 g, 41.1 mmol) was added DIAD (8. 10 mL, 41·1 mmol) to a stirred mixture of THF (200 mL). After stirring for 1.5 hours, the mixture was concentrated in vacuo. The resulting residue was chromatographed on silica gel [70 0 g, CHCl3 / EtOAc (1 0/1 )] to give 4-[(2S,4S)-4-ethyloxy-1- A light yellow oil of methyl butoxypropionyl-2-oxazolidinyl]methoxybenzoate (11 · 8 g, 81%). 1H-NMR (CDC13) δ 1· 48 (s, 9H), 2· 03 (s, 3H), 2. 27 (m, 2Η), 3·46 (m, 1Η), 3·72 (m, 1Η) ), 3·88 (s, 3H), 3·98 (t, J = 9.0 Hz, 1H), 4·2 Bu 4·47 (m, 2H), 5· 31 (br, 1H), 6.96 (br, 2H), 7·98 (d, J=8.8 Hz, 2H). 4-[(2S,4S)-1-tert-butoxycarbonyl-4-yl-2-pyrrolidyl]anthracene methyl decanoate

^ 89112968.ptd .第 477 頁 I t ^ 1283240 五、發明說明（473) 在室溫下於4-[(2S，4S )-4 -乙醯氧基-1-第三丁氧羰基 -4-羥基-2 -咄咯啶基]甲氧苯甲酸甲酯（7·43克，18.9毫莫 耳）溶於MeOH(150毫升）之攪拌溶液中加入催化劑k2C03。於 攪拌1天後，將混合物於真空中濃縮。經由加入CHC 1 33-正 己烷使所產生之殘留物再結晶，而得4-[(2S，4S)-l-第三 丁氧羰基-4-羥基-2 -咄咯啶基]甲氧苯甲酸曱酯（5. 76克， 8 7%)之無色固體。UMR (CDC13) 5 1· 46 (s，9H)、2· 11 (m，1H)、2·35 (br，1H)、3·27-3·65 (m，2H)、3·89 (s，3H)、4·07-4.54 (m，4H)、6·96 (d, J:6.9 Hz, 2H)、7· 99 (d，J 二 6· 9 Hz，2H)。 4-[(2S，4S) - 1-第三丁氧罗炭基-4-甲氧基-2 -吼洛。定基]甲氧 苯甲酸甲酯^ 89112968.ptd . Page 477 I t ^ 1283240 V. INSTRUCTIONS (473) 4-[(2S,4S )-4-Ethyloxy-1-tert-butoxycarbonyl-4- at room temperature Catalyst k2C03 was added to a stirred solution of methyl hydroxy-2-pyridinyl]methoxybenzoate (7.43 g, 18.9 mmol) in MeOH (150 mL). After stirring for 1 day, the mixture was concentrated in vacuo. The resulting residue is recrystallized by the addition of CHC 1 33-n-hexane to give 4-[(2S,4S)-l-t-butoxycarbonyl-4-hydroxy-2-pyridinyl]methoxybenzene. Ethyl formate (5. 76 g, 8 7%) as a colorless solid. UMR (CDC13) 5 1· 46 (s, 9H), 2· 11 (m, 1H), 2·35 (br, 1H), 3·27-3·65 (m, 2H), 3·89 (s , 3H), 4·07-4.54 (m, 4H), 6.96 (d, J: 6.9 Hz, 2H), 7·99 (d, J 6.9 Hz, 2H). 4-[(2S,4S)-1- 1-Tertioxycarbo-4-methoxy-2-indole. Methyl methoxybenzoate

在〇°C下於4-[(2S，4S)-1-第三丁氧羰基-4 -羥基-2 -吡咯 啶基]曱氧苯甲酸曱酯（2.10克，5.98毫莫耳）溶於THF (60 毫升）之攪拌溶液中加入60%油NaH( 3 59毫克，8· 97毫莫 耳）。於攪拌15分鐘後，將Mel(l. 20毫升，8.97毫莫耳）在 相同溫度下加至混合物，並使所產生之混合物於超過1小 時内升溫至室溫。然後在室溫下將6〇%油NaH(359毫克， 8· 97毫莫耳）及Mel (1· 20毫升，8· 97毫莫耳）加至反應混合 物，並攪拌1 4小時。將反應混合物倒入至冰水中，並以 CHCI3萃取。將結合的萃取液以NaHC〇3水溶液及鹽水洗滌。 於在NaJO4上乾燥後，將萃取液於真空中濃縮。使殘留物Dissolved in 4-[(2S,4S)-1-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinyl]oxobenzoate (2.10 g, 5.98 mmol) at 〇 °C A stirred solution of THF (60 ml) was added 60% oil NaH (3 59 mg, 8.97 mmol). After stirring for 15 minutes, Mel (180 ml, 8.97 mmol) was added to the mixture at the same temperature, and the resulting mixture was allowed to warm to room temperature over 1 hour. Then 6 〇% oil NaH (359 mg, 8.97 mmol) and Mel (1·20 mL, 8.97 mmol) were added to the reaction mixture at room temperature and stirred for 14 hours. The reaction mixture was poured into ice water and extracted with CHCI3. The combined extracts were washed with a NaHC 3 aqueous solution and brine. After drying on NaJO4, the extract was concentrated in vacuo. Residue

1283240 五、發明說明（474) 於矽膠[5克，正己烷/Et0Ac(4/l)]上進行層析，而得 4-[(2S，4S)-1-第三丁氧羰基-4-甲氧基-2 -咄咯啶基]甲氧 苯甲酸甲酯（1. 32克，60%)之無色油。1H-NMR (CDC13) 5 1·48 (s, 9H)、2·05 (m，1H)、2·29 (d，J二 14·2 Hz, 1Η)、3·30 (s，3Η)、3.36-4·38 (m，4Η)、6·76 (br， 2H) 、 7·97 (d， J=8·8 Hz, 2H)。 4 - [(2S，4S) - 4-甲氧基-2 -咄咯啶基]甲氧苯甲酸甲酯1283240 V. INSTRUCTION DESCRIPTION (474) Chromatography on 5 g of n-hexane/Et0Ac (4/l) gave 4-[(2S,4S)-1-tert-butoxycarbonyl-4- Methyl 2-methoxy-2-pyridinyl]methoxybenzoate (1.22 g, 60%) as a colorless oil. 1H-NMR (CDC13) 5 1·48 (s, 9H), 2·05 (m, 1H), 2·29 (d, J 2·14 Hz, 1Η), 3·30 (s, 3Η), 3.36-4·38 (m, 4Η), 6.76 (br, 2H), 7.97 (d, J=8·8 Hz, 2H). 4 - [(2S,4S)-4-Methoxy-2-oxaridinyl]methyl methoxybenzoate

在室溫下於4-[(2S，4S) - 1-第三丁.氧羰基-4-甲氧基—2-吡咯啶基]甲氧苯甲酸甲酯（2. 38克，3· 61毫莫耳）溶於CH 2C12(46毫升）之攪拌溶液中加入TFAC23毫升）。於攪拌14小 時後，將混合物於真空中濃縮。經由加入CH2C12及in NaOH 將殘留物稀釋，並以CH2C12萃取。將結合的萃取液以鹽水 洗滌’於N a2 S 04上乾燥，並於真空中濃縮。使殘留物於石夕 膠[50克，CHCl3/MeOH(20/l)]上進行層析，而得 4 - [(2S，4S) - 4-甲氧基-2 - ϋ比17各σ定基]甲氧苯甲酸甲酉旨（950 毫克，99%)之黃色油。1H-NMR (CDC13)(5 2·16 (t， J = 5.3 Hz，1H)、2.72 (s，1H)、2·95 (d，J = 6.8 Hz，1H)、 3.11 (d，J=11.0 Hz，1H)、3·26 (t，J = 1.9 Hz，3H)、 3.52 (br，1H)、3·84 (d，J = 1.7 Hz，3H)、3·92 (s， 1H) 、4.00 (d， J=4.1 Hz， 2H) 、6·88 (m， 2H) 、7·94 (m， 2H)。 4-[(2S，4S)-4-曱氧基-1-[3-甲氧基-4-[Ν’ -（2-曱基苯基）Methyl 4-[(2S,4S)-1- 1-tert-oxycarbonyl-4-methoxy-2-pyrrolidinyl]methoxybenzoate (2. 38 g, 3.61) To a stirred solution of CH 2 C 12 (46 mL) was added THF (23 mL). After stirring for 14 hours, the mixture was concentrated in vacuo. The residue was diluted with CH2C12 and in NaOH and extracted with CH2C12. The combined extracts were washed with brine <RTI ID=0.0># </ RTI> </ RTI> <RTIgt; The residue was chromatographed on Shiqi gum [50 g, CHCl3 / MeOH (20 /l)] to give 4-[(2S,4S)-4-methoxy-2-indole ratio 17 sigma A yellow oil of methoxybenzoic acid (950 mg, 99%). 1H-NMR (CDC13) (5 2·16 (t, J = 5.3 Hz, 1H), 2.72 (s, 1H), 2·95 (d, J = 6.8 Hz, 1H), 3.11 (d, J=11.0) Hz, 1H), 3·26 (t, J = 1.9 Hz, 3H), 3.52 (br, 1H), 3·84 (d, J = 1.7 Hz, 3H), 3.92 (s, 1H), 4.00 (d, J=4.1 Hz, 2H), 6.88 (m, 2H), 7·94 (m, 2H). 4-[(2S,4S)-4-曱oxy-1-[3- Oxy-4-[Ν'-(2-mercaptophenyl)

\\312\2d-code\90-01\89112968.ptd 第 479 頁 1283240 五、發明說明（475) 脲基]苯基乙醯基]-2-咄咯啶基]甲氧笨甲酸甲醋\\312\2d-code\90-01\89112968.ptd Page 479 1283240 V. INSTRUCTIONS (475) Urea-based]phenylethanyl]-2-indolyl]methoxybenzoic acid methyl vinegar

使3-甲氧基-4-[^-(2-甲基苯基）脲基]笨乙酸（3 75毫 克’ 1·19毫莫耳）、4-[(2S，4S)-4-甲氧基—2—咄咯啶基]甲 乳本甲酸甲醋（317毫克’1.19宅莫耳）、edc*HC1(342毫 克，1.79毫莫耳）、H0BT( 24 2毫克，1·79毫莫耳）&amp;Et3N (0.83毫升，5·95毫莫耳）於DMF(5毫升）中之混合物在室溫 下攪拌13小時。將混合物倒入至冰水中，並以Et〇Ac萃 取。將結合的萃取液以冰水及鹽水洗務。於在N a2 s 04上乾 燥後，將萃取液於真空中濃縮。使殘留物於矽膠[5 〇克， CHC13/丙酮（10/1)〜CHCl3/MeOH(20/l)]上進行層析，而得 4 - [(2S，4S) - 4-甲氧基-1 - [3 -甲氧基-4 - [Ν’ -（2-甲基苯基） 脲基]苯基乙醯基]- 2-吼17各°定基]甲氧苯甲酸甲酯（650毫 克，98%)的淡棕色非晶形固體。1H-NMR (CDC13) (5 2· 03 (m，lH)、2.31(s，3H)、2.32(m，lH)、3.29(d，J=l· 0 Hz，3H)、3·5 7-3.68 (m，5H)、3·88 (d，J=1.0 Hz,3-methoxy-4-[^-(2-methylphenyl)ureido] benzoic acid (3 75 mg '1·19 mmol), 4-[(2S,4S)-4-A Oxy- 2-pyrrolidinyl] methyl milk methyl formate (317 mg '1.19 house Moule), edc*HC1 (342 mg, 1.79 mmol), H0BT (24 2 mg, 1.79 mmol) The mixture of &lt;Et3N (0.83 mL, 5·95 mmol) in DMF (5 mL) was stirred at room temperature for 13 hours. The mixture was poured into ice water and extracted with Et 〇Ac. The combined extracts were washed with ice water and saline. After drying on Na 2 s 04, the extract was concentrated in vacuo. The residue was chromatographed on silica gel [5 g, CHC13 / acetone (10/1) - CHCl3 / MeOH (20 / l) to give 4-[(2S,4S)-4-methoxy- 1 - [3 -Methoxy-4 -[Ν' -(2-methylphenyl)ureido]phenylethenyl]-2-ylidene 17 benzyl]methyl methoxybenzoate (650 mg , 98%) of a light brown amorphous solid. 1H-NMR (CDC13) (5 2· 03 (m, lH), 2.31 (s, 3H), 2.32 (m, lH), 3.29 (d, J=l·0 Hz, 3H), 3·5 7- 3.68 (m, 5H), 3.88 (d, J = 1.0 Hz,

3 H )、3 · 9 9 - 4 · 0 6 ( m，2 H )、4 · 4 6 ( m，1 H)、6 · 1 9 ( m， 1H) 、6·80 (s， 1H) 、6.81 (d， J=9.0 Hz， 1H) 、6.96-7· 19 (m，4H)、7·29 (m，2H)、7·50 (d，J = 6.7 Hz，1H)、 7·95 —8.10 (m， 3H); MS(ESI) m/z 562 (MH1)。 於4 - [(2S，4S) - 4 -甲氧基-1-[3 -甲氧基-4 - [Ν’ - (2 -甲基 苯基）脲基]苯基乙醯基]-2 -咄咯啶基]甲氧苯甲酸甲酯3 H ), 3 · 9 9 - 4 · 0 6 ( m, 2 H ), 4 · 4 6 ( m, 1 H), 6 · 1 9 ( m, 1H), 6·80 (s, 1H), 6.81 (d, J=9.0 Hz, 1H), 6.96-7·19 (m, 4H), 7·29 (m, 2H), 7·50 (d, J = 6.7 Hz, 1H), 7.95 — 8.10 (m, 3H); MS (ESI) m/z 562 (MH1). 4-[(2S,4S)-4-Methoxy-1-[3-methoxy-4 -[Ν'-(2-methylphenyl)ureido]phenylethenyl]-2 - hydrazinyl]methyl methoxybenzoate

\\312\2d-code\90-01\89112968.ptd 第 480 頁 1283240 五、發明說明（476) (650毫克，1.16毫莫耳）溶於THF( 18. 5毫升）之溶液中加入 〇· 25N NaOH(18· 5毫升）。於在室溫下攪拌12小時後，將混 合物以IN HC1酸化，並以CHCl3-MeOH(10/l)萃取。將結合 的萃取液於Na2S04上乾燥，並於真空中濃縮。將殘留物於 矽膠[50克，CHCl3/MeOH(20/l)]上進行層析，而得132 ( 540毫克，85%)之無色非晶形固體。IR (KBr) 3354、 2937、1709、1685、1604、1533、1454 /公分；UMR (DMSO-d6) 5 2· 11 (m，2H)、2· 25 (s，3H)、3· 22 (s, 3H)、3.49-3.78 (m, 4H)、3·82 及 3.86 (s, 3H，醯胺異 構物）、3·87-4·52 (m，4H)、6·71-7·17 (m，7H)、7·79 (d，J = 8.1 Ηζ，1Η)、7·86-8·03 (m，3Η)、8·45-8·57 (m, 2Η) ^12.64 (br, 1Η) ； MS (ESI) m/z 548(MH1)； C30H33N3O7 · INa · 1 · 5H20 之分析計算值：C，60. 29 ; H， 6· 07 ; N，7· 03。實測值：C, 59. 90 ; H, 5. 59 ; N， 6· 69 o 實施例1 2 5 4-[(2S，4S) - 1-[4 - [Ν’ -（2-氣苯基）脲基]—3—曱氧笨基乙酸 基]-4-甲氧基-2 -咄咯啶基]曱氧苯甲酸\\312\2d-code\90-01\89112968.ptd Page 480 1283240 V. INSTRUCTIONS (476) (650 mg, 1.16 mmol) dissolved in THF (1. 25N NaOH (18.5 ml). After stirring at room temperature for 12 hours, the mixture was acidified with EtOAc (EtOAc) (EtOAc) The combined extracts were dried over Na2SO4 and concentrated in vacuo. The residue was chromatographed on EtOAc (EtOAc:EtOAc:EtOAc IR (KBr) 3354, 2937, 1709, 1685, 1604, 1533, 1454 / cm; UMR (DMSO-d6) 5 2· 11 (m, 2H), 2 · 25 (s, 3H), 3 · 22 (s , 3H), 3.49-3.78 (m, 4H), 3·82 and 3.86 (s, 3H, guanamine isomers), 3·87-4·52 (m, 4H), 6·71-7·17 (m,7H),7·79 (d,J = 8.1 Ηζ,1Η), 7·86-8·03 (m,3Η), 8·45-8·57 (m, 2Η) ^12.64 (br, 1 Η); MS (ESI) m/z 548 (MH1); C30H33N3O7 · INa · 1 · 5H20 Analysis calculated: C, 60.29; H, 6· 07; N, 7. 03. Found: C, 59.90; H, 5. 59 ; N, 6· 69 o Example 1 2 5 4-[(2S,4S) - 1-[4 - [Ν' -(2-Phenylphenyl) Urea]3-(3-oxooxyphenyl)-4-methoxy-2-pyridinyl]oxobenzoic acid

4 - [(2S，4S)-1 - [4- [Ν’ -（2 -氯苯基）脲基]一3-甲氧苯基乙隨 基]- 4 -甲氧基- 2 -咄咯啶基]甲氧苯甲酸曱酯4-([2S,4S)-1 - [4- [Ν'-(2-Chlorophenyl)ureido]- 3-methoxyphenylethyl]- 4 -methoxy-2-pyrrole Ethyl pyridyl methoxybenzoate

89112968.ptd 第481頁 1283240 五、發明說明（477) ΡΜβ 使4-[Ν’-（2-氯苯基）脲基]-3-甲氧苯乙酸（398毫克，l. 19¾莫耳）、4 - [(2S，4S)-4-曱氧基-2 -吼洛咬基]曱氧苯甲 酸曱酯（317毫克，1·19毫莫耳）、EDC.HC 1(342毫克， 1.79 毫莫耳）、HOB T( 24 2 毫克，1.79 毫莫耳）及Et3N (0.83 毫升，5·95毫莫耳）於DMF (5毫升）中之混合物在室溫下攪 拌1 3小時。將混合物倒入至冰水中，並以ε 10 A c萃取。將 結合的萃取液以冰水及鹽水洗條。於在N a2 S 04上乾燥後， 將萃取液於真空中濃縮。使殘留物於矽膠[50克，CHC13/ 丙酮（10/1)〜CHCl3/MeOH(20/l)]上進行層析，而得4-[ (2S，4S)-1 -[4-[Ν’ -（2-氯苯基）脲基]-3-甲氧苯基乙醯 基]-4-甲氧基-2 -吡咯啶基]甲氧苯甲酸甲酯（ 6 0 0毫克， 87%)的無色非晶形固體。1}1-關1^(^)(：13)(5 1.99-2.06 (m，1Η)、2.34 (d，J = 13.9 Ηζ，1Η)、3·30 (s，3Η)、3· 59 (d，J = 7.4 Ηζ，1Η)、3·62 (d，J = 3.2 Ηζ，2Η)、3.83 (s， 3H) 、3·88 (s， 3H) 、4·00-4·18 (m， 3H) 、4·42 - 4·51 (m，2Η)、6·82-7·07 (m，7Η)、7·28 (d，J 二8·3 Hz, 1Η)、7·35 (dd, J = 7.9、1·5 Ηζ，1Η)、7·94 - 8·00 (m， 3Η) 、 8·18 (d，卜8·3 Hz, 1Η) ; MS(ESI) m/z 582 (MH1)、5 84(MH3)。89112968.ptd Page 481 1283240 V. INSTRUCTIONS (477) ΡΜβ makes 4-[Ν'-(2-chlorophenyl)ureido]-3-methoxyphenylacetic acid (398 mg, 1. 193⁄4 mol), 4 - [(2S,4S)-4-methoxy-2-indolyl] oxime oxime (317 mg, 1.19 mmol), EDC.HC 1 (342 mg, 1.79 mM) A mixture of HOB T (24 2 mg, 1.79 mmol) and Et3N (0.83 mL, 5·95 mmol) in DMF (5 mL) was stirred at room temperature for 13 h. The mixture was poured into ice water and extracted with ε 10 A c. The combined extracts were washed with ice water and brine. After drying on Na 2 S 04, the extract was concentrated in vacuo. The residue was chromatographed on silica gel [50 g, CHC13 / acetone (10/1) - CHCl3 / MeOH (20 / l)] to give 4-[(2S,4S)-1 -[4-[Ν '-(2-Chlorophenyl)ureido]-3-methoxyphenylethenyl]-4-methoxy-2-pyrrolidinyl]methyl methoxybenzoate (600 mg, 87%) a colorless amorphous solid. 1}1-OFF 1^(^)(:13)(5 1.99-2.06 (m,1Η), 2.34 (d, J = 13.9 Ηζ, 1Η), 3·30 (s, 3Η), 3· 59 ( d, J = 7.4 Ηζ, 1Η), 3·62 (d, J = 3.2 Ηζ, 2Η), 3.83 (s, 3H), 3·88 (s, 3H), 4·00-4·18 (m, 3H), 4·42 - 4·51 (m, 2Η), 6·82-7·07 (m, 7Η), 7·28 (d, J 2·8 Hz, 1Η), 7·35 (dd , J = 7.9, 1·5 Ηζ, 1Η), 7·94 - 8·00 (m, 3Η), 8·18 (d, Bu 8·3 Hz, 1Η); MS(ESI) m/z 582 ( MH1), 5 84 (MH3).

於4-[(2S，4S) -1 - [4-[Ν’ -（2 -氯苯基）脲基]- 3 -曱氧苯基 乙醯基]- 4-甲氧基-2 -咄咯啶基]甲氧苯甲酸甲酯（600毫 克，1· 03毫莫耳）溶於THF(1 6毫升）之溶液中加入0· 25N4-[(2S,4S) -1 - [4-[Ν' -(2-Chlorophenyl)ureido]- 3 -indolylphenyl)- 4-methoxy-2-indole Methyl <RTIgt; </RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt;

\\312\2d-code\90-01\89112968.ptd 第 482 頁 1283240 五、發明說明（478)\\312\2d-code\90-01\89112968.ptd Page 482 1283240 V. Description of invention (478)

Na0H(16毫升）。於在室溫下攪拌12小時後，將混合物以1N HC1酸化，並以CHCI3~MeOH( 1 0/1 )萃取。將結合的萃取液 於NaJO4上乾燥’並於真空中濃縮。將殘留物於tlc [CHCl3/MeOH(10/l)]上純化，而得133(495 毫克，75%)之 無色非晶形固體。IR (KBr) 3330 、 3070 、 2937 、 1709 、 1685、1604、1533 /公分；ih-NMR (DMSO-d6) (5 2· 11 (m， 2H)、3·22 (s，3H)、3·56-3·78 (m，4H)、3·81 及3.85 (s，3Η，醯胺異構物）、3·88-4·56 (m，4Η)、6·73 及 6·77 (d，J = 8.1 Ηζ， 1Η，醯胺異構物）U5 及 6·91 (s， 1Η， 醯胺異構物）、7·(Π-7.07 (m，3H)、7·28 (t， J = 8.1 Hz, 1H)、7·43 (d，J二8.1 Hz, 1H)、7·85-7.94 (m, 2H)、7· 97 (d, J = 8.6 Hz, 1H)、8.09 (d，J二8·3 Hz，1H)、 8.90-8.95 (m, 2H) ； MS(FAB) m/z 5 70 CMH1) &gt;572 (MH3)。 實施例1 2 6 4-[(2S, 4S)-1 - [4 - [Ν’ -（2_臭笨基）脲基]-3-甲氧笨基乙酿 基]- 4-曱氧基-2_吼咯啶基]甲氧苯曱酸Na0H (16 ml). After stirring at room temperature for 12 hours, the mixture was acidified with 1N EtOAc and extracted with CHCI 3~MeOH (1 0/1). The combined extracts were dried on NaJO4 and concentrated in vacuo. The residue was purified with EtOAc EtOAc (EtOAc) IR (KBr) 3330, 3070, 2937, 1709, 1685, 1604, 1533 / cm; ih-NMR (DMSO-d6) (5 2· 11 (m, 2H), 3·22 (s, 3H), 3· 56-3·78 (m, 4H), 3.81 and 3.85 (s, 3Η, guanamine isomers), 3·88-4·56 (m, 4Η), 6.73 and 6.77 (d , J = 8.1 Ηζ, 1 Η, guanamine isomers) U5 and 6.91 (s, 1 Η, guanamine isomers), 7·(Π-7.07 (m, 3H), 7·28 (t, J = 8.1 Hz, 1H), 7·43 (d, J 8.1 Hz, 1H), 7.85-7.94 (m, 2H), 7.97 (d, J = 8.6 Hz, 1H), 8.09 (d, J 2 8.3 Hz, 1H), 8.90-8.95 (m, 2H); MS (FAB) m/z 5 70 CMH1) &gt; 572 (MH3). Example 1 2 6 4-[(2S, 4S) -1 - [4 - [Ν' -(2_臭笨基)ureido]-3-methoxyphenylethyl] 4- 4-oxo-2-pyrrolidinyl]methoxybenzoic acid

4 - [(2S，4S) -1 - [4 - [Ν’ - (2 -漠笨基）脲基]- 3-曱氧苯基乙酉t 基]-4-甲氧基-2-咄咯啶基]甲氧苯甲酸甲酯 OMe4 - [(2S,4S) -1 - [4 - [Ν' - (2 - 漠 基))]]]]]]]]]]]]]]]] Methyl benzyl]methoxybenzoate

89112968.ptd 第483頁 1283240 五、發明說明（479) 使4-[N’ -（2-溴苯基）脲基]—3〜甲氧苯乙酸（451毫克，】· 19毫莫耳）、4-[ (2S，4S)-4-曱氧基—2〜咄咯啶基]甲氧苯甲 酸甲醋（317毫克，1· 19毫莫耳）、EDC · HC1 (342毫克， 1.79 毫莫耳）、HOBT(242 毫克，ι·79 毫莫耳）及Et3N (0·83 毫升，5· 95毫莫耳）於DMF(5毫升）中之混合物在室溫下攪 拌13小時。將混合物倒入至冰水中，並以Et〇Ac萃取。將 結合的萃取液以冰水及鹽水洗滌。於在上乾燥後，89112968.ptd Page 483 1283240 V. INSTRUCTIONS (479) 4-[N'-(2-Bromophenyl)ureido]-3 methoxyphenylacetic acid (451 mg, ] 19 mmol), 4-[ (2S,4S)-4-decyloxy-2~-pyridinyl]methoxybenzoic acid methyl vinegar (317 mg, 1.19 mmol), EDC · HC1 (342 mg, 1.79 mmol) The mixture of HOBT (242 mg, ι·79 mmol) and Et3N (0·83 mL, 5·95 mmol) in DMF (5 mL) was stirred at room temperature for 13 hours. The mixture was poured into ice water and extracted with Et EtOAc. The combined extracts were washed with ice water and brine. After drying on the top,

將萃取液於真空中濃縮。使殘留物於矽膠[5 〇克，C π 13 / 丙酮（10/1)]上進行層析，而得4-[(2S，4S)-1-[4-[Ν，-（2 -溴苯基）脲基]-3 -甲氧苯基乙醯基]—4—曱氧基一2 — σ比洛咬 基]甲氧苯甲酸甲酯（ 760毫克，1 〇〇%)的黃色油。1H_NMR (CDC13)6 1.99 - 2.32 (m，1Η)、2·34 (d，J = 13.4 Hz， 1H)、3·30 (s，3H)、3·59 (m，1H)、3·63 (d，J = 3.2 Hz， 2Η)、3·68 (dd, J=12.2、5.1 Hz, 1Η)、3·81 (br， 3H)、3.88 (s, 3H)、3·91-4·16 (m，2H)、4·49-4.51 (m，2H)、6·82-7·15 (m，7H)、7·31 (t, J二8·1 Hz，1H) 、7·52 (d， J=8.1 Hz， 1H) 、7·93-8.00 (m， 3H) 、8·14 (d，J = 8.3 Hz，1H); MS(ESI) m/z 626 (M+ + 1)、628 (MH3)。 於4-[(2S，4S) -1-[4-[Ν’ -（2-溴苯基）脲基]苯基乙醯 基]一4-曱氧基一2-咄咯啶基]甲氧笨甲酸甲酯（760毫克，1. 19毫莫耳）溶於THF(19毫升）之溶液中加入〇. 25Ν NaOH( 19 毫升）。於在室溫下攪拌1 2小時後，將混合物以1 N HC 1酸The extract was concentrated in vacuo. The residue was chromatographed on silica gel [5 gram, C π 13 / acetone (10/1)] to give 4-[(2S,4S)-1-[4-[Ν,-(2-bromo) Phenyl)ureido]-3-methoxyphenylethenyl]-4-indolyloxy-2 - σ piroxime] methyl methoxybenzoate (760 mg, 1 〇〇%) yellow oil . 1H_NMR (CDC13)6 1.99 - 2.32 (m,1Η), 2·34 (d, J = 13.4 Hz, 1H), 3·30 (s, 3H), 3·59 (m, 1H), 3·63 ( d, J = 3.2 Hz, 2Η), 3.68 (dd, J=12.2, 5.1 Hz, 1Η), 3.81 (br, 3H), 3.88 (s, 3H), 3·91-4·16 ( m, 2H), 4·49-4.51 (m, 2H), 6·82-7·15 (m, 7H), 7·31 (t, J 2·8 Hz, 1H), 7·52 (d , J=8.1 Hz, 1H), 7.93-8.00 (m, 3H), 8·14 (d, J = 8.3 Hz, 1H); MS (ESI) m/z 626 (M+ + 1), 628 ( MH3). 4-[(2S,4S) -1-[4-[Ν' -(2-Bromophenyl)ureido]phenylethenyl]- 4-decyloxy-2-bromopyridinyl]- Methyl oxyformate (760 mg, 1.19 mmol) was dissolved in THF (19 mL). EtOAc. After stirring at room temperature for 12 hours, the mixture was treated with 1 N HCl 1 acid.

\\312\2d-code\90-01\89112968.ptd 第 484 頁 1283240 五、發明說明（480) 化，並以(：11(：13_116〇11(10/1)萃取。將結合的萃取液於 Na£ S04上乾燥，並於真空中濃縮。將殘留物於矽膠[5 〇克， CHCl3/MeOH(20/l)]上進行層析，而得 134(580 毫克，78%) 之無色非晶形固體。IR (KBr) 333 0、2935、1 70 9、1685 、1 604、1 529、1 434 / 公分；Μ-NMR (DMSO-d6) 6 2. 11 (m， 2H) 、3·22 (s， 3H) 、3·58-3·78 (m， 4H) 、3·81 及3. 86 (s，3Η，醯胺異構物）、3·92-4·52 (m，4Η)、6·72 (d，J = 8.6 Ηζ，1Η)、6·77 (d, J = 8.3 Ηζ，1Η)、6·85 及 6·91 (s，1H ’ 醯胺異構物）、6·97 (t，J = 7.1 Hz， 1H)、 7.02 及 7.06 (d，J = 8.6 Hz，2H，醯胺異構物）、7·32 (t， J = 7.3 Hz, 1H)、7·59 (dd，J = 8.1、1·0 Hz，1H)、7·94 (dd，J = 8.1、1·2 Hz，2H)、7· 95-7·98 (m，2H)、8·74 (s，1H)、8·94 (s, 1H)、12.63 (br，1H); MS(FAB) m/z 612(MH1)、614(MH3)。 實施例127 4-[(4R)-甲氧基-：l- [3-甲氧基-4-[Ν’ -（2-甲基苯基）脲基] 苯基乙醯基]-（2 S )-吼咯啶曱氧基]苯曱酸 0^\\312\2d-code\90-01\89112968.ptd Page 484 1283240 V. Description of invention (480), extracted with (:11(:13_116〇11(10/1). The combined extract Drying over MgSO4, EtOAc (EtOAc m.) Crystalline solid. IR (KBr) 333 0, 2935, 1 70 9 , 1685 , 1 604, 1 529, 1 434 / cm; Μ-NMR (DMSO-d6) 6 2. 11 (m, 2H), 3.22 (s, 3H), 3·58-3·78 (m, 4H), 3.81 and 3.86 (s, 3Η, guanamine isomers), 3·92-4·52 (m, 4Η) , 6.72 (d, J = 8.6 Ηζ, 1Η), 6.77 (d, J = 8.3 Ηζ, 1Η), 6.85 and 6.91 (s, 1H 'proline isomers), 6· 97 (t, J = 7.1 Hz, 1H), 7.02 and 7.06 (d, J = 8.6 Hz, 2H, guanamine isomer), 7.32 (t, J = 7.3 Hz, 1H), 7·59 ( Dd, J = 8.1, 1·0 Hz, 1H), 7·94 (dd, J = 8.1, 1·2 Hz, 2H), 7·95-7·98 (m, 2H), 8·74 (s , 1H), 8.94 (s, 1H), 12.63 (br, 1H); MS (FAB) m/z 612 (MH1), 614 (MH3). Example 127 4-[(4R)-methoxy - l- [3- methoxy -4- [Ν '- (2- methylphenyl) ureido] phenyl-acetylamino-yl] - (2 S) - piperidine Yue roar slightly yloxy] phenyl Yue acid ^ 0

Me H H OMe 135 卜（第三丁氧羰基）-（4R)-甲氧基-（2S) -脯胺醇Me H H OMe 135 (t-butoxycarbonyl)-(4R)-methoxy-(2S)-prolinol

在室溫下於1-(第三丁氧羰基）-(4R) -甲氧基-(2S) -吼咯At room temperature in 1-(t-butoxycarbonyl)-(4R)-methoxy-(2S)-fluorene

89112968.ptd 第485頁 1283240 五、發明說明（481) =酸（=7克，U.7毫莫耳）溶於thf(25毫升） ^中加入μ3 ·])Μδ(1·66毫升，17·5毫莫耳），並 室溫I授摔隔夜。將混合物蒸發，並以CH2n2^ Μ °將洛液以112〇、鹽水洗條，於Na2S〇4上乾燥，並蒸 S。使殘留物經由於矽膠上利用CHC13—Me0H (501 v/v) 作為洗提液進行管柱層析，純化而得卜（第三丁氧幾 基PUfO-甲氧基一（2幻-脯胺醇（L79克，66%〕之無色油。 H-NMR (CDC13) δ 1· 47 (s，9H)、1. 69-1. 73 (m，1H)、 2·12-2.17 (m，1Η)、3·31 (s，3H)、3·37-3·40 (m， 1H)、3·53-3.62 (m，2H)、3·68-3·73 (m，1H)、3·83-3· 87 (m，1H)、4. 04-4.07 (m，1H)、4·90-4·92 (m，1H) ;MS(FAB) m/z 232(MH1)。 4- [ (4R)-甲氧基一（2S) -吼咯啶甲氧基]苯曱酸甲酯 C〇2Me 於4-羥基苯甲酸甲酯（I 18克，7· 76毫莫耳）、；[-(第三 丁氧羰基）-（4R) -曱氧基-（2S) -脯胺醇（1· 79克，7. 74毫莫 耳）及Ph3P(2· 44克，9.30毫莫耳）溶於THF(30毫升）之攪拌 溶液中加入DIAD(1· 83毫升，9· 29毫莫耳），並使反應混合 物迴流加熱5小時。於冷卻至室溫後，將混合物蒸發。將 殘留物於矽膠上利用甲苯-丙酮（5 : 1，v/v)作為洗提液過 濾而得粗製產物。將此粗製產物溶解於CH2C12(20毫升） 中。將溶液加入TFA(20毫升），並使反應混合物在室溫下89112968.ptd Page 485 1283240 V. INSTRUCTIONS (481) = Acid (= 7 g, U. 7 mmol) dissolved in thf (25 mL) ^ Added μ3 ·]) Μ δ (1·66 ml, 17 · 5 millimoles), and room temperature I was dropped overnight. The mixture was evaporated, and the mixture was washed with aq. The residue was subjected to column chromatography using CHC13-Me0H (501 v/v) as an eluent on silica gel, and purified to obtain a third (butoxybutyryl PUfO-methoxy-(2-phanyl-guanamine). Alcohol (L79 g, 66%) of a colorless oil. H-NMR (CDC13) δ 1· 47 (s, 9H), 1. 69-1. 73 (m, 1H), 2·12-2.17 (m, 1Η) ), 3·31 (s, 3H), 3·37-3·40 (m, 1H), 3·53-3.62 (m, 2H), 3·68-3·73 (m, 1H), 3· 83-3· 87 (m, 1H), 4. 04-4.07 (m, 1H), 4·90-4·92 (m, 1H); MS (FAB) m/z 232 (MH1). 4- [ (4R)-Methoxy-(2S)-pyridinylmethoxy]benzoate methyl ester C〇2Me in methyl 4-hydroxybenzoate (I 18 g, 7.76 mmol); -(T-butoxycarbonyl)-(4R)-decyloxy-(2S)-prolinol (1·79 g, 7.74 mmol) and Ph3P (2.44 g, 9.30 mmol) DIAD (1·83 ml, 9·29 mmol) was added to a stirred solution of THF (30 ml), and the reaction mixture was heated under reflux for 5 hours. After cooling to room temperature, the mixture was evaporated. The crude product was obtained by filtering toluene-acetone (5:1, v/v) as an eluent on silica gel. . The crude product was dissolved in CH2C12 (20 ml). The solution was added TFA (20 mL) and the mixture was reacted at room temperature

第486頁Page 486

1283240 五、發明說明（482) 攪拌隔夜。將混合物於真空中濃縮，並利用飽和NaHC〇s使 成為鹼性。將混合物以chci3萃取，以鹽水洗滌，於k2C03 上乾燥，並蒸發。使殘留物經由於矽膠上利用CHCl3-Me〇H (30:1至30:2，v/v)作為洗提液進行管柱層析，純化而得 4- [ (4R )-甲氧基-（2S)-吼咯啶甲氧基]苯甲酸甲酯（1 · 6 7克 ，2步驟81%)之紅棕色油。1}1-祕1^(00(：13)(5 1.65-1.72 (m， 1H) 、1.89 (bs， 1H) 、2·05-2.22 (m， 1H) 、2·95-3·15 (m，2Η)、3·31 (s，3Η)、3·69-3·76 (m, 1Η)、 3·88 (s，3H)、3·9 卜 4.06 (m，3H)、6·89 - 6·92 (m，2H) 、7·96 -7.98 (m，2H) ; MS(FAB) m/z 266 (MH1)。 4-[(4R)-曱氧基-1 - [3 一甲氧基-4 一 [ν’ 一（2-甲基苯基）脲基] 苯基乙醯基]-(2 S)-吼咯啶甲氧基]苯曱酸甲酯1283240 V. INSTRUCTIONS (482) Stir overnight. The mixture was concentrated in vacuo and made basic with saturated NaHC. The mixture was extracted with chci3, washed with brine, dried over EtOAc, and evaporated. The residue was subjected to column chromatography using CHCl3-Me〇H (30:1 to 30:2, v/v) as an eluent, and purified to give 4-[(4R)-methoxy- (2S)-Ethrolidine methoxy]benzoic acid methyl ester (1 · 67 g, 2 step 81%) of a reddish brown oil. 1}1- secret 1^(00(:13)(5 1.65-1.72 (m, 1H), 1.89 (bs, 1H), 2·05-2.22 (m, 1H), 2·95-3·15 ( m, 2Η), 3·31 (s, 3Η), 3·69-3·76 (m, 1Η), 3·88 (s, 3H), 3·9 Bu 4.06 (m, 3H), 6.89 - 6·92 (m, 2H), 7.96 -7.98 (m, 2H); MS(FAB) m/z 266 (MH1). 4-[(4R)-decyloxy-1 - [3 A Oxy-4 -[ν'-(2-methylphenyl)ureido]phenylphenyl]](2S)-indolyl methoxy]benzoate

使3 -曱氧基-4- [Ν’- (2 -曱基苯基）脲基]苯乙酸（470毫 克’ 1.50¾莫耳）、4 - [(4R) -甲氧基-（2S)-吼口各。定甲氧基] 苯甲酸曱酯（396毫克，1.49毫莫耳）、EDC.HC1(343毫 克’1.7 9毫莫耳）、HOBt(242毫克，l·79毫莫耳）及Et3N (250毫升，1· 79毫莫耳）於THF(10毫升）中之混合物在室溫 下授拌隔夜。將混合物以H2 0稀釋，並以E10 A c萃取。將萃 取液以鹽水洗務，於Na2S04上乾燥，並蒸發。使殘留物經 由於矽膠上利用CHC13-MeOH(100:l，v/v)作為洗提液進行 管柱層析，純化而得4-[ (4R)-甲氧基-1 - [3-甲氧基一4-3-Methoxy-4-[Ν'-(2-mercaptophenyl)ureido]phenylacetic acid (470 mg ' 1.503⁄4 mol), 4 - [(4R)-methoxy-(2S) - 吼 mouth each. Dimethoxy] decyl benzoate (396 mg, 1.49 mmol), EDC.HC1 (343 mg '1.7 9 mmol), HOBt (242 mg, 1.7 mmol) and Et3N (250 ml) A mixture of 1.79 mmoles in THF (10 mL) was stirred overnight at room temperature. The mixture was diluted with H2 0 and extracted with E10 A c. The extract was washed with brine, dried over Na 2 SO 4 and evaporated. The residue was subjected to column chromatography using CHC13-MeOH (100:1, v/v) as an eluent, and purified to give 4-[(4R)-methoxy-1 - [3- Oxygen 4-

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[Ν’ -（2-甲基苯基）脲基]苯基乙醯基]-（2S) -吼咯啶甲氧 基]苯曱酸甲酯（ 822毫克，98%)的白色泡沫。HMR (CDC13) d 2·14 - 2·24 (m，2H)、2·27 (s, 3H)、3·25 (s, 3Η) 、3·51 (s， 3Η) 、3·58-3·73 (m， 4Η) 、3·88 (s， 3Η) 、3·98-4·09 (m， 2Η) 、4·4〇-4·53 (m， 2Η) 、6·67-7· 29 (m 系列，總計 9Η)、7· 57-7· 59 (m， 1 Η)、7 · 9 卜 7 · 9 3 (m, 2H) &gt; 8.04-8.06 (m, 1H)； MS(FAB) m/z 562 (MH1) 〇 於4-[(4R) -甲氧基-：l - [3-甲氧基-4-[Ν’ -（2-曱基苯基） 脲基]苯基乙醯基]-(2S) -吼咯啶甲氧基]苯甲酸曱酯（517 毫克，0·92毫莫耳）溶於THF(5毫升）之攪拌溶液中加入 〇. 5 N N aOH ( 5毫升），並使反應混合物迴流加熱3小時。於 冷卻至室溫後，將混合物倒入至冰的1 N HC 1中，並於減壓 下收集所產生之沈澱物。使粗製固體經由自MeOH-CHC13 -I PE再結晶，純化而得1 35 ( 1 44毫克，29%)之白色結晶粉 末。熔點 NMR (DMSO-d6)5 2·04-2·17 (m， 2Η)、2·25 (s，3Η)、3·21 (s，3Η)、3·56-3·75 (m，4Η) 、3·79 (s， 3Η) 、4·04-4·35 (m， 4Η) 、6·73-7·17 (m 系 列，總計7H)、7·79-7.81 (m，1H)、7·87-7·89 (m，2H) 、7·99 - 8·01 (m，1Η)、8·47 (s，1Η)、8·55 (s，1Η)、 12· 63 (bs，1H) ; MS(FAB) m/z 548 (MH1) ; C3()H33N3 07 · 1/4 H20 之分析計算值：C， 65·26; Η, 6·12; N， 7.61。實 測值：C，65· 36 ; H，6. 45 ; N，7. 24。 實施例1 2 8[Ν'-(2-Methylphenyl)ureido]phenylethenyl]-(2S)-indolyl methoxy]benzoic acid methyl ester (822 mg, 98%) as a white foam. HMR (CDC13) d 2·14 - 2·24 (m, 2H), 2·27 (s, 3H), 3·25 (s, 3Η), 3·51 (s, 3Η), 3·58-3 ·73 (m, 4Η), 3·88 (s, 3Η), 3·98-4·09 (m, 2Η), 4·4〇-4·53 (m, 2Η), 6·67-7· 29 (m series, total 9Η), 7·57-7· 59 (m, 1 Η), 7 · 9 卜 7 · 9 3 (m, 2H) &gt; 8.04-8.06 (m, 1H); MS (FAB m/z 562 (MH1) 〇 to 4-[(4R)-methoxy-:l-[3-methoxy-4-[Ν'-(2-mercaptophenyl)ureido]phenyl 5 NN aOH ( 5 NN a ) ( 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 (ml) and the reaction mixture was heated at reflux for 3 hours. After cooling to room temperature, the mixture was poured into 1 N HCl 1 of ice, and the resulting precipitate was collected under reduced pressure. The crude solid was recrystallized from MeOH-CHC <RTI ID=0.0></RTI> &lt;RTI ID=0.0&gt; Melting point NMR (DMSO-d6) 5 2·04-2·17 (m, 2Η), 2·25 (s, 3Η), 3·21 (s, 3Η), 3·56-3·75 (m, 4Η) ), 3·79 (s, 3Η), 4·04-4·35 (m, 4Η), 6.73-7·17 (m series, total 7H), 7.79-7.81 (m, 1H), 7·87-7·89 (m, 2H), 7·99 - 8·01 (m, 1Η), 8·47 (s, 1Η), 8·55 (s, 1Η), 12· 63 (bs, 1H) ; MS(FAB) m/z 548 (MH1); C3()H33N3 07 · 1/4 H20 Analysis calculated: C, 65·26; Η, 6·12; N, 7.61. Found: C, 65·36; H, 6.45; N, 7.24. Example 1 2 8

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T氧[基4:([2Ns = ρινT oxygen [base 4: ([2Ns = ριν

-C〇2H 卿4 4-[V[4-[N’ _(2-氟苯基）脲基]-3-甲氧笨基乙醯基]-(4R) -甲氧基-（2S ) -咄咯啶曱氧基]苯甲酸甲酉旨 OMe ^〇-Q-C〇2Me 使4-[N -（2-氟本基）脲基]一 3一甲氧笨乙酸（476毫克， 1·50毫莫耳）、4-[(4R)_甲氧基-(2S) -吼洛咬甲氧基]苯甲 酸甲酯（397 毫克，1·50 毫莫耳）、EDC,HC1(344**， 1.79¾ 莫耳）、H0Bt(243 毫克，ΐ·8〇 毫莫耳）及Et3N(250 毫 升’1.79毫莫耳）於THF(l〇毫升）中之混合物在室溫下攪拌 隔夜。將混合物以Ηζ0稀釋，並以EtOAc萃取。將萃取液以 鹽水洗條，於NagS〇4上乾燥，並蒸發。使殘留物經由於石夕 膠上利用CHC “-MeOIK 1 00 : 1，v/v )作為洗提液進行管柱層 析，純化而得4 - [1-[4-[N’~(2-氟苯基）脲基]一3-甲氧苯基 乙醯基]-(4R) -甲氧基-（2S)·-吼咯啶甲氧基]苯甲酸甲酷 (806 毫克，95%)的淡黃色泡沫。iH-NMR (CDC13) 3 2· 14 -2.37(m，2H)、3.28(s，3H)、3,44(s，3H)、3.48-3· 74 (m， 4H) 、3.88 (s，3H) 、4·02-4.15 (m， 2H) 、4·43 - 4.58 (m，2Η)、6·63 - 7·1〇 (m 系列，總計 7Η)、7·68-C〇2H qing 4 4-[V[4-[N' _(2-fluorophenyl)ureido]-3-methoxyphenylethyl]-(4R)-methoxy-(2S) - 咄 曱 曱 曱 ] ] ] OM OM OM OM OM OM OM OM OM OM OM OM OM OM OM OM OM OM OM OM OM OM OM OM OM OM OM OM OM OM OM OM OM OM OM 476 476 476 476 476 476 476 Methyl), 4-[(4R)-methoxy-(2S)-methyl methoxy]benzoic acid methyl ester (397 mg, 1.50 mmol), EDC, HC1 (344** A mixture of 1.793⁄4 mol, H0Bt (243 mg, ΐ························· The mixture was diluted with EtOAc and extracted with EtOAc. The extract was washed with brine, dried over NagS 4 and evaporated. The residue was subjected to column chromatography using CHC "-MeOIK 1 00 : 1, v/v ) as an eluent, and purified to obtain 4 - [1-[4-[N'~(2 -fluorophenyl)ureido]3-methoxyphenylethenyl]-(4R)-methoxy-(2S)--pyrrolidinemethoxy]benzoic acid methyl (806 mg, 95% Light yellow foam. iH-NMR (CDC13) 3 2· 14 -2.37 (m, 2H), 3.28 (s, 3H), 3, 44 (s, 3H), 3.48-3 · 74 (m, 4H) , 3.88 (s, 3H), 4·02-4.15 (m, 2H), 4·43 - 4.58 (m, 2Η), 6·63 - 7·1〇 (m series, total 7Η), 7.68

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1283240 五、發明說明（485) -7·73 (m， 1H) 、7.89-8.02 (m， 4H) 、8·16-8·20 (m， 1H); MS(FAB) m/z 566(M.+1) ο 於4-[1 - [4 - [Ν’ - (2-氟苯基）脲基]- 3-甲氧苯基乙醯基] -(4R)-甲氧基-（2S) -吼咯啶甲氧基]苯甲酸甲酯（491毫 克，0.87毫莫耳）溶於THF(5毫升）之授拌溶液中加入0.5N N a Ο Η ( 5毫升），並使反應混合物迴流加熱3小時。於冷卻至 室溫後’將混合物倒入至冰的1 N H C 1中，並於減壓下收集 所產生之沈澱物。使粗製固體經由自MeOH-CHC13-ΙΡΕ再結 晶’純化而得1 3 6 ( 1 7 3毫克，3 6 % )之白色結晶粉末。溶點 m -116 °C ; 4-NMR (DMS0-d6) δ 2· 08-2· 17 (m，2H)、 3.21 (s，3H)、3·56-3.73 (m，4H)、3·78 (s，3H)、 4· 04-4· 33 (m， 4Η)、6· 74- 7· 22 (m 系列，總計 7Η)、 7·87-7.89 (m，2H)、7·99-8.01 (m，1H)、8·16-8·20 (m，1Η)、8·70 (s，1Η)、9·18 (s, 1Η)、12·64 (br s， 1H) ; MS(FAB) m/z 552 (MH1) ; C29H3()FN3 07 · 0· 15H20 之分 析計算值：C，62.84;H，5.51;F，3·43;Ν，7·58。實 測值·· C，6 3 . 0 8 ; Η，5 · 8 3 ; F， 3. 3 0 ; N，7. 1 5。 實施例1 2 9 OMe 4-[1 - [4 - [『-（2_氯笨基）脲基]一 3一曱氧笨基乙醯基]-(4R) -甲氧基-（2S)-咄咯啶甲氧基]苯曱酸1283240 V. Description of invention (485) -7·73 (m, 1H), 7.89-8.02 (m, 4H), 8·16-8·20 (m, 1H); MS(FAB) m/z 566(M .+1) ο 4-[1 - [4 - [Ν' - (2-Fluorophenyl)ureido]-3-methoxyphenylethyl]-(4R)-methoxy-(2S - a solution of methyl hydrazide methoxy]benzoate (491 mg, 0.87 mmol) in THF (5 mL) was added 0.5 NN a Ο 5 (5 mL) and the reaction mixture was refluxed Heat for 3 hours. After cooling to room temperature, the mixture was poured into 1 N H C 1 of ice, and the resulting precipitate was collected under reduced pressure. The crude solid was purified by recrystallization from MeOH-CHC <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0> Melting point m -116 °C; 4-NMR (DMS0-d6) δ 2· 08-2· 17 (m, 2H), 3.21 (s, 3H), 3.56-3.73 (m, 4H), 3· 78 (s, 3H), 4· 04-4· 33 (m, 4Η), 6· 74- 7· 22 (m series, total 7Η), 7·87-7.89 (m, 2H), 7·99- 8.01 (m, 1H), 8·16-8·20 (m, 1Η), 8·70 (s, 1Η), 9·18 (s, 1Η), 12·64 (br s, 1H); MS ( Analysis calculated for C29H3()FN3 07 · 0· 15H20: C, 62.84; H, 5.51; F, 3·43; Ν, 7.58. Actual measured value·· C,6 3 . 0 8 ; Η,5 · 8 3 ; F, 3. 3 0 ; N, 7. 1 5. Example 1 2 9 OMe 4-[1 - [4 - ["-(2-chlorophenyl)ureido]-3-oxo-oxyphenyl]-(4R)-methoxy-(2S) -pyrrolidine methoxy]benzoic acid

o^Q^c〇2H 137 4-[1-[4 - [Ν’ - (2 -氯苯基）脲基]—3-甲氧苯基乙醯基]-（4R)o^Q^c〇2H 137 4-[1-[4 - [Ν' - (2-Chlorophenyl)ureido]-3-methoxyphenylethenyl]-(4R)

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-甲氧基-（2S) -咄咯啶甲氧基]苯甲酸甲酯-Methoxy-(2S)-indolyl methoxy]benzoic acid methyl ester

使4-[N -（2-氯笨基）脲基]—3 一甲氧苯乙酸（46〇毫克， 1· 37宅莫耳）、4- [ (4R)-甲氧基一（2S)-咄咯啶甲氧基]苯甲 酸甲酯（365毫克，1.38毫莫耳）、EDC*HC 1(316毫克， 1.65¾ 莫耳）、HOBt(223 毫克，1·65 毫莫耳）及Et3N(230 毫 升，1 · 65毫莫耳）於THF( 1 0毫升）中之混合物在室溫下授拌 夜。將混合物以ΙΟ稀釋，並以EtOAc萃取。將萃取液以 鹽水洗務，於NagS〇4上乾燥，並蒸發。使殘留物經由於石夕 膠上利用CHCI3-MeOH( 1 00 : 1，v/v )作為洗提液進行管柱層 析，純化而得4-[1-[4 - [N，- (2 -氯苯基）脲基]- 3-甲氧笨 基乙醯基]-(4R) -甲氧基-（2S) -咄咯啶甲氧基]苯甲酸甲酉旨 (801 毫克，q· y·)的白色泡沫。ih-NMR (CDC13) (5 2.13 — 2·36 (m，2H)、3·27 (s，3H)、3·58 (s，3H)、3·61〜 3·73 (m，4Η)、3·88 (s，3Η)、4·06-4·14 (m，2Η)、 4·43 - 4·56 (m， 2Η)、6·70 - 6·99 (m 系列，總計 5Η)、7·23 -7·42 (m, 4Η)、7·90-8·00 (m，3Η)、8·17-8·20 (m，4-[N-(2-chlorophenyl)ureido]-3 methoxyphenylacetic acid (46 〇 mg, 1. 37 house moles), 4-[(4R)-methoxy one (2S) - Ethrolidine methoxy]methyl benzoate (365 mg, 1.38 mmol), EDC*HC 1 (316 mg, 1.653⁄4 mol), HOBt (223 mg, 1.65 mmol) and Et3N A mixture of (230 ml, 1 · 65 mmol) in THF (10 mL) was stirred at room temperature overnight. The mixture was diluted with hydrazine and extracted with EtOAc. The extract was washed with brine, dried over NagS 4 and evaporated. The residue was subjected to column chromatography using CHCI3-MeOH (1 00:1, v/v) as an eluent, and purified to give 4-[1-[4 - [N,- (2) -Chlorophenyl)ureido]-3-methoxyphenylethyl]-(4R)-methoxy-(2S)-pyridinylmethoxy]benzoic acid formazan (801 mg, q· y·) white foam. ih-NMR (CDC13) (5 2.13 — 2·36 (m, 2H), 3·27 (s, 3H), 3·58 (s, 3H), 3.61~3·73 (m, 4Η), 3·88 (s, 3Η), 4·06-4·14 (m, 2Η), 4·43 - 4·56 (m, 2Η), 6·70 - 6·99 (m series, total 5Η), 7·23 -7·42 (m, 4Η), 7·90-8·00 (m, 3Η), 8·17-8·20 (m,

1Η) ; MS(FAB) m/z 582 (ΜΗ1)。 於4-[1-[4- [N，-(2-氯苯基）脲基卜3-曱氧苯基乙醯基] -（4R)-甲氧基-（2S)-吡咯啶甲氧基]笨甲酸甲酯（541毫 克’0.93毫莫耳）溶於THF(5毫升）之攪拌溶液中加入〇.5n NaOH(5毫升），並使反應混合物迴流加熱3小時。於冷卻至1Η); MS(FAB) m/z 582 (ΜΗ1). 4-[1-[4-[N,-(2-Chlorophenyl)ureidobu-3-methoxyphenylethyl]-(4R)-methoxy-(2S)-pyrrolidine methoxy To a stirred solution of methyl acetonate (541 mg &lt;RTI ID=0.0&gt;&gt; Cool down to

\\312\2d-code\90-01\89112968.ptd 第491頁 1283240 五、發明說明（487) 室温後，將混合物倒入至冰的1 N HC 1中，並於減壓下收集 所產生之沈殿物。使粗製固體經由自M e 0 Η - C H C 13 - I P E再結 晶，純化而得1 3 7 ( 2 81毫克，5 3 % )之白色結晶粉末。熔點 116-119 °C ； 'H-NMR (DMS〇-d6) 5 2.08-2.17 (m, 2H) ^ 3.21 (s，3H)、3·56-3.73 (m，4H)、3·79 (s，3H)、 4·04-4.33 (m，4H)、6.75 (d，J = 8.3 Hz, 1H)、6·87 (s，lH)、7·02 (d，J = 8.3 Hz，3H)、7·28 (t，J = 7.8 Hz, 1H)、7·44 (d, J = 7.8 Hz，1H)、7·87-7·89 (m，2H)、7· 96 (d，J = 8.3 Hz，1H)、8·10 (d，J = 8-3 Hz, 1H)、8.89 (s，1H)、8·93 (s，1H)、12·63 (br s，1H); MS(FAB) m/z 56 8(MH1 ) ; C29H3QC1N3 07 · 1/4H20 之分析計算值：C， 60· 84 ; H，5. 37 ; Cl，6· 19 ; N， 7· 34。實測值：C， 61. 03 ; H， 5· 56 ; Cl, 6·27 ; N， 7· 03 。 實施例1 3 0 4-[1-[4-[『-（2 -溴笨基）脲基]—3一曱氧笨基乙醯基]一（4R) -甲氧基-（2S)-吼咯啶甲氧基]苯甲酸 OMe\\312\2d-code\90-01\89112968.ptd Page 491 1283240 V. INSTRUCTIONS (487) After room temperature, the mixture was poured into 1 N HC 1 of ice and collected under reduced pressure. The temple. The crude solid was recrystallized from Me 0 Η - C H C 13 - I P E and purified to give 1 3 7 ( 2 81 mg, 53 %) of white crystalline powder. Melting point 116-119 °C; 'H-NMR (DMS〇-d6) 5 2.08-2.17 (m, 2H) ^ 3.21 (s,3H),3·56-3.73 (m,4H),3·79 (s , 3H), 4·04-4.33 (m, 4H), 6.75 (d, J = 8.3 Hz, 1H), 6·87 (s, lH), 7·02 (d, J = 8.3 Hz, 3H), 7·28 (t, J = 7.8 Hz, 1H), 7.44 (d, J = 7.8 Hz, 1H), 7·87-7·89 (m, 2H), 7·96 (d, J = 8.3 Hz, 1H), 8·10 (d, J = 8-3 Hz, 1H), 8.89 (s, 1H), 8.93 (s, 1H), 12·63 (br s, 1H); MS (FAB m/z 56 8(MH1) ; C29H3QC1N3 07 · 1/4H20 Analysis calculated: C, 60· 84 ; H, 5. 37 ; Cl, 6 · 19 ; N, 7· 34. Found: C, 61. 03 ; H, 5· 56 ; Cl, 6·27 ; N, 7· 03 . Example 1 3 0 4-[1-[4-[『-(2-Bromophenyl)ureido]-3-oximeoxyphenyl]](4R)-methoxy-(2S)- Acetidine methoxy]benzoic acid OMe

奴⑧々。伽H 138 4-Π- [4-[Ν’ -（2-演笨基）脲基]—3—甲氧笨基乙醯基]一（4R) -甲氧基-（2S ) -吼咯啶甲氧基]苯甲酸甲酯 pMe ΟΜβSlave 8 々.伽H 138 4-Π- [4-[Ν' -(2- 笨 基))]]]-(4-(indolyl)]-(4R)-methoxy-(2S)-fluorene Pyridylmethoxy]methyl benzoate pMe ΟΜβ

\\312\2d-code\90-01\89112968.ptd 第492頁 1283240 五、發明說明（488) 使4-[Ν’ 2-溴苯基）脲基]-3-甲氧苯乙酸（6〇〇毫克， 1.58毫莫耳）、4- [(4R)-甲氧基-（2S)-吼咯啶甲氧基]苯甲 酸甲酯（420毫克，1·58毫莫耳）、EDC*HC 1(364毫克， 1.90毫莫耳）、HOBt(214毫克，1·58毫莫耳）及Et3N(265毫 升’ 1.90¾莫耳）於THF(15毫升）中之混合物在室溫下撥拌 隔夜。將混合物以H20稀釋，並以EtOAc萃取。將萃取液以 鹽水洗滌，於Na2S04上乾燥，並蒸發。使殘留物經由於矽 勝上利用CHCI3-MeOH(100:l，v/v)作為洗提液進行管柱層 析’純化而得4 - [1-[4-[Ν’ - (2 -溴苯基）脲基]- 3 -甲氧苯基 乙醯基]-(4R)-甲氧基-（2S)-吼洛σ定甲氧基]苯曱酸甲酯 (1. 01 克，q· y·)的淡黃色泡沫。1H-NMR (CDC13) 5 2. 13 -2.33 (m, 2H) ^3.27 (s, 3H) ^3.57 (s, 3H) ^3.61- 3·72 (m，4H)、3·88 (s，3H)、4·05-4.14 (m，2H)、 4·43 - 4·57 (m， 2Η)、6.70-7·00 (m 系列，總計 5Η)、7·29 -7·52 (m，4Η)、7·92-8.01 (m，3Η)、8·12-8·15 (m， 1H) ; MS(FAB) m/z 626 (MH1)。 於4-[l-[ 4- [Ν’ -（2-溴苯基）脲基]-3-甲氧苯基乙醯基] -(4R)-甲氧基-（2S)-咄咯啶甲氧基]苯甲酸甲酯（697毫 克’ 1· 11毫莫耳）溶於THF(8毫升）之攪拌溶液中加入〇. 5Ν NaOH(8毫升），並使反應混合物迴流加熱2小時。於冷卻至 室溫後，將混合物倒入至冰的1 N H C 1中，並於減壓下收集 所產生之沈澱物。使粗製固體經由自MeOH-CHCl3-IPE再結 晶，純化而得標題化合物（2 5 2毫克，37%)之白色結晶粉 末。熔點 1 25 - 1 3 0。(：；111-關{?(0肘30-(16)(5 2.08-2.17(111，\\312\2d-code\90-01\89112968.ptd Page 492 1283240 V. INSTRUCTIONS (488) Making 4-[Ν'2-bromophenyl)ureido]-3-methoxyphenylacetic acid (6) 〇〇mg, 1.58 mmol, methyl 4-[(4R)-methoxy-(2S)-decalylmethoxy]benzoate (420 mg, 1.58 mmol), EDC* Mixture of HC 1 (364 mg, 1.90 mmol), HOBt (214 mg, 1.58 mmol) and Et3N (265 mL ' 1.903⁄4 mol) in THF (15 mL) Overnight. The mixture was diluted with H20 and extracted with EtOAc. The extract was washed with brine, dried over Na 2 EtOAc and evaporated. The residue was purified by column chromatography using CHCI3-MeOH (100:1, v/v) as an eluent to obtain 4 - [1-[4-[Ν' - (2-bromo) Phenyl)ureido]- 3 -methoxyphenylethenyl]-(4R)-methoxy-(2S)-indolyl methoxy]benzoic acid methyl ester (1.01 g, q · y·) light yellow foam. 1H-NMR (CDC13) 5 2. 13 -2.33 (m, 2H) ^3.27 (s, 3H) ^3.57 (s, 3H) ^3.61 - 3·72 (m, 4H), 3·88 (s, 3H) ), 4·05-4.14 (m, 2H), 4·43 - 4·57 (m, 2Η), 6.70-7·00 (m series, total 5Η), 7·29 -7·52 (m, 4Η) ), 7.92-8.01 (m, 3 Η), 8·12-8·15 (m, 1H); MS (FAB) m/z 626 (MH1). 4-[l-[4-[Ν'-(2-Bromophenyl)ureido]-3-methoxyphenylethenyl]-(4R)-methoxy-(2S)-indenylpyridine To a stirred solution of methyl methoxy]benzoate (697 mg &lt;RTI ID=0.0&gt;&gt; After cooling to room temperature, the mixture was poured into 1 N H C 1 of ice, and the resulting precipitate was collected under reduced pressure. The crude solid was recrystallized from MeOH-EtOAc (EtOAc) elute Melting point 1 25 - 1 3 0. (:; 111-off {? (0 elbow 30-(16) (5 2.08-2.17 (111,

\\312\2d-c〇de\9〇.〇l\89112968.ptd 第 493 頁 1283240 五、發明說明（489) 2H)、3·21 (s，3H)、3·60-3·72 (m，4H)、3.79 (s，3H) 、3·9 5 - 4.33 (m，4H)、6·75 - 7·08 (m 系列，總計 5H)、 7·3 卜 7.34 (m，1H)、7·59 - 7.61 (m，1H)、7·87 - 7·89 (m, 2Η)、7·93-7·96 (m，2Η)、8·73 (s，1Η)、8·91 (s， 1H) ^12.63 (br s, 1H) ； MS (FAB) m/z 612(M++1) ； C29H 3〇BrN3 07 之分析計算值·· C，56. 87 ; H，4· 94 ; Br，13· 05 ; N, 6.86 ° 實測值：C，5 6.6 7； H, 4.97； Br, 13.07； N, 6· 68 〇 實施例1 3 1 4-[4,4-二氟-l-[3 -甲氧基-4 - [N’_(2-甲基苯基）脲基]苯 基乙醢基]- 2 -吼17各0定甲氧基]苯甲酸\\312\2d-c〇de\9〇.〇l\89112968.ptd Page 493 1283240 V. INSTRUCTIONS (489) 2H), 3·21 (s, 3H), 3·60-3·72 ( m, 4H), 3.79 (s, 3H), 3·9 5 - 4.33 (m, 4H), 6.75 - 7·08 (m series, total 5H), 7·3, 7.34 (m, 1H), 7·59 - 7.61 (m, 1H), 7·87 - 7·89 (m, 2Η), 7·93-7·96 (m, 2Η), 8.73 (s, 1Η), 8.91 ( s, 1H) ^12.63 (br s, 1H) ; MS (FAB) m/z 612 (M++1) ; C29H 3〇BrN3 07 analytical calculation·· C,56.87 ; H,4· 94 ; Br,13· 05 ; N, 6.86 ° Found: C, 5 6.6 7; H, 4.97; Br, 13.07; N, 6· 68 〇 Example 1 3 1 4-[4,4-Difluoro-l -[3 -Methoxy-4 -[N'_(2-methylphenyl)ureido]phenylethenyl]- 2 -吼17 each 0 methoxy]benzoic acid

rV 139rV 139

jpax OMe 卜（第三丁氧羰基）-4_酮基咄咯啶—2-羧酸甲酯Jpax OMe (t-butoxycarbonyl)-4-ketopyrrolidine-methyl 2-carboxylate

Sg^COgMe B〇cSg^COgMe B〇c

於N-Boc脯胺酸甲基酯（2· 0克，8· 15毫莫耳）溶於CH2C12 之攪拌溶液中加入3A分子篩（2克）及PDC(4· 60克，1 2. 2毫 莫耳）。使混合物授拌3天。將混合物過濾通過C e 1 i e t e襯 墊，並將濾液蒸發。使殘留物於石夕膠上利用CHCl3-MeOH (10:1)作為洗提液進行層析’而得卜（第三丁氧羰基）_4 -酮基咄咯啶-2-羧酸甲酯（I·13克，57%)之無色油。1H-NMR (CDC13) 5 1·46-1·48 (in，9Η)、2·56-2·61 (m，1H)、Add 3A molecular sieve (2 g) and PDC (4·60 g, 12.2 m) to a stirred solution of N-Boc ketamine methyl ester (2.0 g, 8.5 mmol) dissolved in CH2C12. Moore). The mixture was allowed to mix for 3 days. The mixture was filtered through a pad of Celi and the filtrate was evaporated. The residue was chromatographed on a solution of CHCl3-MeOH (10:1) as an eluent to obtain methyl (t-butoxycarbonyl)-4-keto-pyridin-2-carboxylate ( I·13 g, 57%) of a colorless oil. 1H-NMR (CDC13) 5 1·46-1·48 (in, 9Η), 2·56-2·61 (m, 1H),

\\312\2d-code\90-01\89112968.ptd 第494頁 1283240 五、發明說明（490) 2.88-3.00 (ra, 1H) &gt;3.77 (s, 3H) ^ 3.82-3.8 8 (m, 2Η) 、4.71-4.83 (m， 1Η)。 羧酸甲酯 1 -（苐二丁氧魏基）_4，4-二it。比σ各唆― (汐乂 C〇2Me\\312\2d-code\90-01\89112968.ptd Page 494 1283240 V. Description of invention (490) 2.88-3.00 (ra, 1H) &gt;3.77 (s, 3H) ^ 3.82-3.8 8 (m, 2Η), 4.71-4.83 (m, 1Η). Methyl carboxylate 1 -(indenyl butyloxy) _4,4-di it. More than σ - (汐乂 C〇2Me

Boc 於卜（第三丁氧幾基）-4-_基吼，各。定_2_叛酸甲醋（113 克，4_65毫莫耳）溶於(：112(：12(20毫升）之冷的（_78。〇攪拌 溶液中加入甲基DAST(1. 1毫升’ U, 6毫莫耳）。使混合物 升溫至室溫。於攪拌15小時後，將混合物倒入至h2〇(5〇* 升）中’並以EtOAc ( 20 0毫升）萃取。將萃取液以鹽水 (2x200宅升）洗膝’於MgSO4上乾燥’並蘇發。使殘留物於 矽膠上利用CHCl3-EtOAc(20:l)作為洗提液進行層析，而' 知1 -（弟二丁氧魏基）- 4，4 - 一氟°比0各°定-2-缓酸甲g旨（885毫 克，72%)的黃色油。iH-NMR (CDC13) 6 l 42 及！ · 47 (各 s，總計 9H)、2.46 (ddd，d = 26.9、13.7、5.1 Hz， 1H)、 2.62-2.78 (m, 1H) '3.75-3.95 (m, 5H) ^4.43-4.57 (m，1H ) 〇 卜（第三丁氧羰基）-4, 4-二氟咄咯啶-2 -羧酸Boc (i, third butoxymethyl)-4-_ylindole, each. Fixed _2_Resert Methyl vinegar (113 g, 4_65 mmol) dissolved in (:112 (:12 (20 ml)) cold (_78. 〇 Adding methyl DAST (1.1 ml 'U) The mixture was warmed to room temperature. After stirring for 15 h, the mixture was poured into EtOAc (EtOAc) (EtOAc) (2x200 house liters) Wash the knees 'dried on MgSO4' and swell. The residue was chromatographed on silica gel using CHCl3-EtOAc (20:1) as the eluent, and 'Knowledge 1 -魏基)- 4,4 - fluoro-pyr ° ° 0 ° ° -2- 酸 酸 甲 甲 (885 mg, 72%) of yellow oil. iH-NMR (CDC13) 6 l 42 and ! · 47 (each s, total 9H), 2.46 (ddd, d = 26.9, 13.7, 5.1 Hz, 1H), 2.62-2.78 (m, 1H) '3.75-3.95 (m, 5H) ^4.43-4.57 (m,1H ) (t-butoxycarbonyl)-4,4-difluoropyridinium-2-carboxylic acid

C〇2H B〇c 於卜（第三丁氧羰基）_4, 4 -二氟咄咯啶-2 -鲮酸甲酯（885 毫克，3· 34毫莫耳）溶於THF( 25毫升）之攪拌溶液中加入C〇2H B〇c Ib (t-butoxycarbonyl)_4,4-difluoropyridin-2-yl decanoate (885 mg, 3.34 mmol) dissolved in THF (25 mL) Add to the stirred solution

\\312\2d-code\90-01\89112968.ptd 第 495 頁 1283240 五、發明說明（491) 0. 2 5N NaOH(26. 7毫升，6. 67毫莫耳），並繼續攪拌1小 時。將混合物倒入至IN HC1 (100毫升）中，並以CHC13 ( 2x200毫升）萃取。將結合的萃取液以鹽水（100毫升）洗 滌，於MgS04上乾燥，並蒸發而得卜（第三丁氧羰基）-4, 4-二氟咄咯啶-2 -羧酸（ 775毫克，92%)之黃色結晶固體。熔 點 lU-intMMMR (CDC13) (5 1·44 及 1.49 (各s,總 計9Η)、2·53 -2.80 (m，2Η)、3· 71-3.90 (m，2Η)、4·20 -4·61 (m，1H); MS(FAB) m/z 2 52 (MH1); C10H15F2O4 之分 析計算值：C，47. 81 ; H，6· 02 ; N， 5· 58。實測值：C， 48. 06 ； H, 6.05； N, 5· 45 ° . 卜（第三丁氧羰基）-4, 4-二氟-2-吼咯啶甲醇 FV-〇h\\312\2d-code\90-01\89112968.ptd Page 495 1283240 V. INSTRUCTIONS (491) 0. 2 5N NaOH (26.7 ml, 6.67 mmol) and continue to stir for 1 hour . The mixture was poured into <RTI ID=0.0># </RTI> </RTI> <RTIgt; The combined extracts were washed with brine (100 mL), dried over MgSO4, and evaporated to give (t-butyloxycarbonyl)-4, 4-difluoropyrrolidine-2-carboxylic acid (775 mg, 92 %) of a yellow crystalline solid. Melting point lU-intMMMR (CDC13) (5 1·44 and 1.49 (each s, total 9Η), 2.53 -2.80 (m, 2Η), 3·71-3.90 (m, 2Η), 4·20 -4· </ RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; 06 ; H, 6.05; N, 5· 45 ° . Bu (t-butoxycarbonyl)-4, 4-difluoro-2-indenyl amide Methanol FV-〇h

Boc 在室溫下於N-(第三丁氧羰基）4，4 -二氟脯胺酸（3.00 克’ 11 · 9毫莫耳）溶於THF(20毫升）之攪拌溶液中加入Bh3 • DMS ( 1 · 1毫升，11 · 9毫莫耳）。使混合物迴流加熱2小 時。於冷卻至室溫後，將混合物於真空中濃縮。經由加入 H20( 1 0 0毫升）使殘留物停止反應，並以cHC丨3 ( 2 x2 0 0毫 升）萃取。將結合的萃取液於MgS〇4上乾燥，並蒗發。使殘 留物於矽膠上利用CHCl3_Et0Ac(4 :丨）作為洗提液進行層 析，而得1-（第二丁氧羰基）—4,4 -二氟—2~呲咯啶甲醇 (2. 11 克，75°/。）之無色油。ih-NMR (CDC13) 6 1· 48 (s 9H) 、 2·04-2·55 (m， 2H) 、 3·59-4·17 (:， 5H)。 ’ 4-[1 -（第三丁氧羰基）—4, 4-二氟-2-吼咯啶曱氧基]笨甲酸Boc Add Bh3 • DMS to a stirred solution of N-(t-butoxycarbonyl) 4,4-difluoroproline (3.00 g '11 · 9 mmol) in THF (20 mL) at room temperature (1 · 1 ml, 11 · 9 mmol). The mixture was heated under reflux for 2 hours. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was quenched by the addition of H20 (10 mL) and extracted with &lt;RTI ID=0.0&gt;&gt; The combined extracts were dried on MgS 4 and burst. The residue was chromatographed on silica gel using CHCl3_Et0Ac (4: 丨) as eluent to give 1-(2,2-butoxycarbonyl)-4,4-difluoro-2-pyrrolidinemethanol (2. Gram, 75 ° /.) of colorless oil. Ih-NMR (CDC13) 6 1· 48 (s 9H) , 2·04-2·55 (m, 2H), 3·59-4·17 (:, 5H). '4-[1-(Tertidinoxycarbonyl)-4,4-difluoro-2-indenylpyridiniumoxy]benzoic acid

1283240 五、發明說明（492) 甲酯1283240 V. INSTRUCTIONS (492) Methyl ester

Boc l^&gt;*C〇2Me 在室溫下於卜（第三丁氧羰基）_4, 4 -二氟-2 -咄咯啶甲醇 (600毫克，2.53毫莫耳）、4-羥基苯甲酸甲酯（462毫克， 3·〇3毫莫耳）、Ph3P( 7 95毫克，3.03毫莫耳）於THF(10毫 升）中之攪拌混合物中加入DIAD( 597微升，3· 03毫莫耳）。 使混合物迴流加熱3小時。於冷卻至室溫後，將混合物於 真空中濃縮。使殘留物於矽膠上利用己烷-EtOAc (4: 1 )作 為洗提液進行層析，而得4-[1-(第三丁氧羰基）-4, 4 -二氟 -2-咄咯啶甲氧基]苯甲酸甲酯（831毫克，88%)之無色油。 -NMR (CDC13) 51 · 48 (s，9H)、2· 53-2· 61 (m，2H)、 3·63 - 4.41 (m 系列，總計 8H)、6·94 (d, J = 8.8 Hz， 2H)、7· 99 (d，J = 8. 8 Hz, 2H) 〇 4-(4, 4 -二氟-2-咄咯啶甲氧基）苯甲酸曱酯Boc l^&gt;*C〇2Me at room temperature in di(t-butoxycarbonyl)_4,4-difluoro-2-oxaridinyl methanol (600 mg, 2.53 mmol), 4-hydroxybenzoic acid Add DIAD (597 μl, 3·03 mmol) to a stirred mixture of methyl ester (462 mg, 3·3 3 mmol), Ph3P (7 95 mg, 3.03 mmol) in THF (10 mL) ). The mixture was heated under reflux for 3 hours. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane-EtOAc (4:1) to give 4-[1-(t-butoxycarbonyl)-4,4-difluoro-2-pyrene. Methyl pyridine methoxy]benzoate (831 mg, 88%) as a colorless oil. -NMR (CDC13) 51 · 48 (s, 9H), 2· 53-2· 61 (m, 2H), 3.63 - 4.41 (m series, total 8H), 6.94 (d, J = 8.8 Hz , 2H), 7·99 (d, J = 8. 8 Hz, 2H) 曱4-(4,4-difluoro-2-indenylpyridylmethoxy)benzoate

使4-[1-(第三丁氧羰基）-4, 4-二氟-2 -咄咯啶甲氧基]苯 甲酸甲酯（ 83 0毫克，2· 23毫莫耳）及TFA(5毫升）於CH2C12(5 毫升）中之混合物攪拌3小時，並於真空中濃縮。利用飽和 NaHC03使殘留物成為鹼性，並以CHC 13 ( 2x2 0 0毫升）萃取。 將結合的萃取液於K2C03上乾燥，並於真空中濃縮而得4-Methyl 4-[1-(t-butoxycarbonyl)-4,4-difluoro-2-pyrrolidinemethoxy]benzoate (83 0 mg, 2·23 mmol) and TFA (5) The mixture was stirred for 3 hours in CH2C12 (5 mL) and concentrated in vacuo. The residue was made basic with saturated NaHC03 and extracted with CH.sub.3 (2×250). The combined extract is dried on K2C03 and concentrated in vacuo to give 4-

\\312\2d-code\90-01\89112968.ptd 第 497 頁 1283240 五、發明說明（493) (4，4_二氟-2 -咄咯啶甲氧基）苯甲酸甲酯（550毫克，91%) 的淡黃色固體。1Η-NMR (CDC13) (5 2· 19 (m， 1H)、2· 43 (m，1H)、3·19-3·41 (m，2H)、3·77 (m，1H)、3·89 (s， 3H) 、4·00-4·09 (m， 2H) 、6·92 (d， J=9.0 Hz， 2H)、 7· 9 9 (d，J = 9· 0 Hz，2H) ; MS(FAB) m/z 272(MH1) ; C13H 15F2N03 之分析計算值：C，57. 56 ; H，5. 57 ; N， 5.16。實 測值·· C，57.65； Η, 5. 67 ； N, 5.16° 4-[4, 4 -二氟-1-[3 -甲氧基-4 - [Ν’ -（2-甲基苯基）脲基]苯 基乙醯基]- 2 -咄咯啶曱氧基]苯甲酸甲酯\\312\2d-code\90-01\89112968.ptd Page 497 1283240 V. INSTRUCTIONS (493) Methyl (4,4-difluoro-2-pyridinylmethoxy)benzoate (550 mg) , 91%) of a pale yellow solid. 1Η-NMR (CDC13) (5 2· 19 (m, 1H), 2·43 (m, 1H), 3·19-3·41 (m, 2H), 3·77 (m, 1H), 3· 89 (s, 3H), 4·00-4·09 (m, 2H), 6.92 (d, J=9.0 Hz, 2H), 7· 9 9 (d, J = 9· 0 Hz, 2H) MS (FAB) m/z 272 (MH1); C,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, N, 5.16° 4-[4, 4-difluoro-1-[3-methoxy-4 -[Ν' -(2-methylphenyl)ureido]phenylethenyl]- 2 -咄Methyl pyridinoxy]benzoate

使4-（4, 4 -二氟-2 -咄咯啶曱氧基）苯甲酸甲酯（ 54 0毫 克，1·99毫莫耳）、3-甲氧基一 4 - [Ν’-（2-甲基苯基）脲基] 苯乙酸（ 626毫克，1·99毫莫耳）、EDC· HC 1(572毫克， 2.99毫莫耳）、11(^1:(催化劑）及1^八？（催化劑）於])犯（1〇毫 升）中之混合物攪拌隔夜。將混合物以EtOAc( 3 0 0毫升）稀 釋，以鹽水（2x1 00毫升）洗滌，於MgS〇4上乾燥，並於真空 中濃縮。使殘留物於矽膠上利用CHC13-MeOH(20 : 1)作為洗 提液進行層析，而得4-[4,4-二氟-1-[3-甲氧基-4 -(2-甲基苯基）脲基]苯基乙醯基]一2-吼咯啶甲氧基]苯甲 酸甲酯（1· 00克，89%)的無色泡沫。(CDCl3) 5 2.31 (s，3H)、2.47 - 2.63 (m，2H)、3·52 - 3·97 (s 及 m 系 列，總計 10H)、4·07-4·30 (m，2H)、4·67-4·69 (m，Methyl 4-(4,4-difluoro-2-pyridinium oxy)benzoate (540 mg, 1.99 mmol), 3-methoxy- 4 - [Ν'-( 2-methylphenyl)ureido]phenylacetic acid (626 mg, 1.99 mmol), EDC·HC 1 (572 mg, 2.99 mmol), 11 (^1: (catalyst) and 1^8 (The catalyst) was stirred in a mixture of (1 ml) overnight. The mixture was diluted with EtOAc (EtOAc) (EtOAc)EtOAc. The residue was chromatographed on silica gel using CHC13-MeOH (20:1) as eluent to give 4-[4,4-difluoro-1-[3-methoxy-4-(2-) (Phenylphenyl)ureido]phenylethenyl]- 2-indoleridinylmethoxy]benzoic acid methyl ester (1 00 g, 89%) of a colorless foam. (CDCl3) 5 2.31 (s, 3H), 2.47 - 2.63 (m, 2H), 3·52 - 3·97 (s and m series, total 10H), 4·07-4·30 (m, 2H), 4·67-4·69 (m,

1283240 五、發明說明（494) -- 1H)、6.45(s，1H)、6.65(d，J《7Hz，1H)、6.74- 、6·84 (d，J48 Hz，2H)、714 ㈠，2H) 、7·24 (m，2H)、7·52 - 7.54 (m，1H)、7·94 &quot;，j = 88 Hz，2H)、8· 09 (d，J = 8. 1 Hz, 1H)。 使4-[4,4-二氟-l-[3-甲氧基-4-[n，〜（2一甲某苯某）脲 基]笨基乙酿基]-2 - u比鳴^定甲氧基]笨甲酸甲醋ϋ克， 1·76毫莫耳）及0.2 5Ν NaOH(14毫升，3 5〇古莫耳）於 THFU4毫升）中之混合物授摔隔夜。將混合^勿以…^丨酸 化，並以CHC13-MeOH(10:l，2x20 0 亳升）萃 萃取液於MgS〇4上乾燥，並菽發。使 /十取將⑽口的 ΓΗΓ1 1 z, m , χ ^ 便歹欠留物於矽膠上利用 CHC13-MeOH(20:l 至 1〇:1)作為洗提液 1 39 ( 65 8毫克，68%)之盔色处曰於太仃層析而付 it mmd mucn」、 …、巴、、、口日日杨末。熔點1 35- 1 40 X： ; 1 Γ:: 4: : 23 (s，3H)、2.49-2.7 3 (m，2H)、 3.36-4.55 (m 糸列，10H)、6 73 (d，J = 8 3 Hz，ih)、6. 84 (s, 1H) ^6.93 (t, J = 7.3 Hz, 1H) ^7.00 (d, J = 8. 31283240 V. INSTRUCTIONS (494) -- 1H), 6.45 (s, 1H), 6.65 (d, J "7Hz, 1H), 6.74, 6.84 (d, J48 Hz, 2H), 714 (1), 2H ), 7·24 (m, 2H), 7.52 - 7.54 (m, 1H), 7·94 &quot;, j = 88 Hz, 2H), 8· 09 (d, J = 8. 1 Hz, 1H ). 4-[4,4-Difluoro-l-[3-methoxy-4-[n,~(2-methyl phenyl) ureido]] phenylyl]-2-an A mixture of methoxyl]benzoic acid methyl ketone, 1.76 mmol, and 0.25 NaOH (14 ml, 3 5 〇 Gu Mo) in THF (4 ml) was dropped overnight. The mixture was acidified and extracted with CHC13-MeOH (10:1, 2×20 0 liters) and dried over MgSO 4 and evaporated. Let /1 (z) ΓΗΓ1 1 z, m , χ ^ 歹 歹 歹 上 利用 利用 利用 利用 利用 利用 CH CH CH CH CH CH CH CH CH CH CH CH CH CH CH CH CH CH CH CH CH CH CH CH 利用 CH CH CH 1 1 1 1 1 1 1 1 1 1 1 1 %) The color of the helmet is 仃 仃 仃 仃 仃 仃 it it it mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm mm Melting point 1 35- 1 40 X: ; 1 Γ:: 4: : 23 (s, 3H), 2.49-2.7 3 (m, 2H), 3.36-4.55 (m 糸, 10H), 6 73 (d, J = 8 3 Hz, ih), 6. 84 (s, 1H) ^6.93 (t, J = 7.3 Hz, 1H) ^7.00 (d, J = 8. 3

Hz，2H)、7·10-7·16 (m，2H)、7·78 (d，J = 8.3 Hz， 1H)、7·86 (d，J = 8.3 Hz，2H)、8·00 (d，J = 8.3 Hz, 1H)、8· 47 (s，1H)、8. 56 (s，1H) ; MS(FAB) m/z 55 4 (M+ + 1) ; C29 H29 F2 N3 〇6 · 3 / 4 h2 〇 之分析計算值：c，6 1 · 4 2 ; H， 5· 44 ; N，7· 06。實測值·· c，6i. 3〇 ; H，5. 44 ; N， 7· 06。 實施例1 3 2 4-Π - [4-[ Ν’ - (2'氯苯基）脲基]一 3一曱氧苯基乙醯基]一4,4一 二氟-2 -咄咯啶甲氧基]笨甲酸Hz, 2H), 7·10-7·16 (m, 2H), 7·78 (d, J = 8.3 Hz, 1H), 7·86 (d, J = 8.3 Hz, 2H), 8·00 ( d, J = 8.3 Hz, 1H), 8·47 (s, 1H), 8.56 (s, 1H); MS(FAB) m/z 55 4 (M+ + 1) ; C29 H29 F2 N3 〇6 · Analysis of 3 / 4 h2 〇: c, 6 1 · 4 2 ; H, 5· 44 ; N, 7. 06. Measured value ·· c,6i. 3〇 ; H,5. 44 ; N, 7· 06. Example 1 3 2 4-Π - [4-[ Ν' - (2' chlorophenyl) ureido] -3- methoxyphenyl ethyl] 4,4 difluoro-2-pyridinium Methoxy]

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第499頁 1283240 五、發明說明（495)Page 499 1283240 V. Description of invention (495)

Cl Η H 〇Me ~〇-co2h 140 :一 [j 一 [4—[N’ 一（2_氣笨基）脲基]-3-甲氧苯基乙醯基] 二氟- 2 -咄咯啶甲氧基]苯甲酸甲酯 ， F p Cl H H 0Me 'Ό^〇〇2Μθ 使4-(4, 4-二氟-2-咄咯啶甲氧基）苯曱酸甲酯（ 22 9古 克，0.845毫莫耳）、4-[Ν，-（2-氣苯基）脲基]—3 —甲急笔 酸（283毫克，〇· 84 5毫莫耳）、EDC · HC1 ( 243毫克，i ^古 莫耳）、H0Bt(催化劑）、DMAp(催化劑）、及_(1 · ^ 混合物攪拌隔夜。將混合物以EtOAc( 30 0毫升）稀釋。將溶 ，^鹽水（2x1 00亳升）洗滌，於MgS〇4上乾燥，並於真空中 Γ縮1使殘留物於矽膠上利用CHC13_EtOAc(2〇:l至4··1)作 2·50-2·67 (m， (d, J= 1. 5 Hz, (d，J = 8· 8 Hz, 7. 23-7. 27 (m, 層析，而得4-[卜[4-[Ν，-(2-氯苯基)脲基 氧=土乙隨基]一4, 4-二氟-2-咄咯啶甲氧基]苯甲酸 甲酉曰482笔克’ 97〇/°)的無色黏性固體。1H-NMR (CDC13)占 2H) 1H) 2H) 、 3.54-4.71 (m 系列，13H) 、 6.69 1H) 、 6. 76 (d， J二8.3 Hz， 1H) 、 6.84 6. 98 (dt，J = 7. 8、1 · 5 Hz，1H)、 (m， 2H) 、 7. 94 (d， Hz，1H)、8· 19 (dd，j = 8, 3、5 Hz，1H) 7. 33 (d， J=8·3 Hz， 1H) 、 7·39 8· 8 Hz，2H)、8· 00 (d，J = 8·3Cl Η H 〇Me ~〇-co2h 140 : one [j -[4-[N'-(2_ oxaphenyl)ureido]-3-methoxyphenylethenyl]difluoro-2-pyrene Methyl pyridine methoxy]benzoate, F p Cl HH 0Me 'Ό^〇〇2Μθ Methyl 4-(4,4-difluoro-2-indenylpyridinylmethoxy)benzoate (22 9 ancient克, 0.845 mmol, 4-[Ν,-(2-phenylphenyl)ureido]-3-inmazanic acid (283 mg, 〇·84 5 mmol), EDC · HC1 (243 mg , i ^古莫耳), H0Bt (catalyst), DMAp (catalyst), and _ (1 · ^ mixture was stirred overnight. The mixture was diluted with EtOAc (30 mL). Dissolved, brine (2×1 00 liters) Washing, drying on MgS〇4, and squeezing in vacuo to make the residue on the silica gel using CHC13_EtOAc (2 〇:1 to 4··1) for 2·50-2·67 (m, (d, J) = 1. 5 Hz, (d, J = 8· 8 Hz, 7. 23-7. 27 (m, chromatography, resulting in 4-[Bu [4-[Ν,-(2-chlorophenyl))urea A colorless viscous solid of 1 NMR (CDC13) - 4, 4-difluoro-2-pyrrolidine methoxy]benzoic acid formazan 482 gram of '97 Å/°). ) 2H) 1H) 2H), 3.54-4.71 (m series, 13H), 6.69 1H) 6. 76 (d, J 8.3 Hz, 1H), 6.84 6. 98 (dt, J = 7. 8 , 1 · 5 Hz, 1H), (m, 2H), 7. 94 (d, Hz, 1H ), 8· 19 (dd, j = 8, 3, 5 Hz, 1H) 7. 33 (d, J=8·3 Hz, 1H), 7·39 8· 8 Hz, 2H), 8· 00 ( d, J = 8·3

第500頁 1283240 五、發明說明（496) 使4-[1-[4 - [N’-(2 -氯苯基）脈基]- 3-甲氧苯基乙酷 基]-4, 4 -二氟-2 -咄咯啶甲氧基]苯甲酸甲酯（480毫克， 0.816毫莫耳）、0.25N NaOH (6.5毫升，1.65毫莫耳）、及 THF(20毫升）之混合物攪拌3天。將混合物倒入至IN HC1 (100 毫升）中，並以CHCl3-MeOH(5 : 1，2x20 0 毫升）萃取。 將結合的萃取液於MgS04上乾燥，並於真空中濃縮。使殘 留物於矽膠上利用CHC13-MeOH(20:l至5:1)進行層析，而 得1 40 ( 2 70毫克，58%)之淡黃色非晶形固體。 1H-NMR (DMS0-d6) 5 2. 4 5-2. 7 4 (m, 2H) 、3. 6 3-4 · 83 (m 系 列，10H)、6·76 (d，J = 8. 3 Hz, 1H)、6·87 (s，1H)、7· 0 0-7.0 5 (m，3H)、7·26-7·30 (m，1H)、7·44 (dd，J 二8· 3、1·2 Hz, 1H)、7. 88-7· 93 (m，2H)、7·98 (d，J = 8.3 Hz，1H)、8.10 (d，J:8.3 Hz，1H)、8·92 (s，1H)、 8· 96 (s，1H) ; MS(FAB) m/z 57 4 (MH1) ; C28H26C1F2N3 06 · H20 之分析計算值：C，56. 81 ; H，4. 77 ; N， 7. 1 0。實測 值：C，56.7 5； Η, 4.69； N, 6.79° 實施例1 3 3 4 - [(2R，3R，4S)-3，4-亞異丙二氧基-1 - [4-[Ν’ -（2-甲基苯 基）脲基]-3-甲氧苯基乙醯基]-2 -吼咯啶基]甲氧苯甲酸Page 500 1283240 V. INSTRUCTIONS (496) Let 4-[1-[4 - [N'-(2-chlorophenyl))]-3-methoxyphenylethyl]-4, 4 - Mixture of methyl difluoro-2-pyrrolidine methoxy]benzoate (480 mg, 0.816 mmol), 0.25 N NaOH (6.5 mL, 1.65 mmol), and THF (20 mL) for 3 days . The mixture was poured into <RTI ID=0.0># </RTI> </RTI> <RTIgt; </RTI> <RTIgt; The combined extracts were dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on silica gel eluting with CHCI <RTI ID=0.0># </RTI> MeOH (20:1 to 5:1) to afford 1 40 (2 70 mg, 58%) of pale yellow amorphous solid. 1H-NMR (DMS0-d6) 5 2. 4 5-2. 7 4 (m, 2H), 3. 6 3-4 · 83 (m series, 10H), 6·76 (d, J = 8. 3 Hz, 1H), 6·87 (s, 1H), 7·0 0-7.0 5 (m, 3H), 7·26-7·30 (m, 1H), 7·44 (dd, J 2·8) 3, 1·2 Hz, 1H), 7. 88-7· 93 (m, 2H), 7·98 (d, J = 8.3 Hz, 1H), 8.10 (d, J: 8.3 Hz, 1H), 8 · 92 (s, 1H), 8 · 96 (s, 1H); MS (FAB) m / z 57 4 (MH1); C28H26C1F2N3 06 · H20 Analysis calculated: C, 56. 81 ; H, 4. 77 ; N, 7. 1 0. Found: C, 56.7 5; Η, 4.69; N, 6.79° Example 1 3 3 4 - [(2R,3R,4S)-3,4-isopropylideneoxy-1 - [4-[Ν '-(2-Methylphenyl)ureido]-3-methoxyphenylethenyl]-2-pyridinyl]methoxybenzoic acid

\\312\2d-code\90-01\89112968.ptd 第501頁 1283240 五、發明說明（497) (2S，3R，4S)-1-爷氧羰基-3, 4-亞異丙二氧基-2-咄咯啶羧 酸\\312\2d-code\90-01\89112968.ptd Page 501 1283240 V. INSTRUCTIONS (497) (2S, 3R, 4S)-1-Oxycarbonyl-3, 4-isopropylidene dioxy -2-pyrrolidinecarboxylic acid

於（2S，3R，4S)_卜苄氧羰基-3,4_亞異丙二氧基-2 -咄咯啶 羧酸甲酯（10. 7克，31.9毫莫耳）溶於THF( 25 0毫升）之溶液 中加入0. 25N Na0H( 255毫升）。於在室溫下攪拌24小時 後，將混合物以IN HC1酸化，並以EtOAc萃取。將結合的 萃取液以鹽水洗滌，將其於Na2S04上乾燥，並於真空中濃 縮，而得（2S，3R，4S)-1-苄氧羰基-3,4-亞異丙二氧基-2-吡咯啶羧酸（9· 87克，96°/〇)之無色油。1H-NMR (CDC13) (5 1.32 (s, 3H) &gt;1.46 (d, J = 2.7 Hz, 3H) ^3.61 (m, 1H) 、3·82 及 3.92 (d，J = 12.7 Hz， 1H，醯胺異構物）、4·58 及 4·64 (s，1H，醯胺異構物）、4·77 (t，J = 5.1 Hz，1H) 、4.83 及 4.89 (d，J = 5.9 Hz, 1H，醯胺異構物）、5.15 及 5.19 (m，2H，醯胺異構物）、7·3ΐ — 7·37 (m，5H)。 (2R，3R，4S)- 1-爷氧羰基-3, 4 -亞異丙二氧基一2-咄咯啶甲 醇Methyl (2S,3R,4S)-benzyloxycarbonyl-3,4-isopropylidenedioxy-2-pyrrolidinecarboxylate (10. 7 g, 31.9 mmol) dissolved in THF (25 00.5) Na0H (255 ml) was added to a solution of 0 ml). After stirring at room temperature for 24 hours, the mixture was acidified with EtOAc andEtOAc. The combined extracts were washed with brine, dried over Na.sub.2SO.sub.sub.sub.sub.sub. a colorless oil of pyrrolidinecarboxylic acid (9·87 g, 96°/〇). 1H-NMR (CDC13) (5 1.32 (s, 3H) &gt; 1.46 (d, J = 2.7 Hz, 3H) ^3.61 (m, 1H), 3·82 and 3.92 (d, J = 12.7 Hz, 1H, Indoleamine isomers), 4·58 and 4·64 (s, 1H, guanamine isomers), 4·77 (t, J = 5.1 Hz, 1H), 4.83 and 4.89 (d, J = 5.9 Hz) , 1H, guanamine isomers), 5.15 and 5.19 (m, 2H, guanamine isomers), 7·3ΐ — 7·37 (m, 5H). (2R, 3R, 4S)- Carbonyl-3,4-isopropylideneoxy-2-pyrrolidinemethanol

在0°C下於（2S，3R，4S)-卜爷氧羰基_3,4-亞異丙二氧基 2 -吼咯啶羧酸（9. 87克，30. 7毫莫耳）溶sTHF( 2〇〇毫升）Dissolved in (2S,3R,4S)-bromooxycarbonyl_3,4-isopropylidenedioxy-2-pyrrolidinecarboxylic acid (9. 87 g, 30. 7 mmol) at 0 °C sTHF (2 ml)

\\312\2d-code\90-01\89112968.ptd 第502頁 1283240 五、發明說明（498) 之攪拌溶液中加入BH3 · DMS(6· 14毫升，61. 4毫莫耳）。使 混合物升溫至室溫，然後迴流加熱2小時。於冷卻至室溫 後，將混合物於真空中濃縮，並經由在〇 下加入水而使 其停止反應。以EtOAc萃取混合物。將結合的萃取液以水 及鹽水洗滌，將其於N a2 S 04上乾燥，並於真空中濃縮。使 殘留物於矽膠[ 2 0 0克，CHCl3/MeOH(20/l)]上進行層析， 而得（21^，31?，45)-1_爷氧羰基-3,4-亞異丙二氧基-2-吡咯 淀甲醇（10. 1 克，100%)之無色油。iH-NMR (CDC13) 5 1. 31 (s，3H)、1·45 (s，3H)、3·56-4.74 (m，7H)、5·14 (s， 2H) 、 7·34 (m， 5H)。 4 - [(2R，3R，4S) -卞氧裁基-3，4 -亞異丙二氧基-2 - 11比洛σ定 基]甲氧苯曱酸甲酯\\312\2d-code\90-01\89112968.ptd Page 502 1283240 V. Inventive Note (498) Add BH3 · DMS (6.4 ml, 61.4 mm) to the stirred solution. The mixture was allowed to warm to room temperature and then heated under reflux for 2 hours. After cooling to room temperature, the mixture was concentrated in vacuo and quenched by adding water under the mixture. The mixture was extracted with EtOAc. The combined extracts were washed with water and brine, dried over EtOAc EtOAc. The residue was chromatographed on silica gel [200 g, CHCl3/MeOH (20/l)] to give (21^,31?,45)-1-methoxycarbonyl-3,4-isopropylidene Dioxy-2-pyrrolidine methanol (10. 1 g, 100%) of a colorless oil. iH-NMR (CDC13) 5 1. 31 (s, 3H), 1·45 (s, 3H), 3·56-4.74 (m, 7H), 5·14 (s, 2H), 7·34 (m , 5H). 4 - [(2R, 3R, 4S) - anthracene-methyl-3,4-isopropylidene dioxy-2 - 11 piroxime] methyl methoxybenzoate

在0°C下在氮氣環境中，於（2R，3R，4S)-1-苄氧羰基 -3, 4-亞異丙二氧基一 2 -吼嘻σ定甲醇（312毫克，〇·64毫莫 耳）、對羥基苯曱酸甲酯（67毫升，0· 70毫莫耳）、PPh (184毫克，0.70毫莫耳）於THF(7毫升）中之攪拌混合^ 加入DIAD(138毫升，〇· 70毫莫耳）。使混合物達到^ 1 並攪拌3小時。於移除溶劑後，使所產生之殘留物於:: [10克，正己烷/EtOAc(4/l)]上進行層析，而得、矽膠 4-[(2R，3R，4S)-苄氧羰基—3, 4-亞異丙二氧基〜呪 基]甲氧苯甲酸甲酯（321毫克，83%)之無色油。定(2R,3R,4S)-1-Benzyloxycarbonyl-3,4-isopropylidene-2-oxanzepine methanol (312 mg, 〇·64) at 0 ° C under nitrogen atmosphere Mol), methyl p-hydroxybenzoate (67 ml, 0. 70 mmol), PPh (184 mg, 0.70 mmol) in THF (7 mL). , 〇 · 70 millimoles). The mixture was brought to ^1 and stirred for 3 hours. After the solvent was removed, the residue was chromatographed on: [10 g, n-hexane / EtOAc (4/l)] to give 4-[(2R,3R,4S)-benzyl A colorless oil of methyl oxycarbonyl-3,4-isopropylidene-indenyl]methoxybenzoate (321 mg, 83%). set

1283240 五、發明說明（499) (CDC13) d 1· 01 (s，6H)、1· 03 (s，3H)、2. 23 (m， 1H)、2·63 (m，1H)、3·61 (d, J = 12.5 Hz, 1H)、 3.80-4.27 (m，4H)、4.84 (br， 1H)、5·01 及5.08 (ABq， J = 12.2 Hz, 1H，醯胺異構物）、6·75-6·87 (m，3H)、 7·19-7·63 (m，15Η)。 4-[(2R，3R，4S)-3,4_亞異丙二氧基-2 -咄咯啶基]甲氧苯甲 酸曱醋1283240 V. INSTRUCTIONS (499) (CDC13) d 1· 01 (s, 6H), 1· 03 (s, 3H), 2. 23 (m, 1H), 2·63 (m, 1H), 3· 61 (d, J = 12.5 Hz, 1H), 3.80-4.27 (m, 4H), 4.84 (br, 1H), 5·01 and 5.08 (ABq, J = 12.2 Hz, 1H, guanamine isomer), 6·75-6·87 (m, 3H), 7·19-7·63 (m, 15Η). 4-[(2R,3R,4S)-3,4-isopropylidenedioxy-2-pyridinyl]methoxybenzoic acid vinegar

使4-[(2R，3R，4S)-1-爷氧羰基-3, 4-亞異丙二氧基—2 —。 咯啶基]甲氧苯甲酸甲酯（2· 37克，5· 76毫莫耳）及^% Pd/C( 240毫克）於EtOH(170毫升）中之懸浮液在室严°卜 '氣環境中攪拌。於攪拌1天後，將催化劑及溶至氣 p ri / ΓΎ R η η喜古、菸τ η ϋ r g η袁Λ冰息备：办、丄.^ ’支成1 0 %4-[(2R,3R,4S)-1-yloxycarbonyl-3,4-isopropylidenedioxy-2. A suspension of methyl pyridyl]methoxybenzoate (2.33 g, 5.76 mmol) and ^% Pd/C (240 mg) in EtOH (170 ml) in a chamber Stir in the environment. After stirring for 1 day, the catalyst and dissolved into gas p ri / ΓΎ R η η Xigu, smoke τ η ϋ r g η Yuan Λ ice content: do, 丄. ^ ′ into 10%

Pd/C( 5 0 0毫克）及THF(50毫升）。使懸浮液在室 溫下在氫氣 環境中攪拌5天。於經由過濾將催化劑移除後，、仕j 真空中濃縮。使殘留物於矽膠[1 00克，CH(：1 (20/1)]上進行層析，而得4-[(2R，3R，4S)^ f 氧基-2 -咣咯啶基]甲氧苯甲酸甲酯（93〇臺古 亞異兩 油。1Η-NMR (CDC13) 5 1· 35 (s，3H)、i 5〇 ° 3· 02 (dd，J = 13 · 7、4. 1 Hz，1 Η)、3· 13 (a ， 丙酉同 1H)、3· 58 (t，J = 6· 3 Hz, 1H)、3· 88 (s， (dd, J = 9.3 ^6.6 Hz, 1H) &gt;4.02 (dd, j = g 1H)、4·74 (d，J = 5.6 Hz，1H)、4·79 (m，1H) 3H) 於 之棕色 3H)、 = 13· 、3· 90Pd/C (500 mg) and THF (50 ml). The suspension was stirred at room temperature for 5 days in a hydrogen atmosphere. After the catalyst was removed by filtration, it was concentrated in a vacuum. The residue was chromatographed on silica gel [100 g, CH (: 1 (20/1)] to give 4-[(2R,3R,4S)^foxy-2-pyridinyl]A Methyl benzoate (93 〇台古亚异两油. 1Η-NMR (CDC13) 5 1· 35 (s, 3H), i 5〇° 3· 02 (dd, J = 13 · 7, 4. 1 Hz,1 Η),3· 13 (a , 酉 酉 with 1H), 3· 58 (t, J = 6· 3 Hz, 1H), 3· 88 (s, (dd, J = 9.3 ^6.6 Hz, 1H) &gt;4.02 (dd, j = g 1H), 4·74 (d, J = 5.6 Hz, 1H), 4·79 (m, 1H) 3H), brown 3H), = 13·, 3· 90

Hz, 9 2, 90Hz, 9 2, 90

12832401283240

(d，J = 9.G Hz, 2H)、7 98 (d， 4-[(2R，3R，4S)、3,4m . Z’ 2H)。 基）脲基]-3-曱氧苯A己於其&quot;7 =基—卜[4—[N，-(2—甲基苯 酯 土乙^基]―2 —咄咯啶基]甲氧苯甲酸甲 使3-甲乳基 -- ηκΓ 4 * , 1 ^ U f基本基）脲基]苯乙酸（437毫 克，1.39笔莫耳）、4—[(2R 3R，4 吡咯啶基]甲氧苯曱酸甲两4498古士，，〇…内(d, J = 9.G Hz, 2H), 7 98 (d, 4-[(2R, 3R, 4S), 3, 4m. Z' 2H). Ureyl]-3-indolylbenzene A has its &quot;7=基-卜[4-[N,-(2-methylphenyl ester)]-2-pyridinyl] Methyl benzoic acid gives 3-methyllacyl--ηκΓ 4 * , 1 ^ U f basic) ureido]phenylacetic acid (437 mg, 1.39 mol), 4-[(2R 3R, 4 pyrrolidinyl) Methotrexate A two 4498 Gus,, 〇...

甲酉曰（428冤克，L 39毫莫耳）、EDC :二=Γ/，2.09毫莫耳)及DMAP(170毫克，I39毫莫 p於DMFC12笔升）中之混合物在室溫下擾拌2Q小時。將混 δ物倒入至冰水中，並以e t 〇 a c萃取。將結合的萃取液以 冰^鹽水洗滌。於在Na2s〇4上乾燥後，將萃取液於真空 中濃縮。使殘留物於矽膠[7〇克，CHCls/丙酮（丨〇/1 )]上進 行層析，而得4-[(2R，3R，4S)-3,4-亞異丙二氧基-1-[4 -[Ν’-（2-甲基苯基）脲基]一3一甲氧苯基乙醯基]一2一咄咯啶 基]甲氧苯甲酸甲酯（8 4 0毫克，1 0 〇 % )的無色非晶形固體。 IR (KBr) 3354、2985、2939、1716、1533、1254 / 公 分；1H-NMR (CDC13) (5 1· 31 (s，3H)、1· 42 (s，3H) 、2·05 (s， 3H) 、3·50 (s， 3H) 、3·55-3·88 (m， 4H)、 3·89 (s，3Η)、4·13 (m，1Η)、4·67 (br，1Η)、4·78 (d， J = 6.1 Hz， 1H)、4·88 (t， J = 5.6 Hz， 1H)、6·46 (s，1H)、6·62 (d，J = 1.5 Hz，1H)、6·74 (m，3H)、A mixture of hyperthyroidism (428 g, L 39 mmol), EDC: di = Γ /, 2.09 mmol) and DMAP (170 mg, I39 mmol in DMFC 12 liters) was disturbed at room temperature Mix for 2Q hours. The mixed delta was poured into ice water and extracted with e t 〇 a c. The combined extracts were washed with ice brine. After drying over Na2s(R)4, the extract was concentrated in vacuo. The residue was chromatographed on silica gel [7 gram, CHCls/acetone (丨〇/1)] to give 4-[(2R,3R,4S)-3,4-isopropylidenedioxy-1 -[4 -[Ν'-(2-methylphenyl)ureido]- 3-methoxyphenylethylidene]- 2 -pyridinyl]methyl methoxybenzoate (800 mg, 1 0 〇%) of a colorless amorphous solid. IR (KBr) 3354, 2985, 2939, 1716, 1533, 1254 / cm; 1H-NMR (CDC13) (5 1 · 31 (s, 3H), 1 · 42 (s, 3H), 2·05 (s, 3H), 3·50 (s, 3H), 3·55-3·88 (m, 4H), 3·89 (s, 3Η), 4·13 (m, 1Η), 4·67 (br, 1Η) ), 4·78 (d, J = 6.1 Hz, 1H), 4·88 (t, J = 5.6 Hz, 1H), 6·46 (s, 1H), 6·62 (d, J = 1.5 Hz, 1H), 6.74 (m, 3H),

\\312\2d-code\90-01\89112968.ptd 第505頁 1283240 五、發明說明（501) 7·〇5 (s，1H)、7·14 (d，J = 7.3 Hz, 1H)、7·23 (m， 2 H)、7 . 5 7 ( d，J = 7 · 8 H z，1 H)、7 · 9 1 - 8 · 0 8 ( m，3 H ); MS(ESI ) m/z 60 4 (MH1) ; C33H37N3 08 · 〇· 6H20 之分析計算 值 ’C，64.50，H，6.27，N，6.84。實測值：c，64.38; H，6·18; N，6.66。 4-[(21?，31?，43)-3,4-二經基-1-[4—[^’一（2-甲基苯基）脲 基]-3-甲氧苯基乙醯基]-2-咄咯啶基]曱氧苯曱酸甲_\\312\2d-code\90-01\89112968.ptd Page 505 1283240 V. INSTRUCTIONS (501) 7·〇5 (s,1H), 7·14 (d, J = 7.3 Hz, 1H), 7·23 (m, 2 H), 7. 5 7 ( d, J = 7 · 8 H z, 1 H), 7 · 9 1 - 8 · 0 8 ( m, 3 H ); MS(ESI ) m /z 60 4 (MH1) ; C33H37N3 08 · 〇· 6H20 Analytical calculated value 'C, 64.50, H, 6.27, N, 6.84. Found: c, 64.38; H, 6.18; N, 6.66. 4-[(21?,31?,43)-3,4-diylidene-1-[4-[^'-(2-methylphenyl)ureido]-3-methoxyphenylacetamidine Alkyl-2-pyrrolidyl]oxobenzoic acid A

使4-[(21^，31?，43)-3,4-亞異丙二氧基—1-[4—[1^_(2一〒 基本基）脈基]_3 -甲氧苯基乙酿基]一2 —吼洛。定基]甲氧苯甲 酸甲酯（183毫克，0.303毫莫耳）及g· HC1 - MeOH(6毫升）之 合物在室溫下授摔1 7小時。將混合物於真空中濃縮。將 殘留物於几(：[(：11(：13/^^011(10/1)]上純化而得4-[(21^ 3R，4S)-3,4-二羥基-：1 - [4-[N’-(2-甲基苯基）脲基]一 3-甲 氧苯基乙醯基]-2-咄咯啶基]甲氧苯甲酸甲酯（162毫克， 95%)之無色非晶形固體。IR (KBr) 3342、1716、1 604、 1 535、1 255 / 公分；M-NMR (CDC13) 5 2· 25 (br，3H)、 3.33-3·75 (m，7H)、3·87 (s, 3H)、4·10 (d，J = 8.3 Hz，1H)、4·24 (s，2H)、4·37 (m，2H)、6·62 -7.94 (m， 13H) ; MS(ESI) m/z 564 (MH1 )。 於4-[(2{?，31^48)-3,4-亞異丙二氧基-1-[4-[1^，_(2-甲 基苯基）脲基]- 3-曱氧笨基乙醯基]-2 - σ比洛°定基]曱氧苯甲4-[(21^,31?,43)-3,4-isopropylidenedioxy-l-[4-[1^_(2 〒 〒 ) ))] _3-methoxyphenyl B-based] one 2 - Luo Luo. A solution of methyl methacrylate (183 mg, 0.303 mmol) and g·HC1 - MeOH (6 mL) was given for 17 hours at room temperature. The mixture was concentrated in vacuo. The residue was purified on several (:[(:13/^^011 (10/1)]) to give 4-[(21^3R,4S)-3,4-dihydroxy-: 1 - [ Methyl 4-[N'-(2-methylphenyl)ureido]-3-methoxyphenylethenyl]-2-oxaridinyl]methoxybenzoate (162 mg, 95%) Colorless amorphous solid. IR (KBr) 3342, 1716, 1 604, 1 535, 1 255 / cm; M-NMR (CDC13) 5 2· 25 (br, 3H), 3.33-3·75 (m, 7H) , 3·87 (s, 3H), 4·10 (d, J = 8.3 Hz, 1H), 4·24 (s, 2H), 4·37 (m, 2H), 6.62 - 7.94 (m, 13H) ; MS (ESI) m/z 564 (MH1). 4-[(2{?,31^48)-3,4-isopropylidenedioxy-1-[4-[1^,_ (2-methylphenyl)ureido]-3-oxooxyindolyl]-2 - σ pyrolol

\\312\2d^code\90-01\89112968.ptd 第506頁 1283240 五、發明說明（502) 酸曱酯（490宅克’0.812毫莫耳）溶於THF(9.8毫升）之溶液 中加入0·25Ν NaOH(9.8毫升）。於在室溫下攪拌4天後，將 混合物以IN HC1酸化，並以CHC13-MeOH(10/l )萃取。將結 合的萃取液於N az S 〇4上乾燥，並於真空中濃縮，而得 141(445毫克’93%)之無色非晶形固體。(KBr) 3354、 2983、2937、1707、1604、1533/公分；ih-NMR (DMSO-d 6)δ 1·24 及 1·26 (s， 3H，醯胺異構物）、ι·26 及 1·32 (s，3Η，醯胺異構物）、2.24 (s，3Η)、3.40 (dd， J=14. 0、5 · 1 Η z，1 Η)、3 · 6 0 (m，2 Η)、3 · 71 (m，1 Η )、3 · 7 6 (s，3H)、3·82 (s，3H)、3·92- 4.9 6 (m，5H)、6·74 及6· 78 (m，1Η ’ 醯胺異構物）、6.83-7·ΐ6 (m，6Η)、7·79 (d， J:8.3 Ηζ， 1Η) 、7·87 (t， J=9.1 Ηζ， 2Η) 、8·01 (m，1H)、8·49 (d，J = 3.4 Hz，1H)、8·57 (s，1H); MS(FAB) m/z 59 0 (MH1) ; C32H35N3 08 ·2·3Η20之分析計算 值：C，60·90;Η，6·32;Ν，6.66。實測值：c，61.00; Η，6.00； Ν, 6· 27 〇 實施例1 3 4 4-[(21?，31?，43)-3,4-二羥基一1一[4-[^，-（2-甲基苯基）脲 基]- 3-甲氧苯基乙醯基]- 2-吼哈咬基]甲氧苯甲酸\\312\2d^code\90-01\89112968.ptd Page 506 1283240 V. Description of the invention (502) Addition of decyl citrate (490 克克 '0.812 mmol) in THF (9.8 ml) 0·25Ν NaOH (9.8 ml). After stirring at room temperature for 4 days, the mixture was acidified with EtOAc (EtOAc) (EtOAc) The combined extracts were dried <RTI ID=0.0></RTI> to EtOAc (EtOAc) (KBr) 3354, 2983, 2937, 1707, 1604, 1533/cm; ih-NMR (DMSO-d 6) δ 1·24 and 1·26 (s, 3H, guanamine isomer), ι·26 and 1·32 (s, 3Η, guanamine isomer), 2.24 (s, 3Η), 3.40 (dd, J=14.0, 5 · 1 Η z, 1 Η), 3 · 6 0 (m, 2 Η), 3 · 71 (m, 1 Η ), 3 · 7 6 (s, 3H), 3·82 (s, 3H), 3.92- 4.9 6 (m, 5H), 6·74 and 6· 78 (m,1Η 'proline isomers), 6.83-7·ΐ6 (m,6Η), 7.79 (d, J:8.3 Ηζ, 1Η), 7·87 (t, J=9.1 Ηζ, 2Η ), 8·01 (m, 1H), 8·49 (d, J = 3.4 Hz, 1H), 8·57 (s, 1H); MS(FAB) m/z 59 0 (MH1) ; C32H35N3 08 · Analysis of 2·3Η20: C, 60·90; Η, 6.32; Ν, 6.66. Found: c, 61.00; Η, 6.00; Ν, 6· 27 〇 Example 1 3 4 4-[(21?, 31?, 43)-3,4-dihydroxy-l-[4-[^, -(2-methylphenyl)ureido]-3-methoxyphenylethylidene]- 2-haha bite base] methoxybenzoic acid

於4-[(21?，3]?，43)-3,4-二羥基-1-[4-[『-(2-曱基苯基）4-[(21?,3]?,43)-3,4-dihydroxy-1-[4-[『-(2-mercaptophenyl)

\\312\2d-code\90-01\89112968.ptd 第507頁 1283240 五、發明說明（503) 脲基]-3-甲氧苯基乙醯基]一2一咄咯啶基]甲氧苯甲酸甲酯 (63毫克’0.112毫莫耳）溶於thf(〇. 89毫升）之溶液中加入 0· 25N NaOH(0· 89毫升）。於在室溫下攪拌3天後，將混合 物以IN HC1酸化，並以CHCl3-MeOH(10/l)萃取。將結合的 萃取液於Na2S04上乾燥，並於真空中濃縮，而得1 42 ( 54毫 克，88%)之無色非晶形固體。ir (KBr) 3356、2958、 2927、1 685、1 6 04、1 53 5、1 255 / 公分；UMR (DMS〇-d 6)5 2.24 (s， 3H)、3.40 (m, 1Η)、3·58 (s, 2H)、 3.66 (dd，J = 9.8、6·6 Hz，1H)、3·80 (s，3H)、 3. 99-4. 30 (m，5H)、5. 10 (br，1H)、6· 72 (d, J = 8.1\\312\2d-code\90-01\89112968.ptd Page 507 1283240 V. INSTRUCTIONS (503) Urea-based]-3-methoxyphenylethylidene]- 2-indolyl]methoxy Methyl benzoate (63 mg '0.112 mmol) was dissolved in a solution of thf (yield: 89 mL) and 0.25N NaOH (0·89 mL). After stirring at room temperature for 3 days, the mixture was acidified with EtOAc (EtOAc) (EtOAc) The combined extracts were dried <RTI ID=0.0></RTI> to <RTI ID=0.0> Ir (KBr) 3356, 2958, 2927, 1 685, 1 6 04, 1 53 5, 1 255 / cm; UMR (DMS〇-d 6) 5 2.24 (s, 3H), 3.40 (m, 1Η), 3 · 58 (s, 2H), 3.66 (dd, J = 9.8, 6·6 Hz, 1H), 3·80 (s, 3H), 3. 99-4. 30 (m, 5H), 5. 10 ( Br,1H),6·72 (d, J = 8.1

Hz，1H)、6.85 (s，1H)、6·93 (t，J = 7.3 Hz，1H)、 7.03 (d, J = 8.8 Hz, 2H) &quot;7.14 (t, J = 8.8 Hz, 2H) '7. 79 (d，J = 8.1 Hz，2H)、7·86 (d，J:8.8 Hz，2H)、7·99 (d，J = 8.3 Hz, 1H)、8·46 (s，1H)、8·56 (s，1H); MS(ESI ) m/z 55 0(MH1) ; C29H31N3 08 · 〇· 85H20 之分析計算 值：C， 61·66; Η， 5.83; N，7.44。實測值：c，62.09; Η, 5.93； Ν, 6. 95 〇 實施例1 3 5 4-[(21?，3143)-1-[4-1^’-（2-氯苯基）脲基]一3一甲氧苯基 乙醯基]-3, 4 -亞異丙二氧基-2 -咄咯啶基]甲氧苯曱酸Hz, 1H), 6.85 (s, 1H), 6.93 (t, J = 7.3 Hz, 1H), 7.03 (d, J = 8.8 Hz, 2H) &quot;7.14 (t, J = 8.8 Hz, 2H) '7. 79 (d, J = 8.1 Hz, 2H), 7·86 (d, J: 8.8 Hz, 2H), 7·99 (d, J = 8.3 Hz, 1H), 8.46 (s, 1H) ), 8·56 (s, 1H); MS (ESI) m/z 55 0 (MH1); C29H31N3 08 · 〇· 85H20 Analysis calculated: C, 61·66; Η, 5.83; N, 7.44. Found: c, 62.09; Η, 5.93; Ν, 6. 95 〇 Example 1 3 5 4-[(21?,3143)-1-[4-1^'-(2-Chlorophenyl)ureido -3 -Methoxyphenylethylidene]-3,4-isopropylidenedioxy-2-pyridinyl]methoxybenzoic acid

\\312\2d-code\90-01\89112968.ptd 第508頁 1283240 五、發明說明（504) 4-[(2R，3R，4S)-1 - [4 - [Ν’ -（2- 氯苯基）脲基]- 3-甲氧笨基 乙醯基]- 3, 4 -亞異丙二氧基-2 -吼洛咬基]甲氧笨甲酸甲酿\\312\2d-code\90-01\89112968.ptd Page 508 1283240 V. INSTRUCTIONS (504) 4-[(2R,3R,4S)-1 - [4 - [Ν' -(2- Chlorine) Phenyl)ureido]-3-methoxybenzylidene]- 3,4-isopropylidenedioxy-2-indolediyl] methoxybenzoic acid

使4-[Ν’ _(2 -氯苯基）脲基]一3-曱氧苯乙酸（487毫克， 1·45毫莫耳）、4-[(2R，3R，4S)-3,4-亞異丙二氧基—2 -咄咯 啶基]曱氧苯曱酸甲酯（447毫克，1.45毫莫耳）、EDC· HC1(418毫克，2·18毫莫耳）及DMAP(177毫克，1. 45毫莫 耳）於DMF (1 2毫升）中之混合物在室溫下攪拌1 9小時。將混 合物倒入至冰水中，並以Et OAc萃取。將結合的萃取液以 冰水及鹽水洗滌。於在Na2S04上乾燥後，將萃取液於真空 中濃縮。使殘留物於矽膠[70克，CHC13 /丙酮（1 〇 /1 )]上進 行層析，而得 4 - [(2R，3R，4S)_1_[4-[N，-（2-氯苯基）脲 基]-3-甲氧苯基乙醯基]-3, 4-亞異丙二氧基-2-吡咯啶基] 甲氧苯甲酸甲酯（8 50毫克，94%)的無色非晶形固體。IR (KBr) 3329、2939、1716、1627、1531、1254 / 公分； UMR (CDC13) 5 1· 33 (s，3H)、1· 43 (s，3H)、3· 56 (s， 3H) 、3·61 (s， 1H) 、3.64 (s， 1H) 、3·70 (m， 1H)、3·79 (d，J = 10.4 Hz，1H)、3·88 (s，3H)、4·14 (dd，J = 9.8、2·2 Hz, 1H)、4·40 (dd，J = 9.8、3·4 Hz， 1H) 、4·67 (s， 1H) 、4·8〇 (d， J=6.1 Hz, 1H) 、4·9〇 (t， J=4.6 Hz， 1H) 、6.65 (d， J=1.7 Hz， 1H) 、6·7卜 6.84 (m，3H)、6·98 (dt，J = 7.6、1·5 Hz，1H)、7·274-[Ν' _(2-Chlorophenyl)ureido] 3-oxooxyphenylacetic acid (487 mg, 1.45 mmol), 4-[(2R,3R,4S)-3,4 Methyl isopropylidene-2-oxazolidinyl benzoate (447 mg, 1.45 mmol), EDC·HC1 (418 mg, 2.18 mmol) and DMAP (177) The mixture was stirred at room temperature for 19 hours at rt (1. 5 mL). The mixture was poured into ice water and extracted with EtOAc. The combined extracts were washed with ice water and brine. After drying over Na 2 SO 4 , the extract was concentrated in vacuo. The residue was chromatographed on silica gel [70 g, CHC13 / acetone (1 〇 /1)] to give 4-[(2R,3R,4S)_1_[4-[N,-(2-chlorophenyl) Urea]-3-methoxyphenylethylidene]-3,4-isopropylidenedioxy-2-pyrrolidinyl] methyl methoxybenzoate (8 50 mg, 94%) of colorless Crystal form solid. IR (KBr) 3329, 2939, 1716, 1627, 1531, 1254 / cm; UMR (CDC13) 5 1· 33 (s, 3H), 1 · 43 (s, 3H), 3 · 56 (s, 3H), 3·61 (s, 1H), 3.64 (s, 1H), 3·70 (m, 1H), 3.79 (d, J = 10.4 Hz, 1H), 3·88 (s, 3H), 4· 14 (dd, J = 9.8, 2·2 Hz, 1H), 4·40 (dd, J = 9.8, 3·4 Hz, 1H), 4·67 (s, 1H), 4·8〇 (d, J=6.1 Hz, 1H), 4·9〇(t, J=4.6 Hz, 1H), 6.65 (d, J=1.7 Hz, 1H), 6·7 b 6.84 (m, 3H), 6·98 ( Dt, J = 7.6, 1·5 Hz, 1H), 7.27

\\312\2d-code\90-01\89112968.ptd 第 509 頁 1283240 五、發明說明（505) (m，2H)、7·33 (dd，J = 8.0、1·2 Hz，2H)、7·90-8·01 (m, 3H)、8·20 (dd，J = 8.3、1·5 Hz，1H); MS(ESI) m/z 6 24 (MH1)、6 2 6 (MH3) ; C32H34N3〇8 · h 4H2〇 之分析計算值： C，59. 19 ; H，5· 71 ; N，6. 47。實測值：C，58· 85 ; H， 5. 35 ; N，6· 21。 4-[(21^，31?，43)-：1-[4-[1^，-（2-氯苯基）脲基]一3一甲氧苯基 乙醯基]-3, 4 -亞異丙二氧基-2^比&quot;各咬基]曱氧苯甲酸甲醋\\312\2d-code\90-01\89112968.ptd Page 509 1283240 V. Description of invention (505) (m, 2H), 7·33 (dd, J = 8.0, 1·2 Hz, 2H), 7·90-8·01 (m, 3H), 8·20 (dd, J = 8.3, 1. 5 Hz, 1H); MS (ESI) m/z 6 24 (MH1), 6 2 6 (MH3) ; C32H34N3〇8 · h 4H2〇 Analysis calculated: C, 59. 19 ; H, 5 · 71 ; N, 6. 47. Found: C, 58·85; H, 5. 35 ; N, 6·21. 4-[(21^,31?,43)-:1-[4-[1^,-(2-chlorophenyl)ureido]-3-methoxyphenylethyl]-3, 4 - Isoisopropyldioxy-2^ ratio &quot;bite base] benzoic acid methyl vinegar

使4 - [(2R，3R，4S)-1-[4 - [Ν〜（2 一氣苯基）脲基卜3一曱氧 苯基乙醯基]-3, 4-亞異丙二氧恭一2—吼咯啶基]曱氧苯曱酸 甲酯（177毫克，0.284毫莫耳）及g· HC1—Me0H(4毫升◊之混 合物在室溫下攪拌8天。將混合物於真空中濃縮。將殘留 物於几(：[(：11(：13/河6〇11(15/1)]上純化而得4-[(21^31?，43) -1-[4- [Ν’-（2-氯苯基）脲基]- 3-甲氧苯基乙醯基]-3, 4 -亞 異丙二氧基-2 -吼咯啶基]甲氧苯甲酸甲酯（140毫克，85%) 之無色非晶形固體。IR (KBr) 3338、2949、1712、1623 、1 604、1 53 3 / 公分；iH-NMR (CDC13) 6 2· 27 (m， 1H)、 2.79 (m，1H)、3·53 (dd，J = 10.5、5·9 Hz, 1H)、3·63 (s，3H)、3·88 (s，3H)、4·21 (d，J = 7.8 Hz，1H)、 4.31 (m，2H)、4·43 (dd，J = 9.8、4·4 Hz, 1H)、4.52 (t，J = 4.6 Hz, 1H)、6·71 (s，1H)、6·80 (m，3H)、 6·99 (t，J = 7.3 Hz，1H)、7·16 (s，1H)、7·21 (s，1H)4 - [(2R,3R,4S)-1-[4 - [Ν~(2-Phenylphenyl)ureido]3-methoxyphenylethyl]-3, 4-isopropylidene Methyl 2-bromopyridinyl]phosphonium benzoate (177 mg, 0.284 mmol) and g. HCl-Me0H (4 mL EtOAc) was stirred at room temperature for 8 days. The mixture was concentrated in vacuo. Purify the residue on several (:[(:13/:13/he 6〇11(15/1)]) to give 4-[(21^31?,43) -1-[4-[Ν'- (2-Chlorophenyl)ureido]-3-methoxyphenylethenyl]-3,4-isopropylidenedioxy-2-pyridinyl]methyl methoxybenzoate (140 mg, 85%) colorless amorphous solid. IR (KBr) 3338, 2949, 1712, 1623, 1 604, 1 53 3 / cm; iH-NMR (CDC13) 6 2· 27 (m, 1H), 2.79 (m, 1H), 3·53 (dd, J = 10.5, 5·9 Hz, 1H), 3·63 (s, 3H), 3·88 (s, 3H), 4·21 (d, J = 7.8 Hz, 1H), 4.31 (m, 2H), 4·43 (dd, J = 9.8, 4·4 Hz, 1H), 4.52 (t, J = 4.6 Hz, 1H), 6·71 (s, 1H), 6 · 80 (m, 3H), 6·99 (t, J = 7.3 Hz, 1H), 7·16 (s, 1H), 7·21 (s, 1H)

\\312\2d-code\90-01\89112968.ptd 第510頁 1283240 五、發明說明（506) 、7·39 (d， J=8.1 Hz， 1H) 、7·91 (d， J=8.6 Hz, 2H)、 8.16 (d，J = 8.3 Hz，1H); MS(ESI) m/z 584CMH1)、 586 (MH3)。 於4-[(2R，3R，4S)-：l-[4-[N，-（2-氯苯基）脲基]-3 -甲氧 苯基乙醯基]- 3, 4-亞異丙二氧基一 2-咄咯啶基]甲氧苯甲酸 甲酯（511毫克，0.819毫莫耳）溶於THF (9.8毫升）之溶液中 加入0· 2 5N NaOH(9· 8毫升）。於在室溫下擾拌20小時後， 將混合物以1 N HC1酸化，並以CHCl3-MeOH( 1 0/1 )萃取。將 結合的萃取液於Na2S04上乾燥，並於真空中濃縮，而得 143(504毫克，100%)之無色非晶形固體。ir (KBr) 3330、2983、2937、1711、1689、1604、1533、1252 / 公 分；1H-NMR (DMS〇-d6)(5 1.26 (s，3H)、1·32 (s，3H)、 3·40 (m，1Η)、3·60 及 3.61 (d， J = 2.5 Ηζ，3Η，醯胺異 構物）、3·62 (m，1H)、3·78 及 3·83 (s，3H，醯胺異構 物）、7·28 (t， J = 7.3 Hz， 1H)、7·43 (d，J = 8.1 Hz, 1H) 、7.78-7.97 (m， 4H) 、8·08 (d，】=8·3 Hz， 1H)、 8.89 (s，1H)、8.92 (s，1H)、12.68 (br，1H); MS(ESI) m/z 610(MH1)、612(MH3)。 實施例1 3 6 4-[(21^，31^43)-1-[4-[^’-（2-氯苯基）脲基]—3一甲氧苯基 乙醯基]-3, 4 -二羥基-2-咣咯啶基]甲氧苯甲酸\\312\2d-code\90-01\89112968.ptd Page 510 1283240 V. Invention description (506), 7.39 (d, J=8.1 Hz, 1H), 7.91 (d, J=8.6 Hz, 2H), 8.16 (d, J = 8.3 Hz, 1H); MS (ESI) m/z 584 CMH1), 586 (MH3). 4-[(2R,3R,4S)-:l-[4-[N,-(2-Chlorophenyl)ureido]-3-methoxyphenylethenyl]- 3, 4-iso To a solution of methyl propyldioxy-2-bromoridinyl]methoxybenzoate (511 mg, 0.819 mmol) in THF (9.8 mL) was added EtOAc (EtOAc) After being scrambled for 20 hours at room temperature, the mixture was acidified with 1N EtOAc and extracted with CHCl3-MeOH (1 0/1). The combined extracts were dried <RTI ID=0.0></RTI> to <RTI ID=0.0> Ir (KBr) 3330, 2983, 2937, 1711, 1689, 1604, 1533, 1252 / cm; 1H-NMR (DMS〇-d6) (5 1.26 (s, 3H), 1·32 (s, 3H), 3 · 40 (m, 1 Η), 3.60 and 3.61 (d, J = 2.5 Ηζ, 3 Η, guanamine isomers), 3·62 (m, 1H), 3·78 and 3·83 (s, 3H , guanamine isomers), 7·28 (t, J = 7.3 Hz, 1H), 7·43 (d, J = 8.1 Hz, 1H), 7.78-7.97 (m, 4H), 8·08 (d ,] = 8·3 Hz, 1H), 8.89 (s, 1H), 8.92 (s, 1H), 12.68 (br, 1H); MS (ESI) m/z 610 (MH1), 612 (MH3). Example 1 3 6 4-[(21^,31^43)-1-[4-[^'-(2-Chlorophenyl)ureido]-3methoxyphenylethyl]-3, 4 -dihydroxy-2-hydrazinyl]methoxybenzoic acid

\\312\2d-code\90-01\89112968.ptd 第511頁 1283240 五、發明說明（507) 於4-[1-[4-[Ν’-（2-氯苯基）脲基]-3-甲氧苯基乙醯基] -3,4 -二羥基-2-咄咯啶甲氧基]苯甲酸曱酯（63毫克， 〇· 108毫莫耳）溶於THF(0· 80毫升）之溶液中加入0. 25Ν NaOH(0· 80毫升）。於在室溫下攪拌3天後，將混合物以1N HCl酸化，並以CHCl3_MeOH(10/l)萃取。將結合的萃取液 於Na2S04上乾燥，並於真空中濃縮，而得144(61毫克， 100%)之無色非晶形固體。IR (KBr) 3338、1 68 7、1 60 4、 1 533、1 255、1169、1 03 6 / 公分；UMR (DMSO-d6) (5 3· 59 (d， J:5.5 Hz， 2H) 、3·61 (m， 1H) 、3·66 (dd， J = 10.0、7·1 Hz，1H)、3·80 (s，3H)、4.00-4.33 (m， 5H)、5·10 (br，1H)、6.74 (d，J = 8.3 Hz，1H)、6·87 (s， 1H) 、7·03 (m， 3H) 、7·28 (t， J=8.3 Hz， 1H)、 7·43 (d，J = 6.6 Hz, 1H)、7.87 (d，J = 8.5 Hz，2H)、7· 95 (d，J = 8.3 Hz，1H)、8.09 (d，J = 8.3 Hz，1H)、8·32 (s，1H)、8·89 (s，1H)、8·93 (s，1H); MS(ESI) m/z 5 70 (MH1)、5 72 (MH3) ; C28H28C1N3 08 · 1· 4H20 之分析計算 值：C，57· 1 9 ; H，5· 14 ; N，7· 15。實測值：C，5 7. 5 2 ; Η, 5. 22 ； Ν, 6. 76 〇 實施例1 3 7 4-U - [4-[Ν’ -（2 -甲基笨基）脲基]—3一甲氧苯基乙醯基] -5 -（R) -苯基-2 -（S)_wb咯啶甲氧基]苯甲酸\\312\2d-code\90-01\89112968.ptd Page 511 1283240 V. INSTRUCTIONS (507) On 4-[1-[4-[Ν'-(2-chlorophenyl)ureido]- 3-methoxyphenylethylidene]-3,4-dihydroxy-2-pyrrolidinemethoxy]benzoate oxime ester (63 mg, 〇·108 mmol) dissolved in THF (0·80 ml) Ν NaOH (0·80 ml) was added to the solution. After stirring at room temperature for 3 days, the mixture was acidified with EtOAc EtOAc (EtOAc) The combined extracts were dried <RTI ID=0.0> IR (KBr) 3338, 1 68 7, 1 60 4, 1 533, 1 255, 1169, 1 03 6 / cm; UMR (DMSO-d6) (5 3· 59 (d, J: 5.5 Hz, 2H), 3·61 (m, 1H), 3.66 (dd, J = 10.0, 7·1 Hz, 1H), 3·80 (s, 3H), 4.00-4.33 (m, 5H), 5·10 (br , 1H), 6.74 (d, J = 8.3 Hz, 1H), 6·87 (s, 1H), 7·03 (m, 3H), 7·28 (t, J=8.3 Hz, 1H), 7· 43 (d, J = 6.6 Hz, 1H), 7.87 (d, J = 8.5 Hz, 2H), 7.95 (d, J = 8.3 Hz, 1H), 8.09 (d, J = 8.3 Hz, 1H), 8·32 (s, 1H), 8·89 (s, 1H), 8.93 (s, 1H); MS (ESI) m/z 5 70 (MH1), 5 72 (MH3); C28H28C1N3 08 · 1 · Analytical calculation of 4H20: C, 57· 1 9 ; H, 5 · 14 ; N, 7 · 15. Actual measured value: C, 5 7. 5 2 ; Η, 5. 22 ; Ν, 6. 76 〇 Example 1 3 7 4-U - [4-[Ν' -(2-methylphenyl)ureido]-3methoxyphenylethyl]-5-(R)-phenyl-2 - ( S)_wb pyridylmethoxy]benzoic acid

\\312\2d-code\90-01\89112968.ptd 第512頁 1283240 五、發明說明（508) [2-（S)-(N-Boc-胺基）-5 -酮基-6 -苯基]戊酸窄醋\\312\2d-code\90-01\89112968.ptd Page 512 1283240 V. INSTRUCTIONS (508) [2-(S)-(N-Boc-Amino)-5-keto-6-benzene Nitrate

在-7 8 °C下於N-Boc-吡咯戊二酸苄酯（8. 93克，28· 〇毫莫 耳）溶於THF(100毫升）之攪拌溶液中加入苯基鋰（1〇M溶於 Eta-環己烧，33· 5毫升，33. 5毫莫耳），並使所產生之混 合物逐漸升溫至-40°C，然後攪拌隔夜。將NH4C1水溶液: 至反應混合物，將THF於真空中移除，然後aEt〇Ac萃取。 將有機層以水洗滌，並於無水NajO4上乾燥，然後於真空 中濃縮。使殘留物於矽膠上利用己烷一Et〇Ac(4: 〇作為^ 提液進行層析，然後自己烷-Et0Ac再結晶而得[2-(S)-(N-Boc-胺基）-5 -酮基-6-苯基]戊酸窄酯（5·〇2克，45%)的 無色針狀物。炼點85-87 C ; NMR (CDC13) 5 1,43 (s 9H)、2·07-2·19 (m，1H)、2·27-2.36 (m, 1H)、2·97-’ 3·13 (m，2H)、4·44 (brs，1H)、5·19 (dd，J = 25.2、 12. 0 Hz， 2H)、5· 19 (重疊，1H)、7. 28-7· 98 (m 系列， 10H) ; MS(ESI) m/z 322 (MHH)。 ’ 5 -苯基-5 -咄咯喵-2-(S) -羧酸芊酯 C〇2Bn 在室溫下於[2_(S)-(N-Boc-胺基）-5 -酮基-6 -笨基]戊酸 爷醋（2.20克，5.54毫莫耳）溶於CH2C12(50毫升）之攪拌溶 液中加入三氟乙酸（1 5毫升），並使所產生之混合物授拌2Phenyllithium (1 〇M) was added to a stirred solution of benzyl N-Boc-pyrrolyl glutamate (8.93 g, 28 〇 mmol) in THF (100 ml) at -7 8 °C. Dissolved in Eta-cyclohexane, 33.5 ml, 33.5 mmol, and the resulting mixture was gradually warmed to -40 ° C then stirred overnight. Aqueous NH4Cl solution: To the reaction mixture, THF was removed in vacuo and then extracted with aEtOAc. The organic layer was washed with water and dried over anhydrous Naj. The residue was subjected to chromatography on ruthenium using hexane-Et〇Ac (4: hydrazine as extract), and then recrystallized from hexane-Et0Ac to give [2-(S)-(N-Boc-amino)- a colorless needle of 5-keto-6-phenyl]pentanoic acid narrow ester (5·〇2 g, 45%). Refining point 85-87 C; NMR (CDC13) 5 1,43 (s 9H), 2·07-2·19 (m,1H), 2·27-2.36 (m, 1H), 2·97-' 3·13 (m, 2H), 4·44 (brs, 1H), 5·19 (dd, J = 25.2, 12. 0 Hz, 2H), 5·19 (overlap, 1H), 7. 28-7. 98 (m series, 10H); MS (ESI) m/z 322 (MHH). '5-Phenyl-5-nonanthracene-2-(S)-carboxylic acid oxime ester C〇2Bn at room temperature in [2_(S)-(N-Boc-amino)-5-keto- 6-stupyl] valeric acid vinegar (2.20 g, 5.54 mmol) in a stirred solution of CH2C12 (50 ml), trifluoroacetic acid (15 ml) was added, and the resulting mixture was mixed 2

1283240 五、發明說明（509) 小時。將混合物於真空中濃縮，並倒入至NaHC〇4水溶液 中，然後以EtOAc萃取。將有機層於無水上乾燥，缺 後於真空中濃縮而得5-苯基-5-毗咯啉— 2_(s)—羧酸笨酷’… (1· 60克，定量）之淡黃色固體。將產物不經進一步的=化 而使用於後續的反應(CDC13) 5 2·20-2.29 (m， 1H)、2·32-2·42 (m，1H)、2·96-3·05 (m，1H)、3.12-;· 21 (m，1H)、4·96-5·00 (m，1H)、5.24 (s，2H)、7·3ΐ 一 7.49 (m，8H)、7·88-7.91 (in，2H); MS(ESI) m/z，280 (MHH) 〇 N-Boc-5-(R) -苯基-（S) -膽胺酸1283240 V. Description of invention (509) hours. The mixture was concentrated in vacuo and poured into EtOAc EtOAc. Drying the organic layer on anhydrous water, and then concentrating in vacuo to give 5-phenyl-5-pyrroline-2-(s)-carboxylic acid stupid '... (1·60 g, quantitative) of pale yellow solid . The product was used in the subsequent reaction without further purification (CDC13) 5 2·20-2.29 (m, 1H), 2·32-2·42 (m, 1H), 2·96-3·05 ( m,1H),3.12-;· 21 (m,1H),4·96-5·00 (m,1H), 5.24 (s,2H), 7·3ΐ a 7.49 (m,8H), 7.88 -7.91 (in, 2H); MS (ESI) m/z, 280 (MHH) 〇N-Boc-5-(R)-phenyl-(S)-choline

N-\ Boc C〇2H 使5-苯基-5-咄咯啉-2-(S) -羧酸窄酯（I 59克，5· 69毫 莫耳）及Pd/C(10%，128毫克）於MeOH(30毫升）中之混合物 在H2中在室溫下攪拌28小時。將混合物過濾，並將濾液於 真空中濃縮。將殘留物溶解於CH3CN-H2〇(3:2，25毫升）， 然後加入二碳酸二-第三丁酯（1 · 8 6克，8· 54毫莫耳）及 1，〇，“〇11(8.54毫升，8.54毫莫耳），並使所產生之混合 物祝拌3 0分鐘。將混合物於真空中濃縮，並倒入至N a η c % 水〉谷液中’然後以E t 〇 A c卒取。將有機層以水、飽和鹽水 洗蘇，於，·無水Na2S04上乾燥，然後於真空中濃縮。使殘留 物於石夕膠上利用CHC13-MeOH(9:l)進行層析，並自己烷 -Et0Ac再結晶而得n-Boc-5-(R)-苯基-（S) -脯胺酸（81 0毫 克 ’49%)之無色固體。熔點us -117。(：； UMR (CDC13)N-\ Boc C〇2H a narrow ester of 5-phenyl-5-nonorphyrin-2-(S)-carboxylate (I 59 g, 5.9 mmol) and Pd/C (10%, 128) The mixture was stirred in MeOH (30 mL) EtOAc. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in CH3CN-H2 (3:2, 25 mL), then di-tert-butyl dicarbonate (1·86 6 g, 8.54 mmol) and 1, 〇, 〇11 (8.54 ml, 8.54 mmol), and the resulting mixture was mixed for 30 minutes. The mixture was concentrated in vacuo and poured into Na η c % water > sap liquid ' then E 〇 A c. The organic layer was washed with water, saturated brine, dried over anhydrous Na2SO4, and then concentrated in vacuo. The residue was purified by chromatography using CHC13-MeOH (9:1). And recrystallized from hexane-Et0Ac to give n-Boc-5-(R)-phenyl-(S)-proline (81 0 mg '49%) as a colorless solid. melting point us - 117. (:; UMR (CDC13)

89112968.ptd 第514頁 1283240 五、發明說明（510) (5 1.13 (s, 9H)、1·43 (brs，1H)、1·96 (brs，1H)、 2.09 (brs，1H)、2·3 卜 2·34 (m，1H)、2·46 (brs， 1H)、4·52 (brs，1H)、4·69 (brs，1H)、7·22 -7.37 (m 5H)。 N-Boc-2-(S)-經甲基-5-(R) -苯基口比洛唆89112968.ptd Page 514 1283240 V. INSTRUCTIONS (510) (5 1.13 (s, 9H), 1.43 (brs, 1H), 1.96 (brs, 1H), 2.09 (brs, 1H), 2· 3 卜2·34 (m,1H), 2·46 (brs, 1H), 4·52 (brs, 1H), 4·69 (brs, 1H), 7.22 -7.37 (m 5H). N- Boc-2-(S)-methyl-5-(R)-phenylphene

在室溫下於N-Boc-5-(R) -苯基-2-(S) -脯胺酸（1· 14克， 3· 91毫莫耳）溶於THF(20毫升）之攪拌溶液中加入ι〇Μ ΒΗ3 •^23(780毫升，7.82毫莫耳），並使所產生之混合物迴 流加熱30分鐘。將混合物倒入至1N HC1水溶液中，並以 EtOAc萃取。將有機層於無水NajO〗上乾燥，然後於真空中 濃縮。使殘留物於矽膠上利用CiiCl3-MeOH (1 0 : 1 )作為洗 提液進行層析，而得N-Boc-2-(S)-羥曱基-5-(R)-苯基。比 嘻唆（1· 11克，定量）之無色油：iH —NMR (CDCl3) 5 1· 19 (brs，9H)、1·65 (brs，1H)、1·83 -1.90 (m，1H)、 1·98 - 2·06 (m，1H)、2·22 - 2.31 (m，1H)、3·75 - 3·86 (m，2Η)、4·16-4·19 (m, 1Η)、4·83 (t，J = 6.8 Ηζ， 1H)、4·89 (brs，1H)、7·19-7.3 (m，5H); MS(ESI) m/z， 278 (M+ + H) 〇 4-[N-Boc-5-(R) -苯基-2-(S) -咄咯啶甲氧基]苯曱酸甲酯Stirring solution of N-Boc-5-(R)-phenyl-2-(S)-proline (1·14 g, 3.9 mmol) dissolved in THF (20 mL) at room temperature Add ι〇Μ ΒΗ3 •^23 (780 ml, 7.82 mmol) and heat the resulting mixture under reflux for 30 minutes. The mixture was poured into 1N aqueous HCl solution and extracted with EtOAc. The organic layer was dried over anhydrous NajO and concentrated in vacuo. The residue was chromatographed on silica gel using CiiCl3-MeOH (1O:1) to afford N-Boc-2-(S)-hydroxyindole-5-(R)-phenyl. Colorless oil (1·11 g, quantitative): iH-NMR (CDCl3) 5 1· 19 (brs, 9H), 1·65 (brs, 1H), 1·83 -1.90 (m, 1H) , 1·98 - 2·06 (m, 1H), 2·22 - 2.31 (m, 1H), 3·75 - 3·86 (m, 2Η), 4·16-4·19 (m, 1Η) , 4·83 (t, J = 6.8 Ηζ, 1H), 4·89 (brs, 1H), 7·19-7.3 (m, 5H); MS (ESI) m/z, 278 (M+ + H) 〇 4-[N-Boc-5-(R)-phenyl-2-(S)-indolyl methoxy]benzoic acid methyl ester

\\312\2d-code\90-01\89112968.ptd 第515頁 1283240 五、發明說明（511)\\312\2d-code\90-01\89112968.ptd Page 515 1283240 V. Description of invention (511)

在室溫下於N-Boc-2 -（S) -羥曱基-5-(R) -苯基η比咯咬（ 1·1〇克，3·97毫莫耳）、三苯膦（1.25克，4·76毫莫耳）及 4-羥基苯甲酸甲酯（724毫克，4.76毫莫耳）之攪拌溶液中 加入偶氮二羧酸二異丙酯（955毫升，4·76毫莫耳），並使 所產生之混合物在60 °C下攪拌45分鐘。將混合物於真空中 濃縮，並使殘留物於矽膠上利用己烷-EtOAc(4 : 1 )作為洗 提液進行層析，而得4-[N_Boc-5-(R) -苯基-2-(S) - σ比π各0定 甲氧基]苯甲酸曱酯（1.31克，80 % )之無色油。UMR (CDC13) 6 1· 19 及1· 47 (brs，總計9H)、2· 09-2· 15 (m， 3H)、2·33-2.37 (m，1H)、3·94 (s，3H)、4·30 (brs， 1H)、4·41 (brs，2H)、4·77 (brs, 1H)、7·03 (d，J = 8.8 Hz，2H)、7·24-7.3 6 (m，5H)、8.03-8.0 6 (m，2H) ;MS(ESI) m/z，412(MHH)。 4-[5-（R) -苯基-2-(S) -吡咯啶甲氧基]笨甲酸曱酯At room temperature in N-Boc-2 -(S)-hydroxyindenyl-5-(R)-phenyl η ratio (1·1 gram, 3.97 mmol), triphenylphosphine ( Add isopropyl diazodicarboxylate (955 ml, 4·76 mmol) to a stirred solution of 1.25 g, 4·76 mmol, and methyl 4-hydroxybenzoate (724 mg, 4.76 mmol). The ear was stirred and the resulting mixture was stirred at 60 ° C for 45 minutes. The mixture was concentrated in vacuo and the residue was crystallised eluted elut elut elut (S) - Colorless oil of 曱 定 0 each of 0 methoxy]benzoic acid benzoate (1.31 g, 80%). UMR (CDC13) 6 1· 19 and 1· 47 (brs, total 9H), 2· 09-2· 15 (m, 3H), 2·33-2.37 (m, 1H), 3·94 (s, 3H ), 4·30 (brs, 1H), 4·41 (brs, 2H), 4·77 (brs, 1H), 7·03 (d, J = 8.8 Hz, 2H), 7·24-7.3 6 ( m, 5H), 8.03-8.0 6 (m, 2H); MS (ESI) m/z, 412 (MHH). 4-[5-(R)-Phenyl-2-(S)-pyrrolidinemethoxy]-p-carboxylate

在室溫下於4-[N - Boc - 5 -（R)~苯基-2-(S) - σ比17各咬曱氧 基]苯甲酸甲酯（1. 28克，3. 11毫莫耳）溶於CH2Cl2 (3〇毫 升）之授拌溶液中加入三氟乙酸（10毫升），並使所產生之 混合物祝掉4 5分鐘。將混合物於真空中濃縮，並倒入至 N a H C 〇3水溶液中，然後以C H C13萃取。將有機層以水洗條， 於無水NaJO4上乾燥，並於真空中濃縮而得4 - [ 5 - (R)-苯基 -2-（S) -咄咯啶甲氧基]苯曱酸甲酯（ 363毫克，定量）之淡4-[N - Boc - 5 -(R)~phenyl-2-(S) - σ ratio 17 octadecyloxy] benzoic acid methyl ester at room temperature (1. 28 g, 3. 11 m Trifluoroacetic acid (10 ml) was added to a stirred solution of CH.sub.2Cl.sub.2 (3 mL). The mixture was concentrated in vacuo and poured into aqueous EtOAc (EtOAc). The organic layer was washed with water, dried over anhydrous Na.sub.4, and concentrated in vacuo to give &lt;RTI ID=0.0&gt; (363 mg, quantitative)

\\312\2d-code\90-01\89112968.ptd 第 516 頁 1283240 五、發明說明（512) 黃色油。將產物不經進一步的純化而使用於後續的反應。 1-NMR (CDC13) 6 1· 7卜1. 83 (m，2H)、2· 03-2· 10 (m， 1H) ^2.15-2.24 (m, 1H) &gt; 3.68 -3.74 (m, 1H) &gt;3.89 (s，3H)、4·01-4·09 (m，2H)、4·28 (t, J = 7.2 Hz，1H) 、6·95 (d，J = 8.8 Hz，2H)、7·22-7·27 (m，1H)、7·33 (t，J = 8.0 Hz，2H)、7·42 (d，J:7.6 Hz，2H)、8·00 (d，J:8.8 Hz，2H); MS(ESI) m/z，312(MHH)、353 (M+ + CH3CN)。 4 - U - [4-[Ν’ -（2 -甲基苯基）脲基]- 3 -甲氧苯基乙醯基]-5 -（R)-苯基- 2 -（S) -吡咯啶甲氧基]苯甲酸甲酯\\312\2d-code\90-01\89112968.ptd Page 516 1283240 V. INSTRUCTIONS (512) Yellow oil. The product was used in the subsequent reaction without further purification. 1-NMR (CDC13) 6 1· 7 Bu 1. 83 (m, 2H), 2· 03-2· 10 (m, 1H) ^ 2.15-2.24 (m, 1H) &gt; 3.68 -3.74 (m, 1H &gt;3.89 (s,3H), 4·01-4·09 (m,2H), 4·28 (t, J = 7.2 Hz, 1H), 6.95 (d, J = 8.8 Hz, 2H) , 7·22-7·27 (m, 1H), 7·33 (t, J = 8.0 Hz, 2H), 7.42 (d, J: 7.6 Hz, 2H), 8·00 (d, J: 8.8 Hz, 2H); MS (ESI) m/z, 312 (MHH), 353 (M+ + CH3CN). 4-U-[4-[Ν'-(2-methylphenyl)ureido]-3-methoxyphenylethenyl]-5-(R)-phenyl-2-(S)-pyrrole Methyl pyridine methoxy]benzoate

在室溫下於4 - [5-(R) -笨基-2 -（S) -咄咯啶甲氧基]苯曱 酸甲醋（135毫克，〇·43毫莫耳）、4-[N，-（2-甲基笨基）脲 基]-3-甲氧苯乙酸（136毫克，〇·43毫莫耳）及N，N-二曱胺 基吼咬（52· 9毫克，〇· 43毫莫耳）溶於DmF(10毫升）之攪拌 溶液中加入EDC ·ΗΠ(90·8毫克，〇·48毫莫耳），並使所 產生之混合物攪拌隔夜。將反應混合物倒入至水中，並以 HftOAc萃取。將有機層以鹽水洗滌，於無水~^3〇4上乾 燥，然後於真空中濃縮。使殘留物於矽膠上利用己烷 - EtOAc(l:5)作為洗提液進行層析，而得4—[丨-h-D， 一 甲基苯基）脲基]—3一甲氧笨基乙醯基]-5-(R) -苯基-2-（S)4-[5-(R)-styl-2-(S)-indolyl methoxy]benzoic acid methyl vinegar (135 mg, 〇·43 mmol), 4-[ at room temperature N,-(2-methylphenyl)ureido]-3-methoxyphenylacetic acid (136 mg, 〇·43 mmol) and N,N-diamine-based bite (52·9 mg, 〇 · 43 mmoles of a solution of DmF (10 ml) was added EDC·ΗΠ (90·8 mg, 〇·48 mmol), and the resulting mixture was stirred overnight. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous~~~~~~~~~~~~~ The residue was chromatographed on ruthenium using hexane-EtOAc (1:5) as eluent to give 4-[丨-hD, monomethylphenyl)ureido]-3 methoxyphenyl Mercapto]-5-(R)-phenyl-2-(S)

1283240 五、發明說明（513) -咄咯啶甲氧基]苯甲酸甲酯（2 7 1毫克，定量）的無色非晶 形固體。1H-NMR (CDC13) 6 2. 00-2· 18 (m，3H)、2· 31-2· 41 (m， 1H) 、2·27 (s， 3H) 、3·31 (s， 2H) 、3·67 (s， 3Η)、3·89 (s, 3Η)、4· 35-4.48 (m，2Η)、4·60 (brs， 1Η)、4·92 (t， J = 6.8 Ηζ， 1Η)、6.51 (d，J = 8.4 Ηζ， 1Η)、6,62 (s，1Η)、6·96 (d，J = 8.8 Ηζ，1Η)、7·11 -7·40 (m 系列，8Η)、7·51 (d，J = 8.0 Hz, 1Η)、7·97 -8·00 (m，2H); MS(ESI) m/z 6 08 (ΜΗΗ)。 在室溫下於4 - [1-[4-[Ν，-（2-甲基苯基）脲基]- 3 -甲氧笨 基乙酿基]- 5 -（R)-苯基-2-(S)-u比洛σ定曱氧基]苯曱酸甲g旨 ( 243毫克，0.40毫莫耳）溶於MeOH-THF(l:l，10毫升）之攪 拌溶液中加入1· 0M NaOH(2· 4毫升，2. 40毫莫耳），並使所 產生之混合物在6 0 °C下加熱攪拌1. 5小時。將反應混合物 倒入至IN HC1中，然後以CHC13萃取。將有機層以鹽水洗 滌，並於無水Na2S04上乾燥，然後於真空中濃縮。將殘留 物於矽膠上利用CHC13-MeOH(10:l)進行層析，而得145 ( 2 24毫克，94%)的無色非晶形固體。iH-NMR (CD3OD)，消 旋異構物之混合物，（5 2.00-2.19 (m，3H)、2·28及2·30 (s，總計3Η)、2.45-2.49 (m，1Η)、3·37 (dd，J = 39、16 Hz, 2H)、3. 77 及 3. 80 (s，總計 3H)、3· 92-5. 1 8 (m 系 列，4H)、6· 48- 8. 03 (m 系、列，i 6H) ; Ms(FAB) m/z 594 (MHH)。 實施例1 3 8 4-[1 - [4-[N’ -（2 -氯笨基）脲基]一 3一曱氧苯基乙醯基]一51283240 V. INSTRUCTIONS (513) - Colorless amorphous solid of methyl hydrazide methoxy]benzoate (271 mg, quantitative). 1H-NMR (CDC13) 6 2. 00-2· 18 (m, 3H), 2· 31-2· 41 (m, 1H), 2·27 (s, 3H), 3·31 (s, 2H) , 3·67 (s, 3Η), 3·89 (s, 3Η), 4·35-4.48 (m, 2Η), 4·60 (brs, 1Η), 4.92 (t, J = 6.8 Ηζ, 1Η), 6.51 (d, J = 8.4 Ηζ, 1Η), 6,62 (s, 1Η), 6.96 (d, J = 8.8 Ηζ, 1Η), 7·11 -7·40 (m series, 8Η) ), 7·51 (d, J = 8.0 Hz, 1 Η), 7·97 -8·00 (m, 2H); MS (ESI) m/z 6 08 (ΜΗΗ). 4-[1-[4-[Ν,-(2-methylphenyl)ureido]-3-methoxyphenyl]]-5-(R)-phenyl-2 at room temperature -(S)-u piroxime 曱 曱 ] ] ] ] 243 243 (243 mg, 0.40 mmol) dissolved in MeOH-THF (l:l, 10 ml) 5小时。 NaOH (2. 4 ml, 2.40 mmol), and the mixture was heated and stirred at 60 ° C for 1.5 hours. The reaction mixture was poured into IN HC1 and then extracted with CHC13. The organic layer was washed with brine and dried over anhydrous Na. The residue was chromatographed on EtOAc (EtOAc:EtOAc) iH-NMR (CD3OD), a mixture of racemic isomers, (5 2.00-2.19 (m, 3H), 2·28 and 2·30 (s, total 3 Η), 2.45-2.49 (m, 1 Η), 3 · 37 (dd, J = 39, 16 Hz, 2H), 3.77 and 3.80 (s, total 3H), 3.92-5. 1 8 (m series, 4H), 6·48- 8. 03 (m series, column, i 6H); Ms(FAB) m/z 594 (MHH). Example 1 3 8 4-[1 - [4-[N' -(2-chlorophenyl)ureido] A 3-methoxyphenyl phenyl group]-5

\\312\2d-code\90-01\89112968.ptd 第518頁 1283240 五、發明說明（514) -(R) -苯基-2-(S) -吼咯啶曱氧基]苯甲酸\\312\2d-code\90-01\89112968.ptd Page 518 1283240 V. INSTRUCTIONS (514) -(R)-Phenyl-2-(S)-indolyloxyl]benzoic acid

4 - [1-[4 - [N -(2 -氯苯基）脲基]- 3 -甲氧苯基乙醯基]一 5-（R)-苯基-2-（S) -吼咯啶甲氧基]笨甲酸甲酉旨4-[1-[4 - [N -(2-Chlorophenyl)ureido]-3-methoxyphenylethenyl]-5-(R)-phenyl-2-(S)-fluorene Pyridylmethoxy]

在室溫下於4 - [5-(R) -苯基-2 -（S) -咄洛ϋ定甲氧基]苯甲 酸甲酉旨（142毫克，〇·46毫莫耳）、4-[Ν，-（2-氯苯基）脲 基]- 3-甲氧苯乙酸（153毫克，0.46毫莫耳）及Ν，Ν-二甲胺 基吼啶（55.7毫克，〇·46毫莫耳）溶於DMF( 1 0毫升）之糌棘 ^ ^ t .EDC - HCK95. 7 $ ^ 5〇 ^ 生之混合物攪拌隔夜。將反應混合物倒入至水中，並以 EtOAc萃取。將有機層以鹽水洗滌，於無水—^匕上乾燥， 然後於真空中濃縮。使殘留物於矽膠上利用己烷一Et〇Ac (1:5)作為洗提液進行層析，而得4 — [1 — [4—[n，—（2—氯笨 基）脲基]-3-甲氧苯基乙醯基]-5-(R) -苯基—2 —(S) -吼略唆 甲氧基]苯曱酸甲酯（ 260毫克，90%)的無色非晶形固體。 1-NMR (CDC13) 6 2· 00-2. 19 (m，3H)、2· 35-2· 44 (m， 1H)、3·35 (s，2H)、3·76 (s，3H)、3.89 (s，3H)、’ 4.38-4.48 (m，2H)、4·63 (brs，1H)、4.94 (t，J = 7 24-[5-(R)-Phenyl-2-(S)-indolyl methoxy]benzoic acid formazan (142 mg, 〇·46 mmol) at room temperature, 4- [Ν,-(2-chlorophenyl)ureido]-3-methoxyphenylacetic acid (153 mg, 0.46 mmol) and hydrazine, hydrazine-dimethylaminopyridine (55.7 mg, 〇·46 mmol) Ear) Soluble in DMF (10 ml). ^ T. EDC - HCK95. 7 $ ^ 5〇^ The mixture was stirred overnight. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous EtOAc EtOAc. The residue was chromatographed on a silica gel using hexane-Et〇Ac (1:5) as an eluent to give 4-[1 - [4-[n,-(2-chlorophenyl)ureido] Colorless amorphous form of methyl 3-methoxyphenylethylidene]-5-(R)-phenyl-2-(S)-methyl hydrazine methoxy]benzoate (260 mg, 90%) solid. 1-NMR (CDC13) 6 2· 00-2. 19 (m, 3H), 2· 35-2· 44 (m, 1H), 3·35 (s, 2H), 3·76 (s, 3H) , 3.89 (s, 3H), ' 4.38-4.48 (m, 2H), 4·63 (brs, 1H), 4.94 (t, J = 7 2

89112968.ptd 第519頁 1283240 五、發明說明（515)89112968.ptd Page 519 1283240 V. Description of invention (515)

Hz, 1H)、6.53 (d，J = 8.4 Hz，1H)、6.66 (s，1H)、 6· 9 6-7· 01 (m，3H)、7· 12-7· 42 (m 系列，8H)、7· 8 7 (d， J = 8.0 Ηζ，1Η)、7·98 (d，J = 8.8 Ηζ，2Η)、8·17_8.19 (m，1H); MS(ESI) m/z 627 (Μ+)、628 (Μ+ + Η)。 在室溫下於4- [1 - [4- [N，-（2-氣苯基）脲基]一3-甲氧苯基 乙醯基]- 5-(R) -苯基-2-(S) -咄略。定甲氧基]苯甲酸曱酯 (251毫克，0·40毫莫耳）溶於MeOH-THF(1:1，10毫升）之擾 拌溶液中加入1·0Μ NaOH(2.4毫升，2.40毫莫耳），並使所 產生之混合物在6 0 °C下加熱攪拌1 · 5小時。將反應混合物 倒入至1 N H C1中’然後以c H C13卒取。將有機層以鹽水洗 滌，並於無水NaJO4上乾燥，然後於真空中濃縮。將殘留 物於矽膠上利用CHCI3-MeOH(10:l)進行層析，而得4-[1 - [4-[Ν’- (2-氯苯基）脲基]—3-甲氧苯基乙醯基]一5_(R)-笨 基-2-(S) -吼洛啶曱氧基]苯甲酸;14 6 (1 81毫克，74%)的無 色非晶形固體。1H-NMR (CD30D)，消旋異構物之混合物， 5 1·99-2.19 (m，3H)、2·42-2·53 (πι，1H)、3·38 (dd， J = 39、15 Hz，2H)、3·79 及 3.80 (s，總計 3H)、3·94 -5· 19 (m 系列，4Η)、6· 49-8· 0 5 (m 系列，16Η) ; MS(FAB) m/z 614CMHH) ; C35H34C1N3 06 ·Η20 之分析計算值：C， 65·06;Η，5·62;Ν，6.50。實測值：c，65.03;H， 5· 75 ; N, 6·45 。 ? 實施例1 3 9 4-[卜[4-[Ν’-（2-溴苯基）脲基]一3-甲氧苯基乙醯基]一5 -（R)_苯基-2- (S) -吼洛唆曱氧基]苯甲酸Hz, 1H), 6.53 (d, J = 8.4 Hz, 1H), 6.66 (s, 1H), 6· 9 6-7· 01 (m, 3H), 7· 12-7· 42 (m series, 8H ), 7· 8 7 (d, J = 8.0 Ηζ, 1Η), 7·98 (d, J = 8.8 Ηζ, 2Η), 8·17_8.19 (m, 1H); MS(ESI) m/z 627 (Μ+), 628 (Μ+ + Η). 4-[1-[4-[N,-(2-Phenylphenyl)ureido]-3-methoxyphenylethenyl]-5-(R)-phenyl-2- at room temperature (S) - Strategy. Add methoxyl]benzoate benzoate (251 mg, 0. 40 mmol) in MeOH-THF (1:1, 10 mL) and add 1·0 NaOH (2.4 mL, 2.40 mmol). Ear) and the resulting mixture was heated and stirred at 60 ° C for 1 · 5 hours. The reaction mixture was poured into 1 N H C1 and then was taken as c H C13. The organic layer was washed with brine and dried over anhydrous Na. The residue was chromatographed on silica gel using CHCI3-MeOH (10:1) to give 4-[1 -[4-[([(chlorophenyl))]] Ethylamino]-5-(R)-p-styl-2-(S)-indolizinyloxy]benzoic acid; 14 6 (1 81 mg, 74%) as a colorless amorphous solid. 1H-NMR (CD30D), a mixture of racemic isomers, 5 1·99-2.19 (m, 3H), 2·42-2·53 (πι, 1H), 3·38 (dd, J = 39, 15 Hz, 2H), 3·79 and 3.80 (s, total 3H), 3·94 -5· 19 (m series, 4Η), 6·49-8· 0 5 (m series, 16Η); MS (FAB m/z 614CMHH) ; C35H34C1N3 06 · Η 20 Analysis calculated: C, 65·06; Η, 5.62; Ν, 6.50. Found: c, 65.03; H, 5·75; N, 6·45. Example 1 3 9 4-[Bu [4-[Ν'-(2-bromophenyl)ureido] 3-methoxyphenylethenyl]-5-(R)-phenyl-2- (S)-indolyloxy]benzoic acid

89112968.ptd 第 520 頁 1283240 五、發明說明（516)89112968.ptd Page 520 1283240 V. Description of invention (516)

147 4 2 一 [N 臭笨基〕服基]-3-甲氧苯基乙酿基]-5 — 00-本基-2-(S)-咄咯啶甲氧基]笨曱酸甲酯147 4 2 a [N odorant base] serving group]-3-methoxyphenyl ethyl aryl]-5 — 00-benyl-2-(S)-fluoreridine methoxy] methyl decanoate

在至/亚下於4-[5-(R) -苯基一 2-(s)_n比嘻。定甲氧基]苯甲 酸甲酯（146毫克，〇· 47毫莫耳）、4—[N，-(2—溴苯基）脲基] 一3-甲氧苯乙酸（178毫克，〇·47毫莫耳）及N，N一二曱胺基咄 咬（57· 4毫克，〇· 47毫莫耳）溶於DMF (10毫升）之攪拌溶液 中加入EDC ·Κ1(9 9.0毫克，0.52毫莫耳），並使所產生之 ’吧合物棍拌隔夜。將反應混合物倒入至水中，並以Ε ^ q a c 萃取。將有機層以鹽水洗滌，於無水NaJO4上乾燥，然後 於真空中濃縮。使殘留物於矽膠上利用己烷—EtOkd · 5) 作為洗提液進行層析，而得4 - [ 1 - [ 4 - [ N ’ ~ ( 2 -臭笨美）服 基]- 3-甲氧苯基乙醯基]- 5-（R) -苯基-2-(S) -吼嘻。定甲p 基]苯甲酸甲酯（ 28 8毫克，91%)的無色非晶形固體二 ^ ]H~NMR (CDC13)5 2.00-2.20 (m, 3H) ^2.34-2 43 1H)、3· 35 (s，2H)、3· 72 (s，3H)、3· 89 (s，· 3H) m’ 4· 38-4. 49 (m，2H)、4· 62 (brs，1H)、4· 94，( t 卜、In the / sub-subsequent to 4-[5-(R)-phenyl- 2-(s)_n than 嘻. Methyl methoxy]benzoate (146 mg, 〇·47 mmol), 4-[N,-(2-bromophenyl)ureido]-3-methoxyphenylacetic acid (178 mg, 〇· 47 mM) and N,N-diamine-based bite (57·4 mg, 〇·47 mmol) dissolved in DMF (10 ml) in a stirred solution of EDC·Κ1 (9 9.0 mg, 0.52) Molly), and make the resulting bar mix overnight. The reaction mixture was poured into water and extracted with Ε^q a c. The organic layer was washed with brine, dried over anhydrous Na. The residue was chromatographed on a silica gel using hexane-EtOkd · 5) as an eluent to obtain 4 - [ 1 - [ 4 - [ N ' ~ ( 2 - stupid) base] 3- 3- Oxyphenyl phenyl group] 5-(R)-phenyl-2-(S)-indole. A colorless amorphous solid of methyl benzoate (28 8 mg, 91%). 2]H~NMR (CDC13)5 2.00-2.20 (m, 3H) ^2.34-2 43 1H), 3· 35 (s, 2H), 3· 72 (s, 3H), 3· 89 (s, · 3H) m' 4· 38-4. 49 (m, 2H), 4· 62 (brs, 1H), 4 · 94,( t 卜,

Hz，1H)、6· 54 (d, J = 8· 4 Hz, 1H)、6· 67 (s，；H) V 2Hz, 1H), 6· 54 (d, J = 8· 4 Hz, 1H), 6·67 (s,; H) V 2

\\312\2d-code\90-01\89112968.ptd 1283240 五、發明說明（517) 6.91 - 7.05 (m， 4H)、7·28 — 7·42 (m 系列，7H) 、7.51 (d， J = 8.0 Hz, 2H)、7·87 (d，J = 8.4 Hz, 1H)、7·99 (d， J = 8.8 Hz, 2H) &gt;8.14 (d, J = 8. 4 Hz, 2H) ； MS(ESI) m/z 672 (M+)、674 (MH2)。 在室溫下於4 - [l-[4-[ Ν’-（2 -溴苯基）脲基]一3 一甲氧苯基 乙醯基]-5-(R) -苯基-2-（S) -咄咯啶甲氧基]苯甲酸曱酯 (270毫克，0·40毫莫耳）溶於Me〇H-THF(1 : 1，1〇毫升）之攪 拌溶液中加入1.0M NaOH(2.0毫升，2.0毫莫耳），並使所 產生之混合物在60 °C下加熱攪拌1小時。將反應混合物倒 入至IN HC1中，然後以CHC13萃取。將有機層以鹽水洗 滌，並於無水Na2S04上乾燥，然後於真空中濃縮。將殘留 物於石夕膠上利用CHC13-MeOH(10:l)進行層析，而得4 - [1 - [4-[N’ -（2-溪苯基）脲基]- 3-曱氧苯基乙酸基]-5-(R)-苯 基-2-(S)_毗咯啶曱氧基]苯甲酸147 (212毫克，80%)的無 色非晶形固體。1H-NMR (CD30D)，消旋異構物之混合物， 5 1·99-2·19 (m， 3H)、2.42-2.53 (m， 1H)、3·38 (dd， J = 39、16 Hz，2H)、3· 7 9 及3· 80 (s，總計3H)、3· 94-5· 19 (m 系列，4Η)、6· 4 9-8· 00 (m 系列，16Η) ; MS(FAB) m/z 658(M+)、6 60 (MH2)。 實施例1 4 0 4-[1-[4 - [Ν’ -（2，6-二氯苯基）脈基]- 3-曱氧苯基乙蕴基 ]-5 -（R) -苯基-2-(S) -吼洛σ定曱氧基]苯甲酸\\312\2d-code\90-01\89112968.ptd 1283240 V. Description of invention (517) 6.91 - 7.05 (m, 4H), 7·28 — 7·42 (m series, 7H), 7.51 (d, J = 8.0 Hz, 2H), 7·87 (d, J = 8.4 Hz, 1H), 7·99 (d, J = 8.8 Hz, 2H) &gt; 8.14 (d, J = 8. 4 Hz, 2H) MS (ESI) m/z 672 (M+), 674 (MH2). 4-[l-[4-[ Ν'-(2-bromophenyl)ureido]- 3-methoxyphenylethenyl]-5-(R)-phenyl-2- at room temperature (S) - Ethrolidine methoxy] benzoic acid oxime ester (270 mg, 0. 40 mmol) dissolved in Me〇H-THF (1:1, 1 mL) in a stirred solution of 1.0 M NaOH (2.0 ml, 2.0 mmol), and the resulting mixture was heated and stirred at 60 ° C for 1 hour. The reaction mixture was poured into IN HC1 and then extracted with CHC13. The organic layer was washed with brine and dried over anhydrous Na. The residue was chromatographed on CH.sub.3-MeOH (10:1) to give 4-[1-[4-[N'-(2-xylphenyl)ureido]-3-oxo Phenylacetate]-5-(R)-phenyl-2-(S)-pyrrolidinyloxy]benzoic acid 147 (212 mg, 80%) as a colorless amorphous solid. 1H-NMR (CD30D), a mixture of racemic isomers, 5 1·99-2·19 (m, 3H), 2.42-2.53 (m, 1H), 3·38 (dd, J = 39, 16 Hz , 2H), 3· 7 9 and 3· 80 (s, total 3H), 3· 94-5· 19 (m series, 4Η), 6· 4 9-8· 00 (m series, 16Η); MS ( FAB) m/z 658 (M+), 6 60 (MH2). Example 1 4 0 4-[1-[4 - [Ν' -(2,6-Dichlorophenyl))] 3-indolyloxyphenyl]]-5-(R)-phenyl -2-(S)-吼洛σ 曱 曱oxy]benzoic acid

\\312\2d-code\90-01\89112968.ptd 第522頁 1283240 五、發明說明（518) 4-[1-[4-[1^’-（2,6-二氣苯基）脲基]-3-甲氧苯基乙醯基 ]-5-（R)-苯基-2-（S) -吼咯啶甲氧基]笨曱酸甲酉旨\\312\2d-code\90-01\89112968.ptd Page 522 1283240 V. INSTRUCTIONS (518) 4-[1-[4-[1^'-(2,6-Diphenyl)urea 3-methoxy-3-ethenyl]-5-(R)-phenyl-2-(S)-indolyl methoxy] 曱 曱 酉

在至溫下於4 - [5 -（R) -笨基-2 -（S)-ntb 口各。定甲氧基]苯甲 酸甲酯（109毫克，0· 35毫莫耳）、4-[N，-（2, 4-二氯苯基） 脲基]-3-甲氧苯乙酸（129毫克，〇·35毫莫耳）及N，N-二甲 胺基咄啶（42·8毫克，0·35毫莫耳）溶於dmf(1 〇毫升）之攪 拌溶液中加入EDC · HC1(73· 4毫克，〇· 39毫莫耳），並使所 產生之混合物攪拌6小時。將反應混合物倒入至水中，並 ^EtOAc萃取。將有機層以鹽水洗滌，於無水12§〇4上乾 燥，然後於真空中濃縮。使殘留物於石夕膠上利用己烷 - EtOAc(l:4)作為洗提液進行層析，而得4—[卜[4—[N,—(2, 6-二氯苯基）脲基]一3-甲氧苯基乙醯基]一5 — (R) -苯基一2一（’ s)-咄咯啶曱氧基]苯曱酸曱酯（2〇8毫克，9〇%)的無色非 形固體。4-關1?(〇0(：13)(^2.〇〇〜2.21(111，31〇、2.33-2· 39 (m，1H)、3·31 (s，2H)、3·69 (s，3H)、3·88 (s， 3Η)、4·34-4·45 (m，2Η)、4.59 (brS，1Η)、4·93 (t， J = 6.8 Ηζ，1Η)、6·47 (d，J = 8 〇 Ηζ，1Η)、6·63 &amp; 1Η)、6·68 (s，1Η)、6·92-6·95 (m，2Η)、7·12-7·41 (mAt the temperature to 4 - [5 - (R) - stupid - 2 - (S) - ntb each. Methyl methoxy]benzoate (109 mg, 0·35 mmol), 4-[N,-(2,4-dichlorophenyl)ureido]-3-methoxyphenylacetic acid (129 mg , 〇·35 mmol) and N,N-dimethylamino acridine (42·8 mg, 0·35 mmol) dissolved in dmf (1 mL) in a stirred solution of EDC · HC1 (73 · 4 mg, 〇·39 mmoles, and the resulting mixture was stirred for 6 hours. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous w. The residue was chromatographed on celite using hexane-EtOAc (1:4) as an eluent to give 4-[[4-[2,6-dichlorophenyl]urea 3-]3-methoxyphenylethenyl]-5-(R)-phenyl-2-iso('s)-indolyloxyl] benzoic acid decyl ester (2〇8 mg, 9〇) %) a colorless, non-form solid. 4-OFF 1?(〇0(:13)(^2.〇〇~2.21(111,31〇, 2.33-2·39 (m,1H), 3·31 (s,2H), 3·69 ( s, 3H), 3·88 (s, 3Η), 4·34-4·45 (m, 2Η), 4.59 (brS, 1Η), 4.93 (t, J = 6.8 Ηζ, 1Η), 6· 47 (d, J = 8 〇Ηζ, 1Η), 6·63 &amp; 1Η), 6.68 (s, 1Η), 6.92-6·95 (m, 2Η), 7·12-7·41 (m

!283240 五、發明說明（519) 系列，9H)、7· 96-8· 01 (m，4H) ; MS(FAB) m/z 66 2 (MUh)。 室溫下於4 - [1-[4-[Ν’-（2, 6-二氯苯基）脲基]-3-甲 氧笨基乙醯基]-5-(R)-笨基一 2-(S)-^b咯啶甲氧基]苯甲酸 甲酉旨（186毫克，0·28毫莫耳）溶於Me〇H - THF(1:1，10毫升） 之授拌溶液中加入1.0M NaOH(1.4毫升，1.4毫莫耳），並 使所產生之混合物在60 °C下加熱攪拌2. 5小時。將反應混 合物倒入至1 N HC1中，然後以CHC13萃取。將有機層以鹽 水洗滌，並於無水Na2S04上乾燥，然後於真空中濃縮。將 殘留物於矽膠上利用CHC13-MeOH(10:l)進行層析，而得 4—[1-[4_[1^’-（2,6-二氯苯基）脲基]一3-甲氧苯基乙醯 基]-5-(R)-苯基-2 -（S) -咄咯啶甲氧基]苯甲酸148(166毫 克，91%)的無色非晶形固體。iH-NMR (CD30D) d 2. 00-2·18 (m，3H)、2.34-2.40 (m，1H)、3·33 (s，2H)、 3.68 (s， 3Η) 、4·37-4.47 (m， 2Η) 、4.61 (brs， 1Η)、 4.94 (t，J = 6.8 Hz，1H)、6·48 (d，J = 8.0 Hz, 1H)、6· 63 (s，1H)、6·96 (d，J = 8.4 Hz，3H)、7.12-7.38 (m 系 列，9H) 、7·95 (d， J=8.0 Hz， 1H) 、8·01 (d， J=8.8 Hz，2H) ; MS(FAB) m/z 648 (MHH)。 實施例1 4 1 4 - [1 - [4-[N’ -（2-漠苯基）脲基]- 3-甲基苯基乙醮基]- δα)- 苯基-2-(S)-吼 咯啶甲 氧基] 苯甲酸 co2h 149!283240 V. Inventions (519) Series, 9H), 7·96-8· 01 (m, 4H); MS (FAB) m/z 66 2 (MUh). 4-[1-[4-[Ν'-(2,6-Dichlorophenyl)ureido]-3-methoxyphenylethyl]-5-(R)- stupyl one at room temperature 2-(S)-^b-bromopyridinemethoxy]benzoic acid formazan (186 mg, 0·28 mmol) dissolved in Me〇H-THF (1:1, 10 mL) in a mixing solution 5小时。 The mixture was heated and stirred at 60 ° C for 2.5 hours. The reaction mixture was poured into 1 N HCl and then extracted with CH. The organic layer was washed with brine and dried over anhydrous Na. The residue was chromatographed on silica gel using CHC13-MeOH (10:1) to give 4-[1-[4_[1^'-(2,6-dichlorophenyl)ureido]3-3- Oxyphenyl phenyl hydrazino]-5-(R)-phenyl-2 -(S)-decalyl methoxy]benzoic acid 148 (166 mg, 91%) as a colorless amorphous solid. iH-NMR (CD30D) d 2. 00-2·18 (m, 3H), 2.34-2.40 (m, 1H), 3·33 (s, 2H), 3.68 (s, 3Η), 4·37-4.47 (m, 2Η), 4.61 (brs, 1Η), 4.94 (t, J = 6.8 Hz, 1H), 6·48 (d, J = 8.0 Hz, 1H), 6· 63 (s, 1H), 6· 96 (d, J = 8.4 Hz, 3H), 7.12-7.38 (m series, 9H), 7.95 (d, J=8.0 Hz, 1H), 8·01 (d, J=8.8 Hz, 2H); MS (FAB) m/z 648 (MHH). Example 1 4 1 4 - [1 - [4-[N' -(2-Molyphenyl)ureido]-3-methylphenylethenyl]- δα)-phenyl-2-(S) - 吼 啶 甲 methoxy] benzoic acid co2h 149

\\312\2d-code\90-01\89112968.ptd 第524頁 1283240\\312\2d-code\90-01\89112968.ptd Page 524 1283240

在至/皿下於4-[5-(R) -苯基-2- (S) -咄略咬甲氧其1策甲 酸甲酷=5毫克，0」0毫莫耳）、4—[N，—（2—漠笨脲基] -3-甲基苯乙酸（146耄克，〇· 40毫莫耳）及N，N一二甲胺基呲 啶（49· 0毫克，0· 40毫莫耳）溶於DMF(1〇毫升）之攪拌溶&quot;液 中加入EDC · HC1(84· 1毫克，〇· 44毫莫耳），並使所產生之 混合物攪拌6小時。將反應混合物倒入至水中，並以Et〇Ac 萃取。將有機層以鹽水洗滌，於無水Na2S〇4上乾燥，然後 於真空中濃縮。使殘留物於矽膠上利用己烷一Et〇Ac(1 ·· 4) 作為洗提液進行層析，而得4-[1-[4-[N，-(2-漠苯基）脲 基]- 3-甲基苯基乙醯基]—5-(R)-笨基-2-(S) -吼咯啶曱氧 基]苯甲酸曱酯（2 3 8毫克，9 0 %)的無色非晶形固體。 4-NMR (CDC13) 6 1.92 (s，3H)、2·09-2·27 (m，3H)、 2·42-2·50 (m，1H)、3·22-3.41 (m，2H)、3.88 (s， 3H)、4·39 (d，J = 4.4 Hz，1H)、4.64 (brs，1H)、5.00 (t，J = 6.8 Hz，1H)、6·72 (s，1H)、6·8卜 6.93 (m 系列， 8H)、7.22 - 7·42 (m 系列，6H)、8·01 (d，J = 8.4 Hz，2H) '8.13 (d, J = 8.0 Hz, ih)； MS(FAB) m/z 656(M+) &gt; 1 1 圓 IRI 1 \\312\2d-code\90-01\89112968.ptd 第525頁 1283240 五、發明說明（521) 6 58 (MH2)。 在室溫下於4-[1-[4-[N，-(2-溴苯基）脲基]-3-甲基苯基 乙醢基]- 5-(R) -苯基-2 -（S) -吼咯啶甲氧基]苯甲酸甲酯 (216毫克，〇·33毫莫耳）溶於Me〇H-THF(1 : 1，10毫升）之攪 拌溶液中加入1. 0M NaOH(l· 7毫升，1.7毫莫耳），並使所 產生之混合物在6 0 °C下加熱攪拌2 · 5小時。將反應混合物 倒入至IN HC1中，然後以CHC13萃取。將有機層以鹽水洗 滌’並於無水Na2S04上乾燥，然後於真空中濃縮。將殘留 物於矽膠上利用CHC13-MeOH(10:l)進行層析，而得149 (166毫克，91%)的無色非晶形固體。ιΗ一NMR (CDCl3) 5 2.01 (s, 3H) ^ 2.0 5-2.25 (m, 3H) ^2.43-2.48 (m, 1H)、3·34 (dd，J = 45、16 Hz, 2H)、4·38-4·45 (m， 2H) 、4·66 (brs, 1H) 、4·99 (t， J=6.8 Hz, 1H) 、6·77 (s，1H)、6·82-6·88 (m，2H)、6·94 (d, J = 8.8 Hz, 2H)、7.15 - 7.55 (m 系列，i〇H)、8·00 (d， J = 88 Hz, 2H)、8·14 (d，J = 7.2 Hz，1H); MS(FAB) m/z 642 (M+)、 644(MH2)。 實施例142 4- Π-[4-[Ν’ - (2 -曱基苯基）脲基]一3 —甲氧苯基乙醯基]一5 -（R) -甲基-2-(S) -吼咯啶甲氧基；|苯曱酸In the / / dish under 4-[5-(R)-phenyl-2-(S)-咄 slightly bite methoxy 1 carboxylic acid methyl = 5 mg, 0" 0 millimoles), 4 - [ N,—(2—indifferent ureido]-3-methylphenylacetic acid (146 g, 〇·40 mmol) and N,N-dimethylaminopyridinium (49·0 mg, 0·40) Methanol) EDC · HC1 (84·1 mg, 〇·44 mmol) was added to a stirred solution of DMF (1 mL), and the resulting mixture was stirred for 6 hours. Pour into water and extract with Et 〇Ac. The organic layer was washed with brine, dried over anhydrous Na 2 EtOAc 4 and then evaporated. 4) Chromatography as an eluent to give 4-[1-[4-[N,-(2-oxaphenyl)ureido]-3-methylphenylethenyl]-5-(R )-Phenyl-2-(S)-decalidinoxy]benzoic acid oxime ester (2 3 8 mg, 90%) as a colorless amorphous solid. 4-NMR (CDC13) 6 1.92 (s, 3H ), 2·09-2·27 (m, 3H), 2·42-2·50 (m, 1H), 3·22-3.41 (m, 2H), 3.88 (s, 3H), 4·39 ( d, J = 4.4 Hz, 1H), 4.64 (brs, 1H), 5.00 (t, J = 6.8 Hz, 1H), 6·72 (s, 1H), 6·8 b 6.93 (m series, 8H), 7.22 - 7·42 (m series, 6H), 8·01 (d, J = 8.4 Hz, 2H ) '8.13 (d, J = 8.0 Hz, ih); MS(FAB) m/z 656(M+) &gt; 1 1 Circle IRI 1 \\312\2d-code\90-01\89112968.ptd Page 525 1283240 V. INSTRUCTIONS (521) 6 58 (MH2). 4-[1-[4-[N,-(2-Bromophenyl)ureido]-3-methylphenylacetamidine at room temperature Methyl]- 5-(R)-phenyl-2-(S)-indolyl methoxy]benzoate (216 mg, 〇·33 mmol) was dissolved in Me〇H-THF (1: 1.0 M NaOH (1.7 ml, 1.7 mmol) was added to the stirred solution, and the resulting mixture was heated and stirred at 60 ° C for 2 · 5 hours. The reaction mixture was poured. The mixture was extracted with CHC13. The organic layer was washed with brine and dried over anhydrous Na.sub.2SO.sub.sub.sub.sub. 149 (166 mg, 91%) of a colorless amorphous solid. Η Η NMR (CDCl3) 5 2.01 (s, 3H) ^ 2.0 5-2.25 (m, 3H) ^2.43-2.48 (m, 1H), 3·34 (dd, J = 45, 16 Hz, 2H), 4 ·38-4·45 (m, 2H), 4·66 (brs, 1H), 4·99 (t, J=6.8 Hz, 1H), 6.77 (s, 1H), 6·82-6· 88 (m, 2H), 6.94 (d, J = 8.8 Hz, 2H), 7.15 - 7.55 (m series, i〇H), 8·00 (d, J = 88 Hz, 2H), 8.14 (d, J = 7.2 Hz, 1H); MS (FAB) m/z 642 (M+), 644 (MH2). Example 142 4-Π-[4-[Ν' - (2-Mercaptophenyl)ureido]-3-methoxyphenylethenyl]-5-(R)-methyl-2-(S ) - 吼 啶 甲 methoxy; | benzoic acid

\\312\2d-code\90-01\89112968.ptd 第526頁 1283240 五、發明說明（522) ^Aoc c〇2Bn 在-7 8 °C下於N-Boc-咄咯戊二酸苄酯（7· 55克，23· 6毫莫 耳）溶於THF( 1 00毫升）之攪拌溶液中加入MeU ( i . 1Μ溶於 Ete，28· 4毫升，32. 4毫莫耳），並使所產生之混合物逐 漸升溫至室溫，然後攪拌隔夜。將nh4C1水溶液加至反應 混合物’將THF於真空中移除，然後Ac萃取。將有機 層以水洗滌，並於無水Na2S04上乾燥，然後於真空中濃 縮。使殘留物於矽膠上利用己烷一Et0Ac(3: 1)作為洗提液 進行層析’而得[2-(S)-(N-Boc-胺基）-5 - 3同基-6-甲基]戊 酸苄酯（5. 02克，45%)的無色針狀物。熔點85-8 7。〇 ; 1 Η-NMR (CDC13) 5 1· 43 (s，9H)、1· 6卜2· 15 (m 系列， 3H)、2·09 (s，3H)、2·4 卜 2.55 (m，2H)、4·3〇 (brs, 1Η)、4·70 (d，J = 5.6 Ηζ，1Η)、5·12-5·21 (m，2Η)、 7.29-7.37 (m，5H); MS(ESI) m/z 336 (MHH)。 N-Boc-5-(R)-甲基-(S)_ 脯胺酸\\312\2d-code\90-01\89112968.ptd Page 526 1283240 V. INSTRUCTIONS (522) ^Aoc c〇2Bn at -7 8 °C in N-Boc-P-glutaric acid benzyl ester (7·55 g, 23.6 mmol), a solution of THF (100 ml) was added to a stirred solution of MeU (i.1 Μ dissolved in Ete, 28. 4 ml, 32. 4 mmol) and The resulting mixture was gradually warmed to room temperature and then stirred overnight. An aqueous solution of nh4C1 was added to the reaction mixture. THF was removed in vacuo and then extracted with Ac. The organic layer was washed with water and dried over anhydrous Na.sub.2SO.sub.4 and then concentrated in vacuo. The residue was chromatographed on ruthenium using hexane-Et0Ac (3:1) as the eluent to give [2-(S)-(N-Boc-amino)-5-3-iso--6- Benzyl methyl valerate (5.02 g, 45%) as a colorless needle. Melting point 85-8 7. 〇; 1 Η-NMR (CDC13) 5 1· 43 (s, 9H), 1·6 Bu 2· 15 (m series, 3H), 2·09 (s, 3H), 2·4 卜 2.55 (m, 2H), 4·3〇(brs, 1Η), 4·70 (d, J = 5.6 Ηζ, 1Η), 5·12-5·21 (m, 2Η), 7.29-7.37 (m, 5H); MS (ESI) m/z 336 (MHH). N-Boc-5-(R)-methyl-(S)_proline

在室溫下於[2-(S) -（N-Bo c -胺基）-5 -酮基-6-甲基]戊酸 苄酯（4· 46克，13· 3毫莫耳）溶於CH2C12(50毫升）之攪拌溶 液中加入三氟乙酸（2 〇毫升），並使所產生之混合物攪拌1 5小時。將混合物於真空中濃縮’並溶解於甲笨中，然後Benzyl [2-(S) -(N-Bo c -amino)-5-keto-6-methyl]pentanoate (4·46 g, 13·3 mmol) dissolved at room temperature Trifluoroacetic acid (2 ml) was added to a stirred solution of CH2C12 (50 mL), and the mixture was stirred for 15 hr. The mixture was concentrated in vacuo and dissolved in a stupid, then

1283240 五、發明說明（523) 蒸發而得5-甲基-5-咄咯啉-2-(S) -羧酸辛酯三氟乙酸鹽 (5 · 7 4克，定量）之粗製棕色油。將此化合物（1 · 9 7克， 5· 94毫莫耳）溶於MeOH(30毫升）加入Pd/C(l〇%，153毫 克），並使所產生之混合物在H2環境中攪拌3天。將混合物 過濾，及將濾液於真空中濃縮而得5-甲基-5-咄洛啶 -2-(S) -叛酸三敦乙酸鹽（956毫克，66%)之粗製白色固 體。在室溫下於此化合物（939毫克，3.86毫莫耳）及二碳 酸二-第三丁酯溶於MeCN-水（15: 1，16毫升）之溶液中加入 1.0M Na0H(8.49毫莫耳，8·49毫升），並使所產生之混合 物擾拌1小時。將所產生之混合物蒸發，並倒入至1 Η H C1 水溶液中，然後以CHCl3/MeOH(5 : 1)萃取。將有機層於無 水NaJO4上乾燥’然後於真空中濃縮。使殘留物於石夕膠上 利用CHC13 - Me0H(7:l)進行層析，而得N-Boc-5-(R)-甲基 -（S) -脯胺酸（711 毫克，80%)之無色油。ih-NMR (CD30D) 5 1.27 (d，J = 6.0 Hz, 3H)、1·41-1·46 (m，9H)、1.62-1· 64 (m，1H)、1·96-2·01 (m，2H)、2·22 (brs，1H)、 3.9 4 (brs, 1H) ^4.17 (brs, 1H) ； MS(ESI) m/z 230 (MHH)。 N-Boc-2-（S)-羥甲基-5-（R) -甲基吡a各ϋ定 在室溫下於N-Boc-5-（R)-甲基-2-（S) -脯胺酸（ι· 〇3克， 4.49¾莫耳）&gt;谷於THF(20ct:升）之攪拌溶液中加入ΒΗ3 •Me2S(1.57cfe升，15.7¾莫耳），並使所產生之混合物迴1283240 V. INSTRUCTION DESCRIPTION (523) A crude brown oil of 5-methyl-5-nonorphyrin-2-(S)-carboxylic acid octyl ester trifluoroacetate (5 · 7.4 g, quantitative) was obtained. This compound (1·97 g, 5.94 mmol) was dissolved in MeOH (30 mL). Pd/C (1%, 153 mg), and the mixture was stirred for 3 days in H2. . The mixture was filtered, and the filtrate was evaporatedjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Add 1.0 M NaHH (8.49 mmol) to a solution of this compound (939 mg, 3.86 mmol) and di-tert-butyl dicarbonate in MeCN-water (15:1, 16 mL) at room temperature. , 8.49 ml), and the resulting mixture was spoiled for 1 hour. The resulting mixture was evaporated and poured into a 1 H aqueous solution of HCI, and then extracted with CHCl3 / MeOH (5:1). The organic layer was dried over anhydrous NaJO4 and then concentrated in vacuo. The residue was chromatographed on CH.sub.3-Me.sub.0 (7:1) to give N-Boc-5-(R)-methyl-(S)-proline (711 mg, 80%) Colorless oil. Ih-NMR (CD30D) 5 1.27 (d, J = 6.0 Hz, 3H), 1·41-1·46 (m, 9H), 1.62-1· 64 (m, 1H), 1.96-2·01 (m, 2H), 2·22 (brs, 1H), 3.9 4 (brs, 1H) ^ 4.17 (brs, 1H); MS (ESI) m/z 230 (MHH). N-Boc-2-(S)-hydroxymethyl-5-(R)-methylpyridine was determined at room temperature in N-Boc-5-(R)-methyl-2-(S) -Proline (Ig 3 g, 4.493⁄4 mol) &gt; Add ΒΗ3 • Me2S (1.57 cfe liter, 15.73⁄4 mol) to a stirred solution of THF (20 ct: liter), and produce Mixture back

89112968.ptd 第 528 頁 1283240 五、發明說明（524) 流加熱5小時。將混合物倒入至1N jjCl水溶液中，並以 EtOAc萃取。將有機層於無水Na2S〇4上乾燥，然後於真空中 濃縮。使殘留物於矽膠上利用己烷—Et〇Ac (1 : 3)作為洗提 液進行層析，而得N-Boc-2一（S)-羥甲基-5-(R)-甲基u比咯 淀（ 838 毫克，87%)之無色油：iH_NMR (CDCl3) 5 κ 17 (d， J = 6.0 Hz，3H)、1·48 (s，9H)、1·48-1·64 (m，2H)、1· 90-2.11 (m， 2H) 、3·52-3.57 (m， 1H) 、3·68-3.70 (m， 1H)、3· 94-4· 13 (m，1H)。 4-[N-Boc-5--甲基-2-（s) -咄咯啶甲氧基]苯曱酸甲酯 一89112968.ptd Page 528 1283240 V. INSTRUCTIONS (524) Flow heating for 5 hours. The mixture was poured into 1N aqueous solution of EtOAc and EtOAc. The organic layer was dried over anhydrous Na.sub.2.sub.4 and then concentrated in vacuo. The residue was chromatographed on ruthenium using hexane-Et〇Ac (1:3) as an eluent to give N-Boc-2-(S)-hydroxymethyl-5-(R)-methyl. u colorless oil ( 838 mg, 87%): iH_NMR (CDCl3) 5 κ 17 (d, J = 6.0 Hz, 3H), 1·48 (s, 9H), 1.48-1·64 ( m, 2H), 1·90-2.11 (m, 2H), 3·52-3.57 (m, 1H), 3.68-3.70 (m, 1H), 3·94-4· 13 (m, 1H) . 4-[N-Boc-5--methyl-2-(s)-indolyl methoxy]benzoic acid methyl ester

Boc^O~-^~~^^c02MeBoc^O~-^~~^^c02Me

在室溫下於N-Boc-2-(S)-羥甲基-5-(R)_甲基毗咯啶 (820毫克，3.81毫莫耳）、三苯膦（1.1〇克，4.19毫莫耳） 及4-經基苯甲酸甲酯（580毫克，3· 81毫莫耳）之攪拌溶液 中加入偶氮二羧酸二異丙酯（841毫升，4· 19毫莫耳），並 使所產生之混合物在60 t下攪拌1小時。將混合物於真空 中濃縮，並使殘留物於矽膠上利用己烷-Et〇Ac(5 :丨）作為 洗提液進行層析，而得4-[n-Boc-5_(R)_曱基-2-(S)-咣口各 唆甲氧基]苯甲酸甲酯（1· 32克，80%)之無色油。1H-NMR (CDC13) d 1.24 (brs，3H)、1·49 (s，9H)、1·55-1·7〇 (m，2Η)、ι·94-2·11 (m，2Η)、3·88 (s，3Η)、3·88 (重 疊，1Η)、4·06-4·20 (m，2Η)、6·93-6·96 (m，2Η)、 7.97 (d，J = 8.8 Ηζ，2H); MS(ESI) m/z，350 (ΜΗΗ)。N-Boc-2-(S)-hydroxymethyl-5-(R)-methylpyrrolidine (820 mg, 3.81 mmol), triphenylphosphine (1.1 g, 4.19 m) at room temperature To a stirred solution of methyl 4-methylbenzoate (580 mg, 3. 81 mmol), diisopropyl azodicarboxylate (841 ml, 4·19 mmol), and The resulting mixture was stirred at 60 t for 1 hour. The mixture was concentrated in vacuo, and the residue was applied to silica gel eluting with hexane-Et?Ac (5: 丨) as eluent to give 4-[n-Boc-5_(R)-fluorenyl -2-(S)-purine methoxymethyl]benzoic acid methyl ester (1·32 g, 80%) of a colorless oil. 1H-NMR (CDC13) d 1.24 (brs, 3H), 1·49 (s, 9H), 1·55-1·7〇 (m, 2Η), ι·94-2·11 (m, 2Η), 3·88 (s, 3Η), 3.88 (overlap, 1Η), 4·06-4·20 (m, 2Η), 6.93-6·96 (m, 2Η), 7.97 (d, J = 8.8 Ηζ, 2H); MS (ESI) m/z, 350 (ΜΗΗ).

1283240 五、發明說明（525) 4-[5-(R) -甲基-2-(S)-咄咯啶甲氧基]笨甲酸甲酯 CO,Me 、&lt;y、 在室溫下於4 - [N -Boc- 5-(R)-甲基-2 -（s) -咄咯啶甲氧 基]苯曱酸曱酯（1. 29克，3· 70毫莫耳）溶於CH2Cl2 (3〇毫 升）之攪拌溶液中加入三氟乙酸（10毫升），並使所產生之 混合物搜拌3 5分鐘。將混合物於真空中濃縮，並倒入至 NaHC〇3水溶液中，然後以CHC13萃取。將有機層以水洗滌， 於無水NaJO4上乾燥，並於真空中濃縮而得4一 [5-（R) -甲基 -2-(S) -吼咯啶甲氧基]苯甲酸甲酯（871毫克，95%)之無色 油。將產物不經進一步的純化而使用於後續的反應。 LR (CDC13) 6 1· 18 (d，J = 6· 4 Hz，3H)、1· 30-1· 40 (m，1H)、1·59-1·67 (m，1H)、1·87-1·97 (m，2H)、 3·19-3·27 (m，1Η)、3·49-3.55 (m，1Η)、3·87 (s， 3H)、3·89-4.05 (m，2H)、6·89 (d，J = 8.8 Hz，2H)、7· 96 (d，J二8·8 Hz，2H); MS(ESI) m/z，250(MHH) 4 - [1 - [4 - [N -(2-甲基笨基）脲基]一3一甲氧苯基乙醯基]一 5-（R)-曱基-2-(S)-咄咯啶曱氧基]苯甲酸甲酯1283240 V. INSTRUCTIONS (525) 4-[5-(R)-Methyl-2-(S)-fluorenyl methoxy] methyl formate, CO, Me, &lt;y, at room temperature 4 - [N-Boc- 5-(R)-Methyl-2 -(s)-indolyl methoxy]benzoic acid decyl ester (1. 29 g, 3.70 mmol) dissolved in CH2Cl2 Trifluoroacetic acid (10 ml) was added to a stirred solution (3 mL), and the mixture was stirred for 35 min. The mixture was concentrated in vacuo and poured into aq. NaHC.sub.3 and then extracted with CH. The organic layer was washed with water, dried over anhydrous Na.sub. 871 mg, 95%) of a colorless oil. The product was used in the subsequent reaction without further purification. LR (CDC13) 6 1· 18 (d, J = 6· 4 Hz, 3H), 1· 30-1· 40 (m, 1H), 1·59-1·67 (m, 1H), 1·87 -1·97 (m, 2H), 3·19-3·27 (m, 1Η), 3·49-3.55 (m, 1Η), 3·87 (s, 3H), 3·89-4.05 (m , 2H), 6·89 (d, J = 8.8 Hz, 2H), 7·96 (d, J 2·8 Hz, 2H); MS (ESI) m/z, 250 (MHH) 4 - [1 - [4-[N-(2-methylphenyl)ureido]-3-methoxyphenylethyl]-5-(R)-indenyl-2-(S)-indenylpyridinium Methyl benzoate

在室溫下於4一 [5 — (R)〜甲基-2-（S) -呲咯啶甲氧基]苯曱 酸甲醋（141毫克，0.57毫莫耳）、4- [N，-（2-甲基苯基）脲4-[5-(R)~Methyl-2-(S)-indolyl methoxy]benzoic acid methyl vinegar (141 mg, 0.57 mmol), 4-[N, at room temperature -(2-methylphenyl)urea

12832401283240

，]-3-甲氧苯乙酸（178毫克，〇. 57毫莫耳）及N，n一二甲胺 基吡啶（69. 〇毫克，〇· 57毫莫耳）溶於DMF(1〇毫升）之攪拌 溶液中加入EDC ·ΗΠ(120毫克，0.62毫莫耳），並使所產 生之混合物攪拌隔夜。將反應混合物倒入至水中，並以 EtOAc萃取。將有機層以鹽水洗滌，於無水Μ。％上乾燥， ，後於真空中濃縮。使殘留物於矽膠上利用Et〇Ac作為洗 提液進行層析，而得4 - [1 - [4 - [N，〜（2-甲基苯基）脲基;|-3 一 甲氧苯基乙醯基]-5-(R)-甲基-2-(S)-吼咯啶甲氧基 ]笨曱酸曱酯（297宅克，96%)的無色非晶形固體。ijj-nmr (CDC13) 6 1· 24-1· 34 (m， 3H)、1· 93-2· 18 (ra 系列，4H) 、2·28 (s，3H)、3·65 (s，3H)、3·88 (s，3H)、3.62- 3·87 (m，3Η)、4·：Π - 4·38 (m 系、列，3Η)、6·42 - 8.06 (m 系列，13H) ; MS(ESI) m/z 546 (MHH)。 在室溫下於4 - [l-[4 - [Ν’-（2-甲基苯基）脲基]一3一甲氧苯 基乙醯基]- 5-（R) -甲基-2-(S) -吡咯啶甲氧基]苯甲酸甲酯 (279毫克，0.51毫莫耳）溶於Me 0H-THF (1:1，10毫升）之攪 拌溶液中加入1.0M NaOH(2.56毫升，2.56毫莫耳），並使 所產生之混合物在60 °C下加熱攪拌2小時。將反應混合物 倒入至IN HC1中，然後以CHC13萃取。將有機層以鹽水洗 條，並於無水Na2S04上乾燥，然後於真空中濃縮。將殘留 物於矽膠上利用CHCl3-MeOH(15:l)進行層析，而得 150 ( 269毫克，99%)的無色非晶形固體。ih — NMr (CD3〇D)， 消旋異構物之混合物，（5 1·28-1.35 (m，3H)、1·74-2· 21 (m 系列，4Η)、2· 28 (s，3Η)、3· 71 -4· 37 (m 系列，,]-3-methoxyphenylacetic acid (178 mg, 〇. 57 mmol) and N,n-dimethylaminopyridine (69. 〇mg, 〇·57 mmol) dissolved in DMF (1 mL) EDC·ΗΠ (120 mg, 0.62 mmol) was added to the stirred solution, and the resulting mixture was stirred overnight. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine and dried over anhydrous. Dry on %, then concentrate in vacuo. The residue was chromatographed on a silica gel using Et〇Ac as an eluent to give 4-[1 -[4-[N,~(2-methylphenyl)ureido;|-3-methoxybenzene A colorless amorphous solid of hydrazino]-5-(R)-methyl-2-(S)-decalidine methoxy] decyl decanoate (297 克, 96%). Ijj-nmr (CDC13) 6 1· 24-1· 34 (m, 3H), 1· 93-2· 18 (ra series, 4H), 2·28 (s, 3H), 3·65 (s, 3H ), 3·88 (s, 3H), 3.62 - 3·87 (m, 3Η), 4·: Π - 4·38 (m system, column, 3Η), 6.42 - 8.06 (m series, 13H) MS (ESI) m/z 546 (MHH). 4-[l-[4 - [Ν'-(2-methylphenyl)ureido]- 3-methoxyphenylethyl]- 5-(R)-methyl-2 at room temperature -(S)-Pyrrolidine methoxy]benzoic acid methyl ester (279 mg, 0.51 mmol) in a stirred solution of Me 0H-THF (1:1, 10 mL), 1.0 M NaOH (2.56 mL, 2.56 mmol), and the resulting mixture was heated and stirred at 60 ° C for 2 hours. The reaction mixture was poured into IN HC1 and then extracted with CHC13. The organic layer was washed with brine and dried over anhydrous Na. The residue was chromatographed on EtOAc (EtOAc:EtOAc) Ih — NMr (CD3〇D), a mixture of racemic isomers, (5 1·28-1.35 (m, 3H), 1.74-2· 21 (m series, 4Η), 2·28 (s, 3Η), 3· 71 -4· 37 (m series,

89112968.ptd 第531頁 1283240 五、發明說明（527) 6H)、6· 76-7· 99 (m 系列，11H) ; MS(ESI) m/z 532 (M+ + H)。 實施例143 4-[反-4-胺基-1-[3-甲氧基-4-[N，-（2-曱基苯基）脲基]苯 基乙醯基]-(2 S) ~咄咯啶基]甲氧苯甲酸89112968.ptd Page 531 1283240 V. INSTRUCTIONS (527) 6H), 6· 76-7· 99 (m series, 11H); MS (ESI) m/z 532 (M+ + H). Example 143 4-[Reverse-4-amino-1-[3-methoxy-4-[N,-(2-mercaptophenyl)ureido]phenylethenyl]-(2S) ~咄咄pyridyl]methoxybenzoic acid

[-(反-1-第三丁氧羰基-4-三氟乙醯胺基—（2S) -咄咯啶基） 曱氧苯甲酸甲酯 ^ COOMe 在〇 C下於4-(反-4_胺基-1-第三丁氧羰基_(2S)_吡咯一 基）甲氧笨甲酸甲醋（1.0克，2.86毫莫耳）及TEA(1 2疋 升，8.6毫莫耳）溶於(：1^12(20.0毫升）之溶液中加入_&gt; 乙酸針（72〇毫克，3.43毫莫耳）。於在室溫下攪拌25一^ 後，將水加至溶液中，ϋ以CH2Cl2萃取。料取液以水、可 滌，然後於NaJO4上乾燥，並於真空中濃縮。使殘 / :於用Et0)c-正己烧(1:3, v/v)作為洗提液進》 s柱層析，純化而付4-(反-1—第三丁氧羰基-三 丁 胺基-(2S)-咄咯啶基）甲氧苯甲酸甲酯（94〇毫克丁74醯 無色油。1H-NMR (CDC13) 6 1.46 (s，9H)、2 〇2 2 ^ 之 Cm, 1H) &gt;2.41-2.52 (m, 1H) &gt; 3.3 0-3.45 (m iH)[-(trans-1-t-butoxycarbonyl-4-trifluoroacetamido-(2S)- oxaridinyl) methyl benzoate = COOMe under 〇C in 4-(trans-4 _Amino-1-tert-butoxycarbonyl _(2S)-pyrrole-based methoxy acetomic acid methyl vinegar (1.0 g, 2.86 mmol) and TEA (1 2 liters, 8.6 mmol) are soluble (: 1^12 (20.0 ml) was added to a solution of _&gt; acetic acid needle (72 mg, 3.43 mmol). After stirring at room temperature for 25 °, water was added to the solution and CH2Cl2 was added. Extraction. The liquid is dehydrated, then dried on NaJO4 and concentrated in vacuo. Residue / : using Et0)c-n-hexane (1:3, v/v) as eluent s column chromatography, purification and the addition of 4- (trans-1 - 3 -butoxycarbonyl - tributylamino - (2S) - pyrrolidinyl) methyl benzoate (94 〇 mg butyl 74 醯 colorless oil 1H-NMR (CDC13) 6 1.46 (s, 9H), 2 〇 2 2 ^ Cm, 1H) &gt; 2.41-2.52 (m, 1H) &gt; 3.3 0-3.45 (m iH)

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3.80-3.90 (m，1Η)、3·88 (s，3H)、4 〇〇一4.3〇 (m，3H) 、4.65-4.75 (m， 1H) 、6·50 (br s， 1H) 、6·91—6·94 (m， 2H) 、 7· 96-7· 99 (m， 2H)。 4-[反-l-[3-甲氧基-4-[N’-(2_甲基苯基）脲基]苯基乙醯 基]-4-三氟乙醯胺基：（2S)-吡咯啶基]甲氧苯甲酸曱酯3.80-3.90 (m,1Η), 3·88 (s,3H), 4〇〇一4.3〇(m,3H), 4.65-4.75 (m, 1H), 6·50 (br s, 1H), 6 · 91—6·94 (m, 2H), 7·96-7· 99 (m, 2H). 4-[Res-l-[3-methoxy-4-[N'-(2-methylphenyl)ureido]phenylethenyl]-4-trifluoroacetamido: (2S) -pyrrolidinyl] methoxy methoxybenzoate

COOMe 在0°C下於4-(反-1-第三卞氧羰基—4—三氟乙醯胺基 _(2S)_吡咯啶基）曱氧苯甲酸甲酯（47〇毫克，i 〇5毫莫耳） 溶於CHzClJlO· 0毫升）之攪拌溶液中加入TFA(5. 〇毫升）。 使反應混合物在室溫下攪拌〇. 5小時。將混合物於真空中 濃縮。將飽和NaHC〇3加至殘留物，並以CH2Ci2萃取了將萃 取液以鹽水洗滌，於NaJO4上乾燥，並於真空中濃縮。將 粗製產物不經進一步的純化而使用於後續的反應。在 下於此粗製f物、3-曱氧基—4—[N，—（2一曱基苯基）脲基] 苯乙酸（314宅克，1.0毫莫耳）、H〇Bt(162毫克，12毫莫 耳）、及二乙胺（417耄升，3·〇毫莫耳）溶於THF (1〇· 〇毫 升）及MeCIKlO. 0耄升）之攪拌溶液中加入EDC · hci( 288毫 克，1 · 5毫莫耳）。使反應混合物在室溫下攪拌丨6小時，並 於真空中濃縮。將水加至殘留物，並以Et〇Ac萃取。將有 機層以飽和NaHC〇3、2M擰檬酸、及飽*NaHC〇3洗滌，然後 於NaJO4上乾燥，並於真空中濃縮。將殘留物經由於矽膠 上利用EtOAc -正己烷（3 ·· 1，v/v)作為洗提液進行管柱層COOMe at 4-(trans-1-thano-oxocarbonyl-4-tetrafluoroacetamido-(2S)-pyrrolidinyl)-p-oxybenzoic acid methyl ester (47 mg, i 〇 at 0 ° C) To a stirred solution of 5 mM (dissolved in CHzClJlO·0 ml) was added TFA (5 ml). The reaction mixture was stirred at room temperature for 5 hours. The mixture was concentrated in vacuo. Saturated NaHC(R)3 was added to the residue, which was crystallised eluted with CH2CI. The crude product was used in the subsequent reaction without further purification. Herein, the crude material, 3-methoxy-4-(N,-(2-mercaptophenyl)ureido]phenylacetic acid (314 oz, 1.0 mmol), H〇Bt (162 mg, Add EDC · hci ( 288 mg) to a stirred solution of THF (1 〇· 〇ml) and MeCIKlO. 0 liters of 12 mM) and diethylamine (417 liters, 3 〇 mmol) , 1 · 5 millimoles). The reaction mixture was stirred at room temperature for 6 h and concentrated in vacuo. Water was added to the residue and extracted with EtOAc. The organic layer was washed with saturated NaHC(R) 3, 2M citric acid and sat. NaHC.sub.3, then dried over Na.sub.4 and concentrated in vacuo. The residue was passed through a ruthenium gel using EtOAc-n-hexane (3··1, v/v) as an eluent.

第533頁 1283240 五、發明說明（529) 析，純化而得4-[反-1 - [3-甲氧基-4 - [N’-(2-甲基苯基） 脲基]苯基乙醯基卜4 -三氟乙醯胺基-(2S) -吼咯啶基]甲氧 苯甲酸甲酯（ 350毫克，52%)之無色油。1H-NMR (CDC13) 5 2.01 -2.10 (m，1H)、2.31 (s，3H)、2·42-2·48 (m, 1H) 、3·45-3.50 (m， 1H) 、3·56-3·59 (m， 5H) 、3·89 (s，3Η)、4·07-4·14 (m，2Η)、4.3 8-4.42 (m，1Η)、 4.5 0-4.6 0 (m，lH)、4.72-4.80(m，lH)、6.33(s， 1Η)、6·60-6·85(πι，3Η)、7·06-7·26(ιη，3Η)、7·48-7· 52 (m，1H)、7· 93-8· 05 (m，3H)。 於4-[反-1-[3 -甲氧基-4 - [Ν’ - (2-甲基苯基）脲基]苯基 乙醯基]-4 -三氟乙醯胺基-(2S) -咄咯啶基]甲氧苯曱酸曱 酯（150毫克，0.23毫莫耳）溶於THF(3.0毫升）及MeOH(2.0 毫升）之攪拌溶液中加入IN NaOH(0· 70毫升，0· 70毫莫 耳）。使混合物在6 0 °C下攪拌1 8小時。將混合物於真空中 濃縮，加入水，並以1N HC1中和。收集所產生之固體，以 水洗滌，並於真空中乾燥而得15 1(1 00毫克，81%)的白色 結晶固體。熔點170-171 °C ; IR (KBr) 3264、2 937、 1604、1535、1415、1376、1255、1224、1033 / 公分； UMR (DMSO-d6)6 1·80-1·90 (m，1H)、2·10-2·20 (m， 1Η)、2·24 (s，3Η)、3·55-3·80 (m，3Η)、3·57 (s， 2Η) 、4·08-4·18 (m， 2Η) 、4·36-4·60 (m， 1Η) 、6·72- 7·16 (m，7Η)、7·77-8·01 (m，4Η)、8·46 (s，1Η)、 8·54 (s，1H) ； MS(FAB) m/z 53 2 (MH1)； C29H32N4 06 · 2· 0H2O 之分析計算值：C， 61· 26 ; H，6. 38 ; N, 9· 85。實Page 533 1283240 V. Inventive Note (529) Analysis, purification gave 4-[trans-1 - [3-methoxy-4 - [N'-(2-methylphenyl) ureido]phenyl A colorless oil of methyl 4-trifluoroacetamido-(2S)-decalidyl]methoxybenzoate (350 mg, 52%). 1H-NMR (CDC13) 5 2.01 -2.10 (m,1H), 2.31 (s,3H), 2·42-2·48 (m, 1H), 3·45-3.50 (m, 1H), 3.56 -3·59 (m, 5H), 3·89 (s, 3Η), 4·07-4·14 (m, 2Η), 4.3 8-4.42 (m, 1Η), 4.5 0-4.6 0 (m, lH), 4.72-4.80 (m, lH), 6.33 (s, 1Η), 6·60-6·85 (πι, 3Η), 7·06-7·26 (ιη, 3Η), 7·48-7 · 52 (m, 1H), 7· 93-8· 05 (m, 3H). 4-[Trans-1-[3-methoxy-4-[Ν'-(2-methylphenyl)ureido]phenylethenyl]-4-trifluoroacetamido-(2S) - oxazolidinyl] methoxybenzoate (150 mg, 0.23 mmol) dissolved in THF (3.0 mL) and MeOH (2.0 mL). · 70 millimoles). The mixture was stirred at 60 ° C for 18 hours. The mixture was concentrated in vacuo, water was added and neutralized with 1N EtOAc. The resulting solid was collected, washed with water and dried in vacuo to give 15 1 (1, 00 mg, 81%) of white crystalline solid. Melting point 170-171 °C; IR (KBr) 3264, 2 937, 1604, 1535, 1415, 1376, 1255, 1224, 1033 / cm; UMR (DMSO-d6) 6 1·80-1·90 (m, 1H ), 2·10-2·20 (m, 1Η), 2·24 (s, 3Η), 3·55-3·80 (m, 3Η), 3·57 (s, 2Η), 4·08- 4·18 (m, 2Η), 4·36-4·60 (m, 1Η), 6.72- 7·16 (m, 7Η), 7·77-8·01 (m, 4Η), 8· 46 (s,1Η), 8·54 (s,1H); MS(FAB) m/z 53 2 (MH1); C29H32N4 06 · 2· 0H2O Analysis calculated: C, 61· 26 ; H, 6. 38 ; N, 9· 85. real

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測值·· C，61 · 0 7 ; Η，6 · 3 2 ; N，9. 5 8。 實施例144 4-[反-4 -胺基-1 - [3-甲氧基-4 - [N，-（2-甲基苯基）脲基]笨 基乙醯基]-（2S) -吼洛咬基]曱氧笨曱酸甲酯hci鹽 nh2 152 在室溫下於4 - [反-1-[3-甲氧基-4 - [『-（2-曱基苯基） 脲基]苯基乙醯基]-4 -三氟乙醯胺基—（2S) -咄咯啶基]曱氧 苯甲酸甲酯（200毫克，0.31毫莫耳）溶於MeOH(4· 0毫升）之 授拌溶液中加入水（2.0毫升）&amp;K2C03 (138毫克，1·0毫莫 耳）。於在室溫下攪拌1 8小時後，將水加至混合物，並以 CH2C12萃取。將萃取液以水洗滌，然後於Na2S04上乾燥，並 於真空中濃縮。將殘留物經由於矽膠上利用MeOH-CH2Cl2 (5 : 9 5至1 5 : 8 5，v/ v)作為洗提液進行管柱層析而純化。將 產物溶解於EtOH(5.0毫升），並加入IN HC1(溶於EtOH)(l. 0毫升，1 · 0毫莫耳）。使混合物於真空中濃縮而得1 5 2 ( 1 2 0 毫克，63%)的非晶形固體。IR (KBr ) 3382、29 48、 2879、1 6 04、1 5 33、1 28 6、1 25 5、7 71 / 公分；UMR (DMSO-d6) 5 2. 25 (s, 3H) &gt;2. 10-2. 30 (m, 2H) &gt; 3.59-3·70 (m，3H)、3·77-3·80 (m，8H)、4·00-4·24 (m，2Η)、4.47-4·67 (m，1Η)、6·70-7·16 (m，7Η)、 7·77-8·00 (m，4Η)、8·49 (s，1Η)、8.55 (s，1H); MS(FAB) m/z 54 7(MH1) ; C3()H34N4 06 · HC1 · 1· 4H20 之分析Measured · · C, 61 · 0 7 ; Η, 6 · 3 2 ; N, 9. 5 8. Example 144 4-[Reverse-4-amino-1 -[3-methoxy-4 -[N,-(2-methylphenyl)ureido]]phenylamino]-(2S) -吼 咬 曱 曱 曱 曱 曱 曱 曱 曱 曱 曱 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在Methyl phenyl hydrazinyl]-4-trifluoroacetamido-(2S)- oxazolidinyl]methyl oxobenzoate (200 mg, 0.31 mmol) dissolved in MeOH (4.0 mL) Water (2.0 ml) &amp; K2C03 (138 mg, 1.0 mmol) was added to the mixing solution. After stirring at room temperature for 18 hours, water was added to the mixture and extracted with CH2C12. The extract was washed with water, dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by column chromatography using MeOH-CH.sub.2Cl.sub.2 (5:95 to 15:85, v/v) as eluent. The product was dissolved in EtOH (5.0 mL) and EtOAc (1 mL, EtOAc). The mixture was concentrated in vacuo to give 1 5 2 (1 2 mg, 63%) of amorphous solid. IR (KBr ) 3382, 29 48, 2879, 1 6 04, 1 5 33, 1 28 6 , 1 25 5, 7 71 / cm; UMR (DMSO-d6) 5 2. 25 (s, 3H) &gt;2 . . . (2, 3H) 4.47-4·67 (m, 1Η), 6·70-7·16 (m, 7Η), 7·77-8·00 (m, 4Η), 8·49 (s, 1Η), 8.55 (s, 1H); MS(FAB) m/z 54 7(MH1) ; C3()H34N4 06 · HC1 · 1· 4H20 analysis

\\312\2d-code\90-01\89112968.ptd 第535頁 1283240 五、發明說明（531) 計算值：C，59· 24 ; H，6. 26 ; N，9· 21 ; C1，5· 83。實測 值：C，59·42;Η，6·42;Ν，9.04;C1，611。 實施例1 4 5 ， 4-[反-1 -[3-曱氧基一4-[N，—（2—甲基笨基）脲基]苯基乙醯 基]-4-曱胺基-（2S)-毗咯啶基]曱氧笨甲酸\\312\2d-code\90-01\89112968.ptd Page 535 1283240 V. Description of invention (531) Calculated value: C, 59· 24 ; H, 6. 26 ; N, 9· 21 ; C1, 5 · 83. Found: C, 59·42; Η, 6.42; Ν, 9.04; C1, 611. Example 1 4 5 , 4-[trans-1 -[3-decyloxy-4-[N,-(2-methylphenyl)ureido]phenylethenyl]-4-indolyl- (2S)-Pyrrolidinyl]oxooxybenzoic acid

NH 〇 一NH 〇 one

Me Η H 〇Me i-[反-1-第二丁氧羰基—4 — (n一甲基三氟乙醯胺基— 咄咯啶基]甲氧苯甲酸甲_Me Η H 〇Me i-[trans-1-second butoxycarbonyl-4(n-methyltrifluoroacetamido-indolyl)methoxybenzoate A

在至溫下於4-(反-1-第三丁氧幾基—4—三氟乙醯胺基 一、（2S)d比洛咬基）甲氧苯甲酸甲酯（ 5 20毫克，1. 17毫莫耳） &gt;谷於DMF/10· 〇耄升）之攪拌溶液中加入K2C〇“321毫克， 2.33¾，耳）及Mel(330毫克，2.33毫莫耳）。使反應混合 ?在5〇。。下攪拌18小時。g水加至混合物中，1以EtOAc :U有t層以水洗•，然後於Na2S〇4上乾燥，並於真 A /辰、、、&quot;。二=留=經由於石夕膠上利用EtOAc-正己烧 甲氧苯甲酸甲醋(3 90 !J三定基] )占 1.46 (9H s)、2 ^ 〇)之無色油。1H一NMR (CDCl3 (各s，總計阳、3 2 · 2,⑼ U，2H)'2·96 及 3·05 ’ 3· 7〇 (m，2H)、3· 88 (s, 3H)、3.Methyl methoxybenzoate (5 20 mg, 1 at 4-(trans-1-tert-butoxymethyl-4-tetrafluoroethylamino)-(2S)d than carbamide at room temperature Add a K2C 〇 “321 mg, 2.333⁄4, ear” and Mel (330 mg, 2.33 mmol) to a stirred solution of 17 mM) &gt; DMF/10· 〇耄). Stir for 15 hours at 5 Torr. g of water was added to the mixture, 1 with EtOAc:U with t layer washed with water, then dried over Na2S 〇4, and then a s, A, s,, &quot; =Retained = a colorless oil of 1.46 (9H s), 2 ^ 〇) by using EtOAc-n-hexane methoxybenzoic acid methyl vinegar (3 90 !J tridecyl) on Shixi gum. 1H-NMR (CDCl3 ( Each s, total yang, 3 2 · 2, (9) U, 2H) '2 · 96 and 3 · 05 ' 3 · 7 〇 (m, 2H), 3 · 88 (s, 3H), 3.

第536頁 1283240 五、發明說明（532)Page 536 1283240 V. Description of invention (532)

95'4.42 (m， 3H) 、5·10-5.40 (m 1H， 2H) 、 7.96-8.00 (m， 2H)。 ’ 6. 89-β. 91 (m, 4 [反-1 - [ 3 -曱氧基-4 -丨 乙醯 曱酸95'4.42 (m, 3H), 5·10-5.40 (m 1H, 2H), 7.96-8.00 (m, 2H). ' 6. 89-β. 91 (m, 4 [trans-1 - [ 3 - methoxy-4-indolyl phthalic acid]

: 以〜甲基苯基）脲基]笨J 基]—4-(N-甲基三氟乙醯胺基〜（2 &gt; 贫Ί m Γ: ~methylphenyl)ureido] stupid J-based] 4-(N-methyltrifluoroacetamido~(2 &gt; barren m Γ

.土、〜吡咯啶基]甲氧I. soil, ~ pyrrolidinyl] methoxy I

Me、 ，'^^-C〇〇Me 胺S cr二於V么1装严二丁氧幾基~4_(n_曱基三氟乙醯 -(2S)-吡咯啶基]甲氧笨甲酸甲醋（39〇毫克， ^耳）溶於CH2C12(8. 〇毫升）之攪拌溶液中加入TFA(5. 〇毫笔 升）。使反應混合物在室溫下攪拌〇. 5小時。將混合物於直 空^濃縮。將飽和NaHC〇3加至殘留物，並以ch2c12萃取。” 將萃取液以鹽水洗滌，於NaJO4上乾燥，並於真空中濃 縮。將粗製產物不經進一步的純化而使用於後續的反應。 在〇°C下於此粗製產物、3-甲氧基一 4 - [N，- (2-甲基苯基） 脲基]苯乙酸（2 7 9毫克，〇·89毫莫耳）、HOBt (143毫克，1. 1毫莫耳）、及三乙胺（246毫升，1.77毫莫耳）溶於THF (8. 〇毫升）及MeCN(8.0毫升）之攪拌溶液中加入EDC ·Η(：1 (2 5 5毫克，1 · 3毫莫耳）。使反應混合物在室溫下攪拌1 6小 時，並於真空中濃縮。將水加至殘留物，並以E 10 A c萃 取。將萃取液以飽和NaHC03、2M檸檬酸、及飽和NaHC03洗 滌，然後於Na2S04上乾燥，並於真空中濃縮。將殘留物經 由於矽膠上利用EtOAc-正己烷（4 : 1，v/v)作為洗提液進行Me, , '^^-C〇〇Me Amine S cr II in V? 1 Packed dibutoxyl group ~4_(n_mercaptotrifluoroacetamidine-(2S)-pyrrolidinyl]methoxybenzoic acid To the stirred solution of methyl vinegar (39 mg, ^ mil) in CH2C12 (8 ml) was added TFA (5. liters). The reaction mixture was stirred at room temperature for 5 hours. The mixture was concentrated to dryness. EtOAc (EtOAc m. Subsequent reaction. The crude product, 3-methoxy-4-[4-,-(2-methylphenyl)ureido]phenylacetic acid (2.79 mg, 〇·89 mmol) at 〇 °C Add EDC to a stirred solution of HOBt (143 mg, 1.1 mmol) and triethylamine (246 mL, 1.77 mmol) in THF (8.4 ml) and MeCN (8.0 mL) · Η (: 1 (2 5 5 mg, 1 · 3 mmol). The reaction mixture was stirred at room temperature for 16 hours and concentrated in vacuo. Water was added to residue and taken to E 10 A c Extraction. The extract is saturated with NaHC03 2M citric acid, and washed with saturated NaHC03, then dried on Na2S04, and concentrated in vacuo and the residue was purified on silica since the EtOAc- hexane. (4: 1, v / v) as eluent.

\\312\2d-code\90-01\89112968.ptd 第537頁 1283240 五、發明說明（533) 管柱層析，純化而得4 - [反-1 一 [3 一曱氧基一4-[Ν’ - (2 -曱基 苯基）脲基]苯基乙醯基]—4 -（Ν_甲基三氟乙醢胺基- (2S)-17比洛α定基）甲氧苯甲酸甲酯（4 8 0愛：克’ 8 2 %)之無色油。 W-NMR (CDC13) (5 2· 1 8-2· 35 (m，2Η)、2· 31 (s，3Η)、 2·87 及 2·97 (各s,總計 3H)、3·45_3·46 (m，3H)、3·47 (s，3H)、3·49 (s, 2H)、3·88 (s，3H)、4·30-4·70 (m， 2H)、5·20-5·40 (m，1H)、6·38-6·43 (m, 1H)、6·67- 6 · 8 6 (m，4 H )、7 · 0 9 - 7 · 2 4 (m，4 H)、7 · 5 1 - 7 · 5 4 ( m，1 H ) 、7·93-8·08 (m， 3H)。 於4-[反-l-[3 -甲氧基-4-[N’-(2-甲基苯基）脲基]苯基 乙醯基]-4-(N-甲基-N-三氟乙醯胺基—（2S) -咄咯啶基）曱 氧苯甲酸甲酯（240毫克，0. 37毫莫耳）溶於THF( 5. 0毫升） 及MeOH(3.0毫升）之攪拌溶液中加入IN NaOH(1.27毫升， 1 · 2 7毫莫耳）。使混合物在6 0 °C下攪拌1 8小時。將混合物 於真空中濃縮，加入水，並以1 N HC 1中和。收集所產生之 固體，以水洗满：，並於真空中乾燥而得1 5 3 ( 1 4 0毫克， 7 0%)的白色結晶固體。熔點1 62- 1 64 °C ; IR (KBr) 333 8、 1 604、1 535、1 2 55、1 03 3、755 / 公分；l-NMR (DMSO-d6) (5 1·85-1·95 (m，1H)、2·10-2·20 (m，1H)、2·24 (s， 3H)、2· 34 及 2· 39 (各s，總計 3 Η )、3 · 4 1 - 3 · 7 1 ( m，3 Η )、 3·58 (s，2Η)、3·80 (s，3Η)、4·05-4·20 (m，2Η)、 4·36-4·60 (m， 1Η) 、6· 73-7.16 (m， 7Η) 、7·77-8·01 (m， 4Η) 、8·45 (s， 1Η) 、8·53 (s， 1H); MS(FAB) m/z 54 7(M+ + 1) ; C3GH34N4 06 · 2. 5H20 之分析計算值：C， 6 0.9 0；\\312\2d-code\90-01\89112968.ptd Page 537 1283240 V. Description of the invention (533) Column chromatography, purification to obtain 4 - [trans-1 -[3 - anoxyl -4 [Ν' - (2-Phenylphenyl)ureido]phenylethenyl]-4((Ν-methyltrifluoroacetamido-(2S)-17), methoxybenzoic acid A colorless oil of methyl ester (480% love: gram '82%). W-NMR (CDC13) (5 2· 1 8-2· 35 (m, 2Η), 2· 31 (s, 3Η), 2·87 and 2.97 (each s, total 3H), 3·45_3· 46 (m, 3H), 3·47 (s, 3H), 3·49 (s, 2H), 3·88 (s, 3H), 4·30-4·70 (m, 2H), 5·20 -5·40 (m,1H),6·38-6·43 (m, 1H), 6·67- 6 · 8 6 (m, 4 H ), 7 · 0 9 - 7 · 2 4 (m, 4 H), 7 · 5 1 - 7 · 5 4 ( m,1 H ), 7·93-8·08 (m, 3H). 4-[trans-l-[3-methoxy-4- [N'-(2-methylphenyl)ureido]phenylethenyl]-4-(N-methyl-N-trifluoroacetamido-(2S)-indenylpyridyl) anthracene Methyl benzoate (240 mg, 0. 37 mmol) was dissolved in THF (0.5 mL) and MeOH (3.0 mL). The mixture was stirred at 60 ° C for 18 hours. The mixture was concentrated in vacuo, water was added, and neutralized with 1 N HCl 1. The resulting solid was collected, washed with water and dried in vacuo. 1 5 3 (1 40 mg, 70%) of a white crystalline solid. m.p. 1 62- 1 64 ° C; IR (KBr) 333 8 , 1 604 , 1 535 , 1 2 55 , 1 03 3 , 755 / Cm; l-NMR (D MSO-d6) (5 1·85-1·95 (m, 1H), 2·10-2·20 (m, 1H), 2·24 (s, 3H), 2·34 and 2· 39 (each s, total 3 Η ), 3 · 4 1 - 3 · 7 1 ( m, 3 Η ), 3·58 (s, 2 Η), 3·80 (s, 3 Η), 4·05-4·20 (m , 2Η), 4·36-4·60 (m, 1Η), 6·73-7.16 (m, 7Η), 7·77-8·01 (m, 4Η), 8·45 (s, 1Η), 8·53 (s, 1H); MS(FAB) m/z 54 7(M+ + 1) ; C3GH34N4 06 · 2. 5H20 Analytical calculated value: C, 6 0.9 0;

\\312\2d-code\90-01\89112968.ptd 第538頁 1283240 五、發明說明（534) ' '~\\312\2d-code\90-01\89112968.ptd Page 538 1283240 V. Inventions (534) ' '~

H，6.64 ; N，9.47。實測值：c，61〇1 ; H，6 5〇 ; N 9.31。 ’ 實施例1 4 6 4-[反-1-[ 3-甲氧基-4 - [N，一（2一甲基苯基）脲基]苯基乙醯 基]-4-甲胺基-（2S)-吼咯啶基]甲氧苯甲酸甲酯H, 6.64; N, 9.47. Found: c, 61 〇 1 ; H, 6 5 〇 ; N 9.31. 'Example 1 4 4 4-[Ret-1-[3-methoxy-4 - [N, mono(2-methylphenyl)ureido]phenylethenyl]-4-methylamino- (2S)-Pyrridinyl]methyl methoxybenzoate

在室溫下於4 - [反-1 - [3-甲氧基一 4—[N，—（2—甲基苯基） 脲基]苯基乙醯基]-4-(N-曱基三氟乙醯胺基一（2S)—咄咯啶 基）甲氧苯曱酸甲酯（240毫克，036毫莫耳）溶於THF(5. 〇 毫升）及MeOH(5.0毫升）之攪拌溶液中加入水（2〇毫升）及 Kg CO3 ( 1 3 8毫克，1 · 〇毫莫耳）。於在室溫下攪拌丨8小時後， 將水加至混合物，並以CH2C12萃取。將萃取液以水洗滌， 然後於N S Ο*上乾燥’並於真空中濃縮。將殘留物經由於 矽膠上利用MeOH-CH2Cl2(5/95至20/80，v/v)作為洗提液進 行管柱層析而純化。將產物溶解於Et〇H( 5· 0毫升），並加 入IN HC1 (溶於EtOH)(0· 71毫升，0.71毫莫耳）。使混合物 於真空中濃縮而得1 54( 1 80毫克，85%)的非晶形固體。IR (KBr) 3311、2692、2453、1712、1 604、1 533 /公分； Μ-NMR (DMS0-d6) 6 2· 24 (s，3H)、2. 15-2· 30 (m， 2H)、2·60 (br s，3H)、3·60-4·20 (m，5H)、3·78-3·8ΐ (m，8Η)、4·47-4.70 (m，1Η)、6·7卜7·16 (m，7Η)、 7·77-8·00 (m，4Η)、8·48 (s， 1Η)、8·55 (s， 1Η)、4-[trans-1 -[3-,4-(2-methylphenyl)ureido]phenylethenyl]-4-(N-fluorenyl) at room temperature Methyl trifluoroacetamido-(2S)-indolyl) methoxybenzoate (240 mg, 036 mmol) in THF (5 ml) and MeOH (5.0 mL) Water (2 ml) and Kg CO3 (1 3 8 mg, 1 · 〇 millimol) were added. After stirring for 8 hours at room temperature, water was added to the mixture and extracted with CH2C12. The extract was washed with water, then dried <RTI ID=0.0> The residue was purified by column chromatography using MeOH-CH2Cl2 (5/95 to 20/80, v/v) as eluent. The product was dissolved in Et.sub.2H (5.0 mL) and then taken to <RTI ID=0.0># </RTI> </RTI> <RTIgt; The mixture was concentrated in vacuo to give 1 54 (1, 80 mg, 85%) of amorphous solid. IR (KBr) 3311, 2692, 2453, 1712, 1 604, 1 533 / cm; Μ-NMR (DMS0-d6) 6 2· 24 (s, 3H), 2. 15-2· 30 (m, 2H) , 2·60 (br s, 3H), 3·60-4·20 (m, 5H), 3·78-3·8ΐ (m, 8Η), 4·47-4.70 (m, 1Η), 6· 7 Bu 7·16 (m, 7Η), 7·77-8·00 (m, 4Η), 8·48 (s, 1Η), 8·55 (s, 1Η),

89112968.ptd 第539頁 1283240 五、發明說明（535) 9·21 (br s，2H); MS(FAB) m/z 561(MH1); C31H36N4〇 · HC1 · 1 . 4H20 之分析計算值：C，59· 83 ; H，6· 45 ; n，6 9. 00 ; Cl，5. 70 ° 實測值·· C，6 0.0 8； H, 6. 51 ; 8. 68 ； Cl, 5.99。 實施例1 4 7 4-[反-4-二甲胺基-1-[ 3-甲氧基-4-[Ν’ -(2-甲基笨基）朋^ 基]苯基乙醯基]-(2S)-吼咯啶基]甲氧苯甲酸、/89112968.ptd Page 539 1283240 V. INSTRUCTIONS (535) 9·21 (br s, 2H); MS(FAB) m/z 561(MH1); C31H36N4〇· HC1 · 1. Analysis of 4H20: C , 59· 83 ; H, 6 · 45 ; n, 6 9. 00 ; Cl, 5. 70 ° measured value · · C, 6 0.0 8; H, 6. 51 ; 8. 68 ; Cl, 5.99. Example 1 4 7 4-[Reverse-4-dimethylamino-1-[3-methoxy-4-[Ν'-(2-methylphenyl)phenyl]phenylethenyl] -(2S)-decalidyl]methoxybenzoic acid, /

NN

反-1-第三丁氧幾基-（2S)-(第三丁基二苯基石夕燒氧基I甲 基-4 -經基吼嘻ϋ定Trans-1-t-butoxymethyl-(2S)-(t-butyldiphenyl oxalate alkoxy-4-methyl-4 - thiol

OHOH

日心 'OTBDPS 在0 °C下於反-1-第三丁氧羰基-（2S) -羥甲基-4-羥基吼 咯啶（2. 17克，1 0· 0毫莫耳）及咪唑（2. 04克，30· 0毫莫耳） 溶於DMF(50毫升）之攪拌溶液中加入TBDPS-Cl(3· 03克， 11 · 0毫莫耳）。使反應混合物在室溫下攪拌1 8小時。加入 水，並以EtOAc萃取。將萃取液以水洗滌，然後於Na2S04上 乾燥，並於真空中濃縮。使殘留物經由於矽膠上利用正己 烷-EtOAc(3:2，v/v)作為洗提液進行管柱層析，純化而得 反-1-第三丁氧羰基-（2S)-(第三丁基二苯基矽烷氧基）曱 基-4 -羥基咄咯啶（1· 5克，33%)之白色結晶固體。1H-NMR (CDC13)6 1.03 (s，9H)、1.25 及 1·32 (各s，9H)、 1.90-2.10 (m， 1Η)、2·30-2·40 (m， 1Η)、3·40-3·80Rixin 'OTBDPS at 0 ° C in trans-1-t-butoxycarbonyl-(2S)-hydroxymethyl-4-hydroxyindole (2.17 g, 10.0 mmol) and imidazole (2. 04 g, 30·0 mmol) In a stirred solution of DMF (50 ml), TBDPS-Cl (3.03 g, 11.0 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours. Water was added and extracted with EtOAc. The extract was washed with water, dried over Na 2 SO 4 and concentrated in vacuo. The residue was subjected to column chromatography using n-hexane-EtOAc (3:2, v/v) as an eluent to obtain the trans-1-t-butoxycarbonyl-(2S)- Tributyldiphenylnonyloxy)nonyl-4-hydroxypyrrolidine (1.5 g, 33%) as a white crystalline solid. 1H-NMR (CDC13)6 1.03 (s, 9H), 1.25 and 1·32 (each s, 9H), 1.90-2.10 (m, 1Η), 2·30-2·40 (m, 1Η), 3· 40-3·80

\\312\2d-code\90-01\89112968.ptd 第 540 頁 1283240 五、發明說明（536) (m，3H)、3.95-4.15 (m，2H)、4·45-4·55 (m，1H)、 7· 37-7. 39 (m，6H)、7.63-7· 64 (m，4H)。 順-4-溴-1_第三丁氧羰基~(2S)-(第三丁基二笨基矽烷氧 基）甲基吼咯啶\\312\2d-code\90-01\89112968.ptd Page 540 1283240 V. INSTRUCTIONS (536) (m, 3H), 3.95-4.15 (m, 2H), 4·45-4·55 (m , 1H), 7·37-7. 39 (m, 6H), 7.63-7. 64 (m, 4H). Cis-4-bromo-1_t-butoxycarbonyl~(2S)-(t-butyldiphenylphosphoryl)methylpyrrolidine

BrBr

BocN ^-OTBDPS 在室溫下於反-1-第三丁氧羰基-(2S)-(第三丁基二苯基 石夕烧氧基）甲基_4 -經基吼嘻σ定（91〇毫克，2·〇毫莫耳）及 Ph3P(628毫克，2·4毫莫耳）溶於THF(2〇毫升）之攪拌溶液 中加入CBi*4 ( 9 9 3毫克，3· 〇毫莫耳）。使反應混合物在室溫 ίϊ拌0並5二時;：入正己烧(4〇毫升）。#所產i之固體 ^ ”二中乾燥。使殘留物經由於矽膠上利用τ： ρ 純化而得順+演為洗提液進行管柱層析， 基石夕烧氧基)甲“二^7/厌基:(旦2…(第三丁基二苯 l-NMR (CDC13) &lt;5 i 〇fi々r 疋里）之凌黃色油。 、2.63 (m，2H)、3 49 m 〜1.31 及1,45 (各s，9H) (m, 1H) nQ rq-4 i.. 7.3…2 (m’ 6H)、7 64_7. .8 .U U，5H)、 胺基+第三丁氧幾基_ H)。 氧基）甲基咄咯啶 k乐一丁基二苯基矽烷BocN ^-OTBDPS at room temperature in trans-1-t-butoxycarbonyl-(2S)-(t-butyldiphenyl-sodium alkoxy)methyl-4-yl-based 吼嘻σ(91〇 Mg, 2·〇 mmol, and Ph3P (628 mg, 2.4 mmol) dissolved in THF (2 mL), added CBi*4 (9 9 3 mg, 3·3 mmol) ). The reaction mixture was stirred at room temperature for 0 and 5:2; and then hexane (4 mL). #的固体的固体^ "2" is dried. The residue is purified by τ: ρ on the tannin extract to obtain the eluent for column chromatography, and the base is oxidized to a base. / anodic group: (1) (t-butyl diphenyl 1-NMR (CDC13) &lt; 5 i 〇fi々r 疋里) of the yellow oil., 2.63 (m, 2H), 3 49 m ~ 1.31 And 1,45 (each s,9H) (m, 1H) nQ rq-4 i.. 7.3...2 (m' 6H), 7 64_7. .8 .UU,5H), amine + third butoxide Base _ H). Oxy)methylpyrrolidine k-butyl-diphenylnonane

OTBDPSOTBDPS

89112968.ptd 第541頁 1283240 五、發明說明（537) 在室溫下於順-4-溴-1-第三丁氧羰基—（2S)-(第三丁基 二苯基矽烷氧基）甲基吼咯啶（48 0毫克，〇· 93毫莫耳）溶&quot;於 DMF(5毫升）之攪拌溶液中加入NaNs(241毫克，3· 70毫莫 耳）。使反應混合物在7 0 X：下攪拌3天。加入水，並以 EtOAc萃取。將萃取液以水洗滌，然後於Na2S〇4上乾燥，並 於真空中濃縮。將粗製產物不經進一步的純化而使用於後 續的反應中。使粗製產物溶於EtOH( 10毫升）之溶液在丨〇% Pd C上於大氣壓力下在至溫下氮化4小時。將催化劑淚 除，及將濾液於真空中濃縮而得反—4-胺基-1—第三丁氧毅 基（2S)-(第二丁基一苯基石夕烧氧基）甲基吼略。定（4〇〇毫 克，95%)之無色油。iH-NMR (CDC13) 6 1· 06 (s，9H)、 1· 32 及 1· 45 (各s,總計 9H)、2· 20-2· 35 (m, 1H)、 3·05-3.18 (m，1H)、3·55-4·05 (m, 6H)、7·35-7·41 (m， 6Η) 、 7. 61-7· 69 (m, 4Η) 。 * 反-1-第三丁氧羰基-(2S)-(第三丁基二苯基石夕烧氧基）甲 基-4-二曱胺基咄咯啶 、N〆 ό89112968.ptd Page 541 1283240 V. INSTRUCTIONS (537) At room temperature in cis-4-bromo-1-t-butoxycarbonyl-(2S)-(t-butyldiphenylnonyloxy)- Add hydrazide (48 0 mg, 〇·93 mmol) to a stirred solution of DMF (5 mL) and add NaNs (241 mg, 3.70 mmol). The reaction mixture was stirred at 70 X: for 3 days. Water was added and extracted with EtOAc. The extract was washed with water, dried over Na 2 EtOAc 4 and concentrated in vacuo. The crude product was used in the subsequent reaction without further purification. A solution of the crude product in EtOH (10 mL) was nitrided on 丨〇% Pd C at atmospheric pressure for 4 hr. The catalyst is decanted, and the filtrate is concentrated in vacuo to give the anti-4-amino-1-t-butoxy-yl (2S)-(t-butyl-phenyl- sulphonyloxy)methyl oxime . A colorless oil (4 gram, 95%). iH-NMR (CDC13) 6 1· 06 (s, 9H), 1·32 and 1·45 (each s, total 9H), 2·20-2· 35 (m, 1H), 3·05-3.18 ( m, 1H), 3·55-4·05 (m, 6H), 7·35-7·41 (m, 6Η), 7. 61-7· 69 (m, 4Η). * trans-1-t-butoxycarbonyl-(2S)-(t-butyldiphenyl oxalate alkoxy)methyl-4-didecylaminopyrrolidine, N〆 ό

Boc ^-OTODPS 在〇°C下於反-4-胺基-1-第三丁氧羰基—（2S)-(第三丁基 二苯基矽烷氧基）曱基咄咯啶（4〇〇毫克，〇·88毫莫耳）、 八(：011(120毫升，2.0毫莫耳）、及37%11(^0水溶液（5 0 0毫 升）溶於MeOH(l〇毫升）之攪拌溶液中加入NaBH3CN (1 j J毫 克，1 · 7 6毫莫耳）。使反應混合物在室溫下攪拌丨8小時。 於在真空中濃縮後，加入水，並以CH2Cl2萃取。將萃取液Boc ^-OTODPS at 〇 ° C in trans-4-amino-1-t-butoxycarbonyl-(2S)-(t-butyldiphenylnonyloxy)decylpyrrole (4〇〇 </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; NaBH3CN (1 j J mg, 1 · 7 6 mmol) was added. The reaction mixture was stirred at room temperature for 8 hours. After concentrating in vacuo, water was added and extracted with CH.sub.2Cl.

\\312\2d-code\90-01\89112968.ptd 第542頁 1283240 五、發明說明（538) 於NaJO4上乾燥，並於真空中濃縮。使殘留物經由於矽膠 上利用MeOH-CH2C12(3: 97，v/v)作為洗提液進行管柱層 析，純化而得反-1-第三丁氧羰基〜（2S) —(第三丁基二苯基 石夕院氧基）曱基-4-二曱胺基吼咯啶（33〇毫克，的淡黃 色油。UMR (CDC13)5 1.06 (s，911)、133及1.45 (各 s，總計9H)、1·80-2·25 (m，2H)、2·23 (br s，6H)、 2 · 9 5 - 4 · 0 5 ( m，6 H )、7. 3 6 - 7 · 3 9 (m, 6 H)、7 · 6 3 - 7 6 5 (m，4H)。 反-1-第三丁氧羰基-4-二曱胺基—（2S)—羥甲基咄咯啶 、N〆\\312\2d-code\90-01\89112968.ptd Page 542 1283240 V. INSTRUCTIONS (538) Dry on NaJO4 and concentrate in vacuo. The residue was subjected to column chromatography using MeOH-CH2C12 (3: 97, v/v) as an eluent, and purified to give trans-1-t-butoxycarbonyl~(2S)-(third Butyl diphenyl oxalate oxy) decyl-4-didecylaminopyrrolidine (33 〇 mg, pale yellow oil. UMR (CDC13) 5 1.06 (s, 911), 133 and 1.45 (each s , total 9H), 1·80-2·25 (m, 2H), 2·23 (br s, 6H), 2 · 9 5 - 4 · 0 5 ( m, 6 H ), 7. 3 6 - 7 · 3 9 (m, 6 H), 7 · 6 3 - 7 6 5 (m, 4H). Trans-1-t-butoxycarbonyl-4-didecylamino-(2S)-hydroxymethylhydrazine Pyridine, N〆

Boc 飞-OH 在o°c下於反-1-第三丁氧羰基—（2s) — (第三丁基二苯基 矽烷氧基）甲基^-二甲胺基咄咯啶（330毫克，0·68毫莫 耳）浴於THF(5耄升）之攪拌溶液中加入TBAF(1· 之溶 液1 · 0毫升1 · 0毫莫耳）。使反應混合物在室溫下攪拌2 小時。將混合物於真空中濃縮。使殘留物經由於 用心〇11-叫(：12(3:97至20:8 0，ν/ν)作為洗提液進行管柱= 析，純化而得第三丁氧幾基_4—二甲胺基一（2S)一羥甲 基咄咯啶（180耄克，定量）之淡黃色油。1H-NMR (CDC1J占 1.47 (s，9H)、2·23 (s，6H)、1 6 5- 1 75 (m，2H)、 2·75一4.10 (:， 4H) 、3·61 (d， J=5.6 Hz, 2H)。 4-[反-1-第三丁氧羰基—4—二甲胺基—（2S)一咄咯啶基]曱氧 苯甲酸甲酯Boc fly-OH at trans--1-butoxycarbonyl-(2s)-(t-butyldiphenylnonyloxy)methyl-dimethylaminopyrrolidine (330 mg) at o°c , 0. 68 millimolar) Bath was added to a stirred solution of THF (5 liters) to add TBAF (1·1 solution 1 · 0 ml 1 · 0 mmol). The reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo. The residue is subjected to a column of 用11-called (:12 (3:97 to 20:8, ν/ν) as an eluent for column column analysis, and purified to obtain a third butoxy group _4 - two A pale yellow oil of methylamino(2S)-hydroxymethyl-pyridinidine (180 g, quantitative). 1H-NMR (CDC1J occupies 1.47 (s, 9H), 2·23 (s, 6H), 1 6 5- 1 75 (m, 2H), 2·75 - 4.10 (:, 4H), 3.61 (d, J = 5.6 Hz, 2H) 4-[trans-1-t-butoxycarbonyl-4- Methyl dimethylamino-(2S)-indolylpyridinyl]oxobenzoate

\\312\2d-code\90-01\89112968.ptd 第543頁 1283240 五、發明說明（539) 在0°C下於反-1-第三丁氧羰基一 4-二曱胺基-（2S)-羥甲 基吡咯啶（1 8 0毫克，〇 · 7 3毫莫耳）、4 -羥基苯甲酸甲酯 (114毫克，0.75毫莫耳）、及ph3p(296毫克，1.13毫莫耳） 溶於THF(10毫升）之攪拌溶液中加入DIAD(227毫克，1.13 耄莫耳）。使反應混合物在7 0 °C下撲:拌1 8小時。將混合物 於真空中濃縮。將殘留物經由於矽膠上利用正己烧—Et〇Ac (1:2，v/v)至 Me0H-CH2Cl2(5:95，v/v)作為洗提液進行管 柱層析’純化而得4-[反-1-第三丁氧幾基—二甲胺基 -（2S)-咄咯啶基]甲氧苯曱酸甲酯（18〇毫克，68%)之淡黃 色油。1 一NMR (CDC13)5 1.46 (s， 9Η)、ι·8〇 — 1 95 (11/ 1H)、2.20-2·23 (m，1H)、2·24 (s，6H)、2 90-2 95 (m，1 Η )、3 · 1 0 - 3 · 3 0 (m，1 Η)、3 · 5 0 - 3 · 6 5 (m 1H)、 3·88 (s，3H)、3·95-4·35 (m，3H)、6·93一r qwm 2H) 、 7. 96-7.98 (m， 2H)。 ’ 4-[反-4-二甲胺基-1 - [3-曱氧基-4-[N，-（2-甲基苯基）脲 基]苯基乙醯基]-（2S)-吼咯啶基]甲氧笨曱酸甲酉旨 丫\\312\2d-code\90-01\89112968.ptd Page 543 1283240 V. Description of the invention (539) at 0 ° C in trans-1-t-butoxycarbonyl-4-indanyl-( 2S)-Hydroxymethylpyrrolidine (180 mg, 〇·7 3 mmol), methyl 4-hydroxybenzoate (114 mg, 0.75 mmol), and ph3p (296 mg, 1.13 mmol) DIAD (227 mg, 1.13 mmol) was added to a stirred solution of THF (10 mL). The reaction mixture was allowed to boil at 70 ° C: mixing for 18 hours. The mixture was concentrated in vacuo. The residue was purified by column chromatography on the tannin extract using EtH-Et〇Ac (1:2, v/v) to Me0H-CH2Cl2 (5:95, v/v) as an eluent. - [Ret-1-butoxybutyryl-dimethylamino-(2S)-decalidyl]methyl methoxybenzoate (18 mg, 68%) as a pale yellow oil. 1 NMR (CDC13) 5 1.46 (s, 9Η), ι·8〇— 1 95 (11/ 1H), 2.20-2·23 (m, 1H), 2·24 (s, 6H), 2 90- 2 95 (m,1 Η ), 3 · 1 0 - 3 · 3 0 (m,1 Η), 3 · 5 0 - 3 · 6 5 (m 1H), 3·88 (s, 3H), 3· 95-4·35 (m, 3H), 6.93-r qwm 2H), 7. 96-7.98 (m, 2H). '4-[Trans-4-dimethylamino-1 -[3-indolyl-4-[N,-(2-methylphenyl)ureido]phenylethenyl]-(2S)-吼 啶 基 ] 甲 甲 甲 甲 甲

Me Η H 〇Me 1 在0 °C下於4-(反-1-第三丁氧羰基-4—二甲胺基-(2S)_咄 咯啶基）甲氧苯甲酸甲酯（ 2 0 0毫克，〇, 53毫莫耳）溶於 CWe毫升）之攪拌溶液中加入TFA(3毫升）'。使^應混合Me Η H 〇Me 1 at 0 ° C in methyl 4-(trans-1-t-butoxycarbonyl-4-dimethylamino-(2S)-pyridinyl)methoxybenzoate (20 TFA (3 ml) was added to a stirred solution of 0 mg, hydrazine, 53 mmol. Make ^ should be mixed

\\312\2d-code\90-01\89112968.ptd 第544頁 1283240 &quot;i、發明說明（540) ' ~ &quot; - 物於至溫下攪拌〇 · 5小時。將混合物於真空中濃縮。將飽 和NaHC〇3加至殘留物，並以CH2C“萃取。將萃取液以鹽水 洗滌，於NaJO4上乾燥，並於真空中濃縮。將粗製產物不 經進一步的純化而使用於後續的反應。在0 °C下於此粗製 產物、3-甲氧基一 4-[N’- (2—曱基苯基）脲基]苯乙酸（166 毫’ 0. 5&gt;3毫莫耳）、H0Bt(71毫克，0.53毫莫耳）、及三 乙胺（140宅升’丨·10毫莫耳）溶於THF(5毫升）及MeCN (5毫 升）之攪拌溶液中加入EDC ·Η(： 1(152毫克，0.79毫莫耳）。 使反應混合物在室溫下攪拌丨6小時，並於真空中濃縮。將 水加至殘留物’並以Et〇Ac萃取。將萃取液以飽和NaHC〇3 洗條’然後於NaJC^上乾燥，並於真空中濃縮。將殘留物 經由於石夕膠上利用Et0Ac至CH2Cl2 一 Me〇H (8:92，v/v)作為 洗提液進行管柱層析，純化而得4_[反—4-二甲胺基_丨—[3 一 曱氧基-4- [Ν’ -（2-曱基苯基）脲基]苯基乙醯基卜（2幻一，比 洛咬基]曱氧苯甲酸甲酯（ 26 0毫克，86%)之無色油。1 Η-NMR (CDC13) 6 ι·95-2·15 (m，3Η)、2·23 (s，6Η)、 2·31 (s，3Η)、3·30-3·34 (m，1Η)、3·57 (s，2Η)、 3.61 (s，3Η)、3· 70-3.75 (m，1Η)、4·1Η·15 (m， 2H)、4·45-4·50 (m，1H)、6·34 (s，1H)、6·72-6·88 (m，4H)、7·08-7·24 (m, 4H)、7·5 卜 7·53 (m，1H)、 7· 92-8· 07 (m，3H)。 於4-[反-4_二曱胺基一 i-[3-甲氧基—4 一 [N，—（2 —甲基苯 基）脲基]苯基乙醯基]-2 -吡咯啶基]甲氧苯曱酸曱酯（260 毫克’ 0· 45毫莫耳）溶於THf(4· 0毫升）及Me〇H(2. 0毫升）之\\312\2d-code\90-01\89112968.ptd Page 544 1283240 &quot;i, invention description (540) ' ~ &quot; - Let the mixture stir until 温 · 5 hours. The mixture was concentrated in vacuo. Saturated NaHC(R)3 was added to EtOAc (EtOAc m. The crude product, 3-methoxy-4-[N'-(2-mercaptophenyl)ureido]phenylacetic acid (166 mM '0.5 gt; 3 mM), H0Bt (0 ° C) Add 71% (0.53 mmol), and triethylamine (140 liters 丨·10 mmol) to a stirred solution of THF (5 mL) and MeCN (5 mL). Add EDC · Η (: 1 ( 152 mg, 0.79 mmol. The reaction mixture was stirred at room temperature for 6 hours and concentrated in vacuo. Water was added to the residue and extracted with Et.Ac. The extract was washed with saturated NaHC. The strip was then dried over NaJC^ and concentrated in vacuo. The residue was purified by column chromatography eluting with Et0Ac to CH2Cl2 -Me?H (8:92, v/v) as eluent , purified to give 4_[trans-4-dimethylamino-indole-[3-methoxy-4-[Ν'-(2-mercaptophenyl)ureido]phenylethylhydrazinyl (2 magic One, Bilo bite base Methyl formate (260 mg, 86%) as a colorless oil. 1 Η-NMR (CDC13) 6 ι·95-2·15 (m,3Η), 2·23 (s,6Η), 2·31 (s , 3Η), 3·30-3·34 (m, 1Η), 3.57 (s, 2Η), 3.61 (s, 3Η), 3·70-3.75 (m, 1Η), 4·1Η·15 ( m, 2H), 4·45-4·50 (m, 1H), 6·34 (s, 1H), 6·72-6·88 (m, 4H), 7·08-7·24 (m, 4H), 7·5 Bu 7·53 (m, 1H), 7· 92-8· 07 (m, 3H). 4-[trans-4-diamine-i-[3-methoxy] —4 —[N,—(2-methylphenyl)ureido]phenylethenyl]-2-pyrrolidinyl]methoxybenzoate (260 mg '0·45 mmol) In THf (4.0 ml) and Me〇H (2.0 ml)

\\312\2d-code\90-01\89112968.ptd 第545頁 1283240 五、發明說明（541) 攪拌溶液中加入IN NaOH(0. 90毫升，〇· 90毫莫耳）。使混 合物在70 °C下攪拌24小時。將混合物於真空中濃縮，加入 水，並以1N HC1中和。收集所產生之固體，以水洗滌，並 於真空中乾燥而得1 5 5 ( 2 0 0毫克，7 9 %)的白色結晶固體。 熔點 145-150 °C; IR (KBr) 3355、2948、1698、1604、 1533、1454、1417、1255、1226、1166、1035、755 / 公 分；1H-NMR (DMS〇-d6) (5 1.82-1.98 (m，1H)、2.08 - 2.11 (m，1H)、2·20 (s，6H)、2·25 (s, 3H)、3·40-3·60 (m， 3Η)、3·64 (s, 2Η)、3·82 (s，3Η)、4·(Η-4.16 (m， 2Η) 、4·36 (m， 1Η) 、6·74-7·15 (m, 7Η) 、7·77-8·02 (m， 4Η) 、8·44 (s， 1Η) 、8·54 (s， 1H); MS(FAB) m/z 561(ΜΗ1) ; C31H36N4 06 · 1· 2Η20 之分析計算值：C， 6 3. 9 5 ; Η，6· 65 ; Ν， 9· 62。實測值：C， 63. 82 ; Η，6· 72 ; Ν， 9· 44。 實施例148 4-[反-4~二曱胺基-1 - [3-甲氧基-4 - [Ν’ -（2-曱基苯基）脲 基]苯基乙醯基]-（2S) -咄咯啶基]甲氧苯曱酸曱酯HC1鹽 、Ν〆\\312\2d-code\90-01\89112968.ptd Page 545 1283240 V. INSTRUCTIONS (541) Add IN NaOH (0. 90 ml, 〇·90 mmol) to the stirred solution. The mixture was stirred at 70 ° C for 24 hours. The mixture was concentrated in vacuo, water was added and neutralized with 1N EtOAc. The resulting solid was collected, washed with water and dried in vacuo to give 1 5 5 (200 mg, 79. Mp 145-150 ° C; IR (KBr) 3355, 2948, 1698, 1604, 1533, 1454, 1417, 1255, 1226, 1166, 1035, 755 / cm; 1H-NMR (DMS 〇-d6) (5 1.82- 1.98 (m,1H), 2.08 - 2.11 (m,1H), 2·20 (s,6H), 2·25 (s, 3H), 3·40-3·60 (m, 3Η), 3·64 (s, 2Η), 3·82 (s, 3Η), 4·(Η-4.16 (m, 2Η), 4·36 (m, 1Η), 6.74-7·15 (m, 7Η), 7 ·77-8·02 (m, 4Η), 8.44 (s, 1Η), 8.54 (s, 1H); MS(FAB) m/z 561(ΜΗ1) ; C31H36N4 06 · 1· 2Η20 analysis Calculated value: C, 6 3. 9 5 ; Η, 6· 65 ; Ν, 9· 62. Found: C, 63. 82 ; Η, 6· 72 ; Ν, 9· 44. Example 148 4-[ Trans-4~diamido-1 -[3-methoxy-4 -[Ν'-(2-mercaptophenyl)ureido]phenylethenyl]-(2S)-indolyl Ammonium methoxybenzoate HC1 salt, hydrazine

Me H Η OMe 3Ό_， COOMeMe H Η OMe 3Ό_, COOMe

HCI 156 在0°C下於反-4-[4-二甲胺基-1 - [3-甲氧基-4-[N，-( 甲基苯基）脲基]苯基乙醯基]-（2S)-^b^咬基]曱氧苯曱酸 (80毫克，0.14毫莫耳）溶於甲苯（4·0毫升）及Me 0H (1.0毫 升）之攪拌溶液中加入TMSCHN2(2· 0M正己烷溶液，1〇〇毫HCI 156 at 0 ° C in trans-4-[4-dimethylamino-1 -[3-methoxy-4-[N,-(methylphenyl)ureido]phenylethenyl] -(2S)-^b^biti] oxime benzoic acid (80 mg, 0.14 mmol) dissolved in toluene (4.0 ml) and Me 0H (1.0 ml) in a stirred solution of TMSCHN2 (2· 0M n-hexane solution, 1 〇〇

\\312\2d-code\90-01\89112968.ptd 第546頁 1283240 五、發明說明（542) &quot; -- 升，0 · 2 0毫莫耳）。使反應混合物在室溫下攪拌丨· 5小時。 將混合物於真空中濃縮。將殘留物經由於石夕膠上利用 Me0H-CH2Cl2(5:95，v/v)作為洗提液進行管柱層析而純 化。將產物溶解於EtOH(5.0毫升），並加入in HC1(溶於 EtOH) ( 2 44微升，0 · 244毫莫耳）。使混合物於真空中濃縮 而得1 5 6 ( 72毫克，88°/〇)的非晶形固體。；^(〇1') 3 345、 2950 、 2586 、 1712 、 1604 、 1511 、 1454 、 1284 、 1255 、 1170、1114、1 0 29、850、7 71 / 公分；M-NMR (DMS〇-d6) 6 2·25 (s，3H)、2.35 -2.37 (m，2H)、2·77 - 2.81 (m， 6H) 、3·62-3.71 (m， 2H) 、3·79-3·81 (m， 8H) 、3·99-4.16 (m，3H)、4·50-4.70 (m，1H)、6·74-7.16 (m， 7Η)、7·77-8·01 (m，4Η)、8·48 (s，1Η)、8·55 (s, 1Η) ; C32H38N4 06 · 1· 0HC1 · 1· 2Η20 之分析計算值：C，60.74 ;H，6.59; Ν，8·85。實測值：C， 61·03;Η， 6·78;Ν， 8.33。 實施例1 4 9 4一 [順一 4 -二曱胺基—1 —[3 -甲氧基-4 一 [Ν，一（2-曱基苯基）脲 基]苯基乙醯基]-(2S)-吼咯啶基]甲氧苯曱酸\\312\2d-code\90-01\89112968.ptd Page 546 1283240 V. Description of the invention (542) &quot; -- l, 0 · 2 0 millimoles). The reaction mixture was stirred at room temperature for 5 hours. The mixture was concentrated in vacuo. The residue was purified by column chromatography using Me0H-CH2Cl2 (5:95, v/v) as an eluent. The product was dissolved in EtOH (5.0 mL) and was taken in &lt;RTI ID=0.0&gt;&gt; The mixture was concentrated in vacuo to give 1 5 6 (yield: &lt ;^(〇1') 3 345, 2950, 2586, 1712, 1604, 1511, 1454, 1284, 1255, 1170, 1114, 1 0 29, 850, 7 71 / cm; M-NMR (DMS〇-d6) 6 2·25 (s,3H), 2.35 -2.37 (m,2H), 2.77 - 2.81 (m, 6H), 3.62-3.71 (m, 2H), 3·79-3·81 (m , 8H), 3·99-4.16 (m, 3H), 4·50-4.70 (m, 1H), 6.74-7.16 (m, 7Η), 7·77-8·01 (m, 4Η), 8·48 (s,1Η), 8·55 (s, 1Η); C32H38N4 06 · 1· 0HC1 · 1· 2Η20 Analysis calculated: C, 60.74; H, 6.59; Ν, 8.85. Found: C, 61·03; Η, 6.78; Ν, 8.33. Example 1 4 9 4 -[cis-1 4 -didecylamino-1-[3-methoxy-4-[indolyl]-(2-mercaptophenyl)ureido]phenylethenyl]-( 2S)-Pyrridinyl]methoxybenzoic acid

COOH Μβ Η Η 〇Me 157COOH Μβ Η Η 〇Me 157

-[順-1-第三丁氧羰基-(2S)-(第三丁基二苯基碎烧氧基） 甲基-4 -咄咯啶基]酞醯亞胺-[cis-1-t-butoxycarbonyl-(2S)-(t-butyldiphenylpyroxy)methyl-4-indenylpyridinyl]indenine

\\312\2d-code\90-01\89112968.ptd 第547頁 1283240\\312\2d-code\90-01\89112968.ptd Page 547 1283240

在〇°C下於順-1-第三丁氧羰基—（2S) — (第三 丁 苯基 矽烷氧基）曱基-4-羥基吼咯啶（1·82毫克，4〇毫ι莫耳）、 駄醯亞胺（647毫克，4·4毫莫耳）、及ph3p(126克、，4·8毫 莫耳溶於THF(2 0毫升）之攪拌溶液中加入DIAD( 889毫克， 4 · 4毫莫耳）。使反應混合物在室溫下攪拌丨8小時。將混合 物於真空中濃縮。將殘留物經由於石夕膠上利用正己烧 - Et0Ac(5/l，v/v)作為洗提液進行管柱層析，純化: N-[順-第三丁氧幾基-(2S) —(第三丁基二苯基矽烷氧 丨甲基-4-吼洛。定基]酜醯亞胺（1.6克，69%)之非晶形固體土。 H-NMR (CDC13) 5 1.0 7 (s，9H)、13〇 及 14 妯In cis °C in cis-1-t-butoxycarbonyl-(2S)-(t-butylphenylnonyloxy)indolyl-4-hydroxypyrrolidine (1·82 mg, 4 〇 millimole Add DIAD (889 mg, 駄醯), 駄醯iamine (647 mg, 4.4 mmol), and ph3p (126 g, 4.8 mmol) dissolved in THF (20 mL). 4 · 4 mmol). The reaction mixture was stirred at room temperature for 8 hours. The mixture was concentrated in vacuo. The residue was applied to the mixture with hexanes - Et0Ac (5/l, v/v) Column chromatography as an eluent, purification: N-[cis-t-butoxy-yl-(2S)-(t-butyldiphenyldecaneoxymethyl-4-indole.] Amorphous solid soil of quinone (1.6 g, 69%) H-NMR (CDC13) 5 1.0 7 (s, 9H), 13 〇 and 14 妯

計9H)、2·27-2.37 (m，1H)、2.94_ 2 96 (m，1H)、3 J -4.09 (m，5H)、4.72 (m，1H)、7. 37_7.38 (m . 7.67-7.74 (m，6H)、7. 84-7.86 (m, 2H)。 ’ :;4甲m第三丁氧幾基(2s)-(第…二笨基錢氧 暴）甲基ϋ比洛咬9H), 2·27-2.37 (m, 1H), 2.94_ 2 96 (m, 1H), 3 J -4.09 (m, 5H), 4.72 (m, 1H), 7. 37_7.38 (m . 7.67-7.74 (m, 6H), 7. 84-7.86 (m, 2H). : :; 4 methyl m third butoxy group (2s) - (the second ... 2 stupid money oxygen storm) methyl ϋ ratio Luo bite

Boc VOTBDPS 在室溫下於N-[順-1-第三丁氧羰基—（2S) —(第三丁旯一 苯基矽烷氧基）甲基-4 -咄咯啶基]酞醯亞胺（ι·6〇克，$ 毫莫耳）溶於EtOH(8毫升）之攪拌溶液中加入Νη2ΝΗ2 · η 〇 74 (206毫克，4· 11毫莫耳）。使反應混合物於70它下2视^】Boc VOTBDPS at room temperature in N-[cis-1-tert-butoxycarbonyl-(2S)-(t-butyl-phenyl-phenyl-alkoxy)methyl-4-pyridinyl]indenine (1·6 gram, $1 ml) was dissolved in EtOH (8 ml) and stirred to give Νη 2 ΝΗ 2 · η 〇 74 (206 mg, 4·11 mmol). Bring the reaction mixture to 70 under it.

\\312\2d-code\90-01\89112968.ptd 第548頁 1283240 五、發明說明（544) - 時。將混合物於真空中濃縮。將所產生之固體據除，並以 CHCI3洗滌。將濾液於真空中濃縮，而得順—4-胺基—丨—第 三丁氧羰基-（2S)-(第三丁基二苯基矽烷氧基）甲^ π比略。定 (1 · 3克，定量）之淡黃色油。將粗製產物不經進步的純％ 化而使用於後續的反應。1H-NMR (CDC13) d 1 · 〇6gH) 、1· 30 及1· 45 (各s，總計9H)、1· 59 (m，1H)、1 Qc；, 1 · 〇b (m,\\312\2d-code\90-01\89112968.ptd Page 548 1283240 V. INSTRUCTIONS (544) - TIME. The mixture was concentrated in vacuo. The solid produced was removed and washed with CHCI3. The filtrate was concentrated in vacuo to give cis-4-amino-indole-tributyloxycarbonyl-(2S)-(t-butyldiphenylnonyloxy)methyl π ratio. A pale yellow oil (1 · 3 g, quantitative). The crude product is used in subsequent reactions without substantial purification. 1H-NMR (CDC13) d 1 · 〇6gH), 1·30 and 1·45 (each s, total 9H), 1.59 (m, 1H), 1 Qc;, 1 · 〇b (m,

1H)、2· 94 (m，1H)、3· 44 (m，1H)、3. 78-4 0 7 r ,TTN • u ( Cm, 4H) 、7.36-7.41 (m，6H)、7·5 卜 7·65 (m，4H)。 順-1-第三丁氧羰基-（2S)-(第三丁基二苯基矽燒氧美）甲 基-4 -二甲胺基吡咯啶 、〆1H), 2· 94 (m, 1H), 3.44 (m, 1H), 3.78-4 0 7 r , TTN • u ( Cm, 4H) , 7.36-7.41 (m, 6H), 7· 5 Bu 7·65 (m, 4H). Cis-1-tert-butoxycarbonyl-(2S)-(t-butyldiphenylfluorenyloxy)methyl-4-dimethylaminopyrrolidine, hydrazine

BocN~^OTBDPS 在0 °C下於順-4-胺基-1-第三丁氧羰基—（2S)-(第三丁基 一^本基碎烧乳基）曱基。比17各ϋ定（1.24克，2.74毫莫耳）、 Ac0H( 3 74微升，5.48毫莫耳）、及37% HCH0水溶液（丨.0毫 升）溶於MeOH(20毫升）之攪拌溶液中加入NaBH3CN ( 3 45毫 克，5 · 4 8毫莫耳）。使反應混合物在室溫下擾拌丨8小時。 於在真空中濃縮後，加入水，並以CH2C12萃取。將萃取液 於NaJO4上乾燥，並於真空中濃縮。使殘留物經由於矽膠 上利用丛〇011-(：112(：12(3:97，\^/〇作為洗提液進行管柱層 析，純化而得順-1-第三丁氧羰基—（2S)-(第三丁基二苯基 矽烷氧基）甲基- 4 -二曱胺基咄咯啶（1 · 1克，8 3 % )的淡黃色 油。1H-NMR (CDC13) 5 1· 05 (s，9H)、1. 29 及1. 45 (各s, 總計9H)、1·95-2.04 (m，1H)、2·2 0-2.26 (m， 1H)、BocN~^OTBDPS is a cis-4-amino-1-t-butoxycarbonyl-(2S)-(t-butyl-mono-based calcined milk base) sulfhydryl group at 0 °C. More than 17 ϋ (1.24 g, 2.74 mmol), Ac0H (3 74 μl, 5.48 mmol), and 37% aqueous HCH0 (丨.0 mL) dissolved in MeOH (20 mL) Add NaBH3CN (3 45 mg, 5 · 4 8 mmol). The reaction mixture was stirred at room temperature for 8 hours. After concentration in vacuo, water was added and extracted with CH2C12. The extract was dried over NaJO4 and concentrated in vacuo. The residue was purified by column chromatography using 〇011-(:112(:12(3:97,\^/〇 as eluent) to obtain cis-1-t-butoxycarbonyl- (2S)-(T-butyldiphenylnonyloxy)methyl-4-nonylaminopyrrolidine (1 · 1 g, 83%) in pale yellow oil. 1H-NMR (CDC13) 5 1· 05 (s, 9H), 1. 29 and 1. 45 (each s, total 9H), 1.95-2.04 (m, 1H), 2·2 0-2.26 (m, 1H),

\\312\2d-code\90-01\89112968.ptd 第549頁 1283240 五、發明說明（545) 2·27 (s，6H)、2·54 (m，1H)、3·00-3·02 (m，1H)、 3.62-4·03 (m，4Η)、7·34 - 7·41 (m，6Η)、7·63 - 7·65 (m，4Η)。 順_ 1 -第二丁氧幾基—4 一二甲胺基-（2 S) -經甲基吼σ各咬 在0 °C下於順-1—第三丁氧羰基—2_ (第三丁基二苯基矽烷 氧基）甲基-4 -二甲胺基咄咯啶（1·丨克，2· 27毫莫耳）溶於 THF(10毫升）之攪拌溶液中加入tbafq . 〇M之THF溶液）（4. 5 毫升，4 · 5毫莫耳）。使反應混合物在室溫下攪拌2小時。 將混合物於真空中濃縮。使殘留物經由於矽膠上利用 MeOH-CH2Cl2(3/97至20/80，v/v)作為洗提液進行管柱層 析，純化而得順-1 _第三丁氧幾基-4 -二曱胺基—（2 s ) 一声 基吼17各〇疋（580毫克’疋里）之&amp;育色油。1H-NMR (CDC1 ) 1.47 (s，9Η)、1.25- 1.96 (m，2Η)、2·25 (s，6Η)、 2.53-2.58 (m，1Η)、3·17-4.02 (m，5Η)。 4-（順-1-第三丁氧羰基-4_二曱胺基—（2S)—,比咯啶基）甲 苯甲酸甲酯 COOMe 在0 °C下於順-1-第三丁氧魏基-4-二曱胺基-(2S)_經甲 基吼咯啶（ 55 5毫克’2. 27毫莫耳）、4_羥基笨曱酸曱酿\\312\2d-code\90-01\89112968.ptd Page 549 1283240 V. Description of invention (545) 2·27 (s, 6H), 2·54 (m, 1H), 3·00-3· 02 (m, 1H), 3.62-4·03 (m, 4Η), 7·34 - 7·41 (m, 6Η), 7·63 - 7·65 (m, 4Η). Cis 1 - 2 -butoxy-yl- 4 - dimethylamino-(2 S) - via methyl 吼σ each bite at 0 ° C in cis-1 - 3 butyloxycarbonyl - 2 _ (third To a stirred solution of THF (10 ml), tbafq was added to butyl diphenyl decyloxy)methyl-4-dimethylaminopyrrolidine (1·g, 2·27 mmol). THF solution) (4.5 ml, 4 · 5 mmol). The reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo. The residue was subjected to column chromatography using MeOH-CH 2 Cl 2 (3/97 to 20/80, v/v) as an eluent, and purified to give cis-1 -t-butoxy-oxyl-4 - Di-ammonium-(2 s ) one base 吼 17 〇疋 (580 mg '疋里) &amp; 1H-NMR (CDC1) 1.47 (s, 9Η), 1.25- 1.96 (m, 2Η), 2·25 (s, 6Η), 2.53-2.58 (m, 1Η), 3·17-4.02 (m, 5Η) . 4-(cis-1-t-butoxycarbonyl-4-diamino-(2S)-,pyrrolidyl)methyl toluate COOMe at 0 °C in cis-1-third butoxy Base-4-diamino-(2S)_ via methyl pyrrolidine (55 5 mg '2.77 mmol), 4 hydroxy hydroxy acid

1283240 五、發明說明（546) (380毫克，2.5毫莫耳）、及Ph3p(1.07克，4.09毫莫耳）溶 於THF(10毫升）之攪拌溶液中加入DIAD(826毫克，4· 09毫 莫耳）。使反應混合物在7 0 °C下攪拌1 8小時。將混合物於 真空中濃縮。將殘留物經由於矽膠上利用正己烷-EtOAc (1/2，v/v)〜MeOH-CH2Cl2(5/95，v/v)作為洗提液進行管柱 層析，純化而得4 -(順-1 -第三丁氧羰基—4—二甲胺基—（2S) -吼咯啶基）曱氧苯甲酸甲酯（ 260毫克，30%)之淡黃色油。 4-NMR (CDC13” 1· 4 5 (s，9H)、1· 7〇一1· 90 (m，η)、 2·26 (s，6H)、2·33 (m，1H)、2·57 (m，iH)、3 〇6 (m， 1H)、3·85-4·23 (m，4H)、3· 88 (s，3H)、6· 93 (m， ’ 2H) 、 7·95 (m， 2H)。 4-[順-4-二甲胺基-i-[3-甲氧基_4-[N，-(2_甲基苯基）脲 基]苯基乙酿基]-(2S) -吼嘻°定基]甲氧笨甲酸甲酉旨1283240 V. Inventive Note (546) (380 mg, 2.5 mmol), and Ph3p (1.07 g, 4.09 mmol) dissolved in THF (10 mL). Add DIAD (826 mg, 4.09 m) Moore). The reaction mixture was stirred at 70 ° C for 18 hours. The mixture was concentrated in vacuo. The residue was subjected to column chromatography using n-hexane-EtOAc (1/2, v/v)~MeOH-CH2Cl2 (5/95, v/v) as an eluent, and purified to give 4 - ( Methyl cis-1 -t-butoxycarbonyl-4-dimethylamino-(2S)-oxaridinyl) oxime benzoate (260 mg, 30%) as a pale yellow oil. 4-NMR (CDC13) 1· 4 5 (s, 9H), 1·7〇1·90 (m, η), 2·26 (s, 6H), 2·33 (m, 1H), 2· 57 (m, iH), 3 〇 6 (m, 1H), 3·85-4·23 (m, 4H), 3·88 (s, 3H), 6· 93 (m, ' 2H) , 7· 95 (m, 2H) 4-[cis-4-dimethylamino-i-[3-methoxy-4-4-[N,-(2-methylphenyl)ureido]phenylethyl ]-(2S) -吼嘻°定基]Methoxybenzoic acid formazan

COOMe 在0 °C下於4-（順-1—第三丁氧羰基-4〜二曱胺基—（2S)—咄 嘻唆基）甲氧苯甲酸甲酯（ 20 8毫克，0· 55毫莫耳）溶於 叫(：12(6毫升）之攪拌溶液中加入TFA(3毫升）。使反應混合 物於室溫下攪拌〇· 5小時。將混合物於真空中濃縮。〜將 和NaHC〇3加至殘留物，並以π/〗2萃取。將萃取液以鹽/ 洗滌’於NaJO4上乾燥，並於真空中濃縮。將粗製產物不 經進一步的純化而使用於後續的反應。在〇它下於此粗製 產物、3-甲氧基一4一 [N，—（2—甲基苯基）脲基]苯乙酸q =COOMe at 0 ° C in methyl 4-(cis-1 -t-butoxycarbonyl-4~diamino-(2S)-fluorenyl) methoxybenzoate (20 8 mg, 0·55 To a stirred solution of (12 (6 ml)) was added EtOAc (3 mL). The mixture was stirred at room temperature for 5 hours. The mixture was concentrated in vacuo. 3, added to the residue, and extracted with π / 。 2. The extract was dried over NaJO 4 with a salt / washed and concentrated in vacuo. The crude product was used in the subsequent reaction without further purification. It is the crude product, 3-methoxy-4-iso[N,-(2-methylphenyl)ureido]phenylacetic acid q =

\\312\2d-code\90-01\89112968.ptd 第551頁 1283240 五、發明說明（547)\\312\2d-code\90-01\89112968.ptd Page 551 1283240 V. Description of invention (547)

毫克’ 0· 55毫莫耳）、H0Bt(74毫克，〇.55毫莫耳）、及三 乙胺（1 53微升，1· 1毫莫耳）溶於THF(6毫升）及MeCN(6毫 升）之攪拌溶液中加入EDC*HC1(160毫克，0·83毫莫耳）。 使反應混合物在室溫下攪拌丨6小時，並於真空中濃縮。將 水加至殘留物，並以Et0Ac萃取。將萃取液以飽和NaHC〇3 洗務’然後於NagSO〗上乾燥，並於真空中濃縮。將殘留物 經由於矽膠上利用EtOAc-CH2Cl2-MeOH (5/95，v/v)作為洗 提液進行管柱層析，純化而得4 一 [順一 4 -二曱胺基一 1 — [ 3 —甲 氧基4-[N -(2-曱基苯基）脲基]苯基乙醯基]—(2S) - π比ti各 °疋基]甲氧本甲酸甲酯（270毫克，47%)之無色油。1H-NMR (CDC13)5 1·95 - 2.04 (m，1Η)、2·25 (s，6Η)、2.32 (s，3Η)、2·61 (m, 1Η)、3·21 (m，1Η)、3·56 - 3·58 (m， 5Η)、3·80-3.83 (m，1Η)、3·88 (s，3Η)、4·18-4·20 (m，1 Η )、4. 41 - 4 · 4 5 (m，2 Η)、6. 3 6 (s，1 Η )、6. 6 8 -6.85 (m，4Η)、7·08-7·25 (m，4Η)、7·52-7·55 (m， 1Η) 、 7·91-8·07 (m， 3Η)。 於4-[順-4 -二曱胺基一 ΐ-[3-甲氧基-4-[Ν，-(2 -甲基笨 基）脲基]苯基乙醯基]-(2S) -吼咯啶基]曱氧苯曱酸曱酯 (270毫克，〇·47毫莫耳）溶於THF(4.0毫升）及MeOH(2.〇毫 升）之攪拌溶液中加入IN NaOH(l · 0毫升，1·〇毫莫耳）。使 混合物在7 0 °C下攪拌1 8小時。將混合物於真空中濃縮，加 入水’並以1 N H C1中和。收集所產生之固體，以水洗條， 並於真空中乾燥而得157(170毫克，65%)的白色結晶固 體。熔點 1 47-1 5 0 °C ; IR (KBr) 335 3、2952、1 700、mM '0·55 mmol, H0Bt (74 mg, 〇.55 mmol), and triethylamine (1 53 μL, 1.1 mmol) dissolved in THF (6 mL) and MeCN ( EDC*HC1 (160 mg, 0·83 mmol) was added to the stirred solution of 6 ml). The reaction mixture was stirred at room temperature for 6 h and concentrated in vacuo. Water was added to the residue and extracted with EtOAc. The extract was washed with saturated NaHC 〇3 then dried over NagSO and concentrated in vacuo. The residue was subjected to column chromatography using EtOAc-CH2Cl2-MeOH (5/95, v/v) as an eluent, and purified to give 4-[[sup. -Methoxy 4-[N-(2-mercaptophenyl)ureido]phenylethenyl]-(2S)-π ratio ti each thiol]methyl methoxybenzoate (270 mg, 47 %) of colorless oil. 1H-NMR (CDC13) 5 1·95 - 2.04 (m, 1Η), 2·25 (s, 6Η), 2.32 (s, 3Η), 2·61 (m, 1Η), 3·21 (m, 1Η) ), 3·56 - 3·58 (m, 5Η), 3·80-3.83 (m, 1Η), 3.88 (s, 3Η), 4·18-4·20 (m, 1 Η), 4 41 - 4 · 4 5 (m, 2 Η), 6. 3 6 (s, 1 Η ), 6. 6 8 -6.85 (m, 4 Η), 7·08-7·25 (m, 4 Η), 7·52-7·55 (m, 1Η), 7·91-8·07 (m, 3Η). 4-[cis-4-diguanamine-indenyl-[3-methoxy-4-[indene-(2-methylphenyl)ureido]phenylethenyl]-(2S)- Add NaOH (l · 0 ml) to a stirred solution of THF (4.0 mL) and MeOH (2 mL). , 1·〇毫莫耳). The mixture was stirred at 70 ° C for 18 hours. The mixture was concentrated in vacuo, water was added and neutralized with 1 N H C1. The solid which was produced was collected, washed with water and dried in vacuo to give 157 (170 mg, 65%) of white crystalline solid. Melting point 1 47-1 5 0 °C; IR (KBr) 335 3, 2952, 1 700,

\\312\2d-code\90-01\89112968.ptd 第552頁 1283240 五、發明說明（548) 1604、1533、1454、1415、1255、1166、1035、755 / 公 分；1H-NMR (DMSO-d6) (5 : 1. 83-1· 84 (m，1H)、2· 08-2.10 (m，1H)、2·21 (br s, 6H)、2·24 (s，3H)、3.00 (m，2Η)、3·60 (s，2Η)、3·78 (s，3Η)、3·85-4·29 (m， 4H)、6·7卜7.16 (m，7H)、7.77-8.01 (m，4Hm)、8·46 (s，1H)、8· 54 (s，1H) ; MS(FAB) m/z 561(M+ + H)+ ; C31H36N4 06 · 2H20 之分析計算值：C， 62. 40 ; H， 6. 76 ; N， 9· 39 ° 實測值：C，62.51 ； H, 6.60； N, 9.36° 實施例1 5 0 4-[順-4 -二甲胺基-1-[3-甲氧基-4-[N’ - (2-甲基苯基）脲 基]苯基乙醯基]-（2S) -咄咯啶基]甲氧苯甲酸甲酯HC1鹽\\312\2d-code\90-01\89112968.ptd Page 552 1283240 V. INSTRUCTIONS (548) 1604, 1533, 1454, 1415, 1255, 1166, 1035, 755 / cm; 1H-NMR (DMSO- D6) (5 : 1. 83-1· 84 (m, 1H), 2· 08-2.10 (m, 1H), 2·21 (br s, 6H), 2·24 (s, 3H), 3.00 ( m, 2Η), 3·60 (s, 2Η), 3·78 (s, 3Η), 3·85-4·29 (m, 4H), 6·7 b 7.16 (m, 7H), 7.77-8.01 (m, 4Hm), 8.46 (s, 1H), 8·54 (s, 1H); MS(FAB) m/z 561(M+ + H)+ ; C31H36N4 06 · 2H20 Analytical calculated value: C, 62. 40 ; H, 6. 76 ; N, 9· 39 ° Found: C, 62.51; H, 6.60; N, 9.36° Example 1 5 0 4-[cis-4-dimethylamino-1- [3-Methoxy-4-[N'-(2-methylphenyl)ureido]phenylethenyl]-(2S)-indolyl]methoxybenzoic acid methyl ester HC1 salt

158 在〇°C下於4 - [順-4 -二甲胺基-1-[3-甲氧基-4-[N，-（2 -甲基苯基）脲基]苯基乙醯基]— (2S) -吼洛唆基]曱氧苯曱酸 (80毫克，〇·14毫莫耳）溶於甲苯（4.0毫升）及Me OH( 1· 0毫 升）之攪拌溶液中加入TMSCHN2(2· 0M己烷溶液，1〇〇微升， 〇 · 2 0毫莫耳）。使反應混合物在室溫下攪拌丨· 5小時。將混 合物於真空中濃縮。將殘留物經由於矽膠上利用Me〇H一 CH2Cl2(5/9 5，v/v)作為洗提液進行管柱層析而純化。將產 物溶解於EtOH(5.0毫升），並加入in HC1(溶於EtOH)(244 微升’ 0 · 2 4 4毫莫耳）。使混合物於真空中濃縮而得丨5 8 ( 7 5 毫克，79%)的非晶形固體。iR (KBr) 3345、29 5〇、24 56158 at 4 ° [cis-4-dimethylamino-1-[3-methoxy-4-[N,-(2-methylphenyl)ureido]phenylethyl) TMPSN2 was added to a stirred solution of toluene (4.0 ml) and Me OH (1.0 mL) in a stirred solution of (2S) 2·0M hexane solution, 1 〇〇 microliter, 〇·20 mmol. The reaction mixture was stirred at room temperature for 5 hours. The mixture was concentrated in vacuo. The residue was purified by column chromatography using Me〇H-CH2Cl2 (5/9 5, v/v) as an eluent. The product was dissolved in EtOH (5.0 mL) and in HCl (dissolved in EtOH) (244 liters &lt;RTIgt; The mixture was concentrated in vacuo to give EtOAc (EtOAc, EtOAc). iR (KBr) 3345, 29 5〇, 24 56

\\312\2d-code\90-01\89112968.ptd 第553頁 1283240 五、發明說明（549) 、1712、1646、1604、1511、1454、1434、1415、1284、 1 257、1168、11 14、103 1、771 / 公分； UMR (DMSO-d6) 5 2· 10-2· 2 0 (m，2H)、2· 25 (s，3H) 、2·83 (m，6H)、3·60-3·62 (m，2H)、3.76-3.81 (m， 8H) 、4·20-4.33 (m， 4H) 、6·71-7·17 (m， 6H) 、7·77-7· 98 (m， 5Η) 、8·47 (s， 1Η) 、8·55 (s， 1H); MS(FAB) m/z 5 74 (MHH)+ ; C32H38N4 06 · 1. 0HC1 · 1· 3H20 之分析計算 值：C， 60·57; Η, 6.61; N，8.83。實測值：C，60.80; Η, 6.82； Ν, 8.44 〇 實施例1 5 1 4-[反-1-[4 - [Ν’ - (2-氣苯基）脲基]- 3-曱氧苯基乙醯基] -4-二甲胺基2S)-咄咯啶基]甲氧苯甲酸\\312\2d-code\90-01\89112968.ptd Page 553 1283240 V. Inventions (549), 1712, 1646, 1604, 1511, 1454, 1434, 1415, 1284, 1 257, 1168, 11 14 , 103 1,771 / cm; UMR (DMSO-d6) 5 2· 10-2· 2 0 (m, 2H), 2 · 25 (s, 3H), 2·83 (m, 6H), 3.60 -3·62 (m, 2H), 3.76-3.81 (m, 8H), 4·20-4.33 (m, 4H), 6·71-7·17 (m, 6H), 7·77-7· 98 (m, 5Η), 8·47 (s, 1Η), 8·55 (s, 1H); MS(FAB) m/z 5 74 (MHH)+ ; C32H38N4 06 · 1. Analysis of 0HC1 · 1· 3H20 Calculated: C, 60·57; Η, 6.61; N, 8.83. Found: C, 60.80; Η, 6.82; Ν, 8.44 〇 Example 1 5 1 4-[trans-1-[4 - [Ν' - (2-Phenylphenyl)ureido]-3-oxobenzene Ethyl thiol]-4-dimethylamino 2S)-indolyl]methoxybenzoic acid

4- [反-1-[4-[Ν’ -（2-氯苯基）脲基]-3-曱氧笨基乙醯基] - 4-二甲胺基-（2S) -咄咯啶基]曱氧苯曱酸甲酯4- [Reverse-1-[4-[Ν' -(2-chlorophenyl)ureido]-3-oximeoxyphenyl] 4-dimethylamino-(2S)-indenylpyridine Methyl benzoate

在0 °C下於4-（反-1-第三丁氧羰基-4 -二甲胺基一（2S)-咄 洛咬基）曱氧苯甲酸甲酯（ 43 0毫克，1. 1毫莫耳）溶於ch2C12 (10· 0毫升）之攪拌溶液中加入TFA( 5 · 〇毫升）。使反應混合 物於室溫下授拌〇 · 5小時。將混合物於真空中濃縮。將飽4-(trans-1-t-butoxycarbonyl-4-dimethylamino-1(2S)-indole) methyl oxabenzoate (43 mg, 1. 1 m) at 0 °C To a stirred solution of ch2C12 (10 mL) was added TFA (5 · 〇 mL). The reaction mixture was allowed to stir at room temperature for 5 hours. The mixture was concentrated in vacuo. Will be full

\\312\2d-codc\90-01\89112968.ptd 第554頁 1283240 五、發明說明（550) ----- 和NaHC〇3加至殘留物，並以CH2Cl2萃取。將萃取液以鹽水 洗滌，於NaJO4上乾燥，並於真空中濃縮。將粗製產物不 經進一步的純化而使用於後續的反應。在〇艺下於此粗製 產物、4 [N -(2 -氯苯基）脲基]一 3—甲氧苯乙酸（368毫 克，^1毫莫耳L、H〇Bt(162毫克，12毫莫耳）、及三乙胺 (417¾ 升，3.0¾ 莫耳）溶於THF(1〇〇 毫升）&amp;MeCN(1〇〇 毫 升）之攪拌溶液中加入EDC · HC 1 ( 288毫克，1β i毫莫耳）。 使反應混合物在室溫下攪拌16小時，並於真空中濃縮。將 水加至殘留物’並以EtOAc萃取。將萃取液以飽和NaHC〇3 、2M檸檬酸、及飽和NaHC〇3洗滌，然後於Na2S〇4上乾燥， 並於真空中濃縮。將殘留物經由於矽膠上利用正己烧 -EtOAc (1 ·· 1，v/v)作為洗提液進行管柱層析，純化而得 4 - [反-1-[4-[Ν’ -（2-氯苯基）脲基]-3-曱氧笨基乙驢 基]-4-二曱胺基-（2S)-咄咯啶基]曱氧苯甲酸酯（53〇毫 克，78%)之無色油。1H-NMR (CDC13) 3 1.94-1.99 (m， 1H)、2.48 (s，9H)、3·06-3. 12 (m，1H)、3 33-3.38 (m，1H)、3·60 (s，2H)、3·68 (s，3H)、3·69-3·80 (m， 1H)、3·88 (s，3H)、4·13-4.20 (m，2H)、4·56 (m， 1 H)、6 · 7 6-7.0 0 (m，5H)、7.22-7.34(in，3H)、7.92-8· 00 (m， 3H) 、 8·17-8·19 (m， 1H)。 關於HC1 鹽：IR (KBr) 3324、2950、2454、1710、1604、 1511、1 284 / 公分；UMR (DMSO-d6) 6 2· 30-2· 40 (m， 2H)、2·77-2·80 (m，6H)、3·60-3·75(ιπ，2Η)、3·75-3· 85 (m，8H)、4·00 - 4·22 (m，3H)、4.50 - 4·75 (m，1H)、\\312\2d-codc\90-01\89112968.ptd Page 554 1283240 V. Description of the invention (550) ----- Add NaHC〇3 to the residue and extract with CH2Cl2. The extract was washed with brine, dried over Na.sub.4, and concentrated in vacuo. The crude product was used in the subsequent reaction without further purification. The crude product, 4 [N-(2-chlorophenyl)ureido]-3-methoxybenzoic acid (368 mg, ^1 mmol, L, H〇Bt (162 mg, 12 m) Add EDC · HC 1 ( 288 mg, 1β i) to a stirred solution of THF (1 mL) &amp; MeCN (1 mL) in a stirred solution of triethylamine (4,3⁄4 liter, 3.03⁄4 mol) The reaction mixture was stirred at room temperature for 16 h and concentrated in vacuo. EtOAc was evaporated from EtOAc EtOAc EtOAc. Washed with 〇3, then dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography using hexane-EtOAc (1··1, v/v) as an eluent. Purification to give 4-[trans-1-[4-[Ν'-(2-chlorophenyl)ureido]-3-indolyloxyindolyl]-4-didecylamino-(2S)-无 啶 基 曱 曱 〇 〇 〇 〇 〇 〇 〇 〇 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 3. 12 (m, 1H), 3 33-3.38 (m, 1H), 3·60 (s, 2H), 3·68 (s, 3H), 3·69-3·80 (m, 1H) 3·88 (s, 3H), 4·13-4.20 (m, 2H), 4·56 (m, 1 H), 6 · 7 6-7.0 0 (m, 5H), 7.22-7.34 (in, 3H ), 7.92-8· 00 (m, 3H), 8·17-8·19 (m, 1H). About HC1 salt: IR (KBr) 3324, 2950, 2454, 1710, 1604, 1511, 1 284 / cm ;UMR (DMSO-d6) 6 2· 30-2· 40 (m, 2H), 2·77-2·80 (m, 6H), 3·60-3·75 (ιπ, 2Η), 3.75 -3· 85 (m, 8H), 4·00 - 4·22 (m, 3H), 4.50 - 4·75 (m, 1H),

\\312\2d-code\90-01\89112968.ptd 第 555 頁 1283240 五、發明說明（551) 6.75-7.43 (m，7H)、7·89- 8.0 9 (m，4H)、8.87 (s，1H) '8.91 (s, 1H) ； MS(FAB) m/z 595 (M+H)+ ； C31H36N4 06 C1 · 1.0HC1 ·1·〇Η20 之分析計算值：C，57.23; H，6·04; N， 8· 61 ; Cl， 1 〇· 90。實測值：C， 57· 43 ; H，6· 08 ; N， 8· 38 ; Cl，1 〇· 73。 於4 - [反-1-[4-[Ν’-（2 -氯苯基）脲基]-3-曱氧苯基乙醯 基]-4 -二甲胺基-（2S)-咣咯啶基]甲氧苯甲酸曱酯（1 90毫 克，〇· 32毫莫耳）溶於THF(3. 0毫升）及MeOH(2· 0毫升）之攪 拌溶液中加入IN NaOH(0. 64毫升，0. 64毫莫耳）。使混合 物在70 °C下攪拌24小時。將混合物於真空中濃縮，加入 水，並以1N HC1中和。收集所產生之固體，以水洗滌，並 於真空中乾燥而得1 5 9 ( 1 5 0毫克，83%)的白色結晶固體。 熔點159-161 t ; IR (KBr) 3318、2 938、1 604、1531、 1 438、1 340 / 公分；NMR (DMSO-d6) 3 2.10-2.40 (m， 8H)、2·50-2.70 (m，2H)、3·85-3·90 (m，5H)、4.02-4· 18 (m，3Η)、4·30 - 4·60 (m，1Η)、6·75-7·43 (m，7Η)、 7.86-8·09 (m，4H)、8·86 (s，1H)、8·91 (s，1H); MS(FAB) m/z 581(M + H)+; C3()H33N4 06 C1 ·1·2Η20 之分析計算 值：C，59. 7 9 ； Η, 5. 92 ； Ν, 9. 30 ° 實測值：C，5 9.6 9; Η, 5.93； Ν, 9.09° 實施例152 4-[順-1-[4-[Ν’ -（2-氯苯基）脲基]-3-甲氧苯基乙醯基] -4 -二甲胺基-（2S)-咄咯啶基]曱氧苯甲酸\\312\2d-code\90-01\89112968.ptd Page 555 1283240 V. INSTRUCTIONS (551) 6.75-7.43 (m,7H), 7·89- 8.0 9 (m,4H), 8.87 (s ,1H) '8.91 (s, 1H) ; MS(FAB) m/z 595 (M+H)+ ; C31H36N4 06 C1 · 1.0HC1 ·1·〇Η20 Analysis calculated: C, 57.23; H,6· 04; N, 8· 61 ; Cl, 1 〇 · 90. Found: C, 57·43; H, 6·08; N, 8·38; Cl, 1 〇· 73. 4-[trans-1-[4-[Ν'-(2-chlorophenyl)ureido]-3-indolylphenylethyl]-4-dimethylamino-(2S)-fluorene To a stirred solution of THF (3.0 ml) and MeOH (2.0 mL) was added IN NaOH (0. 64 mL). , 0. 64 millimoles). The mixture was stirred at 70 ° C for 24 hours. The mixture was concentrated in vacuo, water was added and neutralized with 1N EtOAc. The resulting solid was collected, washed with water and dried in vacuo to give a white solid crystals of 149. Mp 159-161 t ; IR (KBr) 3318, 2 938, 1 604, 1531, 1 438, 1 340 / cm; NMR (DMSO-d6) 3 2.10-2.40 (m, 8H), 2·50-2.70 ( m, 2H), 3·85-3·90 (m, 5H), 4.02-4· 18 (m, 3Η), 4·30 - 4·60 (m, 1Η), 6·75-7·43 ( m,7Η), 7.86-8·09 (m,4H),8·86 (s,1H),8·91 (s,1H); MS(FAB) m/z 581(M + H)+; C3 () Analysis of H33N4 06 C1 ·1·2Η20: C, 59. 7 9 ; Η, 5. 92 ; Ν, 9. 30 ° Measured: C, 5 9.6 9; Η, 5.93; Ν, 9.09° Example 152 4-[cis-1-[4-[Ν'-(2-chlorophenyl)ureido]-3-methoxyphenylethenyl]-4-dimethylamino-(2S)- Acetylpyridyl

\\312\2d-code\90-01\89112968.ptd 第556頁 1283240 五、發明說明（552) 4 [順1 [4-[N -（2〜氣笨基）脲基]一 3-甲氧苯基乙醯基]一 4-一甲胺基-（2S)- π比咯啶基]曱氧苯甲酸甲酯\\312\2d-code\90-01\89112968.ptd Page 556 1283240 V. INSTRUCTIONS (552) 4 [Shun 1 [4-[N -(2~ gas-based)urea]-3-A Oxyphenyl phenyl sulfhydryl]- 4-methylamino-(2S)-π-pyridylidene] methyl benzoate

N -COOMe 在〇 C下於4~(順-1-第三丁氧羰基-4-二曱胺基-(2S)-咄 咯啶基&gt;)曱氧笨曱酸甲酯（1. 2克，3. 2毫莫耳）溶於CH2Cl2 (i〇.〇jfe升）之攪拌溶液中加入TFA(5 ()毫升）。使反應混合 下擾摔〇. 5小時。將混合物於真空中濃縮。將飽 :3加至殘留物’並以CHA萃取。將萃取液以鹽水 ΐί :Γ:2Γ4上乾燥’並於真空中濃縮。將粗製產物不 :物(2 7、：吞化1而使用於後續的反應。在〇。。下於此粗製 -3-甲氧苯^乙酸(33:毫ΐ耳）、4-[Ν’_(2-氯苯基)脲基] 1.〇毫莫耳）、及三乙毫0 ί莫3WHft(L35毫克， 0毫升）及MeCN(4. Q毫升）之^拌.笔 '耳）浴於THF(4. 毫克，L 5毫莫耳^使反二^ 並於真空中濃縮。將水加至㈣：在至，見下攪拌16小時， 萃取液以飽和NaHC〇3並以Et〇Ac萃取。將 ^Na2S04ir^ ^ ^ 膠上利用正己院-Ε t0Ac(】真广：'V將殘留物經由於石夕 析，純化而得4-[順為洗提液進行管柱層 L4 U -氣苯基）脲基]—3 一甲氧N-COOMe under 〇C at 4~(cis-1-t-butoxycarbonyl-4-didecylamino-(2S)- oxazolidinyl) 曱 曱 曱 曱 ( ( (1. 2 To a stirred solution of CH 2 Cl 2 (i 〇 〇 jfe liter) was added TFA (5 () mL). Mix the reaction and disturb the wrestling. 5 hours. The mixture was concentrated in vacuo. Add satiety:3 to the residue&apos; and extract with CHA. The extract was dried over brine ΐ: Γ: 2 Γ 4 and concentrated in vacuo. The crude product is not used: (2,: is used for subsequent reaction. In this case, the crude 3-methoxybenzoic acid (33: milli-ear), 4-[Ν' _(2-Chlorophenyl)ureido] 1. 〇 millimolar, and triethyl 0 ί Mo 3WHft (L35 mg, 0 ml) and MeCN (4. Q ml) of the mixture. Pen 'ears' Bath in THF (4 mg, L 5 mM) and concentrate in vacuo. Add water to (d): </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> Ac extraction: ^Na2S04ir^ ^ ^ on the gel using Zhengjiyuan - Ε t0Ac (] Zhen Guang: 'V will be the residue through the Shi Xi analysis, purification to obtain 4-[Shun as the eluent for the column layer L4 U -gas phenyl)ureido]-3 methoxy

1283240 五、發明說明（553) 苯基乙醯基]- 4-二曱胺基-（2S)-17比洛唆基]曱氧苯曱酸曱 酯（ 50 0 毫克，84%)之無色油。丨11-關1?(^0(：13)61.98-2·50 (m，1H)、2·26 (s，3H)、2.2 5-2.40 (m，1H)、 2·58-2·65 (m， 1H) 、3·20-3·30 (m， 1H) 、3·60 (s， 2H) 、3.64 (s，3H)、3·80-3·90 (m，1H)、3.88 (s，3H)、 4·18-4·20 (m，1H)、4.42-4.46 (m，2H)、6.72-7.00 (m，4H)、7·20-7·35 (m，5H)、7·9 卜 7.94 (m，3H)、 8.18-8·21 (m，1H)。 於4 - [順-1-[4-[Ν’-（2 -氯苯基）脲基]-3-甲氧苯基乙醯 基]-4-二甲胺基-（2S)-咄咯啶基]甲氧苯甲酸甲酯（250毫 克’ 〇· 42毫莫耳）溶於THF(5· 0毫升）及MeOH(3· 0毫升）之攪 拌溶液中加入1 N N aOH ( 1 · 0毫升，1 · 〇毫莫耳）。使混合物 在70 °C下攪拌1 8小時。將混合物於真空中濃縮，加入水， 並以1 N HC1中和。收集所產生之固體，以水洗滌，並於真 空中乾燥而得160(170毫克，70%)的白色結晶固體。溶點 165-167 〇C; IR (KBr) 3328、1604、1531、1164、1033/ &amp;*;1H-NMR(DMSO-d6)(5 1.80-1.90 (m，lH)、2.20-2·50 (m, 7H)、3·60-3·70 (m，2H)、3·77-3.81 (m，5H) 、4·00 -4.30 (m，4H)、6·7 2-7.44 (m，7H)、7.86-8. 10 (m, 4H)、8·88-8·92 (m，2H); MS(FAB) m/z 581(MH1) ;C3QH33N4 06 C1 · 1. 1H20 之分析計算值：C，59. 87 ; H，6. 06 ;N，9. 31。實測值：C， 59· 65 ; H， 5· 76 ; N， 9. 09。 實施例1 5 3 4-[順-1-[4 - [Ν’-（2-氣苯基）脲基]-3-甲氧苯基乙醯基]1283240 V. INSTRUCTIONS (553) Phenylethylamino-4-tetraisoylamino-(2S)-17bipirinyl]nonyloxybenzoate (50 mg, 84%) of colorless oil .丨11-OFF1?(^0(:13)61.98-2.50 (m,1H), 2·26 (s,3H), 2.2 5-2.40 (m,1H), 2·58-2·65 (m, 1H), 3·20-3·30 (m, 1H), 3·60 (s, 2H), 3.64 (s, 3H), 3·80-3·90 (m, 1H), 3.88 ( s, 3H), 4·18-4·20 (m, 1H), 4.42-4.46 (m, 2H), 6.72-7.00 (m, 4H), 7·20-7·35 (m, 5H), 7 ·9 卜7.94 (m,3H), 8.18-8·21 (m,1H). 4 - [cis-1-[4-[Ν'-(2-chlorophenyl)ureido]-3-methyl Oxyphenyl phenylethyl]-4-dimethylamino-(2S)-decalidyl]methyl methoxybenzoate (250 mg '〇·42 mmol) dissolved in THF (5.0 mL) To a stirred solution of MeOH (3.0 mL) was added 1 NN aOH (1························· Water, and neutralized with 1 N HCl. The resulting solid was collected, washed with water and dried in vacuo to give 160 (170 mg, 70%) of white crystalline solid. melting point 165-167 〇C; KBr) 3328, 1604, 1531, 1164, 1033/ &amp;*; 1H-NMR (DMSO-d6) (5 1.80-1.90 (m, lH), 2.20-2·50 (m, 7H), 3·60- 3 70 (m, 2H), 3·77-3.81 (m, 5H), 4·00 - 4.30 (m, 4H), 6·7 2-7.44 (m, 7H), 7.86-8. 10 (m, 4H ), 8·88-8·92 (m, 2H); MS (FAB) m/z 581 (MH1) ; C3QH33N4 06 C1 · 1. Analysis of 1H20: C, 59. 87 ; H, 6. 06 ;N, 9. 31. Found: C, 59· 65 ; H, 5· 76 ; N, 9. 09. Example 1 5 3 4-[cis-1-[4 - [Ν'-(2- Phenyl)ureido]-3-methoxyphenylethenyl]

\\312\2d-code\90-01\89112968.ptd 第558頁 1283240 五、發明說明（554) -4 -（2 -萘石黃醢胺基）-（2S)_ 比洛唆基]甲氧本甲酸\\312\2d-code\90-01\89112968.ptd Page 558 1283240 V. INSTRUCTIONS (554) -4 -(2 -naphthalene xanthine)-(2S)_ 比洛唆基]甲Oxygenic acid

4-（順-1-第三丁氧羰基-4_(2 -萘磺醯胺基）—（2S)_吼哈咬 基）甲氧苯甲酸甲酯 COOMe 在0 °C下於4-(順-1-第三丁氧戴基-4 -胺基-（2S) -吼洛咬 基）甲氧苯甲酸甲酯（200毫克，0·57毫莫耳）及TEA(317毫 升，2· 3毫莫耳）溶於CHC13( 10. 〇毫升）之攪拌溶液中加入 (2-萘基）績醯氣（155毫克，0.68毫莫耳）。使反應混合物 於室溫下擾拌1 8小時。將反應混合物於真空中濃縮。使殘 留物經由於矽膠上利用正己烷-EtOAc(2 ·· 1，v/v)作為洗提 液進行管柱層析，純化而得4-(順-1 -第三丁氧羰基—4 — (2〜 萘石黃醯胺基）-（2 S )-吼咯啶基）甲氧苯甲酸曱酯（2 4 〇毫克， 78%)之淡黃色油。iH_NMR (CDCl3) $ l 25 —l 45 (br &amp; 9H)、1·70-1·80 (m, 1Η)、2·20-2·40 (m，1Η)、3·2〇1 3·50 (m，2H)、3·90 (s，3H)、3·85-4.15 (m，3H)、 4.55-4·65 (m，1H)、6·90-7·10 (m，2H)、7·58-8·〇4 (m， 8Η) 、 8·43 (s， 1Η) 。 · 4-[順-l-[4-[N，-（2-氯苯基）脲基]-3-曱氧苯基乙醯基]4-(cis-1-third-butoxycarbonyl-4_(2-naphthalenesulfonylamino)-(2S)_hahabita methyl methoxybenzoate COOMe at 0 °C at 4-(cis -1-Tertioxybutyryl-4-amino-(2S)-indolyl methyl methacrylate (200 mg, 0. 57 mmol) and TEA (317 ml, 2·3) To a stirred solution of CHC13 (10 ml) was added (2-naphthyl) oxime (155 mg, 0.68 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo. The residue was subjected to column chromatography using n-hexane-EtOAc (2··1, v/v) as an eluent, and purified to give 4-(cis-1 -t-butoxycarbonyl- 4 - (2~naphthalene xanthine)-(2S)-decalidyl) methoxybenzoate (24 mg, 78%) as a pale yellow oil. iH_NMR (CDCl3) $ l 25 —l 45 (br &amp; 9H), 1·70-1·80 (m, 1Η), 2·20-2·40 (m,1Η), 3·2〇1 3· 50 (m, 2H), 3·90 (s, 3H), 3.85-4.15 (m, 3H), 4.55-4·65 (m, 1H), 6·90-7·10 (m, 2H) , 7·58-8·〇4 (m, 8Η), 8·43 (s, 1Η). · 4-[cis-l-[4-[N,-(2-chlorophenyl)ureido]-3-indolylphenylethyl]

89112968.ptd 第559頁 1283240 五、發明說明（555) -4-（2-蔡績SI胺基）—（2s) —咄咯啶基]曱氧苯曱酸甲酯89112968.ptd Page 559 1283240 V. INSTRUCTIONS (555) -4-(2-Xie Ji SI-Amino)-(2s)-Pyrridinyl]Methoxybenzoate

在0 °C下於4-(順-1—第三丁氧羰基-4_(2—萘磺醯胺基）一 (2S) -叫^各唆基）曱氧苯曱酸曱酯（24〇毫克，〇·44毫莫尊） 溶於CH2C12(5· 0毫升）之攪拌溶液中加、TFA(5· 〇毫升）。使 反應混合物於室溫下攪拌0 · 5小時。將混合物於真空中濃 縮。將飽和NaHC〇3加至殘留物，並以π〆、萃取。將萃取 液以鹽水洗條’於Na2S04上乾燥，並於真空中濃縮。將粗 製產物不經進一步的純化而使用於後續的反應。在〇。〇下 於此粗製產物、4-[N’-（2-氯苯基）脲基]-3-曱氧苯乙酸 (147宅克，0.44晕：莫耳）、[{QBt(59毫克，0.44毫莫耳）、 及三乙胺（275毫升，1·9毫莫耳）溶於THF(6. 0毫升）及 MeCN(6· 0毫升）之攪拌溶液中加入EDC · HC1 (127毫克，〇· 66毫莫耳）。使反應混合物在室溫下攪拌丨6小時，並於真 空中濃縮。將水加至殘留物，並以EtOAc萃取。將萃取液 以飽和NaHC〇3、2M檸檬酸、及飽和NaHC03洗滌，然後KNa θ〇4上乾燥，並於真空中濃縮。將殘留物經由於矽膠上利 用正己烷-EtOAc(l : 3，v/v)作為洗提液進行管柱層析，純 化而得4-[順-1-[4-[Ν’-（2-氯苯基）脲基]一 3—甲氧苯基乙 醢基]- 4-（2-萘石黃隨胺基）-(2S) -吼嘻咬基]曱氧苯甲酸甲 酯（200 毫克，65%)之無色油。UMR (CDC13) 5 1. 75 -1 · 8 0 (m，1 Η)、2 · 2 5 - 2 · 4 0 (m，1 Η )、3 · 4 3 (s，2 Η)、34-(cis-1 -t-butyloxycarbonyl-4_(2-naphthalenesulfonylamino)-(2S)-pyrene-based oxime oxime ester at 0 °C (24〇) </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; The reaction mixture was stirred at room temperature for 0.5 hours. The mixture was concentrated in vacuo. Saturated NaHC〇3 was added to the residue and extracted with π〆. The extract was dried over Na 2 SO 4 with brine and concentrated in vacuo. The crude product was used in the subsequent reaction without further purification. Here. The crude product, 4-[N'-(2-chlorophenyl)ureido]-3-indolyl phenylacetic acid (147 oz, 0.44 halo: Moer), [{QBt(59 mg, 0.44) Add EDC · HC1 (127 mg, 〇) to a stirred solution of THF (6.0 mL) and MeCN (6.0 mL) in MeOH (275 mL, 1.9 mmol) · 66 millimoles). The reaction mixture was stirred at room temperature for 6 hours and concentrated in vacuo. Water was added to the residue and extracted with EtOAc. The extract was washed with saturated NaHC 〇3, 2M EtOAc, sat. NaHC03, then dried over K Na θ 〇 4 and concentrated in vacuo. The residue was subjected to column chromatography using n-hexane-EtOAc (1:3, v/v) as an eluent to obtain 4-[cis-1-[4-[Ν'-(2 -Chlorophenyl)ureido]-3-methoxyphenylethenyl]- 4-(2-naphthalene yellow with amino)-(2S)-indenyl] methyl benzoate (200 Mg, 65%) colorless oil. UMR (CDC13) 5 1. 75 -1 · 8 0 (m,1 Η), 2 · 2 5 - 2 · 4 0 (m,1 Η ), 3 · 4 3 (s,2 Η), 3

1283240 五、發明說明（556) 40-3·5〇 (m，1H)、3·60 (s，3H)、3·6 5-3.75 (m，1H)、 3·90 (s，3H)、3·85-3·92 (m, 1H)、3·95-4.0 0 (m，lH) 、4·30 —4.40 (m，1H)、4·6 5-4.75 (m，1H)、6·26 (d， J = 9.3 Hz，1H)、6·50 (d，J=：8.3 Hz，1H)、6·23 (s， 1H)、6·86 (d，J = 8.8 Hz，2H)、6·75-7.01 (m，1H)、 7·23 —7.36 (m，3H)、7.61 - 7.96 (m，9H)、8·20 (d， J=8.1 Hz， 1H) 、 8·43 (s， 1H)。 於4 - [順-1-[4_[N’-（2 -氣苯基）脲基]—3一甲氧苯基乙醯 基]-4-(2 -萘石黃醯胺）-（2S) -吼咯啶基]甲氧苯甲酸甲酯 (200毫克，〇·26毫莫耳）溶於THF (6.0毫升）及Me OH (3.0毫 升）之攪拌溶液中加入IN NaOH(0.5毫升，0.5毫莫耳）。使 此合物在7 〇 °c下挽拌1 8小時。將混合物於真空中濃縮，加 入水，並以1 N H C1中和。收集所產生之固體，以水洗滌， 並於真空中乾燥而得1 6 1 ( 2 1 0毫克，定量）的白色結晶固 體。熔點 1 35 - 1 4 2。(：；11^(〇1〇 333 2、1 685、1 604、 1531、1421、1159 / 公分；UMR (DMSO-d6) 6 1· 75-1.85 (m，1H)、2·05-2·15 (m，1H)、3·05-3·15 (m， 1H)、3·47 (s，2H)、3·60-3·80 (m，2H)、3.73 (s， 3H)、4.05-4.20 (m，3H)、6·51 (d，J = 8.5 Hz，1H)、 6.74 - 7.04 (m，5H)、7·27 - 7.31 (m，1H)、7·43 - 7.45 (m，2H)、7·66-8·17 (m，9H)、8·46 (s，1H)、8·91 (d， J = 9. 5 Hz, 1H) ； MS(FAB) m/z 7 43 (MH1) ； C38H35N4 08 C1 S · 0.5H20之分析計算值：C， 60.67; H，4·82; N， 7.45;1283240 V. Description of invention (556) 40-3·5〇(m,1H), 3·60 (s,3H),3·6 5-3.75 (m,1H), 3·90 (s,3H), 3·85-3·92 (m, 1H), 3·95-4.0 0 (m, lH), 4·30 — 4.40 (m, 1H), 4·6 5-4.75 (m, 1H), 6· 26 (d, J = 9.3 Hz, 1H), 6·50 (d, J=: 8.3 Hz, 1H), 6·23 (s, 1H), 6·86 (d, J = 8.8 Hz, 2H), 6·75-7.01 (m,1H), 7.23 —7.36 (m,3H), 7.61 - 7.96 (m,9H), 8·20 (d, J=8.1 Hz, 1H), 8·43 (s , 1H). 4 - [cis-1-[4_[N'-(2-(phenyl))]]]]]]]]]]]]]]] - hydrazinyl]methyl methoxybenzoate (200 mg, 〇·26 mmol) dissolved in THF (6.0 mL) and Me OH (3.0 mL). Millions of ears). The mixture was stirred at 7 ° C for 18 hours. The mixture was concentrated in vacuo, water was added and neutralized with 1 N H C1. The resulting solid was collected, washed with water and dried in vacuo to give &lt;1&gt; Melting point 1 35 - 1 4 2. (:;11^(〇1〇333 2,1 685,1 604, 1531, 1421,1159 / cm; UMR (DMSO-d6) 6 1· 75-1.85 (m,1H), 2·05-2· 15 (m, 1H), 3·05-3·15 (m, 1H), 3·47 (s, 2H), 3·60-3·80 (m, 2H), 3.73 (s, 3H), 4.05 -4.20 (m, 3H), 6·51 (d, J = 8.5 Hz, 1H), 6.74 - 7.04 (m, 5H), 7.27 - 7.31 (m, 1H), 7.43 - 7.45 (m, 2H), 7·66-8·17 (m, 9H), 8.46 (s, 1H), 8.91 (d, J = 9. 5 Hz, 1H); MS(FAB) m/z 7 43 (MH1) ; C38H35N4 08 C1 S · 0.5H20 calc.: C, 60.67; H, 4.82; N, 7.45;

Cl，4· 26。實測值：C， 6 0. 77 ； H, 4. 84 ; N，7. 21 ； Cl,Cl, 4·26. Found: C, 6 0. 77 ; H, 4. 84 ; N, 7. 21 ; Cl,

\\312\2d-code\90-01\89112968.ptd 第561頁 1283240 五、發明說明（557) 4.90。 實施例154 4 - [1-[4 - [N，-（2_溴苯基）脲基]- 3-甲氧苯基乙醯基]-4 -(2-伸米基磺醯胺基）-(2S) -吼咯啶基]曱氧苯甲酸\\312\2d-code\90-01\89112968.ptd Page 561 1283240 V. Description of the invention (557) 4.90. Example 154 4 - [1-[4 - [N,-(2-bromophenyl)ureido]-3-methoxyphenylethenyl]-4-(2-exetylenesulfonylamino) -(2S)-indolyl]oxybenzoic acid

162 4-（順-1-第三丁氧羰基-4-(2 -伸米基磺醯胺基）_(2S)-吼 咯啶基）曱氧苯甲酸甲酯162 4-(cis-1-t-butoxycarbonyl-4-(2-exetylsulfonylamino)-(2S)-fluorenylpyridyl) methyl benzoate

在0 C下於4-(順-1-第三丁氧獄基-4 -胺基-（2S) -吼17各σ定 基）曱氧苯甲酸甲酯（180毫克，0.51毫莫耳）及TEA (283毫 升，2· 0毫莫耳）溶於CHC13( 10. 0毫升）之攪拌溶液中加入 (2-伸米基）磺醯氣（122毫克，0. 56毫莫耳）。使反應混合 物於室溫下攪拌1 8小時。將反應混合物於真空中濃縮。使 殘留物經由於矽膠上利用正己烷-Et0Ac(3:丨，v/v)作為洗 提液進行管柱層析，純化而得4—(順-1—第三丁氧羰基—4〜 (2 -伸来基磺醯胺基）-(2 §)—吼咯啶基）甲氧苯甲酸甲酯 (170 毫克，62%)之淡黃色油。1H —NMR (CDCl3) 3 κ 4〇 (s， 9H)、1·85- 1.95 (m，1H)、2·29 (s，3H)、2·35-2·45 (m，1H)、2·62 (s，6H)、3·80-4·15 (m，3H)、3·89 (s， 3H)、3·50-3.65 (m，iH)、6·94 (s，2H)、6·94-7.00Methyl oxabenzoate (180 mg, 0.51 mmol) at 4-C in 4-(cis-1-t-butoxy-phenyl-4-amino-(2S)-吼17 sigma) TEA (283 ml, 2.0 mmol) was added to a stirred solution of CH.sub.3 (10. 0 mL). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo. The residue was subjected to column chromatography using n-hexane-Et0Ac (3: 丨, v/v) as an eluent, and purified to give 4-(cis-1 -t-butoxycarbonyl- 4~ ( 2 - Streptylsulfonylamino)-(2 §)-decalidyl) methyl methoxybenzoate (170 mg, 62%) as a pale yellow oil. 1H-NMR (CDCl3) 3 κ 4〇(s, 9H), 1.85- 1.95 (m, 1H), 2·29 (s, 3H), 2·35-2·45 (m, 1H), 2 ·62 (s,6H), 3·80-4·15 (m,3H),3·89 (s, 3H), 3·50-3.65 (m,iH),6·94 (s,2H), 6·94-7.00

第562頁 1283240 五、發明說明（558) --- (m，2 Η )、7 · 9 9 (d，J =： 8 · 8 η z，2 Η)。 4-[1 - [4-[Ν -(2 -溴笨基）脲基]一 3一甲氧苯基乙醯基]一4 -（2-伸米基磺醯胺基）—（2S)—咄咯啶基]曱氧笨曱酸甲酯Page 562 1283240 V. Description of invention (558) --- (m, 2 Η ), 7 · 9 9 (d, J =: 8 · 8 η z, 2 Η). 4-[1 - [4-[Ν-(2-bromophenyl)ureido]-3-methoxyphenylethenyl]- 4-(2-exetylenesulfonylamino)-(2S) —咄 啶 啶 曱 曱 曱 曱 曱

在0 C下於（順-1-第三丁氧羰基_4-(2—伸米基磺醯胺基） -(2S) -咄洛啶基）甲氧苯甲酸甲酯（17〇毫克，〇· 32毫莫耳） 洛於CHgCl/S.Ocfe升）之攪拌溶液中加入TFA(5〇毫升）。使 ^應混合物於室溫下攪拌〇· 5小時。將混合物於真空中濃 鈿。將飽和NaHC〇3加至殘留物，並以⑶〆、萃取。將萃取 液以鹽水洗滌，於υ〇4上乾燥，並於真空中濃縮。將粗 製產物不經進一步的純化而使用於後續的反應。在〇。〇下 於此粗製產物、4-[Ν，-(2—漠笨基）脲基]—3—曱氧苯乙酸 (121¾ 克，0.32¾ 莫耳）、H〇Bt(43 毫克，〇.32 毫莫耳）、 及二乙胺（139毫升，1.0毫莫耳）溶於THF(5. 〇毫升）及 MeCN(5· 0耄升）之攪拌溶液中加入EDC · HC1 (91毫克，At 0 C (methyl cis-1-t-butoxycarbonyl-4-(2-exetylenesulfonylamino)-(2S)-indolyl)methoxybenzoate (17 mg, 〇· 32 mM) Add TFA (5 〇 ml) to the stirred solution of CHgCl/S.Ocfe liter. The mixture was allowed to stir at room temperature for 5 hours. The mixture was concentrated in vacuo. Saturated NaHC〇3 was added to the residue and extracted with (3) hydrazine. The extract was washed with brine, dried over EtOAc 4 and concentrated in vacuo. The crude product was used in the subsequent reaction without further purification. Here. The crude product, 4-[Ν,-(2-indolyl)ureido]-3-oxophenylacetic acid (1213⁄4 g, 0.323⁄4 mol), H〇Bt (43 mg, 〇.32) Add EDC · HC1 (91 mg, mp), and diethylamine (139 ml, 1.0 mmol) in a stirred solution of THF (5 ml) and MeCN (0.5 ml).

〇· 48耄莫耳）。使反應混合物在室溫下攪拌16小時，並於 真空中）辰縮。將水加至殘留物，並以Et〇Ac萃取。將萃取 液以飽和NaHC〇3、2M擰檬酸、及飽和NaHC〇3洗滌，然後於 NaJO4上乾燥，並於真空中濃縮。將殘留物經由於矽膠上 利用正己烷-EtOAc(l:4，v/v)作為洗提液進行管柱層析， 純化而得4-[l-[4-[N，-（2〜溴苯基）脲基]—3-甲氧笨基乙醯 基]-4-（2-伸来基磺醯胺基）—（2S)—吼咯啶基]曱氧苯曱酸〇· 48耄莫耳). The reaction mixture was stirred at room temperature for 16 hours and then was reduced in vacuo. Water was added to the residue and extracted with EtOAc. The extract was washed with saturated NaHC 〇 3, 2M EtOAc, and sat. NaHC.sub.3, then dried over Na.sub.4, and concentrated in vacuo. The residue was purified by column chromatography using n-hexane-EtOAc (1:4, v/v) as eluent to give 4-[l-[4-[N,-(2~ Phenyl)ureido]-3-methoxyphenylethyl]-4-(2-exetylsulfonylamino)-(2S)-indenylpyridyl]nonylbenzoic acid

1283240 五、發明說明（559) 曱酯（210 毫克，83%)之無色油。iH-NMR (CDC13) (5 1 · 85 -1·90 (m，1H)、1·95-2·05 (m，1H)、2.32 (s，3H)、 2.6 (s，6H)、3·4 0-3.5 0 (m，3H)、3·6〇-3·70 (m，2H) 、3·68 (s， 3Η) 、3·89 (s， 3Η) 、3·96-3·99 (m， 1Η)、 3·35-3·45 (m，1H)、3· 70- 3.75 (m，1H)、6·00 (d， J=9.5 Hz， 1H) 、6·57-7·08 (m， 9H) 、7·29-7·34 (m, 1H)、7·5 卜 7.53 (m，1H)、7·92 - 7.96 (m，3H)、8·15 (d，J = 6· 8 Hz, 1H)。 於4-Π - [3-甲氧基一4-[N，-(2-溴苯基）脲基]苯基乙醯 基]一4一（2 -伸米基磺醯胺基）—（2s) _吼咯啶基]甲氧苯甲酸 甲醋（210毫克，〇·26毫莫耳）溶於THF(5. 0毫升）及MeOH (3.0宅升）之授拌溶液中加入;[n NaOH(0.47毫升，〇·47毫 莫耳）。使混合物在7 0 t下攪拌2 4小時。將混合物於真空 中濃縮，加入水，並以1 N H C1中和。收集所產生之固體， 以水洗滌，並於真空中乾燥而得1 6 2 ( 1 8 0毫克，8 7% )的白 色結晶固體。熔點 1 30-1 32。(：；11^(〇1〇 3332、1 6 89、 1604、1529、1155 /公分；NMR (DMSO-d6) (5 1· 70 -1.85 (m，1H)、2·〇2-2·12 (m，1H)、2·25 (s，3H)、 2.52 (s，6H)、3.05-3.12 (m，1H)、3·48 (s，2H)、 3.60-3.70 (m， 2H) 、3.77 (s， 3H) 、3·90-4·20 (m， 3H) 、6·59 (d，J = 8.3 Hz, 1H)、6.77- 6.80 (m，1H)、6·95 - 7.01 (m，4H)、7·3 卜 7.35 (m，1H)、7·60 (d，J = 8.1 Hz，1H)、7·86-7·97 (m，5H)、8·72-8·76 (m，1H)、 8· 89-8· 93 (m， 1H) ; MS(FAB) m/z 779 (M+)、781(MH2);1283240 V. INSTRUCTIONS (559) Ester ester (210 mg, 83%) of a colorless oil. iH-NMR (CDC13) (5 1 · 85 -1·90 (m, 1H), 1.95-2·05 (m, 1H), 2.32 (s, 3H), 2.6 (s, 6H), 3· 4 0-3.5 0 (m, 3H), 3·6〇-3·70 (m, 2H), 3·68 (s, 3Η), 3·89 (s, 3Η), 3·96-3·99 (m, 1Η), 3·35-3·45 (m, 1H), 3·70- 3.75 (m, 1H), 6·00 (d, J=9.5 Hz, 1H), 6.57-7· 08 (m, 9H), 7·29-7·34 (m, 1H), 7·5 卜 7.53 (m, 1H), 7.92 - 7.96 (m, 3H), 8·15 (d, J = 6· 8 Hz, 1H). 4-Π-[3-Methoxy-4-[N,-(2-bromophenyl)ureido]phenylethenyl]- 4 (2 - stretched rice) Phytosulphonyl)-(2s) _ oxazolidinyl] methoxybenzoic acid methyl vinegar (210 mg, 〇 · 26 mmol) dissolved in THF (5.0 ml) and MeOH (3.0 liter) Add to the mixing solution; [n NaOH (0.47 ml, 〇·47 mmol). The mixture was stirred at 70 ° for 24 hours. The mixture was concentrated in vacuo, water was added and neutralized with 1 NH C1 The solid which was obtained was collected, washed with water and dried in vacuo to give EtOAc (1, 1〇3332 1 6 89, 1604, 1529, 1155 / cm; NMR (DMSO-d6) (5 1· 70 -1.85 (m, 1H), 2·〇2-2·12 (m, 1H), 2·25 (s , 3H), 2.52 (s, 6H), 3.05-3.12 (m, 1H), 3·48 (s, 2H), 3.60-3.70 (m, 2H), 3.77 (s, 3H), 3·90-4 ·20 (m, 3H), 6.59 (d, J = 8.3 Hz, 1H), 6.77- 6.80 (m, 1H), 6.95 - 7.01 (m, 4H), 7·3, 7.35 (m, 1H), 7·60 (d, J = 8.1 Hz, 1H), 7·86-7·97 (m, 5H), 8·72-8·76 (m, 1H), 8· 89-8· 93 (m, 1H) ; MS(FAB) m/z 779 (M+), 781 (MH2);

\\312\2d-code\90-01\89112968.ptd 第564頁 1283240\\312\2d-code\90-01\89112968.ptd Page 564 1283240

C37H39N4 08 SBr · 0· 5H20 之分析計算值：c，56. 35 ; Η, 5·11;Ν，7.10;Br， 1〇·ΐ3。實測值：c，56. 39;H， 5·07;Ν，6.89;Br，1〇·25。 實施例1 5 5 4-[1-[4- [Ν’ -（2 -溴笨基）脲基;μ3一甲氧苯基乙醯基]一4 —丹 磺醯胺基-（2 S) -咄咯啶基]曱氧苯曱酸 〇Analysis calculated for C37H39N4 08 SBr · 0· 5H20: c, 56. 35 ; Η, 5·11; Ν, 7.10; Br, 1 〇·ΐ3. Found: c, 56. 39; H, 5·07; Ν, 6.89; Br, 1 〇 · 25. Example 1 5 5 4-[1-[4-[Ν'-(2-Bromophenyl)urea; μ3-methoxyphenylethenyl]-4-dansylamino-(2S) - 咄 啶 啶 曱 曱 曱 曱 曱 曱 曱

4-（順-1 -第三丁氧羰基-4-丹磺醯胺基—（2S) -吼咯啶基）甲 氧苯甲酸甲酯4-(cis-1 -t-butoxycarbonyl-4-dansulphoylamino-(2S)-indolyl)methoxymethyl benzoate

在0°C下於4-(順-1-第三丁氧羰基_4_胺基-（2S) -吼略咬 基）甲氧苯曱酸甲酯（180毫克，0.51毫莫耳）及TEA (283毫 升，2.0毫莫耳）溶於CHC13(10· 0毫升）之攪拌溶液中加入 丹磺醯氯（155毫克，0· 68毫莫耳）。使反應混合物於室溫 下攪拌1 8小時。將反應混合物於真空中濃縮。使殘留物妙 由於矽膠上利用正己烧-EtOAc(2:l，v/v)作為洗提液進行 管柱層析，純化而得4 -(順-1 -第三丁氧羰基〜4 -丹石黃驢胺 基-（2S)-咄咯啶基）甲氧苯甲酸甲酯（200毫克，73%)之淡 黃色油。1H-NMR (CDC13) (5 1· 34 (s， 9H)、1 · 50^ · 6〇 /人 (m，1H)、2·15-2.25 (m，1H)、2·87 (s，6H)、3·15Methyl methoxybenzoate (180 mg, 0.51 mmol) at 0 ° C in 4-(cis-1-t-butoxycarbonyl-4-yl-(2S)-oxime-trimyl) TEA (283 ml, 2.0 mmol) was dissolved in a stirred solution of CHC13 (10.0 mL) and succinyl chloride (155 mg, 0. 68 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography on the tannin extract using hexane-EtOAc (2:1, v/v) as eluent to give 4-(cis-1 -t-butoxycarbonyl~4-dan A yellowish oil of sulphate-(2S)-oxaridinyl)methyl methoxybenzoate (200 mg, 73%). 1H-NMR (CDC13) (5 1· 34 (s, 9H), 1 · 50^ · 6〇/person (m, 1H), 2·15-2.25 (m, 1H), 2·87 (s, 6H ), 3·15

1283240 五、發明說明（561) 1— - -3.22 (m, 1H) ^3.35-3.45 (m, 1H) ^ 3.48-3.52 (m, 1H)、3·80一4·10 (m，3H)、3·91 (s，3H)、7:01 一7.25 (m，4H)、7·50〜7·53 (m，ih)、8·03 (d，J = 8.7 Hz, 2H)、8. 16 (d，J = 8· 5 Hz, 1H)、8· 28 (d，J = 7· 1 Hz， 1H) 、 8·53 (d， j=8 5 Hz， 1H)。 4-[卜[4-[N -(2 -溴笨基）脲基]-3—甲氧苯基乙醯基]一4 一丹 確酿胺基-（2S)-吼咯啶基]曱氧苯甲酸甲酯1283240 V. INSTRUCTIONS (561) 1—————3.22 (m, 1H) ^3.35-3.45 (m, 1H) ^ 3.48-3.52 (m, 1H), 3·80·4·10 (m, 3H), 3·91 (s, 3H), 7:01 a 7.25 (m, 4H), 7·50~7·53 (m, ih), 8·03 (d, J = 8.7 Hz, 2H), 8. 16 (d, J = 8· 5 Hz, 1H), 8·28 (d, J = 7·1 Hz, 1H), 8·53 (d, j=8 5 Hz, 1H). 4-[Bu[4-[N-(2-bromophenyl)ureido]-3-methoxyphenylethenyl]- 4-a-dan-Amino-(2S)-decalridinyl]曱Methyl benzoate

HNiTHNiT

M、 COOMeM, COOMe

。 I 在〇 C下於4:(順-第三丁氧羰基-4 -丹磺醯胺基-(2s) -吼咯啶基）一甲氧笨甲酸甲酯（2〇〇毫克，〇· 34毫莫耳）溶於 CH2Cl2(5· 0毫升）之攪拌溶液中加入TFA(5· 0毫升）。使反應 混合物於室溫下攪拌〇 · 5小時。將混合物於真空中濃縮。 將飽和NaHC〇3加至殘留物，並以萃取。將萃取液以 鹽水洗滌，於NaJC^上乾燥，並於真空中濃縮。將粗製產 物不經進一步的純化而使用於後續的反應。在〇下於此 粗製產物、4-[N’-（2-溴苯基）脲基]- 3-曱氧笨乙酸（129 毫克，0.34毫莫耳）、HOB t(46毫克，0.34毫莫耳）、及三 乙胺（142毫升，1·〇毫莫耳）溶於THF(5. 0毫升）及MeCN(5.0 毫升）之攪拌溶液中加入EDC · HC1 (98毫克，0· 51毫莫 耳）。使反應混合物在室溫下攪拌1 6小時，並於真空中濃 縮。將水加至殘留物，並以E10 A c萃取。將萃取液以飽和 NaHC03、2M檸檬酸、及飽和NaHC03洗滌，然後於Na2S04上乾. I at 4:(cis-t-butoxycarbonyl-4-dansulamide-(2s)-pyridinyl)-methoxy-methoxybenzoic acid methyl ester (2 mg, 〇·34) To a stirred solution of CH 2 Cl 2 (0.5 mL) was added TFA (5.0 mL). The reaction mixture was stirred at room temperature for 5 hours. The mixture was concentrated in vacuo. Saturated NaHC〇3 was added to the residue and extracted. The extract was washed with brine, dried over Na~~~~ The crude product was used in the subsequent reaction without further purification. The crude product, 4-[N'-(2-bromophenyl)ureido]-3-oxooxyacetic acid (129 mg, 0.34 mmol), HOB t (46 mg, 0.34 mmol) Add EDC · HC1 (98 mg, 0·51 mmol) to a stirred solution of triethylamine (142 ml, 1·〇 mmol) dissolved in THF (5.0 mL) and MeCN (5.0 mL) ear). The reaction mixture was stirred at room temperature for 16 hours and concentrated in vacuo. Water was added to the residue and extracted with E10 A c. The extract was washed with saturated NaHC03, 2M citric acid, and saturated NaHC03, then dried over Na2SO4.

\\312\2d-code\90-01\89112968.ptd 第566頁 1283240 五、發明說明（562) 燥’並於真空中濃縮。將殘留物經由於石夕膠上利用正己烧 -EtOAc ( 1 ·· 4 ’ v/v)作為洗提液進行管柱層析，純化而得 4- [卜[4- [Ν’ _(2-&gt;臭笨基）脲基]〜3-甲氧苯基乙醯基]一4一丹 磺醯胺基-（2S)-吡咯啶基]甲氧笨甲酸甲酯（25〇毫克， 8 8%)之無色油。1H-NMR (CDC13) 6 ι·55-1.65 (m，1Η)、 2·15-2·25 (m，1H)、2·87 (s，6H)、3·20 —3.3 5’（m， 3H) 、3·50-3·55 (m， 1H) 、3·67 (s， 3H) 、3·78-3·81 (m，1H)、3·88 -3.93 (m，lH)、3.91(s，3H)、4.28-4·31 (m，1H)、4·65-4·70 (m，1H)、6·35 (d，J = 9.5 Hz，1H)、6.54 (d，J = 8.5 Hz, 1H)、6.63 (s，1H)、 6 · 9 0 - 7 · 1 3 ( m，6 H )、7 · 2 2 - 7 · 3 1 ( m，2 H)、7 · 5 0 - 7 . 5 6 (m， 2H) 、7·88 (d， J=8.0 Hz， 1H) 、7·99 (d， J=9.0 Hz，1H)、8·13-8.16 (m，2H)、8·27 (d，J = 7.6 Hz，1H) 、8. 56 (d， J=8·3 Hz, 1H)。 於4 - [1-[4-[N -（2 -漠苯基）脈基]- 3 -甲氧苯基乙醢 基]-4-丹磺醯胺基-2S-咄咯啶基]甲氧苯曱酸曱酯（ 25 0毫 克，0· 29毫莫耳）溶於THF(5· 0毫升）及MeOH (3. 0毫升）之 攪拌溶液中加入IN NaOH(0· 52毫升，0· 52毫莫耳）。使混 合物在70 °C下攪拌24小時。將混合物於真空中濃縮，加入 水，並以1N HC1中和。收集所產生之固體，以水洗滌，並 於真空中乾燥而得1 63 ( 2 30毫克，94%)的綠色結晶固體。 熔點 138-141 °C; IR (KBr) 3340、2940、1604、1527、 1421、1162、1145 / 公分；4-NMR (DMSO-d6) (5 1· 70-1.80 (m，1Η)、1·98-2.0 6 (m， 1Η)、2·81 (s， 6Η)、\\312\2d-code\90-01\89112968.ptd Page 566 1283240 V. INSTRUCTIONS (562) Drying and concentrating in a vacuum. The residue was purified by column chromatography using hexane-EtOAc (1 ·· 4 ' v/v) as an eluent to obtain 4- [Bu [4- [Ν' _ (2) -&gt;Smelly-based)Ureido]~3-methoxyphenylethylidene]- 4-monosulfonylamino-(2S)-pyrrolidinyl]methyl methoxybenzoate (25 mg, 8 8%) of colorless oil. 1H-NMR (CDC13) 6 ι·55-1.65 (m,1Η), 2·15-2·25 (m,1H), 2·87 (s,6H),3·20 —3.3 5'(m, 3H), 3·50-3·55 (m, 1H), 3.67 (s, 3H), 3·78-3·81 (m, 1H), 3.88 -3.93 (m, lH), 3.91 (s, 3H), 4.28-4·31 (m, 1H), 4·65-4·70 (m, 1H), 6.35 (d, J = 9.5 Hz, 1H), 6.54 (d, J = 8.5 Hz, 1H), 6.63 (s, 1H), 6 · 9 0 - 7 · 1 3 ( m, 6 H ), 7 · 2 2 - 7 · 3 1 ( m, 2 H), 7 · 5 0 - 7 . 5 6 (m, 2H) , 7·88 (d, J=8.0 Hz, 1H), 7·99 (d, J=9.0 Hz, 1H), 8·13-8.16 (m, 2H), 8 · 27 (d, J = 7.6 Hz, 1H), 8.56 (d, J=8·3 Hz, 1H). 4-[1-[4-[N -(2-Molyphenyl)-yl]- 3 -methoxyphenylethenyl]-4-dansylamino-2S-pyridinyl]A Add NaOH (0·52 ml, 0·) to a stirred solution of THF (0.5 mg, 0·29 mmol) in THF (5.0 mL) and MeOH (3.0 mL). 52 millimoles). The mixture was stirred at 70 ° C for 24 hours. The mixture was concentrated in vacuo, water was added and neutralized with 1N EtOAc. The resulting solid was collected, washed with water and dried in vacuo to give 1 &lt;3&gt; Melting point 138-141 °C; IR (KBr) 3340, 2940, 1604, 1527, 1421, 1162, 1145 / cm; 4-NMR (DMSO-d6) (5 1·70-1.80 (m, 1Η), 1· 98-2.0 6 (m, 1Η), 2·81 (s, 6Η),

\\312\2d-code\90-01\89112968.ptd 第567頁 1283240 五、發明說明（563) 3.00-3.10 (m，1H)、3·39-3·40 (m，2H)、3·50-3·80 (m， 3Η) 、3·76 (s， 3Η) 、3·90-4·15 (m， 2Η) 、6·52 (d， J = 9.0 Hz, 1Η)、6·73-7.00 (m，4Η)、7·22-7·35 (m， 2H)、7·55-7·64 (m，3H)、7·83-8·48(ιη,8Η)、8·71-8.76 (m，1Η)、8.88-8.92 (m，1H); MS (FAB) m/z 830 C40H4()N5O8BrS · 〇· 7H20 之分析計算值：C， N，8. 30 ; Br， 9. 47。實測值：C， N, 7· 98 ; Br， 9. 66。 (M+)、832 (MH2) 56.97 ； H， 4. 95 57.06 ； H, 4.86 實施例1 5 6 4 - [4-甲磺醯胺基-l-[4-[N’ -（2-溴苯基）脲基]—3一曱氧苯 基乙醯基]-(2S) -吼咯啶基]曱氧苯曱酸\\312\2d-code\90-01\89112968.ptd Page 567 1283240 V. Description of invention (563) 3.00-3.10 (m, 1H), 3·39-3·40 (m, 2H), 3· 50-3·80 (m, 3Η), 3·76 (s, 3Η), 3·90-4·15 (m, 2Η), 6.52 (d, J = 9.0 Hz, 1Η), 6.73 -7.00 (m, 4Η), 7·22-7·35 (m, 2H), 7·55-7·64 (m, 3H), 7·83-8·48 (ιη, 8Η), 8.71 -8.76 (m,1Η), 8.88-8.92 (m,1H); MS (FAB) m/z 830 C40H4()N5O8BrS · 〇· 7H20 Analysis calculated: C, N, 8. 30 ; Br, 9. 47. Found: C, N, 7·98; Br, 9. 66. (M+), 832 (MH2) 56.97; H, 4. 95 57.06; H, 4.86 Example 1 5 6 4 - [4-Methanesulfonylamino-l-[4-[N'-(2-bromobenzene) Ureido]] 3-indolyl phenyl ethenyl]-(2S)-indolyl] oxobenzoic acid

HNis-Me 4-(順-1-第三丁氧羰基-4-曱磺醯胺基-(2S)-吡咯啶基）曱 氧苯甲酸甲酯 A》 在0 °C If於4-(順-4 -胺基-1-第三丁氧羰基-(2S)-咄咯啶 基）甲乳苯甲酸甲醋（180毫克，〇·51毫莫耳）及ΤΕΑ(283毫 升’2.0毫莫耳）溶於C H C Ι3 (1 0 · 〇毫升）之攪拌溶液中加入 甲續醯氯(88毫克，0· 77毫莫耳）。使反應混合物於室溫下 祝拌1 8小時。將反應混合物於真空中濃縮。使殘留物經由 於石夕膠上利用正己烷_EtOAc(l:l, ν/ν)作為洗提液進行管HNis-Me 4-(cis-1-t-butoxycarbonyl-4-indolesulfonylamino-(2S)-pyrrolidinyl)methyl oxime benzoate A" at 0 °C If at 4-(cis -4 -Amino-1-t-butoxycarbonyl-(2S)-pyridinyl)Methyl benzoic acid methyl vinegar (180 mg, 〇·51 mmol) and ΤΕΑ (283 ml '2.0 mmol) ) A solution of CHC Ι3 (1 0 · 〇ml) was added with hydrazine chloride (88 mg, 0·77 mmol). The reaction mixture was allowed to mix at room temperature for 18 hours. The reaction mixture was concentrated in vacuo. The residue was passed through a mixture of hexane-EtOAc (1:1, ν/ν) as an eluent.

W312\2d-code\90-01\89112968.ptdW312\2d-code\90-01\89112968.ptd

第568頁 1283240 五、發明說明（564) 柱層析，純化而得4 —(順 # p ^ 0丨員—1—第三丁氧羰基-4-甲磺醯胺基 Δ丄1τ ) Τ氧本甲酸甲酯（150毫克，69%)之淡黃 色油。NMR (CDC1 ) λ ，/ , 1U、 0 co 〇 p Li3) 5 1· 45 (s，9H)、1· 98-2· 08 (m， 1Η) ^ 2.52-2.65 (m in \ 0 r l|0、3·55- 3,80 u，lH)、3 8 9 (s，iH)、4 〇〇_ 4.70 (m，4H)、6. Hoo (m，2H)、8 Hz, 2H) 。 · r 1 N 、 ， lH) 、 2·99 (s， 3H) 、 3·40-3·50 00 (d, J = 8· 8 4基[=== HN；SMePage 568 1283240 V. Description of the invention (564) Column chromatography, purification to obtain 4 - (Shun # p ^ 0 — - 1 - T-butoxycarbonyl-4-methanesulfonylamino Δ丄 1τ) Methyl formate (150 mg, 69%) of pale yellow oil. NMR (CDC1 ) λ , / , 1U, 0 co 〇p Li3) 5 1· 45 (s, 9H), 1· 98-2· 08 (m, 1Η) ^ 2.52-2.65 (m in \ 0 rl|0 , 3·55- 3,80 u,lH), 3 8 9 (s,iH), 4 〇〇_ 4.70 (m,4H), 6. Hoo (m,2H), 8 Hz, 2H). · r 1 N , , lH) , 2·99 (s, 3H) , 3·40-3·50 00 (d, J = 8· 8 4 basis [=== HN; SMe

在0 C下於4-(順-I —第三丁氧羰基-4—曱磺醯胺基-(2S) 一咄咯啶基\甲氧苯甲酸甲_(l50毫克，〇·43毫莫耳）溶於 CH2Cl2(5· 0毫升）之攪拌溶液中加入TFA(5. 〇毫升）。使反應 此合物於室溫下攪拌0. 5小時。將混合物於真空中濃縮。 將飽和NaHC〇3加至殘留物，並以CH2Cl2萃取。將萃取液以 鹽水洗滌，於NaJO4上乾燥，並於真空中濃縮。將粗製產 物不經進一步的純化而使用於後續的反應。在Q下於此 粗製產物、4-[Ν’ -（2 -溴笨基）脲基]-3一甲氧苯乙酸（l63毫 克’〇·42毫莫耳）、H0Bt(58毫克，0.43毫莫耳）、及三乙 胺（Π9毫升，I. 3毫莫耳）溶於THF(5· 〇毫升）及MeCN(5· 〇毫 升）之攪拌溶液中加入EDC ·ΗΠ (144毫克，0.75毫莫 耳）。使反應混合物在室溫下攪拌I 6小時，並於真空中濃At 0 C, 4-(cis-I-t-butoxycarbonyl-4-indolesulfonylamino-(2S)-oxazolidinyl-methoxybenzoate-(l50 mg, 〇·43 mmol) To the stirred solution of CH2Cl2 (0.5 ml), TFA (5 ml) was added. The mixture was stirred at room temperature for 0.5 hr. The mixture was concentrated in vacuo. The residue is taken up in EtOAc (EtOAc) (EtOAc (EtOAc) The product, 4-[Ν'-(2-bromophenyl)ureido]-3-methoxyphenylacetic acid (l63 mg '〇·42 mmol), H0Bt (58 mg, 0.43 mmol), and Ethylamine (Π9 ml, 1.3 mmol) was dissolved in THF (5·ml) and MeCN (5·ml). EDC·ΗΠ (144 mg, 0.75 mmol) was added. The mixture was stirred at room temperature for 6 hours and concentrated in vacuo.

第569頁 1283240 五、發明說明（565) 縮。將水加至殘留物，並以E 10 A C萃取。將萃取液以飽和 NaHC03、2M檸檬酸、及飽和NaHC03洗滌，然後於Na2S04上乾 燥，並於真空中濃縮。將殘留物經由於矽膠上利用正己烷 -EtOAc(l:4，v/v)至 EtOH-EtOAc(10%，v/v)作為洗提液進 行管柱層析，純化而得4-[4-甲磺醯胺基-1-[4-[Ν’-（2-溴 苯基）脲基]- 3-甲氧苯基乙醯基]-(2S) -吼咯啶基]甲氧苯 甲酸甲酯（21 0毫克，73%)之無色油。iH-NMR (CDC13) (5 1.9 5-2.0 0 (in, 1H) ^ 2.55-2.6 5 (m, 1H) ^2.17 (s, 3H) 、3.55-3·70 (m， 1H) 、3.60 (s， 2H) 、3·67 (s， 3H) 、3.85-3.90 (m， 1H) 、3·89 (s， 3H) 、3.95-4.18 (m，2 H )、4 · 4 5 - 4 · 5 5 (m，1 H)、4 · 7 0 - 4 · 8 0 (m，1 H )、 5.87 (d，J = 9.3 Hz，1H)、6·73-6·95 (m，5H)、7·09 (s，2H)、7.28- 7.33 (m，1H)、7·51 (d，J = 8.0 Hz， 1H) 、7·93-7·97 (m， 3H) 、8.13 (d， J=8.3 Hz， 1H)。 於4-[4-甲磺醯胺基-1-[4-[N，-（2-溴苯基）脲基]-3-曱 氧苯基乙醯基]-(2S) -吼洛唆基]甲氧苯甲酸曱酯（21〇毫 克’ 〇· 3毫莫耳）溶於THF(5. 0毫升）及MeOH(3· 0毫升）之攪 拌溶液中加入1 N N aOH ( 0 · 8毫升，〇 · 8毫莫耳）。使混合物 在7 0 C下授拌2 4小時。將混合物於真空中濃縮，加入水， 並以1 N HC1中和。收集所產生之固體，以水洗滌，並於真 空中乾燥而得1 6 4 ( 1 70毫克，83%)的白色結晶固體。熔點 1 25-1 2 8。。； IR (KBr) 3 353、1 6 89、1 604、1 52 9、1419、 1155/公分；iH，MR (DMS0-d6) (5 1.88-2.00 (m，1H)、 2.35-2.45 (m，1H)、2·96 (m，3H)、3·15-3·23 (m，Page 569 1283240 V. Description of invention (565) Contraction. Water was added to the residue and extracted with E 10 A C. The extract was washed with saturated NaHC03, 2M EtOAc and sat. NaHC.sub.3. The residue was purified by column chromatography using n-hexane-EtOAc (1:4, v/v) to EtOH-EtOAc (10%, v/v) as eluent. -Methanesulfonamide-1-[4-[Ν'-(2-bromophenyl)ureido]-3-methoxyphenylethenyl]-(2S)-indolyl]methoxybenzene A colorless oil of methyl formate (21 0 mg, 73%). iH-NMR (CDC13) (5 1.9 5-2.0 0 (in, 1H) ^ 2.55-2.6 5 (m, 1H) ^2.17 (s, 3H), 3.55-3·70 (m, 1H), 3.60 (s , 2H), 3.67 (s, 3H), 3.85-3.90 (m, 1H), 3·89 (s, 3H), 3.95-4.18 (m, 2 H ), 4 · 4 5 - 4 · 5 5 (m, 1 H), 4 · 7 0 - 4 · 8 0 (m, 1 H ), 5.87 (d, J = 9.3 Hz, 1H), 6.73-6·95 (m, 5H), 7· 09 (s, 2H), 7.28- 7.33 (m, 1H), 7·51 (d, J = 8.0 Hz, 1H), 7·93-7·97 (m, 3H), 8.13 (d, J=8.3 Hz, 1H). 4-[4-Methanesulfonylamino-1-[4-[N,-(2-bromophenyl)ureido]-3-indolylphenylphenyl]]-(2S - 1 - NN aOH is added to a stirred solution of THF (5.0 ml) and MeOH (3.0 ml) (0 · 8 ml, 〇·8 mmol). The mixture was stirred for 24 hours at 70 C. The mixture was concentrated in vacuo, water was added and neutralized with 1 N HCl. Washed with water and dried in vacuo to give EtOAc (1, EtOAc, EtOAc) 3, 1 6 89, 1 604, 1 52 9, 1419, 1155 / cm; iH, MR (DMS0-d6) (5 1.88-2.00 (m, 1H), 2.35-2.45 (m, 1H), 2.96 (m, 3H), 3·15-3·23 (m,

\\312\2d-code\90-01\89112968.ptd 第570頁 1283240 五、發明說明（566) 1H) 、3·60 (s， 2H) 、3·50-3·70 (m， 1H) 、3·78 (S， 3Η) 、3·80-3·90 (m， 1Η) 、3·95-4·〇5 (m， 1Η) 、4·1〇-4·30 (m，2H)、6·7卜7·03 (m，4H)、7·32 (m，1H)、 7·45 (d，J = 6.8 Hz，1H)、7·60 (d，J = 7.8 Hz，1H)、 7·87_7·95 (m，4H)、8·74 (s，1H)、8·92 (s，1H); MS(FAB) m/z 675 (M+)、677(MH2); C29H31N4〇8BrS ·〇·6Η20 之分析計算值：C，50·75; H，4·73; N，8.16。實測值： C，51· 04 ; Η，4· 62 ; Ν，7· 79。 實施例1 5 7 4-[1-[3-甲氧基一4-[Ν’ -（2-甲基苯基）脲基]笨基乙醯基] -（2S) -八氫吲哚甲氧基]苯甲酸\\312\2d-code\90-01\89112968.ptd Page 570 1283240 V. Description of invention (566) 1H), 3·60 (s, 2H), 3·50-3·70 (m, 1H) , 3·78 (S, 3Η), 3·80-3·90 (m, 1Η), 3·95-4·〇5 (m, 1Η), 4·1〇-4·30 (m, 2H) , 6·7 Bu 7·03 (m, 4H), 7·32 (m, 1H), 7·45 (d, J = 6.8 Hz, 1H), 7·60 (d, J = 7.8 Hz, 1H) , 7·87_7·95 (m, 4H), 8.74 (s, 1H), 8.92 (s, 1H); MS (FAB) m/z 675 (M+), 677 (MH2); C29H31N4〇8BrS · 〇·6Η20 Analysis calculated: C, 50·75; H, 4·73; N, 8.16. Found: C, 51·04 ; Η, 4· 62 ; Ν, 7· 79. Example 1 5 7 4-[1-[3-Methoxy-4-[Ν'-(2-methylphenyl)ureido]]phenylamino]-(2S)-octahydroindole Oxy]benzoic acid

1-（第二丁氧羰基）八氫吲哚_(2s)_羧酸 CX^c〇2h 於八氫叫丨哚—（2S) -羧酸（3.00克，17.7毫莫耳）溶於二氧 ，園（2〇。笔升）之攪拌溶液中加入IN NaOH(45毫升），並使 洛液在0 C下攪拌。在〇°C下於混合物中加入（Boc)20 克，19·5毫莫耳）溶於二氧陸園（25毫升）’並使反應 此合物~在室溫下攪拌1天。將混合物以1 N HC1酸化，並以 Et〇AC萃取。將萃取液以鹽水洗滌，於Na2S04上乾燥，並蒸1-(Secondoxycarbonyl) octahydroindole _(2s)-carboxylic acid CX^c〇2h is soluble in octahydro-(2S)-carboxylic acid (3.00 g, 17.7 mmol) To a stirred solution of oxygen, garden (2 liters, pen liter) was added IN NaOH (45 ml), and the solution was stirred at 0 C. (Boc) 20 g, 19.5 mmoles dissolved in dioxane (25 ml) was added to the mixture at 〇 ° C and the reaction mixture was stirred at room temperature for 1 day. The mixture was acidified with 1 N HCl and extracted with EtOAc. The extract was washed with brine, dried over Na 2 SO 4 and steamed.

第571頁 1283240 五、發明說明（567) 發而得1-(第三丁氧羰基）八氫吲哚-(2S)-羧酸（4. 78克， q· Υ·)的無色固體。熔點 1 30 - 1 32 °C ; UMR (CDC13)占 1· 1〇-1 · 46 (s 及m 系列，總計14H)、1· 65-1· 76 (m， 3H)、 1·90-2·18 (m，2H)、2·26 - 2.3 5 (m，1H)、3·77 - 3·86 (m，1Η)、4·22-4·34 (m，1H); ESI m/z 270 (ΜΗ1)。 卜（第三丁氧羰基）八氫吲哚-（2S )-甲醇Page 571 1283240 V. INSTRUCTION DESCRIPTION (567) A colorless solid of 1-(t-butoxycarbonyl) octahydroindole-(2S)-carboxylic acid (4.78 g, q·Υ·). Melting point 1 30 - 1 32 °C; UMR (CDC13) occupies 1·1〇-1 · 46 (s and m series, total 14H), 1·65-1· 76 (m, 3H), 1·90-2 ·18 (m, 2H), 2·26 - 2.3 5 (m, 1H), 3·77 - 3·86 (m, 1Η), 4·22-4·34 (m, 1H); ESI m/z 270 (ΜΗ1). Bu (t-butoxycarbonyl) octahydroindole-(2S)-methanol

於1-(第三丁氧羰基）八氫吲哚—（2S) -羧酸（1·〇〇克， 3· 71毫莫耳）溶於THFC10毫升）之冷卻的（0 °C)攪拌溶液中 加入BH3 · DMS( 5 30毫升，5. 59毫莫耳），並使反應混合物 在室溫下攪拌隔夜。利用H2 〇使混合物停止反應，並以 EtOAc萃取。將萃取液以鹽水洗滌，於Na2S〇4上乾燥，並蒸 發。使殘留物經由於矽膠上利用CHC13-MeOH (50:1， v/v) 作為洗k液進行管柱層析，純化而得1 _ (第三丁氧魏基）八 氫吲哚-(2S)-甲醇（ 940毫克，99%)之無色油。1H-NMR (CDC13)(5 1.05-1.30 (m，4Η)、1·47 (s，9H)、1.49- 1·74 (m，4Η)、1·82-1·93 (m，3Η)、2·19-2·26 (m， lH)、3.56-3.61(m，lH)、3.70 -3.75 (m，2H)、3.94-3·96 (m，1H); MS(FAB) m/z 25 6 CMH1)。 4-[1-（第三丁氧羰基）一（2S) -八氫吲哚曱氧基]苯曱酸曱酯A cooled (0 ° C) stirred solution of 1-(t-butoxycarbonyl) octahydroindole-(2S)-carboxylic acid (1·〇〇g, 3.71 mmol) dissolved in THF (10 mL) BH3·DMS (5 30 ml, 5.59 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was quenched with H.sub.2 and extracted with EtOAc. The extract was washed with brine, dried over Na 2 EtOAc 4 and evaporated. The residue was subjected to column chromatography using CHC13-MeOH (50:1, v/v) as a washing liquid, and purified to obtain 1 _ (t-butoxy- yl) octahydroindole-(2S) )-Methanol (940 mg, 99%) of a colorless oil. 1H-NMR (CDC13) (5 1.05-1.30 (m, 4Η), 1.47 (s, 9H), 1.49-1.77 (m, 4Η), 1.82-1·93 (m, 3Η), 2·19-2·26 (m, lH), 3.56-3.61 (m, lH), 3.70 -3.75 (m, 2H), 3.94-3·96 (m, 1H); MS(FAB) m/z 25 6 CMH1). 4-[1-(Tertidinoxycarbonyl)-(2S)-octahydroindolyl]benzoate

\\312\2d-code\90-01\89112968.ptd 第572頁 1283240 五、發明說明（568) 於4-羥基苯曱酸甲酯（560毫克，3.68毫莫耳）、：! -（第三 丁氧羰基）八氫吲哚_(2S)-甲醇（940毫克，3.68毫莫耳）及 Ph3P(l· 16克，4·42毫莫耳）溶於THF(20毫升）之冷卻的（0 °C)攪拌溶液中加入DIAD(870毫升，4.42毫莫耳），並使反 應混合物迴流加熱8小時。於冷卻至室溫後，將混合物蒸 發。將殘留物經由於矽膠上利用正己烷-EtOAc (5 : 1，v/v )作為洗提液進行管柱層析，純化而得4 _[ 1-(第三丁氧羰 基）-(2S)-八氫吲哚甲氧基]苯甲酸甲酯（1· 16克，81%)之 無色油。1Ή-NMR (CDC13) 5 1 · 14-1· 47 (s 及m 系列，總計 13H)、1· 60-2· 13 (m 系列，總計6H)、2· 22-2· 28 (m， 1H)、3·75-3·91 (s 及 m 系列，總計 4H)、4·06 - 4·18 (m， 2H)、4·37 (m，1H)、6·94-6·96 (m，2H)、7·96_7·98 (m，2H) ; MS(FAB) m/z 390 (MH1)。 4- [ (2S)-八氫吲哚甲氧基]苯甲酸甲酯 於4-[1-（第三丁氧羰基）—（2S) -八氫哨哚甲氧基]苯甲酸 甲酯（1· 16克，2· 98毫莫耳）溶於CH2C12(10毫升）之攪拌溶 液中加入TFA(1 0毫升），並使反應混合物在室溫下攪拌2小 時。將混合物於真空中濃縮，利用飽和NaHC03使成為鹼 性，並以CHCI3萃取。將萃取液以鹽水洗滌，於k2C03上乾 燥，並蒸發而得4-[(2S)-八氫吲哚甲氧基]笨甲酸甲酯 (860 毫克，q. y·)之棕色油。ih-NMR (CDC13) 6 1· 23-1· 78 (m 系列，總計 10H)、2.00-2·09 (m，2H)、3·14 - 3·18 (m，\\312\2d-code\90-01\89112968.ptd Page 572 1283240 V. INSTRUCTIONS (568) Methyl 4-hydroxybenzoate (560 mg, 3.68 mmol), :! Tributoxycarbonyl) octahydroindole _(2S)-methanol (940 mg, 3.68 mmol) and Ph3P (1.66 g, 4.42 mmol) in THF (20 mL) cooled ( 0 °C) DIAD (870 ml, 4.42 mmol) was added to the stirred solution, and the reaction mixture was heated under reflux for 8 hours. After cooling to room temperature, the mixture was evaporated. The residue was subjected to column chromatography using n-hexane-EtOAc (5:1, v/v) as an eluent to obtain 4 _[ 1-(t-butoxycarbonyl)-(2S). a colorless oil of methyl octahydrofluorenyl methoxy]benzoate (1·16 g, 81%). 1Ή-NMR (CDC13) 5 1 · 14-1· 47 (s and m series, total 13H), 1·60-2· 13 (m series, total 6H), 2·22-2· 28 (m, 1H ), 3·75-3·91 (s and m series, total 4H), 4·06 - 4·18 (m, 2H), 4·37 (m, 1H), 6·94-6·96 (m , 2H), 7·96_7·98 (m, 2H); MS (FAB) m/z 390 (MH1). 4-[(2S)-octahydroindolyl]benzoic acid methyl ester in methyl 4-[1-(t-butoxycarbonyl)-(2S)-octahydroindolylmethoxy]benzoate ( To a stirred solution of CH2C12 (10 mL), EtOAc (EtOAc) The mixture was concentrated in vacuo, made basic with saturated NaHC03 and extracted with CHCI. The extract was washed with brine, dried over EtOAc EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj ih-NMR (CDC13) 6 1· 23-1· 78 (m series, total 10H), 2.00-2·09 (m, 2H), 3·14 - 3·18 (m,

89112968.ptd 第573頁 1283240 五、發明說明（569) 1 Η)、3 . 5 5 - 3 · 6 2 (m，1 Η )、3. 8 8 (s，3 Η)、3 · 9 6 - 4 0 6 (m， 2Η) 、6·92 (d， J=9.1 Hz, 2Η) 、7·97 (d， J=9 189112968.ptd Page 573 1283240 V. Description of invention (569) 1 Η), 3. 5 5 - 3 · 6 2 (m, 1 Η ), 3. 8 8 (s, 3 Η), 3 · 9 6 - 4 0 6 (m, 2Η), 6.92 (d, J=9.1 Hz, 2Η), 7·97 (d, J=9 1

Hz，2H) ; MS(FAB) m/z 290(MH1)。 4-[1 - [3 -甲氧基-4-[N -(2-曱基笨基）脲基]笨基乙醯基 ]-（2 S )-八氩吲哚甲氧基]苯甲酸曱酯 使3-甲氧基-4-[『- (2 -甲基苯基）脲基]苯乙酸（2 98毫 克，0.95毫莫耳）、4-[(2S)-八氫吲哚甲氧基]笨曱酸曱酯 (274毫克，0. 95毫莫耳）、EDC*HC 1(218毫克，1.14毫莫 耳）、HOBt(154 毫克，ΐ·ΐ4 毫莫耳）、Et3N(160 毫升，1.15 宅莫耳）於TH F ( 7耄升）中之混合物在室溫下擾拌隔夜。將 混合物以稀釋，並以EtOAc萃取。將萃取液以鹽水洗 務，於NagSC^上乾燥’並蒸發。使殘留物經由於石夕膠上利 用CHCl3-MeOH(100:l至5〇··ι，v/v)作為洗提液進行管柱層 析，純化而得4-[1-[3-甲氧基-4 - [N，-（2-曱基笨基）脲基] 苯基乙醯基]-(2S)-八氫吲哚曱氧基]笨曱酸甲酯（532毫 克，96%)的白色泡沫。！H —NMr (CDCl3) 6 l 13一2· 〇5 (m 系 列，總計9H)、2·14-2.24 (m, 2H)、2·26 (s，3H)、3·60 (s，2H)、3·62 (s，3H)、3·80- 3.8 5 (m，1H)、3·88 (s， 3 H)、4 · 2 7 - 4 · 3 7 (m，3 h )、6 · 6 2 (s，1 h )、6 · 7 4 - 6 · 7 6 (m，2H)、6·91 (d，J=：8.8 Hz，2H)、7·〇9-7·13 (m, 1 H)、7 · 2 0 - 7 · 2 4 ( m，3 h )、7 · 5 5 (d，j =： 7 · 8 H z，1 H )、Hz, 2H); MS (FAB) m/z 290 (MH1). 4-[1 -[3-methoxy-4-[N-(2-amilyphenyl)ureido]]phenyl(indenyl)-(2S)-octahydrofluorenylmethoxy]benzoic acid Oxime ester 3-methoxy-4-["-(2-methylphenyl)ureido]phenylacetic acid (2 98 mg, 0.95 mmol), 4-[(2S)-octahydrofuran Oxyl] oxalate (274 mg, 0.95 mmol), EDC*HC 1 (218 mg, 1.14 mmol), HOBt (154 mg, ΐ·ΐ4 mmol), Et3N (160) A mixture of ML, 1.15 house moles in TH F (7 liters) was disturbed overnight at room temperature. The mixture was diluted and extracted with EtOAc. The extract was washed with brine, dried over NagSC(s) and evaporated. The residue was subjected to column chromatography using CHCl3-MeOH (100:1 to 5 〇··ι, v/v) as an eluate, and purified to obtain 4-[1-[3-A Oxy-4-[N,-(2-indolyl)ureido]phenylphenyl]](2S)-octahydroindolyl]methyl benzoate (532 mg, 96%) ) white foam. ! H—NMr (CDCl3) 6 l 13–2· 〇5 (m series, total 9H), 2·14-2.24 (m, 2H), 2·26 (s, 3H), 3·60 (s, 2H) , 3·62 (s, 3H), 3·80- 3.8 5 (m, 1H), 3·88 (s, 3 H), 4 · 2 7 - 4 · 3 7 (m, 3 h ), 6 · 6 2 (s, 1 h ), 6 · 7 4 - 6 · 7 6 (m, 2H), 6.91 (d, J =: 8.8 Hz, 2H), 7·〇9-7·13 (m, 1 H), 7 · 2 0 - 7 · 2 4 ( m, 3 h ), 7 · 5 5 (d, j =: 7 · 8 H z, 1 H ),

第574頁 \\312\2d-code\90-01\89112968.ptd 1283240 五、發明說明（570) 7.94 (d, J-8.8 Hz, 2H) ^8.04 (d, J-7. 8 Hz, 1H)； MS(FAB) m/z 58 6 (MH1)。 於4 - [1-[3 -甲氧基-4-[Ν’ -（2-甲基苯基）脲基]苯基乙醯 基]_(2S)_八氫°引17朵甲氧基]苯甲酸甲醋（532毫克，0.91毫 莫耳）溶於THF(5毫升）之攪拌溶液中加入〇. 5N NaOH(5毫 升），並使反應混合物迴流加熱3小時。於冷卻至室溫後， 將混合物倒入至冰的1 N H C1中，並收集所產生之沈澱物。 使粗製固體自MeOH - CHC13 - ΙΡΕ再結晶，而得1 65 ( 278毫 克，54%)之白色結晶粉末。熔點1 30 - 1 34 °C ; UMR (DMS0-d6) 6 1. 16-2. 10 (m 系列，總計9H)、2· 15-2· 30 (s 及 m 系列，總計 4 Η)、3 · 5 5 - 3 · 7 9 ( m, 3 Η)、3 · 8 1 ( s， 3Η) 、3·90-3.95(m，lH)、4.17-4.23(m，2H)、4.34-4·36 (m，1Η)、6·72-6·74 (m，1Η)、6·87-6·88 (m， 1Η)、6·91-6·95 (πι，1Η)、7·03 (d，J = 8.8Hz，2Η)、7· 10-7·16 (m，2Η)、7.78-7·80 (m，1Η)、7·87 (d，J二8.8 Hz，2H)、7·98- 8.0 0 (m，1H)、8·45 (s，1H)、8·54 (s， 1H) &gt;12.61 (br s, 1H) ； MS(FAB) m/z 5 72 (MH1)； C33H37N3 06 · 1/4H20 之分析計算值：C，68· 79 ; H，6· 56 ; N， 7.29。實測值：C， 68·70; H，6.82; N， 6.97。 實施例1 5 8 4 - [卜[4-[N，_(2_氯苯基）脲基]- 3-甲氧苯基乙醯基]-(2S) -八氫吲哚甲氧基]苯甲酸Page 574 \\312\2d-code\90-01\89112968.ptd 1283240 V. Description of the invention (570) 7.94 (d, J-8.8 Hz, 2H) ^8.04 (d, J-7. 8 Hz, 1H MS (FAB) m/z 58 6 (MH1). 4-[1-[3-methoxy-4-[Ν'-(2-methylphenyl)ureido]phenylethenyl]_(2S)_octahydrogen To a stirred solution of benzoic acid methyl acetonate (532 mg, 0.91 mmol) in THF (5 mL), EtOAc. After cooling to room temperature, the mixture was poured into ice 1 N H C1 and the resulting precipitate was collected. The crude solid was recrystallized from MeOH - CHC13 - EtOAc to yield 1 65 (278 g, 54%) of white crystals. Melting point 1 30 - 1 34 °C; UMR (DMS0-d6) 6 1. 16-2. 10 (m series, total 9H), 2· 15-2· 30 (s and m series, total 4 Η), 3 · 5 5 - 3 · 7 9 ( m, 3 Η), 3 · 8 1 ( s, 3Η), 3·90-3.95 (m, lH), 4.17-4.23 (m, 2H), 4.34-4·36 (m,1Η),6·72-6·74 (m,1Η),6·87-6·88 (m, 1Η), 6·91-6·95 (πι,1Η), 7·03 (d , J = 8.8 Hz, 2 Η), 7· 10-7·16 (m, 2 Η), 7.78-7·80 (m, 1 Η), 7·87 (d, J 8.8 Hz, 2H), 7·98 - 8.0 0 (m, 1H), 8·45 (s, 1H), 8·54 (s, 1H) &gt;12.61 (br s, 1H) ; MS(FAB) m/z 5 72 (MH1); C33H37N3 06 · Analysis of 1/4H20: C, 68· 79 ; H, 6.56; N, 7.29. Found: C, 68·70; H, 6.82; N, 6.97. Example 1 5 8 4 - [Bu [4-[N,_(2-chlorophenyl)ureido]-3-methoxyphenylethenyl]-(2S)-octahydrofluorenylmethoxy] benzoic acid

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4-[1 - [4 - [Ν’ -（2 -氣苯基）脲基]一 3一甲 -八氫吲哚甲氧基]笨曱酸曱酿 氧苯基乙醯基]-(2S) 使4-[N’-(2-氯苯基）脲基卜3_甲氧笨乙酸（3〇7毫克， 〇二92毫莫耳）、4-[ (2S)_八氯D㈣甲氧基]苯甲酸甲醋（265 宅克，0.92毫莫耳）、EDC.HC1 (211毫克，11〇毫莫耳）、 肋8“148毫克，1.1〇毫莫耳）、及以3^153毫升，11〇 莫耳）於THF(7毫升）中之混合物在室溫下攪拌隔夜·。將混 合物以札0稀釋，並以EtOAc萃取。將萃取液以鹽水洗滌二 於NazS〇4上乾燥，並蒸發。使殘留物經由於矽膠上利用 CHCl3-MeOH(l 00 : 1至50 : 1，v/v)作為洗提液進行管柱層 析，純化而得4 - [1-[4-[Ν’-（2-氯苯基）脲基]—3-曱氧^美 乙醯基]_(2S) -八氫吲哚甲氧基]苯曱酸曱酯（55〇毫克，土 99%)的白色泡沫。iH-NMR (CDC13) (51.15-2.02 (!„系列， 總什9H)、2.17-2.33 (m， 2H)、3·58 (s， 3H)、3.6^ (s 2 Η)、3 · 8 4 - 3 · 9 0 ( s 及m 系列，總計 4 Η)、4 · 0 6 - 4 · 4 0 (m ’ 3H)、6·7卜6.74 (m，2H)、6·88-7·00 (m，3H)、7·21 — 7.30 (m，2H)、7·62 (s，2H)、7·9 卜 7·95 (m，3H)、 8.17-8.20 (m，1H); MS(FAB) m/z 60 6 (MH1)。 於4-[1-[4-[Ν’-（2-氯苯基）脲基]- 3-甲氧苯基乙醯基 ]-(2S) -八氫吲哚甲氧基]苯甲酸甲酯（ 5 50毫克，〇· 91毫莫4-[1 - [4 - [Ν' -(2 -Phenylphenyl)ureido]-1,3-methyl-octahydroindole methoxy]] 曱 曱 曱 氧 氧 氧 ] ] ]]] (2S ) 4-[N'-(2-chlorophenyl)ureido3-methoxybenzoic acid (3〇7 mg, 〇2 92 mmol), 4-[(2S)_octachloro D(tetra)methoxy Base benzoic acid methyl vinegar (265 house grams, 0.92 millimolar), EDC.HC1 (211 mg, 11 〇 millimolar), rib 8 "148 mg, 1.1 〇 millimolar", and 3^153 ml The mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc, and extracted with EtOAc. The extract was washed with brine and dried over NazS. Evaporation. The residue was subjected to column chromatography using CHCl3-MeOH (100:1 to 50:1, v/v) as an eluent, and purified to give 4-[1-[4-[Ν '-(2-Chlorophenyl)ureido]-3-oxime oxime]-(2S)-octahydrofluorenylmethoxy]benzoate oxime ester (55 mg, soil 99%) White foam. iH-NMR (CDC13) (51.15-2.02 (!„ series, total 9H), 2.17-2.33 (m, 2H), 3·58 (s, 3H), 3.6^ (s 2 Η), 3 · 8 4 - 3 · 9 0 ( s and m Series, total 4 Η), 4 · 0 6 - 4 · 4 0 (m ' 3H), 6·7 b 6.74 (m, 2H), 6·88-7·00 (m, 3H), 7·21 — 7.30 (m, 2H), 7.62 (s, 2H), 7·9 Bu 7·95 (m, 3H), 8.17-8.20 (m, 1H); MS (FAB) m/z 60 6 (MH1) 4-[1-[4-[4-[Ν-(2-Chlorophenyl)ureido]-3-methoxyphenylethenyl]-(2S)-octahydrofluorenylmethoxy]benzoic acid Methyl ester (5 50 mg, 〇·91 mmol)

1283240 五、發明說明（572) 耳）&gt;谷於THF(5宅升）之攪拌溶液中加入〇· 5n Na0H(5毫 升），並使反應混合物迴流加熱5小時。於冷卻至室溫後， 將混合物倒入至冰的1 N H C1中，並收集所產生之沈澱物。 使粗製固體自MeOH-CHCl3-IPE再結晶，而得166(286毫 克，53%)之白色結晶粉末。熔點1 33 - 1 36 °C ; UMR (DMS〇-d6) (5 1. 16-2· 10 (m 系列，總計10H)、2· 24-2. 27 (m，lH)、3.5 5- 3.75 (m，2H)、3.80(s，3H)、3.90-3·96 (m，1Η)、4. 17-4.23 (m，2Η)、4·34-4·36 (m，1Η) 、6·73 - 6.75 (m，1H)、6·88 (d，J = 1.5 Hz，1H)、6·99 - 7. 0 5 (m，3 H)、7 · 2 5 - 7 · 3 0 (m，1 H )、7 · 4 3 (d d，J = 1.5、8·1 Hz，1H)、7·8 7-7.89 (m，2H)、7.95 (d，J = 8.1 Hz，1H)、8·08 (dd，J = 1.5、8·3 Hz，1H)、8·88 (s，1H)、8·92 (s，1H)、12·61 (br s, 1H); MS(FAB) m/z 59 2 (MH1 ) ; C32H34C1N3 06 · 1/4H20 之分析計算值：C， 64· 42 ; H，5. 83 ; N，7. 04 ; Cl， 5. 94。實測值：C， 64· 55 ; H，6. 09 ; N, 6· 64 ; Cl，5· 93。 實施例1 5 9 4-[l-[4-[Ν’ -（2 -溴苯基）脲基]一3一甲氧苯基乙醯基]一（2S) -八氫吲哚甲氧基]苯甲酸1283240 V. INSTRUCTION OF THE INVENTION (572) Ears&gt; In a stirred solution of THF (5 liters), 〇·5n Na0H (5 ml) was added, and the reaction mixture was heated under reflux for 5 hours. After cooling to room temperature, the mixture was poured into ice 1 N H C1 and the resulting precipitate was collected. The crude solid was recrystallized from MeOH-CHCl3-IPH to yield 166 (286 g, Melting point 1 33 - 1 36 °C; UMR (DMS〇-d6) (5 1. 16-2· 10 (m series, total 10H), 2· 24-2. 27 (m, lH), 3.5 5- 3.75 (m, 2H), 3.80 (s, 3H), 3.90-3·96 (m, 1Η), 4. 17-4.23 (m, 2Η), 4·34-4·36 (m, 1Η), 6· 73 - 6.75 (m, 1H), 6.88 (d, J = 1.5 Hz, 1H), 6·99 - 7. 0 5 (m, 3 H), 7 · 2 5 - 7 · 3 0 (m, 1 H ), 7 · 4 3 (dd, J = 1.5, 8·1 Hz, 1H), 7·8 7-7.89 (m, 2H), 7.95 (d, J = 8.1 Hz, 1H), 8.08 (dd, J = 1.5, 8·3 Hz, 1H), 8·88 (s, 1H), 8.92 (s, 1H), 12·61 (br s, 1H); MS(FAB) m/z Anal. Calcd.: C, 64. H,6. 09 ; N, 6· 64 ; Cl,5·93. Example 1 5 9 4-[l-[4-[Ν' -(2-Bromophenyl)ureido]- 3-methoxy Phenylethyl hydrazide]-(2S)-octahydrofluorenylmethoxy]benzoic acid

4-[1-[4-[Ν’ - (2 -溴苯基）脲基]一 3—甲氧苯基乙醯基]-(2S) -八氫吲哚甲氧基]苯曱酸甲酯4-[1-[4-[Ν' - (2-Bromophenyl)ureido]-3-methoxyphenylethenyl]-(2S)-octahydrofluorenylmethoxy]benzoic acid ester

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汉㈣。〜 使4-[Ν’-（2 -溴苯基）脲基]一3 -曱氧苯乙酸（457毫克， 1·21毫莫耳）、4-[(2S) -八氫吲哚甲氧基]苯甲酸曱酿（32〇 毫克，1.21毫莫耳）、EDC*HC 1(277毫克，1·44毫莫耳）、 HOBt(196毫克，1· 45毫莫耳）、及Et3N( 2 0 0毫升，['η古 莫耳）於THF( 7毫升）中之混合物在室溫下攪拌隔夜。將= 合物以％0稀釋，並以EtOAc萃取。將萃取液以鹽水洗滌此 於NagSO4上乾爍，並蒸發。使殘留物經由於矽膠上用 CHCl3-MeOH(100:l，v/v)作為洗提液進行管柱層析， 而得4-[1-[4-[Ν，-(2-溴苯基）脲基]〜3_甲氧笨基乙酿^ 基]-(2S)-八氫吲哚甲氧基]苯曱酸甲酯（423毫 白色泡泳。1H_NMR (CDC13) 154.89 (m 系列 的 8Η) ^ 1.96-2.02 (m, 1H) ^2.16-2.32 (m, 2H) ： 3 13 (s, 2H) ^3.65 (s, 3H) ^3.82-3.86 (m, 1H) .3 88 (s 3H)、4.3G-4.39 (m，3H)、6.75-6.77 (m，2I〇 ’ 6.93 (m，3H)、7.24-7.31 (m，1H)、7 37 . 3H)、7.91-7.99 U， 3H)、8.12_8.15 (m， ih 1 m/z 65 0 (MH1)。 ^ 於4-[l-[4-[Ν’ -（2 -溴苯基）脲基]〜3〜甲氧 基]-(2S)-八氫叫卜朵甲氧基]苯曱酸曱雖（42〇 ^ 4 莫耳）溶於THF(5毫升）之授拌溶液中加入〇· 5ν Ν&amp;〇Η(5毫笔 升)，並使反應混合物迴流加熱5小時。於冷卻至室溫後，Han (four). ~ 4-[Ν'-(2-Bromophenyl)ureido]-3-oxophthalic acid (457 mg, 1.21 mmol), 4-[(2S)-octahydroindole methoxy Benzoic acid brewing (32 mg, 1.21 mmol), EDC*HC 1 (277 mg, 1.44 mmol), HOBt (196 mg, 1.45 mmol), and Et3N (2) A mixture of <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; The compound was diluted with %0 and extracted with EtOAc. The extract was washed with brine and dried over NagSO4 and evaporated. The residue was subjected to column chromatography using CHCl3-MeOH (100:1, v/v) as an eluent to give 4-[1-[4-[Ν,-(2-bromophenyl) Urea]~3_methoxylated ethyl ketone]-[2S)-octahydrofluorenylmethoxy]benzoic acid methyl ester (423 milli white bubble. 1H_NMR (CDC13) 154.89 (m series 8Η) ^ 1.96-2.02 (m, 1H) ^2.16-2.32 (m, 2H) : 3 13 (s, 2H) ^3.65 (s, 3H) ^3.82-3.86 (m, 1H) .3 88 (s 3H ), 4.3G-4.39 (m, 3H), 6.75-6.77 (m, 2I〇' 6.93 (m, 3H), 7.24-7.31 (m, 1H), 7 37 . 3H), 7.91-7.99 U, 3H) , 8.12_8.15 (m, ih 1 m/z 65 0 (MH1). ^ 4-[l-[4-[Ν' -(2-Bromophenyl)ureido]~3~methoxy] -(2S)-octahydro-deuteromethoxy]benzoic acid hydrazine (42〇^4 mol) is dissolved in THF (5 ml) and is added to 授·5ν Ν&amp;〇Η(5 毫Pen liter), and the reaction mixture was heated under reflux for 5 hours. After cooling to room temperature,

\\312\2d-code\90-01 \89112968.ptd 第 578 頁 1283240 五、發明說明（574) 將混合物倒入至冰的1 N HC 1中，並收集所產生之沈澱物。 使粗製固體自MeOH-CHCl3-IPE再結晶，而得1 67 ( 1 97毫 克’ 48%)之白色結晶粉末。熔點118-123 °C ; NMR (DMS0-d6) (5 1. 16-2· 27 (m 系列，總計10H)、3· 56-3· 75 (m，3H)、3.81 (s，3H)、3·90-3·96 (m，1H)、4.17-4.23 (m, 2H) ^4.34-4.36 (m, 1H) &gt; 6.73-6.7 5 (m,\\312\2d-code\90-01 \89112968.ptd Page 578 1283240 V. INSTRUCTIONS (574) The mixture was poured into 1 N HC 1 of ice and the resulting precipitate was collected. The crude solid was recrystallized from MeOH-CHCl3-IPH to yield 1 67 (1. Melting point 118-123 °C; NMR (DMS0-d6) (5 1. 16-2· 27 (m series, total 10H), 3· 56-3· 75 (m, 3H), 3.81 (s, 3H), 3·90-3·96 (m,1H), 4.17-4.23 (m, 2H) ^4.34-4.36 (m, 1H) &gt; 6.73-6.7 5 (m,

1H)、6·88-7.05 (m，4H)、7·30 -7.34 (m，1H)、7·59 -7.61 (m，1H)、7·87-7·96 (m，4H)、8·73 (s，1H)、 8.91 (s, 1H) &gt;12.64 (br s, 1H)； MS(FAB) m/z 636 (M + + 1) ; C32H34BrN3 06 · 1/4H20 之分析計算值：C，59. 96 ; H， 5· 42 ; N，6· 55 ; Br，12· 46。實測值：C， 60· 12 ; H，5. 86 ; N，6. 09 ; Br，12· 47。 實施例1 6 0 4-[3-[3-曱氧基-4-[Ν’ - (2-甲基苯基）脲基]苯基]乙醯基 -4-嘍唑啶基]甲氧苯甲酸 Ο1H), 6.88-7.05 (m, 4H), 7.30 - 7.34 (m, 1H), 7·59 - 7.61 (m, 1H), 7·87-7·96 (m, 4H), 8 · 73 (s, 1H), 8.91 (s, 1H) &gt; 12.64 (br s, 1H); MS (FAB) m/z 636 (M + + 1) ; C32H34BrN3 06 · 1/4H20 Analytical calculations: C, 59. 96 ; H, 5· 42 ; N, 6· 55 ; Br, 12.46. Found: C, 60·12; H, 5.86; N, 6. 09; Br, 12.47. Example 1 6 0 4-[3-[3-曱oxy-4-[Ν' - (2-methylphenyl)ureido]phenyl]ethinyl-4-oxazolidinyl]methoxy Barium benzoate

Me H H 〇Me 168 3-第三丁氧羰基噻唑啶_4-羧酸Me H H 〇Me 168 3-Tertiyloxycarbonylthiazolidine-4-carboxylic acid

於噻唑啶-4 -羧酸（5. 0克，37· 6毫莫耳）溶於DMF( 50. 0毫 升）之攪拌溶液中加入（Boc)2 0(9.8克，45.1毫莫耳）及 T E A (8 · 0毫升）。使反應混合物在室溫下擾拌1 8小時。將水Add (Boc) 2 0 (9.8 g, 45.1 mmol) to a stirred solution of thiazolidine-4-carboxylic acid (5.0 g, 37.6 mmol) in DMF (50.5 mL) TEA (8 · 0 ml). The reaction mixture was stirred at room temperature for 18 hours. Water

\\312\2d-code\90-01\89112968.ptd 第579頁 1283240 五、發明說明（575) 加至混合物，並以EtOAc萃取。將有機層以水洗滌，然後 於N S 〇4上乾燥，並於真空中濃縮。使殘留物經由於石夕膠 上利用EtOAc -正己烷（1 : 3，v/v)作為洗提液進行管柱層 析’純化而得3 -第三丁氧幾基σ塞唾σ定-4 -魏酸（6 · 5克， 74%)的白色結晶固體。iH-NMR (CDC13) 5 1. 49 (br s， 9H)、3· 2 0-3· 30 (m，2H)、4· 0 9-4·87 (m，3H)。 3-第三丁氧羰基一5-羥甲基噻唑啶\\312\2d-code\90-01\89112968.ptd Page 579 1283240 V. Inventive Note (575) Add to the mixture and extract with EtOAc. The organic layer was washed with water then dried over EtOAc EtOAc and evaporated. The residue was purified by column chromatography using EtOAc-n-hexane (1:3, v/v) as an eluent to obtain 3-tert-butoxy-based sigma-salt- 4 - Wei acid (6 · 5 g, 74%) of a white crystalline solid. iH-NMR (CDC13) 5 1. 49 (br s, 9H), 3· 2 0-3· 30 (m, 2H), 4·0 9-4·87 (m, 3H). 3-tert-butoxycarbonyl-5-hydroxymethylthiazolidine

在0 C下於3-第三丁氧幾基嗔°坐淀-4-缓酸（2.3克，10.0毫 莫耳）溶於THF(30毫升）之攪拌溶液中加入bh3 · THF(1· 0M 之THF溶液，20.0毫升’20.0毫莫耳）。於在室溫下擾拌 1. 0小時後，將反應混合物迴流加熱1 · 〇小時。於冷卻後， 將混合物於真空中濃縮。在〇 °C下加入水，並以j；t〇Ac萃 取。將萃取液以水洗務，然後於Na2S04上乾燥，並於真空 中濃縮而得3-第三丁氧羰基-5 -經甲基嗔唑咬（2.〇克，定 量）之無色油。1H-NMR(CDC13)51.48(s，9H)、2.80-2·85 (m，1H)、3·13-3.17 (m，1H)、3·20-3·30 (m， 1H)、3.64-3. 7Ό (m，2H)、4.34 (br s，1H)、4· 60 (br s，1H)。 4 -（3-第三丁氧羰基-4 -噻唑啶基）甲氧笨甲酸甲酯Add bh3 · THF (1·0M) at 0 C in a stirred solution of 3-tert-oxyoxyl oxime-sodium 4-acid (2.3 g, 10.0 mmol) in THF (30 mL) THF solution, 20.0 mL '20.0 mmol. After stirring at room temperature for 1.0 hour, the reaction mixture was heated under reflux for 1 hour. After cooling, the mixture was concentrated in vacuo. Water was added at 〇 ° C and extracted with j; t 〇 Ac. The extract was washed with water, dried over Na2SO4, and concentrated in vacuo to give 3-t-butyloxycarbonyl-5-methane (2 g). 1H-NMR (CDC13) 51.48 (s, 9H), 2.80-2·85 (m, 1H), 3·13-3.17 (m, 1H), 3·20-3·30 (m, 1H), 3.64 3. 7Ό (m, 2H), 4.34 (br s, 1H), 4· 60 (br s, 1H). 4-(3-Tertixocarbonylcarbonyl-4-thiazolyl)methyl methoxybenzoate

在0 °C下於3-第三丁氧羰基-5-羥甲基噻唑啶（I 9克3-tert-butoxycarbonyl-5-hydroxymethylthiazolidine (I 9 g at 0 °C)

89112968.ptd 第580頁 128324089112968.ptd Page 580 1283240

8.7毫莫耳）、4-經基苯甲酸甲酯（13克，8.7毫8.7 millimolar), 4-methylbenzoic acid methyl ester (13 g, 8.7 m)

Ph3P(3. 2克，12· 2毫莫耳）溶於THF(1〇毫升）之〜， 加入DIAD(2.2克，1〇·4毫莫耳）。使反應混合物在夜中 攪拌18小時。將混合物於真空中濃縮。將殘留物細n下 膠上利用£10^-正己烧（1:9,〇4作為洗提液進==23 析’純化而得4_ (3 -第三丁氧羰基—4-噻唑啶基）甲氧曰 酸甲醋（1· 6克’ 52%)之淡黃色油。iH —NMR (CDC1j 3 1 μ (s，9H)、3·：Π - 3·19 (m，2H)、3·88 (s，3H)、4·〇4 一· 4·31 (m，3Η)、4·61 (m，2Η)、6·96 (d，J = 8.8 Ηζ， 2H)、7·98 (d，J = 8.8 Hz，2H)。 4-[3- [3-甲氧基-4 - [Ν’ -（2-甲基苯基）脲基]苯基]乙醯基 -4-噻唑啶基]曱氧苯甲酸甲酯 ιPh3P (3.2 g, 12. 2 mmol) was dissolved in THF (1 mL), and DIAD (2.2 g, 1 〇·4 mmol) was added. The reaction mixture was stirred at night for 18 hours. The mixture was concentrated in vacuo. The residue was finely n-packed and purified by using £10^-n-hexane (1:9, 〇4 as eluent in ==23) to obtain 4_(3 -t-butoxycarbonyl-4-thiazolyl) a pale yellow oil of methoxy methoxyacetic acid (1.6 g '52%). iH-NMR (CDC1j 3 1 μ (s, 9H), 3:: Π - 3·19 (m, 2H), 3 ·88 (s,3H), 4·〇4·············································· d, J = 8.8 Hz, 2H) 4-[3-[3-Methoxy-4 -[Ν' -(2-methylphenyl)ureido]phenyl]ethinyl-4-thiazole Methyl phthalate

Re) Ο COOMe 在0°C下於4_(3-第三丁氧羰基—4 -噻唑啶基）曱氧苯甲酸 曱酯（440毫克，1·25毫莫耳）溶於CH2C12(6毫升）之攪拌溶 液中加入TF A (3毫升）。使反應混合物在室溫下攪拌〇 · 5小 時。將混合物於真空中濃縮。將飽和NaHC03加至殘留物， 並以CHJl2萃取。將萃取液以鹽水洗滌，於Na2S04上乾燥， 並於真空中濃縮。將粗製產物不經進一步的純化而使用於 後續的反應。在0 °C下於此粗製產物（〇 · 6毫莫耳）、3 -甲氧 基-4-[N -(2 -曱基苯基）脈基]苯乙酸（188毫克，0.6毫莫 耳）、H0Bt(81毫克，0.6毫莫耳）、及三乙胺（280毫升，2.Re) Ο COOMe is dissolved in CH 2 C 12 (6 ml) at 0 ° C in 4 -(3-t-butoxycarbonyl-4-thiazolidinyl) decyloxybenzoate (440 mg, 1.25 mmol) To the stirred solution was added TF A (3 mL). The reaction mixture was stirred at room temperature for 5 hours. The mixture was concentrated in vacuo. Saturated NaHC03 was added to the residue and extracted with CHJ12. The extract was washed with brine, dried over Na. The crude product was used in the subsequent reaction without further purification. This crude product (〇·6 mmol), 3-methoxy-4-[N-(2-mercaptophenyl)-based]phenylacetic acid (188 mg, 0.6 mmol) at 0 °C ), H0Bt (81 mg, 0.6 mmol), and triethylamine (280 ml, 2.

\\312\2d-code\90-01\89112968.ptd 第581頁 1283240 五、發明說明（577) 〇宅莫耳）溶於THF(5毫升）及MeCN(5毫升）之攪拌溶液中加 入E|)C · HC1 (1 73毫克，〇· 9毫莫耳）。使反應混合物在室溫 下授拌1 6小時，並於真空中濃縮。將水加至殘留物，並以 EtOAc萃取。將萃取液以飽和NaHC〇3、2M檸檬酸、及飽和 NaHC〇3洗滌，然後於Na2S〇4上乾燥，並於真空中濃縮。將 殘留物經由於矽膠上利用正己烷一Et〇Ac(1 :3，v/v)作為洗 提液進行管柱層析，純化而得4 - [3 - [3-曱氧基-4-[ N，\\312\2d-code\90-01\89112968.ptd Page 581 1283240 V. INSTRUCTIONS (577) 〇家莫耳) Add E to a stirred solution of THF (5 ml) and MeCN (5 ml) |) C · HC1 (1 73 mg, 〇·9 mmol). The reaction mixture was stirred at room temperature for 16 h and concentrated in vacuo. Water was added to the residue and extracted with EtOAc. The extract was washed with saturated aq. NaH.sub.3, 2M EtOAc, sat. The residue was subjected to column chromatography using n-hexane-Et〇Ac (1:3, v/v) as an eluent to obtain 4 - [3 - [3-methoxy-4- [N,

(2曱基本基）脈基]苯基]乙酿基一 4 — 17塞嗤σ定基]甲氧苯甲 酸甲醋（ 340毫克，定量）的非晶形固體。1H — NMR (CDCD 62.31 (s，3H)、3·15-3·16 (m，2H)、3.67-3·69 (m， 5H)、3·88 (s，3H)、4·09-4.14 (m，2H)、4·22-4·90 (m， 3H) 、6.30 (m， 1H) 、6·74-6·96 (m, 4H)、 7·11 -7.25 (m，4H)、7. 49-7.51 (m, 1H)、7. 95-8.12 (m， 3H)。 於4 - [3-[3 -甲氧基-4 - （2-甲基苯基）脲基]苯基]乙 醯基-4 -噻唑啶基]甲氧苯曱酸甲酯（340毫克，0.62毫莫 耳）溶於THF(5· 0毫升）及EtOH(3· 0毫升）之攪拌溶液中加入 IN NaOH(0.62毫升，0.62毫莫耳）。使混合物在7〇°C下攪 拌1 8小時。將混合物於真空中濃縮，加入水，並以1 n HC 1 中和。收集所產生之固體，以水洗滌，並於真空中乾燥而 得1 6 8 ( 2 9 0毫克，8 8 %)之白色結晶固體。熔點1 2 5 -1 2 8 °C ; IR (KBr) 3357、2937、1604、1533、1419、1253、 1166、1 0 33、77 3 / 公分；NMR (DMS0-d6) 5 2· 25 (s， 3H)、3· 05-3·20 (m，2H)、3· 71、3·83及3· 85 (各s，總(2 曱 basic base) phenyl group] phenyl] ethyl aryl group 4 - 17 嗤 嗤 定 ] ] methoxy methacrylate (340 mg, quantitative) of amorphous solid. 1H — NMR (CDCD 62.31 (s, 3H), 3·15-3·16 (m, 2H), 3.67-3·69 (m, 5H), 3·88 (s, 3H), 4·09-4.14 (m, 2H), 4·22-4·90 (m, 3H), 6.30 (m, 1H), 6.74-6·96 (m, 4H), 7·11 -7.25 (m, 4H), 7. 49-7.51 (m, 1H), 7. 95-8.12 (m, 3H). 4-[3-[3-Methoxy-4-(2-methylphenyl)ureido]phenyl Add ethyl hydrazide-4-thiazolidinyl]methoxybenzoate (340 mg, 0.62 mmol) to a stirred solution of THF (5.0 mL) and EtOH (3.0 mL) NaOH (0.62 mL, 0.62 mmol). The mixture was stirred at <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; Washed with water and dried in vacuo to give EtOAc (EtOAc: EtOAc: EtOAc: , 1419, 1253, 1166, 1 0 33, 77 3 / cm; NMR (DMS0-d6) 5 2· 25 (s, 3H), 3· 05-3·20 (m, 2H), 3·71, 3 ·83 and 3.85 (each s, total

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什 5H)、4.03 - 4·15 (m，3H)、4·52 - 4.76 (m，2H)、6 i5 - 6 · 1 7 (m，7 Η)、7 · 7 8 - 8 · 3 0 (m，4 Η )、8 · 3 0 ( m，1 η )、8 56 (m, 1H) ； MS(FAB) m/z 536 (MH1) ； C28H29N3 06 s · · 0· 5H20 之分析計算值：C，61· 75 ; H，5· 55 ; N，7· 72。與 測值·· C， 61 · 72 ; H， 5· 55 ; N, 7· 49。 貝 實施例1 6 1 4 - [3 - [4 - [Ν’ - (2 -氣苯基）脲基]一 3-曱氧笨基乙醯基]—4一 噻唑啶基]甲氧苯甲酸 ^5H), 4.03 - 4·15 (m, 3H), 4·52 - 4.76 (m, 2H), 6 i5 - 6 · 1 7 (m, 7 Η), 7 · 7 8 - 8 · 3 0 ( m,4 Η ), 8 · 3 0 ( m,1 η ), 8 56 (m, 1H) ; MS(FAB) m/z 536 (MH1) ; C28H29N3 06 s · · 0· 5H20 Analytical calculated value: C, 61· 75 ; H, 5 · 55 ; N, 7. 72. And measured · · C, 61 · 72 ; H, 5 · 55 ; N, 7 · 49. Example 1 6 1 4 - [3 - [4 - [Ν' - (2 -Phenylphenyl)ureido]-3-oxooxyphenyl)]-4-thiazolyl]methoxybenzoic acid ^

169 4-[3-[4-[Ν’ - (2 -氣笨基）脲基]—3—甲氧笨基乙醯基卜&amp;一噗 唑啶基]甲氧苯甲酸曱酯 。分 _β C, H H OMe 在0°C下於4 -（3-第三丁氧羰基一 4-噻唑啶基）甲氧笨甲酸 甲酯（600毫克，1.7毫莫耳）溶於CHJl〆6. 0毫升）之授掉^ 液中加入TFA(6.0毫升）。使反應混合物在室溫下攪拌〇 ^ 小時。將混合物於真空中濃縮。將飽和NaHC〇3加至殘留 物，並以CHJl2萃取。將萃取液以鹽水洗滌，於上乾 燥’並於真空中濃縮。將粗製產物不經進一步的純化而使 用於後續的反應。在〇。〇下於此粗製產物、4-[N，-(2 -氣苯 基）脲基]- 3-甲氧笨乙酸（570毫克，1.7毫莫耳）、H〇Bt169 4-[3-[4-[Ν' - (2 - oxalyl) ureido]-3-methoxybenzylidene oxime &amp; oxazolidinyl] methoxy benzoate. _β C, HH OMe Methyl 4-(3-tert-butoxycarbonyl-4-thiazolidinyl)methoxymethoate (600 mg, 1.7 mmol) dissolved in CHJl〆6 at 0 °C . 0 ml) was added to the solution and TFA (6.0 ml) was added. The reaction mixture was stirred at room temperature for 小时 ^ h. The mixture was concentrated in vacuo. Saturated NaHC〇3 was added to the residue and extracted with CHJ12. The extract was washed with brine, dried over EtOAc EtOAc. The crude product was used in the subsequent reaction without further purification. Here. The crude product, 4-[N,-(2-phenylphenyl)ureido]-3-methoxyacetic acid (570 mg, 1.7 mmol), H〇Bt

\\312\2d-code\90-01\89112968.ptd 第583頁 1283240 五、發明說明（579) (230毫克，1·7毫莫耳）、及三乙胺（709毫升，5·1毫莫耳） &gt;谷於THF(10· 0¾升）及MeCN(10v0毫升）之授拌溶液中加入 EDC · HC 1 ( 49 0毫克，2· 55毫莫耳）。使反應混合物在室温 下攪拌1 6小時，並於真空中濃縮。將水加至殘留物，並以 EtOAc萃取。將萃取液以飽和NaHC〇3、2M擰檬酸、及飽和 NaHC〇3洗滌，然後於NaJO4上乾燥，並於真空中濃縮。將 殘留物經由於矽膠上利用正己烷-EtOAc(l : 1，v/v)作為洗 提液進行管柱層析，純化而得4-[3-[4-[N，-（2-氯笨基） 脲基]- 3-甲氧苯基乙醯基]-4-噻唑啶基]甲氧苯甲酸甲酉旨 ( 90 0 毫克，93°/。）的無色油。UMR (CDC13) (53.15 - 3·ι8 (m，2H)、3·70 (s，2H)、3·78 (s，3H)、3·86 (s， 3Η)、4·0 9-4.93 (m，5Η)、6·80-7·01 (m，5Η)、7·19〜 7· 35 (m，4Η)、7· 94-8· 18 (m，4Η)。 於4-[3-[4-[ Ν’ - (2 -氯苯基）脲基]-3-甲氧苯基乙醯 基]-4-噻唑啶基]甲氧苯甲酸曱酯（900毫克，1.6毫莫耳） 溶於THF (8· 0毫升）及MeOH(4. 0毫升）之攪拌溶液中加入1N 心011(3.1毫升，3.1毫莫耳）。使混合物在70°(：下攪拌24小 時。將混合物於真空中濃縮，加入水，並以1 N H C 1中和。 收集所產生之固體，以水洗滌，並於真空中乾燥而得1 6 9 ( 78 0毫克，89%)之白色結晶固體。熔點1 26-1 29 °C ; IR (KBr) 3343 、 2937 、 1604 、 1531 、 1421 、 1245 、 1166 、 1 035、752 / 公分；UMR (DMS0-d6) (5 3· 06-3· 24 (m， 2Η)、3·72-3·85 (m，5Η)、4·02-4·27 (m，3Η)、4·53 〜 4·76 (m, 2Η)、6·74-7·44 (m， 7Η)、7·87-8.3 0 (m，\\312\2d-code\90-01\89112968.ptd Page 583 1283240 V. Description of the invention (579) (230 mg, 1.7 mmol) and triethylamine (709 ml, 5.1 ml) Mole) &gt; Valley EDC · HC 1 (49 0 mg, 2. 55 mmol) was added to the THF (10·03⁄4 L) and MeCN (10 v0 mL). The reaction mixture was stirred at room temperature for 16 h and concentrated in vacuo. Water was added to the residue and extracted with EtOAc. The extract was washed with saturated NaHC 〇3, 2M EtOAc, and sat. NaHC.sub.3, then dried over Na.sub.4, and concentrated in vacuo. The residue was subjected to column chromatography using n-hexane-EtOAc (1:1, v/v) as an eluent to obtain 4-[3-[4-[N,-(2-chloro) A colorless oil of ureido]-3-methoxyphenylethylidene]-4-thiazolidinyl]methoxybenzoate (90 mg, 93°/.). UMR (CDC13) (53.15 - 3·ι8 (m, 2H), 3·70 (s, 2H), 3·78 (s, 3H), 3·86 (s, 3Η), 4·0 9-4.93 ( m,5Η),6·80-7·01 (m,5Η), 7·19~ 7· 35 (m,4Η), 7·94-8· 18 (m,4Η). 4--3- [4-[ Ν' - (2-Chlorophenyl)ureido]-3-methoxyphenylethyl]-4-thiazolidinyl] methoxybenzoate (900 mg, 1.6 mmol) 1N Heart 011 (3.1 ml, 3.1 mmol) was added to a stirred solution of THF (8.0 mL) and MeOH (4.0 mL). The mixture was stirred at 70°. Concentrated in vacuo, water was added and EtOAc EtOAc (EtOAc m. 26-1 29 °C; IR (KBr) 3343, 2937, 1604, 1531, 1421, 1245, 1166, 1 035, 752 / cm; UMR (DMS0-d6) (5 3 · 06-3· 24 (m, 2Η), 3·72-3·85 (m, 5Η), 4·02-4·27 (m, 3Η), 4·53 ～ 4·76 (m, 2Η), 6.74-7·44 ( m, 7Η), 7·87-8.3 0 (m,

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第584頁 1283240 五、發明說明（580) 4H)、8· 8 9-8· 95 (m，2H) ; MS(FAB) m/z 55 6 (MH1); C27H27N3 06 C1S · 〇· 7h2〇 之分析計算值：c，56.9 3； H, 5. 03 ;N，7· 38 ; Cl， 6. 22。實測值·· C， 56. 8 9 ; H， 4. 82 ; N， 7·42 ; Cl， 6· 35 。 ’ 實施例1 6 2 4 - [3 - [4 - [Ν’ -（2 -溴苯基）脲基]_3一甲氧苯基乙醯基卜4 -噻唑啶基]曱氧苯甲酸Page 584 1283240 V. INSTRUCTIONS (580) 4H), 8· 8 9-8· 95 (m, 2H) ; MS(FAB) m/z 55 6 (MH1); C27H27N3 06 C1S · 〇· 7h2 Analytical calculated values: c, 56.9 3; H, 5. 03; N, 7·38; Cl, 6. 22. Found C· 56. 8 9 ; H, 4. 82 ; N, 7·42 ; Cl, 6· 35 . Example 1 6 2 4 - [3 - [4 - [Ν' -(2 -Bromophenyl)ureido]_3-methoxyphenylethenyl-4-thiazolidinyl]oxobenzoic acid

Br Η H 〇Me 170 4_[ 3-[4-[Ν’ -（2-溴苯基）脲基]-3一甲氧苯基乙醯基]一4一 噻唑啶基]甲氧苯甲酸甲酯Br Η H 〇Me 170 4_[ 3-[4-[Ν' -(2-Bromophenyl)ureido]-3-methoxyphenylethenyl]-4-isothiazolidinyl]methoxybenzoate ester

在0 C下於4 -（3-第三丁氧羰基-4 -噻唑啶基）曱氧苯甲酸 甲酯（5 60毫克，1· 6毫莫耳）溶於Ct^Cl〆5· 0毫升）之擾拌溶 液中加入T F A ( 5 · 0宅升）。使反應混合物在室溫下授拌〇 $ 小時。將混合物於真空中濃縮。將飽*NaHC〇3加至殘留 物，並以CHJl2萃取。將萃取液以鹽水洗滌，於上乾 烯，並於真空中濃縮。將粗製產物不經進一步的純化而使 用於後續的反應。在〇它下於此粗製產物、4 — [ n，—（ 2 —漠苯 基）脲基]-3-甲氧苯乙酸（599毫克，16毫莫耳） (213毫克，1·6毫莫耳）、及三乙胺（659毫升，4·7毫莫耳）Methyl 4-(3-tert-butoxycarbonyl-4-thiazolyl)oxybenzoate (5 60 mg, 1.6 mmol) dissolved in Ct^Cl〆5·0 ml at 0 C Add TFA (5 · 0 house liter) to the disturbing solution. The reaction mixture was allowed to stir at room temperature for $ hours. The mixture was concentrated in vacuo. Saturated *NaHC〇3 was added to the residue and extracted with CHJ12. The extract was washed with brine, dried over EtOAc and concentrated in vacuo. The crude product was used in the subsequent reaction without further purification. Under this product, the crude product, 4-[n,-(2-diphenyl)ureido]-3-methoxyphenylacetic acid (599 mg, 16 mmol) (213 mg, 1-6 mmol) Ear), and triethylamine (659 ml, 4·7 mmol)

\\312\2d-code\90-01\89112968.ptd 第585頁 1283240 五、發明說明（581) 溶於THF(10. 0毫升）及MeCN(10· 0毫升）之攪拌溶液中加入 E D C · H C 1 (4 5 5毫克，2 · 4毫菜、耳）。使反應混合物在室溫下 攪拌1 6小時，並於真空中濃纟餐〜。將水加至殘留物，並以 EtOAc萃取。將萃取液以飽和NaHC03、2Μ檸檬酸、及飽和 NaHC03洗滌，然後於Na2S04上乾燥，並於真空中濃縮。將 殘留物經由於矽膠上利用正己烷-Et0Ac(2 : 3，v/v)作為洗 提液進行官柱層析，純化而得4 _ [ 3 - [ 4 * [ N ’ -（ 2 - 臭本基） 脲基]-3-甲氧苯基乙醯基]-4 -噻峻11定基]甲氧苯甲酸甲酉旨 (870 毫克，89%)的無色油。iH - NMR (CDC13) (53·〇〇-3·2〇 (m，3H)、3·70 (s，2H)、3·81 (s，3H)、3·88 (s，3H) 、4·09 -4.23 (m，1Η)、4.42 (d，J = 8.5 Ηζ，1Η)、4.59 (d，J = 8.5 Ηζ，1Η)、4·70-4·92 (m，1Η)、6·81-7·53 (m，9Η)、7· 95-8· 15 (m，4Η) 〇 於4-[3-[4-[Ν’ -（2-溴苯基）脲基]_3-甲氧苯基乙醯基] -4-噻唑啶基]甲氧苯曱酸甲酯（8 70毫克，1. 4毫莫耳）溶於 THF(8· 0毫升）及MeOH(8. 0毫升7)之攪拌溶液中加入1Ν NaOH(2· 8毫升，2· 8毫莫耳）。使混合物在70 °C下攪拌18小 時。將混合物於真空中濃縮，加入水，並以1 N HC1中和。 收集所產生之固體，以水洗滌，並於真空中乾燥而得丨7 〇\\312\2d-code\90-01\89112968.ptd Page 585 1283240 V. INSTRUCTIONS (581) EDC is added to a stirred solution of THF (10.0 ml) and MeCN (10.0 ml). HC 1 (4 5 5 mg, 2 · 4 ham, ears). The reaction mixture was stirred at room temperature for 16 hours and concentrated in vacuo. Water was added to the residue and extracted with EtOAc. The extract was washed with sat. NaHC.sub.3, EtOAc, sat. NaHC.sub.3, and then evaporated. The residue was subjected to column chromatography using n-hexane-Et0Ac (2:3, v/v) as an eluent, and purified to obtain 4 _ [ 3 - [ 4 * [ N ' - ( 2 - odor This group is a colorless oil of ureido]-3-methoxyphenylethylidene]-4-thiophene]methyl methoxybenzoate (870 mg, 89%). iH - NMR (CDC13) (53·〇〇-3·2〇(m,3H), 3·70 (s,2H), 3·81 (s,3H), 3·88 (s,3H), 4 ·09 -4.23 (m,1Η), 4.42 (d, J = 8.5 Ηζ, 1Η), 4.59 (d, J = 8.5 Ηζ, 1Η), 4·70-4·92 (m, 1Η), 6.81 -7·53 (m,9Η), 7·95-8· 15 (m,4Η) 〇 in 4-[3-[4-[Ν' -(2-bromophenyl)ureido]_3-methoxy Methyl phenylacetamido]-4-thiazolidinyl]methoxybenzoate (8 70 mg, 1.4 mmol) dissolved in THF (8.0 mL) and MeOH (8.0 mL) 1 NaOH (2.8 ml, 2.8 mmol) was added to the stirred solution, and the mixture was stirred at 70 ° C for 18 hr. The mixture was concentrated in vacuo, water was added, and neutralized with 1 N HCl. The resulting solid was collected, washed with water and dried in vacuo to give 丨7 〇

( 740毫克，87%)之白色結晶固體。熔點1 25-1 33。(： ； IR (KBr) 3332 、 2935 、 1604 、 1527 、 1421 、 1245 、 1166 、 1 02 7、75 0 / 公分；M-NMR (DMS0-d6) 6 3· 0卜3· 25 (m， 2H)、3·72-3·85 (m，5H)、4·02-4·30 (m，2H)、4·54 (d，J = 8.8 Hz，1H)、4·74-4·87 (m，2H)、6·76-7·〇7(740 mg, 87%) of a white crystalline solid. Melting point 1 25-1 33. (: ; IR (KBr) 3332, 2935, 1604, 1527, 1421, 1245, 1166, 1 02 7, 75 0 / cm; M-NMR (DMS0-d6) 6 3· 0 Bu 3· 25 (m, 2H ), 3·72-3·85 (m, 5H), 4·02-4·30 (m, 2H), 4·54 (d, J = 8.8 Hz, 1H), 4·74-4·87 ( m, 2H), 6·76-7·〇7

\\312\2d-code\90-01\89112968.ptd 第586頁 1283240 五、發明說明（582) (m，5 Η )、7 · 3 0 - 7 · 3 4 (m，1 Η)、7 · 5 9 (d，J = 8 · 1 Η z， 1Η) 、7·86-7·98 (m， 4Η) 、8·74 (s， 1Η) 、8·92-8 94 (s, 1H)；MS(FAB) m/z 60 0 (MH1 ) ； C27H26N3 06 BrS · 0. 3H20 之为析计鼻值.C, 53.52，Η，4·43; Ν，6·94。實測值： C，53· 54 ; Η，4· 45 ; Ν，6· 80。 實施例1 6 3 順-4-[ [1-[3-甲氧基-4_[『-（2-甲基笨基）脲基]苯基乙醯 基]-2-咄咯啶基]甲胺基]環己烷羧酸\\312\2d-code\90-01\89112968.ptd Page 586 1283240 V. Description of invention (582) (m, 5 Η ), 7 · 3 0 - 7 · 3 4 (m, 1 Η), 7 · 5 9 (d, J = 8 · 1 Η z, 1Η), 7·86-7·98 (m, 4Η), 8·74 (s, 1Η), 8.92-8 94 (s, 1H) ;MS(FAB) m/z 60 0 (MH1 ) ; C27H26N3 06 BrS · 0. 3H20 is the analytical nose value. C, 53.52, Η, 4·43; Ν, 6.94. Found: C, 53· 54 ; Η, 4· 45 ; Ν, 6. 80. Example 1 6 3 cis-4-[ [1-[3-methoxy-4_["-(2-methylphenyl)ureido]phenylethenyl]-2-oxazolidinyl]- Amino]cyclohexanecarboxylic acid

Me H H OMe 171 1 - [3-甲氧基-4 - [Ν’-（2-甲基苯基）脲基]苯基乙醯基]一 2S -吡咯啶甲醇Me H H OMe 171 1 - [3-methoxy-4 - [Ν'-(2-methylphenyl)ureido]phenylethenyl]- 2S-pyrrolidinemethanol

在0°C下於2S-咄咯啶甲醇（2.0克，20.0毫莫耳）、3-甲 氧基-4-[N’-（2-甲基苯基）脲基]苯乙酸（6. 28克，20.0毫 莫耳）、H0Bt(71毫克，0.53毫莫耳）、及三乙胺（5.5毫 升’ 40. 0毫莫耳）溶於THF(50· 0毫升）及MeCN(40· 0毫升）之 攪拌溶液中加入EDC · HC1(5· 7克，30. 0毫莫耳）。使反應 混合物在室溫下授拌1 6小時，並於真空中濃縮。將水加至 殘留物，並以EtOAc萃取。將有機層以飽和NaHC03、2M檸 檬酸、及飽和NaHC03洗滌，然後於Na2S04上乾燥，並於真2S-oxaridinyl methanol (2.0 g, 20.0 mmol), 3-methoxy-4-[N'-(2-methylphenyl)ureido]phenylacetic acid at 0 °C (6. 28 g, 20.0 mmol, H0Bt (71 mg, 0.53 mmol), and triethylamine (5.5 ml '40. 0 mmol) dissolved in THF (50·0 mL) and MeCN (40·0) EDC · HC1 (5·7 g, 30.0 mm) was added to the stirred solution of ML). The reaction mixture was stirred at room temperature for 16 h and concentrated in vacuo. Water was added to the residue and extracted with EtOAc. The organic layer was washed with saturated NaHC03, 2M citric acid, and saturated NaHC03, then dried over Na 2 SO 4 and

\\312\2d-code\90-01\89112968.ptd 第587頁 1283240 五、發明說明（583) 空中》辰縮。將殘齒4 CH2C12(1 :9，v/v)經由，石夕膠上利用EtOAc至MeOH-卜[3_甲氧基〜4〜，為洗提液進行管柱層析，純化而得 - 2S-咄咯啶甲醇（7 (2—甲$笨基）脲基]苯基乙醯基]\\312\2d-code\90-01\89112968.ptd Page 587 1283240 V. Description of invention (583) Residue 4 CH2C12 (1:9, v/v) was passed through a mixture of EtOAc to MeOH-Bu [3_methoxy~4~, as an eluent for column chromatography and purification. 2S-Ethrolidine Methanol (7 (2-A-Phenyl) Urea]Phenylethyl]

(CDC13) ά1· 54〜ι ·ς〇产，W)的白色結晶固體。1H一NMR 2. 27 (s，3H)、3、2 广’ 1H)、丄.8〇-2. 04 (m，3H)、 2H) ^3.62 (s, 2H) ； · ^ 1H) '3.54-3.6 5 (m, 1H)、5. 04 (m，1H) . S; 3H)、4. 2卜4· 23 (m’ (,,4H) ^7.52 (d j 7 1 U，3H) '7*09-7·31 u U，J==7· 8 Hz, 1H)、8. 07 (d, J = 8· 0(CDC13) ά1· 54~ι · Produced, W) white crystalline solid. 1H-NMR 2. 27 (s, 3H), 3, 2 wide '1H), 丄.8〇-2. 04 (m, 3H), 2H) ^3.62 (s, 2H) ; · ^ 1H) '3.54 -3.6 5 (m, 1H), 5. 04 (m, 1H) . S; 3H), 4. 2 Bu 4· 23 (m' (,, 4H) ^7.52 (dj 7 1 U, 3H) '7 *09-7·31 u U,J==7· 8 Hz, 1H), 8. 07 (d, J = 8· 0

Hz, 1H J 0 [W3-甲氧基__4_[N，一（2_甲基苯基）脈基]苯基乙醯 基]-2-咣咯灾基]甲胺基]環己烷羧酸苄酯Hz, 1H J 0 [W3-methoxy__4_[N, mono(2-methylphenyl))]phenylethenyl]-2-indolyl]methylamino]cyclohexanecarboxylate Benzyl acetate

Me H H 〇Me 在-78C下於草醯氯㈧^毫升^^毫莫耳”容於⑶/匕 (30· 0毫升）之攪拌溶液中加入DMs〇( 6· 6毫升，〇. 51毫莫 耳）。於5分鐘後，在混合物中加入1 - [ 3-甲氧基一4 - [ N， -（2-甲基苯基）脲基]苯基乙醯基]- 2-吡洛咬甲醇（1.2 克，3· 0毫莫耳）溶於CH2C12(5. 0毫升）。將混合物在-78 °C 下攪拌30分鐘，並加入三乙胺（2· 1毫升，15. 0毫莫耳）。 使混合物在-78 °C下攪拌30分鐘，及在室溫下攪拌30分 鐘。將水加至混合物，並以C H2 C 12萃取。將萃取液以水洗 滌，然後於Na2S04上乾燥，並於真空中濃縮。將粗製產物Me HH 〇Me Add DMs〇 (6. 6 ml, 〇. 51 mmol) to a stirred solution of (3)/匕 (30·0 ml) in a solution of chloroform (8)^ml^^mole in -78C. After 5 minutes, 1-[3-methoxy-4-[N,-(2-methylphenyl)ureido]phenylethenyl]-2-pyrobitine was added to the mixture. Methanol (1.2 g, 3.0 mmol) was dissolved in CH2C12 (5.0 mL). The mixture was stirred at -78 °C for 30 min, and triethylamine (2·1 ml, 15. 0 mmol) The mixture was stirred at -78 ° C for 30 minutes and at room temperature for 30 minutes. Water was added to the mixture and extracted with CH 2 C 12. The extract was washed with water and then dried over Na 2 SO 4 . And concentrated in vacuo. The crude product

\\312\2d-code\90-01\89112968.ptd 第 588 頁 1283240 五、發明說明（584) 不經進一步的純化而使用於後續的反應中。在0 °C下於此 粗製產物、順-4 -胺基環己烷羧酸芊酯（ 76 9毫克，3· 3毫莫 耳）、及AcOH (0· 32毫升）溶於DCE(1 0毫升）之攪拌溶液中 加入NaBH(0Ac)3 (1. 1克，5· 4毫莫耳）。使反應混合物在 室溫下攪拌1 8小時。將混合物於真空中濃縮。將飽和 NaHC03加至殘留物，並以CH2C12萃取。將萃取液以鹽水洗 滌，於N a2 S 04上乾燥，並於真空中濃縮。使殘留物經由於 矽膠上利用MeOH-CH2C12(1 : 9，v/v)作為洗提液進行管柱層 析，純化而得順-4- [[1-[ 3-曱氧基-4- [Ν’ -（2-甲基苯基） 脲基]苯基乙醯基]-2-咄咯啶基]甲胺基]環己烷羧酸苄酯 (1· 5 克，83%)之非晶形固體。1H-NMR (CDC13) 6 1. 40-1.65 (m，6H)、1·8 0- 1.98 (m，6H)、2·26 (s，3H)、 2.45-2.65 (m, 3Η) &gt;2.81-2.86 (m, 1H) ^3.44-3.46 (m， 2H) 、3·56 (s， 2H) 、3·67 (s， 3H) 、3·90-4·15 (m， 1H)、5·09 及 5·11 (各s，總計 2H)、6·74-6.83 (m，3H)、 7·〇7-7·20 (m，4Η)、7.31 -7·35 (m，5Η)、7·53-7·55 (m， 1Η) 、 8· 02-8. 06 (m, 1Η)。 於順-4-[[1-[ 3-甲氧基-4-[Ν’ - (2 -曱基苯基）脲基]笨基 乙醯基]-2 -咄咯啶基]甲胺基]環己烷羧酸笮酯（1 · 5克，2 45毫莫耳）溶於THF(10· 0毫升）及Me〇H(5· 0毫升）之授拌溶 液中加入IN NaOH(3· 68毫升，3· 68毫莫耳）。使混合物在 70 °C下攪拌1 8小時。將混合物於真空中濃縮，加入水，並 以1 N HC1中和。將混合物於真空中濃縮。使殘留物經由於 矽膠上利用MeOH-CHJlJl : 5，v/v)作為洗提液進行管柱声\\312\2d-code\90-01\89112968.ptd Page 588 1283240 V. INSTRUCTIONS (584) Used in subsequent reactions without further purification. The crude product, cis-4-aminocyclohexanecarboxylate (76 9 mg, 3.3 mmol), and AcOH (0.32 mL) were dissolved in DCE at 0 °C (1 0). NaBH(0Ac)3 (1.1 g, 5.4 mmol) was added to the stirred solution of ML). The reaction mixture was stirred at room temperature for 18 hours. The mixture was concentrated in vacuo. Saturated NaHC03 was added to the residue and extracted with CH2C12. The extract was washed with brine, dried over EtOAc EtOAc. The residue was subjected to column chromatography using MeOH-CH2C12 (1:9, v/v) as an eluent to obtain cis-4-[[1-[3-methoxy-4- [Ν'-(2-Methylphenyl)ureido]phenylethenyl]-2-oxaridinyl]methylamino]cyclohexanecarboxylic acid benzyl ester (1.5 g, 83%) Amorphous solid. 1H-NMR (CDC13) 6 1. 40-1.65 (m, 6H), 1·8 0- 1.98 (m, 6H), 2·26 (s, 3H), 2.45-2.65 (m, 3Η) &gt;2.81 -2.86 (m, 1H) ^3.44-3.46 (m, 2H), 3·56 (s, 2H), 3·67 (s, 3H), 3·90-4·15 (m, 1H), 5· 09 and 5·11 (each s, total 2H), 6.74-6.83 (m, 3H), 7·〇7-7·20 (m, 4Η), 7.31 -7·35 (m, 5Η), 7 ·53-7·55 (m, 1Η), 8· 02-8. 06 (m, 1Η). Yushun-4-[[1-[3-methoxy-4-[Ν'-(2-mercaptophenyl)ureido]]phenylamino]-2-pyridinyl]methylamino笮 Cyclohexanecarboxylate (1.5 g, 2 45 mmol) dissolved in THF (10.0 ml) and Me〇H (5.0 ml) into the mixing solution was added IN NaOH (3· 68 ml, 3.68 mmol.) The mixture was stirred at 70 ° C for 18 hours. The mixture was concentrated in vacuo, water was added and neutralized with 1 N EtOAc. The mixture was concentrated in vacuo. The residue was passed through a guanidine gel using MeOH-CHJlJl: 5, v/v) as an eluent

1283240 五、發明說明（585) 析，純化而得1 7 1 ( 940毫克，73%)之非晶形固體。IR (KBr) 3283、29 45、286 0、1 534、1453、1415 / 公分； ^-NMR (DMSO~d6) 5 1.38- 2.0 0 (m, 12H) &gt;2.45 (s, 3H) 、2·30-3·95 (m, 4H) 、3·22-3·75 (m， 2H) 、3·58 (s， 2Η)、3·86 (s，3Η)、4·12 (m，1Η)、6·73-7·16 (m，5Η) 、7·77-7·79 (m，1Η)、7·98-8·02 (m，1Η)、8·51 -8·52 (m, 1Η) ^ 8.57-8.59 (m, 1H)； MS(FAB) m/z 5 23 (MH1) ;C29H38N4 05 · 0· 5NaCl · 2. 2H20 之分析計算值：C，5 8. 8 9 ; H，7· 23 ; N， 9. 47。實測值：C， 59· 21 ; H，7. 11 ; N, 9.11。 實施例164 順-4 - [[1 - [3 -甲氧基-4- [Ν’ - (2-甲基苯基）脈基]苯基乙醢 基]-2-咄咯啶基]甲胺基]環己烷羧酸曱酯HC1鹽 〇ιΝ 又 Njpr^HN〇_1283240 V. Inventive Note (585) Analysis, purification gave 171 (940 mg, 73%) of amorphous solid. IR (KBr) 3283, 29 45, 286 0, 1 534, 1453, 1415 / cm; ^-NMR (DMSO~d6) 5 1.38- 2.0 0 (m, 12H) &gt;2.45 (s, 3H), 2· 30-3·95 (m, 4H), 3·22-3·75 (m, 2H), 3·58 (s, 2Η), 3·86 (s, 3Η), 4·12 (m, 1Η) , 6.73-7·16 (m, 5Η), 7·77-7·79 (m, 1Η), 7·98-8·02 (m, 1Η), 8·51 -8·52 (m, 1Η) ^ 8.57-8.59 (m, 1H); MS(FAB) m/z 5 23 (MH1) ; C29H38N4 05 · 0· 5NaCl · 2. 2H20 Analysis calculated: C, 5 8. 8 9 ; H, 7· 23 ; N, 9. 47. Found: C, 59· 21 ; H, 7.11; N, 9.11. Example 164 cis-4 - [[1 - [3 -methoxy-4-[Ν-(2-methylphenyl))]phenylethenyl]-2-oxazolidinyl] Amino]cyclohexanecarboxylic acid oxime ester HC1 salt 〇ιΝ and Njpr^HN〇_

Me H H OMe 172 在〇 °C下將SOC 12加至MeOH。於攪拌5分鐘後，加入順-4-[Π - [3 -甲氧基-4- [Ν’-（2-甲基苯基）脲基]苯基乙醯基]-2-响略啶基]甲胺基]環己烷羧酸（20 0毫克，〇. 38毫莫 耳）°使混合物於室溫下攪拌5小時。將混合物於真空中濃 縮。將NaHC03水溶液加至殘留物，並以ch2C12萃取。將萃 取液以鹽水洗滌，於Na2S04上乾燥，並於真空中濃縮。使 殘留物經由於矽膠上利用Me〇H-CH2C12(5:95至18:92，v/v) 作為洗提液進行管柱層析而純化。將產物溶解於£1：〇11( 5· 〇Me H H OMe 172 SOC 12 was added to MeOH at 〇 °C. After stirring for 5 minutes, cis-4-[Π-[3-methoxy-4-[Ν'-(2-methylphenyl)ureido]phenylethenyl]-2-tranolidine was added. Methylamino]cyclohexanecarboxylic acid (20 mg, 〇. 38 mmol). The mixture was stirred at room temperature for 5 hr. The mixture was concentrated in vacuo. Aqueous NaHCO3 was added to the residue and extracted with CH2C12. The extract was washed with brine, dried over Na 2 EtOAc and evaporated. The residue was purified by column chromatography using Me〇H-CH2C12 (5:95 to 18:92, v/v) as an eluent. Dissolve the product in £1: 〇11 (5· 〇

\\312\2d-code\90-01\89l12968.ptd 第590頁 1283240 五、發明說明（586) 毫升），並加入lNHCl(溶於EtOH)(1.0毫升，l·0毫莫 耳）。使混合物於真空中濃縮而得1 7 2 ( 1 6 0毫克，74%)的非 晶形固體。IR (KBr) 3247、2950、2875、1731、1671、 1.45-2.10 (m，12H)、2·25 (s，3H)、2·60-2·70 (m， 1Η) 、2·90-3·20 (m， 3Η) 、2·50-2·55 (m， 2Η) 、3·63 (m，5H)、3·86 (s，3H)、4·15-4·30 (m，1H)、6·74 -7.16 (m，5H)、7.76-7.78 (m，1H)、8·0 0-8. 0 9 (m, 1H)、8· 54-8· 70 (m，2H) ; MS(FAB) m/z 5 3 7(MH1) ; C30H 40N4O5 · 1. 0HC1 · 1. 0H2O 之分析計算值：C，6 0. 95 ; H， 7. 33 ； N, 9.48； Cl, 6. 00 ° 實測值·· C，60. 87 ； H, 7. 47 ； N, 8.97； Cl, 5.90。 實施例1 6 5 4-[N-[卜[3-甲氧基-4-[Ν’ -（2-甲基苯基）脲基]笨基乙醯 基]-2 -咄咯啶基]甲基]-Ν-曱胺基]環己烷羧酸\\312\2d-code\90-01\89l12968.ptd Page 590 1283240 V. Inventive Note (586) ml), and add lNHCl (dissolved in EtOH) (1.0 ml, l·0 mmol). The mixture was concentrated in vacuo to give 1 2 2 (1, 60 mg, 74%) of solid. IR (KBr) 3247, 2950, 2875, 1731, 1671, 1.45-2.10 (m, 12H), 2·25 (s, 3H), 2·60-2·70 (m, 1Η), 2·90-3 ·20 (m, 3Η), 2·50-2·55 (m, 2Η), 3·63 (m, 5H), 3·86 (s, 3H), 4·15-4·30 (m, 1H ), 6.74 -7.16 (m, 5H), 7.76-7.78 (m, 1H), 8·0 0-8. 0 9 (m, 1H), 8· 54-8· 70 (m, 2H); MS (FAB) m/z 5 3 7 (MH1); C30H 40N4O5 · 1. 0HC1 · 1. Analysis of 0H2O: C, 6 0. 95 ; H, 7. 33 ; N, 9.48; Cl, 6. 00 ° measured value · · C, 60. 87 ; H, 7. 47 ; N, 8.97; Cl, 5.90. Example 1 6 5 4-[N-[Bu[3-methoxy-4-[Ν'-(2-methylphenyl)ureido]]phenylamino]-2-indolyl] Methyl]-fluorene-nonylamino]cyclohexanecarboxylic acid

QLNiNJpr/^：〇00HQLNiNJpr/^:〇00H

Me H H OMe 173 4 - [N-[：l-[3-曱氧基-4-[Ν’- (2-甲基苯基）脲基]笨基乙醯 基]-2-咄咯啶甲基]-N-甲胺基]環己烷羧酸甲酯 在0 °C下於順-4-[ [1-[ 3-曱氧基-4- [Ν’ -（2-甲基苯基）Me HH OMe 173 4 - [N-[:l-[3-曱oxy-4-[Ν'- (2-methylphenyl)ureido]]phenylamino]-2-pyrrolidine Methyl]-N-methylamino]cyclohexanecarboxylate at 0 ° C in cis-4-[ [1-[ 3-methoxy-4-[Ν' -(2-methylphenyl) )

\\312\2d-code\90-01\89112968.ptd 第591頁 1283240 五、發明說明（587) 脲基]苯基乙醯基]-2-咄咯啶基]甲胺基]環己烷羧酸甲酯 (300 毫克，0.55 毫莫耳）、HCH0 (300 毫升）、及AcOH(6 6 毫 克，1· 1毫莫耳）溶於MeOH(l 0. 0毫升）之攪拌溶液中加入 NaBH3CN(70毫克，1. 1毫莫耳）。使反應混合物在室溫下攪 拌18小時。於在真空中濃縮後，加入水，並以CH2C12萃 取。將萃取液以水洗滌，然後於Na2S04上乾燥，並於真空 中濃縮。使殘留物經由TLC利用MeOH-CH2Cl2(3 : 97，v/v)作 為洗提液’純化而付4-[N - [1 - [3 -甲氧基-4 - [Ν’-（2 -甲基 苯基）脲基]苯基乙驢基]-2 - 各唆甲基]-Ν-甲胺基]環己 烷羧酸甲酯（160毫克，52%)的非晶形固體。1H-NMR (CDCl3 )δ 1.30-2.20 (m, 12Η) &gt;2.27-2.37 (m, 6H) ^2.50-2.60 (m，1H)、3·30-3.80 (m，5H)、3·55 (s，2H)、 3.66-3.73 (m，6H)、4·10-4·20 (m，1H)、6. 60-7.55 (m， 7H) 、8·03 (m， 1H) 、8·15 (m， 1H)。 於4 - [N-[l - [3 -甲氧基-4 - [Ν’- (2-甲基苯基）脲基]苯基 乙醯基]- 2 -ϋ比17各淀甲基]-Ν-甲胺基]環己烧叛酸曱酯（1〇〇 毫克，0·18毫莫耳）溶於THF(5.0毫升）及MeOH(2. 5毫升）之 授拌溶液中加入IN NaOH(0.36毫升，〇·36毫莫耳）。使混 合物於60 °C下攪拌1 8小時。將混合物於真空中濃縮，加入 水，並以1N HC1中和。將混合物於真空中濃縮。使殘留物 經由T L C利用M e Ο Η - C H2 C12 (1 / 4 ’ v / v)作為洗提液，純化而 得173(10毫克，10%)之非晶形固體。IR (KBr) 3440、 2954、1697、1533、1454 /公分；l — NMR (DMSO — d6) (5 1·20-2.30 (m，13H)、2.24 (s，3H)、2·35-4·00 (m，\\312\2d-code\90-01\89112968.ptd Page 591 1283240 V. INSTRUCTIONS (587) Urea-based]phenylethenyl]-2-oxaridinyl]methylamino]cyclohexane Methyl carboxylate (300 mg, 0.55 mmol), HCH0 (300 mL), and AcOH (6 6 mg, 1.1 mmol) dissolved in MeOH (10 mL). (70 mg, 1.1 mmol). The reaction mixture was stirred at room temperature for 18 hours. After concentration in vacuo, water was added and extracted with CH2C12. The extract was washed with water, dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by TLC using MeOH-CH2Cl2 (3:97, v/v) as eluent to afford 4-[N - [1 - [3 - methoxy-4 - [Ν'-(2 - Methylphenyl)ureido]phenylethenyl]-2 -methyl hydrazide methyl]-fluorenyl-methylamino]cyclohexanecarboxylate (160 mg, 52%) as an amorphous solid. 1H-NMR (CDCl3) δ 1.30-2.20 (m, 12Η) &gt; 2.27-2.37 (m, 6H) ^2.50-2.60 (m, 1H), 3·30-3.80 (m, 5H), 3·55 ( s, 2H), 3.66-3.73 (m, 6H), 4·10-4·20 (m, 1H), 6. 60-7.55 (m, 7H), 8·03 (m, 1H), 8.15 (m, 1H). 4-[N-[l - [3 -Methoxy-4 -[Ν'- (2-methylphenyl)ureido]phenylethenyl]-2-pyrene~17] - Ν-methylamino] cyclohexanol oxalate (1 mg, 0·18 mmol) dissolved in THF (5.0 ml) and MeOH (2.5 ml) in the addition of IN NaOH (0.36 ml, 〇·36 mmol). The mixture was stirred at 60 ° C for 18 hours. The mixture was concentrated in vacuo, water was added and neutralized with 1N EtOAc. The mixture was concentrated in vacuo. The residue was purified by using EtOAc (EtOAc / EtOAc (EtOAc) (EtOAc) IR (KBr) 3440, 2954, 1697, 1533, 1454 / cm; l - NMR (DMSO - d6) (5 1 · 20 - 2.30 (m, 13H), 2.24 (s, 3H), 2 · 35-4 · 00 (m,

\\312\2d-code\90-01\89112968.ptd 第592頁 1283240 五、發明說明（588) 13H) ^6.50-8.10 (m, 8H) &gt;8.50 (m, 1H)； MS(FAB) m/z 5 3 7 (M+ + 1) ; “Ν4 05 · 2· ONaCl · 0· 8H20 之分析計算值： C’ 53·94;Η， 6·28;Ν，8.39。實測值：C，54·08;Η， 6.52; Ν, 8.04 〇 實施例1 6 6 4 - [Π-[3-甲氧基-4-[ Ν’ - (2 -甲基苯基）脲基]苯基乙醯基] -（2S)-吼咯啶基]甲氧基]環己烷羧酸\\312\2d-code\90-01\89112968.ptd Page 592 1283240 V. Description of invention (588) 13H) ^6.50-8.10 (m, 8H) &gt; 8.50 (m, 1H); MS (FAB) m/z 5 3 7 (M+ + 1) ; "Ν4 05 · 2· ONaCl · 0· 8H20 Analysis calculated: C' 53·94; Η, 6·28; Ν, 8.39. Found: C, 54 · 08; Η, 6.52; Ν, 8.04 〇 Example 1 6 6 4 - [Π-[3-methoxy-4-[Ν'-(2-methylphenyl)ureido]phenylethenyl -(2S)-Pyrridinyl]methoxy]cyclohexanecarboxylic acid

174 順-4-[ (1-第三丁氧羰基-(2 s)—咄咯啶基）甲氧基]環己烷 羧酸甲酯174 cis-4-[(1-tert-butoxycarbonyl-(2 s)- oxaridinyl)methoxy]cyclohexanecarboxylic acid methyl ester

使4 - ( 1 -第三丁氧羰基一（2 s) -咄咯啶基）甲氧苯曱酸甲酉旨4-(1-butoxycarbonyl-(2 s)-indolyl)methoxybenzoic acid

(1.0克’2.9毫莫耳）及5 % Rh/氧化鋁（50 0毫克）於EtOH (10. 0毫升）及Ac OH (1. 0毫升）中之混合物在室溫在5大氣壓 下氫化36小時。將催化劑濾除，及將濾液於真空中濃縮。 使殘留物經由於矽膠上利用正己烷-EtOAc(6:l，v/v)作為 洗提液進行管枉層析’純化而得順-4 - [( 1 -第三丁氧幾基 -（28)-°比嘻唆基）甲氧基]環己烧羧酸甲g旨（900毫克，gg%) 之淡黃色油。-NMR (CDCI3) 6 1· 46 (s，9H)、1· 46-2.00 (m, 12H)、2·34 (m，1H)、3·2 0-3.5 5 (m，5H)、 3· 67 (s，3H)、3· 84-3· 92 (m， 1H) 〇(1.0 g '2.9 mmol) and a mixture of 5% Rh/alumina (50 mg) in EtOH (10.0 mL) and Ac OH (1.0 mL) were hydrogenated at room temperature at 5 atm. hour. The catalyst was filtered off and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on n-hexane-EtOAc (6:1, v/v) eluting with hexanes to give cis-4 - [(1 -t-butoxy- yl-) 28) - 嘻唆 嘻唆 )) methoxy] cyclohexane carboxylic acid 甲g (900 mg, gg%) pale yellow oil. -NMR (CDCI3) 6 1· 46 (s, 9H), 1·46-2.00 (m, 12H), 2·34 (m, 1H), 3·2 0-3.5 5 (m, 5H), 3· 67 (s, 3H), 3· 84-3· 92 (m, 1H) 〇

\\312\2d-code\90-0l\89112968.ptd 第 593 頁 1283240 五、發明說明（589) 順-4-[ [1-[ 3-甲氧基-4-[N，-（2-甲基苯基）脲基]苯基乙酸 基]-（2 S)-吡咯啶基]甲氧基]環己烷羧酸甲酯\\312\2d-code\90-0l\89112968.ptd Page 593 1283240 V. INSTRUCTIONS (589) cis-4-[ [1-[ 3-methoxy-4-[N,-(2- Methylphenyl)ureido]phenylacetate]-(2S)-pyrrolidinyl]methoxy]cyclohexanecarboxylic acid methyl ester

QlN^NJP^^〇&lt;&gt;c〇〇MeQlN^NJP^^〇&lt;&gt;c〇〇Me

Me Η Η 〇ΜθMe Η Η 〇Μθ

在0 °C下於順-4 - [ (1 —第三丁氧羰基-(2 S)-吼咯啶基）甲 氧基]環己烷羧酸甲酯（9 0 0毫克，2. 6毫莫耳）溶於CH2Cl2 (5· 0毫升）之攪拌溶液中加入TFA( 5. 0毫升）。使反應混合 物於室溫下攪拌〇 · 5小時。將混合物於真空中濃縮。將飽 和NaHC〇3加至殘留物，並以ch2C12萃取。將萃取液以鹽水 洗滌，於NaJO4上乾燥，並於真空中濃縮。將粗製產物不 經進一步的純化而使用於後續的反應。在〇下於此粗製 產物（200毫克，0.83毫莫耳）、3 -甲氧基-4-[N，-（2 -甲^ 苯基）脲基]苯乙酸（ 260毫克，0· 83毫莫耳）、Η〇Βΐ(135^ 克’ 1.0¾莫耳）、及三乙胺（344微升，2·5毫莫耳）溶於 THF(10· 0毫升）及MeCN(10· 〇毫升）之攪拌溶液中加入EDC · HC1 ( 23 8毫克，1· 24毫莫耳）。使反應混合物在室溫下揽摔 16小時，並於真空中濃縮。將水加至殘留物，並以Et〇Ac 萃取。將萃取液以飽和NaHC〇3、2M檸檬酸、及飽*NaHC〇 洗滌，然後於NaJO4上乾燥，並於真空中濃縮。將殘留物3 經由於石夕膠上利用正己烧-Et〇Ac (1:8，v/v)作為洗提液 進行管柱層析，純化而得順-4-[[卜[3-甲氧基—4—[ N, 一（2一 甲基苯基）脲基]苯基乙醯基]-（2S)-吼咯啶基]曱氧基]環 己烷羧酸曱酯（4 60毫克，定量）之非晶形固體。lH —NfRMethyl cis-4 -[(1 -t-butoxycarbonyl-(2S)-inertyryl)methoxy]cyclohexanecarboxylate (900 mg, 2. 6 at 0 °C) To a stirred solution of CH2Cl2 (5.0 mL) was added TFA (0.5 mL). The reaction mixture was stirred at room temperature for 5 hours. The mixture was concentrated in vacuo. Saturated NaHC〇3 was added to the residue and extracted with ch2C12. The extract was washed with brine, dried over Na.sub.4, and concentrated in vacuo. The crude product was used in the subsequent reaction without further purification. The crude product (200 mg, 0.83 mmol), 3-methoxy-4-[N,-(2-methylphenyl)ureido]phenylacetic acid (260 mg, 0·83 m) Mohr), hydrazine (135^g '1.03⁄4 mol), and triethylamine (344 μl, 2.5 mmol) dissolved in THF (10.0 ml) and MeCN (10·ml) EDC · HC1 (23 8 mg, 1.25 mmol) was added to the stirred solution. The reaction mixture was allowed to stand at room temperature for 16 hours and concentrated in vacuo. Water was added to the residue and extracted with Et 〇Ac. The extract was washed with saturated NaHC3, 2M EtOAc and sat. NaHC. The residue 3 was purified by column chromatography on the Shiqi gum using Zhengcao-Et〇Ac (1:8, v/v) as an eluent to obtain cis-4-[[卜[3-甲Oxyl-4-[N,mono(2-methylphenyl)ureido]phenylethenyl]-(2S)-decalridinyl]nonyloxy]cyclohexanecarboxylate (4 60 Mg, quantitative) of amorphous solids. lH — NfR

1283240 五、發明說明（590) (CDC13) δ 1.35-2.10 (m, 12H) '2.15-2.38 (m, 1H)- 2·29 (m，3H)、3·20-3.55 (m，5H)、3·58 (s，2H)、 3·66 (s，3H)、3·73 (s，3H)、4· 20-4.25 (m，1H)、 6·26-6·30 (m，1H)、6·78-6·81 (m，2H)、7·06-7·23 (m，3H)、7·51 -7.52 (m，1H)、8·01 一8·〇3 (m，1H)。 於4-[[l - [3-甲氧基一 4 - [Ν’- (2-甲基苯基）脲基]笨基乙 醯基]-(2S) -毗咯啶基]甲氧基]環己烷羧酸甲酯（46〇毫 克’ 0· 86毫莫耳）溶於THF(10· 0毫升）及EtOH(5.0毫升）之 攪拌溶液中加入IN NaOH(l· 4毫升，1· 4毫莫耳）。使混合 物在6 0 C下攪:拌1 8小時。將混合物於真空中濃縮，加入 水，並以1N HC1中和。收集所產生之固體，以水洗滌，並 於真空中乾燥而得1 74 (370毫克，83%)的白色結晶固體。 熔點 110-113 °C; IR (KBr) 3345、2937、1612、1533、 1 454 / 公分；UMR (DMSO-d6) 6 1.00-2.00 (m，12H)、 2.24 (s, 3H) ^ 2.20-2.30 (m, 1H) ^ 3.20-3.80 (m, 5H)、3·55 (s，2H)、3·85 (s，3H)、4·00-4.18 (m， 1H)、6·7h7.16(m，5H)、7.78(d，J = 8.0Hz，lH)、7· 90 (d，J = 8.3 Hz，1H)、8·45 (s, 1H)、8.54 (s，1H); MS(FAB) m/z 524(ΜΗ1);(：29Η37Ν3 06 ·0·2Η20之分析計算 值：C，66.07; Η，7·15;Ν，7.97。實測值：C，66.02; Η, 7· 14 ; N，7.87。 實施例1 6 7 4- [[1 - [4-[Ν’-（2-氯苯基）脲基]一3-甲氧苯基乙醯基]一 (2S) -咄咯啶基]曱氧基]環己烷羧酸1283240 V. INSTRUCTIONS (590) (CDC13) δ 1.35-2.10 (m, 12H) '2.15-2.38 (m, 1H)- 2·29 (m, 3H), 3·20-3.55 (m, 5H), 3·58 (s, 2H), 3·66 (s, 3H), 3.73 (s, 3H), 4·20-4.25 (m, 1H), 6·26-6·30 (m, 1H) ,6·78-6·81 (m,2H),7·06-7·23 (m,3H),7·51 -7.52 (m,1H),8·01·8·〇3 (m,1H ). 4-[[l-[3-Methoxy-4-[4-(2-methylphenyl)ureido]]phenylamino]-(2S)-aziridinyl]methoxy Add methyl Cyclohexanecarboxylate (46 〇 mg '0·86 mmol) to a stirred solution of THF (10 mL) and EtOH (5.0 mL) and add 1 NaOH (1·4 mL, 1· 4 millimoles). The mixture was stirred at 60 ° C: it was mixed for 18 hours. The mixture was concentrated in vacuo, water was added and neutralized with 1N EtOAc. The resulting solid was collected, washed with water and dried in vacuo to give a white crystals of 1 74 (370 mg, 83%). Melting point 110-113 °C; IR (KBr) 3345, 2937, 1612, 1533, 1 454 / cm; UMR (DMSO-d6) 6 1.00-2.00 (m, 12H), 2.24 (s, 3H) ^ 2.20-2.30 (m, 1H) ^ 3.20-3.80 (m, 5H), 3·55 (s, 2H), 3·85 (s, 3H), 4·00-4.18 (m, 1H), 6·7h7.16 ( m, 5H), 7.78 (d, J = 8.0 Hz, lH), 7.90 (d, J = 8.3 Hz, 1H), 8·45 (s, 1H), 8.54 (s, 1H); MS (FAB m/z 524(ΜΗ1); (:29Η37Ν3 06 ·0·2Η20 analytical calculation: C, 66.07; Η, 7·15; Ν, 7.97. Found: C, 66.02; Η, 7· 14 ; N , 7.87. Example 1 6 7 4- [[1 - [4-[Ν'-(2-Chlorophenyl)ureido] 3-methoxyphenylethenyl]-(2S)-indenylpyridine Alkyloxy]cyclohexanecarboxylic acid

89112968.ptd 第595頁 1283240 五、發明說明（591)89112968.ptd Page 595 1283240 V. Description of invention (591)

175 4-[ Π - [4-[Ν’ -（2-氯苯基）脲基]-3-曱氧苯基乙醯基]一 (2 S)-吼哈σ定基]甲氧基]環己炫叛酸曱酯175 4-[ Π - [4-[Ν' -(2-Chlorophenyl)ureido]-3-indolylphenylethyl]-(2 S)-吼哈σ定基]methoxy] ring Dexterified acid ester

在0。(：下於4-[(1-第三丁氧羰基-2 -咄咯啶基）甲氧基]環 己烷羧酸甲酯（900毫克，2·6毫莫耳）溶於CH2C12( 5· 0毫升） 之攪拌溶液中加入TF A (5 · 0毫升）。使反應混合物於室溫下 攪拌0· 5小時。將混合物於真空中濃縮。將飽和NaHC03加 至殘留物，並以ClCl2萃取。將萃取液以鹽水洗滌，於 N az S 〇4上乾燥，並於真空中濃縮。將粗製產物不經進一步 的純化而使用於後續的反應。在〇。〇下於此粗製產物（2 〇 〇 毫克，〇·83毫莫耳）、4-[N’-（2-氯苯基）脲基]—3 -曱氧苯 乙酸（277¾克’0·83φ莫耳）、H〇Bt(135毫克，1·0毫莫 耳）、及三乙胺（344毫升，2·48毫莫耳）溶於THF(10· 0毫 升）及MeCN(10· 0毫升）之攪拌溶液中加入EDC · HC1 ( 238毫 克’ 1 · 2 4耄莫耳）。使反應混合物在室溫下攪拌1 6小時， 並於真空中濃縮。將水加至殘留物，並以Et〇Ac萃取。將 萃取液以飽和NaHC〇3、2M檸檬酸、及飽*NaHC〇3洗滌，然 後於NaJO4上乾燥’並於真空中濃縮。將殘留物經由於石夕 膠上利用正己烧-EtOAc (1:6，v/v)作為洗提液進行管柱At 0. (: Methyl 4-[(1-tert-butoxycarbonyl-2-pyridinyl)methoxy]cyclohexanecarboxylate (900 mg, 2. 6 mmol) dissolved in CH2C12 (5 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ The extract was washed with brine, dried over EtOAc EtOAc EtOAc EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 〇mg, 〇·83 mmol), 4-[N'-(2-chlorophenyl)ureido]-3-oxophthalic acid (2773⁄4 g '0·83 φ Moule), H〇Bt (135 Adding EDC · HC1 to a stirred solution of THF (10.0 ml) and triethylamine (344 ml, 2·48 mmol) in THF (1.0 mL) and MeCN (10 mL) (238 mg '1 · 2 4 Torr). The reaction mixture was stirred at room temperature for 16 h and concentrated in vacuo. Water was added to the residue and extracted with Et EtOAc. NaHC〇 3, 2M citric acid, and saturated with *NaHC〇3, then dried on NaJO4' and concentrated in vacuo. The residue was applied to the saponin using hexanol-EtOAc (1:6, v/v) as Eluent for column

\\312\2d-code\90-01\89112968.ptd 第596頁 1283240 五、發明說明（592) &quot; ~ ~ 層+析’純化而得4-[[卜[4一 [N，—（2—氯苯基）脲基]一3 一甲氧 苯基乙酿基]-(2 S )-咄咯啶基]曱氧基]環己烷羧酸甲酯 ( 450 毫克 ’ 97%)之無色油。丨H —NMr (CDCl3) 6 l 35 —2· 15 (m，12H)、2. 25 -2.40 (m，1H)、3· 40-3.70 (m，5H)、 3.61(s，2H)、3.66(s，3H)、3.81(s，3H)、4.20-4·30 (m，1H)、6·8卜6.99 (m，3H)、7·17-7·34 (m，3H) 、7·92-7·94 (m，2H)、8·17-8·19 (m，2H)。 於4- [[1 - [4-[N’ -（2-氣苯基）脲基]-3 -甲氧苯基乙醯 基]-（2 S)-咄咯啶基]甲氧基]環己烷羧酸曱4 5 0毫克， 0. 86毫莫耳）溶於THF(10· 0毫升）及MeOH(5· 0毫升）之攪拌 溶液中加入IN NaOH(l. 4毫升，1 · 4毫莫耳）。使混合物在 7 〇 °C下攪拌2 4小時。將混合物於真空中濃縮，加入水，並 以1N HC1中和。收集所產生之固體，以水洗滌，並於真空 中乾燥而得1 7 5 ( 3 7 0毫克，8 4%)的白色結晶固體。熔點 ⑴-115 〇C ; IR (KBr) 3 330、29 38、1 704、1 594、1 53 3、 1 438、1199 / 公分；l-NMR (DMSO-d6) 6 1·00- 2.00 (m， 12H)、2·20- 2.3 0 (m，1H)、3·2 0-3.80 (m，5H)、3·55 (s，2H)、3·85 (s，3H)、4·0 0 - 4.2 0 (m，lH)、6.73-6.75 (m，1H)、6·87 (s，1H)、6·9 9-7.0 3 (m，1H)、 7.25-7.29 (m，1H)、7·42 (d，J = 7.1 Hz, 1H)、7·95 (d，J = 8.3 Hz，1H)、8·08 (d，J二8.0，1H)、8·78 (s， 1H)、8·92 (s，1H); MS(FAB) m/z 544(MH1); C28H34N3 06 C1 · 0· 2H20 之分析計算值：C， 61· 41 ; H， 6· 33 ; N，7· 67 ; Cl，6. 47。實測值：C，61. 37 ; H，6· 32 ; N，\\312\2d-code\90-01\89112968.ptd Page 596 1283240 V. Invention description (592) &quot; ~ ~ Layer + analysis 'purification and get 4-[[卜[4一[N,-( 2-Chlorophenyl)ureido]-3-methoxyphenylethyl]-(2S)-indolyl]methoxy]cyclohexanecarboxylic acid methyl ester (450 mg '97%) Colorless oil.丨H—NMr (CDCl3) 6 l 35 —2· 15 (m,12H), 2. 25 -2.40 (m,1H), 3·40-3.70 (m,5H), 3.61(s,2H), 3.66 (s, 3H), 3.81 (s, 3H), 4.20-4·30 (m, 1H), 6·8 b 6.99 (m, 3H), 7·17-7·34 (m, 3H), 7· 92-7·94 (m, 2H), 8·17-8·19 (m, 2H). 4-[[1 - [4-[N' -(2-Phenylphenyl)ureido]-3-methoxyphenylethenyl]-(2S)-oxaridinyl]methoxy] To a stirred solution of THF (1.00 ml) and MeOH (5.0 ml) was added IN NaOH (1.4 ml, 1 ·············· 4 millimoles). The mixture was stirred at 7 ° C for 24 hours. The mixture was concentrated in vacuo, water was added and neutralized with 1N EtOAc. The resulting solid was collected, washed with water and dried in vacuo to give a white solid crystals of 147. Melting point (1)-115 〇C; IR (KBr) 3 330, 29 38, 1 704, 1 594, 1 53 3, 1 438, 1199 / cm; l-NMR (DMSO-d6) 6 1·00- 2.00 (m , 12H), 2·20- 2.3 0 (m, 1H), 3·2 0-3.80 (m, 5H), 3·55 (s, 2H), 3·85 (s, 3H), 4·0 0 - 4.2 0 (m, lH), 6.73-6.75 (m, 1H), 6·87 (s, 1H), 6·9 9-7.0 3 (m, 1H), 7.25-7.29 (m, 1H), 7 · 42 (d, J = 7.1 Hz, 1H), 7.95 (d, J = 8.3 Hz, 1H), 8·08 (d, J 8.0, 1H), 8·78 (s, 1H), 8 · 92 (s, 1H); MS (FAB) m / z 544 (MH1); C28H34N3 06 C1 · 0 · 2H20 analytical calculations: C, 61 · 41; H, 6 · 33; N, 7 · 67; Cl, 6. 47. Found: C, 61. 37 ; H, 6 · 32 ; N,

\\312\2d-code\90-01\89112968.ptd 第597頁 1283240 五、發明說明（593) 7.56; C1， 6.55。 實施例1 6 8 4 - [1 - [4 - [Ν’-（2〜溴苯基）脲基]—3 一甲氧苯基乙醯基]一（2S) -吼洛咬基]甲氧環己烧羧酸\\312\2d-code\90-01\89112968.ptd Page 597 1283240 V. Description of invention (593) 7.56; C1, 6.55. Example 1 6 8 4 - [1 - [4 - [Ν'-(2~Bromophenyl)ureido]-3 Tetramethoxyphenyl Ethyl]-(2S)-吼洛基基]Methoxy Cyclohexane carboxylic acid

QjNrri^o&lt;&gt;co〇HQjNrri^o&lt;&gt;co〇H

Br Η H iMe 176 4 - [1 - [4 - [Ν’-（2 -溴苯基）脲基]一 3一甲氧苯基乙醯基]一（2S) -吼咯啶基]甲氧基]環己烷羧酸甲酯Br Η H iMe 176 4 - [1 - [4 - [Ν'-(2-bromophenyl)ureido]- 3-methoxyphenylethyl]-(2S)-oxaridinyl]methoxy Methyl cyclohexanecarboxylate

Br H H 〇Me 在0 °C下於4_[(卜第三丁氧羰基—2—咄咯啶基）曱氧基]環 己烧缓酸曱S旨（900毫克，2.6毫莫耳）溶於CH2C12( 5· 0毫升） 之攪拌溶液中加入TFA(5· 0毫升）。使反應混合物於室溫下 授拌0· 5小時。將混合物於真空中濃縮。將飽和NaHC〇3加 至殘留物’並以ClCl2萃取。將萃取液以鹽水洗滌，於 N S Ο*上乾燥’並於真空中濃縮。將粗製產物不經進一步 的純化而使用於後續的反應。在〇它下於此粗製產物（2 〇 〇 毫克，0· 83毫莫耳）、4-[N，-（2-溴苯基）脲基]一3一甲氧苯 乙酸（314毫克，0.83毫莫耳）、H〇Bt(135毫克，1〇毫莫 耳）、及二乙胺（344¾升，2.48毫莫耳）溶於Tup (1〇〇毫 升）及MeCN(10.0宅升）之祝拌溶液中加入edc ·η〇1(238毫 克，1 · 2 4毫莫耳）。使反應混合物在室溫下攪拌丨6小時，Br HH 〇Me is soluble in 4_[(t-butoxycarbonyl-2-pyridinyl) decyloxy]cyclohexanone sulphate at 900 °C (900 mg, 2.6 mmol) at 0 °C TFA (5.0 ml) was added to a stirred solution of CH2C12 (5.0 mL). The reaction mixture was stirred at room temperature for 0.5 hours. The mixture was concentrated in vacuo. Saturated NaHC〇3 was added to the residue&apos; and extracted with ClCl2. The extract was washed with brine, dried <RTI ID=0.0> The crude product was used in the subsequent reaction without further purification. The crude product (2 〇〇 mg, 0·83 mmol), 4-[N,-(2-bromophenyl)ureido]- 3-methoxybenzoic acid (314 mg, 0.83) Millol), H〇Bt (135 mg, 1 mmol), and diethylamine (3443⁄4 liters, 2.48 mmol) dissolved in Tup (1 ml) and MeCN (10.0 house liter) Add edc·η〇1 (238 mg, 1 · 24 mmol) to the mixture. The reaction mixture was stirred at room temperature for 6 hours.

\\312\2d-code\90-01\89112968.ptd 第598頁 1283240 五、發明說明（594) --- 並於真空中濃縮。將水加至殘留物，並以Et〇Ac萃取。將 萃取液以飽和NaHC〇3、2M檸檬酸、及飽*NaHC〇3洗滌，然 後於NaJO4上乾燥，並於真空中濃縮。將殘留物經由於矽 膠上利用正己烷-Et〇Ac( 1 : 6，v/v)作為洗提液進行管柱層 析’純化而得[4 - [1-[4 - [『-（2-溴苯基）脲基]一 3—甲氧 苯基乙醯基]-（2 S)-吡咯啶基]甲氧基]環己烷羧酸曱酯 (450 毫克，90%)之無色油。iH — NMr (CDCl3) 5 i 3〇一2· 1〇 (m，12H)、2·35 -2.40 (m，1H)、3.25-3.70 (m，5H)、3· 84 (s，3H)、4·10-4·25 (m，1H)、6·81-7·06 (m，4H)、 7 · 2 5 - 7 · 3 2 ( m，2 Η )、7 · 5 〇 一 7 · 5 2 (m，1 Η)、7 · 9 〇 一 7 · 9 2 (m，1H)、8· 13-8· 15 (m，1 Η) 〇 於4 - [1-[4 - [Ν’ -（2 -溴苯基）脲基]一3-甲氧苯基乙醯基] -（2S)-吼咯啶基]甲氧環己烷羧酸曱酯（450毫克，〇. 74毫 莫耳）溶於THF(10· 0毫升）及Me〇H(5· 0毫升）之攪拌溶液中 加入IN NaOH(l· 2毫升，1. 2毫莫耳）。使混合物在70 X：下 攪拌2 4小時。將混合物於真空中濃縮，加入水，並以1 n HC1中和。收集所產生之固體，以水洗滌，並於真空中乾 燥而得1 76 ( 3 40毫克，77%)的白色結晶固體。熔點108-111 〇C ; IR (KBr) 3 32 8、29 38、1 70 2、1 5 94、1 5 29、1 434 / 公分；4-NMR (DMSO-d6)6 1·00-2.0 0 (m，12H)、2·15 -2·25 (m，1Η)、3·40-3·75 (m，5Η)、3·48 (s，2Η)、 3·85 (s，3Η)、4· 04-4.15 (m，1Η)、6·70-6·72 (m，1Η) 、6.87 (s，1H)、6.94- 6.9 8 (m，1H)、7·29-7·33 (m， 1H)、7·59 (d，J = 8.1 Hz, 1H)、7·93-7·95 (m，2H)、\\312\2d-code\90-01\89112968.ptd Page 598 1283240 V. Description of the invention (594) --- and concentrate in vacuum. Water was added to the residue and extracted with EtOAc. The extract was washed with saturated NaHC 〇3, 2M EtOAc, and sat. NaHC.sub.3, then dried over NaCI4 and concentrated in vacuo. The residue was purified by column chromatography on n-hexane-Et〇Ac (1:6, v/v) as an eluent to obtain [4 - [1-[4 - [『-(2) -Bromophenyl)ureido]-3-methoxyphenylethenyl]-(2S)-pyrrolidinyl]methoxy]cyclohexanecarboxylate (450 mg, 90%) as a colorless oil . iH — NMr (CDCl3) 5 i 3〇1·1〇(m,12H), 2·35 -2.40 (m,1H), 3.25-3.70 (m,5H),3·84 (s,3H), 4·10-4·25 (m,1H),6·81-7·06 (m,4H), 7 · 2 5 - 7 · 3 2 ( m,2 Η ), 7 · 5 〇一 7 · 5 2 (m,1 Η), 7 · 9 〇一 7 · 9 2 (m,1H), 8· 13-8· 15 (m,1 Η) 〇 in 4 - [1-[4 - [Ν' - (2-Bromophenyl)ureido]-3-methoxyphenylethenyl]-(2S)-oxaridinyl]methoxyxanylcarboxylate (450 mg, 〇. 74 mmol) NaOH (1·2 ml, 1.2 mmol) was added to a stirred solution of THF (10 mL) and Me 〇H (5.0 mL). The mixture was stirred at 70 X: for 24 hours. The mixture was concentrated in vacuo, water was added and neutralized with 1 n EtOAc. The resulting solid was collected, washed with water and dried in vacuo to give a white solid crystals of 1 76 (3 40 mg, 77%). Melting point 108-111 〇C ; IR (KBr) 3 32 8,29 38,1 70 2,1 5 94,1 5 29,1 434 /cm; 4-NMR (DMSO-d6)6 1·00-2.0 0 (m, 12H), 2·15 -2·25 (m, 1Η), 3·40-3·75 (m, 5Η), 3·48 (s, 2Η), 3·85 (s, 3Η), 4· 04-4.15 (m,1Η),6·70-6·72 (m,1Η), 6.87 (s,1H), 6.94-6.9 8 (m,1H), 7·29-7·33 (m , 1H), 7·59 (d, J = 8.1 Hz, 1H), 7·93-7·95 (m, 2H),

\\312\2d-code\90-01\89112968.ptd 第599頁 1283240 五、發明說明（595) 8.73-8.74 (m，⑴、8.91-8.92 “，ih); MS(FAB)— 589 (MH1) ’ C28H34N3 06 Br · 0. 2H2〇 之分析計算值：c，56· 8〇 ;H’ 5· 86 ’ Ν’ 7· 10 ’ Br’ ι3· 49。實測值：c， 56· 66 ; H，5. 83 ; N，6· 97 ; Br，13· 66。 實施例1 6 9 基]苯基乙醯基]-(2 S) -吼 4 - [[1-[4 - [Ν’ -（2-甲基本基）服 咯啶基]甲氧基]環己烷羧酸\\312\2d-code\90-01\89112968.ptd Page 599 1283240 V. Description of the invention (595) 8.73-8.74 (m, (1), 8.91-8.92 ", ih); MS (FAB) - 589 (MH1 ) 'C28H34N3 06 Br · 0. 2H2〇 Analysis calculated: c, 56· 8〇; H' 5· 86 ' Ν' 7· 10 ' Br' ι3· 49. Found: c, 56· 66 ; H , 5.83; N,6·97; Br,13·66. Example 1 6 9 yl]phenylethenyl]-(2 S)-吼4 - [[1-[4 - [Ν' - (2-methyl-based)-pyridyl]methoxy]cyclohexanecarboxylic acid

基]苯基乙醯基]-(2 S ) -吼 4-[ [1 - [4 - [Ν’ -（2-曱基苯基）脲 咯啶基]甲氧基]環己烷羧酸甲酉旨Phenylethyl fluorenyl]-(2 S )-吼4-[ [1 - [4 - [Ν' -(2-decylphenyl)ureridinyl]methoxy]cyclohexanecarboxylic acid A

在(TC下於4-[(卜第三丁氧幾基_2_吼0各咬基）甲氧基]環 己烷羧酸曱醋（450毫克，1.3毫莫耳）溶於CH2Cl2(5〇毫升） 之攪拌溶液中加入TFAC5.0毫升）。使反應混合物於室溫下 攪拌0. 5小時。將混合物，於真空中濃縮。將飽和NaHC〇3加 至殘留物，並以CH/l2萃取。將萃取液以鹽水洗滌，於 N a2 S 04上乾燥，並於真空中濃縮。將粗製產物不經進一步 的純化而使用於後繽的反應。在〇 c下於此粗製產物、 4—[n，_ (2-甲基苯基）脲基]苯乙酸（375毫克，I3亳莫耳） 、H0BU178毫克，1.3毫莫荨）、及三乙胺（550毫升’ 3· 9In TC under 4-[(3,3,3,0,0,0,0) methoxy]cyclohexanecarboxylic acid vinegar (450 mg, 1.3 mmol) dissolved in CH 2 Cl 2 (5搅拌ml) was added to a stirred solution of TFAC (5.0 ml). 5小时。 The reaction mixture was stirred at room temperature for 0.5 hours. The mixture was concentrated in vacuo. Saturated NaHC〇3 was added to the residue and extracted with CH/l2. The extract was washed with brine, dried over EtOAc EtOAc EtOAc The crude product was used in the subsequent reaction without further purification. The crude product, 4-[n,_(2-methylphenyl)ureido]phenylacetic acid (375 mg, I3亳mole), H0BU178 mg, 1.3 mmol, and triethyl b, under 〇c Amine (550 ml ' 3· 9

1283240 五、發明說明（596) 毫莫耳）溶於THF(6· 0毫升）及MeCN(6. 0毫升）之攪拌溶液中 加入EDC · HC1 (380毫克，1. 9毫莫耳）。使反應混合物在室 溫下攪拌1 6小時，並於真空中濃縮。將水加至殘留物，並 以EtOAc萃取。將萃取液以飽和NaHC03、2M檸檬酸、及飽 和NaHC03洗滌，然後於Na2S04上乾燥，並於真空中濃縮。 將殘留物經由於矽膠上利用正己烷—EtOAc(l : 6，v/v)作為 洗提液進行管柱層析，純化而得4_[[1-[4-[N’-(2-甲基 苯基）脲基]苯基乙醯基]-(2S) -咄咯啶基]甲氧基]環己烷 羧酸甲酯（ 520毫克，78%)之無色油。1H-NMR (CDC13) (5 1.30-2.40 (m，13H)、2·21 (s，3H)、3·30-3·80 (m， 7Η) 、3·65 (s， 3Η) 、4·10-4·30 (m， 1Η) 、6·90-7· 20 (m，8Η)、7· 40-7· 70 (m, 2Η)。 於4 - [[1 - [4-[Ν’-（2-甲基苯基）脲基]苯基乙醯基]一 (2S) -吼咯啶基]曱氧基]環己烷羧酸甲酯（52〇毫克，1()毫 莫耳）溶於THF(10· 0毫升）及Me〇H(5. 0毫升）之攪拌溶液中 加入IN NaOH(l· 5毫升，1· 5毫莫耳）。使混合物在7〇 °C下 擾拌2 4小時。將混合物於真空中濃縮，加入水，並以J n HC1中和。收集所產生之固體，以水洗滌，並於真空中乾 燦而得1 7 7 ( 4 5 0毫克，9 1 % )的白色結晶固體。熔點丨〇 7 - 1 11 。。’· IR (KBr) 3353、2938、1 704、1 540、1 454、1 240 / 公分；NMR (DMS0-d6) 1· 20-2· 00 (m，12H)、2· 23 (s，3 Η )、2 · 2 2 - 2 · 2 4 (m，1 Η)、3 · 2 0 - 3 · 8 0 ( m，7 Η)、 4.00-4.18 (m, 1Η) ^6.90-6.94 (m, 1H) &gt;7.10-7.16 (m，5 H )、7 · 3 6 - 7 · 3 8 (m，2 H)、7 · 8 2 - 7 · 8 7 (m，2 H )、</ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; The reaction mixture was stirred at room temperature for 16 h and concentrated in vacuo. Water was added to the residue and extracted with EtOAc. The extract was washed with saturated NaHC03, 2M EtOAc and sat. NaHC.sub.3, and then evaporated. The residue was subjected to column chromatography using n-hexane-EtOAc (1:6, v/v) as an eluent to obtain 4_[[1-[4-[N'-(2-A) Methyl phenyl) ureido]phenylethyl fluorenyl]-(2S)-decalridinyl]methoxy]cyclohexanecarboxylic acid methyl ester (520 mg, 78%) as a colorless oil. 1H-NMR (CDC13) (5 1.30-2.40 (m, 13H), 2·21 (s, 3H), 3·30-3·80 (m, 7Η), 3·65 (s, 3Η), 4· 10-4·30 (m, 1Η), 6·90-7· 20 (m, 8Η), 7·40-7· 70 (m, 2Η). In 4 - [[1 - [4-[Ν' -(2-Methylphenyl)ureido]phenylethenyl]-(2S)-decalridinyl]nonyloxy]cyclohexanecarboxylic acid methyl ester (52 mg, 1 () millimolar In a stirred solution of THF (1.0 mL) and Me〇H (5.0 ml), IN NaOH (1.5 ml, 1.5 mmol) was added. The mixture was disturbed at 7 °C. Mix for 24 hours. Concentrate the mixture in vacuo, add water, and neutralize with J n HCl 1. The resulting solids are collected, washed with water and dried in vacuo to yield 1 7 7 (450 mg, 9 1 %) of white crystalline solid. Melting point 丨〇 7 - 1 11 .. IR (KBr) 3353, 2938, 1 704, 1 540, 1 454, 1 240 / cm; NMR (DMS0-d6) 1· 20-2· 00 (m, 12H), 2· 23 (s, 3 Η ), 2 · 2 2 - 2 · 2 4 (m, 1 Η), 3 · 2 0 - 3 · 8 0 ( m, 7 Η), 4.00-4.18 (m, 1Η) ^6.90-6.94 (m, 1H) &gt;7.10-7.16 (m,5 H ), 7 · 3 6 - 7 · 3 8 (m, 2 H), 7 · 8 2 - 7 · 8 7 (m, 2 H ),

89112968.ptd 第601頁 1283240 五、發明說明（597) 8·89 (s，1H)、12.0 (br s，1H); MS(FAB) m/z 494 (M+ +1)，C28 H35 N3〇5 ·0·2Η2〇 之分析計鼻值.C，67·64; Η, 7·18; Ν， 8·45。實測值：C，67.6 6; Η，7.19; Ν， 8· 24 〇 實施例170 順-4 - [1 - [4 - [Ν’ - (2-氯笨基）脲基]- 3-甲氧苯基乙醯基]一 (2S)-八氫吲哚曱氧基]環己烷羧酸89112968.ptd Page 601 1283240 V. INSTRUCTIONS (597) 8·89 (s, 1H), 12.0 (br s, 1H); MS (FAB) m/z 494 (M+ +1), C28 H35 N3〇5 · 0·2Η2〇 analysis of the nose value. C, 67·64; Η, 7·18; Ν, 8·45. Found: C, 67.6 6; Η, 7.19; Ν, 8· 24 〇 Example 170 cis-4 - [1 - [4 - [Ν' - (2-chlorophenyl)ureido]- 3-methoxy Phenylethyl fluorenyl]-(2S)-octahydroindolyl]cyclohexanecarboxylic acid

^3^c〇〇h [1-第三丁氧幾基-（2S)-八氫4丨噪基]甲醇 在(PC下於[1-第三丁氧幾基-（2S) -八氫叫丨嗓基]缓酸（ 1.0克，3.7毫莫耳）溶於THF( 10· 0毫升）之攪拌溶液中加入 BH3 · THF(1· 0M之THF溶液，8.0毫升）。於在室溫下擾拌 1 · 0小時後，將反應混合物迴流加熱1 · 5小時。於冷卻後， 將混合物於真空中濃縮。在〇 °c下加入水，並以EtoAc萃 取。將萃取液以水洗滌，然後於NaJO4上乾燥，並於真空 中濃縮而得[1-第三丁氧羰基一（2S) -八氫吲哚基]甲醇（947 毫克，定量）之無色油。 4-[1-第三丁氧羰基一（2S)-八氫吲哚甲氧基]笨甲酸甲酯^3^c〇〇h [1-Tertibutoxy-yl-(2S)-octahydro-4-noise]Methanol ((1-tert-butoxy-yl)-(2S)-octahydrogen under PC丨嗓 ] ] ] ] ] 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 THF THF THF THF THF THF THF THF THF THF THF THF THF THF THF THF THF After 1 hour of stirring, the reaction mixture was heated at reflux for 1-5 hours. After cooling, the mixture was concentrated in vacuo. Water was added at EtOAc and extracted with EtoAc. The extract was washed with water and then Drying on NaJO4 and concentrating in vacuo to give [1-t-butoxycarbonyl-(2S)-octahydroindenyl]methanol (947 mg, quantitative) as a colorless oil. Oxycarbonyl-mono(2S)-octahydroindole methoxy] methyl benzoate

BocBoc

Xrco,Xrco,

89112968.ptd 第602頁 1283240 發明說明（598) 於[1-第三丁氧羰基-(2S) -八氫吲哚基]甲醇（947毫克， 3.7¾莫耳）、4_經基苯甲酸甲酯（565毫克，3.7毫莫耳）、 及PhsP(l· 2克，4· 5毫莫耳）溶於THFC10毫升）之攪拌溶液 中加入DIAD( 984毫克，4·5毫莫耳）。使反應混合物在室温 下攪拌1 8小時。將混合物於真空中濃縮。將殘留物經由於 石夕膠上利用正己烧-Et0Ac(9/l，ν/ν)作為洗提液進行管柱 層析，純化而得4-[1-第三丁氧羰基-(2S)-八氫吲哚曱氧89112968.ptd Page 602 1283240 Description of the invention (598) in [1-tert-butoxycarbonyl-(2S)-octahydroindenyl]methanol (947 mg, 3.73⁄4 mol), 4-aminobenzoic acid DIAD (984 mg, 4.55 mmol) was added to a stirred solution of the ester (565 mg, 3.7 mmol) and PhsP (1.2 g, 4.5 mmol) dissolved in THF (10 mL). The reaction mixture was stirred at room temperature for 18 hours. The mixture was concentrated in vacuo. The residue was purified by column chromatography using EtHAc-Et0Ac (9/1, ν/ν) as an eluent to obtain 4-[1-t-butoxycarbonyl-(2S). - octahydroox

基]苯甲酸甲酯（700毫克，50%)之淡黃色油。-NMR (CDC13)5 1.10-2·25 (m, 11Η)、1·45 (s，9Η)、3·88 (s，3Η)、3· 70-4· 20 (m，3Η)、4· 3 6 (br s，1Η)、6· 94 (d，J = 8.8Hz，2H)、7·96 (d，J = 8.5Hz, 2H)。 順-4-[ 1-第三丁氧羰基-(2S )-八氫叫丨哚甲氧基]環己烷羧 酸曱酯A light yellow oil of methyl benzoate (700 mg, 50%). -NMR (CDC13)5 1.10-2·25 (m, 11Η), 1.45 (s, 9Η), 3.88 (s, 3Η), 3·70-4· 20 (m, 3Η), 4· 3 6 (br s,1Η), 6.94 (d, J = 8.8Hz, 2H), 7.96 (d, J = 8.5Hz, 2H). Cis-4-[1-tert-butoxycarbonyl-(2S)-octahydro-decylmethoxy]cyclohexanecarboxylate

使4 - [1-第三丁氧羰基-(2S)-八氫吲哚甲氧基]苯甲酸曱酯 (700毫克，1· 8毫莫耳）及5% Rh /氧化鋁（400毫克）於 EtOH(l 0· 0毫升）及Ac〇H(l. 0毫升）中之混合物在室溫在5大 氣壓下氫化4 8小時。將催化劑濾除，及將濾液於真空中濃 縮。使殘留物經由於矽膠上利用正己烷-EtOAc (7 : 1，v/v )作為洗提液進行管柱層析，純化而得順_ 4 - [ 1 -第三丁氧 Ik基-（2S)-八氫叫丨哮甲氧基]環己烧緩酸甲g旨（6〇〇毫克， 8 5%)之淡黃色油。iH—NMR (CDCl3) 5 1· 1〇一2· 35 (m， 20H)、1·44 (s，9H)、3·45-3·90 (m，5H)、3·80 (s，4-(1-tert-butoxycarbonyl-(2S)-octahydrofluorenylmethoxy]benzoate oxime ester (700 mg, 1.8 mmol) and 5% Rh/alumina (400 mg) A mixture of EtOH (10. 0 mL) and EtOAc (1.0 mL) was then evaporated. The catalyst was filtered off and the filtrate was concentrated in vacuo. The residue was subjected to column chromatography using n-hexane-EtOAc (7:1, v/v) as an eluent, and purified to give cis- 4 -[1 -t-butoxy-Ik--- ) - octahydrogen is called methoxy methoxy] cyclohexanic acid (g 〇〇 mg, 8 5%) of light yellow oil. iH-NMR (CDCl3) 5 1· 1〇1·35 (m, 20H), 1.44 (s, 9H), 3·45-3·90 (m, 5H), 3·80 (s,

W312\2d-code\90-01\89112968.ptd 第603頁 1283240 五、發明說明（599) 3H) 〇 順一 4-[1-[4-[N，-（2-氯苯基）美卜 、与；M rL田卜 个丞^脈暴」3-曱氧苯基乙醯基] -CZS) -八虱吲哚甲氣某1 。w、,A _ 孔丞」％己烷羧酸甲酯 在0 C 下於順-4 -「1—贫一 τβ、,〇! * / 其1俨？ ρ紐缺田 第二丁乳叛基一（2S) -八氫吲哚甲氧 β = /Λ (6GG毫克，1.5毫莫耳）溶於c ( 液中加入TFA(6.0毫升）。使反應混合物 於至 &gt;皿下擾摔0 · 5小時。蔣，曰人你私吉介 了 时/吧合物於真空中濃縮。將飽和W312\2d-code\90-01\89112968.ptd Page 603 1283240 V. INSTRUCTIONS (599) 3H) 〇Shunyi 4-[1-[4-[N,-(2-chlorophenyl) meb, And; M rL Tian Bu 丞 ^ pulse burst "3-曱 oxyphenyl ethoxylated group] -CZS) - gossip gas a certain. w,, A _ 丞 丞 % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % One (2S)-octahydroindole methoxy β = /Λ (6 GG mg, 1.5 mmol) dissolved in c (TFA (6.0 ml) was added to the solution. The reaction mixture was allowed to flow to &gt; 5 hours. Jiang, when you are a private person, you will concentrate in a vacuum. It will be saturated.

NaHC〇3加至殘留物，並以叫〜萃取。將萃取液以鹽水洗 條’於Na2S04上乾燥，並於真空中濃縮。將粗製產物不經 進一步^純化而使用於後續的反應。在Q它下於此粗製產 物（221¾克，〇·75毫莫耳）、4 —[N，-(2—氯苯基）脲基]一3一 甲氧苯乙酸（250毫克，〇·75毫莫耳）、H0Bt( 101毫克， 〇·75毫莫耳）、及三乙胺（312毫升，2·3毫莫耳）溶於THF (10·0毫升）及MeCN(10.0毫升）之攪拌溶液中加入EDC · HC1 (21 6，毫克，1 · 1毫莫耳）。使反應混合物在室溫下攪拌 16小時，並於真空中濃縮。將水加至殘留物，並以Et〇Ac 萃取。將萃取液以飽和NaHC03、2M檸檬酸、及飽和NaHCO, 洗滌，然後於Na2S04上乾燥，並於真空中濃縮。將殘留物 經由於石夕膠上利用正己烧-EtOAc (1:3，v/v)作為洗提液 進行管柱層析，純化而得順-4 - [ 1 _[ 4 - [ N ’ -（ 2 -氣苯基）脲 基]-3-甲氧苯基乙醯基]-(2S)-八氫吲哚甲氧基]環己烷羧Add NaHC〇3 to the residue and call it ~ extraction. The extract was dried over Na 2 SO 4 with brine and concentrated in vacuo. The crude product was used in the subsequent reaction without further purification. Under Q, the crude product (2213⁄4 g, 〇·75 mmol), 4-[N,-(2-chlorophenyl)ureido]-3-methoxybenzoic acid (250 mg, 〇·75) Stirring, H0Bt (101 mg, 〇·75 mmol), and triethylamine (312 ml, 2.3 mmol) dissolved in THF (10·0 mL) and MeCN (10.0 mL) EDC · HC1 (21 6, mg, 1 · 1 mmol) was added to the solution. The reaction mixture was stirred at room temperature for 16 h and concentrated in vacuo. Water was added to the residue and extracted with Et 〇Ac. The extract was washed with saturated NaHC.sub.3, EtOAc (EtOAc)EtOAc. The residue was purified by column chromatography using hexane-EtOAc (1:3, v/v) as an eluent to obtain cis-4 - [ 1 _[ 4 - [ N ' - (2-Phenylphenyl)ureido]-3-methoxyphenylethenyl]-(2S)-octahydrofluorenylmethoxy]cyclohexanecarboxylate

!283240 五、發明說明（600) 酉文甲酉旨（430毫克，94%)之無色油。1H-NMR (CDC13) (5 i·1。-2.40 (m，20H)、3·45 (br s，1H)、3.62 (s，2H) 、3·66 (s，3H)、3·73 (s，3H)、3·60-3·85 (m，2H)、 4·〇9-4·14 (m, 2H)、6·75- 6.98 (m，3H)、7·22-2·46 (m， 4Η) 、7·92 (d， J:8.0 Hz, 1Η) 、8·18 (d， J=8.3 Hz，1H)。 於順-4-[1 -[4- [N，-（2 -氯苯基）脲基]-3-甲氧苯基乙醯 基]-（2S) -八氫吲哚甲氧基]環己烷羧酸甲酯（43 0毫克， 〇· 7毫莫耳）溶於THF(10· 0毫升）及MeOH(5· 0毫升）之攪拌溶 液中加入IN NaOH( 1· 4毫升，1· 4毫莫耳）。使混合物在7〇 C下攪拌2 4小時。將混合物於真空中濃縮，加入水，並以 IN HC1中和。收集所產生之固體，以水洗滌，並於真空中 乾燥而得1 78 (36 0毫克，86%)的白色結晶固體。熔點12〇- 121 °C ; IR (KBr) 3338、29 33、285 9、1614、1 533、1438 / 公分；NMR (CDC13 )6 1.05-2.40 (m，20H)、3.38 -3.50 (m，2H)、3·63 及 3·65 (各s，總計 2H)、3·71 及 3.75 (各s，總計3Η)、3·70-3·80 (m，1Η)、3·93-3·97 (m，1Η)、4·15 (br s，1Η)、6·75 - 6·77 (m, 2Η)、6.93 -6·97 (m，1H)、7·20-7·32 (m，3H)、7·60-7·63 (m， 1Η)、7·85 (d，J = 8.3 Hz, 1Η)、8·16 (d，】 = 8·3 Ηζ， 1H); MS(FAB) m/z 598(MH1); C32H40N3O6Cl ·〇·5Η2〇 之分 析計算值：C，63· 30 ; H，6· 81 ; N， 6· 92 ; Cl， 5· 84 。實測值·· C，63· 68 ; Η, 6. 81 ; Ν， 6· 81 ; Cl， 5· 98。 實施例1 71!283240 V. Inventive Note (600) 酉文甲酉 (430 mg, 94%) of colorless oil. 1H-NMR (CDC13) (5 i·1. - 2.40 (m, 20H), 3·45 (br s, 1H), 3.62 (s, 2H), 3.66 (s, 3H), 3.73 ( s, 3H), 3·60-3·85 (m, 2H), 4·〇9-4·14 (m, 2H), 6.75- 6.98 (m, 3H), 7·22-2·46 (m, 4Η), 7.92 (d, J: 8.0 Hz, 1Η), 8·18 (d, J=8.3 Hz, 1H). Yushun-4-[1 -[4- [N,-( Methyl 2-chlorophenyl)ureido]-3-methoxyphenylethenyl]-(2S)-octahydrofluorenylmethoxy]cyclohexanecarboxylate (43 0 mg, 〇·7 mmol) To a stirred solution of THF (10.0 ml) and MeOH (5.0 mL) was added IN NaOH (1.4 mL, 1.4 mmol). The mixture was stirred at 7 ° C 2 4 The mixture was concentrated in vacuo, water was added, and then purified and evaporated to dryness <RTI ID=0.0>#################################################################### Melting point 12〇- 121 °C; IR (KBr) 3338, 29 33, 285 9, 1614, 1 533, 1438 / cm; NMR (CDC13) 6 1.05-2.40 (m, 20H), 3.38 - 3.50 (m, 2H), 3·63, and 3.65 (each s, total 2H), 3.71 and 3.75 (each s, total 3), 3·70-3· 80 (m,1Η), 3·93-3·97 (m,1Η), 4·15 (br s,1Η), 6.75 - 6·77 (m, 2Η), 6.93 -6·97 (m , 1H), 7·20-7·32 (m, 3H), 7·60-7·63 (m, 1Η), 7.85 (d, J = 8.3 Hz, 1Η), 8·16 (d, 】 = 8·3 Ηζ, 1H); MS(FAB) m/z 598(MH1); C32H40N3O6Cl ·〇·5Η2〇 Analysis calculated: C, 63· 30 ; H,6· 81 ; N, 6· 92 ; Cl, 5· 84. Measured value · · C, 63 · 68 ; Η, 6. 81 ; Ν, 6· 81 ; Cl, 5· 98. Example 1 71

\\312\2d-code\90-01\8Q112968.ptd 第 605 頁 11283240 五、發明說明（601) 順-4-[1 -[4-[Ν’ -（2-溴苯基）脲基]- 3-甲氧苯基乙醯基] -（2S)-八氫吲哚甲氧基]環己烷羧酸\\312\2d-code\90-01\8Q112968.ptd Page 605 11283240 V. Description of the invention (601) cis-4-[1 -[4-[Ν' -(2-bromophenyl)ureido] 3-methoxyphenylethenyl]-(2S)-octahydrofluorenylmethoxy]cyclohexanecarboxylic acid

COOHCOOH

Br H H OMe 179 順-4-[卜[4-[Ν’ -（2-溴苯基）脲基]- 3-甲氧苯基乙醯基] -（2S)-八氫吲嗓甲氧基]環己烷羧酸甲酯Br HH OMe 179 cis-4-[Bu[4-[Ν'-(2-bromophenyl)ureido]-3-methoxyphenylethenyl]-(2S)-octahydrofluorenylmethoxy Methyl cyclohexanecarboxylate

•COOMe 在0 °C下於順-4-[l-第三丁氧羰基—（2S)-八氫吲哚甲氧 基]環己烷羧酸甲酯（600毫克，1.5毫莫耳）溶於ch2C12 (6· 0毫升）之攪拌溶液中加入TFA(6· 〇毫升）。使反應混合 物於室溫下授拌0 · 5小時。將混合物於真空中濃縮。將飽 和NaHC〇3加至殘留物，並以CI^CI2萃取。將萃取液以鹽水 洗滌’於NaJO4上乾燥’並於真空中濃縮。將粗製產物不 經進一步的純化而使用於後續的反應。在〇下於此掣 產物(221毫*，0.75毫莫耳）、4，，—心苯下基於二 -3-甲氧苯乙酸（ 284毫克，〇· 75毫莫耳）、HOBt(101毫克， 0.75¾莫耳）、及三乙胺（312毫升，2.3毫莫耳）溶於THF (10· 0毫升）及MeCN(l〇· 〇毫升）之攪拌溶液中加入EDC · HC1 (21 6宅克，1 · 1耄莫耳）。使反應混合物在室溫下授拌 16小時’並於真空中濃縮。將水加至殘留物，並以Et〇Ac 萃取。將萃取液以飽和NaHC03、2M擰檬酸、及飽和NaHCOq• COOMe is dissolved in cis-4-[l-tert-butoxycarbonyl-(2S)-octahydrofluorenylmethoxy]cyclohexanecarboxylate (600 mg, 1.5 mmol) at 0 °C. TFA (6·ml) was added to a stirred solution of ch2C12 (6.0 mL). The reaction mixture was allowed to mix at room temperature for 0.5 hours. The mixture was concentrated in vacuo. Saturated NaHC〇3 was added to the residue and extracted with CI^CI2. The extract was washed with brine &lt;~~~~~~~~~~~~~~~~~~~~~ The crude product was used in the subsequent reaction without further purification. Under this armpit, the product (221 mA *, 0.75 mmol), 4, - phenyl benzoic acid (284 mg, 〇 · 75 mmol), HOBt (101 mg) , 0.753⁄4 mol), and triethylamine (312 ml, 2.3 mmol) dissolved in THF (10 mL) and MeCN (l〇·〇 ml) in a stirred solution of EDC · HC1 (21 6 house) Gram, 1 · 1 耄 Mo Er). The reaction mixture was allowed to stir at room temperature for 16 h then concentrated in vacuo. Water was added to the residue and extracted with Et 〇Ac. The extract was saturated with NaHC03, 2M citric acid, and saturated NaHCOq.

\\312\2d-code\90-01\89112968.ptd 第606頁 1283240 五、發明說明（602) :ΐ:於ΓΟΓ4上乾燥，並於真空中濃縮。將殘留物 己烧，0Ac (ι:3，ν/ν)作為洗提液 ΪΓ7 3 而得順—4_[1—[4_[『~(2-填苯基）脲 基]-3-甲氧苯基乙酿基卜（2S)_八氫吲哚甲氧基]環己烷羧 酸甲酯（480毫克，96%)之無色油。1H — NMR (CDCl3) 5 h 1〇 -2·40 (m，20H)、3·45 (br s，1H)、3·61 (s，32h)、 3·66 (s，3H)、3·76 (s，3H)、3·60-3·80 (m，2Ή)、 4.11-4.14 (m, 2H) ' 6.76-6.92 (m, 3H) ^7.25-7.32 (m， 3H) 、7·49 (d， J=7.1 Hz， 1H) 、7·90 (d， J:8.0\\312\2d-code\90-01\89112968.ptd Page 606 1283240 V. INSTRUCTIONS (602): ΐ: Dry on ΓΟΓ4 and concentrate in vacuo. The residue was burned, 0Ac (ι:3, ν/ν) was used as the eluent ΪΓ7 3 to obtain cis- 4_[1—[4_[『~(2-filled phenyl)ureido]-3-methoxy A colorless oil of methyl phenyl bromide (2S) _ octahydrofluorenyl methoxy] cyclohexanecarboxylate (480 mg, 96%). 1H — NMR (CDCl3) 5 h 1〇-2·40 (m, 20H), 3·45 (br s, 1H), 3·61 (s, 32h), 3·66 (s, 3H), 3· 76 (s,3H),3·60-3·80 (m,2Ή), 4.11-4.14 (m, 2H) ' 6.76-6.92 (m, 3H) ^7.25-7.32 (m, 3H), 7·49 (d, J=7.1 Hz, 1H), 7.90 (d, J: 8.0

Hz， 1H) 、 8·13 (d， J=8·0 Hz， 1H)。 於順-4-[1 -[4-[Ν’ -（2-溴苯基）脲基]-3-曱氧苯基乙醯 基]-(2S) -八氫吲哚甲氧基]環己烷羧酸甲酯（48〇毫克， 〇· 73毫莫耳）溶於THF(10. 0毫升）及MeOH(5· 0毫升）之攪拌 溶液中加入IN NaOH(l· 5毫升，1 · 5毫莫耳）。使混合物在 7 0 °C下擾拌2 4小時。將混合物於真空中濃縮，加入水，並 以1N H C1中和。收集所產生之固體，以水洗滌，並於真空 中乾燥而得1 79 ( 40 0毫克，85%)的白色結晶固體。熔點115 -120 〇C; IR (KBr) 3332、2933、2859、1704、1592、 1 5 29、1434 / 公分；W-NMR (CDC13) 6 1· 10-2· 40 (m， 20Η)、3· 40-3· 50 (m，2Η)、3· 61 及3· 63 (各s，總計 2Η)、3·75 及 3·78 (各s，總計 3Η)、3·70-3·80 (m， 1Η)、 3.90-3.93 (m，1Η)、4·15 (br s，m)、6·76-6·92 (m， 3H)、7·26-7.30 (m，1H)、7·43-7·52 (m，3H)、7·84-7.8 6 (m, 1H) ^ 8. 10-8. 12 (m, 1H) ； MS(FAB) m/z 64 3Hz, 1H), 8·13 (d, J=8·0 Hz, 1H). Yushun-4-[1-[4-[Ν'-(2-bromophenyl)ureido]-3-indolylphenylethyl]-(2S)-octahydrofluorenylmethoxy] ring Methyl hexanecarboxylate (48 mg, 〇·73 mmol) was dissolved in THF (10.0 mL) and MeOH (5.0 mL). 5 millimoles). The mixture was spoiled at 70 ° C for 24 hours. The mixture was concentrated in vacuo, water was added and neutralized with 1N HCI. The resulting solid was collected, washed with water and dried in vacuo to give a white solid crystals of 1 79 (40 mg, 85%). Mp 115-120 〇C; IR (KBr) 3332, 2933, 2859, 1704, 1592, 1 5 29, 1434 / cm; W-NMR (CDC13) 6 1· 10-2· 40 (m, 20Η), 3 · 40-3· 50 (m, 2Η), 3·61 and 3· 63 (each s, total 2Η), 3·75 and 3.78 (each s, total 3Η), 3·70-3·80 ( m, 1Η), 3.90-3.93 (m,1Η), 4·15 (br s,m),6·76-6·92 (m, 3H), 7·26-7.30 (m,1H), 7· 43-7·52 (m,3H), 7.84-7.8 6 (m, 1H) ^ 8. 10-8. 12 (m, 1H) ; MS(FAB) m/z 64 3

\\312\2d-code\90-01\89112968.ptd 第607頁 1283240 五、發明說明（603) (MH1) ; C32H4GN3 06 Br · 0· 4H20 之分析計算值：C，59· 15 ; H， 6· 33 ; N，6· 49 ; Br，12. 30。實測值·· C，59· 26 ; H， 6· 33 ; N，6· 36 ; Br，12· 37。 實施例172 4-[[1-[3-甲氧基-4 - [Ν’-（2-甲基苯基）脲基]苯基乙醯基 ]-2-吼咯啶基]羰胺基]環己烷羧酸\\312\2d-code\90-01\89112968.ptd Page 607 1283240 V. INSTRUCTIONS (603) (MH1) ; C32H4GN3 06 Br · 0· 4H20 Analysis calculated value: C, 59· 15 ; H, 6· 33 ; N,6· 49 ; Br, 12. 30. Found C·59· 26 ; H, 6· 33 ; N, 6· 36 ; Br, 12· 37. Example 172 4-[[1-[3-Methoxy-4 -[Ν'-(2-methylphenyl)ureido]phenylethenyl]-2-oxaridinyl]carbonylamino Cyclohexanecarboxylic acid

180 順-4-[(1-第三丁氧羰基-2-吡咯啶基）羰胺基]環己烷羧酸 苄酯180 cis-4-[(1-tert-butoxycarbonyl-2-pyrrolidinyl)carbonylamino]cyclohexanecarboxylic acid benzyl ester

在〇°C下於4 -胺基環己烷羧酸苄酯（900毫克，3.9毫莫 耳）、boc-脯胺酸（830毫克，3· 9毫莫耳）、HOBt(521毫 克，3·9毫莫耳）、及三乙胺（ι·6毫升，11.6毫莫耳）溶於 CH2C12(30· 0毫升）之攪拌溶液中加入EDC · HC1 (1· 1克，5. 8 宅莫耳）。使反應混合物在室溫下攪拌1 6小時，並於真空 中濃縮。將水加至殘留物，並以EtOAc萃取。將萃取液以 飽和NaHC〇3、2M檸檬酸、及飽和NaHC03洗滌，然後於㈣叫 上乾燥，並於真空中濃縮。將殘留物經由於石夕膠上利用正 己烷-EtOAc (6:1，v/v)作為洗提液進行管柱層析，純化 而得順-4-[(1-第三丁氧羰基-2-咣咯啶基）羰胺基]環己烷 叛酸卞S旨（600¾克’36%)之非晶形固體。ijj — nmr (CDC13)Benzyl 4-aminocyclohexanecarboxylate (900 mg, 3.9 mmol), boc-proline (830 mg, 3.9 mmol), HOBt (521 mg, 3) at 〇 °C · 9 mM), and triethylamine (ι·6 ml, 11.6 mmol) dissolved in CH2C12 (30·0 ml) in a stirred solution. Add EDC · HC1 (1·1 g, 5. 8 house Mo ear). The reaction mixture was stirred at room temperature for 16 h and concentrated in vacuo. Water was added to the residue and extracted with EtOAc. The extract was washed with saturated NaHC 3, 2M citric acid and sat. NaHC.sub.3 and then dried on (d) and concentrated in vacuo. The residue was subjected to column chromatography using n-hexane-EtOAc (6:1, v/v) as an eluent to afford cis-4-[(1-tert-butoxycarbonyl- 2-Pyrridinyl)carbonylamino]cyclohexane oxalate S (6003⁄4 g '36%) amorphous solid. Ijj — nmr (CDC13)

89112968.ptd 第608頁 1283240 五、發明說明（604) δ 1.44 (s, 9H) ' 1.50 -1.90 (m, 12H) ^ 2.20 -2.26 (m, 1H)、3·25-3·50 (m, 2H)、3·80-3·90 (m，1H)、4·10-4· 25 (m，1Η)、5·12 (s，2Η)、7·35-7·36 (m，5Η)。 4-[[1- [3-甲氧基-4-[Ν’ - (2 -甲基苯基）脲基]苯基乙醯基] -2-咄咯啶基]羰胺基]環己烷羧酸苄酯 〇-COOBn 在0 °C下於順-4 _[(1 -第三丁氧幾基-2 -吼咯咬基.）獄胺 基]環己烷羧酸苄酯（600毫克，1.4毫莫耳）溶於CH2C12 (6· 0毫升）之攪拌溶液中加入TFA(3· 0毫升）。使反應混合物於 室溫下攪拌0 · 5小時。將混合物於真空中濃縮。將飽和 NaHC〇3加至殘留物，並以CH2C12萃取。將萃取液以鹽水洗 條’於N S 04上乾燥’並於真空中濃縮。將粗製產物不經 進一步的純化而使用於後續的反應。在〇它下於此粗製產 物（300毫克，0.7毫莫耳）、3-甲氧基一 4 - [N，- (2 -甲基苯 基）脲基]苯乙酸（220毫克，0.7毫莫耳）、H〇Bt(94毫克， 0.7毫莫耳）、及三乙胺（291毫升，2.1毫莫耳）溶於THF (10·0毫升）及MeCN(10.0毫升）之攪拌溶液中加入edc · HC1 ( 2 0 1毫克，1 · 1毫莫耳）。使反應混合物在室溫下擾拌 1 6小時，並於真空中濃縮。將水加至殘留物，並以Et〇Ac 萃取。將萃取液以飽和NaHC〇3、2M擰檬酸、及飽和NaHC03 洗滌，然後於NaJO4上乾燥，並於真空中濃縮。收集所產 生之固體’並以EtOAc洗務而得4-[[1 一 [3-甲氧基一 4-[N，89112968.ptd Page 608 1283240 V. INSTRUCTIONS (604) δ 1.44 (s, 9H) ' 1.50 -1.90 (m, 12H) ^ 2.20 -2.26 (m, 1H), 3·25-3·50 (m, 2H), 3·80-3·90 (m, 1H), 4·10-4· 25 (m, 1Η), 5·12 (s, 2Η), 7·35-7·36 (m, 5Η) . 4-[[1-[3-methoxy-4-[Ν' - (2-methylphenyl)ureido]phenylethenyl]-2-oxaridinyl]carbonylamino]cyclohexyl Benzyl alkanoate 〇-COOBn at 0 ° C in cis-4 _[(1 -t-butoxy-yl-2-anthracenyl). phenylamino]cyclohexanecarboxylic acid benzyl ester (600 Tm (3.0 ml) was added to a stirred solution of CH2C12 (6.0 mL). The reaction mixture was stirred at room temperature for 0.5 hours. The mixture was concentrated in vacuo. Saturated NaHC〇3 was added to the residue and extracted with CH2C12. The extract was washed with brine <RTI ID=0.0></RTI> <RTI ID=0.0> The crude product was used in the subsequent reaction without further purification. The crude product (300 mg, 0.7 mmol), 3-methoxy-4-[N,-(2-methylphenyl)ureido]phenylacetic acid (220 mg, 0.7 mmol) Erc), H〇Bt (94 mg, 0.7 mmol), and triethylamine (291 ml, 2.1 mmol) dissolved in THF (10 mL) and MeCN (10.0 mL). · HC1 (2 0 1 mg, 1 · 1 mmol). The reaction mixture was stirred at room temperature for 16 h and concentrated in vacuo. Water was added to the residue and extracted with Et 〇Ac. The extract was washed with saturated NaHC 〇3, 2M EtOAc, and sat. NaHC03. The resulting solid was collected and washed with EtOAc to give 4-[[1][3-methoxy- 4-[N,

；\\312\2d-code\90-01\89112968.ptd;\\312\2d-code\90-01\89112968.ptd

第609頁 ! 1283240 五、發明說明（605) -（2-甲基苯基）脲基]苯基乙醯基]—2 -吡洛啶基]羰胺基]環 己烷羧酸苄酯（380毫克，87%)之白色結晶固體。. W-NMR (CDC13) δ 1· 40-2· 15 (m，12H)、2· 28 (m，3H)、 2·30-2·50 (m, 2H)、3·40-3·55 (m，2H)、3·61 (s， 2Η) υι ό，3Η)、3·82 (m，1Η)、4·53 (d，J = 6.3 Ηζ，1Η)、5·10 (s，2Η)、6·42 (s，1Η)、6·77-6·79 (m， 2Η)、7·04-7·34(ιη，9Η)'7.50-7·52(ιη，1Η)、8·05-8· 07 (m，1H)。 於4-[[卜[3-甲氧基-4-[N，-（2-甲基苯基）脲基]苯基乙 醯基]-2 -吡咯啶基]羰胺基]環己烷羧酸爷酯（38 0毫克， 0· 6毫莫耳）溶於THFC10· 0毫升）及EtOH(5· 0毫升）之攪拌溶 液中加入IN NaOH(0.9毫升，0.9毫莫耳）。使混合物在50 °C下攪拌1 8小時。將混合物於真空中濃縮，加入水，並以 1N HC1中和。收集所產生之固體，以水洗滌，並於真空中 乾燥而得1 8 0 ( 2 3 0毫克，71 % )的白色結晶固體。熔點1 3 6 -142 〇C ; IR (KBr) 3345、2940、1 65 0、1 625、1535、1454 / 公分；1 - NMR (DMSO-d6) (5 1·40-2.0 0 (m，12H)、2·24 (s，3Η)、2·30-2·40 (m，1Η)、3·45-3·80 (m，5Η)、 3.86-3.87 (m，3Η)、4·30-4·43 (m，1Η)、6·65-7·30 (m，5Η)、7·70-7·80 (m，1Η)、7·98-8·09 (m，1Η)、 8.46-8.57 (m, 1H) ； MS(FAB) m/z 537(MH1)； C29H36N406 •0·5Η20 之分析計算值：c，63.84; H，6·83; N，10.27 。實測值·· C，64. 18 ; H，6. 91 ; N， 9. 85。 實施例173Page 609! 1283240 V. INSTRUCTIONS (605) -(2-Methylphenyl)ureido]phenylethenyl]-2-pyridinyl]carbonylamino]cyclohexanecarboxylic acid benzyl ester ( 380 mg, 87%) of a white crystalline solid. W-NMR (CDC13) δ 1· 40-2· 15 (m, 12H), 2· 28 (m, 3H), 2·30-2·50 (m, 2H), 3·40-3·55 (m, 2H), 3·61 (s, 2Η) υι ό, 3Η), 3·82 (m, 1Η), 4·53 (d, J = 6.3 Ηζ, 1Η), 5·10 (s, 2Η) ),6·42 (s,1Η),6·77-6·79 (m, 2Η), 7·04-7·34(ιη,9Η)'7.50-7·52(ιη,1Η),8· 05-8· 07 (m, 1H). 4-[[Bu[3-methoxy-4-[N,-(2-methylphenyl)ureido]phenylethenyl]-2-pyrrolidinyl]carbonylamino]cyclohexane To a stirred solution of carboxylic acid ester (38 0 mg, 0.6 mmol) in THF (10 mL) and Et.sub.OH (0.5 mL) was added IN NaOH (0.9 mL, 0.9 m.m.). The mixture was stirred at 50 ° C for 18 hours. The mixture was concentrated in vacuo, water was added and neutralized with 1N EtOAc. The resulting solid was collected, washed with water and dried in vacuo to give &lt;1&gt; Melting point 1 3 6 -142 〇C ; IR (KBr) 3345, 2940, 1 65 0, 1 625, 1535, 1454 / cm; 1 - NMR (DMSO-d6) (5 1·40-2.0 0 (m, 12H ), 2·24 (s, 3Η), 2·30-2·40 (m, 1Η), 3·45-3·80 (m, 5Η), 3.86-3.87 (m, 3Η), 4·30- 4·43 (m, 1Η), 6.65-7·30 (m, 5Η), 7·70-7·80 (m, 1Η), 7·98-8·09 (m, 1Η), 8.46- 8.57 (m, 1H) ; MS (FAB) m/z 537 (MH1); C29H36N406 • 0·5Η20 Analysis calculated: c, 63.84; H, 6·83; N, 10.27. Measured value · · C, 64 18; H, 6.91; N, 9. 85. Example 173

1283240 五、發明說明（606) 4 - [[1 - [4 - [N -（2- Hi苯基）脲基]- 3-甲氧苯基乙醢基]-2-吡咯啶基]羰胺基]環己烷羧酸1283240 V. INSTRUCTIONS (606) 4 - [[1 - [4 - [N -(2-Hiphenyl) Urea]-3-methoxyphenylethyl]-2-pyrrolidinyl]carbonylamine Cyclohexanecarboxylic acid

181 4 - [[1 - [4 -[Ν’ -（2-氯苯基）脲基]- 3-甲氧苯基乙醯基]- 2-吡咯啶基]羰胺基]環己烷羧酸苄酯 在0 °C下於順-4 - [(1 -第三丁氧羰基—2 -吡咯啶基）羰胺 基]環己烷羧酸苄酯（600毫克，1·4毫莫耳）溶於CH2C12 ( 6.0毫升）之攪拌溶液中加入TF A (3 · 0毫升）。使反應混合物 於室溫下擾拌0. 5小時。將混合物於真空中濃縮。將飽和 NaHC〇3加至殘留物，並以CH2C 12萃取。將萃取液以鹽水洗 滌，於NaJO4上乾燥，並於真空中濃縮。將粗製產物不經 進一步的純化而使用於後續的反應。在〇 °c下於此粗製產 物（ 300毫克，0.7毫莫耳）、4-[N’-(2-氯苯基）脲基]一3-甲 乳本乙酸（237宅克’〇·7宅莫耳）、H0Bt(94毫克，〇·7毫莫 耳）、及三乙胺（291毫升，2·1毫莫耳）溶於THF(l〇· 〇毫升） 及MeCN(10.0毫升）之攪拌溶液中加入edc · HC1 (201毫 克’ 1 · 1毫莫耳）。使反應混合物在室溫下攪拌1 6小時，並 於真空中濃縮。將水加至殘留物，並以Et0Ac萃取。將萃 取液以飽和N a H C 〇3、2 Μ檸檬酸、及飽和N a H C 03洗滌，然後181 4 - [[1 - [4 -[Ν- -(2-Chlorophenyl)ureido]-3-methoxyphenylethenyl]-2-pyrrolidinyl]carbonylamino]cyclohexanecarboxylate Benzyl benzyl ester in cis-4-[(1 -t-butoxycarbonyl-2-pyrrolidinyl)carbonylamino]cyclohexanecarboxylic acid benzyl ester (600 mg, 1.4 mmol) at 0 °C TF A (3.0 ml) was added to a stirred solution of CH2C12 (6.0 mL). 5小时。 The reaction mixture was stirred at room temperature for 0.5 hours. The mixture was concentrated in vacuo. Saturated NaHC〇3 was added to the residue and extracted with CH2C12. The extract was washed with brine, dried over Na.sub.4, and concentrated in vacuo. The crude product was used in the subsequent reaction without further purification. The crude product (300 mg, 0.7 mmol), 4-[N'-(2-chlorophenyl)ureido] 3-carboacetic acid (237 克 '〇·7) at 〇 °c House Moh), H0Bt (94 mg, 〇·7 mmol), and triethylamine (291 mL, 2.1 mmol) dissolved in THF (1 〇········· Add edc · HC1 (201 mg '1 · 1 mmol) to the stirred solution. The reaction mixture was stirred at room temperature for 16 h and concentrated in vacuo. Water was added to the residue and extracted with EtOAc. The extract is washed with saturated N a H C 〇3, 2 citric acid, and saturated N a H C 03, then

89112968.ptd 第611頁 1283240 五、發明說明（607) 於NazS〇4上乾燥，並於真空中濃縮。收集所產生之固體， 並以EtOAc洗滌而得4 - [[1 - [4 - [Ν’-（2-氣苯基）脲基]一3-甲 氧笨基乙醯基]-2-咄咯啶基]羰胺基]環己烷羧酸芊酯（31〇 毫克，68%)之白色結晶固體。ih-NMR (CDC13) 3 1 · 40- 2·15 (m，12H)、2·30-2·60 (m, 2H)、3·42-3·55 (m， 2H) 、3·64 (s， 2H) 、3·84 (s， 3H) 、4.55 (d， J=6.1 Hz, 1H) 、5·12 (s， 2H) 、6·8卜7·35 (m， 12H) 、7·96_ 7· 98 (m，1H)、8· 17-8· 19 (m，1H)。 於4-[ [1-[4-[Ν’ - (2-氯苯基）脲基]-3-甲氧苯基乙醯基] -2-吡咯啶基]羰胺基]環己烷羧酸苄酯（310毫克，0.86毫 莫耳）溶於THFC10· 0毫升）及MeOH(5· 0毫升）之攪拌溶液中 加入IN NaOH(0· 7毫升，0· 7毫莫耳）。使混合物在50 °C下 授拌1 8小時。將混合物於真空中濃縮，加入水，並以1 n H C1中和。收集所產生之固體，以水洗滌，並於真空中乾 燥而得1 8 1 ( 2 6 0毫克，9 8 %)的白色結晶固體。熔點1 3 5 - 1 4 0 〇C; IR (KBr) 3328、2938、1594、1533、1438、1203/ 公分；I-NMR (DMSO-d6)6 1·40-2·20 (m，12Η) .、2·30 -2·40 (m, 1H)、3·40-3.80 (m，5H)、3·65-3·85 (m, 3Η)、4·30-4·43(ιη，1Η)、6·66-7·31(ιη，5Η)、7·42-8· 10 (m，2Η)、8· 89-8· 94 (m，2Η) ; MS(FAB) m/z 5 5 7(ΜΗ1) ; C23H33N4 06 C1 · 0· 3Η20 之分析計算值：C，59· 79 ；Η, 6.02； Ν, 9. 96 ； C1, 6. 30 ° 實測值：C, 59.86 ； Η, 6.10； Ν, 9· 60 ; C1，6· 34 〇 實施例17489112968.ptd Page 611 1283240 V. INSTRUCTIONS (607) Dry on NazS〇4 and concentrate in vacuo. The resulting solid was collected and washed with EtOAc to give 4 - [[1 - [4 - [4 - [Ν--(2-phenylphenyl)ureido]- 3-methoxyphenyl)] A pyridyl]carbonylamino]cyclohexanecarboxylate (31 mg, 68%) as a white crystalline solid. Ih-NMR (CDC13) 3 1 · 40- 2·15 (m, 12H), 2·30-2·60 (m, 2H), 3·42-3·55 (m, 2H), 3·64 ( s, 2H), 3·84 (s, 3H), 4.55 (d, J=6.1 Hz, 1H), 5·12 (s, 2H), 6·8 b 7·35 (m, 12H), 7· 96_ 7· 98 (m, 1H), 8· 17-8· 19 (m, 1H). 4-[[1-[4-[Ν'-(2-Chlorophenyl)ureido]-3-methoxyphenylethenyl]-2-pyrrolidinyl]carbonylamino]cyclohexanecarboxylate To a stirred solution of benzyl acetate (310 mg, 0.86 mmol) dissolved in THF (10 mL) and MeOH (0.5 mL) was added IN NaOH (0·7 mL, 0·7 mmol). The mixture was stirred at 50 ° C for 18 hours. The mixture was concentrated in vacuo, water was added and neutralized with 1 n H C1. The resulting solid was collected, washed with water and dried in vacuo to give &lt;1&gt; Melting point 1 3 5 - 1 4 0 〇C; IR (KBr) 3328, 2938, 1594, 1533, 1438, 1203/cm; I-NMR (DMSO-d6) 6 1·40-2·20 (m, 12Η) ., 2·30 -2·40 (m, 1H), 3·40-3.80 (m, 5H), 3·65-3·85 (m, 3Η), 4·30-4·43 (ιη, 1Η) ),6·66-7·31(ιη,5Η), 7·42-8· 10 (m,2Η), 8·89-8· 94 (m,2Η); MS(FAB) m/z 5 5 7(ΜΗ1) ; C23H33N4 06 C1 · 0· 3Η20 Analysis calculated: C, 59· 79 ; Η, 6.02; Ν, 9. 96 ; C1, 6. 30 ° Found: C, 59.86 ; Η, 6.10; Ν, 9· 60 ; C1,6· 34 〇Example 174

\\312\2d-code\90-01\89112968.ptd 第 612 頁 1283240 五、發明說明（608) 4-[1- [3-曱氧基-4-[Ν’ -（2-甲基苯基）脲基]苯基乙醯基 ]-（3S)-咄咯啶氧基]苯甲酸 182 - [：1-苄基-(3S)-吼咯啶氧基]苯甲酸甲酯 於4-羥基苯甲酸甲酯（1. 84克，12· 1毫莫耳）、（R)-1-辛 基-3-吡咯啶醇（2.00毫升，12.1毫莫耳）、及？113?(3.81 克，14· 5毫莫耳）溶於THF(25毫升）之冷卻的（0 °C)攪拌溶 液中加入D IAD(2.86毫升，14.5毫莫耳），並使反應混合物 迴流加熱1 0小時。於冷卻至室溫後，將混合物蒸發。將殘 留物經由於矽膠上利用正己烷一Et0Ac(3 : i，v/v)作為洗提 液進行管柱層析，純化而得4-[丨―辛基—（3S) -吼咯啶氧基] 苯甲酸曱酯（3· 66克，97%)之淡黃色油。1H — NMR (CDC13) δ 1.95-2·02 (m，1H)、2·28-2·”（m，1H)、2·57-2·63 (m，1H)、2·72-2·81 (m，2H)、2·96-3·01 (m，1H)、 3.63-3.71 (m, 2H)、3·87 (s，3H)、4·84-4.8 9 (m， 1H)、6·84 (d，J = 8.8 Hz，2H)、7·23-7·34 (m，5H)、 7· 95 (d，J = 8. 8 Hz，2H)。 4-[(3S )-吼咯啶氧基]苯甲酸甲_\\312\2d-code\90-01\89112968.ptd Page 612 1283240 V. INSTRUCTIONS (608) 4-[1- [3-曱-oxy-4-[Ν' -(2-methylbenzene) Urinyl]phenylethyl]](3S)-decalyloxy]benzoic acid 182 -[:1-benzyl-(3S)-indolyloxy]benzoic acid methyl ester 4- Methyl hydroxybenzoate (1.84 g, 12.1 mmol), (R)-1-octyl-3-pyrrolidin (2.00 mL, 12.1 mmol), and ? 113? (3.81 g, 14.5 mmol) of a cooled (0 ° C) stirred solution of THF (25 mL) was added D IAD (2.86 mL, 14.5 mmol) and the reaction mixture was refluxed. 10 hours. After cooling to room temperature, the mixture was evaporated. The residue was purified by column chromatography on n-hexane-Et0Ac (3: i, v/v) as an eluent to obtain 4-[丨-octyl-(3S)-pyrrolidine oxygen. A pale yellow oil of decyl benzoate (3.66 g, 97%). 1H — NMR (CDC13) δ 1.95-2·02 (m, 1H), 2·28-2·” (m, 1H), 2·57-2·63 (m, 1H), 2·72-2· 81 (m, 2H), 2·96-3·01 (m, 1H), 3.63-3.71 (m, 2H), 3·87 (s, 3H), 4·84-4.8 9 (m, 1H), 6·84 (d, J = 8.8 Hz, 2H), 7·23-7·34 (m, 5H), 7·95 (d, J = 8. 8 Hz, 2H). 4-[(3S )- Acetidineoxy]benzoic acid A

\\312\2d-code\90-01\89112968.ptd 第 613 頁 1283240 co,r 五、發明說明（609) 使4-[1-辛基-（3S)-吡咯啶氧基]笨甲酸曱酯（3· 66克， 11· 8毫莫耳）溶於Me0H(25毫升）之溶液於Pd(〇H)2/C (〇· 73 克’ 2 0重量百分比）上氫化隔夜。將反應混合物過濾以移 除催化劑，並將溶液蒸發而得4_[(3S)-吡咯啶氧基]苯甲 酸甲醋（2· 60克，q· y·)的淡黃色油。1H — NMR (cdcd 5 1.94-2.01 (m, 2H) ^2.09-2.18 (m, 1H) &gt;2.91-2.97 (m，1H)、3·04- 3.09 (m，1H)、3·16-3·23 (m，2H)、 3·88 (s，3Η)、4·88-4·91 (m，1Η)、6·86 (m，2Η)、 7·96-7·98 (m，2H); ESI m/z 2 22(MH1)。 4-[1 -[3-甲氧基-4 - [Ν’ - (2-甲基苯基）脲基]苯基乙醯基] -（3S)-咄17各唆氧基]笨甲酸甲酯 使3-甲氧基-4- [Ν’-（2_甲基苯基）脲基]苯乙酸（449毫 克，1.43毫莫耳）、4-[(3S) -吡咯啶氧基]苯甲酸甲酷 毫克，L43毫莫耳）、EDC*HC1 ( 330 毫克莫=)31、6 HOBt(193 毫克，1· 43 毫莫耳）、及Et3N(24〇 毫升，；[72 毫 莫耳）於THF( 5毫升）中之混合物在室溫下攪拌隔夜。將反 應混合物以稀釋，並以EtOAc萃取。將萃取液以趟水先 滌，於NaJO4上乾燥，並蒸發。使殘留物經由於矽^丄利 用CHCI3-MeOH(l 00 ·· 1至50 ·· 1，v/v)作為洗提液進行管柱層 mm 第614頁 \\312\2d-code\90-01\89112968.ptd 1283240 五、發明說明（610) 析’純化而得4 - [1 - [3 -甲氧基-4-[N，-(2-甲基苯基） 脲基]苯基乙醯基]-(3S) -吡咯啶氧基]苯曱酸甲酯（735毫 克，99%)的淡黃色油。iH-N〇 (CDCl3) δ 2.03-2.31 (s 及m系列，總計5H)、3· 57-3· 78 (m系列，總計9H)、3· 88 (s， 3Η) 、4.95-4.99 (m， 1Η) 、6·73-7·00 (m， 5Η)、 7·06-7·10 (m，1Η)、7·18-7·22 (m，2Η)、7·42-7·46 (m，1Η)、7·57-7·62 (m，1Η)、7·95-8·08 (m，3H); ESI m/z 518(MH1)。 於4 - [1 - [3-甲氧基-4-[N，-（2-甲基苯基）脲基]苯基乙醯 基]-（3S) -咄咯啶氧基]苯甲酸甲酯（627毫克，1.21毫莫 耳）溶於THF(5毫升）之攪拌溶液中加入〇. 5N NaOH(5毫 升），並使反應混合物迴流加熱3小時。於冷卻至室溫後， 將混合物倒入至冰的1 N HC1中，並於減壓下收集所產生之 沈澱物。使粗製固體自MeOH-CHCl3-IPE再結晶，而得 1 82 (235毫克，39%)之白色結晶粉末。熔點131-1 35 °C ; l-NMR (DMSO-d6) 6 2· 0 6-2· 27 (m 系列，總計5H)、 3.5 7-3.64 (111，411)、3.7卜3.88(5及111系列，總計511)、 5.11 及 5.20 (各 m，總計 1H)、6·73-6.77 (m，1H)、 6.88-6.95 (m, 2H) ^ 7.02-7.05 (m, 2H) ^7,11-7.17 (m，2H) '7.79-7.81 (m, 1H)、7·88-7·90 (m，2H)、 7.98-8.03 (m, 1H) ' 8.45-8.47 (m, 1H) ^8.55-8.57 (m，1H)、12.66 (br s，1H); ESI m/z 504 (MH1); C28H29N3 06 · 3/4H20 之分析計算值·· C，65· 04 ; H，5· 95 ; N， 8· 13。實測值·· C，65· 11 ; H，5· 99 ; N，7· 66 °\\312\2d-code\90-01\89112968.ptd Page 613 1283240 co, r V. Description of the invention (609) 4-[1-octyl-(3S)-pyrrolidinyloxy] benzoic acid hydrazine A solution of the ester (3·66 g, 1 1 8 mmol) dissolved in MeOH (25 mL) was hydrogenated over Pd(〇H) 2/C ( 〇· 73 g '20 wt%) overnight. The reaction mixture was filtered to remove the catalyst, and the solution was evaporated to give 4-[(3S)-pyrrolidyloxy]benzoic acid methylacetate (2·60 g, q·y·) as a pale yellow oil. 1H - NMR (cdcd 5 1.94-2.01 (m, 2H) ^2.09-2.18 (m, 1H) &gt;2.91-2.97 (m,1H), 3·04- 3.09 (m,1H),3·16-3 ·23 (m, 2H), 3·88 (s, 3Η), 4·88-4·91 (m, 1Η), 6·86 (m, 2Η), 7·96-7·98 (m, 2H ESI m/z 2 22(MH1) 4-[1 -[3-methoxy-4 -[Ν' - (2-methylphenyl)ureido]phenylethenyl] -(3S )-咄17 唆 唆 ] ] ] 甲酯 笨 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3-methoxy-4-[Ν'-(2-methylphenyl)ureido]phenylacetic acid (449 mg, 1.43 mmol), 4 -[(3S)-pyrrolidinyloxy]benzoic acid methyl gram, L43 millimolar), EDC*HC1 (330 mg mod =) 31, 6 HOBt (193 mg, 1.43 mmol), and Et3N A mixture of (24 mL), EtOAc (5 mL) was evaporated. The reaction mixture was diluted and extracted with EtOAc. The extract was washed with water, dried over NaJO4, and evaporated. The residue was passed through CHCI3-MeOH (100··1 to 50··1, v/v) as an eluent for the column layer mm page 614 \\312\2d-code\90- 01\89112968.ptd 1283240 V. Inventive Note (610) Analysis of 'purification of 4-[1-[3-methoxy-4-[N,-(2-methylphenyl)ureido]phenyl) Methyl]-(3S)-pyrrolidinyloxy]benzoic acid methyl ester (735 mg, 99%) as a pale yellow oil. iH-N〇(CDCl3) δ 2.03-2.31 (s and m series, total 5H), 3·57-3·78 (m series, total 9H), 3·88 (s, 3Η), 4.95-4.99 (m , 1Η), 6.73-7·00 (m, 5Η), 7·06-7·10 (m, 1Η), 7·18-7·22 (m, 2Η), 7·42-7·46 (m, 1Η), 7·57-7·62 (m, 1Η), 7·95-8·08 (m, 3H); ESI m/z 518 (MH1). 4-[1-[3-Methoxy-4-[N,-(2-methylphenyl)ureido]phenylethenyl]-(3S)-indolyloxy]benzoic acid To a stirred solution of EtOAc (5 mL, EtOAc) After cooling to room temperature, the mixture was poured into ice 1 N HCl, and the resulting precipitate was collected under reduced pressure. The crude solid was recrystallized from MeOH-EtOAc (EtOAc) elute Melting point 131-1 35 °C; l-NMR (DMSO-d6) 6 2· 0 6-2· 27 (m series, total 5H), 3.5 7-3.64 (111,411), 3.7 3.88 (5 and 111 Series, total 511), 5.11 and 5.20 (each m, total 1H), 6.73-6.77 (m, 1H), 6.88-6.95 (m, 2H) ^ 7.02-7.05 (m, 2H) ^7,11- 7.17 (m, 2H) '7.79-7.81 (m, 1H), 7·88-7·90 (m, 2H), 7.98-8.03 (m, 1H) ' 8.45-8.47 (m, 1H) ^8.55-8.57 (m, 1H), 12.66 (br s, 1H); ESI m/z 504 (MH1); C28H29N3 06 · 3/4H20 Analytical calculations · · C, 65 · 04 ; H, 5 · 95 ; N, 8 · 13. Measured value·· C,65· 11 ; H,5· 99 ; N,7· 66 °

89112968.ptd 第615頁 128324089112968.ptd Page 615 1283240

五、發明說明（611) f施例1 7 5 4-[l-[4_[N’ -(2-氣笨基）脲基]_3_曱氧苯基乙醯基]一（3S) -吼洛咬氧基]笨甲酸V. INSTRUCTIONS INSTRUCTIONS (611) f EXAMPLE 1 7 5 4-[l-[4_[N' -(2-Azyl) Urea]_3_曱Oxophenyl Ethyl]-(3S)-吼Alkyloxy

4-[l--(2-氣笨基）脲基]_3_甲氧苯基乙醯基卜 (3S) -17比17各雙氧基]苯甲酸甲酯4-[l--(2-indolyl)ureido]_3_methoxyphenylethenyl (3S) -17 to 17 bisoxy]benzoic acid methyl ester

C〇2MeC〇2Me

使4-[Ν’ -（2-氯苯基）脲基]一3一甲氧苯乙酸（41〇毫克， 1.22毫莫耳）、4-[(3S)-咄咯啶氧基]苯甲酸甲酯（270毫 克，1·22毫莫耳）、EDC#HC1(28〇毫克，146毫莫荨）、 HOBt(200cs 克，1.48 毫莫耳）、及Et3N(205 毫升，1.47 毫4-[Ν'-(2-Chlorophenyl)ureido]- 3-methoxybenzoic acid (41 mg, 1.22 mmol), 4-[(3S)-indolyloxy]benzoic acid Methyl ester (270 mg, 12.22 mmol), EDC#HC1 (28 mg, 146 mmol), HOBt (200 cs, 1.48 mmol), and Et3N (205 ml, 1.47 m)

莫耳）於THF(8毫升）中之混合物在室溫下擾拌隔夜。將反 應混合物以仏0稀釋，並以Et0Ac萃取。將萃取液以鹽水洗 滌，於NaJO4上乾燥，並蒸發。使殘留物經由於石夕膠上利 用CHCl3-MeOH(l〇〇: 1至6〇: 1，v/v)作為洗提液進行管枉 層析，純化而得4-[1-[4-[N，-（2-氯苯基）脲基]一3 一甲氧 苯基乙醯基]-(3S)-吼咯啶氧基]苯甲酸甲酯（652毫克， 99%)的白色固體。熔點 200一203 t ; 1{^NMR (CDci3)占 2·06-2·32 (m，2H)、3·60-3·82 (m 系列，總計9Η)、3·88 (s, 3Η)、4·97-5·01 (m，1Η)、6·76〜6·86 (m，4Η)、The mixture in THF (8 mL) was stirred overnight at room temperature. The reaction mixture was diluted with 仏0 and extracted with EtOAc. The extract was washed with brine, dried over Na.sub.4, and evaporated. The residue was purified by pipe chromatography using CHCl3-MeOH (l〇〇: 1 to 6〇: 1, v/v) as an eluent, and 4-[1-[4- [N,-(2-Chlorophenyl)ureido]-3-methoxyphenylethyl]-(3S)-indolyloxy]benzoic acid methyl ester (652 mg, 99%) as a white solid . Melting point 200-203 t ; 1{^NMR (CDci3) accounted for 2·06-2·32 (m, 2H), 3·60-3·82 (m series, total 9Η), 3.88 (s, 3Η) , 4·97-5·01 (m, 1Η), 6.76~6·86 (m, 4Η),

第616頁 1283240 五、發明說明（612) 6.9 5-6.99 (m，1H)、7·23-7.47 (m，4H)、7·9卜7.99 (m，3Η)、8·19-8.21 (m，1H); ESI m/z 537 (Μ+)。 於4 - [l-[4-[N，-（2-氣笨基）脲基]- 3-甲氧苯基乙酿 基]- (3S) -吼咯啶氧基]苯曱酸曱酯（650毫克，U1毫莫 耳）溶於THF(5毫升）之攪拌溶液中加入〇· Na0H(5毫 升），並使反應混合物迴流加熱5小時。於冷卻至室溫後， 將混合物倒入至冰的1 N H C1中’並於減壓下收集所產生之 沈澱物。使粗製固體自MeOH-CHCl3- ΙΡΕ再結晶，而得183 (443毫克，70%)之淡黃色結晶粉末。熔點1 90- 1 93 °C ; !H-NMR (DMSO-d6) 5 2.06-2.27 (m, 2H) ^ 3. 56-3. 62 (m, 4 H)、3. 71 - 3. 8 8 (s 及 m 系列，總計 5 H )、5 · 11 及 5 · 2 0 (各 m，總計 1H)、6·74-6.78 (m，1H)、6·89-6·91 (m，1H)、 7.0 0-7.0 5 (m，3H)、7·26-7·30 (m，1H)、7·43-7·45 (m，1Η)、7·88-7.98 (m，3Η)、8· 08-8.10 (m，1Η)、 8.89-8.95 (m，2H)、12.67 (br s，1H); ESI m/z 5 24(MH1) ; C27H26C1N3 06 · 1/4H20 之分析計算值·· C，61. 36 ;H，5·05; N，7.95; Cl，6·71。實測值：C，61.69; H， 5· 45 ; N，7· 29 ; Cl，6.91。 實施例176 4-[卜[4-[1^’-（2-溴苯基）脲基]-3-甲氧苯基乙醯基]-(33) -咄咯啶氧基]笨甲酸Page 616 1283240 V. Description of invention (612) 6.9 5-6.99 (m, 1H), 7·23-7.47 (m, 4H), 7·9 b 7.99 (m, 3Η), 8·19-8.21 (m , 1H); ESI m/z 537 (Μ+). 4-[1-[4-[N,-(2-Acetyl)ureido]-3-methoxyphenylethyl]-(3S)-indolyloxy]phenyl decanoate (650 mg, U1 mmol) EtOAc (5 mL) was evaporated. After cooling to room temperature, the mixture was poured into ice 1 N H C1 and the resulting precipitate was collected under reduced pressure. The crude solid was recrystallized from MeOH-EtOAc (EtOAc) elute Melting point 1 90- 1 93 ° C ; !H-NMR (DMSO-d6) 5 2.06-2.27 (m, 2H) ^ 3. 56-3. 62 (m, 4 H), 3. 71 - 3. 8 8 (s and m series, total 5 H), 5 · 11 and 5 · 2 0 (each m, total 1H), 6.74-6.78 (m, 1H), 6·89-6·91 (m, 1H) , 7.0 0-7.0 5 (m, 3H), 7·26-7·30 (m, 1H), 7·43-7·45 (m, 1Η), 7·88-7.98 (m, 3Η), 8 · 08-8.10 (m,1Η), 8.89-8.95 (m,2H), 12.67 (br s,1H); ESI m/z 5 24(MH1) ; C27H26C1N3 06 · 1/4H20 analytical calculation ·· C , 61. 36 ; H, 5·05; N, 7.95; Cl, 6.71. Found: C, 61.69; H, 5·45; N, 7. 29; Cl, 6.91. Example 176 4-[Bu [4-[1^'-(2-bromophenyl)ureido]-3-methoxyphenylethenyl]-(33)-indolyloxy]benzoic acid

89112968.ptd 第617頁 1283240 五、發明說明（613) 4-[W 4-[Ν’ -（2-溴苯基）脲基]一3一甲氧苯基乙醯基]— (3S) -吡咯啶氧基]笨甲酸甲酯89112968.ptd Page 617 1283240 V. INSTRUCTIONS (613) 4-[W 4-[Ν' -(2-Bromophenyl)ureido]-3-methoxyphenylethyl]-(3S) - Pyrrolidinoxy] methyl benzoate

使4-[Ν’ 2-溴笨基）脲基]一3一甲氧笨乙酸（54〇毫克， 1.42毫莫耳）、4-[(3S)-咄咯啶氧基]苯曱酸甲酯（315毫 克，1· 42毫莫耳）、EDC · HC1 (328毫克，1· 71毫莫耳）、 HOBt(230^ 克 ’1.70 毫莫耳）、及Et3N(240 毫升，1.72 毫 莫耳）於THF(8毫升）中之混合物在室溫下攪拌隔夜。將反 應混合物以稀釋，並以EtOAc萃取。將萃取液以鹽水洗 滌，於NaJO4上乾燥，並蒸發。使殘留物經由於矽膠上利 用CHCl3-MeOH(100:l至50:1，v/v)作為洗提液進行管柱層 析’純化而得4 - [1-[4 - [N’-(2-溴苯基）脲基]一 3-甲氧苯 基乙醯基]-（3S) -吡咯啶氧基]苯甲酸曱酯（62〇毫克，74%) 的白色泡沫。UMR (CDC13) 6 2.06 - 2·33 (m，2H)、 3·60 -3·82 (m 系列，總計9H)、3·89 (s， 3H)、4·97-5.01 (m，1 Η )、6 · 7 7 - 7 · 0 0 ( m，5 Η )、7 · 2 7 - 7. 4 0 ( m，3 Η )、 7 · 4 9 - 7 · 5 1 (m，1Η)、7 · 9 1 - 7 · 9 9 (m，3 Η)、8 · 1 3 — 8 · 1 7 (m，1H) ; ESI m/z 583 (MH1)。 於4- [l-[4- [Ν’- (2-溴苯基）脲基]一3 一甲氧苯基乙醯 基]-(3S) -咄咯啶氧基]苯甲酸甲酯（620毫克，1.06毫莫 耳）溶於THF(5宅升）之授拌溶液中加入〇· 5N NaOH(5毫 升）’並使反應混合物迴流加熱2 · 5小時。於冷卻至室溫4-[Ν'2-bromophenyl]ureido]- 3-methoxypropanoacetic acid (54 mg, 1.42 mmol), 4-[(3S)-indolyloxy]benzoic acid Ester (315 mg, 1.42 mmol), EDC · HC1 (328 mg, 1.71 mmol), HOBt (230^g '1.70 mmol), and Et3N (240 mL, 1.72 mmol) The mixture in THF (8 mL) was stirred at room temperature overnight. The reaction mixture was diluted and extracted with EtOAc. The extract was washed with brine, dried over Na.sub.4, and evaporated. The residue was purified by column chromatography using CHCl3-MeOH (100:1 to 50:1, v/v) as an eluent to obtain 4 - [1-[4 - [N'-( 2-Bromophenyl)ureido]-3-methoxyphenylethenyl]-(3S)-pyrrolidinyloxy]benzoic acid oxime ester (62 mg, 74%) of white foam. UMR (CDC13) 6 2.06 - 2·33 (m, 2H), 3·60 -3·82 (m series, total 9H), 3·89 (s, 3H), 4·97-5.01 (m, 1 Η ), 6 · 7 7 - 7 · 0 0 ( m,5 Η ), 7 · 2 7 - 7. 4 0 ( m,3 Η ), 7 · 4 9 - 7 · 5 1 (m,1Η), 7 · 9 1 - 7 · 9 9 (m, 3 Η), 8 · 1 3 — 8 · 1 7 (m, 1H) ; ESI m/z 583 (MH1). 4-[l-[4-[4-[Ν-(2-Bromophenyl)ureido]-3-methoxyphenylethenyl]-(3S)-indolyloxy]benzoic acid methyl ester ( 620 mg, 1.06 mmol, of THF (5 liter) was added to 授·5N NaOH (5 mL) and the reaction mixture was heated at reflux for 2 hr. Cool to room temperature

89112968.ptd 第618頁 1283240 五、發明說明（614) ' 後，將混合物倒入至冰的丨N HC 1中，並於減壓下收集所產 生之沈澱物。使粗製固體自MeOH-CHCl3-IPE再結晶，而得 1 8 4 (4 2 1毫克’ 7 0 %)之白色結晶粉末。熔點1 7 3 -1 7 5。(：； 'H-NMR (DMS0-d6) 5 2.06-2.28 (m, 2H) ^ 3. 56-3. 65 (m, 4H)、3· 71 -3· 88 (s 及m 系列，總計5H)、5· 12 及5· 20 (各 m，總計 1H)、6·74-6·78 (m，1H)、6·89-7·05 (m，4H)、 7.31-7.34 (m，1Η)、7·59-7·61 (m，1Η)、7·88-7·98 (m，4H)、8·73-8.74 (m，1H)、8·9卜8·93 (m，1H)、 12.67 (br s，1H) ; ESI m/z 5 6 9 (MH1) ; C27H26BrN3 06 之分 析計算值：C，57.0 5; H，4.61; N，7.39; Br，14.06。 實測值：C，57·57; H，5.12; N， 6.81;Br， 13.96。 實施例177 4 - [1 - [3-甲氧基-4 - [Ν’-（2-甲基苯基）脲基]苯基乙龜基 〇 ，0 ]-（3 R)-吼咯啶氧基]苯甲酸 185 4 - [1-苄基-（3R)-咄咯啶氧基]苯曱酸甲酯 ^C〇2Me Ο 989112968.ptd Page 618 1283240 V. INSTRUCTIONS (614) ' After that, the mixture was poured into ice 丨N HC 1 and the resulting precipitate was collected under reduced pressure. The crude solid was recrystallized from MeOH-CHCl3-IPH to yield 148 (4 2 1 ' 70%) of white crystalline powder. Melting point 1 7 3 -1 7 5. (:; 'H-NMR (DMS0-d6) 5 2.06-2.28 (m, 2H) ^ 3. 56-3. 65 (m, 4H), 3· 71 -3· 88 (s and m series, total 5H ), 5·12 and 5·20 (each m, total 1H), 6.74-6.78 (m, 1H), 6.89-7·05 (m, 4H), 7.31-7.34 (m, 1Η) ), 7·59-7·61 (m, 1Η), 7·88-7·98 (m, 4H), 8.73-8.74 (m, 1H), 8·9 b 8.93 (m, 1H) ), 12.67 (br s, 1H); ESI m/z 5 6 9 (MH1); C27H26BrN3 06: C, 57.0 5; H, 4.61; N, 7.39; Br, 14.06. Found: C, 57·57; H, 5.12; N, 6.81; Br, 13.96. Example 177 4 - [1 - [3-methoxy-4 - [Ν'-(2-methylphenyl)ureido]phenyl Ottomyl hydrazine, 0]-(3 R)-decalyloxy]benzoic acid 185 4 - [1-benzyl-(3R)-indolyloxy]benzoic acid methyl ester ^C〇2Me Ο 9

Bn 於4-羥基笨甲酸甲酯（1. 78克，1 1· 7毫莫耳）、1_苄基 -（3S) -吡咯啶醇（2·07克，11·7毫莫耳）、及Ph3p(3· 68 克，14. 0毫莫耳）溶於THF(25毫升）之冷卻的（〇。〇)攪拌溶 液中加入DIAD(2· 76毫升，14· 0毫莫耳），並使反應混合物Bn is methyl 4-hydroxybenzoate (1. 78 g, 11.7 mmol), 1-benzyl-(3S)-pyrrolidin (2.07 g, 11.7 mmol), And Ph3p (3·68 g, 14.0 mmol) dissolved in THF (25 ml) in a cooled (〇.〇) stirred solution was added DIAD (2·76 ml, 14.0 mmol) and Reaction mixture

89112968.ptd 第619頁 1283240 五、發明說明（615) 迴流加熱1 0小時。於冷卻至室溫後，將混合物蒸發。將殘 留物經由於矽膠上利用正己烷-Et0Ac(3: 1，v/v)作為洗提 液進行管柱層析，純化而得4-[1-苄基-(3R)—咄咯咬氧基] 苯甲酸曱酯（3.56克，98%)之淡黃色油。ijj - NMR (CDC13)5 1.95-2.03 (m，1H)、2·28-2·37 (m，1H)、2·57-2.6^ (m, 1Η)、2·73-2·81 (m，2Η)、2·97-3·01 (m，1Η)、 3 · 6 3 - 3 · 7 2 (m，2 H)、3 · 8 7 (s，3 H )、4 · 8 5 - 4 · 9 0 (m，1 H) 、6·83-6·85 (m，2H)、7·27-7·34 (m，5H)、7·94 —7·97 (m，2Η) ; ESI m/z 312(ΜΗ1)。 4-[ (3R)-哺咯啶氧基]苯甲酸甲酯 C〇2Me 0 0 9 使4-[ 1-窄基-（3R) -咄咯啶氧基]笨甲酸甲酯（3. 56克， 11 · 4毫莫耳）溶於Me0H(25毫升）之溶液於Pd(0H)2/C (0· 72 克，20重量百分比）上氫化隔夜。將反應混合物過濾以移 除催化劑，並將溶液蒸發而得4-[ (3R) -吼咯啶氧基]苯甲 酸甲酯（2· 53克，q· y.)的淡黃色油。UMR (CDC13) 5 1.94-2.18 (m, 3H) ^2.91-2.97 (m, 1H) &gt;3.04-3.09 (m，lH)、3.16-3.22(m，2H)、3.88(s，3H)、4.88-4·91 (m，1H)、6·86-6·89 (m，2H)、7·97-7·99 (m，2H) ;ESI m/z 263[MH1+41 ， （+MeCN)] 0 4-[ 1 -[3-甲氧基-4-[N，- (2-甲基苯基）脲基]苯基乙醯 基]-（3R)-吼咯啶氧基]苯甲酸甲酯89112968.ptd Page 619 1283240 V. INSTRUCTIONS (615) Heating under reflux for 10 hours. After cooling to room temperature, the mixture was evaporated. The residue was purified by column chromatography using n-hexane-Et0Ac (3:1, v/v) as an eluent to obtain 4-[1-benzyl-(3R)-anthracene oxygen. Base] decyl benzoate (3.56 g, 98%) as a pale yellow oil. Ijj - NMR (CDC13) 5 1.95-2.03 (m, 1H), 2·28-2·37 (m, 1H), 2·57-2.6^ (m, 1Η), 2·73-2·81 (m , 2Η), 2·97-3·01 (m, 1Η), 3 · 6 3 - 3 · 7 2 (m, 2 H), 3 · 8 7 (s, 3 H ), 4 · 8 5 - 4 · 9 0 (m, 1 H), 6·83-6·85 (m, 2H), 7·27-7·34 (m, 5H), 7·94 — 7·97 (m, 2Η); ESI m/z 312 (ΜΗ1). 4-[(3R)-Carbendyloxy]benzoic acid methyl ester C〇2Me 0 0 9 4-[1-N-yl-(3R)-indolyloxy] benzoic acid methyl ester (3. 56 </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; The reaction mixture was filtered to remove the catalyst, and the solution was evaporated to give 4-[(3.sup..s.s.s.s.s.s. UMR (CDC13) 5 1.94-2.18 (m, 3H) ^2.91-2.97 (m, 1H) &gt; 3.04-3.09 (m, lH), 3.16-3.22 (m, 2H), 3.88 (s, 3H), 4.88 -4·91 (m, 1H), 6·86-6·89 (m, 2H), 7·97-7·99 (m, 2H); ESI m/z 263 [MH1+41 , (+MeCN) ] 0 4-[ 1 -[3-Methoxy-4-[N,-(2-methylphenyl)ureido]phenylethenyl]-(3R)-indolyloxy]benzoic acid Methyl ester

89112968.ptd 第620頁 128324089112968.ptd Page 620 1283240

C〇2MeC〇2Me

使3甲，基-4 —[N’一（2 一甲基苯基）脈基]苯乙酸（糊毫 ^二1· W毫莫耳）、4—[(3R)—比咯啶氧基]苯甲酸甲酯（324 笔克，ι·α毫莫耳）、EDC ·ΗΠ(33 7毫克，176毫莫耳）、 _t(237宅克，1· 75毫莫耳）、及Et3N(245毫 ίϊ)入ΤίΓ升)中之混合物在室溫 應此口物以Η2〇稀釋，並以Et〇Ac萃取。將萃取液以鹽水洗 滌，於NaJO4上乾燥，並蒸發。使殘留物經由於矽膠上利 用CHC13 - MeOH(l〇〇:1至50:1，v/v)作為洗提液進行管柱層 析，純化而得4-[W3 一甲氧基一 4—[N，—（2 一甲基笨基）脲曰 基]笨基乙醯基]-(3R) -吼咯啶氧基]笨甲酸曱酯（583毫 克，77%)的無色油。iH-NMR (CDC13) 5 2·〇6 —2·23 2Η)、2·30 (s，3Η)、3·58-3·89 (s&amp;m 系列，總計 12Η)、 4·95-4·99 (m，1Η)、6·75-7.00 (m，4Η)、713一7 3〇3,A-4-[N'-(2-methylphenyl)-yl]phenylacetic acid (p-M2), 4-[(3R)-pyrrolidineoxy Methyl benzoate (324 pg, ι·α mmol), EDC · ΗΠ (33 7 mg, 176 mmol), _t (237 克, 1.75 mmol), and Et3N (245) The mixture in the mixture was diluted at 室温2〇 at room temperature and extracted with Et〇Ac. The extract was washed with brine, dried over Na.sub.4, and evaporated. The residue was subjected to column chromatography using CHC13-MeOH (1 50: 1 to 50:1, v/v) as an eluent to obtain 4-[W3-methoxy- 4- [N,-(2-Methylphenyl)carbazide]] (3R)-indolyloxy] benzoic acid oxime ester (583 mg, 77%) as a colorless oil. iH-NMR (CDC13) 5 2·〇6 —2·23 2Η), 2·30 (s, 3Η), 3·58-3·89 (s&amp;m series, total 12Η), 4·95-4· 99 (m, 1Η), 6.75-7.00 (m, 4Η), 713-7 3〇

(m，5H)、7·52-7·57 (m，1H)、7·96-8.03 (m，3H); ESI m/z 518(MH1)。 ’ ’ 於4-[1 - [3-甲氧基-4 - [Ν’ -（2-甲基笨基）脲基]苯基乙酿 基]-（3R)-咄咯啶氧基]苯甲酸甲酯（ 583毫克，ι 13毫莫 耳）溶於THF(5毫升）之攪拌溶液中加入〇·5ν Na0H(5毫、 升），並使反應混合物迴流加熱3小時。於冷卻至室溫後， 將混合物倒入至冰的1 N HC1中，並於減壓下收集所產生之 沈澱物。使粗製固體自MeOH-CHCl3-Et2〇再結晶，而得1 π(m, 5H), 7·52-7·57 (m, 1H), 7.96-8.03 (m, 3H); ESI m/z 518 (MH1). ' ' in 4-[1 - [3-methoxy-4 -[Ν' -(2-methylphenyl)ureido]phenylethyl]](3R)-indolyloxy]benzene Methyl formate (583 mg, ι 13 mmol) was dissolved in THF (5 mL). After cooling to room temperature, the mixture was poured into ice 1 N HCl, and the resulting precipitate was collected under reduced pressure. The crude solid was recrystallized from MeOH-CHCl3-Et2 to give 1 π

1283240 五、發明說明（617) (297毫克，52%)之白色結晶粉末。熔點1 58- 1 62 °C ; 111-關1?(仰30-(16)6 2,〇8-2.31(3及111系列，總計51〇、 3· 54-3· 89 (m 系列，總計9H)、5· 1 1 及5· 20 (各m，總計 1H)、6·72-7.17 (m 系列，總計6H)、7.78-7.80 (m，1H) 、7·87-7·90 (m，2H)、7·98-8·02 (m，2H)、8·46-8·47 (m，1Η)、8·55-8·57 (m，1Η)、12·66 (br s，1Η) ;ESI m/z 5 04(MH1) ; C28H29N3 06 · 1/4H20 之分析計算值： C，66. 19 ; H，5· 85 ; N，8· 27。實測值：C，66· 12 ; H， 5. 77 ； N, 8. 21 〇 實施例178 4-[1 -[4-[Ν’ -（2-氣苯基）脲基]-3-甲氧苯基乙醯基]-(3R) -咄咯啶氧基]苯甲酸1283240 V. Inventive Note (617) (297 mg, 52%) of a white crystalline powder. Melting point 1 58- 1 62 °C; 111-off 1? (Yang 30-(16)6 2, 〇8-2.31 (3 and 111 series, total 51〇, 3· 54-3· 89 (m series, total 9H), 5·1 1 and 5· 20 (each m, total 1H), 6.72-7.17 (m series, total 6H), 7.78-7.80 (m, 1H), 7·87-7·90 (m , 2H), 7·98-8·02 (m, 2H), 8·46-8·47 (m, 1Η), 8·55-8·57 (m, 1Η), 12·66 (br s, 1Η) ; ESI m/z 5 04(MH1) ; C28H29N3 06 · 1/4H20 Analytical calculated value: C, 66. 19 ; H, 5 · 85 ; N, 8 · 27. Found: C, 66· 12 H, 5. 77 ; N, 8. 21 〇 Example 178 4-[1 -[4-[Ν' -(2-Phenylphenyl)ureido]-3-methoxyphenylethenyl]- (3R)-indolyloxy]benzoic acid

186186

Cl Η Μ ΟΜθ 4-[1_[4-[Ν’ -（2 -氣苯基）脲基]-3-曱氧苯基乙醯基]-(3R) -吼咯啶氧基]苯甲酸甲酯Cl Η Μ ΟΜ θ 4-[1_[4-[Ν' -(2-Phenylphenyl)ureido]-3-indolylphenylethyl]-(3R)-indolyloxy]benzoic acid ester

使4-[Ν’-（2-氯苯基）脲基]一 3-甲氧笨乙酸（498毫克， 1.49毫莫耳）、4- [(3R) -咄咯啶氧基]苯f酸甲酯（329毫 克，1· 49毫莫耳）、EDC · HC 1 (342毫克，〗· 78毫莫耳）、 H0BU241 毫克，1· 78 毫莫耳）、&amp;Et3N(25〇 毫升，j 79 毫4-[Ν'-(2-Chlorophenyl)ureido] 3-methoxybenzoic acid (498 mg, 1.49 mmol), 4-[(3R)-indolyloxy]benzenef-acid Methyl ester (329 mg, 1. 49 mmol), EDC · HC 1 (342 mg, 〗 · 78 mmol), H0BU 241 mg, 1. 78 mmol, &amp; Et3N (25 mL, j 79 millimeters

89112968.ptd 第622頁 1283240 &quot;ΐ、發明說明（618) &quot;&quot; ' ' 莫耳）於THF(10毫升）中之混合物在室溫下攪拌隔夜。 應混合物以仏0稀釋^，並以Et0Ac萃取。將萃取液以鹽水洗 滌，於NaJO4上乾燥，並蒸發。使殘留物經由於矽膠上利 用CHCl3-MeOH(100 : 1至50 : 1，v/v)作為洗提液進行管柱層 析，純化而得4 - [1-[4 - [N，-（2-氯苯基）脲基]一3 一甲氧笨^ 乙醯基]-（3R)-咄咯啶氧基]苯甲酸甲酯（561毫克，7〇%)二 白色泡沫。1H-NMR (CDC13) 3 2·05-2.34 (m，2H)、 3·59 - 4.07 (s 及 m 系列，總計 12H)、4.97一5〇2 (m，1H)、 6·75-6·86 (πι，4H)、6·94-7·00 (m，1H)、7·22-7 33 (m，2Η)、7·5 9-7.66 (m，2Η)、7·92-7·99 (m，3Η)、 8·19-8·22 (m, 1H); ESI m/z 538 (ΜΗ1)。 於4-[1-[4-[Ν’ - (2-氯苯基）脲基]一3 一甲氧苯基乙醯基] -(3R) -吼σ各唆氧基]苯甲酸甲酯（561毫克，1·〇4毫莫耳）溶 於丁 HF(5毫升）之攪拌溶液中加入〇·5Ν NaOH(5毫升），並使 反應混合物迴流加熱5小時。於冷卻至室溫後，將混合物 倒入至冰的1 N H C1中，並於減壓下收集所產生之沈澱物。 使粗製固體自MeOH-CHCl3 -Et20再結晶，而得186(361毫 克，66%)之白色結晶粉末。熔點1 9 3-1 94 °C ; UMR (DMS0-d6)5 2·06-2·28 (m，2H)、3·58-3·62 (m，4H)、 3·71 - 3·76 (m， 1Η)、3·83 - 3·89 (s 及 m 系列，總計 4Η)、 5·12 及 5·20 (各m，總計 1H)、6·74-6·78 (m，1H)、6·90 -6·91 (m，1H)、7·0卜7.05 (m，3H)、7·27-7.30 (m， 1Η)、7·43-7·45 (m，1Η)、7·88-7·98 (m，3Η)、8·08-8·10 (m，1H)、8·89-8·96 (m，2H)、12·67 (br s，89112968.ptd Page 622 1283240 &quot;ΐ,发明说明(618) &quot;&quot; ''Mole) A mixture of THF (10 ml) was stirred at room temperature overnight. The mixture should be diluted with 仏0 and extracted with EtOAc. The extract was washed with brine, dried over Na.sub.4, and evaporated. The residue was subjected to column chromatography using CHCl3-MeOH (100:1 to 50:1, v/v) as an eluent, and purified to give 4-[1-[4 - [N,-( 2-Chlorophenyl)ureido]-3-methoxyxo(ethyl)-(3R)-decalyloxy]benzoic acid methyl ester (561 mg, 7 %) was obtained as a white foam. 1H-NMR (CDC13) 3 2·05-2.34 (m, 2H), 3·59 - 4.07 (s and m series, total 12H), 4.97-5 〇2 (m, 1H), 6·75-6· 86 (πι,4H),6·94-7·00 (m,1H), 7·22-7 33 (m,2Η), 7·5 9-7.66 (m,2Η), 7.92-7· 99 (m, 3Η), 8·19-8·22 (m, 1H); ESI m/z 538 (ΜΗ1). 4-[1-[4-[4-[Ν' - (2-Chlorophenyl)ureido]- 3-methoxyphenylethyl]-(3R)-吼σ each methoxy]benzoic acid methyl ester (561 mg, 1·4 mmol) was added to a stirred solution of EtOAc (5 mL). EtOAc······ After cooling to room temperature, the mixture was poured into ice 1 N H C1, and the resulting precipitate was collected under reduced pressure. The crude solid was recrystallized from MeOH-CHCl3 -EtOAc to yield </RTI> </RTI> </ RTI> Melting point 1 9 3-1 94 °C ; UMR (DMS0-d6) 5 2·06-2·28 (m, 2H), 3·58-3·62 (m, 4H), 3·71 - 3·76 (m, 1Η), 3·83 - 3·89 (s and m series, total 4Η), 5·12 and 5·20 (each m, total 1H), 6·74-6·78 (m, 1H) , 6·90 -6·91 (m, 1H), 7·0 Bu 7.05 (m, 3H), 7·27-7.30 (m, 1Η), 7·43-7·45 (m, 1Η), 7 ·88-7·98 (m, 3Η), 8·08-8·10 (m, 1H), 8·89-8·96 (m, 2H), 12·67 (br s,

89112968.ptd 第623頁 128324089112968.ptd Page 623 1283240

1H)’ ESI ra/z 524(M+ + 1)’ C27H26C1N3 06 ·1/4Η2〇 之分析計算 值：C，6ί· 36 ; H，5· 05 ; N，7. 95 ; Cl，6· 71。實測值： C，61· 49 ; H，5· 11 ; N，7· 72 ; C1，7. 08。 · 實施例1 7 9 4- [1-[4 - [1^’-（2-溴苯基）脲基]-3-甲氧苯基乙醯基]—(31^) -咄咯啶氧基]苯甲酸 P&quot;O~c〇2h n〇1H)' ESI ra/z 524(M+ + 1)' C27H26C1N3 06 ·1/4Η2〇 Analytical calculation: C,6ί· 36 ; H,5· 05 ; N,7. 95 ; Cl,6·71. Found: C, 61·49; H, 5·11; N, 7·72; C1, 7.08. · Example 1 7 9 4- [1-[4 - [1^'-(2-Bromophenyl)ureido]-3-methoxyphenylethenyl]-(31^)-pyrrolidineoxy Benzoic acid P&quot;O~c〇2h n〇

Br Μ Η 〇Μβ 187 4-[1 -[4-[Ν’ -（2-溴苯基）脲基]-3-甲氧苯基乙醯基]— (3R) -咄咯啶氧基]苯甲酸甲酯Br Μ Η 〇Μβ 187 4-[1 -[4-[Ν' -(2-Bromophenyl)ureido]-3-methoxyphenylethenyl]-(3R)-indolyloxy] Methyl benzoate

使4- [Ν’ -（2 -溴苯基）脲基]- 3-甲氧苯乙酸（460毫克， 1.21毫莫耳）、4 - [(3R) -吡咯啶氧基]苯曱酸曱酯（269毫 克’1.21毫莫耳）、EDC*HC1(280毫克，1·46毫莫耳）、 H0Bt(197 毫克，1· 46 毫莫耳）、及Et3N(205 毫升，1· 47 毫 莫耳）於THF(10毫升）中之混合物在室溫下擾拌隔夜。將反 應混合物以％ 0稀釋’並以E10 A c萃取。將萃取液以鹽水洗 滌，於NaJO4上乾燥，並蒸發。使殘留物經由於矽膠上利 用CHC13 - MeOH(100:l至60:1，v/v)作為洗提液進行管柱層 析，純化而得4-[1-[4-[Ν’ -（2-溴笨基）脲基]一3一曱氧苯基 乙醯基]-（3R) -咄咯啶氧基]苯甲酸甲酯（555毫克，78%)的4-[Ν'-(2-Bromophenyl)ureido]-3-methoxyphenylacetic acid (460 mg, 1.21 mmol), 4-[(3R)-pyrrolidinyloxy]benzoate Ester (269 mg '1.21 mmol), EDC*HC1 (280 mg, 1.46 mmol), H0Bt (197 mg, 1.46 mmol), and Et3N (205 ml, 1.47 mmol) The mixture in THF (10 mL) was stirred overnight at room temperature. The reaction mixture was diluted at % 0 and extracted with E10 A c. The extract was washed with brine, dried over Na.sub.4, and evaporated. The residue was subjected to column chromatography using CHC13-MeOH (100:1 to 60:1, v/v) as an eluent, and purified to give 4-[1-[4-[Ν'-( 2-bromophenyl)ureido]-trimethyloxyphenylacetamido]-(3R)-indolyloxy]benzoic acid methyl ester (555 mg, 78%)

89112968.ptd 第624頁 1283240 五、發明說明（620) 白色泡沫。1Η-NMR (CDC13) (5 2· 05-2· 33 (m，2H)、89112968.ptd Page 624 1283240 V. INSTRUCTIONS (620) White foam. 1Η-NMR (CDC13) (5 2· 05-2· 33 (m, 2H),

3·60-4·07 (s 及m 系列，總計12H)、4·96-5·〇ΐ (m，in)、 6·76-6·93 (m，5H)、7·28-7·30 (m，1H)、7·48-7·58 (m，3Η)、7·92-7·99 (m，3Η)、8·12-8·16 (m，ih); ESI m/z 582(M+)。 於4-[卜[4-[Ν’ -（2-溴苯基）脲基]-3-甲氧笨基乙醯基]3·60-4·07 (s and m series, total 12H), 4·96-5·〇ΐ (m,in), 6·76-6·93 (m,5H), 7·28-7· 30 (m, 1H), 7·48-7·58 (m, 3Η), 7.92-7·99 (m, 3Η), 8·12-8·16 (m, ih); ESI m/z 582 (M+). 4-[Bu[4-[Ν'-(2-bromophenyl)ureido]-3-methoxyphenyl)]

-（3R)-吼咯啶氧基]苯甲酸曱酯（ 55 5毫克，0· 95毫莫耳）溶 於THF(5毫升）之攪拌溶液中加入〇·5Ν Na0H(5毫升），並使 反應混合物迴流加熱5小時。於冷卻至室溫後，將混合物 倒入至冰的1 N H C1中’並於減壓下收集所產生之沈殿物。 使粗製固體自Me0H-CHCl3-Et20再結晶，而得187(330毫 克，61%)之白色結晶粉末。熔點1 75-1 77 °C ; l-NMR (DMS0-d6) 5 1.99-2.27 (m，2H)、3·56-3·63 (m，4H)、 3.71-3.76 (m，1H)、3·83-3·89 (s 及 m 系列，4H)、5. 12 及5.20 (各m，總計 1H)、6·74-6·78 (m，1H)、6·89-7·〇5 (m，4H)、7.30-7·35 (m，1H)、7·59-7·61 (m，1H)、 7 · 8 8 - 7 · 9 8 (m，4 H)、8 · 7 4 - 8 · 7 6 (m，1H)、8 · 9 2 - 8 · 9 5 (m，1H)、12.68 (br s，1H); ESI m/z 569 (MH1); C27H26BrN3 06 之分析計算值·· C，57. 05 ; H，4. 61 ; N，7. 39 ;Br，14· 06。實測值·· C，56· 91 ; H，4· 66 ; N，7· 20 ;-(3R)-吼 吼 啶 氧基 ] ] 55 55 55 55 55 55 55 55 55 55 55 55 55 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 The reaction mixture was heated under reflux for 5 hours. After cooling to room temperature, the mixture was poured into 1 N H C1 of ice and the resulting precipitate was collected under reduced pressure. The crude solid was recrystallized from MeOH (EtOAc) (EtOAc) Melting point 1 75-1 77 °C; l-NMR (DMS0-d6) 5 1.99-2.27 (m, 2H), 3·56-3·63 (m, 4H), 3.71-3.76 (m, 1H), 3 ·83-3·89 (s and m series, 4H), 5.12 and 5.20 (each m, total 1H), 6.74-6.78 (m, 1H), 6.89-7·〇5 ( m, 4H), 7.30-7·35 (m, 1H), 7·59-7·61 (m, 1H), 7 · 8 8 - 7 · 9 8 (m, 4 H), 8 · 7 4 - 8 · 7 6 (m, 1H), 8 · 9 2 - 8 · 9 5 (m, 1H), 12.68 (br s, 1H); ESI m/z 569 (MH1); C27H26BrN3 06 analytical calculation ·· C, 57. 05 ; H, 4. 61 ; N, 7. 39 ; Br, 14.06. Measured value·· C, 56· 91 ; H, 4· 66 ; N, 7· 20 ;

Br，1 4· 59 o 化合物188至196之合成實施例 實施例1 8 0Br, 1 4 · 59 o Synthesis Examples of Compounds 188 to 196 Example 1 8 0

89112968.ptd 第625頁 1283240 五、發明說明（621)89112968.ptd Page 625 1283240 V. Description of invention (621)

188 將1克之Tentagel PHB樹脂（載入量〇· 29毫莫耳/克）泡 於DMF 25毫升，並加入Fmoc -（4-羧甲基）六氫咄啶（318毫 克’ 〇 · 8 7毫莫耳）。將樹脂振搖5分鐘，然後加入D〗c ( 2 2 〇 毫克，0.27毫升，1.74毫莫耳）及DMAP(106毫克，〇·87毫 莫耳），並使樹脂振搖24小時。 將樹脂排液，並以DMF(3x)、CH30H(3x)及CH2C12(3x)洗 務’然後於真空中乾燥。此樹脂的溴苯藍試驗為陰性。將 樹脂泡於20%六氫咄啶溶於DMF，並振搖4小時。將樹脂排 液，並以 DMF(3x)、CH40H(3x)及 CH3C12(3x)洗滌，然後於 真空中乾燥。此樹脂的溴苯藍試驗為陽性。將樹脂泡於2 5 耄升之DMF中，並加入Fmoc-L-嗎福琳-2-叛酸（307毫克， 〇 · 8 7宅莫耳）。將樹脂振搖5分鐘，然後加入p y β r 〇 p (4 〇 6毫 克，〇·87莫耳）及DIEA(123毫克，0·15毫升，〇·87毫莫 耳），並使樹脂振搖24小時。 將樹脂排液，並以DMF(3x)、CH30H(3x)及CH2C12 (3χ)洗 滌，然後於真空中乾燥。此樹脂的溴苯藍試驗為陰性。將 樹脂泡於20%六氫咄啶溶於DMF，並振搖4小時。將樹脂排 液，並以DMF(3x)、CH30H(3x)及 CH2C12(3x)洗滌，然後於 真空中乾燥。此樹脂的溴苯藍試驗為陽性。將樹脂泡於2 5188 1 gram of Tentagel PHB resin (loading amount 29 29 mmol/g) was bubbled into DMF 25 ml, and Fmoc-(4-carboxymethyl)hexahydroacridine (318 mg' 〇·8 7 m was added. Moore). The resin was shaken for 5 minutes, then D C (2 2 毫克 mg, 0.27 mL, 1.74 mmol) and DMAP (106 mg, 〇·87 mmol) were added and the resin was shaken for 24 hours. The resin was drained and washed with DMF (3x), CH30H (3x) and CH2C12 (3x) and then dried in vacuo. This resin was negative for the bromobenzene blue test. The resin was soaked in 20% hexahydroacridine in DMF and shaken for 4 hours. The resin was drained and washed with DMF (3x), CH40H (3x) and CH3C12 (3x) and then dried in vacuo. This resin was positive for the bromobenzene blue test. The resin was soaked in 25 liters of DMF and added to Fmoc-L-Walfolin-2-Resin (307 mg, 〇 · 8 7 house Mo). The resin was shaken for 5 minutes, then py β r 〇p (4 〇 6 mg, 〇·87 mol) and DIEA (123 mg, 0·15 ml, 〇·87 mmol) were added and the resin was shaken. 24 hours. The resin was drained and washed with DMF (3x), CH30H (3x) and CH2C12 (3 χ) and then dried in vacuo. This resin was negative for the bromobenzene blue test. The resin was soaked in 20% hexahydroacridine in DMF and shaken for 4 hours. The resin was drained and washed with DMF (3x), CH30H (3x) and CH2C12 (3x) and then dried in vacuo. This resin was positive for the bromobenzene blue test. Soak the resin at 2 5

89112968.ptd 第626頁 1283240 五、發明說明（622) 毫升之DMF中，並加入4-鄰甲苯脲基苯乙酸（247毫克， 0.87¾:莫耳）’及使樹脂振搖5分鐘。加入pyBr〇p(4〇6毫 克，0.87莫耳）及DIEA (123毫克，〇·15毫升，0.87毫莫 耳），並使樹脂振搖2 4小時。 將樹脂排液，並以DMF(3x)、CH3OH(3x)及CH2C12 (3χ)洗 滌，然後於真空中乾燥。咚樹脂的溴苯藍試驗為陰性。然 後將樹脂泡於90% TFA溶於CH2C12，並振搖4小時。將樹脂 排液’並收集洗提液。將樹脂泡於新鮮的CIj2c“中，並振 搖3 0分鐘。將樹脂排液，收集洗提液，並與第一部分結 合。將溶劑於真空中移除，並使殘留物自乙酸乙酯—己烷 再結晶，而得85毫克188。 實施例1 8 189112968.ptd Page 626 1283240 V. INSTRUCTIONS (622) In 4 ml of DMF, 4-o-tolyl-phenylphenylacetic acid (247 mg, 0.873⁄4: mole) was added and the resin was shaken for 5 minutes. PyrBrP (4 〇 6 mg, 0.87 mol) and DIEA (123 mg, 〇15 ml, 0.87 mmol) were added and the resin was shaken for 24 hours. The resin was drained and washed with DMF (3x), CH3OH (3x) and CH2C12 (3?) and then dried in vacuo. The bromobenzene blue test of the terpene resin was negative. The resin was then soaked in 90% TFA in CH2C12 and shaken for 4 hours. Drain the resin' and collect the eluent. The resin was bubbled into fresh CIj2c and shaken for 30 minutes. The resin was drained, the eluent was collected and combined with the first part. The solvent was removed in vacuo and the residue was taken from ethyl acetate. The hexane was recrystallized to give 85 mg of 188. Example 1 8 1

將1克之Tentagel PHB樹脂（載入量〇· 29毫莫耳/克）泡 於DMF 25毫升，並加入Fmoc-(4-羧甲基）六氫咄啶（318毫 克，0· 87毫莫耳）。將樹脂振搖5分鐘，然後加入dic(220 毫克’0·27毫升’1.74毫莫耳）及])maP(1〇6毫克，0· 87毫 莫耳）’並使樹脂振搖2 4小時。 將樹脂排液，並以DMF(3x)、CH3OH(3x)及CH2C12(3x)洗1 gram of Tentagel PHB resin (loading amount 29 29 mmol/g) was bubbled into DMF 25 ml, and Fmoc-(4-carboxymethyl)hexahydroacridine (318 mg, 0·87 mmol) was added. ). The resin was shaken for 5 minutes, then dic (220 mg '0 · 27 ml '1.74 mmol) and ]) maP (1 〇 6 mg, 0·87 mmol) and the resin was shaken for 24 hours. . Drain the resin and wash with DMF (3x), CH3OH (3x) and CH2C12 (3x)

89112968.ptd 第627頁 128324089112968.ptd Page 627 1283240

滌，然後於真空中乾燥。此樹脂的漠苯藍試驗為陰性。將 樹脂泡於20%六氫咄啶溶於DMF，並振搖4小時。將樹脂排 液，並以DMF(3x)、CH30H(3x)及CH2C12(3x)洗滌，然後於 ，空中乾燥。此樹脂的溴苯藍試驗為陽性。將樹脂泡於25 毫升之DMF中’並加入Fmoc-L-4-苯基脯胺酸（3〇7毫克， 0.87毫莫耳）。將樹脂振搖5分鐘，然後加入pyBr〇p(4〇6毫 克’ 0. 87毫莫耳）及DIEAC123毫克，〇. 15毫升，〇. 87毫莫 耳），並使樹脂振搖24小時。 、 將樹脂排液，並以DMF(3x)、CH3OH(3x)及CH2C12 (3x)洗 滌，然後於真空中乾燥。此樹脂的溴苯藍試驗為陰性。將 樹脂泡於20%六氫咄啶溶於DMF，並振搖4小時。將樹脂排 液，並以DMF(3x)、CH3OH(3x)及 CH2C12(3x)洗滌，然後於 真空中乾燥。此樹脂的漠苯藍試驗為陽性。將樹脂泡於2 5 毫升之DMF中，並加入4-鄰甲苯脲基苯乙酸（247毫克， 0.87¾莫耳）’及使樹脂振搖5分鐘。加入毫 克，〇·87毫莫耳）及DIEA(123毫克，0.15毫升，〇·87毫莫 耳），並使樹脂振搖24小時。 將樹脂排液，並以DMF(3x)、CH3OH(3x)及CH2C12 (3χ)洗 滌，然後於真空中乾燥。此樹脂的溴苯藍試驗為陰性。然 後將樹脂泡於90% TFA溶於CH2C12，並振搖4小時。將樹脂 排液，並收集洗提液。將樹脂泡於新鮮的CH2C12中，並振 搖3 0分鐘。將樹脂排液，收集洗提液，並與第一部分結 合。將溶劑於真空中移除，並使殘留物自乙酸乙酯-己烷 再結晶，而得82毫克189。Dilute and then dry in vacuum. This resin was negative for the desert blue test. The resin was soaked in 20% hexahydroacridine in DMF and shaken for 4 hours. The resin was drained and washed with DMF (3x), CH30H (3x) and CH2C12 (3x) and then dried in the air. This resin was positive for the bromobenzene blue test. The resin was soaked in 25 ml of DMF' and Fmoc-L-4-phenylglycine (3 〇 7 mg, 0.87 mmol) was added. The resin was shaken for 5 minutes, then pyBr〇p (4 〇 6 mg </ </ RTI> 0. 87 mM) and DIEAC (123 mg, 〇. 15 ml, 〇. 87 mmol) were added and the resin was shaken for 24 hours. The resin was drained and washed with DMF (3x), CH3OH (3x) and CH2C12 (3x), then dried in vacuo. This resin was negative for the bromobenzene blue test. The resin was soaked in 20% hexahydroacridine in DMF and shaken for 4 hours. The resin was drained and washed with DMF (3x), CH3OH (3x) and CH2C12 (3x) and then dried in vacuo. This resin was positive for the indigo blue test. The resin was bubbled into 25 ml of DMF, and 4-o-tolyl-phenylphenylacetic acid (247 mg, 0.873⁄4 mol) was added and the resin was shaken for 5 minutes. Add milligrams (〇·87 mmol) and DIEA (123 mg, 0.15 ml, 〇·87 mmol) and shake the resin for 24 hours. The resin was drained and washed with DMF (3x), CH3OH (3x) and CH2C12 (3?) and then dried in vacuo. This resin was negative for the bromobenzene blue test. The resin was then soaked in 90% TFA in CH2C12 and shaken for 4 hours. The resin was drained and the eluent was collected. The resin was soaked in fresh CH2C12 and shaken for 30 minutes. The resin was drained and the eluate was collected and combined with the first part. The solvent was removed in vacuo and the residue was crystallised from ethyl acetate-hexanesiel

89112968.ptd 第628頁 1283240 五、發明說明（624) 實施例1 8 289112968.ptd Page 628 1283240 V. INSTRUCTIONS (624) EXAMPLE 1 8 2

將1克之了61^3忌61?0樹脂（载入量〇29毫莫耳/克）泡 於DMF 25毫升，並加入Fmoc-4-羧曱基六氫吼畊（318毫 克’0.87耄莫耳）。將樹脂振搖5分鐘，加入j)iC(220毫 克，0.27毫升，1.74毫莫耳）及DMAPC106毫克，〇· 87毫莫 耳），並使樹脂振搖24小時。 、 將樹脂排液，並以DMF(3x)、CH30H(3x)及CH2C12 (3χ)洗 滌’然後於真空中乾燥。此樹脂的溴苯藍試驗為陰性。將 樹脂泡於20%六氫咄啶溶於DMF，並振搖4小時。將樹脂排 液，並以 DMF(3x)、CH30H(3x)及 CH2C12(3x)洗滌，然後於 真空中乾燥。此樹脂的溴苯藍試驗為陽性。將樹脂泡於2 5 毫升之0%?中，並加入？111〇(：-1^-脯胺酸（294毫克，〇87毫莫 耳）。將樹脂振搖5分鐘，然後加入P y B r ο P ( 4 0 6毫克，〇 8 7 毫莫耳）及DIEA (123毫克，0.15毫升，0.87毫莫耳），並使 樹脂振搖24小時。 將樹脂排液，並以DMF(3x)、CH30H(3x)及CH2C12 (3x)洗 永 τ' ’然後於真空中乾燦。此樹脂的 &gt;臭苯藍試驗為险性。將 樹脂泡於20%六氫咄啶溶於DMF，並振搖4小時。將樹脂排1 gram of 61^3 bogey 61?0 resin (loading amount 〇29 mmol/g) soaked in DMF 25 ml, and added Fmoc-4-carboxyindole hexahydro hydrazine (318 mg '0.87 耄 Mo ear). The resin was shaken for 5 minutes, and j)iC (220 mg, 0.27 ml, 1.74 mmol) and DMAPC (106 mg, 〇·87 mmol) were added, and the resin was shaken for 24 hours. The resin was drained and washed with DMF (3x), CH30H (3x) and CH2C12 (3 χ) and then dried in vacuo. This resin was negative for the bromobenzene blue test. The resin was soaked in 20% hexahydroacridine in DMF and shaken for 4 hours. The resin was drained and washed with DMF (3x), CH30H (3x) and CH2C12 (3x) and then dried in vacuo. This resin was positive for the bromobenzene blue test. Soak the resin in 0% of 25 ml and add it? 111〇(:-1^-proline (294 mg, 〇87 mmol). Shake the resin for 5 minutes, then add P y B r ο P ( 4 6 6 mg, 〇 8 7 mmol) And DIEA (123 mg, 0.15 ml, 0.87 mmol), and shake the resin for 24 hours. Drain the resin and wash it with DMF (3x), CH30H (3x) and CH2C12 (3x) and then τ' ' Dry in vacuum. The resin's odor blue test is dangerous. The resin is soaked in 20% hexahydroguanidine dissolved in DMF and shaken for 4 hours.

89112968.ptd 第 629 頁 1283240 五、發明說明（625) 液，並以DMF(3x)、CH3OH(3x)及CH2C12(3x)洗滌，然後於 真空中乾燥。此樹脂的溴苯藍試驗為陽性。將樹脂泡於2 5 毫升之DMF中，並加入4-鄰甲苯脲基笨乙酸（247毫克， 0.87¾:莫耳）’及使樹脂振搖5分鐘。加入pygrop(4〇6毫 克，0.87毫莫耳）及DIEA(123毫克，0·15毫升，〇.87毫莫 耳），並使樹脂振搖24小時。 將樹脂排液，並以DMF(3x)、CH3OH(3x)及CH2C12 (3χ)洗 滌，然後於真空中乾燥。此樹脂的溴苯藍試驗為陰性。然 後將樹脂泡於90% TFA溶於CH2C12，並振搖4小時。將樹脂 排液，並收集洗提液。將樹脂泡於新鮮的⑶,、中，並振 搖3 0分鐘。將樹脂排液，收集洗提液，並與第一部分結 合。將溶劑於真空中移除，並使殘留物自乙酸乙酯-己烷 再結晶’而得78毫克190。 實施例1 8 389112968.ptd Page 629 1283240 V. Inventive Note (625) Liquid, washed with DMF (3x), CH3OH (3x) and CH2C12 (3x), then dried in vacuo. This resin was positive for the bromobenzene blue test. The resin was soaked in 25 ml of DMF, and 4-o-tolyluridoacetic acid (247 mg, 0.873⁄4:m) was added and the resin was shaken for 5 minutes. Pygrop (4 〇 6 mg, 0.87 mmol) and DIEA (123 mg, 0.15 ml, 〇. 87 mmol) were added and the resin was shaken for 24 hours. The resin was drained and washed with DMF (3x), CH3OH (3x) and CH2C12 (3?) and then dried in vacuo. This resin was negative for the bromobenzene blue test. The resin was then soaked in 90% TFA in CH2C12 and shaken for 4 hours. The resin was drained and the eluent was collected. The resin was soaked in fresh (3), medium, and shaken for 30 minutes. The resin was drained and the eluate was collected and combined with the first part. The solvent was removed in vacuo and the residue was crystallised from ethyl acetate-hexane to afford s. Example 1 8 3

將1克之Tentagel PHB樹脂（載入量〇· 29毫莫耳/克）泡 於DMF 25毫升，並加、Fm〇c—異呱啶酸（3〇6毫克，〇· 87毫 莫耳）°將樹脂振搖5分鐘，然後加入DIC( 220毫克，〇· 27 毫升’ 1· 74毫莫耳）及DMAP(1〇6毫克，〇·87毫莫耳），並使1 gram of Tentagel PHB resin (loading amount 29 29 mmol/g) was soaked in DMF 25 ml, and added, Fm〇c-isoxamic acid (3〇6 mg, 〇·87 mmol) The resin was shaken for 5 minutes, then DIC (220 mg, 〇 · 27 ml '1.77 mmol) and DMAP (1 〇 6 mg, 〇·87 mmol) were added and

89112968.ptd 第630頁 1283240 發明說明（626) 樹脂振搖2 4小時。 將樹脂排液，並以DMF(3x)、CH30H(3x)及CH2C12 (3x)洗 滌’然後於真空中乾燥。此樹脂的溴笨藍試驗為2陰性。將 樹脂泡於20%六氫咄啶溶於DMF，並振搖4小時。將樹脂排 液，並以DMF(3x)、CH30H(3x)及CH2C12(3x)洗條，^後曰於 真空中乾燥。此樹脂的溴苯藍試驗為陽性。將樹脂泡於2 $ t升之DMF中，並加入Fmoc-L -脯胺酸（294毫克，q 87毫莫 耳）。將樹脂振搖5分鐘，加入PyBroP( 406毫龙，〇 π毫莫 耳）及DIEA(123毫克，0· 15毫升，0· 87毫莫耳），並使樹脂 振搖2 4小時。 將樹脂排液，並以MF(3x)、CH30H(3x)及CH2C12 (3χ)洗 滌，然後於真空中乾燥。此樹脂的溴苯藍試驗為陰性。將 樹脂泡於20%六氫咄啶溶於DMF，並振搖4小時。將樹脂排 液，並以DMF(3x)、CH30H(3x)及CH2C12(3x)洗滌，然後於 真空中乾燥。此樹脂的漠苯藍試驗為陽性。將樹脂泡於2 5 毫升之DMF中，並加入4-鄰甲苯脲基苯乙酸（247亳克， 0.87¾莫耳）’及使樹脂振搖5分鐘。加入PyBr〇p(4〇6毫 克，〇·87毫莫耳）及DIEAC123毫克，0.15毫升，〇·87毫莫 耳），並使樹脂振搖24小時。 將樹脂排液，並以DMF(3x)、CH3OH(3x)及CH2C12 (3χ)洗 務’然後於真空中乾無。此樹脂的 &gt;臭苯監試驗為陰性。然 後將樹脂泡於90% TFA溶於CH2C12，並振搖4小時。將樹脂 排液，並收集洗提液。將樹脂泡於新鮮的CH2C12中，並振 搖3 0分鐘。將樹脂排液，收集洗提液，並與第一部分結89112968.ptd Page 630 1283240 Description of the invention (626) The resin was shaken for 24 hours. The resin was drained and washed with DMF (3x), CH30H (3x) and CH2C12 (3x) and then dried in vacuo. The bromine blue test of this resin was 2 negative. The resin was soaked in 20% hexahydroacridine in DMF and shaken for 4 hours. The resin was drained and washed with DMF (3x), CH30H (3x) and CH2C12 (3x), then dried in vacuo. This resin was positive for the bromobenzene blue test. The resin was bubbled into 2 D of DMF and Fmoc-L-proline (294 mg, q 87 mmol) was added. The resin was shaken for 5 minutes, PyBroP (406 mAh, π π mmol) and DIEA (123 mg, 0.25 ml, 0·87 mmol) were added, and the resin was shaken for 24 hours. The resin was drained and washed with MF (3x), CH30H (3x) and CH2C12 (3 χ) and then dried in vacuo. This resin was negative for the bromobenzene blue test. The resin was soaked in 20% hexahydroacridine in DMF and shaken for 4 hours. The resin was drained and washed with DMF (3x), CH30H (3x) and CH2C12 (3x) and then dried in vacuo. This resin was positive for the indigo blue test. The resin was bubbled into 25 ml of DMF and 4-o-tolyl-phenylphenylacetic acid (247 g, 0.873⁄4 mol) was added and the resin was shaken for 5 minutes. PyBr〇p (4〇6 mg, 〇·87 mmol) and DIEAC (123 mg, 0.15 ml, 〇·87 mmol) were added and the resin was shaken for 24 hours. The resin was drained and washed with DMF (3x), CH3OH (3x) and CH2C12 (3 s) and then dried in vacuo. The &gt; odor benzene test of this resin was negative. The resin was then soaked in 90% TFA in CH2C12 and shaken for 4 hours. The resin was drained and the eluent was collected. The resin was soaked in fresh CH2C12 and shaken for 30 minutes. Drain the resin, collect the eluent, and combine with the first part

1283240 五、發明說明（627) 合。將溶劑於真空中移除，並使殘留物自乙酸乙酯—己烷 再結晶，而得73毫克191。 實施例1841283240 V. Description of invention (627). The solvent was removed in vacuo and the residue was crystallised from EtOAc EtOAc Example 184

將1克之了61^8261?1^樹脂（載入量〇.29毫莫耳/克）泡 於DMF 25毫升，並加入Fmoc-（4-羧甲基）六氫咄啶（31 8毫 克’ 0 · 8 7耄莫耳）。將樹脂振搖5分鐘，加入j) I c ( 2 2 0毫 克，〇·27毫升，1.74毫莫耳）及DMAP(106毫克，〇. 87毫莫 耳），並使樹脂振搖24小時。 將樹脂排液，並以DMF(3x)、CH30H(3x)及CH2C12 (3x)洗 滌’然後於真空中乾燥。此樹脂的溴苯藍試驗為陰性。將 樹脂泡於20%六氫咄啶溶於DMF，並振搖4小時。將樹脂排 液，並以 DMF ( 3x)、CH3OH (3x)及CH2C12 ( 3x)洗滌，然後於 真空中乾燥。此樹脂的溴苯藍試驗為陽性。將樹脂泡於25 毫升之DMF中，並加入Fmoc-L -脯胺酸（ 2 94毫克，〇· 87毫莫 耳），將樹脂振搖5分鐘，然後加入pyRrop(4〇β毫克，〇 毫莫耳）及DIEA(123毫克’0.15毫升，〇·87毫莫耳），並使 樹脂振搖2 4小時。 將樹脂排液，並以DMF(3x)、CH3〇H(3x)及CH2C12 (3χ)洗 條，然後於真空中乾燥。此樹脂的溴苯藍試驗為陰性。將1 gram of 61^8261?1^ resin (loading amount 29.29 mmol/g) was bubbled into DMF 25 ml, and Fmoc-(4-carboxymethyl)hexahydroacridine (31 8 mg' was added. 0 · 8 7耄莫耳). The resin was shaken for 5 minutes, and j) I c (2 20 mg, 〇·27 ml, 1.74 mmol) and DMAP (106 mg, 〇. 87 mmol) were added, and the resin was shaken for 24 hours. The resin was drained and washed with DMF (3x), CH30H (3x) and CH2C12 (3x) and then dried in vacuo. This resin was negative for the bromobenzene blue test. The resin was soaked in 20% hexahydroacridine in DMF and shaken for 4 hours. The resin was drained and washed with DMF (3x), CH3OH (3x) and CH2C12 (3x), then dried in vacuo. This resin was positive for the bromobenzene blue test. The resin was soaked in 25 ml of DMF, and Fmoc-L-proline (2 94 mg, 〇·87 mmol) was added. The resin was shaken for 5 minutes, then pyRrop (4 〇β mg, 〇 加入Moore) and DIEA (123 mg '0.15 ml, 〇·87 mmol) and shake the resin for 24 hours. The resin was drained and washed with DMF (3x), CH3 〇H (3x) and CH2C12 (3 χ) and then dried in vacuo. This resin was negative for the bromobenzene blue test. will

1283240 五、發明說明（628) 樹脂泡於20%六氫吡啶溶於DMF，並振搖4小時。將樹脂排 液，並以DMF(3x)、CH30H(3x)及CH2C12(3x)洗蘇，』後曰於 真空中乾燥。此樹脂的溴苯藍試驗為陽性。將樹脂泡於2 5 宅升之DMF中，並加入Fmoc-3-胺基-2-酮基-1-咄略咬乙酸 醋（331毫克，〇· 87毫莫耳），及使樹脂振搖5分鐘。加入1283240 V. INSTRUCTIONS (628) Resin soaked in 20% hexahydropyridine dissolved in DMF and shaken for 4 hours. The resin was drained and washed with DMF (3x), CH30H (3x) and CH2C12 (3x), and dried in vacuo. This resin was positive for the bromobenzene blue test. The resin was soaked in 2 5 liters of DMF, and Fmoc-3-amino-2-keto-1-one-slightly bite acetic vinegar (331 mg, 〇·87 mmol) was added, and the resin was shaken. 5 minutes. Join

PyBr〇P(406毫克，0.87毫莫耳）及DIEA (123毫克，〇」5毫 升，〇· 87毫莫耳），並使樹脂振搖24小時。 · 將樹脂排液，並以DMF(3x)、CH3OH(3x)及 CH2C12 (3x)洗 2後於真空中乾燥。此樹脂的演苯藍試驗為陰性。缺 後將樹脂泡於90% TFA溶於CHJl2，並振搖4小時。將樹脂' 排液，並收集洗提液。將樹脂泡於新鮮的CH2Cl2中，並振 搖3 0分鐘。將樹脂排液，收集洗提液，並與第一部分結 合。將溶劑於真空中移除，並使殘留物自乙酸乙酯-己烷 再結晶，而得69毫克192。 實施例丄8 FiPyBr〇P (406 mg, 0.87 mmol) and DIEA (123 mg, 〇 5 liters, 〇·87 mmol) were shaken for 24 hours. • The resin was drained and washed with DMF (3x), CH3OH (3x) and CH2C12 (3x) and dried in vacuo. This resin was negative for the benzene blue test. After the absence, the resin was soaked in 90% TFA dissolved in CHJ12 and shaken for 4 hours. Drain the resin and collect the eluent. The resin was soaked in fresh CH2Cl2 and shaken for 30 minutes. The resin was drained and the eluate was collected and combined with the first part. The solvent was removed in vacuo and the residue was crystallised from EtOAc EtOAc Example 丄 8 Fi

將郴甲本異硫氰酸酯（1〇〇克，67·1毫莫耳）溶於“Ο毫 升CI^Cl2之溶液置於250毫升的圓底燒瓶内。此溶液冷卻至 -78 °C ’並使氨氣（過量）發泡通過1 〇分鐘。立即生成一沈 殿物’並發現其為期望的產物鄰甲苯硫脲。將反應混合物 過濾’並經由利用冷卻的CH2C丨2徹底洗滌而收集固體。將The indole isothiocyanate (1 g, 67·1 mmol) was dissolved in a solution of Οml CI^Cl2 in a 250 ml round bottom flask. The solution was cooled to -78 °C. 'Allow ammonia (excess) to foam through 1 。 minutes. Immediately generate a sediment and find it as the desired product o-toluene thiourea. Filter the reaction mixture' and collect it by washing thoroughly with cooled CH2C丨2 Solid. Will

89112968.ptd 第633頁 I283240 ----——— 白色固體於真空中乾燥，而提供10· 12克（92%產率）之期望 的鄰甲笨硫脲。 ’ ▲經由加入碘甲烷（9.1克，62毫莫耳）溶於無水曱醇（1〇〇 毫升）而將鄰甲苯硫脲（10· 12克，61毫莫耳）甲基化。使反 應在至溫下攪拌6小時，然後於真空中濃縮。將殘留物倒 入至氣化銨水溶液中，並以EtOAc萃取3x。將結合的有機 物質乾燥，並於真空中濃縮而得8· 7克（84%產率）的2一甲基 一2〜硫基鄰甲苯假脲。將假脲（8· 7克，51毫莫耳）在室溫$ 溶解於甲醇（100毫升）及六氫咄啶（8· 7克，1〇2毫莫耳f 中。將混合物攪拌隔夜，然後於真空中濃縮，而得9· 2克 之產物S旨的淡黃色固體。將此固體利用Li 〇Η皂化而得9 · 〇 克之期望的最終緩酸1 9 3。89112968.ptd Page 633 I283240 ----- The white solid was dried in vacuo to provide 10.12 g (92% yield) of desired o-methyl thiourea. o o-Methyl thiourea (10·12 g, 61 mmol) was methylated by the addition of methyl iodide (9.1 g, 62 mmol) dissolved in anhydrous methanol (1 mL). The reaction was allowed to stir at ambient temperature for 6 hours and then concentrated in vacuo. The residue was poured into an aqueous solution of ammonium sulfate and extracted with EtOAc EtOAc. The combined organic material was dried and concentrated in vacuo to give &lt;RTI ID=0.0&gt;&gt; The pseudourea (7.8 g, 51 mmol) was dissolved in methanol (100 ml) and hexahydroacridine (8. 7 g, 1 〇 2 mmol) at room temperature. The mixture was stirred overnight. It was then concentrated in vacuo to give 9.2 g of the product as a pale-yellow solid. The solid was saponified with Li?

將甲基-4-胺基苯乙酸酯（4.0克，25毫莫耳）溶解於 CHJl〆1〇〇毫升），及於此溶液中加入鄰甲苯異硫氰酸酯 (3 · 7克’ 2 5毫莫耳）。將反應混合物迴流加熱4小時，然後 冷卻至室溫。將溶液倒入至IN HC1中，然後以EtOAc萃取 3x ’於MgS〇4上乾燥，並於真空中濃縮，而得5· 2克（67%產 率）的硫脲甲基酯。將此酯使用L i 〇H皂化而得5 · 〇克之期望 的4-（鄰甲苯硫脲基）笨乙酸194。 實施例187Methyl-4-aminophenylacetate (4.0 g, 25 mmol) was dissolved in CHJl (1 mL), and o-toluene isothiocyanate (3 · 7 g' was added to the solution. 2 5 millimoles). The reaction mixture was heated under reflux for 4 hours and then cooled to room temperature. The solution was poured into <RTI ID=0.0># </RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; This ester was saponified with Li(R)H to give the desired 4-(o-tolylthioureido) acetoacetate 194. Example 187

\\312\2d-code\90-01\89112968.ptd 第634頁 1283240 五、發明說明（630) 4-[1- [3-甲氧基-4 -[Ν’ - (2-甲基笨基）脲基]苯基乙醯基] -（2S，3R，4R)-3, 4 -二經基-2 -吼咯啶羰基卜卜六氫咄啡乙\\312\2d-code\90-01\89112968.ptd Page 634 1283240 V. INSTRUCTIONS (630) 4-[1- [3-Methoxy-4 -[Ν' - (2-methyl stupid) Ureido]phenyl phenyl hydrazino] -(2S,3R,4R)-3,4-di-diyl-2-pyridinyl carbonyl ib hexahydro benzoate

195 4-[ 1-[ 3-甲氧基-4-[Ν’ -（2-甲基笨基）脲基;]苯基乙醯基] -（2S，3R，4R)-3, 4-二羥基-2 -吼咯啶羰基]一卜六氫吡畊乙 酸乙酯 ΟΗ195 4-[ 1-[ 3-methoxy-4-[Ν' -(2-methylphenyl)ureido;]phenylphenyl]](2S,3R,4R)-3, 4- Dihydroxy-2-pyrrolidinylcarbonyl]-dihexahydropyrrole ethyl acetate

使4 - [1-[3-甲氧基-4 - [Ν’ -（2-甲基苯基）脲基]笨基乙醯 基]-(2S，3R，4R)-3,4-亞異丙二氧基-2-吼洛唆戴基]-1-六 氫吼畊乙酸乙酯（1 · 2 7克，1 · 9 9毫莫耳）溶於飽和HC 1 (氣 、體）-MeOH(20毫升）之溶液在室溫下攪拌2小時，並將Me〇H 蒸發掉。將殘留物以飽和NaHC03溶液溶解，並以CHC 13-Me0H(4 : 1，v/v)萃取。將萃取液以鹽水洗滌，於Mgs〇4上 乾燥’並濃縮至乾。利用C H C 13 - M e 0 Η ( 5 : 1，v / v )作為洗提 液將殘留物進行層析，得4-[ 1-[ 3-甲氧基-4-[Ν，-（2-甲 基苯基）脲基]苯基乙醯基]-(2S，3R，4R)-3,4-二羥基_2-吡咯啶羰基]-卜六氫咄啡乙酸乙酯（990毫克，83%)之黃色 非晶形固體。IR (KBr) 3338 、 2937 、 2830 、 1743 、 1625 、1 600、1 53 2、1 4 54 / 公分；M-NMR (CDC13) 5 1. 25 (t，4-[1-[3-Methoxy-4 -[Ν' -(2-methylphenyl)ureido]]phenylamino]-(2S,3R,4R)-3,4-Asia Isopropyl dioxy-2-indolyl Daichi]-1-hexahydroindole ethyl acetate (1 · 27 g, 1 · 9 9 mmol) dissolved in saturated HC 1 (gas, body) - A solution of MeOH (20 mL) was stirred at room temperature for 2 h and then evaporated. The residue was dissolved in a saturated NaHC03 solution and extracted with CHC 13-Me. The extract was washed with brine, dried over MgSO 4 and concentrated to dryness. The residue was chromatographed using CHC 13 - M e 0 Η ( 5 : 1, v / v ) as an eluent to give 4-[ 1-[3-methoxy-4-[Ν,-(2- Methylphenyl)ureido]phenylethenyl]-(2S,3R,4R)-3,4-dihydroxy-2-pyrrolidinylcarbonyl]- hexahydropyridinylacetate (990 mg, 83 %) yellow amorphous solid. IR (KBr) 3338, 2937, 2830, 1743, 1625, 1 600, 1 53 2, 1 4 54 / cm; M-NMR (CDC13) 5 1. 25 (t,

\\312\2d-code\90-01\89112968.ptd 第635頁 1283240 五、發明說明（631) J=7.1 Hz， 3H) 、2·20 (s， 3H) 、2· 46-2.56 (m， 4H)、 3.15 (s, 2H)、3·40-3·72 (m，9H)、3·62 (s，3H)、 4.01-4.08(m，2H)、4.16(q，J = 7.1Hz，2H)、4.22 (m，1H)、4·72 (d，J = 2.9 Hz，1H)、6·68 (d，J = 7.6 Hz，1H)、6·72 (s，1H)、7·06 (t，J = 7.6 Hz，1H)、 7·15-7·18 (m, 3H)、7·52-7·56 (m，2H)、7·90 (d, J = 8. 3 Hz, 1H) ； MS(FAB) ra/z 5 98 (MH1) ° 於4 - [1 - [3 -甲氧基-4 -[Ν’ -（2-甲基苯基）脲基]苯基乙酿 基]-(28，3148)-3,4-二經基-2-吼洛咬幾基]-1-六氫吼坪 乙酸乙酯（870毫克，1·46毫莫耳）溶於THF(15毫升）之溶液 中加入0.25Ν NaOH(7.00毫升，1.75毫莫耳）。於在室溫下 擾拌3 · 5小時後，將反應混合物濃縮。將殘留物以水稀 釋，並在0 °C下以IN HC1中和。將混合物藉由離子交換樹 脂（HP-20，三菱化學（Mitsubishi Chemical))濃縮及純 化，而得4-[1 -[3-甲氧基-4-[Ν’ - (2 -甲基苯基）脲基]苯基 乙醯基]-（28，31^，41〇-3，4-二經基-2_吼洛唆幾基]_1-六亂 吼°井乙酸1 9 5 ( 6 4 5毫克，7 8 % )之無色非晶形固體。I R (KBr) 3330、29 37、1 62 7、1 535、1 454 / 公分；UMR (DMSO-d6) 6 2.25 (s，3H)、2·38 (m，1H)、2·42-2.58 (m，2H)、2·64 (m，1H)、3·01 (s，2H)、3·13-3·71 (m， 8H)、3·88 (s，3H)、3·89 (m, 1H)、4·05 (m，1H)、 4· 58 (d，J = 3· 2 Hz, 1H)、6· 76 (dd，J = 8· 3、1· 5 Hz, 1H)、6·9 卜 6·95 (m，2H)、7·10 - 7.16 (m，2H)、7·/79 (d，J = 8.3 Ηζ，1Η)、8·00 (d，&gt;8·3 Ηζ，1Η)、8·49\\312\2d-code\90-01\89112968.ptd Page 635 1283240 V. Description of invention (631) J=7.1 Hz, 3H), 2·20 (s, 3H), 2·46-2.56 (m , 4H), 3.15 (s, 2H), 3·40-3·72 (m, 9H), 3·62 (s, 3H), 4.01-4.08 (m, 2H), 4.16 (q, J = 7.1 Hz) , 2H), 4.22 (m, 1H), 4·72 (d, J = 2.9 Hz, 1H), 6.68 (d, J = 7.6 Hz, 1H), 6.72 (s, 1H), 7· 06 (t, J = 7.6 Hz, 1H), 7·15-7·18 (m, 3H), 7·52-7·56 (m, 2H), 7·90 (d, J = 8. 3 Hz , 1H) ; MS(FAB) ra/z 5 98 (MH1) ° at 4 - [1 - [3 -methoxy-4 -[Ν' -(2-methylphenyl)ureido]phenyl Stuffed base]-(28,3148)-3,4-diylidene-2-indolyl ethyl acetate]-1-hexahydroindole ethyl acetate (870 mg, 1.46 mmol) dissolved in THF (15 ml) was added 0.25 NaOH (7.00 mL, 1.75 mmol). After stirring for 3.5 hours at room temperature, the reaction mixture was concentrated. The residue was diluted with water and neutralized with IN HCl at 0 °C. The mixture was concentrated and purified by ion exchange resin (HP-20, Mitsubishi Chemical) to give 4-[1-[3-methoxy-4-[Ν'-(2-methylphenyl) Urea]phenyl phenyl hydrazino]-(28,31^,41〇-3,4-diylidene-2 吼 唆 唆 ] ]]]----------------------- 5 mg, 7 8 %) of a colorless amorphous solid. IR (KBr) 3330, 29 37, 1 62 7 , 1 535, 1 454 / cm; UMR (DMSO-d6) 6 2.25 (s, 3H), 2· 38 (m, 1H), 2·42-2.58 (m, 2H), 2·64 (m, 1H), 3·01 (s, 2H), 3·13-3·71 (m, 8H), 3 · 88 (s, 3H), 3·89 (m, 1H), 4·05 (m, 1H), 4·58 (d, J = 3· 2 Hz, 1H), 6. 76 (dd, J = 8·3,1· 5 Hz, 1H), 6·9 Bu 6·95 (m, 2H), 7·10 - 7.16 (m, 2H), 7·/79 (d, J = 8.3 Ηζ, 1Η) , 8·00 (d,&gt;8·3 Ηζ,1Η), 8.49

\\312\2d-code\90-01\89112968.ptd 第636頁 1283240 五、發明說明（632) (s, 1H)、8·57 (s，1H); MS(FAB) m/z 570 (MH1); C28H35N5 08 *2.75H20 之分析計算值：C，54.32 ;H，6.59; N，11 · 3 1。實測值：5 4 · 0 7 ; Η，6 · 11 ; N， 1 1 · 0 0。 iAMlM 公}〇H 196 在2-胺基-4-噻唑乙酸（4克，25毫莫1辈）於1:1 CH2C1 : 丙酮（1 0 0毫升）之懸浮液中加入鄰甲苯異氰酸酯（3 · 5克， 2 6宅莫耳）。使混合物迴流加熱8小時，此時生成黃色沈澱 物。將沈澱物過濾，並將固體以大量1 : 1 CH2C12 :丙_洗 滌。將固體利用熱甲醇再結晶，並於真空中乾燥而得4. 8 克（66%產率）之期望的2-(鄰甲笨脈基）~4-°塞唾乙酸196。 也合物197至λ34之合成實施例 實施例1 8 9\\312\2d-code\90-01\89112968.ptd Page 636 1283240 V. Description of invention (632) (s, 1H), 8.57 (s, 1H); MS (FAB) m/z 570 ( Analysis calculated for C28H35N5 08 *2.75H20: C, 54.32; H, 6.59; N, 11 · 3 1. Found: 5 4 · 0 7 ; Η, 6 · 11 ; N, 1 1 · 0 0. iAMlM male}〇H 196 Add o-toluene isocyanate (3 · · · · · · · · · · · · · 5 grams, 2 6 house Mo ears). The mixture was heated under reflux for 8 hours at which time a yellow precipitate formed. The precipitate was filtered and the solid was washed with a large amount of 1:1 CH2C12: C. The solid was recrystallized from hot methanol and dried in vacuo to give 2.8 g (yield: 66% yield) of desired 2-(o. Synthesis Example of Compounds 197 to λ34 Example 1 8 9

於圓底燒瓶中，將3-溴苯甲胺（3. 00克，16. 13毫莫耳） 溶解於二氧陸圜-水（丨··丨）中，並加入固態Na2c〇3直至ρΗ為 9· 9為止。加入b〇C2〇 (3· 87克，17.74毫莫耳），並使反應 物在室溫下攪拌1 2小時。將反應混合物倒入至1 n CH 1中， 並以乙酸乙酯萃取水層3χ。然後將結合的有機層以水、鹽 水洗滌’接著於無水Mgs〇4上乾燥。將溶液過濾，並將溶 劑於減壓下移除。利用急速層析將產物純化。（4 : 1己烷一 乙酸乙酯）產量4. 39克197。In a round bottom flask, 3-bromobenzylamine (3.0 g, 16.13 mmol) was dissolved in dioxane-water (丨··丨), and solid Na2c〇3 was added until ρΗ It is until 9·9. b〇C2〇 (3·87 g, 17.74 mmol) was added and the reaction was stirred at room temperature for 12 h. The reaction mixture was poured into 1 n CH 1 and aqueous layer was extracted with ethyl acetate. The combined organic layer was then washed with water, brine and then dried over anhydrous Mgs4. The solution was filtered and the solvent was removed under reduced pressure. The product was purified by flash chromatography. (4: 1 hexane-ethyl acetate) yield 4. 39 g 197.

89112968.ptd 第637頁 1283240 五、發明說明（633)89112968.ptd Page 637 1283240 V. Description of invention (633)

在氬氣中將Boc-經保護苯甲胺（2· 〇〇克，6· 99毫莫耳）溶解 於無水THF中。將反應冷卻至-78 °C。將雙（三曱矽烷基）醯 胺鋰（1 3 · 9 8毫升，1 3. 9 8毫莫耳）於1 〇分鐘内加入。將反應 在- 7 8 °C下攪拌1小時，然後快速加入碘甲烷（1 · 9 8克， 1 3 · 9 8毫莫耳，0 · 8 7毫升）。使反應緩慢升溫至室溫，並攪 拌隔夜。將反應倒入至1 N C Η1中，並以乙酸乙酯萃取水層 3 X。將溶液過濾，並將溶劑於減壓下移除。利用急速層析 將產物分離。（7:1己烧-乙酸乙酯）產量ΐ·68克198。 B〇C、N，V^V^^C〇2CH3 將Boc-經保護3一溴爷基甲基胺（1· 68克，5· 6〇毫莫耳）置 於壓力管内。然後將管裝入DMF、醋酸鈉（〇· 51克，6· Μ毫 莫耳）、P(鄰甲苯基）3(〇· 51克，6· 16毫莫耳）、及Pd (0 A c )2 ( 〇 · 2 5克，1 · 1 2毫莫耳）。將管以氬氣沖洗丨〇分鐘， 然，加入丙烯酸甲酯（〇· 53克，0· 53毫莫耳，〇· 55毫升）。 將笞，封’並加熱至1 3 5 °c 2 4小時。使反應冷卻至〇 ， f將管緩慢打開。將溶液倒入至IN HC1中，並以乙酸乙酯 萃取水層3 X。將結合的有機層以水、鹽水洗滌，接著於 MgS〇4上乾燥。將溶液過濾，並將溶劑於減壓下移除。利Boc-protected benzylamine (2·g, 6.99 mmol) was dissolved in anhydrous THF under argon. The reaction was cooled to -78 °C. Lithium bis(tridecyl) guanamine (1 3 · 9 8 ml, 1 3. 9 8 mmol) was added over 1 Torr. The reaction was stirred at -78 ° C for 1 hour, then iodomethane (1 · 9 8 g, 1 3 · 9 8 mmol, 0 · 8 7 mL) was added rapidly. The reaction was allowed to warm slowly to room temperature and stirred overnight. The reaction was poured into 1 N C Η1 and the aqueous layer was extracted with ethyl acetate. The solution was filtered and the solvent was removed under reduced pressure. The product was isolated by rapid chromatography. (7:1 hexane-ethyl acetate) yield ΐ·68 g 198. B〇C, N, V^V^^C〇2CH3 Boc-protected 3-monobromomethylamine (1·68 g, 5.6 mM millimolar) was placed in a pressure tube. The tube was then charged with DMF, sodium acetate (〇·51 g, 6·Μ mmol), P (o-tolyl) 3 (〇·51 g, 6.1 16 mmol), and Pd (0 A c ) 2 ( 〇 · 2 5 grams, 1 · 1 2 millimoles). The tube was flushed with argon for a few minutes, then methyl acrylate (〇·53 g, 0·53 mmol, 〇·55 ml) was added. The crucible was sealed and heated to 1 3 5 °c for 24 hours. Allow the reaction to cool to 〇, f slowly open the tube. The solution was poured into IN HC1 and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, brine, and dried over MgS. The solution was filtered and the solvent was removed under reduced pressure. Profit

第638頁 1283240 五、發明說明（634) 用急速層析將產物分離。（6 : 1己烧-乙酸乙酯）產量1.60克 199 〇 CH3 KJ CH3 200 將Boc-經保護3-溴爷基甲基胺（ΐ·〇〇克，3·33毫莫耳）置 於壓力管内。然後將管裝入DMF、醋酸鈉（〇· 3.0克，3. 36毫 莫耳）、P(鄰甲苯基）3(〇·20克，〇·66毫莫耳）、及Pd (0 A c )2 (〇 · 1 5克，〇 · 6 6毫莫耳）。將管以氬氣沖洗1 〇分鐘， 然後加入丙烯酸甲酯（〇·37克，3.66毫莫耳，0.39毫升）。 將管密封，並加熱至1 3 5 °C 2 4小時。使反應冷卻至〇 °c， 並將管緩慢打開。將溶液倒入至1 N HC1中，並以乙酸乙酯 萃取水層3 X。將結合的有機層以水、鹽水洗滌，接著於 MgS〇4上乾燥。將溶液過濾，並將溶劑於減壓下移除。利 用急速層析將產物分離。（6:1己院-乙酸乙酯）產量no克 200 〇Page 638 1283240 V. INSTRUCTIONS (634) The product is isolated by rapid chromatography. (6: 1 hexane-ethyl acetate) Yield 1.60 g 199 〇CH3 KJ CH3 200 Place Boc-protected 3-bromo-mercaptomethylamine (ΐ·〇〇克, 3·33 mmol) under pressure Inside the tube. The tube was then charged with DMF, sodium acetate (〇·3.0 g, 3.36 mmol), P(o-tolyl)3 (〇·20 g, 〇·66 mmol), and Pd (0 A c ) 2 (〇 · 1 5 grams, 〇 · 6 6 millimoles). The tube was flushed with argon for 1 Torr, then methyl acrylate (37 g, 3.66 mmol, 0.39 mL) was added. The tube was sealed and heated to 1 3 5 ° C for 4 hours. Allow the reaction to cool to 〇 °c and slowly open the tube. The solution was poured into 1 N HCl and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, brine, and dried over MgS. The solution was filtered and the solvent was removed under reduced pressure. The product was isolated by flash chromatography. (6:1 ancestral home - ethyl acetate) yield no gram 200 〇

將α，召-不飽和酯（1.60克，5.49毫莫耳）置於帕爾 (Paar)容器内，並溶解於乙酸乙酯中。加入克） ，並利用Η將容器加壓至50 ps i。將容器攪拌丨2小時。利 用氬氣沖洗帕爾容器，並經由過濾通過矽藻土而移除催化The α,CAM-unsaturated ester (1.60 g, 5.49 mmol) was placed in a Paar container and dissolved in ethyl acetate. Add gram) and use Η to pressurize the container to 50 ps i. The container was stirred for 2 hours. Flush the Parr vessel with argon and remove the catalysis by filtration through the diatomaceous earth

89112968.ptd 第 639 頁 1283240 五、發明說明（635) 劑❹將溶劍於減壓下移除。產量160克2〇1。89112968.ptd Page 639 1283240 V. INSTRUCTIONS (635) The agent removes the solution under reduced pressure. The yield is 160 g 2〇1.

Boc、 ^〇〇2〇Ηβ ch3 202 將甲基-，石-不飽和酯（1· 克，3· 16毫莫耳）置於 帕爾容器内，並溶解於乙酸乙酯中。加入pd/c，並利用馬 將容，加壓至50 psi。將容器攪拌12小時。利用氬氣沖^ 帕爾容，並經由過濾通過矽藻土而移除催化劑。將溶劑 於減壓下移除。產量996.41克202 ./ · ... — ... ?H3 Η Η 办丫加〇T^2CH3 203 ，6〇(：酯（3 04毫克，1〇.4毫莫耳）溶解於(：112(：12，並加入 過量的三氟乙酸。然後將反應攪拌2小時。將溶劑移除， 將殘留物溶解於乙酸乙酯，並以飽和NaHC〇3溶液洗滌。將 有機層以水、鹽水洗滌，接著於Na2S〇4上乾燥。將溶液過 濾，並將溶劑於減壓下移除。將殘留物溶解於C扎c i2 -d MF，並加入H0Bt(154· 30 毫克，1· 14 毫莫耳）、4-2[n,2 (4P曱本脲）-本乙酸（3 2 4.11毫克，1·14毫莫耳）及edcI (218· 53毫克，1. 14毫莫耳）。使反應攪拌24小時。將溶液 倒入至1N HC 1中，並以乙酸乙酯萃取水層3χ。將結合的有 機層以水、鹽水洗滌，接著KMgS〇4上乾燥。將溶液過 濾’並將溶劑於減壓下移除。利用急速層析將產物分離。 I W312\2d-code\90-01\89112968.ptd 第640頁 1283240Boc, ^〇〇2〇Ηβ ch3 202 A methyl-, stone-unsaturated ester (1 g, 3.16 mmol) was placed in a Parr vessel and dissolved in ethyl acetate. Add pd/c and use a horse to pressurize to 50 psi. The vessel was stirred for 12 hours. The argon gas was used to flush the Parr and the catalyst was removed by filtration through the diatomaceous earth. The solvent was removed under reduced pressure. Yield: 996.41 g 202 ./ · ... — ... ? H3 Η 丫 丫 〇 ^ T^2CH3 203 , 6 〇 (: ester (3 04 mg, 1 〇. 4 mmol) dissolved in (: 112 (:12, and an excess of trifluoroacetic acid was added. The reaction was then stirred for 2 hours. The solvent was removed, the residue was taken in ethyl acetate and washed with sat. NaHC EtOAc. Then, it was dried over Na2S〇4. The solution was filtered, and the solvent was removed under reduced pressure. The residue was dissolved in C.sub.2, i.sub.2 -d MF, and H0Bt (154·30 mg, 1·14 mmol) was added. Ear), 4-2 [n, 2 (4P guanidine) - this acetic acid (3 2 4.11 mg, 1.14 mmol) and edcI (218 · 53 mg, 1. 14 mmol). Stir for 24 hours. The solution was poured into 1 N HCl and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water, brine, and then dried over KMgS. Remove under reduced pressure. Separate the product by rapid chromatography. I W312\2d-code\90-01\89112968.ptd Page 640 1283240

(乙酸乙酯）產量380.32毫克203。(ethyl acetate) yield 380.32 mg 203.

將酷（ 380· 32毫克，〇· 80毫莫耳）溶解於乙醇-水（4:丨）， 並加入NaOH。然後使反應加熱至5〇 2小時。TLC(乙酸乙 醋）顯示不存在起始物料。將反應冷卻至室溫。將溶液倒 入至IN CH1中，並以乙酸乙酯萃取水層3χ。將結合的有機 層以水、鹽水洗滌，接著於心3〇4上乾燥。將溶液過濾， 並將〉谷劑於減壓下移除。使殘留物自乙酸乙酯-己烧再結 晶。產量319.40毫克204。 實施例1 9 0Cool (380·32 mg, 〇·80 mmol) in ethanol-water (4: 丨) and add NaOH. The reaction was then heated to 5 Torr for 2 hours. TLC (acetic acid acetate) showed the absence of starting material. The reaction was cooled to room temperature. The solution was poured into IN CH1 and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, brine, and dried on a heart of 3 〇4. The solution was filtered and the gluten was removed under reduced pressure. The residue was recrystallized from ethyl acetate-hexane. The yield was 319.40 mg 204. Example 1 9 0

?Η3Η 將Boc酯（209.60毫克，0.65毫莫耳）溶解於CH2C12，並加 入過量的三氟乙酸。然後將反應攪拌2小時。將溶劑移 除’將殘留物溶解於乙酸乙酯，並以飽和Najjc〇3溶液洗 滌。將有機層以水、鹽水洗滌，接著於Na2S〇4上乾燥。將 溶液過濾、，並將溶劑於減壓下移除。將殘留物溶解於 CH2C12-DMF，並加入 H〇Bt( 9 7.4 5 毫克，〇·72 毫莫耳）、 4-[Ν’ -（鄰甲苯脲）-苯乙酸（2〇4· 7〇毫克，〇· 72毫莫耳）及 EDCK138· 03毫克，〇· 72毫莫耳）。使反應攪拌24小時。將?? 3? Boc ester (209.60 mg, 0.65 mmol) was dissolved in CH2C12, and an excess of trifluoroacetic acid was added. The reaction was then stirred for 2 hours. The solvent was removed. The residue was dissolved in ethyl acetate and washed with saturated Najjc. The organic layer was washed with water, brine and dried over Na.sub.2.sub.4. The solution was filtered and the solvent was removed under reduced pressure. The residue was dissolved in CH2C12-DMF, and H〇Bt (9 7.4 5 mg, 〇·72 mmol), 4-[Ν'-(o-tolurea)-phenylacetic acid (2〇4·7〇 mg) was added. , 〇 · 72 millimoles) and EDCK138 · 03 mg, 〇 · 72 millimoles). The reaction was allowed to stir for 24 hours. will

12832401283240

五、發明說明（637) 溶液倒入至1 N H C1中’並以乙酸乙酯萃取水層3 χ。將结人 的有機層以水、鹽水洗滌，接著於MgS〇4上乾燥。將溶液 過濾，並將溶劑於減壓下移除。利用急速層析將產物分 離。（乙酸乙酯）產量237. 8毫克20 5。 刀V. INSTRUCTIONS (637) The solution was poured into 1 N H C1 and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water, brine, and dried over MgS 4 . The solution was filtered and the solvent was removed under reduced pressure. The product was separated by rapid chromatography. (ethyl acetate) yield 237. 8 mg 20 5 . Knife

206 將酯（237· 8毫克，〇· 49毫莫耳）溶解於乙醇—水（4:丨）， 並加入NaOH。然後使反應加熱至5〇它2小時。TLC(乙酸乙 酯）顯示不存在起始物料。·將反應冷卻至室溫。將溶液倒 :至IN HC1中’並以乙酸乙酯萃取水層3χ。將結合的 層以水、鹽水洗滌，接著於MgS〇4上乾燥。將溶液過濾， 咸气下移除。使殘留物自乙酸乙醋-己烷再結 日日。產里207.8¾克2〇6。 實施例1 9 1 H I氣異嗜琳(1 2· 20 * ’ 91. 60毫莫耳）溶解於 =升）中，並冷卻至—10°C。邊將内部溫度維持於 ' C ’邊將濃HN〇3(9. 0毫升）缓慢加至溶液。.當添加办志 ^使反應靜置，並於12小時内緩慢升溫至室；：力將= 此合物綾杈加至冰中，並利用N使水溶 將… 層，萃取4次。將結合的有機層以水洗丨條化接著將於水206 The ester (237. 8 mg, 〇·49 mmol) was dissolved in ethanol-water (4: 丨) and NaOH was added. The reaction was then heated to 5 Torr for 2 hours. TLC (ethyl acetate) showed the absence of starting material. • Cool the reaction to room temperature. The solution was poured: into IN HC1' and the aqueous layer was extracted with ethyl acetate. The combined layers were washed with water, brine, and then dried over MgS 4 . The solution was filtered and removed under salty air. The residue was re-consolidated from ethyl acetate-hexane. The production is 207.83⁄4 grams 2〇6. Example 1 9 1 H I gas heterophilic (1 2 · 20 * '91. 60 mmol) was dissolved in = liter) and cooled to -10 °C. Concentrated HN〇3 (9.0 ml) was slowly added to the solution while maintaining the internal temperature at 'C'. When adding the agent ^ Let the reaction stand and slowly warm to the chamber within 12 hours;: force = the compound is added to the ice, and the layer is extracted with N, and the mixture is extracted 4 times. The combined organic layer is washed with water and then placed in water

第642頁 1283240 五、發明說明（638) ϋ〇4上乾燥。將溶液過濾、，並將溶劑於減壓下移除。將 ΐίΐί棕ί:溶解於乙醇’並加入濃HC1。經由過滤收 9n7 固體，並將其於真空中乾燥。產量8.0克 z U 7 °Page 642 1283240 V. INSTRUCTIONS (638) Dry on ϋ〇4. The solution was filtered and the solvent was removed under reduced pressure. Dissolve ΐίΐί brown: dissolved in ethanol' and add concentrated HC1. 9n7 solid was collected via filtration and dried in vacuo. Yield 8.0 g z U 7 °

co2ch3 o2n 208 將6 -硝基-1，2,3,4-四氫異喳啉（1.00克，561毫莫耳） 溶解於乙醇。然後加入溴乙酸甲酯（0· 86克，5· 61毫莫 耳，0.53毫升）及三乙胺（1.17克，1159毫莫耳，162毫 升），並將混合物迴流加熱5小時。使溶液冷卻至室溫，並 將洛液於真空中濃縮。將溶液加至水中，並以乙酸乙酯萃 取水層3x。將結合的有機層於Na2s〇4上乾燥，過濾，並將 &gt;谷劑於減壓下移除。利用急速層析將產物分離（3 :丨己烷一 乙酸乙酯）。產量702毫克208。Co2ch3 o2n 208 6-Nitro-1,2,3,4-tetrahydroisoindoline (1.00 g, 561 mmol) was dissolved in ethanol. Then methyl bromoacetate (0.86 g, 5.61 mmol, 0.53 ml) and triethylamine (1.17 g, 1159 mmol, 162 ml) were added, and the mixture was heated under reflux for 5 hours. The solution was allowed to cool to room temperature and the solution was concentrated in vacuo. The solution was added to water, and the aqueous layer was extracted 3× with ethyl acetate. The combined organic layers were dried over Na.sub.2, filtered, and &gt; The product was isolated by flash chromatography (3: hexane-ethyl acetate). Yield 702 mg 208.

八 co2ch3 h2n 209 將以上的醋（702毫克，2.81毫莫耳）置於帕爾容器内， 並溶解於乙醇中。加入Pd/C(100毫克），並利用h2將容器 加壓至5 0 p s i。將谷器擾拌2 4小時。利用氬氣沖洗帕爾容 器，並經由過濾通過矽藻土而移除催化劑。將溶劑於減壓 下移除。1H-NMR僅顯現期望的產物。產量587毫克209。Eight co2ch3 h2n 209 The above vinegar (702 mg, 2.81 mmol) was placed in a Parr container and dissolved in ethanol. Pd/C (100 mg) was added and the vessel was pressurized to 50 p s i using h2. Spoil the bar for 24 hours. The Parr container was flushed with argon and the catalyst was removed by filtration through diatomaceous earth. The solvent was removed under reduced pressure. 1H-NMR showed only the desired product. Yield 587 mg 209.

89112968.ptd 第643頁 128324089112968.ptd Page 643 1283240

在氬氣中將苯胺（587·0毫克，2· 66毫莫耳）溶解於無水 CH2C12及咄啶中。使反應冷卻至〇 °c。將3-曱氧基—4 — (n，一 本脲基）本基乙醯氯（837.70毫克，2.66毫莫耳）之cu2ci溶 液於5分鐘内加入。然後使反應升溫至室溫，並授拌隔2 夜。然後將反應混合物倒入至1 N NC1中，並以乙酸乙醋萃 取水層3 X。接者將結合的有機層以飽和n a H C 03、水、鹽水 洗；條’然後於MgS〇4上乾紐。將溶液過滤’並將溶劑於減 壓下移除。利用急速層析將產物分離（乙酸乙酯）。產量 618·36 毫克210 。Aniline (587·0 mg, 2.66 mmol) was dissolved in anhydrous CH2C12 and acridine under argon. The reaction was allowed to cool to 〇 °c. A cu2ci solution of 3-mercaptooxy-4-(n, a ureido)-benzhydryl chloride (837.70 mg, 2.66 mmol) was added over 5 minutes. The reaction was then allowed to warm to room temperature and allowed to mix for 2 nights. The reaction mixture was then poured into 1 N NC1 and the aqueous layer was extracted with EtOAc. The combined organic layer was washed with saturated n a H C 03, water, brine; the strip was then dried on MgS〇4. The solution was filtered&apos; and the solvent was removed under reduced pressure. The product was isolated by flash chromatography (ethyl acetate). Yield 618·36 mg 210.

將以上的甲基酯（618. 36毫克，1 · 20毫莫耳）溶解於無水 丁1^-112()，並加入1^ 0( 558.0 7毫克，13.30毫莫耳）。使反應 混合物在室溫下授拌2 4小時。將反應倒入至1N H C1中，並 以乙酸乙酯萃取水層3χ。接著將結合的有機層以水、鹽水 洗滌，然後於MgS04上乾燥。將溶液過濾，並將溶劑於減 壓下移除。經由再結晶將產物純化。（己烷-乙酸乙酯）。 產量60 0毫克211。 實施例192The above methyl ester (618.36 mg, 1 · 20 mmol) was dissolved in anhydrous butyl 1^-112(), and 1^0 (558.0 7 mg, 13.30 mmol) was added. The reaction mixture was allowed to stir at room temperature for 24 hours. The reaction was poured into 1 N H C1 and aqueous layer was extracted with ethyl acetate. The combined organic layers were then washed with water, brine and dried over MgS04. The solution was filtered and the solvent was removed under reduced pressure. The product was purified via recrystallization. (Hexane-ethyl acetate). The yield is 60 mg 211. Example 192

丨 1283240丨 1283240

在氬氣中將3 -硝苯基丙酸（1·〇〇克，5·ΐ2毫莫耳）、、六刀 無水THF中。使反應冷卻至〇。〇，並於1〇分鐘内加入^解於 THF(1· 0Μ，15· 37毫莫耳，15. 37毫升）。使反應在〇 拌1小時，然後利用水使其緩慢停止反應。使溶液緩怦祝 溫至室溫’然後倒入至IN HC1中。以乙酸乙酯將水層&amp; 3 X。接著將結合的有機層以飽和n a H C 〇3、水、鹽水洗供 然後於MgS〇4上乾燥。將溶液過濾，並將溶劑於減壓下 除。利用急速層析將產物分離（1 :1己烷-乙酸乙醋）。 &gt; 旦 909· 0毫克212。 -曰。量3-N-phenylphenylpropionic acid (1·〇〇g, 5·ΐ2 mmol), and six-knife anhydrous THF were placed under argon. The reaction was allowed to cool to hydrazine. 〇, and added THF (1·0Μ, 15.37 mmol, 15.37 ml) in 1 min. The reaction was allowed to stir for 1 hour, and then the reaction was slowly stopped with water. The solution was allowed to warm to room temperature and then poured into IN HC1. The aqueous layer &amp; 3 X was taken with ethyl acetate. The combined organic layer was then washed with saturated n a H C 〇 3, water, brine and dried over MgS 4 . The solution was filtered and the solvent was removed under reduced pressure. The product was isolated by flash chromatography (1:1 hexane-ethyl acetate). &gt; 909. 0 mg 212. - Hey. the amount

213 將3-硝苯基丙醇（ 909·0毫克，5· 02毫莫耳）溶解於無水 CHgCl2。在氣氣中於第二個圓底燒瓶内，將（c〇ci)2 (700.65宅克’5.52毫莫耳，〇·48毫升）加至無水ch2C12。 然後使（COC1 ^-CH2C12溶液冷卻至-69 °C，並緩慢加入 DMSO(8 6 2· 56毫克，1L4毫莫耳，〇178毫升）。使反應在213 3-Nitrophenylpropanol (909·0 mg, 5.02 mmol) was dissolved in anhydrous CHgCl2. (c〇ci) 2 (700.65 克克&apos;5.52 mmol, 〇·48 ml) was added to anhydrous ch2C12 in a second round bottom flask in air. Then (COC1 ^-CH2C12 solution was cooled to -69 ° C, and DMSO (8 6 2 · 56 mg, 1 L 4 mmol, 〇 178 ml) was added slowly.

- 6 0 °C下攪拌5分鐘，然後將醇溶液經由插管在5分鐘内加 入。使反應混合物在—60 t下攪拌i小時，然後加入Et3N (2.54克’ 25.10¾莫耳，3.50毫升），並使反應緩慢升溫 至室溫。將反應倒入至丨N HC1中，並以乙酸乙酯萃取水層 3χ。將結合的有機層以飽和NaHC〇3、水、鹽水洗滌，然後 於MgS〇4上乾燥。將溶液過濾，並將溶劑於減壓下移除。- Stir at 60 °C for 5 minutes, then add the alcohol solution via a cannula for 5 minutes. The reaction mixture was stirred at -60 t for 1 h then Et3N (2.54 g &lt;RTIgt;&quot;&quot;&quot;&quot;&quot;&quot;&quot;&quot; The reaction was poured into 丨N HCl, and aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated NaHC 3, water, brine and dried over &lt;RTIgt; The solution was filtered and the solvent was removed under reduced pressure.

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物料。將醛2 1 3不經進一步純化 而 I 1283240 五、發明說明（641) HI-NMR顯示不存在起始 使用。 o2nmaterials. The aldehyde 2 1 3 was not further purified. I 1283240 V. Inventive Note (641) HI-NMR showed no initial use. O2n

214 在鼠氣中於圓底燒瓶内，將NaH(132· 48毫克，5· &amp;毫莫 耳）於無水THF中泡成淤漿。將溶解於無水THF中 ”酸三乙醋U.31克，5.52毫莫耳，&quot;8毫升)經二 器緩k加入。將反應混合物在室溫下攪拌3〇分鐘。將在氬 氣下溶解於無水THF中之以上的醛經由注射器於1〇分鐘内 加至膦酸酯溶液。將反應混合物攪拌12小時。將反應倒入 至IN HC1中，並以乙酸乙酯萃取水層3χ。接著將結合的有 機層以飽和NaHC〇3、水、鹽水洗滌，然後於MgS〇4上乾燥。 將溶液過濾，並將溶劑於減壓下移除。利用急速層析將產 物分離（1:1乙酸乙酯-己烧）。產量992.0毫克214。 h2n ,co2ch2ch3 ch3 215 將以上的α,召-不飽和酯（992.0毫克，3.77毫莫耳）置 於帕爾容器内，並溶解於乙醇中。將容器以氬氣沖洗，並 加入Pd/C(200.0毫克），將氬氣以在50 psi下之H2置換。 然後將帕爾容器振搖1 2小時。利用氬氣將氫氣自容器沖 洗，並經由過濾通過矽藻土而移除催化劑。將溶劑於減壓 下移除。1H-NMR僅顯現期望的產物。產量851.2毫克215。214 NaH (132·48 mg, 5· &amp; millimolar) was bubbled into anhydrous THF in a round bottom flask. Dissolved in anhydrous THF "U.31 g of acetic acid triacetate, 5.52 mmol, &quot; 8 ml) was added via a slow buffer. The reaction mixture was stirred at room temperature for 3 minutes. Under argon The above aldehyde dissolved in anhydrous THF was added to the phosphonate solution via syringe over 1 min. The reaction mixture was stirred for 12 hours. The reaction was poured into IN HCl, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated NaHC(R), water, brine and dried over &lt;RTI ID=0.0&gt;&gt; Ethyl ester-hexane.) Yield 992.0 mg 214. h2n, co2ch2ch3 ch3 215 The above α, s-unsaturated ester (992.0 mg, 3.77 mmol) was placed in a Parr container and dissolved in ethanol. The vessel was flushed with argon and Pd/C (200.0 mg) was added and argon was replaced with H2 at 50 psi. The Parr vessel was then shaken for 12 hours. Hydrogen was purged from the vessel with argon and via The catalyst was removed by filtration through diatomaceous earth. The solvent was removed under reduced pressure. 1H-NM R only showed the desired product. Yield 851.2 mg 215.

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五、發明說明（642)V. Description of the invention (642)

在氬氣中將以上的苯胺（850.0毫克，3·61毫莫耳）溶解 於無水CHgCl2及咄啶中。使反應冷卻至〇。〇。將3-甲氧基 -4-（Ν’ -苯脲基）苯基乙醯氯（1· 14克，3· 61毫莫耳）之 CHgCl2溶液於5分鐘内加入。然後使反應升溫至室溫，並授 拌隔夜。然後將反應混合物倒入至1 N HC1中，並以乙酸乙 酯萃取水層3x。接著將結合的有機層以飽和NaHC03、水、 鹽水洗滌，然後於MgS〇4上乾燥。將溶液過濾，並將溶劑 於減壓下移除。利用急速層析將產物分離（乙酸乙酯）。產 量576. 0毫克216。The above aniline (850.0 mg, 3.61 mmol) was dissolved in anhydrous CHgCl2 and acridine under argon. The reaction was allowed to cool to hydrazine. Hey. A solution of 3-methoxy-4-(Ν'-phenylureido)phenylethylidene chloride (1.41 g, 3.61 mmol) in CHgCl2 was added over 5 min. The reaction was then allowed to warm to room temperature and was allowed to stand overnight. The reaction mixture was then poured into 1 N HCl and the aqueous layer was extracted 3x with ethyl acetate. The combined organic layers were then washed with saturated NaHC03, water, brine and dried over MgSO4. The solution was filtered and the solvent was removed under reduced pressure. The product was isolated by flash chromatography (ethyl acetate). Yield 576. 0 mg 216.

、將以上的乙基酯（576.0毫克，毫莫耳）溶解於乙醇—水， 並加入NaOH。使反應混合物加熱至5〇它2小時。使反應冷 卻至至溫’然後倒入至1 N HC 1中。將水層以乙酸乙酯萃取 3次。接著將結合的有機層以水、鹽水洗滌，然後於MgS〇4 上乾煉。將溶液過濾，並將溶劑於減壓下移除。利用The above ethyl ester (576.0 mg, millimolar) was dissolved in ethanol-water and NaOH was added. The reaction mixture was heated to 5 Torr for 2 hours. The reaction was allowed to cool to temperature and then poured into 1 N HC 1 . The aqueous layer was extracted with ethyl acetate three times. The combined organic layers were then washed with water, brine and then dried over MgS〇4. The solution was filtered and the solvent was removed under reduced pressure. use

Sep-Pak管柱將產物純化。產量534毫克217。 實施例1 9 3The product was purified on a Sep-Pak column. Yield 534 mg 217. Example 1 9 3

!1283240!1283240

使1克的王氏樹脂（tentagel S-ΡΗΒ 〇·3毫莫耳載入量） 懸浮於3-(Fmoc-胺基）苯丙酸（361· 31毫克，〇· 90毫莫 耳）、DMAP(l〇9· 95 毫克，0· 90 毫莫耳）、Η0Β 243· 63 毫 克’0.90毫莫耳）、及DIC(227.16毫克，1.80毫莫耳， 〇· 28毫升）溶於DMF及CI^C I2之混合物的溶液中。將混合物 振搖20小時並排液。將樹脂2 1 8以DMF、MeOH、CH2C12洗 滌，並於減壓下乾燥。1 gram of Wang resin (tentagel S-ΡΗΒ 〇·3 mmol loading) was suspended in 3-(Fmoc-amino) phenylpropionic acid (361·31 mg, 〇·90 mmol), DMAP (l〇9·95 mg, 0·90 mmol), Η0Β 243· 63 mg '0.90 mmol, and DIC (227.16 mg, 1.80 mmol, 〇·28 ml) dissolved in DMF and CI^ A solution of a mixture of C I2. The mixture was shaken for 20 hours and drained. The resin 2 18 was washed with DMF, MeOH, CH 2 C 12 and dried under reduced pressure.

於以上的樹脂（5 00毫克，0· 15毫莫耳）中加入六氫吡咬 - DMF之溶液（5 0% v/v，4毫升），並將混合物振搖4小時。 將樹脂以DMF、MeOH、CHC12洗條。於樹脂中加入tm〇F及異 丁醛（1 0 8. 1 7毫克，1 · 5 0毫莫耳，0 · 1 3毫升）。使混合物振 搖1 2小時。將樹脂排液，泡於Me0H- 1 % AcOH中，並加入 NaCNBH3(l 50· 0毫克，2· 39毫莫耳）。將樹脂振搖6小時。 將樹脂排液，並以MeOH、MeOH-Et3N、MeOH、DMF、CH2C12 洗滌。於樹脂中加入TFA溶於CH2C12之溶液（30% v/v，3毫 升），並將混合物振搖5小時。將混合物過濾，並將濾液於 真空中濃縮。利用Sep-Pak管柱將殘留物純化。於移除溶 劑後，將Et2Q加至殘留物，並收集固體而得1 5毫克之21 9 的結晶固體。To the above resin (500 mg, 0.15 mmol) was added a solution of hexahydropyridin-DMF (50% v/v, 4 mL) and the mixture was shaken for 4 hr. The resin was washed with DMF, MeOH, CHC12. To the resin were added tm〇F and isobutyraldehyde (1 0 8. 17 mg, 1 · 50 mmol, 0 · 13 ml). The mixture was shaken for 12 hours. The resin was drained, soaked in Me0H-1% AcOH, and NaCNBH3 (10.5 mg, 2.39 mmol) was added. The resin was shaken for 6 hours. The resin was drained and washed with MeOH, MeOH-EtOAc, MeOH, DMF, CH. A solution of TFA in CH2C12 (30% v/v, 3 ml) was added to the resin, and the mixture was shaken for 5 hours. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified using a Sep-Pak column. After removing the solvent, Et2Q was added to the residue, and the solid was collected to give 15 mg of 21 9 of crystalline solid.

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^OH^OH

f^OHF^OH

將Tentagel ΡΗΒ樹脂（1·〇克，載入量0·29毫莫耳/克） 泡於25毫升之DMF中，並加入6 -溴己酸（169毫克，〇·87毫 莫耳）。將樹脂振搖5分鐘，然後加入DIC(220毫克，〇. 27 毫升，1· 74毫莫耳）及DM AP (3 5毫克，0.29毫莫耳），並使 樹脂振搖1 4小時。將樹脂排液，並以DMF (3x)、CH30H(3x) 及CH2C12 (3x)洗滌，然後於真空中乾燥。 將樹脂加入2，2-二甲基-1,3 -二氧五圜-4-甲胺（227毫 克，1.74毫莫耳）及碘化鋰（232毫克，1.74毫莫耳）溶於15 毫升DMF之溶液。將樹脂在室溫下振搖1 4小時。將樹脂排 液，並以DMF(3x)、CH30H(3x)及CH2C12(3x)洗滌，然後於 真空中乾燥。此樹脂的溴苯藍試驗為陽性。 將樹脂泡於25毫升之DMF中，並加入4-鄰甲笨脲基一3-曱 氧苯乙酸（2 4 7毫克，0 · 8 7毫莫耳），及使樹脂振搖5分鐘。 加入PyBroP( 40 6 毫克，0.87毫莫耳）及DIEA(123毫克， 0 · 1 5毫升，0 · 8 7毫莫耳），並使樹脂振搖1 4小時。將樹脂 排液，並以DMF(3x)、CH30H(3x)及 CH2C12(3x)洗條，然後 於真空中乾燥。此樹脂的溴苯藍試驗為陰性。 然後將樹脂泡於90% TFA溶於CH2C12，並振搖4小時。將 樹脂排液’並收集洗提液。將樹脂泡於新鮮的Cjjcι2中， 並振搖3 0分鐘。將樹脂排液，收集洗提液，並與第一部分Tentagel® resin (1·〇g, loading 0·29 mmol/g) was bubbled into 25 ml of DMF and 6-bromohexanoic acid (169 mg, 〇·87 mmol) was added. The resin was shaken for 5 minutes, then DIC (220 mg, 〇. 27 mL, 1.74 mmol) and DM AP (3 5 mg, 0.29 mmol) were added and the resin was shaken for 14 hours. The resin was drained and washed with DMF (3x), CH30H (3x) and CH2C12 (3x) then dried in vacuo. The resin was added to 2,2-dimethyl-1,3-dioxapenta-4-methylamine (227 mg, 1.74 mmol) and lithium iodide (232 mg, 1.74 mmol) dissolved in 15 ml. A solution of DMF. The resin was shaken at room temperature for 14 hours. The resin was drained and washed with DMF (3x), CH30H (3x) and CH2C12 (3x) and then dried in vacuo. This resin was positive for the bromobenzene blue test. The resin was soaked in 25 ml of DMF, and 4-o-methylidazolyl-3-oxooxyphenylacetic acid (247 mg, 0.87 mmol) was added, and the resin was shaken for 5 minutes. PyBroP (40 6 mg, 0.87 mmol) and DIEA (123 mg, 0 · 15 ml, 0 · 8 7 mmol) were added and the resin was shaken for 14 hours. The resin was drained and washed with DMF (3x), CH30H (3x) and CH2C12 (3x) and dried in vacuo. This resin was negative for the bromobenzene blue test. The resin was then soaked in 90% TFA in CH2C12 and shaken for 4 hours. Drain the resin' and collect the eluent. The resin was soaked in fresh Cjjcι 2 and shaken for 30 minutes. Drain the resin, collect the eluent, and with the first part

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並使殘留物自乙酸乙酯-己 結合。將溶劑於真空中移除 院再結晶，而得5 6毫克2 2 0。 實施例1 9 5The residue was combined with ethyl acetate-hexane. The solvent was removed in a vacuum and recrystallized to give 5 6 mg of 2 2 0. Example 1 9 5

221 將1克之Tentagel ΡΗΒ樹脂（載入量〇· 29毫莫耳/克）泡 於DMF 25笔升，並加入Fmoc —7-胺基庚酸（319毫克，〇·87 毫莫耳）。將樹脂振搖5分鐘，加入DIC(22〇毫克，〇.27毫 =，1· 74耄莫耳）及DMAPU06毫克，〇· 87毫莫耳），並使樹 月曰振搖24小時。將樹脂排液，並以DMF(3x)、CH3〇H(3x)及 CI^Cl2 (3x)洗滌，然後於真空中乾燥。此樹脂的溴苯藍試 驗為陰性。將樹脂泡於20%六氫咄啶溶於DMF，並振搖4小 時。將樹脂排液，並以DMF(3x)、CH30H(3x)及CH2C12(3x) 洗滌，然後於真空中乾燥。此樹脂的溴苯藍試驗為陽性。 將樹脂泡於25毫升之DMF中，.並加入4-鄰曱苯脲基一3一甲 氧苯乙酸（247毫克’〇· 87毫莫耳），將樹脂振搖5分鐘。加 入？761'〇?(406毫克，〇.87毫莫耳）及〇^人（123毫克，〇15 毫升，0 · 8 7毫莫耳），並使樹脂振搖ί 4小時。將樹脂排 液，並以DMF(3x)、CH3OH(3x)及CH2C12 (3x)洗滌，然後於 真空中乾燥。此樹脂的溴苯藍試驗為陽性。 然後將樹脂泡於90% TFA溶於CH2C12，並振搖4小時。將221 One gram of Tentagel® resin (loading amount 29 29 mmol/g) was bubbled into DMF 25 liters and Fmoc-7-aminoheptanoic acid (319 mg, 〇·87 mmol) was added. The resin was shaken for 5 minutes, and DIC (22 mg, 〇.27 mA = 1.74 耄mol) and DMAPU (06 mg, 〇·87 mmol) were added, and the tree was shaken for 24 hours. The resin was drained and washed with DMF (3x), CH3 〇H (3x) and CI^Cl2 (3x) and then dried in vacuo. This resin was negative for the bromobenzene blue test. The resin was soaked in 20% hexahydroacridine in DMF and shaken for 4 hours. The resin was drained and washed with DMF (3x), CH30H (3x) and CH2C12 (3x) then dried in vacuo. This resin was positive for the bromobenzene blue test. The resin was bubbled into 25 ml of DMF, and 4-o-phthalazyl-3-methoxybenzeneacetic acid (247 mg '〇·87 mmol) was added, and the resin was shaken for 5 minutes. Add? 761' 〇? (406 mg, 〇.87 mmol) and 〇^ (123 mg, 〇15 ml, 0 · 8 7 mmol), and shake the resin for 4 hours. The resin was drained and washed with DMF (3x), CH3OH (3x) and CH2C12 (3x) and then dried in vacuo. This resin was positive for the bromobenzene blue test. The resin was then soaked in 90% TFA in CH2C12 and shaken for 4 hours. will

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樹脂排液，並收集洗提液。將 並振搖3 0分鐘。將樹脂排液， 結合。將溶劑於真空中移除， 烷再結晶，而得6 6毫克2 2 1。 實施例1 9 6 樹脂泡於新鮮的CHC12中， 收集洗提液，並與第一部分 並使以留物自乙酸乙S旨-己The resin was drained and the eluent was collected. Shake and shake for 30 minutes. The resin is drained and combined. The solvent was removed in vacuo and the alkane was crystallised to give 6 6 mg 2 2 1 . Example 1 9 6 resin was bubbled into fresh CHC12, and the eluent was collected and combined with the first part and the residue was made from acetic acid

222 在-78 °c下於草醯氯（3. 8克，30毫莫耳）溶於CH2C12 (100 毫升）之溶液中在30分鐘内逐滴加入DMSO( 2. 4克，31毫莫 耳）。於此溶液中在1 5分鐘内逐滴加入N-Boc-脯胺醇（5 · 0 克，25毫莫耳）。將反應在—78 °C下攪拌3小時，然後經由 冷添加IN HC1而停止反應，以EtOAc萃取3x，乾燥，及於 真空中濃縮而得粗製脯胺醛，將其進行層析（25% EtOAc / 己烷）而得3· 8克之期望產物。 產生（三苯亞膦烷基）丁酸甲酯（6·9克，19毫莫耳）溶於 THF(10 0毫升）之溶液。在-78 °C下加入LiHMDS(l 0毫升之 2· 0 Μ溶液，20毫莫耳），然後攪拌1小時。接著將以上的 脯胺醛（3· 8克，10毫莫耳）以一份加入，並使混合物於4小 時内升溫至室溫。經由加入IN HC1使反應停止，以EtOAc 萃取3x，乾燥，及於真空中濃縮而得粗製炫，將其進行層 析（25% EtOAc/己烷）而得2.9克之期望產物。 經由將烯（2.9克，10毫莫耳）置於乙醇（20毫升）中’並222 DMSO (2.4 g, 31 mmol) was added dropwise over 30 minutes at -78 °c in a solution of chlorophyll chloride (3.8 g, 30 mmol) dissolved in CH2C12 (100 mL). ). N-Boc-prolinol (5.0 g, 25 mmol) was added dropwise to this solution over 15 minutes. The reaction was stirred at -78 °C for 3 h then quenched with EtOAc (EtOAc)EtOAc. / hexane) gives 3.8 g of the desired product. A solution of (triphenylphosphinylalkyl)methyl butyrate (6.9 g, 19 mmol) dissolved in THF (10 mL) was obtained. LiHMDS (10 ml of a 2.0 Torr solution, 20 mmol) was added at -78 °C, followed by stirring for 1 hour. The above guanamine (3.8 g, 10 mmol) was then added in one portion, and the mixture was allowed to warm to room temperature over 4 hours. The reaction was quenched with EtOAc (EtOAc)EtOAc.EtOAc. By placing an alkene (2.9 g, 10 mmol) in ethanol (20 mL)&apos;

\\312\2d-code\90-01\89112968.ptd 第651頁 1283240 五、發明說明(647) 加入催化量的10% Pd/C，隨後在40 psi下進行帕爾氫化4 小時而進行烯之氫化，將所產生之烷不經純化而使用。經 由在室溫下加入1 : 1 TFA/CH2C 12將“。基團移除。使反應授 拌2小時，並將溶劑於真空中移除。將粗製胺丨· 9克不經進 一步的純化而使用。 產生以上之自由胺（1.9克，10毫莫耳）溶於CH2C12 (100 毫升）之溶液。在室溫下於此溶液中加入EDCI (2· 95克，10 耄莫耳）、DMAP(1.2克，10毫莫耳）、及4-鄰曱苯脲基一 3 -甲乳苯乙酸（3 · 1 5克，1 0毫莫耳）。使反應混合物挽拌4小 時，然後經由加入IN HC1使反應停止，以EtOAc萃取3x， 乾燥，及於真空中濃縮。將此粗製醯胺進行層析（5% Me〇H /CH2C12)而得1·95克之期望產物。 將酯（1.95克，4.2毫莫耳）溶解於1:1 THF-H20，並在室 溫下加入Li0H。然後使反應混合物攪拌3小時。將溶液倒 入至IN HC1中，並以EtOAc萃取水層3x。將結合的有機層 以水、鹽水洗滌，並於無水硫酸鎂上乾燥。將溶液過濾， 並將溶劑於減壓下移除。然後利用冷乙醚將固體研製而得 1· 65克之期望的羧酸222。 實施例1 9 7\\312\2d-code\90-01\89112968.ptd Page 651 1283240 V. INSTRUCTIONS (647) Adding a catalytic amount of 10% Pd/C, followed by Paler hydrogenation at 40 psi for 4 hours to carry out the olefin The hydrogenation was carried out and the resulting alkane was used without purification. The ". group was removed by the addition of 1:1 TFA / CH2C 12 at room temperature. The reaction was allowed to stand for 2 hours and the solvent was removed in vacuo. The crude amine s. 9 g was purified without further purification. Use to produce a solution of the above free amine (1.9 g, 10 mmol) dissolved in CH2C12 (100 mL). Add EDCI (2.95 g, 10 Torr) to DMAP at room temperature. 1.2 g, 10 mmol, and 4-o-phenylurea-3-3-methylphenylacetic acid (3 · 15 g, 10 mmol). The reaction mixture was allowed to mix for 4 hours and then added via IN. The reaction was quenched with EtOAc (EtOAc) (EtOAc m.jjjjjjjj </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; The organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. The solution was filtered and the solvent was removed under reduced pressure. The solid was triturated to give 1. 65 g of the desired carboxylic acid 222. Example 197

於8-胺基辛酸甲酯（2·0克，12毫莫耳）溶於1:1二氧陸Methyl 8-aminooctanoate (2.0 g, 12 mmol) dissolved in 1:1 dioxane

\\312\2d-code\90-01\89112968.ptd 第 652 頁 1283240 五、發明說明（648) 圜：水（100毫升）之溶液中加入B〇c酐（2·8克，13毫莫耳） 及Kz CO3 ( 1 0克）。使此溶液在室溫下攪拌1 4小時。然後將反 應倒入至IN HC1中，以EtOAc萃取3x，乾燥，並於真空中 濃縮。將此粗製胺基甲酸酯進行層析（50% EtOAc /己烧） 而得2. 7克之期望產物。 將Boc-經保護胺經由將其置於THF( 75毫升）中，隨後在 - 78°C下加入LiHMDS(25毫升之2.0 Μ溶液，50毫莫耳），然 後使此溶液攪拌3 0分鐘，並將碘甲烷（7 · 2克，5 0毫莫耳） 以一份加入，並使反應混合物升溫至室溫隔夜而曱基化。 經由加入IN HC1使反應停止，以EtOAc萃取3χ，乾燥，及 於真空中）展备§。將粗製之甲基化胺基甲酸g旨進行層析（5 〇 % EtOAc /己烷）而得1.9克之期望的二甲基產物。 經由在室溫下加入1 : 1 TFA/CH2C1將Boc基團移除。使反 應攪拌2小時，並將溶劑於真空中移除。將粗製胺9 〇〇毫克 不經進一步的純化而使用。 產生以上之自由胺（900毫克，4. 5毫莫耳）溶於CH2C12 (1 0 0毫升）之溶液。在室溫下於此溶液中加入EDc丨（8丨.3 3 克’ 4· 5毫莫耳）、DMAP( 567毫克，4· 5毫莫耳）、及4-鄰曱 苯脲基-3-甲氧苯乙酸（1·45克，4.6毫莫耳）。使反應混合 物攪拌4小時，然後經由加入IN HC1使反應停止，以Et0Ac 萃取3x ’乾燥’及於真空中濃縮。將此粗製醯胺進行層析 (5% MeOH /CH2C12)而得1· 2克之期望產物。 將酯（1·2克，2.4毫莫耳）溶解於1:1 THF-H20，並在室 溫下加入Li0H。然後使反應混合物攪拌3小時。將溶液倒\\312\2d-code\90-01\89112968.ptd Page 652 1283240 V. INSTRUCTIONS (648) 圜: Add B〇c anhydride to the solution of water (100 ml) (2·8 g, 13 mmol) Ear) and Kz CO3 (10 grams). This solution was stirred at room temperature for 14 hours. The reaction was then poured into EtOAc (3 mL),EtOAcEtOAc The resulting product was obtained by chromatography (50% EtOAc / hexanes). The Boc-protected amine was placed in THF (75 mL), then LiHMDS (25 mL of a solution of EtOAc, 50 mM) was added at -78 ° C, then the solution was stirred for 30 min. Methyl iodide (7.2 g, 50 mmol) was added in one portion and the reaction mixture was allowed to warm to room temperature overnight. The reaction was quenched by the addition of IN HCl, extracted with EtOAc (3 EtOAc) and dried and evaporated. The crude methylated carbamic acid g was chromatographed (5 〇 % EtOAc / hexanes) to afford 1.9 g of the desired dimethyl product. The Boc group was removed via the addition of 1:1 TFA/CH2C1 at room temperature. The reaction was allowed to stir for 2 hours and the solvent was removed in vacuo. The crude amine 9 mg was used without further purification. A solution of the above free amine (900 mg, 4.5 mmol) dissolved in CH2C12 (10 mL) was obtained. Ec丨(8丨.3 3 g '4.55 mmol), DMAP (567 mg, 4.5 mmol), and 4-o-phthalazyl-3 were added to this solution at room temperature. - methoxyphenylacetic acid (1·45 g, 4.6 mmol). The reaction mixture was allowed to stir for 4 h then quenched with EtOAc EtOAc (EtOAc)EtOAc. The crude decylamine was chromatographed (5% MeOH / CH.sub.2 C.sub.2) to afford 1-2 g of desired product. The ester (1.2 g, 2.4 mmol) was dissolved in 1:1 THF-H20 and LiOH was added at room temperature. The reaction mixture was then stirred for 3 hours. Pour the solution

| \\312\2d-code\90-01\89112968.ptd 第653頁 1283240 五、發明說明（649) ：-- 入至IN HC1中，並以Et〇Ac萃取水層仏。將結合的有機層 以水、鹽水洗滌，然後於無水硫酸鎂上乾燥。將溶液過 濾，並將溶劑於減壓下移除。然後利用冷乙醚將固體研製 而得1· 01克之期望的羧酸223。 實施例1 9 8\\312\2d-code\90-01\89112968.ptd Page 653 1283240 V. INSTRUCTIONS (649) :-- Enter IN HC1 and extract the water layer with Et〇Ac. The combined organic layers were washed with water, brine and dried over anhydrous magnesium sulfate. The solution was filtered and the solvent was removed under reduced pressure. The solid was then triturated with cold diethyl ether to give 1.01 g of the desired carboxylic acid 223. Example 1 9 8

224 在^胺基笨乙酸（10克，66毫莫耳）於1··1 CH2C12:丙酮 (j 0 0毫升）之懸浮液中加入鄰甲苯異氰酸酯（8 8克，6 6毫 莫耳）。使混合物迴流加熱2小時，此時生成白色沈澱物c 將沈澱物過濾，並將固體以大量1:1 CH2C12 ··丙酮洗滌。 將固體利用熱甲醇再結晶，並於真空中乾燥而得141克 (75%產率）之期望的4-（鄰甲苯脲基）苯乙酸224。 實施例1 9 9To a suspension of 1 -aminoacetic acid (10 g, 66 mmol) in 1·1 CH2C12: acetone (j 0 mL) was added o-toluene isocyanate (8 g, 6 6 m). The mixture was heated under reflux for 2 hours at which time a white precipitate was formed to crystallize the precipitate, and the solid was washed with a large amount of 1:1 CH2C12··acetone. The solid was recrystallized from hot methanol and dried in vacuo to yield 141 g (yield: Example 1 9 9

225 在2胺基—4,噻唑乙酸（4克，25毫莫耳）於1:1 CH2C1 : 丙，(/〇〇毫升）之懸浮液中加入鄰曱苯異氰酸酯（3· 5克， 2 6毫莫耳）。使混合物迴流加熱8小時，此時生成黃色沈澱 物。將沈殺物過渡，並將固體以大量1 : 1 CH2C12 ··丙酮洗 體利用熱甲醇再結晶，並於真空中乾燥而得4· 8 。產率）之期望的2-(鄰甲苯脲基）—4—噻唑乙酸225。225 In the suspension of 2Amino-4, thiazoleacetic acid (4 g, 25 mmol) in 1:1 CH2C1: propyl, (/ml), o-phenylene isocyanate (3.5 g, 2 6 Millions of ears). The mixture was heated under reflux for 8 hours at which time a yellow precipitate formed. The precipitate was transferred and the solid was recrystallized from hot methanol with a large amount of 1:1 CH2C12·· acetone wash and dried in vacuo to give 4.8. The desired 2-(o-tolualdehyde)-4-thiazoleacetic acid 225.

第654頁 ；1283240 五、發明說明（650) 實施例200Page 654; 1283240 V. Description of the Invention (650) Example 200

將3-溴-4-羥基苯甲腈（5. 〇〇克，25· 25毫莫耳）溶解於 DMF。加入苯曱溴（4.75克，27.78毫莫耳，3.30毫升）及 Cs2C〇3(16.45克’50.50毫莫耳），並使反應加熱至2 小時。將溶液冷卻至室溫，並倒入至IN HC1中。將水層以 乙酸乙酯萃取2χ。將結合的有機層以水、鹽水洗條，然後 於MgS〇4上乾燥。將溶液過濾，並將溶劑於減壓下移除。 利用急速層析將產物分離。（己烷至8 : 1己烷-乙酸乙酽 量8·90 克226 。3-Bromo-4-hydroxybenzonitrile (5. gram, 25.25 mmol) was dissolved in DMF. Phenylhydrazine bromide (4.75 g, 27.78 mmol, 3.30 ml) and Cs2C〇3 (16.45 g &apos;50.50 mmol) were added and the reaction was heated to 2 h. The solution was cooled to room temperature and poured into IN HC1. The aqueous layer was extracted with 2 EtOAc. The combined organic layers were washed with water, brine and dried over MgS 4 . The solution was filtered and the solvent was removed under reduced pressure. The product was isolated by rapid chromatography. (Hexane to 8:1 hexane-acetic acid acetamidine 8.90 g 226 。).

h3c/ch3h h3cH3c/ch3h h3c

227 在氬氣中將3一溴一4-羥基苯甲腈（1· 50克，5· 21毫莫耳） f解於無水DMF，並使溶液冷卻至(TC。將BH3-THF (10.41 笔升二10· 41毫莫耳）經由注射器於5分鐘内加入。然後使 反應0物升溫至室溫’接著迴流加 2小時。 慢加入甲醇。當不再觀察到放氣二 (ι Μ 至，皿，^並加入過量的IN NaOH溶液。加入b〇C2〇 .5· 73毫莫耳），並使反應混合物在室溫下攪拌12 ”守。將溶液倒入至1N HC1中，並以乙酸乙酯萃取水層227 3 -Bromo- 4-hydroxybenzonitrile (1·50 g, 5·21 mmol) was dissolved in anhydrous DMF under argon, and the solution was cooled to (TC. BH3-THF (10.41)升二·10·41 mmol) was added via syringe over 5 minutes. The reaction was then allowed to warm to room temperature. Then reflux was added for 2 hours. Slowly added methanol. When no venting was observed (1 ι ,, Dish, and add an excess of IN NaOH solution. Add b〇C2〇.5·73 mmol(), and stir the reaction mixture at room temperature for 12 ”. Pour the solution into 1N HCl and use acetic acid. Ethyl ether extraction layer

1283240 I、發明綱（651) ' &quot;： &quot; ：--~~~ 3x。將結合的有機層以水、鹽水洗滌，接著於“3〇4上乾 燥。將溶液過濾，並將溶劑於減壓下移除。利用急速層 將產物分離。（7:1 ^酸乙酯-己烷）產量18〇克227。 h3c ch3 228 在氬氣中將Boc-經保護苯甲胺（1·8〇克，毫莫耳）溶 解於無水THF中。將反應冷卻至—78 t。將雙（三甲矽烷基） 醯胺鋰（13·77毫升，13.77毫莫耳）於1〇分鐘内加入。將反 應在-78°C下攪拌1小時，快速加入碘甲烷（1· 95毫升， 13· 77毫莫耳，〇· 86毫升）。使反應緩慢升溫至室溫，並攪 拌隔夜。將反應倒入至1 N HC1中，並以乙酸乙酯萃取水層 3x。將溶液過濾，並將溶劑於減壓下移除。利用急速層析 將產物分離。（7:1己坑-乙酸乙酯）產量1.7〇克228。 h3c、 229 將4-（N-甲基-Boc_胺甲基）-2-溴苄氧酚（1· 70克，4· 18 毫莫耳）置於壓力管内。然後將管裝入MF、醋酸鈉（〇· 38 克，4· 60毫莫耳）、dppp(0· 35克，〇·84毫莫耳）、及 Pd(0Ac)2 ( 0· 1 9克，0· 84毫莫耳）。將管以氬氣沖洗1 〇分 鐘，然後加入丙烯酸甲酯（0.40克，4. 60毫莫耳，0.41毫 升）。將管密封，並加熱至1 3 5 °C 2 4小時。使反應冷卻至01283240 I. Invention (651) ' &quot;: &quot; :--~~~ 3x. The combined organic layers were washed with water, brine, then dried over &lt;3&gt;4. The solution was filtered and the solvent was removed under reduced pressure. The product was separated using a rapid layer. (7:1 &lt; Hexane) Yield 18 gram 227. h3c ch3 228 Boc-protected benzylamine (1·8 gram, millimolar) was dissolved in anhydrous THF under argon. The reaction was cooled to -78. Bis(trimethyldecyl) lithium decylamine (13.77 ml, 13.77 mmol) was added over 1 min. The reaction was stirred at -78 °C for 1 hour and iodomethane (1·95 mL, 13) was quickly added. · 77 mmol, 〇· 86 ml). The reaction was slowly warmed to room temperature and stirred overnight. The reaction was poured into 1 N EtOAc, and the aqueous layer was extracted 3× with ethyl acetate. The solvent was removed under reduced pressure. The product was isolated by flash chromatography. (7:1 hexanes-ethyl acetate) yield 1.7 gram 228. h3c, 229 4-(N-methyl-Boc-amine methyl -2-Bromobenzylphenol (1·70 g, 4·18 mmol) was placed in a pressure tube, then the tube was charged with MF, sodium acetate (〇·38 g, 4·60 mmol), dppp (0 · 35 g, 〇·84 mmol, and Pd(0Ac) 2 (0.19 g, 0·84 mmol). Rinse the tube with argon for 1 , minutes, then add methyl acrylate (0.40)克, 4.60 mmol, 0.41 ml). The tube was sealed and heated to 1 3 5 ° C for 4 hours. The reaction was cooled to 0.

[W312\2d-code\90-01\89112968.ptd 第 656 頁 1283240 五、發明說明（652) C，並將管緩慢打開。將 乙酯萃取水層3x。將結合的有機=1N HC1中’並以乙酸 於MgS〇4上乾燥。將溶液 θ以水、鹽水洗滌，接著 利用急速層析將產物分離Γ(6 ^將溶劑於減壓下移除。 克229。 物刀離。（6:1己燒-乙酸乙醋）產量112 Η3ατγΗ Ύ0 將不飽和酯（3 07. 40毫克，〇 古2i〇 、 並加入過量m。使反=室下U耳）溶解於叫“， f下移除’並將殘留物於高度真空中乾燥。將溶劑；:減 及將殘留物溶解於乙酸乙酯中，&amp;以飽和陳〇3溶液洗 條。將有機層以水、鹽水洗條，接著於NaS〇4上乾燥。將 溶液過濾，並將溶劑於減壓下移除。將殘留物溶解於 CHCj2-DMF，並加入 H〇Bt(ll〇.99 毫克，0.892 毫莫耳）、3一 甲氧基-4-(N7-苯脲基）苯乙酸（2 58. 3 1毫克，〇· 82毫莫耳） 及EDCI ( 1 57. 20毫克，〇. 82毫莫耳）。使反應攪拌24小時。 將溶液例入至1N HC1中，並以乙酸乙酯萃取水層3x。將結 合的有機層以水、鹽水洗滌，接著於MgS〇4上乾燥。將溶。 液過濾，並將溶劑於減壓下移除。利用急速層析將產物分 離。（乙酸乙酯）產量296· 30毫克230。 刀 Η3α. rar €〇2〇Η3 h3cc ^Th ch3 HTO· 231 \\312\2d-code\90-01\89112968.ptd 第657頁 1283240 五、發明說明（653) 將不飽和酯（296 η , Λ t ^ ϋ ^ ^ φ .λ *冤克，0·49毫莫耳）溶解於EtOAc 下之ΐΐΐ Ii°APd/c(75毫克）°將氨氣以在1大氣屋 3 ί 小時。將氫氣移除，並以氬置換。 經由過濾'通過m 土而移除催化劑，並將㈣土塾以乙酸 乙酯洗滌3X。將溶劑於減壓下移除。H1_NMR僅顯現期望的 產物。無需進一步的純化。產量233.00毫克231。[W312\2d-code\90-01\89112968.ptd Page 656 1283240 V. Inventive Note (652) C, and slowly open the tube. The ethyl ester was extracted into the aqueous layer 3x. The combined organic = 1 N HCl was &apos; dried on acetic acid on MgS〇4. The solution θ was washed with water, brine, and then the product was separated by flash chromatography (6^ solvent was removed under reduced pressure. s. 229. Knife off. (6:1 hexane-ethyl acetate) yield 112 Η3ατγΗ Ύ0 will be an unsaturated ester (3 07. 40 mg, 2古 2i 〇, and add an excess of m. Let the reverse = subventricular U ear) dissolved in the so-called "removal under f" and the residue is dried in a high vacuum The solvent was reduced: and the residue was dissolved in ethyl acetate, &amp; washed with saturated sat. 3 solution. The organic layer was washed with water and brine, and then dried over Na.sub.4. The solvent was removed under reduced pressure. The residue was dissolved in CHCj2-DMF and H.sub.2B (l.sup.99 mg, 0.892 m.m.), 3-methoxy-4-(N7-phenylurea) Phenylacetic acid (2 58. 31 mg, 〇 · 82 mmol) and EDCI (1 57. 20 mg, 〇. 82 mmol). Stir the reaction for 24 hours. Add the solution to 1N HC1. The aqueous layer was extracted 3x with ethyl acetate. The combined organic layer was washed with water, brine, and then dried over &lt;RTI ID=0.0&gt; Removal. Separate the product by flash chromatography. (ethyl acetate) yield 296 · 30 mg 230. Knife 3α. rar €〇2〇Η3 h3cc ^Th ch3 HTO· 231 \\312\2d-code\90-01 \89112968.ptd Page 657 1283240 V. INSTRUCTIONS (653) Dissolve the unsaturated ester (296 η , Λ t ^ ϋ ^ ^ φ .λ * gram, 0·49 mmol) under EtOAc Ii °APd/c (75 mg) ° Ammonia gas is taken at 1 atmosphere for 3 ίh. The hydrogen is removed and replaced with argon. The catalyst is removed by filtration 'passing m soil, and (4) soil is treated with acetic acid The ester was washed 3X. The solvent was removed under reduced pressure. H1 NMR showed only the desired product. No further purification was used. Yield 233.00 mg.

H3^K/^V&quot;N^s^CC)2H 232 將酯（ 233.0 0毫克，〇·45毫莫耳）溶解於THF-Η20 (4:1) ，並加入LiOH(94· 41毫克’ 2· 25毫莫耳）。使反應混合物 在室溫下攪拌24小時。將溶液倒入至1 N HC1中，並以乙酸 乙酯萃取水層3x。將結合的有機層以水、鹽水洗滌，然後 於Na2S04上乾燥。將洛液過慮，並將溶劑於減壓下移除。 將產物以乙醚-己炼（1 : 1)冼裊，並於真空中乾燥。產量 211.58 毫克232 。 實施例201 八 ，Γ〇^〇 &gt;古，0.13宅莫耳）溶解於苯，並加入對 將羧酸（65· 00毫无 吝苗1、丄 1刀入對 ，0.06¾莫耳）。加入狄恩—史拔香 甲苯磺酸（10. 00毫无 ° ^ 89112968.ptd 1283240 五、發明說明（654) 阱，並將溶液迴流加熱2 4小時。使反應冷卻至它、w # | 土至 &gt;益，並倒 入至飽和NaHC〇3中。將有機層分離，並將水層 和 Cj θ夂乙*酉曰 卒取3x。將結合的有機層以水、鹽水洗滌，並於^ s〇上 乾燥。將溶液過濾，並將溶劑於減壓下移除。利用2条^層 析將產物分離。（4 : 1己烷-乙酸乙酯至乙酸乙酸）產^ 曰 29· 00毫克23 3。 里 實施例202H3^K/^V&quot;N^s^CC)2H 232 The ester (233.0 0 mg, 〇·45 mmol) was dissolved in THF-Η20 (4:1) and LiOH (94·41 mg' 2 was added. · 25 millimoles). The reaction mixture was stirred at room temperature for 24 hours. The solution was poured into 1 N HCl and the aqueous layer was extracted 3x with ethyl acetate. The combined organic layers were washed with water, brine and dried over Na2SO4. The solution was taken care of and the solvent was removed under reduced pressure. The product was purified by ether-hexane (1:1) and dried in vacuo. Yield 211.58 mg 232. Example 201 VIII, Γ〇^〇 &gt; ancient, 0.13 house Moer) dissolved in benzene, and added to the carboxylic acid (65·00 no seedlings 1, 丄 1 knife pair, 0.063⁄4 moles). Add Dean-Sprajto toluenesulfonic acid (10. 00 no ° ^ 89112968.ptd 1283240 V, invention (654) trap, and reflux the solution for 24 hours. Allow the reaction to cool to it, w # | To &gt; benefits, and pour into saturated NaHC〇3. Separate the organic layer and draw the water layer and Cj θ夂乙*酉曰 3x. The combined organic layer is washed with water, brine, and at ^ Dry on s. The solution was filtered, and the solvent was removed under reduced pressure. The product was separated by two chromatography. (4:1 hexane-ethyl acetate to acetic acid) yield 曰29· 00 mg 23 3. Example 202

BrN^N^C02Et 234 5-溴菸鹼酸（5·15，25·49毫莫耳）溶解於lt〇H，並加入 4 S 〇4 (1耄升）。使溶液迴流加熱2 4小時。使溶液冷卻至室 溫並濃縮。然後將溶液加至飽和NaHC〇3，並將水層以Et2〇 萃取3x。將結合的有機層於NaJO4上乾燥，過濾，並將j容 劑於減壓下移除。此產物對於下一步驟而言夠純。產量 5·42 克234 。BrN^N^C02Et 234 5-bromonicotinic acid (5·15,25·49 mmol) dissolved in lt〇H and added 4 S 〇4 (1 liter). The solution was heated to reflux for 24 hours. The solution was allowed to cool to room temperature and concentrated. The solution was then added to saturated NaHC〇3 and the aqueous layer was extracted 3× with Et.sub.2. The combined organic layers were dried over NaJO4, filtered, and the solvent was removed under reduced pressure. This product is pure enough for the next step. The output is 5.42 grams 234.

、OH 將5_溴路驗酸乙酯（5·40克，23.47毫莫耳）溶解於95% EtOH，並在室溫下緩慢加入NaBH4(8· 31克，225·69毫莫 耳）。於添加後，將溶液在室溫下攪拌24小時。將水緩慢 加至溶液，然後將混合物攪拌4小時。將EtOH於減壓下移OH 5o-bromo acid ethyl ester (5·40 g, 23.47 mmol) was dissolved in 95% EtOH, and NaBH4 (8·31 g, 225·69 mmol) was slowly added at room temperature. After the addition, the solution was stirred at room temperature for 24 hours. Water was slowly added to the solution, and then the mixture was stirred for 4 hours. Move EtOH down under reduced pressure

\\312\2d-code\90-01\89112968.ptd 第659頁 1283240 五、發明說明（655) 除，並將水層以CI^Cl萃取3χ。將結合的有機層於Na2S〇4上 乾燥，過濾’並將溶劑於減壓下移除。利用急速層析將產 物分離（2:1乙酸乙酯-己烷）產量2·12克235。\\312\2d-code\90-01\89112968.ptd Page 659 1283240 V. INSTRUCTIONS (655) In addition, the water layer is extracted 3 times with CI^Cl. The combined organic layers were dried over Na.sub.2.sub.4, filtered and solvent was removed under reduced pressure. The product was isolated by rapid chromatography (2:1 ethyl acetate-hexane) yield 2.12 g.

將苯甲醇（2· 12克，11· 28毫莫耳）溶解於Et2〇，並使 HC1 (g)發泡通過溶液1 〇分鐘。將溶液於室溫下攪拌1小 時，然後經由過濾收集固體。將固體以Et20洗滌，然後乾 餘。將HC 1鹽加至S0C12 ’並將混合物迴流加熱1 · 5小時。 使溶液冷卻至室溫’並將E t2 0於真空中乾燥。產量2 . 4 2克 236 〇Benzyl alcohol (2·12 g, 11.28 mmol) was dissolved in Et2〇, and HC1 (g) was foamed through the solution for 1 minute. The solution was stirred at room temperature for 1 hour and then the solid was collected by filtration. The solid was washed with Et20 and then dried. The HC 1 salt was added to S0C12' and the mixture was heated under reflux for 1.5 hours. The solution was allowed to cool to room temperature and the Et20 was dried in vacuo. Production 2. 4 2 grams 236 〇

在室溫下將苯甲氣（2. 42克，9· 96毫莫耳）於1小時内加 至CH3NH2(7 5· 9毫升，2· 5M溶於EtOH)。使反應於室溫下授 拌4 8小時。將溶液濃縮，並加至飽和N a H C 03。將水層以乙 酸乙酯萃取3χ。將結合的有機層於Na2S04上乾燥，過濾， 並將溶劑於減壓下移除。產量1. 19克237。Benzoic gas (2.22 g, 9.96 mmol) was added to CH3NH2 (75.9 mL, 2.5 M dissolved in EtOH) over 1 hour. The reaction was allowed to stand at room temperature for 48 hours. The solution was concentrated and added to saturated NaH03. The aqueous layer was extracted with ethyl acetate (3 EtOAc). The combined organic layers were dried over Na.sub.2SO.sub.sub.sub.sub. Yield 1. 19 g 237.

238 3-溴-5-（N-甲基胺甲基）吡啶（19· 1克，5. 01毫莫耳）溶238 3-bromo-5-(N-methylaminomethyl)pyridine (19·1 g, 5. 01 mmol)

\\312\2d-code\90-01\89112968.ptd 第660頁 1283240\\312\2d-code\90-01\89112968.ptd Page 660 1283240

解於DMF，並加入三乙胺（0·90克，124毫升，8 89毫莫 耳）。加入Β〇4〇(1·55克，7·1〇毫莫耳），並使反應混合 在室溫下攪拌48小時。將溶液倒入至丨N HC1中，並以乙萨 乙醋萃取水層3x。將結合的有機層以水、鹽水洗滌，並= NaJO4上乾燥。將溶液過濾，並將溶劑於減壓下移除。利〈 用急速層析將產物分離（2%甲醇-ch2C12)產量1· 6克238。 將α -甲基丙烯酸之鈉鹽（500克，46·27毫莫耳）溶解於 DMF ’並在室溫下加入苯甲溴（8· 7〇克，5〇· 89毫莫耳）。然 後加入碳酸鉀（7. 03克，50· 89毫莫耳），並使溶液加熱至… 5 0 °C 24小時。將溶液倒入至&quot;JJC1中，並以乙醚萃取水 層3x，。將結合的有機層以水、鹽水洗滌，並於Na2S04上乾 燥。將溶液過濾，並將溶劑小心地於減壓下移除。利用急 速層析將產物分離（2%乙醚-戊烷）產量6. 93克239。Solution to DMF and add triethylamine (0·90 g, 124 ml, 8 89 mmol). Β〇4〇 (1·55 g, 7.1 mmol) was added, and the reaction mixture was stirred at room temperature for 48 hours. The solution was poured into 丨N HCl and the aqueous layer was extracted 3x with EtOAc. The combined organic layers were washed with water, brine, and dried on NaJO4. The solution was filtered and the solvent was removed under reduced pressure. The product was isolated by flash chromatography (2% methanol-ch2C12) yield 6.6 g 238. The sodium salt of α-methacrylic acid (500 g, 46·27 mmol) was dissolved in DMF ' and benzyl bromide (7.8 g, 5 〇 89 mmol) was added at room temperature. Then potassium carbonate (7.03 g, 50·89 mmol) was added and the solution was heated to 50 ° C for 24 hours. Pour the solution into &quot;JJC1 and extract the aqueous layer 3x with diethyl ether. The combined organic layers were washed with water, brine and dried over Na2SO. The solution was filtered and the solvent was carefully removed under reduced pressure. The yield of the product was separated by flash chromatography (2% diethyl ether-pentane).

將3-溴-5 -（N-甲基-B〇c-胺甲基）咄啶（700.00毫克， 2.33毫莫耳）置於壓力管内。然後將管裝入、三乙胺 (260.05 毫克，2.57毫莫耳，〇.36毫升）、（1???( 1 93.85 毫 克 ’ 〇· 47 毫莫耳）、&amp;Pd(〇Ac)2(105· 52 毫克，〇· 47 毫莫 耳）°將管以氬氣沖洗1 〇分鐘，然後加入曱基丙烯酸苄酯3-Bromo-5-(N-methyl-B〇c-aminemethyl)acridine (700.00 mg, 2.33 mmol) was placed in a pressure tube. The tube was then charged with triethylamine (260.05 mg, 2.57 mmol, 〇.36 ml), (1 ??? (1 93.85 mg ' 〇 · 47 mM), &amp; Pd (〇Ac) 2 (105· 52 mg, 〇·47 mmol) ° Flush the tube with argon for 1 , minutes, then add benzyl methacrylate

12832401283240

^52.=6¾克，2·57毫莫耳），將管密封，並加熱至135〇c 24小日守。使反應冷卻至(rc ’並將管緩慢打開。將溶液倒 :至1N ΗΠ中’並以乙酸乙醋萃取水層3χ。將結合的有機 層以水、鹽水洗滌，並於MgS〇4上乾燥。將溶液過滤，並 將溶劑於減壓下移除。利用急迷層析將產物分離(6:1己烷 -乙酸乙酯）產量78 5. 23毫克240。^52.=63⁄4g, 2.57 millimoles), seal the tube and heat it to 135〇c 24 hours. The reaction was cooled to (rc ' and the tube was slowly opened. The solution was poured into 1 N ΗΠ 并 and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water, brine and dried over MgSO. The solution was filtered, and the solvent was removed under reduced pressure. The product was separated (6:1 hexane-ethyl acetate) by flash chromatography.

將不飽和醋（3 92.61毫克，0.99毫莫耳）溶解於(：112(：12， 並加入過量TFA。使反應在室溫下攪拌4小時。將溶劑於減 壓下移除’並將殘留物於咼度真空中乾燥。將溶劑移除， 及將殘留物溶解於乙酸乙酯中，並以飽和NaHC03溶液洗 滌。將有機層以水、鹽水洗滌，接著於NaS04上乾燥。將 溶液過濾，並將溶劑於減壓下移除。將殘留物溶解於 CH2C12-DMF，並加入HOBt(147.53 毫克，ι·〇9 毫莫耳）、3一 甲氧基-4 - [Ν’ -（苯脲基）苯乙酸（342. 64毫克，1·〇9毫莫 耳）及EDCK2 08· 96毫克，1· 09毫莫耳）。使反應攪拌24小 時。將溶液倒入至1 N HC 1中，並以乙酸乙酯萃取水層3 χ。 將結合的有機層以水、鹽水洗滌，接著於MgS04上乾燥。 將溶液過濾，並將溶劑於減壓下移除。利用急速層析將產 物分離。（乙酸乙酯）363· 79毫克241。Dissolve the unsaturated vinegar (3 92.61 mg, 0.99 mmol) in (: 112 (: 12, and add excess TFA. Allow the reaction to stir at room temperature for 4 hours. Remove the solvent under reduced pressure) and leave the residue The mixture was dried over EtOAc (EtOAc). The solvent was removed under reduced pressure. The residue was dissolved in CH2C12-DMF, and HOBt (147.53 mg, ι·〇9 mM), 3-methoxy-4-[[]-(phenylurea) Phenylacetic acid (342.64 mg, 1·〇9 mmol) and EDCK2 08·96 mg, 1.09 mmol. The reaction was stirred for 24 hours. The solution was poured into 1 N HC 1 . The aqueous layer was extracted with EtOAc (3 mL). EtOAc (EtOAc)EtOAc. (ethyl acetate) 363·79 mg 241.

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242 將不飽^酯（ 3 63· 〇〇毫克，〇· 6 1毫莫耳）溶解於CH3〇H 中，並在氬氣中加入Pd/C(l 00· 〇0毫克）。將氬氣以在J大 氣壓下之氫置換，並攪拌24小時。將氫氣移除，並以氬置 換。經由過濾通過矽藻土而移除催化劑，並將矽藻土墊以 乙酸乙酯洗滌3x。將溶劑於減壓下移除qH1-NMR僅顯現期 望的產物。將固體以乙醚洗滌，並於高度真空中乾燥。遙 量254· 79毫克24 2。 八 實施例2 0 3242 Dissolve the unsaturated ester (3 63· 〇〇 mg, 〇·6 1 mmol) in CH 3 〇H, and add Pd/C (100 〇 0 mg) to argon. Argon was replaced with hydrogen at J atmosphere and stirred for 24 hours. The hydrogen was removed and replaced with argon. The catalyst was removed by filtration through diatomaceous earth and the celite pad was washed 3x with ethyl acetate. The solvent was removed under reduced pressure to give the desired product. The solid was washed with diethyl ether and dried under high vacuum. Remote 254·79 mg 24 2. Eight embodiment 2 0 3

243 將3、-氰基苯甲醛（9· μ克，71· 76毫莫耳）溶解於乙 並冷卻至0 t。將NaBH4(2· 71克，71· 76毫莫耳）小份旦^， 加入、。將溶液在〇 °C下攪拌3〇分鐘，然後使其升溫至1地 溫，並攪拌1小時。將反應緩慢倒入至丨N Hc丨中，並^ 酸乙酯萃取水層3χ。將結合的有機層以水、鹽水洗浓^，乙、 後於MgS〇4上乾燥。將溶液過濾，並將溶劑於減壓下移 除。將殘留物溶解於DMF，並加入咪唑（2· 08克，3〇 5〇古243 3,-Cyanobenzaldehyde (9 μg, 71·76 mmol) was dissolved in B and cooled to 0 t. NaBH4 (2·71 g, 71·76 mmol) was added in small portions. The solution was stirred at 〇 ° C for 3 Torr, then allowed to warm to 1 temp. and stirred for 1 hr. The reaction was slowly poured into 丨N Hc丨, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water, brine, and dried over MgS 4 . The solution was filtered and the solvent was removed under reduced pressure. The residue was dissolved in DMF and added with imidazole (2. 08 g, 3 〇 5 〇 ancient

\\312\2d-code\90-01\89112968.ptd 第663頁 1283240 五、發明說明（659) ^耳），然後再加入TBDPSCIU.61克，16.78毫莫耳，436 毫升），並使反應在室溫下攪拌1 2小時。將溶液倒入至工n HC1中，並以乙酸乙醋萃取水層3χ。將結合的有機層以 水、鹽水洗滌，然後於MgS〇4上乾燥。將溶液過濾，S 溶劑於減壓下移除。利用急速層析將產物分離。“（7 .【己 -乙酸乙酯至4·· 1己烷-乙酸乙酯）產量16· 23克24 3。· 吮 H3 h3 244 將經矽烷基保護3-氰基苯甲醇（8· 50克，34· 36毫 溶解於乙酸乙酯，並加入Bo A 0(8.25克，37. 7g毫1耳） 加入Pd/C(l· 0克），並利用50 psi下之氫將帕爾1器加 壓。將容器振搖24小時，然後利用氬氣將氫沖掉/並1^ 過濾、通過石夕藻土塾而移除催化劑。將石夕萍土 w W〆 U /所工从乙酸乙g旨洗 滌3x。將溶劑於減壓下移除，並利用急速芦榀 〜/日竹將產物分離 (10:1己烷-乙酸乙酯）產量11· 10克244。\\312\2d-code\90-01\89112968.ptd Page 663 1283240 V. Description of invention (659) ^ ear), then add TBDPSCIU.61g, 16.78 millimolar, 436 ml), and react Stir at room temperature for 12 hours. The solution was poured into the work HC1 and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, brine and dried over MgSO 4 . The solution was filtered and the S solvent was removed under reduced pressure. The product was isolated by rapid chromatography. "(7. [hexyl-ethyl acetate to 4··1 hexane-ethyl acetate) yield 16 · 23 g 24 3 ·· 吮H3 h3 244 protected by decyl alkyl 3-cyanobenzyl alcohol (8 · 50克, 34·36 mM dissolved in ethyl acetate, and added Bo A 0 (8.25 g, 37.7 g lb 1 lb) to Pd/C (1.0 g), and using Palladium at 50 psi Pressurize the vessel. Shake the vessel for 24 hours, then flush the hydrogen with argon gas and filter it through the Shixiazao soil to remove the catalyst. The solvent was washed 3x, the solvent was removed under reduced pressure, and the product was separated (10:1 hexane-ethyl acetate) using a rapid reed ~/Nippon bamboo to yield 11.10 g of 244.

245 在氬氣中將經0-石夕烧基-N-Boc〜保護之笨甲醇（5 〇〇 14.22毫莫耳）溶解於無水了1^中。將反應冷卻至—78。〇克：’ 雙（三甲矽烷基）醯胺鋰（42.67毫升，42. 67毫莫耳）於。1 鐘内加入。將反應在-78 °C下攪拌1小時，然德此於1 〇分 …、1文贤迷加入操 甲烷（6.06克，42·67毫莫耳，2.66毫升）。佶只愈 ^ 1定反應緩慢升245 The o-methanol (5 〇〇 14.22 mmol) protected with 0-stone-N-Boc~ was dissolved in anhydrous water under argon. The reaction was cooled to -78. 〇克: 'Bis(trimethyldecyl) guanamine lithium (42.67 ml, 42.67 mmol). Join within 1 hour. The reaction was stirred at -78 °C for 1 hour, then it was added to methane (6.06 g, 42.67 mmol, 2.66 ml) at 1 〇.佶 only more than 1

1283240 五 、發明說明（660) 溫至室溫’並攪拌隔夜。將反應倒入至1N HC1中，並以乙 酸乙S旨萃取水層3x。將溶液過濾，並將溶劑於減壓下移 除。利用急速層析將產物分離。（2 %乙酸乙酯—己烧）產量 4 · 7 克2 4 5 〇1283240 V. INSTRUCTIONS (660) Warm to room temperature and stir overnight. The reaction was poured into 1N HCl and the aqueous layer was extracted 3x with ethyl acetate. The solution was filtered and the solvent was removed under reduced pressure. The product was isolated by rapid chromatography. (2% ethyl acetate-hexane) yield 4 · 7 g 2 4 5 〇

246 在室溫下將經〇-矽烷基-N-Boc -保護之苯甲醇（4.7克， 9· 60毫莫耳）溶解於THF及TBAF(14· 39毫升，1· 〇M溶於 THF)。將溶液攪拌4小時。tlc顯示不存在起始物料。將反 應倒入至IN HC1中，並以乙酸乙酯萃取水層3χ。將溶液過 濾，並將溶劑於減壓下移除。利用急速層析將產物分離。 (4:1己烷-乙酸乙酯至己烷—乙酸乙酯）產量2 39 246。 ·246 Benzyl-N-Boc-protected benzyl alcohol (4.7 g, 9·60 mmol) was dissolved in THF and TBAF (14·39 mL, 1·M in THF) at room temperature. . The solution was stirred for 4 hours. Tlc shows that there is no starting material. The reaction was poured into IN HC1 and the aqueous layer was extracted with ethyl acetate. The solution was filtered and the solvent was removed under reduced pressure. The product was isolated by rapid chromatography. (4:1 hexane-ethyl acetate to hexane-ethyl acetate) yield 2 39 246. ·

247 在氬氣中將經Ν-曱基B〇c-保護之苯甲醇（1〇〇克，3 ，莫耳）溶解於無水ch2ci2中。加入三笨膦（1.·46克，5\57 鼋莫耳），並使溶液冷卻至〇°c。將溶解於無水CH2Ci中 四溴化碳（1.85克，5. 57毫莫耳）於1〇分鐘内加入。^溶液 於〇 °C下If ΦΗ小時，，然後將溶劑於減壓下移除。將殘/物 溶解於Eta，並經由過濾將所產生之固體移除，收集濾 液，並將溶劑於減壓下移除。利用急速層析將產物^247 The hydrazine-fluorenyl B 〇 c-protected benzyl alcohol (1 gram, 3, mole) was dissolved in anhydrous ch 2 ci 2 under argon. Add triphenylphosphine (1.·46 g, 5\57 mol) and allow the solution to cool to 〇°c. Dissolved in anhydrous CH2Ci, carbon tetrabromide (1.85 g, 5.57 mmol) was added over 1 minute. ^ Solution If Φ Η hours at 〇 ° C, then remove the solvent under reduced pressure. The residue was dissolved in Eta, and the resulting solid was removed by filtration, the filtrate was collected, and the solvent was removed under reduced pressure. Rapid product chromatography

\\312\2d-code\90-01\89112968.ptd 第665頁 248 1283240 五、發明說明（661) (2%乙醚-戊烧）產量1· 15克247\\312\2d-code\90-01\89112968.ptd Page 665 248 1283240 V. Description of Invention (661) (2% Ethyl-Ethylene) Production 1·15 g 247

och3 h3 H3CACH3 亡㈠3 在氬氣中在-78°C下，將LHMDSC3.23毫升，3.23毫莫耳） 加至無水DME中。將溶解於無水j)ME中之丁酸甲酯（3〇〇'古 克，2. 94毫莫耳，0.33毫升）於15分鐘内加入 在-78 °C下攪拌1小時。將溶解於無水DME中之經3 —N—甲基 -N-Boc-保護之苯甲溴（1· 〇2克，3· 23莫耳）於15分鐘内二 至此烯醇酯溶液，然後使溶液緩慢升溫至—2 〇CJc，並攬拌4 小時。將反應倒入至IN HC1中，並以乙酸乙酯萃取水層 3x。將溶液過濾’並將溶劑於減壓下移除。利用急速層析 將產物分離。（3%乙酸。乙酯-己烷）產量4U毫克248。曰Och3 h3 H3CACH3 (3) 3 LHMDSC (3.23 ml, 3.23 mmol) was added to anhydrous DME at -78 °C under argon. Methyl butyrate (3 〇〇 'guc, 2.94 mmol, 0.33 ml) dissolved in anhydrous j) ME was added over 15 minutes and stirred at -78 °C for 1 hour. 3-N-methyl-N-Boc-protected benzyl bromide (1·2 g, 3·23 mol) dissolved in anhydrous DME was added to the enol ester solution in 15 minutes, and then The solution was slowly warmed to -2 〇CJc and stirred for 4 hours. The reaction was poured into 1 HCl and the aqueous layer was extracted 3× with ethyl acetate. The solution was filtered&apos; and the solvent was removed under reduced pressure. The product was isolated by rapid chromatography. (3% acetic acid. ethyl ester-hexane) yield 4 U mg 248.曰

WY^〇ch3 將Boc酯（121.60毫克，0·36毫莫耳）溶解於ch2c12，並加 入過量三氟乙酸。然後使反應攪拌2小時。將溶劑移除， 並將殘留物溶解於乙酸乙酯中，並以飽和NaHC03溶液洗 滌。將有機層以水、鹽水洗滌，接著於Na2s〇4上乾燥。將 溶液過濾，並將溶劑於減壓下移除。將殘留物溶解於 CH2CI2-DMF ’ 並加入HOBt(54.1〇 毫克，〇·4〇 毫莫耳）、3一曱 氧基-4-(Ν’-(苯脲基）苯乙酸（125.74毫克，〇·40毫莫耳） 及EDCI (77. 0毫克’ 〇· 40毫莫耳）。使反應攪拌24小時。將WY^〇ch3 Boc ester (121.60 mg, 0·36 mmol) was dissolved in ch2c12, and excess trifluoroacetic acid was added. The reaction was then stirred for 2 hours. The solvent was removed, and the residue was dissolved in ethyl acetate and washed with sat. NaHC03. The organic layer was washed with water, brine and dried over Na2s. The solution was filtered and the solvent was removed under reduced pressure. The residue was dissolved in CH2CI2-DMF' and HOBt (54.1 mg, 〇·4 mmol), 3-methoxy-4-(Ν'-(phenylureido)phenylacetic acid (125.74 mg, 〇) was added. · 40 millimoles) and EDCI (77. 0 mg '〇 40 mmol). Stir the reaction for 24 hours.

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五、發明說明（662) KG至？，中’並以乙酸乙酯萃取水層I將結合 ^慮’並將溶劑於減壓下移除。利用急逮層析將 離。（乙酸乙酯）產量1 65. 20毫克249。V. Description of the invention (662) KG to? , and the aqueous layer I was extracted with ethyl acetate to combine and the solvent was removed under reduced pressure. Use emergency arrest chromatography to separate. (ethyl acetate) yield 1 65. 20 mg 249.

將酯（16· 20，0· 31毫莫耳）溶解於乙醇—水（4:丨），並加 入N_aOH。然後使反應加熱至5〇。〇 2小時。tlc(乙酸乙酯） 顯示不存在起始物料。將反應冷卻至室溫。將溶液倒入至 IN HC1中，並將水層以乙酸乙酯萃取3χ。將結合的有機層 以水、鹽水洗滌，然後於MgS〇4上乾燥。將溶液過濾，並 將/容劑於減壓下移除。使殘留物自乙酸乙酯-己烷再結 晶。產量120.00毫克250。 實施例204The ester (16·20, 0.13 mmol) was dissolved in ethanol-water (4: 丨) and N_aOH was added. The reaction was then heated to 5 Torr. 〇 2 hours. Tlc (ethyl acetate) showed no starting material. The reaction was cooled to room temperature. The solution was poured into IN HC1 and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, brine and dried over MgS 4 . The solution was filtered and the solvent was removed under reduced pressure. The residue was recrystallized from ethyl acetate-hexane. The yield is 120.00 mg 250. Example 204

251 在氬氣中在-78 °C下，將丁内酯（250毫克，2.90毫莫 耳’223.20毫升）於1〇分鐘内加至LHMDS( 2. 90毫升，1. 0 Μ251 Butyrolactone (250 mg, 2.90 mmol) 223.20 mL was added to LHMDS (2. 90 mL, 1.0 Μ) over 1 min in argon at -78 °C.

溶於己烷）溶於THF。使溶液在-7 8 °C下攪拌1小時。將溶解 於無水DME中之經3-N-曱基-N-Boc-保護之苯曱溴（991· 24 毫克，2 · 9 0毫莫耳）於1 5分鐘内加至此烯醇酯溶液，然後 使溶液緩慢升溫至室溫，並攪拌1 2小時。將反應倒入至1 NDissolved in hexane) dissolved in THF. The solution was stirred at -78 ° C for 1 hour. The 3-N-mercapto-N-Boc-protected phenylhydrazine bromide (991.24 mg, 2·90 mmol) dissolved in anhydrous DME was added to the enol ester solution over 15 minutes. The solution was then slowly warmed to room temperature and stirred for 12 hours. Pour the reaction to 1 N

\\312\2d-code\90-01\89112968.ptd 第667頁 1283240 五、發明說明（663) HVr並以乙酸乙酯萃取水層3X。將溶液過滤'，並將溶 刎於減壓下移除。利用急速層析將產物分離。（4:1己烷一 乙酸乙酯至1:1乙酸乙己烷)產量5〇118毫克251 。 H3ca\\312\2d-code\90-01\89112968.ptd Page 667 1283240 V. INSTRUCTIONS (663) HVr and extract the aqueous layer 3X with ethyl acetate. The solution was filtered and the solution was removed under reduced pressure. The product was isolated by rapid chromatography. (4:1 hexane-ethyl acetate to 1:1 ethyl acetate) yield 5〇118 mg 251. H3ca

252 將肋〇:酯（2 5 0.0 0毫克，0.78毫莫耳）溶解於(：112(：12,並加 入過量三氟乙酸。使反應攪拌2小時。將溶劑移除，並將 殘留物溶解於乙酸乙酯中，並以飽和NaHC〇3溶液洗滌。將 有機層以水、鹽水洗滌，接著KMgS〇4上乾燥。將溶液過 濾，並將溶劑於減壓下移除。將殘留物溶解於c % 一 DMF，並加入H0Bt(116· 40毫克，〇· 86毫莫耳）、32—曱2氧基 -4-（Ν’ -（苯脲基）苯乙酸（27〇· 33毫克，〇· 86毫莫耳）及土 EDCU165· 06毫克，〇· 86毫莫耳）。使反應攪拌24小時。將 溶液倒入至1 N HC1中，並以乙酸乙酯萃取水層3χ。將結合 的有機層以水、鹽水洗滌，接著於心5〇4上乾燥。將溶液 過濾，並將溶劑於減壓下移除。利用急速層析將產物分 離。（乙酸乙酯）產量119·〇〇毫克252。 實施例2 0 5 3-甲氧基-4-[2-[3 -甲氧基-4-[Ν，-（2-甲基笨基）脲基]苯 基乙醯基]-Ν-曱基胺基乙氧基]苯甲酸252 The rib: ester (2 5 0.0 0 mg, 0.78 mmol) was dissolved in (: 112 (: 12) and excess trifluoroacetic acid was added. The reaction was stirred for 2 hours. The solvent was removed and the residue was dissolved. It was washed with ethyl acetate and washed with a saturated NaHC solution. The organic layer was washed with water, brine, and then dried over KMgS.4. The solution was filtered and the solvent was removed under reduced pressure. c % a DMF, and added H0Bt (116·40 mg, 〇·86 mmol), 32-曱2 oxy-4-(Ν'-(phenylureido)phenylacetic acid (27〇·33 mg, 〇 · 86 mM) and soil EDCU 165 · 06 mg, 〇 · 86 mmol.) The reaction was stirred for 24 hours. The solution was poured into 1 N HCl and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over EtOAc EtOAc EtOAc EtOAc. 252. Example 2 0 5 3-Methoxy-4-[2-[3-methoxy-4-[indene,-(2-methylphenyl)ureido]phenylethenyl]-oxime - mercaptoamine Ethoxy]benzoic acid

CH3 (^yCOOHCH3 (^yCOOH

Cl ? 0 〇CH3 ch3h H 〇ch3 253Cl ? 0 〇CH3 ch3h H 〇ch3 253

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於N-甲基乙醇胺（3·1〇克，41·27毫莫耳）、EtN(u 8〇毫 升，84.66毫莫耳）溶於DMF —H2〇(3:1，v/v，3〇毫升）之攪 拌冷卻（0 °C )溶液中於15分鐘内逐滴加入氣甲酸辛酯 (25. 40克，49· 13毫莫耳）之30%甲苯溶液。使所產生之混 合物在室溫下攪拌1天。將混合物以Et〇Ac萃取。將萃取液 以飽和NaHC〇3、鹽水洗滌，於NaS〇4上乾燥，並蒸發。使殘 留物經由於石夕膠上利用正己烷：Et〇Ac(3: 1，v/v)接著再 利用CHCI3作為洗提液進行管柱層析，純化而得4· 67克 (54% )Ν-甲基-Ν-（爷氧羰基）乙醇胺之無色油。 1-NMR (CDC13) (5 1. 82 (bs，1Η)、3· 00 (s，3Η)、3· 46 (bs， 2H) 、3·77 (bs ，2Η) 、5·13 (s， 2H) 、7·29-7 36 (m， 5H)。 於4-羥基-3-甲氧苯甲酸乙酯（2· 〇1克，1〇· 25毫莫耳）、 N-甲基-N-（苄氧羰基）乙醇胺（211克，ι〇〇8毫莫耳）、 PPh3 (3· 26克，12.43毫莫耳）溶於thf之攪拌溶液中加入 DIAD(2· 65毫升’ 13· 46毫莫耳），並使反應混合物迴流加 熱隔仪。將混合物蒸發，並使殘留物於石夕膠上利用正己烧 /EtOAc(5:l，v/v)作為洗提液進行短管柱層析，而得3 一曱 氧基-4-[2-甲基-2-(苄氧羰基）胺乙氧基]苯甲酸乙酯的粗 製產物。 於此粗製產物（5.20克，13.42毫莫耳）溶於EtOH (50毫 升）之溶液中加入AcOH(5毫升），並使溶液在5% pd/C上氫 化4小時。將混合物過濾以移除催化劑，並將濾液蒸發。 將殘留物以CHCI3稀釋，並以飽和NaHC〇3、鹽水洗滌，於N-methylethanolamine (3.11 g, 41·27 mmol), EtN (u 8 mL, 84.66 mmol) dissolved in DMF-H2〇 (3:1, v/v, 3〇) A stirred, cooled (0 ° C) solution of ML) was added dropwise to a 30% toluene solution of octyl p-formate (25.40 g, 49·13 mmol) over 15 minutes. The resulting mixture was stirred at room temperature for 1 day. The mixture was extracted with Et 〇Ac. The extract was washed with saturated NaHC3, brine, dried over Nas. The residue was purified by column chromatography using hexane:Et〇Ac (3:1, v/v) and then using CHCI3 as an eluent to obtain 4·67 g (54%). A colorless oil of Ν-methyl-hydrazine-(- oxycarbonyl)ethanolamine. 1-NMR (CDC13) (5 1. 82 (bs, 1Η), 3·00 (s, 3Η), 3·46 (bs, 2H), 3·77 (bs, 2Η), 5·13 (s, 2H), 7·29-7 36 (m, 5H). Ethyl 4-hydroxy-3-methoxybenzoate (2·〇1 g, 1〇·25 mmol), N-methyl-N -(Benzyloxycarbonyl)ethanolamine (211 g, ι 8 mmol), PPh3 (3.26 g, 12.43 mmol) dissolved in thf stirred solution added DIAD (2·65 ml '13· 46 Milliole), and the reaction mixture was refluxed to heat the separator. The mixture was evaporated, and the residue was applied to a mixture of hexanes/EtOAc (5:1, v/v) as an eluent. The crude product of ethyl 3-methoxy-4-[2-methyl-2-(benzyloxycarbonyl)amine ethoxy]benzoate was obtained as the crude product (5.20 g, 13.42 m. AcOH (5 ml) was added to a solution of EtOH (50 ml), and the solution was hydrogenated over 5% pd / C for 4 hr. The mixture was filtered to remove the catalyst and the filtrate was evaporated. Dilute and wash with saturated NaHC〇3, brine,

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NaS04上乾燥，並蒸發。使殘留物於矽膠上利用chc“ ：NaS04 was dried and evaporated. Make the residue on the silicone using chc" :

MeOH( 10.1 V//v)作為洗提液進行層析，而得510毫克（2牛MeOH ( 10.1 V//v) was used as an eluent to give 510 mg (2 N)

驟20%)3-甲氧基-4-甲其脫r气宜、# 見C2V τ礼丞4 u甲基胺乙乳基）苯甲酸乙酯的黃色 油0 、 M-NMR (CDC13) 5 1· 39 (t，3H，J = 7· 3 Hz)、1· 82 (bs， 1H) 、2.52 (s， 3H) 、3.04 (t， 2H， J=5.3 Hz) 、3·91 (s，3H)、4·18 (t，2H，&gt;5.3 Hz)、4·36 (q，2H，J = 7· 3 Hz)、6.90 (d, 1H，J = 8.3 Hz)、7·55 (d，1H，J = 2.〇20%) 3-methoxy-4-methylpyrazine, #见C2V τ礼4u methylamine ethyl lactyl) ethyl benzoate yellow oil 0, M-NMR (CDC13) 5 1· 39 (t, 3H, J = 7· 3 Hz), 1·82 (bs, 1H), 2.52 (s, 3H), 3.04 (t, 2H, J=5.3 Hz), 3.91 (s, 3H), 4·18 (t, 2H, &gt; 5.3 Hz), 4·36 (q, 2H, J = 7.3 Hz), 6.90 (d, 1H, J = 8.3 Hz), 7·55 (d ,1H,J = 2.〇

Hz)、7· 65 (dd，1H，J = 2· 0、8· 3 Hz)。 於3-曱氧基-4-(2-甲基胺乙氧基）苯曱酸乙酯（51〇毫 克，2· 01毫莫耳）溶於DMF(1 3毫升）之攪拌溶液中加入3 -甲 氧基-4-[N’-（2-曱基苯基）脲基]苯基乙酸之五氟苯酯 (900毫克，1.87毫莫耳）及Et3N(0.420毫升，3·01毫莫 耳），並使所產生之混合物攪拌2天。將混合物以EtOAc稀 釋，以IN HC1、飽和NaHC03、鹽水洗滌，並於NaS04上乾 燥。於蒸發後，將殘留物經由於矽膠上利用CHC13 :MeOH (50:1，v/v)進行管柱層析，純化而得880毫克（85%)之3-甲氧基- 4 - [2 - [3 -曱氧基-4-[N，- (2-甲基苯基）脲基]苯基 乙醯基]-N-甲基胺基乙氧基]苯甲酸乙酯的無色非晶形固 體。 UMR (CDC13) 5 1· 37-1· 41 (m，3H)、2· 28 (s，3H)、 3.03 及 3·18 (s，3H)、3·56 (s，2Η)、3·65 (s，2H)、 3·75-3·87 (m，6H)、4· 06-4.24 ( 2H，m)、4·33-4·39 (m， 2Η)、6·68- 8.08 (m 系列，12Η)。Hz), 7·65 (dd, 1H, J = 2·0, 8·3 Hz). Add 3 to a stirred solution of ethyl 3-methoxy-4-(2-methylaminoethoxy)benzoate (51 mg, 2.01 mmol) in DMF (13 mL) -Methoxy-4-[N'-(2-mercaptophenyl)ureido]phenylacetic acid pentafluorophenyl ester (900 mg, 1.87 mmol) and Et3N (0.420 ml, 3·01 mmol) Ear) and the resulting mixture was stirred for 2 days. The mixture was diluted with EtOAc, washed with EtOAc EtOAc EtOAc. After evaporation, the residue was purified by column chromatography eluting with CHC13:MeOH (50:1, v/v) to afford 880 mg (85%) of 3-methoxy- 4 - [2 - colorless amorphous form of [3-methoxy-4-[N,-(2-methylphenyl)ureido]phenylethenyl]-N-methylaminoethoxy]benzoate solid. UMR (CDC13) 5 1· 37-1· 41 (m, 3H), 2· 28 (s, 3H), 3.03 and 3·18 (s, 3H), 3·56 (s, 2Η), 3.65 (s, 2H), 3·75-3·87 (m, 6H), 4· 06-4.24 ( 2H, m), 4·33-4·39 (m, 2Η), 6.68- 8.08 (m Series, 12Η).

1283240 五、發明說明（666) 於3-甲氧基-4-[2-[3-曱氧基-4- [Ν’ -（2-甲基苯基）脲 基]苯基乙醯基]-Ν-甲基胺基乙氧基]苯甲酸乙酯（880毫 克，1. 601毫莫耳）溶於THF(15毫升）之溶液中加入〇· 25Ν NaOH(1 5毫升）。然後使反應混合物迴流加熱隔夜。將混合 物倒入至IN HC1( 100毫升）中，並收集固體。使粗製固體 自MeOH - CHC13再結晶而得135毫克（16%)3-甲氧基-4-[2-[ 3- 甲氧基-4-Ν’-（2-甲基苯基）脲基]苯基乙醯基]- N-甲基 胺基乙氧基]苯甲酸2 53的白色粉末。 IR (KBr) 1 70 0 /公分；UMR (DMS0-d6)6 2·25 (s， 3Η)、2·50 (s, 2Η)、2.91 及3·12 (s，3Η)、3·53-3·76 (m ’2Η)、3·80 (s，3Η)、3·84 (s，3Η)、4·16-4·21 (m， 2H)、6· 72-8· 5 6 (m 系列，12H)、12· 68 (bs，1H); MS(FAB) m/z 522(MH1) ; C28H31N3 07 ·1Η20 之分析計算值·· C，62·33;Η，6.16;Ν, 6·63。實測值：c，62·17;Η， 6· 05 ; Ν，7· 57。 ’ 實施例2 0 6 4- [ [2-[3-甲氧基-4-[Ν，-（2-甲基苯基）脲基]苯基乙醯基] 甲胺基]乙氧基]異酞酸1283240 V. INSTRUCTIONS (666) on 3-methoxy-4-[2-[3-曱oxy-4-[Ν'-(2-methylphenyl)ureido]phenylethenyl] To a solution of ethyl hydrazine-methylaminoethoxy]benzoate (880 mg, 1.601 mmol) in THF (15 mL) was added EtOAc······· The reaction mixture was then heated to reflux overnight. The mixture was poured into IN HCl (100 mL) and a solid was collected. The crude solid was recrystallized from MeOH-CHC13 to yield 135 mg (16%) of 3-methoxy-4-[2-[3-methoxy-4-indole-(2-methylphenyl)ureido A white powder of phenylethenyl]-N-methylaminoethoxy]benzoic acid 2 53 . IR (KBr) 1 70 0 / cm; UMR (DMS0-d6) 6 2·25 (s, 3Η), 2·50 (s, 2Η), 2.91 and 3·12 (s, 3Η), 3·53- 3·76 (m '2Η), 3·80 (s, 3Η), 3.84 (s, 3Η), 4·16-4·21 (m, 2H), 6·72-8· 5 6 (m Series, 12H), 12·68 (bs, 1H); MS(FAB) m/z 522(MH1); C28H31N3 07 ·1Η20 analytical calculation·· C, 62·33; Η, 6.16; Ν, 6· 63. Found: c, 62·17; Η, 6· 05 ; Ν, 7. 57. 'Example 2 0 6 4- [ [2-[3-Methoxy-4-[Ν,-(2-methylphenyl)ureido]phenylethenyl]methylamino]ethoxy] Isophthalic acid

COOHCOOH

254 在室溫下於Ν-甲基-Ν-苄氧羰基乙醇胺（1〇5克，5〇2毫 莫耳）、4-羥基異酞酸二甲酯（1〇5克，500毫莫耳）、 PhsPCl· 59克，6· 06莫耳）溶於丁HF(2〇毫升）之攪拌溶液中254 at room temperature in Ν-methyl-hydrazine-benzyloxycarbonylethanolamine (1 〇 5 g, 5 〇 2 mmol), dimethyl 4-hydroxyisophthalate (1 〇 5 g, 500 mmol) ), PhsPCl·59 g, 6.06 mol) dissolved in a stirred solution of HF (2 mL)

89112968.ptd 第671頁 1283240 五、發明說明（667) 加入DIADC1· 28毫升，6. 50毫莫耳）。然後使所產生之混合 物迴流加熱隔夜。於冷卻至室溫後，將混合物蒸發。將殘 留物溶解於EtOH，並加入5% Pd/C( 200毫克）。使所產生之 攪拌混合物在1大氣壓下氫化2小時。將混合物過濾以移除 催化劑’並將滤液蒸發。使殘留物經由於石夕膠上利用 CHCl3_MeOH(30:l，v/v)作為洗提液進行管柱層析，純化 而得280毫克（2步驟36 % )4-(2-曱基胺基乙氧基）異酞酸 二甲酯的油。 l-NMR (CDC13) 6 1· 68 (s，1H)、2. 53 (s，3H)、3· 01 -3·04 (m，2H)、3·89 (s，3H)、3·90 (s，3Η)、4·21-4·23 (m，2H)、7·00 (d，1H，J = 8.8 Hz)、8·14 (dd， 1H，J = 2.4、8·8 Hz)、8·50 (d，1H，J = 2.4 Hz); MS(FAB) m/z 268(MH1)。 於4-(2-甲基胺基乙氧基）異酞酸二曱酯（4iQ毫克，1.53 毫莫耳）溶於DMF( 1 3毫升）之擾拌溶液中加入3-甲氧基 - 4-[N’-（2-甲基苯基）脲基]苯基乙酸之五氟苯酯毫 克，1· 46毫莫耳）及Et3N(340微升，2· 44毫莫耳），並使所 產生之混合物攪拌隔夜。將混合物以EtOAc稀釋，以in HC1、飽和NaHC〇3、及鹽水洗滌。將溶液於NaS04±乾燥， 並蒸發而得780毫克（95%)之4 - [2- [3-甲氧基-4- [N，-（2-甲 基苯基）脲基]苯基乙醯基]甲胺基乙氧基]異酞酸二甲醋的 結晶粉末。 1-NMR (CDC13) 5 2· 2 9 (s，3H)、3· 24 (s，3H)、3· 59 (s, 3H)、3.67-3.68 (m，2H)、3·84 (s，3H)、3 91 (s89112968.ptd Page 671 1283240 V. Description of invention (667) Add DIADC1·28 ml, 6. 50 millimoles). The resulting mixture was then refluxed and heated overnight. After cooling to room temperature, the mixture was evaporated. The residue was dissolved in EtOH and 5% Pd/C (200 mg) was added. The resulting stirred mixture was hydrogenated at 1 atm for 2 hours. The mixture was filtered to remove the catalyst&apos; and the filtrate was evaporated. The residue was subjected to column chromatography using CHCl3_MeOH (30:1, v/v) as an eluent to obtain 280 mg (2 steps 36%) 4-(2-mercaptoamine group). An oil of ethoxy) dimethyl isononanoate. l-NMR (CDC13) 6 1· 68 (s, 1H), 2. 53 (s, 3H), 3· 01 -3·04 (m, 2H), 3·89 (s, 3H), 3.90 (s, 3Η), 4·21-4·23 (m, 2H), 7·00 (d, 1H, J = 8.8 Hz), 8·14 (dd, 1H, J = 2.4, 8·8 Hz) , 8·50 (d, 1H, J = 2.4 Hz); MS (FAB) m/z 268 (MH1). 3-methoxy- 4 was added to a scrambled solution of 4-(2-methylaminoethoxy)isodecanoate (4iQ mg, 1.53 mmol) dissolved in DMF (13 mL). - [N'-(2-methylphenyl)ureido]phenylacetic acid pentafluorophenyl ester mg, 1.46 mmol) and Et3N (340 μL, 2.444 mmol) and The resulting mixture was stirred overnight. The mixture was diluted with EtOAc and washed with EtOAc, sat. NaHC. The solution was dried over NaS04 and evaporated to give 780 mg (95%) of 4-[2-[3-methoxy-4-[N,-(2-methylphenyl)ureido]phenyl A crystalline powder of mercapto]methylaminoethoxy]isophthalic acid dimethyl vinegar. 1-NMR (CDC13) 5 2· 2 9 (s, 3H), 3· 24 (s, 3H), 3· 59 (s, 3H), 3.67-3.68 (m, 2H), 3.84 (s, 3H), 3 91 (s

89112968.ptd 第672頁 1283240 五、發明說明（668) 3H)、3.8卜3.86 (m，2H)、4·25-4·28 (m，2H)、6·51 -8. 48 (m 系列，12Η) ; MS(FAB) m/z 56 4 (ΜΗ1)。 於4-[2-[3 -甲氧基-4-[Ν’ -（2-甲基苯基）脲基]笨基乙醯 基]甲胺基乙氧基]異酞酸二甲酯（780毫克，1.384毫莫耳） 溶於THF(30毫升）之溶液中加入0.25Ν NaOH(30毫升）。然 後使所產生之混合物迴流加熱隔夜。將混合物倒入至冰的 IN HC 1(200 毫升，5 7%)中，得4 - [[2 - [4-甲氧基-4 - [Ν’ -（ 2-甲基苯基）脲基]苯基乙醯基]甲胺基]乙氧基]異酞酸254 的白色結晶粉末。熔點1 39-141 °C ; IR (KBr) 1 70 0 /公 分；1H-NMR (DMSO-d6) 6 2.94 (s，3Η)、3·18 (s，3H)、 3· 62-3· 86 (m，總計8Η)、4· 24-4· 2 8 (m，2Η)、6· 74-8· 58 (m 系列，總計12Η)、1 2. 91 (bs，1Η) ; MS(FAB) m/z 5 36 (MH1) ; C28H29N3 08 · 2. 5HC1 之分析計算值：C，5 3. 6 6 ; H，5· 07 ; N， 6. 70。實測值：C， 53· 80 ; H，4· 64 ; N， 6. 70 ° 實施例2 0 7 3 -甲氧基-4-[2 - [3 -甲氧基-4-[Ν’ - (2-甲基苯基）脲基]苯 基乙醯基]胺基乙氧基]苯曱酸89112968.ptd Page 672 1283240 V. Description of invention (668) 3H), 3.8 Bu 3.86 (m, 2H), 4·25-4·28 (m, 2H), 6·51 -8. 48 (m series, 12Η); MS(FAB) m/z 56 4 (ΜΗ1). 4-[2-[3-Methoxy-4-[Ν'-(2-methylphenyl)ureido]]phenylamino]methylaminoethoxy]isophthalic acid dimethyl ester ( 780 mg, 1.384 mmoles. 0.25 NaOH (30 mL) was added to a solution of THF (30 mL). The resulting mixture was then refluxed and heated overnight. The mixture was poured into ice in IN HC 1 (200 mL, 5 7%) to give 4-[[2-[4-methoxy-4-[[s]-(2-methylphenyl)ureido) A white crystalline powder of phenylethenyl]methylamino]ethoxy]isodecanoic acid 254. Melting point 1 39-141 °C; IR (KBr) 1 70 0 /cm; 1H-NMR (DMSO-d6) 6 2.94 (s, 3Η), 3·18 (s, 3H), 3·62-3· 86 (m, total 8Η), 4· 24-4· 2 8 (m, 2Η), 6·74-8· 58 (m series, total 12Η), 1 2. 91 (bs, 1Η); MS (FAB) m/z 5 36 (MH1) ; C28H29N3 08 · 2. Analysis of 5HC1: C, 5 3. 6 6 ; H, 5 · 07 ; N, 6. 70. Found: C, 53·80; H, 4·64; N, 6. 70 ° Example 2 0 7 3 -Methoxy-4-[2 - [3 -methoxy-4-[Ν' - (2-methylphenyl)ureido]phenylethenyl]aminoethoxy]benzoic acid

在室溫下於2-乙醇胺（5.16克，84.48毫莫耳）、Et3N (23· 50毫升，168· 60毫升）溶於二氧陸圜-H20( 1/1，160毫 升）之溶液中逐滴加入（Boc)20 ( 23. 40毫升，1 01· 86毫莫In a solution of 2-ethanolamine (5.16 g, 84.48 mmol), Et3N (23.50 ml, 168·60 ml) dissolved in dioxane-H20 (1/1, 160 ml) at room temperature Add (Boc) 20 ( 23. 40 ml, 1 01·86 mm)

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耳）。使反應混合物在室溫下攪拌2天❶將所產生之混合 以CHCI3稀釋，以0.5N HC1、飽和NaHC〇3、及鹽水洗滌。將 分離的有機層於NaS〇4上乾燥，並蒸發而得u. 86克（87%) 之N_Boc-2-乙醇胺的油〇 ^-NMR (CDC13) 5 1.45 (s, 9H) ^ 3. 29-3. 31 (m, 2H) 3· 7卜3· 72 (m，2H)。 ’ 於4 -羥基-3-甲氧笨曱酸乙酯（146克，7·44毫莫耳）、 ^6〇(：乙醇胺（1.19克，7.38毫莫耳）、即}13(253克，965 毫莫耳）溶於THF(30毫升）之攪拌溶液中加入毫 升，9 · 6 5毫莫耳），然後使所產生之混合物迴流加熱隔 夜。將混合物蒸發而得一粗製膠。將此粗製產物溶解於 CH2C12(20毫升）及TFA(20毫升）中。使所產生之混合物在室 溫下攪拌2 · 5小時。將混合物於真空中濃縮，並利用飽和 NaHC〇3使殘留物成為驗性。將萃取液以鹽水洗條，於 上乾燥，並蒸發而得1.61克（2步驟90%)3-曱氧基-4-(2 基乙氧基）苯甲酸乙醋的黃色油。 UMR (CDC13)(5 1.39 (t，3H，J = 7.3 Ηζ)、3·14-3 17 (m，2H)、3·92 (s，3H)、4.09-4.11 (m，2H)、4.36 (q 2 H，J = 7 · 3 H z)、6 . 8 9 ( d，1 H，J = 8 · 3 H z)、7 · 5 6 (d， 1H，J:2· 0 Hz)、7· 66 (dd，1H，J = 2· 0、8· 3 Hz)。 於3-甲氧基-4 -（2-胺基乙氧基）苯甲酸乙g旨（250毫克， 1· 04毫莫耳）及3-甲氧基-4 - [N7 -（2-曱基苯基）脲基]苯基 乙酸之五氟本酯（500¾克’1.〇4毫莫耳）之授拌溶液中加 入E % N ( 21 0微升’ 3 · 0 1毫莫耳），並使所產生之混合物擾ear). The reaction mixture was stirred at room temperature for 2 days, and the resulting mixture was diluted with CHCI 3 and washed with 0.5N EtOAc, sat. The separated organic layer was dried over Na.sub.4.sub.4, and evaporated. -3. 31 (m, 2H) 3· 7 Bu 3· 72 (m, 2H). 'Ethyl 4-hydroxy-3-methoxyoxetate (146 g, 7.44 mmol), ^6 〇 (: ethanolamine (1.19 g, 7.38 mmol), ie, 13 (253 g, 965 ml of a stirred solution of THF (30 ml) was added to a solution of 9.5 mL, and then the mixture was refluxed and heated overnight. The mixture was evaporated to give a crude gum. The crude product was dissolved in CH2C12 (20 mL) The resulting mixture was stirred at room temperature for 2.5 hours. The mixture was concentrated in vacuo and the residue was purified using saturated NaHC. The extract was washed with brine, dried and evaporated to give 1.61 g (yel. UMR (CDC13) (5 1.39 (t, 3H, J = 7.3 Ηζ), 3·14-3 17 (m, 2H), 3.92 (s, 3H), 4.09-4.11 (m, 2H), 4.36 ( q 2 H, J = 7 · 3 H z), 6. 8 9 ( d,1 H, J = 8 · 3 H z), 7 · 5 6 (d, 1H, J: 2· 0 Hz), 7 · 66 (dd, 1H, J = 2· 0, 8· 3 Hz). For the 3-methoxy-4-(2-aminoethoxy)benzoic acid, g (250 mg, 1.04 m) Mixture of pentafluorobenzate (5003⁄4g '1. 〇4 millimolar) of 3-methoxy-4-[N7-(2-mercaptophenyl)ureido]phenylacetic acid Add E % N ( 21 0 μl ' 3 · 0 1 mmol) and disturb the resulting mixture

1283240 五、發明說明（670) 拌2天。將0.25N NaOH(20毫升）及THF(20毫升）加至混合 物，並使所產生之混合物迴流加熱隔夜。於冷卻後，將混 合物蒸發，並經由加入1 N H C 1使殘留物酸化。將混合物以 CHC13萃取，並將萃取液以鹽水洗滌，於NaS04上乾燥，並 蒸發。使所得之粗製固體自CHC13再結晶而得110毫克（2步 驟2 0%)之3-甲氧基-4-[2- [3 -甲氧基-4- [Ν’ -（2-（甲基苯 基）脲基）苯基乙醯基]胺基乙氧基]笨甲酸255的白色結晶 粉末。 熔點 180-181 °C ; IR (KBr) 1 687 / 公分；iH-NMR (DMSO-d6 )δ 2· 24 (s，3H)、3. 37 (s，2H)、3· 3 8 (s，2H)、 3.4卜3.50 (m，2H)、3.81 (s，3H)、3.83 (s，3H)、 4 · 0 6 - 4 . 0 8 ( m， 2 H )、6 · 7 6 - 8 · 5 5 (m 系列，總計 1 2 H ); MS(FAB) m/z 5 0 8 (MH1) ; C27H29N3 07 · 1 / 2H20 之分析計算 值：C， 62·78;Η， 5·85;Ν，8.13。實測值：c，62·46; Η，5· 69 ; Ν，8· 03。 實施例2 0 8 3-甲氧基-4-[2 - [3 -甲氧基-4 - [Ν’ -（2-甲基苯基）脲基]苯 基乙醯基]乙基胺基乙氧基]苯甲酸1283240 V. Description of invention (670) Mix for 2 days. 0.25 N NaOH (20 mL) and THF (20 mL) were added to the mixture and the mixture was refluxed and evaporated overnight. After cooling, the mixture was evaporated and the residue was acidified with 1 N H C1. The mixture was extracted with CH.sub.3, and the mixture was washed with brine, dried over Nas. The resulting crude solid was recrystallized from CHC13 to give 110 mg (2 step 20%) of 3-methoxy-4-[2-[3 -methoxy-4-[[s]] A white crystalline powder of phenylphenyl)ureido)phenylethenyl]aminoethoxy]benzoic acid 255. Melting point 180-181 °C; IR (KBr) 1 687 / cm; iH-NMR (DMSO-d6) δ 2· 24 (s, 3H), 3. 37 (s, 2H), 3· 3 8 (s, 2H), 3.4 Bu 3.50 (m, 2H), 3.81 (s, 3H), 3.83 (s, 3H), 4 · 0 6 - 4 . 0 8 ( m, 2 H ), 6 · 7 6 - 8 · 5 5 (m series, total 1 2 H ); MS (FAB) m/z 5 0 8 (MH1) ; C27H29N3 07 · 1 / 2H20 analytical calculated values: C, 62·78; Η, 5·85; 8.13. Found: c, 62·46; Η, 5· 69 ; Ν, 8· 03. Example 2 0 8 3-Methoxy-4-[2-[3-methoxy-4-[Ν'-(2-methylphenyl)ureido]phenylethenyl]ethylamino Ethoxy]benzoic acid

256 於3-甲氧基-4- (2 -胺基乙氧基）笨甲酸乙g旨（1 Q3克， 8.07宅莫耳）及Et3N(2.00宅升’ 14.35毫莫耳）之冷卻（〇 °C)溶液中加入TFAA(1.35t升’9·56毫莫耳），並使所產256 of 3-methoxy-4-(2-aminoethoxy) benzoic acid B g (1 Q3 g, 8.07 house Moule) and Et3N (2.00 house liter ' 14.35 mmol) cooling (〇 °C) Add TFAA (1.35t liter '9·56 millimolar) to the solution and make it

\\312\2d-code\90-01\89112968.ptd 第 675 頁 1283240 五、發明說明（671) 生之混合物在室溫下攪拌隔夜。將所產生之混合物以Et 〇 稀釋，並以飽和NaHCO、in CH1、H2〇、及鹽水連續洗滌2。 將萃取液於NaJO4上乾燥，並蒸發而得122克（45%)3—甲氧 基-3-(2-N-三氟乙醯胺乙氧基）苯甲酸乙酯的油。 JH-NMR (CDC13) ^ 1. 39 (t, 3H, J = 7. 3 Hz) . 3. 77-3. 81 (m， 2H) 、3·92 (s, 3H) 、4·18-4.20 (m， 2H) 、4·37 (α 2Η，J = 7.3 Hz)、6·92 (d，1Η, J = 8.7 Hz)、7·59 (d 1H，J = 2.0 Hz)、7·67 (dd，1H，J = 2 〇、&quot; Hz);， MS(FAB) m/z 335(M+)、290(M+-〇Et)。 在室溫下於3-甲氧基—4 —(2 — N一三氟乙醯胺乙氧基）苯甲 酸乙酯（1· 20克，3· 58毫莫耳）之攪拌溶液中。使所產生之 混合物在6〇°C下攪拌2天。將混合物以EtOAc稀釋，以in HC1，、鹽水連續洗滌，並於Na2S〇4上乾燥。將溶劑蒸發，並 使，留物經，於矽膠上利用正己烷一Et〇Ac(2:丨，v/v)作為 洗提液進行官柱層析，純化而得99〇毫克（76%)3 —甲氧基 4 [ 2 N乙基N二鼠乙酸胺基]乙氧苯甲酸乙醋的黃色結 晶固體。 ^-NMR (CDCI3) ά 1.28-1.31 (m5 3H) &gt; 1. 37-1. 40 (m, 3H)、3·64-3.69 (m，2H)、3·81 -3.84 (m，2H)、3·92 (s，3H)、4·27-4.30 (m，2H)、4·34-4·39 (m，2H)、 6·89 (d，1H，J = 8.3 Hz)、7·55 (d，1H，J = 2.0 Hz)、 7-6 6 (dd, 1H, J = 2. 〇 &gt;8.3 Hz) ； MS (FAB) m/z 364 (MH1) 〇 於3 甲氧基-4-[2-(N-乙基三氟乙醯胺基）乙氧基]苯\\312\2d-code\90-01\89112968.ptd Page 675 1283240 V. INSTRUCTIONS (671) The raw mixture was stirred overnight at room temperature. The resulting mixture was diluted with Et , and washed successively with saturated NaHCO, in CH1, H.sub.2, and brine. The extract was dried over NaJO4 and evaporated to give &lt;RTI ID=0.0&gt;0&gt; JH-NMR (CDC13) ^ 1. 39 (t, 3H, J = 7. 3 Hz) . 3. 77-3. 81 (m, 2H), 3.92 (s, 3H), 4·18-4.20 (m, 2H), 4·37 (α 2Η, J = 7.3 Hz), 6.92 (d, 1Η, J = 8.7 Hz), 7·59 (d 1H, J = 2.0 Hz), 7·67 ( Dd, 1H, J = 2 〇, &quot;Hz);, MS(FAB) m/z 335(M+), 290(M+-〇Et). This was stirred at room temperature in a stirred solution of ethyl 3-methoxy-4-(2-N-trifluoroacetamidoethoxy)benzoate (1·20 g, 3. 58 mmol). The resulting mixture was stirred at 6 ° C for 2 days. The mixture was diluted with EtOAc, washed sequentially with EtOAc EtOAc EtOAc The solvent was evaporated, and the residue was subjected to column chromatography on a silica gel using n-hexane-Et〇Ac (2: 丨, v/v) as an eluent to obtain 99 mg (76%). A yellow crystalline solid of 3-methoxy-4-[ 2 Nethyl N-dimethylacetate]ethoxy acetoacetate. ^-NMR (CDCI3) ά 1.28-1.31 (m5 3H) &gt; 1. 37-1. 40 (m, 3H), 3·64-3.69 (m, 2H), 3.81 -3.84 (m, 2H) , 3·92 (s, 3H), 4·27-4.30 (m, 2H), 4·34-4·39 (m, 2H), 6·89 (d, 1H, J = 8.3 Hz), 7· 55 (d, 1H, J = 2.0 Hz), 7-6 6 (dd, 1H, J = 2. 〇 &gt; 8.3 Hz); MS (FAB) m/z 364 (MH1) 〇3 methoxy- 4-[2-(N-ethyltrifluoroacetamido)ethoxy]benzene

\\312\2d-code\90-01\89112968.ptd 第676頁 1283240 、發明說明（672) 甲酉夂乙酿（ 99 9 0毫克’ 2· 73毫莫耳）溶於THF —MeOH-H〇 (2： H ^v/v，20毫升）之攪拌溶液中加入K2C〇3(56()毫克， 4、· 0 5毫莫耳），並使所產生之混合物攪拌隔夜。將混合物 以HO稀釋，並以Et〇Ac萃取。將萃取液以飽和、鹽 水連，洗滌，於NaJO4上乾燥，並蒸發而得8〇〇毫克（q y ) 3-甲氧基-4-(2-乙基胺基乙氧基）苯曱酸乙酯的油。 ^-NMR (CDC13) 5 1.15 (t, 3H, J^7. 3 Hz) &gt;1.39 (t, 3H，&gt;7·3 Hz)、1·76 (bs，1H)、2·74 (q，2H，J = 7.3\\312\2d-code\90-01\89112968.ptd Page 676 1283240, invention description (672) Hyperthyroidism (99 9 0 mg '2.73 mmol) dissolved in THF - MeOH-H K2C〇3 (56 () mg, 4, 0 5 mmol) was added to a stirred solution of hydrazine (2:H^v/v, 20 mL), and the mixture was stirred overnight. The mixture was diluted with HO and extracted with EtOAc. The extract was washed with saturated brine, washed, dried over NaJO4, and evaporated to give &lt;RTI ID=0.0&gt; Ester oil. ^-NMR (CDC13) 5 1.15 (t, 3H, J^7. 3 Hz) &gt;1.39 (t, 3H, &gt; 7·3 Hz), 1·76 (bs, 1H), 2·74 (q , 2H, J = 7.3

Hz)、3.〇8 (t，2H，K4 Hz)、3·91 (s，3H)、4·18 (t, 2H, J = 5.4 Hz) ^4.36 (q, 2H, J = 7. 3 Hz) &gt;6.90 (d， 1H， J=8.3 Hz) 、7·55 (d， 1H， J=2.0 Hz) 、7·66 (dd，1H，J = 2.0、8·3 Hz); MS(FAB) m/z 268(MH1)。 於3-甲氧基-4 -（2-乙胺基乙氧基）苯甲酸乙酯（29〇毫 ^ ’ 1· 08毫莫耳）及3一甲氧基一4一 [N，-( 2-甲基苯基）脲基] 苯基乙酸之五氟苯酯（5〇2毫克，；ι·05毫莫耳）溶於DMF(7毫 升）之攪拌溶液中加入Et3N(250微升，1.79毫莫耳），並使 所產生之混合物攪拌隔夜。將混合物以Et〇Ac稀釋，以 〇· 5N HC1、鹽水洗滌，並於Na2S〇4上乾燥。將溶劑蒸發， 並使殘留物經由於矽膠上利用⑶口厂“⑽㈠^^/“作 為洗提液進行管柱層析，純化而得55〇毫克（93%)之3—甲氧 基-4-[2-[3-甲氧基—4- [N，-（2-曱基苯基）脲基]苯基乙醯 基]乙基胺基乙氧基]苯甲酸乙酯的非晶形固體。 'H-NMR (CDCI3) 5 1.11-1.18 (m, 3H) Μ. 37-1. 41 (m, 3H)、2·30 (s，3H)、3·47-3·53 (m，2H)、3·61 -3·75Hz), 3.〇8 (t, 2H, K4 Hz), 3·91 (s, 3H), 4·18 (t, 2H, J = 5.4 Hz) ^4.36 (q, 2H, J = 7. 3 Hz) &gt;6.90 (d, 1H, J=8.3 Hz), 7·55 (d, 1H, J=2.0 Hz), 7.66 (dd, 1H, J = 2.0, 8·3 Hz); MS ( FAB) m/z 268 (MH1). Ethyl 3-methoxy-4-(2-ethylaminoethoxy)benzoate (29 〇m ^ '1·08 mmol) and 3-methoxy-4-one [N,-( 2-Methylphenyl)ureido] Phenylacetic acid pentafluorophenyl ester (5〇2 mg,; ι·05 mmol) dissolved in DMF (7 ml) in a stirred solution of Et3N (250 μl, 1.79 millimoles) and the resulting mixture was stirred overnight. The mixture was diluted with Et 〇Ac, washed with EtOAc EtOAc EtOAc (EtOAc) The solvent was evaporated, and the residue was purified by column chromatography on (3) (3) (1)^^/" as an eluent to obtain 55 mg (93%) of 3-methoxy-4. -Amorphous solid of [2-[3-methoxy-4-[N,-(2-mercaptophenyl)ureido]phenylethenyl]ethylaminoethoxy]benzoate . 'H-NMR (CDCI3) 5 1.11-1.18 (m, 3H) Μ. 37-1. 41 (m, 3H), 2·30 (s, 3H), 3·47-3·53 (m, 2H) , 3.61 -3·75

1283240 五、發明說明（673) (m， 7H) 、3·84 (s， 3H) 、4·03-4·27 (m， 2H)、 4 · 3 3 - 4 · 3 9 ( m， 2 Η )、6 · 3 4 - 8 · 0 7 ( m 系列，總計 1 2 Η )。 於3-甲氧基-4 - [2-[3-甲氧基-4-[N，-（2-甲基苯基）脲 基]本基乙醯基]乙基胺基乙氧基]苯甲酸乙醋（550毫克， 〇· 98毫莫耳）溶於THF(15毫升）之溶液中加入〇· 25N NaOH (1 5毫升）。然後使所產生之混合物迴流加熱2天。將混合 物倒入至IN HC1中，並收集固體。使粗製固體自EtOH-CHC13再結晶，而得182毫克（35%)3-甲氧基-4 - [2-[3-甲 氧基-4-[Ν’-（2-曱基苯基）脲基]苯基乙醯基]乙基胺基乙 氧基]苯曱酸2 56的白色結晶粉末。熔點11 5-118 °C ; IR (KBr) 1 707 / 公分；NMR (DMSO-d6)6 1·02-1·12 (m， 3Η) 、2·25 (s， 3Η) 、2.50 (s， 2Η) 、3·35-3·89 (m, 10Η)、4· 1卜4· 16 (m，2Η)、6· 7 卜8. 5 6 (m 系列，總計 12H) 、12·65 (bs， 1H); MS(FAB) m/z 536CMH1); C29H33N3 07 · 3/4H20 之分析計算值：C，63· 43 ; H，6· 33 ; N， 7· 65。實測值：C， 63. 3 4 ; H，6· 28 ; N，7. 28。 實施例209 3 -硝基-4 - [2 - [3 -曱氧基-4-[N -(2_甲基本基）脈基]本基 乙醯基]胺基乙氧基]苯甲酸1283240 V. INSTRUCTIONS (673) (m, 7H), 3.84 (s, 3H), 4·03-4·27 (m, 2H), 4 · 3 3 - 4 · 3 9 ( m, 2 Η ), 6 · 3 4 - 8 · 0 7 (m series, total 1 2 Η). 3-methoxy-4-[2-[3-methoxy-4-[N,-(2-methylphenyl)ureido]]benylethyl]ethylaminoethoxy] To a solution of acetoacetate (550 mg, 〇 98 mmol) in THF (15 mL) was added EtOAc········· The resulting mixture was then heated under reflux for 2 days. The mixture was poured into IN HC1 and the solid was collected. The crude solid was recrystallized from EtOH-CHC13 to give 182 mg (35%) of 3-methoxy-4-[2-[3-methoxy-4-[[s]-(2-mercaptophenyl) A white crystalline powder of ureido]phenylethenyl]ethylaminoethoxy]benzoic acid 2 56. Melting point 11 5-118 °C; IR (KBr) 1 707 / cm; NMR (DMSO-d6) 6 1·02-1·12 (m, 3Η), 2·25 (s, 3Η), 2.50 (s, 2Η), 3·35-3·89 (m, 10Η), 4·1 Bu 4· 16 (m, 2Η), 6· 7 Bu 8. 5 6 (m series, total 12H), 12·65 (bs , 1H); MS (FAB) m/z 536CMH1); C29H33N3 07 · 3/4H20 Analytical calculated value: C, 63 · 43 ; H, 6 · 33 ; N, 7 · 65. Found: C, 63. 3 4 ; H, 6· 28 ; N, 7. 28. Example 209 3 -Nitro-4 - [2- [3 - decyloxy-4-[N-(2-methylphenyl)]carbonyl] benzyl Ethyl]aminoethoxy]benzoic acid

在室溫下於4-羥基-3 -硝基苯甲酸（5·18克，28·29毫莫 耳）溶於苯-MeOH(4/l，ν/ν，140毫升）之攪拌溶液中加入Add to a stirred solution of 4-hydroxy-3-nitrobenzoic acid (5·18 g, 28.29 mmol) in benzene-MeOH (4/1, ν/ν, 140 mL) at room temperature

\\312\2d-code\90-01\89112968.ptd 第678頁 1283240 五、發明說明（674) TMSCHN2(14· 10毫升，28.20毫莫耳，㈣己烷溶液），並使 所產生之混合物攪拌隔夜。將混合物蒸發，並使殘留物經 由於矽膠上利用CHCI3作為洗提液進行管柱層析，純化而 得4· 18克（75%)3_硝基-4-羥基笨甲酸甲酯的黃色結晶固 體。 ^-NMR (CDCI3) (53.95 (s, 3H) &gt;7.22 (d, 1H, J = 8.8\\312\2d-code\90-01\89112968.ptd Page 678 1283240 V. INSTRUCTIONS (674) TMSCHN2 (14·10 ml, 28.20 mmol, (iv) hexane solution) and the resulting mixture Stir overnight. The mixture was evaporated, and the residue was purified by column chromatography using CHCI3 as eluent on silica gel to give 4·18 g (75%) of yellow crystals of methyl 3-nitro-4-hydroxybenzoate. solid. ^-NMR (CDCI3) (53.95 (s, 3H) &gt; 7.22 (d, 1H, J = 8.8

Hz)、8·24 (dd，1H，J = 2.〇、8·8 Hz)、8·83 (d, 1H, J = 2·0 Hz)、10·89 (s, 1H)。 於3 -硝基-4 -羥基苯甲酸甲酯（198克，10·4毫莫耳）、 N-Boc乙醇胺（1.63克，10.li毫莫耳）及PPh3(3, 43克， 13.08毫莫耳）溶於THF(40毫升）之攪拌溶液中加入diad (2 · 5 7宅升’ 1 3. 0 5耄莫耳）’然後使反應混合物迴流加熱 隔夜。使所產生之混合物蒸發而得一膠，將殘留的粗製膠 溶解於CHgCl (30毫升）及TFA(30毫升）中，並使混合物在室 溫下攪拌1小時。將混合物於真空中濃縮，並利用飽和 NaHC〇3使成為鹼性。將混合物以CHC1萃取，以鹽水洗滌， 並於NaJO4上乾燥。將溶劑於真空中蒸發而得油性殘留 物，將其經由於矽膠上利用（：11(：13-116〇11(20:1，¥/¥)作為 洗提液進行管柱層析，純化而得92 0毫克（2步驟27%)之3 -硝基-4-（2-胺基乙氧基）苯甲酸甲酯的膠。 ^-NMR (CDC13)^3.16-3.19 (m, 1H) &gt;3.53-3.57 (m, 1H)、3·90 及 3·94 (s，3H)、3·95_3·98 (m, 1H)、 4.2 卜 4.24 (m，1H)、6·89 - 6.91 及 7·11-7·13 (m，1H)、 8·03-8·19 及 8·21 (m，1Η)、8·52 及 8·86 (m，1Η)。Hz), 8·24 (dd, 1H, J = 2.〇, 8·8 Hz), 8.83 (d, 1H, J = 2·0 Hz), 10·89 (s, 1H). Methyl 3-nitro-4-hydroxybenzoate (198 g, 10.4 mmol), N-Boc ethanolamine (1.63 g, 10.li mmol) and PPh3 (3, 43 g, 13.08 m) To a stirred solution of THF (40 mL) was added diad (2 · 5 7 house liters &lt;RTI ID=0.0&gt; The resulting mixture was evaporated to give a gum, which was dissolved in CHgCl (30 ml) and TFA (30 ml), and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo and made basic with saturated NaHC. The mixture was extracted with CH.sub.1, washed with brine and dried over NaCI. The solvent was evaporated in vacuo to obtain an oily residue, which was purified by column chromatography on a silica gel using (11::13-116〇11 (20:1, ¥/¥) as an eluent. 92 0 mg (2 step 27%) of a gum of methyl 3-nitro-4-(2-aminoethoxy)benzoate. ^-NMR (CDC13)^3.16-3.19 (m, 1H) &gt ;3.53-3.57 (m, 1H), 3·90 and 3.94 (s, 3H), 3·95_3·98 (m, 1H), 4.2 4.24 (m, 1H), 6.89 - 6.91 and 7 ·11-7·13 (m, 1H), 8·03-8·19, and 8·21 (m, 1Η), 8.52, and 8·86 (m, 1Η).

89112968.ptd 第679頁 1283240 五、發明說明（675) 於3-甲氧基-4 - [Ν’ - (2-甲基苯基）脲基]笨基乙酸之五氟 本S旨（1·86克’ 3.87宅莫耳）及3 -硝基-4-(2 -胺基乙氧基） 苯甲酸甲酯（0·93克，3.87毫莫耳）溶於DMF(27毫升）之攪 拌溶液中加入Et3N(0. 90毫升，6. 46毫莫耳），並使所產生 之混合物攪拌隔夜。將混合物倒入至隔夜。將混合物倒入 至〇· 5N HC1中，並收集所產生之固體。將粗製固體溶解於 THF-0.25N NaOH(l/l，20毫升），並使所產生之混合物迴 流加熱隔夜。將混合物以EtOAc萃取，以鹽水洗滌，於 Na2S04上乾燥，並蒸發。使粗製固體自CHCl3-EtOH再結晶 ，而得60毫克（2步驟3%)之3_硝基-4-[2- [3-曱氧基-4-[Ν’- (2-曱基苯基）脲基]苯基乙醯基]胺基乙氧基]苯曱酸 2 5 7的黃色結晶固體。 熔點112-115。〇;111-關1^(0%30-(16)(5 2.24(3，31〇、 3·37-3·66 (m，7Η)、3·84 (s，3Η)、4·27-4·30 (m， 1Η)、6·74-8·56 (m 系列，總計 12H); MS(FAB) m/z 523 (MH1) ; C26H26N4 08 · 3/2H20 之分析計算值：C，56. 83 ; Η, 5· 32 ; N，1〇· 20。實測值：C，56. 66 ; H，4· 90 ; N， 9.33。 實施例21 0 3-甲氧基-4- [2-[3-甲氧基-4 - [Ν’ _(2-氟苯基）脲基]苯基 乙醯基]乙胺基乙氧基]苯甲酸89112968.ptd Page 679 1283240 V. INSTRUCTION DESCRIPTION (675) Pentylene fluoride in 3-methoxy-4 -[Ν' - (2-methylphenyl)ureido] streptoacetic acid 86 g of ' 3.87 house moules and 3 - nitro-4-(2-aminoethoxy) benzoic acid methyl ester (0·93 g, 3.87 mmol) dissolved in DMF (27 ml) Et3N (0. 90 ml, 6.46 mmol) was added and the resulting mixture was stirred overnight. Pour the mixture into overnight. The mixture was poured into 〇·5N HCl and the resulting solid was collected. The crude solid was dissolved in THF- 0.25N NaOH (l/l, 20 mL) and the mixture was refluxed and warmed overnight. The mixture was extracted with EtOAc (EtOAc)EtOAc. The crude solid was recrystallized from CHCl3-EtOH to give 60 mg (2 step 3%) of 3-nitro-4-[2-[3-] oxy-4-[Ν'-(2-mercaptobenzene) A yellow crystalline solid of ureido]phenylethenyl]aminoethoxy]benzoic acid 2 5 7 . Mp 112-115. 〇; 111- Guan 1^(0%30-(16)(5 2.24(3,31〇, 3·37-3.66 (m,7Η), 3.84 (s,3Η), 4·27- 4·30 (m, 1Η), 6.74-8·56 (m series, total 12H); MS(FAB) m/z 523 (MH1) ; C26H26N4 08 · 3/2H20 Analysis calculated: C, 56 83; Η, 5·32 ; N,1〇· 20. Found: C, 56. 66; H, 4.90; N, 9.33. Example 21 0 3-methoxy-4- [2- [3-Methoxy-4 -[Ν' _(2-fluorophenyl)ureido]phenylethenyl]ethylaminoethoxy]benzoic acid

258258

89112968.ptd 第680頁 1283240 五、發明說明（676) -— 於3-甲氧基-4-[Ν’ - (2 -氟苯基）脲基]苯基乙酸之五氟 S曰（135¾克，0.28¾莫耳）及3-甲氧基-4- (2-乙胺基乙氧 基）苯甲酸乙酯（78毫克，〇· 29毫莫耳）之攪拌溶液$加= E % N ( 0 · 1毫升’ 0 · 7 2毫莫耳），並使所產生之混合物挽拌 隔夜。將所產生之混合物以EtOAc稀釋，以〇. 5N HC 1、δ® 水連續洗滌，於NaS〇4上乾燥，並蒸發。使殘留物經由^ 矽膠上利用CHCl3-MeOH(50:l，v/v)作為洗提液進行管柱 層析，純化而得160毫克（q.y.)之3-曱氧基一 4 一 [2 - [3-甲氧 基-4-[Ν’_(2 -氟苯基）脲基]苯基乙醯基]乙胺基乙氧基]苯 甲酸乙S旨的油。 1 Η-NMR (CDC13 ) 6 1 · 1 3-1 · 23 (m，3Η)、1 · 3 7 - 1 · 40 (m， 3 Η)、2 . 9 0 - 3 · 8 9 (m，1 2 Η)、4 · 0 9 - 4 · 2 8 (m，2 Η )、 4 · 3 3 - 4. 3 9 ( m， 2 Η )、6 · 7 0 - 8 · 21 (m 系列，總計 1 2 Η )。 於3-曱氧基-4-[2-[3-甲氧基-4-[N，-(2_氟苯基）脲基] 苯基乙醯基]乙基胺基乙氧基]苯甲酸乙酯（16〇毫克，〇.28 毫莫耳）溶於THF(5毫升）之攪拌溶液中加入〇. 25N NaOH(5 毫升），並使所產生之混合物迴流加熱隔夜。將混合物倒 入至IN HC1中，並收集固體。使粗製固體自Et〇H_CHCl3 — 正己烷再結晶，而得70毫克（46% )3-甲氧基-4- [ 2- [ 3-甲氧 基-4-[N’-（2 -氟苯基）脲基]苯基乙醯基]乙基胺基乙氧基] 苯甲酸258的黃色結晶粉末。 熔點 105-110°C; IR (KBr) 1 687 /公分；1 -NMR (DMS〇-d6 )5 1· 00-1· 10 (m，3H)、2·48 (s，2H)、3· 35-3· 81 (m， 10H)、4· 13-4· 14 (m，2H)、6· 7 0-9· 15 (m 系列，12H);89112968.ptd Page 680 1283240 V. INSTRUCTIONS INSTRUCTIONS (676) - pentafluoro-S 曰 (1353⁄4 g) in 3-methoxy-4-[Ν'-(2-fluorophenyl)ureido]phenylacetic acid , 0.283⁄4 moles) and 3-methoxy-4-(2-ethylaminoethoxy)benzoic acid ethyl ester (78 mg, 〇·29 mmol) stirred solution $plus = E % N ( 0 · 1 ml '0 · 7 2 mmol" and mix the resulting mixture overnight. The resulting mixture was diluted with EtOAc and washed sequentially with EtOAc EtOAc EtOAc. The residue was subjected to column chromatography using CHCl3-MeOH (50:1, v/v) as an eluent to obtain 160 mg (qy) of 3-decyloxy-4-one [2 - An oil of the formula [3-methoxy-4-[Ν'_(2-fluorophenyl)ureido]phenylethenyl]ethylaminoethoxy]benzoic acid. 1 Η-NMR (CDC13) 6 1 · 1 3-1 · 23 (m, 3 Η), 1 · 3 7 - 1 · 40 (m, 3 Η), 2. 9 0 - 3 · 8 9 (m, 1 2 Η), 4 · 0 9 - 4 · 2 8 (m, 2 Η ), 4 · 3 3 - 4. 3 9 ( m, 2 Η ), 6 · 7 0 - 8 · 21 (m series, total 1 2 Η ). 3-methoxy-4-(2-[3-methoxy-4-[N,-(2-fluorophenyl)ureido]phenylphenyl]ethylamino]ethoxy]benzene Ethyl formate (16 mg, 〇.28 mmol) was dissolved in THF (5 mL). EtOAc EtOAc. The mixture was poured into IN HC1 and the solid was collected. The crude solid was recrystallized from Et.sub.H.sub.H.sub.CH.sub.3.sup.-hexanes to give 70 mg (46%) of 3-methoxy-4-[2-[3-methoxy-4-[N'-(2-fluorobenzene) A yellow crystalline powder of ureido]phenylethenyl]ethylaminoethoxy]benzoic acid 258. Mp 105-110 ° C; IR (KBr) 1 687 / cm; 1-NMR (DMS 〇-d6) 5 1· 00-1· 10 (m, 3H), 2·48 (s, 2H), 3· 35-3· 81 (m, 10H), 4· 13-4· 14 (m, 2H), 6· 7 0-9· 15 (m series, 12H);

1283240 五、發明說明（677) MS(FAB) m/z 54 0 (MH1); C28H3GFN3 07 ·ι/2Η2〇之分析計算 值·· C， 61· 31 ; Η，5· 82 ; Ν，7· 47。實測值：c，61· 05 ; Η, 5. 82 ； Ν, 7.47。 實施例2 1 1 4 - [4 - [3 -甲氧基- 4-[Ν’ -（2-甲基苯基）脲基]苯基]乙醯基 -1 -六氫σ比嘴苯甲酸1283240 V. INSTRUCTIONS (677) MS(FAB) m/z 54 0 (MH1); C28H3GFN3 07 ·ι/2Η2〇 Analytical calculations·· C, 61· 31 ; Η, 5· 82 ; Ν, 7· 47. Found: c, 61· 05 ; Η, 5. 82 ; Ν, 7.47. Example 2 1 1 4 - [4 - [3 -Methoxy-4-[Ν'-(2-methylphenyl)ureido]phenyl]ethenyl-1 -hexahydro-pyridinium

使1-六氫咄啡羧酸第三丁酯（1.00克，5.37毫莫耳）、4-氟苯甲酸乙酯（903毫克，5.37毫莫耳）、及1(2(：〇3(1.11克， 8. 06毫莫耳）於DMF (10毫升）中之攪拌混合物於丨2〇 °c下加 熱隔夜。於冷卻後，將混合物以E10 A c ( 3 0 0毫升）稀釋，隨 後以鹽水（2X 2 0 0毫升）洗務，於M gS04上乾燥，並蒸發。使 殘留物於碎膠上利用CHClg-EtOAc(20:l至4:1，v/v)作為 洗提液進行層析，而得2 57毫克（14%)之4-[4-(第三丁氧羰 基）-卜六氫咄哜基]酸苯曱酸乙酯的淡黃色非晶形固體。 IR (KBr) 1701、1612 / 公分；UMR (CDC13) 5 1· 37 !(3H，t，J = 7.3 Hz)、1·49 (9H，s)、3·30 (4H，t，J二5· 4 Hz)、3.58 (4H，t，J = 5.4 Hz)、4·33 (2H，q，J = 7.3 Hz)、6·87 (2H，d，J = 8.8 Hz)、7·94 (2H，dt，J=8.8、 2· 4 Hz) ; MS(FAB) m/z 33 5 (M+ + 1 ) ; C18H26N2 04 之分析計算 值：C，64·54;Η，7·84;Ν，8·38。實測值：c，6 4.3 9;The third butyl hexahydroquinonecarboxylate (1.00 g, 5.37 mmol), ethyl 4-fluorobenzoate (903 mg, 5.37 mmol), and 1 (2 (: 〇 3 (1.11) The mixture was stirred at 丨2 ° ° C overnight. After cooling, the mixture was diluted with E10 A c (300 mL) and then brine. (2X 2 0 0 mL), washed, dried over MgSO4, and evaporated. EtOAc EtOAc EtOAc The pale yellow amorphous solid of 2 57 mg (14%) of 4-[4-(t-butoxycarbonyl)-hexahydroindenyl] benzoic acid ethyl ester. IR (KBr) 1701 1612 / cm; UMR (CDC13) 5 1· 37 !(3H,t,J = 7.3 Hz), 1·49 (9H, s), 3·30 (4H, t, J 2·5 Hz), 3.58 (4H, t, J = 5.4 Hz), 4·33 (2H, q, J = 7.3 Hz), 6.87 (2H, d, J = 8.8 Hz), 7·94 (2H, dt, J=8.8 , 2· 4 Hz); MS(FAB) m/z 33 5 (M+ + 1 ) ; C18H26N2 04 analytical calculated value: C, 64·54; Η, 7.84; Ν, 8.38. Found: c,6 4.3 9;

\\312\2d-code\90-01\89112968.ptd 第682頁 1283240 五、發明說明（678) ----- H，7.89； N, 8. 38 〇 於4-[4-(第三丁氧幾基）-1-六氫吼嘴基]苯甲酸乙^ (240毫克，0· 718毫莫耳）溶於CH2C12(5毫升）之搜掉溶^夜中 加入T F A ( 5毫升），並使所產生之混合物攪拌3小時。將混 合物於真空中濃縮，並經由加入飽和N a H C 〇3使殘留物成為 鹼性，隨後以CHC13(2x100毫升）萃取。將結合的萃取液於 NaC〇3上乾燥，並蒸發而得168毫克（100%) 4-(1-六氫吼坪 基）苯曱酸乙酯的黃色油。 β-NMR (CDC13) 5 1· 37 (3H，t，J:7. 3 Hz)、3. 03 (4H， t，J = 4.9 Hz)、3·29 (4H，t，】=4·9 Hz)、4·33 (2H，q J = 7.3 Hz)、6·87 (2H, dt，J = 8.8、2.4 Hz)、7.91-7.94 (2H, m)。 於4-( 1-六氫咄啡基）苯甲酸乙酯（170毫克，〇· 73 0毫莫 耳）及3-甲氧基-4 - [Ν’ -（2-曱基苯基）脲基]笨乙酸（229毫 克，0. 730毫莫耳）溶於DMF( 10毫升）之攪拌溶液中加入 EDC-HC1C210 毫克，1·1〇 毫莫耳）、DMAP(催化量）、及HOBt (催化量），並使混合物攪拌隔夜。將混合物倒入至HO ( 1 〇 〇 毫升）中，並利用吸濾收集固體。使殘留物自C η C 13 -正己 烷再結晶，而得29 0毫克（75%)4-[4-[3_甲氧基-4_[Ν，-（2 - 甲基苯基）脲基]苯基]乙酸基—1—六氫。比哨：苯甲酸乙酯的無 色結晶粉末。 熔點 208-210 °C; IR (KBr) 1711、1695 /公分； (CDC13) 5 1· 37 (3H，t，J = 7· 3 Hz)、2. 29 (3H，s)、3. 14 (2H， t， J=4.9 Hz) 、3·28 (2H， t， J=4.9 Hz) 、3·62\\312\2d-code\90-01\89112968.ptd Page 682 1283240 V. Invention description (678) ----- H, 7.89; N, 8. 38 4- in 4-[4-(third Butyloxy)-1-hexahydropyridinyl]benzoic acid ethyl bromide (240 mg, 0·718 mmol) was dissolved in CH2C12 (5 mL), and TFA (5 mL) was added. The resulting mixture was stirred for 3 hours. The mixture was concentrated in vacuo and the residue was taken to dryness eluted eluted eluting eluting The combined extracts were dried over Na.sub.3.sub.3, and evaporated to yield 168 mg (100%) of ethyl 4-(1-hexahydroindole) ethyl benzoate. β-NMR (CDC13) 5 1· 37 (3H, t, J: 7. 3 Hz), 3. 03 (4H, t, J = 4.9 Hz), 3·29 (4H, t, 】=4·9 Hz), 4·33 (2H, q J = 7.3 Hz), 6.87 (2H, dt, J = 8.8, 2.4 Hz), 7.91-7.94 (2H, m). Ethyl 4-(1-hexahydroindolyl)benzoate (170 mg, 〇·73 0 mmol) and 3-methoxy-4 -[Ν'-(2-mercaptophenyl)urea Ethyl acetate (229 mg, 0. 730 mmol) dissolved in DMF (10 ml) in a stirred solution of EDC-HC1C 210 mg, 1.1 mM millimolar, DMAP (catalytic amount), and HOBt ( Catalytic amount) and the mixture was stirred overnight. The mixture was poured into HO (1 〇 毫升 ml) and the solid was collected by suction filtration. The residue was recrystallized from C η C 13 -n-hexane to give 290 mg (75%) of 4-[4-[3-methoxy-4-[[[,]-(2-methylphenyl)ureido] Phenyl]acetate-1-hexahydro. Comparative whistle: a colorless crystalline powder of ethyl benzoate. Mp 208-210 ° C; IR (KBr) 1711, 1695 / cm; (CDC13) 5 1· 37 (3H, t, J = 7 · 3 Hz), 2. 29 (3H, s), 3. 14 ( 2H, t, J=4.9 Hz), 3·28 (2H, t, J=4.9 Hz), 3.62

\\312\2d-code\90-01\89112968.ptd 第683頁 1283240 五、發明說明（679) (2H， t， J=4.9 Ηζ) 、3·71 (3H， s) 、3·72 (2H， s)、 3·79 (2Η，t，J = 4.9 Hz)、4·33 (2Η，q，J = 7.3 Hz)、6· 38 (1H，s)、6·78-6·99 (4H，m)、7·13-7.24 (4H，m) ! 7·50 (1H，d，J = 7.8 Hz)、7·92 (2H，d，J = 8.8 Hz)、8· 12 (1H, d, J = 7.8 Hz)； MS(FAB) m/z 531(MH1); C3QH34N4 05 · 0. 5H20 之分析計算值：C，6 6. 77 ; H，6. 54 ; M， 10. 38。實測值：C，66· 89 ; H， 6· 39 ; N， 10· 45。 於4-[4-[3-甲氧基-4-[Ν’ - (2-甲基苯基）脲基]苯基]乙 醯基-1-六氫吼畊苯曱酸乙酯（ 29 0毫克，〇. 547毫莫耳）溶 於MeOH-THF(2 : 1，ν/ν，15毫升）之攪拌溶液中加入0· 25Ν NaOH(5毫升，1. 25毫莫耳），並使混合物迴流加熱3小時。 將混合物倒入至冰的1 N HC1 (1 00毫升）中，並利用吸濾收 集固體。使殘留物自C H C 13 - M e Ο Η再結晶，而得1 9 0毫克 (69°/。）4-[4-[3_甲氧基-4-[Ν’ -（2 -甲基苯基）脲基]苯基]乙 醯基-1-六氫呲畊苯甲酸259的黃色結晶粉末。 熔點24 0-245 °〇;111-關1^(0肘30)(52.24(311，5)、 3·17-3·50 (8Η，m)、3·72 (2Η，s)、3·86 (3Η, s)、 6·77 (1Η，d，J = 8.3 Hz)、6·90 (1Η, s)、6·91-6·96 (3H，m)、7.1卜7.17 (2H, m)、7· 7 6-7.80 ( 3H，m)、 8.03 (1H，d，J = 8.3 Hz)、8·47 (1H，s)、8·58 (1H， s)、12· 30 ( 1H，s) ; C28H3QN4 05 · H20 之分析計算值：C， 64. 60 ; H，6. 20 ; N，10. 76。實測值：C，64. 6 4 ; H, 5· 85 ; N，10· 51。 實施例21 2\\312\2d-code\90-01\89112968.ptd Page 683 1283240 V. Description of invention (679) (2H, t, J=4.9 Ηζ), 3·71 (3H, s), 3.72 ( 2H, s), 3.79 (2Η, t, J = 4.9 Hz), 4·33 (2Η, q, J = 7.3 Hz), 6·38 (1H, s), 6.78-6·99 ( 4H,m),7·13-7.24 (4H,m) ! 7·50 (1H,d,J = 7.8 Hz), 7.92 (2H,d,J = 8.8 Hz), 8·12 (1H, d, J = 7.8 Hz); MS (FAB) m/z 531 (MH1); C3QH34N4 05 · 0. 5H20 Analysis calculated: C, 6 6. 77 ; H, 6. 54 ; M, 10. 38. Found: C, 66·89; H, 6·39; N, 10·45. 4-[4-[3-Methoxy-4-[Ν-(2-methylphenyl)ureido]phenyl]ethenyl-1-hexahydroindole oleyl phthalate (29 0 mg, 547. 547 mmol; dissolved in MeOH-THF (2:1, ν / ν, 15 mL), 0.25 NaOH (5 mL, 1.25 mmol), and The mixture was heated under reflux for 3 hours. The mixture was poured into 1 N HCl (1 mL) of ice and concentrated to afford solids. The residue was recrystallized from CHC 13 - M e Ο , to give 19 mg (69 ° /.) 4-[4-[3-methoxy-4-[Ν'-(2-methylbenzene) Yellow crystalline powder of ureido]phenyl]ethenyl-1-hexahydroindole benzoic acid 259. Melting point 24 0-245 °〇; 111-off 1^(0 elbow 30) (52.24(311,5), 3·17-3·50 (8Η,m), 3·72 (2Η,s), 3· 86 (3Η, s), 6·77 (1Η, d, J = 8.3 Hz), 6.90 (1Η, s), 6·91-6·96 (3H, m), 7.1 7.17 (2H, m ), 7· 7 6-7.80 ( 3H,m), 8.03 (1H,d,J = 8.3 Hz), 8.47 (1H, s), 8·58 (1H, s), 12· 30 ( 1H, s) ; C28H3QN4 05 · H20 Analysis calculated: C, 64. 60 ; H, 6. 20 ; N, 10. 76. Found: C, 64. 6 4 ; H, 5· 85 ; N, 10· 51. Example 21 2

\\312\2d-code\90-01\89112968.ptd 第 684 頁 1283240 五、發明說明（680) (R) - 3-甲氧基一4-[2-[3-甲氧基-4-[N，-（2-甲基苯基）脲 基]苯基乙醯基]苯基乙醯胺基]-1—丙氧基]苯甲酸\\312\2d-code\90-01\89112968.ptd Page 684 1283240 V. INSTRUCTIONS (680) (R)-3-Methoxy-4-[2-[3-methoxy-4- [N,-(2-methylphenyl)ureido]phenylethenyl]phenylethenylamino]-1-propoxy]benzoic acid

260 於（R)-2-胺基-1-丙醇（3· 01克，〇· 〇4毫莫耳）及Et3N (6·7〇 毫升，0.05 毫升）溶於DMF-HO(l :1，v/v)(40 毫升）之 冷卻（0°〇溶液中加入“〇(：)20(1〇.〇毫升，〇.〇4毫莫耳）， 並使所產生之混合物在室溫下攪拌2天。將混合物以EtOAc 稀釋，以H20、鹽水洗滌，於Na2S04上乾燥，並蒸發而得 6.91克（98%)(R)-2-N-第三丁氧幾胺基-1-丙醇的無色油。 UMR (CDC13) 6 1· 15 (d，3H，J = 6.8 Hz)、1·45 (s， 9H)、3·48-3·53 (m，1H)、3·62 - 3·66 (m，1H)、3·76-3·77 (m，1H) ; MS(FAB) m/z 176(MH1)、120(M+-tBu)。 於4-羥基-3-甲氧苯曱酸乙酯（7.74克，0.04毫莫耳）、 (R)-2-N-第三丁氧羰胺基-1-丙醇（6·91克，0·04莫耳）及 Ph3P(13· 44克，0· 05莫耳）溶於THF(70毫升）之攪拌溶液中 加入偶氮二羧酸二異丙酯（DIAD )(10.0毫升，〇.〇5毫莫 耳）’並使所產生之混合物迴流加熱隔夜。於冷卻至室溫 後，將溶劑蒸發。將混合物溶解於CH2C12(50毫升）及TFA (30毫升）中，並使溶液在室溫下攪拌1小時。於在真空中 濃縮後，將殘留物倒入至飽和NaHC03中，並以CHC13萃取。 將萃取液以鹽水洗滌，於NagSO4上乾燥，以CHC13作為洗提 液而得7· 93克（2步驟79%) (R)-3-甲氧基-4-(2-胺基一丙260 in (R)-2-amino-1-propanol (3.01 g, 〇·〇 4 mmol) and Et3N (6.7 μm, 0.05 ml) dissolved in DMF-HO (l:1) , v/v) (40 ml) of cooling (0 ° 〇 solution was added "〇 (:) 20 (1 〇. 〇 ml, 〇. 〇 4 mmol), and the resulting mixture was at room temperature Stirred for 2 days. The mixture was diluted with EtOAc (EtOAc) EtOAc.EtOAc. A colorless oil of alcohol. UMR (CDC13) 6 1· 15 (d, 3H, J = 6.8 Hz), 1·45 (s, 9H), 3·48-3·53 (m, 1H), 3.62 - 3·66 (m,1H), 3·76-3·77 (m,1H); MS(FAB) m/z 176(MH1), 120(M+-tBu). 4-hydroxy-3-methoxy Ethyl benzoate (7.74 g, 0.04 mmol), (R)-2-N-tert-butoxycarbonylamino-1-propanol (6.91 g, 0.04 mol) and Ph3P ( 13·44 g, 0·05 mol), a solution of diazodicarboxylate (DIAD) (10.0 ml, 〇.〇5 mmol) was added to a stirred solution of THF (70 ml). The resulting mixture was heated to reflux overnight. After cooling to room temperature, the solvent was evaporated. The mixture was dissolved in CH.sub.2Cl.sub.2 (50 mL). The extract was washed with brine, dried over NagSO4, and taken with CHC13 as an eluent to give 7.93 g (2 steps 79%) (R)-3-methoxy-4-(2-amino-propan-propyl)

\\312\2d-code\90-01\89112968.ptd 第685頁 1283240 五、發明說明（681) 氧基）苯曱酸乙酯的黃色油。 l-NMR (CDC13) (5 1· 90 (d，3H，J = 6. 8 Hz)、1. 39 (t， 3 H，J = 7 · 3 H z )、1 · 7 2 ( b s，2 H)、3 · 4 2 - 3 · 4 7 ( m，1 H )、 3·74-3·89 (m，1H)、3.91 (s，3H)、3·96-4·00 (m， 1H) 、4.35 (q， 2H， J=7.3 Hz) 、6·88 (d， 1H， J=8.3 Hz) 、7·55 (d， 1H, J=2.0 Hz) 、7·65 (dd， 1H， J=2.0 、 8.3 Hz) ; MS(FAB) m/z 254(MH1)。 於3-甲氧基-4 - [Ν’-（2 -曱基苯基）脲基]苯基乙酸五氟苯 酯（459毫克，〇· 96毫莫耳）及（R)-3-甲氧基—4-(2-胺基丙 氧基）苯甲酸乙酯（242毫克，0.96毫莫耳）溶於DMF( 5毫升） 之攪拌溶液中加入EtsN( 2 0 0微升，1. 43毫莫耳），並使所 產生之混合物攪拌2小時。將混合物以EtOAc稀釋，以〇, 5N HC1、鹽水洗滌，於NaJO4上乾燥，並蒸發。使殘留物經由 於矽膠上利用CHCI3-MeOH(50:l，v/v)作為洗提液進行管 柱層析，純化而得3 6 0毫克（69%)(R) - 3-甲氧基-- [3 - 甲氧基-4 - [Ν’ - (2-曱基苯基）脲基]苯基乙醯胺基卜工一丙 氧基]苯甲酸乙酯的無色結晶固體。 1-NMR (CDC13) 5 1· 2 3- 1. 28 (m，3Η)、1· 38-1· 41 (t， 3H, J = 7.3 Hz)、2·32 (s, 3H)、3.50-4.13 (m，總計 11H)、4· 36 (q，2H，J = 7· 3 Hz)、6· 65-8· 13 (m 系列，總 計12H)。 、，&quot; 於（1〇-3-甲氧基-4-[2-[3-甲氧基-4-[^’-(2-甲基苯基） 脲基]苯基乙醯胺基]-1-丙氧基]苯甲酸乙g旨（360毫克， 0.66宅莫耳）溶於THF-MeOH(20毫升，9:1，v/v)之授摔溶\\312\2d-code\90-01\89112968.ptd Page 685 1283240 V. INSTRUCTIONS (681) A yellow oil of ethyl phenyl) benzoate. l-NMR (CDC13) (5 1· 90 (d, 3H, J = 6. 8 Hz), 1. 39 (t, 3 H, J = 7 · 3 H z ), 1 · 7 2 ( bs, 2 H), 3 · 4 2 - 3 · 4 7 ( m, 1 H ), 3·74-3·89 (m, 1H), 3.91 (s, 3H), 3·96-4·00 (m, 1H) ), 4.35 (q, 2H, J=7.3 Hz), 6.88 (d, 1H, J=8.3 Hz), 7·55 (d, 1H, J=2.0 Hz), 7·65 (dd, 1H, J=2.0, 8.3 Hz); MS(FAB) m/z 254(MH1). 3-methoxy-4-[Ν'-(2-mercaptophenyl)ureido]phenylacetic acid pentafluorobenzene Ester (459 mg, 〇·96 mmol) and ethyl (R)-3-methoxy-4-(2-aminopropoxy)benzoate (242 mg, 0.96 mmol) dissolved in DMF (5 ml) of a stirred solution was added EtsN (200 mL, 1.43 mmol), and the mixture was stirred for 2 hr. The mixture was diluted with EtOAc and washed with EtOAc Drying on NaJO4, and evaporating. The residue was purified by column chromatography using CHCI3-MeOH (50:1, v/v) as eluent, and purified to yield 3600 mg (69%). R) - 3-methoxy-[3 - methoxy-4 - [Ν' - (2-mercaptophenyl) ureido]phenyl a colorless crystalline solid of decylamine-propoxy]benzoic acid ethyl ester. 1-NMR (CDC13) 5 1· 2 3- 1. 28 (m, 3 Η), 1·38-1· 41 (t, 3H, J = 7.3 Hz), 2·32 (s, 3H), 3.50-4.13 (m, total 11H), 4·36 (q, 2H, J = 7·3 Hz), 6·65-8· 13 (m series, total 12H). ,, &quot; in (1〇-3-methoxy-4-[2-[3-methoxy-4-[^'-(2-methylphenyl))urea Phenylethylamino-1-phenyloxy]benzoic acid (360 mg, 0.66 houser) dissolved in THF-MeOH (20 ml, 9:1, v/v) Dissolve

\\312\2d-code\90-01\89112968.ptd 第686頁 1283240 五、發明說明（682) 液中加入0 · 2 5 N N a 0 Η ( 1 0毫升），並使所產生之混合物迴流 加熱隔夜。將混合物倒入至冰的1 N H C1中，並收集沈澱 物。使粗製固體自CHC13 -正己烷再結晶，而得172毫克 (50 %)(R)-3-甲氧基-4 - [2-[3-甲氧基-4-[Ν’ - (2 -甲基苯 基）脲基]苯基乙醢胺基]-1 -丙氧基]苯曱酸2 6 0的白色結晶 粉末。 熔點 1 6 8- 1 69 °C; IR (KBr) 1 687 /公分；UMR (DMSO-d6 )5 1·18 (d， 3H， J = 6.8 Hz)、2·24 (s， 3H)、2·50 -2.51(m，2H)、3.80(s，3H)、3.84(s，3H)、3.87-4·06 (m，2H)、4.07 - 4.14 (m，1H)、6·76 - 8·57 (m 系列， 總計12H)、12. 6 6 (bs，1H) ; MS(FAB) m/z 522 (MH1) ; C 28H31N3 07 · 3/4H20 之分析計算值：C，62· 85 ; H，6. 1 2 ; N， 7· 85。實測值：C， 62. 7 7 ; H，5. 95 ; N，7. 79。 實施例21 3 4-[[2-[3-甲氧基-4-[N’-（2 -甲基苯基）脲基]苯基乙醯基] 烯丙胺基]乙氧基]苯甲酸 CH3H η ά〇Η3\\312\2d-code\90-01\89112968.ptd Page 686 1283240 V. INSTRUCTIONS (682) Add 0 · 2 5 NN a 0 Η (10 ml) to the liquid and reflux the resulting mixture Heat overnight. The mixture was poured into 1 N H C1 of ice, and a precipitate was collected. The crude solid was recrystallized from CHC13-n-hexane to give 172 mg (50%) of (R)-3-methoxy-4-[2-[3-methoxy-4-[Ν' - (2- A white crystalline powder of methylphenyl)ureido]phenylethenylamino]-1-propoxy]benzoic acid 260. Melting point 1 6 8- 1 69 °C; IR (KBr) 1 687 / cm; UMR (DMSO-d6) 5 1·18 (d, 3H, J = 6.8 Hz), 2·24 (s, 3H), 2 ·50 -2.51 (m, 2H), 3.80 (s, 3H), 3.84 (s, 3H), 3.87-4.06 (m, 2H), 4.07 - 4.14 (m, 1H), 6.76 - 8· 57 (m series, total 12H), 12.6 6 (bs, 1H); MS(FAB) m/z 522 (MH1) ; C 28H31N3 07 · 3/4H20 analytical calculated value: C, 62· 85 ; H , 6. 1 2 ; N, 7· 85. Found: C, 62. 7 7 ; H, 5. 95 ; N, 7.79. Example 21 3 4-[[2-[3-Methoxy-4-[N'-(2-methylphenyl)ureido]phenylethenyl]allylamino]ethoxy]benzoic acid CH3H η ά〇Η3

OH 於4-(2-N-三氟乙醯胺基乙氧基3-曱氧苯曱酸乙酯（ 3.5克，10.4毫莫耳）及}(2(：03(2· 3克，16.4毫莫耳）於 DMF(20毫升）中之攪拌混合物中加入丙烯基溴（14. 2毫升， 16· 5毫莫耳），並使所產生之混合物在65 °C下攪拌4 5分 鐘。於冷卻後，將水加至混合物，並以EtOAc萃取。將萃OH in ethyl 4-(2-N-trifluoroacetamidoethoxy 3-indoleoxybenzoate (3.5 g, 10.4 mmol) and (2 (:03 (2.3 g, 16.4) To a stirred mixture of DMF (20 mL) was added propylene bromide (14.2 mL, 10.5 mmol), and the resulting mixture was stirred at 65 ° C for 45 minutes. After cooling, water was added to the mixture and extracted with EtOAc.

\\312\2d-code\90-01\89112968.ptd 第687頁 1283240 五、發明說明（683) 取液以鹽水洗務’於NaJO4上乾燥，並於真空中蒸發。將 殘留物溶解於THF-Me0H-H20(l:l:l，v/v/v)(3〇4'升%，並 加入KCO〆2· 3克，16· 4毫莫耳）。使所產生之混合物在室 溫下稅摔1 6小時。將混合物以E10 A c稀釋，以鹽水洗滌， 於N S 〇4上乾燥，並蒸發。使殘留物於石夕膠上利用c η c 13 : NeOH(95:5至95:5，ν/ν)作為洗提液進行層析，而得2·9克 (199%)之4-（2 -烯丙胺基乙氧基）-3 -曱氧苯甲酸乙酯的淡 黃色油。 l-NMR (CDC13，400MHz) 6 1· 39 (t，3Η，J = 7· 3 Hz)、 3.07 (t，2H，J = 5.3 Hz)、3·34 (d，2H，】 = 5·9 Hz)、 3·91 (s，3H)、4·18 (t，2H，J = 5.4 Hz)、4·35 (dd， 2H，J = 7.3 Hz、14·1 Hz)、5·12 (d，1H，J = l〇.3 Hz)、 5.22 (dd， 1H， J=1.5 Hz 、17·1 Hz) 、5·92 (m， 2H)、 6.90 (d，1H，J = 8.3 Hz)、7·55 (d，1H，J = 1.5 Hz)、 7·65 (dd，. 1H，J = 2.0 Hz、8.3 Hz); MS(FAB) m/z 278、 280 (M + H)+。 在室溫下於4 -（2 -烯丙胺基乙氧基）一3 一甲氧苯曱酸乙酯 (578毫克，2.1毫莫耳）、3-甲氧基一 4 - [N，-（2-甲基苯基） 脲基]苯乙酸（ 650毫克，2· 1毫莫耳）、HOBt(420毫克， 3· 11毫莫耳）、及DMAP(催化量）於DMF(4毫升）中之攪拌混 合物中加入EDC( 596毫克，2· 11毫莫耳）。使所產生之混合 物再在室溫下多攪拌1 8小時。將混合物倒入至1 n HC 1中， 並以EtOAc萃取。將萃取液以鹽水洗滌，於Na2s〇4上乾燥， 並於真空中蒸發。使殘留物於矽膠上利用CHC13 ·· EtOAc\\312\2d-code\90-01\89112968.ptd Page 687 1283240 V. INSTRUCTIONS (683) The liquid was washed with brine and dried on NaJO4 and evaporated in vacuo. The residue was dissolved in THF-Me0H-H20 (1:1:1, v/v/v) (3 〇 4 liter %, and KCO 〆 2·3 g, 16. 4 mmol). The resulting mixture was allowed to fall for 16 hours at room temperature. The mixture was diluted with E10 A c, washed with brine, dried over EtOAc and evaporated. The residue was chromatographed on the Shiqi gum using c η c 13 : NeOH (95:5 to 95:5, ν/ν) as an eluent to obtain 2·9 g (199%) of 4-( A pale yellow oil of ethyl 2- allylaminoethoxy)-3-nonoxybenzoate. l-NMR (CDC13, 400MHz) 6 1· 39 (t, 3Η, J = 7· 3 Hz), 3.07 (t, 2H, J = 5.3 Hz), 3·34 (d, 2H, ] = 5·9 Hz), 3·91 (s, 3H), 4·18 (t, 2H, J = 5.4 Hz), 4·35 (dd, 2H, J = 7.3 Hz, 14·1 Hz), 5·12 (d , 1H, J = l〇.3 Hz), 5.22 (dd, 1H, J=1.5 Hz, 17·1 Hz), 5.92 (m, 2H), 6.90 (d, 1H, J = 8.3 Hz), 7·55 (d, 1H, J = 1.5 Hz), 7·65 (dd, . 1H, J = 2.0 Hz, 8.3 Hz); MS (FAB) m/z 278, 280 (M + H)+. Ethyl 4-(2-allylaminoethoxy)-3-methoxybenzoate (578 mg, 2.1 mmol) at room temperature, 3-methoxy-4-[N,-( 2-methylphenyl)ureido]phenylacetic acid (650 mg, 2.1 mmol), HOBt (420 mg, 3.111 mmol), and DMAP (catalytic amount) in DMF (4 mL) EDC (596 mg, 2.11 mmol) was added to the stirred mixture. The resulting mixture was stirred for a further 18 hours at room temperature. The mixture was poured into 1 n HCl 1 and extracted with EtOAc. The extract was washed with brine, dried over Na.sub.2, and evaporated in vacuo. The residue was applied to silica gel using CHC13 ·· EtOAc

89112968.ptd 第688頁 1283240 五、發明說明（684) --- (95 : 5至1 : 1，v/v)作為洗提液進行層析，而得i克（84%)之 3:甲氧基-4- [[2-[ 3-甲氧基[N，一（2-甲基苯基）脲基] 苯基乙蕴基]烯丙胺基]乙氧基]笨甲酸的淡黃色膠。 ^-NMR (CDC13 5 4 0 0MHz) 5 1. 39 (t, 3H, J = 7. 3 Hz) &gt; 2· 29 (s，3H)、3· 58 及 3. 63 (s，總計 3H)、3. 7 0-3 · 77 (m，2H)、3·83 及 3.87 (s，3H)、4·〇5 —4·ΐ3 (m，2H)、 4.25 (m，1H)、4·36 (q, 1H, j = 7.〇 Hz)、5 〇4一5·22 (m，2H)、5·73 (m，1H)、6·32&amp;6.47 (s,lH)、6.69-6.85(in，2H)、7.12(m，2H)、7.23(m，2H)、7.50- 7.65 (m, 2H) ^8.05 (d, 1H, J,7.8 Hz)； MS(FAB) m/z 576 (M + H)+。 使3-甲氧基-4- [ [2-[e-曱氧基一4一 [N，一（2一甲基苯基）脲 基]苯基乙醯基]烯丙胺基]乙氧基]苯甲酸（5〇毫克，〇.〇9 毫莫耳）於 THF-MeOH(l:l，v/v)(2 毫升）&amp;1N Na〇H (〇·ΐ35 毫升’ 0 · 1 3 5毫莫耳）中之混合物在室溫下攪拌丨5小時，及 在50 °C下3小時。將混合物倒入至冰的1 ν HC1中。收集固 體，以水洗滌，並風乾。使粗製固體自CHCl3—正己烷再結 晶’而得38毫克（77%)4-[[2 - [3 -曱氧基-4 - [N，-（2-曱基苯 基）脲基]苯基乙醯基]烯丙胺基]乙氧基]苯甲酸2βΐ的白 色結晶物質。 熔點 125-130 °C; IR (KBr) 3319、2939、1687、1647、 1601、1535、1456、1417、1269、1223、1034、760 / 公 分；1H-NMR (DMS0-d6，400 MHz) 5 2. 29 (s，3H)、3· 68 (s，2H)、3·75-3.85 (m，8H)、4·05 (br, 1H)、4·1989112968.ptd Page 688 1283240 V. INSTRUCTIONS (684) --- (95: 5 to 1: 1, v/v) as an eluent for chromatography, and i g (84%) of 3: A Light yellow gum of oxy-4-[[2-[3-methoxy[N,-(2-methylphenyl)ureido]phenyl)-allylamine]ethoxy]benzoic acid . ^-NMR (CDC13 5 4 0 0MHz) 5 1. 39 (t, 3H, J = 7. 3 Hz) &gt; 2· 29 (s, 3H), 3·58 and 3.63 (s, total 3H) , 3. 7 0-3 · 77 (m, 2H), 3·83 and 3.87 (s, 3H), 4·〇5 — 4·ΐ3 (m, 2H), 4.25 (m, 1H), 4.36 (q, 1H, j = 7.〇Hz), 5 〇4 to 5·22 (m, 2H), 5.73 (m, 1H), 6·32 &amp; 6.47 (s, lH), 6.69-6.85 ( In, 2H), 7.12 (m, 2H), 7.23 (m, 2H), 7.50 - 7.65 (m, 2H) ^ 8.05 (d, 1H, J, 7.8 Hz); MS (FAB) m/z 576 (M + H)+. 3-methoxy-4-[[2-[e-decyloxy-4-yl[N,mono(2-methylphenyl)ureido]phenylethenyl]allylamino]ethoxylate Benzoic acid (5 mg, 〇.〇9 mmol) in THF-MeOH (1:1, v/v) (2 mL) &amp; 1N Na〇H (〇·ΐ35 ml ' 0 · 1 3 5 The mixture in millimolar was stirred at room temperature for 5 hours and at 50 °C for 3 hours. The mixture was poured into 1 ν HC1 of ice. The solid was collected, washed with water, and air dried. The crude solid was recrystallized from CHCl3-n-hexane to give 38 mg (77%) of 4-[[2-[3 - decyloxy-4 -[N,-(2-nonylphenyl)ureido]benzene White crystalline material of 2βΐ of ethionyl]allylamine]ethoxy]benzoic acid. Melting point 125-130 ° C; IR (KBr) 3319, 2939, 1687, 1647, 1601, 1535, 1456, 1417, 1269, 1223, 1034, 760 / cm; 1H-NMR (DMS0-d6, 400 MHz) 5 2 . 29 (s, 3H), 3· 68 (s, 2H), 3·75-3.85 (m, 8H), 4·05 (br, 1H), 4·19

\\312\2d-code\90-01\89112968.ptd 第689頁 1283240\\312\2d-code\90-01\89112968.ptd Page 689 1283240

(m，3H)、5·10-5·25 (m，2H)、5·65-5·90 (m，1H 6· 75 (m，1H)、6. 85 (s，1 Η)、6· 92 (m，1H)、7 ' -7.20 (m，3H)、7·48 (d，1H，】 = 1〇·2 Hz)、7 56 〇2 1H)、7· 79 (d，1H，J = 6· 8 Hz)、8· 01(m，lm ’ 〇 (m， 1H)、8· 56 (d，1H, J = 4·4 Hz)、12· 7 (br，1H) · C MS(FAB) m/z 548 (M + H)+; C3()H33N3 07 ·0·5Η2〇之分析 ^ _ 值：C， 64. 74 ; H， 6· 16 ; N，7· 55。實測值：/ 計算 Η, 6. 07 ; N，7· 55。 ’ 64. ?2 實施例2 1 4 3-甲氧基-4 - [[2 - [3-甲氧基-4-[Ν’ - (2-甲基笨義） 基乙醯基]-（2 -嗎福啉基）乙胺基]乙氧基]苯甲^ 脲基](m, 3H), 5·10-5·25 (m, 2H), 5·65-5·90 (m, 1H 6· 75 (m, 1H), 6. 85 (s, 1 Η), 6 · 92 (m,1H), 7 ' -7.20 (m,3H), 7·48 (d,1H,] = 1〇·2 Hz), 7 56 〇2 1H), 7· 79 (d,1H, J = 6· 8 Hz), 8. 01 (m, lm ' 〇 (m, 1H), 8.56 (d, 1H, J = 4·4 Hz), 12· 7 (br, 1H) · C MS (FAB) m/z 548 (M + H)+; C3()H33N3 07 ·0·5Η2〇 analysis^ _ Value: C, 64. 74 ; H, 6· 16 ; N,7· 55. Measured value :/ Calculate Η, 6. 07 ; N,7· 55. ' 64. ?2 Example 2 1 4 3-Methoxy-4 - [[2 - [3-methoxy-4-[Ν' - (2-methyl succinyl) ethionyl]-(2-norfosyl)ethylamino]ethoxy]benzaldehyde ureido]

於^甲氧基-4-[[2-[3-甲氧基-4-[Ν，_(2_甲基苯基）脲 基]本基乙醯基]烯丙胺基]乙氧基]笨甲酸（g$Q毫克， 1· 65宅莫耳）溶於THF : 1〇(7毫升）之攪拌溶液中加入Ν — 基嗎福啉氧化物（579毫克，4.95毫莫耳）及四氧化鐵 (0·2Μ水溶液）（0.413毫升，0·08毫莫耳）。使所產生之混 合物在室溫下攪拌3小時。將飽和NaHS〇3加至混合物，並 使混合物過濾通過矽藻土。以E10Ac萃取濾液。將萃取液 以鹽水洗滌，於MgS04上乾燥，並於真空中蒸發。將殘留 物溶解於 THF-Me0H-H20(l:1:1，v/v/v)(i2 毫升），並加入甲methoxy-4-[[2-[3-methoxy-4-[Ν,_(2-methylphenyl)ureido]] benzylidene]allylamino]ethoxy] Stupic formic acid (g$Q mg, 1.65 houser) was dissolved in THF: 1 Torr (7 ml) was added to a stirred solution of ruthenium-quinazoline oxide (579 mg, 4.95 mmol) and tetraoxide. Iron (0. 2 Μ aqueous solution) (0.413 ml, 0. 08 mmol). The resulting mixture was stirred at room temperature for 3 hours. Saturated NaHS(R) 3 was added to the mixture and the mixture was filtered through celite. The filtrate was extracted with E10Ac. The extract was washed with brine, dried over MgSO4 and evaporated in vacuo. The residue was dissolved in THF-Me0H-H20 (1:1:1, v/v/v) (i2 mL) and added

\\312\2d-code\90-01\89112968.ptd 第690頁 1283240 五、發明說明（686) 過碘酸納（318毫克’ 1&gt;5毫莫耳）^使所產生之混合物在環 境溫度下授拌1小時。將現合物以Et〇Ac稀釋，以鹽水洗 滌，於_4上乾燥。將溶劑於真空中蒸發，而得⑽毫克 (89%)=3-甲氧基-4-[[2-[3-甲氧基_4_[^，_(2_甲基苯基） 脲基]苯基乙醯基]-N-甲醯甲胺基]乙氧基]苯甲酸乙酯的 淡黃色膠。 'H-NMR (CDC13 &gt;4〇OMHz) 5 1.39 (t, 3H, J = 7 3 Hz) 29 (s, 3H) ^3.31-3.95 (m, 11H) .4. 10-4.42 (m . 5H)、6.5 卜 6.82 (m，3H)、7 1〇一7 25 “，3h)、7’5〇 ::、U〇 (m，1H)、8.1〇 (m，1H)、9 5〇(m .; MS(FAB) m/z 578 (M + H)+ 〇 Λ室ΛΛ^[[2_[3_甲氧基_4-[N’—（2-甲基苯基）脲基] :基乙醯基]-N-甲醯甲胺基]乙氧基]笨甲酸乙酯(2 克，0.46毫莫耳）、嗎福琳（〇〇4毫升，4 59毫莫耳）、及 AcOH( 0. 263窀升，4. 6毫莫耳）於Et〇H(3毫升）中之 合物中加入NaBH3CN(288毫克，4.6毫莫耳）。使所f生 物在室溫下攪拌15小時，並將混合物⑽敝稀釋， f在C：下加入飽和NaHC〇3。使所產生之混合物在下攪 小時。WtOAc萃取混合物。將萃取液以鹽水洗終， :=?4上乾煉’並於真空中蒸發。將殘留物 用CHCl3 :MeOH(95:5，v/v)作為洗提液 利 « ^(7U) f ^^4-[[2-[3- f (2! J λ 笨基）脲基]苯基乙醯基]一2一（嗎福啾其、 土 甲酸乙醋的油^ (馬細琳基）乙胺基]乙氧基]笨\\312\2d-code\90-01\89112968.ptd Page 690 1283240 V. INSTRUCTIONS (686) Sodium periodate (318 mg '1> 5 mmol) ^ The resulting mixture is at ambient temperature Mix for 1 hour. The mixture was diluted with Et 〇Ac, washed with brine and dried over EtOAc. The solvent was evaporated in vacuo to give (10) mg (yield: 89%) of 3-methoxy-4-[[2-[3-methoxy-4-[[ a pale yellow gum of ethyl phenyl ethionyl]-N-methyl hydrazine methyl ethoxy] benzoate. 'H-NMR (CDC13 &gt; 4〇OMHz) 5 1.39 (t, 3H, J = 7 3 Hz) 29 (s, 3H) ^3.31-3.95 (m, 11H) .4. 10-4.42 (m . 5H ), 6.5 6.8 6.82 (m, 3H), 7 1 〇 1 7 25 ", 3h), 7'5 〇::, U 〇 (m, 1H), 8.1 〇 (m, 1H), 9 5 〇 (m .; MS(FAB) m/z 578 (M + H)+ 〇Λ室ΛΛ^[[2_[3_methoxy_4-[N'-(2-methylphenyl)ureido]: group Ethyl]-N-methylaminomethyl]ethoxy] benzoic acid ethyl ester (2 g, 0.46 mmol), carbaryl (〇〇 4 ml, 4 59 mmol), and AcOH ( 0. 263 liters, 4.6 mM, NaBH3CN (288 mg, 4.6 mmol) was added to Et.sub.H (3 mL). The mixture (10) is diluted, and f is added to a saturated NaHC〇3 under C:. The resulting mixture is stirred for an hour. The mixture is extracted with WtOAc. The extract is washed with brine, and then dried. Evaporation. The residue was treated with CHCl3: MeOH (95:5, v/v) as eluent « ^(7U) f ^^4-[[2-[3-f (2! J λ stupid) Urea-based phenyl hydrazinyl]-one-one (Isofosin, oil of ethyl formate) ^ (Ma Xilinji Ethylamino]ethoxy] stupid

1283240 五、發明說明（687) UMR (CDC13，40 0MHz) (5 1· 28 (t，3H，J = 7· 0 Hz)、 2.31 (s，3H)、2·48 (brs，4H)、2·52 (m，2H)、3.60-3.91 (m，16H)、4.11 及4·28 (m，總計2H)、4·39 (q， 2H, J = 7.0 Hz)、6·70-6·85 (m，4H)、7·15 (m，2H)、 7·50-7·63 (m，3H)、8·08 (d，1H，J = 8.0 Hz); MS(FAB) m/z 64 9 (M + H)+。 使3-甲氧基-4-[[2 - [3-甲氧基-4 - [N，-（2-甲基苯基）脲 基]苯基乙醯基]-(2 -嗎福琳基）乙胺基]乙氧基]苯曱酸乙 酯（265毫克，0.46毫莫耳）於THF(4毫升）及IN NaOH(0.984 毫升）中之混合物在5 0 °C下攪拌1 5小時。經由加入1 n H C1 將混合物之pH調整至7.4，並以CHC13 :MeOH(9:l，ν/ν)萃 取。將萃取液以鹽水洗滌，於MgS04上乾燥，並於真空中 蒸發。利用E t2 0使殘留物結晶，而得1 6 0毫克（7 8 % )之3 -甲 氧基-4-[[2-[ 3-曱氧基-4-[Ν’ -(2-曱基苯基）脲基]苯基乙 醯基]-(2 -嗎福啉基）乙胺基]乙氧基]苯甲酸262的白色結 晶物質。 熔點 1 2 5-1 30 °C ; IR (KBr) 3346、2 956、2937、1 7 0 5、 1622 、 1599 、 1537 、 1456 、 1417 、 1299 、 1114 、 1032 、 752 / 公分；UMR (CD3OD，4 0 0MHz) (5 2· 29 (s，3H)、 2.49-2.64 (m，6H)、3·65- 3.8 5 (m，16H)、4·13 (m, 1Η)、4·26 (m，1Η)、6.78-7·04 (m，4Η)、7·18 (m， 2Η)、7·55-7·64 (m，3Η)、7·99 (m，2H); MS(FAB) m/z 621 (M + H)+ ; C33H4GN4 08 · 2. 5H20 之分析計算值：C, 59. 54 ;H， 6.81； N, 8. 42 ° 實測值：C， 59. 71 ; H， 6.35； N,1283240 V. INSTRUCTIONS (687) UMR (CDC13, 40 0MHz) (5 1· 28 (t, 3H, J = 7· 0 Hz), 2.31 (s, 3H), 2·48 (brs, 4H), 2 · 52 (m, 2H), 3.60-3.91 (m, 16H), 4.11 and 4·28 (m, total 2H), 4·39 (q, 2H, J = 7.0 Hz), 6.70-6·85 (m, 4H), 7·15 (m, 2H), 7·50-7·63 (m, 3H), 8·08 (d, 1H, J = 8.0 Hz); MS(FAB) m/z 64 9 (M + H)+. 3-methoxy-4-[[2-[3-methoxy-4-[N-(2-methylphenyl)ureido]phenylethyl) a mixture of ethyl 2-amino-2-ethoxy]benzoate (265 mg, 0.46 mmol) in THF (4 mL) and IN NaOH (0.984 mL) Stir for 15 hours at 0 ° C. The pH of the mixture was adjusted to 7.4 by addition of 1 n H C1 and extracted with CHC 13 : MeOH (9:1, ν / ν). The extract was washed with brine and dried on MgSO. And evaporating in vacuo. The residue was crystallised from EtOAc to give EtOAc (EtOAc) White knot of Ν'-(2-mercaptophenyl)ureido]phenylethenyl]-(2-norbulinyl)ethylamino]ethoxy]benzoic acid 262 Melting point: 1 2 5-1 30 °C; IR (KBr) 3346, 2 956, 2937, 1 7 0 5, 1622, 1599, 1537, 1456, 1417, 1299, 1114, 1032, 752 / cm; UMR ( CD3OD, 4 0 0MHz) (5 2· 29 (s, 3H), 2.49-2.64 (m, 6H), 3·65- 3.8 5 (m, 16H), 4·13 (m, 1Η), 4·26 (m, 1Η), 6.78-7·04 (m, 4Η), 7.18 (m, 2Η), 7·55-7·64 (m, 3Η), 7·99 (m, 2H); MS ( m/z 621 (M + H)+ ; C33H4GN4 08 · 2. 5H20 Analysis calculated: C, 59. 54 ; H, 6.81; N, 8. 42 ° Found: C, 59. 71 ; , 6.35; N,

\\312\2d-code\90-01\89112968.ptd 第 692 頁 1283240 五、發明說明（688) 7.98。 實施例2 1 5 3-甲氧基-4-[[2- [3-甲氧基-4-[N，_(2-甲基苯基）脲基]笨 基乙酿基][(2-(4-甲基-丨-六氫呲啡基））乙胺基]乙氧基] 苯曱酸\\312\2d-code\90-01\89112968.ptd Page 692 1283240 V. Description of invention (688) 7.98. Example 2 1 5 3-methoxy-4-[[2-[3-methoxy-4-[N,_(2-methylphenyl)ureido]]]]]] -(4-methyl-indole-hexahydroindolyl))ethylamino]ethoxy]benzoic acid

在室溫下於3-甲氧基一 4 - [[2-[3-曱氧基-4-[N，-（2-甲基 苯基）脲基]苯基乙醯基]_N—甲醯甲胺基]乙氧基]苯曱酸 乙醋（242毫克，〇·42毫莫耳）、N_曱基六氫吡畊（0.465毫 升’ 4· 2毫莫耳）、及Ac〇H(〇. 24〇毫升，4.2毫莫耳）於 Et0H(3毫升）中之攪拌混合物中加ANaBH3CN( 2 6 3毫克， 4· 2毫莫耳）。使所產生之混合物在室溫下攪拌丨5小時。將 混合物以EtOAc稀釋，並在〇 下加入飽和NaHC03。使所產 生之混合物在0 °C下攪拌〇 · 5小時。以EtOAc萃取混合物。 將萃取液以鹽水洗滌，於MgS〇4上乾燥，並於真空中蒸 發。將殘留物於矽膠上利用CHCl3 : MeOH(95: 5，v/v)作為 洗提液進行層析而得195毫克（70%)之3-甲氧基-4-[[2-[3-甲氧基-4 - [Ν’-（2-甲基苯基）脲基]苯基乙醯基][2 一（4-曱 基-1-六氫咄畊基）]乙胺基]乙氧基]苯甲酸乙酯的油。 UMR (CDC13，400ΜΗζ)5 1.23 (t，3Η，J = 7.0 Hz)、 2.25 (s，3H)、2.29 (s，3H)、2·50 (br m，12H)、3-methoxy-4-[[2-[3-]oxy-4-[N,-(2-methylphenyl)ureido]phenylethenyl]_N-A at room temperature Methylamino]ethoxy]benzoic acid ethyl vinegar (242 mg, 〇·42 mmol), N_mercaptohexahydropyrazine (0.465 ml '4.2 mm), and Ac〇H (〇. 24 mL, 4.2 mmol) Add AABH3CN (2 63 mg, 4.2 mmol) to a stirred mixture of Et0H (3 mL). The resulting mixture was stirred at room temperature for 5 hours. The mixture was diluted with EtOAc and sat. NaHC.sub.3 was added. The resulting mixture was stirred at 0 ° C for 5 hours. The mixture was extracted with EtOAc. The extract was washed with brine, dried over MgSO 4 and evaporated in vacuo. The residue was chromatographed on silica gel using CHCl3: MeOH (95: 5, v/v) to afford 195 mg (70%) of 3-methoxy-4-[[2-[3- Methoxy-4 -[Ν'-(2-methylphenyl)ureido]phenylethenyl][2-(4-mercapto-1-hexahydroindole)]ethylamino]B An oil of ethyl benzoate. UMR (CDC13,400ΜΗζ)5 1.23 (t,3Η,J = 7.0 Hz), 2.25 (s,3H), 2.29 (s,3H), 2·50 (br m,12H),

\\312\2d-code\90-01\89112968.ptd 第 693 頁 1283240 五、發明說明（689) 3·44-3·85 (m，12H)、4·10 (br，1H)、4·22 (br，1H)、 4.35 (m，2H)、6· 70-6.85 (m，3H)、6·98 (s, 1H)、 7·10 (m，1H)、7.20 (m，2H)、7·40 (m，1H)、7·60 -7.70 (m, 3H) &gt;8.05 (d, 1H, J = 7.8 Hz)； MS(FAB) m/z 662 (M + H)+。 使3-甲氧基-4 - [[2-[3 -甲氧基-4-[N，-（2-甲基苯基）脲 基]苯基乙醯基][2-(4-甲基-1-六氫咄畊基）]乙胺基]乙氧 基]苯甲酸乙酯（195毫克，0.30毫莫耳）於THF: M eOH( 4: 1， v/v)(5毫升）及IN NaOH(0· 885公升）中之混合物在50 °C下 攪拌1 5小時。經由加入1 N HC1將混合物之pH調整至7. 4， 並以CHC13 :MeOH(9:l，v/v)萃取。將萃取液以鹽水洗 滌，於MgS04上乾燥，並於真空中蒸發。利用Et20使殘留物 結晶，而得141毫克（75%)之3-甲氧基-4-[[2 - [3-曱氧基-4-[Ν’-（2-曱基苯基）脲基]苯基乙醯基][2-(4-曱基-1-六 氫咄畊基）]乙胺基]乙氧基]苯甲酸2 6 3的白色結晶物質。 熔點 155-160 °C; IR (KBr) 2937、1537、783 / 公分； 1Η-N MR (CD3OD，40 0 MHz) (5 2·29 (s，3H)、2.49-2.80 (m，15H)、3·60-3·85 (m，9H)、3·92 (s，1H)、4·12 (m，1H)、4·25 (m，1H)、6·78-7·20 (m，6H)、7·61 (m， 3H)、8. 00 (m，1H) ; MS(FAB) m/z 632 (M)+ ; C34H43N5〇7 · 2· 5H20 之分析計算值：C，60. 16 ; H，7. 13 ; N， 10. 32。 實測值：C， 59. 72 ; H， 6. 86 ; N，9· 97。 實施例21 6 3-甲氧基-4-[[ 2- [3-曱氧基-4-[Ν’-（2-甲基苯基）脲基]笨\\312\2d-code\90-01\89112968.ptd Page 693 1283240 V. INSTRUCTIONS (689) 3·44-3·85 (m, 12H), 4·10 (br, 1H), 4· 22 (br,1H), 4.35 (m,2H),6·70-6.85 (m,3H),6·98 (s, 1H), 7·10 (m,1H), 7.20 (m,2H), 7·40 (m, 1H), 7.60 -7.70 (m, 3H) &gt; 8.05 (d, 1H, J = 7.8 Hz); MS (FAB) m/z 662 (M + H)+. 3-methoxy-4-[[2-[3-methoxy-4-[N,-(2-methylphenyl)ureido]phenylethenyl][2-(4-A Ethyl-1-hexahydroindole base)]ethylamino]ethoxy]benzoic acid ethyl ester (195 mg, 0.30 mmol) in THF: M eOH (4:1, v/v) (5 ml) The mixture in IN NaOH (0·885 liters) was stirred at 50 ° C for 15 hours. The pH of the mixture was adjusted to 7.4 by the addition of 1 N HCl and extracted with CHC13:MeOH (9:1, v/v). The extract was washed with brine, dried over MgSO4 and evaporated in vacuo. The residue was crystallized from Et20 to give 141 mg (75%) of 3-methoxy-4-[[2-[3-]-oxy-4-[[rho]-(2-nonylphenyl)urea A white crystalline material of phenylethyl hydrazino][2-(4-mercapto-1-hexahydroindole)]ethylamino]ethoxy]benzoic acid 2 6 3 . Melting point 155-160 °C; IR (KBr) 2937, 1537, 783 / cm; 1Η-N MR (CD3OD, 40 0 MHz) (5 2·29 (s, 3H), 2.49-2.80 (m, 15H), 3·60-3·85 (m, 9H), 3.92 (s, 1H), 4·12 (m, 1H), 4·25 (m, 1H), 6·78-7·20 (m, 6H), 7·61 (m, 3H), 8. 00 (m, 1H); MS(FAB) m/z 632 (M)+ ; C34H43N5〇7 · 2· 5H20 Analytical calculated value: C, 60. 16; H, 7.13; N, 10. 32. Found: C, 59.72; H, 6. 86; N, 9.97. Example 21 6 3-methoxy-4-[[ 2 - [3-曱oxy-4-[Ν'-(2-methylphenyl)ureido] stupid

\\312\2d-code\90-01\89112968.ptd 第 694 頁 1283240 五、發明說明（690) 基乙醯基]-2 -環丙胺基]乙胺基]乙氧基]苯甲酸\\312\2d-code\90-01\89112968.ptd Page 694 1283240 V. INSTRUCTIONS (690) Ethyl acetyl]-2-cyclopropylamino]ethylamino]ethoxy]benzoic acid

在室溫下於3-曱氧基-4-[ [2-[ 3-甲氧基-4-[N，-（2-甲基 苯基）脲基]苯基乙醯基]-2 -環丙胺基]乙胺基]乙氧基]苯 甲酸乙酯（26 7毫克，0· 46毫莫耳）、環丙胺（0· 32毫升， 4.6毫莫耳）、及AcOH(0.264毫升，4.6毫莫耳）於Et0H(3毫 升）中之攪拌混合物中加入NaBH3CN( 2 99毫克，4. 6毫莫 耳）。使所產生之混合物在室溫下攪拌1 5小時。將混合物3-methoxy-4-([2-[3-methoxy-4-[N,-(2-methylphenyl)ureido]phenylethenyl]-2 - at room temperature Ethyl propylamino]ethylamino]ethoxy]benzoate (26 7 mg, 0.446 mmol), cyclopropylamine (0.22 ml, 4.6 mmol), and AcOH (0.264 mL, 4.6) To a stirred mixture of EtOAc (3 mL). The resulting mixture was stirred at room temperature for 15 hours. Mixture

以EtOAc稀釋，並在〇 °c下加入飽和NaHC〇3。使所產生之混 合物在〇°C下攪拌0.5小時。以EtOAc萃取混合物。將萃^ 液以鹽水洗滌，於MgS〇4上乾燥，並於真空中蒸發。將殘 留物於石夕膠上利用CHCl3 ••MeOiKWJ，v/v)作1%先提液進 行層析而得156毫克（55%)之3-甲氧基-4〜[[2〜[3_甲氧A -4-[Ν’ -(2-甲基苯基）脲基]苯基乙醯基環丙胺&quot;乙 胺基]乙氧基]苯曱酸乙醋的油。Dilute with EtOAc and add sat NaHC 〇3 at EtOAc. The resulting mixture was stirred at 〇 ° C for 0.5 hours. The mixture was extracted with EtOAc. The extract was washed with brine, dried over MgSO 4 and evaporated in vacuo. The residue was chromatographed on a Shijiao gel using CHCl3 ••MeOiKWJ, v/v) as a 1% first extract to obtain 156 mg (55%) of 3-methoxy-4~[[2~[3 An oil of methoxy- -4-[Ν'-(2-methylphenyl)ureido]phenylethenylcyclopropylamine &quot;ethylamino]ethoxy]benzoic acid ethyl vinegar.

1 -NMR (CDC13，40 0ΜΗζ)6 0.35 (m，4Η)、丨 22 (br s 3H)、2· 10 (m，1H)、2· 20 (s，3H)、2. 42 (br 2Η)Γ ^ 2·90 (br s， 2H)、3·60 —3·80 (m， 10H)、」 J 4.10 (br, 1H)、4· 22 (br，1H)、4· 33 (br，2H)、6· 72 3R) 7· 05-7· 30 (m，4H)、7· 55 (m，4H)、8· 〇6 化二 1R) MS(FAB) m/z 619 (M+H)+ 。 ’1 - NMR (CDC13, 40 0 ΜΗζ) 6 0.35 (m, 4 Η), 丨 22 (br s 3H), 2· 10 (m, 1H), 2· 20 (s, 3H), 2. 42 (br 2 Η) Γ ^ 2·90 (br s, 2H), 3·60 —3·80 (m, 10H),” J 4.10 (br, 1H), 4· 22 (br, 1H), 4· 33 (br, 2H ),6· 72 3R) 7· 05-7· 30 (m,4H), 7· 55 (m,4H),8·〇6 2D) MS(FAB) m/z 619 (M+H) + . ’

1283240 五、發明說明（691) 使3-甲氧基-4-[ [2-[3-甲氧基-4- [Ν’ -（2-甲基笨基）脲 基]苯基乙醯基]-Ν-[2 -環丙胺基]乙胺基]乙氧基]笨曱酸 乙酯（195 毫克，0·30 毫莫耳）於 THF:MeOH(4:l， ν/ν)(5 毫 升）及IN NaOH( 0. 7 56毫升）中之混合物在50 °C下攪拌15小 時。經由加入IN HC1將混合物之PH調整至7. 4，並以CHC1 3 : Me0H(9 : 1，v/v)萃取。將萃取液以鹽水洗滌，於MgS〇4 上乾燥，並於真空中蒸發。利用Et20使殘留物結晶，而得 57毫克（38 %)之3 -甲氧基-4 - [[2 - [3 -甲氧基-4 - [N，- (2-甲基苯基）脲基]苯基乙醯基]-[2-環丙胺基]乙胺基] 乙氧基]苯甲酸2 64的白色結晶物質。 熔點 135-140 °C; IR (KBr) 3324、2937、1535、1032、 7 54 / 公分；1H-NMR (CD3OD，40 0 MHz) 6 0· 50-0· 73 (m， 4H)、2·29 (s，3H)、2·53 (m，1H)、2·98 (m，1H)、 3.21 (m，1H)、3·58-3.88 (m，11H)、3·91 (s，1H)、 4.09 (m，1H)、4.25 (m，1H)、6·7 6-6.92 (m，3H)、 7.01 (m，1H)、7·18 (m，2H)、7.60 (m，3H)、8·00 (d， J = 8.3 Hz, 1H)； MS(FAB) m/z 591 (M + H)+ ； C32H38N4 07 · 3·0Η2Ο之分析計算值：C，59·62; H，6.88; N， 8.69。實 測值：C，5 9.25； H, 6. 29 ； N, 8.29° 實施例2 1 7 4-[[2-[3-甲氧基-4 - [Ν’ -（2 -氟苯基）脲基]苯基乙醯基]-N-甲胺基]乙氧基]苯甲酸1283240 V. INSTRUCTIONS (691) 3-methoxy-4-[[2-[3-methoxy-4-[Ν'-(2-methylphenyl)ureido]phenylethyl) ]-Ν-[2-cyclopropylamino]ethylamino]ethoxy]ethyl decanoate (195 mg, 0·30 mmol) in THF:MeOH (4:1, ν/ν) The mixture in milliliters and IN NaOH (0.76 ml) was stirred at 50 °C for 15 hours. The pH of the mixture was adjusted to 7.4 by the addition of IN HC1 and extracted with CHC1 3 : Me0H (9:1, v/v). The extract was washed with brine, dried over MgSO4 and evaporated in vacuo. The residue was crystallized from Et20 to give 57 mg (yield: 38%) of 3-methoxy-4 - [[2 - [3 -methoxy-4-[N,-(2-methylphenyl))urea A white crystalline material of phenylethyl fluorenyl]-[2-cyclopropylamino]ethylamino]ethoxy]benzoic acid 2 64 . Mp 135-140 ° C; IR (KBr) 3324, 2937, 1535, 1032, 7 54 / cm; 1H-NMR (CD3OD, 40 0 MHz) 6 0· 50-0· 73 (m, 4H), 2· 29 (s,3H), 2·53 (m,1H), 2·98 (m,1H), 3.21 (m,1H), 3·58-3.88 (m,11H),3·91 (s,1H ), 4.09 (m, 1H), 4.25 (m, 1H), 6·7 6-6.92 (m, 3H), 7.01 (m, 1H), 7·18 (m, 2H), 7.60 (m, 3H) , 8·00 (d, J = 8.3 Hz, 1H); MS(FAB) m/z 591 (M + H)+ ; C32H38N4 07 · 3·0Η2Ο Analysis calculated: C, 59·62; H, 6.88 ; N, 8.69. Found: C, 5 9.25; H, 6. 29; N, 8.29° Example 2 1 7 4-[[2-[3-Methoxy-4 -[Ν'-(2-fluorophenyl)urea] Phenylethyl fluorenyl]-N-methylamino]ethoxy]benzoic acid

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3-氣-4 - [2-[3〜甲氧基一 4 一 [N，一（2 — 基一N—甲胺基乙氧基]笨甲酸 氟苯基）脲基]苯基乙醯3-Gas-4 - [2-[3~Methoxy-4[N,1(2-yl-N-methylaminoethoxy)]benzoic acid fluorophenyl)ureido]phenyl acetamidine

pu ^v^COOH 266 於2—(NJ卞氧羰基—N—曱基）乙醇胺（3.01克，14.4毫莫 耳、3-氯-4 -羥基苯甲酸甲酯（2·68克，14·4毫莫耳）、 Ph3【（5· 65克，21.5毫莫耳）溶於THF(3〇毫升）之冷（〇。〇攪 拌洛，，加入偶氮二羧酸二異丙酯（DIAD)(4· 25毫升， 、·/宅莫耳）並使所產生之混合物迴流加熱隔夜。將溶 液蒸發掉’經由在矽膠上以CHC13作為洗提液進行管柱層 析，將殘留物純化而得3· 90克（72%)3—氯—4—[2-(N—苄氧羰 基-N-甲胺基）乙氧基]苯甲酸甲酯的淡黃色固體。 尺 UMR (CDC 13)占 3.15 (s, 3H)、3.74-3.76 (m，2H)、 3.89 (s，3H)、4·17-4.27 (m，2H)、5·14 (s，2H)、 6·8卜6·94 (m，1Η)、7·33-7·36 (m，5Η)、7·85-7·92 (m，1Η)、8· 05 (bs，1Η)。 使3-氯-4-[2-（Ν-;氧羰基一 ν_甲胺基）乙氧基]苯甲酸甲 酉旨（3· 90克’ 1〇· 〇3毫莫耳）溶於Et〇Ac —Ac〇H(4〇毫升，！ ： l v/v)之溶液在5% Pd-C(1 · 95克，50重量百分比）上在3大氣 壓下氫化2小時。將混合物過濾，並將濾液以飽和NaHC〇3 洗滌，將鹼性水層以CHC 13萃取，以鹽水洗滌，並蒸發而 得3-氯-4 -（N-甲胺乙氧基）笨曱酸甲酯及4 - [2-(N-甲胺基）Pu ^v^COOH 266 in 2-(NJ卞 oxycarbonyl-N-fluorenyl)ethanolamine (3.01 g, 14.4 mmol, methyl 3-chloro-4-hydroxybenzoate (2·68 g, 14.4) Millol), Ph3 [(5·65 g, 21.5 mmol) dissolved in THF (3 mL) cold (〇. 〇 stirred, added diazonodicarboxylate (DIAD) ( 4·25 ml, ······························································································· · 90 g (72%) of 3-chloro-4-[2-(N-benzyloxycarbonyl-N-methylamino)ethoxy]benzoic acid methyl ester as a pale yellow solid. UMR (CDC 13) occupies 3.15 (s, 3H), 3.74-3.76 (m, 2H), 3.89 (s, 3H), 4·17-4.27 (m, 2H), 5·14 (s, 2H), 6·8 b 6·94 ( m,1Η),7·33-7·36 (m,5Η), 7·85-7·92 (m,1Η),8· 05 (bs,1Η). 3-chloro-4-[2- (Ν-; oxycarbonyl-v-methylamino)ethoxy]benzoic acid formazan (3·90 g '1〇·〇3 mmol) dissolved in Et〇Ac —Ac〇H (4〇 ml ,! : lv/v) solution at 5% Pd-C (1 · 95 The mixture was hydrogenated for 2 hours at 3 atm. The mixture was filtered, and the filtrate was washed with saturated NaHC 〇3, and the basic aqueous layer was extracted with CH.sub.3, washed with brine and evaporated to give 3-chloro- 4-(N-methylamine ethoxy) methyl benzoate and 4-[2-(N-methylamino)

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乙氧基]苯甲酸甲酯之標題化合物（1· 61克）之不可分離混 合物的淡黃色油。 290a 及 29 0a 之混合物，(CDCl3) 5 252-252及 2·53 一 2·54 (各m，3H)、2.9 8 - 3.00 及 3.03 - 3.0 5 (各爪，各 2H)、3·88 及 3.99 (各s,各 3H)、4,U-4」4 及 4.18 - 4·2〇A pale yellow oil of the insoluble mixture of the title compound (1·61 g) of ethoxy]methyl benzoate. a mixture of 290a and 29 0a, (CDCl3) 5 252-252 and 2·53 a 2.54 (each m, 3H), 2.9 8 - 3.00 and 3.03 - 3.0 5 (each claw, 2H each), 3.88 and 3.99 (each s, each 3H), 4, U-4"4 and 4.18 - 4·2〇

(各m，各 2Η)、6·91-6·96 及 7.90 - 8.0 5 (m 系列她钟 7H) 〇 …一I 使3:甲氧基-4-[N，-(2-氟苯基）脲基]苯基乙醯基]酸 ( 392毫克）、3-氯-4-[2-（N-甲胺基）乙氧基]苯甲酸甲酯及 4 [2 (N甲胺基）乙氧基]苯甲酸甲酯之混合物（Ms毫 克）、EDC(氫氯酸鹽）（ 35 4毫克）、HOBt( 250毫克）、及 DMAP( 2 5 0毫克）於DMF(8毫升）中之混合物在室溫下攪拌6小 時。將混合物以EtOAc稀釋，以〇 · 5N HC1、鹽水洗滌，於 N S 〇4上乾燥，並蒸發。使殘留物經由於石夕膠上利用1 %(each m, each 2Η), 6·91-6·96 and 7.90 - 8.0 5 (m series her clock 7H) 〇...I I make 3: methoxy-4-[N,-(2-fluorophenyl) Ureido]phenylethenyl]acid (392 mg), 3-chloro-4-[2-(N-methylamino)ethoxy]benzoic acid methyl ester and 4 [2 (N-methylamino) Mixture of methyl ethoxy]benzoate (Ms mg), EDC (hydrochloride) (35 4 mg), HOBt (250 mg), and DMAP (250 mg) in DMF (8 mL) The mixture was stirred at room temperature for 6 hours. The mixture was diluted with EtOAc, washed with EtOAc EtOAc EtOAc. Allow the residue to pass 1% on the stone

Me0Η浴於CHC ls作為洗提液進行管柱層析，純化而得氯 -4-[[ 2- [3-甲氧基-4-[Ν’ -（2-氟苯基）脲基]苯基乙醯 基]-Ν-甲胺基乙氧基]苯甲酸甲酯及4一 [[2-[3-曱氧基 - 4-[Ν’-（2-氟苯基）脲基]苯基乙醯基]_Ν—甲胺乙氧基]笨 曱酸酯（5 5 0毫克）之混合物的棕色非晶形固體。 於3-氯-4-[[2- [3-甲氧基-4-[Ν，- (2-氟苯基）脲基]苯基 乙醯基]-Ν-甲胺基乙氧基]苯甲酸曱酯及4一[[2-[3-甲氧基 -4_[Ν’-（2-氟苯基）脲基]苯基乙醯基]甲胺乙氧基]笨 甲酸酯之此混合物（ 550毫克）溶於THF-Me0Η( 20毫升，1 : 1， ν/ν)之授拌溶液中加入0.5Ν NaOH(10毫升），並使所產生The Me0 bath was purified by column chromatography on CHC ls as an eluent to obtain chloro-4-[[2-[3-methoxy-4-[Ν'-(2-fluorophenyl)ureido]benzene. Methyl ethyl hydrazide]-Ν-methylaminoethoxy]benzoic acid methyl ester and 4-[[2-[3-曱oxy-4-(Ν)-(2-fluorophenyl)ureido]benzene A brown amorphous solid of a mixture of thioglycolyl]-hydrazine-methylamine ethoxy] acetoate (550 mg). 3-Chloro-4-[[2-[3-methoxy-4-[indolyl]-(2-fluorophenyl)ureido]phenylethenyl]-anthracene-methylaminoethoxy] Ethyl benzoate and 4-[[2-[3-methoxy-4_[Ν'-(2-fluorophenyl)ureido]phenylethenyl]methylamine ethoxy] benzoate This mixture (550 mg) was dissolved in THF-Me0 (20 mL, 1:1, ν/ν), and 0.5 NaOH (10 mL) was added to the mixture.

1283240 五、發明說明（694) 之混合物迴流加熱6小時。將混合物倒入至冰的丨N HC 1 中’並收集固體。利用製備TLC以10% MeOH溶於CHCI3作為 洗提液，將粗製固體純化而得4 一 [[2-[3-甲氧基-4-[N， -(2-氟苯基）脲基]苯基乙醯基]一 n一曱胺乙氧基]苯甲酸 265 ( 56毫克，白色非晶形固體）及3一氣一4一 [[2一 [3一甲氣基 -4 - [Ν’ -（2-氟苯基）脲基]苯基乙醯基]—2-N-甲胺基乙氧 基]苯甲酸26 6 (8 8毫克，棕色非晶形固體）。 實施例21 8 4-[ [2-[ 3-甲氧基-4-[Ν’ - (2 -甲基苯基）脲基.]苯基乙醯基 甲胺基]乙氧基]苯甲酸 土1283240 V. The mixture of invention (694) was heated under reflux for 6 hours. The mixture was poured into ice 丨N HC 1 ' and the solid was collected. The crude solid was purified by preparative TLC with 10% MeOH dissolved in CHCI3 as eluent to give 4-[[2-[3-methoxy-4-[N,-(2-fluorophenyl)ureido] Phenylethyl hydrazide]-n-nonylamine ethoxy]benzoic acid 265 (56 mg, white amorphous solid) and 3 gas-a-4 [[2][3-methoxymethyl-4-[Ν' - (2-Fluorophenyl)ureido]phenylethenyl]-2-N-methylaminoethoxy]benzoic acid 26 6 (8 8 mg, brown amorphous solid). Example 21 8 4-[ [2-[ 3-Methoxy-4-[Ν-(2-methylphenyl)ureido]]phenylethenylmethylamino]ethoxy]benzoic acid earth

3-氣-4- [[2-[ 3-甲氧基-4-[Ν，-（2-氟苯基）脲基]苯基乙 醯基]- 2-Ν-甲胺基乙氧基]苯甲酸3-Gas-4-[[2-[ 3-methoxy-4-[indolyl]-(2-fluorophenyl)ureido]phenylethenyl]-2-ylidene-methylaminoethoxy ]benzoic acid

使4-[2 -（Ν-甲基-2 -胺基）乙氧基]-3 -氯苯甲酸甲酯（292 毫克’1.2毫莫耳）、3-甲氧基-4 - [Ν，- (2-甲基苯基）脲基 ]苯乙酸（377毫克，1.2毫莫耳）、EDC(345毫克，1.8毫莫 耳）、H0Bt(243 毫克，1.8 毫莫耳）、及DMAP(29 毫克，〇· 24 毫莫耳）於DM F ( 2 · 7毫升）中之混合物在室溫下攪拌6小時。 將混合物倒入至冰的IN HC1中，並以EtOAc稀釋。將萃取 液以鹽水洗滌，於MgS〇4上乾燥，並於真空中蒸發。使殘Methyl 4-[2-(indolyl-2-amino)ethoxy]-3-chlorobenzoate (292 mg '1.2 mmol), 3-methoxy-4 - [Ν, - (2-methylphenyl)ureido]phenylacetic acid (377 mg, 1.2 mmol), EDC (345 mg, 1.8 mmol), H0Bt (243 mg, 1.8 mmol), and DMAP (29) The mixture in DMF (2.7 ml) was stirred at room temperature for 6 hours. The mixture was poured into ice in EtOAc and diluted with EtOAc. The extract was washed with brine, dried over MgSO 4 and evaporated in vacuo. Make up

1283240 五、發明說明（695) &quot; ----- 留物於石夕膠上利用CHC13: Et0AC(95:5至0:100，v/v)作為 洗提液進行層析，而得3一氯—4_[[2_[3_甲氧基_4_[N，—d 甲基苯基）脲基]苯基乙醯基]甲胺基]乙氧基]苯甲酸甲gt 及4-[[2-[3-甲氧基-4-[N，-(2-甲基苯基）脲基]笨基乙曰隨 基]曱胺基]乙氧基]苯曱酸甲酯之不可分離混合物（489毫 克）的淡黃色油。 使3-氯-4 - [[2 - [3-曱氧基-4-[N，- (2-甲基苯基）脲基]笨 基乙醯基]曱胺基]乙氧基]苯曱酸甲酯及4一[[2一[3—甲氧基 -4 - [Ν’ - (2-甲基苯基）脲基]苯基乙醯基]甲胺基]乙氧基] 笨甲酸甲酯（ 489毫克之混合物）於THF-MeOH(4毫升，1 : i， v/v)中之混合物在50 °C下攪拌1 5小時。將混合物倒入至冰 的1 N HC1中。收集固體，以水洗滌，並風乾。利用製備 TLC以CHCI3 : MeOH(93· 7，v/v)作為洗提液，將粗製固體純 化而得4 - [[2-[3 -甲氧基-4- [Ν’-（2-甲基苯基）脲基]苯基 乙醯基]甲胺基]乙氧基]苯甲酸2 67( 1 80毫克，2步驟31%二 結晶物質）及3 -氯-4-[[2-[3 -甲氧基-4 - [Ν’-（2-曱基笨基） 脲基]苯基乙醯基]甲胺基]乙氧基]苯甲酸2 68(280毫克，2 步驟44%之結晶物質）。 熔點 145 - ΙδΟπ;1!! - NMR(DMSO-d6,4 0 0MHz)5 2.31 (s， 3H)、3·05 及 3.19 (s，3H)、3.35 及 3·38 (s，3H)、 3·72-3·85 (m，7Η)、4·09 及4.23 (m，總計21〇、6.79-7.20 (m，7H)、7·60 (m，1H)、7·86-8·〇9 (m，3H); MS(FAB) m/z 49 3 (Μ + Η)+; C27H29N3 06 ·1·75Η20之分析計算 值：C，62.0 0； Η, 6. 26 ； Ν, 8· 03。實測值：C，6 2· 1 6 ;1283240 V. Inventive Note (695) &quot; ----- Retaining on the Shixi gum using CHC13: Et0AC (95:5 to 0:100, v/v) as the eluent for chromatography, and 3 Monochloro-4_[[2_[3_methoxy_4_[N,-d-methylphenyl)ureido]phenylethenyl]methylamino]ethoxy]benzoic acid gt and 4-[ Insolubility of [2-[3-methoxy-4-[N,-(2-methylphenyl)ureido]] benzylamino] benzylamino] ethoxy] benzoate Mixture (489 mg) of light yellow oil. 3-Chloro-4 - [[2 - [3-曱-oxy-4-[N,-(2-methylphenyl)ureido]] phenylethyl] decyl] ethoxy]benzene Methyl decanoate and 4-[[2-[3-methoxy-4-[[Ν-(2-methylphenyl)ureido]phenylethyl]methylamino]ethoxy] stupid A mixture of methyl formate (mixture 489 mg) in THF-MeOH (4 mL, 1 : i, v/v) was stirred at 50 ° C for 15 h. The mixture was poured into 1 N HCl of ice. The solid was collected, washed with water and air dried. The crude solid was purified by preparative TLC with CHCI3: MeOH (93·7, v/v) as eluent to give 4-[[2-[3-methoxy-4-[Ν'-(2-) Phenyl)ureido]phenylethenyl]methylamino]ethoxy]benzoic acid 2 67 (1 80 mg, 2 steps 31% dicrystalline material) and 3-chloro-4-[[2-[ 3-methoxy-4 -[Ν'-(2-amilyphenyl)ureido]phenylethenyl]methylamino]ethoxy]benzoic acid 2 68 (280 mg, 2 steps 44%) Crystalline substance). Melting point 145 - ΙδΟπ;1!! - NMR (DMSO-d6,400 MHz) 5 2.31 (s, 3H), 3·05 and 3.19 (s, 3H), 3.35 and 3.38 (s, 3H), 3 ·72-3·85 (m, 7Η), 4·09 and 4.23 (m, total 21〇, 6.79-7.20 (m, 7H), 7·60 (m, 1H), 7·86-8·〇9 (m,3H); MS(FAB) m/z 49 3 (Μ + Η)+; C27H29N3 06 ·1·75Η20 Analysis calculated: C, 62.0 0; Η, 6. 26 ; Ν, 8· 03. Found: C, 6 2· 1 6 ;

1283240 五、發明說明（696) H, 5. 88 ； N, 7.82。 熔點 1 4 5- 1 5 0 t： ; UMR (DMS0-d6，4 0 0MHz) 6 2· 29 (s, 3H)、3.06 及 3.26 (s，3H) '3.31 及 3.35 (s，3H)、3.85 一 3.94 (m，4H)、4·18 及 4·32 (m，總計 2H)、6·75-6·85 (m，2Η)、6·99-7·20 (m，4Η)、7·59 (m，1Η)、7·90-8.02 (m，3Η) ； MS(FAB) m/z 5 26 (M + H)+ ； C27H28C1N3 06 · 2.0 H20之分析計算值：c，57·70; H，5·74; N，7.48。實 測值：C，57. 99 ; H，5. 53 ; N， 7. 07。 實施例2 1 9 4 - [3-[3-甲氧基-4 - [Ν’ - (2-曱基苯基）脲基]苯基乙醯基]一 N-曱胺基]-1 -丙基]苯曱酸1283240 V. INSTRUCTIONS (696) H, 5. 88 ; N, 7.82. Melting point 1 4 5- 1 5 0 t: ; UMR (DMS0-d6, 4 0 0MHz) 6 2· 29 (s, 3H), 3.06 and 3.26 (s, 3H) '3.31 and 3.35 (s, 3H), 3.85 1.94 (m, 4H), 4.18 and 4.32 (m, total 2H), 6.75-6.85 (m, 2Η), 6.99-7.20 (m, 4Η), 7· 59 (m,1Η), 7·90-8.02 (m,3Η); MS(FAB) m/z 5 26 (M + H)+ ; C27H28C1N3 06 · 2.0 H20 Analysis calculated: c, 57·70; H, 5·74; N, 7.48. Found: C, 57. 99; H, 5. 53 ; N, 7. 07. Example 2 1 9 4 - [3-[3-Methoxy-4 -[Ν' - (2-Mercaptophenyl)ureido]phenylethenyl]-N-nonylamino]-1 - Propyl]benzoic acid

OOH CH3 )ch3 269 於4 -膦酸甲基苯甲酸三乙酯（ι·22克，4. 05毫莫耳）溶於 THF(10毫升）之冷的（-78。〇)攪拌溶液中加入NaHMDS(l. 0M 溶於THF) (4· 0毫升，4.0毫莫耳），並使所產生之混合物在 相同溫度下攪拌1小時。在該溫度下將2-(N—芊氧羰基—N一 曱胺基）乙酸（700毫克，3.38毫莫耳）溶於THF( 5毫升）之溶 液緩k加至此溶液，並使混合物邊攪拌邊在2小時内升溫 至室溫。經由加入飽和NH4C 1(1 00毫升）使溶液停止反應， 並以EtOAc萃取。將萃取液以鹽水（2〇〇毫升）洗滌，於 MgS〇4上乾燥’並蒸發。使殘留物於石夕膠上利用chc 13-EtOAc(20:l，v/v)作為洗提液進行層析，而得81Q毫克OOH CH3 )ch3 269 was added to a cold (-78. 〇) stirred solution of tetraethyl 4-phosphonomethylbenzoate (m. 22 g, 0.45 mmol) dissolved in THF (10 mL). NaHMDS (1.0 M in THF) (4.0 mL, 4.0 m.m.), and the mixture was stirred at the same temperature for one hour. At this temperature, a solution of 2-(N-methoxycarbonyl-N-indenyl)acetic acid (700 mg, 3.38 mmol) dissolved in THF (5 ml) was added to the solution, and the mixture was stirred. Warm to room temperature within 2 hours. The solution was quenched by the addition of saturated aq. EtOAc (EtOAc)EtOAc. The extract was washed with brine (2 mL), dried over &lt;RTI ID=0.0&gt; The residue was chromatographed on chrysophane using chc 13-EtOAc (20:1, v/v) as eluent to give 81 Q.

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(68%)之（E) - 4-[3-( N-爷氧羰基—n_甲胺基）-1-丙烯基苯甲 酸乙S旨的黃色油。 HMR (CDC13) 6 1· 40 (t, J = 7. 3 Hz，3H)、2· 95 (m 2H)、4·09 (m，2H)、4·35-4·40 (m，2H)、5·17 (s，’ 2H) 、 6·26-6·64 (m 系列，2H) 、 7·36 (m， 7H) 、 7. ( J=8·3 Hz， 2H) 。 * 使（E)-4 - [3 -（N-卞氧幾基一 N-甲胺基）-1-丙稀基笨甲, 乙醋（810毫克，2.29毫莫耳）溶於£1：011-八(：011(10:1，”/ 22笔升）之擾拌溶液於5% Pd-C(1克）上氫化3天。將現入 過濾，並將濾液蒸發。利用飽和NaHC03使殘留物成為^ 性，並以CHCI3萃取。將萃取液於Na2C〇3上乾燥，並蒸^ 得438毫克（8 6%) 4-（3-甲胺基-i_丙基）苯甲酸乙酯的黃&amp; ^ 油0 W-NMR (CDC13) (5 1. 39 (t，J = 7· 3 Hz，3H)、1· 82 “ 2H)、2·43 (s，3H)、2.61 (t，J = 7.3 Hz, 2H)、2·72 (t，J = 7· 3 Hz，2H)、3· 33 (br s, 1H)、4· 36 (q，j” ^ Hz, 2H) ^7.25 (d, J = 8.3 Hz, 2H) ^7.96 (d, J = g ^(68%) of (E) 4-[3-(N-- yloxycarbonyl-n-methylamino)-1-propenylbenzoic acid B-yellow oil. HMR (CDC13) 6 1· 40 (t, J = 7. 3 Hz, 3H), 2· 95 (m 2H), 4·09 (m, 2H), 4·35-4·40 (m, 2H) , 5·17 (s, ' 2H) , 6·26-6·64 (m series, 2H), 7·36 (m, 7H), 7. ( J=8·3 Hz, 2H). * Dissolve (E)-4 - [3 -(N-decyloxy-N-methylamino)-1-propenyl benzoate, vinegar (810 mg, 2.29 mmol) in £1: The turbulent solution of 011-eight (: 011 (10:1," / 22 liters) was hydrogenated on 5% Pd-C (1 g) for 3 days. The filtrate was filtered and the filtrate was evaporated. Using saturated NaHC03 The residue was extracted and extracted with CHCI3. The extract was dried over Na.sub.2 C.sub.3 and evaporated to yield 438 mg (8 6%) of ethyl 4-(3-methylamino-i-propyl)benzoate. Yellow &amp; ^ Oil 0 W-NMR (CDC13) (5 1. 39 (t, J = 7. 3 Hz, 3H), 1·82 "2H), 2·43 (s, 3H), 2.61 (t , J = 7.3 Hz, 2H), 2·72 (t, J = 7· 3 Hz, 2H), 3· 33 (br s, 1H), 4· 36 (q,j” ^ Hz, 2H) ^7.25 (d, J = 8.3 Hz, 2H) ^7.96 (d, J = g ^

Hz， 2H) 。 · 於3-甲氧基-4- [N，-2-曱基苯基]脲基]苯乙酸（4 56毫 克，1· 45毫莫耳）及4-(3 -曱胺基-1-丙基）苯甲酸乙 毫克，1· 45毫莫耳）之攪拌溶液中加入EDC —HC1 (417毫克， 2.16¾莫耳）、H0Bt(催化劑）、及DMAP(催化量）溶於 DMF (1 0毫升）’並使所產生之混合:物攪拌隔夜。將混合物 以丑1:(^(：( 300毫升）稀釋，以鹽水洗滌，於“3〇4上乾燥，Hz, 2H). · 3-methoxy-4-[N,-2-mercaptophenyl]ureido]phenylacetic acid (4 56 mg, 1.45 mmol) and 4-(3-aminoamine-1- Add EDC-HC1 (417 mg, 2.163⁄4 mol), H0Bt (catalyst), and DMAP (catalytic amount) to DMF (1 0) in a stirred solution of propyl)ethyl benzoate (1,45 mmol). ML)' and mix the resulting: stir overnight. The mixture was diluted with ugly 1: (^ (: 300 ml), washed with brine, dried on "3 〇 4,

1283240 五、發明說明（698) 並蒸發。使殘留物於矽膠上利用CHC13- EtOH(10 : 1 )進行 層析，而得5 0 3毫克（71%)之4-[3-[3-甲氧基-4-[N，-（2-甲 基苯基）脲基]苯基乙醯基-N-曱胺基]-1 -丙基]苯甲酸乙 S旨的黃色油。 MS(FAB) m/z 518 (M + H)+ 於4-[3-[ 3 -甲氧基-4 - [Ν’ -（2-甲基苯基）脲基]苯基乙 醯基-Ν-甲胺基]-1 -丙基]苯甲酸乙酯（550毫克，0.966毫 莫耳）溶於THF(8毫升）之攪拌溶液中加入〇·25Ν NaOH(8毫 升），並使混合物迴流加熱隔夜。將所產生之溶液倒入至 冰的1 N HC1 ( 1 0 0毫升）中，並利用吸濾收集固體。將固體 溶解於CHCIJIOO毫升），並於MgS〇4上乾燥。於移除溶劑 後，使殘留物於矽膠上利用CHC13-MeOH(10:l至5:1。v/v) 進行層析，而得13毫克（28%)之4-[3-[3-曱氧基-4-[N，- (2-甲基本基）服基]苯基乙酿基-N-甲胺基]一1-丙基]笨甲 酸269的淡黃色非晶形固體。 1 - NMR(DMS0 - d6)d 1.68 - 1.8 0 (m，2H)、2.24(s，3H) 、2·57 (m，2H)、2·81 及 2·97 (各s，總計 3H)、3·33 (m， 2H)、3·57-3·61 (m，2H)、3·84 (s，3H)、6·71 (dd， J = 29.8、8·3 Hz，1H)、6·87 (d，J = 11.2 Hz，1H)、6·93 (t，J = 7.3 Hz, 1H)、7·15 (m，2H)、7·28 (m，2H)、 7.79 (d，J = 8.3 Hz，1H)、7·84-7·87 (m，2H)、8.〇2 (d，J = 8.3 Hz，1H)、8.49 (d，J = 7.3 Hz，1H)、8·58 (d，J:4.9 Hz，1H); MS(FAB) m/z 490 (MH1); C28H31N3〇 •1/2H20 之分析計算值：c，6 7.4 5; H，6.47; N，8.43 /1283240 V. Description of invention (698) and evaporation. The residue was chromatographed on silica gel using CHC13- EtOH (10:1) to yield 503 mg (71%) of 4-[3-[3-methoxy-4-[N,-(2) -Methylphenyl)ureido]phenylethenyl-N-nonylamino]-1 -propyl]benzoic acid A solid yellow oil. MS (FAB) m/z 518 (M + H) + in 4-[3-[ 3 -methoxy-4 - [Ν' -(2-methylphenyl)ureido]phenylethenyl-搅拌·25Ν NaOH (8 ml) was added to a stirred solution of Ν-methylamino]-1 -propyl]benzoic acid ethyl ester (550 mg, 0.966 mmol) dissolved in THF (8 mL). Heat overnight. The resulting solution was poured into 1 N HCl (100 mL) of ice and the solid was collected by suction filtration. The solid was dissolved in CHCIJIOO) and dried on MgS〇4. After removing the solvent, the residue was chromatographed on silica gel using CHC13-MeOH (10:1 to 5:1 v/v) to give 13 mg (28%) of 4-[3-[3- A pale yellow amorphous solid of methoxy-4-[N,-(2-methylphenyl)carbonyl]phenylethyl-N-methylamino]- 1-propyl] benzoic acid 269. 1 - NMR (DMS0 - d6)d 1.68 - 1.8 0 (m, 2H), 2.24 (s, 3H), 2·57 (m, 2H), 2·81 and 2.97 (each s, total 3H), 3·33 (m, 2H), 3·57-3·61 (m, 2H), 3.84 (s, 3H), 6.71 (dd, J = 29.8, 8·3 Hz, 1H), 6 ·87 (d, J = 11.2 Hz, 1H), 6.93 (t, J = 7.3 Hz, 1H), 7·15 (m, 2H), 7·28 (m, 2H), 7.79 (d, J = 8.3 Hz, 1H), 7·84-7·87 (m, 2H), 8. 〇 2 (d, J = 8.3 Hz, 1H), 8.49 (d, J = 7.3 Hz, 1H), 8.58 (d, J: 4.9 Hz, 1H); MS (FAB) m/z 490 (MH1); C28H31N3 〇•1/2H20 Analysis calculated: c,6 7.4 5; H,6.47; N,8.43 /

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第703頁 1283240 五、發明說明（699) 8. 02 實測值：C，67. 27 ; H，6. 51 ; N， 實施例2 2 0 [4 - [ΙΓ -（2-甲基苯基）脲基]苯基乙醯基卜N一甲胺 基]乙氧基]笨甲酸Page 703 1283240 V. INSTRUCTIONS (699) 8. 02 Measured values: C, 67. 27; H, 6. 51; N, Example 2 2 0 [4 - [ΙΓ -(2-methylphenyl) Ureido]phenyl acetyl sulfonyl N-methylamino] ethoxy] benzoic acid

((^^COOH 270 卜氣-4- [[2-[4-[Ν，-（ 2-甲基苯基）脲基]苯基乙醯基]一Ν一 甲胺基]乙氧基]苯甲酸((^^COOH 270 Buqi-4-[[2-[4-[Ν,-(2-methylphenyl)ureido]phenylethenyl]-indenylamino]ethoxy] benzoic acid

使4-[Ν’-（2-甲基笨基）脲基]苯基乙酸五氟苯酯（562毫 克Μ·29毫莫耳）、3 -氯-4 - [2 -（Ν-甲胺基）乙氧基]苯曱酸 曱醋之混合物（ 3 04 毫克）及Et3N( 2 60 毫升）溶於DMF(8毫升） 之溶液在室溫下攪拌4小時。將混合物以Et〇Ac稀釋，以〇· 5N HC1、鹽水洗滌，於Na2S〇4上乾燥，並蒸發。將殘留物 ，由於石夕膠上利用CHCl3_MeO( 50 : 1，v/v)作為洗提液進行 管柱層析’純化而得3一氯-4 - [[2-[4 - [N，-（2〜甲基笨美） 脲基]笨基乙醯基]-N-甲胺基]乙氧基]苯甲酸甲_及^一 [[2-[4-[N’-（2-甲基苯基）脲基]苯基乙酿基]-N一甲胺基] 乙氧基]苯甲酸甲酯之混合物（6 7 0毫克）的油。 於此混合物（6 70毫克）在1'犯-河6〇11(20毫升，1:1，¥/^) 中之攪拌懸浮液中加入0· 5N NaOH(10毫升），並使所產生4-[Ν'-(2-methylphenyl)ureido]phenylacetic acid pentafluorophenyl ester (562 mg Μ·29 mmol), 3-chloro-4-[2-(Ν-methylamine) A solution of a mixture of ethoxy]benzoic acid vinegar (3,04 mg) and Et3N (2,60 ml) in DMF (8 ml) was stirred at room temperature for 4 hr. The mixture was diluted with Et.sub.Ac, washed with EtOAc EtOAc EtOAc. The residue was purified by column chromatography using CHCl3_MeO (50:1, v/v) as an eluent to obtain 3-chloro-4 - [[2-[4 - [N,- (2~methyl stupid) Urea-based] phenylamino]-N-methylamino]ethoxy]benzoic acid A- and ^1[[2-[4-[N'-(2-A An oil of a mixture of phenylphenyl)ureido]phenylethyl]-N-methylamino]ethoxyethyl benzoate (670 mg). To this mixture (6 70 mg) was added 0. 5N NaOH (10 ml) in a stirred suspension of 1' pirin-he 6 〇 11 (20 ml, 1:1, ¥/^) and produced

第704頁 W312\2d-code\90-01\89112968.ptd 1283240 五、發明說明（700) 之混合物迴流加熱6小日卑 〜 ^ ^ ^ ^ A 时。將溶液倒入至冰的1N HC 1中， 並收集固體。利用製備镇麻 ΡΠΡ1 ^ ^ /專層層析術（TLC)以10% MeOH溶於 CHC13作為洗提液，將鈿制门_ , Γ M, r 0 ^ ^ μ- \ 衣固體純化而得73毫克4-[[2 - [4- [N -(2 -曱基苯基）脲其]^ # ..m ^〇Γ7Λ Η 基]本基乙醯基]-Ν-甲胺基]乙氧基] 本甲酸270之非晶形固體芬11η&gt; _ “、 暇及 110 宅克3 -氣-4-[ [2-[4-[Ν， -（2-甲基笨基）脈基 土」本基乙醯基]一Ν-甲胺基]乙氧基]苯 甲酸271之白色非晶形固^。 實施例221 (S)-4-[2-[3 -甲氧基〜4〜[Ν，一（2—曱基苯基）脲基]苯基乙醯 胺基]- 1-丙氧基]苯甲酸 Η ^γΟΟΟΗ 272Page 704 W312\2d-code\90-01\89112968.ptd 1283240 V. Inventive Note (700) The mixture is heated under reflux for 6 hours pm ~ ^ ^ ^ ^ A. The solution was poured into ice 1N HC 1 and a solid was collected. The prepared solid _, Γ M, r 0 ^ ^ μ- \ </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> 4-[[2-[4-[N-(2-]-phenylphenyl)urea] Base] Benzoic acid 270 amorphous solid fen 11η&gt; _ ", 暇 and 110 克克三-气-4-[ [2-[4-[Ν, -(2-methyl phenyl) basal soil" A white amorphous form of ruthenium-methylamino]ethoxy]benzoic acid 271. Example 221 (S)-4-[2-[3-methoxy~4~[Ν, mono(2-nonylphenyl)ureido]phenylethylamino]- 1-propoxy] Benzoic acid Η ^γΟΟΟΗ 272

6η3Η Η iCH 於（S)_2-胺基-1-丙醇（2· 〇8克，27· 7毫莫耳）及Et3N (4.63毫升，33·2毫莫耳）溶於DMF —η2〇(4〇毫升，1 : i， v/v)之冷卻（0C)溶液中加入（b〇c)2〇(636毫升，27.7毫 莫耳），並使所產生之溶液在室溫下攪拌2天。將Η2〇加至 混合物，並以EtOAc萃取。將萃取液以鹽水洗滌，並於Na θ〇4上乾燥。將溶劑蒸發而得4· 24克（87%) (S)-2-(N-第三 丁氧幾胺基）-1 -丙醇的無色油。 'H-NMR (CDC13) 5 1.14 (d, 3H, J = 6. 8 Hz) M. 45 (s,6η3Η Η iCH is soluble in DMF-η2〇(S)_2-amino-1-propanol (2·〇8 g, 27·7 mmol) and Et3N (4.63 ml, 33·2 mmol). 4 liters, 1 : i, v/v) of cooled (0C) solution was added (b〇c) 2 〇 (636 ml, 27.7 mmol), and the resulting solution was stirred at room temperature for 2 days. . Η2〇 was added to the mixture and extracted with EtOAc. The extract was washed with brine and dried over Na θ 4 . The solvent was evaporated to give 4,24 g (yield: 87%) of (S)-2-(N-t-butoxyaminoamino)-1-propanol as a colorless oil. 'H-NMR (CDC13) 5 1.14 (d, 3H, J = 6. 8 Hz) M. 45 (s,

\\312\2d-code\90-01\89112968.ptd 第705頁 1283240 五、發明說明（701) 莫耳）、4-羥基苯曱酸甲酯（〇·89克，5.85毫莫耳）、及ph 3Ρ(1· 98克，7· 55莫耳）溶於THF(20毫升）之冷卻（〇。〇溶劑 中加入偶氮二羧酸二異丙酯（DIAD)(1· 49毫升，7· 57毫莫θ 耳），並使所產生之混合物迴流加熱隔夜。將溶液蒸發， 並將殘留物溶解於CH2C12(20毫升）及TFA(10毫升）中。使混 合物在室溫下攪拌1 · 5小時。將溶液於真空中濃縮，並以 飽和NaHC〇3處理殘留物。將混合物以CHCI3萃取，以鹽水洗 務’於N S 〇4上乾燥’並蒸發。使殘留物經由於石夕膠上利 用CHCl3-MeOH(50:l，v/v)進行管柱層析，純化而得‘go毫 克（2步驟3 9°/〇)之（S)-4-(2 -胺基-1-丙氧基）笨曱酸曱酯的 淡黃色油。 'H-NMR (CDCI3) 5 1.19 (d, 3 H, J = 6. 4 Hz) ^ 3. 3 5-3. 39 (m，1H)、3·72- 3.76 (m，1H)、3·89 (s，3H)、3·9〇一\\312\2d-code\90-01\89112968.ptd Page 705 1283240 V. Description of invention (701) Mole), methyl 4-hydroxybenzoate (〇·89 g, 5.85 mmol), And ph 3 Ρ (1·98 g, 7.55 mol) was dissolved in THF (20 ml) to cool (〇. 〇 solvent was added with diisopropyl azodicarboxylate (DIAD) (1·49 ml, 7 · 57 mmol θ ear), and the resulting mixture was refluxed and heated overnight. The solution was evaporated and the residue was crystalljjjjjjjjjjjj After 5 hours, the solution was concentrated in vacuo and the residue was taken eluted with sat. NaHC.sub.3. The mixture was extracted with CHCI3, washed with brine &lt; Column chromatography with CHCl3-MeOH (50:1, v/v) was carried out to give &lt;&lt;&gt;&gt;&&&&&&&&&&&&&&&& a pale yellow oil of oxy) decyl decanoate. 'H-NMR (CDCI3) 5 1.19 (d, 3 H, J = 6. 4 Hz) ^ 3. 3 5-3. 39 (m, 1H), 3·72- 3.76 (m, 1H), 3·89 (s, 3H), 3·9〇一

3.94 (m，1H)、6·92 (d, 2H，J = 8.8 Hz)、7·99 (d，2H J=8·8 Hz)。 ’ ’ 使3-甲氧基-4-[N，-（2 -甲基苯基）脲基]苯基乙酸五氟^笨 酯（505毫克，ΐ·〇5毫莫耳）、（s)-4-(2 -胺基-1-丙氧基）苯 甲酸甲酯（220毫克，1·〇5毫莫耳）、及Et3N(0.220毫升， 1 · 58毫莫耳）於DMF (8毫升）中之混合物在室溫下授拌3小 時。將混合物以EtOAc稀釋，以〇· 5N HC1、鹽水洗滌，並 於Na2S04上乾燥。於移除溶劑後，使殘留物自Me〇H— -正己烷再結晶，而得29 0毫克（55%)(S) - 4-[2 - [3-甲氧基 一4 一 [N’—（2-甲基苯基）脲基]苯基乙醯胺基]-卜丙氧基]苯 甲酸甲酯的白色結晶粉末。3.94 (m, 1H), 6.92 (d, 2H, J = 8.8 Hz), 7·99 (d, 2H J = 8·8 Hz). ' ' 3- 3-methoxy-4-[N,-(2-methylphenyl)ureido]phenylacetic acid pentafluorophene ester (505 mg, ΐ·〇 5 mmol), (s) Methyl 4-(2-amino-1-propoxy)benzoate (220 mg, 1·5 5 mmol), and Et3N (0.220 mL, 1 · 58 mmol) in DMF (8 mL) The mixture was stirred at room temperature for 3 hours. The mixture was diluted with EtOAc, washed with EtOAc EtOAc EtOAc. After removing the solvent, the residue was recrystallized from Me〇H--n-hexane to give 29 0 mg (55%) of (S) - 4-[2 - [3-methoxy-[1][N' A white crystalline powder of methyl (2-methylphenyl)ureido]phenylethenylamino]-p-propoxy]benzoate.

\\312\2d-code\90-01\89l12968.ptd 1283240 五、發明說明（702) -NMR (DMSO-d6) 5 1 · 18 (d，3H，J = 6. 8 Hz)、2· 2 4 (s， 3H) 、3·36 (s， 2H) 、3·80 (s， 3H) 、3·82 (s， 3H)、 3.93-4.03(m，2H)、4.09-4.14(m，lH)、6.75-8.57(m 系列，總計1 3 H)。 於（S)-4 - [2 - [3 -甲氧基-4-[Ν’ - (2 -甲基苯基）脲基]苯 基乙醯胺基]-1-丙氧基]苯甲酸甲酯（290毫克，0.57毫莫 耳）溶於THF-MeOH(20毫升，HI, ν/ν)之攪拌溶液中加入 〇 · 5N NaOH (2 0毫升），並使溶液迴流加熱2小時。將混合物 倒入至冰的1 N HC1中，並以CHC13-MeOH(10 : 1，v/v)萃 取。將萃取液以鹽水洗滌，於Na2S04上乾燥，並蒸發。使 殘留物自MeOH-CHC13-正己烷再結晶，而得158毫克（56%) (S)-4-[2-[3_[甲氧基-4 -[N，-（2-甲基苯基）脲基]苯基乙 醯胺基]-卜丙氧基]苯曱酸2 72的白色結晶粉末。 熔點 198-ZOKCPH-NMR (DMSO-d6)(5 1.18 (d，3H，J = 6.3 Hz)、2·24 (s，3H)、3·36 (s，2H)、3·82 (s, 3H)、3·87-4.10 (m，2H)、4·10-4·16 (m，1H)、6·75 - 6· 78 (m，1Η)、6·92-7·02 (m，4Η)、7·11-7·18 (m，2Η)、 7.78-7.80 (m，1Η)、7·86-7·89 (m，2Η)、7·98-8·〇〇 (m，1Η)、8·12-8·14 (m，1Η)、8·46 (s，1Η)、8·55 (s， 1H) &gt;12.62 (bs, 1H) ； MS (FAB) m/z 492 (MH1) ； C27H29N 3〇6 · 1/2H20 之分析計算值：C，64. 79 ; H， 6. 04 ; N， 8.21。實測值：C， 64.36; H，5.85; N，8.21。 實施例2 2 2 (S) - 4-[2-[4-[N’-(2-甲基笨基）脲基]苯基乙驢胺基]- 1 一\\312\2d-code\90-01\89l12968.ptd 1283240 V. Inventive Note (702) - NMR (DMSO-d6) 5 1 · 18 (d, 3H, J = 6. 8 Hz), 2· 2 4 (s, 3H), 3·36 (s, 2H), 3·80 (s, 3H), 3·82 (s, 3H), 3.93-4.03 (m, 2H), 4.09-4.14 (m, lH ), 6.75-8.57 (m series, totaling 1 3 H). (S)-4 - [2 - [3 -Methoxy-4-[Ν' - (2-methylphenyl)ureido]phenylethylamino]-1-propoxy]benzoic acid Methyl ester (290 mg, 0.57 mmol) was dissolved in THF-MeOH (20 mL, EtOAc, EtOAc). The mixture was poured into ice 1 N HCl and extracted with CHC13-MeOH (10:1, v/v). The extract was washed with brine, dried over Na 2 EtOAc and evaporated. The residue was recrystallized from MeOH-CHC13-n-hexane to give 158 mg (56%) of (S) -4-[2-[3-[Methoxy-4 -[N,-(2-methylphenyl) a white crystalline powder of ureido]phenylethylamino]-ipropoxy]benzoic acid 2 72. 198-ZOKCPH-NMR (DMSO-d6) (5 1.18 (d, 3H, J = 6.3 Hz), 2·24 (s, 3H), 3·36 (s, 2H), 3·82 (s, 3H) ),3·87-4.10 (m,2H),4·10-4·16 (m,1H),6·75 - 6· 78 (m,1Η),6·92-7·02 (m,4Η) ), 7·11-7·18 (m, 2Η), 7.78-7.80 (m, 1Η), 7·86-7·89 (m, 2Η), 7·98-8·〇〇 (m, 1Η) ,8·12-8·14 (m,1Η),8·46 (s,1Η),8·55 (s, 1H) &gt;12.62 (bs, 1H) ; MS (FAB) m/z 492 (MH1 ; C27H29N 3〇6 · 1/2H20 Analysis calculated: C, 64.79; H, 6. 04; N, 8.21. Found: C, 64.36; H, 5.85; N, 8.21. Example 2 2 2 (S) - 4-[2-[4-[N'-(2-methylphenyl)ureido]phenylethylamino]- 1

\\312\2d-code\90-01\89112968.ptd 第 707 頁 1283240 五、發明說明（703) 丙氧基]苯甲酸\\312\2d-code\90-01\89112968.ptd Page 707 1283240 V. INSTRUCTIONS (703) Propoxy]benzoic acid

使4-[Ν’ - (2-甲基苯基）脲基]苯基乙酸五氟苯酯（56〇毫 克’1·24毫莫耳）、（s) - 4-（2-胺基- 1-丙氧基）苯曱酸甲酯 ( 260毫克，κ 24毫莫耳）、Et3N(0· 26〇毫升，1· 87毫莫耳） 於DMF(8毫升）中之混合物在室溫下攪拌3小時。將混合物 以EtOAc稀釋，並將溶液以〇·5Ν HC1、鹽水洗滌，及於Na 2S〇4上乾燥。於移除溶劑後，使殘留物經由自Me〇H- CHC1 3-正己烷再結晶，純化而得210毫克（36%) (S)-4-[2-[3 -甲氧基-4-[Ν’ -（2-甲基苯基）脲基]苯基乙醯胺基]- ；1-丙 氧基]苯甲酸的白色結晶粉末。 l-NMR (DMS0-d6) δ 1 · 17 (d，3Η，J = 6. 8 Hz)、2· 2 4 (s， 3H)、3·32 (s，2H)、3·81 (s, 3H)、3.92-4·03 (m，2H) 、4·08-4·15 (m，1H)、6·9 2-6.95 (m，1H)、7·04-7·06 (m，2H)、7·12-7.18 (m，4H)、7·35-7·39 (m，2H)、 7.83-7.85 (m, 1H) ^7.89-7.92 (m, 3H) '8.12-8.14 (m, 1H) 、 8· 97 (s, 1H)。 於（S) - 4-[2 - [4-[N _(2-甲基苯基）脈基]苯基乙酿胺 基]-1-丙氧基]苯甲酸甲酯（200毫克，0.42毫莫耳）溶於 THF-MeOH(10毫升，1/1，v/v)之攪拌溶液中加入0.5N NaOH( 1 0毫升），並使混合物迴流加熱2小時。將混合物倒 入至冰的IN HC1中，並收集固體。使粗製固體自MeOH-4-[Ν'-(2-methylphenyl)ureido]phenylacetic acid pentafluorophenyl ester (56〇 mg '1·24 mmol), (s)-4-(2-amino group- a mixture of methyl 1-propyloxy)benzoate (260 mg, κ 24 mmol), Et3N (0.26 mL, 1·87 mmol) in DMF (8 mL) at room temperature Stir for 3 hours. The mixture was diluted with EtOAc and the solution was washed with EtOAc EtOAc EtOAc. After removing the solvent, the residue was recrystallized from Me 〇H-CHC1 3- n-hexane to afford 210 mg (36%) of (S)-4-[2-[3-methoxy-4- A white crystalline powder of [Ν'-(2-methylphenyl)ureido]phenylethenylamino]-; 1-propoxy]benzoic acid. l-NMR (DMS0-d6) δ 1 · 17 (d, 3Η, J = 6. 8 Hz), 2· 2 4 (s, 3H), 3·32 (s, 2H), 3·81 (s, 3H), 3.92-4·03 (m, 2H), 4·08-4·15 (m, 1H), 6·9 2-6.95 (m, 1H), 7·04-7·06 (m, 2H ),7·12-7.18 (m,4H),7·35-7·39 (m,2H), 7.83-7.85 (m, 1H) ^7.89-7.92 (m, 3H) '8.12-8.14 (m, 1H), 8.97 (s, 1H). (S) - 4-[2 - [4-[N _(2-methylphenyl) phenyl]phenylethylamino]-1-propoxy]benzoic acid methyl ester (200 mg, 0.42 To a stirred solution of THF-MeOH (10 mL, 1/1, v/v) was added 0.5N NaOH (10 mL). The mixture was poured into ice IN HCl and a solid was collected. Make crude solids from MeOH-

\\312\2d-code\90-01\89112968.ptd 第708頁 1283240 五、發明說明（704) CHC13-正己烷再結晶，而得68毫克（34%) (S)-4 - [2-[4-[N’ -（2-甲基苯基）脲基]苯基乙醯胺基]—卜 丙氧基]苯甲酸2 73的白色結晶粉末。 熔點 26 2-(DMS〇-d6) 5 1.17 (d，3H，J = 6·8 Hz)、2·24 (s，3H)、3·32 (s，2H)、3·91-4·02 (m， 2Η)、4·09-4·15 (m，1Η)、6·92-6·96(ιη，1Η)、7·(η-7·〇3 (m，2Η)、7·12-7·20 (m，4Η)、7·36-7·40 (m， 2Η)、7·83-7·95 (m，4Η)、8·12-8·14 (m，1Η)、8·99 (s，1Η)、12·63 (bs，1H); MS(FAB) m/z 462 (MH1); C 26 H27 N3 05 · 1 / 4 H2 0 之分析計算值：C，6 7 · 0 1 ; Η，5. 9 5 ; N， 9· 02。實測值：C， 67. 1 3 ; H, 5. 90 ; N，9. 02。 實施例2 2 3 (S)-3-氣-4 - [2 - [4-[Ν’ - (2-甲基苯基）脲基]苯基乙醯胺 基]-1-丙氧基]苯甲酸\\312\2d-code\90-01\89112968.ptd Page 708 1283240 V. INSTRUCTIONS (704) CHC13-n-hexane is recrystallized to give 68 mg (34%) (S)-4 - [2- A white crystalline powder of [4-[N'-(2-methylphenyl)ureido]phenylethenylamino]-p-propoxy]benzoic acid 2 73. Melting point 26 2-(DMS〇-d6) 5 1.17 (d,3H,J = 6·8 Hz), 2·24 (s,3H), 3·32 (s,2H),3·91-4·02 (m, 2Η), 4·09-4·15 (m, 1Η), 6.92-6·96 (ιη, 1Η), 7·(η-7·〇3 (m, 2Η), 7·12 -7·20 (m, 4Η), 7·36-7·40 (m, 2Η), 7·83-7·95 (m, 4Η), 8·12-8·14 (m, 1Η), 8 · 99 (s, 1Η), 12·63 (bs, 1H); MS (FAB) m/z 462 (MH1); C 26 H27 N3 05 · 1 / 4 H2 0 Analysis calculated: C, 6 7 · 0 1 ; Η, 5. 9 5 ; N, 9· 02. Found: C, 67. 1 3 ; H, 5. 90 ; N, 9. 02. Example 2 2 3 (S)-3- gas -4 - [2-[4-[Ν' - (2-methylphenyl)ureido]phenylethylamino]-1-propoxy]benzoic acid

於（S)-2-(N-第三丁氧羰胺基）—；[—丙醇（1〇5克，5·99毫 莫耳）、3-氯-4-羥基苯曱酸甲酯（1· 12克，6· 〇〇毫莫耳）、 及Ph3P(2. 36克，9. 00毫莫耳）溶於THF(2〇毫升）之冷卻（〇 °C )溶液中加入偶氮二羧酸二異丙酯（D丨AD κ j · 7 7毫升，8. 9 9 ^:莫耳）’並使所產生之混合物迴流加熱2天。將溶液蒸 發，並將殘留物溶解於CH2C12(20毫升）及TFA(10毫升）中。 使所產生之混合物在室溫下攪拌1 · 5小時。將溶液於真空(S)-2-(N-Tertiyloxycarbonylamino)-;[-propanol (1〇5g, 5.99mmol), 3-chloro-4-hydroxybenzoate (1·12 g, 6·〇〇 mmol), and Ph3P (2. 36 g, 9.00 mmol) in THF (2 mL) cooled (〇°C) solution was added with azo Diisopropyl dicarboxylate (D丨AD κ j · 7 7 ml, 8.9 9 ^: mole) and the resulting mixture was heated under reflux for 2 days. The solution was evaporated and the residue was crystalljjjjjjjjj The resulting mixture was stirred at room temperature for 1.5 hours. Put the solution in vacuum

第709頁 1283240 五、發明說明（705) 中濃縮’並將殘留物溶解於CHCI3。將混合物以h2〇萃取， 並經由加入飽和NaHC〇3使水層成為鹼性。以CHCl3萃取此驗 性水層。將萃取液以鹽水洗滌，於Na2S〇4上乾燥，並蒸發 而付660宅克（2步驟32%)之（S)-3〜氯—4-(2 -胺基-1-丙氧 基）苯甲酸曱酯的無色油。 ^-NMR (CDCI3) (5 1.21 (d, 3H, j,6. 4 Hz) ^3.41-3.48 (m，lH)、3.77-3.81(m，lH)、3.89(s，3H)、3.98-4·01 (m，1H)、6·9 卜 6.94 (m，1H)、7·90 - 7·93 (m，1H) 、8.05-8.06 (m， 1H)。 使4-[Ν’ -（2-曱基苯基）脲基]笨基乙酸五氟苯酯（5〇8毫 克’1.13毫莫耳）、（S)-3-氯-4-(2-胺基-1-丙氧基）苯甲 酸曱酯（275毫克，1.13毫莫耳）、及Et3N(0.240毫升， 1 · 72耄莫耳）於DMF (1 0毫升）中之混合物在室溫下攪拌隔 夜。將混合物以EtOAc稀釋，及將溶液以〇· 5N HC1、飽和 NaHC〇3、鹽水洗滌，於Na2S04上乾燥，並蒸發。使殘留物 自MeOH-CHC13-正己烷再結晶，而得240毫克（42%)(S)-3 -氯-4 - [2 - [4 - [Ν’ -（2-甲基苯基）脲基]苯基乙醯胺基]一1一 丙氧基]苯甲酸曱酯的白色結晶粉末。 UMR (DMSO-d6) 6 1.21 (d，3Η，J = 6.4 Hz)、2.25 (s， 3H)、3.33 (s，2H)、3·82 (s, 3H)、4·04-4.14 (m， 3Η)、6.90-6·94(πι，1Η)、7·11-7·16(ιη，4Η)、7·29-7·38 (m，3H)、7·83-7·94 (m，3H)、8.13-8.17 (m，2H) 、9·34 (s，1H); MS(FAB) m/z 510(M+)。 於（S) -3-氯-4 - [2-[4-[Ν’ - (2-曱基苯基）脲基]笨基乙醯Page 709 1283240 V. Inventive Note (705) Concentrate in 'and dissolve the residue in CHCI3. The mixture was extracted with h2, and the aqueous layer was made basic by the addition of saturated NaHC. The aqueous layer was extracted with CHCl3. The extract was washed with brine, dried over Na 2 S 〇 4 and evaporated to afford s s ( s s s s s s s s s s s s A colorless oil of decyl benzoate. ^-NMR (CDCI3) (5 1.21 (d, 3H, j, 6. 4 Hz) ^3.41-3.48 (m, lH), 3.77-3.81 (m, lH), 3.89 (s, 3H), 3.98-4 ·01 (m,1H),6·9 卜 6.94 (m,1H), 7·90 - 7·93 (m,1H), 8.05-8.06 (m, 1H). Make 4-[Ν' -(2 -nonylphenyl)ureido]p-fluorophenyl acetate (5〇8 mg '1.13 mmol), (S)-3-chloro-4-(2-amino-1-propoxy) A mixture of decyl benzoate (275 mg, 1.13 mmol) and EtOAc (EtOAc) (EtOAc) The solution was washed with EtOAc EtOAc (aq. A white crystalline powder of 3-chloro-4-[2- [4-[2-methylphenyl]ureido]phenylethenylamino]-l-propoxy]benzoic acid oxime ester. UMR (DMSO-d6) 6 1.21 (d, 3Η, J = 6.4 Hz), 2.25 (s, 3H), 3.33 (s, 2H), 3·82 (s, 3H), 4·04-4.14 (m, 3Η), 6.90-6·94 (πι, 1Η), 7·11-7·16 (ιη, 4Η), 7·29-7·3 8 (m, 3H), 7·83-7·94 (m, 3H), 8.13-8.17 (m, 2H), 9·34 (s, 1H); MS (FAB) m/z 510 (M+). (S)-3-chloro-4 - [2-[4-[Ν' - (2-mercaptophenyl)ureido]]

\\312\2d-code\90-01\89112968.ptd 第 710 頁 1283240 五、發明說明（706) 胺基]- ：1-丙氧基]苯曱酸甲酯（ 24 0毫克，〇·47毫莫耳）溶於 THF-MeOH(10毫升，1/1，ν/ν)之攪拌溶液中加入〇·5Ν\\312\2d-code\90-01\89112968.ptd Page 710 1283240 V. INSTRUCTIONS (706) Amino]-: 1-propoxy]benzoic acid methyl ester (24 0 mg, 〇·47 mM·5Ν dissolved in a stirred solution of THF-MeOH (10 ml, 1/1, ν/ν)

NaOH (1 0毫升），並使所產生之混合物迴流加熱隔夜。將混 合物倒入至冰的1N HC1中，並收集固體。使粗製固體自 MeOH-CHC13 -正己烧再結晶，而得98毫克（42%) (S)-3 -氣 -4-[2 - [4- [Ν’- (2-甲基苯基）脲基]苯基乙醢胺基]-1-丙 氧基]苯曱酸274的白色結晶粉末。 熔點228-231 tJH-NMR (DMS0-d6) 6 1.20 (d， 3Η， J = 6·3 Hz) 、2·24 (s， 3H) 、3.34 (s， 2H) 、4·02-4·18 (m， 3H)、6. 92-6· 95 (m， 1H)、7· 12-7· 42 (m 系列，總計 7H)、7· 8 2-8. 18 (m 系列，總計5H)、9· 12 (s， 1H); MS(FAB) m/z 49 6 (M+)、4 97 (MH1);C26H26C1N3 05 . 1 / 2H20 之 分析計算值：C，61·84;Η， 5.39; Cl，7·02; N， 8·32。 實測值：C， 61· 76 ; Η, 5. 25 ; Cl， 7· 09 ; N，8· 25。 實施例224 (S)-3-氣-4-[2-[3 -甲氧基-4-[Ν’-(2-甲基苯基）脲基]苯 基乙醯胺基]-卜丙氧基]苯甲酸NaOH (10 mL) and the resulting mixture was reflux heated overnight. The mixture was poured into ice 1N HCl and the solid was collected. The crude solid was recrystallized from MeOH-CHC13-n-hexane to give 98 mg (42%) of (S) - 3 - s. A white crystalline powder of phenyl ethionyl]-1-propoxy]benzoic acid 274. Mp 228-231 tJH-NMR (DMS0-d6) 6 1.20 (d, 3Η, J = 6·3 Hz), 2·24 (s, 3H), 3.34 (s, 2H), 4·02-4·18 (m, 3H), 6. 92-6. 95 (m, 1H), 7·12-7· 42 (m series, total 7H), 7·8 2-8. 18 (m series, total 5H), 9· 12 (s, 1H); MS(FAB) m/z 49 6 (M+), 4 97 (MH1); C26H26C1N3 05 . 1 / 2H20 Analysis calculated: C, 61·84; Η, 5.39; Cl , 7·02; N, 8·32. Found: C, 61·76; Η, 5. 25 ; Cl, 7· 09 ; N, 8· 25. Example 224 (S)-3-Gas-4-[2-[3-methoxy-4-[Ν'-(2-methylphenyl)ureido]phenylethenylamino]-br Oxy]benzoic acid

使3-甲氧基-4 - [Ν，-（2 -甲基苯基）脲基]苯基乙酸五氟苯 酯（513毫克，1.07毫莫耳）、（S)-3-氯-4-(2 -胺基-1-丙氧 基）苯甲酸甲酯（260毫克，1.07毫莫耳）、及Et3N(220微 升，1.58毫莫耳）於DMF( 10毫升）中之混合物在室溫下攪拌3-methoxy-4-[Ν,-(2-methylphenyl)ureido]phenylacetic acid pentafluorophenyl ester (513 mg, 1.07 mmol), (S)-3-chloro-4 -(2-Amino-1-propoxy)benzoic acid methyl ester (260 mg, 1.07 mmol), and a mixture of Et3N (220 μL, 1.58 mmol) in DMF (10 mL) Stirring under temperature

\\312\2d-code\90-01\89112968.ptd 第 711 買 1283240 五、發明說明（707) 隔夜。將混合物以E10 A c稀釋，及將溶液以飽和N a H C 03洗 滌，於Na2S04上乾燥，並蒸發。使殘留物自MeOH-CHCl3-EtOAc-正己烷再結晶，而得4〇〇毫克（69%) (S)-3-氯-4-[N -(2~甲基本基）脈基]苯基乙酿胺基]一 1一丙氧基]苯甲酸 曱酯的淡棕色結晶粉末。 l-NMR (DMS0-d6) 6 1 · 21 (d，3H，J = 6· 4 Hz)、2· 24 (s， 3H) 、3.37 (s， 2H) 、3·82 (s， 3H) 、3·83 (s， 3H)、 4.04-4·12 (m， 3H) 、6·75-6.77 (m， 1H) 、6·9卜6.95 (m，2H)、7.1 卜7.17 (m，2H)、7·29-7·31 (m，1H)、 7.78-7.99 (m, 4H) ^8.12-8.13 (m, 1H) &gt;8.46 (s, 1H)、8· 55 (s，1H)。 於（S)-3-氯-4-[2-[3-甲氧基-4-[N’-（2-甲基苯基）脲 基]苯基乙醯胺基]-卜丙氧基]苯甲酸甲酯（400毫克，〇. 74 耄莫耳）溶於THF-MeOH(20毫升，1/1，v/v)之攪拌溶液中 加入0· 5N NaOH( 20毫升），並使所產生之混合物迴流加熱 隔夜。將混合物倒入至冰的1 N H C 1中，並收集固體。使粗 製固體自Me0H-CHCl3-Et20再結晶，而得200毫克（51%) (s) - 3-氯-4-[2-[3-甲氧基-4-[ Ν’ -（2-曱基苯基）脲基]苯基乙 酿胺基]-1-丙乳基]本甲酸275的淡標色結晶粉末。 熔點 1 9 8-20 1 °0：;111-關1?(训30-(16)5 1.21((1，311，了 = 6 8 Hz)、2.24 (s，3Η)、3.37 (s，2Η)、3.84 (s，3Η)、、 4 · 0 0 - 4 · 1 5 ( m， 3 Η )、6 · 7 6 - 7 · 2 8 (m 系列，總計 6 Η )、 7· 77-8· 14 (m 系列，總計5Η)、8· 46 (s， 1Η)、8· 56 (s， 1H); MS(FAB) m/z 526 (M+)、528 (MH2); C27H28C1N3 06 ·\\312\2d-code\90-01\89112968.ptd No. 711 Buy 1283240 V. Invention description (707) Overnight. The mixture was diluted with E10 A c, and the solution was washed with sat. NaH CH03, dried over Na? The residue was recrystallized from MeOH-CHCl3-EtOAc-hexanes to afford 4 mg (yield: 69%) of (S)-3-chloro-4-[N-(2-methylphenyl) phenyl]phenyl A light brown crystalline powder of acetaminophen-1 -propoxy]benzoic acid oxime ester. l-NMR (DMS0-d6) 6 1 · 21 (d, 3H, J = 6· 4 Hz), 2· 24 (s, 3H), 3.37 (s, 2H), 3·82 (s, 3H), 3·83 (s, 3H), 4.04-4·12 (m, 3H), 6.75-6.77 (m, 1H), 6. 9 b 6.95 (m, 2H), 7.1 b 7.17 (m, 2H) , 7·29-7·31 (m, 1H), 7.78-7.99 (m, 4H) ^8.12-8.13 (m, 1H) &gt; 8.46 (s, 1H), 8.55 (s, 1H). (S)-3-Chloro-4-[2-[3-methoxy-4-[N'-(2-methylphenyl)ureido]phenylethylamino]-propoxy Methyl benzoate (400 mg, 〇. 74 耄mol) was dissolved in THF-MeOH (20 mL, 1/1, v/v). EtOAc (20 mL) The resulting mixture was refluxed and heated overnight. The mixture was poured into 1 N H C 1 of ice and a solid was collected. The crude solid was recrystallized from Me0H-CHCl3-Et20 to give 200 mg (51%) of (s)- 3-chloro-4-[2-[3-methoxy-4-[ Phenylphenyl)ureido]phenylethylamino]-1-propanyl]Non-standard crystalline powder of the present formic acid 275. Melting point 1 9 8-20 1 °0:; 111-off 1? (train 30-(16)5 1.21 ((1,311, == 6 8 Hz), 2.24 (s, 3Η), 3.37 (s, 2Η) ), 3.84 (s, 3Η), 4 · 0 0 - 4 · 1 5 ( m, 3 Η ), 6 · 7 6 - 7 · 2 8 (m series, total 6 Η), 7· 77-8· 14 (m series, total 5Η), 8·46 (s, 1Η), 8.56 (s, 1H); MS(FAB) m/z 526 (M+), 528 (MH2); C27H28C1N3 06 ·

W312\2d-code\90-01\89112968.ptd 第712頁 1283240 五、發明說明（708) 1/4H20 之分析計算值：C，61· 13 ; H，5· 42 ; C1，6· 68 ; N，7.92。實測值：C，60.97; H，5.48;C1，6·86;Ν， 7· 89 〇 實施例225 3-二甲胺基-4-[2-[3-甲氧基-4 - [Ν’ _(2-曱基苯基）脲基] 苯基乙醯基]甲胺基]乙.氧基]苯甲酸W312\2d-code\90-01\89112968.ptd Page 712 1283240 V. Description of invention (708) Analysis and calculation of 1/4H20: C, 61·13; H, 5·42; C1, 6·68; N, 7.92. Found: C, 60.97; H, 5.48; C1, 6·86; Ν, 7· 89 〇 Example 225 3-dimethylamino-4-[2-[3-methoxy-4 - [Ν' _(2-Mercaptophenyl)ureido]phenylphenylmercapto]methylamino]ethyloxy]benzoic acid

rM ^vCOOH 276 0Η3Η H 0CH3 於2-(N-Boc-N-曱胺基）乙醇（3克，17毫莫耳）、4 -羥基 -3 -硝基苯曱酸曱酯（3.38克，17毫莫耳）、及Ph3P(5· 4 克，21毫莫耳）溶於THF(20毫升）之冷卻（〇 °C)攪拌溶液中 加入偶氮二羧酸二異丙酯（DIAD)(4毫升，21毫莫耳），並 使所產生之混合物迴流加熱1 5小時。將溶液蒸發掉。使殘 留物於矽膠上利用CHC13 :MeOH(100:l至4:1，v/v)作為、、先 提液進行層析，而得2.5克（39%)之4 - [2 -（N-甲基胺'美 乙氧基]- 3 -硝基苯甲酸甲酯的淡黃色油。 女土rM ^vCOOH 276 0Η3Η H 0CH3 in 2-(N-Boc-N-decylamino)ethanol (3 g, 17 mmol), 4-hydroxy-3-nitrobenzoic acid decyl ester (3.38 g, 17 Add isopropyl azodicarboxylate (DIAD) to a stirred solution of THF (20 ml) in THF (20 mL) in THF (20 mL). Milliliter, 21 mmol, and the resulting mixture was heated under reflux for 15 hours. The solution was evaporated off. The residue was chromatographed on a silica gel using CHC13: MeOH (100:1 to 4:1, v/v) as the first extract, and 2.5 g (39%) of 4 - [2 - (N- a pale yellow oil of methylamine 'Methoxyethoxy}- 3-nitrobenzoate.

NMR (CDC13，40 0MHz) ά 2· 82 (s，3H)、3 M J = 4.5 Hz) ^3.95 (s, 3H) ^4.54 (t, 2H, J：4 5 H \ ^ 7 · 2 6 (d，1 H，J = 8 · 8 H z )、8 · 2 5 (d，1 H, J =： § · 8 h z) 8· 56 (s，1H) ; MS(FAB) m/z 25 5 (MH1)。 ’ ”、 乙酸（9 9 2毫 確基笨甲 胺乙氧基） 使3-甲氧基-4 - [Ν’_(2 -甲基笨基）脲基]笨基 克’3.11毫莫耳）、4-（\-甲基-2-胺乙氧基）一3 — 酸甲酯（80 0毫克，3. 11毫莫耳）、4-(N-甲基—2一NMR (CDC13, 40 0MHz) ά 2· 82 (s, 3H), 3 MJ = 4.5 Hz) ^3.95 (s, 3H) ^4.54 (t, 2H, J:4 5 H \ ^ 7 · 2 6 (d , 1 H, J = 8 · 8 H z ), 8 · 2 5 (d, 1 H, J =: § · 8 hz) 8· 56 (s, 1H) ; MS(FAB) m/z 25 5 ( MH1). ' ”, acetic acid (9 9 2 mM benzylamine ethoxy) 3-methoxy-4 - [Ν'_(2-methylphenyl)ureido] stupid gram '3.11 Millol), 4-(\-methyl-2-amine ethoxy)- 3 -acid methyl ester (80 0 mg, 3.11 mmol), 4-(N-methyl-2)

1283240 五、發明說明（709) ' -- 硝基苯甲酸甲酷（8〇〇毫克，311毫莫耳）及4-DMAp (77 笔克，0.^63毫莫耳）、H〇Bt(64〇毫克，4·7毫莫耳）、及 EjCOH毫克」4· 7毫莫耳）於DMF(20毫升）中之混合物在室 /里下撥摔隔夜。將混合物以Et〇Ac稀釋，及將溶液以〇· 5N CH1、飽和NaHC03、鹽水洗滌，於Na2s〇4上乾燥，並蒗發。 使殘留物於矽膠上利用CHCl3 : Et〇Ac(95:5至〇:1〇〇 ”，\/ν) 作為洗提液進行層析，而得587毫克（34%)之3-硝基_4一 [[2 - [3 -曱氧基-4-[ Ν’- (2-甲基苯基）脲基]苯基乙醯基] 甲胺基]乙氧基]苯甲酸甲酯的淡黃色油。 l-NMR (CDC13，40 0ΜΗζ)6 2.31 (s，3Η)、3·05 (s，1Η) 、3·23 (s，2Η)、3·71 (s，2Η)、3·83 (s，3Η)、3·85 (m，3Η)、3·94 (s, 3Η)、4·19 及 4.39 (m，總計 2Η)、 6·80 (m，2Η)、7·05 (m，1Η)、7·22 (m，3Η)、7.62 (d， 1H，J = 8.2 Hz)、8·02 (d，1H，J = 8.2 Hz)、8·21 (dd， 1H，J = 2.1 Hz、8.8 Hz)、8.55 (d，1H，J = 2.1 Hz); MS(FAB) m/z 551 (MH1) o 使3-硝基-4-[ [2- [3-甲氧基-4-[N，-（2-曱基苯基）脲基] 苯基乙醯基]甲胺基]乙氧基]笨甲酸甲酯（587毫.克，1.1毫 莫耳）及5% Pd-C( 6 00 毫克）於THF-MeOH-AcOH(l : 1 : 1，v/v, 150毫升）之混合物在45 psi下氫化1 8小時。利用吸濾將不 溶解的催化劑移除，及將濾液於真空中蒸發而得55 5毫克 (100 % )3-胺基~4 - [[2 - [3 -甲氧基-4-[Ν’-（2-甲基苯基）脲 基]苯基乙醯基]甲胺基]乙氧基]苯甲酸甲酯的淡黃色膠。 4-NMR (CDC13 ，400ΜΗζ)6 2.29 (s， 3Η) 、3·08 (m， 1Η)1283240 V. INSTRUCTIONS (709) ' -- Nitrobenzoic acid (8 〇〇 mg, 311 mmol) and 4-DMAp (77 gram, 0.^63 millimoles), H〇Bt ( A mixture of 64 mg, 4.7 mmol, and EjCOH (4. 7 mmol) in DMF (20 mL) was dropped in the room/under. The mixture was diluted with Et 〇Ac, and the solution was washed with 〇 5N CH1, saturated NaHC03, brine, dried over Na 2 s s 4 and swelled. The residue was chromatographed on a silica gel using CHCl3: Et?Ac (95:5 to 〇:1 〇〇), \/ν) as an eluent to give 587 mg (34%) of 3-nitro. 4-[[2- [3-]-methoxy-4-[Ν--(2-methylphenyl)ureido]phenylethenyl]methylamino]ethoxy]benzoic acid methyl ester Yellow oil. l-NMR (CDC13, 40 0ΜΗζ)6 2.31 (s, 3Η), 3·05 (s, 1Η), 3·23 (s, 2Η), 3·71 (s, 2Η), 3·83 (s, 3Η), 3·85 (m, 3Η), 3·94 (s, 3Η), 4·19 and 4.39 (m, total 2Η), 6·80 (m, 2Η), 7·05 (m , 1Η), 7·22 (m, 3Η), 7.62 (d, 1H, J = 8.2 Hz), 8·02 (d, 1H, J = 8.2 Hz), 8·21 (dd, 1H, J = 2.1 Hz, 8.8 Hz), 8.55 (d, 1H, J = 2.1 Hz); MS(FAB) m/z 551 (MH1) o 3-nitro-4-[ [2- [3-methoxy-4 -[N,-(2-Mercaptophenyl)ureido]phenylphenylmercapto]methylamino]ethoxy] benzoic acid methyl ester (587 mM., 1.1 mmol) and 5% Pd- a mixture of C (600 mg) in THF-MeOH-AcOH (1:1:1, v/v, 150 ml) was hydrogenated at 45 psi for 18 hours. The insoluble catalyst was removed by suction filtration and The filtrate is true Evaporation to give 55 5 mg (100%) of 3-amino~4 - [[2 - [3-methoxy-4-[Ν--(2-methylphenyl)ureido]phenyl hydrazide Light yellow gum of methyl]methylamino]ethoxy]benzoate. 4-NMR (CDC13,400ΜΗζ)6 2.29 (s, 3Η), 3·08 (m, 1Η)

\\312\2d-code\90-01\89112968.ptd 第 714 頁 1283240 五、發明說明（710) 、3·19 (s，2H)、3.65 (s, 1H)、3.73-3.8 0 (m，3H)、 3·84 (s，3H)、3.87 (s，3H)、4·19 及 4.40 (m，總計 2H) 、6·70-6.82 (m， 2H) 、7·02-7·29 (m, 6H) 、7·60 (d， 1H， J=7.8 Hz) 、7·92-7·99 (m， 3H); MS(FAB) m/z 521(MH1)。 在室溫下於3-胺基-4-[[2 - [3-甲氧基-4-[N，-（2-甲基苯 基）脲基]苯基乙醯基]甲胺基]乙氧基]苯曱酸曱酯（555毫 克’1.1毫莫耳）、甲醛（1〇毫升）、及AcOH(〇. 58毫升，10 毫莫耳）溶於MeCN( 10毫升）之攪拌溶液中加入NaBH3CN (0 · 6 7克，1 0毫莫耳），並使所產生之混合物在相同溫度下 攪拌15小時。將飽和NaHC03加至混合物，並以CHC13萃取。 將萃取液以鹽水洗滌，於MgS04上乾燥，並於真空中蒸 發。將殘留物於矽膠上利用甲苯：丙酮（7 : 3至1 : 1，v/ v ) 作為洗提液進行層析而付123宅克（21%)之3 -二曱胺基-4 -[[2-[3 -曱氧基-4 - [Ν’-（2-甲基苯基）脲基]苯基乙醯基] 甲胺基]乙氧基]苯甲酸甲酯的油。 !H-NMR (CDC13 ， 400MHz) 6 2.30 (s， 3Η) 、 2.70 (s， 3Η) 、2·75 (s，3H)、3·〇5 (s，1H)、3·18 (s，2H)、3·61 (s， 3H) 、3·70 (s， 1H) 、3·80 (m， 3H) 、3·86 (s， 3H) 、4·07 及 4·22 (2m，總計21〇、6.28(111，11〇、6.70-6·80 (m，3H)、7·03 (m, 1H)、7·15-7·25 (m，4H)、 7.46-7·65 (m，2Η)、8.02 (m，1H); MS (FAB) m/z 548 (MH1)。 使3-二甲胺基-4- [ [2-[3-甲氧基-4-[Ν’ -(2-甲基苯基）\\312\2d-code\90-01\89112968.ptd Page 714 1283240 V. INSTRUCTIONS (710), 3·19 (s, 2H), 3.65 (s, 1H), 3.73-3.8 0 (m, 3H), 3·84 (s, 3H), 3.87 (s, 3H), 4·19 and 4.40 (m, total 2H), 6.70-6.82 (m, 2H), 7·02-7·29 ( m, 6H), 7·60 (d, 1H, J = 7.8 Hz), 7.92-7·99 (m, 3H); MS (FAB) m/z 521 (MH1). 3-Amino-4-[[2-[3-methoxy-4-[N,-(2-methylphenyl)ureido]phenylethyl]methylamino] at room temperature Ethyl ethoxy] benzoate (555 mg '1.1 mmol), formaldehyde (1 mL), and AcOH (〇. 58 mL, 10 mmol) dissolved in a stirred solution of MeCN (10 mL) NaBH3CN (0 · 6 7 g, 10 mmol) was added, and the resulting mixture was stirred at the same temperature for 15 hours. Saturated NaHC03 was added to the mixture and extracted with CHC13. The extract was washed with brine, dried over MgSO 4 and evaporated in vacuo. The residue was chromatographed on a silica gel using toluene:acetone (7:3 to 1:1, v/v) as an eluent to afford 123 g (21%) of 3-diamine-4-[ An oil of [2-[3-oxo-4-yl][Ν'-(2-methylphenyl)ureido]phenylethenyl]methylamino]ethoxy]benzoic acid methyl ester. !H-NMR (CDC13, 400MHz) 6 2.30 (s, 3Η), 2.70 (s, 3Η), 2·75 (s, 3H), 3·〇5 (s, 1H), 3·18 (s, 2H ), 3·61 (s, 3H), 3·70 (s, 1H), 3·80 (m, 3H), 3·86 (s, 3H), 4·07 and 4·22 (2m, total 21 〇, 6.28 (111, 11 〇, 6.70-6.80 (m, 3H), 7·03 (m, 1H), 7·15-7·25 (m, 4H), 7.46-7·65 (m, 2Η), 8.02 (m, 1H); MS (FAB) m/z 548 (MH1). 3- 3-Methylamino-4-[ [2-[3-methoxy-4-[Ν' - ( 2-methylphenyl)

\\312\2d-code\90-01\89112968.ptd 第715頁 1283240 五、發明說明（711) 脲基苯基乙醯基]甲胺基]乙氧基]苯曱酸甲酯（123毫克， 〇·22 毫莫耳）於 THFC15 毫升）及 IN NaOH( 0.085 毫升，0.885 毫莫耳）中之攪拌混合物迴流加熱1 5小時。經由加入1 N HC1將混合物之PH調整至5·0，並以CHC13 :MeOH (9:1， v/v)萃取。將萃取液以鹽水洗滌，於MgS04上乾燥，並於 真空中蒸發。利用Et20-正己烷使殘留物結晶，而得11 8毫 克（100%)之3-二曱胺基-4 - [[2- [3-甲氧基-4 - [Ν’ - (2-甲基 苯基）脲基]苯基乙醯基]甲胺基]乙氧基]苯甲酸276的白色 結晶物質。 熔點 125-130 °C; IR (KBr) 3346、2940、1620、1597、 1535、1456、1417、1227、1039、754 /公分；UMR (CD3OD，4 00MHz) 5 2· 29 (s，3H)、2· 70 (s，3H)、2· 79 (s， 2H) 、3·05 (s， 1H) 、3·22 (s， 2H) 、3·75 (s， 3H) 、3·85 (m，4H)、4·15 及 4.28 (m，2H)、6·78-7·05 (m， 4Η)、7·18 (m，2Η)、7·55 - 7·70 (m，3Η)、7·98 (m， 1Η) ; MS(FAB) m/Z 53 5 (ΜΗ1) ; C29H34N4 06 · 2. 0Η2Ο 之分析 計算值：C，61. 04 ; H，6· 71 ; N，9· 82。實測值：c，61 15 ； Η, 6· 43 ; Ν，8· 94。 &gt; * 實施例2 2 6 3-二甲胺基-4 - [[2 - [3-曱氧基-4- [Ν’ - (2-氟笨基）脲基]苯 基乙醯基]曱胺基]乙氧基]笨甲酸 &amp;\\312\2d-code\90-01\89112968.ptd Page 715 1283240 V. INSTRUCTIONS (711) Urea-Phenylphenylethyl]methylamino]ethoxy]benzoic acid methyl ester (123 mg The stirred mixture in THF (15 mL) in THF (15 mL) and IN NaOH (0.085 mL, 0.885 mM) was heated under reflux for 15 hours. The pH of the mixture was adjusted to 5.0 by the addition of 1 N HCl and extracted with CHC13:MeOH (9:1, v/v). The extract was washed with brine, dried over MgSO4 and evaporated in vacuo. The residue was crystallized from Et20-n-hexane to give &lt;RTI ID=0.0&gt;&gt; Phenylphenyl)ureido]phenylethenyl]methylamino]ethoxy]benzoic acid 276 as a white crystalline material. Melting point 125-130 ° C; IR (KBr) 3346, 2940, 1620, 1597, 1535, 1456, 1417, 1227, 1039, 754 / cm; UMR (CD3OD, 4 00MHz) 5 2 · 29 (s, 3H), 2· 70 (s, 3H), 2· 79 (s, 2H), 3·05 (s, 1H), 3·22 (s, 2H), 3·75 (s, 3H), 3·85 (m , 4H), 4·15 and 4.28 (m, 2H), 6·78-7·05 (m, 4Η), 7·18 (m, 2Η), 7·55 - 7·70 (m, 3Η), 7·98 (m, 1Η) ; MS(FAB) m/Z 53 5 (ΜΗ1) ; C29H34N4 06 · 2. 0Η2Ο Analysis calculated: C, 61. 04 ; H,6· 71 ; N,9· 82 . Found: c, 61 15 ; Η, 6· 43 ; Ν, 8. 94. &gt; * Example 2 2 6 3-Dimethylamino-4 - [[2 - [3-曱oxy-4-[Ν' - (2-fluorophenyl)ureido]phenylethenyl] Amidino]ethoxy]benzoic acid &amp;

1283240 五、發明說明（712) 使3 -甲氧基-4 - [Ν’ - (2 -氟苯基）脲基]苯基乙酸（1克，3. 11毫莫耳）、4-[2_[(Ν-甲基-2-胺基）乙氧基]-3 -硝基苯甲 酸甲酯（800毫克，3.11毫莫耳）及4-DMAP (77毫克，〇· 63 毫莫耳）、HOBt(640毫克，4.7毫莫耳）、及EDC( 9 04毫克， 4. 7毫莫耳）於DMF( 20毫升）中之混合物在室溫下攪拌隔 夜。將混合物以EtOAc稀釋，及將溶液以〇· 5N HC1、飽和 NaHC03、鹽水洗滌，於Na2S04上乾燥，並蒸發。使殘留物 於石夕膠上利用CHCl3-EtOAc(95:5至0:100，v/v)作為洗提 液進行層析，而得420毫克（19%)之3-硝基_4-[[2-[3-氟 -4-[Ν’ -（2-氟苯基）脲基]苯基乙醯基]曱胺基]乙氧基]苯 甲酸甲酯的淡黃色油。 4-NMR (CDC13，40 0ΜΗζ)6 3·04 (s，1Η)、3·24 (s，2Η) 、3·72 (s，1Η)、3.85 (s，3Η)、3·90 (m，3Η)、3·93 (s，3Η)、4·16 及 4.39 (2m, 3Η)、6·80 (m，2Η)、6.99 (m，1H)、7.05 (m，2H)、7·22 (d，1H，J = 8.8 Hz)、 7·51 (s，2H)、8.00 (m，1H)、8·08 (m，1H)、8·21 (d， 1H，J = 8.6 Hz)、8.51 (s，1H); MS(FAB) m/z 555(M+ + 〇〇 使3-硝基-4-[ [2- [3-甲氧基-4-[Ν’ -（2-氟苯基）脲基] 苯基乙醯基]甲胺基]乙氧基]苯甲酸甲酯（420毫克，0.76 毫莫耳）及5% Pd-C(l 克）於THF-MeOH-AcOH(l : 1 : 1，ν/ν， 1 5 0毫升）中之混合物在4 5 p s i下氫化1 8小時。利用吸濾將 不溶解的催化劑移除，及將濾液於真空中蒸發而得3 9 7毫 克（100%)3 -胺基-4 - [[2 - [3-甲氧基-4-[N’ _(2-敗苯基）脈1283240 V. INSTRUCTIONS (712) 3 -Methoxy-4 -[Ν' - (2-fluorophenyl)ureido]phenylacetic acid (1 g, 3.11 mmol), 4-[2_ [(Ν-Methyl-2-amino)ethoxy]-3-nitrobenzoic acid methyl ester (800 mg, 3.11 mmol) and 4-DMAP (77 mg, 〇· 63 mmol), A mixture of HOBt (640 mg, 4.7 mmol) and EDC (9 04 mg, 4. 7 mmol) in DMF (20 mL) was stirred overnight at room temperature. The mixture was diluted with EtOAc and EtOAc (EtOAc)EtOAc. The residue was chromatographed on silica gel using CHCl3-EtOAc (95:5 to 0:100, v/v) as eluent to give 420 mg (19%) of 3-nitro-4-[ A pale yellow oil of [2-[3-fluoro-4-[Ν'-(2-fluorophenyl)ureido]phenylethenyl]nonylamino]ethoxy]benzoic acid methyl ester. 4-NMR (CDC13, 40 0ΜΗζ) 6 3·04 (s, 1Η), 3·24 (s, 2Η), 3.72 (s, 1Η), 3.85 (s, 3Η), 3·90 (m, 3Η), 3·93 (s, 3Η), 4·16 and 4.39 (2m, 3Η), 6·80 (m, 2Η), 6.99 (m, 1H), 7.05 (m, 2H), 7·22 ( d, 1H, J = 8.8 Hz), 7·51 (s, 2H), 8.00 (m, 1H), 8·08 (m, 1H), 8·21 (d, 1H, J = 8.6 Hz), 8.51 (s,1H); MS(FAB) m/z 555 (M+ + 〇〇 3-nitro-4-[ [2-[3-methoxy-4-[Ν' -(2-fluorophenyl) Ureido]phenylphenylmercapto]methylamino]ethoxy]benzoic acid methyl ester (420 mg, 0.76 mmol) and 5% Pd-C (1 g) in THF-MeOH-AcOH (l: The mixture in 1 : 1, ν / ν, 150 ml) was hydrogenated at 45 psi for 18 hours. The insoluble catalyst was removed by suction filtration, and the filtrate was evaporated in vacuo to give 3.9 mg. (100%) 3-amino-4 - [[2 - [3-methoxy-4-[N' _(2-phenylene)) vein

\\312\2d-code\90-01\89112968.ptd 第 717 頁 1283240 五、發明說明（713) 基]苯基乙醯基]甲胺基]乙氧基]笨曱酸甲酯的淡黃色膠。 4-NMRv (CDC13，40 0MHz) 6 3· 0 5 及3. 13 (s，總計3H)、 3.66 (s，3H)、3·70 (s，2H)、3·65-3·90 (m，4H)、 3.86 (s，3H)、4·10 及 4.23 (m，2H)、6·70 - 6.83 (m, 3 Η)、6 · 9 8 - 7 · 1 5 (m，6 Η)、7 · 2 5 - 7 . 4 3 (m，2 Η)、7 · 9 9 (m, 1Η)、8·13 (m，1H); MS(FAB) m/z 525 (ΜΗ1)。 在室溫下於3-胺基-4-[[2-[3-甲氧基-4-[1^，-(2_氟苯 基）脲基]苯基乙醯基]曱胺基]乙氧基]苯甲酸曱酯（397毫 克，0.76毫莫耳）、甲醛（10毫升）、及ac〇h(〇. 43毫升，7. 6毫莫耳）溶於MeCN(10毫升）之攪拌溶液中加入NaBH3cN (0 · 48克，7· 6毫莫耳），並使所產生之混合物在相同溫度 下攪拌1 5小時。將飽和NaHC03加至混合物，並以CHC13萃 取。將％取液以鹽水洗蘇，於MgS04上乾燥，並於真空中 蒸發。將殘留物於矽膠上利用甲苯：丙酮（7 : 3至丨：1， v/v)作為洗提液進行層析而得123毫克（21%)之3 -二甲胺基 -4-[ [2-[ 3-曱氧基-4-[Ν’ - (2-甲基苯基）脲基]苯基乙醯 基]甲胺基]乙氧基]苯甲酸甲酯的油。 l-NMR (CDC13，400MHz) 6 2· 74 (s，3Η)、2· 77 (s， 3H)、3·08 (s，1H)、3·22 (s，2H)、3·52 (s，3H)、 3.61 (s，1H)、3·83 (m，3H)、3.88 (s，3H)、4·12 及 4·23 (m，總計2H)、6·68 (s，1H)、6·78 (m，2H)、6·98 (m，2H)、7·10 (m，1H)、7·55-7·68 (m，4H)、7·99 (m， 1Η)、8·16 (t，1Η，J = 8.3 Hz); MS(FAB) m/z 553 (MH1)。\\312\2d-code\90-01\89112968.ptd Page 717 1283240 V. INSTRUCTIONS (713) Base] Phenylethyl hydrazide] methylamino] ethoxy] methyl benzoate gum. 4-NMRv (CDC13, 40 0MHz) 6 3· 0 5 and 3. 13 (s, total 3H), 3.66 (s, 3H), 3·70 (s, 2H), 3·65-3·90 (m , 4H), 3.86 (s, 3H), 4·10 and 4.23 (m, 2H), 6.70 - 6.83 (m, 3 Η), 6 · 9 8 - 7 · 1 5 (m, 6 Η), 7 · 2 5 - 7 . 4 3 (m, 2 Η), 7 · 9 9 (m, 1 Η), 8·13 (m, 1H); MS (FAB) m/z 525 (ΜΗ1). 3-Amino-4-[[2-[3-methoxy-4-[1^,-(2-fluorophenyl)ureido]phenylethenyl]nonylamino] at room temperature Ethyl ethoxy]benzoate (397 mg, 0.76 mmol), formaldehyde (10 ml), and ac〇h (〇. 43 ml, 7.6 mmol) dissolved in MeCN (10 mL). NaBH3cN (0 · 48 g, 7.6 mmol) was added to the solution, and the resulting mixture was stirred at the same temperature for 15 hours. Saturated NaHC03 was added to the mixture and extracted with CHC13. The % solution was washed with brine, dried over MgS04 and evaporated in vacuo. The residue was chromatographed on silica gel using toluene:acetone (7:3 to 丨:1, v/v) as eluent to give 123 mg (21%) of 3-dimethylamino-4-[ An oil of 2-[3-methoxy-4-[Ν'-(2-methylphenyl)ureido]phenylethenyl]methylamino]ethoxy]benzoic acid methyl ester. l-NMR (CDC13, 400MHz) 6 2· 74 (s, 3Η), 2· 77 (s, 3H), 3·08 (s, 1H), 3·22 (s, 2H), 3·52 (s , 3H), 3.61 (s, 1H), 3·83 (m, 3H), 3.88 (s, 3H), 4·12 and 4·23 (m, total 2H), 6.68 (s, 1H), 6·78 (m, 2H), 6·98 (m, 2H), 7·10 (m, 1H), 7·55-7·68 (m, 4H), 7·99 (m, 1Η), 8 · 16 (t, 1 Η, J = 8.3 Hz); MS (FAB) m/z 553 (MH1).

1283240 五、發明說明（714) 使3-二曱胺基-4-[[2 - [3-曱氧基-4- [Ν’-（-氟苯基）脲基 ]笨基乙醯基]曱胺基]乙氧基]苯曱酸甲酯（61毫克，〇·11 毫莫耳）於THF(15毫升）及IN NaOH(0.22毫升，〇·22毫莫 耳）中之攪拌混合物迴流加熱1 5小時。經由加入1 N HC 1將 混合物之pH調整至5.0，並以CHC13 :MeOH (9:1，v/v)萃 取。將萃取液以鹽水洗滌，以Me〇H :丙酮（93 : 7，v/v)作 為洗提液，而得37毫克（63%)之3-二甲胺基-4-[ [2-[3-甲 氧基-4-[Ν’ - (2〜氟苯基）脲基]苯基乙醯基]甲胺基]乙氧 基]苯甲酸27 7的白色結晶物質。 炫點 1 2 0-1 25 °C ; ih-NMR (CD30D，40 0MHz) 6 2· 60 (s， 4H)、2·78 (s，2H)、3·06 (s，1H)、3·22 (s, 2H)、 3.75 (s，3H)、3·85-3.92 (m，4H)、4·17 及 4.29 (m，總 計 2H)、6·80 - 7.12 (m，6H)、7·6 卜 7·70 (m，2H)、8·00 (m, 1H)&gt;8.08 (m5 1H)；MS(FAB) 539 (MH1 ) ； C28H31FN406 •2·75Η20 之分析計算值：c，57·ΐ8; H，6.26; N， 9.53° 實測值：C， 57· 20 ; H， 5. 62 ; N，9. 06。 f施例2 2 7 3-二甲胺基-4-[[2-[ 4-[N，-（2-甲基苯基）脲基]苯基乙醯 基]甲胺基]乙氧基]苯甲酸1283240 V. INSTRUCTIONS INSTRUCTION (714) 3- 3-Aminoamino-4-[[2-[3-methoxy-4-[Ν--(-fluorophenyl)ureido]]phenylamino] Methylamine ethoxy] benzoate (61 mg, 〇·11 mmol) was heated under reflux with stirring mixture of THF (15 mL) and IN NaOH (0.22 mL, 〇·22 mmol) 1 5 hours. The pH of the mixture was adjusted to 5.0 via the addition of 1 N HCl and extracted with CHC13:MeOH (9:1, v/v). The extract was washed with brine, using Me〇H:acetone (93:7, v/v) as the eluent to give 37 mg (63%) of 3-dimethylamino-4-[[2-[ A white crystalline material of 3-methoxy-4-[Ν'-(2~fluorophenyl)ureido]phenylethenyl]methylamino]ethoxy]benzoic acid 27 7 . Hyun point 1 2 0-1 25 °C; ih-NMR (CD30D, 40 0MHz) 6 2· 60 (s, 4H), 2·78 (s, 2H), 3·06 (s, 1H), 3· 22 (s, 2H), 3.75 (s, 3H), 3.85-3.92 (m, 4H), 4·17 and 4.29 (m, total 2H), 6.80 - 7.12 (m, 6H), 7· 6 卜7·70 (m, 2H), 8·00 (m, 1H) &gt; 8.08 (m5 1H); MS (FAB) 539 (MH1 ) ; C28H31FN406 • 2·75Η20 Analysis calculated value: c, 57· Ϊ́8; H, 6.26; N, 9.53° Found: C, 57·20; H, 5. 62 ; N, 9. 06. f Example 2 2 7 3-Dimethylamino-4-[[2-[4-[N,-(2-methylphenyl)ureido]phenylethenyl]methylamino]ethoxy ]benzoic acid

278 使[4-[N’ -（2〜甲基苯基）脲基]苯基]乙酸五氟笨酯（1· 42278 [4-[N' -(2~Methylphenyl)ureido]phenyl]acetic acid pentafluoroester (1·42

\\312\2d-code\90-01\89112968.ptd 第719頁 1283240 五、發明說明（715) 克’3.15宅莫耳）、4 - [2-[(N-甲基-2 -胺基）乙氧基]- 3-石肖 基苯甲酸曱酯（800毫克，3. 15毫莫耳）及三乙胺（0.66毫 升，4. 73毫莫耳）於DMF( 8毫升）中之混合物在50 °C下攪拌 15小時。將混合物倒入至冰的in HC1中，並以CHC13萃 取。將萃取液以鹽水洗滌，於Na2S04上乾燥，並蒸發。使 殘留物於矽膠上利用CHC13 :EtOAc(95:5至0:100，v/v)作 為洗提液進行層析，而得1.04克（63%)之3-硝基-4-[[2-[4 -[Ν’-（2-甲基苯基）脲基]苯基乙醯基]甲胺基]乙氧基] 笨甲酸曱酯的淡黃色油。 l-NMR (CDC13，40 0ΜΗζ)(5 2.30 (s，3Η)、2.90、3.02 及 3·05 (s，總計 1Η)、3.22 (s，2Η)、3·71 (s，1Η)、3.85 (m， 3Η) 、3·93 (s， 3Η) 、4·19及4.39 (m， 2Η) 、7·02 (m，1H)、7·19 (m，4H)、7·35 (d，1H，J = 8.3 Hz)、 7.40 (d，1H，J = 8.0 Hz)、7.55 (s，2H)、7·70 (m， 1H)、8.22 (d，1H, J:6.7 Hz)、8.51 (s，1H); MS(FAB) m/z 521 (M+ + 1)。 使3-硝基-4-[ [2-[4-[Ν’ -(2_甲基苯基）脲基]苯基乙醯 基]甲胺基]乙氧基]苯甲酸甲酯（1.04克，2毫莫耳）及5 %\\312\2d-code\90-01\89112968.ptd Page 719 1283240 V. INSTRUCTIONS (715) gram '3.15 house Moer), 4 - [2-[(N-methyl-2-amino group) a mixture of ethoxylated 3-methylsuccinylbenzoate (800 mg, 3.15 mmol) and triethylamine (0.66 mL, 4.73 mmol) in DMF (8 mL) at 50 Stir at ° C for 15 hours. The mixture was poured into ice in HC1 and extracted with CHC13. The extract was washed with brine, dried over Na 2 EtOAc and evaporated. The residue was chromatographed on silica gel using CHC13:EtOAc (95:5 to 0:100, v/v) as eluent to give 1.04 g (63%) of 3-nitro-4-[[2 - [4 - [Ν'-(2-Methylphenyl)ureido]phenylethinyl]methylamino]ethoxy] benzoic acid decyl ester as a pale yellow oil. l-NMR (CDC13, 40 0ΜΗζ) (5 2.30 (s, 3Η), 2.90, 3.02, and 3.05 (s, total 1Η), 3.22 (s, 2Η), 3.71 (s, 1Η), 3.85 ( m, 3Η), 3·93 (s, 3Η), 4·19 and 4.39 (m, 2Η), 7·02 (m, 1H), 7·19 (m, 4H), 7·35 (d, 1H) , J = 8.3 Hz), 7.40 (d, 1H, J = 8.0 Hz), 7.55 (s, 2H), 7·70 (m, 1H), 8.22 (d, 1H, J: 6.7 Hz), 8.51 (s ,1H); MS(FAB) m/z 521 (M+ + 1). 3-nitro-4-[[2-[4-[Ν[-(2-methylphenyl)ureido]phenyl Ethylmethyl]methylamino]ethoxy]benzoic acid methyl ester (1.04 g, 2 mmol) and 5%

Pd - C(1.2 克）於THF - MeOH - AcOH(l:l:l，v/v， 150 毫升）中 之混合物在45 psi下氫化1 8小時。利用吸濾將不溶解的催 化劑移除，及將濾液於真空中蒸發而得3-胺基-4-[ [2-[ 4-[Ν’- (2-甲基苯基）脲基]苯基乙醯基]甲胺基]乙氧基]苯 甲酸曱酯的淡黃色膠。 在室溫下於3 -胺基-4-[ [2-[4-[Ν’ -（2-曱基笨基）脲基]A mixture of Pd-C (1.2 g) in THF - MeOH - AcOH (1:1:1, v/v, 150 ml) was hydrogenated at 45 psi for 18 hours. The insoluble catalyst is removed by suction filtration, and the filtrate is evaporated in vacuo to give 3-amino-4-[[2-[4-[4-[Ν'-(2-methylphenyl)ureido]benzene A pale yellow gum of decyl]methylamino]ethoxy]benzoate. 3-Amino-4-[[2-[4-[Ν'-(2-mercapto))urea] at room temperature

\\312\2d-code\90-01\89112968.ptd 第 720 頁 1283240\\312\2d-code\90-01\89112968.ptd Page 720 1283240

五、發明說明（716) 苯基乙醯基]甲胺基]乙氧基]笨甲酸曱酯、甲醛（5毫升）、 及AcOH(l· 14毫升，20毫莫耳）溶於MeCN(5毫升）之攪拌溶 液中加入NaBHsCN( 1 · 2 6克’ 20毫莫耳），並使所產生之混 合物在相同溫度下授拌1 5小時。將飽和NaHC〇3加至混合 物，並以CHCI3萃取。將萃取液以鹽水洗滌，於MgS^上乾 燥，並於真空中蒸發。將殘留物於矽膠上利用甲苯：丙_ (7: 3至1 : 1，v/v)作為洗提液進行層析而得85毫克（2步驟 ，8%)之3-二甲胺基-4-[ [2-[4-2-甲基苯基）脲基]苯 基乙醯基]甲胺基]乙氧基]苯甲酸曱醋的油。 iH-NMR (CDC13，40 0MHz) 5 2· 12 (s, 3H)、2· 73 (s，3H) 、2·75 (s， 3H) 、3·05 (s， 1Η) 、3·20 (s， 2H) 、3·60 (s，1 Η )、3 · 8 0 (m，3 Η)、3 · 8 8 ( s，3 Η )、4 · 1 7 ( m， 2H)、6.95-7.28 (m，8H)、7.55-7. 75 (m，3H); MS(FAB) m/z 518(MH1 )。 使3-二甲胺基-4- [[2-[4-[N，-(-氟苯基）脲基]苯基乙醯 基]甲胺基]乙氧基]苯甲酸甲酯（ap3i5201)(85毫克，0.16 毫莫耳）於THF(15毫升）及IN NaOH(0.32毫升，0.32毫莫 耳）中之攪拌混合物迴流加熱1 5小時。經由加入1 N HC1將 化合物之口1!5周整至5.0’並以(]11013:^16〇11(9:1，\^/\〇萃 取。將萃取液以鹽水洗務，於MgS04上乾燥，並於真空中 蒸發。使殘留物自E t2 0結晶，而得5 3毫克（6 5 %)之3 -二甲 胺基-4 - [[2-[3-曱氧基-4-[Ν’-（2-甲基苯基）脲基]苯基 乙醯基]曱胺基]乙氧基]苯甲酸2 7 8的白色結晶物質。 熔點110-115°〇;111-關1?(00300,40〇龍2)(5 2.29(3，5. Description of the invention (716) Ethyl phenyl hydrazide] methylamino] ethoxy] decyl decanoate, formaldehyde (5 ml), and AcOH (1.4 ml, 20 mM) are dissolved in MeCN (5) NaBHsCN (1 · 2 6 g '20 mmol) was added to the stirred solution of ML), and the resulting mixture was stirred at the same temperature for 15 hours. Saturated NaHC〇3 was added to the mixture and extracted with CHCI3. The extract was washed with brine, dried over MgSO4 and evaporated in vacuo. The residue was chromatographed on silica gel using toluene: C- (7:3 to 1:1, v/v) as eluent to give 85 mg (2 steps, 8%) of 3-dimethylamino- An oil of 4-[[2-[4-2-methylphenyl)ureido]phenylethenyl]methylamino]ethoxy]benzoic acid vinegar. iH-NMR (CDC13, 40 0MHz) 5 2· 12 (s, 3H), 2· 73 (s, 3H), 2·75 (s, 3H), 3·05 (s, 1Η), 3·20 ( s, 2H), 3·60 (s, 1 Η ), 3 · 8 0 (m, 3 Η), 3 · 8 8 ( s, 3 Η ), 4 · 1 7 ( m, 2H), 6.95-7.28 (m, 8H), 7.55-7. 75 (m, 3H); MS (FAB) m/z 518 (MH1). Methyl 3-dimethylamino-4-[[2-[4-[N,-(-fluorophenyl)ureido]phenylethenyl]methylamino]ethoxy]benzoate (ap3i5201) The stirred mixture in THF (15 mL) and IN NaOH (0.32 mL, 0.32 m. The compound was aliquoted by adding 1 N HCl for 1! 5 weeks to 5.0' and extracted with (]11013:^16〇11 (9:1, \^/\〇. The extract was washed with brine on MgS04 Dry and evaporate in vacuo. The residue is crystallised from Et20 to give &lt;RTI ID=0.0&gt;&gt; [Ν'-(2-Methylphenyl)ureido]phenylethenyl]nonylamino]ethoxy]benzoic acid 273 white crystalline material. Melting point 110-115 ° 〇; 111-off 1 ?(00300,40〇龙2)(5 2.29(3,

\\312\2d-code\90-01\89112968.ptd 第721頁 1283240 五、發明說明（717) 3H) 、2·75 (s， 3H) 、2.76 (s, 3H) 、3·〇2 (s， 1H)、 3·20 (s，2Η)、3·72 (s, 1Η)、3·85 (m，3Η)、4·18 及 4·28 (m，總計2Η)、6·95-7.03 (m，2Η)、7·18 (m，4Η) 、7·34 (d，1Η，J:8.3 Hz)、7·38 (d，in，J = 8.8 Hz)、 7·62 (d，1H，J = 8.3 Hz)、7.66 (s，ih)、7.80 (m， 1H) ; MS(FAB) m/z 505(M+ + 1)。 實施例228 3-異丙胺基-4-[[2-[3-甲氧基-4 - [Ν’—（2-氟苯基）脲基]笨 基乙醯基]甲胺基]乙氧基]苯甲酸\\312\2d-code\90-01\89112968.ptd Page 721 1283240 V. Description of invention (717) 3H), 2·75 (s, 3H), 2.76 (s, 3H), 3·〇2 ( s, 1H), 3·20 (s, 2Η), 3·72 (s, 1Η), 3·85 (m, 3Η), 4·18 and 4·28 (m, total 2Η), 6.95- 7.03 (m, 2Η), 7.18 (m, 4Η), 7.34 (d, 1Η, J: 8.3 Hz), 7.38 (d, in, J = 8.8 Hz), 7·62 (d, 1H, J = 8.3 Hz), 7.66 (s, ih), 7.80 (m, 1H); MS (FAB) m/z 505 (M+ + 1). Example 228 3-Isopropylamino-4-[[2-[3-methoxy-4 -[Ν'-(2-fluorophenyl)ureido]]phenylamino]methylamino]ethoxy Benzoic acid

於3-胺基-4-[ [2- [3-甲氧基-4-[Ν’〜（2_氟苯基）脲基]苯基 乙醯基]甲胺基]乙氧基]苯甲酸甲酯（1〇〇毫克，〇19毫莫 耳）於丙酮/Ac0H/DMF(13毫升，6:6:1，ν/ν/ν)中之冷卻 (〇°C)溶液中加入NaBaH3CN( 30 0毫克），並使所產生之^合 物在室溫下授拌6 0小時。將混合物倒入至飽和N a H c %，並 利用吸濾收集固體。將沈澱物溶解於CHC13 (20亳升），並 將溶液以鹽水洗滌，於MgS04上乾燥，並於減壓下蒸發。 將殘留物於矽膠板上利用甲苯：丙g同（2 : 1，v / v )作為洗提 液進行層析而得108毫克（loo%)之3-異丙胺基-4-[[2-[3 -甲氧基-4-[Ν’ -（2 -氟苯基）脲基]苯基乙醯基]甲胺基]乙 氧基]苯甲酸甲酯的無色油。 ^-NMR (CDC13 5400MHz)5 1.20 (m, 1H) ^2.88 (s, 6H)3-Amino-4-[[2-[3-methoxy-4-[Ν'~(2-fluorophenyl)ureido]phenylethenyl]methylamino]ethoxy]benzene Methyl formate (1 mg, 〇19 mmol) NaBaH3CN was added to a cooled (〇°C) solution in acetone/Ac0H/DMF (13 mL, 6:6:1, ν/ν/ν) 30 mg) and the resulting compound was allowed to mix for 60 hours at room temperature. The mixture was poured to saturation N a H c %, and the solid was collected by suction filtration. The precipitate was dissolved in CHC13 (20 liters), and the solution was washed with brine, dried over MgSO4, and evaporated. The residue was chromatographed on a silica gel plate with toluene: propyl g and (2:1, v / v) as an eluent to give 108 mg (loo%) of 3-isopropylamino-4-[[2- A colorless oil of [3-methoxy-4-[Ν'-(2-fluorophenyl)ureido]phenylethenyl]methylamino]ethoxy]benzoic acid methyl ester. ^-NMR (CDC13 5400MHz) 5 1.20 (m, 1H) ^2.88 (s, 6H)

\\312\2d-code\90-01\89112968.ptd 第722頁 1283240 五、發明說明（718) 、3.02 及 3.12 (s，總計 3H)、3· 53 (s，2H)、3. 60-3. 80 (m, 7H) 、3.85 (s， 3H) 、4·10及4·20 (m， 2H) 、6·65 -675 (m，2Η)、6·90-7·08 (m，2Η)、7·22-7·35 (m， 2H) 、8·02 (s， 2H) 、8.10 (m， 2H) 、8·21 (br， 1H)、 8. 33 (br, 1H) ; MS(FAB) m/z 5 66 (M+ + 1)。 使3-異丙胺基-4 - [[2 - [3-甲氧基-4 - [Ν’ -(-氟苯基）脈 基]苯基乙醯基]甲胺基]乙氧基]苯甲酸甲酯（116毫克， 〇·22毫莫耳）、0·25Ν NaOH(6毫升）、及THF(6毫升）之攪拌 混合物迴流加熱8小時。將混合物倒入至水（2 0 0毫升）中， 利用IN HC1酸化，並利用吸濾收集固體。使固體自CHC13-正己烧-二異丙_1再結晶，而得56毫克（50%)之3 -異丙胺基 -4 - [[2 - [3-甲氧基-4 - [Ν’ -（2 -氟苯基）脲基]苯基乙醯基] 甲胺基]乙氧基]苯甲酸2 79的無色結晶粉末。 熔點 1 9 5-2 0 0 °0：;111-關1?(〇0300,40 01^1^)5 1.15-1.20 (m, 6Η)、3.01 (s，1Η)、3·12 (s，2Η)、3·48-3·60 (m， 1H)、3·68 (s，3H)、3·75 (s，2H)、3·82 (s，1H)、 3.86 (m，3H)、4·15-4·23 (m，2H)、6·80 (m, 3H)、 4.15-4·23 (m，2H)、6·80 (m, 3H)、6·98 (m，1H)、 7·1〇 (m，2H)、7·20 及 7.25 (s，總計 1H)、7·32 (m， 1Η)、7· 98 (m，1Η)、8· 05 (m，1Η) ; MS(FAB) m/z 55 2 (M + H)+ ; C29H33FN4 06 · 1· 0H2O 之分析計算值：C，61· 04 ; H， 6.18； N, 9. 82 ° 實測值：C，61.36； H, 6.25; N, 9.45。 實施例229\\312\2d-code\90-01\89112968.ptd Page 722 1283240 V. Description of invention (718), 3.02 and 3.12 (s, total 3H), 3·53 (s, 2H), 3. 60- 3. 80 (m, 7H), 3.85 (s, 3H), 4·10 and 4·20 (m, 2H), 6.65 -675 (m, 2Η), 6·90-7·08 (m, 2Η), 7·22-7·35 (m, 2H), 8·02 (s, 2H), 8.10 (m, 2H), 8·21 (br, 1H), 8. 33 (br, 1H); MS (FAB) m/z 5 66 (M + + 1). 3-Isopropylamino-4 - [[2 - [3-methoxy-4 - [Ν' -(-fluorophenyl))]phenylethyl]methylamino]ethoxy]benzene A stirred mixture of methyl formate (116 mg, 〇 22 mmol), 0.25 NaOH (6 mL), and THF (6 mL) was heated under reflux for 8 hours. The mixture was poured into water (200 mL), acidified with &lt The solid was recrystallized from CHC13-n-hexane-diisopropyl-1 to give 56 mg (50%) of 3-isopropylamino-4 - [[2 - [3-methoxy-4 - [Ν' - (2-Fluorophenyl)ureido]phenylethenyl]methylamino]ethoxy]benzoic acid 2 79 colorless crystalline powder. Melting point 1 9 5-2 0 0 °0:; 111-off 1?(〇0300,40 01^1^)5 1.15-1.20 (m, 6Η), 3.01 (s,1Η), 3·12 (s, 2Η), 3·48-3·60 (m, 1H), 3.68 (s, 3H), 3·75 (s, 2H), 3·82 (s, 1H), 3.86 (m, 3H), 4·15-4·23 (m, 2H), 6·80 (m, 3H), 4.15-4·23 (m, 2H), 6·80 (m, 3H), 6·98 (m, 1H) , 7·1〇(m, 2H), 7.20 and 7.25 (s, total 1H), 7·32 (m, 1Η), 7·98 (m, 1Η), 8. 05 (m, 1Η); MS (FAB) m/z 55 2 (M + H) + ; C29H33FN4 06 · 1 · 0H2O: C, 61·04; H, 6.18; N, 9. 82 ° Found: C, 61.36; H, 6.25; N, 9.45. Example 229

\\312\2d-code\90-01\89112968.ptd 第723頁 1283240 五、發明說明（719) 4 - [[1 - [4 - [Ν’ -（2-氟苯基）脲基]-3-甲氧苯基乙醯基]一2 一 甲胺基]- 2-甲基-2-丙氧基]苯甲酸\\312\2d-code\90-01\89112968.ptd Page 723 1283240 V. INSTRUCTIONS (719) 4 - [[1 - [4 - [Ν' -(2-Fluorophenyl)ureido]- 3-methoxyphenylethylidene]-2-methylamino]-2-methyl-2-propoxy]benzoic acid

280 在5至10 °c下於2 -胺基-2-甲基-1-丙醇（8·4克，93.89毫 莫耳）及三乙胺（11.4克，0.013莫耳）溶於dmf -水（1 : 1， ν/ν，100毫升）之攪拌溶液中加入二碳酸二第三丁酯（^5 克，0 · 11 5莫耳）。使所產生之溶液在室溫下攪拌2小時。 將混合物以水（1 〇〇毫升）稀釋，並以Et〇Ac萃取。將萃取液 以鹽水洗滌，於NazS〇4上乾燥，並蒸發。使殘留物於矽膠 板上利用CC丨2作為洗提液進行層析，而得1 2克（6 8 %)之2 -第三丁氧羰胺基—2-甲基-1-丙酵的糖漿。 ^-NMR (CDClg) δ 1.25 (s, 6H) '1.43 (s, 9H) &gt;3.59 (d，J = 8· 3 Hz, 2H)、4. 68 (br，1H)。 在至；jdl下於2-第二丁氧幾胺基一 2-甲基—i —丙醇（5·7克， 30.11毫莫耳）及粉末狀NaOH(6· 7克，0.151莫耳）於Et20 (200宅升）中之授掉懸浮液中加入對甲苯石黃酿氣（6.9克， 3 6 · 1 4毫莫耳）。使所產生之攪拌混合物迴流加熱8小時。 於冷卻後，將冰水（1〇〇毫升）加至溶液中，利用正己烷研 製。收集固體而得8· 5克（82· 2%)之2-第三丁氧羰胺基—2-甲基-1 -丙基對甲笨磺酸酯的結晶物質。 UMR (CDC13)6 1·26 (s，6H)、1·38 (s，9H)、2·37 (s，3Η)、4·05 (s，2Η)、4·49 (br，1Η)、7·34 (d，280 at 2 to 10 -10 ° C in 2-amino-2-methyl-1-propanol (8.4 g, 93.89 mmol) and triethylamine (11.4 g, 0.013 mol) dissolved in dmf - To a stirred solution of water (1:1, ν/ν, 100 ml) was added dibutyl succinate (5 g, 0. 11 5 m). The resulting solution was stirred at room temperature for 2 hours. The mixture was diluted with water (1 mL) and extracted with EtOAc. The extract was washed with brine, dried over Naz EtOAc 4 and evaporated. The residue was chromatographed on a silica gel plate using CC丨2 as an eluent to obtain 12 g (68%) of 2-tert-butoxycarbonylamino-2-methyl-1-propanin. syrup. ^-NMR (CDClg) δ 1.25 (s, 6H) '1.43 (s, 9H) &gt; 3.59 (d, J = 8 · 3 Hz, 2H), 4. 68 (br, 1H). Under the condition; jdl under 2-second butoxyamino- 2-methyl-i-propanol (5·7 g, 30.11 mmol) and powdered NaOH (6.7 g, 0.151 m) Add p-toluene yellow gas (6.9 g, 3 6 · 1 4 mmol) to the suspended suspension in Et20 (200 liters). The resulting stirred mixture was heated under reflux for 8 hours. After cooling, ice water (1 ml) was added to the solution and the mixture was crystallized from n-hexane. The solid was collected to give 8.5 g (82. 2%) of a crystalline material of 2-t-butoxycarbonylamino-2-methyl-1 -propyl-p- succinate. UMR (CDC13)6 1·26 (s,6H),1·38 (s,9H), 2·37 (s,3Η), 4·05 (s,2Η), 4·49 (br,1Η), 7·34 (d,

89112968.ptd 第724頁 1283240 五、發明說明（720) J 三2τΊ78 (d，J = 7.8 Hz，2H)。 克，23. 88—毫/^ 5 甲基一1_丙基對甲苯續酸醋（8. 2 EM(2。。毫升f中耳i==〇H(6. U，◦.⑸莫耳)於 後，將混合物㈣二;V物迴流加熱10小時。於冷卻 乾焯，並Ϋ I 慮液以水、鹽水洗滌，於¥〇4上 d t ί:使殘留物於石夕膠上利用正己烧:[丄 第=丁 V ^洗提液進行層析，而得2.7克（66.2%)之卜 1二 基一甲基丙烯亞胺的油。 s, 9H).,5 克在ί ;)於：第二氧幾基基丙稀亞胺(U3 莫耳）、容7^ Λ 酸甲醋（800毫克，6. 26毫 (〇 12;毫：Λ ?:、升)之揽拌溶液中加入三I化硼乙趟 多攪拌3：：使所產生之溶液再在相同溫度下 ΐ ΓΛ 物以水、鹽水洗條，於W〇4上乾 v/v)^A^^^ ^ / 上利用正己烷：EtOAc(6:l， r?^13&quot;1·33 - --4^ssi-；3,6 y: .3 H:’ 2H)、3.9。（s’ 3H)、5。5 加，⑴、 •V ; ’ 2H)、7.97 (d，J = 8.8 Hz，2H)。 使4:(1-第三丁氧羰胺基_2_甲基_2_丙氧基）苯 (4M耄克，1· 42毫莫耳）及茴香醚（〇. 155毫升，i 42毫曰 耳）於CH2Cl2(15毫升）及TFA(3毫升）中之混合物在.室溫下授 \\312\2d-code\90-01\89112968.ptd 第725頁 1283240 五、發明說明（721) 拌3小時。將混合物蒸發掉。將殘留物溶解於CH2C12 (30毫 升），並經由添加〇· 5N NaOH使成為鹼性。將CH2C12層分 離，於Na2S04上乾燥，並蒸發。使殘留物於矽膠上利用 CHJl2作為洗提液進行層析，而得370毫克（100%) 4-(1-胺 基-2-甲基-2-丙氧基）苯甲酸曱酯的膠。 ^-NMR (CDC13) ά 1.34 (s, 6H) ^2.87 (s, 2H) &gt;3.90 (s，3H)、7·10 (d，j = 8.8 Hz, 2H)、7·97 (d，J = 8.8 Hz, 2H)。 在0°C下於4-(1-胺基一 2 一甲基一 2 一丙氧基）苯甲酸甲酯 (370毫克’1.66毫莫耳）及三乙胺（〇35毫升，2.49毫莫 耳）溶於Cljl 5毫升）之攪拌溶液中加入三氟乙酸酐 (0· 316宅升’ 2· 24毫莫耳）。於在相同溫度下攪拌1小時 後，將水加。至溶液中。將CH2Cl2層分離，以水洗滌，於 NazS〇4上乾燥’並蒸發。使殘留物於矽膠（2〇毫升）上利用 ci^ci2作為洗提液進行層析，而得53〇毫克（1〇〇%)4—(丨一三 氟乙醯胺斧-2-甲基丙氧基）苯甲酸甲酯的膠。將此化 合物進一步的純化而使用於後續的反應。 舻三氟乙醯胺基—2—甲基-2-丙㊄基)苯甲 文日 ^ ’丨· 66毫莫耳）及KC03 ( 345毫克，2· 49毫 莫耳）於DMF(10毫升）中夕牌扯、曰人仏3山是兄 ^ 斗9 9 7古苜i、 中之攪拌化合物中加入Me I ( 0 · 1 4毫 升，2.37¾莫耳）〇传％方 時。將混合物倒入至=產生*之混合物f室溫下攪拌18小 鹽水洗務，於Na2S04上^ 二卒取。將卒取液以 尤Π 4上乾燥，並蒸發。殘留物為膠，將苴 不經進-步的純化而使用於後續的反應。 將” _ ΙΙΗ \\312\2d-code\90-01\89112968.ptd 第726頁 1283240 五、發明說明（722) --- 將以上的粗製殘留物溶解於Me〇H( 10毫升）。於此授掉溶 液中加入加入水（5毫升）及NaCOJ 352毫克，3· 32毫莫耳/奋 ，並使所產生之混合物在室溫下攪拌5小時。將混合物倒 入至水中，並以CHCI3萃取。將萃取液以水洗滌，於 NaJO4上乾燥，並蒸發。使殘留物於矽膠上利用CHCi3作 洗提液進行層析，而得3 90毫克（1〇〇%)4〜（1_甲胺基—32—甲、 基_2-丙氧基）苯甲酸甲酯的膠。 UMR (CDC13)(5 1·37 (s，6H)、2.51 (s，3H)、3·89 (s，3Η)、6.92 (d，J = 8.8 Ηζ，2Η)、7·97 (d J = 8 889112968.ptd Page 724 1283240 V. INSTRUCTIONS (720) J 3 2τΊ78 (d, J = 7.8 Hz, 2H).克, 23. 88-mmol / ^ 5 methyl - 1 - propyl p-toluene acid vinegar (8.2 EM (2 ml. ft f middle ear i == 〇 H (6. U, ◦. (5) Moer After that, the mixture (4) is used; the V is heated under reflux for 10 hours. The mixture is cooled and dried, and the solution is washed with water and brine, and dt ί is used on the ¥4: the residue is used on the Shiji gum. Calcination: [丄第=丁V^Eluent was chromatographed to obtain 2.7 g (66.2%) of the oil of 1 bis-methacrylimine. s, 9H)., 5 g in ί ;) In: a second oxygen propylene amide (U3 Mo), a volume of 7 Λ acid vinegar (800 mg, 6. 26 mM (〇 12; 毫: Λ?:, liter) in the mixing solution Add 3 borax acetonide and stir 3:: The resulting solution is further washed at the same temperature with water, brine, and dried on W〇4)^A^^^^ / N-hexane: EtOAc (6:1, r?^13&quot;1·33 - -4^ssi-; 3,6 y: .3 H: ' 2H), 3.9. (s' 3H), 5. 5 plus, (1), • V; ' 2H), 7.97 (d, J = 8.8 Hz, 2H). 4: (1-tert-butoxycarbonylamino-2-phenyl-2-propoxy)benzene (4M gram, 1.42 mmol) and anisole (〇. 155 ml, i 42 m Mixture of CH2Cl2 (15 ml) and TFA (3 ml) at room temperature under \\312\2d-code\90-01\89112968.ptd Page 725 1283240 V. Description of invention (721) Mix for 3 hours. The mixture was evaporated off. The residue was dissolved in CH2C12 (30 mL) and made basic by the addition of 〇·5N NaOH. The CH2C12 layer was separated, dried over Na2SO4 and evaporated. The residue was chromatographed on silica gel eluting with CHJl2 as eluent to give 370 mg (100%) of the ethyl ester of 4-(1-amino-2-methyl-2-propoxy)benzoate. ^-NMR (CDC13) ά 1.34 (s, 6H) ^2.87 (s, 2H) &gt;3.90 (s,3H), 7·10 (d,j = 8.8 Hz, 2H), 7·97 (d, J = 8.8 Hz, 2H). Methyl 4-(1-amino-2-methyl-2-bromo)benzoate (370 mg '1.66 mmol) and triethylamine (〇35 ml, 2.49 mmol) at 0 °C Trifluoroacetic anhydride (0· 316 liter '2·24 mmol) was added to the stirred solution of the ear (dissolved in Cljl 5 ml). After stirring at the same temperature for 1 hour, water was added. Into the solution. The CH 2 Cl 2 layer was separated, washed with water, dried over Naz EtOAc 4 and evaporated. The residue was chromatographed on silica gel (2 mL) using ci^ci2 as eluent to give 53 mg (1%) of 4-(丨-trifluoroacetamidamine-2-methyl A gel of methyl propionate). This compound was further purified for use in subsequent reactions.舻Trifluoroacetamido-2-methyl-2-propenyl) benzoic acid ^ '丨 · 66 millimoles) and KC03 (345 mg, 2. 49 millimoles) in DMF (10 ml) ) 中夕牌扯,曰人仏3山 is the brother ^ 斗9 9 7 古苜i, in the stirring compound added Me I (0 · 1 4 ml, 2.373⁄4 mol) 〇 % %. The mixture was poured into a mixture of = and * was stirred at room temperature for 18 hours with brine, and taken on Na2S04. The stroke fluid was dried on AU 4 and evaporated. The residue is a gum which is used in subsequent reactions without further purification. " _ ΙΙΗ \\312\2d-code\90-01\89112968.ptd Page 726 1283240 V. INSTRUCTIONS (722) --- Dissolve the above crude residue in Me〇H (10 ml). To the solution was added water (5 ml) and NaCOJ 352 mg, 3·32 mmol/h, and the resulting mixture was stirred at room temperature for 5 hours. The mixture was poured into water and CHCI3 The extract was washed with water, dried on NaJO4, and evaporated. The residue was chromatographed on CH.sub.2 using CHCi3 as eluent to give 3 90 mg (1%) 4~(1_A Amine-methyl-32-methyl-2-ylpropoxy)benzoate. UMR (CDC13) (5 1·37 (s, 6H), 2.51 (s, 3H), 3.89 (s, 3Η), 6.92 (d, J = 8.8 Ηζ, 2Η), 7.97 (d J = 8 8

Hz， 2H) 。 ’ · 在環境溫度下於4-( 1-甲胺基一2-甲基一2-丙氧基）苯曱酸 甲酯（2 0 0毫克，〇.84毫莫耳）、4一[『一（2-氟苯基）脲基卜 3-甲氧苯基乙酸（2 68毫克，〇·84毫莫耳）、4 — DMAp (125毫 克，1三〇耄莫耳）於DMF(5毫升）中之攪拌混合物中加入EDc ( 220毫克，1· 14毫莫耳）。使所產生之混合物再在環境溫 度下多授拌1 〇小時。將混合物倒入至水中，並以Et〇Ac萃 取。將萃取液以鹽水洗•，於Ν_4上乾燥，並蒸發。利 用CH2Cl2&amp;EtO將殘留物研製而得2〇〇毫克（44· 1%) 4一 [[卜 [4-[Ν’ -（2-氟苯基）脲基卜3—甲氧苯基]甲胺基]一2一甲基 -丙氧基]苯甲酸甲酯的結晶物質。 &gt;H-NMR (CDCI3). 1.36Λ1.31 '(^s, 6H) . 3.24-3.88 (s 系列，13H)、6. 65-8. 20 (m 系列，14H)。 使4-[[l-[4-[N -(2-氟笨基）脲基]_3_甲氧苯基乙醯 基]甲胺基]-2-甲基-2-丙氧基]苯曱酸甲酯（18〇毫克，Hz, 2H). ' · 4-(1-Methylamino- 2-methyl- 2-propoxy)benzoic acid methyl ester (200 mg, 〇.84 mmol) at ambient temperature, 4 [[ 1-(2-Fluorophenyl)ureido-3-methoxyphenylacetic acid (2 68 mg, 〇·84 mmol), 4 —DMAp (125 mg, 1 Torr) in DMF (5 ml) EDC (220 mg, 1.44 mmol) was added to the stirred mixture. The resulting mixture was mixed for an additional 1 hour at ambient temperature. The mixture was poured into water and extracted with Et 〇Ac. The extract was washed with brine, dried over Ν4, and evaporated. The residue was triturated with CH2Cl2 & EtO to give 2 mg (44·1%) 4[[Bu [4-[Ν' -(2-fluorophenyl)ureido) 3-methoxyphenyl] A crystalline material of methylamino]methyl-2-methyl-propoxy]benzoate. &gt;H-NMR (CDCI3). 1.36Λ1.31 '(^s, 6H) . 3.24-3.88 (s series, 13H), 6. 65-8. 20 (m series, 14H). 4-[[l-[4-[N-(2-Fluorophenyl)ureido]_3-methoxyphenylethenyl]methylamino]-2-methyl-2-propoxy]benzene Methyl decanoate (18 〇 mg,

1283240 五、發明說明（723) 〇· 335毫莫耳）於THF(3毫升）及0· 25N Na0H(4毫升）中之混 合物在室溫下攪拌4小時。將混合物倒入至冰的1 n HC1 ( 5 晕升）中。收集固體，以水洗滌，並風乾。使粗製固體自 EtOH-CHC13-正己烷再結晶，而得70毫克（40%)之4-[[；1 -[4 - [Ν’ -（2-氟苯基）脲基]—3—甲氧苯基乙醯基]甲胺基一2一 甲基-2 -丙氧基]苯曱酸2 80的微細針狀物。 溶點 20 0-7 (DMS0-d6) 6 1.26 及 1.33 (各s， 6H)、3. 70-3. 81 (s 系列，7H)、3· 8 3 (s，3H)、6· 75-8· 20 (m 系列，1 〇H)、8. 71 (s， 1H)、9· 17 (br s， 1H)、 12. 72 (s，1H)。 實施例2 3 0 (S) -3-氯-4-[2-[3 -甲氧基-4-[N，-（2-氟苯基）脲基]苯基 乙醯胺基]-1-丙氧基]苯甲酸A mixture of THF (3 ml) and 0.25N NaH (4 mL) Pour the mixture into 1 n HC1 (5 halo) of ice. The solid was collected, washed with water and air dried. The crude solid was recrystallized from EtOH-CHC13-n-hexane to give 70 mg (40%) of 4-[[(1 -[4 - [Ν]-(2-fluorophenyl)ureido]-3. A fine needle of oxyphenylethyl hydrazide]methylamino-2-methyl-2-propoxy]benzoic acid 2 80. Melting point 20 0-7 (DMS0-d6) 6 1.26 and 1.33 (each s, 6H), 3. 70-3. 81 (s series, 7H), 3· 8 3 (s, 3H), 6· 75- 8· 20 (m series, 1 〇H), 8.71 (s, 1H), 9·17 (br s, 1H), 12. 72 (s, 1H). Example 2 3 0 (S) -3-chloro-4-[2-[3-methoxy-4-[N,-(2-fluorophenyl)ureido]phenylethenylamino]-1 -propoxy]benzoic acid

使3-甲氧基-[4-[Ν’-（2-氟苯基）脲基]苯乙酸（327毫 克’1·〇3毫莫耳）、（s)-3-氯-4-(2 -胺基-1-丙氧基）苯曱 酸甲醋（ 250毫克，1· 〇3毫莫耳）、EDC(氫氯酸鹽）（2 9 5毫 克’1.54毫莫耳）、HOBt(208毫克，1.54莫耳）、及DMAP (25¾克’ 0.20¾莫耳）於dmf(8毫升）中之混合物在室溫下 棍拌隔夜。將混合物以E10 A c稀釋，以-· n n H C 1、鹽水洗 條’於Na2S04上乾燥，並蒸發。使殘留物自CHCl3 —Et〇Ac再 結晶，而得3 0 8毫克（5 5 % )之白色結晶粉末。3-methoxy-[4-[Ν'-(2-fluorophenyl)ureido]phenylacetic acid (327 mg '1·〇3 mmol), (s)-3-chloro-4-( 2-Amino-1-propoxy)benzoic acid methyl vinegar (250 mg, 1·〇3 mmol), EDC (hydrochloride) (29.5 mg '1.54 mmol), HOBt ( A mixture of 208 mg, 1.54 moles, and DMAP (253⁄4 g '0.203⁄4 mol) in dmf (8 ml) was stirred overnight at room temperature. The mixture was diluted with E10 A c, dried over Na 2 SO 4 with &lt;RTI ID=0.0&gt; The residue was recrystallized from CHCl3-Et?Ac to give 308 mg (55%) of white crystalline powder.

W3l2\2d-code\90-01\89112968.ptd 第728頁 1283240 五、發明說明（724) JH-NMR (CDCI3) 5 1.29 (d, 3 H, J-6. 8 Hz) ^3.51 (s, 2H)、3·84 (s，3H)、3.88 (s，3H)、4·(Η - 4.08 (m， 2H) 、4·38-4·39 (m， 1H) 、6·25 (d, 1H， J二8.3 Hz)、 6.78-6.83 (m, 2H) &gt;6.90-6.95 (m, 2H) &gt;7.02-7.11 (m, 2H)、7·89 ( dd，1 H，J = 2 · 0、8 · 8 Hz )、8 · 0 2 (d， 1H，J = 2.4 Hz)、8.20 (d，1H，J = 8.3 Hz)、8·27-8.31 (m， 1H) 、 8· 53 (s， 1H) 、 8.84 (s， 1H)。 於（S)-3-氣-4-[2 - [4 - [甲氧基-4 - [Ν’ - (2-氟苯基）脲基] 苯基乙醯胺基]-1-丙氧基]苯甲酸曱S旨（308毫克，0.57毫 莫耳）溶於THF-MeOH(10毫升，1 : 1，v/v)之溶液中加入 0 1 5 N N a Ο Η (1 0毫升），並使反應混合物迴流加熱1小時。將 混合物倒入至冰的1 N H C 1中，並收集固體。使粗製固體經 由自MeOH-CHC13 -正己烷再結晶，純化而得196毫克（65%) (S)-3-氯-4-[2-[ 4-[甲氧基-4-[Ν’ -(2-氟苯基）脲基]苯 基乙醯胺基]-卜丙氧基]苯甲酸2 8 1的白色結晶粉末。 熔點 188-ΗΙΤ：;1!!-NMR (DMS0-d6)6 1.21 (d， 3Η， J = 6.4 Hz)、3·38 (s，2H)、3·83 (s，3H)、4·02-4·18 (m， 3H)、6· 78 - 7· 29 (m 系列，總計 6 Η)、7 · 8 5 - 8 · 0 0 ( m， 3 Η) 、8·12-8.19 (m，2Η)、8·70 (s，1Η)、9·17 (s，1Η)、 12. 98 (bs，1H) ; MS(FAB) m/z 5 30 (M+)、531(MH1)、532 (MH2) ; C26H25C1FN3 06 · 1/4H20 之分析計算值：C， 58.4 3 ； H, 4.81； Cl , 6.63； F, 3. 55 ; N，7. 86 ° 實測值：C， 58. 45 ； H, 4. 83 ； Cl, 6.68； F, 3. 38 ； N, 7.79° 實施例231W3l2\2d-code\90-01\89112968.ptd Page 728 1283240 V. Description of invention (724) JH-NMR (CDCI3) 5 1.29 (d, 3 H, J-6. 8 Hz) ^3.51 (s, 2H), 3·84 (s, 3H), 3.88 (s, 3H), 4·(Η - 4.08 (m, 2H), 4·38-4·39 (m, 1H), 6·25 (d, 1H, J 8.3 Hz), 6.78-6.83 (m, 2H) &gt; 6.90-6.95 (m, 2H) &gt; 7.02-7.11 (m, 2H), 7·89 ( dd, 1 H, J = 2 · 0,8 · 8 Hz ), 8 · 0 2 (d, 1H, J = 2.4 Hz), 8.20 (d, 1H, J = 8.3 Hz), 8.27-8.31 (m, 1H), 8· 53 ( s, 1H), 8.84 (s, 1H). (S)-3-Gas-4-[2 - [4- [Methoxy-4] [Ν'-(2-fluorophenyl)ureido] Phenylethylamino-1-phenyloxy]benzoate 曱S (308 mg, 0.57 mmol) was dissolved in THF-MeOH (10 mL, 1:1 v/v) 1 5 NN a Ο Η (10 ml), and the reaction mixture was heated under reflux for 1 h. The mixture was poured into iced 1 NHC 1 and solid was collected. The crude solid was recrystallized from MeOH-CHC13-hexane. Purified to give 196 mg (65%) (S)-3-chloro-4-[2-[4-[methoxy-4-[Ν'-(2-fluorophenyl)ureido]phenyl醯White crystalline powder of benzylidene-benzoic acid benzoic acid. mp 188-ΗΙΤ:;1!!-NMR (DMS0-d6)6 1.21 (d, 3 Η, J = 6.4 Hz), 3.38 (s, 2H), 3·83 (s, 3H), 4·02-4·18 (m, 3H), 6·78 - 7· 29 (m series, total 6 Η), 7 · 8 5 - 8 · 0 0 ( m, 3 Η) , 8·12-8.19 (m, 2Η), 8·70 (s, 1Η), 9·17 (s, 1Η), 12. 98 (bs, 1H); MS ( FAB) m/z 5 30 (M+), 531 (MH1), 532 (MH2); C26H25C1FN3 06 · 1/4H20 Analysis calculated: C, 58.4 3 ; H, 4.81; Cl, 6.63; F, 3. 55 ; N, 7. 86 ° Found: C, 58.45; H, 4. 83; Cl, 6.68; F, 3. 38; N, 7.79° Example 231

\\312\2d-code\90-01\89112968.ptd 第729頁 1283240 五、發明說明（725) &quot;一&quot; 4-[[2-[3-甲氧基—4 - [Ν’ - (2 -甲基苯基）脲基]苯基乙醯基] 甲胺基]苯甲酸\\312\2d-code\90-01\89112968.ptd Page 729 1283240 V. Description of invention (725) &quot;One&quot; 4-[[2-[3-methoxy-4 - [Ν' - (2-methylphenyl)ureido]phenylethenyl]methylamino]benzoic acid

將Ν-卞氧幾基一 Ν-甲胺基乙_(1·77克，ΐ·ι毫莫耳）溶於 甲苯（3毫升）之攪拌溶液加入4-胺基苯甲酸甲酯（1·29克， 8· 5毫莫耳），並使混合物在室溫下攪拌1小時。將反應混 合物於減壓下蒸發，並將殘留物溶解於MeCNd 5毫升）中。 於溶液中加入Ac0(2.44毫升，43毫莫耳）及NaBH3CN(2.67 克’ 4 3毫莫耳），並使所產生之混合物在室溫下授拌1 5小 時。經由加入飽和NaHC03使反應停止。將混合物以£ t〇Ac 萃取，以鹽水洗滌，於MgS04上乾燥，並蒸發。將殘留物 於石夕膠上利用正己烧：Et0Ac(7:l，v/v)作為洗提液進行 層析，而得1.26克（43%)之4 - [2-[(N-窄氧羰基-N-甲胺基） 乙胺基]苯甲S复甲酯的無色油。 'H-NMR (CDC13 5 40 0MHz) 5 2.96 (s, 3H) &gt;3.32 (br m, 2H)、3·50-3·60 (m，2H)、3·82 (s，3H)、5·15 (各d， 2H，J=14.6 Hz)、6·35 及 6.58 (m，總計 2H)、7·36 (s， 5Η)、7·76 及 7·84 (m，總計 2H); MS(FAB) m/z 342 (Μ+ + 1)。 於4 - [2-[(Ν-苄氧羰基-Ν-曱胺基）乙胺基]苯曱酸曱酯 (1· 26克，3. 68毫莫耳）溶於MeOH(20毫升）之攪拌溶液中加 入5重量百分比Pd-C( 70 0毫克），並使混合物在室溫下氫化Add 4-aminobenzoic acid methyl ester (1···················································································· 29 g, 8.5 mmol, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was evaporated under reduced pressure. Ac0 (2.44 ml, 43 mmol) and NaBH3CN (2.67 g &lt; 4 3 mmol) were added to the solution, and the resulting mixture was stirred at room temperature for 15 hours. The reaction was stopped by the addition of saturated NaHC03. The mixture was extracted with EtOAc (br.), washed with brine, dried over EtOAc and evaporated. The residue was chromatographed on the Shiqi gum using Et0Ac (7:1, v/v) as the eluent to obtain 1.26 g (43%) of 4-[2-[(N-narrow oxygen). A colorless oil of carbonyl-N-methylamino)ethylamino]benzoic acid. 'H-NMR (CDC13 5 40 0MHz) 5 2.96 (s, 3H) &gt;3.32 (br m, 2H), 3·50-3·60 (m, 2H), 3·82 (s, 3H), 5 · 15 (each d, 2H, J = 14.6 Hz), 6.35 and 6.58 (m, total 2H), 7·36 (s, 5Η), 7.76 and 7.84 (m, total 2H); MS (FAB) m/z 342 (Μ+ + 1). 4-[2-[(Ν-Benzyloxycarbonyl-indole-nonylamino)ethylamino]benzoic acid decyl ester (1·26 g, 3.68 mmol) dissolved in MeOH (20 mL) 5 parts by weight of Pd-C (70 mg) was added to the stirred solution, and the mixture was hydrogenated at room temperature.

\\312\2d-code\90-01\89112968.ptd 第730頁 1283240 五、發明說明（726) (3大氣壓）4小時。將混合物過濾，並將濾液於減壓下蒸 發，而得600毫克（78%)4-[2 - [(N-甲胺基）乙胺基]苯曱酸 甲酯的無色油。 1-NMR (CDC13，400MHz) 6 2. 46 (s，3H)、2· 88 (t，2H， J = 5.5 Hz)、3·27 (br s，2H)、3·85 (s，3H)、6.57 (d， 2H, J = 8.8 Hz) ^7.85 (d, 2H, J = 8.8 Hz)； MS(FAB) m/z 209 (MH1)。 於4-[ 2-(N-甲胺基）乙胺基]苯甲酸乙酯（590毫克，2.83 毫莫耳）、3-曱氧基-4-[Ν’ -（2-甲基苯基）脲基]苯乙酸 (891毫克，2.83毫莫耳）溶於DMF(1 4毫升）之攪拌溶液中加 入EDC(815毫克，4.25毫莫耳）、HOBt( 574毫克，4.25毫莫 耳）、及4-DAMPC519毫克，4· 25毫莫耳），並使所產生之混 合物在室溫下攪拌隔夜。將混合物倒入至1 N HC1中，並利 用吸濾收集固體。使粗製固體經由於矽膠（中壓）上利用 CHC13- EtOAc(10:0至7:3，v/v)作為洗提液進行層析，純 化而得1· 25克（87%)之4 - [[2 - [3-曱氧基-4- [Ν’ -（2-甲基苯 基）脲基]苯基乙醯基]甲胺基]乙胺基]苯曱酸曱酯的淡黃 色油。 UMR (CDC13，400ΜΗζ)(5 3.18 (s，2Η)、3.05 及 3·32 (s，總計 2Η)、3·72-3·85 (m，9Η)、4·12 及 4·23 (m，總計 2H)、6·78 (m，3H)、7·05 (t，1H，J = 7.5 Hz)、7.20 (m，2H)、7·43-7·50 (ra，3H)、7·62 (d，1H，J = 8.8 Hz)、8·05 (d，1H，J = 8.8 Hz); MS(FAB) m/z 50 5 (MH1)。\\312\2d-code\90-01\89112968.ptd Page 730 1283240 V. Description of invention (726) (3 atmospheres) for 4 hours. The mixture was filtered, and the filtrate was evaporated, evaporated, mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 1-NMR (CDC13, 400MHz) 6 2. 46 (s, 3H), 2·88 (t, 2H, J = 5.5 Hz), 3·27 (br s, 2H), 3·85 (s, 3H) , 6.57 (d, 2H, J = 8.8 Hz) ^7.85 (d, 2H, J = 8.8 Hz); MS(FAB) m/z 209 (MH1). Ethyl 4-[2-(N-methylamino)ethylamino]benzoate (590 mg, 2.83 mmol), 3-methoxy-4-[Ν'-(2-methylphenyl) Ethyl phenylacetic acid (891 mg, 2.83 mmol) dissolved in DMF (14 ml) was added EDC (815 mg, 4.25 mmol), HOBt (574 mg, 4.25 mmol), And 4-DAMPC 519 mg, 4.6 mmol, and the resulting mixture was stirred overnight at room temperature. The mixture was poured into 1 N HCl and the solid was collected by suction filtration. The crude solid was chromatographed on a silica gel (medium pressure) using CHC13-EtOAc (10:0 to 7:3, v/v) as eluent, and purified to give 1.25 g (87%) of 4 - [[2 - [3-methoxy-4-[Ν'-(2-methylphenyl)ureido]phenylethenyl]methylamino]ethylamino]benzoic acid decyl acetate oil. UMR (CDC13, 400ΜΗζ) (5 3.18 (s, 2Η), 3.05 and 3.32 (s, total 2Η), 3·72-3·85 (m, 9Η), 4·12 and 4·23 (m, Total 2H), 6·78 (m, 3H), 7·05 (t, 1H, J = 7.5 Hz), 7.20 (m, 2H), 7·43-7·50 (ra, 3H), 7.62 (d, 1H, J = 8.8 Hz), 8.05 (d, 1H, J = 8.8 Hz); MS (FAB) m/z 50 5 (MH1).

89112968.ptd 第731頁 1283240 五、發明說明（727) 使4-[[2 - [3-甲氧基-4 - [N，-(2 -甲基苯基）脲基]苯基乙 醯基]甲胺基]乙胺基]笨甲酸甲酯（300毫克，0.6毫莫耳） 於0· 25N NaOH(6毫升）及THF(6毫升）中之攪拌混合物迴流 加熱8小時。將混合物倒入至水中，並利用1N H C1酸化。 利用吸濾收集固體。使粗製固體自正己烷-二異丙醚再結 晶，而得20 2毫克（69%)之4-[[2 - [4-甲氧基-4-[Ν，-(2-甲 基苯基）脲基]苯基乙醯基]甲胺基]乙胺基]苯甲酸2 82的 淡黃色結晶粉末。 熔點 115-120 °C; IR (KBr) 3346、2935、1603、1531、 1 454、1417、1 2 57、1174、1 0 3 6、7 54 / 公分；NMR (CD3OD，4 00MHz) 6 2· 28 (s，3H)、2· 98 (s，1H)、3· 10 (s，2H)、3·35-3.42 (m，2H)、3·53-3·65 (m，3H)、 3.70 (s，1H)、3·80 及 3·82 (s, 3H)、6·60-6·85 (m， 4H)、7·02 (m, 1H)、7·18 (m，2H)、7·58 (m，1H)、 7.82 (m, 2H) &gt;7.96 (m, 1H)； MS(FAB) m/z 491(MH1) 實施例232 (S) -3-氯-4-[2 - [[N-甲基-N - [3- 甲氧基—4一 [n，- (2-氟苯 基）脈基]本基乙酿基]胺基]-1-丙氧基]苯曱酸89112968.ptd Page 731 1283240 V. INSTRUCTIONS (727) Making 4-[[2-[3-methoxy-4 - [N,-(2-methylphenyl)ureido]phenylethyl) Methylamino]ethylamino] benzoic acid methyl ester (300 mg, 0.6 mmol) was stirred and heated under reflux for 8 hours in EtOAc (EtOAc) (EtOAc) The mixture was poured into water and acidified with 1N H C1. The solid was collected by suction filtration. The crude solid was recrystallized from n-hexane-diisopropyl ether to give 20 2 mg (yield: 69%) of 4-[[2-[4-[ A pale yellow crystalline powder of ureido]phenylethenyl]methylamino]ethylamino]benzoic acid 2 82 . Mp 115-120 ° C; IR (KBr) 3346, 2935, 1603, 1531, 1 454, 1417, 1 2 57, 1174, 1 0 3 6 , 7 54 / cm; NMR (CD3OD, 4 00MHz) 6 2· 28 (s, 3H), 2· 98 (s, 1H), 3· 10 (s, 2H), 3·35-3.42 (m, 2H), 3·53-3·65 (m, 3H), 3.70 (s, 1H), 3·80 and 3.82 (s, 3H), 6·60-6·85 (m, 4H), 7·02 (m, 1H), 7·18 (m, 2H), 7·58 (m, 1H), 7.82 (m, 2H) &gt; 7.96 (m, 1H); MS (FAB) m/z 491 (MH1) Example 232 (S) -3-chloro-4-[2 - [[N-Methyl-N-[3-methoxy-4-iso[n,-(2-fluorophenyl))yl]]-ylethyl]amino]-1-propoxy]benzene Tannic acid

283 於（S)-3-氯-4-（2-胺基-1-丙氧基）苯甲酸曱酯〇· 74 克，7.14毫莫耳）溶於〇112(：12(20亳升）之冷卻（〇。(：：）溶液中 加入Εΐ3Ν(1·19毫升，8.54毫莫耳）及三氟乙酸酐（71?八八）283 (S)-3-chloro-4-(2-amido-1-propoxy)benzoate oxime 〇· 74 g, 7.14 mmoles) dissolved in 〇112 (:12 (20 liters) Cooling (〇.(::) solution was added with Εΐ3Ν (1·19 ml, 8.54 mmol) and trifluoroacetic anhydride (71? 88)

\\312\2d-code\90-01\89112968.ptd 第732頁 1283240 五、發明說明（728) (1 · 1 1毫升，7 · 8 6毫莫耳），並使反應混合物在相同溫度下 攪拌隔夜。將混合物以CHC13稀釋，以〇· 5N HC1、鹽水洗 滌，於Na2S04上乾燥，並蒸發。使殘留物自CHC13 -正己烷 再結晶’而得1.59克（66%)(S)-3 -氯_4_(2 -三氟乙醯胺基 -1 -丙氧基）苯甲酸酯的白色結晶物質。 熔點 1 2 2- 1 25 1:1-NMR (CDC13)5 1·48 (d，3H，J = 6.8 Hz)、3·91 (s, 3H)、4·10-4·19 (m, 2H)、4·47-4·52 (m，lH)、6.68(bs，lH)、6.92 -6.94 (m，lH)、7.93-7· 95 (m，1H)、8. 0 7-8· 08 (m，1H) ; MS(FAB) m/z 34 0 (M+ + 1) ; C13H13C1F3N04 之分析計算值：C，45. 96 ; H， 3·86; Cl，10.44; F，16·78; N，4.12。實測值：c， 45.88; H，3.97; Cl，1(K24;F，16·72; N，4.18。 於（S)-3-氣-4-( 2-三氟乙醯胺基一丨-丙氧基）笨甲酸曱酯 (800毫克，2.36毫莫耳）溶於DMF (5毫升）之攪拌溶液中加 AK2C03 ( 65 1 毫莫耳，4.71 毫莫耳）及 μ6ι(〇·22 毫升，3.53 笔莫耳），並使反應混合物在6 〇 X；下攪拌隔夜。將混合物 以EtOAc稀釋，以〇·5Ν HC1、鹽水洗滌，於Na2S〇4上乾燥， 並蒸發。使殘留物經由於矽膠上利用5% Et〇Ac溶於CHCl3 作為洗提液進行管柱層析，純化而得85〇毫克（1 〇〇%) (S)-3-氯-4-[2-[(N-甲基-N-三氟乙醯胺基）」一丙氧基]苯 甲酸甲酯的無色油。\\312\2d-code\90-01\89112968.ptd Page 732 1283240 V. Description of invention (728) (1 · 1 1 ml, 7 · 8 6 mmol) and subject the reaction mixture to the same temperature Stir overnight. The mixture was diluted with CH.sub.3, washed with EtOAc EtOAc EtOAc. The residue was recrystallized from CHC13-n-hexane to give a white color of 1.59 g (66%) of (S)-3-chloro-4-4(2-trifluoroethylamino-1-propoxy)benzoate. Crystalline material. Melting point 1 2 2- 1 25 1:1-NMR (CDC13) 5 1·48 (d, 3H, J = 6.8 Hz), 3·91 (s, 3H), 4·10-4·19 (m, 2H ), 4·47-4·52 (m, lH), 6.68 (bs, lH), 6.92 - 6.94 (m, lH), 7.93-7·95 (m, 1H), 8. 0 7-8· 08 (m,1H); MS (FAB) m/z 34 0 (M+ + 1); C13H13C1F3N04: C, 45.96; H, 3·86; Cl, 10.44; F,16·78; , 4.12. Found: c, 45.88; H, 3.97; Cl, 1 (K24; F, 16.72; N, 4.18. (S)-3- gas-4-(2-trifluoroethylamino)- Add AK2C03 (65 1 mmol, 4.71 mmol) and μ6 ((22 ml) to a stirred solution of propionate formate (800 mg, 2.36 mmol) in DMF (5 mL). 3.53 </ RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> The column was chromatographed with 5% Et〇Ac dissolved in CHCl3 as an eluent, and purified to obtain 85 mg (1%) (S)-3-chloro-4-[2-[(N-A) A colorless oil of methyl-N-trifluoroethylamino)-propyl-propoxy]benzoate.

1283240 五、發明說明（729) J = 2.0、8·3 Hz)、8.06 (d，1H，J = 2.0 Hz)。 於（S) -3-氣-4-[2- [(N-曱基-N -三氟乙醯胺基）一1 一丙氧 基]苯甲酸甲酯（880毫克，2.49毫莫耳）溶於Me〇H-H20 (10 毫升，1 ·· 1，v/v)之攪拌溶液中加入KC03 ( 526毫克，3. 73 毫莫耳），並使所產生之混合物在室溫下攪拌隔夜。將混 合物以EtOAc稀釋，以、鹽水洗滌，於υ〇4上乾燥， 並蒸發而得4 6 0毫克（72%) (S)-3-氯-4-(2-甲胺基-1-丙氧 基）苯甲酸酯的無色油。 !H-NMR (CDC13) (5 1.20 (d, 3H, J = 6. 4 Hz) ^2.51 (s, 3H) 、3·07-3.12 (m, 1H) 、3.89 (s， 3H) 、3·92-4·04 (m，2H)、6·93 - 6·95 (m，1H)、7·9 0 - 7.93 (m，1H)、 8· 0 5-8. 0 6 (m，1H)。 使3-甲氧基-4-[Ν’-（2 -氟苯基）脲基]苯基乙酸（296毫 克’0.3毫莫耳）、（S)-3-氯-4 -（2-甲胺基-1-丙氧基）苯甲 酸甲酯（240毫克，〇· 93毫莫耳）、EDC(氫氯酸鹽）（ 2 69毫 克，1· 40毫莫耳）、HOBt (189毫克，1·40毫莫耳）、及DMAP (23毫克，0.19毫莫耳）於DMF (8毫升）中之混合物在室溫下 授拌1 · 5小時。將混合物以E 10 A c稀釋，以〇 · 5 N H C1、鹽水 洗條’於N S 〇4上乾燥’並蒸發。使殘留物經由於石夕膠上 利用5% MeOH溶於CHC13作為洗提液進行管柱層析，純化而 得 520 毫克（100 % )(S)-3-氯-4 - [2 - N-曱基-N-]3- 甲氧基 -4-[N’ - (2-氟苯基）脲基]苯基乙醯基]胺基]—1—丙氧基]苯 甲酸甲酯的紅棕色非晶形固體。 於此產物（520毫克，〇·93毫莫耳）溶於DMF(l〇毫升）之攪1283240 V. Description of invention (729) J = 2.0, 8·3 Hz), 8.06 (d, 1H, J = 2.0 Hz). Methyl (S)-3-ox-4-[2-[(N-fluorenyl-N-trifluoroacetamido)-l-propoxy]benzoate (880 mg, 2.49 mmol) KC03 (526 mg, 3.73 mmol) was added to a stirred solution of Me〇H-H20 (10 ml, 1 ··1, v/v), and the resulting mixture was stirred overnight at room temperature. . The mixture was diluted with EtOAc, washed with EtOAc EtOAc EtOAc EtOAcjjjjjjjjjjjjjjjj A colorless oil of oxy)benzoate. !H-NMR (CDC13) (5 1.20 (d, 3H, J = 6. 4 Hz) ^2.51 (s, 3H), 3·07-3.12 (m, 1H), 3.89 (s, 3H), 3· 92-4·04 (m, 2H), 6.93 - 6·95 (m, 1H), 7·9 0 - 7.93 (m, 1H), 8· 0 5-8. 0 6 (m, 1H) 3-methoxy-4-[Ν'-(2-fluorophenyl)ureido]phenylacetic acid (296 mg '0.3 mmol), (S)-3-chloro-4 -(2- Methylamino-1-propoxy)benzoate (240 mg, 〇·93 mmol), EDC (hydrochloride) (2 69 mg, 1400 mmol), HOBt (189 mg) , a mixture of DMAP (23 mg, 0.19 mmol) in DMF (8 mL) was stirred at room temperature for 1.5 hours. The mixture was diluted with E 10 A c to NH· 5 NH C1, brine wash strip 'dryed on NS 〇 4' and evaporated. The residue was purified by column chromatography using 5% MeOH in CHC13 as an eluent. Mg (100%) (S)-3-chloro-4 - [2-N-indolyl-N-]3-methoxy-4-[N'-(2-fluorophenyl)ureido]phenyl a reddish brown amorphous solid of methylamino]amino]-1-propoxy]benzoate. (520 mg, 0.93 mmol square) was dissolved in DMF (l〇 ml) was stirred

\\312\2d-code\90-01\89112968.ptd 第734頁 1283240 五、發明說明（730) 拌溶液中加入0.5N NaOH(l〇毫升），並使所產生之混合物 迴流加熱3小時。將混合物倒入至冰的1 N HC 1中，並收集 固體。使粗製固體自CHC13-Et20再結晶，而得170毫克（2步 驟3 7%)之（S)-3-氯-4-[2- [N-甲基-N-[ 3-曱氧基-4-[Ν’ -（2-氟苯基）脲基]苯基乙醯基]胺基]-卜丙氧基]苯甲酸 2 8 3的白色結晶粉末。 熔點 142-(DMS0-d6)(5 1.13-1.20 (m, 3Η) 、2·74 及 2.94 (s，3H)、3·65 (s，2H)、3·82 及 3·84 (s， 3 Η)、4 · 1 3 - 4 · 2 2 (m，2 Η )、4 · 5 3 及 4 · 9 1 - 4 · 9 2 ( m，1 Η )、 6·7 卜 7.29 (m 系列，總計 6Η)、7·86 - 8·02 (m，3Η)、 8·15-8·19 (m，1H)、8·71 (s，1H)、9·17 (s，1H)、 13· 00 (bs，1H) ; MS(FAB) m/z 544 (M+)、54 5(M+ + 1); C27H27C1FN3 06 · 1/4H20 之分析計算值：C，59.13； H, 5. 05 ;Cl，6· 46 ; F， 3. 46 ; N， 7· 66。實測值：C， 59. 19 ; H， 4· 99 ; Cl, 6. 64 ; F, 3. 23 ; N，7·55。 實施例2 3 3 (S)-3-氯-4-[2-[N-甲基-N- [3-曱氧基-4-[Ν’ -（2- 甲基苯 基）脲基]苯基乙醯基]胺基卜卜丙氧基]苯曱酸\\312\2d-code\90-01\89112968.ptd Page 734 1283240 V. INSTRUCTIONS (730) 0.5N NaOH (10 ml) was added to the mixed solution, and the resulting mixture was heated under reflux for 3 hours. The mixture was poured into 1 N HCl 1 of ice and a solid was collected. The crude solid was recrystallized from CHC13-Et20 to give &lt;RTI ID=0.0&gt;&gt; A white crystalline powder of 4-[Ν'-(2-fluorophenyl)ureido]phenylethenyl]amino]-p-propoxy]benzoic acid 283. Melting point 142-(DMS0-d6) (5 1.13-1.20 (m, 3Η), 2.74 and 2.94 (s, 3H), 3·65 (s, 2H), 3·82 and 3.84 (s, 3 Η), 4 · 1 3 - 4 · 2 2 (m, 2 Η ), 4 · 5 3 and 4 · 9 1 - 4 · 9 2 ( m,1 Η ), 6·7 卜 7.29 (m series, total 6Η), 7·86 - 8·02 (m, 3Η), 8·15-8·19 (m, 1H), 8·71 (s, 1H), 9·17 (s, 1H), 13· 00 (bs, 1H); MS (FAB) m/z 544 (M+), 54 5 (M+ + 1); C27H27C1FN3 06 · 1/4H20 Analysis calculated: C, 59.13; H, 5. 05 ; Cl, 6 · 46; F, 3. 46 ; N, 7· 66. Found: C, 59. 19 ; H, 4· 99 ; Cl, 6. 64 ; F, 3. 23 ; N, 7.55. 2 3 3 (S)-3-Chloro-4-[2-[N-methyl-N-[3-曱-oxy-4-[Ν'-(2-methylphenyl)ureido]phenyl Ethyl hydrazide

使3-甲氧基-4-[Ν’-（2_甲基苯基）脲基]苯乙酸（261毫 克，0.83毫莫耳）、（S)_ 3 -氣-4-(2-甲胺基-1-丙氧基）苯 甲酸甲酯（214毫克，0· 83毫莫耳）、EDC(氫氯酸鹽）（ 23 9毫3-methoxy-4-[Ν'-(2-methylphenyl)ureido]phenylacetic acid (261 mg, 0.83 mmol), (S)-3- gas -4-(2-A Methylamino-1-propoxy)benzoate (214 mg, 0·83 mmol), EDC (hydrochloride) (23 9 m)

\\312\2d-code\90-01\89112968.ptd 第735頁 1283240 五、發明說明（731) —-- 克，1· 25毫莫耳）、H0Bt(168毫克，124毫莫耳）、 DMAP(20毫克，〇· ! 6毫莫耳）於DMF(8毫升）中之混合物 溫下攪拌2小時。將混合物以Et〇Ac稀釋，以〇· 5Ν Η。、 水洗滌，於υ〇4上乾燥，並蒸發。使殘留物經由於 π 上利用CHCl3-MeOH(50:l，ν/ν)作為洗提液進行管桎層勝 析，純化而得47 0毫克（100%) (S)-3-氣-4-[2-N-甲基—&quot;N、 [3-曱氧基-4- [Ν’ - (2-甲基苯基）脲基]笨基乙醯基]胺 -1 -丙氧基]苯曱酸甲酯之淡黃色非晶形固體。 土 於以上產物（470毫克，0.95毫莫耳）溶於THF(10毫升） 攪拌溶液中加入0.5N NaOH(10毫升），並使反應混合物^ 流加熱3小時。將混合物倒入至冰的1 n HC1中，並收集固 體。使粗製固體自CHCI3-Et2〇再結晶，而得1 6 8毫克（2步 驟 ’ 33%)(S) - 3-氣-4 - [2 - [N-甲基 -N-[3-甲氧基-4-[N， -（2-甲基苯基）脲基]笨基乙醢基]胺基]一1 一丙氧基]笨甲 酸284的淡黃色結晶粉末。 熔點 1 2 5-1 30 C^H-NMR (DMS0-d6) 5 1.13-1.19 (m，3h) 、2·24 (s，3H)、2·74 及 2.94 (s，3H)、3·65 (s，2H)、 3·83 及 3.85 (s，3H)、4·14-4·22 (m，2H)、4·91-4·93 (m，1Η)、6·70 - 6·74 (m，1Η)、6·84 (m，1Η)、 6·92-6·95 (m，1Η)、7·11-7·17 (m，2Η)、7·25-7·29 (m，1Η)、7· 78- 7.80 (m，1Η)、7·85-7·93 (m, 2Η)、 7·99-8·02 (m，1Η)、8·46 (s，1Η)、8·56 (s，1Η)、 12· 99 (bs，1Η) ; MS(FAB) m/z 540 (Μ+)、54UM+ + 1); C28H30C1N3 06 · 1/2Η20 之分析計算值：C， 61.26 ； Η, 5.69;\\312\2d-code\90-01\89112968.ptd Page 735 1283240 V. Description of invention (731) —-- grams, 1 · 25 millimoles, H0Bt (168 mg, 124 millimoles), DMAP (20 mg, 〇·6 mmol) was stirred in a mixture of DMF (8 mL) for 2 hr. The mixture was diluted with Et〇Ac to 〇·5Ν Η. Wash with water, dry on υ〇4, and evaporate. The residue was subjected to a tube layer by using CHCl3-MeOH (50:1, ν/ν) as an eluent, and purified to obtain 47 0 mg (100%) (S)-3-gas-4. -[2-N-methyl-&quot;N, [3-methoxy-4-[Ν'-(2-methylphenyl)ureido]]phenylamino]amine-1-propoxy a pale yellow amorphous solid of methyl benzoate. The residue was dissolved in THF (10 mL). The mixture was poured into 1 n of HC1 in ice and the solid was collected. The crude solid was recrystallized from CHCI3-Et2〇 to give 168 mg (2 steps '33%) (S)-3-3--4-[2-[N-methyl-N-[3-methoxy A pale yellow crystalline powder of benzyl-4-[N,-(2-methylphenyl)ureido]phenylidene]amino]-l-propoxy]benzoic acid 284. Melting point 1 2 5-1 30 C^H-NMR (DMS0-d6) 5 1.13-1.19 (m, 3h), 2·24 (s, 3H), 2·74 and 2.94 (s, 3H), 3.65 (s, 2H), 3·83 and 3.85 (s, 3H), 4·14-4·22 (m, 2H), 4·91-4·93 (m, 1Η), 6.70 - 6.74 (m, 1Η), 6.84 (m, 1Η), 6.92-6·95 (m, 1Η), 7·11-7·17 (m, 2Η), 7·25-7·29 (m ,1Η),7·78- 7.80 (m,1Η), 7·85-7·93 (m, 2Η), 7·99-8·02 (m,1Η), 8·46 (s,1Η), 8·56 (s,1Η), 12·99 (bs,1Η); MS(FAB) m/z 540 (Μ+), 54UM+ + 1); C28H30C1N3 06 · 1/2Η20 Analysis calculated: C, 61.26 ; Η, 5.69;

\\312\2d-code\90-01\89112968.ptd 第736頁 1283240 五、發明說明（732) N，7.65。實測值：C，61.15; Η，5.58; N，7.51 實施例2 3 4 · 3-異丙胺基-4-[[2-[3-甲氧基-4-[Ν’-(2-甲基苯基）脲基 ]苯基乙醯基]曱胺基]乙氧基]苯甲酸\\312\2d-code\90-01\89112968.ptd Page 736 1283240 V. Description of invention (732) N, 7.65. Found: C, 61.15; Η, 5.58; N, 7.51 Example 2 3 4 · 3-Isopropylamino-4-[[2-[3-methoxy-4-[Ν'-(2-methyl) Phenyl)ureido]phenylethenyl]nonylamino]ethoxy]benzoic acid

285 於3-胺基-4-[ [2- [3-甲氧基-4-[N，-（2-甲基苯基）脲基 ]苯基乙醯基]甲胺基]乙氧基]苯甲酸曱酯（3〇〇毫克，〇·58 毫莫耳）溶於乙酸酯-Ac0H-DMF(13毫升，6:6: 1，ν/ν/ν)之 冷的（〇°C)攪拌溶液中加入NaBH3CN( 300毫克），並使所產 生之混合物在室溫下授摔6 0小時。將混合物倒入至飽和 NaHC〇3中，並以CHC13萃取。將萃取液以鹽水洗務，於 MgS04上乾燥，並蒸發而得2 80毫克（86%)之3 -異丙胺基 -4 - [[2-[3-甲氧基-4_[N’-(2-甲基苯基）脲基]苯基乙醯 基]甲胺基]乙氧基]苯甲酸甲酯的無色油。 l-NMR (CDC13 ， 400MHz) ά 1.21 (m， 6H) 、 2.30 (s， 3H) 、3.05 及 3.10 (s，總計 2Η)、3·59 (s，3Η)、3·62-3·81 (m， 6Η) 、3·89 (s， 3Η) 、4·10 及4.21 (m， 2Η) 、6·65-6·80 (m，4Η)、7·10 (m，1Η)、7·20 (s，3Η)、7·32 (m， 2Η) 、7·54 (d， 1Η， J=8.3 Hz) 、8·〇〇 (s， 1Η) 、8·07 (d，1H，】 = 8·3 Hz); MS(FAB) m/z 563 (MH1)。 使3-異丙胺基-4- [ [2-[3-曱氧基-4-[Ν’ -(2-曱基苯基） 脲基]苯基乙醯基]甲胺基]乙氧基]笨甲酸甲酯（280毫克，285. 3-Amino-4-[[2-[3-methoxy-4-[N,-(2-methylphenyl)ureido]phenylethyl]methylamino]ethoxy ] decyl benzoate (3 〇〇 mg, 〇·58 mmol) is dissolved in acetate-Ac0H-DMF (13 ml, 6:6: 1, ν/ν/ν) cold (〇°C NaBH3CN (300 mg) was added to the stirred solution, and the resulting mixture was allowed to fall for 60 hours at room temperature. The mixture was poured into saturated NaHC(R)3 and extracted with CHC13. The extract was washed with brine, dried over MgSO4 and evaporated to give &lt;RTI ID=0.0&gt;&gt;&&&&&&&&&&&& A colorless oil of methyl 2-methylphenyl)ureido]phenylethenyl]methylamino]ethoxy]benzoate. l-NMR (CDC13, 400MHz) ά 1.21 (m, 6H), 2.30 (s, 3H), 3.05 and 3.10 (s, total 2Η), 3·59 (s, 3Η), 3·62-3·81 ( m, 6Η), 3·89 (s, 3Η), 4·10 and 4.21 (m, 2Η), 6·65-6·80 (m, 4Η), 7·10 (m, 1Η), 7·20 (s, 3Η), 7·32 (m, 2Η), 7·54 (d, 1Η, J=8.3 Hz), 8·〇〇(s, 1Η), 8·07 (d,1H,] = 8 · 3 Hz); MS (FAB) m/z 563 (MH1). 3-Isopropylamino-4-[[2-[3-曱oxy-4-[Ν'-(2-mercaptophenyl)ureido]phenylethenyl]methylamino]ethoxy Methyl formate (280 mg,

\\312\2d-code\90-01\89112968.ptd 第737頁 1283240 五、發明說明（733) 0. 5毫莫耳）於0· 25N Na0H(6毫升）及THF(6毫升）中之授拌 混合物迴流加熱8小時。將混合物倒入至水（2 〇 〇毫升）中， 利用IN HC1酸化，並利用吸濾收集固體。使固體自CHC1, - 〇 正己烧-二異丙醚再結晶，而得202毫克（74%)之3 -異丙胺 基-4 - [[2 - [3-甲氧基-4-[Ν’- (2-甲基苯基）脲基]苯基乙 醯基]甲胺基]乙氧基]苯甲酸285的淡黃色結晶粉末。 熔點 1 30- 1 35 °C ; UMR (CD3OD，40 0MHz) (5 1· 18 及1· 22 (d，總計 6 Η，J = 6 · 3 Η z)、2. 2 9 及 2 · 3 2 (s，總計 3 Η)、 3.04 及 3·14 (s，總計2H)、3·60-3·90 (m，9H)、4·16 及 4·25 (m，總計2Η)、6·80 (m，3Η)、7·02 (m，1Η)、 7.12-7·24 (m，3H)、7.29-7.38 (m，1H)、7·59 (uj ih) 、8·02 (m，1H); MS(FAB) m/z 548 (M + H)+; C3QH36N4 06 之 分析計鼻值· C，6 5 · 6 8，H，6 · 6 1。實測值：。，658〇; H， 6. 83 。 實施例2 3 5 4-[[2-[3-曱氧基-4-[N’-(2-甲基苯基）脲基]笨基乙醯基] 甲胺基]乙基]曱胺基苯甲酸\\312\2d-code\90-01\89112968.ptd Page 737 1283240 V. Description of the invention (733) 0. 5 millimoles) in 0. 25N Na0H (6 mL) and THF (6 mL) The mixture was heated under reflux for 8 hours. The mixture was poured into water (2 mL), acidified with IN HCl, and collected by suction. The solid was recrystallized from CHC1, - 〇 hex hexane-diisopropyl ether to give 202 mg (74%) of 3-isopropylamino-4 - [[2 - [3-methoxy-4-[Ν' - (2-Methylphenyl)ureido]phenylethenyl]methylamino]ethoxy]benzoic acid 285 as a pale yellow crystalline powder. Melting point 1 30- 1 35 °C; UMR (CD3OD, 40 0MHz) (5 1· 18 and 1· 22 (d, total 6 Η, J = 6 · 3 Η z), 2. 2 9 and 2 · 3 2 (s, total 3 Η), 3.04 and 3·14 (s, total 2H), 3·60-3·90 (m, 9H), 4·16 and 4·25 (m, total 2Η), 6·80 (m, 3Η), 7·02 (m, 1Η), 7.12-7·24 (m, 3H), 7.29-7.38 (m, 1H), 7·59 (uj ih), 8·02 (m, 1H) MS(FAB) m/z 548 (M + H)+; C3QH36N4 06 Analytical value of the nose · C, 6 5 · 6 8, H, 6 · 6 1. Found: 658 〇; H, 6. 83. Example 2 3 5 4-[[2-[3-曱-oxy-4-[N'-(2-methylphenyl)ureido]]phenylamino]methylamino] Amidinobenzoic acid

CH3 ^yCOOH CH3H η 〇ch3 286 於4-[[ 2-[3_甲氧基-4-[Ν’-（2-甲基笨基）脲基]苯基乙 醯基]曱胺基]乙基]胺基苯甲酸甲酯（300毫克，〇·6毫莫 耳）溶於MeCN-甲醛-AcOH(ll毫升，8:2: 1，ν/ν/ν)之冷的 (0 °C)攪拌溶液中加入NaBH3CN(187毫克，2· 40毫莫耳^，CH3 ^yCOOH CH3H η 〇ch3 286 in 4-[[ 2-[3_methoxy-4-[Ν'-(2-methylphenyl)ureido]phenylethenyl]nonylamino]B Methyl amino benzoate (300 mg, 〇·6 mmol) dissolved in MeCN-formaldehyde-AcOH (ll mL, 8:2:1, ν/ν/ν) cold (0 °C) NaBH3CN (187 mg, 2·40 mmol) was added to the stirred solution.

89112968.ptd 第738頁 1283240 五、發明說明（734) 並使所產生之混合物在室溫下攪拌18小時。將混合物倒入 至飽和NaHC〇3中，並以CHC13萃取。將萃取液以鹽水洗滌， 於MgS〇4上乾燥，並蒸發而得30 9毫克（1〇〇%)之4一[[2—[3一 甲氧基-4-[N’ - (2-甲基苯基）脲基]苯基乙醯基]一2 - N，-甲 胺基]乙基]曱胺基苯曱酸甲酯的無色油。 1 -NMR (CDC13，40 0MHz) 3 2.30 (m，3H)、2. 98 (m，7H) 、3.46-3·72 (m, 9H)、3·82 (m，3H)、6·32 (m，1H)、 6·55-6·75 (m，4H)、7·05-7·50 (m，2H)、7·82-8·02 (m，4H); MS(FAB) m/z 518 (ΜΗ1)。 使4- [ [2-[ 3-甲氧基-4-[Ν’ - (2-甲基苯基）脲基]苯基乙 醯基]-2-Ν’ -甲胺基]乙基]甲胺基苯甲酸甲酯（309毫克， 〇· 6毫莫耳）於IN NaOH(2· 4毫升）及THF(10毫升）中之攪拌 混合物迴流加熱8小時。將混合物倒入至水（ 200毫升）中， 經由加入IN HC1而酸化。利用吸濾收集固體。使粗製固體 自CHC13-正己烷-二異丙醚再結晶，而得211毫克（70%)之 4-[[2-[ 3-甲氧基-4-[ Ν’ -（2-甲基苯基）脲基]苯基乙醯 基]-2-甲胺基]乙基]甲胺基苯甲酸286的淡黃色結晶粉 末。 熔點 1 25-1 30 °C ; IR (KBr) 3 33 8、2933、1601、1 529、 1182、1 036、752 / 公分；UMR (CD3OD，400MHz) J 2·28 及 2.29 (s，3H)、2·95-3·02 (m，6H)、3·60 (br， 6Η)、3·80 (s, 1Η)、3·86 (s，2Η)、6·60-6·82 (m， 4H)、7·(Π - 7.18 (m，3H)、7·58 (m，1H)、7·82 - 7·99 (m, 3Η) ; MS(FAB) m/z 504 (ΜΗ1) ; C28H32N4 05 · 2· 25Η20 之89112968.ptd Page 738 1283240 V. INSTRUCTIONS (734) The resulting mixture was stirred at room temperature for 18 hours. The mixture was poured into saturated NaHC〇3 and extracted with CHC13. The extract was washed with brine, dried over MgS 4 and evaporated to yield 30 9 mg (1%) of 4-[[2-[3-methoxy-4-[N' - (2- A colorless oil of methylphenyl)ureido]phenylethenyl]2- 2,N-methylamino]ethyl]decyl benzoyl phthalate. 1 - NMR (CDC13, 40 0MHz) 3 2.30 (m, 3H), 2. 98 (m, 7H), 3.46-3.72 (m, 9H), 3.82 (m, 3H), 6.32 ( m,1H), 6·55-6·75 (m,4H), 7·05-7·50 (m,2H), 7·82-8·02 (m,4H); MS(FAB) m/ z 518 (ΜΗ1). 4-[ [2-[ 3-Methoxy-4-[Ν' - (2-methylphenyl)ureido]phenylethenyl]-2-Ν'-methylamino]ethyl] Methyl dimethyl benzoate (309 mg, 〇 6 mmol) was stirred and heated under reflux for 8 hrs in EtOAc (2 mL). The mixture was poured into water (200 mL) and acidified with EtOAc. The solid was collected by suction filtration. The crude solid was recrystallized from CHC13-n-hexane-diisopropyl ether to give 211 mg (70%) of 4-[[2-[ 3-methoxy-4-[ A pale yellow crystalline powder of ureido]phenylethenyl]-2-methylamino]ethyl]methylaminobenzoic acid 286. Melting point 1 25-1 30 °C; IR (KBr) 3 33 8, 2933, 1601, 1 529, 1182, 1 036, 752 / cm; UMR (CD3OD, 400MHz) J 2·28 and 2.29 (s, 3H) , 2·95-3·02 (m, 6H), 3·60 (br, 6Η), 3·80 (s, 1Η), 3·86 (s, 2Η), 6·60-6·82 (m , 4H), 7·(Π - 7.18 (m, 3H), 7·58 (m, 1H), 7·82 - 7·99 (m, 3Η); MS (FAB) m/z 504 (ΜΗ1); C28H32N4 05 · 2· 25Η20

89112968.ptd 第739頁 1283240 五、發明說明（735) 分析計算值·· C，61·69 ; Η，6·75 ; Ν，ι〇·28。實測值· C，62· 19 ; Η，6· 31 ; Ν，9· 60。 ' ' 實施例236 (5)-3-氯-4-[2-|^-爷基-1^-[3-甲氧基一4-1^，-（2-氟苯基）89112968.ptd Page 739 1283240 V. INSTRUCTIONS (735) Analytical calculations·· C, 61·69 ; Η, 6·75 ; Ν, ι〇·28. Measured value · C, 62 · 19 ; Η, 6· 31 ; Ν, 9· 60. ' ' Example 236 (5)-3-Chloro-4-[2-|^--yl-1--[3-methoxy-4-1-,-(2-fluorophenyl)

於NaBH3CN(985毫克，15· 68毫莫耳）溶於Me〇H(5毫升）之攪 拌溶液中加入（S)-3-氯-4-（2-胺基-1-丙氧基）笨曱酸甲二 (382毫克，1. 57毫莫耳）及苯甲醛（〇· 19毫升）溶於Me〇H(5 毫升）之溶液，並使所產生之混合物在室溫下擾拌隔夜。 利用使混合物停止反應，並以chci3萃取。將萃:液以 鹽水洗條’於N az S 〇4上乾燥’並蒸發。使殘留物經由於石夕 膠上利用CHCI3 :MeOH(30:l，v/v)作為洗提液進行管柱層 析，純化而得336毫克（64%)之（S) - 3-氯_4-(2-N-苄胺基 -1 -丙氧基）苯甲酸酯的無色油。 287 H-NMR (CDC13)3 1.22 (d，3H，J = 6.4 Ηζ)、3·21-3·25 (m，1H)、3.84-4·03 (m，總計7H)、6·89-6.91 (m，1H) 、7 · 2 3 - 7 · 3 7 (m，5 Η)、7 · 8 9 - 7 · 91 ( m，1 Η)、8 · 〇 5 (m， 1Η)。使3-甲氧基-4 - [Ν’-（2-氟苯基）脲基]笨基乙酸（320 愛克’1.01愛;莫耳）、（S) — 3_氯-4 -（2 - N-苄胺基-丙氧 基）苯甲酸甲酯（ 336毫克，1· 〇1毫莫耳）、EDC(氫氯酸 鹽）（289毫克，1.51毫莫耳）、HOB t( 204毫克，1· 51毫莫Add (S)-3-chloro-4-(2-amino-1-propoxy) stupid to a stirred solution of NaBH3CN (985 mg, 15.68 mmol) in Me 〇H (5 mL) A solution of methyl ruthenate (382 mg, 1.57 mmol) and benzaldehyde (〇 19 ml) in Me〇H (5 mL) was added and the resulting mixture was stirred overnight at room temperature. The mixture was quenched by reaction and extracted with chci3. The extract was washed with brine to dry on 'N az S 〇 4 ' and evaporated. The residue was subjected to column chromatography using CHCI3: MeOH (30:1, v/v) as an eluent to obtain 336 mg (64%) of (S)-3-chloro- A colorless oil of 4-(2-N-benzylamino-1-propoxy)benzoate. 287 H-NMR (CDC13) 3 1.22 (d, 3H, J = 6.4 Ηζ), 3·21-3·25 (m, 1H), 3.84-4·03 (m, total 7H), 6.89-6.91 (m, 1H), 7 · 2 3 - 7 · 3 7 (m, 5 Η), 7 · 8 9 - 7 · 91 ( m, 1 Η), 8 · 〇 5 (m, 1 Η). 3-methoxy-4 -[Ν'-(2-fluorophenyl)ureido] stupid acetic acid (320 EK '1.01 love; Moer), (S) - 3_ chloro-4 - (2 - N-benzylamino-propoxy)benzoic acid methyl ester (336 mg, 1·〇1 mmol), EDC (hydrochloride) (289 mg, 1.51 mmol), HOB t (204 mg ,1·51 mm

第740頁 89112968.ptd 1283240Page 740 89112968.ptd 1283240

耳）及DMAP(25毫克，〇· 20毫莫耳）於DMF(7毫升）中之混合 物在室溫下攪拌2天。將混合物以Et〇Ac稀釋，以鹽水洗 滌，於NazS〇4上乾燥，並蒸發。使殘留物經由於矽膠上利 用CHC13 :MeOH(50:l，v/v)作為洗提液進行管柱層析，純 化而得607毫克（95%)(S)-3-氯-4- [N-爷基-N-[3-甲氧基 - 4-[N -(2-氟笨基）脲基]笨基乙醯基]胺基_ι —丙氧基]苯 甲酸曱酯的淡黃色非晶形固體。 NMR (CDC13) (5 1.20-1.27 (m，3H)、3·62 (s，2H)、 3· 73-4· 16 (m 系列，總計9Η，包括在3· 88 及3. 89ppm 之s， 3H)、4·71 (bs，2H)、6·67-7·38 (m 系列，總計 12H)、 7· 77-8· 17 (m 系列，總計5H)。 於（S) -3-氯-4-[2 - [N-窄基-N-[3 - 甲氧基-4-[N，-（2-氟 苯基）脲基]苯基乙醯基]胺基-1—丙氧基]苯甲酸甲酯（6〇7 毫克，〇· 96毫莫耳）溶於THF(6毫升）之攪拌溶液中加入 〇· 5N NaOH(6毫升），並使所產生之混合物迴流加熱隔夜。 將混合物倒入至冰的1 N HC1中，並收集固體。使粗製固體 再結晶而得192毫克（32%) (S)-3-氣-4-[2-[N-窄基-N-[ 3-甲氧基-4-[Ν’-（2-氟苯基）脲基]苯基乙醯基]胺基]-；1-丙 氧基]苯甲酸287的白色結晶粉末。 熔點 1 25- 1 30 1:1-NMR (DMSO-d6)6 1·07-1·23 (m，3H) 、3·76 (s，2H)、3·85 (s，3H)、3·90-4.26 (m，3H)、 4·56 (s，2Η)、6·66 - 7·38 (m 系列，總計 10Η)、7·82-8· 20 (m 系列，總計5Η)、8· 70-8· 74 (m， 1Η)、9· 18-9· 20 (m，1H)、13· 02 (bs，1H) ; MS(FAB) m/z 621 (MH1);The mixture of the ear and DMAP (25 mg, 〇 20 mmol) in DMF (7 mL) was stirred at room temperature for 2 days. The mixture was diluted with Et EtOAc, washed with brine, dried over Naz. The residue was subjected to column chromatography using CHC13: MeOH (50:1, v/v) as eluent to give 607 mg (95%) of (S)-3-chloro-4-[ N-G-yl-N-[3-methoxy-4-[N-(2-fluorophenyl)ureido]]phenylamino]amino-yl-propoxy]benzoate Yellow amorphous solid. NMR (CDC13) (5 1.20-1.27 (m, 3H), 3·62 (s, 2H), 3· 73-4· 16 (m series, total 9Η, included in 3.88 and 3. 89ppm s, 3H), 4·71 (bs, 2H), 6·67-7·38 (m series, total 12H), 7·77-8· 17 (m series, total 5H). (S) -3-chloro -4-[2-[N-Narrow-N-[3-methoxy-4-[N,-(2-fluorophenyl)ureido]phenylethenyl]amino-1-propoxy Methyl benzoate (6 〇 7 mg, 〇·96 mmol) was dissolved in THF (6 mL). EtOAc········ The mixture was poured into ice 1 N HCl, and a solid was collected. The crude solid was recrystallized to give 192 mg (32%) of (S)-3- -4- -4-[2-[N-n-n--N- [3-methoxy-4-[Ν'-(2-fluorophenyl)ureido]phenylethenyl]amino]-; 1-propoxy]benzoic acid 287 as a white crystalline powder. 25- 1 30 1:1-NMR (DMSO-d6)6 1·07-1·23 (m,3H), 3·76 (s,2H), 3·85 (s,3H),3·90- 4.26 (m, 3H), 4·56 (s, 2Η), 6.66 - 7·38 (m series, total 10Η), 7·82-8· 20 (m series, total 5Η), 8· 70-8· 74 (m, 1Η), 9· 18-9· 20 (m, 1H), 13· 02 (bs, 1H); MS(FAB) m/z 621 (MH1);

89112968.ptd 第741頁 1283240 五、發明說明（737) C33 H31 C1 F Ν3 06 · 1 / 4 H2 0 之分析計算值：。β 3 4 fi · Η 5 Π 8 -1，5.BS；F, 3.04； N, e.73〇^r；C as：/,;0：, 5· 16 ; Cl, 5· 75 ; F，2· 95 ; N，6· 55。 實施例2 3 7 3-Ν-異丙基-Ν-甲胺基-4-[[2-[3-甲氧基—4一 [Ν, _(2_甲基 苯基）脲基]苯基乙醯基]甲胺基]乙氧基]苯曱酸89112968.ptd Page 741 1283240 V. INSTRUCTIONS (737) C33 H31 C1 F Ν3 06 · 1 / 4 H2 0 Analysis calculated value: . β 3 4 fi · Η 5 Π 8 -1,5.BS;F, 3.04; N, e.73〇^r; C as:/,;0:, 5· 16 ; Cl, 5· 75 ; F, 2· 95 ; N, 6· 55. Example 2 3 7 3-Ν-isopropyl-indole-methylamino-4-[[2-[3-methoxy-4-yl[Ν, _(2-methylphenyl)ureido]benzene Ethylamino]ethoxy]benzoic acid

^xrC00H 0Η3Η H 0cH3 1 H3(XCH3 288 於3-異丙胺基-4-[ [2-[3-甲氧基一4一 [N，—（2-甲基苯基） 脲基]苯基乙醯基]甲胺基]乙氧基]笨甲酸甲酯（324毫克， 0.58宅莫耳）溶於CH3CN-甲盤-AcOH(ll毫升，8:2:1， v/v/v)之冷的（〇°C)攪拌溶液中加入NaBH3CN(145毫克， 2 · 3 0毫莫耳），並使所產生之混合物在室溫下攪拌丨8小 時。將混合物倒入至飽.和NaHC03中，並利用吸濾收集固 體。將粗製固體溶解於CHC13(20毫升），並將溶液以鹽水 洗滌，於MgS04上乾燥，及蒸發而得317毫克（95%)之3-(N — 異丙基-N-甲胺基）一4-[[2 - [3_甲氧基-4 - [N，-(2-甲基苯 基）脲基]苯基乙醯基]曱胺基]乙氧基]苯甲酸甲酯的無色 油。 UR (CDC13) 6 1· 〇2 (m，6H)、2· 29 (s，3H)、2· 63 (m，3H)、3·02-3·20 (m，3H)、3·49-3.80 (m，8H)、 3.88 (s，3H)、4·〇6 及 4·21 (m，總計 2H)、6·59 (m，1H) 、6·76 (m，2H)、7·Η - 7·23 (m，3H)、7·50-7·62 (m，^xrC00H 0Η3Η H 0cH3 1 H3(XCH3 288 in 3-isopropylamino-4-[[2-[3-methoxy-4-41[N,-(2-methylphenyl)ureido]phenyl) Methyl]methylamino] ethoxy] methyl benzoate (324 mg, 0.58 house moles) was dissolved in CH3CN-A-AcOH (ll cc, 8:2:1, v/v/v) NaBH3CN (145 mg, 2·30 mmol) was added to the stirred solution, and the resulting mixture was stirred at room temperature for 8 hours. The mixture was poured into saturated and NaHC03. The solid was collected by suction filtration. The crude solid was dissolved in CH.sub.3 (20 mL), and the solution was washed with brine, dried over EtOAc, and evaporated to yield 317 mg (95%) of 3-(N- isopropyl- N-methylamino)-4-[[2 - [3_methoxy-4-[N,-(2-methylphenyl)ureido]phenylethyl] decylamino]ethoxy a colorless oil of methyl benzoate. UR (CDC13) 6 1· 〇2 (m, 6H), 2· 29 (s, 3H), 2· 63 (m, 3H), 3·02-3·20 ( m, 3H), 3·49-3.80 (m, 8H), 3.88 (s, 3H), 4·〇6 and 4·21 (m, total 2H), 6.59 (m, 1H), 6.76 (m, 2H), 7·Η - 7·23 (m, 3H), 7·50-7·62 (m,

ΜΜ

89112968.ptd 第742頁 1283240 五、發明說明（738) 3H) &gt;8.05 (d, 1H, J = 8.3 Hz)； MS(FAB) m/z 576 (M+ + 1)0 使3-（N-異丙基-N-甲胺基）-4-[[2 - [3-甲氧基-4-[N，-(2-甲基苯基）脲基]苯基乙醯基]甲胺基]乙氧基]苯甲酸 甲酯（317毫克，0.55毫莫耳）於0.25N Na0H(8.2毫升）及 THF (8毫升）中之攪拌混合物迴流加熱8小時。將混合物倒 入至水（2 00毫升）中，經由加入IN HC1而酸化，並利用吸 濾收集固體。使粗製固體自CHC13-正己烷-二異丙醚再結 晶，而得246毫克（80%)之3-(N-異丙基-N-甲胺基）- 4-[[ 2 - [3_甲氧基-4- [Ν’ -（2-甲基苯基）脲基]苯基乙醯基]曱 胺基]乙氧基]苯甲酸288的淡黃色結晶粉末。 熔點 1 3 0- 1 35 °C ; IR (KBr) 2970、1 537、1 0 38、75 4 / 公 分；1H-NMR (CD3OD) 6 1· 12 (m，6H)、2. 29 (s，3H)、 2·76 (m，1H)、2·89 (s，2H)、3·02 (s，1H)、3·21 (s， 2H) ^3.72 (s, 2H)、3. 80 (s, 3H)、3· 84 (m，3H)、 4.13 及 4.40 (m，總計 2H)、6· 76 (d，1H，J = 7· 8 Hz)、 6·86 (s，1H)、7.〇〇 (m，2H)、7·18 (m，3H)、7·57 (d， 1H，J = 7.8 Hz)、7·95 (m，2H); MS(FAB) m/z 562 (M+ + 1) ; C31H38N4 06 · 2· 〇H20 之分析計算值·· C，62· 19 ; H， 7· 07 ; N，9. 36。實測值·· C，62· 54 ; H，6· 85 ; N， 8.90。 實施例2 3 8 3 -（1-六氫吼σ定基）- 4 - [[2-[3-甲氧基-4 - [Ν’ _(2 -貌苯基） 脲基]苯基乙醯基]甲胺基]乙氧基]苯甲酸89112968.ptd Page 742 1283240 V. INSTRUCTIONS (738) 3H) &gt; 8.05 (d, 1H, J = 8.3 Hz); MS(FAB) m/z 576 (M+ + 1)0 makes 3-(N- Isopropyl-N-methylamino)-4-[[2-[3-methoxy-4-[N,-(2-methylphenyl)ureido]phenylethenyl]methylamino The stirred mixture of ethoxy]methyl benzoate (317 mg, 0.55 mmol) in EtOAc (EtOAc m. The mixture was poured into water (200 mL), acidified by addition of &lt The crude solid was recrystallized from CHC13-n-hexane-diisopropyl ether to give 246 mg (yield: &lt;RTI ID=0.0&gt;&gt; A pale yellow crystalline powder of methoxy-4-[Ν'-(2-methylphenyl)ureido]phenylethenyl]nonylamino]ethoxy]benzoic acid 288. Melting point 1 3 0- 1 35 ° C; IR (KBr) 2970, 1 537, 1 0 38, 75 4 / cm; 1H-NMR (CD3OD) 6 1· 12 (m, 6H), 2. 29 (s, 3H), 2·76 (m, 1H), 2·89 (s, 2H), 3·02 (s, 1H), 3·21 (s, 2H) ^ 3.72 (s, 2H), 3. 80 ( s, 3H), 3·84 (m, 3H), 4.13 and 4.40 (m, total 2H), 6.76 (d, 1H, J = 7·8 Hz), 6·86 (s, 1H), 7 .〇〇(m,2H),7·18 (m,3H),7·57 (d, 1H,J = 7.8 Hz), 7.95 (m, 2H); MS(FAB) m/z 562 ( M+ + 1) ; C31H38N4 06 · 2· 分析H20 analytical calculation ······················· Found C·62· 54 ; H,6· 85 ; N, 8.90. Example 2 3 8 3 -(1-hexahydroindole sigma)- 4 - [[2-[3-methoxy-4 - [Ν' _(2-phenylene) ureido]phenyl) Methylamino]ethoxy]benzoic acid

\\312\2d-code\90-01\89112968.ptd 第743頁 1283240\\312\2d-code\90-01\89112968.ptd Page 743 1283240

289 在0 °C下於3-胺基-4-[ [2-[3-甲氧基一4 - [N，-2 -氟苯基] 脲基]苯基乙醯基]甲胺基]乙氧基]苯甲酸甲酯（3〇〇毫克， 〇· 57毫莫耳）溶於THF(2毫升）之攪拌溶液中加入戊二醛 (50%水溶液）（1.13毫升，·69毫莫耳）溶於Me〇H(l· 4毫 升）、THF(0.993 毫升）、及3N H2S04 (0.942 毫升）之溶液。 在室溫下於此溶液中加入NaBH3CN(150毫克）、DMF(5毫升） 及MeOH (2毫升），並使所產生之混合物攪拌丨5小時。將混 合物倒入至飽和NaHC〇3中，並萃取壓力。使殘留物於矽膠 上利一用甲苯：丙酮（7 : 3，v/ v)作為洗提液進行層析，而得 145毫克（43%) 3-（1-六氫吡啶基）一4一[[2 一 [3_甲氧基一4一[ N’-(2-氟苯基）脲基]苯基乙醯基]曱胺基]環氧基]苯甲酸 曱S旨的無色油。 LR (CDC13，40_z) (5 1· 58-1· 72 (m，6H)、2. 8 0-2·92 (m，4H)、3·26 (s，2H)、3·58 (s，2H)、3·69 (s， 2Η)、3.80-3·89 (m，7Η)、4.22 (m，2Η)、6.72 (s，1Η) 、6·78 (m，2H)、6·95 - 7.18 (m，2H)、7·32 (s，1H)、 7·60 (s，1H)、7·63 (d，1H, J = 7.8 Hz)、7·98 (d，1H， J = 7.8 Hz) '8.18 (m，1H); MS(FAB) m/z 593 (M+.l)。 使3 -（1-六氫咄啶基）-4- [[2-[3-曱氧基-4-[N，-（2-氟笨 基）脲基]苯基乙醯基]曱胺基]乙氧基]苯曱酸甲酯（290毫 克’0.49毫莫耳）、1N NaOH(1.95毫升）於MeOH(5毫升）及289 3-amino-4-[[2-[3-methoxy-4-[N,-2-fluorophenyl]ureido]phenylethenyl]methylamino] at 0 °C Methyl ethoxy]benzoate (3 〇〇 mg, 〇·57 mmol) was dissolved in THF (2 mL), and glutaraldehyde (50% aqueous solution) (1.13 ml, · 69 mmol) was added. A solution of Me〇H (1.4 ml), THF (0.993 ml), and 3N H2S04 (0.942 mL). NaBH3CN (150 mg), DMF (5 ml) and MeOH (2 ml) were then added to the mixture and the mixture was stirred for 5 hours. The mixture was poured into saturated NaHC〇3 and the pressure was extracted. The residue was chromatographed on toluene using a toluene:acetone (7:3, v/v) as an eluent to give 145 mg (43%) of 3-(1-hexahydropyridyl)-4. [[2]-[3-Methoxy-4-iso[4-(2-fluorophenyl)ureido]phenylethenyl]nonylamino]cyclooxy]benzoic acid oxime S is a colorless oil. LR (CDC13, 40_z) (5 1· 58-1· 72 (m, 6H), 2. 8 0-2·92 (m, 4H), 3·26 (s, 2H), 3·58 (s, 2H), 3·69 (s, 2Η), 3.80-3·89 (m, 7Η), 4.22 (m, 2Η), 6.72 (s, 1Η), 6.78 (m, 2H), 6.95 - 7.18 (m, 2H), 7·32 (s, 1H), 7·60 (s, 1H), 7·63 (d, 1H, J = 7.8 Hz), 7·98 (d, 1H, J = 7.8 Hz) '8.18 (m,1H); MS(FAB) m/z 593 (M+.l). 3 -(1-hexahydroacridinyl)-4-[[2-[3-methoxy- 4-[N,-(2-Fluorophenyl)ureido]phenylethenyl]nonylamino]ethoxy]benzoic acid methyl ester (290 mg '0.49 mmol), 1 N NaOH (1.95 ml) ) in MeOH (5 ml) and

1283240 五、發明說明（740) THF ( 1 0毫升）中之攪拌混合物迴流加熱4小時。將混合物倒 入至水（ 2 0 0毫升）中，利用IN HC1酸化（ρΗ = 4· 〇)，及以 CHC13-MeOH(9 ·· 1，ν/ν)萃取。將結合的萃取液於MgS04上乾 燥，並蒸發。使殘留物自二異丙醚-己烷再結晶，而得2 0 1 毫克（71%)之3-（1-六氫吼啶基）-4-[[2-[3-甲氧基-4-[Ν’ -（2-氟苯基）脲基]苯基乙醯基]甲胺基]乙氧基]苯甲酸 289的淡黃色結晶粉末。 熔點 125-130 〇C; IR (KBr) 3338、2935、1599 ^ 1 5 37、 1041、752 / 公分；NMR (CD3OD) 6 1· 52-1 · 73 (m， 6H)、2·88 (s，3H)、2·98 (br，1H)、3·09 (s，1H)、 3.23 (s，2H)、3·66 (s，2H)、3·75 (s，1H)、3.82 (s， 4H)、4·13 及 4.29 (m，總計 2H)、6·78 (m，2H)、6·99 (m，2H)、7·10 (m，2H)、7一. 60- 7.7 0 (m，2H)、7·96- 8.07 (m, 2H) ； MS(FAB) m/z 57 8 (MH1)； C31H35FN4〇6 · 0·5Η2Ο 之分析計算值：C，63·36;Η，6.17;N， 9.53。實 測值：C，63. 22 ; Η，6· 15 ; Ν，9· 1 6。 實施例239 3 -胺基-4-[[2-[3-甲氧基-4-[Ν -(2 -甲基笨基）服基]苯基 乙醯基]甲胺基]乙氧基]苯甲酸1283240 V. INSTRUCTION DESCRIPTION (740) The stirred mixture in THF (10 mL) was heated under reflux for 4 hours. The mixture was poured into water (200 mL), acidified with &lt;RTI ID=0.0&gt;&gt; The combined extracts were dried on MgS04 and evaporated. The residue was recrystallized from diisopropyl ether-hexane to give 2 1 1 mg (71%) of 3-(1-hexahydroacridinyl)-4-[[2-[3-methoxy- A pale yellow crystalline powder of 4-[Ν'-(2-fluorophenyl)ureido]phenylethenyl]methylamino]ethoxy]benzoic acid 289. Melting point 125-130 〇C; IR (KBr) 3338, 2935, 1599 ^ 1 5 37, 1041, 752 / cm; NMR (CD3OD) 6 1· 52-1 · 73 (m, 6H), 2·88 (s , 3H), 2·98 (br, 1H), 3·09 (s, 1H), 3.23 (s, 2H), 3.66 (s, 2H), 3·75 (s, 1H), 3.82 (s , 4H), 4·13 and 4.29 (m, total 2H), 6.78 (m, 2H), 6.99 (m, 2H), 7·10 (m, 2H), 7: 60-7.7 0 (m, 2H), 7·96- 8.07 (m, 2H); MS (FAB) m/z 57 8 (MH1); C31H35FN4〇6 · 0·5Η2Ο Analysis calculated: C, 63·36; 6.17; N, 9.53. Found: C, 63. 22; Η, 6·15 ; Ν, 9·16. Example 239 3 -Amino-4-[[2-[3-methoxy-4-[Ν-(2-methylphenyl))]phenylethenyl]methylamino]ethoxy ]benzoic acid

於3-胺基-4-[ [2- [3-甲氧基-4- [Ν’ -（2-甲基笨基）脲基] 苯基乙醯基]甲胺基]乙氧基]苯甲酸甲酯（300毫克，〇583-Amino-4-[[2-[3-methoxy-4-[Ν'-(2-methylphenyl)ureido]phenylphenyl]methylamino]ethoxy] Methyl benzoate (300 mg, 〇58

\\312\2d-code\90-01\89112968.ptd 第 745 頁 1283240 五、發明說明（741) 毫莫耳）溶於MeOH-THF(2 : 1，v/v，1 2毫升）之攪拌溶液中 加入0 · 2 5 N N a 0 Η ( 9毫升），並使所產生之混合物迴流加熱 1 6小時。將混合物倒入至水（1 0 0毫升）中，並經由加入1 ν HC1而酸化。利用吸濾收集固體。使殘留物自二異丙醚再 結晶’而得243毫克（83%) 3 -胺基-4 - [[2-[3-甲氧基-4-[ Ν’ - (2-曱基苯基）脲基]苯基乙醯基]甲胺基]乙氧基]苯曱 酸2 9 0的黃色結晶粉末。 熔點125-13〇1;11?(〇1〇 3346、2 935、1 533、1211、 1 034、75 6、6 37 / 公分；NMR (DMS0-d6) 6 2· 29 (s， 3H)、3·05 (s，1H)、3·72 - 3.8 5 (m，7H)、4·12 及 4.25 (m，總計2Η)、6·76_6·89 (m，3Η)、7·00 (m，1Η)、7·18 (m，2H)、7·39 (m，2H)、7·60 (d，1H，J二7.8 Hz)、 7. 96 (m， 1H) ; C27H3GN4 06 · 0· 5H20 之分析計算值：c， 62·90;Η，6·06;Ν，10.87。實測值：C，6 3.0 3; H， 6· 14 ; N，10. 56。 實施例240 3 -（1-六氫吼啶基）-4 - [[2 - [3-甲氧基-4 - [N，_(2 -甲基苯 基）脲基]苯基乙醯基]甲胺基]乙氧基]苯甲酸\\312\2d-code\90-01\89112968.ptd Page 745 1283240 V. INSTRUCTIONS (741) Millol) Stir in MeOH-THF (2: 1, v/v, 12 mL) 0 · 2 5 NN a 0 Η (9 ml) was added to the solution, and the resulting mixture was heated under reflux for 16 hours. The mixture was poured into water (100 mL) and acidified by addition of 1 EtOAc. The solid was collected by suction filtration. The residue was recrystallized from diisopropyl ether to give 243 mg (83%) of 3 -amino-4 - [[2-[3-methoxy-4-[ Ν' - (2-nonylphenyl) A yellow crystalline powder of ureido]phenylethenyl]methylamino]ethoxy]benzoic acid 290. Melting point 125-13〇1; 11? (〇1〇3346, 2 935, 1 533, 1211, 1 034, 75 6 , 6 37 / cm; NMR (DMS0-d6) 6 2· 29 (s, 3H), 3·05 (s, 1H), 3·72 - 3.8 5 (m, 7H), 4·12 and 4.25 (m, total 2Η), 6.76_6·89 (m, 3Η), 7·00 (m, 1Η), 7·18 (m, 2H), 7·39 (m, 2H), 7·60 (d, 1H, J 2 7.8 Hz), 7. 96 (m, 1H); C27H3GN4 06 · 0· 5H20 Analysis calculated: c, 62·90; Η, 6·06; Ν, 10.87. Found: C, 6 3.0 3; H, 6· 14 ; N, 10. 56. Example 240 3 - (1 Hexahydroacridinyl)-4 - [[2 - [3-methoxy-4-[N,-(2-methylphenyl)ureido]phenylethyl]methylamino]ethoxy ]benzoic acid

於3-胺基-4-[ [2- [3-曱氧基-4-[N，-（2-甲基笨基）脲基] 苯基乙醯基]甲胺基]乙氧基]苯甲酸甲酯（573毫克，1·；[毫 莫耳）溶於THF-MeOH(2:l，v/v, 6毫升）之冷卻攪拌溶液中3-Amino-4-[[2-[3-]oxy-4-[N,-(2-methylphenyl)ureido]phenylphenyl]methylamino]ethoxy] Methyl benzoate (573 mg, 1·; [mole] dissolved in THF-MeOH (2:1, v/v, 6 mL)

1283240 五、發明說明（742) 加入戊二醛（〇·423毫升，2·2毫莫耳）、3N H2S04 (1.83毫 升，5· 5毫莫耳）、及NaBH3CN(27&amp;毫克，4. 4毫莫耳）。使 所產生之混合物在室溫下攪拌1 8小時。將混合物倒入至飽 和NaHC03 ( 1 0 0毫升）中，並利用吸濾收集固體。使粗製固 體經由於石夕膠上利用甲苯-丙g同（1〇:〇至4:1，v/v)進行管 柱層析，純化而得240毫克（37%) 3-(1-六氫咄啶基）-4 -[[2-[3 -甲氧基-4-[ Ν’-（2-甲基苯基）脲基]苯基乙醯基] 甲胺基]乙氧基]苯曱酸甲酯290的膠。 UMR (CD3OD) 6 1· 5 2- 1. 72 (m，6Η)、2· 30 (s，3Η)、 2.36 (s，2H)、2·89 (br s，3H)、2·98 (m，1H)、3·05 (s， 1H) 、3·20 (s， 2H) 、3·68 (s， 2H) 、3·69 (m， 2H) 、3·79 (m， 2H) 、3·88 (s， 2H) 、4·08 及4.21 (m， 2H)、 6·35 及 6.42 (s，總計 1H)、6·70 (s，1H)、6·70 (s，1H) 、6.79 (m，2H)、7·09- 7.2 4 (m，4H)、7·50-7.65 (m，3H)、8·05 (d，1H，J = 8.3 Hz); MS(FAB) m/z 588 (MH1)。 使3-（1-六氫吡啶基）-4-[[2-[3-甲氧基-4-[^，-（2-甲基 苯基）脲基]苯基乙醯基]甲胺基]乙氧基]苯曱酸曱酯（240 毫克，0·41毫莫耳）、1N Na〇H(1.63毫升）於MeOH(6.5毫 升）、1〇(5毫升）、及THF(6. 5毫升）中之攪拌混合物迴流 加熱11小時。將混合物倒入至水（2 〇 〇毫升）中，經由加入 IN HC1酸化直至pH = 4· 〇為止，並利用吸濾收集固體。以 CHCl3-MeOH(9:l，v/v ’30毫升x3)萃取水層。將沈澱物溶 解於結合的有機萃取液中。將有機層於MgS〇4上乾燥，並1283240 V. INSTRUCTIONS (742) Add glutaraldehyde (〇·423 ml, 2·2 mmol), 3N H2S04 (1.83 ml, 5·5 mmol), and NaBH3CN (27 &amp; mg, 4.4) Millions of ears). The resulting mixture was stirred at room temperature for 18 hours. The mixture was poured into saturated NaHC03 (100 mL) and the solid was collected by suction filtration. The crude solid was purified by column chromatography on toluene-propanol (1 〇: 〇 to 4:1, v/v) to obtain 240 mg (37%) 3-(1-hexa). Hydroziridinyl)-4 -[[2-[3-methoxy-4-[Ν--(2-methylphenyl)ureido]phenylethenyl]methylamino]ethoxy] A gel of methyl benzoate 290. UMR (CD3OD) 6 1· 5 2- 1. 72 (m, 6Η), 2· 30 (s, 3Η), 2.36 (s, 2H), 2·89 (br s, 3H), 2·98 (m , 1H), 3·05 (s, 1H), 3·20 (s, 2H), 3·68 (s, 2H), 3·69 (m, 2H), 3·79 (m, 2H), 3 · 88 (s, 2H), 4·08 and 4.21 (m, 2H), 6·35 and 6.42 (s, total 1H), 6.70 (s, 1H), 6.70 (s, 1H), 6.79 (m, 2H), 7·09- 7.2 4 (m, 4H), 7·50-7.65 (m, 3H), 8·05 (d, 1H, J = 8.3 Hz); MS(FAB) m/z 588 (MH1). 3-(1-Hexhydropyridyl)-4-[[2-[3-methoxy-4-[^,-(2-methylphenyl)ureido]phenylethenyl]methylamine Ethyl ethoxy] benzoic acid oxime ester (240 mg, 0.41 mmol), 1N Na〇H (1.63 mL) in MeOH (6.5 mL), 1 EtOAc (5 mL) The stirred mixture in 5 ml) was heated under reflux for 11 hours. The mixture was poured into water (2 mL), acidified by addition of IN HCl to pH = 4 〇, and the solid was collected by suction filtration. The aqueous layer was extracted with CHCl3-MeOH (9:1, v/v&apos; The precipitate is dissolved in the combined organic extract. Dry the organic layer on MgS〇4 and

1283240 五、發明說明（743) 蒸發。使殘留物自二異丙醚結晶，而得151毫克（65%)之 3-（1-六氫吼啶基）-4-[ [2-[3-甲氧基-4-[N，-（2-甲基苯 基）脲基]笨基乙醯基]甲胺基]乙氧基]苯甲酸2 91的淡黃色 結晶粉末。 熔點 1 20- 1 25 °C ; IR (KBr) 3 35 4、2935、1535、1252、 1217、1034、754、638/公分；UMR (CD30D) (5 1· 55-1·72 (m，6Η)、2.30 (s，3Η)、2·89 (br，2Η)、2·98 (br, 1Η)·、3·09 (s，1H)、3·22 (s，2H)、3·69 (s，3H) 、3.74 (s，1H)、3·83 (m，4H)、4·12 及 4·28 (m，總計 2H)、6·75 (m，2H)、6·88-7·02 (m，1H)、7·17 (m, 2H) 、7·58-7.73 (m，4H)、7·99 (d，1H，J = 8.3 Hz); MS (FAB) m/z 574 (MH1) ; C32H38N4 06 · 0· 5H20 之分析計算值： C，65. 85 ; Η, 6· 73 ; N，9· 60。實測值：C，65· 94 ; H， 6. 88 ； N, 9.03° 實施例241 3 -胺基-4 - [[2 - [3-甲氧基-4 - [Ν’ -（2 -氟苯基）脲基]苯基乙 醯基]甲胺基]乙氧基]苯曱酸1283240 V. Description of invention (743) Evaporation. The residue was crystallized from diisopropyl ether to give 151 mg (65%) of 3-(1-hexahydroacridinyl)-4-[[2-[3-methoxy-4-[N,- A pale yellow crystalline powder of (2-methylphenyl)ureido]pyridylethyl]methylamino]ethoxy]benzoic acid 2 91. Melting point 1 20- 1 25 °C; IR (KBr) 3 35 4, 2935, 1535, 1252, 1217, 1034, 754, 638 / cm; UMR (CD30D) (5 1 · 55-1 · 72 (m, 6 Η ), 2.30 (s, 3Η), 2·89 (br, 2Η), 2·98 (br, 1Η)·, 3·09 (s, 1H), 3·22 (s, 2H), 3·69 ( s, 3H), 3.74 (s, 1H), 3·83 (m, 4H), 4·12 and 4·28 (m, total 2H), 6.75 (m, 2H), 6·88-7· 02 (m,1H),7·17 (m, 2H), 7·58-7.73 (m,4H), 7·99 (d,1H,J = 8.3 Hz); MS (FAB) m/z 574 ( MH1) ; C32H38N4 06 · 0· 5H20 Analysis calculated: C, 65. 85 ; Η, 6· 73 ; N, 9· 60. Found: C, 65· 94 ; H, 6. 88 ; N, 9.03 ° Example 241 3 -Amino-4 - [[2 - [3-methoxy-4 -[Ν' -(2-fluorophenyl)ureido]phenylethyl]methylamino] ethoxylate Benzoic acid

使3-胺基-4-[ [2-[3-甲氧基一4-[Ν’ -(2-氟苯基）脲基]苯 基乙醯基]甲胺基]乙氧基]苯甲酸甲酯（250毫克，0.48毫 莫耳）、1N NaOH(1.91 毫升）、MeOH(8 毫升）、Η20(6 毫 升）、及THF (8毫升）之攪拌混合物迴流加熱1 〇小時。將混3-Amino-4-[[2-[3-methoxy-l4-[Ν'-(2-fluorophenyl)ureido]phenylethenyl]methylamino]ethoxy]benzene A stirred mixture of methyl formate (250 mg, 0.48 mmol), 1N NaOH (1.91 mL), MeOH (8 mL), EtOAc (EtOAc) Will mix

89112968.ptd 第748頁 1283240 五、發明說明（744) 合物倒入至水（ 200毫升）中，經由加入IN HC1酸化（pH = 4 · 8 )，並利用吸濾收集固體。使粗製固體自二異丙醚再結 晶’而得2〇9毫克（86%)之3-胺基- [[2 - [3-甲氧基-4- [Ν’ -（2-氟苯基）脲基]苯基乙醯基]甲胺基]乙氧基]苯甲酸 292的淡黃色結晶粉末。 熔點125-130 °C ; IR (KBr) 3325、2935、1 537、1 20 9、 1 032、752、449 / 公分；NMR (CD3OD) 5 3· 05 (s， 1H)、3·31 (s，2H)、3·77 (m，3H)、3·80 (s，1H)、 3.84 (m，3H)、4·14-4·26 (m，2H)、6.80-6.87 (m, 3H) 、7 · 0 1 (m，1 H)、7 · 1 〇 (m, 2 H)、7 · 3 9 (m，2 H )、7 · 8 0 (m，1H)、8.07 (m，1H); MS(FAB) m/z 510 (MH1); C26H27FN4 06 · 0· 5H2〇 之分析計算值·· C，60.11； H, 5. 43 ； F，3·66; N，1〇·87。實測值：C， 60·29;Η，5.40; F， 3· 60 ; N，10· 59 0 實施例2 4 2 (S) 一 3 一胺基-4 - [[2-[3-甲氧基-4-[Ν’-(2-曱基苯基）脲基 ]苯基乙醯胺基]一1 一丙氧基]苯甲酸89112968.ptd Page 748 1283240 V. Inventive Note (744) The compound was poured into water (200 ml), acidified (pH = 4 · 8) by addition of IN HCl, and the solid was collected by suction filtration. The crude solid was recrystallized from diisopropyl ether to give 2 〇 9 mg (86%) of 3-amino-[[2 - [3-methoxy-4-[Ν'-(2-fluorophenyl) A pale yellow crystalline powder of ureido]phenylethenyl]methylamino]ethoxy]benzoic acid 292. Melting point 125-130 °C; IR (KBr) 3325, 2935, 1 537, 1 20 9 , 1 032, 752, 449 / cm; NMR (CD3OD) 5 3· 05 (s, 1H), 3·31 (s , 2H), 3·77 (m, 3H), 3·80 (s, 1H), 3.84 (m, 3H), 4·14-4·26 (m, 2H), 6.80-6.87 (m, 3H) , 7 · 0 1 (m, 1 H), 7 · 1 〇 (m, 2 H), 7 · 3 9 (m, 2 H ), 7 · 8 0 (m, 1H), 8.07 (m, 1H) ; MS (FAB) m / z 510 (MH1); C26H27FN4 06 · 0 · 5H2 分析 analytical calculations · · C, 60.11; H, 5. 43 ; F, 3 · 66; N, 1 〇 · 87. Found: C, 60·29; Η, 5.40; F, 3· 60 ; N, 10· 59 0 Example 2 4 2 (S) A 3-amino-4 - [[2-[3-methoxy -4-[Ν'-(2-Mercaptophenyl)ureido]phenylethenylamino]-1-propoxy]benzoic acid

；ΟΟΗ ΝΗ2 在室溫下於（S)-2-(Ν-第三丁氧幾胺基）-1-丙醇（0· 90 克，5· ^毫莫；）、4-羥基苯甲酸曱酯（1· 01克，5· 12毫莫 耳）、及Ph3PU·75克，6·67毫莫耳）溶於THF(15毫升）之攪 拌溶液中力3口入偶氮二羧酸二異丙醋（DIAD) (1.31毫升’;ΟΟΗ ΝΗ 2 at room temperature in (S)-2-(anthracene-t-butoxyamino)-1-propanol (0·90 g, 5·^ mmol;), 4-hydroxybenzoate hydrazine Ester (1·01 g, 5·12 mmol), and Ph3PU·75 g, 6.67 mmol) dissolved in THF (15 ml) in a stirred solution of 3 azodicarboxylic acid dimer Vinyl vinegar (DIAD) (1.31 ml'

第749頁 89112968.ptd 1283240 五、發明說明（745) 6 · 6 5毫莫耳）’並使所產生之混合物迴流加熱隔夜。將溶 液蒸發’並將殘留物溶解於CH2Cl2(2〇毫升）及TFA(i〇毫升） 中。使混合物在室溫下攪拌3小時。將混合物於真空中濃 縮。將殘留物溶解於CHC13，以飽和NaHC〇3、鹽水洗滌，於 NaJO4上乾燥，並蒸發。將殘留物經由於矽膠上利用5% MeOH溶於CHC：3作為洗提液進行管柱層析，純化而得313毫 克（24 % )(S) - 3 -硝基一 4 一（2 -胺基-1-丙氧基）苯甲酸甲酯的 淡黃色油。 ^-NMR (CDC13) 5 1.22 (d, 3H, J = 6. 8 Hz) ^ 3. 43-3. 48 (m，1H)、3·69- 3.87 (m，2H)、3.89 (s，3H)、6·93-6 · 9 5 (m，1 Η )、7 · 9 9 - 8 · 0 2 (m，1 Η)、8 · 1 8 - 8 · 2 1 (m， 1H)。 ’ 使3-甲氧基-4-[Ν’-（2_甲基苯基）脲基]苯基乙酸五氟苯 酯（591毫克，1·23毫莫耳）、（S)-3 -硝基-4-(2-Ν-胺基-1 一 丙氧基）苯甲酸甲酯（313毫克，1.23毫莫耳）、Et3N(257毫 克’ 1.84毫莫耳）於DMF( 5毫升）中之混合物在室溫下攪拌2 天。將混合物以EtOAc稀釋，以〇·5Ν HC1、鹽水洗滌，於 N az S 〇4上乾燥’並蒸發。使殘留物經由於石夕膠上利用$ % MeOH溶於CHCI3作為洗提液進行管桎層析，純化而得3丨〇毫 克（46%)(S)-3-硝基-4-[2-[3-甲氧基—4—[N，-(2—甲基苯 基）脲基]苯基乙醯胺基]-1-丙氧基]苯曱酸曱g旨的膠。 ^-NMR (CDCI3) δ 1.28 (d, 3H, J = 6.8 Hz) 31 s 3H)、3·49 (s，2H)、3.71 (s，3H)、3.92 (s，3H)、’ 4.14-4.16 (m，2H)、4· 38-4·41 (m，1H)、5 8 8一5 9〇Page 749 89112968.ptd 1283240 V. Description of the invention (745) 6 · 6 5 millimoles) and the resulting mixture is refluxed and heated overnight. The solution was evaporated and the residue was dissolved in CH.sub.2Cl.sub.2 (2 mL). The mixture was stirred at room temperature for 3 hours. The mixture was concentrated in vacuo. The residue was dissolved in CH.sub.3, washed with sat. NaHC.sub.3, brine, dried over NaCI and evaporated. The residue was purified by column chromatography using 5% MeOH in CH.sub.3:3 as eluent to afford 313 mg (24%) of (S) - 3 -nitro- 4- (2-amine A pale yellow oil of methyl 1-propoxy)benzoate. ^-NMR (CDC13) 5 1.22 (d, 3H, J = 6. 8 Hz) ^ 3. 43-3. 48 (m, 1H), 3.69- 3.87 (m, 2H), 3.89 (s, 3H) ),6·93-6 · 9 5 (m,1 Η ), 7 · 9 9 - 8 · 0 2 (m,1 Η), 8 · 1 8 - 8 · 2 1 (m, 1H). '3-methoxy-4-[Ν'-(2-methylphenyl)ureido]phenylacetic acid pentafluorophenyl ester (591 mg, 1.23 mmol), (S)-3 - Methyl nitro-4-(2-indole-amino-1-propoxy)benzoate (313 mg, 1.23 mmol), Et3N (257 mg &lt;&lt;&gt;&gt; The mixture was stirred at room temperature for 2 days. The mixture was diluted with EtOAc, washed with EtOAc EtOAc EtOAc. The residue was purified by column chromatography on silica gel using EtOAc (MeOH) eluting with CHCI3 as eluent, yielding 3 mM (46%) (S)-3-nitro-4-[2 -[3-methoxy-4-[N,-(2-methylphenyl)ureido]phenylethenylamino]-1-propoxy]benzoic acid 曱g. ^-NMR (CDCI3) δ 1.28 (d, 3H, J = 6.8 Hz) 31 s 3H), 3·49 (s, 2H), 3.71 (s, 3H), 3.92 (s, 3H), ' 4.14-4.16 (m, 2H), 4·38-4·41 (m, 1H), 5 8 8 to 5 9

1283240 五、發明說明（746) (m，1H)、6·49 (s，1H)、6·70-6·71 Cm，1H)、6·77-6·79 (m，1Η)、7·05-7·30 (m，4Η)、7·5 5-7.5 7 (m， lH)、8.0 2-8.0 6 (m，2H)、8.16-8.19(m，lH)、8.51-8.52 (m，1H) ; MS(FAB) m/z 551 (MH1) 0 使（S)-3 -硝基-4 - [2-[3-曱氧基-4 - [Ν’ _(曱基笨基）脲 基]苯基乙醯胺基-1-丙氧基]苯甲酸甲酯（310毫克，〇.56 毫莫耳）溶於MeOH-THF(l 0毫升，1 : 1，ν/ν)之攪拌溶液在 5% Pd-C( 50毫克，16重量百分比）上氫化隔夜。將混合物 過濾以移除催化劑，並將濾液蒸發而得（S)-3-胺基-4-[2 - [3-甲氧基-4-[ Ν’ - (2-曱基苯基）脲基]笨基乙醯胺基]一 1-丙氧基]苯甲酸酯（240毫克）的膠。 於以上粗製產物（ 220毫克）溶於THF-MeOH(10毫升，1 : 1， ν/ν)之攪拌溶液中加入0.5N NaOH(10毫升），並使所產生 之混合物迴流加熱2小時。將混合物倒入至冰的H2 0中，並 經由加入IN HC1使水層成為酸性（pH 4· 8)。收集固體，並 使粗製固體自MeOH_CHCl3-正己烷再結晶，而得116毫克（2 步驟44%) (S)-3-胺基-4-[2-[3-曱氧基—4- [Ν’ -（2-曱基笨 基）脲基]苯基乙贐胺基-1-丙氧基]苯甲酸293的淡黃色結 晶粉末。 熔點20 0-204 °(：;111-關1?(1)»130-(16)(5 1.21((1，311，}= 6·8 Ηζ)、2·24 (s，3Η)、3.37 (s，2Η)、3·80 (s，3Η) 、3·83 -3.99 (m，2Η)、4·10-4·19 (m，ΐΗ)、4·99 (bs， 2H)、6. 75-7. 23 (m 系列，總計8H)、7· 79 (d， 1H， J=7· 81283240 V. INSTRUCTIONS (746) (m, 1H), 6.49 (s, 1H), 6·70-6·71 Cm, 1H), 6·77-6·79 (m, 1Η), 7· 05-7·30 (m, 4Η), 7·5 5-7.5 7 (m, lH), 8.0 2-8.0 6 (m, 2H), 8.16-8.19 (m, lH), 8.51-8.52 (m, 1H) ; MS(FAB) m/z 551 (MH1) 0 (S)-3 -Nitro-4 - [2-[3-曱oxy-4 - [Ν' _(indolyl)]urea Methyl phenyl acetamido-1-propoxy]benzoate (310 mg, 〇.56 mmol) dissolved in MeOH-THF (10 mL, 1:1, ν / ν) The solution was hydrogenated over 5% Pd-C (50 mg, 16 weight percent) overnight. The mixture was filtered to remove the catalyst, and the filtrate was evaporated to give (S)-3-amino-4-[2-[3-methoxy-4-[[upsilon]-(2-mercaptophenyl)urea a gum of a nonylaminoethylamino-1-propyloxy]benzoate (240 mg). To a stirred solution of the above crude product (220 mg), EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj The mixture was poured into ice H2 0 and the aqueous layer was made acidic (pH 4·8) by the addition of IN HCl. The solid was collected and the crude solid was recrystallised from MeOH <RTI ID=0.0># </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; A pale yellow crystalline powder of '-(2-indolyl) ureido]phenylethylamino-1-propoxy]benzoic acid 293. Melting point 20 0-204 °(:; 111-off 1?(1)»130-(16)(5 1.21((1,311,}= 6·8 Ηζ), 2·24 (s,3Η), 3.37 (s, 2Η), 3·80 (s, 3Η), 3.83 -3.99 (m, 2Η), 4·10-4·19 (m, ΐΗ), 4·99 (bs, 2H), 6. 75-7. 23 (m series, total 8H), 7·79 (d, 1H, J=7·8

Hz)、7.98 (d，1H，J = 7.8 Hz)、8·17 (d，1H，J = 8.3Hz), 7.98 (d, 1H, J = 7.8 Hz), 8·17 (d, 1H, J = 8.3

\\312\2d-code\90-01\89112968.ptd 第751頁 1283240 五、發明說明（747) Ηζ)、8·46 (s，1H)、8.55 (s，1H); MS(FAB) m/z 507 (MH1) ; C27H3QN4〇6 · 1/2H20 之分析計算值：C，62. 90 ; Η, 6· 06 ; N， 10· 87。實測值·· c，62. 85 ; H，6· 10 ; N， 10.51。 實施例243 (S)-4 - [2 - [3-甲氧基-4 一 [ν’ -（2 -溴苯基）脲基]苯基乙醯胺 基]-1-丙氧基]笨甲酸\\312\2d-code\90-01\89112968.ptd Page 751 1283240 V. INSTRUCTIONS (747) Ηζ), 8.46 (s, 1H), 8.55 (s, 1H); MS(FAB) m /z 507 (MH1) ; C27H3QN4〇6 · 1/2H20 Analysis calculated: C, 62. 90 ; Η, 6· 06 ; N, 10· 87. Found C·62.85; H,6· 10 ; N, 10.51. Example 243 (S)-4 - [2- [3-methoxy-4-[ν'-(2-bromophenyl)ureido]phenylethylamino]-1-propoxy] Formic acid

於（S) - 2-(N-第三丁氧羰胺基）-1-丙醇（6.74克，0.04毫 莫耳）、4 -羥基苯甲酸苄酯（8.78克，0.04毫莫耳）、及 Ph3P(15. 13克，〇·〇6毫莫耳）溶於THF(l〇〇毫升）之冷卻（〇 °C)攪拌溶液中加入偶氮二羧酸二異丙酯（DIAD)(1丨· 4毫 升，0· 06毫莫耳），並使所產生之混合物迴流加熱隔夜。 將溶液蒸發，並將殘留物溶解於CH2C12(30毫升）及TFA (30 毫升）中。使所產生之溶液在室溫下攪拌3〇分鐘，並將溶 液蒸發。將殘留物〉谷解於CHCL，以飽和MaHC03洗蘇，於 NaJO4上乾燥，並蒸發。將殘留物經由於矽膠上利用CHCi 至CHC13 :MeOH(9:l，v/v)作為洗提液進行管柱層析，純3 化而得6.63克（2步驟，60%)(幻—2一（2—胺基—1—丙氧基）苯 甲酸苄酯的黃色油。 1 JH-NMR (CDCI3) 5 1. 18 (d, (m, 1H) ^3.71-3.75 (m, 1 ，J=6·3 Hz， 3H) 、 3·35-3·39 1H) 、 3· 90-3·93 (m， 1H)、(S)-2-(N-T-butoxycarbonylamino)-1-propanol (6.74 g, 0.04 mmol), benzyl 4-hydroxybenzoate (8.78 g, 0.04 mmol), And Ph3P (15. 13 g, 〇·〇 6 mmol) dissolved in THF (10 ml) cooled (〇 ° C) stirred solution was added diazo azodicarboxylate (DIAD) (1丨·4 ml, 0·06 mmol, and the resulting mixture was refluxed and heated overnight. The solution was evaporated and the residue was crystalljjjjjjjjjj The resulting solution was stirred at room temperature for 3 minutes and the solution was evaporated. The residue was lysed in CHCL, washed with saturated NaHC03, dried over NaJO4, and evaporated. The residue was subjected to column chromatography using CHCi to CHC13: MeOH (9:1, v/v) as an eluent, and purified to give 6.63 g (2 steps, 60%). Yellow oil of benzyl 2-(amino-l-propoxy)benzoate. 1 JH-NMR (CDCI3) 5 1. 18 (d, (m, 1H) ^3.71-3.75 (m, 1 ,J =6·3 Hz, 3H), 3·35-3·39 1H), 3·90-3·93 (m, 1H),

1283240 五、發明說明（748) 5.34 (s，2H)、6·90-6·93 (m，2H)、7·32-7·46 (m，5H) 、8· (Η -8· 04 (m，2Η) 〇 使（S) - 2-（2 -胺基-1-丙氧基）笨甲酸酯（361毫克，127 毫莫耳）、EDC(氫氣酸鹽）（364毫克，1.90毫莫耳）、H0Bt (256¾克’1.89耄莫耳）、及4-DMAP (31毫克，0.25毫莫 耳）於DMF (8毫升）中之混合物在室溫下攪拌隔夜。將混合 物以EtOAc稀釋’以0.5N HC1、鹽水洗滌，於Na2s〇4上乾 燥，並蒸發。使殘留物經由於矽膠上利用CHcl3至5% Me〇H &gt;谷於CHCI3·作為洗提液進行管柱層析，純化而得476毫克1283240 V. INSTRUCTIONS (748) 5.34 (s, 2H), 6·90-6·93 (m, 2H), 7·32-7·46 (m, 5H), 8· (Η -8· 04 ( m, 2 Η) ( (S) - 2-(2-Amino-1-propoxy) benzoate (361 mg, 127 mmol), EDC (hydrogenate) (364 mg, 1.90 m) A mixture of H.sub.2, H.sub.2 (.sup.), EtOAc (EtOAc), EtOAc (EtOAc) Washing with 0.5N HCl, brine, drying on Na2s 〇4, and evaporating. The residue was purified by column chromatography using CHCl3 to 5% Me〇H &gt; And got 476 mg

(58%) (S)-4-[2-[3-甲氧基-4- [N，-（2-溴苯基）脲基]苯基 乙醢胺基]-1-丙氧基]苯甲酸苄酯的棕色固體。 l-NMR (CDC13) (5 1.25-1.28 (m，3H)、3.51 (s，2H)、 3.74 (s，3H)、3.95-3.97 (m，2H)、4·36-4·39 (m， 1H)、5·33 (s，2H)、6·75-6·94 (m，5H)、7·26-7 7〇 (m， 8H) 、 7.99-8.26 (m， 5H)。(58%) (S)-4-[2-[3-methoxy-4-[N,-(2-bromophenyl)ureido]phenylethylamino]-1-propoxy] Benzyl benzoate as a brown solid. l-NMR (CDC13) (5 1.25-1.28 (m, 3H), 3.51 (s, 2H), 3.74 (s, 3H), 3.95-3.97 (m, 2H), 4·36-4·39 (m, 1H), 5·33 (s, 2H), 6·75-6·94 (m, 5H), 7·26-7 7〇 (m, 8H), 7.99-8.26 (m, 5H).

於（S)-4-[2-[3-曱氧基-4-[Ν’ -（2-溴笨基）脲基]笨基乙 酿胺基]-1-丙氧基]苯甲酸苄酯（476毫克，h39毫莫耳）溶 於THF(10毫升）之攪拌溶液中加入〇·5Ν NaOH(10毫升），並 使所產生之混合物迴流加熱2小時。將混合物倒入至冰的 IN HC1中，並收集固體。使粗製固體自Me〇H — CHCl3 —正己 烷再結晶，而得240毫克（59%) (S) - 4-[2 - [3-曱氧基一4 - [Ν’- (2 -溴苯基）脲基]苯基乙醯胺基卜卜丙氧基]苯甲酸 2 9 4的白色結晶粉末。 熔點202-205 1:1-NMR (DMS0-d6)6 ι·18 (d，J = 6 8 1283240 五、發明說明（749)(S)-4-[2-[3-曱oxy-4-[Ν'-(2-bromophenyl)ureido]]phenylamino]-1-propoxy]benzoic acid benzyl To a stirred solution of EtOAc (EtOAc (EtOAc)EtOAc. The mixture was poured into ice IN HCl and the solid was collected. The crude solid was recrystallized from Me 〇 H - CHCl 3 - n-hexane to give 240 mg (59%) of (S) - 4-[2 - [3-methoxy-l-[2-[2-bromobenzene] A white crystalline powder of ureido]phenyl acetoamine sulfapropoxy]benzoic acid 294. Melting point 202-205 1:1-NMR (DMS0-d6) 6 ι·18 (d, J = 6 8 1283240 V. Description of invention (749)

Hz，3H)、3·37 (s，2H)、3.82 (s，3H)、3·92-4·00 (m， 2H)、4·03 - 4.15 (m，1H)、6·77-6·79 (m，1H)、6·93 -7·03 (m，4H)、7·30-7·34 (m，1H)、7·59-7·61 (m， 1Η)、7·87-7·97 (m，4Η)、8·13-8·15 (m，1Η)、8·73 (s，1H)、8·91 (s，1H)、12·63 (bs，1H); MS(FAB) m/z 55 7 (MH1 ) ; C26H26BrN3 06 之分析計算值：c，56. 12 ; H， 4. 71 ; Br，1 4· 36 ; N，7. 55。實測值：c，56. 1 1 ; H， 4· 74 ; Br，14· 56 ; N，7· 49。 實施例244 (S)-4 - [[2-[3-甲氧基-4 - [N’_(2_甲基苯基）脲基]苯基乙 醯基]-（2 -胺苄基）胺基]-1 一丙氧基]苯甲酸 ° ch3Hz, 3H), 3·37 (s, 2H), 3.82 (s, 3H), 3·92-4·00 (m, 2H), 4·03 - 4.15 (m, 1H), 6·77-6 ·79 (m,1H),6·93 -7·03 (m,4H), 7·30-7·34 (m,1H), 7·59-7·61 (m, 1Η), 7·87 -7·97 (m, 4Η), 8·13-8·15 (m, 1Η), 8.73 (s, 1H), 8.91 (s, 1H), 12·63 (bs, 1H); MS (FAB) m/z 552 (MH): Found: C, s, s, s, s, s, s, s, s, s, s. Found: c, 56.1 1 ; H, 4· 74 ; Br, 14· 56 ; N, 7. 49. Example 244 (S)-4 - [[2-[3-Methoxy-4-[N'-(2-methylphenyl)ureido]phenylethenyl]-(2-aminebenzyl) Amino]-1-propoxy]benzoic acid ° ch3

XOOH 295 &gt;於（3)-4-2-胺基一1—丙氧基）苯甲酸爷酯（15()克，5.26 毫莫耳）-確基苯甲醛（〇· 78克，5· 76毫莫耳）溶於Me〇H一 Ac0H(16毫升，15:1，v/v)之冷卻（〇。〇攪拌溶液中加入 克，26. 3毫莫耳），並使所產生之混合物在 室溫下擾+拌隔夜。利用飽和NaHC〇3使混合物停止反應，並 以E^OAc萃取。將萃取液以鹽水洗滌，於上乾燥，並 蒸务°將殘留物經由於矽膠上利用CHCl3至5% Me〇H溶於 CHCl3作為洗提液進行管柱層析，純化而得931毫克（42%) 之（S)-4-[2-(2〜硝苄胺基）-〗—丙氧基]笨甲酸苄酯的黃色 油0XOOH 295 &gt; (3)-4-2-amino-1-propoxy)benzoic acid ester (15 () g, 5.26 mmol) - benzylbenzaldehyde (〇·78 g, 5· 76 mmol), dissolved in Me〇H-Ac0H (16 ml, 15:1, v/v) (〇. 克 〇 〇 , , , , , , , , , , , , , , , , , , , , , , Scramble + mix overnight at room temperature. The mixture was quenched with saturated NaHC(R)3 and extracted with EtOAc. The extract was washed with brine, dried, and evaporated. The residue was purified by column chromatography eluting with CHCl3 to 5% Me〇H in CHCl3 as an eluent to obtain 931 mg (42). %) yellow oil of (S)-4-[2-(2~nitrobenzylamino)-]propoxy]benzoic acid benzyl ester 0

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第754頁 1283240 五、發明說明（750) -NMR (CDC13) (5 1.21 (d，J = 6.4 Hz，3H)、3.13-3 18 (m，1H)、3·88-3·97 (m，2H)、4·06-4.20 (m，2H)、 5.34 (s，2H)、6·89-6.94 (m，2H)、7·29-7·65 (m，8H) 、7·94-8·03 (m，3H); MS(FAB) m/z 421(MH1)。 ’ 使3-曱乳基-4 - [N -(2-曱基苯基）脲基]苯基乙酸五敦苯 酯（460毫克，0.96毫莫耳）、（S)-4-[2-(2-硝笮胺基）一卜 丙氧基]苯曱酸芊酯（403毫克，〇· 96毫莫耳）、及E^n(2〇〇 毫升，1· 43毫莫耳）於DMF(8毫升）中之混合物在室溫下攪 拌隔夜。將混合物以EtOAc稀釋，以〇· 5N HC1、鹽水洗 滌’於NagSO4上乾燥’並蒸發。使殘留物經由於石夕膝上利 用1% MeOH溶於CHCI3作為洗提液進行管柱層析，純化而得 504 毫克（73%)之（S) -4 - [[2-[3-曱氧基一 4 - [N，_(2-甲基苯 基）脲基]苯基乙醯基]-(2 -硝苄基）胺基]—1—丙氧基]苯甲 酸苄酯的棕色非晶形固體。 MS(FAB) m/z 717(MH1)。 使（3)-4-[[2-[3-甲氧基-4-[1^’-(2-曱基苯基）脲基]苯 基]-(2 -硝苄基）胺基]-卜丙氧基]笨曱酸苄酯（5〇4毫克， 〇·7〇毫莫耳）溶於MeOH-THF(ll毫升，1〇:1，v/v)之攪拌溶 液在Pd-C(100毫克，20重量百分比）上在3大氣壓下氫 化隔仪。將混合物過濾以移除催化劑，並將濾液茱發。利 用製備TLC以5% MeOH溶於CHCI3作為洗提液，將殘留物純 化而知 115 聋：克（27%) (S)-4 - [[2 - [3 -甲氧基 -4-[N，-甲 基苯基）脲基]苯基乙醯基]一（2-胺乙醯基）—（2_胺苄基）胺 基]-1-丙氧基]苯甲酸295的白色粉末。 1283240 五、發明說明（751) MS(FAB) m/z 597CMH1)。 實施例2 4 5 (S)-4-[[2-[3_甲氧基-4-[N’-（2 -溴苯基）脲基]苯基乙醯 基]-（2_硝苄基）胺基]-1-丙氧基]苯曱酸Page 754 1283240 V. INSTRUCTIONS (750) - NMR (CDC13) (5 1.21 (d, J = 6.4 Hz, 3H), 3.13-3 18 (m, 1H), 3.88-3.97 (m, 2H), 4·06-4.20 (m, 2H), 5.34 (s, 2H), 6·89-6.94 (m, 2H), 7·29-7·65 (m, 8H), 7·94-8 · 03 (m, 3H); MS (FAB) m/z 421 (MH1). 'Methyl 3-mercapto-4 - [N-(2-mercaptophenyl)ureido]phenylacetic acid Ester (460 mg, 0.96 mmol), (S)-4-[2-(2-nitriloamino)-p-propoxy]benzoic acid decyl ester (403 mg, 〇·96 mmol) The mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc and washed with EtOAc····························· Drying on NagSO4' and evaporating. The residue was purified by column chromatography using 1% MeOH in CHCI3 eluting with EtOAc (EtOAc) eluting 504 mg (73%) of (S) -4 - [ [2-[3-曱-oxy-4-[N,-(2-methylphenyl)ureido]phenylethenyl]-(2-nitrobenzyl)amino]-1-propoxy a brown amorphous solid of benzyl benzoate MS (FAB) m/z 717 (MH1). 4-[[2-[3-methoxy-4-[1^'-(2-mercaptophenyl)ureido]phenyl]-(2-nitrobenzyl)amino]-propoxy Benzyl benzoate (5〇4 mg, 〇·7〇 mmol) dissolved in MeOH-THF (ll ml, 1〇:1, v/v) in Pd-C (100 mg, 20) The mixture was filtered at a pressure of 3 atm. The mixture was filtered to remove the catalyst and the filtrate was flashed. The residue was purified by preparative TLC with 5% MeOH dissolved in CHCI3 as eluent. (27%) (S)-4 - [[2 - [3 -methoxy-4-[N,-methylphenyl)ureido]phenylethenyl]-(2-aminoethyl) a white powder of (2-aminobenzyl)amino]-1-propoxy]benzoic acid 295. 1283240 V. INSTRUCTIONS (751) MS (FAB) m/z 597CMH1). Example 2 4 5 (S)-4-[[2-[3_methoxy-4-[N'-(2-bromophenyl)ureido]phenylethenyl]-(2-nitrobenzyl Amino]-1-propoxy]benzoic acid

於（S) -4-（2_胺基-1_丙氧基）苯曱酸苄酯（ι·5〇克，5.26 毫莫耳）及2-硝基苯甲醛（〇.87克，5.76毫莫耳）溶於心〇11 -Ac0H(16毫升，15: 1，ν/ν)之冷卻（〇 °C)攪拌溶液中加入Benzyl (S)-4-(2-amino-1-propoxy)benzoate (ι·5〇克, 5.26 mmol) and 2-nitrobenzaldehyde (〇.87 g, 5.76 Millol) is added to the stirring solution of 11-Ac0H (16 ml, 15: 1, ν / ν) (〇 ° C)

NaBH3CN(1.65克’26.3毫莫耳），並使所產生之混合物在 室溫下攪拌隔夜。利用飽和NaHC〇3使混合物停止反應，並 以EtOAc萃取。將萃取液以鹽水洗滌，於Na2S〇4上乾燥，並 蒸發。將殘留物經由於矽膠上利用CHC13至5% MeOH溶於 CHCI3作為洗提液進行管柱層析，純化而得931毫克（42%) 之（S)-4-[2-(2_硝辛胺基）-卜丙氧基]苯甲酸苄酯的黃色 油。 l-NMR (CDC13) ά 1.21 (d，3H，J = 6.4 Ηζ)、3.13-3.18 (m，1H) '3.88-3·97 (m，2H)、4·06-4·20 (m，2H)、 5·34 (s，2H)、6·89-6·94 (m，2H)、7·29-7·65 (m，8H) 、7·94-8·〇3 (m，3H); MS(FAB) m/z 42KMH1)。 使3-甲氧基-4-[N，_(2-溴苯基）脲基]苯基乙酸五氟苯酯 (476毫克’1.26毫莫耳）、（3)-4-[2-（2-硝窄胺基）-1-丙 氧基]笨甲酸笮酯（ 528毫克，1· 26毫莫耳）、EDC(氫氣酸NaBH3CN (1.65 g &lt;26.3 mmol) and the resulting mixture was stirred overnight at room temperature. The mixture was quenched with saturated NaHC EtOAc and extracted with EtOAc. The extract was washed with brine, dried over Na 2 EtOAc & evaporated. The residue was purified by column chromatography using CHC13 to 5% MeOH dissolved in CHCI3 as eluent to give 931 mg (42%) of (S)-4-[2-(2-nitridin) Yellow oil of benzyl)-p-propoxy]benzyl benzoate. l-NMR (CDC13) ά 1.21 (d, 3H, J = 6.4 Ηζ), 3.13-3.18 (m, 1H) '3.88-3·97 (m, 2H), 4·06-4·20 (m, 2H) ), 5·34 (s, 2H), 6·89-6·94 (m, 2H), 7·29-7·65 (m, 8H), 7·94-8·〇3 (m, 3H) ; MS (FAB) m/z 42KMH1). 3-methoxy-4-[N,-(2-bromophenyl)ureido]phenylacetic acid pentafluorophenyl ester (476 mg '1.26 mmol), (3)-4-[2-( 2-Nitrate amino)-1-propoxy] benzoic acid decyl ester (528 mg, 1.25 mmol), EDC (hydrogen acid)

89112968.ptd 第756頁 1283240 五、發明說明（752) 鹽）（361毫克，1· 88毫莫耳）、H0Bt(255毫克，ι 89毫莫 耳）、及DMAP(30毫克，〇· 25毫莫耳）於DMF(10毫升）中之混 合物在室溫下攪拌隔夜，及在6 〇 〇c下i天。將混合物以 EtOAc稀釋，以〇·5Ν HC1、鹽水洗滌，於Na2S〇4上乾燥，並 蒸發。使殘留物經由於矽膠上利用CHCl3至2% Me〇H溶於 011(：13作為洗提液進行管柱層析，純化而得（§) — 4 — [[2—[3一 甲氧基_4_[N’ -（2 -溴苯基）脲基]苯基乙醯基卜（2 -硝苄基） 胺基]-：1 -丙氧基]苯曱酸苄酯的油，將其不經進一步的純 化而使用於後續的反應。89112968.ptd Page 756 1283240 V. INSTRUCTIONS (752) SALT (361 mg, 1. 88 mmol), H0Bt (255 mg, ι 89 mmol), and DMAP (30 mg, 〇· 25 毫) The mixture of Mole in DMF (10 mL) was stirred overnight at room temperature and was taken at 6 〇〇c. The mixture was diluted with EtOAc, washed with EtOAc EtOAc EtOAc. The residue was purified by chromatography on a silica gel using CHCl 3 to 2% Me〇H in 011 (: 13 as an eluent to obtain (§) — 4 — [[2—[3-methoxy] _4_[N'-(2-Bromophenyl)ureido]phenylethenyl (2-nitrobenzyl)amino]-:1-propoxy]benzoic acid benzyl ester oil, The subsequent reaction was used without further purification.

於以上粗製產物溶於THF-MeOH(10毫升，1:1，v/v)之攪 拌溶液中加入0 · 5 N N a 0 Η (1 0毫升），並使所產生之混合物 迴流加熱3小時。將混合物倒入至冰的η20中，並利用工Ν HC1使鹼性水層成為酸性（ΡΗ 4· 3)。收集固體，並利用製 備TLC以5% MeOH溶於CHC13作為洗提液，將粗製固體純化 而得162 毫克（2 步驟，19%) (S)-4-[ [2-[3-甲氧基一4-[N， -(2-溴苯基）脲基]苯基乙醯基]— (2 -硝苄基）胺基]-卜丙氧 基]苯甲酸296的白色非晶形固體。To the stirred solution of the above crude product in THF-MeOH (10 ml, 1:1, v/v), 0·5 N N a Η (10 ml) was added, and the resulting mixture was heated under reflux for 3 hours. The mixture was poured into η20 of ice, and the alkaline aqueous layer was made acidic by using the working hydrazine HC1 (ΡΗ4.3). The solid was collected and purified by preparative TLC eluting with CH.sub.3 MeOH (MeOH) EtOAc (EtOAc: EtOAc A white amorphous solid of 4-[N,-(2-bromophenyl)ureido]phenylethenyl]-(2-nitrobenzyl)amino]-propoxy]benzoic acid 296.

MS(FAB) m/z 692CM+ + 1); C33H31BrN4 08 ·7/4Η20 之分析計算 值：C，54· 82 ; Η，4· 81 ; Ν，7· 75。實測值：C，54. 80 ; H，4· 61 ; N，7.24。 實施例246 4-[2-N-[ 3-甲氧基-4-[Ν’ 2-甲基苯基）脲基]苯基乙醯胺MS (FAB) m / z 692CM + + 1); C33H31BrN4 08 · 7 / 4 Η 20 analytical calculations: C, 54 · 82; Η, 4 · 81; Ν, 7 · 75. Found: C, 54. 80; H, 4· 61 ; N, 7.24. Example 246 4-[2-N-[3-Methoxy-4-[Ν'2-methylphenyl]ureido]phenyletheneamine

89112968.ptd 第757頁 1283240 五、發明說明（753) 於2-(N-第三丁氧羰胺基）乙醇（3.20克，19.9毫莫耳）、 4-羥基苯甲酸甲酯（3·〇2克，19·9毫莫耳）及Ph3P (6. 25 克’ 23· 8毫莫耳）溶於THF(50毫升）之冷卻（0。〇溶液中於5 分鐘内逐滴加入DIAD(4· 69毫升，23· 8毫莫耳）。使反應混 合物迴流加熱3小時。將混合物蒸發，並將殘留物溶解於 CHJl〆30毫升）及TFA (30毫升）中。使反應混合物在室溫 下攪拌隔夜。將混合物於真空中濃縮，並將殘留物溶解於 CHC ls及H2 0。利用飽和NaHC 03使溶液成為驗性，並以cHc 1 萃取。將萃取液以鹽水洗滌，於NaJO4上乾燥，並蒸發。3 將殘留物經由於矽膠上利用CHCI3-MeOH(30: 1，v/v)作為 洗提液進行管柱層析，純化而得4 -（ 2 -胺乙氧基）苯甲酸'甲 酯（1· 03 克，2 步驟34%)的無色油。iH-NMR (CDC13) 5 3.10-3.13(m，2H)、3.89(S，3H)、4.03-4.06(m，2H) 、6.92-6.94 (m， 2H) 、7·98-8·00 (m， 2H)。 一使3-甲氧基-4-[N，-（2-甲基苯基）脲基]苯基乙酸（557 毫克，1.77¾莫耳）、4-（2-胺乙氧基）苯甲酸甲酯（346毫 克，1.77毫莫耳）、EDC*HC1(408毫克，2·13毫莫耳）、 H0Bt(287毫克，2.12毫莫耳）及DMAP(52毫克，〇·43毫莫 耳）於DMF(10宅升）中之混合物在室溫下攪拌2天。將混人 物以EtOAc及比0稀釋。收集所產生之沈澱物，而得 - Ν-[3-甲氧基-4-[Ν’-（2-甲基苯基）脲基]笨基乙醯胺爲 乙氧基]苯甲酸甲酯（ 598毫克，69%)的白色結晶粉末。土89112968.ptd Page 757 1283240 V. INSTRUCTIONS (753) Ethyl 2-(N-T-butoxycarbonylamino)ethanol (3.20 g, 19.9 mmol), methyl 4-hydroxybenzoate (3·〇 2 g, 19.9 mmol, and Ph3P (6.25 g '23·8 mmol) dissolved in THF (50 ml). (0. 〇 solution was added dropwise to DIAD in 5 min. The reaction mixture was heated to reflux for 3 h. The mixture was evaporated and evaporated, mjjjjjjjjj The reaction mixture was allowed to stir at room temperature overnight. The mixture was concentrated in vacuo and the residue was dissolved in CHC s and H. The solution was made detectable with saturated NaHC03 and extracted with cHc1. The extract was washed with brine, dried over Na.sub.4, and evaporated. 3 The residue was subjected to column chromatography using CHCI3-MeOH (30:1, v/v) as an eluent, and purified to give 4-(2-aminoethoxy)benzoic acid 'methyl ester ( 1·03 g, 2 steps 34%) of a colorless oil. iH-NMR (CDC13) 5 3.10-3.13 (m, 2H), 3.89 (S, 3H), 4.03-4.06 (m, 2H), 6.92-6.94 (m, 2H), 7·98-8·00 (m , 2H). 3-methoxy-4-[N,-(2-methylphenyl)ureido]phenylacetic acid (557 mg, 1.773⁄4 mol), 4-(2-aminoethoxy)benzoic acid Methyl ester (346 mg, 1.77 mmol), EDC*HC1 (408 mg, 2.13 mmol), H0Bt (287 mg, 2.12 mmol) and DMAP (52 mg, 〇·43 mmol) The mixture in DMF (10 house liters) was stirred at room temperature for 2 days. The mixture was diluted with EtOAc and 0. The resulting precipitate was collected, and - Ν-[3-methoxy-4-[Ν'-(2-methylphenyl)ureido]] benzylamine was methyl ethoxy]benzoate (598 mg, 69%) of a white crystalline powder. earth

1283240 五、發明說明（754) &quot; UMR (DMS0-d6) 6 2. 23 (s，3H)、3· 36 (s，2H)、 3.42-3.45 (m，2H)、3·79 (s，3H)、3·81 (s，3H)、 4.02-4.0 9 (m，2H)、6·73-6·75 (m，1H)、6·90-6·94 (m，2H)、7·02-7·04 (m，2H)、7·09-7·15 (m，2H)、 7·77-7·79 (m，1H)、7·88-7·90 (m，2H)、7·95-7·98 (m，1H)、8·23-8.24 (m，1H)、8·44 (s，1H)、8·53 (s 1H) ; MS(FAB) m/z 4 92(MH1) ; C27H29N3 06 · l/4H2〇 之分析計 算值·· C，65· 38 ; H，5· 99 ; N，8· 47。實測值：C，65. 26 ;H，5· 99 ; N，8· 49。 於4-[2-N-[ 3-甲氧基-4 - [Ν’ -（2-甲基苯基）脲基]苯基乙 醯胺基]乙氧基]苯甲酸甲酯（280毫克，0·57毫莫耳）溶於 THF - MeOH(l〇毫升，1:1，ν/ν)之攪拌溶液中加入0.5Ν N a Ο Η (1 0毫升），並使反應混合物迴流加熱5小時。將混合 物冷卻至室溫，並倒入至冰的1 N H C1中。收集所產生之沈 澱物，並使其自£1:20-〇11(：13-%6〇11再結晶，而得297 ( 1 35毫 克，50%)的白色結晶粉末。1H-NMR (DMSO-d6)(5 2.24 (s， 3H)、3·38 (s，2H)、3·43-3·47 (m，2H)、3·82 (s，3H) 、4·06-4·09 (m，2H)、6. 76-6.78 (m，1H)、6·92-7·17 (m，6H)、7·79 (d，J = 8.1 Hz，1H)、7·88-7.89 (m，2H) 、7·98 (d，J = 8.1 Hz，1H)、8·24-8·27 (m，1H)、8·45 (s，1H)、8· 5 5 (s，1H) ; MS(FAB) m/z 478(M+ + 1); C26H27N3 06 M/4H20 之分析計算值：C，64·79;Η, 5·75;Ν， 8· 72。實測值：C，64· 67 ; H，5· 63 ; N，8· 60。 實施例2471283240 V. INSTRUCTIONS (754) &quot; UMR (DMS0-d6) 6 2. 23 (s, 3H), 3· 36 (s, 2H), 3.42-3.45 (m, 2H), 3.79 (s, 3H), 3·81 (s, 3H), 4.02-4.0 9 (m, 2H), 6.73-6·75 (m, 1H), 6·90-6·94 (m, 2H), 7· 02-7·04 (m, 2H), 7·09-7·15 (m, 2H), 7·77-7·79 (m, 1H), 7·88-7·90 (m, 2H), 7·95-7·98 (m,1H), 8·23-8.24 (m,1H), 8·44 (s,1H), 8·53 (s 1H) ; MS(FAB) m/z 4 92 (MH1) ; C27H29N3 06 · l/4H2 分析 analytical calculation · · C, 65 · 38 ; H, 5 · 99 ; N, 8. 47. Found: C, 65. 26; H, 5. 99; N, 8. 49. Methyl 4-[2-N-[ 3-methoxy-4 -[Ν' -(2-methylphenyl)ureido]phenylethenylamino]ethoxy]benzoate (280 mg , 0.57 mmol, 0.5 ΝN a Ο Η (10 ml) was added to a stirred solution of THF-MeOH (1 mL, 1:1, ν/ν), and the reaction mixture was heated under reflux. hour. The mixture was cooled to room temperature and poured into 1 N H C1 ice. The resulting precipitate was collected and recrystallized from £1:20-〇11 (: 13-% 6 〇 11 to give 297 (1 35 mg, 50%) of white crystalline powder. 1H-NMR (DMSO) -d6)(5 2.24 (s, 3H), 3·38 (s, 2H), 3·43-3·47 (m, 2H), 3·82 (s, 3H), 4·06-4·09 (m, 2H), 6. 76-6.78 (m, 1H), 6.92-7·17 (m, 6H), 7.79 (d, J = 8.1 Hz, 1H), 7·88-7.89 ( m, 2H), 7·98 (d, J = 8.1 Hz, 1H), 8·24-8·27 (m, 1H), 8·45 (s, 1H), 8· 5 5 (s, 1H) ; MS(FAB) m/z 478 (M+ + 1); C26H27N3 06 M/4H20 Analysis calculated: C, 64·79; Η, 5·75; Ν, 8· 72. Found: C, 64· 67 ; H, 5 · 63 ; N, 8 · 60. Example 247

89112968.ptd 第759頁 1283240 發明說明（755) (S)-4-[2-N - [4-[Ν’-（2-溴苯基）脲基]—3—甲氧苯基乙醯胺 基]-1-丙氧基]苯甲酸89112968.ptd Page 759 1283240 Description of the invention (755) (S)-4-[2-N - [4-[Ν'-(2-Bromophenyl)ureido]-3-methoxyphenylacetamide Alkyl-1-propoxy]benzoic acid

298 (S)-4-(2 -胺基-1-丙氧基）苯甲酸苄酯 於（S)-2-(N-第三丁氧羰胺基）—丨-丙醇（6· 74克，〇· 〇4莫 耳）、4-羥基苯甲酸苄酯（8·78克，〇·〇4莫耳）、及Ph3P (15.13克，0.06莫耳）溶於丁111?(1〇()毫升）之冷卻（〇。(：）攪拌 1·18 (d，J = 6.3 Hz，3H)、3·35 — 3·39 (m，1H)、3·;1〜 3 · 7 5 ( m，1Η)、3 · 9 0 - 3 · 9 3 (m，1 Η)、5 · 3 4 ( s，2 Η)、298 (S)-4-(2-Amino-1-propoxy)benzoic acid benzyl ester in (S)-2-(N-tert-butoxycarbonylamino)-hydrazine-propanol (6·74)克,〇·〇4mol), benzyl 4-hydroxybenzoate (8·78 g, 〇·〇4 molar), and Ph3P (15.13 g, 0.06 mol) are dissolved in butyl 111?(1〇( )ml) cooling (〇.(:) stirring 1.18 (d, J = 6.3 Hz, 3H), 3·35 - 3·39 (m, 1H), 3·; 1~ 3 · 7 5 ( m ,1Η),3 · 9 0 - 3 · 9 3 (m,1 Η), 5 · 3 4 ( s,2 Η),

溶液中加入DIAD(11· 4毫升，〇· 〇6莫耳），並使反應混合物 迴流加熱隔夜。將溶液蒸發，並將殘留物溶解於CIj2 c込（3 〇 毫升）及TFA(30毫升）中。使溶液在室溫下攪拌3〇分鐘，並 將溶液於真空中濃縮。將殘留物溶解於CHC丨3，以飽和 NaHC〇3洗滌，於NaJO4上乾燥，並蒸發。將殘留物經由於 矽膠上利用CHC13至CHC13-MeOH (9:1，v/v)作為洗提液進 行管柱層析’純化而得（S)-4-(2-胺基-1-丙氧基）笨甲酸 苄酯（6· 63克，2步驟，60%)的黃色油。iH-NMR (CDCl3) ^ 1283240 五、發明說明（756) (S)-4-[2-N-[4-[Ν’ -（2-溴苯基）脲基]-3-甲氧苯基乙醯胺 基]- ：1 -丙氧基]苯甲酸苄酯DIAD (11.4 ml, 〇·〇6 mol) was added to the solution, and the reaction mixture was heated to reflux overnight. The solution was evaporated and the residue was taken in EtOAc EtOAc (EtOAc) The solution was allowed to stir at room temperature for 3 minutes and the solution was concentrated in vacuo. The residue was dissolved in CH.sub.3, washed with sat. NaHC.sub.3, dried over Na.sub.4, and evaporated. The residue was purified by column chromatography using CHC13 to CHC13-MeOH (9:1, v/v) as an eluent to obtain (S)-4-(2-amino-1-propane Oxyl) benzyl benzoate (6. 63 g, 2 steps, 60%) of a yellow oil. iH-NMR (CDCl3) ^ 1283240 V. Inventive Note (756) (S)-4-[2-N-[4-[Ν'-(2-Bromophenyl)ureido]-3-methoxyphenyl Benzylamino]-:1-propoxy]benzoic acid benzyl ester

V^c jCrc〇2Bn 使4 - [Ν’-（2 -溴苯基）脲基]-3 -甲氧苯基乙酸（480毫克， 1· 27毫莫耳）、（S) - 4-(2 -胺基-1_丙氧基）苯甲酸窄醋（361 毫克，1.27毫莫耳）、EDC ·Η(： 1(364毫克，1·90毫莫耳）、 HOBt( 256毫克，1· 89毫莫耳）及DMAP(31毫克，〇· 25毫莫 耳）於DMF (8毫升）中之混合物在室溫下攪拌隔夜。將混合 物以EtOk稀釋，以〇·5Ν HC1、鹽水洗滌，於Μ。％上乾 燥’並蒸發。使殘留物經由於矽膠上利用CHCl3至5% Me〇H 洛於CHCI3作為洗提液進行管柱層析，純化而得（s) —4一 [^2 - [4-[N -(2 -溴苯基）脲基]—3—甲氧苯基乙醯胺基]―丨一丙 氧基]苯甲酸苄酯（476毫克，58%)的棕色固體。1H —nmr (CDC13) 5 1· 25-1· 28 (m，3H)、3· 51 (s，2H)、3·以 (s 3H) ^3.95-3.97 (m, 2H) ^4.36^4.39 (m, 1H) 、5·33 (s，2H)、6.75〜6·94 (m，5H)、7·26-7 70 (m 8H)、7·99-8·26 (m，5H)。 ··’〇〜， 102 ^ϋ[2-N-[4-[N，—（2 一漠、笨基）脲基]一3 曱氧苯基 乙醯胺基]-1-丙氧基]笨甲酸 胺基-卜丙氧基审缺朴, 丫乳本基乙醯 ⑴毫升)之旨(4二毫㈠.39毫莫耳)溶於 合液中加入0.5N NaOH(10毫升），並使V^c jCrc〇2Bn gives 4 - [Ν'-(2-bromophenyl)ureido]-3-methoxyphenylacetic acid (480 mg, 1.7 mmol), (S) - 4-(( 2-Amino-1-propoxy)benzoic acid narrow vinegar (361 mg, 1.27 mmol), EDC · Η (: 1 (364 mg, 1.90 mmol), HOBt (256 mg, 1· The mixture was stirred at room temperature overnight. The mixture was diluted with EtOk and washed with 〇······································ Μ%% dry' and evaporate. The residue is subjected to column chromatography by chromatography using CHCl3 to 5% Me〇H on CHCI3 as an eluent to obtain (s) - 4 - [2 - [4-[N-(2-Bromophenyl)ureido]-3-methoxyphenylacetamido]-hydrazinyloxy]benzoic acid benzyl ester (476 mg, 58%) as a brown solid. 1H—nmr (CDC13) 5 1· 25-1· 28 (m, 3H), 3· 51 (s, 2H), 3·(s 3H) ^3.95-3.97 (m, 2H) ^4.36^4.39 ( m, 1H), 5·33 (s, 2H), 6.75 to 6·94 (m, 5H), 7·26-7 70 (m 8H), 7·99-8·26 (m, 5H). ·'〇~, 102^ϋ[2-N-[4-[N,—(2 , succinyl) ureido]- 3 oxiranyl phenylacetamido]-1-propoxy] benzoic acid amine-bupropoxy acetal, 丫 本 本 醯 醯 (1) ml) 4 s (one). 39 millimolar) dissolved in the mixture and added 0.5N NaOH (10 ml), and

89112968.ptd 第761頁 1283240 五、發明說明（757) 反應混合物迴流加熱2小時。將混合物甸入至冰的…HC1 中，並收集所產生之沈澱物。使粗製固體經由自Me〇H -CHCI3··正己烷再結晶，純化而得298( 240毫克，59%)的白 色結晶粉末。iH-NMR (DMS0-d6) 5 1· 18 (d，J = 6· 8 Hz， 3H)、3·37 (s，2H)、3·82 (s，3H)、3·92-4.00 (m，2H) ^4.03-4.15 (m, 1H) . 6. 77-6. 79 (m, 1H) &gt;6.93-7.03 (m，4H)、7·30-7·34 (m，1H)、7·59-7·61 (m，1H)、 7.87-7.97 (m, 4H) ^8.13-8.15 (m, 1H) ^8.73 (s, 1H)、8·91 (s，1H)、12·63 (bs，1H); MS(FAB) m/z 557 (M+ + 1) ; C26H26BrN3 06 之分析計算值：C，56· 12 ; H， 4· 71 ; Br，14· 36 ; N，7· 55。實測值：C，56. 11 ; H， 4. 74 ; Br，14. 56 ; N，7· 49。 實施例248 (S)-4-[2-N-[[ 3-甲氧基一4 一 [N’—（2_甲基苯基）脲基]苯基] -N-甲基乙醯胺基]一卜丙氧基]苯曱酸89112968.ptd Page 761 1283240 V. INSTRUCTIONS (757) The reaction mixture was heated under reflux for 2 hours. The mixture was taken up into ice HCl1 and the resulting precipitate was collected. The crude solid was recrystallized from Me 〇H-CHCI3··hexane to afford 298 (240 mg, 59%) of white crystal powder. iH-NMR (DMS0-d6) 5 1· 18 (d, J = 6· 8 Hz, 3H), 3·37 (s, 2H), 3·82 (s, 3H), 3·92-4.00 (m , 2H) ^4.03-4.15 (m, 1H) . 6. 77-6. 79 (m, 1H) &gt;6.93-7.03 (m, 4H), 7·30-7·34 (m, 1H), 7 ·59-7·61 (m,1H), 7.87-7.97 (m, 4H) ^8.13-8.15 (m, 1H) ^8.73 (s, 1H), 8.91 (s, 1H), 12·63 ( Bs,1H); MS (FAB) m/z 557 (M+ + 1); C26H26BrN3 06 Analysis calculated: C, 56·12; H, 4· 71; Br, 14· 36; N, 7. 55. Found: C, 56.11; H, 4. 74; Br, 14.56; N, 7. 49. Example 248 (S)-4-[2-N-[[ 3-methoxy-1,4-[N'-(2-methylphenyl)ureido]phenyl]-N-methylacetamide P-propoxy]benzoic acid

Me ^ ^ 〇Μβ 299 (S)_4-[2-[(Ν-第 酯 丁氧幾基）胺基]-1-丙氧基]笨曱酸曱 〇〇2Μθ 於（S)-2-[U—第三丁氧羰基）胺基卜卜丙醇（3· 克Me ^ ^ 〇Μβ 299 (S)_4-[2-[(Ν-第酯丁oxy)amino]-1-propoxy] 曱 曱 曱〇〇 2Μθ in (S)-2-[ U-Terti-butoxycarbonyl) Aminylbupropanol (3 g

89112968.ptd 第762頁 1283240 五、發明說明（758) 17·6毫莫耳）、4 -羥基苯甲酸甲酯（2·67克，17.6毫莫耳） 及Ph3P (5.53克，21.1毫莫耳）溶於THFC35毫升）之冷卻（〇 °C )溶液中逐滴加入D IAD (4 · 1 5毫升，2 1 · 1毫莫耳）。使反 應混合物迴流加熱隔夜。將混合物蒸發，並將殘留物經由 於石夕膠上利用正己烧-Et0Ac(5:l, v/v)作為洗提液進行管 柱層析，純化而得（S)-4-[2-[(N-第三丁氧羰基）胺基卜卜 丙氧基]苯甲酸甲酯（1.24克，23%)的白色固體。 M-NMR (CDC13)6 1.30 (d，J = 6.8 Hz, 3H)、1.45 (s 9 Η)、3 · 8 9 ( s，3 Η )、3 · 8 9 - 3 · 9 9 (m，2 Η )、4 · 0 7 ( m， 1Η) 、4.76 (m， 1Η) 、6·9卜6.93 (m， 2Η) 、7·98-8.00 (m，2H); MS(FAB) m/z 310(MH1)。 (S)-4-（2_胺基-1-丙氧基）苯甲酸甲酉旨89112968.ptd Page 762 1283240 V. INSTRUCTIONS (758) 17·6 mmoles, methyl 4-hydroxybenzoate (2.66 g, 17.6 mmol) and Ph3P (5.53 g, 21.1 mmol) D IAD (4 · 15 ml, 2 1 · 1 mmol) was added dropwise to a cooled (〇 ° C ) solution in THF (35 mL). The reaction mixture was refluxed and heated overnight. The mixture was evaporated, and the residue was purified by column chromatography using hexane-Et0Ac (5:1, v/v) as an eluent to obtain (S)-4-[2- Methyl [(N-tert-butoxycarbonyl)aminodibupropoxy]benzoate (1.24 g, 23%) as a white solid. M-NMR (CDC13)6 1.30 (d, J = 6.8 Hz, 3H), 1.45 (s 9 Η), 3 · 8 9 ( s, 3 Η ), 3 · 8 9 - 3 · 9 9 (m, 2 Η ), 4 · 0 7 ( m, 1Η), 4.76 (m, 1Η), 6. 9 b 6.93 (m, 2Η), 7·98-8.00 (m, 2H); MS(FAB) m/z 310 (MH1). (S)-4-(2-amino-1-propoxy)benzoic acid formazan

於（S)-4 - [2 - [(N -第三丁氧羰基）胺基]—；[—丙氧基]笨甲 酸甲酯（1· 24克，4· 01毫莫耳）溶於CH2Cl2(l〇毫升）之授掉 溶液中加入T F A (1 0毫升）’並使反應混合物於室溫下授掉 隔夜。將混合物於真空中濃縮，並利用飽和N a η C 03使成為 驗性。以CHC Ι3萃取混合物，以鹽水洗條，於&amp;c〇3上乾 燥，並蒸發而得（S) - 4-(2 -胺基-1-丙氧基）苯甲酸甲_ ( 790 毫克，94%)的黃色油。iH-NMR (CDC13) $ 1. 19 (d， J = 6.7 Hz，3H)、3·34-3·42 (m，1H)、3·7〇-3·77 (m， 1H)、3· 86-3. 94 (s 及m 系列，總計4H)、6· 92 (d， J = 9· 〇Methyl (S)-4 -[2-[(N-tert-butoxycarbonyl)amino]-;[-propoxy]benzoic acid (1·24 g, 4·01 mmol) is soluble TFA (10 mL) was added to the solution of CH2Cl2 (1 mL) and the mixture was allowed to stand overnight at room temperature. The mixture was concentrated in vacuo and made aq. sat. The mixture was extracted with CHC Ι3, washed with brine, dried over &amp;c, and evaporated to give (S) 4-(2-amino-1-propoxy)benzoic acid methyl ( 790 mg, 94%) yellow oil. iH-NMR (CDC13) $ 1. 19 (d, J = 6.7 Hz, 3H), 3·34-3·42 (m, 1H), 3·7〇-3·77 (m, 1H), 3· 86-3. 94 (s and m series, total 4H), 6.92 (d, J = 9· 〇

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Hz， 2H) 、 7. 98 (d， J=9.0 Hz, 2H)。 (S)-4 - [2-(三氟乙醯胺基）-i一丙氧基]苯甲酸甲酯Hz, 2H), 7. 98 (d, J=9.0 Hz, 2H). (S)-4 - [2-(Trifluoroethylamino)-i-propoxy]benzoic acid methyl ester

於（S) - 4 -（2 -胺基-1-丙氧基）苯甲酸甲酯（79〇毫克， 3.78¾莫耳）及Et3N(630毫升，4·52毫莫耳）溶於THF(10毫 升）之冷卻（〇 °C)溶液中加入TFAAC 64 0毫升，4. 53毫莫 耳），並使反應混合物在室溫下攪# 4天。將混合物以0 · 5N HC1稀釋，並以CHC13萃取。將萃取液以鹽水洗滌，於心⑶3 上乾燥，並蒸發。使殘留物經由自正己烧—CHC!3再結晶 ，純化而得（S)-4-[2-(三氟乙醯胺基）-卜丙氧基]苯曱酸 曱酯（7 9 0毫克，69%)的白色結晶物質。1Η一NMR (CDC13) δ 1.42 (d，J = 6.8 Hz，3H)、3·89 (s，3H)、4·01 一4·13 (m，2H)、4·44-4·50 (m，1H)、6·57-6·61 (m，1H)、 6·92 (d，J = 9.0 Hz，2H)、8·00 (d, J = 9·0 Hz，2H); MS(FAB) m/Z 30 6 (MH1) ; C13H14F3N〇4 之分析計算值：C， 51. 15 ; H，4· 62 ; F, 18· 67 ; N，4· 59。實測值：C， 51· 14 ; H，4· 60 ; F，18· 50 ; N，4· 54 0 (S)-4-[2-[(N-甲基）三氟乙醯胺基]一卜丙氧基]苯曱酸甲 酯Methyl (S)-4-(2-amino-1-propoxy)benzoate (79 mg, 3.783⁄4 mol) and Et3N (630 ml, 4.52 mmol) were dissolved in THF ( To a cooled (〇 ° C) solution of 10 mL) was added TFAAC (40 mL, 4.6 mmol) and the reaction mixture was stirred at room temperature for #4. The mixture was diluted with 0. 5N HCl and extracted with CH.sub.3. The extract was washed with brine, dried on a heart (3) 3 and evaporated. The residue was recrystallized from n-hexane-CHC! 3 to give (S)-4-[2-(trifluoroethylamino)-propoxy]benzoic acid decyl ester (79 mg) , 69%) of white crystalline material. 1Η NMR (CDC13) δ 1.42 (d, J = 6.8 Hz, 3H), 3·89 (s, 3H), 4·01, 4·13 (m, 2H), 4·44-4·50 (m , 1H), 6·57-6·61 (m, 1H), 6.92 (d, J = 9.0 Hz, 2H), 8·00 (d, J = 9·0 Hz, 2H); MS (FAB m/Z 30 6 (MH1); C13H14F3N〇4 analytical value: C, 51.15; H,4·62; F, 18·67; N,4·59. Found: C, 51·14; H, 4· 60 ; F, 18· 50 ; N, 4· 54 0 (S)-4-[2-[(N-methyl)trifluoroacetamido] Methyl propyloxy]benzoate

於（S)-4-[2-(三氟乙醯胺基）- 1-丙氧基]苯曱酸甲酯 (695毫克，2·28毫莫耳）及]{2(：03 ( 63〇毫克，4·56毫莫耳）溶Methyl (S)-4-[2-(trifluoroacetamido)-1-propoxy]benzoate (695 mg, 2·28 mmol) and]{2(:03 (63) 〇mg, 4.56 millimolar) dissolved

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於DMF(10毫升）之攪拌溶液中加入MeI(21〇毫升，3. 37毫莫 耳），並使反應混合物在室溫下攪拌2天。將混合物以、 稀釋，並以EtOAc萃取。將萃取液以鹽水洗滌，於上 乾燦，並洛發。使殘留物經由於石夕膠上利用Ε七〇 A c — c η c 1 (1 : 1 9，ν / ν )作為洗提液進行管柱層析，純化而得（$) — 4 — [2-[(Ν-甲基）三氟乙醯胺基pi—丙氧基]苯甲酸甲酯（72〇 毫克，99%)的白色固體。 熔點73-75 UH-NMR (CDC13) d 1·36-1·39 (m，3Η)、 2.96 及 3·10 (各s，總計 3H)、3·89 (s，3H)、3·99-4·ΐ4 (m，2Η)、4·84-4.92 (m，1Η)、6·8 8-6.92 (m，2Η)、 7.98-8.0 0 (m，2H); MS(FAB) m/z 32 0 (MH1); C14H16F3N〇 之分析計算值：C，52.67; H，5.05; F，17.85; N， 。實測值·· C，5 2· 76 ; H，5· 09 ; F， 17. 53 ; N， 4· 32。 (S)- 4-[2 -（N-甲胺基）-1-丙氧基]苯甲酸甲酯MeI (21 ml, 3.37 mmol) was added to a stirred solution of DMF (10 mL), and the mixture was stirred at room temperature for 2 days. The mixture was diluted with EtOAc and extracted with EtOAc. The extract was washed with brine, dried and dried. The residue was purified by column chromatography on the Shiqi gum using Ε7〇A c — c η c 1 (1:1 9, ν / ν ) as an eluent to obtain ($) — 4 — 2-[(Ν-Methyl)trifluoroacetamido-pi-propoxy]benzoic acid methyl ester (72 mg, 99%) as a white solid. Melting point 73-75 UH-NMR (CDC13) d 1·36-1·39 (m, 3Η), 2.96 and 3·10 (each s, total 3H), 3·89 (s, 3H), 3·99- 4·ΐ4 (m, 2Η), 4.84-4.92 (m, 1Η), 6·8 8-6.92 (m, 2Η), 7.98-8.0 0 (m, 2H); MS(FAB) m/z 32 Analysis calculated for C14H16F3N: C, 52.67; H, 5.05; F, 17.85; N, . Found C·5 2· 76 ; H,5· 09 ; F, 17. 53 ; N, 4· 32. (S)- 4-[2-(N-Methylamino)-1-propoxy]benzoic acid methyl ester

於（S)-4-[2-[(N -曱基）三氟乙醯胺基卜！ 一丙氧基;]笨甲 酸甲酯（710毫克，2.22毫莫耳）溶於MeOH — H2〇(10毫升，i : 1，v/v)之攪拌溶液中加入K2CO3 ( 4 6 0毫克，3· 33毫莫耳）， 並使反應混合物在室溫下攪拌隔夜。將混合物以H2〇稀 釋，並以EtOAc萃取。將萃取液以鹽水洗滌，於Na2S〇4上乾 燥，並蒸發而得（S)-4-[ 2-（N-甲胺基）—卜丙氧基]苯甲酸 甲酯（430 毫克，87°/。）的無色油。4-關1^(〇〇(：13)(51.17(S)-4-[2-[(N-fluorenyl)trifluoroacetamido! Monopropoxyl; methyl benzoate (710 mg, 2.22 mmol) dissolved in MeOH - H2 hydrazine (10 mL, i: 1, v/v) was added K2CO3 (460 mg, 3) • 33 mmol), and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with H.sub.2 and extracted with EtOAc. The extract was washed with brine, dried over Na.sub.sub.sub.sub.sub.sub.sub.sub.sub.ss.ssssssssssssssssssssssss /.) Colorless oil. 4-off 1^(〇〇(:13)(51.17

\\312\2d-code\90-01\89112968.ptd 第765頁 1283240 五、發明說明（761) (d, J = 6.6 Hz, 3H) ^2.48 (s, 3H) ^ 2.98-3.0 6 (m, 1H) 、3.86 - 3.96 (s 及 m 系列，總計 5H)、6·92 (d, J = 9.0 Hz, 2H)、7· 98 (d，J = 9· 0 Hz，2H)。 (S) - 4-[2-N-[[3 -甲氧基-4 - [Ν’ -（2-甲基苯基）脲基]苯基] -Ν-甲基乙醯胺基]-卜丙氧基]苯曱酸曱酯\\312\2d-code\90-01\89112968.ptd Page 765 1283240 V. INSTRUCTIONS (761) (d, J = 6.6 Hz, 3H) ^2.48 (s, 3H) ^ 2.98-3.0 6 (m , 1H), 3.86 - 3.96 (s and m series, total 5H), 6.92 (d, J = 9.0 Hz, 2H), 7·98 (d, J = 9·0 Hz, 2H). (S) - 4-[2-N-[[3-methoxy-4 -[Ν' -(2-methylphenyl)ureido]phenyl]-indole-methylethylamino]- Ethyl benzoate

使3-甲氧基-4-[Ν’- (2 -甲基苯基）脲基]笨基乙酸（6〇5毫 克，1.93毫莫耳）、（s)-4-[2-(N -甲胺基）-卜丙氧基]苯甲 酸甲酯（430毫克，1.93毫莫耳）、EDC*HC 1(444毫克， 2.32 毫莫耳）、HOBt(313 毫克，2.32 毫莫耳）、Et3N( 320 毫 升’ 2.30¾莫耳）於THF(13毫升）中之混合物在室溫下攪掉 隔夜。將混合物以比0稀釋，並以EtOAc萃取。將萃取液以 鹽水洗蘇，於N a2 S 04上乾燥，並蒸發。使殘留物經由於石夕 膠上利用CHC13 - MeOH(100:l至75:1，v/v)作為洗提液進行 管柱層析，純化而得（S)-4-[2-N - [[3-曱氧基-4-[N，-（2〜 甲基苯基）脲基]苯基]- N-甲基乙醯胺基]-1 一丙氧基]笨甲 酸甲酯（9 53毫克，95°/。）的白色泡沫。111-關1^(〇0(：13)(1 1.12-1.13 及 1.25-1.27 (各m，總計 3H)、2.27 (s，3H)、 2· 84 及 2· 92 (各s，總計 3H)、3. 63 (s，3H)、3· 67 (s， 2H)、3· 7卜4. 05 (s 及m 系列，總計5H)、4· 39-4. 44 及 4.96-5.01 (各m，總計 1H)、6.66-6·85 (m，5H)、 7·09 - 7·27 (m，4H)、7·53 - 7·55 (m，1H)、7·92-7·983-methoxy-4-[Ν'-(2-methylphenyl)ureido]pyrustyylacetate (6〇5 mg, 1.93 mmol), (s)-4-[2-(N -Methylamino)-p-propoxy]benzoic acid methyl ester (430 mg, 1.93 mmol), EDC*HC 1 (444 mg, 2.32 mmol), HOBt (313 mg, 2.32 mmol), A mixture of Et3N (320 mL ' 2.303⁄4 mol) in THF (13 mL) was stirred overnight at room temperature. The mixture was diluted to 0 and extracted with EtOAc. The extract was washed with brine, dried over Na 2 S 04 and evaporated. The residue was subjected to column chromatography using CHC13-MeOH (100:1 to 75:1, v/v) as an eluent, and purified to obtain (S)-4-[2-N- [[3-曱-oxy-4-[N,-(2~methylphenyl)ureido]phenyl]-N-methylacetamido]-1-propoxy]methyl benzoate ( 9 53 mg, 95 ° /.) white foam. 111-OFF 1^(〇0(:13)(1 1.12-1.13 and 1.25-1.27 (each m, total 3H), 2.27 (s, 3H), 2·84 and 2.92 (each s, total 3H) , 3. 63 (s, 3H), 3·67 (s, 2H), 3·7 Bu 4. 05 (s and m series, total 5H), 4·39-4. 44 and 4.96-5.01 (each m , total 1H), 6.66-6.85 (m, 5H), 7·09 - 7·27 (m, 4H), 7·53 - 7·55 (m, 1H), 7.92-7·98

1283240 五、發明說明（762) (m， 2H) 、8·04-8·08 (m， 1H); MS(FAB) m/z 520 (MH1) ; C29H33N3 06 · 11/4H20 之分析計算值：C，61. 20 ; h， 6. 82 ; N，7· 38。實測值：C，61 · 14 ; H，5. 86 ; N， 7.16。 於（S)-4-[2-N-[[3-甲氧基-4-[Ν’ -(2-甲基苯基）脲基] 苯基]- N-甲基乙醯胺基]-1-丙氧基]苯甲酸甲酯（663毫 克，1. 28毫莫耳）溶於THF(5毫升）之攪拌溶液中加入5n NaOH( 5毫升），並使反應混合物迴流加熱5小時。於冷卻至 室溫後，將混合物倒入至冰的1 N HC 1中，並於減壓下收集 所產生之沈澱物。將粗製固體溶解於CHC I3並蒸發。將殘 留物以Et20洗滌，而得1 0 3 (46 5毫克，72%)的白色非晶形 固體。1 -NMR (DMSO-d6) 6 1· 1卜 1· 15 (m，3H)、2· 25 (s，3H)、2. 73 及2· 88 (各s，總計3H)、3· 60-3· 76 (m， 2H)、3·83 (s，3H)、4·03-4·ΐ2 (m，2H)、4·41-4.50 及 4.48-4.94 (各m，總計 1Η)、6. 71-6.76 (m，1Η)、6·84 -6.86 (m，1H)、6·9卜7·01 (m，3H)、7·Π-7.12 (m， 2Η)、7·78-7·80 (m，1Η)、7·86-7.90 (m，2Η)、8·01 -8·03 (m，1Η)、8·45 (s，1Η)、8·54 (s，1H); MS(FAB) m/z 52 0 (MH1 ) ; C28H31N3 06 · 3/2H2〇 之分析計算值：C， 6 3· 15 ; H，6. 43 ; N，7· 89。實測值：C，63· 09 ; H， 5. 99 ； N, 7.64° 實施例249 4 - [2-N-[3-甲氧基-4 - [Ν’- (2-甲基苯基）脲基]笨基乙醯胺 基]-2-甲基-1-丙氧基]苯曱酸1283240 V. Description of invention (762) (m, 2H), 8·04-8·08 (m, 1H); MS(FAB) m/z 520 (MH1) ; C29H33N3 06 · 11/4H20 Analytical calculations: C, 61. 20 ; h, 6. 82 ; N, 7. 38. Found: C, 61 · 14 ; H, 5.86; N, 7.16. (S)-4-[2-N-[[3-methoxy-4-[Ν'-(2-methylphenyl)ureido]phenyl]-N-methylethylamino] Methyl -1-propoxy]benzoate (663 mg, 1.28 mmol) was dissolved in THF (5 mL) EtOAc (5 mL). After cooling to room temperature, the mixture was poured into 1 N HCl 1 of ice, and the resulting precipitate was collected under reduced pressure. The crude solid was dissolved in CHC I3 and evaporated. The residue was washed with EtOAc (EtOAc EtOAc). 1 - NMR (DMSO-d6) 6 1· 1 Bu 1· 15 (m, 3H), 2 · 25 (s, 3H), 2. 73 and 2. 88 (each s, total 3H), 3· 60- 3· 76 (m, 2H), 3·83 (s, 3H), 4·03-4·ΐ2 (m, 2H), 4·41-4.50 and 4.48-4.94 (each m, total 1Η), 6. 71-6.76 (m,1Η), 6.84 -6.86 (m,1H),6·9 Bu 7·01 (m,3H),7·Π-7.12 (m, 2Η), 7·78-7· 80 (m, 1Η), 7·86-7.90 (m, 2Η), 8·01 -8·03 (m, 1Η), 8·45 (s, 1Η), 8·54 (s, 1H); MS (FAB) m/z 52 0 (MH1); C28H31N3 06 · 3/2H2 分析 calc.: C, 6 3 · 15 ; H, 6. 43 ; N, 7. 89. Found: C, 63·09; H, 5. 99; N, 7.64° Example 249 4 - [2-N-[3-Methoxy-4 - [Ν'- (2-methylphenyl) Ureido] phenylaminoamine]-2-methyl-1-propoxy]benzoic acid

\\312\2d-code\90-01\89112968.ptd 第767頁 1283240 五、發明說明（763)\\312\2d-code\90-01\89112968.ptd Page 767 1283240 V. Description of invention (763)

2，2-二甲基-3-（4-甲氧魏基）苯氧丙酸2,2-dimethyl-3-(4-methoxywei)phenoxypropionic acid

C〇2Me 使4-羥基苯甲酸甲酯（3克，19· 72毫莫耳）、K2C03(6. 8 克，49.3毫莫耳）、3 -氯三甲基乙酸（2.9克，21.69毫莫 耳）及催化量之K 1 ( 20 0毫克）於DMF(70毫升）中之攪拌混合 物在氮氣流中在1 0 0 °C下加熱1 4天。將混合物倒入至冰水 中，並以EtOAc萃取。將萃取液以鹽水洗滌，於Na2S04上乾 燥，並蒸發。使殘留物於矽膠（50毫升）上利用CHC13-EtOH(10:l， v/v)作為洗提液進行層析，而得2,2-二甲基 -3-(4-甲氧羰基）苯氧丙酸（1克，23%)的非晶形固體。 _ (CDC13) 6 1· 37 (s, 6H)、3· 89 (s，3H)、4· 03 (s， 2H) 、6·92 (d， J=9 Hz, 2H) 、7·98 (d， J=9 Hz， 2H)° 4 - [l-(2 -胺基-2 -甲基）丙氧基]笨甲酸甲酯 H2N, 在室溫下於2，2-二曱基-3 -（4-曱氧幾基）苯氧丙酸（720 毫克，2.85毫莫耳）及三乙胺（0.46毫升，3. 28毫莫耳）於 第三-BuOH(l 0毫升）及苯（10毫升）中之攪拌混合物中加入C〇2Me methyl 4-hydroxybenzoate (3 g, 19.72 mmol), K2C03 (6.8 g, 49.3 mmol), 3-chlorotrimethylacetic acid (2.9 g, 21.69 mmol) The stirred mixture of K 1 (20 mg) in DMF (70 mL) was heated in a stream of nitrogen at 10 ° C for 14 days. The mixture was poured into ice water and extracted with EtOAc. The extract was washed with brine, dried over Na 2 EtOAc and evaporated. The residue was chromatographed on silica gel (50 ml) using CHC13-EtOH (10:1, v/v) as eluent to give 2,2-dimethyl-3-(4-methoxycarbonyl) Amorphous solids of phenoxypropionic acid (1 g, 23%). _ (CDC13) 6 1· 37 (s, 6H), 3· 89 (s, 3H), 4· 03 (s, 2H), 6.92 (d, J=9 Hz, 2H), 7·98 ( d, J=9 Hz, 2H)° 4 - [l-(2-Amino-2-methyl)propoxy]methyl benzoate H2N, at 2,2-dimercapto-3 at room temperature -(4-oxooxy)phenoxypropionic acid (720 mg, 2.85 mmol) and triethylamine (0.46 ml, 3.28 mmol) in the third-BuOH (10 mL) and benzene ( Add to the stirred mixture in 10 ml)

\\312\2d-code\90-01\89112968.ptd 第768頁 1283240 五、發明說明（764) 〜 疊氮二苯填醯（870毫克，3.14毫莫耳）溶於苯（3毫升）之、、容 液。使所產生之混合物迴流加熱2 0小時。於冷卻後，將水 的1 N HC1 (5毫升）加至混合物，並以甲笨萃取。將萃取'、、 以鹽水洗滌，於NaJO4上乾燥，並蒸發。將殘留物於石夕膠&lt; (50毫升）上利用曱苯-EtOAc(10:l，v/v)作為洗提液進^ 層析，而得4 - [1-（2 -胺基-2 -甲基）丙氧基]苯曱酸甲能的 膠（5 2 0耄克）’將其不經進一步的純化而使用於後續的反 應。1H-NMR (CDC13) 61.41 (s，9H)、3.89 (s，3H)、 4.04 (s，2H)、4.69 (br s，1H)、6·94 (dd， J = 2 及7\\312\2d-code\90-01\89112968.ptd Page 768 1283240 V. INSTRUCTIONS (764) ~ Azide Diphenyl Filler (870 mg, 3.14 mmol) is soluble in benzene (3 mL) , and liquid. The resulting mixture was heated to reflux for 20 hours. After cooling, 1 N HCl (5 mL) of water was added to mixture and extracted with EtOAc. The extract was extracted, washed with brine, dried over NaJO4 and evaporated. The residue was chromatographed on a mixture of benzene-EtOAc (10:1, v/v) eluted with EtOAc (EtOAc) 2-Methyl)propoxy]benzoic acid methylenic (5200 g) was used for subsequent reactions without further purification. 1H-NMR (CDC13) 61.41 (s, 9H), 3.89 (s, 3H), 4.04 (s, 2H), 4.69 (br s, 1H), 6.94 (dd, J = 2 and 7

Hz，2H)、7· 98 (dd，J = 2 及7 Hz)。 使4-[1-(2 _甲基-2-第三丁氧羰胺基）丙氧基]苯甲酸甲 酯（520毫克）及茴香醚（〇」75毫升，1.61毫莫耳）溶於 CH2C12(5毫升）及TFA(3毫升）之溶液在室溫下攪拌18小時。 將混合物蒸發掉。將殘留物溶解於c % c込，並經由添加飽 和NaHC〇3使混合物成為鹼性。將分離的CIj2Cl2層於Na2S〇4及 NaJO3上乾燥’並蒸發。使殘留物於矽膠上利用CHCl3-EtOH(10:l，v/v)作為洗提液進行層析，而得4—[丨―（2-胺 基-2_甲基）丙氧基]笨曱酸甲酯（25〇毫克，39%，兩步驟） 的膠。1 -NMR (CDC13) 53.75 (s，2H)、3·89 (s，3H)、 6·93 (d，J = 8.8 Ηζ，2Η)、7·98 (d，J = 8.8 Ηζ，2Η)。 4-[2-Ν-[3-甲氧基—4—[Ν，一（2—甲基苯基）脲基]苯基乙醯 胺基]-2-甲基-1-丙氧基]苯甲酸甲酯Hz, 2H), 7·98 (dd, J = 2 and 7 Hz). Dissolve methyl 4-[1-(2-methyl-2-t-butoxycarbonylamino)propoxy]benzoate (520 mg) and anisole (75 ml, 1.61 mmol) A solution of CH2C12 (5 mL) and TFA (3 mL) was stirred at room temperature for 18 hours. The mixture was evaporated off. The residue was dissolved in c% c込 and the mixture was made basic by the addition of saturated NaHC〇3. The separated CIj2Cl2 layer was dried on Na2S〇4 and NaJO3' and evaporated. The residue was chromatographed on a silica gel using CHCl3-EtOH (10:1, v/v) as an eluent to give 4-[丨-(2-amino-2-methyl)propoxy] Methyl decanoate (25 mg, 39%, two steps) of the gum. 1 - NMR (CDC13) 53.75 (s, 2H), 3·89 (s, 3H), 6.93 (d, J = 8.8 Ηζ, 2 Η), 7·98 (d, J = 8.8 Ηζ, 2 Η). 4-[2-Ν-[3-methoxy-4-[[Ν, mono(2-methylphenyl)ureido]phenylethylamino]-2-methyl-1-propoxy] Methyl benzoate

\\312\2d-code\90-01\89112968.ptd 第769頁 1283240 五、發明說明（765) ' -- 在，溫下於4-[&gt;1-（ 2-胺基-2〜甲基）丙氧基]苯曱酸甲酯 (250¾克，1.12¾莫耳）、3 -甲氧基一4一 [N，—（2 一甲基苯基） 脲基]苯乙酸（ 3 52毫克，1·12毫莫耳）、4_DMAp(165毫 克，1.34毫莫耳）於DMF(10毫升）中之搜拌混合物中加入 Ε^、·ΗΠ (29 0 ¾克，1.51毫莫耳）。使所產生之混合物在 室溫下攪拌1 8小時。將混合物倒入至冰水中。收集固體， 以水洗滌並風乾。將粗製固體經由利用“以厂以⑽ (4:1，v/v)作為洗提液進行矽膠管柱層析，純化而得4一[ 2-N - [3-曱氧基-4 - [Ν’ -（2-甲基苯基）脲基]苯基乙醯胺 基]甲基-1-丙氧基]苯甲酸甲酯（58〇毫克，qy)之結 晶物質。IR (KBr) 3350、3286、1712、1687、1637、 1606/公分；NMR (CDCl3)5l 39 (s，6H)、2 33 (s， 3H)、3·41 (s，2H)、3·63 (s，3H)、3·88 (s，3H)、 4·05 (s，2H)、5·44 (br s，1H)、6·33 (br s，1H)、 6.79 (d，J = 8.3 Hz，2H)、7·12 (s，1H)、7·18 (t， J = 7.5 Hz，1H)、7.53 (d，J = 7.8 Hz, 1H)、7·94 (d， J = 7.8 Hz，2H)、8·14 (d，j = 8.3 Hz，1H); MS(FAB) m/z 520 (M+ + 1 ) , C29H33N3 06 之分析計算值：c，67· 〇4 ; H，6. 4〇 ’ N，8.09。實測值：c， 66,86; HU6; N， 。 在室溫下於4-[2-[3-甲氧基_4_[N，一（2一曱基苯基）脲基] 苯基^醯胺基]-2-曱基〜2〜丙氧基]苯甲酸曱酯（510毫克， 〇· 98宅莫耳）之攪拌溶液中加入〇· 25N Na〇H(8毫升，2毫莫 耳）。使所產生之混合物在環境溫度下攪拌丨8小時。將混\\312\2d-code\90-01\89112968.ptd Page 769 1283240 V. INSTRUCTIONS (765) ' -- At, under 4-[&gt;1-(2-Amino-2~A) Methyl)propoxy]benzoic acid methyl ester (2503⁄4 g, 1.123⁄4 mol), 3-methoxy-4-one [N,-(2-methylphenyl)ureido]phenylacetic acid (3 52 mg 1^,·ΗΠ (29 0 3⁄4 g, 1.51 mmol) was added to a mixture of 4 DMAp (165 mg, 1.34 mmol) in DMF (10 mL). The resulting mixture was stirred at room temperature for 18 hours. Pour the mixture into ice water. The solid was collected, washed with water and air dried. The crude solid was purified by hydrazine column chromatography using (10) (4:1, v/v) as an eluent to obtain 4-[2-N-[3-decyloxy-4-[ Crystalline material of methyl '-(2-methylphenyl)ureido]phenylethylamino)methyl-1-propoxy]benzoate (58 mg, qy). IR (KBr) 3350 , 3286, 1712, 1687, 1637, 1606/cm; NMR (CDCl3) 5l 39 (s, 6H), 2 33 (s, 3H), 3·41 (s, 2H), 3·63 (s, 3H) , 3·88 (s, 3H), 4·05 (s, 2H), 5·44 (br s, 1H), 6·33 (br s, 1H), 6.79 (d, J = 8.3 Hz, 2H) , 7·12 (s, 1H), 7.18 (t, J = 7.5 Hz, 1H), 7.53 (d, J = 7.8 Hz, 1H), 7·94 (d, J = 7.8 Hz, 2H), 8·14 (d,j = 8.3 Hz,1H); MS(FAB) m/z 520 (M+ + 1 ) , C29H33N3 06 analytical calculation: c,67· 〇4 ; H,6. 4〇' N , 8.09. Found: c, 66, 86; HU6; N, at room temperature in 4-[2-[3-methoxy_4_[N, mono(2-indenylphenyl)ureido] Add 〇·25N Na〇H (8 mM) to a stirred solution of phenyl hydrazino]-2-mercapto~2~propoxy]benzoic acid oxime ester (510 mg, 〇·98 house Moule) , 2 mM Mo ears). The mixture arising Shu was stirred at ambient temperature for 8 hours. The mixture

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第770頁 1283240 五、發明說明（766) 合物倒入至冰的1 N HC 1 ( 5毫升）中。收集固體，以水洗滌 並風乾。使粗製固體自CHCl3-EtOH-Et20再結晶，而得300 (480 毫克，97°/〇)的微細針狀物。IR (KBr) ^ 33 46、32 94 、1 687、1 63 7、1 6 04 / 公分；UMR (DMSO-d6) (5 1 . 35 (s， 6H) 、2·24 (s， 3H) 、3·33 (s， 2H) 、3·80 (s， 3H) 、4.15 (s， 2Η) 、6·75 (d， J=8.3 Ηζ， 1Η) 、6.88 (s， 1H)、6·95-6.99 (m，3H)、7·：Π - 7·17 (m，3H)、7·80 (d，J二8·3 Ηζ，1Η)、7·82 (s，1Η)、7·87 (d, J = 8.8 Hz， 2H) 、7·98 (d， J=7.8 Hz, 1H) 、8·45 (s， 1H)、 8.54 (s， 1H) 、 12.62 (br s， 1H); MS(FAB) m/z 506 (MH1) ; C28H31N3 06 之分析計算值：C，6 6. 52 ; H，6. 18 ; N， 8· 31。實測值·· C， 66. 2 2 ; H, 6. 28 ; N，8. 1 1。 實施例2 5 0 3 -胺基-4-[2 - N-[4-[N’-（2-氯苯基）脲基]-3一曱氧笨基乙 醯胺基]-2-曱基-1-丙氧基]苯甲酸Page 770 1283240 V. INSTRUCTIONS (766) The compound was poured into 1 N HC 1 (5 mL) of ice. The solid was collected, washed with water and air dried. The crude solid was recrystallized from CHCl3-EtOH-Et.sub.2 to afford 300 ( 480 mg, IR (KBr) ^ 33 46, 32 94 , 1 687, 1 63 7 , 1 6 04 / cm; UMR (DMSO-d6) (5 1 . 35 (s, 6H), 2·24 (s, 3H), 3·33 (s, 2H), 3·80 (s, 3H), 4.15 (s, 2Η), 6.75 (d, J=8.3 Ηζ, 1Η), 6.88 (s, 1H), 6.95- 6.99 (m, 3H), 7·: Π - 7·17 (m, 3H), 7·80 (d, J 2·8 Ηζ, 1Η), 7·82 (s, 1Η), 7·87 ( d, J = 8.8 Hz, 2H), 7·98 (d, J=7.8 Hz, 1H), 8·45 (s, 1H), 8.54 (s, 1H), 12.62 (br s, 1H); MS ( Analysis of calculated values for C/o 506 (MH1); C28H31N3 06: C,6 6. 52 ; H,6. 18 ; N, 8· 31. Measured value·· C, 66. 2 2 ; H, 6 28; N, 8. 1 1. Example 2 5 0 3 -Amino-4-[2-N-[4-[N'-(2-chlorophenyl)ureido]-3-anthracene Ethylamino]-2-mercapto-1-propoxy]benzoic acid

4-埃-2~~石肖基紛 no2 在0-5 °C下於4 -胺基-2 -硝基酚（10克，64.88毫莫耳）溶 於AcOH (70宅升）及DMSO( 20毫升）之攪拌溶液中加入濃 。在低於20 °C下於此攪拌溶液中在丨〇分鐘内逐滴加入2 44-A-2~~ Shi Xiaoji no2 at 4-5 °C in 4-amino-2-nitrophenol (10 g, 64.88 mmol) dissolved in AcOH (70 house liters) and DMSO (20 ml) Concentration is added to the stirred solution. Add 2 4 dropwise to this stirred solution at less than 20 ° C in 丨〇 minutes

1283240 五、發明說明（767)1283240 V. Description of invention (767)

NaN02 (5· 4克，77· 9毫莫耳）溶於水（5毫升）之溶液。使所 產生之混合物再在5 °C下攪拌〇. 5小時。將此混合物於1 〇分 鐘内倒入至K 1(30克，0· 182莫耳）及催化量之Cu粉末（2 00 毫克）溶於冰水（2 0 0毫升）之攪拌溶液中。使所產生之混合 物再在環境溫度下1小時。以CH2C 12萃取混合物。將萃取液 以飽和Na2S2 03及鹽水連續洗滌。將有機層於Na2S04上乾 燥，並蒸發。使殘留物於矽膠（5 0毫升）上利用C HC U - 〇A solution of NaN02 (5·4 g, 77·9 mmol) dissolved in water (5 ml). The resulting mixture was further stirred at 5 ° C for 5 hours. This mixture was poured into a stirred solution of K 1 (30 g, 0·182 mol) and a catalytic amount of Cu powder (200 mg) in ice water (200 ml) in 1 Torr. The resulting mixture was again allowed to stand at ambient temperature for 1 hour. The mixture was extracted with CH2C12. The extract was washed successively with saturated Na2S2 03 and brine. The organic layer was dried over Na 2 SO 4 and evaporated. The residue was applied to silicone (50 ml) using C HC U - 〇

EtOAc(3:l，v/v)作為洗提液進行層析，而得4-碘—2-硝基 酚（2. 5 克，1 5%)的黃色結晶物質。ih-NMR (CDC13) 5 6· 94 (d，J = 8.8 Hz, 1H)、7·82 (dd, J = 2 及 8·8 Hz, 1H) 、8·42 (d，J = 2 Hz，1H)、1〇·49 (s，1H)。 3 -（4 -蛾-2 -硝基）苯氧基-2，2 -二甲基丙酸甲酯Ethyl acetate (3:1, v/v) was used as an eluent to give 4-y[pi]-2-nitrophenol (2.5 g, 5%) as a yellow crystalline material. ih-NMR (CDC13) 5 6· 94 (d, J = 8.8 Hz, 1H), 7·82 (dd, J = 2 and 8·8 Hz, 1H), 8.42 (d, J = 2 Hz, 1H), 1〇·49 (s, 1H). 3-(4-Hyp-2 -nitro)phenoxy-2,2-dimethylpropanoate

在冰水浴冷卻下於4-碘-2-硝基酚（2克，7· 75毫莫耳）、 •基三甲基乙酸甲基酯（1〇5克，7. 92毫莫耳）及PPh3 (2.3 克，8· 68毫莫耳）溶於THF(1 0毫升）之攪拌溶液中逐滴加入 DIAD(1. 77克’ 8. 30毫莫耳）溶於thf(2毫升）之溶液。然後 使所產生之混合物迴流加熱1 8小時。於冷卻後，將混合物 蒸發掉。使殘留物於矽膠（1 〇〇毫升）上利用曱笨一Et〇Ac (4 : 1，v/v)作為洗提液進行層析，而得3_(4 -蛾-2-硝基）苯氧 基-2, 2 -二曱基丙酸曱酯（2·9克，q.y·)的結晶物質。 1-NMR (CDC13) 6 1· 34 (s，6H)、3· 71 (s，3H)、4· 084-iodo-2-nitrophenol (2 g, 7.75 mmol), methyl 3-methylacetate (1 〇 5 g, 7.92 mmol) and cooled in an ice water bath PPh3 (2.3 g, 8.68 mmol) dissolved in THF (10 mL) was added dropwise to a solution of DIAD (1. 77 g ' 8. 30 mmol) dissolved in thf (2 mL). . The resulting mixture was then heated under reflux for 18 hours. After cooling, the mixture was evaporated. The residue was chromatographed on a silica gel (1 mL) using a solution of Et-Ac (4:1, v/v) as an eluent to give 3-(4-mole-2-nitro)benzene. A crystalline material of oxa-2,2-dimercaptopropionate (2.9 g, qy·). 1-NMR (CDC13) 6 1· 34 (s, 6H), 3· 71 (s, 3H), 4· 08

\\312\2d-code\90-01\89112968.ptd 第772頁 1283240 五、發明說明（768) (s, 2H)、6.86 (d，J = 8.8 Hz，1H)、7.78 (dd，J = 2 及 8·8 Hz， 1H) 、 8·12 (d， Hz， 1H)。 3 -（4 -破-2-硝基）笨氧基—2, 2 -二甲基丙酸\\312\2d-code\90-01\89112968.ptd Page 772 1283240 V. INSTRUCTIONS (768) (s, 2H), 6.86 (d, J = 8.8 Hz, 1H), 7.78 (dd, J = 2 and 8·8 Hz, 1H), 8·12 (d, Hz, 1H). 3-(4-de-2-yl)phenyloxy-2,2-dimethylpropionic acid

使3-（4 -碘-2 -硝基）苯氧基一 2，2 -二甲基丙酸甲酯（2. 8 克，7·38毫莫耳）於THF(15毫升）及0.25N NaOH(60毫升， 1 5莫耳）中之混合物在環境溫度下丨8小時。將混合物倒入 至冰的1 N HC 1 ( 2 0毫升）中。收集固體，以水洗滌並風乾。 使粗製固體自CHC13-EtOH-ΙΡΕ再結晶，而得3-（4-碘-2-确 基）苯氧基-2, 2 -二甲基丙酸（2· 〇克，74%)之結晶物質。熔 點 1 65- 1 82 〇C ; IR (KBr) 1 71 6、1 525、1 344 / 公分； 'H-NMR (CDC13)(5 1.38 (s, 6H) ^4.10 (s, 2H) ^6.86 (d，J = 8.8 Hz, 1H)、7·79 (dd, J = 2.2 及 8·8 Hz， 1H)、 8.12 (d, ] = 2 Hz, 1H) ； MS(FAB) m/z 366 (MH1); C29H33N3 06 之分析計算值：c，36. 18 ; H，3. 18 ; N，3. 84。 實測值·· C， 36. 85 ; H， 3. 35 ; N，3. 79。 3-硝基-4-(2-第三丁氧羰胺基_2—曱基—丨―丙氧基）碘苯Methyl 3-(4-iodo-2-nitro)phenoxy-2,2-dimethylpropanoate (2.8 g, 7.38 mmol) in THF (15 mL) and 0.25N The mixture in NaOH (60 mL, 15 mol) was entrided at ambient temperature for 8 hours. The mixture was poured into 1 N HCl (20 mL) of ice. The solid was collected, washed with water and air dried. The crude solid was recrystallized from CHC13-EtOH-oxime to give crystals of 3-(4-iodo-2-decyl)phenoxy-2,2-dimethylpropanoic acid (2·g, 74%). substance. Melting point 1 65- 1 82 〇C ; IR (KBr) 1 71 6 , 1 525 , 1 344 / cm ; 'H-NMR (CDC13) (5 1.38 (s, 6H) ^4.10 (s, 2H) ^6.86 ( d, J = 8.8 Hz, 1H), 7·79 (dd, J = 2.2 and 8·8 Hz, 1H), 8.12 (d, ] = 2 Hz, 1H) ; MS(FAB) m/z 366 (MH1 ); C29H33N3 06 Analysis calculated: c, 36. 18 ; H, 3. 18 ; N, 3. 84. Measured value · · C, 36. 85 ; H, 3. 35 ; N, 3. 79. 3 -nitro-4-(2-tert-butoxycarbonylamino-2-indoleyl-hydrazine-propoxy)iodobenzene

在室溫下於3_ (4/碘〜2〜硝基）苯氧基—2, 2—二曱基丙酸 (1.93克，5.29宅莫耳）及三乙胺（59〇毫克，5·81毫莫耳） 於第三-Bu0H(15毫升）及甲苯（15毫升）中之攪拌混合物中At room temperature in 3_(4/iodo~2~nitro)phenoxy-2,2-dimercaptopropionic acid (1.93 g, 5.29 house moles) and triethylamine (59 mg, 5.81) Milliol) in a stirred mixture of a third-Bu0H (15 ml) and toluene (15 ml)

\\312\2d-code\90-01\89112968.ptd 第773頁 1283240 五、發明說明（769)\\312\2d-code\90-01\89112968.ptd Page 773 1283240 V. Description of invention (769)

加入疊氮二苯碌醯（1.53克，5.55毫莫耳）溶於甲苯（3毫 升）之溶液。然後使所產生之混合物迴流加熱2 〇小時。於 冷卻後，將冰的IN HC1 (5毫升）加至混合物，並以甲笨萃 取。將萃取液以鹽水洗滌，於NajO4上乾燥，並蒸發。將 殘留物於矽膠（50毫升）上利用甲苯-EtOAc(10: i v/v)作 為洗提液進行層析，而得3 -确基-4-(2 -第三丁氧叛胺基 〜2 -甲基-1—丙氧基）碘笨（ι·91克，83%)的膠。UMR (CDC13) 6 1. 38 (s，9H)、1· 39 (s，6H)、4· 19 (s，2H) 、4·67 (br s，1H)、6·88 (d，J = 8.8 Hz，1H)、7·77 (dd，J = 2.0 及 8·8 Hz，1H)、8·12 (d，J = 2.0 Hz，1H)。 4-(2-第三丁氧羧胺基-2-曱基-1-丙氧基）一3 一硝基苯曱酸 甲酯 使3 -硝基-4-(2-第三丁氧羰胺基-2-甲基-1-丙氧基）碘 苯（1.9克，4.36毫莫耳）、Pd(0Ac)2及1,3-雙（二苯膦基） 丙烷（dppp)(90毫克，0.22毫莫耳）於三乙胺-MeOH-DMS0 (1:2:5，v/v，48毫升）中之混合物在CO(氣體）流中在70°C 下攪拌6小時。於冷卻後，將混合物倒入至水中，並以 EtOAc萃取。將萃取液以鹽水洗滌，於Na2S04上乾燥，並蒸 發。將殘留物於矽膠（50毫升）上利用甲苯-EtOAc(6 : 1， v/v)作為洗提液進行層析，而得4-(2-第三丁氧羰胺基-2_ 甲基-1-丙氧基）-3-硝基苯甲酸甲酯（ 820毫克，51%)的 膠。1H-NMR (CDCl3)(n.38 (s，9H)、1.42 (s，6H)、A solution of azide diphenyl hydrazine (1.53 g, 5.55 mmol) dissolved in toluene (3 ml) was added. The resulting mixture was then heated under reflux for 2 hrs. After cooling, ice IN HCI (5 mL) was added to the mixture and taken up in vacuo. The extract was washed with brine, dried over NajEtOAc and evaporated. The residue was chromatographed on silica gel (50 ml) using toluene-EtOAc (10: iv/v) as eluent to give 3----- 4----- -Methyl-1 -propoxy)iodo stupid (ι·91 g, 83%) gum. UMR (CDC13) 6 1. 38 (s, 9H), 1. 39 (s, 6H), 4· 19 (s, 2H), 4·67 (br s, 1H), 6. 88 (d, J = 8.8 Hz, 1H), 7·77 (dd, J = 2.0 and 8·8 Hz, 1H), 8·12 (d, J = 2.0 Hz, 1H). Methyl 4-(2-t-butoxycarbonylamino-2-mercapto-1-propoxy)-3-nitrobenzoate gives 3-nitro-4-(2-tert-butoxycarbonyl) Amino-2-methyl-1-propoxy)iodobenzene (1.9 g, 4.36 mmol), Pd(0Ac)2 and 1,3-bis(diphenylphosphino)propane (dppp) (90 mg A mixture of 0.22 mmoles in triethylamine-MeOH-DMS0 (1:2:5, v/v, 48 mL) was stirred in a CO (gas) stream at 70 ° C for 6 hours. After cooling, the mixture was poured into water and extracted with EtOAc. The extract was washed with brine, dried over Na 2 SO 4 and evaporated. The residue was chromatographed on silica gel (50 ml) using toluene-EtOAc (6:1 v/v) as eluent to give 4-(2-t-butoxycarbonylamino-2-methyl) Methyl 1-propoxy)-3-nitrobenzoate (820 mg, 51%). 1H-NMR (CDCl3) (n.38 (s, 9H), 1.42 (s, 6H),

\\3l2\2d-code\90-01\89112968.ptd 第 774 頁 1283240 五、發明說明（770) 3·93 (s，3H)、4·29 (s，2H)、4.67 (br s，1H)、7·15 (d，J = 8.8 Ηζ，1Η)、8·18 (dd，J=1.7 及 8·8 Ηζ，1Η)、 8·52 (d，J=1.7 Hz，1H)。 4-(2-胺基-2-甲基-i —丙氧基）-3 —三氟乙醯胺基苯曱酸甲 酯 ^Ύ〇〇2Μθ cf3 使4-(2_第三丁氧羰胺基-2—甲基—丨―丙氧基）-3 -硝基苯 甲酸甲醋（ 35 0毫克，〇. 95毫莫耳）及5% pd_c(7〇毫克）於 EtOH(30毫升）中之攪拌混合物在大氣氫氣壓力下在室溫下 氫化20小時。利用吸濾將不溶解的？(1催化劑移除，並以 EtOH洗滌。將濾液蒸發而得4 —(2 -第三丁氧羰胺基-2-甲 基）-；1-丙氧基-3 -胺基笨甲酸曱酯的膠，將其不經進一步 的純化而使用於後續的反應。(CDC13) 5 1 · 41 (s, 9H)、1·43 (s， 6H)、3·86 (s， 3H)、4·07 (s, 2H)、 4·67 (br s，1Η)、6·80 (d，J = 8.5 Hz, 1Η)、7·39 (d， J = 2.2 Hz，1H)、7·44 (dd，J = 2.2 及 8·5 Hz，1H)。 在0-5 C下於以上之4—(2—第三丁氧羰胺基—2-甲基）_1-丙氧基-3 -胺基笨甲酸甲酯及三乙胺（〇.2()毫升，143毫莫 耳）於CΗ，1〆10毫升）中之攪拌混合物中加入三氟乙酸酐 (0.182毫升，1.28毫莫耳）溶於CH2C“（3毫升）之溶液。使 所產生之混合物在室溫下攪拌1小時。將冰的飽和NaHC〇3 加至混合物，並以CH2C12萃取。將萃取液以鹽水洗滌，於\\3l2\2d-code\90-01\89112968.ptd Page 774 1283240 V. Description of invention (770) 3·93 (s, 3H), 4·29 (s, 2H), 4.67 (br s, 1H ), 7·15 (d, J = 8.8 Ηζ, 1Η), 8.18 (dd, J=1.7 and 8·8 Ηζ, 1Η), 8·52 (d, J=1.7 Hz, 1H). 4-(2-Amino-2-methyl-i-propoxy)-3-trifluoroacetamidobenzoic acid methyl ester^Ύ〇〇2Μθ cf3 4-(2_t-butoxycarbonyl) Amino-2-methyl-oxime-propoxy)-3-nitrobenzoic acid methyl vinegar (35 0 mg, 〇. 95 mmol) and 5% pd_c (7 〇 mg) in EtOH (30 ml) The stirred mixture was hydrogenated at room temperature for 20 hours under atmospheric hydrogen pressure. Will it be dissolved by suction filtration? (1) The catalyst was removed and washed with EtOH. The filtrate was evaporated to give 4-(2-tritoxycarbonylamino-2-methyl)-; 1-propoxy-3-aminobenzoate The gum was used in the subsequent reaction without further purification. (CDC13) 5 1 · 41 (s, 9H), 1.43 (s, 6H), 3·86 (s, 3H), 4· 07 (s, 2H), 4·67 (br s, 1Η), 6·80 (d, J = 8.5 Hz, 1Η), 7·39 (d, J = 2.2 Hz, 1H), 7·44 (dd , J = 2.2 and 8·5 Hz, 1H). 4-(2-t-butoxycarbonylamino-2-methyl)-1-propoxy-3-amine group at 0-5 C above Trifluoroacetic anhydride (0.182 ml, 1.28 mmol) was dissolved in a stirred mixture of methyl benzoate and triethylamine ( 〇.2 (1 mL, 143 mmol) in EtOAc (1 EtOAc) CH2C "(3 ml) solution. The resulting mixture was stirred at room temperature for 1 hour. Ice saturated NaHC 〇3 was added to the mixture and extracted with CH2C12.

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第775頁 1283240 五、發明說明（771)Page 775 1283240 V. Description of invention (771)

Na2S〇4上乾燥，並蒸發。將殘留物溶解於CH2C12 (5毫升）， 並加入茴香醚（〇·1〇5毫升，095毫莫耳）及TFA (2毫升）。 使所產生之混合物在室溫下攪拌1 8小時。將混合物於真空 中蒸發，並將殘留物以CH2C12稀釋及經由加入飽和NaHC03 使成為鹼性。將分離的CH2C12層於Na2S04上乾燥，並蒸發。 使殘留物於矽膠（50毫升）上利用CHCl3-EtOH(99:l，v/v) 作為洗提液進行層析，而得4-(2-胺基—2-曱基-1-丙氧基） -3-二氟乙醯胺基苯曱酸甲酯（631毫克，3步驟63%)的膠。 ]H-NMR (CDC13) (5 1 . 29 (s, 9H, tert-Bu) &gt;3.86 (s, 2H, CH2)、3·91 (s，3H)、6·99 (d，J = 8.5 Hz，1H)、7.91 (dd’ HQ 及 8·5 Hz，1H)、8.83 (d，J = 8.5 Hz，1H)。 4-[2-N - [4-[Ν’ _( 2-氯苯基）脲基]一 3—甲氧苯基乙醯胺 基]-2-甲基-1-丙氧基]-3-三氟乙醯胺基笨甲酸曱酯 八 Η 在室溫下於4-(2-胺基-2-甲基）—卜丙氧基—3_三氟乙醯 胺基苯曱酸曱酯（2 0 0毫克，0.59 8毫莫耳）、4一[『—（2 — 苯基）脲基]-3-甲氧苯基乙酸（21〇毫克，〇· 598毫莫耳' 4-ΜΑΡ (90宅克，0.72¾莫耳）kDMF(7毫升）中之 合物中加入EDC · HC1(160毫克，〇 古曾甘、，士 凡u · 8 1笔莫耳）。使所產生 之混合物在室溫下攪拌2 0小時。蔣、、曰人从^ τ 收集固體，以水洗滌並風乾。將扣制㈤/ τ , 、 时粗製固體經由利用CHC 1 -Dry on Na2S〇4 and evaporate. The residue was dissolved in EtOAc (5 mL). The resulting mixture was stirred at room temperature for 18 hours. The mixture was evaporated in vacuo and the residue was diluted with CH.sub.2 C.sub. The separated CH 2 C 12 layer was dried over Na 2 SO 4 and evaporated. The residue was chromatographed on silica gel (50 ml) using CHCl3-EtOH (99:1, v/v) as eluent to give 4-(2-amino-2-mercapto-1-propoxyl) Methyl -3-difluoroacetamidobenzoate (631 mg, 3 steps 63%) of the gum. ]H-NMR (CDC13) (5 1 . 29 (s, 9H, tert-Bu) &gt;3.86 (s, 2H, CH2), 3·91 (s, 3H), 6·99 (d, J = 8.5 Hz, 1H), 7.91 (dd' HQ and 8·5 Hz, 1H), 8.83 (d, J = 8.5 Hz, 1H). 4-[2-N - [4-[Ν' _( 2-chlorobenzene) Ureyl] ureido]-3-methoxyphenylacetamido]-2-methyl-1-propoxy]-3-trifluoroacetamido benzoate oxime oxime at room temperature at 4 -(2-Amino-2-methyl)-p-propoxy-3-trifluoroacetamidobenzoate (200 mg, 0.59 8 mmol), 4 [[-( 2 —Phenyl)ureido]-3-methoxyphenylacetic acid (21 〇 mg, 〇· 598 mmol) 4-ΜΑΡ (90 克, 0.723⁄4 mol) in kDMF (7 ml) EDC · HC1 (160 mg, 〇古曾甘, 士凡u · 8 1 莫耳) was added, and the resulting mixture was stirred at room temperature for 20 hours. Jiang, 曰 people collected solids from ^ τ , washed with water and air dried. Will buckle (five) / τ, when the crude solids through the use of CHC 1 -

Et0H(98:2，ν/ν)作為洗提液進田π“ 延仃石夕膠官柱層析，純化而Et0H (98:2, ν / ν) as an eluent into the field π "Yanshi Shijiao official column chromatography, purification

1283240 五、發明說明（772)1283240 V. Description of invention (772)

得4 - [2 - N- [4-[Ν’-（2-氯苯基）脲基]-3-甲氧笨基乙醯胺 基]-2-甲基-1-丙氧基]- 3 -三氟乙醯胺基笨曱酸甲g旨（58〇 毫克，q. y·)的結晶物質。UMR (CDC13) 3 !h-NMR (CDC13) (M.42 (s，6H)、3·42 (s，2H)、3.69 (s， 3H)、3·89 (s，3H)、4·23 (s，2H)、5·33 (br s，1H)、 6.66 (s，1H)、6·71 (m，1H)、6·92 (d，J = 8.5 Hz， 1H)、7.02 (m，1H)、7·09 (m，2H)、7.29 (m，ih)、 7.37 (d，J 二 8.0 Hz, 1H)、7·87 (dd，J = 2 及8.5 Hz， 1H)、7·97 (d，J = 8.0 Hz，1H)、8.19 (d，J = 8.2 H;， 1H) 、8·59 (br s， 1H) 、8.74 (d， J=2.〇 Hz， 1H)。’ 在環境溫度下於4-[2-N-[4-[Ν’ -（2-氯笨基）脲基]一3 —甲 氧苯基乙醯胺基]-2-甲基-1-丙氧基]-3 -三氟乙醢胺基笨 甲酸甲酯（32 0毫克，0· 4 92毫莫耳）溶於THF(2毫升）之攪掉 溶液中加入0. 25N NaOH(6毫升，1.5毫莫耳）。使所產生之 混合物攪拌2 0小時。將混合物倒入至冰的1 N H C 1 ( 2毫升） 中。收集固體，以水洗滌，並風乾。使粗製固體自CHC 13-Et0H-Et20再結晶，而得3 0 1 ( 2 40毫克，89%)之微細針狀 物。IR (KBr) u 3338 、 3296 、 1691 、 1641 / 公分；1 Η-NMR (CDC13) 6 1 -NMR (DMSO-d6) 5 1.37 (s，6H)、 3.35 (s，2H)、3·77 (s，3H)、4·05 (s，2H)、4·96 (br s，1H)、6·75 (br d，J = 8. 3 Hz, 1H)、6.78 (d，J = 8. 3 Hz，1H)、6·87 (d，J = 1.7 Hz, 1H)、7·01 (m，1H)、 7·15 (dd，J = 2 及 8·5 Hz，1H)、7·24 (d，J = 2 Hz，1H)、 7.27 (dt, J = 2.0 及 8.5 Hz, 1H)、7·43 (dd， J = 2 及 8.04-[2-N-[4-[Ν'-(2-Chlorophenyl)ureido]-3-methoxyphenylethylamino]-2-methyl-1-propoxy]- A crystalline material of 3-trifluoroacetamido-based azelaic acid (58 mg, q. y·). UMR (CDC13) 3 !h-NMR (CDC13) (M.42 (s, 6H), 3.42 (s, 2H), 3.69 (s, 3H), 3·89 (s, 3H), 4·23 (s, 2H), 5·33 (br s, 1H), 6.66 (s, 1H), 6·71 (m, 1H), 6.92 (d, J = 8.5 Hz, 1H), 7.02 (m, 1H), 7·09 (m, 2H), 7.29 (m, ih), 7.37 (d, J 2 8.0 Hz, 1H), 7·87 (dd, J = 2 and 8.5 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H), 8.19 (d, J = 8.2 H;, 1H), 8·59 (br s, 1H), 8.74 (d, J=2.〇Hz, 1H). 4-[2-N-[4-[Ν' -(2-chlorophenyl)ureido]-3-methoxyphenylethylamino]-2-methyl-1-propoxy at ambient temperature 25N NaOH (6 ml, 1.5), a solution of methyl trifluoroacetic acid methyl ester (32 mg, 0.42 mmol) dissolved in THF (2 ml). The resulting mixture was stirred for 20 hours. The mixture was poured into EtOAc (EtOAc) (EtOAc). Et20 recrystallized to give 3 0 1 (2 40 mg, 89%) of fine needles. IR (KBr) u 3338, 3296, 1691, 1641 / 1; Η-NMR (CDC13) 6 1 -NMR (DMSO-d6) 5 1.37 (s, 6H), 3.35 (s, 2H), 3·77 (s, 3H), 4·05 (s, 2H) , 4·96 (br s, 1H), 6.75 (br d, J = 8. 3 Hz, 1H), 6.78 (d, J = 8. 3 Hz, 1H), 6·87 (d, J = 1.7 Hz, 1H), 7·01 (m, 1H), 7·15 (dd, J = 2 and 8·5 Hz, 1H), 7·24 (d, J = 2 Hz, 1H), 7.27 (dt , J = 2.0 and 8.5 Hz, 1H), 7·43 (dd, J = 2 and 8.0

\\312\2d-code\90-01\89112968.ptd 第777頁 1283240 五、發明說明（773)\\312\2d-code\90-01\89112968.ptd Page 777 1283240 V. Description of invention (773)

Hz, 1H) 、7·78 (br s， 1H) 、7·90 (d， J=8.0 Hz， 1H)、 8.08 (dd，J = 2 及 8.3 Hz，1H)、8·85 (s，1H)、8.89 (s, 1H)、12.23 (br s，1H) ; MS(FAB) m/z 541 (MH1); C27H29C1N406 之分析計算值：c，58.00; H，5.59; N，10.02 。實測值：C，57.97; H，5.39; N，10.01。 實施例2 5 1 2-乙醯胺基-4-[2-N - [3-甲氧基-4-[N，-（2-甲基苯基）脲基 ]苯基]- N-甲基乙醯胺基]乙基胺基苯甲酸Hz, 1H), 7·78 (br s, 1H), 7·90 (d, J=8.0 Hz, 1H), 8.08 (dd, J = 2 and 8.3 Hz, 1H), 8·85 (s, 1H) , 8.89 (s, 1H), 12.23 (br s, 1H); MS (FAB) m/z 541 (MH1); C27H29C1N406 calc.: C, 58.00; H, 5.59; N, 10.02. Found: C, 57.97; H, 5.39; N, 10.01. Example 2 5 1 2-Ethylamino-4-[2-N-[3-methoxy-4-[N,-(2-methylphenyl)ureido]phenyl]-N-A Ethylamino]ethylaminobenzoic acid

NHAcNHAc

302 2 -乙醯胺基-4 -硝基苯甲酸甲酯 人义NHAc 在0 °C下於2-乙醯胺基-4-硝基苯甲酸（1· 28克，5· 71毫 莫耳）溶於苯-MeOH(4:l，v/v，25毫升）之攪拌溶液中加入 三甲矽烷基重氮甲烷（2. 0M正己烷溶液，4.28毫升，8.56 毫莫耳）。使攪拌在室溫下持續1 8小時。將反應倒入至己 院中，並經由過濾收集所產生之沈殿物，而得2 -乙醯胺基 -4-硝基苯曱酸甲酯（1· 32克，97%)之白色固體；熔點無數 據；1H-NMR (400 MHz, CDC13) 52.30 (s，3H)、4·00 (s， 3Η)、7·88 (m，1Η)、8·18 (dd，J = 2.〇 Hz、8·8 Ηζ，302 2 -Ethylamino-4-nitrobenzoic acid methyl ester human NHAc at 0 °C in 2-ethylamino-4-nitrobenzoic acid (1·28 g, 5.71 mmol) To a stirred solution of benzene-MeOH (4:1, v/v, 25 mL) was added &lt;RTI ID=0.0&gt;&gt;&gt; Stirring was allowed to continue at room temperature for 18 hours. The reaction was poured into a home, and the resulting sediment was collected by filtration to give a white solid of methyl 2-acetamido-4-nitrobenzoate (1·32 g, 97%); Melting point no data; 1H-NMR (400 MHz, CDC13) 52.30 (s, 3H), 4·00 (s, 3Η), 7·88 (m, 1Η), 8·18 (dd, J = 2.〇Hz , 8·8 Ηζ,

1H)、9·60 (t，J = 2.2 Hz，1H)、11·10 (s，1H) ; MS1H), 9·60 (t, J = 2.2 Hz, 1H), 11·10 (s, 1H); MS

89112968.ptd 第778頁 1283240 五、發明說明（774) (ESI) m/z 238 (M+)。 2-乙醯胺基-4-胺基笨甲酸甲酯89112968.ptd Page 778 1283240 V. INSTRUCTIONS (774) (ESI) m/z 238 (M+). 2-Ethylamino-4-aminobenzoic acid methyl ester

於2-乙醯胺基-4-硝基苯甲酸甲酯（1· 31克，5. 50毫莫 耳）溶於MeOH(30毫升）之溶液中加入5% Pd /破（195毫 克），並在室溫下在H2氣體（3大氣壓）中持續攪拌1 8小時。 將催化劑過濾掉，並將混合物蒸發。利用CHC13-MeOH-己 烷使所產生之粗製固體再結晶，而得2 -乙醯胺基-4 -胺基 苯甲酸甲酯（1· 03克，90%)之白色固體。UMR (400 MHz, CDC13) (52.23 (s，3H)、3·82 (s，3H)、4·20 (s， 2Η)、6·30 (dd，J = 2.5 Hz、8·8 Hz, 1Η)、7·80 (d， J二8·8 Ηζ，1Η)、8·06 (s，1Η)、11·26 (s，1H); MS(FAB) m/z 208 (Μ+)。 2-乙醯胺基-4-[2-(Ν-第三丁氧羰基-Ν-甲胺基）乙胺基]笨 甲酸曱酯Add 5% Pd / broken (195 mg) to a solution of methyl 2-acetamido-4-nitrobenzoate (1·31 g, 5.50 mmol) in MeOH (30 mL). Stirring was continued for 18 hours at room temperature in H 2 gas (3 atm). The catalyst was filtered off and the mixture was evaporated. The resulting crude solid was recrystallized from CH.sub.3-MeOH-hexanes to afford ethyl 2-acetyiamino-4-aminobenzoate (1. 03 g, 90%) as a white solid. UMR (400 MHz, CDC13) (52.23 (s, 3H), 3·82 (s, 3H), 4·20 (s, 2Η), 6.30 (dd, J = 2.5 Hz, 8·8 Hz, 1Η ), 7·80 (d, J 2·8 Ηζ, 1Η), 8·06 (s, 1Η), 11·26 (s, 1H); MS(FAB) m/z 208 (Μ+). 2 -Ethylamino-4-[2-(indolyl-tert-butoxycarbonyl-indole-methylamino)ethylamino] benzoic acid oxime ester

於2-乙醯胺基-4_胺基苯甲酸甲酯（300毫克，ι·44毫莫 耳）及Ν-第三丁氧羰基_Ν-甲基甘胺醛（499毫克，2·88毫莫 耳）溶於1，2 -二氯乙烷（30毫升）之冷卻溶液中加入NaBH (0Ac)3 ( 964毫克，4·32毫莫耳），並在0°C下持續擾拌64 小時。將混合物倒入至飽和NaHC〇3中，並以CHC13(50毫升Methyl 2-acetamido-4-aminobenzoate (300 mg, ι·44 mmol) and Ν-t-butoxycarbonyl-Ν-methylglycine aldehyde (499 mg, 2.88) To a cooled solution of 1,2-dichloroethane (30 ml) was added NaBH(0Ac)3 (964 mg, 4.32 mmol) and continued to stir at 0 °C. hour. Pour the mixture into saturated NaHC〇3 and use CHC13 (50 ml)

第779頁 1283240 五、發明說明（775)Page 779 1283240 V. Description of invention (775)

x3)萃取，以鹽水洗滌，並於MgS〇4上乾燥。於在真空中移 除溶劑後，使殘留物於矽膠（中壓層析系統·· γΑΜΑΖΕΝ YFLC-5404 - FC，己烷-EtOAc自9:1至2:1之線性梯度）上進 行層析，而得2-乙醯胺基-4 - [2-(N〜第三丁氧裁基—n—甲胺 基）乙胺基]苯甲酸甲酯（451毫克，86%)之無色油。iH — NMR (CDC13，40 0 MHz) δ 1. 48 (s，9H)、2· 2 2 (s，3H)、 2.90 (s，3Η)、3·32 (m，2Η)、3·50 (m，2Η)、3·80 (s， 3Η)、6·20 (dd，】 = 2·2 Hz、8·8 Ηζ， 1Η)、7·80 (m， 1Η)、7·95 (m，1Η)、11·30 (brs，1H); MS(FAB) m/z 36 6 (ΜΗ1)。 2-乙醯胺基-4- [2-（Ν-甲胺基）乙胺基]苯甲酸曱酯 ^又二NHAc 於2-乙醯胺基-4-[2-(N-第三丁氧羰基-N-甲胺基）乙胺 基]苯甲酸甲酯（450毫克，1·23毫莫耳）溶於二氣甲烧（5毫 升）之攪拌溶液中加入TFA(5毫升），並在室溫下持續攪拌 1 8小時。於在真空中移除溶劑後，將殘留物溶解於CHC13 (200毫升），以鹽水、飽和NaHC03洗滌，並於MgS04上乾 燥。將溶劑移除而得2_乙醯胺基-4-[2-(N-甲胺基）乙胺 基]苯甲酸甲酯（ 298毫克，88%)的無色油。1H-NMR (CDC13 ，40 0 MHz) 5 2·21 (s，3H)、2· 46 (s，3H)、2· 88 (m， 2H)、3·31 (m，2H)、3·83 (s，3H)、4·85 (br，1H)、6. 24 (dd，J = 2.5 Hz、8·8 Hz，1H)、7·80 (d，J = 8.8 Hz, 1H)、7·99 (d，J = 2.5 Hz，1H); MS(FAB) m/z 266X3) Extract, wash with brine and dry on MgS〇4. After removing the solvent in vacuo, the residue was chromatographed on EtOAc (EtOAc EtOAc EtOAc EtOAc EtOAc There was obtained a colorless oil of 2-ethylaminoamino-4-[2-(N~t-butoxy-decyl-n-methylamino)ethylamino]benzoate (451 mg, 86%). iH — NMR (CDC13, 40 0 MHz) δ 1. 48 (s, 9H), 2· 2 2 (s, 3H), 2.90 (s, 3Η), 3·32 (m, 2Η), 3·50 ( m, 2Η), 3·80 (s, 3Η), 6·20 (dd,] = 2·2 Hz, 8·8 Ηζ, 1Η), 7·80 (m, 1Η), 7·95 (m, 1Η), 11·30 (brs, 1H); MS(FAB) m/z 36 6 (ΜΗ1). 2-Ethylamino-4-[2-(Ν-methylamino)ethylamino]benzoic acid oxime^ and two NHAc in 2-ethylamido-4-[2-(N-third Methyl oxycarbonyl-N-methylamino)ethylamino]benzoate (450 mg, 1.23 mmol) was dissolved in a stirred solution of methane (5 mL). Stirring was continued for 18 hours at room temperature. The residue was dissolved in CH.sub.3 (EtOAc) (EtOAc) elute The solvent was removed to give the title compound (EtOAc m. 1H-NMR (CDC13, 40 0 MHz) 5 2·21 (s, 3H), 2·46 (s, 3H), 2·88 (m, 2H), 3·31 (m, 2H), 3·83 (s, 3H), 4.85 (br, 1H), 6. 24 (dd, J = 2.5 Hz, 8·8 Hz, 1H), 7·80 (d, J = 8.8 Hz, 1H), 7· 99 (d, J = 2.5 Hz, 1H); MS(FAB) m/z 266

89112968.ptd 第780頁 1283240 五、發明說明（776) (MH1) 〇 2-乙醢胺基-4- [2-N-[ 3-甲氧基-4-[N，-（2-甲基苯基）脲 基]苯基]- N-甲基乙醯胺基]乙基胺基苯甲酸曱酯89112968.ptd Page 780 1283240 V. INSTRUCTIONS (776) (MH1) 〇2-Ethylamino-4-[2-N-[ 3-methoxy-4-[N,-(2-methyl) Phenyl)ureido]phenyl]-N-methylacetamido]ethylaminobenzoate

使2-乙醯胺基-4-[2-(N-甲胺基）乙胺基]苯甲酸甲酯Methyl 2-acetamido-4-[2-(N-methylamino)ethylamino]benzoate

(145毫克，0·55毫莫耳）、3-甲氧基-4 - [N，-(2-甲基苯基） 脲基]苯基乙酸（172毫克，0.55毫莫耳）、EDC ·Η(： 1(158 耄克’0.83宅莫耳）、H0Bt(141毫克，1.05毫莫耳）、及 DMAPC13毫克，〇· 11毫莫耳）於DMF(10毫升）中之混合物攪 拌18小時。將混合物以EtOAc(300毫升）稀釋，以鹽水洗 蘇，並於MgS〇4上乾燥。於移除溶劑後，使殘留物於矽膠 (中壓層析系統：YAMAZEN YFLC-5404-FC，CHC13-MeOH 自 1 0 0 · 0至7 0 : 3 0之線性梯度）上進行層析，而得2 —乙醢胺基 -4-[2-N-[3-甲氧基-4-[N’ _(2-甲基苯基）脲基]苯基] 甲基乙醯胺基]乙基胺基苯甲酸甲酯（309毫克，1〇〇%)之非 晶形泡沫。1H-NMR (CDC13)(5 2·22 (s，3Η)、2·30 (s， 3Η)、3·02 (s，3Η)、3·35 (m，2Η)、3·58 (s，3Η)、(145 mg, 0·55 mmol), 3-methoxy-4 - [N,-(2-methylphenyl)ureido]phenylacetic acid (172 mg, 0.55 mmol), EDC. A mixture of hydrazine (: 1 (158 gram of '0.83 house Moule), H0Bt (141 mg, 1.05 mmol), and DMAPC (13 mg, 〇 11 mmol) in DMF (10 ml) was stirred for 18 hours. The mixture was diluted with EtOAc (300 mL), washed with brine and dried over EtOAc. After the solvent was removed, the residue was chromatographed on a silica gel (medium pressure chromatography system: YAMAZEN YFLC-5404-FC, CHC13-MeOH from a linear gradient from 00 to 0:30:30). 2-Ethylamino-4-[2-N-[3-methoxy-4-[N' _(2-methylphenyl)ureido]phenyl]methylethenyl] Amorphous foam of methyl aminobenzoate (309 mg, 1%). 1H-NMR (CDC13) (5 2·22 (s, 3Η), 2·30 (s, 3Η), 3·02 (s, 3Η), 3·35 (m, 2Η), 3·58 (s, 3Η),

3· 50-3· 74 (m，4Η)、3. 85 (s，3Η)、6. 20 (m, 1H)、 6.58 (s，1H)、6·65-6.75 (m，3H)、7.13 (m，2H)、 7.40-7.50 (m，2H)、7·75 (m，2H)、7·90 (m，1H)、 8.0 0 (m, 1H) ^ 11. 3 2 (s, 1H) ； MS (FAB) m/z 562 (MH1) 〇3· 50-3· 74 (m, 4Η), 3.85 (s, 3Η), 6. 20 (m, 1H), 6.58 (s, 1H), 6.65-6.75 (m, 3H), 7.13 (m, 2H), 7.40-7.50 (m, 2H), 7.75 (m, 2H), 7·90 (m, 1H), 8.0 0 (m, 1H) ^ 11. 3 2 (s, 1H) ; MS (FAB) m/z 562 (MH1) 〇

89112968.ptd 第781頁 1283240 五、發明說明（777) 在室溫下於2-乙醯胺基-4 - [2 - N-[3-甲氧基-4-[N，-（2 -甲基苯基）脲基]苯基]-N-甲基乙醯胺基]乙基胺基苯甲酸 甲酯（ 3 0 9 毫克，〇·55 毫莫耳）溶於 THF-MeOH(l:l，v/v， 9 毫升）之溶液中加入〇· 25N NaOH(4. 4毫升，1· 1毫莫耳）， 並迴流加熱。在迴流下持續攪拌1 8小時。將反應混合物倒 入至水中，並利用1. ON HC1酸化至pH 5. 0。使所產生之沈 澱物利用己烷-乙醚再結晶，而得30 2 ( 1 75毫克，58%)之淡 紅色粉末。1H-NMR (CD30D) (5 2.16 (d, J = 4.8 Hz，3H)、 2·28 (d，J = 4.2 Hz，3H)、2·98 及3.10 (2s，總計3H)、 3.35 (m，2H)、3·68 (m，4H)、3·81 及3.84 (2s，總計 3H)、6·30 (m，1H)、6·60-6·82 (m，2H)、7·0〇 (m，1H) 、7·15 (m，2H)、7·53 (m，1H)、7·77-7·96 (m，3H); MS(FAB) m/z 548 (MH1);C29H33N5 06 . 0.5H20之分析計算 值：C，62. 5 8 ； Η, 6.16； N, 1 2· 58 ° 實測值：C，62· 55 ;H， 6. 31 ； N, 12.15。 實施例2 5 2 2-乙醯胺基-4 -[2-N -[4 - [Ν’ -（2-漠苯基）脈基]- 3-甲氧本 基]-N-甲基乙醯胺基]乙基胺基笨甲酸89112968.ptd Page 781 1283240 V. INSTRUCTIONS (777) 2-Ethylamino-4 - [2-N-[3-methoxy-4-[N,-(2-A) Methylphenyl)ureido]phenyl]-N-methylacetamido]ethylaminobenzylbenzoate (3 0 9 mg, 〇·55 mmol) dissolved in THF-MeOH (l:l v·25N NaOH (4.4 ml, 1.1 mmol) was added to the solution of v/v, 9 ml) and heated under reflux. Stirring was continued for 18 hours under reflux. The reaction mixture was poured into water and acidified to pH 5.0 with 1. ON HCl. The resulting precipitate was recrystallized from hexane-diethyl ether to give 30 2 (1 75 mg, 58%) of pale red powder. 1H-NMR (CD30D) (5 2.16 (d, J = 4.8 Hz, 3H), 2·28 (d, J = 4.2 Hz, 3H), 2·98 and 3.10 (2s, total 3H), 3.35 (m, 2H), 3·68 (m, 4H), 3.81 and 3.84 (2s, total 3H), 6·30 (m, 1H), 6·60-6·82 (m, 2H), 7·0〇 (m, 1H), 7·15 (m, 2H), 7·53 (m, 1H), 7·77-7·96 (m, 3H); MS (FAB) m/z 548 (MH1); C29H33N5 06 . Analysis of 0.5H20: C, 62. 5 8 ; Η, 6.16; N, 1 2 · 58 ° Found: C, 62·55; H, 6. 31; N, 12.15. Example 2 5 2 2-Ethylidene-4 -[2-N -[4 - [Ν' -(2-Molyphenyl))] 3-methoxybenzyl]-N-methylethylamino] Ethylamine

303 2-乙醯胺基-4-[2 - N-[4_[N’ -（2-漠苯基）脈基]- 3-甲乳本 基]-N-甲基乙醯胺基]乙基胺基笨曱酸甲酯303 2-Ethylamino-4-[2-N-[4_[N'-(2-indolyl)-yl]- 3-methyllacyl]-N-methylacetamido] Methylamino alum

\\312\2d-code\90-01\89112968.ptd 第 782 頁 1283240 五、發明說明（778) 使2-乙醯胺基-4-(2-N-甲胺基-1-乙胺基）苯甲酸甲酯 (145毫克，〇· 55毫莫耳）、3 -曱氧基-4-[N，-（2-溴苯基） 脲基]苯基乙酸（ 20 9毫克，0· 55毫莫耳）、EDC · HC1 (158毫 克，0.83毫莫耳）、HOBt(141毫克，1.05毫莫耳）、及 DMAPC13毫克，〇· 11毫莫耳）於DMF(10毫升）中之混合物授 拌18小時。將混合物以EtOAc( 30 0毫升）稀釋，以鹽水洗 條’並於MgSO4上乾燥。於移除溶劑後，使殘留物於；5夕膠 (中壓層析系統：YAMAZEN YFLC- 540 4-FC，CHCl3-Me〇H 自 1 0 0 : 0至7 0 : 3 0之線性梯度）上進行層析，而得2 -乙醢胺基 -4- [2-N- [4 - [Ν’ -（2 -溴苯基）脲基]-3-甲氧苯基]- N-甲基 乙醯胺基]乙基胺基苯曱酸曱酯（ 294毫克，85%)之非晶形土 泡沫。NMR (CDC13) (5 2. 21 (s，3Η)、3· 05 (s，3Η)、 3·40 (m，2H)、3·65-3.70 (m，4H)、3·78 (s，3H)、 3.86 (s，3Η)、6·21 (m，1Η)、6·79 (m，2Η)、6·93 (m 1H)、7·10 (d，J=10.3 Hz，1H)、7·30 (m，1H)、7.42 ’ (m，1H)、7·61 (m，1H)、7·78 - 7·85 (m，2H)、7·93 (m 2H)、8· 13 (m，1H) ; MS(FAB) m/z 627 (M+)。 ’ 在室溫下於2-乙醯胺基-4-[3-曱氧基-4- [N，- (2-溴笨 基）脲基]笨基乙醯胺基]- 2-N-甲胺基-1-乙基胺基笨甲峻 甲酯（294 毫克，0·47 毫莫耳）溶於 THF 一 Me0H(1:i，ν/ν， δ 毫升）之溶液中加入0·25Ν NaOH(3.8毫升，0·94毫莫耳）， 並迴流加熱。在迴流下持續攪拌1 8小時。將反應混合物倒\\312\2d-code\90-01\89112968.ptd Page 782 1283240 V. INSTRUCTIONS (778) 2-Ethylamino-4-(2-N-methylamino-1-ethylamino) Methyl benzoate (145 mg, 〇·55 mmol), 3-methoxy-4-[N,-(2-bromophenyl)ureido]phenylacetic acid (20 9 mg, 0·55) Mixture of mM, EDC, HC1 (158 mg, 0.83 mmol), HOBt (141 mg, 1.05 mmol), and DMAPC (13 mg, 〇·11 mmol) in DMF (10 mL) Mix for 18 hours. The mixture was diluted with EtOAc (30 mL) EtOAc. After removing the solvent, the residue is allowed to be; 5 yam (medium pressure chromatography system: YAMAZEN YFLC-540 4-FC, CHCl3-Me〇H from 1 0 0: 0 to 7 0: 30 linear gradient) Chromatography was carried out to obtain 2-acetamido-4-[2-N-[4-[[Ν-(2-bromophenyl)ureido]-3-methoxyphenyl]-N- Amorphous earth foam of decylaminoethyl phenyl phthalate (294 mg, 85%). NMR (CDC13) (5 2. 21 (s, 3Η), 3· 05 (s, 3Η), 3·40 (m, 2H), 3·65-3.70 (m, 4H), 3·78 (s, 3H), 3.86 (s, 3Η), 6.21 (m, 1Η), 6.79 (m, 2Η), 6.93 (m 1H), 7·10 (d, J = 10.3 Hz, 1H), 7·30 (m, 1H), 7.42 ' (m, 1H), 7.61 (m, 1H), 7·78 - 7·85 (m, 2H), 7·93 (m 2H), 8·13 (m,1H); MS(FAB) m/z 627 (M+). ' 2-Ethylamino-4-[3-methoxy-4-[N,- (2-bromo) at room temperature Styrenyl) ureido] phenylaminoamine] 2-N-methylamino-1-ethylamine benzomethyl methyl ester (294 mg, 0·47 mmol) dissolved in THF-Me0H ( 0:25 NaOH (3.8 ml, 0·94 mmol) was added to a solution of 1:i, ν/ν, δ ml), and heated under reflux. Stirring was continued for 18 hours under reflux. The reaction mixture was poured.

\\312\2d-code\90-01\89112968.ptd 第783頁 1283240 五、發明說明（779) 入至水中，並利用1· ON HC1酸化至pH 5· 0。使所產生之沈 澱物利用己烧-乙鱗再結晶，而得3 0 3之白色粉末（2 1 〇毫 克，73%);熔點 1 5 5-1 6 0。(：；111-題1?(00300)6 2 2,18((1， J = 5.5 Hz，3H)、3.00 及 3.12 (2s，總計 3H)、3·39 (m， 1H) 、3·60 (m， 4H) 、3·70 (s， 1H) 、3·85及3·86 (2s， 總計3H)、6·31 (m，1H)、6·68 (m，1H)、6·78 (m， 1H)、6·78 及 6.85 (2m，總計 1H)、6·97 (m，1H)、7·3〇 (m，1H)、7·56 (m，1H)、7·80-7·95 (m，4H) ; MS(ESI) m/z 613 (M+) ; (：28^1^5 06 · 〇· 75H20 之分析計算值：C， 53·64，H，5·22; N， 11.17。實測值：◦，53.89; H， 5·23 ; N， 10. 69 。 ’ 實施例2 5 3 4 - [2-N- [[4 - [Ν’ -（2 -氣苯基）脲基]—3一甲氧苯基]_N 一苯基 乙醯胺基]乙氧基]笨甲酸 &amp;\\312\2d-code\90-01\89112968.ptd Page 783 1283240 V. INSTRUCTIONS (779) Into the water and acidified to pH 5.0 with 1·ON HC1. The resulting precipitate was recrystallized from hexane-ethyl scale to give a white powder of 303 (2 1 〇m, 73%); melting point 1 5 5-1 6 0. (:; 111-question 1?(00300)6 2 2,18((1, J = 5.5 Hz, 3H), 3.00 and 3.12 (2s, total 3H), 3·39 (m, 1H), 3.60 (m, 4H), 3·70 (s, 1H), 3·85, and 3·86 (2s, total 3H), 6.31 (m, 1H), 6.68 (m, 1H), 6.78 (m, 1H), 6.78 and 6.85 (2m, total 1H), 6.97 (m, 1H), 7·3〇 (m, 1H), 7·56 (m, 1H), 7·80- 7·95 (m,4H) ; MS (ESI) m/z 613 (M+); (:28^1^5 06 · 〇· 75H20 Analysis calculated: C, 53·64, H, 5·22; N, 11.17. Found: ◦, 53.89; H, 5·23; N, 10. 69. 'Example 2 5 3 4 - [2-N- [[4 - [Ν' - (2 - phenyl) Ureido]-3 methoxyphenyl]_N-phenylethyl hydrazinyl] ethoxy] benzoic acid &amp;

304 4-[2-（N-苯胺基）乙氧基]笨甲酸甲酯 Ο ^^COOMe 在室溫下於4-[2-(曱磺醯氧基）乙氧基]苯甲酸甲酯 (2·74克’1〇毫莫耳）溶於MeCN(5〇毫升）之溶液中加入苯胺 (9· 1晕升’ 1 〇〇毫莫耳）。使反應在迴流下攪拌64小時。將 混合物倒入至H20( 20 0毫升）中，以Et〇Ac(10〇毫升χ2)萃304 4-[2-(N-anilino)ethoxy]methyl benzoate Ο ^^COOMe at room temperature in methyl 4-[2-(nonylsulfonyloxy)ethoxy]benzoate ( 2.74 g of '1 〇 millimolar) was dissolved in MeCN (5 〇 ml) to add aniline (9·1 halo' 1 〇〇 millimolar). The reaction was allowed to stir under reflux for 64 hours. Pour the mixture into H20 (20 ml) and extract with Et〇Ac (10 mL)

\\312\2d-code\90-0l\89112968.ptd 第784頁 1283240 五、發明說明（780) 取，於MgS04上乾燥。於在真空中移除溶劑後，將未反應 的苯胺經由在80 °C下與甲苯（1〇毫升x3)共同蒸發而於真空 中移除。使殘留物於矽膠（中壓層析系統：YAM A ZEN YFLC-5404-FC，0 50 毫米 x 150 毫米，CHC13)上進行層 析，而得4-[2 -（N-苯胺基）乙氧基]苯甲酸曱酯（2·23克， 82%)的無色油。1H-NMR (CDC13)6 3.56 (t，J = 5.1 Hz, 2H) 、3·90 (s， 3H) 、4·21 (t， J=5.1 Hz， 2H) 、6·68 (dd， J=1.0 Hz 、8·6 Hz， 2H) 、6·75 (t， J=7.3 Hz， 1H) 、7·20 (AB 型d， J=7.3 Hz， 2H) 、8.00 (d， J=9.1 Hz, 2H); MS(ESI) m/z 272 (MH1)。 4-[2-N-[[4 - [Ν’ -（2-氯苯基）脲基]- 3-甲氧苯基]-N -苯基 乙醯胺基]乙氧基]苯曱酸甲酯\\312\2d-code\90-0l\89112968.ptd Page 784 1283240 V. Description of invention (780) Take and dry on MgS04. After removing the solvent in vacuo, the unreacted aniline was removed in vacuo by co-evaporation with toluene (1 liters x 3) at 80 °C. The residue was chromatographed on silica gel (medium pressure chromatography system: YAM A ZEN YFLC-5404-FC, 0 50 mm x 150 mm, CHC13) to give 4-[2-(N-anilino)ethoxy A colorless oil of benzyl benzoate (2.23 g, 82%). 1H-NMR (CDC13)6 3.56 (t, J = 5.1 Hz, 2H), 3·90 (s, 3H), 4·21 (t, J=5.1 Hz, 2H), 6.68 (dd, J= 1.0 Hz, 8·6 Hz, 2H), 6.75 (t, J=7.3 Hz, 1H), 7·20 (AB type d, J=7.3 Hz, 2H), 8.00 (d, J=9.1 Hz, 2H); MS (ESI) m/z 272 (MH1). 4-[2-N-[[4 - [Ν' -(2-Chlorophenyl)ureido]-3-methoxyphenyl]-N-phenylethylamino]ethoxy]benzoic acid Methyl ester

使4 - [2-（N-苯胺基）乙氧基]苯甲酸甲酯（136毫克，0.5 毫莫耳）、3-甲氧基-4-[Ν’ - (2 -氣苯基）脲基]苯基乙酸 (167毫克，0.5毫莫耳）及pyB〇P (781毫克，0.75毫莫耳）、 i - PrNEt2(261微升，〇· 96毫莫耳）於DMF(10毫升）中之混合 物攪拌18小時。將混合物以EtOAc(l 00毫升）稀釋，以1N HC1、鹽水洗滌，並於MgS04上乾燥。使殘留物與甲苯（1 0 毫升x3)共同蒸發以移除DMF。使殘留物於TLC(MERCK，矽 膠60，2毫米，2板，CHC l3-MeOH，20:1)上進行層析，而 得4-[2-N-[[4- [Ν’-（2-氯苯基）脲基]- 3-甲氧苯基]-N-苯Methyl 4-[2-(N-anilino)ethoxy]benzoate (136 mg, 0.5 mmol), 3-methoxy-4-[Ν'-(2-phenylphenyl)urea Phenylacetic acid (167 mg, 0.5 mmol) and pyB〇P (781 mg, 0.75 mmol), i- PrNEt2 (261 μL, 〇·96 mmol) in DMF (10 mL) The mixture was stirred for 18 hours. The mixture was diluted with EtOAc (EtOAc) (EtOAc)EtOAc. The residue was co-evaporated with toluene (10 mL x 3) to remove DMF. The residue was chromatographed on TLC (MeOH, EtOAc, EtOAc, EtOAc, EtOAc, EtOAc -chlorophenyl)ureido]-3-methoxyphenyl]-N-benzene

\\312\2d-code\90-01\89112968.ptd 第785頁 1283240 五、發明說明（781) 基乙醯胺基]乙氧基]苯甲酸曱酯（129毫克，44%)的白色非 晶形泡沫。1H-NMR (CDC13) 5 3· 42 (s，1H)、3· 69 (d J = 8.3 Hz，1H)、3·74 (s，3H)、3·87 (s，3H)、4·1〇’ (m，2H)、4·23 (m，2H)、6·48-7·44 (m，13H)、7·93 (d， J=9.3 Hz， 2H) 、8·18 (dd， J=1.5 Hz 、8·3 Hz 1H) ; MS(ESI) m/z 588 (M+)。 ’ 在室溫下於4- [2 -N- [[4 - [Ν’ - (2-氯苯基）脲基]一3一甲氧 苯基]-N-苯基乙醯胺基]乙氧基]苯甲酸甲酯（124毫克， 0· 19毫莫耳）溶於THF-Me0H(6:l，v/v，3毫升）之溶液中加 入0.5N Na0H(2毫升，1毫莫耳），並於密封瓶中迴流加 熱。在迴流下持續攪拌1 5小時。將反應混合物倒入至水 中，利用1.0N HC1 酸化，以CHC13-Me0H(2:l，20 毫升x3) 萃取，並於MgS04上乾燥。於移除溶劑後，利用CHC13-己烷 -乙醚使殘留物結晶，而得3〇4(77毫克，64%)的白色粉 末。1H-NMR (CD30D) 5 3· 45 (s，2H)、3· 79 (s，3H)、4· 12 (m，2H)、4·22 (m，2H)、6·48 (dd，J = 2.0 Hz、8·3 Hz, 1H)、6·61 (d，J = 2.0 Hz, 1H)、6·87 (d，J = 8.8 Hz, 2H)、7·00 (m，ih)、7·22 (m，3H)、7·36 (m， 1H)、7·43 (m，3H)、7·90 (d，J = 8.3 Hz, 1H)、7.95 (d，J:8.8 Hz，2H) '8.02 (dd，J = 1.5 Hz、8·3 Hz， IH) ; MS(ESI) m/z 574 (m+) ; c31H28C1N3 06 · 〇· 5H20 之分析 計算值：C，63· 86 ; H，5· 01 ; N， 7. 21。實測值：C， 63· 67 ; Η, 4· 91 ; N， 6· 99 。 f施例2 5 4\\312\2d-code\90-01\89112968.ptd Page 785 1283240 V. INSTRUCTIONS (781) Ethyl acetamino] ethoxy] benzoic acid oxime ester (129 mg, 44%) of white non Crystal foam. 1H-NMR (CDC13) 5 3· 42 (s, 1H), 3· 69 (d J = 8.3 Hz, 1H), 3·74 (s, 3H), 3·87 (s, 3H), 4·1 〇' (m, 2H), 4·23 (m, 2H), 6·48-7·44 (m, 13H), 7.93 (d, J = 9.3 Hz, 2H), 8·18 (dd, J = 1.5 Hz, 8·3 Hz 1H); MS (ESI) m/z 588 (M+). ' at 4-(2-(-[2-([[[[[[[[[[[[[[[[[[2-]]]]]]]]]]]]]]]]] Methyl oxy]benzoate (124 mg, 0·19 mmol) was dissolved in THF-Me0H (6:1, v/v, 3 mL). 0.5 N NaH (2 mL, 1 mmol) ) and heated under reflux in a sealed bottle. Stirring was continued for 15 hours under reflux. The reaction mixture was poured into water, acidified with EtOAc EtOAc (EtOAc)EtOAc. After the solvent was removed, the residue was crystallised from mjjjjjjjjjjjjjj 1H-NMR (CD30D) 5 3· 45 (s, 2H), 3· 79 (s, 3H), 4· 12 (m, 2H), 4·22 (m, 2H), 6·48 (dd, J = 2.0 Hz, 8·3 Hz, 1H), 6·61 (d, J = 2.0 Hz, 1H), 6·87 (d, J = 8.8 Hz, 2H), 7·00 (m, ih), 7 · 22 (m, 3H), 7·36 (m, 1H), 7·43 (m, 3H), 7·90 (d, J = 8.3 Hz, 1H), 7.95 (d, J: 8.8 Hz, 2H ) '8.02 (dd, J = 1.5 Hz, 8·3 Hz, IH); MS(ESI) m/z 574 (m+) ; c31H28C1N3 06 · 〇· 5H20 Analysis calculated: C, 63· 86 ; H, 5· 01 ; N, 7. 21. Found: C, 63· 67 ; Η, 4· 91 ; N, 6· 99 . fExample 2 5 4

89112968.ptd 第786頁 1283240 五、發明說明（782) (S)-4 - [2-N - [[3-甲氧基—4- [Ν’-（2 -甲基苯基）脲基]苯基 ]_Ν-（2-胺苄基）乙醯胺基]-1 一丙氧基]苯甲酸89112968.ptd Page 786 1283240 V. INSTRUCTIONS (782) (S)-4 - [2-N - [[3-methoxy-4-[Ν'-(2-methylphenyl)ureido]] Phenyl]-Ν-(2-aminobenzyl)acetamido]-1-propoxy]benzoic acid

305 (S)-4 - [2-(2 -硝基苄胺基）-；[一丙氧基]苯甲酸苄酯 〇2ΝΠ ^wCOjBn305 (S)-4 - [2-(2-Nitrobenzylamino)-; [-propoxy]benzoic acid benzyl ester 〇2ΝΠ ^wCOjBn

HNv^〇IJI 於（S)-4-（2 -胺基-1-丙氧基）苯甲酸苄酯（ι·5〇克，5.26 毫莫耳）及2 -硝基笨曱醛（0.87克，5·76毫莫耳）溶於HNv^〇IJI Benzyl (S)-4-(2-amino-1-propoxy)benzoate (ι·5〇克, 5.26 mmol) and 2-nitrofurfural (0.87 g) , 5·76 millimolar) soluble

Me0H-Ac0H(16毫升，15:1，ν/ν)之冷卻（0°C)溶液中加入Add Me0H-Ac0H (16 ml, 15:1, ν/ν) to a cooled (0 ° C) solution

NaBH3CN(1.65克，26·3毫莫耳），並使反應混合物在室溫 下授拌隔夜。利用飽和NaHC03使混合物停止反應，並以 EtOAc萃取。將萃取液以鹽水洗滌，於ν%3〇4上乾燥，並蒸 發。將殘留物經由於矽膠上利用CHC13至5% MeOH溶於CHC13 作為洗提液進行管柱層析，純化而得（S)-4_[2-(2-硝基苄 胺基）-1_丙氧基]苯甲酸苄酯（931毫克，42%)的黃色油。 l-NMR (CDC13) 5 1· 21 (d，J = 6· 4 Hz，3H)、3· 13-3· 18 (m，1H)、3·88-3·97 (m，2H)、4·06-4·20 (m，2H)、 5·34 (s，2H)、6·89-6·94 (m，2H)、7·29-7·65 (m，8H) 、7·94-8·〇3 (m，3H); MS(FAB) m/z 42KMH1)。 &lt;^卜4-[24-[[3-甲氧基-4—[1^’—（2-甲基苯基）脲基]苯基] N (2石肖卞基）乙酿胺基]—1一丙氧基]苯甲酸窄酉旨NaBH3CN (1.65 g, 26.3 mmol) was allowed to stand overnight at room temperature. The mixture was quenched with saturated NaHC03 and extracted with EtOAc. The extract was washed with brine, dried over MgSO.sub.3, and evaporated. The residue was subjected to column chromatography using CHC13 to 5% MeOH dissolved in CHC13 as an eluent to obtain (S)-4_[2-(2-nitrobenzylamino)-1-propane. Benzyl benzoate (931 mg, 42%) in yellow oil. l-NMR (CDC13) 5 1· 21 (d, J = 6· 4 Hz, 3H), 3·13-3· 18 (m, 1H), 3·88-3·97 (m, 2H), 4 ·06-4·20 (m, 2H), 5·34 (s, 2H), 6·89-6·94 (m, 2H), 7·29-7·65 (m, 8H), 7.94 -8·〇3 (m,3H); MS(FAB) m/z 42KMH1). &lt;^卜4-[24-[[3-methoxy-4-[1^'-(2-methylphenyl)ureido]phenyl] N (2 fluorenyl) ethoxylated amine]- 1 -propoxy]benzoic acid

第787頁 89112968.ptd 1283240 五、發明說明（783) 〇ίΝη s/N^nAjlPage 787 89112968.ptd 1283240 V. Description of invention (783) 〇ίΝη s/N^nAjl

AW 使3-甲氧基-4-[N，-(2-甲基苯基）脲基]苯基乙酸五氣笨 酯（460毫克，0.96毫莫耳）、（幻_4_[2_(2_硝窄胺基）_卜 丙氧基]苯f酸辛醋（403毫克，〇. 96毫莫耳）及Et3N(2〇〇毫 升，1. 43毫莫耳）於DMF(8毫升）中之混合物在室溫下攪拌 隔夜。將混合物以EtOAc稀釋，以〇· 5N HC1、鹽水洗條， 於NazS〇4上乾煉，並蒸發。使殘留物經由於矽膠上利用1 % MeOH溶於CHCI3作為洗提液進行管柱層析，純化而得（s)一 4-[2-N-[[ 3-曱氧基-4-[Ν’-（2-曱基笨基）脲基]苯基]一 Ν -（2 -硝苄基）乙醯胺基]—卜丙氧基]苯甲酸苄酯（5〇4毫 克，73%)的棕色非晶形固體。MS(FAB) m/z 717(ΜΗ1)。 使（S) - 4-[2 - Ν-[[3-甲氧基-4 - [Ν’-(2-甲基苯基）脲基] 苯基]-Ν-(2 -硝苄基）乙醯胺基]—1—丙氧基]苯甲酸苄酯 ( 504毫克’0.70毫莫耳）溶於MeOH-THF(11毫升，10:1， v/v)之攪拌溶液在5% Pd-C(100毫克，20重量百分比）上在 3大氣壓下氫化隔夜。將混合物過濾以移除催化劑，並將 濾液蒸發。利用製備薄層層析術以5% MeOH溶於CHC13作為 洗提液，將殘留物純化而得305 ( 1 1 5毫克，27%)的白色粉 末。MS(FAB) m/z 597(MH1) 0 實施例255 (S)-4- [2-N-[ [4-[Ν’ -（2-溴苯基）脲基]-3-甲氧苯基]-N -（2-硝苄基）乙醯胺基卜ι_丙氧基]苯甲酸AW makes 5-methoxy-4-[N,-(2-methylphenyl)ureido]phenylacetic acid penta-ester (460 mg, 0.96 mmol), (幻_4_[2_(2 _Narrow-n-amino) _ propyloxy] benzene f acid vinegar (403 mg, 〇. 96 mmol) and Et3N (2 〇〇 ml, 1.43 mmol) in DMF (8 mL) The mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc. The eluent is subjected to column chromatography and purified to obtain (s) 4-[2-N-[[3-methoxy-4-[Ν'-(2-indolyl)ureido]phenyl a brown amorphous solid of -(2-nitrobenzyl)acetamido]-p-propoxy]benzoic acid benzyl ester (5 〇 4 mg, 73%). MS (FAB) m/z 717 ( ΜΗ1). (S) - 4-[2 - Ν-[[3-methoxy-4 - [Ν'-(2-methylphenyl)ureido]phenyl]-indole-(2-nitrate Benzyl benzyl)acetamido]-1-propoxy]benzoic acid benzyl ester (504 mg '0.70 mmol) dissolved in MeOH-THF (11 mL, 10:1, v/v) % Pd-C (100 mg, 20 weight percent) Hydrogenation was carried out overnight at 3 atmospheres. The mixture was filtered to remove the catalyst, and the filtrate was evaporated. The residue was purified by preparative thin-layer chromatography eluting with 5% MeOH in CHC13 to give 305 (1 155 mg) , 27%) of white powder. MS (FAB) m/z 597 (MH1) 0 Example 255 (S) -4- [2-N-[ [4-[Ν' -(2-bromophenyl)urea 3-methoxy-3-(2-nitrobenzyl)-N-(2-nitrobenzyl)acetamido-phenyl-propoxy]benzoic acid

89112968.ptd 第788頁 128324089112968.ptd Page 788 1283240

五、發明說明（784) 306 酯 (S)-4-[2-（2-硝基辛胺基）-1一丙氧基]苯曱酸苄V. INSTRUCTIONS INSTRUCTION (784) 306 Ester (S)-4-[2-(2-Nitrooctylamino)-1-propoxy]benzoic acid benzyl

C〇2Bn 於（S) - 4-（2_胺基-1-丙氧基）笨甲酸爷酯（ι·5〇克，5·26 t莫耳）及2 -石肖基苯曱酸（0.87克，5.76毫莫耳）溶於μ e〇H - Ac OH (16毫升，15:1，v/v)之冷卻（0°C)溶液中加入 NaBI^CNCl· 65克，26· 3毫莫耳），並使反應混合物在室溫 下攪拌隔夜。利用飽和NaHC03使混合物停止反應，並以 EtOAc萃取。將萃取液以鹽水洗滌，於Na2S04上乾燥，並蒸 發。將殘留物經由於矽膠上利用CHC13至5% MeOH溶於 C H C 13作為洗提液進行管柱層析，純化而得（§ ) — 4 - [ 2 - ( 2 - 硝基苄胺基）-卜丙氧基]笨甲酸苄酯（931毫克，42%)的黃 色油。 4-NMR (CDC13) 5 1· 21 (d，J = 6· 4 Ηζ，3Η)、3· 13-3· 18 («ι，1Η)、3·88-3·97 (m，2Η)、4·06-4·20 (m，2Η)、 5·34 (s，2H)、6·89-6·94 (m，2H)、7·29-7·65 (m， 8H)、7·94-8·03 (m，3H); FAB-MAS m/z 42KMH1)。 使4 - [Ν’-（2-溴苯基）脲基]-3-甲氧苯基乙酸（476毫克， 1.26晕:莫耳）、（s) - 4 - [2 -（2-硝基爷胺基）-1-丙氧基]苯曱 酸辛酯（ 528毫克，1· 26毫莫耳）、EDC · HC1(361毫克， 1·88毫莫耳）、H〇Bt( 255毫克，1·89毫莫耳）及DMAP (30毫 克’〇·25毫莫耳）於dmf( 1 0毫升）中之混合物在室溫下授拌C〇2Bn in (S)-4-(2-amino-1-propoxy) benzoic acid ester (ι·5〇克, 5·26 tmol) and 2-石 肖基苯苯酸 (0.87 g) , 5.76 mmol; dissolved in μ e〇H - Ac OH (16 ml, 15:1, v/v) in a cooled (0 ° C) solution, added NaBI^CNCl· 65 g, 26.3 mmol The reaction mixture was stirred at room temperature overnight. The mixture was quenched with saturated NaHC03 and extracted with EtOAc. The extract was washed with brine, dried over Na 2 SO 4 and evaporated. The residue was purified by column chromatography on CHC 13 to 5% MeOH in CHC 13 as an eluent to obtain (§) - 4 - [ 2 - ( 2 - nitrobenzylamino)- Propyloxy] benzyl benzoate (931 mg, 42%) in yellow oil. 4-NMR (CDC13) 5 1· 21 (d, J = 6· 4 Ηζ, 3Η), 3· 13-3· 18 («ι, 1Η), 3·88-3·97 (m, 2Η), 4·06-4·20 (m, 2Η), 5·34 (s, 2H), 6·89-6·94 (m, 2H), 7·29-7·65 (m, 8H), 7· 94-8·03 (m, 3H); FAB-MAS m/z 42KMH1). 4 - [Ν'-(2-bromophenyl)ureido]-3-methoxyphenylacetic acid (476 mg, 1.26 halo: mol), (s) - 4 - [2- (2-nitro) Oxylamine-1-propoxy]benzoic acid octyl ester (528 mg, 1.25 mmol), EDC · HC1 (361 mg, 1.88 mmol), H〇Bt (255 mg, 1 · 89 millimoles) and a mixture of DMAP (30 mg '〇 · 25 mmol) in dmf (10 ml) at room temperature

89112968.ptd 第789頁 1283240 五、發明說明（785) 隔夜。反應可能不完全，因此使反應混合物在6 0 X：下攪拌 1天。將混合物以EtOAc稀釋，以〇· 5N HC1、鹽水洗滌，於 Na2S04上乾燥，並蒸發。使殘留物經由於矽膠上利用CHCl3 至2% MeOH溶於CHC13作為洗提液進行管柱層析，純化而得 標題化合物的粗製油。於此粗製產物溶於THF-Me〇H(1〇毫 升’1:1，v/v)之授拌溶液中加入q.5N NaOH(10毫升），並 使反應混合物迴流加熱3小時。將混合物倒入至冰的&amp; 〇 中，並利用IN HC1使鹼性水層酸化（ρΗ 4· 3)。收集所產生 之沈版物，並利用製備薄層層析術以5 % μ e 0 Η溶於c H C13作 為洗提液，將粗製固體純化而得3060 62毫克，2步驟， 19%)的白色非晶形固體。 MS(FAB) m/z 692(MH1) ; C33H31BrN408 · 7/4Η20 之分析計算 值：C，54.82; Η，4·81;Ν，7.75。實測值：c, 54.80; Η, 4· 61 ; Ν， 7· 24 。 ’ ’ 實施例2 5 6 4 - [2 - Ν - ί哀丙基-Ν - [4 - [Ν _(2 -氯苯基）脲基]一3 一甲氧苯基] 乙醯胺基]乙氧基笨甲酸 &amp;89112968.ptd Page 789 1283240 V. Description of invention (785) Overnight. The reaction may not be complete, so the reaction mixture was stirred at 60 X: for 1 day. The mixture was diluted with EtOAc, washed with EtOAc EtOAc EtOAc. The residue was purified by column chromatography eluting with EtOAc EtOAc EtOAc EtOAc The crude product was dissolved in THF-Me EtOAc (1 mL, EtOAc, EtOAc) The mixture was poured into ice &amp; , and the basic aqueous layer was acidified (ρ Η 4.3) using IN HC1. The resulting plate was collected and purified by preparative thin layer chromatography with 5 % μ e 0 Η dissolved in c H C13 as an eluent, and the crude solid was purified to obtain 3060 62 mg, 2 steps, 19%). White amorphous solid. MS (FAB) m/z 692 (MH1); C33H31BrN408 · 7/4 Η 20 analytical value: C, 54.82; Η, 4·81; Ν, 7.75. Found: c, 54.80; Η, 4· 61 ; Ν, 7· 24 . ' ' Example 2 5 6 4 - [2 - Ν - ί propyl - Ν - [4 - [Ν _(2-chlorophenyl) ureido]] 3-methoxyphenyl] ethoxylated] Ethoxybenzoic acid &amp;

307307

89112968.ptd 第790頁 1283240 五、發明說明（786) 使4-（2 -環丙胺乙氧基）苯甲酸甲酯（29〇毫克，i 23毫莫 耳）、4-[N -(2-氯苯基）脲基]- 3-曱氧苯乙酸（412毫克，、 1.23 毫莫耳）、EDC*HC1(354 毫克，1.85 毫莫耳）、H0Bt (催化劑）及DMAP(催化劑）於DMF(10毫升）中之混合物授摔 隔夜。使混合物在EtOAc( 30 0毫升）與4〇(1〇〇毫升）之間分 配。將有機相分離，以鹽水（2x1 〇〇毫升）洗滌，於“3〇4上 乾燥’並蒸發。使殘留物於矽膠上利用CHC13—Me〇H(2〇 · j ) 作為洗提液進行層析，而得4-[2-N-環丙基-N-[4-[N，-（2-氯苯基）脲基]- 3-甲氧苯基]乙醯胺基]乙氧基苯甲酸甲_ (5 0 6 :¾克’ 7 5 % )之黃色黏性油。 NMR (CDC13) 6 〇· 90-0.97 (m，4H)、2.75 (m，1H)、 3·61 (s，3H)、3·79 (t，J = 5.4 Hz, 2H)、3·87 (s，3H) 、3·88 (s，2H)、4·16 (t，J = 5.4 Hz，2H)、6 76-6 80 (MU，（dt，JOU Hz，1H)、7 2;676: “，2H)、7·53 (s，1H)、7·56 (s，1H)、7·93 (d，J = 8·3 Hz， 3H) 、8·19 (dd， J=8.3 、1·5 Hz， 1H)。89112968.ptd Page 790 1283240 V. INSTRUCTIONS (786) Methyl 4-(2-cyclopropylamine ethoxy)benzoate (29 mg, i 23 mmol), 4-[N-(2- Chlorophenyl)ureido]-3-oxophenylacetic acid (412 mg, 1.23 mmol), EDC*HC1 (354 mg, 1.85 mmol), H0Bt (catalyst) and DMAP (catalyst) in DMF ( The mixture in 10 ml) was dropped overnight. The mixture was partitioned between EtOAc (30 mL) and EtOAc (EtOAc). The organic phase was separated, washed with brine (2×1 mL), dried over &lt;3&gt;4 and evaporated. The residue was applied to the silica gel using CHC13-Me〇H(2〇·j) as the eluent. Analysis, 4-[2-N-cyclopropyl-N-[4-[N,-(2-chlorophenyl)ureido]-3-methoxyphenyl]ethinyl]ethoxy Yellow viscous oil of benzoic acid methyl ketone (5 0 6 : 3⁄4 g '75 %) NMR (CDC13) 6 〇 · 90-0.97 (m, 4H), 2.75 (m, 1H), 3·61 (s , 3H), 3·79 (t, J = 5.4 Hz, 2H), 3·87 (s, 3H), 3·88 (s, 2H), 4·16 (t, J = 5.4 Hz, 2H), 6 76-6 80 (MU, (dt, JOU Hz, 1H), 7 2; 676: ", 2H), 7·53 (s, 1H), 7·56 (s, 1H), 7·93 (d , J = 8·3 Hz, 3H), 8·19 (dd, J=8.3, 1. 5 Hz, 1H).

〜於4 - [2 - N-環丙基-N - [4 - [Ν’- (2-氯笨基）脲基]一3一甲氧 本基]乙醢胺基]乙氧基苯甲酸甲醋（5〇6毫克，〇·9ΐ7毫莫 耳）溶於THF(7毫升）之攪拌溶液中加入〇· 25N Na〇H(7· 3毫 升，1· 83毫莫耳）。於攪拌隔夜後，將混合物倒入至1N ^1(50 毫升）中，並利用 CHC13 - MeOH(4:l，2x20 0 毫升）萃 取。使結合的萃取液於MgS〇4上乾燥並蒸發。使殘留物於 石夕膠上利用CHCI3-MeOH(20 : 1至1 〇 : 1 )作為洗提液進行層~4 - [2-N-cyclopropyl-N-[4- [[Ν-(2-chlorophenyl)ureido]] 3-methoxybenzyl] ethanoyl]ethoxybenzoic acid Methyl vinegar (5 〇 6 mg, 〇·9 ΐ 7 mmol) was dissolved in THF (7 ml) and 〇·25N Na〇H (7.3 ml, 1.83 mmol). After stirring overnight, the mixture was poured into 1N^1 (50 mL) eluted eluting with CHCI 13 - MeOH (4:1, 2×20 mL). The combined extracts were dried over MgS 4 and evaporated. The residue was applied to Shishijiao using CHCI3-MeOH (20:1 to 1 〇:1) as the eluent

89ll2968.Ptd 第791頁 1283240 五、發明說明（787) 析’而得307 (40 3毫克，82%)之無色非晶形固體。ih — nmr (DMSO) 5 0.86-0.91 (m，4H)、2.75 (m，1H)、3.69 (t， J = 5.5 Hz，2H)、3·81 (s，3H)、3·84 (s，2H)、4·16 (t, J = 5.5 Hz, 2H) &gt;6.76 (d, J = 8.3 Hz, 1H) &gt;6.88 (s, 1H) &gt; 6.97- 7.04 (m, 3H) &gt;7.28 (t, J = 7. 8 Hz, 1H)、7·44 (d，J = 7.8 Hz，1H)、7.88 (d，J = 8.8 Hz， 2H) 、7.96 (d， J=8.1 Hz， 1H) 、8·1〇 (d， Hz，89ll2968.Ptd Page 791 1283240 V. Inventive Note (787) A yield of 307 (40 3 mg, 82%) of a colorless amorphous solid. Ih — nmr (DMSO) 5 0.86-0.91 (m, 4H), 2.75 (m, 1H), 3.69 (t, J = 5.5 Hz, 2H), 3·81 (s, 3H), 3.84 (s, 2H), 4·16 (t, J = 5.5 Hz, 2H) &gt; 6.76 (d, J = 8.3 Hz, 1H) &gt;6.88 (s, 1H) &gt; 6.97- 7.04 (m, 3H) &gt; 7.28 (t, J = 7. 8 Hz, 1H), 7.44 (d, J = 7.8 Hz, 1H), 7.88 (d, J = 8.8 Hz, 2H), 7.96 (d, J = 8.1 Hz, 1H) , 8·1〇 (d, Hz,

1H) 、 8.89 (s， 1H) 、 8.93 (s， 1H) 、 12.65 (s， br s); MS(FAB) m/z 53 8 (MH1)·，C28H28C1N3 06 之分析計算值：C， 62·51;Η，5·25;Ν，7.81。實測值：c，61·85;Η， 5· 42 ; Ν， 7· 41。 實施例2 5 7 4 - [2 - Ν -環己基-Ν - [3-甲氧基-4-[Ν’ -（2-甲基苯基）脲基] 苯基]乙醯胺基]乙氧基苯甲酸1H), 8.89 (s, 1H), 8.93 (s, 1H), 12.65 (s, br s); MS(FAB) m/z 53 8 (MH1)·, C28H28C1N3 06 Analytical calculations: C, 62· 51; Η, 5·25; Ν, 7.81. Found: c, 61·85; Η, 5·42; Ν, 7· 41. Example 2 5 7 4 - [2 - Ν-cyclohexyl-fluorene-[3-methoxy-4-[Ν'-(2-methylphenyl)ureido]phenyl]acetamido] Oxybenzoic acid

Mo ** Μ ΡMo ** Μ Ρ

^^COOH 308 4 -（2 - N -環己胺基）乙氧苯甲酸甲酯 Q HN_ ja1 COOMe^^COOH 308 4 -(2-N-cyclohexylamino)methyl ethoxybenzoate Q HN_ ja1 COOMe

在室溫下於4 - [(2-甲磺醯氧基）-1-乙氧基]苯甲酸甲酯 (2· 74克，10毫莫耳）溶於MeCN(50毫升）之溶液中加入環己 胺（5 · 7 2毫升’ 5 0宅莫耳）。使反應在迴流下授摔1 §小時。 將混合物倒入至10( 2 00毫升）中，以EtOAc(i〇〇毫升X2)萃Add to a solution of methyl 4-[(2-methylsulfonyloxy)-1-ethoxy]benzoate (2·74 g, 10 mmol) in MeCN (50 mL) at room temperature Cyclohexylamine (5 · 7 2 ml '50 0 house Mo). The reaction was allowed to fall for 1 § hours under reflux. The mixture was poured into 10 (200 mL) and extracted with EtOAc (EtOAc EtOAc)

\\312\2d-code\90-01\89112968.ptd 第792頁 !283240 五、發明說明（788) =’於MgS04上乾燥。於移除溶劑後，使殘留物於矽膠（中 ，層析系統：YAMAZEN YFLC-5404 - FC，（/)50 毫米X 150 毫 米’CHCl3-EtOAc自10:0至1:1之線性梯度）上進行層析， 而得4 -（2-N-環己胺基）乙氧基苯甲酸甲酯（2.43克，88%) 的無色油。1H-NMR (CDC13) 6 1· 1〇 (m，2H)、1. 25 (m， 2Η)、1·60 (br，2H)、1·73 (m，2H)、1·90 (br，2H)、 2.49 (m，1H)、3·02 (t，J = 5.2 Hz，2H)、3·88 (s， 3H)、4·12 (t，J = 5.2 Hz，2H)、6·90 (d，J = 6.90 Hz, 2H)、7·99 (d，J = 7.99 Hz，2H); MS(ESI) m/z 278 (M+ + 1)。 4 - [2-N -環己基-N - [3-曱氧基-4-[n，-（2-曱基苯基）脲基] 苯基]乙醯胺基]乙氧基苯甲酸甲酯\\312\2d-code\90-01\89112968.ptd Page 792 !283240 V. Description of invention (788) =' Dry on MgS04. After removing the solvent, the residue was applied to a silicone (medium, chromatography system: YAMAZEN YFLC-5404 - FC, (/) 50 mm X 150 mm 'CHCl3-EtOAc from a linear gradient from 10:0 to 1:1) Chromatography gave 4-(2-N-cyclohexylamino)ethoxybenzoic acid methyl ester (2.43 g, 88%). 1H-NMR (CDC13) 6 1· 1〇(m, 2H), 1. 25 (m, 2Η), 1·60 (br, 2H), 1.73 (m, 2H), 1·90 (br, 2H), 2.49 (m, 1H), 3·02 (t, J = 5.2 Hz, 2H), 3·88 (s, 3H), 4·12 (t, J = 5.2 Hz, 2H), 6.90 (d, J = 6.90 Hz, 2H), 7·99 (d, J = 7.99 Hz, 2H); MS (ESI) m/z 278 (M+ + 1). 4-[2-N-Cyclohexyl-N-[3-decyloxy-4-[n,-(2-mercaptophenyl)ureido]phenyl]ethinyl]ethoxybenzoate ester

使4 -（2-N-環己胺基）乙氧基苯曱酸甲酯（139毫克，0.5 毫莫耳）、3_甲氧基-4-[N，- (2-甲基苯基）脲基]苯基乙酸 (157毫克，0.5毫莫耳）、EDC*HC1(144毫克，0.75毫莫 耳）、HOBt(128 毫克，〇·95 毫莫耳）、及DMAP(12 毫克，0· 1 毫莫耳）於DM F ( 2 · 5毫升）中之混合物攪拌1 8小時。將混合 物以EtOAc( 2 0 0毫升）稀釋，以in HC1及鹽水洗滌，並於 MgS〇4上乾燥。於移除溶劑後，使殘留物於矽膠（中壓層析 系統：丫八^1八2£1^丫？乙(：-5 4 0 4-？(：，（：11(：13-£1:0八(3 10:0至1:4 之線性梯度）上進行層析，而得4-[2-N-環己基-N-[ 3-曱氧Methyl 4-(2-N-cyclohexylamino)ethoxybenzoate (139 mg, 0.5 mmol), 3-methoxy-4-[N,-(2-methylphenyl) Urea-based phenylacetic acid (157 mg, 0.5 mmol), EDC*HC1 (144 mg, 0.75 mmol), HOBt (128 mg, 〇·95 mmol), and DMAP (12 mg, 0) · 1 mmol of the mixture in DM F (2.5 ml) was stirred for 18 hours. The mixture was diluted with EtOAc (EtOAc) (EtOAc)EtOAc. After removing the solvent, the residue is applied to the silicone (medium pressure chromatography system: 丫8^1 8 2 1 1 丫? B (:-5 4 0 4-?(:,(:11(:13-£) Chromatography on 1:0-8 (linear gradient of 3 10:0 to 1:4) gave 4-[2-N-cyclohexyl-N-[3-oxo

\\312\2d-code\90-01\89112968.ptd 第793頁 1283240 五、發明說明（789) ，二匕Γ基笨基)脲基]笨基]乙醯胺基]乙氧基苯甲 1文ηδ : 〇笔克，86%)的非晶形泡沫。1H-NMR (CDC13)占 h 8-1.80 (ra, 10H) .2.3〇 (S, 3H) . 3.60-3.79 (m, W、3.88 (s，3H)、4.16 (m，2H)、6 3〇 &amp; ih)、 6.70-6.83 (m, 2H) &gt;6.88 (d, 2H, J = 9.〇 Hz) ^7.12 (m，2H)、7.23 (m，1H)、7.60 (d，1H, J = 8.3 Hz)、 7.92 (d, 2H，J = 9.〇 Hz)、8.1〇 (d，1H，J = 8.0 Hz); MS(ESI ) m/z 574 (MH1)。 ^室溫下於4 - [2 - N-環己基-n - [3-甲氧基一 4 一 [n，_(2-甲 基苯基）脲基]苯基]乙醯胺基]乙氧基笨甲酸甲酯（247毫 克’0.43毫莫耳）溶於THF-MeOH(6:l，v/v，7毫升）之溶液 中加入0· 5N NaOH( 3. 4毫升，〇· 84毫莫耳），並於密封瓶中 迴流加熱。在迴流下持續攪拌1 8小時。將反應混合物倒入 至水中，利用1.0N HC1酸化，以CHC13 - MeOH(2:l ，20毫升 x3)萃取，並於MgS04上乾燥。於移除溶劑後，利用CHC13- 己烷-乙醚使殘留物結晶，而得3 〇 8 ( 1 9 6毫克，8 1 % )的白色 粉末。NMR (CD30D) 6 〇· 90-1· 82 (m，10H)、2· 29 (s， 3H) 、3·62 (m， 2H) 、3·78 (s， 3H) 、3·8〇 (m， 3H)、 4.12 (m，2Η)、6·82 (m，2Η)、6.96 (m，3Η)、7·16 (m， 2Η)、7· 58 (d，J = 7. 7 Ηζ，1Η)、7· 92 (m，3Η) ; MS(ESI) m/z 56 0 (MH1) ; C32H37N3 06 · 〇· 5H20 之分析計算值：C， 67·59;Η，6·74;Ν，7·39。實測值：C，67·83;Η， 6· 80 ; N， 7.13。 實施例258\\312\2d-code\90-01\89112968.ptd Page 793 1283240 V. INSTRUCTIONS (789) , 匕Γ 匕Γ ) ) ) 脲 脲 脲 ] ] ] ] ] ] ] ] ] ] ] ] ] 1 ηδ : 〇 gram, 86%) of amorphous foam. 1H-NMR (CDC13) accounts for h 8-1.80 (ra, 10H) .2.3〇(S, 3H) . 3.60-3.79 (m, W, 3.88 (s, 3H), 4.16 (m, 2H), 6 3〇 &amp; ih), 6.70-6.83 (m, 2H) &gt; 6.88 (d, 2H, J = 9.〇Hz) ^7.12 (m, 2H), 7.23 (m, 1H), 7.60 (d, 1H, J = 8.3 Hz), 7.92 (d, 2H, J = 9.〇Hz), 8.1 〇 (d, 1H, J = 8.0 Hz); MS (ESI) m/z 574 (MH1). ^ at room temperature in 4-[2-N-cyclohexyl-n-[3-methoxy-tetra-[n,-(2-methylphenyl)ureido]phenyl]acetamido] Methyl oxyformate (247 mg '0.43 mmol) was dissolved in THF-MeOH (6:1, v/v, 7 mL). EtOAc. Mohr) and heated under reflux in a sealed bottle. Stirring was continued for 18 hours under reflux. The reaction mixture was poured into water, acidified with EtOAc EtOAc (EtOAc)EtOAc. After the solvent was removed, the residue was crystallised eluted eluted elut elut elut elut elut elut elut elut elut NMR (CD30D) 6 〇· 90-1· 82 (m,10H), 2· 29 (s, 3H), 3·62 (m, 2H), 3·78 (s, 3H), 3·8〇 ( m, 3H), 4.12 (m, 2Η), 6.82 (m, 2Η), 6.96 (m, 3Η), 7·16 (m, 2Η), 7·58 (d, J = 7. 7 Ηζ, 1Η), 7· 92 (m, 3Η); MS(ESI) m/z 56 0 (MH1) ; C32H37N3 06 · 〇· 5H20 Analysis calculated: C, 67·59; Η, 6.74; Ν, 7.39. Found: C, 67·83; Η, 6·80; N, 7.13. Example 258

\\312\2d-code\90-01\89112968.ptd 第794頁 1283240 五、發明說明（790) 4_[2_N —[4一 [N’-(2 -氯苯基）脲基]-3-甲氧苯基]-N-炔丙基 乙醯胺基]乙氧基苯曱酸 ΓΥ000Η\\312\2d-code\90-01\89112968.ptd Page 794 1283240 V. INSTRUCTIONS (790) 4_[2_N —[4-[N'-(2-Chlorophenyl)ureido]-3- Methoxyphenyl]-N-propargylethylammonium]ethoxybenzoate ΓΥ000Η

Cl Η Η ΟΜβ 309 4-（2-N -炔丙基胺基）乙氧苯甲酸甲酯 /ts^COOMeCl Η ΟΜ ΟΜβ 309 4-(2-N-propargylamino) ethoxybenzoic acid methyl ester /ts^COOMe

HnO〇XJ 在室溫下於4-[(2-甲磺醯氧基）-;ι一乙氧基]苯甲酸曱酯 (2· 74克’ 1〇毫莫耳）溶於MeCN(5〇毫升）之溶液中加入炔丙 胺（3. 4 3毫升，5 0毫莫耳）。使反應在迴流下攪拌1 8小時。 將混合物倒入至1〇( 2 00毫升）中，以EtOAc(100毫升x2)萃 取，於MgS04上乾燥。於在真空中移除溶劑後，使殘留物 於矽膠（中壓層析系統：丫八頁八2£1^丫卩1^-54〇4-代，05〇毫 米X 150毫米，CHC13-EtOAc自10:0至9:1之線性梯度）上進 行層析，而得4-(2-N-炔丙基胺基）乙氧苯甲酸曱酯（2. 33 克，100%)的無色油。iH-NMR (CDC13) (5 2· 28 (d，J = 2· 4 Hz, 1H) 、3·11 (t， J=5.1 Hz， 2H) 、3·52 (d， J=2.4 Hz, 2H) 、3.88 (s, 3H) 、4.15 (t， J=5.1 Hz， 2H)、 6.90 (d, J = 8.8 Hz, 2H) &gt;7.98 (d, J = 8. 8 Hz, 2H)； MS(ESI) m/z 234 (MH1)。 4 - [2-N - [4 - [Ν’ -（2 -氯苯基）脲基]- 3 -甲氧笨基]—N-炔丙基 乙醯胺基]乙氧苯曱酸甲酯HnO〇XJ is soluble in MeCN (5〇) at room temperature in 4-[(2-methanesulfonyloxy)-; ι-ethoxy]benzoate oxime ester (2·74 g '1 〇 mmol) Add propargylamine (3.43 ml, 50 mmol) to a solution of ML). The reaction was allowed to stir at reflux for 18 hours. The mixture was poured into 1 EtOAc (EtOAc) (EtOAc) After removing the solvent in vacuo, the residue was applied to a silica gel (medium pressure chromatography system: 丫8 八8 2 1 丫卩 1^-54 〇 4-generation, 05 〇 mm X 150 mm, CHC13-EtOAc Chromatography on a linear gradient from 10:0 to 9:1 gave 4-(2-N-propargylamino) ethoxybenzoate (2.33 g, 100%) as a colorless oil . iH-NMR (CDC13) (5 2· 28 (d, J = 2· 4 Hz, 1H), 3·11 (t, J=5.1 Hz, 2H), 3·52 (d, J=2.4 Hz, 2H ), 3.88 (s, 3H), 4.15 (t, J = 5.1 Hz, 2H), 6.90 (d, J = 8.8 Hz, 2H) &gt; 7.98 (d, J = 8. 8 Hz, 2H); MS ( ESI) m/z 234 (MH1). 4 - [2-N - [4 - [Ν' -(2-Chlorophenyl)ureido]- 3 -methoxyphenyl]-N-propargyl Methyl ethoxybenzoate

COOMeCOOMe

\\312\2d-code\90-01\89112968.ptd 第795頁 1283240 五、發明說明（791) 使4-（2-N-炔丙基胺基）乙氧苯甲酸甲酯（117毫克，〇. 5 毫莫耳）、3-曱氧基-4-[N，-（2-氯苯基）脲基]笨基乙酸 (167毫克，〇·5毫莫耳）、EDC*HC1(144毫克，〇·75毫莫 耳）、H0Bt(128 毫克，〇·96 毫莫耳）、及DMAP(12 毫克，〇· 1 毫莫耳）於DMF(10毫升）中之混合物攪拌18小時。將混合物 以EtOAc(100毫升）稀釋，以in HC1、鹽水洗滌，並於 MgS04上乾燥。使殘留物與甲苯（1 〇毫升χ3)共同蒸發以移 除DMF。使殘留物於TLC(MERCK，矽膠60，2毫米，2板， (：11(：13-％6〇11，20:1)上進行層析，而得4-[2-1^-[4-[^’-（2-氯苯基）脲基]-3-甲氧苯基卜N_炔丙基乙醯胺基]乙氧苯 甲酸甲酯（ 244毫克，89%)的白色非晶形泡沫。l-NMR (CDC13) (5 2· 20 及2· 32 (2m，總計 1H)、3· 72 (s，2H)、 3·83 (m，5H)、3·88 (s，3H)、4·〇9-4·35 (m，4H)、 6·77-6.86 (m，4Η)、6·99 (m，1Η)、7·11 (m，2Η)、 7·24 (m，1Η)、7·34 (d，J = 7.9 Ηζ，1Η)、7·96 (m， 3H)、8·18 (dd，】 = 1·5 Hz、8·3 Hz，1H); MS(ESI) m/z 550 (M+)。 在室溫下於4 -[2 -N- [4 - [N，-（2 -氣苯基）脲基]- 3-甲氧苯 基]-N-炔丙基乙醯胺基]乙氧苯甲酸甲酯（ 240毫克，〇· 44 毫莫耳）溶於THF-MeOH-H20(2:2:l，v/v，10毫升）之溶液 中加入NaOH( 500毫克，12. 5毫莫耳）。在室溫下持續攪拌2 小時。將反應混合物倒入至水中，利用1 · 0N HC 1酸化，以\\312\2d-code\90-01\89112968.ptd Page 795 1283240 V. INSTRUCTIONS (791) Methyl 4-(2-N-propargylamino)ethoxybenzoate (117 mg, 5. 5 mM), 3-methoxy-4-[N,-(2-chlorophenyl)ureido] phenylacetate (167 mg, 〇·5 mmol), EDC*HC1 (144 A mixture of MeOH (75 ml), H0Bt (128 mg, 〇·96 mmol), and DMAP (12 mg, 〇·1 mmol) in DMF (10 mL) was stirred for 18 hours. The mixture was diluted with EtOAc (EtOAc) (EtOAc)EtOAc. The residue was co-evaporated with toluene (1 mL χ3) to remove DMF. The residue was chromatographed on TLC (MERCK, silica gel 60, 2 mm, 2 plates, (: 11 (: 13-% 6 〇 11, 20:1)) to give 4-[2-1^-[4 -[^'-(2-Chlorophenyl)ureido]-3-methoxyphenylbu-N-propargylethylamino]methyl ethoxybenzoate (244 mg, 89%) as white amorphous Foam. l-NMR (CDC13) (5 2· 20 and 2· 32 (2m, total 1H), 3·72 (s, 2H), 3·83 (m, 5H), 3.88 (s, 3H) , 4·〇9-4·35 (m, 4H), 6·77-6.86 (m, 4Η), 6.99 (m, 1Η), 7·11 (m, 2Η), 7·24 (m, 1Η), 7·34 (d, J = 7.9 Ηζ, 1Η), 7·96 (m, 3H), 8·18 (dd,] = 1·5 Hz, 8·3 Hz, 1H); MS (ESI m/z 550 (M+) at room temperature in 4-[2-N-[4- [N,-(2-(phenylphenyl))]]-3-methoxyphenyl]-N-yne Add NaOH to THF-MeOH-H20 (2:2:1, v/v, 10 mL) in propylacetamido]methyl ethoxybenzoate (240 mg, 〇· 44 mmol) (500 mg, 12.5 mmol). Stirring was continued for 2 hours at room temperature. The reaction mixture was poured into water and acidified with 1 · 0N HCl.

\\312\2d-code\90-01\89112968.ptd 第796頁 1283240 五、發明說明（792) CHC13-Me0H(2:l，20毫升x3)萃取，並於MgS04上乾燥。使 殘留物於TLC(Whatman，1 毫米，3 板，CHCl3-MeOH，92 : 8) 上進行層析，而得309 ( 2 0 2毫克，86%)的白色固體。1 H-NMR (CD30D)6 2.60 及 2·81 (2d，J = 2.5 Hz,總計 1H)、3·79-3·94 (m, 4H)、3·85 (s，3H)、4·15 (m， 1Η)、4·24 (m，1Η)、4·32 (m，2Η)、6·80 (d，J = 8.3 Hz， 1H) 、6·85 (d, J=4.3 Hz, 1H) 、6.94 (m， 2H)、 7.02(m，lH)、7.25(ni，lH)、7.38(m，lH)、7.87-8.02 (m, 4H) ； MS(ESI) m/z 53 6 (MH1)； C28H26C1N3 06 · 2.25 H20 之分析計算值：C，58.33; H, 5.33; N， 7.29。 實測值：C， 58. 23 ; H，4. 77 ; N，6. 91。 實施例2 5 9 4-[2-N-烯丙基-N-[4-[Ν’ - ( 2-氯苯基）脲基]一3一甲氧苯基] 乙醯胺基]乙氧基苯曱酸 4 - [2-N -烯丙基-N-[4 - [Ν’ - (2-氯笨基）脲基;|一3 一曱氧苯基] 乙醯胺基]乙氧基苯甲酸曱酯\\312\2d-code\90-01\89112968.ptd Page 796 1283240 V. INSTRUCTIONS (792) CHC13-Me0H (2:1, 20 ml x 3) was extracted and dried on MgS04. The residue was chromatographed on EtOAc EtOAc (EtOAc:EtOAc 1 H-NMR (CD30D) 6 2.60 and 2·81 (2d, J = 2.5 Hz, total 1H), 3·79-3·94 (m, 4H), 3·85 (s, 3H), 4·15 (m, 1Η), 4·24 (m, 1Η), 4·32 (m, 2Η), 6·80 (d, J = 8.3 Hz, 1H), 6.85 (d, J=4.3 Hz, 1H ) 6.94 (m, 2H), 7.02 (m, lH), 7.25 (ni, lH), 7.38 (m, lH), 7.87-8.02 (m, 4H); MS (ESI) m/z 53 6 (MH1) C28H26C1N3 06 · 2.25 H20 Analysis calculated: C, 58.33; H, 5.33; N, 7.29. Found: C, 58. 23; H, 4.77; N, 6.91. Example 2 5 9 4-[2-N-allyl-N-[4-[Ν' - (2-chlorophenyl)ureido]- 3-methoxyphenyl]ethylamino] ethoxylate Benzobenzoic acid 4-[2-N-allyl-N-[4-][Ν'-(2-chlorophenyl)urea;|1-3-methoxyphenyl]ethylamino]ethoxy Ethyl benzoate

使4 -（2-Ν-烯丙胺基）乙氧基苯甲酸曱酯（118毫克，〇·5 毫莫耳）、3-甲氧基-4-[Ν’-(2-氣笨基）脲基]苯基乙酸Ethyl 4-(2-indole-1-yl)ethoxybenzoate (118 mg, 〇·5 mmol), 3-methoxy-4-[Ν'-(2-gas base) Ureido]phenylacetic acid

\\312\2d-code\90-01\89112968.ptd 第797頁 1283240 五、發明說明（793) (167 毫克 ’0.5 毫莫耳）、EDC*HC1(144 克，0.75 毫莫 耳）、HOBt(128 毫克，〇·95 毫莫耳）、及 DMAP(12 毫克，0· 1 毫莫耳）於DMF(2· 5毫升）中之混合物攪拌18小時。將混合 物以EtOAc( 3 0 0毫升）稀釋，以in HC1及鹽水洗滌，並於 MgS〇4上乾燥。於移除溶劑後，使殘留物於矽膠（中壓層析 系統：YAMAZEN YFLC-54 04-FC，CHC13-EtOAc 100:0 至85: 15之線性梯度）上進行層析，而得3i〇a( 253毫克，92%)的 非晶形泡沫。UMR (CDC13) δ 3· 65-3· 85 (m，4H)、 3.73 (s，3H)、3·88 (s，3H)、5.08 (m，2H)、4·22 (m， 2Η)、5·10-5·24 (m，2Η)、5.76 (m，1Η)、6.77 (m， 2 Η)、6 · 8 5 ( m，2 Η )、6 · 9 9 (m，1 Η )、7 · 0 6 ( m，2 Η )、 7.26 (m，1H)、7·34 (d，1H，《Ι = 8·1 Hz)、7·94 (d，2H, J = 8.8 Hz)、7·98 (m, 1H)、8.18 (d, 1H，J = 6.9 Hz); MS(FAB) m/z 55 2 (M+)。 實施例260 4 - [2 - N -烯丙基-N-[4 - [Ν’ - (2-氣苯基）脲基]一3 一曱氧苯基] 乙醯胺基]乙氧基笨甲酸\\312\2d-code\90-01\89112968.ptd Page 797 1283240 V. INSTRUCTIONS (793) (167 mg '0.5 mM), EDC*HC1 (144 g, 0.75 mmol), HOBt (128 mg, 〇·95 mmol), and a mixture of DMAP (12 mg, 0·1 mmol) in DMF (2.5 mL) was stirred for 18 hours. The mixture was diluted with EtOAc (EtOAc) (EtOAc)EtOAc. After removing the solvent, the residue was chromatographed on a silica gel (medium pressure chromatography system: YAMAZEN YFLC-54 04-FC, CHC13-EtOAc 100:0 to 85:15) to give 3i〇a (253 mg, 92%) of an amorphous foam. UMR (CDC13) δ 3· 65-3· 85 (m, 4H), 3.73 (s, 3H), 3.88 (s, 3H), 5.08 (m, 2H), 4·22 (m, 2Η), 5·10-5·24 (m, 2Η), 5.76 (m, 1Η), 6.77 (m, 2 Η), 6 · 8 5 ( m, 2 Η ), 6 · 9 9 (m, 1 Η ), 7 · 0 6 ( m, 2 Η ), 7.26 (m, 1H), 7·34 (d, 1H, "Ι = 8·1 Hz), 7.94 (d, 2H, J = 8.8 Hz), 7 · 98 (m, 1H), 8.18 (d, 1H, J = 6.9 Hz); MS (FAB) m/z 55 2 (M+). Example 260 4 - [2-N-allyl-N-[4-[[indolyl]-(2-phenylphenyl)ureido]- 3-indolyloxyphenyl]ethinyl]ethoxylate Formic acid

、 pyCOOHpyCOOH

Cl H H OMe 310 在室溫下於4-[2-N-烯丙基-N-[4-[N，-（2 -氯苯基）脲基] -3-甲氧苯基]乙醯胺基]乙氧基苯甲酸曱酉旨（25〇毫克， 0.45毫莫耳）溶於THF-MeOH(l:l, v/v，8毫升）之溶液中加 入0· 25N NaOH(3· 6毫升，0· 91毫莫耳），並迴流加熱。在Cl HH OMe 310 at room temperature in 4-[2-N-allyl-N-[4-[N,-(2-chlorophenyl)ureido]-3-methoxyphenyl]acetamide Add 0.25 N NaOH (3 · 6 ml) to a solution of THF-MeOH (1:1, v/v, 8 mL) in acetoxybenzoic acid (25 mg, 0.45 mmol) , 0·91 millimoles), and heated under reflux. in

\\312\2d-code\90-01\89112968.ptd 第798頁 1283240 五、發明說明（794) 迴抓下持績授拌1 §小時。將反應混合物倒入至水中，並利 用1. 〇N HC1酸化。經由過濾收集所產生之沈澱物。利用己 炫-乙醚使沈殿物再結晶，而得3 1 〇的白色粉末（1 95毫克， 80%)〇1H-NMR (CD3OD)(5 3.61 (s, 1H)&gt;3.76 (s, 3H)- 3.82 (m，1H)、3·85 (s，1H)、3·88 (m, 1H)、4·11 -4.25 (m， 4H) 、5·12-5.25 (m, 2H) 、5·81 (m， 1H)、 6.78 (d，1H，J = 8.3 Hz)、6.82 (m，1H)、6·92 (m， 2H)、7.01 (m，1H)、7·26 (m，1H)、7·37 (m，1H)、 7. 9 6 (m, 3H) &gt;8.02 (m, 1H) ； MS (FAB) m/z 5 37 (M+)； C28H28C1N3 06 · 1/4H20 之分析計算值：C，61. 99 ; H， 5. 30 ; N，7.75。實測值：C，62.00; H，5.56; N，7.76。 f施例2 6 1 4 - [2 - N -烯丙基-N - [4- [Ν’ -(2 -溴苯基）脲基]一3 一曱氧苯基] 乙醯胺基]乙氧基苯甲酸 &amp; ' Br H H lMe 311 4 - [2-N -烯丙基-N-[4-[N’-(2 -溴苯基）脲基]一 3一曱氧笨基 乙醯胺基]乙氧基苯曱酸曱酯 &amp;\\312\2d-code\90-01\89112968.ptd Page 798 1283240 V. Description of the invention (794) Back to the grasp of the performance of the mixing 1 § hours. The reaction mixture was poured into water and acidified using 1. 〇N HCl. The resulting precipitate was collected via filtration. Recrystallized from the smectite-diethyl ether to give a white powder (1 95 mg, 80%) 〇1H-NMR (CD3OD) (5 3.61 (s, 1H) &gt; 3.76 (s, 3H) - 3.82 (m, 1H), 3·85 (s, 1H), 3·88 (m, 1H), 4·11 - 4.25 (m, 4H), 5·12-5.25 (m, 2H), 5· 81 (m, 1H), 6.78 (d, 1H, J = 8.3 Hz), 6.82 (m, 1H), 6.92 (m, 2H), 7.01 (m, 1H), 7·26 (m, 1H) ,7·37 (m,1H), 7. 9 6 (m, 3H) &gt;8.02 (m, 1H) ; MS (FAB) m/z 5 37 (M+); C28H28C1N3 06 · 1/4H20 Value: C, 61.99; H, 5. 30; N, 7.75. Found: C, 62.00; H, 5.56; N, 7.76. f. Example 2 6 1 4 - [2 - N -allyl - N - [4- [Ν' -(2 -Bromophenyl)ureido]- 3-indolyloxyphenyl] ethanoylamino]ethoxybenzoic acid &amp; ' Br HH lMe 311 4 - [2-N -allyl-N-[4-[N'-(2-bromophenyl)ureido]- 3-indolyloxybenzylamino]ethoxybenzoate oxime &amp;

使4-(2-N-烯丙胺基）乙氧基笨甲酸甲酯（118毫克，〇 5 毫莫耳）、4-[Ν’ -（2-漠苯基）脲基]—3一甲氧笨基乙酸（19〇Methyl 4-(2-N-allylamino)ethoxybenzoate (118 mg, 〇5 mmol), 4-[Ν'-(2-Molyphenyl)ureido]-3 Oxygen-based acetic acid (19〇

1283240 五、發明說明（795) 毫克，0.5毫莫耳）、EDC ·Η(：1(144毫克，0·75毫莫耳）、 HOBt(128毫克，〇·95毫莫耳）、及DMAP(12毫克，0. 1毫莫 耳）於DMF ( 2 · 5毫升）中之混合物攪拌1 8小時。將混合物以 EtOAc( 3 0 0毫升）稀釋，以IN HC1及鹽水洗滌，並於MgS04 上乾燥。於移除溶劑後，使殘留物於矽膠（中壓層析系 統：YAMAZEN YFLC-5404-FC ，CHCl3-EtOAc 100:0 至70:30 之線性梯度）上進行層析，而得4-[2-N-烯丙基-N-[4-[N， -（2-溴苯基）脲基]—3-甲氧苯基]乙醯胺基]乙氧基苯甲酸 甲酯（2 51毫克，84%)的非晶形泡沫。 ^-NMR (CDC13) (5 3.65-3.85 (m, 4H) &gt; 3. 73 (s, 3H) &gt; 3·88 (s，3H)、4·08 (m，2H)、4·22 (m，2H)、5·1〇-5·25 (m，2Η)、5.78 (m，1Η)、6·79 (in, 1Η)、6·85 (m， 3H)、6· 93 (m，1H)、7· 02 (m，2H)、7· 30 (m，1H)、 ’ 7·51 (m，1H)、7.94 (d，2H，J = 8.8 Hz)、7·97 (m 1H)、8.14 (m，1H); MS(FAB) m/z 596 (M+)。 在室溫下於4-[2-N-烯丙基-N-[4-[Ν’ 〜（2 -溴苯基）脲美] - 3 -甲氧笨基]乙蕴胺基]乙氧基苯甲酸甲醋（251毫克， 0· 42毫莫耳）溶於THF-MeOH(l:l, v/v，8毫升）之溶液中加 入〇. 25N NaOH(3· 4毫升，0· 84毫莫耳），並迴流加熱。在° 迴流下持續攪拌1 8小時。將反應混合物倒入至水中，並利 用1· ON HC1酸化。經由過濾收集所產生之沈澱物。利用己 烷-乙醚使沈澱物再結晶，而得3 11 (1 9 2毫克，7 8% )的白色 粉末。NMR (CD30D) 6 3· 61 (s，3H)、3· 77 (s，3H)、 3· 80 (m，1H)、3· 85 (s，1H)、3. 88 (s，iH)、4, 12—、1283240 V. Description of the invention (795) mg, 0.5 mmol), EDC · Η (: 1 (144 mg, 0·75 mmol), HOBt (128 mg, 〇·95 mmol), and DMAP ( The mixture was stirred for 18 hours in EtOAc (3 mL), washed with EtOAc (30 mL) and washed with &lt;RTI ID=0.0&gt; After removing the solvent, the residue was chromatographed on a silica gel (medium pressure chromatography system: YAMAZEN YFLC-5404-FC, CHCl3-EtOAc 100:0 to 70:30) to give 4-[ Methyl 2-N-allyl-N-[4-[N,-(2-bromophenyl)ureido]-3-methoxyphenyl]ethylammonium]ethoxybenzoate (2 51 Mg, 84%) of amorphous foam. ^-NMR (CDC13) (5 3.65-3.85 (m, 4H) &gt; 3. 73 (s, 3H) &gt; 3·88 (s, 3H), 4·08 (m, 2H), 4·22 (m, 2H), 5·1〇-5·25 (m, 2Η), 5.78 (m, 1Η), 6.79 (in, 1Η), 6.85 (m , 3H), 6· 93 (m, 1H), 7· 02 (m, 2H), 7·30 (m, 1H), '7·51 (m, 1H), 7.94 (d, 2H, J = 8.8 Hz), 7.97 (m 1H), 8.14 (m, 1H); MS (FAB) m/z 596 (M+). Warm to 4-[2-N-allyl-N-[4-[Ν' ～(2-bromophenyl)urea]-3-methoxyphenyl]ethylamino]ethoxybenzene Formic acid methyl vinegar (251 mg, 0.42 mmol) was dissolved in THF-MeOH (1:1, v/v, 8 mL). N. 25N NaOH (3·4 ml, 0·84 mmol) The mixture was heated under reflux, and stirring was continued for 18 hours under reflux. The reaction mixture was poured into water and acidified with 1·ON HC1. The resulting precipitate was collected by filtration. Recrystallization, giving a white powder of 3 11 (1 2 2 mg, 7 8%). NMR (CD30D) 6 3 · 61 (s, 3H), 3 · 77 (s, 3H), 3 · 80 (m, 1H), 3·85 (s, 1H), 3. 88 (s, iH), 4, 12-,

1283240 五、發明說明（796) 4.25 (m，4H)、5·12-5·23 (m，2H)、5·81 (m，1H)、 6·76 (m，1H)、6·82 (m，1H)、6·93 (m，3H)、7·29 (m， 1H)、7· 56 (m，1H)、7· 94 (m，4H) ; MS(FAB) m/z 58 2 (M+) ; C28H28BrN3 06 之分析計算值：c，57· 74 ; H，4. 85 ; N， 7. 21。實測值·· C，57· 40 ; h，5. 07 ; N，7. 04。 關於 115 之HC1 鹽：C28H27BrN3〇6 · 〇· 25H20 之分析計算值·· c， 55· 23 i H’ 4· 55 ; Ν’ 6· 90。實測值·· c，54· 98 ; H， 4. 71 ； Ν, 6.53° 實施例262 4-[2-Ν -烯丙基-Ν-[3-甲基—4一 [Ν，一（2一甲基苯基）脲基]苯 基]乙醯胺基]乙氧基笨甲酸 312 4 - [2-N-烯丙基-N-[3-甲基—4 - [N，-（2-曱基苯基）脲基]苯 基]乙醯胺基]乙氧基苯甲酸甲醋 -COOMe 使4 -（2 - N-烯丙胺基-1-乙基）乙氧基苯曱酸甲酯毫 克，0.37毫莫耳）、3-甲基-4 - [N，- (2-甲基苯基）脲基]苯 基乙酸（100毫克，〇·37毫莫耳）、EDC · HC1(105毫克， 0.56毫莫耳）、HOBt(95毫克，0.70毫莫耳）、及DMAP(9毫 克，〇· 07毫莫耳）於DMF( 7· 4毫升）中之混合物攪拌18小1283240 V. INSTRUCTIONS (796) 4.25 (m, 4H), 5·12-5·23 (m, 2H), 5·81 (m, 1H), 6·76 (m, 1H), 6·82 ( m,1H),6·93 (m,3H), 7·29 (m, 1H), 7·56 (m,1H), 7·94 (m,4H); MS(FAB) m/z 58 2 (M+) ; C28H28BrN3 06 calc.: c, 57·74; H, 4. 85; N, 7. 21. Measured value·· C, 57· 40 ; h, 5. 07 ; N, 7. 04. About 115 HC1 salt: C28H27BrN3〇6 · 〇· 25H20 Analytical calculation value·· c, 55· 23 i H' 4· 55 ; Ν' 6· 90. Found C·54·98 ; H, 4. 71 ; Ν, 6.53° Example 262 4-[2-Ν-allyl-Ν-[3-methyl-4[Ν,一(2) Monomethylphenyl)ureido]phenyl]ethinylamino]ethoxy acetonic acid 312 4 - [2-N-allyl-N-[3-methyl- 4 - [N,-(2 -nonylphenyl)ureido]phenyl]acetamido]ethoxybenzoic acid methyl vinegar-COOMe 4 -(2-N-allylamino-1-ethyl)ethoxybenzoic acid Methyl ester, 0.37 mmol, 3-methyl-4 -[N,-(2-methylphenyl)ureido]phenylacetic acid (100 mg, 〇·37 mmol), EDC · HC1 ( a mixture of 105 mg, 0.56 mmol, HOBt (95 mg, 0.70 mmol), and DMAP (9 mg, 〇 07 mmol) in DMF (7.4 ml)

\\312\2d-code\90-01\89112968.ptd 第801頁 1283240 五、發明說明（797) 時。將混合物以EtOAc(l 00毫升）稀釋，以in HC1及鹽水洗 滌，並於MgS〇4上乾燥。使殘留物與甲苯（ίο毫升χ3)共同 洛發以移除DMF。使殘留物於TLC(Whatman，PLK-5F，2 板’CHC13-MeOH，97:3)上進行層析，而得4—[2 - N -烯丙基 -N- [3-曱基-4-[Ν’ -（2-甲基苯基）脲基]苯基]乙醯胺基]乙 氧基苯甲酸甲酯（190毫克，100%)的白色非晶形泡沫。1 11-關1?(〇0(：13)(5 2.0及2.09(23，總計31〇、2.20及2,21 (s，總計3Η)、3·62 (s，2Η)、3·76 (m，2Η)、3.9〇 (s， 3H)、3·99 (m，1H)、4·08 (m，2H)、4·11 (m，1H)、 6.28 (m, 2H)、5·78 (m, 1H)、6·88 (d，J = 8.8 Hz， 2H)、7·05 (m，1H)、7·12 (m，1H)、7.21 (m，1H)、 7·58 (m，2H)、7·95 (d，J = 8.8 Hz，2H)、8·02 (m， 1H); MS(FAB) m/z 516 (M. + l)。 在室溫下於4-[2 - N-烯丙基-N - [3 -甲基-4 - [N，-（2〜甲美 苯基）脲基]苯基]乙醯胺基]乙氧基苯曱酸甲酯（217毫土 〇·43毫莫耳）溶於THF-MeOH(6:l，v/v，7毫升）之溶液 入0·5Ν Na〇H(1.9毫升，〇·86毫莫耳），並迴流加熱。於= 封瓶中在迴流下持續攪拌2小時。將反應混合物倒入至 中，利用1. ON HC1 酸化，以CHC13-MeOH(2:l，20 毫升χ37 萃取，並於MgS〇4上乾燥。於移除溶劑後，利用。_ -乙醚使殘留物結晶，而得312(84毫克，38%)的白色3於己烷 末。1H-NMR (CD30D) 6 2· 18 及2· 24 (s，總計3H)、2 习3〇 (d，J = 4.9 Hz，3H)、3·70 (s，1H)、3.78 (m，2H)·、 3·88 (s，1H)、4·12 (m，4H)、5·20 (m，2H)、5 /\\312\2d-code\90-01\89112968.ptd Page 801 1283240 V. Inventions (797). The mixture was diluted with EtOAc (10 mL), washed with EtOAc and brine The residue was combined with toluene (ίο mlχ3) to remove DMF. The residue was chromatographed on TLC (Whatman, PLK-5F, 2 plate 'CHC13-MeOH, 97:3) to give 4-[2-N-allyl-N-[3-indolyl-4 -[Ν'-(2-Methylphenyl)ureido]phenyl]ethylammonium] ethoxybenzoic acid methyl ester (190 mg, 100%) as a white amorphous foam. 1 11-Off 1?(〇0(:13)(5 2.0 and 2.09 (23, total 31〇, 2.20 and 2,21 (s, total 3Η), 3.62 (s, 2Η), 3.76 ( m, 2Η), 3.9〇(s, 3H), 3·99 (m, 1H), 4·08 (m, 2H), 4·11 (m, 1H), 6.28 (m, 2H), 5.78 (m, 1H), 6.88 (d, J = 8.8 Hz, 2H), 7·05 (m, 1H), 7·12 (m, 1H), 7.21 (m, 1H), 7·58 (m , 2H), 7·95 (d, J = 8.8 Hz, 2H), 8·02 (m, 1H); MS(FAB) m/z 516 (M. + l). at room temperature at 4-[ 2-N-allyl-N-[3-methyl-4-[N,-(2~methylphenyl)ureido]phenyl]acetamido]ethoxy benzoate 217 mM 43·43 mmoles) A solution of THF-MeOH (6:1, v/v, 7 mL) was taken in 0.5 Ν Na〇H (1.9 mL, 〇·86 mmol) and refluxed Heating. Stirring was continued for 2 hours under reflux in a flask. The reaction mixture was poured into the mixture and acidified with EtOAc EtOAc (EtOAc: EtOAc (EtOAc) After the solvent was removed, the residue was crystallised eluted eluted eluted eluted eluted eluted eluted eluted eluted eluted eluted of (s , total 3H), 2 习3〇 (d, J = 4.9 Hz, 3H), 3·70 (s, 1H), 3.78 (m, 2H)·, 3·88 (s, 1H), 4·12 ( m, 4H), 5·20 (m, 2H), 5 /

1283240 五、發明說明（798) 1H) ^6.92-7.20 (m, 7H) &gt;7.58 (m, 2H) .7.96 (m, 2H) ;MS(ESI) m/z 50 2 (IT) ; C29H31N3 05 之分析計算值：c1283240 V. INSTRUCTIONS (798) 1H) ^6.92-7.20 (m, 7H) &gt; 7.58 (m, 2H) .7.96 (m, 2H) ; MS (ESI) m/z 50 2 (IT) ; C29H31N3 05 Analytical calculated value: c

69·44; H，6.23; N，8.38。實測值：c, 68 99; H 6. 39 ; N，8. 03 ° · &gt; ’ 實施例263 4-[2-N-烯丙基-N-[3-氯-4-[Ν’ -(2-甲基苯基）脲基]苯基] 乙醯胺基]乙氧基苯甲酸69·44; H, 6.23; N, 8.38. Found: c, 68 99; H 6. 39 ; N, 8. 03 ° · &gt; ' Example 263 4-[2-N-allyl-N-[3-chloro-4-[Ν' - (2-methylphenyl)ureido]phenyl]ethylammonium]ethoxybenzoic acid

4-[2-N -烯丙基-N-[3-氯-4-[N， 乙醯胺基]乙氧基苯甲酸曱酯 313 -（2-甲基笨基）脲基]苯基]4-[2-N-allyl-N-[3-chloro-4-[N,ethylamino]ethoxybenzoate 313-(2-methylphenyl)ureido]phenyl ]

COOMe 於4 -（2-N-烯丙胺乙氧基）苯甲酸甲酯（141毫克，〇6〇毫 莫耳）及3-氯-4-[Ν’ -（2-甲基苯基）脲基]苯基乙酸（191毫 克’0.60耄莫耳）溶於DMF(5^升）之攪拌溶液中加入⑽。- HC1C172· 5 毫克，0· 90 毫莫耳）、HOBt(154 毫克，1· 14 毫莫 耳）、及DMAP(15毫克’0.12毫莫耳），並在室溫下持續揽 拌隔仪。將混合物以E10 A c ( 5 0毫升）稀釋，並以1 μ H C1 (χ3)、1Μ NaOH(xl )、及鹽水洗滌。將混合物於無水MgS〇4 上乾综’並於減壓下 &gt;辰細而得4_[2-N-婦丙基- N- [3 -氣-4 - [Ν’-（2-甲基苯基）脲基]苯基]乙醯胺基]乙氧基苯甲酸COOMe in methyl 4-(2-N-allylamine ethoxy)benzoate (141 mg, 〇6〇 mmol) and 3-chloro-4-[Ν'-(2-methylphenyl)urea (10) was added to a stirred solution of phenylacetic acid (191 mg '0.60 Torr) dissolved in DMF (5 liters). - HC1C172· 5 mg, 0·90 mM), HOBt (154 mg, 1.44 mmol), and DMAP (15 mg '0.12 mmol), and continue to stand at room temperature. The mixture was diluted with E10 A c (50 mL) and washed with 1 μH C1 (χ3), 1 NaOH (xl), and brine. The mixture was dried on anhydrous MgS〇4 and dried under reduced pressure to give 4-[2-N-propylpropyl-N-[3- gas-4-[Ν'-(2-methyl) Phenyl)ureido]phenyl]ethinyl]ethoxybenzoic acid

\\312\2d-code\90-01\89112968.ptd 第803頁 1283240 五、發明說明（799) 甲酯（ 3 5 0毫克，109%)的白色粉末。NMR (CDC13) 5 2·35 (s，3H)、3·60 (s，1H)、3·75 (m，2H)、3·90 (s， 3Η)、4·10 (m，4Η)、4.21 (m，1Η)、5·20 (m，2Η)、 5·80 (m，1Η)、6·50 (s，1Η)、6·85 (m，2Η)、7·08 (m， 2H)、7·20 (m，4H)、7·50 (d，J = 8.1 Hz，1H)、7·95 (d，J = 8· 1 Hz，2H)、8· 12 (d，J = 8· 1 Hz，1H) ; MS(ESI) m/z 53 6 (MHH)。 在室溫下於4- [2-N-烯丙基-N-[ 3-氯-4-[ Ν’ -(2-甲基苯 基）脲基]苯基]乙醯胺基]乙氧基苯甲酸甲酯（321毫克， 〇· 6 毫莫耳）溶於THF-Me0H-H20(2:2:l，v/v，30 毫升）之攪 拌溶液中加入NaOH( 50 0毫克，12. 5毫莫耳）。在室溫下持 續攪拌1 8小時。將反應混合物倒入至水中，以乙醚洗滌， 利用1M HC1酸化，以CHC13 - MeOH(2:l，20毫升x3)萃取， 於無水MgS04上乾燥，並於減壓下濃縮。利用CHC13 /正己烷 使殘留物固化而得3 1 3 ( 2 83毫克，83%)的白色固體。IR (KBr) ·· 3345、1581、1529、1 24 3、1167 / 公分；l-NMR (CD3OD) (5 2. 30 (s，3H)、3. 71 (s，1H)、3. 78 (m，1H) 、3·82 (m，1H)、3·89 (s，1H)、4·10 (m，1H)、4·19 (m，2H)、4· 21 (t，J = 5.4 Hz，1H)、5· 20 (m，2H)、 5·82 (m，1H)、6.95 (m，2H)、7.03 (m，1H)、7·18 (m， 3H)、7.28 (s，1H)、7·60 (d，J = 8.1 Hz，1H)、7.99 (m，3H) ; MS(ESI) m/z 522 (MH1) ; C28H28C1N3 05 · 1· 75H 20 之分析計算值：C， 60. 76 ; H，5. 74 ; N，7. 59。實測 值：C， 60· 43 ; H， 5· 34 ; N， 7· 17。\\312\2d-code\90-01\89112968.ptd Page 803 1283240 V. INSTRUCTIONS (799) Methyl ester (350 mg, 109%) white powder. NMR (CDC13) 5 2·35 (s, 3H), 3·60 (s, 1H), 3·75 (m, 2H), 3·90 (s, 3Η), 4·10 (m, 4Η), 4.21 (m, 1Η), 5·20 (m, 2Η), 5·80 (m, 1Η), 6·50 (s, 1Η), 6.85 (m, 2Η), 7·08 (m, 2H) ), 7·20 (m, 4H), 7·50 (d, J = 8.1 Hz, 1H), 7·95 (d, J = 8· 1 Hz, 2H), 8·12 (d, J = 8 · 1 Hz, 1H); MS (ESI) m/z 53 6 (MHH). 4-[2-N-allyl-N-[3-chloro-4-[indolyl]-(2-methylphenyl)ureido]phenyl]ethylammonium] ethoxylate at room temperature Methyl benzoate (321 mg, 〇·6 mmol) was dissolved in THF-Me0H-H20 (2:2:1, v/v, 30 mL). 5 millimoles). Stirring was continued for 18 hours at room temperature. The reaction mixture was poured with EtOAc EtOAc EtOAc. The residue was solidified using CH.sub.13 /hexanes to afford 3 &lt;3&gt; IR (KBr) · · 3345, 1581, 1529, 1 24 3, 1167 / cm; l-NMR (CD3OD) (5 2. 30 (s, 3H), 3. 71 (s, 1H), 3.78 ( m, 1H), 3·82 (m, 1H), 3·89 (s, 1H), 4·10 (m, 1H), 4·19 (m, 2H), 4· 21 (t, J = 5.4 Hz, 1H), 5·20 (m, 2H), 5.82 (m, 1H), 6.95 (m, 2H), 7.03 (m, 1H), 7·18 (m, 3H), 7.28 (s, 1H), 7·60 (d, J = 8.1 Hz, 1H), 7.99 (m, 3H); MS (ESI) m/z 522 (MH1); C28H28C1N3 05 · 1· 75H 20 Analysis calculated: C, 60. 76 ; H, 5. 74 ; N, 7. 59. Found: C, 60· 43 ; H, 5· 34 ; N, 7.17.

\\312\2d-code\90-01\89112968.ptd 第804頁 1283240 五、發明說明（800) 實施例2 6 4 4 - [2 - N - [2 -（4 -嗎福琳基）乙基]- N-[3_甲乳基4 [N (2 甲基苯基）脲基]苯基]乙醯胺基]乙氧基苯甲酸甲8旨\\312\2d-code\90-01\89112968.ptd Page 804 1283240 V. INSTRUCTIONS (800) EMBODIMENT 2 6 4 4 - [2 - N - [2 - (4 - Mofflinky) B Base]-N-[3_methyllacyl 4 [N(2methylphenyl)ureido]phenyl]acetamido]ethoxybenzoic acid

C。⑽ 4_[2-N-甲醯甲基-N-[3-甲氧基-4-[N，-（2-甲基苯基）脈基 ]苯基]乙醯胺基]乙氧基苯曱酸甲酯C. (10) 4_[2-N-Mexylmethyl-N-[3-methoxy-4-[N,-(2-methylphenyl)] phenyl] phenyl] ethinyl] ethoxybenzene Methyl decanoate

於4-[2-N-(2, 3-二羥基-1-丙基）- [3-甲氧基一 4'[N 一（2一 甲基苯基）脲基]苯基乙醯胺基]乙氧基]苯甲酸甲81 (1·83# 克，3.24 毫莫耳）溶於 THF-MeOH-40(1:1:1 v/v/^， 15 宅 升）之攪拌溶液中加入過碘酸鈉（2.08克，9·71宅莫耳）’ 並在室溫下攪拌18小時。將飽和Na2S203 ( 5 0毫升）加至反應 混合物，並使混合物攪拌1小時。將混合物以EtOAc (1 00 毫升X3)萃取，以鹽水洗滌，於MgS〇4上乾燥。將溶劑移心 而得4 - [2- N-甲醢甲基-N - [3 -甲氧基-4-[Ν’ -（2—甲| ” 脲基]苯基乙醯胺基]乙氧基]苯甲酸甲酯（1· 73克， 的非晶形泡沫。1H-NMR (CDC13) 5 2· 32 (t， 3H J = 2 Hz)、3·33-4·30 (m，8H)、3·72 (s，3H)、3·8’6 (s · 3Η)、6·20 (m，1Η)、6·70 (m，1Η)、6·8〇 (m，4Η'，、 7. 06 (m，1H)、7· 18 (m，1H)、7· 26 (m，1H)， 、4-[2-N-(2,3-Dihydroxy-1-propyl)-[3-methoxy-4'[N-(2-methylphenyl)ureido]phenylacetamide Ethoxy]benzoic acid methyl 81 (1·83# g, 3.24 mmol) was dissolved in a stirred solution of THF-MeOH-40 (1:1:1 v/v/^, 15 liter) Sodium periodate (2.08 g, 9.71 house Mo) was stirred at room temperature for 18 hours. Saturated Na2S203 (50 mL) was added to the mixture and mixture was stirred for one hour. The mixture was extracted with EtOAc (1 mL (EtOAc)EtOAc. The solvent is transferred to give 4-[2-N-methylindolemethyl-N-[3-methoxy-4-[Ν'-(2-methyl] ureido]phenylethenyl] Methyl oxy]benzoate (1·73 g, amorphous foam. 1H-NMR (CDC13) 5 2· 32 (t, 3H J = 2 Hz), 3·33-4·30 (m, 8H) , 3·72 (s, 3H), 3·8'6 (s · 3Η), 6·20 (m, 1Η), 6.70 (m, 1Η), 6·8〇 (m, 4Η', 7. 06 (m, 1H), 7· 18 (m, 1H), 7·26 (m, 1H), ,

12832401283240

A J = 7.4 Hz)、7·96 (m，2H)、8·10 (m，1Η)、9·57 及 9·63 (2s，總計 1H); MS(FAB) m/z 534 (MH1)。 在室溫下於4 - [2- N-甲醯甲基一 n-[3一甲氧基一 4 一 [N，—（2〜 甲基苯基）脲基]苯基乙醯胺基]乙氧基]苯甲酸曱酯 耄克，0.75毫莫耳）溶於EtOH( 7· 5毫升）之攪拌溶液中加入 嗎福琳（654微升，7.5毫莫耳）及醋酸（429微升，7.5毫莫 耳）。使反應在室溫下攪拌5分鐘，然後冷卻至〇。〇。於此 冷卻溶液中加入NaBH3CN(471毫克，7.5毫莫耳），並在室 溫下持續攪拌1小時。將混合物倒入至飽*NaHC〇3中，並 以EtOAc(50毫升χ3)萃取，以鹽水洗滌，及於MgS04上乾 燥。於在真空中移除溶劑後，使殘留物於矽膠（中壓層析 系統：YAMAZEN YFLC-5404-FC，甲苯-丙酮100 : 0 至1 : 1 之 線性梯度）上進行層析，而得31 4 (346毫克，76%)之白色非 晶形泡沫。1Η-NMR (CDC13，4 00MHz) (5 2· 31 (s，3H)、 2.46 (m，4H)、3·52-3·79 (m，12H)、3·70 (d，3H， J = 2.7 Hz)、4.05 及 4·22 (m，總計 2Η)、6·24 及 6.29 (s， 總計 1H)、6·73 (m，2H)、6·85 (m，2H)、7·07 (s，1H) 、7·17 (in, 1H)、7·25 (m，2H)、7·50 (t，1H，J = 7.3 Hz)、7.96 (m，2H)、8·08 (m，1H); MS(FAB) m/z 605 (MH1) ; C33H4QN4 07 · 1/2H20 之分析計算值：C，64. 58 ; H, 6· 73 ; N，9· 13。實測值：C，64. 9 5 ; H，6· 88 ; N， 8· 82。 關於118之HC1鹽：C33H41C1N4 07 · 2· 5H20之分析計算值： C，57. 76 ; H，6· 76 ; N，8. 16 ; Cl，5· 17。實測值·· C，A J = 7.4 Hz), 7.96 (m, 2H), 8·10 (m, 1 Η), 9·57 and 9·63 (2s, total 1H); MS (FAB) m/z 534 (MH1). 4-[2-N-methylindolemethyl-n-[3-methoxy-tetra-[N,-(2-~methylphenyl)ureido]phenylethenylamino] at room temperature Add phenoline (654 μl, 7.5 mmol) and acetic acid (429 μl) to a stirred solution of EtOH (7.5 mL) in EtOH (7.5 mL). 7.5 millimoles). The reaction was allowed to stir at room temperature for 5 minutes and then cooled to hydrazine. Hey. NaBH3CN (471 mg, 7.5 mmol) was added to the cooled solution, and stirring was continued at room temperature for 1 hour. The mixture was poured into a saturated solution of EtOAc (50 mL EtOAc). After removing the solvent in vacuo, the residue was chromatographed on a silica gel (medium pressure chromatography system: YAMAZEN YFLC-5404-FC, toluene-acetone 100:0 to 1:1 linear gradient) to give 31 4 (346 mg, 76%) of a white amorphous foam. 1Η-NMR (CDC13, 4 00MHz) (5 2· 31 (s, 3H), 2.46 (m, 4H), 3·52-3·79 (m, 12H), 3·70 (d, 3H, J = 2.7 Hz), 4.05 and 4·22 (m, total 2Η), 6·24 and 6.29 (s, total 1H), 6.73 (m, 2H), 6.85 (m, 2H), 7·07 ( s, 1H), 7·17 (in, 1H), 7·25 (m, 2H), 7·50 (t, 1H, J = 7.3 Hz), 7.96 (m, 2H), 8·08 (m, 1H); MS (FAB) m/z 605 (MH1); C33H4QN4 07 · 1/2H20 Analysis calculated: C, 64. 58 ; H, 6· 73 ; N, 9 · 13. Found: C, 64 9 5 ; H,6· 88 ; N, 8· 82. For HC1 salt of 118: C33H41C1N4 07 · 2· 5H20 Analysis calculated: C, 57. 76 ; H,6· 76 ; N,8. 16 ; Cl, 5· 17. Actual measured value·· C,

89112968.ptd 第806頁 1283240 五、發明說明（802) 58· 29 ; H，6· 81 ; N，7· 42 ; C1，5· 05。 實施例2 6 5 4_[2-1^-[2-（4-嗎福琳基）乙基]1-[3-甲氧基-4-[1^，-（2- 甲基苯基）脲基]苯基]乙醯胺基]乙氧基苯曱酸89112968.ptd Page 806 1283240 V. INSTRUCTIONS (802) 58· 29 ; H,6· 81 ; N,7· 42 ; C1,5· 05. Example 2 6 5 4_[2-1^-[2-(4-moffolinyl)ethyl]1-[3-methoxy-4-[1^,-(2-methylphenyl) Ureido]phenyl]acetamido]ethoxybenzoic acid

COOH 在室溫下於4 - [2 -N-[2-(4 -嗎福啉基）乙基]—N - [3 -甲氧 基-4 - [Ν’- (2 -甲基苯基）脲基]笨基]乙醯胺基]乙氧基苯甲 酸甲酉旨（146毫克，0.24毫莫耳）溶於THF 一 Me0H〇 ·· ν/ν， 6毫升）之溶液中加入0.25Ν NaOH(l. 9毫升，0·48毫莫 耳），並迴流加熱。在迴流下持續攪拌丨8小時。將反應混 合物倒入至水中，並利用1· ON HC1酸化。以CHC13-MeOH (3: 1 ’ v/v, 30毫升X5)萃取混合物。將結合的有機溶劑於 MgS〇4上乾燥。於移除溶劑後，利用乙醚使殘留物結晶而 得315(102毫克，71〇/〇)之白色粉末。111一麗1^((：1)3〇1))(5 2.28 (d，J = 3.0 Hz，3H)、2·46 (m，1H)、2·40 (m, 1H) 、2·56 (m，1Η)、2·63 (m，1Η)、3·62-3·80 (m，12Η)、 3·85 (s，3H)、4·12 (m，1H)、4·26 (m，1H)、6·82 (m, 2H) ^6.96 (m, 2H) &gt;7.01 (m, ih) &gt;7.17 (m, 2H) ^ 7.58 (d，J = 7.8 Hz，1H)、7·93 (m，3H); MS(FAB) m/z 591 (M+) ; C32H38N4〇7 ·ι·〇η20 之分析計算值：C，63.14; H，6·62; N， 9·20。實測值：c，63·48; H，6·66; N， 8· 79。COOH at 4 - [2-N-[2-(4-norfosyl)ethyl]-N-[3-methoxy-4-[Ν'-(2-methylphenyl) at room temperature脲 脲 ] 笨 ] ] ] ] ] 146 146 146 146 146 146 146 146 146 146 146 146 146 146 146 146 146 146 146 146 146 146 146 146 146 146 146 146 146 146 146 146 146 146 146 146 146 146 146 146 146 146 146 NaOH (1.9 ml, 0. 48 mmol) and heated under reflux. Stirring was continued for 8 hours under reflux. The reaction mixture was poured into water and acidified with 1·ON HC1. The mixture was extracted with CHC13-MeOH (3: 1 s v/v, 30 mL X5). The combined organic solvent was dried on MgS〇4. After the solvent was removed, the residue was crystallised from diethyl ether to afford 315 (102 mg, 71 〇 / 。) white powder. 111一丽1^((:1)3〇1))(5 2.28 (d, J = 3.0 Hz, 3H), 2·46 (m, 1H), 2·40 (m, 1H), 2.56 (m, 1Η), 2·63 (m, 1Η), 3·62-3·80 (m, 12Η), 3·85 (s, 3H), 4·12 (m, 1H), 4·26 ( m,1H),6·82 (m, 2H) ^6.96 (m, 2H) &gt;7.01 (m, ih) &gt;7.17 (m, 2H) ^ 7.58 (d, J = 7.8 Hz, 1H), 7 · · · · · · · · · · · · · · · Value: c, 63·48; H, 6·66; N, 8·79.

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第807頁 1283240 五、發明說明（803) 實施例2 6 6 4_[2-N -環丙基-N-[3-甲氧基-4 - [Ν’ -（2-甲基苯基）脲基] 苯基]乙醯胺基]乙氧基苯甲酸Page 807 1283240 V. INSTRUCTIONS (803) EXAMPLE 2 6 6 4_[2-N-Cyclopropyl-N-[3-methoxy-4 -[Ν'-(2-methylphenyl)urea Phenyl]acetamido]ethoxybenzoic acid

co2h 316 4-甲醯曱氧基苯甲酸甲酯Co2h 316 4-methylmethyloxybenzoate

〇&quot;&quot;CHO C〇2Me 於4-(2-羥乙氧基）苯甲酸甲酯（5.00克，25.5毫莫耳）、 DMS0(18. 1 毫升，255 毫莫耳）、Et3N(17.7 毫升，127.5 毫 莫耳）溶於CH2C 12 ( 2 0 0毫升）之攪拌溶液中加入S03 · Py( 12. 2克，76. 5毫莫耳）。於攪拌5小時後，將混合物於真空 中濃縮，並以H20 ( 1 0 0毫升）稀釋殘留物。將混合物以 EtOAc(2x200毫升）萃取。將結合的萃取液以鹽水（100毫 升）洗滌，於（MgS04)上乾燥，並蒸發。使殘留物於矽膠上 利用己烷-EtOAc (4:1)進行層析，而得4-甲醯曱氧基苯曱 酸甲酯及4-羥基苯甲酸甲酯之4 : 1混合物（2. 00克）的白色 固體。UMR (CDC13) (5 3. 90 (s，3H)、4. 64 (d, J = l. 0 Hz, 2H) 、6·92 (d， J=9.0 Hz， 2H) 、8·02 (d， J=9.0〇&quot;&quot;CHO C〇2Me in methyl 4-(2-hydroxyethoxy)benzoate (5.00 g, 25.5 mmol), DMS0 (18.1 ml, 255 mmol), Et3N (17.7 ML, 127.5 mmol, dissolved in a stirred solution of CH2C12 (200 mL) was added S03 · Py ( 12. 2 g, 76.5 mmol). After stirring for 5 hours, the mixture was concentrated in vacuo and EtOAc EtOAc m. The mixture was extracted with EtOAc (2×200 mL). The combined extracts were washed with brine (100 mL), dried (MgSO4) and evaporated. The residue was chromatographed on silica gel eluting with hexane-EtOAc (4:1) to yield 4:1 mixture of methyl 4-methyl benzooxybenzoate and methyl 4-hydroxybenzoate (2. 00 g) of a white solid. UMR (CDC13) (5 3. 90 (s, 3H), 4.64 (d, J = l. 0 Hz, 2H), 6.92 (d, J=9.0 Hz, 2H), 8·02 (d , J=9.0

Hz, 2H) 、 9· 86 (d， J=l·0 Hz, 1H)。 4-(2 -環丙胺乙氧基）苯甲酸甲酯 S7 ^v^C〇2MeHz, 2H), 9·86 (d, J=l·0 Hz, 1H). Methyl 4-(2-cyclopropylamine ethoxy)benzoate S7 ^v^C〇2Me

\\312\2d-code\90-01\89112968.ptd 第808頁 1283240 五、發明說明（804) 一 於4甲醯甲氧基笨甲酸甲酯及4一羥基苯甲酸甲酯（ι 〇〇 克）之4 : 1混合物及環丙胺（4 2 5微升，6 ·丨8毫莫耳）溶於 M^eOH AcOH(lJ):，11毫升）之攪拌溶液中加人NaBH3CN(681 毫克，10· 莫耳）。於攪拌隔夜後，經由加入飽和 NaHC&gt;(50宅升）使混合物停止反應，並以CHC13(2x2〇〇* 升）萃取。將結合的萃取液於MgS〇4上乾燥，並蒸發。使殘 留物於矽膠上利用CHCI3-MeOH(20:l)進行層析，而得4 一 (2-環丙胺乙氧基）苯甲酸曱酯（5 95毫克，49%)之無色油。 W-NMR (CDC13) (5 〇· 3 7-0· 49 (m，4H)、1· 91 (m，1H)、 2.18-2.23 (m，1H)、3·11 (t，J = 5.2 Hz，2H)、3·88 (s，3H)、4·12 (t，J = 5.2 Hz, 2H)、6·92 (d，J = 8.8\\312\2d-code\90-01\89112968.ptd Page 808 1283240 V. INSTRUCTIONS (804) I. Methyl 4-methoxy methoxybenzoate and methyl 4-hydroxybenzoate (ι 〇〇克) 4: 1 mixture and cyclopropylamine (4 2 5 μL, 6 · 丨 8 mmol) dissolved in M ^ eOH AcOH (lJ):, 11 ml) in a stirred solution of NaBH3CN (681 mg, 10· Moer). After stirring overnight, the mixture was quenched by the addition of saturated NaHC &lt;&gt;&gt; (50 liters) and extracted with CHC13 (2x2 〇〇* liter). The combined extracts were dried over MgS 4 and evaporated. The residue was chromatographed on EtOAc (EtOAc) eluting W-NMR (CDC13) (5 〇· 3 7-0· 49 (m, 4H), 1.91 (m, 1H), 2.18-2.23 (m, 1H), 3·11 (t, J = 5.2 Hz , 2H), 3·88 (s, 3H), 4·12 (t, J = 5.2 Hz, 2H), 6.92 (d, J = 8.8

Hz，2H)、7· 98 (d，J = 8· 8 Hz，2H)。 4 - [2-N -環丙基-N-[3 -甲氧基-4-[N，-（2-甲基苯基）脲基] 苯基]乙醯胺基]乙氧基苯甲酸甲酯Hz, 2H), 7·98 (d, J = 8·8 Hz, 2H). 4-[2-N-Cyclopropyl-N-[3-methoxy-4-[N,-(2-methylphenyl)ureido]phenyl]acetamido]ethoxybenzoic acid Methyl ester

C〇2Me 使4-（2 -環丙胺乙氧基）苯甲酸甲酯（290毫克，1·23毫莫 耳）、3 -甲氧基-4 - [Ν’ _( 2-甲基苯基）脲基]苯基乙酸（387 毫克，1· 23毫莫耳）、EDC · HC 1 ( 354毫克，1. 85毫莫耳）、 H0Bt(催化劑）' 及DMAP(催化劑）於DMF(10毫升）中之混合 物攪拌隔夜。使混合物在EtOAc( 300毫升）與1120 (1〇〇毫 升）之間分配。將有機相分離，以鹽水（2 X1 0 〇毫升）洗滌， 於MgS04上乾燥，並蒸發。使殘留物於矽膠上利用CHC13-C〇2Me methyl 4-(2-cyclopropylamine ethoxy)benzoate (290 mg, 1.25 mmol), 3-methoxy-4 - [Ν' _(2-methylphenyl) Urea]phenylacetic acid (387 mg, 1.25 mmol), EDC · HC 1 (354 mg, 1.85 mmol), H0Bt (catalyst)' and DMAP (catalyst) in DMF (10 ml) The mixture in the mixture was stirred overnight. The mixture was partitioned between EtOAc (300 mL) and 1120 (1 mL). The organic phase was separated, washed with brine (2×10 mL), dried over EtOAc and evaporated. Make the residue on the tannin using CHC13-

\\312\2d-code\90-01\89112968.ptd 第809頁 1283240 五、發明說明（805) --------\\312\2d-code\90-01\89112968.ptd Page 809 1283240 V. Inventions (805) --------

MeOH(50:l)進行層析，而得4—[2_n 一環丙基-N 一 [3—甲氧基 -4 - [Ν’ -（2-曱基苯基）脲基]苯基]乙醯胺基]乙氧基苯甲 酸甲酯（426毫克，65%)之黃色黏性油。1H-NMR (CDCl3) d: 〇·90-0.97 (m，4H)、2·28 (s，3H)、3.6g (s，3H)、 3.77 (t，J = 5.4 Hz，2H)、3·85 (s，2H)、3·87 (s，3h) 、4·15 (t，J = 5.4 Hz，2H)、6·6〇_6·8ι (m，5h)、7·〇9 -7.23(m’4H)、7.57(d，j=：8.3Hz，1H)、792-7.95 (m，2H)、8· 04 (d，J = 8· 3 Hz，1H)。 於4-[2-[N-環丙基-[3-甲氧基一4_[N，一（2一甲基苯基）脲 苯基]乙醯胺基]乙氧基]笨甲酸甲酯（426毫克，〇·8〇1 毫莫耳）溶於THF(7毫升）之攪拌溶液中加入〇· 25N Na〇H (6. 4毫升’ 1 · 6 0毫莫耳）。於攪拌隔夜後，將混合物倒入 至IN HC1(50 毫升）中，並利用CHC13-MeOH(4: 1， 2x2 0 0 毫 升）萃取。使結合的萃取液於MgS04上乾燥並蒸發。使殘留 物於矽膠上利用（：11(：13^6〇11(20:1至1〇:1)作為洗提液進行 層析，而得3 1 6 ( 33 3毫克，80%)之無色非晶形固體。 l-NMR (DMSO) (5 0·86-0·91 (m，4H)、2·25 (s，3H)、 2·74 (m，1Η)、3·69 (t，J = 5.5 Ηζ，2Η)、3·81 (s， 3Η)、3·83 (s，2Η)、4·15 (t，J = 5.5 Ηζ，2Η)、6·75 (d，J = 8.3 Ηζ，1Η)、6·87 (s，1Η)、6·92-6·99 (m， 3Η)、7.1卜7.17 (m，2Η)、7·81 (d, J = 8.1 Ηζ，1Η)、 7.88(d，J = 8.5Hz，2H)、8.01(d，j = 8.iHz，lH)、8· 47 (s，1H)、8·55 (s，1H)、12.96 (s，br s); MS(FAB) m/z 51 8(MH1) ; C29H31N306 之分析計算值：C， 67· 30 ; H，Chromatography with MeOH (50:1) gave 4-[2_n-cyclopropyl-N-[3-methoxy-4-[Ν'-(2-mercaptophenyl)ureido]phenyl] A yellow viscous oil of methyl glutamine]ethyl ethoxybenzoate (426 mg, 65%). 1H-NMR (CDCl3) d: 〇·90-0.97 (m, 4H), 2·28 (s, 3H), 3.6g (s, 3H), 3.77 (t, J = 5.4 Hz, 2H), 3· 85 (s, 2H), 3·87 (s, 3h), 4·15 (t, J = 5.4 Hz, 2H), 6·6〇_6·8ι (m, 5h), 7·〇9 -7.23 (m'4H), 7.57 (d, j =: 8.3 Hz, 1H), 792-7.95 (m, 2H), 8·04 (d, J = 8·3 Hz, 1H). Methyl 4-[2-[N-cyclopropyl-[3-methoxy-4-[N,mono(2-methylphenyl)ureaphenyl]ethanoylamino]ethoxy] benzoate (426 mg, 〇·8 〇 1 mmol) was added to a stirred solution of THF (7 mL) and 〇··············· After stirring overnight, the mixture was poured into EtOAc (50 mL). The combined extracts were dried over MgS04 and evaporated. The residue was chromatographed on a silica gel (:11(:13^6〇11 (20:1 to 1〇:1) as an eluent to obtain 3 16 (33 3 mg, 80%) colorless. Amorphous solid. l-NMR (DMSO) (5 0·86-0·91 (m, 4H), 2·25 (s, 3H), 2·74 (m, 1Η), 3·69 (t, J = 5.5 Ηζ, 2Η), 3·81 (s, 3Η), 3·83 (s, 2Η), 4·15 (t, J = 5.5 Ηζ, 2Η), 6.75 (d, J = 8.3 Ηζ, 1Η), 6·87 (s, 1Η), 6.92-6·99 (m, 3Η), 7.1 7.17 (m, 2Η), 7·81 (d, J = 8.1 Ηζ, 1Η), 7.88 ( d, J = 8.5 Hz, 2H), 8.01 (d, j = 8.iHz, lH), 8·47 (s, 1H), 8·55 (s, 1H), 12.96 (s, br s); MS (FAB) m/z 51 8(MH1) ; C29H31N306 calc.: C, 67·30; H,

\\312\2d-code\90-01\89112968.ptd 第 810 頁 1283240 五、發明說明（806) 6. 04 ; N，8· 12。實測值：C，66. 71 ; H，6· 26 ; N， 7.82。 實施例2 6 7 4 - [2 -N-[2 -（N，，N，-二甲胺基）一卜乙基]-N - [4- [N&quot; -（2-氣 苯基）脲基]-3-甲氧苯基]乙醯胺基]乙氧基苯曱酸\\312\2d-code\90-01\89112968.ptd Page 810 1283240 V. Description of invention (806) 6. 04 ; N, 8· 12. Found: C, 66. 71 ; H, 6 · 26 ; N, 7.82. Example 2 6 7 4 - [2-N-[2-(N,,N,-dimethylamino)-i-ethyl]-N-[4-[N&quot;-(2-phenylphenyl)ureido] -3-methoxyphenyl]acetamido]ethoxybenzoic acid

317 在室溫下於4 - [2-N-[2-（Ν’，Ν’ -二甲胺基）一卜乙基]一N - [4-[Νπ-(2-氣苯基）脲基]曱氧苯基]乙醯胺基]乙氧基 苯甲酸甲酯（1〇〇毫克，〇·17毫莫耳）溶於thf - MeOH (1 : 1， v/v，3毫升）之溶液中加入0.25N NaOH(2.0毫升，0.5毫莫 耳），並迴流加熱。在迴流下持續攪拌3小時。將反應混合 物倒入至水中，並利用1. ON HC1酸化至PH 5. 0。於在真空 中移除有機溶劑後，使所產生之混合物利用HP-2 0 (H20-MeOH 100:0 至 〇:1〇〇)進行層析，而得 317(63 毫克， 64%)之白色粉末。iH-NMR (CD30D) 5 2. 41 (s，2H)、2· 65 (s，3H)、2·69 (s，3H)、3.02 (m，2H)、3·62-3·85 (m，4Η)、3· 84 (s，3Η)、4· 05 及4· 22 (m，總計2Η)、 6·82-6·88 (m，4H)、7·02 (m，1H)、7·25 (m，1H)、 7·38 (m，1H)、7.92 (m，2H)、8.01 (m，2H); MS(FAB) m/z 569 (M+) ; C29H33C1N4 06 ·3·0Η2Ο 之分析計算值：C， 55. 90 ; Η, 6· 31 ; N，8· 99。實測值·· C，56. 40 ; H， 6. 50 ； N， 8. 08 〇317 at 4 - [2-N-[2-(Ν',Ν'-dimethylamino)-i-ethyl]-N-[4-[Νπ-(2-phenylphenyl)ureido] Methyl oxyphenyl]ethyl hydrazide] ethoxybenzoate (1 〇〇 mg, 〇 17 mmol) dissolved in thf - MeOH (1:1, v/v, 3 mL) 0.25 N NaOH (2.0 mL, 0.5 mmol) was added and heated under reflux. Stirring was continued for 3 hours under reflux. The reaction mixture was poured into water and acidified to pH 5.0 with 1. ON HCl. After removing the organic solvent in vacuo, the resulting mixture was chromatographed using EtOAc (H20-MeOH: EtOAc: EtOAc: EtOAc: powder. iH-NMR (CD30D) 5 2. 41 (s, 2H), 2·65 (s, 3H), 2·69 (s, 3H), 3.02 (m, 2H), 3·62-3·85 (m , 4Η), 3· 84 (s, 3Η), 4· 05 and 4· 22 (m, total 2Η), 6·82-6·88 (m, 4H), 7·02 (m, 1H), 7 · 25 (m, 1H), 7·38 (m, 1H), 7.92 (m, 2H), 8.01 (m, 2H); MS (FAB) m/z 569 (M+); C29H33C1N4 06 ·3·0Η2 Analytical calculations: C, 55. 90; Η, 6· 31 ; N, 8. 99. Measured value·· C,56. 40 ; H, 6. 50 ; N, 8. 08 〇

89112968.ptd 第811頁 128324089112968.ptd Page 811 1283240

ίΜΜΙΜ. V】琳基）乙基]-Ν—[3_甲氧基一4一 [Ν，-（2-土本土脲土]笨基]乙醯胺基]乙氧基苯甲酸異丙酯 ^&lt;^^^COOi Pr ,€r 318 在至溫下於4-[ 2-N-[2-（4 -嗎福啉基）乙基]-N- [3 -曱氧 ^ 4 [N^_(2 -曱基苯基）脲基]笨基]乙醯胺基]乙氧基笨甲 酸（ 250毫克’ 〇. 42毫莫耳）溶於DMF(2毫升）之攪拌溶液中 加入碘異丙烷（264微升，2.53毫莫耳）及](2(：03 (88毫克， 〇· 64晕莫耳）。使反應在50 °C下攪拌2小時。將混合物倒入 至鹽水中’並以CHC13 (50毫升x3)萃取，以鹽水洗滌，並 於MgS〇4上乾燥。於在真空中移除溶劑後，使殘留物於矽 膠（中壓層析系統：YAMAZEN YFLC-5404-FC，甲苯-丙酮 100 : 0至40 : 6 0之線性梯度）上進行層析，而得31 8(261毫 克’ 97%)之白色非晶形泡沫。iH-NMR (CDC13，40 0 ΜΗζ) ά 1·35 (s，3Η)、1.36 (s，3Η)、2.31 (s，3Η)、2·45 (m， 4Η)、2·50 (m, 2Η)、3·55-3·78 (m, 10Η)、3·70 (s， 3H)、4·05 及 4.20 (t，J = 5.2 Hz，總計 2H)、5·22 (m， 1H)、6·24 及 6·33 (2s，總計 1H)、6·70-6·83 (m，4H)、 7·〇8 (s，1Η)、7·15 (m，1Η)、7·22 (m，1Η)、7·40 (t， J = 9.0 Hz，1H)、7·96 (d，】 = 8·8 Hz，1H)、7·97 (d, J = 8.8 Hz，1H)、8·〇7 (t，J = 7.8 Hz，1H); MS(FAB) m/z 633 (MH1) ; C35H44N4 07 · 0· 75H20 之分析計算值：C， 65. 05ΜΜΙΜ V V V ) ) 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基^&lt;^^^COOi Pr , €r 318 at 4-(2-N-[2-(4-norfosyl)ethyl]-N-[3-anthraceneoxy] 4 [N] Add iodine to a stirred solution of ^_(2-nonylphenyl)ureido]phenyl]acetamido]ethoxy acetonic acid (250 mg 〇. 42 mmol) in DMF (2 mL) Isopropane (264 μl, 2.53 mmol) and ] (2 (: 03 (88 mg, 〇· 64 ν). The reaction was stirred at 50 ° C for 2 hours. The mixture was poured into brine. Extracted with CHC13 (50 ml x 3), washed with brine and dried over MgSO4. After the solvent was removed in vacuo, the residue was applied to EtOAc (YMEZEN YFLC-5404-FC, Chromatography on a linear gradient of toluene-acetone 100: 0 to 40: 60) yielded 31 8 (261 mg &apos; 97%) of white amorphous foam. iH-NMR (CDC13, 40 0 ΜΗζ) ά 1· 35 (s, 3Η), 1.36 (s, 3Η), 2.31 (s, 3Η), 2·45 (m, 4Η), 2·50 (m, 2Η), 3·55-3·78 (m, 10Η) ), 3.70 ( s, 3H), 4·05 and 4.20 (t, J = 5.2 Hz, total 2H), 5·22 (m, 1H), 6·24 and 6·33 (2s, total 1H), 6·70-6 ·83 (m, 4H), 7·〇8 (s, 1Η), 7·15 (m, 1Η), 7·22 (m, 1Η), 7·40 (t, J = 9.0 Hz, 1H), 7·96 (d,] = 8·8 Hz, 1H), 7·97 (d, J = 8.8 Hz, 1H), 8·〇7 (t, J = 7.8 Hz, 1H); MS(FAB) m /z 633 (MH1) ; C35H44N4 07 · 0· 75H20 Analysis calculated: C, 65. 05

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;Η, 7. 10 ; N，8. 67。實測值：C，65, 19 ; H，7 〇9 8· 50。 ’ 實施例2 6 9 4 - [2 - N-[2 -（3,3 -二氟-：l …比咯啶基）乙基卜N_[4—[N，—（2〜 溴苯基）脲基]-3-甲氧苯基]p醯胺基]乙氧基苯甲酸鈉鹽;Η, 7. 10 ; N, 8. 67. Found: C, 65, 19 ; H, 7 〇 9 8 · 50. 'Example 2 6 9 4 - [2 - N-[2 -(3,3 -difluoro-:l ...pyrrolidyl)ethyl b) N_[4-[N,-(2~ bromophenyl) Ureido]-3-methoxyphenyl]p醯amino] ethoxybenzoic acid sodium salt

4- [2-N- [2-（3, 3 -二氟-1-吡咯啶基）乙基]—N—[4—[N，—（2〜 溴笨基）脲基]_3-甲氧苯基]乙醯胺基]乙氧基苯曱酸甲酽4-[2-N-[2-(3,3-Difluoro-1-pyrrolidinyl)ethyl]-N-[4-[N,-(2~ bromophenyl)ureido]_3-A Oxyphenyl phenyl acetamino] ethoxybenzoic acid

在室溫下於4- [2 -N-甲醯甲基—N-[3-甲氧基一 4- [N，~(2〜 /臭本基）脲基]苯基]乙醯胺基]乙氧基苯甲酸甲酯毫 克，〇·5毫莫耳）溶於1，2 -二氯乙烧（3·6毫升）之攪拌溶液 中加入3, 3 -二氟咄咯啶AcOH鹽（420毫克，2.5毫莫耳）。使 反應在室溫下攪拌5分鐘，然後冷卻至〇 t。於此冷卻溶液 中加入NaBH(OAc)3 (530毫克，2.5毫莫耳），並在室溫下 持續祝摔4小時。將混合物倒入至飽和n a H C 03中，以C H C 1 (50毫升χ3)萃取，以鹽水洗滌，並於MgS04上乾燥。於在 真空中移除溶劑後，使殘留物於矽膠（中壓層析系統： YAMAZEN YFLC-5404-FC，CHC13-MeOH 10:0 至97:3 之線性 梯度）上進行層析’而得4-[2-N-[2-(3,3-二氟-ΐ-ϋ比略σ定4-[2-N-Carbendylmethyl-N-[3-methoxy-4-[N,~(2~/smoke)ureido]phenyl]ethinylamino at room temperature To a stirred solution of 1,2-dichloroethane (3·6 ml) was added 3,3-difluoropyrrolidine AcOH salt (methanol ethoxy benzoate, 〇·5 mmol). 420 mg, 2.5 millimoles). The reaction was allowed to stir at room temperature for 5 minutes and then cooled to 〇t. NaBH(OAc)3 (530 mg, 2.5 mmol) was added to the cooled solution, and the mixture was allowed to fall for 4 hours at room temperature. The mixture was poured into saturated n a H C 03, extracted with CHCI (EtOAc (EtOAc) After removing the solvent in vacuo, the residue was chromatographed on a silica gel (medium pressure chromatography system: YAMAZEN YFLC-5404-FC, CHC13-MeOH 10:0 to 97:3). -[2-N-[2-(3,3-Difluoro-ΐ-ϋ-ϋ比略σ定

89112968.ptd 第813頁 1283240 五、發明說明（809) 基）乙基]- N-[4 - [Ν’ -（2 -溴苯基）脲基]一 3—曱氧苯基]乙醯 胺基]乙氧基苯甲酸甲酯（345毫克，100%)之白色非晶形泡 沫。1H-NMR (CDC13，4 00 ΜΗζ) δ 2.20-2.80 (m，6Η)、 3·48 (m，2H)、3·70-3·80 (m，9H)、3·89 (s，3H)、 4·09 (m，1Η)、4·21 (m，1Η)、6·79-6·85 (m，4Η)、 6.93 (m，1H)、7·08 (m，2H)、7·30 (m，1H)、7·50 (m， 1H)、7·96 (m，3H)、8·13 (dd，J=1.5 Hz、8·3 Hz, 1H) ;MS(ESI) m/z 68 9 (M+)。 在室溫下於4-[2-N-[2-(3,3-二氟-丨—吡咯啶基）乙基]一 N-[4-[ Ν’ - (2 -溴苯基）脲基]甲氧苯基]乙醯胺基]乙氧 基苯甲酸甲酯（345毫克，〇·5毫莫耳）溶於THF 一 Me〇H u ··工， v/v，8毫升）之溶液中加入〇· 25N NaOH(4毫升，1· 〇毫莫 耳），並迴流加熱。在迴流下持續攪拌6小時。將溶劑移 除，及使殘留物於HP-20(H20-MeOH，0:100至1〇〇:〇)上進 行層析’而得3 1 9 ( 306毫克，91%)之淡紅色粉末。ih-NMR (CD30D ’400MHz) 6 2.20-2.90(m，6H)、3·60 (m，2H)、 3.70-3.92 (m，9Η)、4·10 (m，1Η)、4·22 (m, 1Η)、 6.84 (m，4H)、6·96 (m，1H)、7·30 (m，1H)、7·55 (m, 1H)、7· 93 (m，3H)、7· 97 (m，ih) ; MS(ESI) m/z 67 6 (MH1) ; C31H32BrF2N4 06 · 2· 5H2〇 之分析計算值：c，5 2. 85 ; H，5· 29 ; N， 7. 95。實測值：c， 52. 67 ; H，5. 20 ; N， 8.11。 實施例270 4-[21-（^-甲氧基1’-甲胺基）乙基一1^-[3-曱氧基4-[^&quot;-89112968.ptd Page 813 1283240 V. INSTRUCTIONS (809) yl)ethyl]-N-[4 - [Ν'-(2-bromophenyl)ureido]-3-oxooxyphenyl]acetamide A white amorphous foam of methyl ethoxybenzoate (345 mg, 100%). 1H-NMR (CDC13, 400 ΜΗζ) δ 2.20-2.80 (m, 6Η), 3·48 (m, 2H), 3·70-3·80 (m, 9H), 3·89 (s, 3H) , 4·09 (m, 1Η), 4·21 (m, 1Η), 6.79-6·85 (m, 4Η), 6.93 (m, 1H), 7·08 (m, 2H), 7· 30 (m, 1H), 7·50 (m, 1H), 7·96 (m, 3H), 8·13 (dd, J=1.5 Hz, 8·3 Hz, 1H); MS(ESI) m/ z 68 9 (M+). 4-[2-N-[2-(3,3-Difluoro-indole-pyrrolidinyl)ethyl]-N-[4-[ Ν' - (2-bromophenyl)urea at room temperature Methyl methoxyphenyl]ethyl acetamino] ethoxybenzoate (345 mg, 〇·5 mmol) dissolved in THF -Me 〇H u ···, v/v, 8 ml) To the solution was added 〇·25N NaOH (4 ml, 1·〇 mmol) and heated under reflux. Stirring was continued for 6 hours under reflux. The solvent was removed and the residue was purified eluting EtOAc EtOAc EtOAc EtOAc ih-NMR (CD30D '400MHz) 6 2.20-2.90 (m, 6H), 3·60 (m, 2H), 3.70-3.92 (m, 9Η), 4·10 (m, 1Η), 4·22 (m , 1Η), 6.84 (m, 4H), 6.96 (m, 1H), 7·30 (m, 1H), 7·55 (m, 1H), 7·93 (m, 3H), 7.97 (m, ih); MS (ESI) m/z 67 6 (MH1); C31H32BrF2N4 06 · 2 · 5H2 〇 Analysis calculated: c, 5 2. 85 ; H, 5 · 29 ; N, 7. 95. Found: c, 52. 67 ; H, 5. 20 ; N, 8.11. Example 270 4-[21-(^-Methoxy 1'-methylamino)ethyl- 1^-[3-decyloxy 4-[^&quot;-

\\312\2d-code\90-01\89112968.ptd 第 814 頁 1283240 五'發明說明（_ / 〇 基本基）脲基]苯基]乙醮胺基]乙氧苯甲酸納鹽 一 Ο 0 Na‘\\312\2d-code\90-01\89112968.ptd Page 814 1283240 Five' invention description (_ / 〇 basic base) ureido] phenyl] acetamidine] ethoxybenzoic acid sodium salt Ο 0 Na'

;N) jfyV “ 人仍^。 ' Ν〜（Ν -甲氧基-Ν’-甲胺基）乙基-Ν一 [3一甲氧基一 4-[Ν (2甲基苯基）脲基]苯基]乙醯胺基]乙氧苯甲酸曱酯;N) jfyV "People still ^. 'Ν~(Ν-methoxy-Ν'-methylamino)ethyl-Ν-[3-methoxy-4-[Ν(2methylphenyl)urea Ethyl]phenyl]ethylammonium acetate

〇0 COOMe 在室溫下於4-[2-N-甲醯曱基-[3-甲氧基_4_[N，-（2-甲 基苯基）脲基]苯基乙醯胺基]乙氧基]苯甲酸甲酯（35〇毫 克’ 〇· 66毫莫耳）溶於EtOH( 13毫升）之攪拌溶液中加入鹽 甲氧基一N—甲基胺（6 37毫克，6. 6毫莫耳）。使反應在 室溫下攪拌5分鐘，然後冷卻至〇。於此冷卻溶液中加入 NaB，CN(l〇5毫克，165毫莫耳），並在室溫下持續攪拌18 亡時。將混合物倒入至飽和NaHC〇3中，以CHC13(5〇毫升χ3) ^取/以鹽水洗滌，並於MgS04上乾燥。於在真空中移除 後’使殘^物於矽膠（中壓層析系統：YAMAZEN YFLC 54j4 — FC ’甲笨〜丙酮9:1至2 :3之線性梯度）上進行層析， 而付4^[ 2-N-（N〜甲氧基一N，一甲胺基）乙基κ 3一甲氧基 -4_[N&quot; -（2:甲基笨基）脲基]苯基]乙醯胺基]乙氧苯甲酸 甲酉曰（3 44宅克’ 91%)之白色非晶形泡沫。1H —N〇 (CDCl3， 400 MHz) 5 2· 29 (s，3H)、2· 5 2 及2· 58 (s，總計3H)、 2·79 (m，2H)、3·49-3.76 (m，9H)、3·88 (s，3H) 、4·05 及4·20 (m，總計 2H)、6·69- 6.86 (m，5H)、7·10〇0 COOMe at room temperature in 4-[2-N-carbamimido-[3-methoxy-4-[N-(2-methylphenyl)ureido]phenylethylamino] Add a salt of methoxy-N-methylamine (6 37 mg, 6.6) to a stirred solution of methyl ethoxy]benzoate (35 mg of '·66 mmol) in EtOH (13 ml). Millions of ears). The reaction was allowed to stir at room temperature for 5 minutes and then cooled to hydrazine. NaB, CN (10 mg, 165 mmol) was added to the cooled solution, and stirring was continued at room temperature for 18 days. The mixture was poured into saturated NaHC(R)3, washed with CH.sub.3 (5 mL, EtOAc), washed with brine and dried over EtOAc. After removal in a vacuum, the residue was chromatographed on a silicone (medium pressure chromatography system: YAMAZEN YFLC 54j4 - FC 'A linear ~ 9:1 to 2:3 linear gradient), and 4 ^[2-N-(N~Methoxy-N,monomethylamino)ethyl κ 3-methoxy-4_[N&quot;-(2:methylphenyl)ureido]phenyl]acetamidine Amino] ethoxybenzoic acid formazan (3 44 house grams '91%) of white amorphous foam. 1H —N〇(CDCl3, 400 MHz) 5 2· 29 (s,3H), 2· 5 2 and 2· 58 (s, total 3H), 2·79 (m, 2H), 3·49-3.76 ( m, 9H), 3·88 (s, 3H), 4·05 and 4·20 (m, total 2H), 6.69- 6.86 (m, 5H), 7·10

u謂腦_ 帛8l5頁 1283240 五、發明說明（811) (m，1H)、7·20 (m，2H)、7.29 (m，1H)、7·44 (m，1H) 、7·94 及 7·99 (d，J = 8.6 Ηζ，總計 2Η)、8·06 (m， 1H); MS(FAB) m/z 579(MH1) ; C31H38N4 07 ·2·5Η20之分析計算 值：C，59.70; Η，6.95; N，8.98。實測值：C，59.58; Η, 6.65; Ν, 8. 90 ° 在室溫下於4-[2-Ν-（Ν’ -曱氧基-Ν’ -甲胺基）乙基一ν-[ 3-甲氧基-4 - [Νπ -（2-甲基苯基）脲基]苯基]乙醯胺基]乙氧苯 甲酸甲酯（138毫克，0.24毫莫耳）溶於THF-MeOH (1 : 1， v/v，4毫升）之溶液中加入0.25N NaOH(1.9毫升，0.48毫 莫耳），並迴流加熱。在迴流下持續攪拌1 8小時。將溶劑 移除，及使殘留物於HP-20 (H20-M eOH，100:0至〇:1〇〇)上 進行層析，而得320(140毫克，100%)之白色粉末。 1-關1?(^0301))(5 2.2 9(5，311)、2.54及2.56(23，總計 3H)、2·82 (m，2H)、3·48 (m，2H)、3·65-5.8 0 (m， 9H)、4·09 及 4.21 (2m，總計 2H)、6·80 (m，4H)、7·00 (t，J = 7.5 Hz，1H)、7·18 (m，2H)、7·57 (d，J = 7.8 Hz，1H)、—·88 (m，2H)、7·99 (m，1H); MS(FAB) m/z 565 (M+ + 1) ; C3QH35N4〇7Na · 1. 〇H20 之分析計算值：c， 59· 59 ; H，6· 17 ; N，9· 27。實測值·· C，59. 10 ; H， 6. 28 ； N, 8.86° 實施例271 4 - [2- I-(N’_甲氧基-Ν’ -甲胺基）乙基-N-[4- [N，-（2_溴苯 基）脲基]- 3 -甲氧苯基乙醢胺基]乙氧基]苯甲酸u is the brain _ 帛 8l5 page 1283240 five, invention description (811) (m, 1H), 7 · 20 (m, 2H), 7.29 (m, 1H), 7 · 44 (m, 1H), 7.94 and 7·99 (d, J = 8.6 Ηζ, total 2Η), 8·06 (m, 1H); MS(FAB) m/z 579(MH1) ; C31H38N4 07 ·2·5Η20 Analysis calculated value: C, 59.70 ; Η, 6.95; N, 8.98. Found: C, 59.58; Η, 6.65; Ν, 8. 90 ° at room temperature in 4-[2-Ν-(Ν'-曱-oxy-Ν'-methylamino)ethyl-v-[ 3-Methoxy-4-[Νπ-(2-methylphenyl)ureido]phenyl]acetamido]methyl ethoxybenzoate (138 mg, 0.24 mmol) dissolved in THF-MeOH (1:1, v/v, 4 ml) was added 0.25 N NaOH (1.9 mL, 0.48 mmol) and heated under reflux. Stirring was continued for 18 hours under reflux. The solvent was removed, and the residue was applied to EtOAcjjjjjjjjjj 1-off 1?(^0301))(5 2.2 9(5,311), 2.54 and 2.56 (23, total 3H), 2·82 (m, 2H), 3·48 (m, 2H), 3· 65-5.8 0 (m, 9H), 4·09 and 4.21 (2m, total 2H), 6·80 (m, 4H), 7·00 (t, J = 7.5 Hz, 1H), 7·18 (m , 2H), 7·57 (d, J = 7.8 Hz, 1H), -88 (m, 2H), 7·99 (m, 1H); MS (FAB) m/z 565 (M+ + 1); C3QH35N4〇7Na · 1. Analytical calculated value of 〇H20: c, 59· 59 ; H,6· 17 ; N,9· 27. Measured value·· C,59. 10 ; H, 6. 28 ; N, 8.86 ° Example 271 4 - [2- I-(N'-methoxy-oxime'-methylamino)ethyl-N-[4-[N,-(2-bromophenyl)ureido]- 3 -methoxyphenylacetamido]ethoxy]benzoic acid

\\312\2d-code\90-01\89112968.ptd 第816頁 1283240\\312\2d-code\90-01\89112968.ptd Page 816 1283240

e 在室溫下於4-[2-N-甲醯甲基-N_[3_ 漠苯基）服基]苯基]乙酿胺基]乙氧美 二4 (2~ 士 一社甘、 乳暴本甲酸甲酯（209毫 克，0.35宅莫耳）溶於Et0H(7毫升）之授拌溶液中加入n一 氧基-N-甲基胺HC1鹽（341毫克，3.5毫莫）。 溫下攪拌5分鐘’然後冷卻至〇t。於此冷卻溶液中力^至 NaBH(OAc)3 ( 3 70毫克，i.75毫莫耳），並在室溫下持續攪 拌18小時。將混合物倒入至飽和NaHC〇3中，以CHC13(5〇毫 升x3)萃取’並於MgS〇4上乾燥。於移除溶劑後，使殘留物 於TLC(Whatman，PLK-5F，2 板，CHCl3-MeOH，98 : 2)上進e at room temperature in 4-[2-N-formylmethyl-N_[3_ lyophilyl] phenyl] phenyl] ethanoyl] ethoxy urethane 4 (2~ 士一社甘,乳Add methyl n-oxy-N-methylamine HC1 salt (341 mg, 3.5 mmol) to a solution of methyl benzoate (209 mg, 0.35 house mole) dissolved in Et0H (7 mL). Stir for 5 minutes' then cool to 〇t. Cool the solution to NaBH(OAc)3 (3 70 mg, i.75 mmol) and continue stirring at room temperature for 18 hours. To a saturated NaHC(R)3, extracted with CHC13 (5 mL) (3) and dried over <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </ RTI> </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> </ RTI> After removal of solvent, the residue was applied to TLC (Whatman, PLK-5F, 2 plates, CHCl3-MeOH, 98 : 2) Progressive

行層析，而得4-[ 2-N-（N，-曱氧基一N，-甲胺基）乙基-ΜΗ-[Ν’ -(2- 漠苯基） 脲基]—3— 甲氧苯 基乙醯 胺基] 乙 氧基] 苯甲酸甲酯（89毫克，40%)之白色非晶形泡沫。ih-NMR (CDC13，4 00 MHz) (5 2· 5 2 及2. 60 (2s，3Η)、2· 8 0 (m， 2H)、3·48 及 3·50 (2s，總計 3H)、3·65 (m，2H)、3·72 (s， 3Η) 、3·77 (m， 4Η) 、3·90 (s， 3Η) 、4·08 (m， 1Η) 、4·22 (m，1H)、6·82 (m，5H)、7·12 (s，2H)、7·30 (m， 1H) 、7·52 (d， J=8.1 Hz， 1H) 、7·94 (m， 3H)、Chromatography to give 4-[2-N-(N,-methoxy-N,-methylamino)ethyl-indole-[Ν'-(2- phenylphenyl)ureido]-3 Methoxyphenylacetamido] ethoxy] methyl benzoate (89 mg, 40%) as a white amorphous foam. ih-NMR (CDC13, 4 00 MHz) (5 2· 5 2 and 2.60 (2s, 3Η), 2·800 (m, 2H), 3·48 and 3·50 (2s, total 3H), 3·65 (m, 2H), 3·72 (s, 3Η), 3·77 (m, 4Η), 3·90 (s, 3Η), 4·08 (m, 1Η), 4·22 (m , 1H), 6·82 (m, 5H), 7·12 (s, 2H), 7·30 (m, 1H), 7·52 (d, J=8.1 Hz, 1H), 7·94 (m , 3H),

12832401283240

8·15 (d，J = 8.3 Hz，1H); MS(ESI) m/z 643 (M+)。 在室溫下於4-[2-N-(N，-甲氧基-N，-甲胺基）乙基一N—[4 - [Ν’- (2 -溴苯基）脲基]—3-甲氧苯基乙醯胺基]乙氧基]笨 甲酸甲酯（89毫克，0.14毫莫耳）溶於THF - MeOH (5: 1， v/v，6毫升）之溶液中加入〇· 5N NaOH(l· 4毫升，〇· 7毫莫 耳）’並在密封玻璃瓶中迴流加熱。在迴流下持續授拌3小 時。將反應倒入至水中，並以1 N HC 1酸化至pH 5，以 CHCl3-Me0H(2:l，v/v，30 毫升 x3)萃取，於 MgS04 上乾燥。 將溶劑於真空中移除而得32 1 (53毫克，60%)之白色粉末。 UMR (CD30D ’40 0MHz)(5 2.62 及 2·64 (2s，總計 3H)、 2.80 (m，2H)、3·50 (d，J=7.3 Hz，3H)、3·63-3.88 (m，6H)、4·12 (m，1H)、4·25 (m，1H)、6·82-7.00 (m， 5X)、7·30 (m，1H)、7·58 (m, 1H)、7·95 (m，4H); MS(FAB) m/z 62 9 (M+) ，C29H33BrN4 07 · 〇· 25H20 之分析計算 值.C, 54.94，H， 5·33，N，8·84。實測值：c 55 39; Η, 5· 53 ; Ν, 8· 23。 &gt; 實施例272 4- [2 -Ν -（Ν’，Ν’ -二烯丙基）乙基-Ν - [3-甲氧基一4-[Νπ -（2-甲基苯基）脲基]苯基]乙醯胺基]乙氧基笨甲酸納鹽8·15 (d, J = 8.3 Hz, 1H); MS (ESI) m/z 643 (M+). 4-[2-N-(N,-methoxy-N,-methylamino)ethyl-N-[4-[[Ν(-(2-bromophenyl)ureido]]] Methyl 3-methoxyphenylacetamido]ethoxy] benzoate (89 mg, 0.14 mmol) was dissolved in THF - MeOH (5:1, v/v, 6 mL) · 5N NaOH (1.4 ml, 〇·7 mmol)' and heated under reflux in a sealed glass vial. The mixing was continued for 3 hours under reflux. The reaction was poured into water and acidified to pH 5 with 1N EtOAc then EtOAc (EtOAc) The solvent was removed in vacuo to give 32 1 (53 mg, 60%) of white powder. UMR (CD30D '40 0MHz) (5 2.62 and 2·64 (2s, total 3H), 2.80 (m, 2H), 3·50 (d, J=7.3 Hz, 3H), 3.63-3.88 (m, 6H), 4·12 (m, 1H), 4·25 (m, 1H), 6.82-7.00 (m, 5X), 7·30 (m, 1H), 7·58 (m, 1H), 7·95 (m, 4H); MS (FAB) m/z 62 9 (M+), C29H33BrN4 07 · 〇 · 25H20 Analytical calculated value. C, 54.94, H, 5·33, N, 8.84. Value: c 55 39; Η, 5· 53 ; Ν, 8· 23. &gt; Example 272 4- [2 -Ν -(Ν',Ν'-diallyl)ethyl-Ν - [3- Methoxy-4-[Νπ-(2-methylphenyl)ureido]phenyl]ethinylamino]ethoxy oxocarboxylate

_ 322 4 - [2 -Ν -（Ν’，Ν’ -二烯丙基）G 基-Ν - [3-甲氧基一4 - [Ν&quot; -（2 - 甲基笨基）脲基]苯基]乙醯胺基]乙氧基笨甲酸甲酯_ 322 4 - [2 -Ν -(Ν',Ν'-diallyl)G-yl-indole - [3-methoxy- 4 - [Ν&quot; -(2 -methylphenyl)ureido] Phenyl]ethylammonium]ethoxylated methyl ester

1283240 五、發明說明（814)1283240 V. Description of invention (814)

COOMe 在室溫下於4-[2-N-甲醯甲基一 N-[3 -甲氧基-4 - [N，-（2-甲基苯基）脲基]苯基]乙醯胺基]乙氧基苯甲酸甲酯（4〇〇 毫克’ 0·75毫莫耳）溶於Et0H(15毫升）之攪拌溶液中加入 二烯丙胺（926微升，7·5毫莫耳）及醋酸（429微升，7.5毫 莫耳）。使反應在室溫下攪拌5分鐘，然後冷卻至〇 ι。於 此冷卻溶液中加入NaBHJNCllS毫克，1·9毫莫耳），並在 至溫下持續攪拌1小時。將混合物倒入至飽和心以〇中， = EtOAc(50毫升χ3)萃取，以鹽水洗滌，並於心如/上乾 燥於在真空中移除溶劑後’使殘留物於石夕膠（中壓層析 系統：YAMAZEN YFLC-54 04-FC，甲苯-丙㈣9-丨至卜丨之線 性梯度）上進行層析，而得4-[2-N-(N，，N，-二烯丙基）乙基 -N-[3-甲氧基-4-[N”-（2-甲基苯基）脲基]苯基]乙醯胺 基]乙氧基苯曱酸甲酯（3 85毫克，84%)之白色非晶形泡 沫。1H-NMR (CDC13，4 00 ΜΗζ) δ 2. 30 (s，3{1)日:/ (m，2H)、3·09 (m，4H)、3·49 (m，2H)、，3 60 (s· 2H) 2H)、5·01-5·20 (m，4H)、4·79 (m，2H) 、3.70 (m，5H)、3·89 (s，3H)、4』2及4.19 (2m，’總計 6· 30 及6· 32 (2s，總計 1Η)、6·70-6·84 (m，5Η)、7·〇8 (m 1Η)、 7.14 (m，1H)、7·25 (m，1H)、7·60 (m，1H)、7 93 及7 98 (2d，J = 8.8 Hz，2H)、8·03 及 8·〇6 (2d，j = 8 3 Hz 1H) ; MS(FAB) m/z 615(MH1)。 * ’COOMe at room temperature in 4-[2-N-formylmethyl-N-[3-methoxy-4-[N-(2-methylphenyl)ureido]phenyl]acetamide Add allylamine (926 μl, 7.5 mmol) to a stirred solution of methyl ethoxybenzoate (4 〇〇 mg '0.75 mmol) in EtOAc (15 mL) Acetic acid (429 μl, 7.5 mmol). The reaction was allowed to stir at room temperature for 5 minutes and then cooled to 〇. To this cooled solution was added NaBHJNCllS mg, 1.9 mmol, and stirring was continued for 1 hour at ambient temperature. The mixture was poured into a saturated solution and extracted with EtOAc (50 mL EtOAc), washed with brine, and then dried and dried in vacuo to remove solvent in vacuo. Chromatography system: YAMAZEN YFLC-54 04-FC, toluene-propane (tetra) 9-丨 to a linear gradient of dip), to give 4-[2-N-(N,,N,-diallyl) Ethyl-N-[3-methoxy-4-[N"-(2-methylphenyl)ureido]phenyl]acetamido]ethoxy benzoate (3 85 mg) , 84%) white amorphous foam. 1H-NMR (CDC13, 400 ΜΗζ) δ 2. 30 (s, 3{1) day: / (m, 2H), 3·09 (m, 4H), 3 ·49 (m, 2H), 3 60 (s· 2H) 2H), 5·01-5·20 (m, 4H), 4·79 (m, 2H), 3.70 (m, 5H), 3· 89 (s, 3H), 4′′ 2 and 4.19 (2m, 'total 6·30 and 6.32 (2s, total 1Η), 6.70-6·84 (m, 5Η), 7·〇8 (m 1Η), 7.14 (m, 1H), 7·25 (m, 1H), 7·60 (m, 1H), 7 93 and 7 98 (2d, J = 8.8 Hz, 2H), 8·03 and 8· 〇6 (2d, j = 8 3 Hz 1H); MS(FAB) m/z 615(MH1). * '

\\312\2d-code\90-01\89112968.ptd 第819頁 1283240 五、發明說明（815) ~ 4 - [2-N -（N’，N’ -二烯丙基）乙基一 N—[3一甲氧基一4 — [N，，—（2一 甲基苯基）脲基]苯基]乙醯胺基]乙氧基苯曱酸甲酯HC1鹽\\312\2d-code\90-01\89112968.ptd Page 819 1283240 V. INSTRUCTIONS (815) ~ 4 - [2-N -(N',N'-Diallyl)ethyl-N —[3-methoxy-4-[N,,-(2-methylphenyl)ureido]phenyl]ethinylamino]ethoxybenzoic acid methyl ester HC1 salt

在室溫下於4 - [2 - N-(N’，N，-二烯丙基）乙基K3 -甲氧 基-4-[Νπ -（2-甲基苯基）脲基]苯基]乙醯胺基]乙氧基笨甲 酸甲醋（ 385毫克，〇· 63毫莫耳）溶於Me〇H(3毫升）之攪拌溶 液中加入IN HC 1 ( 7 56微升，〇· 76毫莫耳）。使反應在室溫 攪拌5分鐘，然後蒸發而得4-[21-(^，^-二烯丙基）乙基 -N-[3-曱氧基-4 - [N&quot;- (2 -曱基苯基）脲基]苯基]乙醯胺 基]乙氧基苯曱酸甲酯HC1鹽（ 385毫克，99%)之非晶形泡 沫。C35 H43 C1 N4 06 · 0 · 5 H2 0 之分析計算值：c, 6 3. 6 7 ; Η， 6· 72 ; Ν，8. 49。實測值：C，63. 67 ; Η，6. 69 ; Ν， 8.43。 ’ 在室溫下於4- [2 -Ν-(Ν’，Ν’ -二烯丙基）乙基一ν- [3 -甲氧 基-4 - [『-（2-甲基苯基）脲基]苯基]乙醯胺基]乙氧基苯甲 酸醋（175 毫克，0·29 毫莫耳）溶於 THF-MeOH(l:l，ν/ν， 20 毫升）之溶液中加入0.25Ν Na0H(2.5毫升，〇·63毫莫耳）， 並迴流加熱。在迴流下持續攪拌1小時。將溶劑移除，及 使殘留物於HP-20(H20-MeOH，1〇〇:〇至〇:1〇〇)上進行層 析’而得322(160毫克，94%)之白色粉末。iH-NMR (CD30D) 5 2 · 2 9 (s， 3 Η)、2 · 6 0 ( t，J = 6 · 9 H z， 1 Η )、2 · 6 7 ( t， J = 7.0 Ηζ，1Η)、3·10 (d，J = 6.6 Ηζ，2Η)、3·14 (d，4-[2-N-(N',N,-diallyl)ethyl K3-methoxy-4-[Νπ-(2-methylphenyl)ureido]phenyl at room temperature醯 醯 基 76 76 76 76 76 76 76 76 76 76 76 76 76 76 76 76 76 76 76 76 76 76 76 76 76 76 76 76 76 76 76 76 76 76 Millions of ears). The reaction was allowed to stir at room temperature for 5 minutes and then evaporated to give 4-[21-(^,^-diallyl)ethyl-N-[3-methoxy-4-([N&quot;- Alkylphenyl)ureido]phenyl]ethinylamino]ethoxybenzoic acid methyl ester HC1 salt (385 mg, 99%) of an amorphous foam. C35 H43 C1 N4 06 · 0 · 5 H2 0 Analysis calculated: c, 6 3. 6 7 ; Η, 6· 72 ; Ν, 8. 49. Found: C, 63. 67; Η, 6. 69 ; Ν, 8.43. ' at 4-(2-(-)-diallyl)ethyl-v-[3-methoxy-4-[[-(2-methylphenyl)] at room temperature Ureido]phenyl]acetamido]ethoxybenzoic acid vinegar (175 mg, 0·29 mmol) was dissolved in THF-MeOH (1:1, ν/ν, 20 mL). Ν Na0H (2.5 ml, 〇·63 mmol), and heated under reflux. Stirring was continued for 1 hour under reflux. The solvent was removed, and the residue was crystallised from EtOAc (H20-MeOH, EtOAc: EtOAc: EtOAc) iH-NMR (CD30D) 5 2 · 2 9 (s, 3 Η), 2 · 6 0 ( t, J = 6 · 9 H z, 1 Η ), 2 · 6 7 ( t, J = 7.0 Ηζ, 1Η ), 3·10 (d, J = 6.6 Ηζ, 2 Η), 3·14 (d,

\\312\2d-code\90-01\89112968.ptd 第820頁 1283240 五、發明說明（816) ^ J = 6.6 Hz，2H)、3·59 (m，2H)、3·6 9-3.80 (m，4H) 、3·80 (s， 3H) 、4.06 (t， J=5.2 Hz, 4.21 (t， J=5l\\312\2d-code\90-01\89112968.ptd Page 820 1283240 V. INSTRUCTIONS (816) ^ J = 6.6 Hz, 2H), 3·59 (m, 2H), 3·6 9-3.80 (m, 4H), 3·80 (s, 3H), 4.06 (t, J=5.2 Hz, 4.21 (t, J=5l

Hz， 1H) 、5·15 (m， 4H) 、5.80 (m， 2H) 、6.79 (m， 2H) 、6.84 (d，J = 8.8 Hz，2H)、7.00 (t，J = 7.5 Hz，iH)、 7·14 (m，2H)、7.48 (m，1H)、7·91 (dd，J = 6.1 Hz、8 8 Hz，2H)、8· 00 (m，1H) ; MS(FAB) m/z 601(M+) ; · C34H39N406 Na · 〇· 5H20 之分析計算值：C，64· 65 ; H，6. 38 ; N，8.87。實測值：c，6 4.5 3; H，6.58; N，8.78。 實施例273 4 - [2-N-(N，N -二稀丙基）乙基-N - [4_[N’-(2-氣笨基）服 基]-3-甲氧笨基乙醯胺基]乙氧基]苯曱酸鈉鹽Hz, 1H), 5·15 (m, 4H), 5.80 (m, 2H), 6.79 (m, 2H), 6.84 (d, J = 8.8 Hz, 2H), 7.00 (t, J = 7.5 Hz, iH ), 7·14 (m, 2H), 7.48 (m, 1H), 7·91 (dd, J = 6.1 Hz, 8 8 Hz, 2H), 8·00 (m, 1H); MS(FAB) m /z 601(M+) ; · C34H39N406 Na · 〇 · 5H20 Analysis calculated: C, 64 · 65 ; H, 6. 38 ; N, 8.87. Found: c, 6 4.5 3; H, 6.58; N, 8.78. Example 273 4 - [2-N-(N,N-Dipropyl)ethyl-N-[4_[N'-(2- oxa)-yl]-3-methoxybenzylidene Amino]ethoxy]benzoic acid sodium salt

Cl ^ H ΟΜθ 3^3 烯丙基）乙基-N-[4-[N，-（2-氣笨基）服 COONa 基]-3 -甲氧笨基乙醯胺基]乙氧基]苯甲酸甲酯Cl ^ H ΟΜ θ 3^3 allyl) ethyl-N-[4-[N,-(2-indolyl)COONa-based]-3-methoxyphenylacetamido]ethoxy] Methyl benzoate

在室溫下於4-[2-N-甲醯甲基-N-[4-[Ν’ - (2-氯笨基）服 基]-3-甲氧苯基乙醯胺基]乙氧基]苯甲酸甲酯（1〇〇毫克， 0· 18毫莫耳）溶於EtOH(3· 6毫升）之攪拌溶液中加入二歸丙 胺（ 223微升，1. 81毫莫耳）。使反應在室溫下攪拌5分鐘， 然後冷卻至0 °C。於此冷卻溶液中加入AcOH(l〇4微升， 1· 81毫莫耳）及NaBH3CN(28毫克，0·45毫莫耳），並在室溫4-[2-N-carbomethyl-N-[4-[Ν'-(2-chlorophenyl)-yl]-3-methoxyphenylethylamino] ethoxylate at room temperature Methyl benzoate (1 mg, 0·18 mmol) was dissolved in EtOH (3.6 mL) in EtOAc ( 223 liters, 1. 81 mM). The reaction was allowed to stir at room temperature for 5 minutes and then cooled to 0 °C. AcOH (1 〇 4 μl, 1.81 mmol) and NaBH 3CN (28 mg, 0. 45 mmol) were added to the cooled solution at room temperature.

\\312\2d-code\90-01\89112968.ptd 第821頁 1283240 五、發明說明（817) 下持續攪拌1 8小時。將混合物倒入至飽和NaHC03中，以 CHC13(30毫升χ3)萃取，以鹽水洗滌，並於MgS04上乾燥。 於在真空中移除溶劑後，使殘留物於矽膠（中壓層析系 統：YAMAZEN YFLC-5404-FC ，CHCl3-MeOH 10:1 至20:1 之 線性梯度）上進行層析，而得4-[2-N-(N，，N，-二烯丙基）乙 基-N-[4-[N，-（2 -氯苯基）脲基]-3-甲氧苯基乙醯胺基]乙 氧基]苯甲酸曱酯（96毫克，83%)之白色非晶形泡沫。 -NMR (CDC13，40 0 MHz) (5 2· 60 (m，2H)、3· 0 9 (d， J = 6.4 Hz, 1H)、3·11 (d，J = 6.4 Hz，3H)、3·52 (m， 2H)、3·61 (s，2H)、3·70-3·80 (m，5H)、3·86 (s，3H) 、4·05 及 4·20 (2m，總計 2H)、5·06-5·21 (m，4H)、5·80 (m, 2Η)、6·7 卜 6·85 (m，4Η)、6·98 (m，1Η)、7·22 (m， 1H)、7·32 (m，3H)、7·93 (d，J = 7.8 Hz，2H)、7·98 (m，1H)、8·18 (dd, J=1.5 Hz、8·2 Hz，1H); MS(ESI) m/z 635(M+) 〇 在室溫下於4-[2-N-（N’，N’-二烯丙基）乙基-N-[4-[N， -（2 -氯苯基）脲基]-3-甲氧苯基乙醯胺基]乙氧基]笨曱酸 曱酯（96毫克，0.15毫莫耳）溶於THF-MeOH(l:l， v/v， 8毫 升）之溶液中加入0.25N NaOH(3.91毫升，0·98毫莫耳）， 並加熱至50 °C。在迴流下持續攪拌6小時。將溶劑移除， 及使殘留物於HP-20(¾O-MeOH，0 : 100至100: 0)上進行層 析，而得323 ( 88毫克，94%)之白色粉末。111-隨1^((：1)3〇1)， 400MHz) (5 2· 61 (m，2H)、3· 10 (s, 2H)、3· 1 2 (s，2H) 、3·59 (m，2H)、3·70 (s，2H)、3·78 (m，2H)、3·82\\312\2d-code\90-01\89112968.ptd Page 821 1283240 V. Inventive Note (817) Continue to stir for 18 hours. The mixture was poured into saturated NaHC03, extracted with CH.sub.3 (30 mL EtOAc), washed with brine and dried After removing the solvent in vacuo, the residue was chromatographed on a silica gel (medium pressure chromatography system: YAMAZEN YFLC-5404-FC, CHCl3-MeOH 10:1 to 20:1 linear gradient) to give 4 -[2-N-(N,,N,-diallyl)ethyl-N-[4-[N,-(2-chlorophenyl)ureido]-3-methoxyphenylacetamide A white amorphous foam of ethoxy]benzoic acid benzoate (96 mg, 83%). -NMR (CDC13, 40 0 MHz) (5 2· 60 (m, 2H), 3·0 9 (d, J = 6.4 Hz, 1H), 3·11 (d, J = 6.4 Hz, 3H), 3 · 52 (m, 2H), 3·61 (s, 2H), 3·70-3·80 (m, 5H), 3·86 (s, 3H), 4·05 and 4·20 (2m, total 2H), 5·06-5·21 (m, 4H), 5·80 (m, 2Η), 6·7 Bu 6·85 (m, 4Η), 6·98 (m, 1Η), 7.22 (m, 1H), 7·32 (m, 3H), 7·93 (d, J = 7.8 Hz, 2H), 7·98 (m, 1H), 8·18 (dd, J=1.5 Hz, 8 · 2 Hz, 1H); MS (ESI) m/z 635 (M+) 〇 at room temperature in 4-[2-N-(N',N'-diallyl)ethyl-N-[4 -[N,-(2-chlorophenyl)ureido]-3-methoxyphenylacetamido]ethoxy] decyl decanoate (96 mg, 0.15 mmol) dissolved in THF-MeOH (l:l, v/v, 8 ml) was added 0.25 N NaOH (3.91 mL, 0·98 mmol) and heated to 50 ° C. Stirring was continued for 6 hours under reflux. And the residue was chromatographed on HP-20 (3⁄4 O-MeOH, 0: 100 to 100: 0) to give 323 (88 mg, 94%) of white powder. ) 3〇1), 400MHz) (5 2· 61 (m, 2H), 3· 10 (s, 2H), 3· 1 2 ( s, 2H), 3·59 (m, 2H), 3·70 (s, 2H), 3·78 (m, 2H), 3.82

\\312\2d-code\90-01\89112968.ptd 第 822 頁 1283240 五、發明說明（818) (s，3 Η )、4 · 1 0 ( m，1 Η )、4 · 2 1 ( m，1 Η )、5 · 1 8 ( m，4 Η ) 、5·81 (m，2H)、6·82 (m，4H)、7·01 (t，J = 7.8 Hz， 1H)、7·25 (m，1H)、7·39 (d，J = 7.8 Hz，1H)、7·90 (m, 2H) - 8. 02 (m, 2H) ； MS(ESI) m/z 621(M+)； C33H36ClN4 06 Na · 1· 25H20 之分析計算值：C，59. 55 ； H, 5· 83 ; N，8· 42 ° 實測值：C，59· 90 ; H，5.74; N， 7.96。 實施例2 7 4 4-[2-N - [3-甲氧基-4-[Ν’ -（2-曱基苯基）脲基]笨基]—N 一甲 基乙醯胺基]乙基-1 -六氫吡畊乙酸 \ Η Η 324 4-（2 -羥乙基）-1-六氫咄畊乙酸乙酯 L^N^.C〇2Et 在0°C下於卜（2 -羥乙基）六氫吡ϋ井（5.21克，40.0毫莫 耳）及1(2(：03 ( 8. 76克，63· 4毫莫耳）在CH3CN( 100毫升）中之 攪拌懸浮液中加入溴乙酸乙酯（5 · 6 0毫升’ 5 0 · 5毫莫耳）。 使反應混合物迴流加熱5小時，以Et0Ac稀釋’並以水及鹽 水洗滌。將萃取液於Na2S04上乾燥，濃縮至乾而得4-(2-羥 乙基）_卜六氫吡畊乙酸乙酯（9· 65克’ 100%)的黃色油。 M-NMR (CDC13)(5 1.23 (t，3H，J = 7.3 Ηζ)、2·51 -2.61\\312\2d-code\90-01\89112968.ptd Page 822 1283240 V. Description of invention (818) (s,3 Η ), 4 · 1 0 ( m,1 Η ), 4 · 2 1 ( m , 1 Η ), 5 · 1 8 ( m, 4 Η ), 5·81 (m, 2H), 6·82 (m, 4H), 7·01 (t, J = 7.8 Hz, 1H), 7· 25 (m, 1H), 7·39 (d, J = 7.8 Hz, 1H), 7·90 (m, 2H) - 8. 02 (m, 2H) ; MS (ESI) m/z 621 (M+) C33H36ClN4 06 Na · 1 · 25H20 calcd.: C, 59. 55; H, 5· 83; N, 8· 42 ° Found: C, 59·90; H, 5.74; N, 7.96. Example 2 7 4 4-[2-N - [3-methoxy-4-[Ν'-(2-mercaptophenyl)ureido]]]-N-methylethylammonium] Base-1 - hexahydropyrrolic acid \ Η 324 324 4-(2-hydroxyethyl)-1-hexahydroindole acetate L^N^.C〇2Et at 0 °C in Bu (2 - Hydroxyethyl) hexahydropyridinium well (5.21 g, 40.0 mmol) and 1 (2::03 (8 76 g, 63. 4 mmol) in a stirred suspension in CH3CN (100 mL) Ethyl bromoacetate (5·60 mL of 550 mM) was added. The reaction mixture was heated under reflux for 5 hrs, diluted with EtOAc and washed with water and brine. The extract was dried over Na.sub.2SO. Dry 4-(2-hydroxyethyl)- hexahydropyrrole ethyl acetate (9·65 g '100%) in yellow oil. M-NMR (CDC13) (5 1.23 (t, 3H, J = 7.3 Ηζ), 2·51 - 2.61

\\312\2d-code\90-01\89112968.ptd 第823頁 1283240 (m，11H)、3·22 (s，2Η)、3·61 (t，2H，J = 5.4 Hz)、 4· 19 (q，2H，J = 7. 3 Hz) 〇 甲基2，4 -二琐基笨石黃醢胺\\312\2d-code\90-01\89112968.ptd Page 823 1283240 (m, 11H), 3·22 (s, 2Η), 3.61 (t, 2H, J = 5.4 Hz), 4· 19 (q, 2H, J = 7. 3 Hz) 〇methyl 2,4 - bicidyl stupid

在0C下於2,4-二硝基苯磺醯氯（1〇克，3.75毫莫耳）及 咄啶（0· 34毫升’ 4· 20毫莫耳）溶於THF(19毫升）之溶液中 逐滴加入甲基胺（2· 〇M THF溶液，2· 3毫升，4. 60毫莫 耳）。使反應混合物攪拌1小時，經由加入丨N HC丨溶液停止 反應，並以EtOAc萃取。將萃取液以飽和NaHC03溶液及鹽 水洗滌，於Na2S04上乾燥，並濃縮至乾。使殘留物自 EtOAc - Et20再結晶，而得甲基2,4-二硝基苯磺醯胺（ 546毫 克，56°/。）的無色固體。iH-NMR (DMS0) (5 2· 60 (d，3H， J = 4.9 Hz)、8·22 (d，1H，J = 8.8 Hz)、8.31 (q，1H， J=4.9 Hz) 、 8.66 (dd， 1H， J=8·8 、 2·0 Hz) 、 8·90 (d， 1H，J = 2· 0 Hz)。 4-[2-[N_(2，4-二硝基笨石黃醯基）_N-甲胺基]乙基]- 1-六氫 咄畊乙酸乙酯a solution of 2,4-dinitrobenzenesulfonyl chloride (1 g, 3.75 mmol) and acridine (0.43 ml '4·20 mmol) in THF (19 mL) at 0C Methylamine (2· 〇M THF solution, 2.3 ml, 4.60 mmol) was added dropwise. The reaction mixture was stirred for 1 h, then quenched with EtOAc EtOAc EtOAc. The extract was washed with a saturated NaHCO.sub.3 solution and brine, dried over Na? The residue was recrystallized from EtOAc to EtOAc (EtOAc:EtOAc) iH-NMR (DMS0) (5 2· 60 (d, 3H, J = 4.9 Hz), 8.22 (d, 1H, J = 8.8 Hz), 8.31 (q, 1H, J = 4.9 Hz), 8.66 ( Dd, 1H, J=8·8, 2·0 Hz), 8·90 (d, 1H, J = 2· 0 Hz). 4-[2-[N_(2,4-Dinitro stupid yellow fluorenyl) )_N-Methylamino]ethyl]- 1-hexahydroindole

Oi^CO.Et o2n 在0°C下於4-(2 -羥乙基）-1-六氫吡啡乙酸乙酯（452毫 克，2.09毫莫耳）、甲基2, 4-二硝基苯磺醯胺（546毫克，Oi^CO.Et o2n at 0 ° C in ethyl 4-(2-hydroxyethyl)-1-hexahydropyramidate (452 mg, 2.09 mmol), methyl 2, 4-dinitro Phenylsulfonamide (546 mg,

\\312\2d-code\90-01\89112968.ptd 第824頁 1283240 五、發明說明（820) 2.09¾莫耳）及pph3 (658毫克，2.51毫莫耳）溶於thf之溶 液中加入DIAD(0.50^升’251宅莫耳）。於在室溫下授拌 17小時後，將反應混合物濃縮至乾。利用Et〇Ac—Me〇H(1〇 1)將殘留物進行層析，而得4-[2-[N-(2,4-二硝基苯磺醯 基）-N-甲胺基]乙基]-1-六氫咄畊乙酸乙酯（864毫克， 90%)的淡紅色油。NMR (CDC13)6 1·27 (t， 3H J = 6 Hz) 、2·35-2.63 (m， 10H) 、2·98 (s， 3H) 、3·20 (s， 2H)、3·41 (t，2H, J = 6.8 Hz)、4·17 (q，2H，J = 6.8 Hz)、8·33 (d，1H，J = 8.3 Hz)、8·46 (d，1H，J = 2.0 Hz)、8· 50 (dd，1H，J = 8· 3、2· 0 Hz)。 4 -（2-甲胺乙基）-1-六氫吼畊乙酸乙酯 HN、 、〇 l\xC〇2Et 使4-[2-[N-（2, 4-二硝基苯磺醯基）—N一甲胺基]乙基卜卜 六氫吼°井乙酸乙酯（8 6 4毫克，1 · 8 8毫莫耳）、硫醇乙酸（ 0.17毫升，2.44毫莫耳）及Et3N(0.53毫升，3.76毫莫耳） 溶於CH2C12(25毫升）之溶液在室溫下攪拌3小時。將反應混 合物濃縮，以飽和NaHC03溶液稀釋，將其以Et2〇洗滌，並 濃縮而得4 - ( 2 -甲胺乙基）-1 -六氫ϋ比畊乙酸乙酯（3 8 8毫 克，90%)的淡紅色油。NMR (CDC13)(5 1.27 (t， 3Η， J = 6.8 Hz)、2·50 (s，3H)、2·53-2·60 (m，8H)、2·75 (t，2Η，J = 5.9 Hz)、3·20 (s，2Η)、4·18 (d，2Η，J = 6. 8 Hz)〇 4-[2-N-[3-甲氧基-4-[Ν’-（2-甲基笨基）脲基]笨基]_N-甲\\312\2d-code\90-01\89112968.ptd Page 824 1283240 V. Invention description (820) 2.093⁄4 mol) and pph3 (658 mg, 2.51 mmol) dissolved in thf solution added DIAD (0.50 ^ liter '251 house Moer). After 17 hours at room temperature, the reaction mixture was concentrated to dryness. The residue was chromatographed using Et 〇Ac-Me 〇H (1 〇 1) to give 4-[2-[N-(2,4-dinitrophenylsulfonyl)-N-methylamino] Ethyl]-1-hexahydroindoleic acid (864 mg, 90%) in pale red oil. NMR (CDC13)6 1·27 (t, 3H J = 6 Hz), 2·35-2.63 (m, 10H), 2·98 (s, 3H), 3·20 (s, 2H), 3.41 (t, 2H, J = 6.8 Hz), 4·17 (q, 2H, J = 6.8 Hz), 8.33 (d, 1H, J = 8.3 Hz), 8.46 (d, 1H, J = 2.0 Hz), 8·50 (dd, 1H, J = 8·3, 2·0 Hz). 4-(2-[2-(N-(2,4-dinitrophenylsulfonyl)-[2-[N-(2,4-dinitrophenylsulfonyl)] 4-(2-methylaminoethyl)-1-hexahydroindole acetate HN, 〇l\xC〇2Et )-N-methylamino]ethyl bup hexahydroindole ° ethyl acetate (8.64 mg, 1 · 8 8 mmol), thiol acetic acid (0.17 ml, 2.44 mmol) and Et3N ( 0.53 ml, 3.76 mmoles. A solution of CH2C12 (25 mL) was stirred at room temperature for 3 hours. The reaction mixture was concentrated, diluted with a saturated NaHC03 solution, washed with Et.sub.2, and concentrated to give 4-(2-methylaminoethyl)-1 - hexahydroindole to ethyl acetate (3 8 8 mg, 90 %) light red oil. NMR (CDC13) (5 1.27 (t, 3Η, J = 6.8 Hz), 2·50 (s, 3H), 2·53-2·60 (m, 8H), 2·75 (t, 2Η, J = 5.9 Hz), 3·20 (s, 2Η), 4·18 (d, 2Η, J = 6. 8 Hz) 〇 4-[2-N-[3-methoxy-4-[Ν'-( 2-methylphenyl)ureido] stupid]_N-A

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第825頁 1283240 五、發明說明（821) 基乙酿胺基]乙基-1 -六氮吼σ井乙酸乙醋Page 825 1283240 V. INSTRUCTIONS (821) Ethylamino]ethyl-1 -hexanitropurine σ well acetic acid ethyl vinegar

v^C〇2Et 使4-(2-甲胺乙基）-卜六氫吼啡乙酸乙酯（388毫克， 1.69毫莫耳）、Et3N(0.32毫升，2.25毫莫耳）及DMAP(46毫 克’0·38毫莫耳）溶於DMF(15毫升）之溶液在室溫下攪拌15 分鐘，然後將（ 532毫克，1· 69毫莫耳）、H0Bt( 103毫克， 〇· 76毫莫耳）及EDC · HCK486毫克，2· 53毫莫耳）加至反應 混合物，將其在室溫下攪拌1 5小時。將反應混合物以 EtOAc稀釋，將其以鹽水洗滌，於Na2S04上乾燥，並濃縮至 乾。利用CHCl3-MeOH(10:l，v/v)將殘留物進行層析，而 得4-[2-N-[3-甲氧基-4-[Ν’-（2-甲基苯基）脲基]苯基]-Ν-曱基乙醯胺基]乙基-1-六氫吡畊乙酸乙酯（889毫克， DMF 之混合物）的淡紅色油。iH-NMR (CDC13) 5 1· 25-1. 29 (m，3H)、2·29 (s，3H)、2·42-2·63 (m，10H)、3·20、 3.18 (各s，總計3Η)、3·55、3·40 (各t，總計2Η，J = 6.8 Hz)、3·65、3·69 (各s，總計 2H)、3·72 (s，3H)、4·15 -4.21 (m，2Η)、6·50 (m，1Η)、6·77-6·81 (m，8Η)、 7 · 11 - 7 · 2 4 (m, 3 Η)、7 · 5 3 (d，1 Η, J = 8 · 3 Η ζ)、8 · 0 2 (s，1Η)、8· 06 (d，1Η，J = 7. 8 Ηζ)。 於4-[2-Ν-[3-甲氧基-4-[Ν’ -（2-曱基苯基）脲基]苯基 ]_N-甲基乙醯胺基]乙基-1-六氫吼°丼乙酸乙酯（889毫克， 1. 69毫莫耳）溶於THF-EtOH(5 : 1，v/v，18毫升）之攪拌溶v^C〇2Et Ethyl 4-(2-methylaminoethyl)-hexahydropyruphate (388 mg, 1.69 mmol), Et3N (0.32 mL, 2.25 mmol) and DMAP (46 mg) A solution of '0·38 mmoles in DMF (15 ml) was stirred at room temperature for 15 minutes, then (532 mg, 1.69 mmol), H0Bt (103 mg, 〇·76 mmol) And EDC · HCK 486 mg, 2. 53 mmoles) was added to the reaction mixture, which was stirred at room temperature for 15 hours. The reaction mixture was diluted with EtOAc EtOAc m. The residue was chromatographed using CHCl3-MeOH (10:1, v/v) to afford 4-[2-N-[3-methoxy-4-[[s]-(2-methylphenyl) A reddish oil of ureido]phenyl]-indole-mercaptoamino]ethyl-1-hexahydropyrrole ethyl acetate (889 mg, a mixture of DMF). iH-NMR (CDC13) 5 1· 25-1. 29 (m, 3H), 2·29 (s, 3H), 2·42-2·63 (m, 10H), 3·20, 3.18 (each s , total 3Η), 3·55, 3·40 (each t, total 2Η, J = 6.8 Hz), 3·65, 3·69 (each s, total 2H), 3·72 (s, 3H), 4 ·15 -4.21 (m, 2Η), 6·50 (m, 1Η), 6·77-6·81 (m, 8Η), 7 · 11 - 7 · 2 4 (m, 3 Η), 7 · 5 3 (d,1 Η, J = 8 · 3 Η ζ), 8 · 0 2 (s, 1Η), 8· 06 (d, 1Η, J = 7. 8 Ηζ). 4-[2-Ν-[3-Methoxy-4-[Ν'-(2-mercaptophenyl)ureido]phenyl]_N-methylacetamido]ethyl-1-6 Ethyl acetate (889 mg, 1.69 mmol) dissolved in THF-EtOH (5:1, v/v, 18 mL)

89112968.ptd 第826頁 128324089112968.ptd Page 826 1283240

液中加入4N NaOH(0· 84毫升，3· 38毫莫耳）。使反應混合 物在室溫下攪拌4小時，利用in HC1調整至ρΗ 7· 5，並以 CHCl3-Me0H(4:l，v/v)卒取。將結合的萃取液於上乾 燥，並濃縮而得324(21 8毫克，2步驟26%)之棕色非晶形泡 沫。IR (KBr) η 3299 、 3004 、 1700 、 1627 、 1598 、 1536 / 公分；NMR (DMSO) 5 2· 25 (s，3Η)、2· 36-2· 62 (m，10Η).、2·84、2·99 (各s，總計 3H)、3·13、3·14 (各 s，總計 2Η)、3·38-3·45 (m，2Η)、3·61、3·65 (各s，總 計2H)、3·86 (s，3H)、6·74 (t，1H，J = 7.8 Hz)、6·87 (s, 1H) &gt;6.93 (t, 1H, J = 7.8 Hz) '7.11-7.17 (m, 2H) 、7·79 (d，1H, J = 7.8 Hz)、8·01 (d，1H，J = 7.8 Hz)、 8·47 (s，1H)、8.57 (s，1H); MS(FAB) m/z 498 (MH1) ; C26H35N5 05 · 2HC1 · H20 之分析計算值：C，53. 06 ; H，6·67; N， 11·89。實測值：C， 53.04; H，6.15 實施例275 卜[2-[N- ·甲基-N-[ 3-甲氧基-4-[Ν’ - (2-甲基笨基）脲基]苯 基]乙醯胺基]乙基]-4-六氫咄啶乙酸 卜[2_(Ν-苄氧羰基-Ν-甲胺基）乙基]-4-亞六氫咄啶乙酸乙 酯4N NaOH (0·84 ml, 3·38 mmol) was added to the solution. The reaction mixture was stirred at room temperature for 4 hours, adjusted to ρ Η 7.5 with in HCl, and was taken from CHCl3-Me0H (4:1, v/v). The combined extracts were dried and concentrated to give 324 (21 g, 2%, 26%) of brown amorphous foam. IR (KBr) η 3299 , 3004 , 1700 , 1627 , 1598 , 1536 / cm ; NMR (DMSO ) 5 2· 25 (s, 3Η), 2· 36-2· 62 (m, 10Η)., 2.84 , 2·99 (each s, total 3H), 3·13, 3·14 (each s, total 2Η), 3·38-3·45 (m, 2Η), 3·61, 3·65 (each s , total 2H), 3·86 (s, 3H), 6.74 (t, 1H, J = 7.8 Hz), 6·87 (s, 1H) &gt; 6.93 (t, 1H, J = 7.8 Hz) ' 7.11-7.17 (m, 2H), 7.79 (d, 1H, J = 7.8 Hz), 8·01 (d, 1H, J = 7.8 Hz), 8·47 (s, 1H), 8.57 (s, 1H); MS (FAB) m/z 498 (MH1); C26H35N5 05 · 2HC1 · H20 Analysis calculated: C, 53. 06; H, 6·67; N, 11·89. Found: C, 53.04; H, 6.15 Example 275 [2-[N-Methyl-N-[3-methoxy-4-[Ν'-(2-methylphenyl)ureido] Phenyl]acetamido]ethyl]-4-hexahydroacridineacetate [2_(Ν-benzyloxycarbonyl-fluorenyl-methylamino)ethyl]-4- hexahydroacridine ethyl acetate

89112968.ptd 第827頁 128324089112968.ptd Page 827 1283240

H辛氧幾基-N—甲胺基）乙酿（2. 〇7克，i 〇 耳）及4 -亞六虱咄啶乙酸乙_ 、H octyloxy-N-methylamino) ethyl (2. 克7 g, i 〇 ear) and 4- hexacidodine B _,

MeOH-AcOH(l〇:l，v/v，22^ .克’1〇.〇=莫耳）溶於 CNG.32克，20毫莫耳），並授拌溶液中加入NaBH3MeOH-AcOH (l〇:l,v/v, 22^.g '1〇.〇=mole) was dissolved in CNG.32 g, 20 mmol), and NaBH3 was added to the mixing solution.

NaHC〇3(2J)0宅，）使混合物停止反應，並以cHci3 (gxl50笔升）萃取。將結合的萃取液於邮〇4上乾燥，並菽 發。將殘f物於矽膠上利用CHCl3 — Et〇H(4〇:1，v/v)進行… 層析，而付W2-(N-苄氧羰基—N_甲胺基）乙基卜4一亞六氫 咄啶乙酸乙酯（1· 71克，47%)的無色油。1H_NMR (CDCl3)占 1·25 (t，J = 7.3 Hz，3H)、2·16 (m，2H)、2·57 (m， 4H)、2.95 (m，7H)、3·44 (m，2H)、4.13 (q，J = 7.3 Hz, 2H)、5·12 (s，2H)、5·49-5.53 (m，1H)、7.35 (m， 5H)。 1-(2-甲胺乙基）-4 -六氫咄啶乙酸乙醋NaHC〇3(2J)0 house,) The mixture was stopped and extracted with cHci3 (gxl50 liters). The combined extracts were dried on post 4 and burst. The residual material was chromatographed on CK3 by using CHCl3 - Et〇H (4〇:1, v/v), and W2-(N-benzyloxycarbonyl-N-methylamino)ethyl b 4 Ethyl hexahydropyridinium ethyl acetate (1·71 g, 47%) as a colorless oil. 1H_NMR (CDCl3) accounts for 1.25 (t, J = 7.3 Hz, 3H), 2·16 (m, 2H), 2·57 (m, 4H), 2.95 (m, 7H), 3·44 (m, 2H), 4.13 (q, J = 7.3 Hz, 2H), 5·12 (s, 2H), 5·49-5.53 (m, 1H), 7.35 (m, 5H). 1-(2-methylaminoethyl)-4-hexahydroacridine acetate

厂 C〇2Et k^NH 使卜[2-(N -苄氧羰基-N-甲胺基）乙基]-4-亞六氫呲啶乙 酸乙酯（1.70 克，4·72 毫莫耳）溶於 EtOH - AcOH(20:l, v/v， 21毫升）之溶液在5% Pd/C(2克）上在攪拌下氫化3天。將混 合物過濾，並將濾液於真空中濃縮。利用飽和NaHC〇3使殘 留物成為鹼性，並以CHC 13 ( 3 0 0毫升）萃取。將萃取液於Plant C〇2Et k^NH 卜[2-(N-Benzyloxycarbonyl-N-methylamino)ethyl]-4- hexahydroacridine ethyl acetate (1.70 g, 4.72 mmol) A solution of EtOH-AcOH (20:1, v/v, 21 mL) was hydrogenated on 5% Pd / C (2 g) with stirring for 3d. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was made basic with saturated NaHC 〇3 and extracted with CHC 13 (30 mL). Extract the solution

\\312\2d-code\90-01\89112968.ptd 第828頁 1283240 五、發明說明（824)\\312\2d-code\90-01\89112968.ptd Page 828 1283240 V. Description of invention (824)

NagCO3上乾燥，並蒸發而得1 —(2—曱胺乙基）—4 -六氫咄啶乙 酸乙醋（813毫克，75%)的黃色油。iH-NMR (CDCl3) 6 h 25 (t，J = 7.3 Hz，3H)、1·68-1·81 (m，5H)、1·97 (t， J = 11.2 Hz，2H)、2·22 (d，J = 7.3 Hz，2H)、2·43-2·47 (m，5H)、2.66 (t，】 = Hz，2H)、2·85-2·90 (m，2H) 、4·13 (q， J=7·3 Hz， 2H)。 卜[2-[N-甲基-N - [3-甲氧基一4 一 [N，- (2—甲基苯基）脲基]苯 基]乙醯胺基]乙基]-4-六氫咄σ定乙酸乙酯The mixture was dried over Na.sub.3CO.sub.3 and evaporated. iH-NMR (CDCl3) 6 h 25 (t, J = 7.3 Hz, 3H), 1.68-1·81 (m, 5H), 1.97 (t, J = 11.2 Hz, 2H), 2·22 (d, J = 7.3 Hz, 2H), 2·43-2·47 (m, 5H), 2.66 (t,] = Hz, 2H), 2·85-2·90 (m, 2H), 4· 13 (q, J=7·3 Hz, 2H). [2-[N-Methyl-N-[3-methoxy-4-iso[N,-(2-methylphenyl)ureido]phenyl]ethinyl]ethyl]-4- Hexahydropyridinium succinate

於3-甲氧基-4-[Ν’ -（2 -甲基苯基）脲基]苯基乙酸（55 0毫 克’1·75毫莫耳）及卜（2 -甲胺乙基）_4 -六氫咄啶乙酸乙酯 (400毫克’1.75毫莫耳）溶於DMF(1〇毫升）之攪拌溶液中加 入EDC · HC 1 ( 5 03毫克，2· 63毫莫耳）、HOBt(催化劑）、及 DMAP(催化劑），並持續攪拌隔夜。將混合物以Et〇Ac ( 30 0耄升）稀釋，以鹽水（2〇〇毫升）洗滌，於MgS〇4上乾 燥，並蒸發。使殘留物於矽膠上利用CHC13_Et〇H u 〇 : i， v/v)進行層析，而得1 一 [2 - [N-甲基一 N 一 [3 一甲氧基一 4 - [N， -（2-甲基苯基）脲基]苯基]乙醯胺基]乙基]—4—六氫吼啶 乙酸乙醋（697毫克，76%)的黃色膠。ijj-NMR (CDC13) 5 1.19 - 2·06 (m 系、列，12H)、2·21 (t，J = 7.8 Hz，2H)、 2.28 (s，3H)、2·41 (t，】 = 7·3 Hz， 1H)、2.46 (t， J = Hz，1H)、2·80-2.89 (m，2H)、2·95 及3·01 (各s，3-methoxy-4-[Ν'-(2-methylphenyl)ureido]phenylacetic acid (55 0 mg '1·75 mmol) and Bu (2-methylaminoethyl)_4 Ethyl hexahydroacridine ethyl acetate (400 mg '1.75 mmol) dissolved in DMF (1 mL) was added EDC · HC 1 (5 03 mg, 2. 63 mmol), HOBt (catalyst ), and DMAP (catalyst), and continue to stir overnight. The mixture was diluted with EtOAc (30 mL), washed with brine (2 mL), dried over EtOAc and evaporated. The residue was chromatographed on silica gel using CHC13_Et〇H u 〇: i, v/v) to give 1-[2-[N-methyl-N-[3-methoxy-4-[N, -(2-Methylphenyl)ureido]phenyl]acetamido]ethyl]-tetrahydroacridine acetic acid ethyl acetate (697 mg, 76%) of a yellow gum. Ijj-NMR (CDC13) 5 1.19 - 2·06 (m system, column, 12H), 2·21 (t, J = 7.8 Hz, 2H), 2.28 (s, 3H), 2·41 (t,] = 7·3 Hz, 1H), 2.46 (t, J = Hz, 1H), 2·80-2.89 (m, 2H), 2·95 and 3·01 (each s,

\\312\2d-code\90-0l\89112968.ptd 第829頁 1283240 五、發明說明（825) 總 #3Η)、3·40 及3.50 (各t，J = 6.8 Hz，總計 2H)、3.64 -3· 75 (m，5H)、4. 09-4. 16 (m，2H)、6 59 (s 1H)、 7.27 (m，3H)、7·54 (d，】=8·3 Hz，1H)、8·〇6 (dd， J = 8· 3、2. 4 Hz，1H) 〇 於I - [2-[N-甲基1一[3一甲氧基一 4—[N，一（2一甲基苯基）脲 基]苯基^乙醯胺基]乙基]-4 -六氫咄啶乙酸乙酯（6 9 〇毫克 ，1· 32笔莫耳）溶於thf( 11毫升）之攪拌溶液中加入〇· 25N NaOH水溶液（11毫升，2·75毫莫耳），並持續攪拌隔夜。將 混合物以Η2〇( 50毫升）稀釋，以1 ν HC1中和，並以CHC13-MeOH(2:l, v/v，3x100毫升）萃取。將結合的萃取液於 MgS〇4上乾燥’並蒸發。將殘留液溶解於Me〇H(5〇毫升）， 並將活性奴（2克）加至此溶液。使懸浮液在攪拌下迴流3 〇 分鐘’並過濾通過矽藻土。將濾液蒸發，利用cHC丨3將殘 禱物研I ’並加入己烧直至生成沈殿物為止。收集此沈殺 物，並於真空中乾燥而得32 5 ( 75毫克，11%)之白色非晶形 固體。4-NMR (DMS0) (5 1· 19-2· 99 (m 系列，總計1 7H)、 3 · 3 2 - 3 · 4 3 (m，4 Η)、3 · 6 2 - 3 · 6 5 (m，2 Η)、3 · 8 6 ( s， 3Η)、6·73 (t，J = 8.3 Hz, 1Η)、6·87 (s，1Η)、6·93 (t，J = 7.8 Hz，1H)、7·：Π - 7·17 (m，2H)、7·79 (d， J = 8.3 Hz，1H)、8·01 (d，J = 8.3 Hz，1H)、8·47 (s， 1H)、8·57 (s， 1H); MS —FAB m/z 497 (M+ + l); C27H36N405 • HC1 之分析計算值：C，60· 84 ; H，7· 00 ; N， 10· 51。實 測值：C，60. 97 ; H，7· 14 ; N， 10. 17。\\312\2d-code\90-0l\89112968.ptd Page 829 1283240 V. Invention description (825) Total #3Η), 3·40 and 3.50 (each t, J = 6.8 Hz, total 2H), 3.64 -3· 75 (m, 5H), 4. 09-4. 16 (m, 2H), 6 59 (s 1H), 7.27 (m, 3H), 7·54 (d, 】=8·3 Hz, 1H), 8·〇6 (dd, J = 8·3, 2. 4 Hz, 1H) I I - [2-[N-methyl 1 -[3-methoxy-4-[N, one (2-Methylphenyl)ureido]phenyl[Ethylamino]ethyl]4-hexahydroacridine ethyl acetate (6 9 〇 mg, 1·32 moles) is soluble in thf ( 11 To a stirred solution of 5%) was added 〇 25N aqueous NaOH (11 mL, 2·75 mmol) and stirring was continued overnight. The mixture was diluted with EtOAc (50 mL), EtOAc (EtOAc) (EtOAc) The combined extracts were dried on MgS〇4 and evaporated. The residual solution was dissolved in Me〇H (5 mL), and an active slave (2 g) was added to the solution. The suspension was refluxed for 3 〇 minutes with stirring&apos; and filtered through diatomaceous earth. The filtrate was evaporated, and the residue was triturated with cHC 丨 3 and added to the chill until the sputum was formed. The precipitate was collected and dried in vacuo to give &lt;RTI ID=0.0&gt;&gt; 4-NMR (DMS0) (5 1· 19-2· 99 (m series, total 1 7H), 3 · 3 2 - 3 · 4 3 (m, 4 Η), 3 · 6 2 - 3 · 6 5 ( m, 2 Η), 3 · 8 6 ( s, 3 Η), 6.73 (t, J = 8.3 Hz, 1 Η), 6·87 (s, 1 Η), 6.93 (t, J = 7.8 Hz, 1H), 7·: Π - 7·17 (m, 2H), 7·79 (d, J = 8.3 Hz, 1H), 8·01 (d, J = 8.3 Hz, 1H), 8·47 (s , 1H), 8·57 (s, 1H); MS —FAB m/z 497 (M+ + l); C27H36N405 • Analytical calculation of HC1: C, 60· 84 ; H,7· 00 ; N, 10· 51. Found: C, 60. 97; H, 7·14; N, 10. 17.

\\312\2d-code\90-01\89112968.ptd 第830頁 1283240 五、發明說明（826) 實施例27fi 卜[2-[N_甲基_N_[4_[N，_(2_甲基苯基）脲基]笨基]乙酿胺 基]乙基]-4 -六氫吼唆乙酸 卜[2-[Ν一甲基_Ν_[4_[Ν’_(2_甲基苯基）脲基]苯基]乙醯胺 基]乙基]-4-六氫吡啶乙酸乙酯 於1-(2-甲胺乙基）-4-六氫17比咬乙酸乙酯（4〇〇毫克， 1·75宅莫耳）及Et3N(366微升’2.63毫莫耳）溶於DMF(10毫 升）之攪拌溶液中加入4 -（Ν’ - (2-甲基苯基）脲基）苯基乙酸 五氟苯酯（ 788毫克，1.75毫莫耳），並持續攪拌隔夜。將 混合物以EtOAc( 30 0毫升）稀釋，以鹽水（2〇〇毫升）洗滌， 於MgS〇4上乾燥’並蒸發。使殘留物於矽膠上利用cjjci3 - EtOH(10:l，v/v)進行層析，而得^[2—^ 一甲基 -N-[4 - [N -(2-甲基苯基）脲基]苯基]乙醯胺基]乙基]一4一 六氫吼咬乙酸乙酯（ 630毫克，73%)的無色油。 * =1 - [2-[N-甲基-N—[4一 [N，一（2—甲基苯基）脲基]苯基]乙 酿胺基]乙基]-4 -六氫咄啶乙酸乙酯（63〇毫克，l 27毫莫 耳）=於THF(、10宅升）之攪拌溶液中加入〇· 25N Na〇H水溶液 (1〇毫升）’並持續攪拌隔夜。將反應混合物以H20( 1 00毫\\312\2d-code\90-01\89112968.ptd Page 830 1283240 V. Description of the Invention (826) Example 27fi [2-[N_Methyl_N_[4_[N,_(2_A Phenyl)ureido]acyl]ethylamino]ethyl]-4-hexahydroindoleacetic acid [2-[Ν-methyl_Ν_[4_[Ν'_(2_methylphenyl) Ethyl phenyl] phenyl] acetamido] ethyl]-4- hexahydropyridine ethyl acetate in 1-(2-methylaminoethyl)-4-hexahydro 17 ratio ethyl acetate (4 〇〇 Add 4 -(Ν' - (2-methylphenyl)ureido) to a stirred solution of DM (1,75 m) and Et3N (366 μl '2.63 mmol) in DMF (10 mL) Pentafluorophenyl phenylacetate (788 mg, 1.75 mmol) and stirring was continued overnight. The mixture was diluted with EtOAc (30 mL) and brine (EtOAc) The residue was chromatographed on silica gel using cjjci3 - EtOH (10:1, v/v) to give [2-(1 -[N-(2-methylphenyl)). Urea]Phenyl]ethylammonium]ethyl]-tetrahydropyrene (Ethyl acetate) (630 mg, 73%) as a colorless oil. * =1 - [2-[N-Methyl-N-[4-[N,-(2-methylphenyl)ureido]phenyl]ethanoyl]ethyl]-4-hexahydroindole Ethyl acetate (63 mg, l 27 mmol) = THF (25 mL) was stirred and stirred overnight. The reaction mixture was H20 (100 00 m

第831頁 1283240 ----^ 五、發明說明（827) 升）稀釋，以U HC1 中和，並以CHCi3_Me〇H(2:1， v/v， 3x100毫升）萃取。將結合的萃取液於MgS〇4上乾燥，並蒸 發。利用CHC 13將殘留物研製，並加入己烧直至生成沈殿 物為止。收集此沈殿物，並於真空中乾燥而得3 2 6 ( 2 〇毫 克，3%)之白色非晶形固體。iH-NMR (DMSO) (5 1 · 6y (m， 5H)、2·15 (m，4H)、2·24 (s，2H)、2·50 (m，2H)、 2. 83 及2· 99 (各s，總計 3H)、3· 32-3· 49 (m，4H)、3· 63 (d，J = 6.8 Ηζ，2Η)、6·9卜6·95 (m，1Η)、7·13 (m， 4H)、7·39 (d，J = 8.3 Hz，2H)、7·83 (d，J = 7.3 Hz， 1H)、7· 97 (m，1H)、9· 12 (m，1H) ; MS(FAB) m/z 46 7 (M+l)。 實施例277 4 - [2 - N - [4- [Ν’ - (2 -曱基本基）脈基]苯基]- N-甲基乙酿胺 基]乙基-1 -六氫17比啡乙酸 ,co2h 327 4-[2 - N - [4-[N，-（2 -甲基苯基）脲基]苯基]- N-甲基乙醯胺 基]乙基-1-六氫咄啡乙酸乙酯 ,C〇，Et 使4-(2-甲胺乙基）-1_六氫吡畊乙酸乙酯（700毫克， 3.05毫莫耳）、£七3吖0.64毫升，4.58毫莫耳）及1)1^?(75毫Page 831 1283240 ----^ V. Description of the invention (827) Dilute, neutralize with U HC1 and extract with CHCi3_Me〇H (2:1, v/v, 3x100 ml). The combined extracts were dried on MgS 4 and evaporated. The residue was triturated using CHC 13 and added to a burn until a smatter was formed. The precipitate was collected and dried in vacuo to give 3 2 6 (2 g, 3%) of white amorphous solid. iH-NMR (DMSO) (5 1 · 6y (m, 5H), 2·15 (m, 4H), 2·24 (s, 2H), 2·50 (m, 2H), 2. 83 and 2· 99 (each s, total 3H), 3·32-3· 49 (m, 4H), 3· 63 (d, J = 6.8 Ηζ, 2Η), 6·9 b 6·95 (m, 1Η), 7 ·13 (m, 4H), 7·39 (d, J = 8.3 Hz, 2H), 7·83 (d, J = 7.3 Hz, 1H), 7·97 (m, 1H), 9·12 (m , 1H); MS (FAB) m/z 46 7 (M+l). Example 277 4 - [2 - N - [4- [Ν ' - (2 - 曱 曱 ) ) ] N-methylethylamino]ethyl-1 -hexahydro-17-p-mentalic acid, co2h 327 4-[2-N-[4-[N,-(2-methylphenyl)ureido]phenyl ]--N-Methylethylamino-amino]ethyl-1-hexahydromorphine ethyl acetate, C 〇, Et makes 4-(2-methylaminoethyl)-1_hexahydropyrrole ethyl acetate ( 700 mg, 3.05 mmol, £7, 3, 0.64 ml, 4.58 mmol) and 1) 1^? (75 m

\\312\2d-code\90-01\89112968.ptd 第832頁 1283240 五、發明說明（828) 克’0.61耄莫耳）溶於THF(15毫升）之溶液在室溫下攪拌3〇 分鐘’然後將4-[N’- (2-甲基苯基）脲基]苯基乙酸（917毫\\312\2d-code\90-01\89112968.ptd Page 832 1283240 V. INSTRUCTIONS (828) A solution of gram '0.61 耄mol) dissolved in THF (15 ml) was stirred at room temperature for 3 min. 'then 4-[N'-(2-methylphenyl)ureido]phenylacetic acid (917 mM

克’3.05毫莫耳）、HOBt(82毫克，〇·61毫莫耳）及EDC· HC1(879^克，4·58毫莫耳）加至反應混合物，將其在室溫 下攪拌12小時。將反應混合物以EtOAc稀釋，將其以鹽水 洗滌，於Na2S04上乾燥，並濃縮至乾。利用CHCi3_Me〇H (10:1，v/v)將殘留物進行層析，而得4—[2 - N-[4-[N，-(2-克 '3.05 mmol, HOBt (82 mg, 〇·61 mmol) and EDC·HC1 (879 gram, 4.58 mmol) were added to the reaction mixture, which was stirred at room temperature for 12 hours. . The reaction mixture was diluted with EtOAc (EtOAc)EtOAc. The residue was chromatographed using CHCi3_Me〇H (10:1, v/v) to give 4-[2-N-[4-[N,-(2-

甲基苯基）脲基]苯基]-N-甲基乙醯胺基]乙基一 1—六氫，比嘈 乙酸乙酯（9 9 6毫克，6 6 % )的黃色非晶形泡沫。1 η -腿R (CDC13) (5 1·25 -1·29 (m, 3Η)、2.20 (s，3Η)、2·47-2· 58 (m，10Η)、2·97、3·05 (各s，總計3H)、3·17、3·20 (各s，總計2Η)、3·45、3·52 (各d,總計2Η，J = 6.8 Ηζ，）、3·64、3·68 (各s，2H)、4·15 - 4.21 (m，2H)、 7.01 -7·19 (m, 8H)、7·48 (m，1H)、7·64 (m，1H); MS(FAB) m/z 496 (MH1)。Methylphenyl)ureido]phenyl]-N-methylacetamido]ethyl-1-hexahydro, a yellow amorphous foam of ethyl acetate (99.6 mg, 6 6 %). 1 η - leg R (CDC13) (5 1·25 -1·29 (m, 3Η), 2.20 (s, 3Η), 2·47-2· 58 (m, 10Η), 2.97, 3.05 (each s, total 3H), 3·17, 3·20 (each s, total 2Η), 3·45, 3·52 (each d, total 2Η, J = 6.8 Ηζ,), 3·64, 3· 68 (each s, 2H), 4·15 - 4.21 (m, 2H), 7.01 -7·19 (m, 8H), 7·48 (m, 1H), 7·64 (m, 1H); MS ( FAB) m/z 496 (MH1).

於4 - [2-N-[4 - [Ν’-(2-甲基苯基）脲基]苯基]一 n-曱基乙 醯胺基]乙基-1-六氫吼畊乙酸乙酯（996毫克，2.01毫莫 耳）溶於THF-EtOH( 5 : 1， 1 2毫升）之攪拌溶液中加入4N4-[2-N-[4 - [Ν'-(2-Methylphenyl)ureido]phenyl]-n-mercaptoethylamino]ethyl-1-hexahydroindole The ester (996 mg, 2.01 mmol) was dissolved in THF-EtOH (5:1, 12 mL).

NaOH(l · 0毫升，4· 00毫莫耳）。使反應混合物在室溫下攪 拌4小時，利用1 N HC1調整至pH 7. 5，並以CHCl3-MeOH (4·· 1，v/v)萃取。將結合的萃取液於MgS04上乾燥，並濃 縮而得327( 7 3毫克，8%)之黃色非晶形泡沫。ir (KBr) η 3338、2925、2850、2821、1704、1627、1540 / 公分； UMR (DMS0)6 2.24 (s，3Η)、2·33-2·61 (m，10Η)、NaOH (l · 0 ml, 4·00 mmol). The reaction mixture was stirred at room temperature for 4 hours, then adjusted to pH 7.5 using 1 N EtOAc, and extracted with CHCl3-MeOH (4··1, v/v). The combined extracts were dried over MgS04 and concentrated to give 327 (73 mg, 8%) of yellow amorphous foam. Ir (KBr) η 3338, 2925, 2850, 2821, 1704, 1627, 1540 / cm; UMR (DMS0)6 2.24 (s, 3Η), 2·33-2·61 (m, 10Η),

\\312\2d-code\90-01\89112968.ptd 第 833 頁 1283240\\312\2d-code\90-01\89112968.ptd Page 833 1283240

五、發明說明（829) 2.82、2.95 (各s，總計3Η)、3·〇〇、3 〇 2Η)、3.39 (t’ 2H，J = 6.8 Ηζ)、3 6〇、 ，s—十她 2Η)、6.92 (t，1HJ = 7.8Hz)、7 G9_ η :十 4Η.44 (m，2Η)、7·76、7.77 (各 (. 8.46、8.53 (各s，1Η)、9·54、9 59 (各 . MS(FAB) m/z 468 C25H33N5〇5 ·2ΗΠ 之分析 值6·53;Ν，12.96。實測值： ;H，6. 45 ; N，11. 58。 實施例278 4_[2-N-[4-[N’-(2-氣苯基）脲基卜3一甲 醯胺基]乙基-1-六氫吡畊乙酸 土」以T ^ ^V. Description of invention (829) 2.82, 2.95 (each s, total 3 Η), 3·〇〇, 3 〇 2Η), 3.39 (t' 2H, J = 6.8 Ηζ), 3 6〇, s-10 she 2Η ), 6.92 (t, 1HJ = 7.8Hz), 7 G9_ η: ten 4Η.44 (m, 2Η), 7.76, 7.77 (each (. 8.46, 8.53 (each s, 1Η), 9.54, 9 59 (each. MS(FAB) m/z 468 C25H33N5 〇5 · 2 ΗΠ analytical value 6.53; Ν, 12.96. Found: H, 6.45; N, 11.58. Example 278 4_[2 -N-[4-[N'-(2-Phenylphenyl)ureidobu 3-methylammonium]ethyl-1-hexahydropyrazole acetate" to T ^ ^

,C〇2H 328 4-[2-N-[4-[N’-(2-氟苯基）脲基]_3_甲氧苯基]_N_曱基乙 醯胺基]乙基-1 -六氫咄畊乙酸乙酯 .C〇aEt 使4-(2-曱胺乙基）-i —六氫咄嘴乙酸乙酯（695毫克， 3· 03 宅莫=)+、Et3N(0· 64 毫升，4· 58 毫莫耳）及DMAp(75 毫 克，0 · 61耄莫耳）溶於dm (a毫升）之溶液在室溫下授拌η 分鐘，然後將4-[N，-（2-氟笨基）脲基]-3-甲氧笨基乙酸 (965毫克，3·03毫莫耳）、H〇Bt(82毫克，0.61毫莫耳）及,C〇2H 328 4-[2-N-[4-[N'-(2-Fluorophenyl)ureido]_3_methoxyphenyl]_N_mercaptoethylamino]ethyl-1 - Hexahydroindole vinegar. C〇aEt 4-(2-Amidinoethyl)-i-hexahydropyrene ethyl acetate (695 mg, 3·03 house Mo =)+, Et3N (0·64 ML, 4·58 mM) and DMAp (75 mg, 0 · 61 mM) dissolved in dm (a ml) at room temperature for η min, then 4-[N,-(2 -Fluorophenyl)ureido]-3-methoxyphenylacetic acid (965 mg, 3·03 mmol), H〇Bt (82 mg, 0.61 mmol) and

89112968.ptd 第834頁 1283240 五、發明說明（830) EDC ·Η(：1(872毫克，4.54毫莫耳）加至反應混合物，將其 在室溫下攪拌12小時。將反應混合物以EtOAc稀釋，將其 以鹽水洗滌，於Na2S04上乾燥，並濃縮至乾。利用CHC13-89112968.ptd Page 834 1283240 V. INSTRUCTIONS (830) EDC · Η (: 1 (872 mg, 4.54 mmol) was added to the reaction mixture, which was stirred at room temperature for 12 hours. The reaction mixture was diluted with EtOAc. It was washed with brine, dried over Na 2 SO 4 and concentrated to dryness.

MeOH(10:l，v/v)將殘留物進行層析，而得4-[2-N - [4- [Ν’ - (2 -氟苯基）脲基]-3-甲氧苯基]-N-甲基乙醯胺基]乙 基-1 -六氫咄畊乙酸乙酯（1 · 2 1克，DMF之混合物）的黑色 油。1H-NMR (CDC13) δ 1.2 4- 1.29 (m，3Η)、2·45-2.59 (m，10Η)、2· 98、3· 05 (各s，總計 3H)、3· 1 7、3 . 20 (各s，總計2H)、3· 44、3. 52 (各t，總計2H，J = 6. 8 Hz)、3·66 (s，2H)、4·15-4·21 (m，2H)、6·77-6·78 (m，2Η)、6·79-7.11 (m，3Η)、7·68-7·95 (m, 2Η)、 7·64 (寬s，1H)、8·20 (t，1H，J = 7.8 Hz); MS(FAB) m/z 53 0 (MH1)。 於4-[2 - N - [4 -[Ν’-（2-氟苯基）脲基]一3 一曱氧苯基]一N 一曱 基乙醯胺基]乙基_ 1 -六氫吼畊乙酸乙酯（1 · 2 1克，DMF之混 合物）溶於THF-EtOH(5:l，v/v， 12毫升）之攪拌溶液中加 入4N NaOH(1.0宅升’4.00宅莫耳）。使反應混合物在室溫 下授拌4小時’利用1 N H C1調整至p Η 7 · 5，並以C H C 13 -MeOH (4:1，ν/ν)萃取。將結合的萃取液於MgS〇4上乾燥， 並濃縮而得3 2 8 ( 7 8毫克，5 % 2步驟）之棕色非晶形泡浓。 IR (KBr) η 3299、2940、2830、1704、1627、1598、 1 536 /公分；Μ-NMR (DMSO) 5 2·36-2·61 (m，10Η)、 2·83、2·98 (各s，總計 3H)、3·11 (s，2H)、3 37-3 43 (m，2H)、3·62、3·65 (各s，總計2H)、3·85 (s，3H)、The residue was chromatographed with MeOH (10:1, v/v) to give 4-[2-N-[4-[Ν[-(2-fluorophenyl)ureido]-3-methoxyphenyl A black oil of ethyl acetate (1 · 21 g, a mixture of DMF) of -N-methylacetamido]ethyl-1 -hexahydroindole. 1H-NMR (CDC13) δ 1.2 4- 1.29 (m, 3Η), 2·45-2.59 (m, 10Η), 2·98, 3. 05 (each s, total 3H), 3·1 7 and 3. 20 (each s, total 2H), 3·44, 3.52 (each t, total 2H, J = 6. 8 Hz), 3.66 (s, 2H), 4·15-4·21 (m, 2H), 6·77-6·78 (m, 2Η), 6.79-7.11 (m, 3Η), 7·68-7·95 (m, 2Η), 7·64 (width s, 1H), 8·20 (t, 1H, J = 7.8 Hz); MS (FAB) m/z 53 0 (MH1). 4-[2 - N - [4 -[Ν'-(2-Fluorophenyl)ureido]- 3-indolyloxyphenyl]-N-mercaptoethylamino]ethyl-1 -hexahydro Ethyl acetate (1 · 21 g, mixture of DMF) was dissolved in THF-EtOH (5:1, v/v, 12 ml) in a stirred solution of 4N NaOH (1.0 liter '4.00 house Moule) . The reaction mixture was stirred at room temperature for 4 hours and was adjusted to &lt;RTI ID=0.0&gt;&gt;&gt; The combined extracts were dried over MgS(R)4 and concentrated to give abr. EtOAc (EtOAc). IR (KBr) η 3299, 2940, 2830, 1704, 1627, 1598, 1 536 / cm; Μ-NMR (DMSO) 5 2·36-2·61 (m, 10Η), 2·83, 2·98 ( Each s, total 3H), 3·11 (s, 2H), 3 37-3 43 (m, 2H), 3·62, 3·65 (each s, total 2H), 3·85 (s, 3H) ,

1283240 五、發明說明（831) 6·75 (m，1H)、6·87 (s，1H)、6·98 (s，1H)、7·12 (t, 1Η, J = 7. 8 Hz)、7·20、7.23 (各d，2H, J = 7· 8 Hz) 、8·01 (d，1H，J = 7.8 Hz)、8·17 (t，1H，J = 7.8 Hz)、 8.72 (s，1H)、9·19 (s，1H); MS(FAB) m/z 502 (MH1) ; C25H32FN5 05 · 2HC1 · 0· 5H20 之分析計算值：C， 51· 46 ; H，6· 05 ; N，12. 00。實測值：C，51· 08 ; H， 5· 69 ; N, . 11 · 27。 實施例279 3-氟-1 - [2-N-曱基-N-[ 3-甲氧基-4- [Ν’-（2-甲基苯基）脲 基]苯基]乙醯胺基]乙基六氫吼啶乙酸1283240 V. INSTRUCTIONS (831) 6·75 (m, 1H), 6·87 (s, 1H), 6·98 (s, 1H), 7·12 (t, 1Η, J = 7. 8 Hz) , 7·20, 7.23 (each d, 2H, J = 7· 8 Hz), 8·01 (d, 1H, J = 7.8 Hz), 8·17 (t, 1H, J = 7.8 Hz), 8.72 ( s,1H),9·19 (s,1H); MS(FAB) m/z 502 (MH1) ; C25H32FN5 05 · 2HC1 · 0· 5H20 Analysis calculated: C, 51· 46 ; H,6· 05 ; N, 12. 00. Found: C, 51·08; H, 5· 69 ; N, . 11 · 27. Example 279 3-Fluoro-1 -[2-N-indolyl-N-[3-methoxy-4-[Ν'-(2-methylphenyl)ureido]phenyl]ethinylamino Ethyl hexahydroacridine acetic acid

Me ζΧ 叉 丫Me ζΧ fork 丫

Me Η Η 〇Μβ k^k^C〇2H 329 卜第三丁氧羰基—1，2, 3, 6_四氫-4-(三甲矽烷氧基）咄啶Me Η 〇Μ 〇Μβ k^k^C〇2H 329 tert-butoxycarbonyl-1,2,3,6-tetrahydro-4-(trimethyldecyloxy)acridine

在室溫下於卜第三丁氧羰基-4-六氫吡啶酮（14· 9克， 74. 8毫莫耳）溶於DMF(35毫升）之攪拌溶液中加入TMSC1 (11.4毫升，89.7毫莫耳），然後逐滴加入£1^(25.0毫 升，179毫莫耳），並使反應混合物在80 °C下加熱18小時。 將己烷加至反應混合物，並將所產生之混合物以飽和 NaHC03及鹽水洗滌，於Na2S04上乾燥，並濃縮至乾。利用 己烷-EtOAc(5:l，v/v)作為洗提液將殘留物進行層析，得 1-第二丁氧搂基-1，2，3，6-四氮-4-（三甲梦烧氧基比咬TMS1 (11.4 ml, 89.7 m) was added to a stirred solution of tributyloxycarbonyl-4-hexahydropyridone (14·9 g, 74.8 mmol) dissolved in DMF (35 ml) at room temperature. Moth), then £1 (25.0 mL, 179 mmol) was added dropwise and the mixture was heated at <RTI ID=0.0># </ RTI> </RTI> <RTIgt; Hexane was added to the reaction mixture, and the resulting mixture was washed with sat. NaHC03 and brine, dried over Na2SO. The residue was chromatographed using hexane-EtOAc (5:1, v/v) as eluent to give 1-2-butoxy-l-yl-1,2,3,6-tetrazole-4-(trimethyl) Dream burns oxygen than bite

89112968.ptd 第836頁 1283240 五、發明說明（832) (20· 4 克，99%)的黃色油。1H-NMR (CDC13) 5 0· 19 (s， 9H)、1·46 (s，9H)、2·05-2·15 (m，2H)、3·48-3·56 (m，2H)、3.83-3.91 (m，2Η)、4·79 (寬s，1Η)。 1-第三丁氧幾基-3_氟-4 -六氫吼唆g同89112968.ptd Page 836 1283240 V. INSTRUCTIONS (832) (20·4 g, 99%) of yellow oil. 1H-NMR (CDC13) 5 0· 19 (s, 9H), 1·46 (s, 9H), 2·05-2·15 (m, 2H), 3·48-3·56 (m, 2H) , 3.83-3.91 (m, 2Η), 4.79 (width s, 1Η). 1-tert-butoxymethyl-3-fluoro-4-hexahydroindole

BocBoc

在室溫下於卜第三丁氧羰基-1，2, 3, 6-四氫-4-(三甲石夕 烷氧基）咄啶（20·4克，75.0毫莫耳）溶於CH3CN( 5 0 0毫升） 之溶液中加入SelectfluorTM(29.2克，82.5毫莫耳），並使 反應混合物攪拌2小時。將E tOAc加至反應混合物，將混合 物以鹽水洗滌，於Na2S〇4上乾燥，並濃縮至乾。利用CHC13 -MeOH(6 ·· 1，v/v)作為洗提液將殘留物進行層析，得丨一第 三丁氧幾基-3-氣-4〜六氫咄啶酮（14· 5克，89%)的無色 油。1H-NMR (CDC13) $ ι·5〇 (s，9Η)、2·44 (t，J = 6.9 Hz，1H)、2·48-2·63 (m，2H)、3·26 (ddd，J = 13.5、1〇· 5、3·9 Hz，1H)、3·72 (t，J = 6.9 Hz，1H)、4·16 (m， 1H)、4·42 (m，1H)、4·83 (dt，49·2、6·9 Hz，1H)。 (1-丁氧羰基-3-氟亞六氫咄啶_4 -基）乙酸乙酯It is dissolved in CH3CN at room temperature with tributyloxycarbonyl-1,2,3,6-tetrahydro-4-(trimethylsulfanyloxy)acridine (20·4 g, 75.0 mmol). SelectfluorTM (29.2 g, 82.5 mmol) was added to a solution of 500 mL) and the mixture was stirred for 2 hr. EtOAc was added to the reaction mixture, the mixture was washed with brine, dried over Na.sub.2, and evaporated to dry. The residue was chromatographed with CHC13-MeOH (6··1, v/v) as an eluent to give a tris-butoxy-3-yl-3-cyclo-4-hexahydroacridone (14·5). Gram, 89%) of a colorless oil. 1H-NMR (CDC13) $ ι·5〇(s,9Η), 2·44 (t, J = 6.9 Hz, 1H), 2·48-2·63 (m, 2H), 3·26 (ddd, J = 13.5, 1〇· 5,3·9 Hz, 1H), 3·72 (t, J = 6.9 Hz, 1H), 4·16 (m, 1H), 4·42 (m, 1H), 4 · 83 (dt, 4·2, 6·9 Hz, 1H). (1-butoxycarbonyl-3-fluoroihexahydroacridine-4-yl)ethyl acetate

C〇2Et 在-78 C下於膦酸乙酸三乙酯（3.72克，16·6毫莫耳）溶 於THF(70毫升）之溶液中加入雙（三甲矽烷基）醯胺鋰u · 〇Μ THF溶液，15. 5毫升，15· 5毫莫耳）。於在相同溫度下攪拌C〇2Et bis(trimethyldecyl) guanamine lithium u · 〇Μ was added to a solution of triethyl phosphonate (3.72 g, 16.6 mmol) in THF (70 ml) at -78 C. THF solution, 15. 5 ml, 15. 5 mmol. Stirring at the same temperature

\\312\2d-code\90-01\89112968.ptd 第837頁 1283240 五、發明說明（833) 1小時後，將1-第三丁氧羰基-3-氟-4-六氫咄啶酮（3. 02 克，1 3 · 9毫莫耳）加至反應混合物。使混合物在相同溫度 下攪拌30分鐘，經由加入飽和NH4C1溶液停止反應，並以 EtOAc萃取。將萃取液以鹽水洗滌，於Na2S04上乾燥，並濃 縮至乾。利用己烷-EtOAc(8 : 1，v/v)作為洗提液將殘留物 進行層析，得（1- 丁氧羰基-3-氟亞六氫吡啶-4-基）乙酸乙 酯（3·23 克，81°/。）的無色固體。W-NMR 6 1.30 (t， J = 7. 1 Hz，3H)、1·48 (s，9H)、2·10 (m，1H)、2·56 (m， 1H)、2·77 (m，1H)、3·13-3·54 (m，2H)、3·70 (m, 1H)、4· 17、4· 18 (各q，J = 7· 1 Hz，總計2H)、5· 82、 5 · 9 8 (各 s，總計 1 Η)、6 · 4 1 (各 d，J = 4 6 · 9 Η z，總計 1 Η) ;MS(FAB) m/z 288 (ΜΗ1)。 1-第三丁氧幾基-3-1-4 -六氫°比°定乙酸乙醋\\312\2d-code\90-01\89112968.ptd Page 837 1283240 V. INSTRUCTIONS (833) After 1 hour, 1-tert-butoxycarbonyl-3-fluoro-4-hexahydroacridone (3.02 g, 1 3 · 9 mmol) was added to the reaction mixture. The mixture was stirred at the same temperature for 30 min, then quenched with EtOAc EtOAc. The extract was washed with brine, dried over Na 2 SO 4 and concentrated to dry. The residue was chromatographed using hexane-EtOAc (EtOAc: EtOAc (EtOAc) · 23 g, 81 ° /.) of a colorless solid. W-NMR 6 1.30 (t, J = 7. 1 Hz, 3H), 1·48 (s, 9H), 2·10 (m, 1H), 2·56 (m, 1H), 2·77 (m , 1H), 3·13-3·54 (m, 2H), 3·70 (m, 1H), 4·17, 4·18 (each q, J = 7· 1 Hz, total 2H), 5· 82, 5 · 9 8 (each s, total 1 Η), 6 · 4 1 (each d, J = 4 6 · 9 Η z, total 1 Η); MS (FAB) m/z 288 (ΜΗ1). 1-tert-butoxymethyl-3-1-4-hexahydrogen ratio

使（1- 丁氧羰基-3-氟亞六氫吡啶-4 -基）乙酸乙酯（1· 32 克，4.59毫莫耳）溶於THF(30毫升）之溶液在Pd-C (TMEDA 錯合物，6 6 · 0毫克）上在氫氣中在室溫下氫化2小時。將催 化劑過濾掉，並將濾液濃縮至乾。利用己烷-EtOAc (9: 1， v / v)作為洗提液將殘留物進行層析，得1 —第三丁氧羰基 -3-氟-4-六氫咄啶乙酸乙酯（ 653毫克，73°/。）的無色油。 l-NMR (CDC13) 3 1· 26 (t，J = 7· 1 Hz，3H)、1· 45 (s， 9H)、1·53-1.79 (m，2H)、1·92-2·09 (m，2H)、2·31 (dd，J = 16.4、6·9 Hz，1H)、2·52 (dd，J = 16.4、7·3A solution of (1-butoxycarbonyl-3-fluoropyridin-4-yl)acetate (1·32 g, 4.59 mmol) in THF (30 mL) in Pd-C (TMEDA) The compound, 6 6 · 0 mg) was hydrogenated in hydrogen at room temperature for 2 hours. The catalyst was filtered off and the filtrate was concentrated to dryness. The residue was chromatographed eluting hexane-EtOAc (9:1 v / v) , 73 ° /.) of colorless oil. l-NMR (CDC13) 3 1· 26 (t, J = 7· 1 Hz, 3H), 1·45 (s, 9H), 1.53-1.79 (m, 2H), 1.92-2·09 (m, 2H), 2·31 (dd, J = 16.4, 6·9 Hz, 1H), 2·52 (dd, J = 16.4, 7. 3

\\312\2d-code\90-01\89112968.ptd 第838頁 1283240 五、發明說明（834)\\312\2d-code\90-01\89112968.ptd Page 838 1283240 V. Description of invention (834)

Hz, 1H) '2.61-3.06 (m, 2H) &gt;4.14 (q, J = 7.1 Hz, 2H)、4·28-4·77 (m, 2H); 13C NMR (CDC13) 14·29、25· 80、28·42、35·99、36·20、60·55、79·78、86·72、 88.48、154·94、171·93; FAB-MS m/z 290 (ΜΗ1)。 3-氟-4 -六氫咄啶乙酸乙酯 hn^y&quot;f 在〇 C下於1-第二丁氧幾基—氣_4_六氫Π比σ定乙酸乙醋 ( 653毫克，2· 26毫莫耳）溶於Ch2C12(10毫升）之溶液中加入 TFA(5毫升）。於在室溫下攪拌4小時後，將反應混合物濃 縮。將殘留物以飽和NaHC03溶液溶解，並以THF-EtOAc( 1 : 1，v/v)萃取。將萃取液於MgS04上乾燥，並濃縮而得3-氟 - 4-六氫吡啶乙酸乙酯（4 20毫克，98%)的黃色油。ih-NMR (CDC13) ^ 1.2 6 (t, J = 7. 4 Hz, 3H) &gt; 1. 68- 1. 8 0 (m, 2H)、2·18 (m，1H)、2·32 (dd，J=16.6、6·8 Hz，1H)、 2.54 (dd, J = 16.6、7.5 Hz，1H)、2.82 (m，1H)、 2·90、3·00 (各d，J = 14.4 Hz，總計 1H)、3·31 (m，1H) 、3·51 (m， 1H) 、4·15 (q， J=7.4 Hz， 2H) 、4·82 、4·71 (各寬s，總計1H)。 3-氟-l-[2-(N-第三丁氧羰基-N-甲胺基）乙基]-4-六氫咄 啶乙酸乙酯Hz, 1H) '2.61-3.06 (m, 2H) &gt;4.14 (q, J = 7.1 Hz, 2H), 4·28-4·77 (m, 2H); 13C NMR (CDC13) 14·29, 25 · 80, 28·42, 35·99, 36·20, 60·55, 79·78, 86·72, 88.48, 154·94, 171·93; FAB-MS m/z 290 (ΜΗ1). 3-Fluoro-4-hexahydroacridine ethyl acetate hn^y&quot;f in 〇C at 1-second butoxy-yl-gas _4_hexahydroindole sigma acetate vinegar (653 mg, 2 · Teflon (5 ml) was added to a solution of Ch2C12 (10 mL). After stirring at room temperature for 4 hours, the reaction mixture was concentrated. The residue was taken up in aq. EtOAc (EtOAc)EtOAc The extract was dried over EtOAc (EtOAc)EtOAc. Ih-NMR (CDC13) ^ 1.2 6 (t, J = 7. 4 Hz, 3H) &gt; 1. 68- 1. 8 0 (m, 2H), 2·18 (m, 1H), 2·32 ( Dd, J = 16.6, 6·8 Hz, 1H), 2.54 (dd, J = 16.6, 7.5 Hz, 1H), 2.82 (m, 1H), 2·90, 3·00 (each d, J = 14.4 Hz , total 1H), 3·31 (m, 1H), 3·51 (m, 1H), 4·15 (q, J=7.4 Hz, 2H), 4·82, 4·71 (each width s, total 1H). 3-Fluoro-l-[2-(N-tert-butoxycarbonyl-N-methylamino)ethyl]-4-hexahydroacridine ethyl acetate

Me cc C〇2Et 在室溫下於3_氟-4-六氫吡啶乙酸乙酯（230毫克，1.22Me cc C〇2Et Ethyl 3-fluoro-4-hexahydropyridine at room temperature (230 mg, 1.22

\\312\2d-code\90-01\89112968.ptd 第839頁 1283240 五、發明說明（835) 宅莫耳）及2-(N-第三丁氧幾基一 N-甲胺基）乙酸（211毫克， 1· 22毫莫耳）溶於THF(5毫升）之溶液中加入NaBH(0Ac)3 (386毫克，1. 82毫莫耳）及醋酸（70.0毫升，1.22毫莫 耳）。於攪拌24小時後，經由加入飽和NaHC03溶液使反應 混合物停止反應，並以EtOAc萃取。將萃取液以鹽水洗 務，於Na2C03上乾燥，並濃縮至乾。利用CHC13-MeOH(6 : 1， v/v)作為洗提液將殘留物進行層析，得3 一氟-丨-[2-(n-第 三丁氧羰基-N-甲胺基）乙基]-4-六氫咄啶乙酸乙酯（236毫 克，56%)的淡紅色油。〖Η-NMR (CDC13) δ 1. 25 (t，J = 7. 1\\312\2d-code\90-01\89112968.ptd Page 839 1283240 V. INSTRUCTIONS (835) ZIMOL) and 2-(N-T-butoxy-yl-N-methylamino)acetic acid (211 mg, 1.25 mmol) was added to a solution of THF (5 mL). NaHH (EtOAc) After stirring for 24 hours, the reaction mixture was quenched with EtOAc EtOAc. The extract was washed with brine, dried over Na 2 CH. The residue was chromatographed using CHC13-MeOH (6:1, v/v) as eluent to give 3-fluoro-[2-(n-t-butoxycarbonyl-N-methylamino) Ethyl -4- hexahydroacridine ethyl acetate (236 mg, 56%) as a pale red oil. Η-NMR (CDC13) δ 1. 25 (t, J = 7. 1

Hz，3H)、1.45(s，9H)、i53、1.79(m，2H)、1.90-2·09 (m，2H)、2·15 (dd，J = 16.4、7·1 Hz，1H)、2·45 -2.58 (m，2H)、2·87 (s，3H)、2· 90-2.99 (m，2H)、 3 · 2 0 (m，1 H )、3 · 2 4 - 3 · 4 5 (m，2 H)、4 · 1 4 (q，j = 7 · 1Hz, 3H), 1.45 (s, 9H), i53, 1.79 (m, 2H), 1.90-2·09 (m, 2H), 2·15 (dd, J = 16.4, 7·1 Hz, 1H), 2·45 -2.58 (m, 2H), 2·87 (s, 3H), 2·90-2.99 (m, 2H), 3 · 2 0 (m, 1 H ), 3 · 2 4 - 3 · 4 5 (m, 2 H), 4 · 1 4 (q, j = 7 · 1

Hz，2H)、4·61、4·73 (各寬 s，1H) ; ESI 一 MS m/z 347。 3-氟-1 - [2 -（N-甲胺基）乙基]- 4-六氫咄啶乙酸乙酯Hz, 2H), 4·61, 4.73 (each width s, 1H); ESI-MS m/z 347. 3-fluoro-1 -[2-(N-methylamino)ethyl]- 4-hexahydroacridine ethyl acetate

Me 在0°C下於3-氟-1-[2-(Ν-第三丁氧羰基_N_甲胺基）乙 基]-4-六氫吼咬乙酸乙醋（2 36毫克，〇. 68毫莫耳）溶於 (：Η，12(10毫升）之溶液中加入TFA(5毫升）。於在室溫下攪 样4小時後’將反應混合物濃縮。將殘留物以飽和NaHC〇3 溶液溶解，並以CHCI3萃取。將萃取液於MgS〇4上乾燥，並 濃縮而得3-乳甲胺基）乙基]_4_六氫吼唆乙酸乙 醋（1Π 毫克，70%)的淡紅色油。iH、NMr (CDCl3) ά i 26Me at 0 ° C in 3-fluoro-1-[2-(indole-t-butoxycarbonyl-N-methylamino)ethyl]-4-hexahydroindole acetoacetate (2 36 mg, hydrazine To a solution of (: Η, 12 (10 ml), TFA (5 ml) was added. After stirring at room temperature for 4 hours, the reaction mixture was concentrated. The residue was saturated NaHC. 3 The solution is dissolved and extracted with CHCI 3. The extract is dried on MgS 4 and concentrated to give 3-carbomethylamino)ethyl]_4_hexahydroacetic acid ethyl acetate (1 mg, 70%) Light red oil. iH, NMr (CDCl3) ά i 26

W312\2d-code\90-01\89112968.ptd 第840頁 1283240 五、發明說明（836) (t, J = 7.1 Hz，3H)、1.58 (m，1H)、1·70 (m，1H)、 1·99 (m，1H)、2·14 (m，1H)、2·27-2·33 (m，1H)、 2·47 (s，3H)、2·48-2·56 (m，4H)、2·72 (t: j=6 3W312\2d-code\90-01\89112968.ptd Page 840 1283240 V. INSTRUCTIONS (836) (t, J = 7.1 Hz, 3H), 1.58 (m, 1H), 1·70 (m, 1H) , 1·99 (m, 1H), 2·14 (m, 1H), 2·27-2·33 (m, 1H), 2·47 (s, 3H), 2·48-2·56 (m , 4H), 2·72 (t: j=6 3

Hz， 2H) 、2·90 (m， 1H) 、3·16 (m， 1H) 、4u (q ’J= 7.1 Hz, 2H) &gt;4.67 (d, 1=48.3 Hz, 1H) ； ESI-MS m/z 247 CMH1) 〇 3-氟-1-[2- N-甲基-N-[3-甲氧基-4 - [Ν’ -（2〜甲基苯某）脈 基]苯基]乙醯胺基]乙基_4_六氫咄啶乙酸乙酉旨 於3-甲氧基-4 - [Ν’-(2-甲基苯基）脲基]笨基乙酸（164毫 克’0.52宅莫耳）、3_氟-1 - [2_(N-甲胺基）乙基]一* 一六氫 咄啶乙酸乙酯（117毫克，〇· 47毫莫耳）、Et3N(〇· 1〇毫升， 〇· 71毫莫耳）、及H0Bt(13· 0毫克，0· 09毫莫耳）溶於THF(5 毫升）之溶液中加入EDC ·Η(Μ(137毫克，〇·7ΐ毫莫耳）。於 在室溫下擾拌8小時後’將反應混合物以水稀釋，並以 EtOAc萃取。將萃取液以鹽水洗滌，於上乾燥，並濃 縮至乾。利用甲苯-丙酮（1 ·· 2，ν/ν)作為洗提液將殘留物 進行層析，得3-氟-1 - [2-Ν-甲基-Ν-[3〜甲氧基-4-[Ν， -（2-甲基苯基）脲基]苯基]乙醯胺基]乙基-4_六氫吡啶乙 酸乙酯（160 *克，62%)的黃色非晶形固體。 1H-NMR (CDC 13) 5 1 24-1 ?8 , / w i. i. (mj 3Η) . 51-2. 23 (m, 7Η)、2· 26 (s，3Η)、2 3 9Η、 〆 &quot;乙·(s， 2Η) 、 2·39-2· 56 (m，Hz, 2H), 2·90 (m, 1H), 3·16 (m, 1H), 4u (q 'J= 7.1 Hz, 2H) &gt;4.67 (d, 1=48.3 Hz, 1H) ; ESI- MS m/z 247 CMH1) 〇3-fluoro-1-[2- N-methyl-N-[3-methoxy-4 - [Ν'-(2~methylphenyl))]phenyl Ethylamino]ethyl_4_hexahydroacridineacetate is intended for 3-methoxy-4 -[Ν'-(2-methylphenyl)ureido] stupyl acetic acid (164 mg '0.52 House Moer), 3_Fluoro-1 - [2_(N-methylamino)ethyl]-*hexahydroacridine ethyl acetate (117 mg, 〇·47 mmol), Et3N (〇·1 〇ml, 〇·71 mmol, and H0Bt (13.0 mg, 0·09 mmol) dissolved in THF (5 ml). Add EDC · Η (137 (137 mg, 〇·7ΐ ΐ After stirring for 8 hours at room temperature, the reaction mixture was diluted with water and extracted with EtOAc. The extract was washed with brine, dried and evaporated to dryness. · 2, ν / ν) The residue was chromatographed as an eluent to give 3-fluoro-1 -[2-Ν-methyl-Ν-[3~methoxy-4-[Ν, -(2 -methylphenyl)ureido]phenyl]acetamido]ethyl-4_hexahydropyridyl Ethyl acetate (160 g, 62%) of a yellow amorphous solid. 1H-NMR (CDC 13) 5 1 24-1 ?8 , / w ii (mj 3 Η) . 51-2. 23 (m, 7 Η ), 2·26 (s, 3Η), 2 3 9Η, 〆&quot; B·(s, 2Η), 2·39-2· 56 (m,

1283240 五、發明說明（837) 3H)、2·88 (m，1H)、2·95、3.03 (各S，總計3H)、3·11 (m， 1Η) 、3·44 (m， 1Η) 、3·56 (m， 1Η) 、3·64 (s， 2H)、3·68 (s，3H)、4·11-4·17 (m，2H)、4·57、4·69 (各s，總計 1Η)、6·72-6·82 (m，2Η)、7·10-7·33 (m， 5Η) 、7.54 (d， J=8.1 Ηζ， 1Η) 、8·06 (d， J=8.1 Hz, 1H) ; ESI-MS m/z 543 (MH1)。 於3-氟-1-[ 2-N-甲基-N-[ 3-甲氧基-4-[N，- (2 -甲基苯 基）脲基]苯基]乙醯胺基]乙基-4-六氫吼。定乙酸乙醋（160 毫克，〇· 29毫莫耳）溶於THF(3毫升）之溶液中加入〇· 25Ν NaOH( 1 ·30毫升，0·32毫莫耳）。於在室溫下攪拌1小時 後，將反應混合物濃縮。在0 °C下將殘留物以水稀釋，並 以1 N HC1中和。將混合物濃縮，並藉由離子交換樹脂 (HP-20，三菱化學）純化而得329 ( 1 1 0毫克，74%)之黃色非 晶形固體。IR (KBr) 3343、29 37、1 700、161 7、1 58 9、 1535、1486、1455、1417 /公分；UMR (CD3OD) (5 1· 57 -1.72 (m，2H)、1·98 (m，1H)、2·26 (m，1H)、2·28 (s，3H)、2·37-2·59 (m，3H)、2·6 6-2.89 (m，2H)、 2· 95、3· 09 (各s，總計 3H)、3. 14 (m，1H)、3· 40 (m， 1H)、3·51 (m，1H)、3.59 (m，1H)、3.72 (s，2H)、 3·78 (m，1H)、3·89 (s，3H)、4·69、4.81 (各s，總計 1H)、6· 79 (dd，J = 8· 1、1· 5 Hz，1H)、6· 90 (寬s，1H) 、7·01 (t，J = 7.8 Hz，1H)、7·13 - 7.19 (m，2H)、7·58 (d，J = 7· 8 Hz，1H)、8· 00 (d，J = 8· 1 Hz，1H) ; ESI -MS m/z 51 5 (M+ + l) ; C27H35FN4 05 · H20 之分析計算值：C，1283240 V. INSTRUCTIONS (837) 3H), 2·88 (m, 1H), 2.95, 3.03 (each S, total 3H), 3·11 (m, 1Η), 3·44 (m, 1Η) , 3·56 (m, 1Η), 3·64 (s, 2H), 3·68 (s, 3H), 4·11-4·17 (m, 2H), 4·57, 4·69 (each s, total 1Η), 6.72-6·82 (m, 2Η), 7·10-7·33 (m, 5Η), 7.54 (d, J=8.1 Ηζ, 1Η), 8·06 (d, J = 8.1 Hz, 1H); ESI-MS m/z 543 (MH1). 3-Fluoro-1-[2-N-methyl-N-[3-methoxy-4-[N,-(2-methylphenyl)ureido]phenyl]acetamido] Base-4-hexahydroindole. To a solution of acetonitrile (160 mg, 〇·29 mmol) dissolved in THF (3 mL) was added 〇· 25 Ν NaOH (1·30 mL, 0·32 mmol). After stirring at room temperature for 1 hour, the reaction mixture was concentrated. The residue was diluted with water at 0 °C and neutralized with 1 N HCl. The mixture was concentrated and purified by ion-exchange resin (HP-20, &lt;RTI ID=0.0&gt;&gt; IR (KBr) 3343, 29 37, 1 700, 161 7, 1 58 9 , 1535, 1486, 1455, 1417 / cm; UMR (CD3OD) (5 1· 57 -1.72 (m, 2H), 1·98 ( m,1H), 2·26 (m,1H), 2·28 (s,3H), 2·37-2·59 (m,3H), 2·6 6-2.89 (m,2H), 2· 95,3·09 (each s, total 3H), 3. 14 (m, 1H), 3·40 (m, 1H), 3·51 (m, 1H), 3.59 (m, 1H), 3.72 (s , 2H), 3·78 (m, 1H), 3·89 (s, 3H), 4·69, 4.81 (each s, total 1H), 6·79 (dd, J = 8·1, 1·5 Hz, 1H), 6·90 (width s, 1H), 7·01 (t, J = 7.8 Hz, 1H), 7·13 - 7.19 (m, 2H), 7·58 (d, J = 7· 8 Hz, 1H), 8·00 (d, J = 8·1 Hz, 1H); ESI -MS m/z 51 5 (M+ + l) ; C27H35FN4 05 · H20 Analysis calculated: C,

\\312\2d-code\90-01\89112968.ptd 第842頁 1283240 五、發明說明（838) 60.89; Η，7.00; Ν，10.52° 實測值：C，61.09; Η， 6. 80 ； Ν，9.87° 實施例280 4 - [2 - Ν-[2-(4-氟苯氧基）乙基]- Ν-[3-甲氧基-4-[Ν’ -（2-甲基苯基）脈基]苯基]乙酿胺基]乙基六氮吼°井基-1-乙酸\\312\2d-code\90-01\89112968.ptd Page 842 1283240 V. Description of invention (838) 60.89; Η, 7.00; Ν, 10.52° Measured value: C, 61.09; Η, 6. 80 ; Ν , 9.87° Example 280 4 - [2- Ν-[2-(4-fluorophenoxy)ethyl]-indole-[3-methoxy-4-[Ν'-(2-methylphenyl) Phenyl]phenyl]ethinyl]ethylhexaazepine

Me Η H C〇2H 330 1 - [2-(N-辛基-N_第三丁氧幾胺基）乙氧基]-4-氣苯Me Η H C〇2H 330 1 - [2-(N-octyl-N_t-butoxyamino)ethoxy]-4-benzene

和 fTFAnd fTF

BocNv^〜 在室溫下於2 -（N-芊基-N-第三丁氧羰胺基）乙醇（6.85 克，27.3毫莫耳）、4-氟酚（3.07克，27·3毫莫耳）及PPh3 (7·83克，30·0毫莫耳）溶於THFC100毫升）之溶液中加入 DIAD( 6. 00毫升，30. 0毫莫耳）。於攪拌3小時後，將反應 混合物濃縮。利用己烷-EtOAc(8:l，v/v)作為洗提液將殘 留物進行層析，得卜[2-(N-笮基-N-第三丁氧羰胺基）乙氧 基]-4-氟苯（8· 19 克，64%)的黃色油。1H-NMR (CDC13) 5 1.42-1.50 (m, 9H) ^3.41-3.67 (m, 2H) ^3.91-4.11 (m，2H)、4·51 -4.63 (m，2H)、6·73-6.85 (m，2H)、 6· 89-6· 98 (m，2H)、7. 24 (m，5H) ； FAB-MS m/z 346 (MH1)。 1 -（2-N-爷胺乙氧基）-4-氟苯BocNv^~ at 2 -(N-decyl-N-t-butoxycarbonylamino)ethanol (6.85 g, 27.3 mmol), 4-fluorophenol (3.07 g, 27.3 mmol) at room temperature To the solution of PPh3 (7·83 g, 30·0 mmol) dissolved in THF (100 ml) was added DIAD (6.0 00 ml, 30. 0 mmol). After stirring for 3 hours, the reaction mixture was concentrated. The residue was chromatographed using hexane-EtOAc (8:1, v/v) as eluent to give [2-(N-decyl-N-t-butoxycarbonylamino)ethoxy] 4-fluorobenzene (8·19 g, 64%) of yellow oil. 1H-NMR (CDC13) 5 1.42-1.50 (m, 9H) ^3.41-3.67 (m, 2H) ^3.91-4.11 (m, 2H), 4·51 - 4.63 (m, 2H), 6.73-6.85 (m, 2H), 6·89-6· 98 (m, 2H), 7. 24 (m, 5H); FAB-MS m/z 346 (MH1). 1-(2-N-tyranamine ethoxy)-4-fluorobenzene

^0J〇rF^0J〇rF

89112968.ptd 第843頁 1283240 五、發明說明（839) 在0°C下於1-[2-(N_芊基-N-第三丁氧羰胺基）乙氧 基]-4-氟苯（8·19克，23.7毫莫耳）溶於ch2C12(50毫升）之89112968.ptd Page 843 1283240 V. INSTRUCTIONS (839) 1-[2-(N-Mercapto-N-T-butoxycarbonylamino)ethoxy]-4-fluorobenzene at 0 ° C (8·19 g, 23.7 mmol) dissolved in ch2C12 (50 ml)

溶液中加入T F A ( 4 0毫升）。於在室溫下攪拌1小時後，將反 應混合物濃縮。將殘留物以飽和NaHC03溶液溶解，並以 CHC13萃取。將萃取液以鹽水洗滌，於Na2S04上乾燥，並濃 縮而得卜（2-N-苄胺乙氧基）-4-氟苯（4· 39克，75%)的淡紅 色油。UMR (CDC13) 6 3.00 (t, J = 5.2 Hz, 2H)、3.87 (s，2H)、4·04 (t，J = 5.2 Hz，2H)、6·80-6·85 (m，2H) 、6·92-6·98 (m，2H)、7·23-7·36 (m，5H) ; FAB-MS m/z 246 (MH1) o 4 - [2-N-苄基_N-[2-(4-氟苯氧基）乙基]胺基]乙基六氫吼 畊基-1 -乙酸乙酯 ΒπΝν^Ν^ C〇2Et 使1-(2 - N-苄胺乙氧基）-4 -氟苯（1.08克，4.40毫莫 耳）、4-(2 -溴乙基）六氫吼喷基-1-乙酸乙酯（1· 23克， 4.40 毫莫耳）、及K2C03((K61 克，17.9 毫莫耳）在ch3CN(50 毫升）中之混合物迴流加熱8小時。將所產生之混合物過 濾，並將濾液濃縮至乾。利用甲苯-丙酮（3 : 1，v/v)作為 洗提液將殘留物進行層析，得4 - [ 2-N-爷基-N- [ 2-( 4 氧基）乙基]胺基]乙基六氫吼啡基_1-乙酸乙酯（1·5ι克 77°/。）的淡紅色油。l-NMR (CDC13) 5 1· 27 (t，J = 7 1 ’ • x Hz,T F A (40 ml) was added to the solution. After stirring at room temperature for 1 hour, the reaction mixture was concentrated. The residue was dissolved in a saturated NaHC03 solution and extracted with CH.sub.3. The extract was washed with brine, dried over Na.sub.2SO.sub.sub.sub.sub.sub.sub.sub.sub. UMR (CDC13) 6 3.00 (t, J = 5.2 Hz, 2H), 3.87 (s, 2H), 4·04 (t, J = 5.2 Hz, 2H), 6·80-6·85 (m, 2H) , 6.92-6·98 (m, 2H), 7·23-7·36 (m, 5H); FAB-MS m/z 246 (MH1) o 4 - [2-N-benzyl_N- [2-(4-Fluorophenoxy)ethyl]amino]ethylhexahydroindole cultivating base-1 -ethyl acetate ΒπΝν^Ν^ C〇2Et 1-(2-N-benzylamine ethoxylate -4 -fluorobenzene (1.08 g, 4.40 mmol), 4-(2-bromoethyl)hexahydroindole-1-acetic acid ethyl ester (1·23 g, 4.40 mmol), and K2C03 ((K61 g, 17.9 mmol) mixture in ch3CN (50 mL) was heated under reflux for 8 h. The mixture was filtered and concentrated to dryness. Toluene-acetone (3:1, v/v The residue was chromatographed as an eluent to give 4-[2-N--yl-N-[2-(4-oxy)ethyl]amino]ethylhexahydroindolyl-1-acetic acid Light red oil of ethyl ester (1·5 ιg 77°/.). l-NMR (CDC13) 5 1· 27 (t, J = 7 1 ' • x Hz,

1283240 五、發明說明（840) 3H)、2·3 卜 2.66 (m，10H)、2·75 (t，J = 6.6 Hz，2H)、 2·90 (t，J = 6.1 Hz，2H)、3·18 (s，2H)、3·72 (s， 2 H)、3 · 9 7 (t， J = 6 · 1 H z，2 H)、4 · 1 7 (q，j = 7 · i h z， 2H) 、6·75-6.79 (m， 2H) 、6·9卜6.96 (m， 2H) 、7·21-7· 35 (m， 5H) ; FAB-MS m/z 444 (MH1)。 4 - [2-N-[2-(4-氟苯氧基）乙基]胺基]乙基六氫吼畊基— 乙酸乙醋 ΗΝχ^Ν、| C〇2Et 使4-[2-N-爷基-N-[2-(4-氟苯氧基）乙基]胺基]乙基六 氫吼畊基-1-乙酸乙酯（1.50克，3.38毫莫耳）溶於EtOH (30毫升）之溶液在5% Pd-C(53.1%濕，0.73克）上在氫氣中 氫化4小時。將催化劑過濾掉，並將濾液濃縮。將殘留物 以飽和NaHC03溶液溶解，並以CHC13萃取。將萃取液以鹽水 洗滌，於Na2S04上乾燥，並濃縮而得4-[2-1^_[2-(4-氟苯氧 基）乙基]胺基]乙基六氫咄畊基-1 -乙酸乙酯（1. 1 2克，94% )的淡紅色油。UMR (CDC13)(5 1.27 (t，J = 7.1 Hz， 3H)、1.81 (寬s，1Η)、2·47-2.66 (m，12Η)、3·〇〇 (t， J二5· 4 Hz，2H)、3· 20 (s，2H)、4· 03 (t，J = 5.4 Hz, 2H)、4·18 (q，J = 7.1 Hz，2H)、6·8 卜 6.85 (m，2H)、 6·90-6·99 (m，2H) ; FAB-MS m/z 354 (MH1)。 4-[2-N - [2-（4-氟苯氧基）乙基]-N-[ 3-曱氧基-4- [Ν’ _(2_ 甲基苯基）脲基]笨基]乙醯胺基]乙基六氫吼畊基-1_乙酸 乙酯1283240 V. Description of invention (840) 3H), 2·3 Bu 2.66 (m, 10H), 2·75 (t, J = 6.6 Hz, 2H), 2·90 (t, J = 6.1 Hz, 2H), 3·18 (s, 2H), 3·72 (s, 2 H), 3 · 9 7 (t, J = 6 · 1 H z, 2 H), 4 · 1 7 (q, j = 7 · ihz , 2H), 6·75-6.79 (m, 2H), 6. 9 b 6.96 (m, 2H), 7·21-7· 35 (m, 5H); FAB-MS m/z 444 (MH1). 4-[2-N-[2-(4-Fluorophenoxy)ethyl]amino]ethylhexahydroindole cultivating - ethyl acetate ΗΝχ Ν, | C〇2Et 4-[2-N -Y-based-N-[2-(4-fluorophenoxy)ethyl]amino]ethylhexahydroindole oleyl-1-acetic acid ethyl ester (1.50 g, 3.38 mmol) dissolved in EtOH (30) A solution of cc) was hydrogenated over 5% Pd-C (53.1% wet, 0.73 g) in hydrogen for 4 h. The catalyst was filtered off and the filtrate was concentrated. The residue was dissolved in a saturated NaHC03 solution and extracted with CH.sub.3. The extract was washed with brine, dried over Na 2 SO 4 and concentrated to give 4-[2-[2-(4-fluorophenoxy)ethyl]amino]ethylhexahydroindole - Ethyl acetate (1.12 g, 94%) of light red oil. UMR (CDC13) (5 1.27 (t, J = 7.1 Hz, 3H), 1.81 (width s, 1 Η), 2·47-2.66 (m, 12 Η), 3·〇〇 (t, J 2 5. 4 Hz , 2H), 3· 20 (s, 2H), 4· 03 (t, J = 5.4 Hz, 2H), 4·18 (q, J = 7.1 Hz, 2H), 6·8 b 6.85 (m, 2H ), 6·90-6·99 (m, 2H); FAB-MS m/z 354 (MH1). 4-[2-N - [2-(4-Fluorophenoxy)ethyl]-N- [ 3-decyloxy-4-[Ν' _(2-methylphenyl)ureido]]ylamino]ethylaminoethyl hexahydroindole-1-ethyl acetate

繼__Following __

\\312\2d-code\90-01\89112968.ptd 第845頁 1283240 五、發明說明（841)\\312\2d-code\90-01\89112968.ptd Page 845 1283240 V. Description of Invention (841)

在室，下於3-甲氧基—4- [N，- (2-甲基苯基）脲基]苯基乙 酸（485宅克’1·54毫莫耳）、4-[2-N-[2-(4-氟苯氧基）乙 基]胺基]乙基六氫咄畊基-丨―乙酸乙酯（545毫克，154毫 莫耳）、Et3N(0.32毫升，2.32毫莫耳）、及H0Bt(41· 5毫 克，〇· 31毫莫耳）溶於THF(15毫升）之溶液中加入EDC · HC 1 (88 3毫克’ 2· 32毫莫耳）。於攪拌24小時後，將反應混 合物以水稀釋，並以CHCl3-MeOH( 10 : 1，v/v)萃取。將萃 取液以鹽水洗滌’於Na2S04上乾燥，並濃縮至乾。利用 CHC13 - Me0H(4:l，v/v)作為洗提液將殘留物進行層析，而 得4 - [2 - N-[2 -（4 -氟笨氧基）乙基]-N-[3-甲氧基-4 - [Ν’ -(2-甲基苯基）脲基]苯基]乙醯胺基]乙基六氫吼喷基-1 -乙酸乙酯（ 53 2毫克，53%)的黃色非晶形固體。l-NMR (CDC13) 5 1· 26、1· 27 (各t，J = 7. 1 Hz，總計3H)、2· 2 7 (s，3H)、2. 51-2· 63 (m，1 OH)、3· 16、3. 19 (各s，總計 2H)、3· 5卜3· 56 (m，2H)、3· 63、3· 67 (各s，總計2H)、 3.69-3.81 (m，5H)、3.95、4·1〇 (各t，J = 5·2 Hz，總計 2H)、4· 16、4· 18 (各q，J = 7· 1 Hz，總計2H)、6· 5 6 (d， J = 8.1 Hz，1H)、6·72-6·78 (m，4H)、6·89-6.98 (m， 2H)、7·12 (t，J = 7.6 Hz，1H)、7·20-7·23 (m，3H)、7· 51 (d，J = 7.6 Hz，1H)、8·04 (d，J = 8.1 Hz，1H); FAB-MS m/z 650 (MH1)。In the chamber, under 3-methoxy-4-[N,-(2-methylphenyl)ureido]phenylacetic acid (485 克克'1·54 mmol), 4-[2-N -[2-(4-Fluorophenoxy)ethyl]amino]ethylhexahydroindole cultivating-indole-ethyl acetate (545 mg, 154 mmol), Et3N (0.32 ml, 2.32 mmol) And H0Bt (41.5 mg, 〇 31 mmol) dissolved in THF (15 mL) was added EDC · HC 1 (88 3 mg ' 2 · 32 mmol). After stirring for 24 hours, the reaction mixture was diluted with water and extracted with CHCI3-MeOH (10:1, v/v). The extract was washed with brine and dried over Na.sub.2SO.sub.4 and concentrated to dry. The residue was chromatographed using CHC13-Me0H (4:1, v/v) as eluent to give 4-[2-(2-(4-fluoro)ethyl)-N- [3-Methoxy-4 -[Ν'-(2-methylphenyl)ureido]phenyl]acetamido]ethylhexahydroindole-1 - ethyl acetate (53 2 mg, 53%) yellow amorphous solid. l-NMR (CDC13) 5 1· 26, 1· 27 (each t, J = 7. 1 Hz, total 3H), 2· 2 7 (s, 3H), 2. 51-2· 63 (m, 1 OH), 3·16, 3.19 (each s, total 2H), 3·5 Bu 3· 56 (m, 2H), 3·63, 3·67 (each s, total 2H), 3.69-3.81 ( m, 5H), 3.95, 4·1〇 (each t, J = 5·2 Hz, total 2H), 4·16, 4·18 (each q, J = 7· 1 Hz, total 2H), 6· 5 6 (d, J = 8.1 Hz, 1H), 6·72-6·78 (m, 4H), 6·89-6.98 (m, 2H), 7·12 (t, J = 7.6 Hz, 1H) , 7·20-7·23 (m, 3H), 7· 51 (d, J = 7.6 Hz, 1H), 8·04 (d, J = 8.1 Hz, 1H); FAB-MS m/z 650 ( MH1).

\\312\2d-code\90-01\89112968.ptd 第846頁 1283240 五、發明說明（842) 在室溫下於4 - [2-N-[2 -（4-氟苯氧基）乙基]—N-[3-甲氧 基-4-[Ν’ -(2-甲基苯基）脲基]苯基]乙醯胺基]乙基六氫吼 嘴基-1-乙酸乙酯（532毫克，〇·82毫莫耳）溶於二氧陸圜（8 毫升）之溶液中逐滴加入〇· 25Ν Na0H(5· 00毫升，1. 25毫莫 耳）’並使反應混合物攪拌1小時。將所產生之混合物濃 縮，以水稀釋，並在〇 °c下以IN HC1中和。以CHCl3-MeOH (4: 1，v/v)萃取混合物。將萃取液以鹽水洗滌，於 Na2S04上乾燥’並濃縮至乾。利用CHC13-MeOH(3:l，v/v) 作為洗提液將殘留物進行層析，而得330 ( 1 68毫克，33%) 的淡黃色非晶形固體。IR (KBr) 3338、2938、2829、 1635、1533、1506、1454、1415 /公分；UMR (DMSO-d6 2·25 (s，3H)、2·3 7-2·48 (m，6H)、2·53_2·67 (m， 6H)、3·09 (m，2H)、3·44-3·49 (m，2H)、3·64-3·69 (m，2Η)、3·72 (s，2Η)、3·80、3·84 (各s，總計 3Η)、 4·06-4·09 (m，2H)、6·73 (m，1H)、6·85 (s，1H)、 6·9卜6·97 (m，3H)、7·07-7·18 (m，4H)、7·78 (d，J = 8·1 Hz，1H)、8·00 (dd，J = 8.1、2·7 Hz，1H)、8·53 (m，1H)、8· 59 (m，1H) ; FAB-MS m/z 622 (M+ + 1); C33 H4〇 F N5 06 · 2 H C1 之分析計算值：c，5 7 · 0 6 ; H，6 · 0 9 ; N， 10· 08。實測值：c，56. 83 ; H，6. 05 ; N，9· 90。 實施例281 4 - [2-N-[2 -（4-乙醯苯氧基）乙基]一 N-[3-甲氧基-4-[Ν’ - (2-甲基苯基）脲基]苯基]乙醯胺基]乙基六氫咄畊基_ι 一乙 酸\\312\2d-code\90-01\89112968.ptd Page 846 1283240 V. INSTRUCTIONS (842) at room temperature in 4 - [2-N-[2 -(4-fluorophenoxy) ]]-N-[3-methoxy-4-[Ν'-(2-methylphenyl)ureido]phenyl]acetamido]ethylhexahydropyranyl-1-ethyl acetate (532 mg, 〇·82 mmol) dissolved in dioxane (8 ml) in a solution of 〇·25Ν Na0H (5·00 ml, 1.25 mmol) and the reaction mixture was stirred. 1 hour. The resulting mixture was concentrated, diluted with water, and neutralized with IN HCl at 〇 °c. The mixture was extracted with CHCl3-MeOH (4:1, v/v). The extract was washed with brine, dried <RTI ID=0.0> The residue was chromatographed eluting EtOAc (EtOAc:EtOAc:EtOAc IR (KBr) 3338, 2938, 2829, 1635, 1533, 1506, 1454, 1415 / cm; UMR (DMSO-d6 2·25 (s, 3H), 2·3 7-2·48 (m, 6H), 2·53_2·67 (m, 6H), 3·09 (m, 2H), 3·44-3·49 (m, 2H), 3·64-3·69 (m, 2Η), 3·72 ( s, 2Η), 3·80, 3.84 (each s, total 3Η), 4·06-4·09 (m, 2H), 6.73 (m, 1H), 6.85 (s, 1H) , 6·9 Bu 6·97 (m, 3H), 7·07-7·18 (m, 4H), 7·78 (d, J = 8·1 Hz, 1H), 8·00 (dd, J = 8.1, 2·7 Hz, 1H), 8·53 (m, 1H), 8·59 (m, 1H); FAB-MS m/z 622 (M+ + 1); C33 H4〇F N5 06 · 2 Analysis calculated for H C1: c, 5 7 · 0 6 ; H, 6 · 0 9 ; N, 10· 08. Found: c, 56. 83; H, 6. 05; N, 9· 90. Example 281 4 - [2-N-[2-(4-Ethylphenoxy)ethyl]-N-[3-methoxy-4-[Ν'-(2-methylphenyl)ureido Phenyl]acetamido]ethylhexahydroindole cultivating base_ι-acetic acid

89112968.ptd 第847頁 1283240 五、發明說明（843)89112968.ptd Page 847 1283240 V. INSTRUCTIONS (843)

co2h 331 4 - [2-(N-辛基-N-第三丁氧羰胺基）乙氧基]苯乙酉同Co2h 331 4 - [2-(N-octyl-N-t-butoxycarbonylamino)ethoxy]phenidinium

在室温下於2-(N-苄基-N-第三丁氧羰胺基）乙醇（5. g〇 克，23·5毫莫耳）、4 -羥基苯乙酮（3.18克，23·5毫莫耳） 及PPh3(6· 74克’ 25· 8宅莫耳）溶於THF(l〇〇毫升）之溶液中 加入DIAD(5· 20毫升，25· 8毫莫耳）。將反應混合物迴流加 熱4小時並濃縮。利用己烧-E10 A c ( 5 : 1，v / v)作為洗提液 將殘留物進行層析，得4-[2-(N-苄基-N-第三丁氧幾胺基） 乙乳基]本乙嗣（3.64克’42%)的黃色油。ijj - NMR (CDC1 ) 5 1.43-1.65 (m，9H)、2·55 (s，3H)、3·41 -3 69 (m 2H)、4.02-4.24 (m，2H)、4.4 9-4.66 (m，2H)、6 81- 6 · 9 3 (m，2 H)、7 · 1 9 - 7 · 3 7 (m，5 H)、7 · 91 (d，j = 8 82-(N-Benzyl-N-t-butoxycarbonylamino)ethanol (5. g gram, 23.5 mmol), 4-hydroxyacetophenone (3.18 g, 23·) at room temperature Add 3 D of DIA (5·20 ml, 25.8 mmol) to a solution of PPh3 (6·74 g '25·8 houser) dissolved in THF (10 mL). The reaction mixture was heated at reflux for 4 h and concentrated. The residue was chromatographed using hexane-E10 A c (5:1, v / v) as an eluent to give 4-[2-(N-benzyl-N-t-butoxyamino) Milky base] This ethyl hydrazine (3.64 g '42%) of yellow oil. Ijj - NMR (CDC1 ) 5 1.43-1.65 (m, 9H), 2·55 (s, 3H), 3·41 -3 69 (m 2H), 4.02-4.24 (m, 2H), 4.4 9-4.66 ( m, 2H), 6 81- 6 · 9 3 (m, 2 H), 7 · 1 9 - 7 · 3 7 (m, 5 H), 7 · 91 (d, j = 8 8

Hz, 2H) ; FAB-MS m/z 370 (MH1)。 4 -（2-N-芊胺乙氧基）苯乙酉同Hz, 2H) ; FAB-MS m/z 370 (MH1). 4-(2-N-decylamine ethoxy)phenidinium

在0°C下於4-[2-(N-芊基-N-第三丁氧羰胺基）乙氧基]笨 乙嗣（3. 05克，8. 26毫莫耳）溶於cj^ci2 (30毫升）之溶液中 加入TFA(20毫升）。於在室溫下攪拌2小時後，將反應混合 物濃縮。將殘留物以飽和NaHC〇3溶液溶解，並以CHC^共〇 3 「4-[2-(N-Mercapto-N-t-butoxycarbonylamino)ethoxy]ethylidene (3. 05 g, 8.26 mmol) dissolved in cj at 0 ° C To the solution of ^ci2 (30 ml) was added TFA (20 mL). After stirring at room temperature for 2 hours, the reaction mixture was concentrated. Dissolve the residue in a saturated NaHC〇3 solution and coexist with CHC^ 3

89112968.ptd 第848頁 1283240 五、發明說明（844) 取。將萃取液以鹽水洗滌，於Na2S04上乾燥，並濃縮而得 4-(2-N-苄胺乙氧基）苯乙酮（2.21克，99%)的淡紅色油。 UMR (CDC13) 6 2· 04 (寬s，1H)、2. 55 (s，3H)、3· 0 5 (t，J = 5.4 Hz，2H)、3·88 (s，2H)、4·15 (t，J = 5.4 Hz， 2H) 、6·92 (d， J二8.9 Hz， 2H) 、7·24-7·36 (m, 5H) 、7·91 (d，J = 8.9 Hz, 2H); FAB-MS m/z 270 (MH1) o 4-(2 -溴乙基）六氫咄畊基-1_乙酸乙酯 L^N^C〇2Et 在0°C下於4-(2 -羥乙基）六氫咄畊基-1-乙酸乙酯（π. 3 克，52.1毫莫耳）及CBr4(20.7克，62·5毫莫耳）溶於ch2C12 ( 20 0毫升）之溶液中逐份加入PPh3(19· 2克，73·0毫莫耳） ，並使反應混合物攪拌3 0分鐘。將己烷加至混合物，將沈 澱物過濾掉，及將濾液濃縮而得4-(2-溴乙基）六氫吡讲基 -卜乙酸乙酯（13· 7克，94%)的黃色油。ih-NMR (CDC13) 6 1.27 (t, -J = 7.1 Hz, 3H) &gt;2.61-2.78 (m, 8H) ^2.81 (t，J二7.6 Hz，2H)、3·20 (s，2H)、3·42 (t，J = 7.689112968.ptd Page 848 1283240 V. Description of invention (844) Take. The extract was washed with brine, dried over Na2~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ UMR (CDC13) 6 2· 04 (width s, 1H), 2. 55 (s, 3H), 3· 0 5 (t, J = 5.4 Hz, 2H), 3·88 (s, 2H), 4· 15 (t, J = 5.4 Hz, 2H), 6.92 (d, J 8.9 Hz, 2H), 7·24-7·36 (m, 5H), 7·91 (d, J = 8.9 Hz, 2H); FAB-MS m/z 270 (MH1) o 4-(2-bromoethyl)hexahydroquinone tillage-1_ethyl acetate L^N^C〇2Et at 0°C at 4-( 2-Hydroxyethyl)hexahydroindolyl-1-acetic acid (π. 3 g, 52.1 mmol) and CBr4 (20.7 g, 62·5 mmol) dissolved in ch2C12 (20 mL) PPh3 (19.2 g, 73.0 mmol) was added portionwise to the solution, and the reaction mixture was stirred for 30 min. Hexane was added to the mixture, the precipitate was filtered off, and the filtrate was concentrated to give 4-(2-bromoethyl)hexahydropyryl-ethylacetate (13.7 g, 94%) of yellow oil. . Ih-NMR (CDC13) 6 1.27 (t, -J = 7.1 Hz, 3H) &gt;2.61-2.78 (m, 8H) ^2.81 (t, J 2 7.6 Hz, 2H), 3·20 (s, 2H) , 3·42 (t, J = 7.6

Hz, 3H)、4· 18 U，J = 7· 1 Hz，2H)。 4 - [2 - [N-苄基- N- [2-(4-乙醢苯氧基）乙基]胺基]乙基六氫 °比0井基-1 -乙酸乙S旨 Ο*、 C〇2Et 使4-(2-N-苄胺乙氧基）苯乙酮（681毫克，2.52毫莫 耳）、4-(2 -溴乙基）六氫咄畊基-1-乙酸乙酯（7〇5毫克，Hz, 3H), 4· 18 U, J = 7· 1 Hz, 2H). 4-[2-[N-Benzyl-N-[2-(4-acetamidophenoxy)ethyl]amino]ethylhexahydrogen ratio 0 well base-1 -acetic acid B. C〇2Et 4-(2-N-benzylamine ethoxy)acetophenone (681 mg, 2.52 mmol), 4-(2-bromoethyl)hexahydroindole-l-ethyl acetate (7〇5 mg,

89112968.ptd 第849頁 1283240 五、發明說明（845) 2· 52 耄莫耳）、及](2(：〇3 ( 349 克，2· 52 毫莫耳）在CH3CN(10 毫 升）中之混合物迴流加熱2 2小時。將所產生之混合物過 濾，並將濾液濃縮至乾。利用曱笨-丙酮（1 ··丨，v/v)作為 洗提液將殘留物進行層析，得4-[2-[N-苄基— n-[ 2-(4-乙 醯苯氧基）乙基]胺基]乙基六氫吼畊基—1-乙酸乙酯（92〇毫 克，78%)的淡紅色油。iH —NMr (CDCl3) I.”（t，J = 7189112968.ptd Page 849 1283240 V. INSTRUCTIONS (845) 2· 52 耄莫耳), and](2(:〇3 (349 g, 2·52 mmol) in CH3CN (10 ml) The mixture was heated under reflux for 2 hours, and the resulting mixture was filtered, and the filtrate was concentrated to dryness. The residue was chromatographed using EtOAc (1···, v/v) as eluent to give 4-[ 2-[N-Benzyl-n-[2-(4-ethylphenoxy)ethyl]amino]ethylhexahydroindole-l-ethyl acetate (92 mg, 78%) Light red oil. iH —NMr (CDCl3) I.” (t, J = 71

Hz，3H)、2·45-2·53 (m，10H)、2·55 (s，3H)、2·76 (t，J = 6.8 Hz，2H)、2·94 (t，J = 6.1 Hz，2H)、3·18Hz, 3H), 2·45-2·53 (m, 10H), 2·55 (s, 3H), 2·76 (t, J = 6.8 Hz, 2H), 2·94 (t, J = 6.1 Hz, 2H), 3.18

(s，2H)、.3·73 (s，2H) '4.06 (t，J = 6.1 Hz，2H)、 4·17 (q， J=7.1 Hz， 2H) 、6·85 (d， J=7.1 Hz， 2H)、 7.22-7·35 (m，5H)、7.90 (d，J = 7.1 Hz, 2H) ; FAB-MS m/z 468 (MH1) 〇 4_[2-N-[2-(4_乙醯苯氧基）乙基]胺基]乙基六氫吡畊基 - 1 -乙酸乙涵旨 hC:(s, 2H), .3·73 (s, 2H) '4.06 (t, J = 6.1 Hz, 2H), 4·17 (q, J=7.1 Hz, 2H), 6.85 (d, J= 7.1 Hz, 2H), 7.22-7·35 (m, 5H), 7.90 (d, J = 7.1 Hz, 2H); FAB-MS m/z 468 (MH1) 〇4_[2-N-[2-( 4_Ethylphenoxy)ethyl]amino]ethylhexahydropyrrole- 1 -acetic acid B

XT C〇2EtXT C〇2Et

卞基-N-[2~(4_乙醯苯氧基）乙基]胺基]乙基 酸乙si(92〇毫* ’97毫莫耳）溶於Et〇H 山# ， 士 α LC53· 1%濕，510耄克）上在氫氣 中鼠化4小日τγ。將催化添丨丨说，奋4占 .v . ^ M urn ^ 刈過濾掉，並將濾液濃縮。將殘留 物以飽和NaHC03溶液溶解# 畔 並以CHC 萃取。將萃取液以鹽 水洗滌’於Na2S04上乾燥并、曲 ^ ϋ A w a 1 Ηώ ^ Ί 並浪縮而得4-[2-Ν-[2-(4-乙醯 本乳基）乙基]胺基]乙農二与,.^ ,卞-N-[2~(4_Ethylphenoxy)ethyl]amino]ethyl acid ethyl Si (92〇 milli* '97 mmol) is soluble in Et〇H Mountain # ,士α LC53 · 1% wet, 510 gram) was incubated in hydrogen for 4 days of τγ. The catalyst was added, and Fen 4 was occupied by .v . ^ M urn ^ 刈 filtered, and the filtrate was concentrated. The residue was dissolved in saturated NaHC03 solution and extracted with CHC. The extract was washed with brine to dry on Na2S04, and then ^A wa 1 Ηώ ^ Ί and swelled to give 4-[2-Ν-[2-(4-ethyl sulfonyl)ethyl]amine Base] Bunong II and , .^ ,

卷/、虱咄畊基-1 -乙酸乙酯（6 9 〇毫Roll /, 虱咄耕基-1 - ethyl acetate (6 9 〇 〇

第850頁 1283240 五、發明說明（846) 克，93%)的淡紅色油。ih-NMR (CDC13)(5 1.27 (t，J = 7.1 Hz，3H)、2·55 (s，3H)、2·46-2.5 4 (m，10H)、2·78 (t，J = 6.2 Hz，2H)、3·04 (t，J = 5.2 Hz，2H)、3·20 (s，2H)、4·13 (t，J = 5· 2 Hz，2H)、4· 18 U，J = 7· 1Page 850 1283240 V. Description of invention (846) grams, 93%) of light red oil. ih-NMR (CDC13) (5 1.27 (t, J = 7.1 Hz, 3H), 2·55 (s, 3H), 2·46-2.5 4 (m, 10H), 2·78 (t, J = 6.2 Hz, 2H), 3·04 (t, J = 5.2 Hz, 2H), 3·20 (s, 2H), 4·13 (t, J = 5· 2 Hz, 2H), 4· 18 U, J = 7· 1

Hz，2H)、6.92 (d，J = 8.8 Hz, 2H)、7·92 (d, J = 8.8 Hz，2H); FAB-MS m/z 378 (MH1)。 4 - [2-N - [2-(4-乙醯笨氧基）乙基]-N - [3-甲氧基-4-[N，- (2-甲基苯基）脲基]笨基]乙醯胺基]乙基六氫吼坪基-1 一乙 酸乙酯 在室溫下於3-曱氧基-4- [N，- (2-甲基苯基）脲基]苯基乙 酸（ 558毫克，1·77毫莫耳）、4-[2-N-[2-(4-乙醯笨氧基） 乙基]胺基]乙基六氫吡畊基-1-乙酸乙酯（670毫克，1.77 毫莫耳）、Et3N(0.38毫升，2.66毫莫耳）、及HOBt (50.0克，0.35毫莫耳）溶於THF(1〇毫升）之溶液中加入EDC • HC 1 ( 883毫克’ 2· 32毫莫耳）。於攪拌15小時後，將反應 混合物以水稀釋’並以011(]13-116〇11(10:1，¥/\〇萃取 。將萃取液以鹽水洗滌，於Na2s〇4上乾燥，並濃縮至乾。 利用CHCl3-MeOH(4: 1，v/v)作為洗提液將殘留物進行層 析，而得4_[2-N - [2-（4-乙醯苯氧基）乙基卜甲氧基 -4-[Ν’ -(2-甲基苯基）脲基]苯基]乙醯胺基]乙基六氫吼 畊基-1-乙酸乙Sa (724毫克，η%)的黃色非晶形固體。Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 7.92 (d, J = 8.8 Hz, 2H); FAB-MS m/z 378 (MH1). 4-[2-N-[2-(4-Ethyloxy)ethyl]-N-[3-methoxy-4-[N,-(2-methylphenyl)ureido] Ethylamino]ethylhexahydroindolyl-1 ethyl acetate at room temperature in 3-methoxy-4-[N,-(2-methylphenyl)ureido]phenyl Acetic acid (558 mg, 1.77 mmol), 4-[2-N-[2-(4-ethinyloxy)ethyl]amino]ethylhexahydropyrryl-1-acetic acid Add EDC • HC 1 (Ester (670 mg, 1.77 mmol), Et3N (0.38 mL, 2.66 mmol), and HOBt (50.0 g, 0.35 mmol) in THF (1 mL) 883 mg '2·32 mAh). After stirring for 15 hours, the reaction mixture was diluted with water and extracted with 011(] 13-116 〇 11 (10:1, hexanes.). The extract was washed with brine, dried over Na.sub.2, and concentrated. The residue was chromatographed using CHCl3-MeOH (4:1, v/v) as eluent to give 4-[2-N-[2-(4-ethylphenoxy)ethyl b. Methoxy-4-[Ν'-(2-methylphenyl)ureido]phenyl]acetamido]ethylhexahydroindolyl-1-acetic acid ethyl E (724 mg, η%) Yellow amorphous solid.

\\312\2d-code\90-01\89112968.ptd 第851頁 1283240 五、發明說明（847) M-NMR (CDC13) 5 1· 25、1· 27 (各t，J = 7· 1 Hz，總計3H) 、2·29 (s，3H)、2·45-2·51 (m，8H)、2·54 (s，3H)、 2.55-2·63 (m，2Η)、3·17、3·19 (各s，總計 2Η)、3·51 -3·55 (m，2Η)、3·60 (s，2Η)、3.69 (s，3Η)、3·7卜 3·78 (m，2Η)、4·04-4·23 (m，4Η)、6·47 (m，1Η，J = 8·1 Hz)、6·72-6·76 (m，2H)、6·85 (d，J = 8.8 Hz, 2H)、7·12-7·19 (m，2H)、7·20-7·24 (m，2H)、7·51 (d，8.1 Hz，1H)、7·88 (d，J = 8.8 Hz，2H)、8·04 (d， J = 8.1 Hz, 1H); FAB-MS m/z 674 (M+ + 1) 〇 在室溫下於4-[2_1^-[2-(4-乙醯苯氧基）乙基]-1^-[3-甲 氧基-4- [Ν’-（2_甲基苯基）脲基]苯基]乙醯胺基]乙基六氫 咄畊基-1-乙酸乙酯（724毫克，1· 07毫莫耳）溶於THF(10毫 升）之溶液中逐滴加入〇· 25N Na0H(6· 50毫升，1. 61毫莫 耳），並使反應混合物攪拌1小時。將所產生之混合物濃 縮，以水稀釋，並在0 °C下以IN HC1中和。以CHC13-MeOH (4: 1，v/v)萃取混合物。將萃取液以鹽水洗滌，於Na2S04 上乾燥，並濃縮至乾。利用CHCl3-MeOH(3: 1，v/v)作為洗 提液將殘留物進行層析，而得33 1 ( 450毫克，65%)的淡黃 色非晶形固體。IR (KBr) 3345、2 938、282 1、1 673、 1631、1 598、1533、1 455、1417 / 公分；UMR (DMS0-d6 )(5 2·25 (s, 3H)、2.35-2.47 (m， 8H)、2·51 (s， 3H) 、2·53-2·58 (m，2H)、2·96 (s，2H)、3·46-3·50 (m， 2Η)、3·69 (s，2Η)、3·73-3.77 (m，2Η)、3·80、3·83 (各s，總計3Η)、4·19-4·22 (m，2Η)、6·73 (m, 1Η)、\\312\2d-code\90-01\89112968.ptd Page 851 1283240 V. INSTRUCTIONS (847) M-NMR (CDC13) 5 1· 25, 1· 27 (each t, J = 7· 1 Hz , total 3H), 2·29 (s, 3H), 2·45-2·51 (m, 8H), 2·54 (s, 3H), 2.55-2·63 (m, 2Η), 3.17 , 3·19 (each s, total 2Η), 3·51 -3·55 (m, 2Η), 3·60 (s, 2Η), 3.69 (s, 3Η), 3·7 Bu 3·78 (m , 2Η), 4·04-4·23 (m, 4Η), 6·47 (m, 1Η, J = 8·1 Hz), 6.72-6·76 (m, 2H), 6.85 ( d, J = 8.8 Hz, 2H), 7·12-7·19 (m, 2H), 7·20-7·24 (m, 2H), 7·51 (d, 8.1 Hz, 1H), 7· 88 (d, J = 8.8 Hz, 2H), 8·04 (d, J = 8.1 Hz, 1H); FAB-MS m/z 674 (M+ + 1) 〇 at room temperature at 4-[2_1^- [2-(4-Ethylphenoxy)ethyl]-1^-[3-methoxy-4-[Ν'-(2-methylphenyl)ureido]phenyl]acetamido Ethyl hexahydroindolyl-1-acetic acid ethyl ester (724 mg, 1.07 mmol) dissolved in THF (10 ml) was added dropwise 〇·25N Na0H (6·50 ml, 1. 61 mmol) and the reaction mixture was stirred for 1 hour. The resulting mixture was concentrated, diluted with water, and neutralized with IN HCl at 0 °C. The mixture was extracted with CHC13-MeOH (4:1, v/v). The extract was washed with brine, dried over Na 2 EtOAc and concentrated to dry. The residue was chromatographed eluting with EtOAc (EtOAc:EtOAc) IR (KBr) 3345, 2 938, 282 1, 1 673, 1631, 1 598, 1533, 1 455, 1417 / cm; UMR (DMS0-d6) (5 2·25 (s, 3H), 2.35-2.47 ( m, 8H), 2·51 (s, 3H), 2·53-2·58 (m, 2H), 2·96 (s, 2H), 3·46-3·50 (m, 2Η), 3 ·69 (s, 2Η), 3.73-3.77 (m, 2Η), 3·80, 3·83 (each s, total 3Η), 4·19-4·22 (m, 2Η), 6.73 (m, 1Η),

89112968.ptd 第852頁 1283240 五、發明說明（848) 6.85 (s，1H)、6·92 (t，J = 7.3 Hz，1H)、7·30 (d， J=7.3 Hz， 2H) 、7·10-7·16 (m， 2H) 、7.79 (d， J=8.3 Hz，1H)、7·90-7.95 (m，2H)、8·00 (t，J = 8.3 Hz， 1H)、8·55 (m，1H)、8.61 (m，1H); FAB-MS m/z 646 (MH1 ) ; C35H43N5 07 · 2HC1 · 1H20 之分析計算值·· C，57· 06 ; H，6.43; N, 9. 51。實測值：C，59.17； H，6.32; N， 9· 6卜 實施例2 8 289112968.ptd Page 852 1283240 V. INSTRUCTIONS (848) 6.85 (s, 1H), 6.92 (t, J = 7.3 Hz, 1H), 7·30 (d, J = 7.3 Hz, 2H), 7 ·10-7·16 (m, 2H), 7.79 (d, J=8.3 Hz, 1H), 7·90-7.95 (m, 2H), 8·00 (t, J = 8.3 Hz, 1H), 8 · 55 (m, 1H), 8.61 (m, 1H); FAB-MS m/z 646 (MH1 ) ; C35H43N5 07 · 2HC1 · 1H20 Analytical calculations · · C, 57 · 06 ; H, 6.43; N, 9. 51. Found: C, 59.17; H, 6.32; N, 9·6 b Example 2 8 2

4 - [2- N- [4 - [Ν’ -（2 -漠苯基）脈基]-3-甲氧苯基]- N-辛基乙 醯胺基]乙基-1 -六氫咄啶基乙酸4 - [2- N- [4 - [Ν' -(2 - 苯基 phenyl) yl)-3-methoxyphenyl]- N-octyl acetylamino]ethyl-1 -hexahydroindole Acrylacetic acid

4-[2-N-[4-[Ν’ -（2_溴苯基）脲基]-3-甲氧苯基]-N-苄基乙 醯胺基]乙基-1 -六氫吼啶基乙酸甲酯4-[2-N-[4-[Ν' -(2-bromophenyl)ureido]-3-methoxyphenyl]-N-benzylethylamino]ethyl-1 -hexahydroindole Methyl pyridine

4-（2 -羥乙基）-卜六氫咄啶乙酸苄酯 ΗΟ ,C〇2Bn 使六氫吡啶乙醇（10. 0克，77. 4毫莫耳）、2 -溴乙酸苄酯 (17. 8克，77· 6毫莫耳）及1(2(：03(21· 4克，155毫莫耳）在 CH3CN( 200毫升）中之混合物在攪拌下迴流加熱2小時。經4-(2-Hydroxyethyl)- hexahydroacridine benzyl acetate oxime, C〇2Bn hexahydropyridine ethanol (10.0 g, 77.4 mmol), 2-bromobenzyl acetate (17 A mixture of 8 g, 77·6 mmol, and 1 (2 (:03 (21.4 g, 155 mmol)) in CH3CN (200 mL) was heated under reflux for 2 hours.

89112968.ptd 第853頁 1283240 五、發明說明（849) 由過濾將不溶解的固體移除，並將濾液於真空中濃縮。將 殘留物倒入至冰的IN HC1中，並以CHC13萃取。將有機層 以水洗滌，於無水Na2S04上乾燥，並於真空中濃縮。將殘 留物於矽膠上利用EtOAc作為洗提液進行層析，而得4 -（2 -經乙基）-卜六氫吡啶乙酸爷酯（16· 3克，76%)的無色油。 Η-NMR (CDC13) 1.31-1.40 (m，3H)、1.52 (dd，J = 12.8、6·3 Hz，2H)、1·68 (brd，J = l〇.〇 Hz，3H)、2·16 (t，J = 11.6 Hz，2H)、2.92 (brd，J = 11.6 Hz，2H)、 3·24 (s，2H)、3·69 (t，J = 6.8 Hz, 2H)、5·16 (s， 2H) 、 7·35 (m， 5H)。 (4_N-羰苄氧甲基六氫咣啶基）乙醛 ^-CO.Bn 於4-(2 -經乙基）-卜六氫咄啶乙酸苄酯（14·9克，53.8毫 莫耳）溶於CH2C12(150毫升）之攪拌溶液中加入ΕΪ3ν (37. 5 毫升，269毫莫耳）及DMS〇(41· 6毫升，538毫莫耳）。使反 應混合物冷卻至〇 °C，並逐份加入s〇3 · py (25· 7克，1 6 1毫 莫耳），及使所產生之混合物在室溫下攪拌隔夜。將混合 物於真空中濃縮，並以水稀釋殘留物，隨後以E ^ 〇萃取。 將有機層以水洗滌，於無水Na2C03上乾燥，並於真空中濃 縮:使殘留物於矽膠上利用Et〇Ac_己烷（2:〇作為洗提液 進行層析，而得（4-N-羰苄氧甲基六氫咄啶基）乙醛（4. 63 克 ’ 31%)的無色油。1H — NMR (CDCl3) 6 h 36一κ 46 (m， • m,89112968.ptd Page 853 1283240 V. INSTRUCTIONS (849) The insoluble solids were removed by filtration and the filtrate was concentrated in vacuo. The residue was poured into ice in IN HC1 and extracted with CHC13. The organic layer was washed with water, dried over anhydrous Na. The residue was chromatographed on EtOAc EtOAc (EtOAc) Η-NMR (CDC13) 1.31-1.40 (m, 3H), 1.52 (dd, J = 12.8, 6.3 Hz, 2H), 1.68 (brd, J = l〇.〇Hz, 3H), 2· 16 (t, J = 11.6 Hz, 2H), 2.92 (brd, J = 11.6 Hz, 2H), 3·24 (s, 2H), 3·69 (t, J = 6.8 Hz, 2H), 5.16 (s, 2H), 7·35 (m, 5H). (4_N-Carbobenzyloxymethylhexahydroacridinyl)acetaldehyde^-CO.Bn in 4-(2-ethyl-ethyl)-hexahydroacridine acetate (14·9 g, 53.8 mmol)搅拌3ν (37. 5 ml, 269 mmol) and DMS 〇 (41. 6 ml, 538 mmol) were added to a stirred solution of CH2C12 (150 mL). The reaction mixture was cooled to 〇 ° C, and s 〇 3 · py (25·7 g, 161 mM) was added portionwise, and the resulting mixture was stirred overnight at room temperature. The mixture was concentrated in vacuo and the residue was diluted with water and then extracted with EtOAc. The organic layer was washed with water, dried over anhydrous Na.sub.2CO.sub.3, and concentrated in vacuo. - carbonylbenzyloxymethyl hexahydroacridinyl) acetaldehyde (4.63 g '31%) as a colorless oil. 1H - NMR (CDCl3) 6 h 36 κ 46 (m, • m,

2H)、1·69 (br s，2H)、1· 72 (br s，1H)、1· 90 ( ’2H), 1·69 (br s, 2H), 1·72 (br s, 1H), 1·90 ( ’

第854頁 1283240 五、發明說明（850) 1H)、2.21 (dt，J = 11.6、2·4 Hz, 2H)、2·37 (dd，J = 6. 8、1·6 Hz，2H)、2·92 (d，J = 11.6 Hz，2H)、3·25 (s， 2 H)、5 · 1 6 (s，2 H)、7 · 3 5 (m，5 H)、9 · 7 7 (t，J = 2 · 0Page 854 1283240 V. INSTRUCTIONS (850) 1H), 2.21 (dt, J = 11.6, 2·4 Hz, 2H), 2·37 (dd, J = 6. 8 , 1·6 Hz, 2H), 2·92 (d, J = 11.6 Hz, 2H), 3·25 (s, 2 H), 5 · 1 6 (s, 2 H), 7 · 3 5 (m, 5 H), 9 · 7 7 (t, J = 2 · 0

Hz, 1H) 〇 · ’ · N一苄基-2-[4-(N- M爷氧甲基六氫u比唆基）]乙胺Hz, 1H) 〇 · ′ · N-benzyl-2-[4-(N-M-oxymethylhexahydrou-indenyl)]ethylamine

於^苯甲胺（1.06毫升，9.75毫莫耳）溶於^〇11(20毫 升）之攪拌溶液中加入AcOH( 560毫升，9.75毫莫耳）及 (4 - N-羰苄氧曱基六氫咄啶基）乙醛（179克，6.5〇毫莫耳） 溶於Me0H(5毫升），並冷卻至〇°C。將NaBH3CN( 645毫克， 9 · 7 5毫莫耳）以一份加入，並使所產生之混合物在室溫下 擾拌隔夜。將混合物於真空中濃縮，並將殘留物倒入至 NaHC〇3水溶液中，然後以CHCI3萃取。將有機層以水洗蘇， 於無水N S Ο*上乾燥’並於真空中濃縮。使殘留物於石夕膠 上利用CHCI3-MeOH-EtOAc(10:l:l)作為洗提液進行層析， 而得N_苄基- 2- [4-(N-幾笮氧甲基六氫吼咬基）]乙胺（872 毫克，37%)之無色油。1H-NMR (CDC13)3 1·36〜ι 46 (m， 2H)、1·69 (brs，2H)、1·72 (brs，1H)、1·9〇 (m，1H) 、2·21 (dt，J = 11.6、2·4 Hz，2H)、2·37 ⑷，j = 6.8、 1.6 Hz, 2H)、2·92 (d，J = 11.6 Hz，2H)、3·25 (s， 2H)、5·16 (s，2H)、7·35 (m，5H)、9.77 (t，j = 2.〇Add AcOH (560 ml, 9.75 mmol) and (4 - N-Carbobenzyl sulfonyl) to a stirred solution of benzylamine (1.06 mL, 9.75 mmol) in EtOAc (20 mL). Hydroziridinyl) acetaldehyde (179 g, 6.5 mmol) was dissolved in MeOH (5 mL) and cooled to EtOAc. NaBH3CN (645 mg, 97.5 mmol) was added in one portion and the resulting mixture was stirred overnight at room temperature. The mixture was concentrated in vacuo and the residue was poured into aqueous NaHCI3 and then extracted with CHCI. The organic layer was washed with water, dried over anhydrous EtOAc, and concentrated in vacuo. The residue was chromatographed on CH.sub.3, using CHCI3-MeOH-EtOAc (10:1:1) as eluent to give N-benzyl-2-[4- Hydrogen oxime)] Ethylamine (872 mg, 37%) of a colorless oil. 1H-NMR (CDC13)3 1·36~ι 46 (m, 2H), 1.69 (brs, 2H), 1.72 (brs, 1H), 1·9〇 (m, 1H), 2·21 (dt, J = 11.6, 2·4 Hz, 2H), 2·37 (4), j = 6.8, 1.6 Hz, 2H), 2.92 (d, J = 11.6 Hz, 2H), 3·25 (s, 2H), 5·16 (s, 2H), 7·35 (m, 5H), 9.77 (t, j = 2.〇

Hz， 1H) 〇Hz, 1H) 〇

89112968.ptd 第855頁 1283240 4-[2-N-[4-[N’ -(2-漠苯基）脲基卜3_甲氧苯基]_n_爷基乙 醯胺基]乙基-1 -六氫吡啶基乙酸辛酉旨89112968.ptd Page 855 1283240 4-[2-N-[4-[N' -(2-Molyphenyl)ureido3_methoxyphenyl]_n_arylethylamino]ethyl- 1 - hexahydropyridyl acetic acid

\xC〇2Bn 在室溫下於N-苄基-2-[4-(N-羰笮氧甲基六氫吡啶基）] 乙胺（ 356毫克，0.972毫莫耳）、4-[n，—（2一溴苯基）脲 基]-3-甲氧苯基乙酸（369毫克，〇· 972毫莫耳）及n，n一二甲 胺基苄啶（119毫克，〇·972毫莫耳）溶於DMF(15毫升）之攪 拌溶液中加入EDC ·ΗΠ ( 372毫克，ΐ·94毫莫耳），並使所 產生之混合物攪拌隔夜。將反應混合物倒入至水中，並以 E^OAc萃取。將有機層以鹽水洗滌，並於無水心4〇4上乾 燥’然後於真空中濃縮。使殘留物於石夕膠上利用 CHClfMeOH(10:l)作為洗提液進行層析，而得 4- [2-N- [4- [Ν’-（2 -溴苯基）脲基]-3-甲氧苯基]—N一苄基 乙醯胺基]乙基-1—六氫咄啶基乙酸苄酯（61丨毫克，86%)之 無色油。1H-NMR (CDC13)消旋異構物之混合物5 1· 15- 2·〇9 (m 系列，7H) 、2.06-2·14 (m， 2H) 、2.84-2.96 (m， 2H)、3·17-3·23 (s，總計2H)、3·21 及3·23 (s，總計 2H)、3.38-3.42 (m，1H)、3.65 及3.73 (s，總計 2H)、 3·83 及 3.84 (s，總計 3H)、4·49 (s，1H)、4·60 (s，1H )、5· 15 (d，J = 2· 8 Hz，2H)、6· 74-7· 83 (m 系列，16H )、7·51-7·53 (m，1H)、7·94-8·02 (m，1H)、8·18 (d， J = 8.4 Hz, 2H); MS(FAB) m/z 727 (M+)、729 (MH2)。\xC〇2Bn at room temperature in N-benzyl-2-[4-(N-carbonyloxymethylhexahydropyridinyl)ethylamine (356 mg, 0.972 mmol), 4-[n, -(2-Butylphenyl)ureido]-3-methoxyphenylacetic acid (369 mg, 〇·972 mmol) and n,n-dimethylaminobenzylpyridine (119 mg, 〇·972 mmol) To the stirred solution of DMF (15 mL) was added EDC··············· The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine and dried over EtOAc EtOAc EtOAc. The residue was chromatographed on silica gel using CHClfMeOH (10:1) as eluent to give 4-[2-N-[4-[4-[(2-bromophenyl)ureido]- 3-methoxyphenyl]-N-benzylethylindolyl]ethyl-1-hexahydroacridinyl benzyl acetate (61 mg, 86%) as a colorless oil. 1H-NMR (CDC13) mixture of racemic isomers 5 1· 15- 2·〇9 (m series, 7H), 2.06-2·14 (m, 2H), 2.84-2.96 (m, 2H), 3 · 17-3·23 (s, total 2H), 3·21 and 3·23 (s, total 2H), 3.38-3.42 (m, 1H), 3.65 and 3.73 (s, total 2H), 3.83 and 3.84 (s, total 3H), 4·49 (s, 1H), 4·60 (s, 1H), 5·15 (d, J = 2·8 Hz, 2H), 6·74-7· 83 ( m series, 16H), 7·51-7·53 (m, 1H), 7·94-8·02 (m, 1H), 8·18 (d, J = 8.4 Hz, 2H); MS (FAB) m/z 727 (M+), 729 (MH2).

89112968.ptd 第856頁 1283240 五、發明說明（852) ~ 在室溫下於4-[2-N-[4-[N，-（2 -溴苯基）脲基]一3-曱氧笨 基]-N-窄基己醯胺基]乙基—1—六氫咄啶基乙酸苄酯（347毫 克，0.477¾莫耳）溶於MeOH-H2 0(5:1，6毫升）之攪拌溶液 中加入Li0H(13· 6毫克，〇· 57毫莫耳），並使所產生之混合 物擾拌隔夜。將反應混合物倒入至水中，並以1 Ν η C1水溶 液將溶液中和’然後以CHC13萃取。將有機層以鹽水洗 滌，並於無水NazS〇4上乾燥，然後於真空中濃縮。使殘留 物於矽膠上利用CHCI3-MeOH( 1 〇 : 1 )作為洗提液進行層析， 而分別得到3 32( 97· 3毫克，32%)的無色非晶形固體及3 33 (168毫克，54%)的無色非晶形固體。332 ; iH-NMR (CD30D) 消旋異構物之混合物6 1.2 9- 1.90 (111系列，71〇、2.75-2·86(ιη， 2Η)、3·28-3·51 (m 系列，6Η)、3·74 及 3.78 (s，總計 2Η)、3·87 及 3·89 (s，總計 3Η)、4·66 (s，1Η) 、4.85 (s, 1H)、6·79-7·00 化系列，3H)、7.16 (d， J = 7.2 Hz，1H)、7·23-7·37 (m，5H)、7·57 (dd，J = 8.4、1.2[^，11〇、7.8 8-8.00 (111系列，21〇;^13(^八6) m/z 63 7 (M+)、639 (MH2)。 333 ; M-NMR (CDC13)，消旋異構物之混合物（5 1. 15-2· 11 (m 系列，7H)、2· 8 9-2· 9 7 (m，2H)、3· 17-3· 49 (m 系列， 6H)、3· 17 及 3· 18 (s，總計 3H)、3· 70 及 3· 71 (s，總計 3H)、3·83 及 3.84 (s,總計 2H)、4·49、4·60 及 4·71 (s， 總計2Η)、6· 75-8· 16 (m 系列，14Η) ; MS(FAB) m/z 651 (M+)、653 (MH2)。 實施例28389112968.ptd Page 856 1283240 V. INSTRUCTIONS (852) ~ 4-[2-N-[4-[N,-(2-Bromophenyl)ureido]- 3-oxo-oxygen at room temperature Benzyl]-N-narrowyl hexylamino]ethyl benzyl-1-hexahydroacridinylacetate (347 mg, 0.4773⁄4 mol) dissolved in MeOH-H 2 0 (5:1, 6 mL) LiOH (13. 6 mg, 〇·57 mmol) was added to the solution, and the resulting mixture was stirred overnight. The reaction mixture was poured into water, and the solution was neutralized with a 1 Ν η C1 aqueous solution and then extracted with CHC13. The organic layer was washed with brine and dried over anhydrous Naz. The residue was chromatographed on a silica gel using CHCI3-MeOH (1 〇: 1 ) as eluent to give 3 32 (97·3 mg, 32%) as a colorless amorphous solid and 3 33 (168 mg, 54%) of a colorless amorphous solid. 332 ; iH-NMR (CD30D) mixture of racemic isomers 6 1.2 9- 1.90 (111 series, 71〇, 2.75-2·86 (ιη, 2Η), 3·28-3·51 (m series, 6Η) ), 3·74 and 3.78 (s, total 2Η), 3.87 and 3.89 (s, total 3Η), 4.66 (s, 1Η), 4.85 (s, 1H), 6.79-7· 00 series, 3H), 7.16 (d, J = 7.2 Hz, 1H), 7·23-7·37 (m, 5H), 7·57 (dd, J = 8.4, 1.2 [^, 11〇, 7.8 8-8.00 (111 series, 21〇; ^13(^八6) m/z 63 7 (M+), 639 (MH2) 333 ; M-NMR (CDC13), a mixture of racemic isomers (5 1 15-2· 11 (m series, 7H), 2· 8 9-2· 9 7 (m, 2H), 3· 17-3· 49 (m series, 6H), 3·17 and 3· 18 ( s, total 3H), 3·70 and 3.71 (s, total 3H), 3·83 and 3.84 (s, total 2H), 4·49, 4·60 and 4·71 (s, total 2Η), 6· 75-8· 16 (m series, 14Η); MS(FAB) m/z 651 (M+), 653 (MH2). Example 283

\\312\2d-code\90-01\89112968.ptd 第857頁 1283240\\312\2d-code\90-01\89112968.ptd Page 857 1283240

五、發明說明（853) 4-[2叫-[4-|^’-（2-氣笨基）—3—甲氧脲基]苯基]一1^ 醢胺基]乙基-1-六氫吼咬基乙酸V. INSTRUCTIONS INSTRUCTIONS (853) 4-[2]-[4-|^'-(2-Acetyl)-3-methoxyureido]phenyl]- 1^ decylamino]ethyl-1- Hexahydroquinone

334 4-[2-N - [4-[N’ -（2 -氣苯基）—3一甲氧脲基；]苯基卜N—窄基乙 醯胺基]乙基-1 -六氫咄啶基乙酸苄酯334 4-[2-N - [4-[N' -(2-Phenylphenyl)-3-methoxyureido;]phenylphenyl N-n-ylethylamino]ethyl-1 -hexahydro Benzyl acridine acetate

在室溫下於N-苄基-2-[4-(N-羰爷氧甲基六氫咄啶基）] 乙胺（3 72毫克，1.11毫莫耳）、4 — [1^，一（2—氣苯基）脲基] - 3-甲氧笨基]乙酸（758毫克，；i U毫莫耳）及N，N一二甲胺 基吼咬（136毫克，1·11毫莫耳）溶於DMF(15毫升）之攪拌溶 液中加入EDC ·ΗΠ(426毫克，2.22毫莫耳），並使所產生 之混合物攪拌1 2小時。將反應混合物倒入至水中，並以 EtOAc萃取。將有機層以鹽水洗滌，並於無水Na2S〇4上乾 燥，然後於真空中濃縮。使殘留物於矽膠上利用CHC13-MeOH(10:l)作為洗提液進行層析，而得4-[2-Ν-[4-[Ν’ -（ 2-氯苯基）-3 -曱氧脲基]苯基]-Ν_窄基乙醯胺基]乙基-1 -六氫吡啶基乙酸爷酯（ 66 8毫克，88%)之淡黃色油。！H-NMR (CDC13)消旋異構物之混合物（5 1·15 -1·83 (m系列，7H) 、2·04-2·13 (m，2H)、2·83 - 2.95 (m，2H)、2.88 及 2·99 (s，總計 2Η)、3·20 及 3.23 (s，總計 2Η)、3·20-3·23 (重N-Benzyl-2-[4-(N-carbonyloxymethylhexahydroacridinyl)]ethylamine (3 72 mg, 1.11 mmol), 4 - [1^, one at room temperature (2-Phenylphenyl)ureido]-3-methoxyphenyl]acetic acid (758 mg; i U millimolar) and N,N-dimethylamino-based bite (136 mg, 11.11 mmol) Ethyl acetate (426 mg, 2.22 mmol) was added to a stirred solution of DMF (15 mL), and the mixture was stirred for 12 hours. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine and dried over anhydrous Na. The residue was chromatographed on a silica gel using CHC13-MeOH (10:1) as eluent to give 4-[2-[-[[[[[[[[[[[[[[[[ Oxyureido]phenyl]-indole-n-n-ylethylamino]ethyl-1 -hexahydropyridyl acetate (66 8 mg, 88%) as a pale yellow oil. ! H-NMR (CDC13) mixture of racemic isomers (5 1·15 -1·83 (m series, 7H), 2·04-2·13 (m, 2H), 2·83 - 2.95 (m, 2H), 2.88 and 2.99 (s, total 2Η), 3·20 and 3.23 (s, total 2Η), 3·20-3·23 (heavy

\\312\2d-code\90-01\89112968.ptd 第858頁 1283240 五、發明說明（854) 疊，1H)、3.38-3·42 (m，1H)、3·65-3·74 (m，3H)、 4.50 (s，1H)、4·61 (s，1H)、5·14 (d，J = 4.4 Hz，2H) 、6·72-6·82 (m 系列，2H)、6·9 4 - 6.99 (m， 1H)、7.13 -7· 50 (m 系列，14H)、7· 94-8· 0 2 (m，1H)、8· 18 (d， J = 8.0 Hz，2H); MS(FAB) m/z 6 83 (MHH)。 4 - [2-N - [4-[Ν’ - (2 -氯笨基）-3-甲氧脲基]苯基]-N-爷基乙 醯胺基]乙基-1-六氫吼°定基乙酸甲醋\\312\2d-code\90-01\89112968.ptd Page 858 1283240 V. Description of invention (854) Stack, 1H), 3.38-3.42 (m, 1H), 3·65-3·74 ( m, 3H), 4.50 (s, 1H), 4·61 (s, 1H), 5·14 (d, J = 4.4 Hz, 2H), 6.72-6·82 (m series, 2H), 6 ·9 4 - 6.99 (m, 1H), 7.13 -7· 50 (m series, 14H), 7· 94-8· 0 2 (m, 1H), 8· 18 (d, J = 8.0 Hz, 2H) MS (FAB) m/z 6 83 (MHH). 4-[2-N-[4-[Ν' - (2-Chlorophenyl)-3-methoxyureido]phenyl]-N-aryl-ethylamino]ethyl-1-hexahydroindole °-based acetic acid methyl vinegar

在室溫下於4-[2-N-[4-[N，-（2 -氯苯基）-3-曱氧脲基]苯 基]-N-芊基乙醯胺基]乙基-1-六氫咄啶基乙酸苄酯（63 3毫 克，〇·93毫莫耳）溶於Me〇H-H20(l〇:l，10毫升）之攪拌溶 液中加入LiOH(24· 4毫克，1 · 〇2毫莫耳），並使所產生之混 合物攪拌隔夜。將反應混合物倒入至水中，並以1 N HC 1水 溶液將溶液中和，然後以CHC13萃取。將有機層以鹽水洗 蘇’並於無水NaJO4上乾燥，然後於真空中濃縮。使殘留 物於矽膠上利用CHCI3-MeOH(20 : 1 )作為洗提液進行層析， 而得4-[2-N-[4-[N’ -（2_氣苯基）-3-甲氧脲基]苯基]— 苄基乙醯胺基]乙基-1-六氫咄啶基乙酸甲酯（5〇4毫克， 89%)的無色非晶形固體。1H — NMR (CDCl3)消旋異構物之混 合物 6 1·26 -1.64 Cm 系列，7H)、2〇2_21〇 (m， 2h)、 2.86 (t, J=10.4 Hz, 2H) ^3.17 (d, J = 8. 0 Hz, 2H) ^ 3·16-3·22 (m，重疊，1H)、3.40 (t， J = 7.6 Hz， 1H)、4-[2-N-[4-[N,-(2-Chlorophenyl)-3-indolyl]phenyl]-N-mercaptoethylamino]ethyl- Benzyl 1-hexahydroacridinylacetate (63 3 mg, 〇·93 mmol) was dissolved in a stirred solution of Me〇H-H20 (1 〇:1, 10 mL). LiOH (24·4 mg, 1 · 〇 2 mmol) and the resulting mixture was stirred overnight. The reaction mixture was poured into water, and the solution was neutralized with a 1 N HCl aqueous solution, and then extracted with CHC13. The organic layer was washed with brine and dried over anhydrous Na.sub.4 and then concentrated in vacuo. The residue was chromatographed on silica gel using CHCI3-MeOH (20:1) as the eluent to give 4-[2-N-[4-[N'-(2- phenylphenyl)-3- A colorless amorphous solid of oxyureido]phenyl]-benzylacetamido]ethyl-1-hexahydroacridinylacetate (5 〇 4 mg, 89%). 1H-NMR (CDCl3) mixture of racemic isomers 6 1·26 -1.64 Cm series, 7H), 2〇2_21〇(m, 2h), 2.86 (t, J=10.4 Hz, 2H) ^3.17 (d , J = 8. 0 Hz, 2H) ^ 3·16-3·22 (m, overlap, 1H), 3.40 (t, J = 7.6 Hz, 1H),

\\312\2d-code\90-01\89112968.ptd 第859頁 1283240 五、發明說明（855) 3· 48 (s，1H)、3. 65 及 3. 73 (s，總計 2H)、3· 7 0 及3· 7 1 (s，總計 3H)、3· 79 及 3· 80 (s，總計 3H)、4· 50、4 · 60 及 4.70(3，總計21〇、6.7 3-6.85 (111系列，21〇、6.98(1；， J 二 7.6 Hz, 1H)、7·13-7·37 (m 系列，9H)、7·96 (m， ιΗ) 、8·18 (d，J = 8.0 Hz，2H); MS(FAB) m/z 607 (MHH)。\\312\2d-code\90-01\89112968.ptd Page 859 1283240 V. Inventions (855) 3·48 (s, 1H), 3.65 and 3.73 (s, total 2H), 3 · 7 0 and 3· 7 1 (s, total 3H), 3·79 and 3·80 (s, total 3H), 4·50, 4 · 60 and 4.70 (3, total 21〇, 6.7 3-6.85 ( 111 series, 21〇, 6.98(1;, J 2 7.6 Hz, 1H), 7·13-7·37 (m series, 9H), 7·96 (m, ιΗ), 8·18 (d, J = 8.0 Hz, 2H); MS (FAB) m/z 607 (MHH).

138 4 - [2 _N-[4-[Ν’ - (2 -氣苯基）-3-甲氧脲基]笨基]—N -苄基乙醯胺基]乙基-1-六氫吼咬基乙酸 在室溫下於4-[2-N-[4_[N，-（2 -氯苯基）-3-曱氧脲基]笨 基]-N-芊基乙醯胺基]乙基-1-六氫吼唆基乙酸曱醋（177毫 克，0.292毫莫耳）溶於MeOH-H20(5:l，6毫升）之攪拌溶液 中加入L i OH ( 21 · 6毫克，0 · 9 0毫莫耳），並使所產生之混合 物攪拌4小時。將反應混合物倒入至水中，並以1 N HC 1水 溶液將溶液中和，然後以CHC 13萃取。將有機層以鹽水洗 滌，並於無水Na2S04上乾燥，然後濃縮而得33 4 ( 1 55毫 克，92%)的無色非晶形固體。NMR (CD30D)消旋異構物 之混合物 5 1· 28-1· 90 (m 系列，7H)、2· 84 (brs， 2H)、 3·30 - 3·52 (m 系列，6H)、3·74 及 3·82 (s，總計 2H)、 3.87 及 3.88 (s，總計 3H)、4· 63 (s，1H)、4· 66 (s，1H) 、6·79 - 7·05 (m 系列，3H)、7·16 (d，J = 7.2 Hz, 1H)、 7.24-7.40 (m，5H)、7.88 (s，1H)、7.98-8.04 (m 系列， 2H); MS(ESI) m/z 593 (M+)、615(M+ + Na+)。 應明瞭雖然本發明已就詳細說明的特定具體例說明於文 中，但此等具體例係經由一般原理的說明呈現，本發明並 不一定受限於此。熟悉技藝人士當可容易明瞭任何給定材138 4 - [2 _N-[4-[Ν' - (2-Phenylphenyl)-3-methoxyureido]]]-N-benzylacetamido]ethyl-1-hexahydroindole Bite-based acetic acid at room temperature in 4-[2-N-[4_[N,-(2-chlorophenyl)-3-indolyloxy]phenyl]]-N-mercaptoacetamido] Lithium-1-hexahydroindenyl acetic acid vinegar (177 mg, 0.292 mmol) was dissolved in MeOH-H20 (5:1, 6 mL). 90 mmol, and the resulting mixture was stirred for 4 hours. The reaction mixture was poured into water, and the solution was neutralized with 1 N HCl aqueous solution and then extracted with CH. The organic layer was washed with EtOAc (EtOAc m. NMR (CD30D) mixture of racemic isomers 5 1· 28-1· 90 (m series, 7H), 2·84 (brs, 2H), 3·30 - 3·52 (m series, 6H), 3 ·74 and 3.82 (s, total 2H), 3.87 and 3.88 (s, total 3H), 4·63 (s, 1H), 4·66 (s, 1H), 6.79 - 7·05 (m Series, 3H), 7·16 (d, J = 7.2 Hz, 1H), 7.24-7.40 (m, 5H), 7.88 (s, 1H), 7.98-8.04 (m series, 2H); MS(ESI) m /z 593 (M+), 615 (M+ + Na+). It is to be understood that the specific embodiments of the present invention have been described in detail herein by way of the description Familiar with the skilled person, it is easy to understand any given material.

\\312\2d-code\90-01\89112968.ptd 第860頁 1283240 五、發明說明（856) 料或方法步驟的修改及變化，而不脫離以下之申請專利範 圍的真正精神及範圍，且所有此等修改皆係包括在本發明 之範圍内。 \\312\2d-code\90-01\89112968.ptd 第861頁 1283240 圖式簡單說明 第862頁 \\312\2d-code\90-01\89112968.ptd 94. 4. 發明專利說明書 1283240 &gt; 發明名稱 中文 VLA-4抑制劑化合物 英文 VLA-4 INHIBITOR COMPOUNDS--- 發明人 姓名 (中文） 1. 町永信雄 2. +山敦 3. 千葉淳 姓名 (英文） L '----- 2· 3· 國籍 1·曰本2.曰本3.曰本 __ 住、居所 h農案幕葛西—丁目16#13號弟-製藥株式会社 2·同 r x 3.同1 申請人 姓名 (名稱） (中文） 1. 第一製藥股份有限公司 - ----- 2. 藥典藥物發現公司 姓名 (名稱） (英文） 國籍 1. 第 1 条株式云社(DAIICHI PHARMACEUTirAI ΓΩ ΙΤΠ、 2. Pharmacopeia Dmg Discovery, i^ UUUlL tU.，LTD·) 1.日本2.美國 ' '---：- 住、居所 (事務所) 1. 日本國東厅、都中央區日本橋二丁目I4^1n咕 2. 美國新澤西州克蘭伯里市伊斯特帕妓顆〇〇號 代表人 姓名 (中文） 1. 林田清 -—- 2. 布萊恩Μ波斯納 代表人 姓名 (英文） L --- 2. Brian M. Posner\\312\2d-code\90-01\89112968.ptd Page 860 1283240 V. INSTRUCTIONS (856) Modifications and changes in material or method steps without departing from the true spirit and scope of the following claims. All such modifications are intended to be included within the scope of the present invention. \\312\2d-code\90-01\89112968.ptd Page 861 1283240 Schematic description 862 \\312\2d-code\90-01\89112968.ptd 94. 4. Invention patent specification 1283240 &gt Inventor Name Chinese VLA-4 Inhibitor Compound English VLA-4 INHIBITOR COMPOUNDS--- Name of Inventor (Chinese) 1. Machio Shinshin 2. 2. Shan Dun 3. Chiba Name (English) L '----- 2· 3· Nationality 1·曰本2.曰本3.曰本__ 住,居所h 农案幕葛西—丁目16#13号弟-制药株式会社2·同rx 3.同1 Applicant's name ( Name) (Chinese) 1. First Pharmaceutical Co., Ltd. - ----- 2. Pharmacopoeia Drug Discovery Company Name (Name) (English) Nationality 1. Article 1 Plant Type Cloud Society (DAIICHI PHARMACEUTirAI ΓΩ ΙΤΠ, 2. Pharmacopeia Dmg Discovery, i^ UUUlL tU., LTD·) 1. Japan 2. United States ' '---:- Residence, residence (office) 1. Japan’s East Hall, Dukasaka Nihonbashi 2-chome I4^1n咕2 Name of the representative of Eastpara, Clanbury, New Jersey, USA (Chinese) 1. Lin Tianqing--- 2. Name of Brian Bosna representative ( Text) L --- 2. Brian M. Posner

I 9么年（/月么1曰 修正 —-—~ 替1 申請曰期： 89.6.30 1 案號：89112968 ! 公告木 類別：π H，/U丨&quot;丨/^ ---*------- 匕\總檔\89\89112968\89112968(替換）-2. ptc 第 1 頁I 9 years (/months 1曰 correction---~ for 1 application period: 89.6.30 1 case number: 89112968! Announcement wood category: π H, /U丨&quot;丨/^ ---*- ------ 匕\总档\89\89112968\89112968 (replace)-2. ptc page 1

Claims (1)

六 1· '一種以化學式（I)表不之化合物或其gg W、 WV /X \〆 \|VI (1) 修正 1補充 本？ Am r 4 其中： W為未經取代苯基，或具有1至5個分別選自包人c _ 基、鹵原子、CrC4烷氧基、-OH及-CFa之群之烷 _ Τ〈取代基的經 取代苯基； W1係未經取代伸苯基，或具有1至4個選自包含c —c ^ 基、c广〇4烧乳基及_原子之群之取代基的經取代伸笨其 A 係=0; ^ R 係-（CH2)n-， 其中 η係1或2 ; X 係-C(0)-； Μ係Six 1· 'A compound expressed by the chemical formula (I) or its gg W, WV /X \〆 \|VI (1) Amendment 1 Supplement? Am r 4 wherein: W is an unsubstituted phenyl group, or has 1 to 5 alkyl groups selected from the group consisting of a human c- group, a halogen atom, a CrC4 alkoxy group, -OH and -CFa. Substituted phenyl; W1 is an unsubstituted phenyl group, or has 1 to 4 substituents selected from the group consisting of a c-c ^ group, a c 4 saponin group, and a _ atom group Its A system = 0; ^ R system - (CH2) n-, where η is 1 or 2; X is -C(0)-; 1283240 ---案號89112968_年月日 修正___ 六、申請專利範圍 為二價毗咯啶、噻唑啶或（4啉基團，其中該氮原 子係連接至X之點； R1、R2及R3係分別為一 Η、- 0 Η、- N H2、鹵原子、未經取代 -(：6烷基、經苯基匕-C4烷氧基取代之q -C6烷基、苯基、 。1-〇4烧氧基、單〇1-(：6烧胺基、二(^-(^烧胺基、（：1-()6烧續醯 胺基、未經取代苯磺醯胺基、經q -C6烷基取代之苯磺醯胺 基、未經取代萘磺醯胺基、經二q -C6烷胺基取代之萘磺醯 胺基、未經取代苯氧基、具有一選自包含羧基及齒原子之 群之取代基的經取代苯氧基、萘氧基、喳啉氧基，或 R1、R2及R3其中之兩個一起形成未經取代匕-c3伸烷二氧 基、具有1至3個分別選自q -C6烧基之取代基的經取代q —c3 伸烧一氧基、未經取代3_、4-、5-、6_或7-員碳環殘基或 具有1至3個分別選自（^-(：6烷基之取代基的經取代3-、4-、 5-、6-或7-員碳環殘基； R4係-H或CrC6烷基； Y係直接鍵或選自包含- C(0)-、-C(0)NH-、C2 - C6伸烯 基、q-C6伸炔基及-(CH2)kY2-之群之二價基根，其中k係 〇、1、2或3 ;及Y2係直接鍵或選自包含—s一、 - S(0)-、-S(0)2-及-NY3-之群之二價基根，其中γ3係一}1或 。1 - C1〇 烧基； Z係未經取代伸苯基、具有一選自包含叛基、q — c4燒氧 基、鹵原子、-N02、-NH2、Ci-Q烷基、二烷胺基及 G - ce烧醯胺基之群之取代基的經取代伸苯基、伸萘基、未 經取代伸雜環基、經叛基或齒原子取代之伸雜環基、或1283240 --- Case No. 89112968_ Amendment ___ Six, the scope of application for the patent is divalent pyrrolidine, thiazolidine or (4 phenyl group, where the nitrogen atom is connected to the point of X; R1, R2 and R3 is a fluorene, -0 Η, -N H2, a halogen atom, an unsubstituted-(: 6 alkyl group, a q-C6 alkyl group substituted with a phenyl fluorene-C4 alkoxy group, a phenyl group, a phenyl group, -〇4 alkoxy group, monoterpene 1-(:6-burning amine group, bis(^-(^-amino group, (:1-()6), anthranyl group, unsubstituted benzenesulfonylamino group, a benzenesulfonylamino group substituted with a q-C6 alkyl group, an unsubstituted naphthosulfonylamino group, a naphthosulfonylamino group substituted with a diq-C6 alkylamino group, an unsubstituted phenoxy group, having one selected from a substituted phenoxy group, a naphthyloxy group, a porphyrinoxy group containing a substituent of a group of a carboxyl group and a tooth atom, or two of R1, R2 and R3 together form an unsubstituted fluorene-c3 alkylenedioxy group, Substituted q-c3 exo-oxylated, unsubstituted 3_, 4-, 5-, 6- or 7-membered carbocyclic residue having 1 to 3 substituents each selected from the group consisting of q-C6 alkyl or Having 1 to 3 substituted 3-, 4-, 5-, 6- or respectively selected from (^-(6 alkyl substituent) a 7-membered carbocyclic residue; R4 is a -H or CrC6 alkyl group; a Y-based direct bond or is selected from the group consisting of -C(0)-, -C(0)NH-, C2-C6-alkenyl, q-C6 a divalent radical group of alkynyl group and -(CH2)kY2-, wherein k is 〇, 1, 2 or 3; and Y2 is a direct bond or is selected from the group consisting of -s-, -S(0)-, - a divalent radix of a group of S(0)2- and -NY3-, wherein γ3 is a 1-1 or a C1-alkyl group; the Z-system is unsubstituted and has a phenyl group, a substituted phenyl group, a naphthyl group, a substituent of a group of a group of a group of a group of a group of a group of a group of a group of a group of a group of a group of a group of a group of a group of a group of a group of a group of a group; An unsubstituted heterocyclic group, a substituted or substituted heterocyclic group, or 12832401283240 六、申請專利範圍 匕一c?伸環烷基； 曰 修正 其中伸雜環基係選自伸哌啶基、伸吼啶基或伸哌11秦基； A1係直接鍵或-（CH2)t-，其中，t係1、2或3 ;及 R5係〜0H或匕-匕烷氧基，或 Μ係 ~~R11-Z3-Q2-L1 其中， R11係Sixth, the scope of application for patents c c 伸 伸 伸 ; ; ; ; 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 其中 杂环 杂环 杂环 杂环 杂环 杂环 杂环 杂环 杂环 杂环 杂环 杂环 杂环 杂环 杂环 杂环 杂环 杂环 杂环 杂环 杂环 杂环- wherein t is 1, 2 or 3; and R5 is ~0H or 匕-decyloxy, or lanthanide ~~R11-Z3-Q2-L1 wherein R11 is 或-NR12 - 其中， R12係-Η、未經取代Q _C1()烧基、具有一選自包含C3〜C7環 燒胺基烧氧基Q-Ce烧胺基、二C2-C1G烯胺基、笨氧 基、經幽原子取代之苯氧基、經q-c6烷醯基取代之笨氧 基、—0H、哧啉基、哌啳基、經q _C6烷基取代之哌嗉基、 二ci —C6烷胺基、咄咯啶基、及經鹵原子取代之吡咯啶基之 群之取代基的經取代Q q 〇烧基、C3 - C7環烧基、苯基、未 經取代苄基、具有一選自包含-N〇2及-nh2之群之取代基的 經取代苄基、c2-c1()烯基、或c2-c1()炔基， 左手邊的鍵係連接至-X-之點，及右手邊的鍵係連接至-Z3 之點；Or -NR12 - wherein R12 is a deuterium, unsubstituted Q_C1() alkyl group, having one selected from the group consisting of a C3~C7 cycloalkylamine alkoxy Q-Ce arunyl group, a di-C2-C1G enamine group , phenoxy, phenoxy substituted by specthalo, phenyloxy substituted by q-c6 alkyl fluorenyl, -0H, porphyrinyl, piperidinyl, piperidinyl substituted by q_C6 alkyl, Ci-C6 alkylamino, pyrrolidinyl, and substituted substituents of a halogen atom-substituted pyrrolidinyl group substituted Q q fluorenyl, C 3 -C 7 cycloalkyl, phenyl, unsubstituted benzyl a substituted benzyl group, a c2-c1() alkenyl group, or a c2-c1() alkynyl group selected from the group consisting of a group consisting of -N〇2 and -nh2, the left-hand bond is linked to -X - the point, and the key on the right hand side is connected to the point of -Z3; 總檔\89\89112968\89112968(替換）-3.ptc 第 865 頁 1283240 案號 89112968_ 年Total file\89\89112968\89112968 (replace)-3.ptc Page 865 1283240 Case number 89112968_ Year 六、申請專利範圍 仗蘭 γ經基團， Ζ3係直接鍵或具有1至1 2個碳原子之二價脂族 其中一個碳原子可經-〇-或-NR13-取代， 仏t &gt; 其中R13係-Η或^-匕烷基，以及連接至脂族 或兩個氫原子可經q -C6烷基取代；或6. The patent application scope of the indigo γ-permeating group, the Ζ3 series direct bond or the divalent aliphatic group having 1 to 12 carbon atoms, one of which may be substituted by -〇- or -NR13-, 仏t &gt; R13 is -Η or ^-decyl, and is attached to an aliphatic or two hydrogen atoms which may be substituted by q-C6 alkyl; or Z3係 其中 X係0或1 ;Z3 is where X is 0 or 1; y係1、2或3 ;及 R14係-Η、-0H或鹵原子，或 Ζ3係 ηςη μ»、丨或 5 當R11係-NR12時 Z3 係 ζ4—| R14a 其中，z4 係, 其中，R14a係-Η、-OH、Crk烷基或鹵原子；或24係 或丨^， ,、y is 1, 2 or 3; and R14 is -Η, -OH or halogen atom, or Ζ3 is ηςη μ», 丨 or 5, when R11 is -NR12, Z3 is ζ4-| R14a wherein z4 is, wherein R14a Η-Η, -OH, Crk alkyl or a halogen atom; or 24 series or 丨^, , 其中，左手邊的鍵係連接至Ru之點，及右爭邊的鍵係連接 至Q2之點； Q2係選自包含未經取代伸苯基、具有1至5個分別選自包 含-oh、c4烷氧基、羧基、一N〇2、一训2、鹵原子、單c^c6 烷胺基、二q-c：6烷胺基、哌嗉基及Ci_Ce烷羰胺基之 6 代基的經取代伸苯基、伸萘基及伸吼啶基之 _ τ &lt;--彳貝基Wherein, the bond on the left-hand side is connected to the point of Ru, and the bond on the right-handed edge is connected to the point of Q2; Q2 is selected from the group consisting of unsubstituted phenyl groups, and 1 to 5 are respectively selected from the group consisting of -oh, a C6 alkoxy group, a carboxyl group, a N 〇 2, a training 2, a halogen atom, a mono c ^ c 6 alkylamino group, a di qc: 6 alkylamino group, a piperidinyl group and a Ci_Ce alkylcarbonyl group. Substituting phenyl, anthranyl and anthranyl _ τ &lt;--mube 1283240 曰 修正 SS—89112968 六、申請專利範圍 根， 或 其中R丨7及W係分別選自_H L1 係-C02i^-C0,， ％烷基，及 其中R19為C! -C6炫基。 2. 如申請專利範圍第1項之化合物 ， 或在其鄰位具有1至5個分；自:含二 基及齒原子之群之取代基的經取代苯基。 s G Ce烷 3. 如申請專利範圍第2項之化合物或其鹽，” ^經取代伸苯基，或在其_NH之鄰位具有一選自包 氣 基、q -Ce烷基及函原子之群之取代基的經取代伸苯美。 4. 如申請專利範圍第3項之化合物或其鹽，其中，^為 在其-Μ之鄰位具有一選自包含甲氧基、Ci_Ce烷基及齒原 子之群之取代基的經取代伸苯基。 5 ·如申請專利範圍第1項之化合物或其鹽，其中，r -CH2-。 八 ”、、 6 ·如申請專利範圍第1、2、3、4或5項之化合物或其 鹽，其中，Μ為 / ^ ‘1 R4 Z—A rN- C:\總檔\89\89112968\89112968(替換）-3.ptc 第 867 頁 1283240 ___1 號891129RS___车月日 倏正 六、申請專利範圍 7 ·如申明專利範圍第6項之化合物或其鹽，其中1283240 曰 Amendment SS—89112968 VI. Scope of Application Patent Root, or where R丨7 and W are respectively selected from _H L1 series-C02i^-C0, % alkyl, and wherein R19 is C!-C6 炫. 2. A compound as claimed in claim 1 or 1 to 5 in its ortho; a substituted phenyl group containing a substituent of a group of a diradical and a tooth atom. s G Cealkane 3. The compound of claim 2 or a salt thereof, "^ is substituted with a phenyl group, or has an aerated group, a q-Ce alkyl group and a Substituting a substituent of a group of atoms to a phenylene group. 4. A compound according to claim 3 or a salt thereof, wherein ^ is in the ortho position to the oxime thereof, and one is selected from the group consisting of a methoxy group and a Ci_Ce alkane. a substituted phenyl group of a substituent of a group of a base group and a group of teeth. 5 A compound of the above formula 1 or a salt thereof, wherein r -CH 2 - 8", 6 is as claimed in claim 1 a compound of 2, 3, 4 or 5 or a salt thereof, wherein Μ is / ^ '1 R4 Z-A rN- C:\总档\89\89112968\89112968 (replacement)-3.ptc page 867 1283240 ___1 No. 891129RS___车月日倏正六, application for patent scope 7 · If the compound of claim 6 or its salt, 係二價吼洛唆基團，而氮原子係連接至X之點。 8 ·如申請專利範圍第6項之化合物或其鹽，其中，Rl、R2 及R3之至少一基根為-0H或鹵原子。It is a divalent quinone group, and the nitrogen atom is attached to the point of X. 8. A compound according to claim 6 or a salt thereof, wherein at least one of R1, R2 and R3 is -OH or a halogen atom. 9 ·如申凊專利範圍第6項之化合物或其鹽，其中，γ係 (：2-(：6伸烯基、C2-(：6伸炔基或—（CH2)kY2—，其中γ2係直接鍵、 --s(0)-或-ΝΥ3-及Υ3 為—Η。 1 0 ·如申請專利範圍第9項之化合物或其鹽，其中，Υ2係 - 0-或一 ΝΗ-。 11.如申請專利範圍第6項之化合物或其鹽，其中，R4 為-Η。 1 2 ·如申請專利範圍第6項之化合物或其鹽，其中，A1為 直接鍵。 1 3 ·如申請專利範圍第丨2項之化合物或其鹽，其中，R5 為0H。 八9. A compound according to claim 6 or a salt thereof, wherein the γ system (: 2-(:6-alkenyl group, C2-(:6-exetylene group or -(CH2)kY2-), wherein γ2 system The direct bond, --s(0)- or -ΝΥ3- and Υ3 are -Η. 1 0 · The compound of claim 9 or a salt thereof, wherein Υ2 is -0- or one ΝΗ-. The compound of claim 6 or a salt thereof, wherein R4 is -Η. 1 2 · A compound according to claim 6 or a salt thereof, wherein A1 is a direct bond. 1 3 · If the patent application scope The compound of Item 2 or a salt thereof, wherein R5 is 0H. 14·如申明專利範圍第12項之化合物或其鹽，其中，γ為 -CH2〇_ ,及Ζ為未經取代伸苯基、具有一選自包含綾基、… C^C4烷氧基、函原子、-n〇2、-NH2、C!-C6烷基、二c广c俨 胺基及C! -C6烷醯胺基之群之取代基的經取代伸苯基1、^元一 取代伸雜環基、具有一選自包含羧基及_原子之^之經 取代The compound of claim 12 or a salt thereof, wherein γ is -CH2〇_, and Ζ is an unsubstituted phenyl group, and one is selected from the group consisting of a fluorenyl group, a C^C4 alkoxy group, Substituted phenyl, 1, and 1-substituted ones of the substituents of the atom, -n〇2, -NH2, C!-C6 alkyl, di-c-c-amino group and C!-C6 alkanoamine group a heterocyclic group having a substituent selected from the group consisting of a carboxyl group and a _ atom 1283240 ΛΜ^89112968 在月日 條正 六、申請專利範圍 土之、、、二取代伸雜環基、或&amp; _ C7伸壤烧基’其中伸雜環基係 選自伸娘啶基、伸吡啶基或伸哌嗉基。 1 5 ·如申請專利範圍第6項之化合物或其鹽，其中r5 為Ci - C4烧氧基。 1 6·如申請專利範圍第1、2、3、4或5項之化合物或其 鹽，其中，Μ為 ’、 \ R11-Z3-Q2_L1 〇 由專利範圍第16項之化合物或其鹽，其係選自 由以下化a物組成之群：1283240 ΛΜ^89112968 In the month of the Japanese version of the six, the patent application scope of the earth,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, Base or piperidinyl. A compound according to claim 6 or a salt thereof, wherein r5 is a Ci-C4 alkoxy group. 1 6) The compound of claim 1, 2, 3, 4 or 5 or a salt thereof, wherein Μ is ', \ R11-Z3-Q2_L1 〇 is a compound of the scope of claim 16 or a salt thereof, Is selected from the group consisting of: C:\ 總檔\89\89112968\89112968(替換）-3 第869頁 1283240C:\ Total file\89\89112968\89112968 (replace)-3 Page 869 1283240 C:\總檔\89\89112968\89112968(替換）-3.ptc 第 870 頁 1283240C:\Total file\89\89112968\89112968 (replace)-3.ptc Page 870 1283240 C:\總檔\89\89112968\89112968(替換）-3.ptc 第 871 頁 1283240C:\Total file\89\89112968\89112968 (replace)-3.ptc Page 871 1283240 C:\總檔\89\89112968\89112968(替換）-3.ptc 第 872 頁 1283240 案號 89112968 年月曰 修正C:\Total file\89\89112968\89112968 (replace)-3.ptc Page 872 1283240 Case No. 89112968 Yearly revision Correction C:\總檔\89\89112968\89112968(替換）-3.ptc 第 873 頁 1283240 案號 89112968 年月曰 修正 六、申請專利範圍 Me H H 〇Me OBn Me H H OMeQi 人 Cl H H OMe Me H H OMe Me H H OMe OH Q^nAn kL η ηC:\总档\89\89112968\89112968 (replacement)-3.ptc Page 873 1283240 Case No. 89112968 Lunar New Year Amendment VI, Patent Application Me HH 〇Me OBn Me HH OMeQi Person Cl HH OMe Me HH OMe Me HH OMe OH Q^nAn kL η η Ο '-ο- OMe «〇 OH Me Η 〇Me -N N- C02H Me、·.Me A。分 COOH Me OMe C:\總檔\89\89112968\89112968(替換）-3.ptc 第 874 頁 1283240 案號 89112968 年月曰 修正 六、申請專利範圍 I V.〇hQ-CO〇H Me、 MeΟ '-ο- OMe «〇 OH Me Η 〇Me -N N- C02H Me,·.Me A. COOH Me OMe C:\Total file\89\89112968\89112968 (replacement)-3.ptc Page 874 1283240 Case No. 89112968 Year of the month Amendment VI. Patent application scope I V.〇hQ-CO〇H Me, Me Χϊ COOH II Η Η ΟΜβΧϊ COOH II Η ΟΜ ΟΜβ νη2 &lt;y COOHΗη2 &lt;y COOH C:\總檔\89\89112968\89112968(替換）-3.ptc 第 875 頁 1283240C:\Total file\89\89112968\89112968 (replace)-3.ptc Page 875 1283240 C:\總檔\89\89112968\89112968(替換）-3.ptc 第 876 頁C:\Total file\89\89112968\89112968 (replace)-3.ptc Page 876 12832401283240 C:\總檔\89\89112968\89112968(替換）-3.ptc 第 877 頁 1283240C:\Total file\89\89112968\89112968 (replace)-3.ptc Page 877 1283240 12832401283240 12832401283240 C:\總檔\89\89112968\89112968(替換）-3.ptc 第 880 頁C:\Total file\89\89112968\89112968 (replace)-3.ptc Page 880 12832401283240 C:\總檔\89\89112968\89112968(替換）-3.ptc 第 881 頁 1283240C:\Total file\89\89112968\89112968 (replace)-3.ptc Page 881 1283240 C:\總檔\89\89112968\89112968(替換）-3.ptc 第 882 頁 1283240C:\Total file\89\89112968\89112968 (replace)-3.ptc Page 882 1283240 C:\總檔\89\89112968\89112968(替換）-3.ptc 第 883 頁 1283240C:\Total file\89\89112968\89112968 (replace)-3.ptc Page 883 1283240 C:\總檔\89\89112968\89112968(替換）-3.ptc 第 884 頁 1283240 案號 89112968 年月曰_修正 六、申請專利範圍C:\General file\89\89112968\89112968 (replace)-3.ptc Page 884 1283240 Case No. 89112968 Year of the month _ Amendment VI. Patent application scope &quot;N N Ql Η H&quot;N N Ql Η H COOH NHg Br H H OMe / co2h 〇 -OH OH Br 〆〇COOH NHg Br H H OMe / co2h 〇 -OH OH Br 〆〇 p 1 Li U MU Cl H H OMe C:\總檔\89\89112968\89112968(替換）-3.ptc 第 885 頁 1283240 _案號89112968_年月日 修正 六、申請專利範圍p 1 Li U MU Cl H H OMe C:\Total file\89\89112968\89112968 (replacement)-3.ptc Page 885 1283240 _ Case number 89112968_Yearly date Correction VI. Patent application scope C:\總檔\89\89112968\89112968(替換）-3.ptc 第 886 頁 1283240 案號 89112968 年月曰 修正 六、申請專利範圍 α Η Η 曝 I Η H TMe C〇^H NH2 xr COOH NH Xr COOH Br Η H 〇Me CO.H co2h 0丨 Η H 〇Me Ρ^Ν°Ν^Ρ^° ^〇O-C〇2H Cl Η Η 〇 Me L H H όΜβ kA^ Me Η Η ΟΜβ ?A^\Xc〇2h ^NiNjrr^N\ Me H H OMeC:\总档\89\89112968\89112968 (replacement)-3.ptc Page 886 1283240 Case No. 89112968 Lunar New Year Amendment VI, Patent Application Range α Η 曝 Exposure I Η H TMe C〇^H NH2 xr COOH NH Xr COOH Br Η H 〇Me CO.H co2h 0丨Η H 〇Me Ρ^Ν°Ν^Ρ^° ^〇OC〇2H Cl Η 〇 〇Me LHH όΜβ kA^ Me Η Η ΟΜβ ?A^\Xc〇 2h ^NiNjrr^N\ Me HH OMe 〇-^)-COOH〇-^)-COOH OMe -COOH C:\總檔\89\89112968\89112968(替換）-3.ptc 第 887 頁 1283240OMe -COOH C:\Total file\89\89112968\89112968 (replace)-3.ptc Page 887 1283240 C:\總檔\89\89112968\89112968(替換）-3.ptc 第 888 頁 1283240C:\Total file\89\89112968\89112968 (replace)-3.ptc Page 888 1283240 C:\總檔\89\89112968\89112968(替換）-3.ptc 第 889 頁 1283240 案號 89112968 年月曰 修正 六、申請專利範圍C:\Total file\89\89112968\89112968 (replace)-3.ptc Page 889 1283240 Case No. 89112968 Year of the month Amendment VI. Patent application scope Br M M OMe 分C00H Cl Η H OMe Cl OMeBr M M OMe by C00H Cl Η H OMe Cl OMe ο .sx N_^-o-^^-cooh HN· 〇 Br H H OMe h h iMeο .sx N_^-o-^^-cooh HN· 〇 Br H H OMe h h iMe -〇&quot;c ^-°-^^c〇2h Cl H H OMe V. 亡 ~ό^η 亡 ^〇-等 (：:\總檔\89\89112968\89112968(替換）-3.ptc 第 890 頁 1283240-〇&quot;c ^-°-^^c〇2h Cl HH OMe V. 死~ό^η 死^〇-etc (::\总档\89\89112968\89112968 (replace)-3.ptc 890 Page 1283240 C:\總檔\89\89112968\89112968(替換）-3.ptc 第 891 頁 1283240C:\Total file\89\89112968\89112968 (replace)-3.ptc Page 891 1283240 1283240 案號 89112968 年月曰 修正 六、申請專利範圍 F Me Η Η F XX C00H λ μ Μ1283240 Case No. 89112968 Year of the month Amendment VI. Patent application scope F Me Η Η F XX C00H λ μ Μ °-〇-°°2η ίλΛ He Η I 'ία C00H ,4rA tx C00H°-〇-°°2η ίλΛ He Η I 'ία C00H ,4rA tx C00H C00H QAM 1 9.如申請專利範圍第1項之化合物或其鹽，其係用於製 備治療與哺乳動物之VLA-4相關細胞黏著有關之狀態之醫 藥組成物。 2 0.如申請專利範圍第1項之化合物或其鹽，其係用於製 備治療發炎反應、自體免疫反應及腫瘤轉移之醫藥組成 物。 2 1.如申請專利範圍第1項之化合物或其鹽，其係用於製 備治療哮喘、糠尿病、關節炎、牛皮癣、多發性硬化症、 發炎性腸疾及移植排斥之醫藥組成物。C00H QAM 1 9. The compound of claim 1 or a salt thereof for use in the preparation of a pharmaceutical composition for treating a state associated with VLA-4-related cell adhesion in a mammal. A compound according to claim 1 or a salt thereof for use in the preparation of a pharmaceutical composition for treating an inflammatory response, an autoimmune response, and a tumor metastasis. 2 1. A compound according to claim 1 or a salt thereof for use in the manufacture of a pharmaceutical composition for the treatment of asthma, diabetes, arthritis, psoriasis, multiple sclerosis, inflammatory bowel disease and transplant rejection. C:\總檔\89\89112968\89112968(替換）-3.ptc 第 893 頁C:\Total file\89\89112968\89112968 (replace)-3.ptc Page 893
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