TWI269791B - omega-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors - Google Patents

omega-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors Download PDF

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Publication number
TWI269791B
TWI269791B TW089100575A TW89100575A TWI269791B TW I269791 B TWI269791 B TW I269791B TW 089100575 A TW089100575 A TW 089100575A TW 89100575 A TW89100575 A TW 89100575A TW I269791 B TWI269791 B TW I269791B
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Taiwan
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acid
phenyl
substituted
group
halogen
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TW089100575A
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Chinese (zh)
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Uday Khire
Bernd Riedl
Timothy B Lowinger
Jill E Wood
William J Scott
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Bayer Pharmaceuticals Corp
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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
    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D211/78—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
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    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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Abstract

This invention relates to the use of a group of aryl ureas in treating raf mediated diseases, and pharmaceutical compositions for use in such therapy.

Description

1269791 A7 B7 五、發明說明（1 ) 相關申請案的交互參考資料 這是於1 9 9 9年2月2 5日所提出之序號 0 9 / 2 5 7，2 6 6的部分連續申請案和於1 9 9 9年 1月13日提出之序號6 0/1 15 ，877的部分連續 申請案。 本發明的範圍 本發明關於一組芳基脲類其在治療由r a f所促成之 疾病中的用途，以及用於此類治療中的藥學組成物。 本發明的背景 致癌基因P 2 1 ^ a s是促成人類固態惡性腫瘤之發展 與惡化的主要因素，而且在3 0%之所有人類的癌症中此 種基因會發生突變（波爾頓等人著Ann. Rep. Med. Chem. 1 994，29，1 65-74; Bos. Cancer Res. 1 989，49，4682-9 )。 在幾乎所有的組織中，正常且未經過突變之型式的r a s 蛋白質是一種由生長因子受體所指揮之訊號轉導串聯效應 的主要成分（阿路克等人著，趨勢生化科學1 9 9 4， 19 ，27 9 — 83)。在生化方面，r as是一種鳥嘌 呤核苷酸結合蛋白質，而且，介於經G T P -連接活化與 G D P —連接休止型式之間的循環是受到r a s &gt;內生性 G T P酶活性和其它調節性蛋白質的嚴格控制。在癌症細 胞中之r a s變種中，內生性G T P酶昀活性減小，因此 ，該蛋白質傳遞了實質的生長訊號至下游作用器（如： 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） ¥衣—— (請先閱讀背面之注意事項再填寫本頁) 訂---------泰 經濟部智慧財產局員工消費合作社印製 -4- 1269791 A7 經 濟 部 智 慧 財 產 局 消 費 合 作 社 印 製 五、發明說明（3 ) 類的癌症，由於這 導串聯效應來決定 的方式（即：經由 本發明的化合物可 、......_ 瘤（如：肺、胰臟 病（如：骨髓性白 瘤）。、 本發明提供通 和雜芳基二者，這 發明也提供一種用 促成之疾病的方法 化酶的化合物以及 生長的化合物、組 B7 些癌症的進展是由r a s蛋白質訊號轉 ，因此它們對經由阻斷串聯效應來治療 抑制r a f催化酶）具感受性。因此， 用來治療癌症’包括固態癌症，如：癌 、甲狀腺、膀胱或大腸的癌），骨髓疾 血病）或腺腫瘤（如：絨毛的大腸腺腫1269791 A7 B7 V. INSTRUCTIONS (1) Cross-references to the relevant application This is a partial application for the serial number 0 9 / 2 5 7, 2 6 6 proposed on February 25, 1999. A partial application for the serial number 6 0/1 15 , 877 filed on January 13, 1999. Scope of the Invention The present invention relates to the use of a group of aryl ureas for the treatment of diseases caused by r a f, and pharmaceutical compositions for use in such treatments. The background oncogene P 2 1 ^ as of the present invention is a major factor contributing to the development and deterioration of human solid malignant tumors, and this gene is mutated in 30% of all human cancers (Bolton et al. Ann) Rep. Med. Chem. 1 994,29,1 65-74; Bos. Cancer Res. 1 989,49,4682-9). In almost all tissues, the normal and unmutated version of the ras protein is a major component of the signal transduction cascade effect under the growth factor receptor (Aluk et al., Trend Biochemical Science 1 9 9 4 , 19, 27 9 — 83). In terms of biochemistry, r as is a guanine nucleotide-binding protein, and the cycle between GTP-linked activation and GDP-linked quiescence is affected by ras &gt; endogenous GTPase activity and other regulatory proteins. Strict control. In the ras variety in cancer cells, the endogenous GTPase activity is reduced, so the protein transmits a substantial growth signal to the downstream agent (eg: This paper scale applies the Chinese National Standard (CNS) A4 specification (210 X) 297 mm) ¥衣- (Please read the notes on the back and fill out this page) Order---------Thailand Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed -4- 1269791 A7 Ministry of Economics The property bureau consumer cooperatives printed five, inventions (3) of the type of cancer, due to the way of this tandem effect (ie: via the compounds of the invention, ... _ tumors (such as: lungs, pancreas Dirty diseases (such as: myeloid leukoma). The present invention provides both a pass and a heteroaryl group, and the invention also provides a compound for the development of a compound using a disease-promoting method, and a compound for growth, group B7 The ras protein signals are transduced, so they are sensitive to the inhibition of raf-catalyzed enzymes by blocking the tandem effect. Therefore, they are used to treat cancers, including solid cancers such as cancer, thyroid, and bladder. Cancer of the cyst or large intestine), bone marrow disease, or glandular tumor (eg, vulgar glandular adenoma)

常被描述爲芳基脲的化合物，包括芳基 些化合物會抑制r a f催化酶通路。本 來治療人類或哺乳動物中，由r a f所 。因此，本發明係針對可抑制r a f催 用來治療由i* a f催化酶促成之癌細胞 成物和方法（其中所給予的爲一種式I 所示之化合物或其藥學上可接受的鹽）。 A - D - B ( I ) 在式I中’ D是一 NH— C (〇）—NH —， A是一種至多4 0個碳原子之經取代的式：一 l —( 。的部分，此處l是一種5或6員，直接連接至 D的環形結構，L 1包含一種經取代之具有至少5員的環形 部分，Μ是一種具有至少一個原子的橋鍵基團，Q是一個 從1一3的整數；且L和L·1的各個環形結構含有〇—4員 的氮、氧和硫，且 B是一種經取代或未經取代的，至多3 〇個碳原子的 ，至多三環的芳基或雜芳基部分，它帶有至少一個直接連 ------1-----裝--------'訂--------- (請先閱讀背面之注意事項再填寫本頁)Compounds often described as aryl ureas, including aryl groups, inhibit the r a fo catalytic enzyme pathway. Originally treated in humans or mammals, by r a f . Accordingly, the present invention is directed to a cancer cell product and method (which is administered a compound of formula I or a pharmaceutically acceptable salt thereof) which is capable of inhibiting r a f catalysis by the i* a f catalytic enzyme. A - D - B ( I ) In the formula I, 'D is an NH—C(〇)—NH—, A is a substituted formula of up to 40 carbon atoms: a part of l-(. Wherein l is a 5 or 6 member, directly attached to the ring structure of D, L 1 comprises a substituted ring portion having at least 5 members, Μ is a bridge group having at least one atom, and Q is a An integer of 3; and each of the ring structures of L and L·1 contains nitrogen, oxygen, and sulfur of the indole, and B is a substituted or unsubstituted, up to 3 carbon atoms, up to three rings An aryl or heteroaryl moiety with at least one direct link ------1-------------' order--------- (please Read the notes on the back and fill out this page.)

1269791 A7 B7 五、發明說明（4 ) 接至D的6員環形結構，此環形結構含有0至4員的氮、 氧和硫， (請先閱讀背面之注意事項再填寫本頁) 其中L 1是由至少一個選自如下群體的取代基所取代： —S〇2rx ，一 C (〇）尺乂和一C (NRy) Rz，1269791 A7 B7 V. INSTRUCTIONS (4) A 6-member ring structure connected to D. This ring structure contains 0 to 4 members of nitrogen, oxygen and sulfur. (Please read the notes on the back and fill out this page.) Where L 1 Is substituted by at least one substituent selected from the group consisting of: -S〇2rx, a C (〇) ruler and a C (NRy) Rz,

Ry是氫或一種以碳爲基礎，至多2 4個碳原子的部分 ’此部分隨意地含有選自N，S或0的雜原子並隨意地經 鹵素所取代，至多爲每一個都是鹵基，Ry is hydrogen or a carbon-based moiety of up to 24 carbon atoms. This moiety optionally contains a hetero atom selected from N, S or 0 and is optionally substituted by halogen, at most each of which is a halo group. ,

Rz是氯或一*種至多3 0個碳原子的以碳爲基礎的部分 ’此部分隨意地含有選自N，S和〇的雜原子並隨意地由 如下群體所取代：鹵素，羥基和以碳爲基礎之至多2 4個 碳原子的取代基，這些取代基隨意地含有選自N，S和〇 的雜原子並隨意地被鹵素所取代；Rz is a carbon or a carbon-based moiety of up to 30 carbon atoms. This moiety optionally contains a hetero atom selected from the group consisting of N, S and hydrazine and is optionally substituted by the following groups: halogen, hydroxy and a carbon-based substituent of up to 24 carbon atoms, these substituents optionally containing a hetero atom selected from N, S and hydrazine and optionally substituted by a halogen;

Rx是Rz或NRaRb，此處Ra和Rb係 a)各自獨立地爲氫， 經濟部智慧財產局員工消費合作社印制衣 一*種至多3 0個原子的以碳爲基礎的部分，此 部分隨意地含有選自N，S和0的雜原子且隨意地被鹵素 ，羥基和至多2 4個碳原子的以碳爲基礎的取代基所取代 ，這些取代基隨意地含有選自N，S和0的雜原子並隨意 地被鹵素所取代，或 —〇Si (1^)3，此處11^是氫或至多2 4個 碳原子之以碳爲基礎的部分，此部分隨意地含有選自N， S和0的雜原子並隨意地被鹵素，羥基和至多2 4個碳原 子之以碳爲基礎的取代基所取代，這些取代基隨意地含有 選自N，S，和〇的雜原子並隨意地被鹵素所取代；或 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 1269791 A7 B7 五、發明說明（5 ) (請先閱讀背面之注意事項再填寫本頁) b ) R a和R b 一起形成①一種5 一 7員的雜環構造， 此雑環構造係由1 一 3個選自N，S，和〇的雜原子所構 成，或②一種經取代之5 - 7員的雜環構造，此構造係由 1 一 3個選自經取代之N，S和〇的雜原子所構成，這些 雜原子可被如下群體所取代：鹵素，羥基或至多2 4個碳 原子之以碳爲基礎的取代基（這些取代基隨意地含有選自 N，0 ’和S的雜原子並隨意地被鹵素所取代）；或 c) Ra或Rb其中之一是一 c (〇）一，一種連接至 L·部分的C 1 一 C 5二價伸烷基基團或經取代之c 1 一 C 5二 價伸烷基基團以形成至少含有5員的環形構造，其中該經 取代之C i 一 C 5二價伸烷基基團的取代基係選自由如下的 群體中：鹵素，羥基和军多2 4個碳原子之以碳爲基礎的 取代基，這些取代基隨意地含有選自N，S，和0的雜原 子並隨意地被鹵素所取代； 此處的B係經取代的，L係經取代的或l 1係額外地經 取代的’該取代基係選自如下之群體：鹵素（至多爲每一 個都是鹵基），及Wn，此處η是〇 — 3 ; 其中各W係各自獨立地選自如下群體中：一 CN， 經濟部智慧財產局員工消費合作社印製 —COSH7， 一 c (〇）NR7r7，—c (〇)— R7, 一 N〇2 — ，一 OR? ， 一 SR? ， 一 NR7R7 ， —NR7C (〇）〇R7， 一 NR7C (〇）R7， -Q - A r及至多2 4個碳原子之以碳爲基礎的部份，此 部份隨意地含有選自N，S，和◦的雜原子並隨意地被一 或多個獨立地選自如下群體的取代基所取代：- C N， 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -8 - 1269791 A7 B7 五、發明說明（6 ) ~C〇2R7，-C(〇)-R^,_C(〇)NR7R7, ~or7,~'sR7j-nr7r7,_n〇2, (請先閱讀背面之注意事項再填寫本頁) —Nr7c(〇）R7，一nR7C(〇）〇r7及鹵素（至 多爲每一個都是鹵基）；這些取代基所帶有的各個r7各自 獨1L地選自Η或含有至多2 4個碳原子的以碳爲基礎的部 份’此部份隨意地含有選自N，S，和〇的雜原子並隨意 地被鹵素所取代， 其中 Q 是一〇一，—S —，ν (R7)—， 一（CH2)m—，— c (0)〜，—CH (0Η) 一， -(CH2)ra〇—，一（CH2)mS —， 一（CH2) mN (R7)-，- 〇（CH2) m- CHXa ，-CX、-，- S - (CH2)m 和 —N(R7) (CH2)m —，此處m 二 1 — 3，且 Xa 是鹵 素；及 經濟部智慧財產局員工消費合作社印刹农 A r是一種5 一或6 一員的芳香族構造物，此構造物 含有0 — 2員選自如下群體的雜原子：.氮，氧和硫（可隨 意地被鹵素所取代，至多爲每一個都是鹵基）並隨意地被 Z n i所取代，其中n 1是〇至3且各個z係各自獨立地選 自如下之群體：一CN，一 C〇2R7，一 C (〇）一R7 ，一c (〇）NR7R7 ’ 一NOS ，一〇R7 ， 一 SR7 ， -NR7R7，- NR7C(〇）R7， 一 NR7C (〇）〇r7，及一種含有至多24個碳原子的 以碳爲基礎的部分，此部份隨意地含有選自N，S，和〇 的雜原子並隨意地被一或多個選自如下群體的取代基所取 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -9- 經濟部智慧財產局員工消費合作社印制π 1269791 A7 B7 五、發明說明（7 ) 代：一 CN，一 C〇2R7，一 C〇R7， 一 C (〇）NR7R7，一 〇R7， 一 SR7，— n〇2， 一nr7r7，一NR7C(〇）R7，及 一 NR7C (〇)〇R7，所帶有的R7定義同上。 在式I中，合適的雜芳基團包括，但不侷限於，含5 - 1 2個碳原子的芳香環或含1 一 3個環的環系（其中至 少有一個環是芳香環），其中在一或多個環中的一或多個 ，如：1 一 4個，碳原子可以被氧，氮或硫原子所取代。 通常各個環具有3 - 7個原子。例如：B可以是2 -或3 一呋喃基，2 —或3 -噻嗯基，2 —或4 一三哄基，1 一 ’ 2 -或3 —哦咯基，1—，2 -，4 一或5 —咪嗤基， 1 一，3 —，4 —或5 — D比嗤基，2 —，4 —或5 — 口等口坐 基，3 -，4 一或5 -異哼唑基，2 -，4 一或5 —噻唑 基，3 —，4 一或5 —異噻唑基，2 —，3 —或4 一吡啶 基，2 -，4 —，5 —或6 -嚼卩定基，1 ，2，3 —三口坐 一 1 一，— 4 —，或—5 —基，1 ，2，4 —三嗤―1 — ，一 3 —或—5 —基，1—或 5 —四口坐基，1 ，2，3 — 口琴二p坐—4 —或—5 —基，1 ，2 ’ 4 —吗二η坐—3 —或 一5 -基，1 ，3，4 —噻二 D坐—2 —或一 5 —基，1 ， 2，4 —哼二嗤—3 - 或一 5 - 基，1 ，3，4 —噻二口坐 一 2 —或—5 —基，1 ，2，4 —噚二唑 一 3 —或—5 — 基，1 ，3 ,4 —噻二唑—2 —或—5 -基，1 ，3 ，4 一噻二唑—3 —或—5 —基，1，2，3 —噻二唑—4 — 或—5 —基，2 —，3 -，4 —，5 —或 6 — 2H —噻喃 -----J.-------------訂--------- (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -10- 1269791 A7 五、發明說明（8 ) __B7 經濟部智慧財產局員工消費合作社印剔衣 基 y 2 — j 3 或 4 — 4 Η — 噻 喃 基 3 — 或 4 — 嗒 哄 基 嗒 畊 基 2 — 3 — ， 4 — y 5 — 6 — 或 7 — 苯 並 呋 喃 基 1 2 — 3 — 5 4 — 5 5 — j 6 — 或 7 一 苯 並 噻 嗯 基 1 — 2 一 3 — &gt; 4 — y 5 — 6 — 或 7 — 吲 哚 基 ， 1 — 2 — 4 — 或 5 — 苯 並 咪 口坐 基 y 1 — 3 — &gt; 4 — 5 一 6 — 或 7 — 苯 並 吡 唑 基 &gt; 2 — 4 — 5 — 6 — 或 7 — 苯 並 口咢 唑 基 j 3 — 1 4 — ， 5 — y 6 — 或 7 — 苯 並 異 nf 唑 基 1 — 1 3 — 4 — 5 — ， 6 — 或 7 — 苯 並 噻 唑 基 ， 2 — &gt; 4 — y 5 — ， 6 — 或 7 — 苯 並 異 噻 唑 基 ， 2 — ， 4 — ， 5 — ， 6 — 或 7 — 苯 並 — 1 y 3 — 口咢 二 唑 基 ， 2 — ， 3 — j 4 — 5 — 6 — 7 — 或 8 — 喹 啉 基 ， 1 — y 3 — 4 — 5 — ， 6 — &gt; 7 — j 8 — 異 喹 啉 基 j 1 — 2 — y 3 — 4 — 或 9 — 咔 唑 基 1 — 2 — 3 — j 4 — 5 — ? 6 — ) 7 — 7 8 — 或 9 — 吖 D定 基 或 2 — 7 4 — ， 5 — j 6 — 7 — 或 8 — 口奎 唑 啉 基 &gt; 或 額 外 隨 意 地 經 取 代 的 苯 基 y 2 — 或 3 — 噻 嗯 基 j 1 y 3 4 — 噻 二 唑 基 3 — 吡 咯 基 3 — 吡 唑 基 2 — 噻 唑 基 或 5 — 噻 唑 基 7 等 等 〇 例 如 B 可 以 是 4 — 甲 基 — 苯 基 j 5 — 甲 基 — 2 — 噻 嗯 基 4 — 甲 基 — 2 — 噻 嗯 基 j 1 — 甲 基 — 3 — 吡 咯 基 1 — 甲 基 一 3 — 吡 口坐 基 5 — 甲 基 — 2 — 噻 唑 基 或 5 — 甲 基 — 1 y 2 5 4 -噻二唑- -2 - -基。 合 適 的 烷 基 團 和 基 團 ( 如 院 氧 基 5 等 等 ) 的 烷 基 部 分 共 包 括 甲 基 乙 基 ， 丙 基 ， 丁 基 等 等 j 包 括 所 有 的 直 鏈 型 和 有 側 鏈 的 異 構 物 j 如 ： 異 丙 基 ， 異 丁 基 二 級 一 丁 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -11 - (請先閱讀背面之注意事項再填寫本頁) 1269791 A7 B7 五、發明說明（9 ) &gt; 基，三級一丁基，等等。 不含雜原子之合適的芳基團包括，如：苯基和1 一和 2 -萘基。 此處所使用的、'環烷基〃 一詞是指帶有或不帶有烷基 取代基的環形構造物，如：、、C 4環烷基〃包括了：經甲基 取代之環丙基基團及環丁基基團。此處所使用之、、環烷基 〃一詞也包括飽和之雜環基團。 合適的鹵素基團包括F，C 1 ，Br ，及/或I ，當 烷基團被鹵素取代時，取代數可能爲從1個原子被取代至 每個原子都被取代（即：在一個基團上的所有Η原子都被 一個鹵素原子所取代），在一個指定的基團部分上也可能 有混合的鹵素原子型的取代作用。 本發明也關於式I所示之化合物。 本發明也關於式I所示之藥學上可接受的鹽類。合適 之藥學上可接受的鹽類爲內行人士所熟知，包括了無機和 有機酸類的鹼式鹽，這些無機和有機酸類有··氫氯酸’氫 溴酸，硫酸，磷酸，甲磺酸，二氟甲磺酸，苯磺酸，對一 甲苯磺酸，1 一萘磺酸，2 -萘磺酸，醋酸’三氟醋酸’ 蘋果酸，酒石酸，檸檬酸，乳酸，草酸，琥珀酸，反一丁 烯二酸，順一丁烯二酸，苯甲酸，水楊酸，苯乙酸，及扁 桃酸。另外，藥學上可接受的鹽包括無機鹼的酸式鹽’如 :含如下群體的鹽類：鹼性陽離子（如·· L i + ’ N a +或 K + )，鹼土陽離子（如：Mg2+，Ca2 + 或 Ba2+)， 銨陽離子，以及有機鹼的酸式鹽，包括經脂族及芳香族取 (請先閱讀背面之注意事項再填寫本頁) --------&quot;訂 —-------- 經濟部智慧財產局員工消費合作社印製 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -12- 經濟部智慧財產局員工消費合作社印製 1269791 A7 -—___ B7 ____ 五、發明說明（1〇) · 代的銨，及季銨陽離子，如：那些由如下群體之質子化或 過烷基化作用所產生者：三乙胺，N，N -二乙胺，N， N —二環己胺，賴胺酸，吡啶，N，N —二甲胺基吡啶（ DMAP) ，1 ’ 4 —二氮雜雙環〔2 · 2 · 2〕辛烷（ D A B C 0 ) ’ 1 ，5 —二氮雜雙環〔4 · 3 · 〇〕壬一 5 —烯（DBN)及 1 ，8 -二氮雜雙環〔5 . 4 · 0〕 十一'碳一 7 - 嫌（DBU)。 §午多式I所示之化合物具有不對稱的碳並因此而具有 外消旋及光學上活性的型式。用來分離鏡像體的和非鏡像 •1Δ體異構體的混合物的方法爲內行人士所熟知。本發明包 含任何已分離之式I中所說明之具有r a f抑制活性的外 消旋或光學上活性的化合物。 一般製備方法 式I所示之化合物可以利用已知之化學反應和步驟來 製備，有些是從可購買到的起始物質來製備的。然而，下 述所提供之一般製備方法是用來幫助內行人士合成這些化 合物’在接下去的實驗部分則提供較詳細的實施例。 經取代之苯胺可利用標準方法來製備（馬契，進階有 機化學第三版；約翰威利：紐約（1 9 8 5 )。拉洛克、 廣泛的有機變換作用；V C Η出版者：紐約（1 9 8 9 ) )。如圖表I中所顯示的，芳基胺類通常是利用硝芳基類 的還原作用來合成的，此作用是金屬催化劑，如：N i ， P d，或P t ，和Η 2，或一種氫化物轉移劑，如：甲酸鹽 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公爱） ------------裝---------訂--------- (請先閱讀背面之注意事項再填寫本頁) -13- 1269791Rx is Rz or NRaRb, where Ra and Rb are a) each independently hydrogen, and the Ministry of Economic Affairs' Intellectual Property Office employee consumption cooperative prints a carbon-based part of up to 30 atoms. Containing a hetero atom selected from N, S and 0 and optionally substituted by a halogen, a hydroxyl group and a carbon-based substituent of up to 24 carbon atoms, these substituents optionally contain a group selected from N, S and 0. a hetero atom and optionally substituted by a halogen, or -〇Si(1^)3, where 11^ is hydrogen or a carbon-based moiety of up to 24 carbon atoms, optionally containing N selected from N , the heteroatoms of S and 0 are optionally substituted by a halogen, a hydroxyl group and a carbon-based substituent of up to 24 carbon atoms, these substituents optionally containing a hetero atom selected from N, S, and fluorene Feel free to be replaced by halogen; or this paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1269791 A7 B7 V. Invention description (5) (Please read the note on the back and fill out this page) b) R a and R b together form a heterocyclic structure of 5 to 7 members, this anthracene ring structure a heterocyclic structure consisting of 1 to 3 heteroatoms selected from N, S, and deuterium, or 2 substituted 5-7 members, the structure consisting of 1 to 3 selected from substituted N, S And heterocyclic atoms of hydrazine, which may be substituted by a halogen, a hydroxyl group or a carbon-based substituent of up to 24 carbon atoms (these substituents optionally contain a group selected from N, 0 ' and a hetero atom of S is optionally substituted by a halogen; or c) one of Ra or Rb is a c (〇)-, a C 1 -C 5 divalent alkylene group attached to the L moiety or Substituted c 1 -C 5 divalent alkylene group to form a ring structure having at least 5 members, wherein the substituted C i -C 5 divalent alkyl group substituent is selected from the group consisting of In the group: a halogen-based, hydroxy group and a carbon-based substituent of 24 carbon atoms, these substituents optionally contain a hetero atom selected from N, S, and 0 and are optionally substituted by a halogen; Substituted B, L-substituted or l 1 additionally substituted 'the substituent is selected from the group consisting of halogen ( Most of them are halo), and Wn, where η is 〇-3; wherein each W system is independently selected from the following groups: one CN, Ministry of Economic Affairs, Intellectual Property Bureau, employee consumption cooperative, COSH7, A c (〇) NR7r7, —c (〇)—R7, an N〇2 — , an OR?, an SR?, an NR7R7, —NR7C (〇)〇R7, an NR7C (〇)R7, -Q- A r and a carbon-based moiety of up to 24 carbon atoms, optionally containing a hetero atom selected from N, S, and deuterium and optionally randomly selected from one or more of the following groups Substituted by: - CN, This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -8 - 1269791 A7 B7 V. Invention description (6 ) ~C〇2R7,-C(〇) -R^, _C(〇)NR7R7, ~or7,~'sR7j-nr7r7,_n〇2, (please read the notes on the back and fill out this page) —Nr7c(〇)R7,一nR7C(〇)〇r7 And halogen (at most, each is a halo group); each of the r7 carried by these substituents is independently selected from hydrazine or a carbon-based moiety containing up to 24 carbon atoms. Ground a hetero atom selected from N, S, and deuterium and optionally substituted by a halogen, wherein Q is mono-, -S-, ν(R7)-, one (CH2)m-, -c(0)~, —CH (0Η) I, -(CH2)ra〇—,—(CH2)mS —, —(CH2) mN (R7)-,-〇(CH2) m-CHXa ,-CX,-,- S - ( CH2)m and -N(R7) (CH2)m — where m 2 1-3, and Xa is halogen; and the Intellectual Property Office of the Ministry of Economic Affairs, the consumer cooperative cooperative, is a kind of 5 or 6 An aromatic structure comprising 0 to 2 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur (optionally substituted by halogen, at most each of which is a halo) and optionally Z Substituted by ni, wherein n 1 is 〇 to 3 and each z-line is independently selected from the group consisting of: CN, C 〇 2R7, C (〇)-R7, C (〇) NR7R7 '-NOS, a 〇R7, an SR7, -NR7R7, -NR7C(〇)R7, an NR7C(〇)〇r7, and a carbon-based moiety having up to 24 carbon atoms, optionally containing N selected from the group consisting of N , S, and 杂 heteroatoms are randomly Or a plurality of substituents selected from the following groups are taken according to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) -9- Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing π 1269791 A7 B7 V. DESCRIPTION OF THE INVENTION (7) Generation: a CN, a C〇2R7, a C〇R7, a C (〇)NR7R7, a R7, an SR7, an n〇2, an nr7r7, an NR7C (〇) R7, and An NR7C (〇) 〇 R7, with the definition of R7 is the same as above. In Formula I, suitable heteroaryl groups include, but are not limited to, an aromatic ring having 5 to 12 carbon atoms or a ring system having 1 to 3 rings (at least one of which is an aromatic ring), One or more of the one or more rings, such as: one to four, the carbon atom may be replaced by an oxygen, nitrogen or sulfur atom. Usually each ring has 3 - 7 atoms. For example: B may be 2 - or 3 - furanyl, 2 - or 3 - thiol, 2 - or 4 - tridecyl, 1 - 2 - or 3 - o-yl, 1-, 2-, 4 One or 5 - mercapto, 1 -, 3 -, 4 - or 5 - D is more than fluorenyl, 2 -, 4 - or 5 - orally, 3 -, 4 - or 5 -isoxazolyl , 2 -, 4 or 5 - thiazolyl, 3 -, 4 - or 5 -isothiazolyl, 2 -, 3 - or 4 -pyridyl, 2 -, 4 -, 5 - or 6 - chelate, 1 , 2, 3 — three to sit 1 1 , — 4 —, or —5 — base, 1 , 2, 4 — 3嗤 —1 — , 3 — or — 5 —, 1 — or 5 — 4 Sitting base, 1, 2, 3 — harmonica two p sitting — 4 — or — 5 — base, 1 , 2 ' 4 — 2 η sitting — 3 — or a 5-base, 1 , 3, 4 — thiazide D Sit — 2 — or a 5-base, 1, 2, 4 — 哼 嗤 — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — , 4 - oxadiazole - 3 - or - 5 - group, 1, 3, 4 - thiadiazole - 2 - or -5 -yl, 1, 3, 4 - thiadiazole - 3 - or -5 -yl ,1,2,3 —thiadiazole-4 Or -5 - base, 2 -, 3 -, 4 -, 5 - or 6 - 2H - thiopyran-----J.------------- order----- ---- (Please read the note on the back and fill out this page.) This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -10- 1269791 A7 V. Invention Description (8) __B7 Economy Department of Intellectual Property, Staff Consumer Cooperatives, Printing Press, y 2 — j 3 or 4 — 4 — thiopyranyl 3 — or 4 — 嗒哄 嗒 嗒 2 2, 3 — y 5 — 6 — or 7 —benzofuranyl 1 2 — 3 — 5 4 — 5 5 — j 6 — or 7-benzothiathiol 1 — 2 — 3 — &gt; 4 — y 5 — 6 — or 7 — fluorenyl, 1 — 2 — 4 — or 5 — benzopyrenes y 1 — 3 — &gt; 4 — 5 — 6 — or 7 — benzopyrazolyl” 2 — 4 — 5 — 6 — or 7 — benzo Oroxazolyl j 3 — 1 4 — , 5 — y 6 — or 7 — benzoiso-nfazolyl 1 — 1 3 — 4 — 5 — , 6 — or 7 — benzothiazolyl, 2 — &gt; 4 — y 5 — , 6 — or 7 — Benzoisothiazolyl, 2 — , 4 — , 5 — , 6 — or 7 — Benzo- 1 y 3 — Oroxadiazole, 2 — , 3 — j 4 — 5 — 6 — 7 — or 8 — quinolyl, 1 — y 3 — 4 — 5 — , 6 — &gt; 7 — j 8 — isoquinolinyl j 1 — 2 — y 3 — 4 — or 9 — carbazolyl 1 — 2 — 3 — j 4 — 5 — ? 6 — ) 7 — 7 8 — or 9 — 吖D fixed or 2 — 7 4 — , 5 — j 6 — 7 — or 8 — quinazolinyl> or extra random Disubstituted phenyl y 2 — or 3 — thiol j 1 y 3 4 — thiadiazolyl 3 —pyrrolyl 3 —pyrazolyl 2 —thiazolyl or 5 —thiazolyl 7 and the like, for example B Is 4-methyl-phenylj 5 -methyl-2 - thiol 4 - methyl-2 - thiol j 1 - methyl - 3 - pyrrolyl 1 - methyl - 3 - pyridine 5 —Methyl-2 —thiazolyl or 5-methyl- 1 y 2 5 4 -thiadiazole-2-yl-yl. Suitable alkyl groups and alkyl groups of groups (eg, oxime 5, etc.) include methyl ethyl, propyl, butyl, etc. j including all linear and side chain isomers j Such as: Isopropyl, isobutyl secondary Ding paper scale applicable to China National Standard (CNS) A4 specification (210 X 297 mm) -11 - (Please read the back of the note before filling this page) 1269791 A7 B7 V. Inventive Note (9) &gt; Base, Tertiary Butyl, and the like. Suitable aryl groups which do not contain a hetero atom include, for example, a phenyl group and a mono- and 2-naphthyl group. The term 'cycloalkyl hydrazine as used herein, refers to a cyclic structure with or without an alkyl substituent, such as: , C 4 cycloalkyl fluorene includes: methyl substituted cyclopropyl. a group and a cyclobutyl group. The term cycloalkyl hydrazine as used herein also includes saturated heterocyclic groups. Suitable halogen groups include F, C 1 , Br, and/or I. When the alkyl group is substituted by a halogen, the number of substitutions may be substituted from 1 atom to each atom (ie, at a base) All of the helium atoms on the group are replaced by a halogen atom. There may also be substitutions of mixed halogen atoms on a given group moiety. The invention also relates to compounds of formula I. The invention also relates to pharmaceutically acceptable salts of formula I. Suitable pharmaceutically acceptable salts are well known to those skilled in the art and include basic salts of inorganic and organic acids, such as hydrochloric acid, hydroperic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, Difluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 1-naphthalenesulfonic acid, 2-naphthalenesulfonic acid, acetic acid 'trifluoroacetic acid' malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, anti Monobutyric acid, cis-monocarboxylic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid. Further, the pharmaceutically acceptable salt includes an acid salt of an inorganic base such as a salt containing a basic cation (e.g., L i + 'N a + or K + ), an alkaline earth cation (e.g., Mg2+). , Ca2+ or Ba2+), ammonium cations, and acid salts of organic bases, including aliphatic and aromatic (please read the back of the note before you fill out this page) --------&quot; —-------- Ministry of Economic Affairs, Intellectual Property Bureau, Staff and Consumer Cooperatives, Printed Paper Size Applicable to China National Standard (CNS) A4 Specification (210 X 297 mm) -12- Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumption Cooperatives 1269791 A7 -____ B7 ____ V. Description of the invention (1〇) · Generation of ammonium, and quaternary ammonium cations, such as those produced by protonation or peralkylation of the following groups: triethylamine, N , N-diethylamine, N, N-dicyclohexylamine, lysine, pyridine, N,N-dimethylaminopyridine (DMAP), 1 '4-diazabicyclo[2 · 2 · 2] Octane (DABC 0 ) ' 1,5-diazabicyclo[4 ·3 · 〇]壬-5-ene (DBN) and 1,8-diazabicyclo[5 . 4 · 0 11 'a carbon 7-- too (DBU). § The compound of formula I has an asymmetric carbon and thus has a racemic and optically active form. Methods for separating mixtures of mirror images and non-mirrored • 1 Δ isomers are well known to those skilled in the art. The present invention comprises any isolated racemic or optically active compound having the r a f inhibitory activity as described in Formula I. General Preparation Methods The compounds of formula I can be prepared using known chemical reactions and procedures, some of which are prepared from commercially available starting materials. However, the general preparation methods provided below are intended to assist laymen in synthesizing these compounds'. In the next experimental section, more detailed examples are provided. Substituted aniline can be prepared using standard methods (Machi, Advanced Organic Chemistry Third Edition; John Willy: New York (1 9.8). Larlock, Extensive Organic Transformation; VC Η Publisher: New York ( 1 9 8 9 )). As shown in Figure I, arylamines are typically synthesized using the reduction of nitroaryls, which are metal catalysts such as: N i , P d, or P t , and Η 2, or a Hydride transfer agent, such as: formate, this paper scale applies to China National Standard (CNS) A4 specifications (210 X 297 public) ------------ Packing -------- -Book--------- (Please read the notes on the back and fill out this page) -13- 1269791

ArNOn Α7 Β7 五、發明說明（11) » ，環己二燔’或氫硼化物來進行的（雷蘭德，氫化作用的 方法；學院出版社：倫敦，U K ( 1 9 8 5 ))。硝芳基 類也可利用一種強的氫化物來源（如：L i a 1 Η 4 )直接 被還原（施丹-潘尼，在有機合成作用中經由氫鋁化物或 氫硼化物進行的還原作用；V C Η出版者：紐約（ 19 9 1))，或者是利用一種通常是在酸性介質中的零 價金屬，如：F e ，Sn或Ca來直接被還原。有許多方 法都可用來合成硝芳基類（馬契，進階有機化學，第三版 ;約翰威利：紐約（1 9 8 5 )，拉洛克，廣泛的有機變 換作用；V C Η出版者：紐約（1 9 8 9 ))。 η2/催化劑 (如:Ni, Pd，Pt) _[Η：] Μ(0) (如:Fe，Sn，Ca)ArNOn Α7 Β7 5, invention description (11) », cyclohexanide or borohydride (Leland, method of hydrogenation; College Press: London, U K (1 9 8 5)). Nitroaryls can also be directly reduced by a strong source of hydride (eg, Li ia 1 Η 4 ) (Stan-Pani, reduction by organoaluminum or borohydride in organic synthesis; VC Η Publisher: New York (19 9 1)), or directly reduced by a zero-valent metal, such as: F e , Sn or Ca, usually in an acidic medium. There are many ways to synthesize nitrates (Machi, Advanced Organic Chemistry, Third Edition; John Willy: New York (1, 9 5), Larlock, Extensive Organic Transformation; VC Η Publisher: New York (1 9 8 9)). Η2/catalyst (eg Ni, Pd, Pt) _[Η:] Μ(0) (eg Fe, Sn, Ca)

ArNHn |裝—— (請先閱讀背面之注意事項再填寫本頁) I訂——·---- 經濟部智慧財產局員工消費合作社印製 圖表I 硝芳基類還原成芳基胺類的作用 通常’硝芳基類可利用HN〇 3或替代之n〇2 —來源 經由親電子之芳香族硝化作用來形成。硝芳基類可在硝化 作用之前先進一步加工過因此，硝芳基類是以 HNO,ArNHn | Packing - (Please read the notes on the back and fill out this page) I book -·---- Ministry of Economic Affairs Intellectual Property Bureau employees consumption cooperatives printed chart I nitro-aryls reduced to arylamines The role of the 'nitroaryl group can be formed by HN〇3 or alternatively n〇2—the source is formed by electrophilic aromatic nitration. The nitro aryl group can be further processed before nitrification. Therefore, the nitro aryl group is HNO.

Ar-H ΑγΝΟ〇Ar-H ΑγΝΟ〇

來取代。 可能的離基團（如：FTo replace. Possible leaving group (eg F

C Β 等等）在以親 争 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -14- 1269791 a7 B7 五、發明說明（12) . 核劑’如：硫醇鹽（示範於圖表Π中）或苯酸鹽處理時可 能會發生取代反應。硝芳基類也可能發生、阿爾曼型〃（ Ullman-type )偶合反應（圖表Π )。C Β etc.) Apply the Chinese National Standard (CNS) A4 specification (210 X 297 mm) to the scale of this paper. -14- 1269791 a7 B7 V. Inventive Note (12) . Nuclear agent 'eg: thiolate Substitution reactions may occur when (exemplified in the graph) or during benzoate treatment. Nillman-type coupling reactions (graph Π) may also occur in nitroaryl groups.

0〇N0〇N

R 1R 1

ArSH 鹼 〇2N&gt;-\\ S_ArArSH base 〇2N&gt;-\\ S_Ar

02N02N

RR

R ^-SH 3R ^-SH 3

Br—A二 Cu〇/驗 (請先閱讀背面之注意事項再填寫本頁) 圖表Π 利用硝芳基類進行的經選擇之親核芳香族取代作 用 硝芳基類也可進行由過渡金屬促成的交叉偶合反應。 例如：硝芳基親電子劑，如：硝芳基的溴化物，碘化物或 三氟甲烷磺酸酯可與芳基親核劑類，如：芳基硼酸類（鈴 木反應，示範於下），芳基錫類（ '、史提爾〃 Stille反應） 或芳基鋅類（Negishi 、、奈吉西〃反應）進行由鈀促成之交 叉偶合反應以產生聯芳基（5)。 經濟部智慧財產局員工消費合作社印製Br-A two Cu〇/test (please read the notes on the back and fill out this page). Chart 经 Selected nucleophilic aromatic substitutions using nitroaryls can also be made from transition metals. Cross coupling reaction. For example: nitroaryl electrophiles, such as: nitroaryl bromide, iodide or trifluoromethane sulfonate can be combined with aryl nucleophiles, such as: aryl boronic acid (Suzuki reaction, demonstrated below) The aryltins (', Steyr's Stille reaction) or the aryl zincs (Negishi, Nygicilidine reaction) undergo a cross-coupling reaction promoted by palladium to produce a biaryl group (5). Ministry of Economic Affairs, Intellectual Property Bureau, employee consumption cooperative, printing

o2n RO2n R

ArB(〇R，)2 Pd(0)ArB(〇R,)2 Pd(0)

02N R 硝芳基類或苯胺類可以氯磺酸處理來轉化成相對應之 芳香烴基磺醯氯（7 )。將磺醯氯與一種氟化物的來源（ 如：K F )進行反應以產生磺醯氟（8 )。在一種氟化物 來源（如：三（二甲胺基）锍二氟基三甲基矽酸鹽（ 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -15- 1269791 A7 B7 五、發明說明（彳3) 丁 A S F ))的存在下，將磺醯氟8與三甲基甲矽烷基三 氟甲烷進行反應可產生相對應之三氟甲基硕（9)。或者 ’磺醯氯可以以如：鋅汞齊還原成芳香烴硫醇（1 〇 )。 在驗的存在下，將硫醇1 〇與CHC 1 F2進行反應可產生 二氟甲基硫醇（1 1 )，此化合物可以利用多種氧化劑（ 包括C r〇3 -醋酸酐）來氧化成硕（1 2 )(施達瓦等人 著 Zh·· 〇rg. Khim. 1 970，6，（568)。 -R Me3SiCF302N R Nitroaryl or aniline can be converted to the corresponding aromatic hydrocarbon sulfonium chloride (7) by treatment with chlorosulfonic acid. The sulfonium chloride is reacted with a source of fluoride (e.g., KF) to produce sulfonium fluoride (8). In a fluoride source (eg: tris(dimethylamino) fluorene difluorotrimethyl decanoate (this paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) -15- 1269791 A7 B7 V. INSTRUCTION DESCRIPTION (彳3) The reaction of sulfonium fluoride 8 with trimethylformamidine trifluoromethane in the presence of butyl ASF)) produces the corresponding trifluoromethyl group (9). Alternatively, 'sulfonyl chloride can be reduced to an aromatic hydrocarbon thiol (1 〇) by, for example, zinc amalgam. In the presence of the test, the reaction of thiol 1 hydrazine with CHC 1 F2 produces difluoromethyl thiol (1 1 ), which can be oxidized to a large amount by using various oxidizing agents (including C 〇 3 - acetic anhydride). (1 2 ) (Shidawa et al. Zh·· 〇rg. Khim. 1 970, 6, (568). -R Me3SiCF3

SO2CF3 SCHF. -R -R 9 11 (請先閱讀背面之注意事項再填寫本頁) [〇】 經濟部智慧財產局員工消費合作社印製 1 so2CHF2 •R 12 圖表瓜 經選擇之經氟化的芳基硕合成方法 如圖表IV中所顯示的，非對稱性脲形成方法會牽涉到 一種異氰酸芳酯（1 4 )和一種芳基胺（1 3 )的反應。 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -16- 1269791 A7 B7 瓦、發明說明（14 ) · 該異氰酸雜芳酯可以經由以光氣或與光氣相等的物質來處 理雜芳基胺以進行合成，該與光氣相等的物質，如：氯甲 •一一 ^ / 一 ^氣），雙（三氟甲基）碳酸酯（三光氣 鑛基二咪嗤（CD I)。該異氰酸酯也 可從一種雜環的羧酸衍生物，如：酯類，酸性鹵化物或酐 (Curtius-type )重組衍生而來。因此 與一種疊氮化物的來源進行反應，再 妾著進行重組可產生異氰酸酯。相對應之羧酸（1 7 )也 玎利用二苯基磷醯疊氮化物（D P P A )或類似試劑來進 吁、、克提斯型〃重組作用。 A「1—NH2 13SO2CF3 SCHF. -R -R 9 11 (Please read the note on the back and fill out this page) [〇] Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 1 so2CHF2 •R 12 chart selected meridian fluoride The synthesis method of the base is shown in Figure IV. The asymmetric urea formation process involves the reaction of an aryl isocyanate (14) and an arylamine (13). This paper scale is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) -16-1269791 A7 B7 watt, invention description (14) · The isocyanate isocyanate can be passed through phosgene or photo-vapor a substance to treat a heteroarylamine for synthesis, such as a photo-vapor phase, such as: chloroform, bis(trifluoromethyl)carbonate, or bis (trifluoromethyl) carbonate嗤 (CD I). The isocyanate can also be recombined from a heterocyclic carboxylic acid derivative such as an ester, acid halide or anhydride (Curtius-type), thus reacting with a source of azide. The isocyanate can be produced by recombination, and the corresponding carboxylic acid (17) is also subjected to recombination by using diphenylphosphonium azide (DPPA) or the like. "1-NH2 13

酸三氯甲酯、 )，或 N , N 經由 '、克提斯型 將酸性衍生物 (請先閱讀背面之注意事項再填寫本頁)Acid trichloromethyl ester, ), or N, N via ', Cresic type, acidic derivatives (please read the back of the note before you fill out this page)

COCU A「1 一 NC〇 14 Η2Ν-ΑΓ2 a「1、n人〆 Η Η 15 裝--------訂i 經濟部智慧財產局員工消費合作社印製 ν3*^/ 〇 〇 Αγ1/^Χ Αγ1/^〇Η 16 17 圖表IV 經選擇之非對稱型脲的形成方法 最後，脲類還可利用內行人士所熟悉的方法來進一步 處理。 本發明也包括藥學上的組成物，包括：式.I所示之化 合物和一種生理學上可接受的載體。 這些化合物可以以劑量單位的配方型式經由口服的，COCU A"1一NC〇14 Η2Ν-ΑΓ2 a"1, n人〆Η Η 15 Pack--------Book i Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative print ν3*^/ 〇〇Αγ1/ ^Χ Αγ1/^〇Η 16 17 Figure IV Method of Formation of Selected Asymmetric Urea Finally, urea can be further processed by methods familiar to those skilled in the art. The present invention also encompasses pharmaceutically acceptable compositions, including: a compound of the formula I and a physiologically acceptable carrier. These compounds can be administered orally in dosage unit dosage forms,

DPPA 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 1269791 A7 B7 五、發明說明（15) ， (請先閱讀背面之注意事項再填寫本頁) 局部的，腸胃道外的、或噴灑的或肛門的途徑來給藥。、、 經由注射給藥〃一詞包括靜脈內的，肌肉內的，經皮膚的 注射以及利用浸潤的技術。一或多種化合物可與一或多種 非毒性之藥學上可接受的載體一起存在，而且，如需要時 可加入其它的活性成分。 用於口服的組成物可根據任何本領域中已知之製備藥 學組成物的合適方法來製備。此種組成物可含一或多種選 自如下群體的試劑：稀釋劑、甜味劑、調味劑、調色劑和 保存劑以提供美味的製品。藥片中含有與非毒性之藥學上 可接受的賦形劑（適合用於製做藥片者）混合在一起的活 性成分。這些賦形劑可爲，如：惰性稀釋劑，如：碳酸鈣 ，碳酸鈉，乳糖，磷酸鈣或磷酸鈉；顆粒劑及崩解劑，如 :玉米粉，或藻朊酸；及連接劑，如：硬脂酸鎂’硬脂酸 或滑石粉。該藥片可不包膜或經由已知技術加以包膜以延 遲在胃腸道中的崩解和吸收並藉此提供一種在長期間內的 持續作用。例如，可使用一種時間延遲物質，如：一硬脂 酸甘油酯或二硬脂酸甘油酯。這些化合物也可製成固體的 快速釋出型式。 經濟部智慧財產局員工消費合作社印製 用於口服的配方也可以硬膠囊的型式存在，其中該活 性成分係與一種惰性固體稀釋劑混合在一起’此類稀釋劑 有，如：碳酸鈣，磷酸鈣或高嶺土’或’也可以以軟膠囊 的型式存在，其中該活性成分係與水或油性介.質混合在一 起，此類介質有，如：花生油’液態石臘或橄欖油。 水溶性懸浮液含有與適合型水溶性懸液之賦形劑混合 -18- 本紙張尺度適用中國國家標準（CNS)A4規格（210 x 297公爱） 1269791 A7 B7 五、發明說明（16) » 在一起的活性物質。此類賦形劑爲懸浮劑，如：羧甲基纖 維素鈉，甲基纖維素’羥丙基甲基纖維素，藻朊酸鈉，聚 乙烯吡咯烷酮，黃蓍膠和金合歡膠；分散劑或濕潤劑可爲 天然之磷脂例如：卵磷脂’或帶有脂肪酸的烯化氧的濃縮 產品例如：聚氧化硬脂酸乙二醇酯，或帶有衍生自脂肪酸 和己糖醇之部分酯類的環氧乙烷濃縮產品，如：聚氧基山 梨糖醇-油酸乙二醇酯，或帶有衍生自脂肪酸和己糖酸酐 之部分酯類的環氧乙烷濃縮產品，如：聚山梨糖醇酐-油 酸乙二醇酯。水溶性懸浮液中也可含一或多種保存劑，如 :乙基，或正-丙基，對-羥基苯甲酸酯，一或多種調色 劑，一或多種調味劑，及一或多種甜味劑，如：蔗糖或糖 精。 適合經由加入水來製備水溶性懸浮液的可分散粉末和 顆粒是將其活性成分與分散劑或濕潤劑懸浮劑及一或多種 保存劑混合在一起。合適的分散或濕潤劑及懸浮劑的實施 例爲如上述者。額外的賦形劑，如：甜味劑、調味劑和調 色劑也可加入其中。 化合物也可存於非水溶性液體配方中，如：油性懸浮 液可經由將活性成分懸浮於蔬菜油中（如：花生油、橄欖 油、芝蔴油）或懸浮於礦物油中（如：液態石蠟）來製劑 。該油性懸浮液中可包含有濃稠劑，例如：蜂鱲，硬石蠟 或鯨鱲醇。甜味劑（如：那些前述者）及調味劑也可加入 其中以提供美味的口服製劑。這些組成物可經由加入一種 抗氧化劑（如：菸鹼酸）來加以保存。 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） (請先閱讀背面之注意事項再填寫本頁) 裝 __丁—_______. 11 -νό· - 經濟部智慧財產局員工消費合作社印製 1269791 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明（17) · 本發明的藥學組成物也可爲水包油乳化液的型式。該 油相可爲一種蔬菜油，如：橄欖油或花生油，或一種礦物 油（如：液體石蠟）或這些的混合物。合適的乳化劑可爲 天然膠，如：金合歡膠或黃蓍膠，天然的磷脂，如：大豆 ，卵磷脂及酯類或衍生自脂肪酸及己糖醇酐類的部分酯類 ，例如：山梨糖醇酐-油酸酯及該部分酯類與環氧乙烷的 濃縮產物，如：聚氧基山梨糖醇酐-油酸乙二醇酯。該乳 液中也可含甜味劑及調味劑。 糖漿及驰劑也可與甜味劑共同製劑，如：甘油，丙二 醇，山梨糖醇或蔗糖。此類配方也可含有緩和劑、保存劑 及調味劑和調色劑。 該化合物也可以用於肛門給藥的栓劑型式來給予。這 些組成物可以經由將藥物與合適之非刺激性賦形劑混合來 製備，這些賦形劑在平常溫度下爲固體，但在肛溫下爲液 體，並且也因此可在肛門中溶解以釋出藥物。這些物質包 括可可油及聚乙二醇。 此處所揭示之適用於式I所示之化合物的所有攝生法 中，每日口服劑量以從0 · 0 1至2 0 0毫克/全部體重 的公斤數較佳。該適於注射給藥（包括：靜脈內、肌肉內 、皮下及腸胃道外的注射途徑）及利用注入技術給藥的每 日劑量以從0 · 0 1至2 0 0毫克/全部體重的公斤數較 佳。每日的局部給藥劑量以介於每日給予1至4次，從 〇·1至200毫克者較佳。該每日吸入的劑量以從 〇·01至10毫克/全部體重公斤數較佳。 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -20 - ------1-------------訂 —-------- (請先閱讀背面之注意事項再填寫本頁) 1269791 A7 B7 五、發明說明（18) . (請先閱讀背面之注意事項再填寫本頁) 內行人士可感知給藥的特殊方法是根據許多因素來決 定。這些因素在給予治療時都會例行列入考慮。內行人士 可感知給予一個指定病人之特定劑量是根據許多因素來決 定，包括：所給予之化合物的特殊活性、年齡、體重、健 康、性別、飮食、時間和給予途徑、排泄速率，等等。內 行人士還可感知治療的理想進程（即：治療模式和在指定 天數中所給予之式I所示之化合物或其藥學上可接受之鹽 的劑量的每日數目）可以由內行人士利用傳統治療測試來 確認。 然而，需了解的是：適用於任何特殊病人之特殊劑量 會根據許多因素來決定，這些因素包括所使用之特定化合 物的活性、年齢、體重、一般健康、性別、飮食、給藥時 間、給藥途徑及排泄速率、藥物組成和所治療之病況的嚴 重性。 經濟部智慧財產局員工消費合作社印制衣 上述和下述所列舉的所有申請案、專利和刊物的全部 揭示內容在此倂爲參考資料，包括：暫時性申請序號 6 0/115 ，877 (1999 年 1 月 13 曰提出）及 非暫時性申請序號〇9 / 2 5 7 ，2 6 6 ( 1 9 9 9年2 月2 5日提出）。 這些化合物可從已知之化合物（或可從那些可由已知 化合物製備得到之起始物質）製備得到，如：經由下述之 一般製備方法。所指定之用來抑制r a f催化酶的化合物 的活性可例行根據如：下述之步驟來分析。下列實施例僅 用來說明而非在任一方面限制本發明。 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -21 - 1269791 A7 B7 五、發明說明（19) · 實施例 (請先閱讀背面之注意事項再填寫本頁) 所有的反應都是在乾燥氬氣或乾燥氮氣的正壓下於經 火焰乾燥或烤箱乾燥的玻璃容器內進行，並拌有磁石攪拌 ，除非另外指出。經由針筒或導管將感受性液體和溶液通 過橡皮隔膜轉移導入反應容器中。除非另外說明A在減壓 下進行濃縮〃 一詞是指利用一種約1 5毫米汞柱的''布奇 / ( Biichi )旋轉蒸發器。除非另外說明， ''在高真空器下 〃一詞是指一種〇 · 4 - 1 · 〇毫米汞柱的真空器。 所有的報讀溫度爲未修正過的攝氏溫度（°C )。除非 另外指出，所有的份數和百分比都是以重量計。 經濟部智慧財產局員工消費合作社印制取 '使用商品等級的試劑和溶劑而不需要進一步純化。N 一環己基一 N &gt; —(甲基聚苯乙烯）碳二醯胺是從 ''卡爾 生物—諾瓦生化公司（Calbiochem-Novabiochem)購得。3 一特一丁基苯胺，5 —特一 丁基一 2 —甲氧基苯胺，4 一 溴基一 3 —（三氟甲基）苯胺，4 —氯基一 3 —（三氟甲 基）苯胺，2 —甲氧基一 5—(三氟甲基）苯胺，4 一特 一 丁基一 2 -硝基苯胺，3 —胺基一 2 —蔡酚，4 一異氰 酸基苯甲酸乙酯，N —乙醯一 4 一氯基一 2 —甲氧基一5 一（三氟甲基）苯胺和4 一氯基一 3 -（三氟甲基）苯基 異氰酸酯係由購買取得，使用時不需進一步純化。3 -胺 基一 2 -甲氧基喹啉（E ·周等人著， W 0 98/00402 ;Α·可迪等人著， ΕΡ 542，609 ; IBID生物有機醫用化學3， 1995，129) ，4 — (3 —氨基甲醯苯氧基）—1 本纸張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -22- 1269791 經濟部智慧財產局員工消費合作社印制衣 A7 B7 五、發明說明（20) , 〜硝基苯（K ·伊卡瓦 Yakugakll Zaschi 79，1 959，760;DPPA This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1269791 A7 B7 V. Invention description (15), (Please read the note on the back and fill out this page) Local, gastrointestinal Or a spray or anal route for administration. The term "administered by injection" includes intravenous, intramuscular, transdermal injection and techniques utilizing infiltration. One or more compounds may be present together with one or more non-toxic pharmaceutically acceptable carriers, and other active ingredients may be added if desired. Compositions for oral administration can be prepared according to any suitable method known in the art for preparing pharmaceutical compositions. Such compositions may contain one or more agents selected from the group consisting of diluents, sweeteners, flavoring agents, toners, and preservatives to provide a savoury product. The tablet contains active ingredients which are mixed with a non-toxic pharmaceutically acceptable excipient which is suitable for use as a tablet. These excipients may be, for example, an inert diluent such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granules and disintegrants such as corn flour or alginic acid; and a linker, Such as: magnesium stearate 'stearic acid or talcum powder. The tablet may be enveloped or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a long period of time. For example, a time delay material such as monoglyceryl stearate or glyceryl distearate may be employed. These compounds can also be formulated as a solid release form. The formula for oral administration printed by the Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs may also be in the form of a hard capsule, wherein the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, phosphoric acid. Calcium or kaolin 'or' may also be present in the form of a soft capsule, wherein the active ingredient is mixed with water or an oily medium such as peanut oil 'liquid paraffin or olive oil. The water-soluble suspension contains a mixture with a suitable water-soluble suspension. -18- This paper size applies to the Chinese National Standard (CNS) A4 specification (210 x 297 public) 1269791 A7 B7 V. Description of invention (16) » Active substances together. Such excipients are suspending agents, such as: sodium carboxymethylcellulose, methylcellulose 'hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth and acacia; dispersing agents Or the humectant may be a natural phospholipid such as lecithin or a concentrated product of an alkylene oxide with a fatty acid such as polyethylene stearate or a partial ester derived from a fatty acid and a hexitol. Ethylene oxide concentrate products, such as: polyoxysorbitol-ethylene glycol oleate, or concentrated ethylene oxide products with partial esters derived from fatty acids and hexanoic anhydride, such as polysorbitol Anhydride - ethylene oleate. The water-soluble suspension may also contain one or more preservatives such as: ethyl, or n-propyl, p-hydroxybenzoate, one or more toners, one or more flavoring agents, and one or more Sweeteners such as sucrose or saccharin. Dispersible powders and granules suitable for the preparation of water-soluble suspensions by the addition of water are those in which the active ingredient is mixed with a dispersing or wetting agent suspension and one or more preservatives. Examples of suitable dispersing or wetting agents and suspending agents are as described above. Additional excipients such as sweeteners, flavoring agents and coloring agents may also be added. The compound may also be present in a water-insoluble liquid formulation, such as an oily suspension by suspending the active ingredient in vegetable oil (eg peanut oil, olive oil, sesame oil) or suspended in mineral oil (eg liquid paraffin). preparation. The oily suspension may contain a thickening agent such as bee sting, hard paraffin or whale sterol. Sweetening agents (such as those mentioned above) and flavoring agents can also be added to provide a delicious oral preparation. These compositions can be preserved by the addition of an antioxidant such as niacin. This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back and fill out this page). __丁—_______. 11 -νό· - Ministry of Economic Affairs Intellectual Property Office employees Consumer Cooperatives Printed 1269791 Economic Intelligence Bureau Intellectual Property Bureau Staff Consumer Cooperative Printed A7 B7 V. Inventive Note (17) · The pharmaceutical composition of the present invention may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil such as olive oil or peanut oil, or a mineral oil such as liquid paraffin or a mixture of these. Suitable emulsifiers may be natural gums such as acacia or tragacanth, natural phospholipids such as: soy, lecithin and esters or partial esters derived from fatty acids and hexitols, for example: sorbus A sugar alcohol-oleate and a concentrated product of the partial ester and ethylene oxide, such as polyoxysorbitol-ethylene glycol oleate. The emulsion may also contain sweeteners and flavoring agents. Syrups and granules may also be co-formulated with sweeteners such as glycerin, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, and a flavoring and toner. The compound can also be administered in the form of a suppository for anal administration. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and which can therefore be dissolved in the anus to release drug. These materials include cocoa butter and polyethylene glycol. In all of the regimens disclosed herein for use in the compounds of formula I, the daily oral dose is preferably from 0. 01 to 200 mg/kg body weight. The injection is suitable for injection (including intravenous, intramuscular, subcutaneous and parenteral routes of injection) and the daily dose administered by the infusion technique is from 0. 01 to 200 mg/kg of body weight. Preferably. The daily topical dose is preferably between 1 and 4 times a day, preferably from 1 to 200 mg. The daily inhaled dose is preferably from 〇·01 to 10 mg/kg of total body weight. This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -20 - ------1------------- Order ------- -- (Please read the notes on the back and fill out this page) 1269791 A7 B7 V. Inventions (18) . (Please read the notes on the back and fill out this page.) The special method that the insider can perceive is based on Many factors are determined. These factors are routinely considered when given treatment. The average person can perceive the specific dosage given to a given patient based on a number of factors, including: the particular activity, age, weight, health, sex, foraging, time and route of administration, rate of excretion, etc. of the compound administered. The practitioner can also perceive the ideal course of treatment (ie, the mode of treatment and the daily number of doses of the compound of formula I or its pharmaceutically acceptable salt given in a given number of days) can be used by practitioners for traditional treatment Test to confirm. However, it is important to understand that the specific dosage for any particular patient will be determined by a number of factors, including the activity of the particular compound used, age, weight, general health, sex, foraging, time of administration, giving The route of the drug and the rate of excretion, the composition of the drug, and the severity of the condition being treated. Printed by the Intellectual Property Office of the Ministry of Economic Affairs, the Consumer Cooperatives, and the entire disclosures of all the applications, patents, and publications listed above and below are included herein, including: Temporary Application No. 6 0/115, 877 (1999) Issued on January 13th, 2013) and non-transient application number 〇9 / 2 5 7 , 2 6 6 (proposed on February 25, 1999). These compounds can be prepared from known compounds (or those which can be prepared from known compounds), for example, by the following general preparation methods. The activity of the compound designated to inhibit the r a f catalytic enzyme can be routinely analyzed according to, for example, the following procedure. The following examples are intended to illustrate and not to limit the invention in any way. This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) -21 - 1269791 A7 B7 5. Invention description (19) · Example (please read the notes on the back and fill out this page) The reaction was carried out in a flame-dried or oven-dried glass vessel under positive pressure of dry argon or dry nitrogen, and stirred with a magnet, unless otherwise indicated. The susceptibility liquid and solution are transferred into the reaction vessel through a rubber septum via a syringe or catheter. Unless otherwise stated, A is concentrated under reduced pressure. The term refers to the use of a ''Buichi' rotary evaporator of about 15 mmHg. Unless otherwise stated, the term 'under high vacuum' refers to a vacuum of 〇 · 4 - 1 · 〇 mm Hg. All enrollment temperatures are uncorrected Celsius (°C). All parts and percentages are by weight unless otherwise indicated. The Ministry of Economic Affairs' Intellectual Property Office employee consumption cooperative prints 'Use commodity grade reagents and solvents without further purification. N-cyclohexyl-N &gt; - (methyl polystyrene) carbon diamine is commercially available from ''Carbiochem-Novabiochem'. 3 monotert-butylaniline, 5-tert-butyl-2-methoxyaniline, 4-monobromo-3-trifluoromethylaniline, 4-chloro-3-yl-(trifluoromethyl) Aniline, 2-methoxy-5-(trifluoromethyl)aniline, 4-tert-butyl-2-nitroaniline, 3-amino-2-oxanol, 4-isocyanatobenzoate B Ester, N-acetamidine-4-chloro-1,methoxy-5-(trifluoromethyl)aniline and 4-chloro-3-trifluoromethylphenylisocyanate are purchased and used. No further purification is required. 3-Amino-2-methoxyquinoline (E. Zhou et al., W 0 98/00402; Α·Kadi et al., 542 542, 609; IBID Bioorganic Medical Chemistry 3, 1995, 129 ), 4 — (3 —Aminomethyl phenoxy)—1 This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -22- 1269791 Printed by the Intellectual Property Office of the Ministry of Economic Affairs Clothing A7 B7 V, invention description (20), ~ nitrobenzene (K · Ikawa Yakugakll Zaschi 79, 1 959, 760;

Chem. Abstr. 53，1 959，1 276 1 6 )、3 -特—丁苯基異氰酸 酯（〇·羅等人著，DE 2 ，436 ，1〇8).和2 — 甲氧基一 5 —（三氟甲基）苯基異氰酸酯（K .伊諾卡等 人著 JP 42，〇25，〇67; IBID Kogyo Kagaku Zasshi 70，1 967，491 )的合成方法先前已有說明。 薄層色層分析法（TLC)是利用瓦特曼®(Whatman®) 經預先包膜之玻璃底的矽膠60A F-254 250 微米盤來進行。盤的具像化可利用一或多種下列技術來進 行：（a )紫外線照射，（b )暴露於碘蒸氣，（c )將 反應盤浸泡於含1 0 %磷鉬酸的乙醇溶液，然後再加熱之 ，（d )將反應盤浸泡在硫酸鈽溶液中，然後再加熱之， 及/或（e )將反應盤浸泡在2，4 一二硝苯基肼的酸性 乙醇溶液中，.然後再加熱之。利用2 3 0 — 4 0 0網篩 E Μ科學®矽膠來進行管柱色層分析法（閃蒸層析法）。 利用 ''湯姆斯—胡佛〃 （Thomas-Hoover )熔點儀器或 美特勒（Mettler ) F P 6 6自動熔點儀器來決定熔點（ m p )並且不加以修正。利用&amp;美特森4 〇 2 0銀河系列 分光光度計〃 （Mattson 4020 Galaxy Series )來取得、、付 里葉〃變換紅外線光譜。質子（1 Η )核磁共振（N μ R ) 譜是以通用電器GN-Ω 300 (3〇〇ΜΗζ)分光 計（以M e 4 S i ( (5 〇 · 〇 〇 )或剩餘之經質子化溶劑 (C H C 1 3 (5 7 · 2 6 ； M e 0 Η δ 3.30; D Μ S 0 δ 2.49)爲標準）來測量。碳（13(：) 本紙張尺度適用中國國家標準（CNS)A4規格（210 χ 297公釐） ------r-----Aw ^--------訂--------- (請先閱讀背面之注意事項再填寫本頁) 1269791 A7 B7 五、發明說明（21) NMR光譜是以一種通用電器gn—q 300(75 M H z )分光計（以溶劑（c D C 1 3 5 77.0; M e 〇 〇 - d a ； 5 49*0；DMSO-de5 (請先閱讀背面之注意事項再填寫本頁) 3 9 · 5 )做爲標準）來測纛的。低解析質譜（M s )和 經濟部智慧財產局員工消費合作社印制衣 筒解析質譜（H R M S .)是以電子撞擊（e I )質譜或快 速原子炮擊（F A Β )質譜來取得。電子撞擊質譜（ε j 一 M S )是以一種配備有 ''真空計量去吸附化學離子化探 針〃（用於、、樣本導入〃）的惠普5 9 8 9 Α質議儀來取 得。將離子來源維持在2 . 5 0 °C。電子撞撃離子化作用是 以7 0 e V的電子能和3 0 0 v A的捕捉流來進行。液態 一鈽二級離子質譜（F A B〜M S )(此爲一種合乎時代 之快速原子炮擊法）是利用一種、、卡洛托斯槪念1 一 Η分 光計〃 （Kratos Concept bH )來取得。化學離子化質譜（ C I — MS)是利用一種惠譜MS —引擎（5 9 8 9 A) (以甲烷或氨做爲試劑氣體（1 X 1 〇— 4陶爾至 2 · 5 X 1. 0 — 4陶爾））來取得。直接插入之去吸附化學 離子化（D C I )探針（真空計量公司）是在1 〇秒內從 〇- 1 · 5安培開始斜降並在所有的微量樣本都消失後（ 〜1 一 2分鐘）維持在1 0安培。以每次掃描2秒鐘的速 度，從50 — 800 amu進行光譜的掃描。HPLC -電子噴霧（HPLC ES— MS)是利用配備有①四元 啷筒，②不同波長偵測器，③C 一 1 8管柱，及④芬尼根（ Fmmgan LCQ離子捕捉分光計之惠普1 1 〇 0 HPLC 來取得。光譜是根據來源中之離子數’利用可變更的離子 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -24- 1269791 A7 五、發明說明（22 ) 時間，從1 2 〇 - 8 〇 〇 a m u進行掃描。氣相層析法一 離子:¾擇性質譜（GC_MS )是以〜種配有Hp__丄聚 甲基砍嗣管柱（0 · 33mM包膜；25m&gt;&lt;0 · 2mm )和惠普5 9 7 1質量選擇性偵測器（離子化能量γ〇 e V )的惠普5 8 9 〇氣相層析法來取得。成分分析是由 維伯森唼克維利實驗室（紐澤西州麥迪生市）來執行。 所有的化合物都顯示出與指定之構造一致的Ν μ R譜 ，LRMS和元素分析或hrmS。 縮寫和字頭的列表： · 經濟部智慧財產局員工消費合作社印制衣Chem. Abstr. 53,1 959,1 276 1 6 ), 3-tert-Butyl isocyanate (〇·Ro, et al., DE 2,436,1〇8). and 2 —Methoxy-5. The synthesis method of (trifluoromethyl)phenylisocyanate (K. Enoch et al. JP 42, 〇 25, 〇 67; IBID Kogyo Kagaku Zasshi 70, 1 967, 491) has been previously described. Thin layer chromatography (TLC) was performed on a pre-coated glass bottom silicone 60A F-254 250 micron disk using Whatman®. The visualization of the disc can be performed using one or more of the following techniques: (a) ultraviolet radiation, (b) exposure to iodine vapor, (c) immersion of the reaction disk in an ethanol solution containing 10% phosphomolybdic acid, and then Heating, (d) soaking the reaction disk in a barium sulfate solution, and then heating it, and / or (e) soaking the reaction disk in an acidic ethanol solution of 2,4 dinitrophenyl hydrazine, and then Heat it. Column chromatography (flash chromatography) was performed using a 2 3 0 — 4 0 0 mesh sieve E Μ Science® silicone. The melting point (m p ) is determined using the ''Thomas-Hoover' melting point apparatus or the Mettler F P 6 6 automatic melting point apparatus and is not corrected. Use the &amp;Matson 4 〇 2 0 Galaxy Series Spectrophotometer 〃 (Mattson 4020 Galaxy Series) to obtain and convert the ray spectrum to the infrared spectrum. The proton (1 Η) nuclear magnetic resonance (N μ R ) spectrum is a general-purpose GN-Ω 300 (3〇〇ΜΗζ) spectrometer (with Me 4 S i ((5 〇· 〇〇) or the remaining protonation) The solvent (CHC 1 3 (5 7 · 2 6 ; M e 0 Η δ 3.30; D Μ S 0 δ 2.49) is the standard). Carbon (13(:) This paper scale applies to the Chinese National Standard (CNS) A4 specification. (210 χ 297 mm) ------r-----Aw ^--------Book--------- (Please read the notes on the back and fill in the form) Page) 1269791 A7 B7 V. INSTRUCTIONS (21) NMR spectroscopy is a general-purpose electrical appliance gn-q 300 (75 MH z ) spectrometer (with solvent (c DC 1 3 5 77.0; M e 〇〇-da; 5 49 *0; DMSO-de5 (please read the note on the back and then fill out this page) 3 9 · 5 ) as a standard) to measure 。. Low-resolution mass spectrometry (M s ) and the Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative Cartridge Analytical Mass Spectrometry (HRMS) is obtained by electron impact (e I ) mass spectrometry or fast atomic bombardment (FA Β ) mass spectrometry. Electron impact mass spectrometry (ε j - MS ) is equipped with a ''vacuum metering desorption Chemical ionization probe , the sample was introduced into the 5) HP 5 9 8 9 Α 议 来 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 v A capture stream is carried out. Liquid one-stage secondary ion mass spectrometry (FAB~MS) (this is a fast-time atomic bombardment method) is to use one, Carlotus mourning 1 Η spectrometer 〃 ( Kratos Concept bH). Chemical ionization mass spectrometry (CI-MS) utilizes a MS-engine (5 9 8 9 A) (using methane or ammonia as reagent gas (1 X 1 〇 - 4 Torr to 2 · 5 X 1. 0 — 4 Taur))). The direct insertion of the desorption chemical ionization (DCI) probe (vacuum metering company) starts from 〇 - 1 · 5 amps in 1 sec. And after all the traces disappeared (~1 to 2 minutes), the temperature was maintained at 10 amps. The spectrum was scanned from 50-800 amu at a rate of 2 seconds per scan. HPLC-electron spray (HPLC ES— MS) is equipped with a four-element tube, 2 different wavelength detectors, 3C-18 column, and 4 Finnegan Fmmgan LCQ ion spectrometer to capture the HP 11 square 0 HPLC to obtain. The spectrum is based on the number of ions in the source 'Using the ionic paper size that can be changed applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) -24-1269791 A7 V. Invention description (22) Time, from 1 2 〇 - 8 〇〇 amu for scanning. Gas Chromatography One ion: 3⁄4 Selective Mass Spectrometry (GC_MS) is a kind of Hp__丄 polymethyl chopping column (0 · 33mM envelope; 25m > &lt; 0 · 2mm) and HP 5 9 7 1 mass selective detector (ionized energy γ〇e V) was obtained by HP 5 8 9 〇 gas chromatography. The compositional analysis was performed by the Weibosen Kyivli Laboratory (Madison, New Jersey). All compounds showed Ν μ R spectra, LRMS and elemental analysis or hrmS consistent with the specified construction. List of abbreviations and prefixes: · Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives, Printed Clothes

A c Ο Η a n h atm B〇C C D I cone d dec D M A C D Μ P U D M F D M S〇 D P P A 醋酸 無水的 大氣 特-丁氧羰基 1，1 &gt; 一羰基二咪唑 濃縮的 天 分解 N，N —二甲基乙醯胺 1，3 —二甲基一3，4 一 2 (1H)—嘧D定酮 6 —四基 ------------裝--------訂--------- (請先閱讀背面之注意事項再填寫本頁)A c Ο Η anh atm B〇CCDI cone d dec DMACD Μ PUDMFDMS〇DPPA acetic acid anhydrous atmospheric 1,4-butoxycarbonyl 1,1 &gt; carbonyl diimidazole concentrated day decomposition N,N-dimethylacetamide 1 ,3-dimethyl-3,4-2 (1H)-pyrimidine D-one 6-tetrayl------------------- ----- (Please read the notes on the back and fill out this page)

N N —二甲基甲醯胺 二甲基亞硕 二苯基磷醯基化疊氮 本纸張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -25- 1269791 A7 B7 五、發明說明（23 )NN - dimethylformamide dimethyl sulfide diphenylphosphonium azide paper size applicable to China National Standard (CNS) A4 specification (210 X 297 mm) -25- 1269791 A7 B7 V. Description of invention (23)

I EDCI 1一（3 —二甲基胺丙基）—3 —乙基碳 二醯胺I EDCI 1 -(3-dimethylaminopropyl)-3-ethylidene diamine

EtOAc 醋酸乙酯 E t 〇 Η 乙醇（1 〇 〇 % ) E t 2 0 二乙醚 E t 3 N 三乙胺· h . 小時 Η 〇 B T 1 一羥基苯並三唑 m—CPBA 3—氯基過氧苯甲酸 M e 0 Η 甲醇EtOAc ethyl acetate E t 乙醇 ethanol (1 〇〇%) E t 2 0 diethyl ether E t 3 N triethylamine · h . hour 〇 BT 1 monohydroxybenzotriazole m-CPBA 3 - chloro group Oxybenzoic acid M e 0 Η methanol

Pet； ether 石油醚（沸點範圍3 0 — 6 0 °C ) temp· 溫度 T H F 四氫咲喃 TFA 三氟Ac〇Η T f 三氟甲碯醯 A · 用於合成經取代之苯胺類的一般方法 A 1 · 經由合成醚，再進行酯的皂化作用，庫爾修斯重 組作用和氨基甲酸酯的去保護作用來形成芳基胺 的一般方法。 9χ C02Me 〇Me - 本紙張尺度適用中國國家標準（CNS)A4規格（210 χ 297公釐） (請先閬讀背面之注意事項再填寫本頁) -裝 1T---------^0. 經濟部智慧財產局員工消費合作社印製 1269791 Α7 Β7 經濟部智慧財產局員工消費合作社印製 五、發明說明（24) , 步驟1· 3—甲氧基一2—萘甲酸甲酯 在室溫下，將含3 —經基一 2 —萘甲酸甲酯（ 10 · 1克，50 . 1毫莫耳）和K2C〇3 (7 · 96克 ，57 · 6毫莫耳）的DMF ( 200毫升）漿液攪拌 15分鐘，再以碘甲烷（3 · 43毫升，55 · 1毫莫耳 )處理之。將混合物在室溫下攪拌一整晚再以水（2 0 0 毫升&gt;處理之。以Et〇Ac (2x200毫升）萃取所 產生的混合物。以飽和N a C 1溶液（1 0 0毫升）淸洗 合倂的有機層，乾燥後（M g S 0 4 )，在減壓下濃縮之（ 約0 · 4mmHg —整夜）以產生3 —甲氧基一 2 —萘甲 酸甲酯，此爲一種琥珀色油（1 0 · 3 0克）： 'H-NMR (DMSO-de) 5 2.7〇（s，3H)，2.85(s，3H)， 7 * 3 8 ( a ρ p t，J=8.〇9Hz，lH) ’ 7 · 4 4 ( s，1 Η )， 7 · 5 3 ( a p p t，J 二 8·09Ηζ，1Η) ’ 7.84(d，J = 8.〇9Hz，lH)， 7·9〇（3，1Η)，8·21(3，1Η)° 〇Me 步驟2· 3 —甲氧基一 2 —萘甲酸 在室溫下，將含3 —甲氧基一 2 —萘甲酸甲酯（ 6 · 28克，29 · 1〇毫莫耳）和水（10毫升）的甲 ------------裝--------訂--------- (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -27 - 1269791 A7 Ά/ B7 五、發明說明（25) · 醇（1 0 0毫升）溶液以1 N的N a〇Η溶液（3 3 . 4 毫升，3 3 · 4毫莫耳）進行處理。在回流溫度下將混合 物加熱3小時，冷卻至室溫並以1 0 %檸檬酸溶液使之成 爲酸性。將所產生的溶液以E t〇A c ( 2 X 1 q 〇毫升 )進行萃取。以飽和N a c 1溶液淸洗合倂的有機層，乾 燥後（M g S 0 4 )再於減壓下進行濃縮。以己院將剩餘物 加以硏磨再以己烷淸洗數次以產生3 —甲氧基- 2 -萘甲 酸，此爲一種白色固犛（5· 40克，92%) ·· 'H-NMR (DMSO-de) 5 3 · 8 8 ( s，3 Η )， 7·34 — 7·41(ιη，2Η)， 7.49 — 7·54(ιη，1Η)， 7.8 3 (d，卜 8·09Ηζ，1Η)， 7.91(d，J=8.〇9Hz，lH)， 8 . 1 9 ( s，1 Η )， 1 2 · 8 3 ( b r s，lH)°Ether petroleum ether (boiling point range 30-60 °C) temp·temperature THF tetrahydrofurfuryl TFA trifluoroAc〇Η T f trifluoromethyl hydrazine A · general method for the synthesis of substituted anilines A 1 · A general method for the formation of arylamines via the synthesis of ethers followed by saponification of the esters, the reorganization of the Coursius and the deprotection of the carbamate. 9χ C02Me 〇Me - This paper size applies to China National Standard (CNS) A4 specification (210 297 297 mm) (please read the note on the back and fill out this page) - Install 1T--------- ^0. Ministry of Economic Affairs, Intellectual Property Bureau, Staff and Consumer Cooperatives, Printed 1269791 Α7 Β7 Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives, Printing 5, Inventions (24), Step 1·3—Methoxy-2-naphthoic acid methyl ester At room temperature, DMF containing 3-amino-methyl 2-naphthoate (10 · 1 g, 50.1 mmol) and K2C〇3 (7 · 96 g, 57 · 6 mmol) The slurry was stirred for 15 minutes and treated with methyl iodide (3 · 43 ml, 55 · 1 mmol). The mixture was stirred at room temperature overnight and then treated with water (200 mL). The mixture was extracted with Et.sub.2 (2.times. The organic layer of the hydrazine was washed, dried (M g S 0 4 ), concentrated under reduced pressure (about 0. 4 mmHg - overnight) to give methyl 3-methoxy-2-naphthoate, which is An amber oil (1 0 · 30 g): 'H-NMR (DMSO-de) 5 2.7 〇 (s, 3H), 2.85 (s, 3H), 7 * 3 8 ( a ρ pt, J=8 .〇9Hz,lH) ' 7 · 4 4 ( s,1 Η ), 7 · 5 3 ( appt,J 2·8·09Ηζ,1Η) ' 7.84(d,J = 8.〇9Hz,lH), 7· 9〇(3,1Η),8·21(3,1Η)° 〇Me Step 2· 3 —Methoxy-2 naphthoic acid will contain 3-methoxy-2-naphthoic acid at room temperature Ester (6 · 28 g, 29 · 1 〇 millimol) and water (10 ml) of A ----------------------------- ---- (Please read the notes on the back and fill out this page.) This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) -27 - 1269791 A7 Ά / B7 V. Invention Description (25 · The alcohol (100 ml) solution was treated with a 1 N Na solution (3 3 4 ml, 3 3 · 4 mmol). The mixture was heated at reflux temperature for 3 hours and cooled to room. Warm and make it acidic with 10% citric acid solution. The resulting solution is extracted with E t〇A c ( 2 X 1 q 〇 ml). The organic layer of hydrazine is washed with a saturated N ac 1 solution. After drying (M g S 0 4 ), it was concentrated under reduced pressure. The residue was honed in a hexane and washed several times with hexane to give 3-methoxy-2-naphthoic acid, which is a kind White solid (5·40 g, 92%) ··H-NMR (DMSO-de) 5 3 · 8 8 ( s, 3 Η ), 7·34 — 7·41 (ιη, 2Η), 7.49 — 7·54(ιη,1Η), 7.8 3 (d, Bu 8·09Ηζ, 1Η), 7.91 (d, J=8.〇9Hz, lH), 8. 1 9 ( s,1 Η ), 1 2 · 8 3 ( brs,lH)°

步驟3 · 2 —（N -（碳苄氧基）胺基—3 —甲氧萘 在室溫下，將含3_甲氧基一 2 —萘甲酸（3 · 36 克，16 · 6毫莫耳）和Et3N (2 · 59毫升， 1 8 · 6毫莫耳）的無水甲苯（7 0毫升）溶液在室溫下 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） (請先閱讀背面之注意事項再填寫本頁) 裝--------訂----- 蠢. 經濟部智慧財產局員工消費合作社印製 -28- 1269791 A7 B7 五、發明說明（26 ) , 攪拌1 5分鐘再經由吸管以含D P P A ( 5 . 1 2克， (請先閱讀背面之注意事項再填寫本頁) 18·6毫莫耳）的甲苯（1〇毫升）溶液處理之。在 8 0 °C下，將所產生的混合物加熱2小時。在將混合物冷 卻至室溫之後，經由注射筒將苄基醇（2 · 〇 6毫升， 2 0毫莫耳）加入其中。然後，將混合物加溫至8 0 °C — 整夜。將所產生之混合物冷卻至室溫，以1 0 %檸檬酸溶 液驟冷之後，以E t〇Ac (‘2x100毫升）萃取之。 以飽和N a C 1溶液淸洗合倂的有機層，乾燥後（ M g S〇4 )在減壓下濃縮之。以管柱層析法（1 4 % E t 0 A c / 8 6 %己烷）將剩餘物加以純化以產生2 -(N -碳韦r氧基）胺基一 3 -甲氧基萘，此爲·一種淡黃色 油（5 · 1克，1〇〇％ ): 'H-NMR (DMSO-ds) δ 3-8 9(s，3H) ，5.17(s，2H)， 7.27 — 7.44 (m，8H)， 7·7 2 — 7-75 (m，2H)， 8.20(s，lH)，8.76(s，1H)。 經濟部智慧財產局員工消費合作社印製 OMe · 步驟4· 2-胺基一3—甲氧基萘 將含2 -（N —碳苄氧基）胺基一 3 —甲氧基萘（ 5 ·〇克，16 · 3 毫莫耳）和 lO^Pd/c (〇 · 5 克）的Et〇Ac (70毫升）漿液維持在h2 a t m ( 本纸張尺度適用中國國家標準（CNS)A4規格（210 X 297公爱） -29- 1269791 A7 B7 五、發明說明（27 ) · 氣珠），室溫下一整夜。將所產生之混合物通過塞里特土 ® 加以過濾並在減壓下加以濃縮以產生2 -胺基- 3 -甲氧 基萘，此爲一種淡粉紅色粉末（2. 40克，85%): 'H-NMR CDMSO-de) 5 3-86(s，3H) ，6.86(s，2H)， 7·〇4 — 7·16(ιη，2Η)， 7.43(d，J = 8.0Hz，lH)， 7.56(d，J=8.〇Hz，lH);Step 3 · 2 —(N -(Carbbenzyloxy)amino-3-methoxynaphthalene will contain 3-methoxy-2-naphthoic acid at room temperature (3 · 36 g, 16 · 6 mmol) Ear) and Et3N (2 · 59 ml, 1 8 · 6 mmol) anhydrous toluene (70 ml) solution at room temperature This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) (Please read the notes on the back and fill out this page) ------------- Stupid. Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing -28- 1269791 A7 B7 V. Invention Description (26), stir for 15 minutes and then treated with a solution of DPPA (5.12 g, (please read the back of the note below) 18·6 mmol) in toluene (1 mL) via a pipette The resulting mixture was heated for 2 hours at 80 ° C. After cooling the mixture to room temperature, benzyl alcohol (2 · 〇 6 ml, 20 mmol) was added via a syringe. Then, the mixture was warmed to 80 ° C - overnight. The resulting mixture was cooled to room temperature and quenched with 10% citric acid solution, followed by E t〇Ac ('2x100 m The organic layer of the combined hydrazine was washed with a saturated NaCl1 solution, dried (M g S 〇 4 ) and concentrated under reduced pressure. Column chromatography (1 4 % E t 0 A c / 8 6 % hexane) The residue was purified to give 2-(N-carbo-r-oxy)amino-3-methoxynaphthalene as a pale yellow oil (5 · 1 g, 1 〇〇% ): 'H-NMR (DMSO-ds) δ 3-8 9(s,3H) , 5.17(s,2H), 7.27 — 7.44 (m,8H), 7·7 2 — 7-75 ( m, 2H), 8.20 (s, lH), 8.76 (s, 1H). Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed OMe · Step 4 · 2-Amino 3-methoxynaphthalene will contain 2 - ( N-Carbobenzyloxy)amino-3-methoxynaphthalene (5·〇克, 16 · 3 mmol) and lO^Pd/c (〇·5 g) of Et〇Ac (70 ml) slurry Maintain at h2 atm (This paper scale applies Chinese National Standard (CNS) A4 specification (210 X 297 public) -29- 1269791 A7 B7 V. Invention description (27) · Air beads), room temperature overnight. The resulting mixture was filtered through Celite® and concentrated under reduced pressure to give 2-amino-3-methoxynaphthalene. Is a pale pink powder (2.40 g, 85%): 'H-NMR CDMSO-de) 5 3-86 (s, 3H), 6.86 (s, 2H), 7·〇4 — 7·16 ( Ιη, 2Η), 7.43(d, J = 8.0Hz, lH), 7.56(d, J=8.〇Hz, lH);

El- MS m/z .l73(M+)。 A 2 · 經由形成氨基甲醯吡啶，再與芳基胺進行親核性 偶合作用來合成ω—氨基甲醯苯胺。4 一（2 — Ν —甲基氨基甲醯一 4 —吡啶氧基）苯胺 (請先閱讀背面之注意事項再填寫本頁)El-MS m/z .l73 (M+). A 2 · Synthesis of ω-carbamidine aniline by formation of methotrexate and nucleophilic coupling with arylamine. 4 one (2 - Ν - methylaminocarbamidine - 4 - pyridinoxy) aniline (please read the notes on the back and fill out this page)

經濟部智慧財產局員工消費合作社印製 步驟1 a · 經由曼尼西（Menisci )反應來合成4 —氯基 一 N —甲基—2 —吡啶羧醯胺 注意：這是一種高危險性，有爆炸可能性的反應。在 室溫下，在一含有4 一氯吡啶（10 · 0克）的N -甲基 甲醯胺（2 5 0毫升）攪拌溶液中加入濃硫酸（3 · 5 5 毫升）以製造放熱作用。將Η 2〇2 ( 3 0 % w t含於水中 ，17毫升）加入其中，再接著加入FeS〇4· 7H2〇 (〇· 5 6克）以製造另一次放熱。將所產生之混合物在 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -30- 1269791 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明（28) · 室溫下’黑暗中攪拌1小時，再慢慢加溫至超過4小時， 達到4 5 C。當氣泡現象消退後，將反應物在6 c下加 熱1 6小時。以Η 2〇（7 0 0毫升）稀釋所產生之不透明 棕色溶液’再以1 0 % N a〇Η溶液（2 5 0毫升）稀 釋之。以E t〇A c ( 3 X 5 0 〇毫升）萃取所產生之混 合物。以飽和之N a C 1溶液（3 X 1 5 0毫升）分別淸 洗有機相，再將它們合倂在一起，乾燥（M g S〇4 )後， 再藉助E t〇A c將它們通過矽膠墊加以過濾。將所產生 的棕色油經由管柱層析法加以純化（梯度是從5 0 % E t 〇Ac/5 0% 己院至 80% EtOAc/20% 己烷）。將所產生的黃色油在〇 t下進行結晶化作用7 2 小時以產生4 —氣基一 N —甲基一 2 —吼π定竣醯胺（ 〇·61 克，5-3%) ：TLC (50%Et〇Ac/ 50%己烷）Rf 0*50； iH — NMR(CDC13)5 3.〇4(d，J = 5.1Hz，3H)， 7.43(dd’ J = 5.4，2.4Hz，lH)， 7 · 9 6 ( b r s，1H)，8.21(s，1H)， 8.44(d，J = 5.1Hz，iH);Ministry of Economic Affairs Intellectual Property Bureau Staff Consumption Cooperative Printing Step 1 a · Synthesis of 4-chloro-N-methyl-2-pyridine carboxamide by Mannisci reaction Note: This is a high risk, The possibility of an explosion. Concentrated sulfuric acid (3 · 5 5 ml) was added to a stirred solution of N-methylformamide (250 ml) containing 4-chloropyridine (10·0 g) at room temperature to give an exotherm. Η 2〇2 (30% w t in water, 17 ml) was added thereto, followed by FeS〇4·7H2〇 (〇·6 6 g) to make another exotherm. The resulting mixture is applied to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) on the paper scale. -30- 1269791 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed A7 B7 V. Invention Description (28) · Room Stir in the dark for 1 hour, then slowly warm to over 4 hours to reach 4 5 C. After the bubble phenomenon subsided, the reaction was heated at 6 c for 16 hours. The opaque brown solution produced by diluting Η 2〇 (700 ml) was then diluted with a 10% N a 〇Η solution (250 ml). The resulting mixture was extracted with E t 〇 A c (3 X 50 〇 ml). The organic phase was washed with a saturated N a C 1 solution (3 X 150 ml), and they were combined together, dried (M g S〇4 ), and passed through E t〇A c The silicone pad is filtered. The resulting brown oil was purified by column chromatography (gradient from <RTI ID=0.0># </ RTI> </ RTI> </ RTI> <RTIgt; The resulting yellow oil was crystallized at 〇t for 72 hours to give a 4-gas group-N-methyl-2 吼π-decylamine (〇·61 g, 5-3%): TLC (50% Et 〇Ac / 50% hexane) Rf 0*50; iH - NMR (CDC13) 5 3. 〇 4 (d, J = 5.1 Hz, 3H), 7.43 (dd' J = 5.4, 2.4 Hz, lH), 7 · 9 6 ( brs, 1H), 8.21 (s, 1H), 8.44 (d, J = 5.1 Hz, iH);

Cl— MS m/z 171((m + H)+)。 cl^|pY^c,Cl-MS m/z 171 ((m + H)+). Cl^|pY^c,

HCI 步驟lb · 經由皮考啉酸來合成4 一氯哦11定一 2 —碳醯 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公复） ------------·裝--------訂--------- (請先閱讀背面之注意事項再填寫本頁) -31 - 1269791 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明（29) 氯氫氯酸鹽 在4 0 °C和5 0 %之間將無水D M F ( 6 · 〇毫升） 慢慢地加入S〇C 1 2 ( 1 8 0毫升）中。在該溫度範圍內 將溶液攪拌1 0分鐘，然後，在3 0分鐘的期間內，將皮 考啉酸（60 · 0克，487毫莫耳）一部分一部分地加 入其中。將所產生的溶液在7 2 °C下加熱（有劇烈的S〇2 發生）· 1 6小時以產生一種黃色固體沈澱物。將所產生的 混合物冷卻至室溫，以甲苯（5 0 0毫升）稀釋之並將之 濃縮至2 0 0毫升。將甲苯的加入/濃縮過程重覆進行二 次。將所產生之幾近乾燥的剩餘物加以過濾並以甲苯（2 X 2 0 0毫升）淸洗固體，再將其在高度真空下乾燥4小 時以產生4 -氯基吡啶- 2 -碳醯氯氫氯酸鹽，此爲一種 黃橘色固體（92·〇克，89%)。 〇 °丨W^〇Me hci 步驟2 · 4 -氯吡啶一 2 -羧酸甲酯氫氯酸鹽的合成 在40 — 48 t下，將無水DMF (10 · 0毫升） 慢慢地加入S〇C 1 2 ( 3 0 0毫升）中。在該溫度範圍內 將溶液攪拌1 0分鐘，然後，在3 0分鐘的期間內將皮考 啉酸（100克，812毫莫耳）加入其中。在72 °C下 ，將所產生之溶液加熱（有劇烈的S〇2發生）.1 6小時以 產生一種黃色固體。將所產生的混合物冷卻至室溫，以甲 苯（5 0 0毫升）稀釋之並濃縮至2 0 〇毫升。重覆進行 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） —32 ------；------裝--------訂--------- (請先閱讀背面之注意事項再填寫本頁) 1269791 A7 B7 五、發明說明（30 ) · (請先閱讀背面之注意事項再填寫本頁) 甲苯的加入/濃縮過程二次。將所產生之幾近乾燥的剩餘 物加以過濾並以甲苯（5 0毫升淸洗該固體，再於高度真 空下乾燥4小時以產生4 -氯吡啶- 2 -碳醯氯氫氯酸鹽 ，此爲一種蒼白色固體（27 · 2克，16%)。此物質 先暫擱一邊。 在能將內部溫度保持在5 5 °C的速率下，將紅色過濾 液加入Me 0H ( 2. 0 0毫升）中。在室溫下將內容物攪 拌4 5分，冷卻至5 °C並以E t 2〇（2 0 0毫升）一滴滴 地處理之。將所產生之固體加以過濾，以E t 2〇（2 0 0 毫升）淸洗後，在3 5 °C，減壓環境下加以乾燥以提供4 一氯吡啶一 2 —羧酸甲酯氫氯酸鹽，此爲一種白色固體（ 110 克，65%):mp* 1 Q 8 — 112 XH-NMR (DMSO-de) 5 3 · 8 8 ( s，3 Η )； 7.82(dd，J = 5.5，2.2Hz，lH); 8-〇8(d，J = 2.2Hz，lH); 8.68(d，J = 5- 5Hz，lH); 1 0 · 6 8 ( b r s，lH); 經濟部智慧財產局員工消費合作社印製 Η P L C ES— MS m / z 17 2 ( ( M + H ) + )HCI Step lb · Synthesis of 4 Chlorine via Picolinic Acid 11 Set 1 - Carbon Paper This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public) --------- ---·装--------book--------- (please read the notes on the back and fill out this page) -31 - 1269791 Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative A7 B7 V. INSTRUCTIONS (29) Chlorochlorate is slowly added to S〇C 1 2 (180 ml) between 40 ° C and 50 % anhydrous DMF ( 6 · 〇 ml) . The solution was stirred for 10 minutes in this temperature range, and then picoline acid (60 · 0 g, 487 mmol) was partially added thereto over a period of 30 minutes. The resulting solution was heated at 72 ° C (with vigorous S〇 2 occurring) for 16 hours to produce a yellow solid precipitate. The resulting mixture was cooled to room temperature, diluted with toluene (500 mL) and concentrated to EtOAc. The addition/concentration process of toluene was repeated twice. The nearly dried residue produced was filtered and the solid was washed with toluene (2×200 mL) and then dried under high vacuum for 4 hours to yield 4-chloropyridine-2-carbon Hydrochloride, this is a yellow-orange solid (92 gram, 89%). 〇°丨W^〇Me hci Step 2 · Synthesis of 4 -Chloropyridine-2-carboxylate Hydrochloride Hydrochloride Anhydrous DMF (10 · 0 ml) was slowly added to S at 40 - 48 t C 1 2 (300 ml). The solution was stirred for 10 minutes in this temperature range, and then picolinic acid (100 g, 812 mmol) was added thereto over a period of 30 minutes. The resulting solution was heated (with vigorous S〇2 occurring) at 72 °C for 16 hours to give a yellow solid. The resulting mixture was cooled to room temperature, diluted with toluene (500 mL) and concentrated to EtOAc. Repeatedly apply this paper scale to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) —32 ------;------Install--------Set--- ------ (Please read the notes on the back and fill out this page) 1269791 A7 B7 V. Inventions (30) · (Please read the notes on the back and fill out this page) Addition/concentration process of toluene Times. The nearly dried residue produced was filtered and washed with toluene (50 mL) and dried under high vacuum for 4 hours to yield 4-chloropyridin-2-carbonium chloride hydrochloride. It is a pale solid (27 · 2 g, 16%). This material is temporarily placed on the side. At a rate that maintains the internal temperature at 5 5 ° C, the red filtrate is added to Me 0H (2.0 ml). The contents were stirred at room temperature for 45 minutes, cooled to 5 ° C and treated dropwise with Et 2 〇 (200 mL). The resulting solid was filtered to give Et 2 After rinsing (200 ml), it was dried at 35 ° C under reduced pressure to give 4-chloropyridin-2-carboxylate hydrochloride as a white solid (110 g, 65%): mp* 1 Q 8 — 112 XH-NMR (DMSO-de) 5 3 · 8 8 ( s, 3 Η ); 7.82 (dd, J = 5.5, 2.2 Hz, lH); 8-〇8 ( d, J = 2.2Hz, lH); 8.68 (d, J = 5- 5Hz, lH); 1 0 · 6 8 ( brs, lH); Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing Η PLC ES- MS m / z 17 2 ( ( M + H ) + )

步驟3 a · 從4 一氯吡啶一 2 —羧酸甲酯合成4 一氯基 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 1269791 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明（31 ) * 一 N —甲基一 2 —吡啶羧醯胺 在0°C下，以含〇 · 2莫耳濃度甲胺之THF (1升 )溶液處理含4 -氯吡啶- 2 -羧酸甲酯氫氯酸鹽（ 8 9 · 0克，4 2 8毫莫耳）的甲醇（7 5毫升）懸浮液 ，處理速度爲能使內部溫度維持在5 °C下的速度。將所產 生的混合物貯存在3 °C，5小時，然後，在減壓下進行濃 縮。將所產生的固體懸浮液於E t〇A c ( 1升）中並過 濾之。以飽和的N a C 1溶液（5 0 0毫升）淸洗該濾液 ，乾燥（N a 2 S 0 4 )後在減壓下加以濃縮以產生4 一氯 基一 N -甲基一 2 -吡啶羧醯胺，此爲一種淡黃色結晶（ 71·2 克，97%) :mp 4 1 - 4 3 °C ； 'H-NMR (DMSO-de) 5 2 · 8 1 ( s，3 Η )， 7.74(dd，J = 5.1，2-2Hz，lH)， 8*00(d,J=:2-2,lH)， 8.61(d，J = 5-lHz，lH)， 8 · 8 5 ( b r d，lH);Step 3 a · Synthesis of 4-chloropyridine-2-carboxylic acid methyl ester 4 Chlorine basic paper scale Applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1269791 Printed by the Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative A7 B7 V. INSTRUCTIONS (31) * A N-methyl-2-pyridine carboxamide is treated with a solution of 4-chloro in THF (1 liter) containing 〇·2 molar concentration of methylamine at 0 °C. a suspension of methyl pyridine-2-carboxylate hydrochloride (8 9 · 0 g, 4 2 8 mmol) in methanol (75 mL) at a rate to maintain the internal temperature at 5 ° C speed. The resulting mixture was stored at 3 ° C for 5 hours, and then concentrated under reduced pressure. The resulting solid suspension was taken up in E t〇A c (1 L) and filtered. The filtrate was washed with a saturated NaCI1 solution (500 mL), dried (N a 2 S 0 4 ) and concentrated under reduced pressure to give 4-chloro-N-methyl-2-pyridine. Carboxylamamine, which is a pale yellow crystal (71. 2 g, 97%): mp 4 1 - 4 3 ° C; 'H-NMR (DMSO-de) 5 2 · 8 1 (s, 3 Η ), 7.74 (dd, J = 5.1, 2-2 Hz, lH), 8*00 (d, J =: 2-2, lH), 8.61 (d, J = 5-lHz, lH), 8 · 8 5 (brd ,lH);

Cl— MS m/z 171 ( (M + H)+) °Cl— MS m/z 171 ( (M + H)+) °

步驟3 b · 從4 一氯吡啶一 2 —碳醯氯來合成4 一氯基 一 N —甲基一2 —吡啶羧醯胺 在Ot下，將4 一氯吡碇一 2 -碳醯氯氫氯酸鹽（ 本紙張尺度適用中國國家標準（CNS)A4規格（210 x 297公釐）-34 - ------r--I--Aw --------訂—-------I (請先閱讀背面之注意事項再填寫本頁) 1269791 5毫莫耳）一部分一部分地加入含 A7 B7 五、發明說明（32 7 ·〇克 2 _ 〇莫耳濃度甲胺的T H F ( 1 〇 〇毫升）溶液和 M e ^ H 2 〇毫升）的混合物中。將所產生的混合物在 3 C下貯存4小時，然後，在減壓下濃縮之。將所產生之 幾近乾燥的固體懸浮於E t〇A c ( 1 〇 0毫升）中並過 #之。以飽和的N a ^ 1溶液（2 X 1 0 0毫升）淸洗濾 '液、乾燥（N a 2 S〇4 )後再於減壓下進行濃縮以產生4 一氯基一 N 一甲基一 2 -吡啶羧醯胺，此爲一種黃色結晶 固體（4-95 克，88%) :mp 37 — 4CTC。Step 3 b · Synthesis of 4 monochloro-N-methyl-2-pyridine carboxamide from 4-chloropyridine-2-chloroindole chloride 4 O-pyridinium-2-carbonium chlorohydrin at Ot Chlorate (This paper scale applies to China National Standard (CNS) A4 specification (210 x 297 mm) -34 - ------r--I--Aw -------- order-- ------I (please read the note on the back and then fill out this page) 1269791 5 millimoles) Partially added with A7 B7 V. Invention description (32 7 · 〇克 2 _ 〇 Mo Er concentration A A mixture of the amine in THF (1 mL) and M.sub.2H. The resulting mixture was stored at 3 C for 4 hours and then concentrated under reduced pressure. The nearly dry solid produced was suspended in E t〇A c (1 〇 0 ml) and passed through #. The solution was washed with a saturated Na solution (2×10 mL), dried (N a 2 S 〇 4 ) and then concentrated under reduced pressure to give 4-chloro-N-methyl. A 2-pyridine carboxamide, which is a yellow crystalline solid (4-95 g, 88%): mp 37 - 4 CTC.

步驟4 · 4 一（2 —（N —甲基氨基甲醯）一4 —吡啶 氧基）苯胺 以特—丁氧化鉀（1〇 · 29克，91 · 7毫莫耳） 來處理含有4 一胺基苯酚（9 · 60克，88 · 0毫莫耳 )的無水D M F ( 1 5 0毫升）溶液，並在室溫下將所產 生的紅棕色混合物攪拌2小時。以4 一氯基一 Ν -甲基一 2 -吡啶羧醯胺（15 · 〇克，87 _ 9毫莫耳）及 K2C〇3 (6 · 50克，47 · 0毫莫耳）來處理內容物 ’並在8 〇 °C下加熱8小時。將混合物冷卻至室溫再於 E t〇A c ( 5〇〇毫升）和飽和N a c 1溶液（5〇0 毫升）之間進行分離。以E t 〇 A c ( 3 0 0毫升）將水 溶液相進行反萃取。以飽和的N a c 1溶液（4&gt;&lt;10〇0 1本纸張尺度適用中國國家標準(CNS)A4規格(210 χ 297公爱1 . 35 - ------1-----裝--------訂--------- (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 1269791 A7 _____JB7_____ 五、發明說明（33) · (請先閱讀背面之注意事項再填寫本頁) 毫升）來淸洗合倂的有機層，乾燥（N a 2· S〇4 )後，在 減壓下進行濃縮。將所產生之固體於3 5。(：下，減壓環境 中進行乾燥3小時，以產生4 一（ 2 —（ N —甲基氨基甲 醯）一 4 一吡啶氧基）苯胺，此爲一種淡棕色固體（ 17 . 9 克，84%) ： 'H-NMR (DMSO-de) 5 2-77(d，J=4.8Hz，3H)， 5 · 1 7 ( b r s，2H) ， 6 · 64 ， 6 · 86,(AA^BB^ 四重線，J=8 ·4 Η z，4 Η )， 7.06 (dd，J = 5.5，2.5Hz，lH)， 7.33(d，J=2.5Hz，lH)， 8.44(d，J = 5- 5Hz，lH)， 8 · 7 3 ( b r d，1 H ); HPLC ES— MS m / z 2 4 4 ( ( M + H ) + ) 經濟部智慧財產局員工消費合作社印製 A 3 · 經由親核性芳香族的加成作用，再接著進行硝基 芳香烴的還原作用來合成苯胺類的一般方法。ί —(4 一胺基苯氧基）異吲哚滿—1，3 —二酮Step 4 · 4 One (2-(N-methylaminoformamidine)-4-pyridyloxy)aniline is treated with potassium butylate (1〇·29 g, 91·7 mmol). A solution of the aminophenol (9 · 60 g, 88 · 0 mmol) in dry DMF (150 mL), and the mixture was stirred for 2 hours at room temperature. Treat content with 4-chloro-indenyl-methyl-2-pyridine carboxamide (15 · gram, 87 _ 9 mmol) and K2C 〇 3 (6 · 50 g, 47 · 0 mmol) ' and heat at 8 ° C for 8 hours. The mixture was cooled to room temperature and then separated between EtOAc (5 mL) and sat. NaCI (EtOAc). The aqueous solution phase was back extracted with E t 〇 A c (300 ml). Saturated N ac 1 solution (4 &gt;&lt; 10 〇 0 1 paper scale applicable to China National Standard (CNS) A4 specification (210 χ 297 public love 1. 35 - ------1---- -装--------Book--------- (Please read the note on the back and then fill out this page) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1269791 A7 _____JB7_____ V. Invention Description (33) · (Please read the precautions on the back and fill out this page) ML) to wash the organic layer of the mixture, dry (N a 2 · S〇4), and concentrate under reduced pressure. The solid was dried at 35 ° under a reduced pressure atmosphere for 3 hours to give 4-(2-(N-methylaminoformamidine)-4-pyridyloxy)phenylamine as a pale brown solid. (17. 9 g, 84%): 'H-NMR (DMSO-de) 5 2-77 (d, J = 4.8 Hz, 3H), 5 · 1 7 (brs, 2H), 6 · 64, 6 · 86, (AA^BB^ quadruple line, J=8 · 4 Η z, 4 Η ), 7.06 (dd, J = 5.5, 2.5 Hz, lH), 7.33 (d, J = 2.5 Hz, lH), 8.44 (d, J = 5- 5Hz, lH), 8 · 7 3 ( brd, 1 H ); HPLC ES-MS m / z 2 4 4 ( ( M + H ) + ) Ministry of Economics Intellectual Property Employee-consumer cooperatives print A 3 · General method for the synthesis of anilines via the addition of nucleophilic aromatics followed by the reduction of nitroaromatics. ί —(4-Aminophenoxy)isoindole哚满—1,3 —dione

步驟1 · 5 —經基異问丨噪滿一 1 ’ 3 —二嗣的合成 將4 一經基酿酸（5 · 0克，27 · 45毫莫耳）慢 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -36- 1269791 Α7 Β7 五、發明說明（34) * 慢地加入含碳酸銨（5 · 2 8克，5 4 · 9毫莫耳）的濃 A c〇Η ( 2 5毫升）混合物中。在1 2 0 °C下，將所產 生的混合物加熱4 5分鐘，然後，再將此透明、亮黃色的 混合物在1 6 0 °C下加熱2小時。將所產生的混合物維持 在1 6 0 °C下並將之濃縮至約1 5毫升後再使之冷卻至室 溫並以IN Na〇Η溶液來將之調整成pH 10。將 混合物冷卻至0 °C並以1 N H C 1溶液將之慢慢酸化成 pH 5。經由過濾來收集所產生的沈澱物並在減壓環境 下將之進行乾燥以產生5 -羥基異吲哚滿一 1 ，3 -二酮 ，此爲一種淡黃色的粉末產物（3 · 2 4克，7 2 % ): 'H-NMR (DMSO-de) 5 7·〇0 — 7.03(m，2H)， 7.56 (d，J = 9.3Hz，lH)。 (請先閱讀背面之注意事項再填寫本頁)Step 1 · 5 — The basis of the 异 丨 满 满 ' ' 1 ' 3 - 嗣 嗣 将 将 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 ) A4 size (210 X 297 mm) -36- 1269791 Α7 Β7 V. Description of invention (34) * Slowly add concentrated A c〇 containing ammonium carbonate (5 · 28 g, 5 4 · 9 mmol) Η (25 ml) in the mixture. The resulting mixture was heated at 1 20 ° C for 45 minutes, and then the clear, bright yellow mixture was heated at 160 ° C for 2 hours. The resulting mixture was maintained at 160 ° C and concentrated to about 15 ml and then allowed to cool to room temperature and adjusted to pH 10 with an IN Na solution. The mixture was cooled to 0 ° C and slowly acidified to pH 5 with a 1 N H C 1 solution. The resulting precipitate was collected by filtration and dried under reduced pressure to give 5-hydroxyisoindan-1,3-dione as a pale yellow powder product (3 · 2 4 g , 7 2 % ): 'H-NMR (DMSO-de) 5 7·〇0 — 7.03 (m, 2H), 7.56 (d, J = 9.3 Hz, lH). (Please read the notes on the back and fill out this page)

〇 經濟部智慧財產局員工消費合作社印製 步驟2 · 5 —（ 4 一硝基苯氧基）異吲哚滿一 1，3 — 二酮的合成 在0 °C下，將含5 -羥基異吲哚滿一 1 ，3 —二酮（ 3 · 2克，1 9 · 6毫莫耳）的D M F溶液一滴滴地加入 一攪拌中的含NaH (1 · 1克，44 · 9毫莫耳）的 D M F ( 4 0毫升）漿液。使該淡黃綠色混合物冷卻回室 溫並攪拌1小時後，再經由注射筒將1 一氟基一 4 一硝基 苯（2 · 67克，18 · 7毫莫耳）成分3 — 4部分加入 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -37- 1269791 Α7 Β7 五、發明說明（35) · 其中。將所產生的混合物在7 0 °C下加熱一整晚，然後， 使之冷卻至室溫，再以水（1 5 0毫升）慢慢地稀釋之， 並以E t〇A c ( 2 X 1 0 0毫升）萃取之。將合倂的有 機層加以乾燥（M g S 0 4 )並在減壓下濃縮之以產生5 -(4 一硝基苯氧基）異巧丨d朵滿一 1 ，3 -二酮，此爲一種 黃色固體（3 · 3 克，62%) : TLC (3 0%〇 Ministry of Economic Affairs, Intellectual Property Bureau, Staff and Consumer Cooperatives, Printing Step 2 · 5 —( 4 -Nitrophenoxy)isoindole -1,3-dione synthesis at 0 °C, containing 5-hydroxyl A DMF solution containing 1 , 3 - diketone ( 3 · 2 g, 1 9 · 6 mmol) was added dropwise with a stirred NaH (1 · 1 g, 44 · 9 mmol) DMF (40 ml) slurry. The yellowish green mixture was allowed to cool back to room temperature and stirred for 1 hour, and then 1 fluoro-4-tetranitrobenzene (2 · 67 g, 18 · 7 mmol) of the components 3 - 4 was added via a syringe. This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) -37- 1269791 Α7 Β7 5. Inventive Note (35) · Among them. The resulting mixture was heated at 70 ° C overnight, then allowed to cool to room temperature, then slowly diluted with water (150 ml), and taken to E t 〇 A c ( 2 X 1 0 0 ml) extracted. The combined organic layer is dried (M g S 0 4 ) and concentrated under reduced pressure to give 5-(4-nitrophenoxy) hydrazide d to a 1,3-dione. Is a yellow solid (3 · 3 g, 62%): TLC (30%)

Et〇Ac/7〇％己烷）Rf 〇·28; XH-NMR (DMS.O-d6) (5 7.32(d，卜 12Hz，2H)， 7·52 — 7·57(ιη，2Η)， 7.89(d，J=7.8Hz，lH)， 8.29(d，J = 9Hz，2H)， 1 1 * 4 3 ( b r s，lH);Et〇Ac/7〇% hexane)Rf 〇·28; XH-NMR (DMS.O-d6) (5 7.32(d, Bu 12Hz, 2H), 7·52 — 7·57(ιη, 2Η), 7.89 (d, J = 7.8 Hz, lH), 8.29 (d, J = 9 Hz, 2H), 1 1 * 4 3 (brs, lH);

Cl— MS m / z 285((M + H) +，100%) (請先閱讀背面之注意事項再填寫本頁)Cl— MS m / z 285((M + H) +, 100%) (Please read the notes on the back and fill out this page)

經濟部智慧財產局員工消費合作社印製 步驟3 · 5 —（ 4 一胺基苯氧基）異巧丨噪滿一 1 ’ 3 - 二酮的合成 將含5 — ( 4 -硝基苯氧基）異吲哚滿一 1 ，3 —二 酮（0 · 6克，2 · 11毫莫耳）的濃Ac〇.Η (12毫 升）溶液和水（0 · 1毫升）在氬氣流下進行攪拌，同時 ，將鐵粉（0 . 5 9克，5 5 · 9毫莫耳）慢慢地加入其 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） _ 38 _ A7 1269791 ___B7__ 五、發明說明（36 ) &gt; 中。將此混合物在室溫下攪拌7 2小時’再以水（2 5毫 升）稀釋之並以E t〇Ac (3x50毫升）萃取之。將 合倂的有機層加以乾燥（M g S 0 4 )並在減壓下加以濃縮 以產生5 —（ 4 一胺基苯氧基）異吲哚滿一 1 ，3 —二酮 ，此爲一種棕色固體（0 · 4克，7 5 % ) * T L C ( 50% Et〇Ac/50%己燒）Rf 0·27; 1 Η - N MR (DMSO-de) 5 5 * 1 4 ( b r s，2H)， 6.62(d，J=8^7Hz，2H)， 6.84(d，J 二 8·7Ηζ，2Η)， 7.〇3(d，J = 2.1Hz，lH)， 7-23(dd，lH)， 7.75(d，J=8.4Hz，lH)， ll-02(s，lH)； HPLC ES - MS m / z 255((M + H) +， 1〇〇％ 。 A 4 * 用來合成吡咯基苯胺的一般方法。將5 -特一丁 基一 2 —（2，5 —二甲基吡咯基）苯胺的合成Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperatives, Printing Step 3 · 5 —( 4 -Aminophenoxy), a complex of 1 ' 3 -dione, will contain 5-(4-nitrophenoxy) A solution of isopropanol (0 · 6 g, 2 · 11 mmol) of concentrated Ac 〇. Η (12 ml) and water (0 · 1 ml) were stirred under a stream of argon. At the same time, iron powder (0.59 g, 5 5 · 9 mmol) was slowly added to its paper scale for the Chinese National Standard (CNS) A4 specification (210 X 297 mm) _ 38 _ A7 1269791 ___B7__ V. Invention description (36) &gt; The mixture was stirred at room temperature for 7 hours and then diluted with water (25 mL) and extracted with EtOAc (3.times.50 mL). The combined organic layer is dried (M g S 0 4 ) and concentrated under reduced pressure to give 5-(4-aminophenoxy)isoindole-1,3-dione, which is a Brown solid (0 · 4 g, 7 5 %) * TLC (50% Et〇Ac / 50% hexane) Rf 0·27; 1 Η - N MR (DMSO-de) 5 5 * 1 4 (brs, 2H ), 6.62(d, J=8^7Hz, 2H), 6.84(d, J 2·8Ηζ7Η, 2Η), 7.〇3(d, J = 2.1Hz, lH), 7-23(dd,lH ), 7.75 (d, J = 8.4 Hz, lH), ll-02 (s, lH); HPLC ES - MS m / z 255 ((M + H) +, 1%. A 4 * for synthesis General method for pyrrolyl aniline. Synthesis of 5-tert-butyl-2-(2,5-dimethylpyryl)aniline

步驟1 · 1 一（4 —特—丁基—2 —硝苯基）—2，5 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） (請先閱讀背面之注意事項再填寫本頁) 0 i mmmmMm n n mmmMmm maMmm m 一.口、I an mmmmmf Kmmmme ·_ϋ Φ. 經濟部智慧財產局員工消費合作社印製 -39- 1269791 A7 B7 五、發明說明（37) · 一二甲基吡咯的合成 將A c〇Η ( 〇 ’· 1毫升）和丙酮基丙酮（ 〇· 299克，2 · 63毫莫耳）經由注射筒加入一攪拌 中之含2—硝基一4一特一丁基苯胺（0·5克， 2 · 5 7毫莫耳）的環己烷（1 〇毫升）溶液中。將所產 生的混合物在1 2 0 °C下加熱7 2小時，經共沸作用移除 揮發物。將反應混合物冷卻至室溫，以C Η 2 C 1 2 ( 1 〇 毫升）稀釋之並接著以IN HC1溶液（15毫升）， 1 N Na〇H溶液（15毫升）和飽和NaCl溶液（ 1 5毫升）淸洗之，乾燥（M g S〇4 )後再於減壓環境下 進行濃縮。經由管柱層析法將所產生之橘棕色固體加以純 化（60克31〇2;梯度從6% Et〇Ac/94%己 院至25% Et〇Ac/75%己烷）以產生1—(4 一特—丁基一 2 —硝苯基）—2，5 —二甲基吡咯，此爲 一種橘黃色固體（0 · 34克，49%) : TLC ( 15% E t 0 A c /85%己烷）Rf 0·67; 1 Η Ν Μ R ( C D C 1 3 ) d 1.34(s，9H)， 1.89(s，6H) ，5-84(s，2H)， 7.19 — 7.24(m，lH)， 7.62(dd，lH)， 7.88(d，卜 2.4Hz，lH);Step 1 · 1 One (4 - Tetrabutyl-2-nitrophenyl) - 2,5 This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back first) Fill in this page again) 0 i mmmmMm nn mmmMmm maMmm m I. mouth, I an mmmmmf Kmmmme ·_ϋ Φ. Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing -39- 1269791 A7 B7 V. Invention description (37) · One two Synthesis of methylpyrrole A c〇Η (〇'·1 ml) and acetone-acetone (〇·299 g, 2 · 63 mmol) were added via syringe to a 2-nitro-4-one Tetrabutylaniline (0.5 g, 2 · 5 7 mmol) in cyclohexane (1 mL). The resulting mixture was heated at 120 ° C for 72 hours and the volatiles were removed by azeotrope. The reaction mixture was cooled to room temperature, diluted with C Η 2 C 1 2 (1 mL) and then with 1N HCl solution (15 mL), 1 N Na 〇H solution (15 mL) and saturated NaCl solution (1 5毫升), rinsed, dried (M g S〇4) and concentrated under reduced pressure. The resulting orange-brown solid was purified by column chromatography (60 g 31 〇 2; gradient from 6% Et 〇Ac / 94% hexanes to 25% Et sAc / 75% hexane) to yield 1 - (4 mono-butyl-2-nitrophenyl)- 2,5-dimethylpyrrole, an orange solid (0 · 34 g, 49%): TLC ( 15% E t 0 A c / 85% hexane) Rf 0·67; 1 Η Ν Μ R ( CDC 1 3 ) d 1.34 (s, 9H), 1.89 (s, 6H), 5-84 (s, 2H), 7.19 — 7.24 (m, lH), 7.62 (dd, lH), 7.88 (d, Bu 2.4 Hz, lH);

Cl — MS m / z 273 ( (Μ + Η) +，·50%)。 本紙張尺度適用中國國家標準（CNS)A4規格（210 x 297公釐） (請先閱讀背面之注意事項再填寫本頁) 裝.—------訂----Cl — MS m / z 273 ( (Μ + Η) +, · 50%). This paper size applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm) (please read the notes on the back and fill out this page). Pack.—------Book----

S 經濟部智慧財產局員工消費合作社印製 1269791 A7 B7 五、發明說明（ 38S Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 1269791 A7 B7 V. Invention description ( 38

步驟 一特一丁基一2- ^，5 —二甲基吡咯基 苯胺 在Η 2氣（氣球）下，將含1 4 一特一丁基—2 硝苯基）一 2，5 —二甲基吡咯（〇 · 341克， 1·25毫旲耳）’10% Pd/C(〇.〇56克） 和E t〇A c ( 5 0毫升）的漿液攪拌7 2小時，然後經 由一塞里特⑧墊加以過濾。將過濾液在減壓下加以濃縮以產 生5 -特一丁基一2 —（2，5〜二甲基吡咯基）苯胺， 此爲黃色固體（〇 · 3〇克，99%) : TLC ( E t 0 A c /90%己烷）Rf 〇 Ο % 4 3; 1 Η Ν Μ R ( C D C 1 (5 2 8 ( s ，9 Η ) 1 8 7-1 (m Η I I n i I -ϋ ϋ ϋ —^1 ϋ ι_ϋ ammMm n mmMme n n in 一 tv a n i··— mmamm an -ϋ Μϋ n I (請先閱讀背面之注意事項再填寫本頁) 5 8 5 ( b r s ，2 Η ) 73 — 6-96 (m，3H)， 經濟部智慧財產局員工消費合作社印製 7 * 2 8 ( b r 1 H )。 A 5 · 經由親核性芳香族的取代作用來合成苯胺類的一 般方法。4 — (2 — (N —甲基氨基甲醯）〜4 -吡啶氧基）- 2 -甲基苯胺氫氯酸鹽的合成作 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -41 - 1269791 A7 B7 五、發明說明（39 )Step 1 - monobutyl- 2-, 5-dimethylpyrrolidine will contain 1 4 mono-butyl-2-nitrophenyl) 2,5-dimethyl under Η 2 gas (balloon) A solution of 10% Pd/C (〇.〇56 g) and E t〇A c (50 ml) was stirred for 7 2 hours, then passed through a stopper. The Ritter 8 pad is filtered. The filtrate was concentrated under reduced pressure to give 5-t-butyl-2-(2,5-dimethylpyryl)aniline as a yellow solid (3·3 g, 99%): TLC ( E t 0 A c /90% hexane)Rf 〇Ο % 4 3; 1 Η Ν Μ R ( CDC 1 (5 2 8 ( s ,9 Η ) 1 8 7-1 (m Η II ni I -ϋ ϋ ϋ —^1 ϋ ι_ϋ ammMm n mmMme nn in a tv ani··— mmamm an -ϋ Μϋ n I (Please read the back note first and then fill out this page) 5 8 5 ( brs , 2 Η ) 73 — 6- 96 (m, 3H), Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, Printed 7 * 2 8 ( br 1 H ). A 5 · General method for the synthesis of anilines via the substitution of nucleophilic aromatics. 4 — ( 2 —(N-Methylaminocarbamidine)~4-pyridinyloxy)-2-methylaniline hydrochloride is synthesized according to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). -41 - 1269791 A7 B7 V. Description of invention (39)

Me 以特一丁氧化鉀（10 · 86克，96 · 77毫莫耳 )來處理含4 一胺基一 3 —甲基苯酚（5 · 45克， 44 · 2 5毫莫耳）的乾二甲基乙醯胺（7 5毫升）溶液 ’並將此黑色混合物在室溫下攪拌直至錐瓶達到室溫。然 後，以4 一氯基一 N —甲基一 2 —吡啶羧醯胺來處理內容 物（方法A2，步驟3b ; 7 · 52克，44 · 2毫莫耳 )並在1 1 0 °C下加熱8小時。將混合物冷卻至室溫並以 水稀釋之（75毫升）。以E t〇Ac (5X100毫升 )來萃取有機層。以飽和的N a C 1溶液（2 0 0毫升） 淸洗有機層，乾燥（M g S 0 4 )後再於減壓下加以濃縮。 以E t 2〇（5 0毫升）處理剩餘的黑色油並以音波處理之 。然後，以HC1 (1M，在Et2〇中；1〇〇毫升）處 理之並在室溫下攪拌5分鐘。將所產生的暗粉紅色固體（ 7 · 0 4克，2 4 · 1毫莫耳）經由過濾方法從溶液中移 除並在使用前將之貯存於0 °C，無氧的環境下： 1 H NMR (DMSO-de) (5 2 · 4 1 ( s，3 Η )， 2.78(d，J=4.4Hz’3H)， 4 · 9 3 ( b r s，2H)， 7.19(dd，J=8.5，2.6Hz，lH)， 7.23(dd，J = 5.5，2.6Hz，lH)， 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） (請先閱讀背面之注意事項再填寫本頁) —— 訂i 經濟部智慧財產局員工消費合作社印製 -42- 1269791 經濟部智慧財產局員工消費合作社印製 Α7 Β7 五、發明說明（40) 7.26(d，J = 2.6Hz，lH)， 7.55(d，J = 2.6Hz，lH)， 7* 64 (dj Ι=8·8Ηζ » 1Η)， 8.55(d，J = 5.9Hz，lH)， 8·99 (q’ j=4.8Hz，1H)。 A 6 ··經由N -保護作用，親核性芳香族的取代作用和 去保護作用’從羥基苯胺類來合成苯胺類的一般 方法。4 一（2 —（N —甲基氨基甲醯）一4 — 吡啶氧基）一 2 -氯苯胺的合成Me treated with potassium monobutoxide (10 · 86 g, 96 · 77 mmol) to treat 4-amino-3-methylphenol (5 · 45 g, 44 · 25 mmol) Methyl acetamide (75 ml) solution and the black mixture was stirred at room temperature until the flask reached room temperature. The contents were then treated with 4-chloro-N-methyl-2-pyridine carboxamide (Method A2, Step 3b; 7 · 52 g, 44 · 2 mmol) and at 1 10 ° C Heat for 8 hours. The mixture was cooled to room temperature and diluted with water (75 mL). The organic layer was extracted with EtOAc (5×100 mL). The organic layer was washed with aq. EtOAc (EtOAc) (EtOAc) The remaining black oil was treated with E t 2 〇 (50 mL) and treated with sonication. Then, it was treated with HCl (1M in Et 2 ;; 1 liter) and stirred at room temperature for 5 minutes. The resulting dark pink solid (7.44 g, 2 4 · 1 mmol) was removed from the solution by filtration and stored at 0 °C in an anaerobic environment before use: 1 H NMR (DMSO-de) (5 2 · 4 1 ( s, 3 Η ), 2.78 (d, J = 4.4 Hz '3H), 4 · 9 3 (brs, 2H), 7.19 (dd, J = 8.5, 2.6Hz, lH), 7.23 (dd, J = 5.5, 2.6Hz, lH), the paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back and fill in the form) Page) —— Book i Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed-42- 1269791 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed Β7 Β7 V. Invention Description (40) 7.26(d, J = 2.6Hz, lH) , 7.55(d, J = 2.6Hz, lH), 7* 64 (dj Ι=8·8Ηζ » 1Η), 8.55(d, J = 5.9Hz, lH), 8·99 (q' j=4.8Hz, 1H) A 6 · · N-protection, nucleophilic aromatic substitution and deprotection 'General method for the synthesis of anilines from hydroxyanilines. 4 I (2 - (N - methylamino)醯) a combination of 4-pyridyloxy)-2-chloroaniline

步驟1 · 3 —氯基一 4 一（2，2，2 —三氟乙醯胺基 )苯酚的合成 將鐵（3 · 24克’ 58 · 00毫莫耳）加入擾泮中 的TFA ( 2 0 0笔升）中。將2 —氯基一 4 一硝基苯酌 (10 · 0克，58 · 0毫莫耳）和三氟醋酸酐（20毫 升）加入此漿液中。在室溫下，將此灰色漿液攪拌6天。 將鐵從溶液中濾出，並將剩餘物質在減壓下進行濃縮。將 所產生之灰色固體溶於水中（2 0毫升）。將一飽和的 N a H C〇3溶液（5 0毫升）加入此所產生的黃色溶液中 再將沈澱下來的固體從溶液中移除。以碳酸氫鈉溶液將濾 液慢慢地驟冷直到可見到產品從溶液中分離出來（利用一 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -43- ---------------------^--------- (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 1269791 A7 B7 五、發明說明（41) , 種迷你操作小瓶來測定）。以E t〇A c ( 3 X 1 2 5毫 升）萃取稍微混濁之黃色溶液。以飽和之N a C 1溶液（ 1 2 5毫升）來淸洗合倂的有機層’乾燥（M g S 0 4 )後 ，在減壓下加以濃縮。該1H NMR(DMSO-de) 表示該硝基苯酚起始物質和所需要之3 -氯基-4 -（2 ，2 ，2 —三氟乙醯胺基）苯酚的1 : 1比例。該粗產品 可直接用於下一個步驟中，不需要再·進一步純化。 〇Step 1 · Synthesis of 3-chloro-tetra-(1,2,2-trifluoroacetamido)phenol Iron (3 · 24 g '58 · 00 mmol) was added to the TFA in the scramble ( 2 0 0 pens up). 2-Chloro-4-tetranitrobenzene (10 · 0 g, 58 · 0 mmol) and trifluoroacetic anhydride (20 ml) were added to the slurry. The gray slurry was stirred for 6 days at room temperature. Iron was filtered from the solution, and the remaining material was concentrated under reduced pressure. The resulting gray solid was dissolved in water (20 mL). A saturated solution of N a H C 3 (50 mL) was added to the resulting yellow solution and the precipitated solid was removed from the solution. The filtrate was slowly quenched with sodium bicarbonate solution until the product was separated from the solution (using a paper scale applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) -43- ---- -----------------^--------- (Please read the notes on the back and fill out this page) Printed by the Intellectual Property Office of the Ministry of Economic Affairs 1269791 A7 B7 V. Description of invention (41), a mini-operating vial for measurement). A slightly turbid yellow solution was extracted with E t 〇 A c (3 X 1 2 5 mL). The combined organic layer was washed with a saturated NaCI solution (1 25 mL) and dried (M??? The 1H NMR (DMSO-de) represents a 1:1 ratio of the nitrophenol starting material to the desired 3-chloro-4(2,2,2-trifluoroacetamido)phenol. This crude product can be used directly in the next step without further purification. 〇

步驟2 · 4 —（2 - (N —甲基氨基甲醯）一 4 一吡啶 氧基）一 2 —氯苯基（222 —三氟基）乙醯 胺的合成 以特一丁氧化鉀（5 · 16克，45 · 98毫莫耳） 來處理含有粗3 —氯基—4— (2，2，2 -三氟乙醯胺 基）苯酚（5 · 62克，23 · 46毫莫耳）的乾二甲基 i醯胺（5 〇毫升）溶液並將棕黃色混合物在室溫下加以 攪拌直到該錐瓶已冷卻至室溫。以4 -氯基- N —甲基-2 -吡啶羧醯胺（方法a 2，步驟3 b ; 1 · 9 9克， 1 1 · 7毫莫耳）來處理所產生的混合物並在氬氣、 1 0 0 °C下加熱4天。將黑色的反應混合物冷卻至室溫並 倒入冷水（1〇〇毫升）中。以Et〇Ac (3x75毫 升）萃取該混合物並將合倂的有機層在減壓下加以濃縮。 經由管柱層析法（梯度從2 〇 % E t〇A c /石油醚至 本紙張尺度適用中國國家標準（CNS)A4規格（21〇 x 297公釐） (請先閱讀背面之注意事項再填寫本頁) 訂----- -44- 1269791 A7 B7 五、發明說明（42) , 4 % E t 0 A c /石油醚）將剩餘的棕色油加以純化以 產生4— (2— (N —甲基氨基甲醯）一 4 一吡啶氧基） 一 2 -氣苯基（2 2 2 —二氟基）乙醯胺，此爲一種黃色 固體（8 · 59克，23 · ◦毫莫耳）。Step 2 · 4 -(2-(N-methylaminocarbamidine)-4-pyridyloxy)-2-chlorophenyl(222-trifluoro)acetamide as a special potassium monobutoxide (5 · 16 g, 45 · 98 mM) to treat crude 3-chloro-4-(2,2,2-trifluoroacetamido) phenol (5 · 62 g, 23 · 46 mmol) A solution of dry dimethyl i-amine (5 mL) and the brown-yellow mixture was stirred at room temperature until the flask had cooled to room temperature. The resulting mixture was treated with 4-chloro-N-methyl-2-pyridine carboxamide (Method a 2, Step 3 b; 1 · 9 9 g, 1 1 · 7 mmol) and argon Heat at 1 0 0 °C for 4 days. The black reaction mixture was cooled to room temperature and poured into cold water (1 mL). The mixture was extracted with Et EtOAc (3 x 75 mL) and the organic layer was concentrated under reduced pressure. By column chromatography (gradient from 2 〇% E t〇A c / petroleum ether to this paper scale applies Chinese National Standard (CNS) A4 specification (21〇x 297 mm) (please read the notes on the back first) Fill in this page) Order-----44- 1269791 A7 B7 V. Inventive Note (42), 4% E t 0 A c / petroleum ether) Purify the remaining brown oil to produce 4- (2 - ( N-methylcarbamidine)-tetra-pyridyloxy)-2-2-phenylphenyl(2 2 2 -difluoro)acetamide, which is a yellow solid (8 · 59 g, 23 · ◦ 莫ear).

NHMe 步驟3 · 4— (2 —（N —甲基氨基甲醯）一 4 一吡啶* 氧基）一2-氯苯胺的合成 WIN Na〇Η溶液（20毫升）來處理含粗4 一 (2 —（Ν —甲基氨基甲醯）一 4 一吡啶氧基）一 2 —氯 苯基（222 —三氟基）乙醯胺（8 · 59克，23 · 0 毫莫耳）的乾4 一二噚烷（2 0毫升）溶液。將此棕色溶 液攪拌8小時。在此溶液中加入E t〇A c ( 4 0毫升） 。以E t〇A c ( 3 X 4 0毫升）來萃取綠色有機層並將 溶劑加以濃縮以產生4 一（ 2 -（ N —甲基氨基甲醯）一 4 一吼d定氧基）一 2 -氯苯胺，此爲一種綠色油，靜置時 --------------------訂-------- (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 會固化（2 · 8 6克 〇 3 0毫莫耳）： 1 H NMR ( D M S 0 - d 6 ) 5 2-77(d，J=4-8Hz，3H)， 5 · 5 1 ( s，2 Η )， 6.60(dd，J = 8.5，2.6Hz 6.76(d，J = 2.6Hz，lH)， 7.〇3(d，J = 8.5Hz，lH)，NHMe Step 3 · 4—(2-(N-methylaminocarbamidine)-4-pyridyl*oxy)- 2-chloroaniline Synthesis WIN Na〇Η solution (20 ml) to treat the crude 4 (2) —(Ν-Methylaminocarbamidine)-4-pyridyloxy)-2-chlorophenyl(222-trifluoro)acetamide (8 · 59 g, 23 · 0 mmol) of dry 4 Dioxane (20 ml) solution. This brown solution was stirred for 8 hours. To this solution was added E t 〇 A c (40 ml). The green organic layer was extracted with E t 〇A c (3×40 mL) and the solvent was concentrated to give 4-(2-(N-methylaminocarbazide)-4 吼d-oxyl)-2 -Chloroaniline, this is a kind of green oil, when it is still -------------------- Order-------- (Please read the notes on the back first) Fill in this page again) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing will be cured (2 · 8 6 g 〇 3 0 mmol): 1 H NMR ( DMS 0 - d 6 ) 5 2-77 (d, J = 4-8Hz, 3H), 5 · 5 1 ( s, 2 Η ), 6.60 (dd, J = 8.5, 2.6 Hz 6.76 (d, J = 2.6 Hz, lH), 7. 〇 3 (d, J = 8.5 Hz, lH),

H 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -45- 1269791 A7 B7 五、發明說明（43) , 7.〇7(dd，J = 5.5，2.6’Hz’lH)， (請先閱讀背面之注意事項再填寫本頁) 7· 27 (d? j = 2- 6Hz j lH)， 8.46(d，J = 5.5Hz，lH)， 8.75(q，J=4.8，lH)。 A7 · 將醯基化的苯胺去保護的一般方法。4 一氯基一 • 2 —甲氧基一 5 —（三氟甲基）苯胺的合成 cf3 1H This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -45-1269791 A7 B7 V. Invention description (43) , 7.〇7 (dd, J = 5.5, 2.6'Hz'lH ), (please read the notes on the back and fill out this page) 7· 27 (d? j = 2- 6Hz j lH), 8.46 (d, J = 5.5Hz, lH), 8.75 (q, J=4.8, lH). A7 · General method for deprotecting thiolated anilines. Synthesis of 4-chloro-mono- 2-methoxy-5-(trifluoromethyl)aniline cf3 1

Clxi ; T&quot;nh2 〇Me 經濟部智慧財產局員工消費合作社印製 將3 —氯基一 6 —（N —乙醯基）—4 一（三氟甲基 )苯甲醚（4 · 00克，14 · 95毫莫耳）溶於6M H C 1溶液（2 4毫升）中，並將此懸浮液在回流溫度下 加熱1小時。將所產生的溶液冷卻至室溫’在此期間內， 它會稍稍地固化。以水（2 0毫升）稀釋所產生的混合物 ，然後，以固體N a〇Η和飽和N a H C 0 3溶液的組合物 處理之直到溶液成爲鹼性。以C H 2 C 1 2 ( 3 X 5 0毫升 )來萃取有機層。將合倂的有機層在M g S 0 4上加以乾燥 並於減壓下進行濃縮以產生4 一氯基一 2 -甲氧基一 5 -(三氟甲基）苯胺，此爲一種棕色油（3 · 20克， 14· 2 毫莫耳）NMR (DMSO-de) 5 3.84(s，3H) ，5.30(s，2H)， 7 · 0 1 ( s，2 Η )。 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -46- 1269791 A7 B7 五、發明說明（44) - » A 8 · 用於合成ο -院氧基一 ω -殘苯基苯胺的一般方 法。4 一 （3— (N —甲基氨基甲醯）—4一甲 氧基苯氧基）苯胺的合成Clxi ; T&quot;nh2 〇Me Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 3-Chloryl-6-(N-ethenyl)-4 mono(trifluoromethyl)anisole (4 · 00 g, 14 · 95 mmoles was dissolved in 6M HCl 1 solution (24 mL) and the suspension was heated at reflux temperature for 1 hour. The resulting solution was cooled to room temperature during which time it solidified slightly. The resulting mixture was diluted with water (20 ml) and then treated with a composition of solid Na 〇Η and saturated NaH OC 3 solution until the solution became basic. The organic layer was extracted with CH 2 C 1 2 (3×150 mL). The combined organic layer was dried over MgSO4 and concentrated under reduced pressure to give &lt;RTI ID=0.0&gt;&gt; (3 · 20 g, 14 · 2 mmol) NMR (DMSO-de) 5 3.84 (s, 3H), 5.30 (s, 2H), 7 · 0 1 (s, 2 Η ). This paper scale is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) -46- 1269791 A7 B7 V. Invention description (44) - » A 8 · For synthesis ο -Oxyloxy-omega-residue The general method of aniline. Synthesis of 4-(3-(N-methylaminocarbamidine)-4-methoxyphenoxy)aniline

〇Me 〇Me 步驟1 4 (3 —甲氧羰基一4 一甲氧基苯氧基）一 1 一硝基苯： 將K 2 C〇3 ( 5克）和硫酸二甲酯（3 · 5毫升）加 入含4— (3 —羧基一 4 一烴基苯氧基） 硝基苯 依方法A 1 3，步驟1中所說明的方式從2，5 —二羥基 苯甲酸製備得到，12毫莫耳）的丙酮（50毫升）溶液 中。將所產生的混合物在回流溫度下加熱一整晚，然後將 之冷卻至室溫並經由一塞里特@墊將之加以過濾。在減壓下 將所產生的溶液加以濃縮，使之吸附至S i 0 2上並以管柱 層析法加以純化（5 0 % E t〇A c / 5 0 %己烷）以 產生4 一（3 —甲氧羰基—4 —甲氧基苯氧基） 硝 (請先閱讀背面之注意事項再填寫本頁) 衣 -訂---------· 經濟部智慧財產局員工消費合作社印製 基苯，此爲一種黃色粉末（3克），：熔點1 1 5 - 1 1 8 °C 。〇Me 〇Me Step 1 4 (3-methoxycarbonyl-4-methoxyphenoxy)-mononitrobenzene: K 2 C〇3 (5 g) and dimethyl sulfate (3 · 5 ml) Adding a 4-(3-carboxy-4-monohydrocarbylphenoxy) nitrobenzene method A 1 3, prepared in the manner described in Step 1 from 2,5-dihydroxybenzoic acid, 12 mmol) Acetone (50 ml) solution. The resulting mixture was heated at reflux temperature overnight, then cooled to room temperature and filtered through a Celite @ pad. The resulting solution was concentrated under reduced pressure, adsorbed onto SiO 2 and purified by column chromatography (50% E t 〇A c / 50% hexane) to yield 4 (3 -Methoxycarbonyl-4-methoxyphenoxy) Nitrogen (please read the notes on the back and fill out this page) Clothing-booking---------· Ministry of Economic Affairs Intellectual Property Bureau staff consumption The cooperative printed base benzene, which was a yellow powder (3 g), melting point 1 1 5 - 1 18 °C.

步驟2 · 4 — (3 —羧基一 4 一甲氧基苯氧基）一1 硝基苯 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -47- 1269791 Pi/ B7 五、發明說明（45) » 將4 一 （3 —甲氧基羰基一 4 —甲氧基苯氧基）一 1 —硝基苯（1· 2克），Κ〇Η(〇·33克）和水（5 毫升）加入M e〇Η ( 4 5毫升）中，並將此混合物在室 溫下攪拌一整夜，然後再於回流下加熱4小時。將所產生 的混合物冷卻至室溫並在減壓下進行濃縮。將剩餘物溶於 水（5 0毫升）中，並以1 N H C 1溶液使之成爲酸性 。以E t〇A c ( 5 0毫升）萃取所產生的混合物。將有 機層加以乾燥（M g S 0 4 )並在減壓下加以濃縮以產生4 (3 —羧基—4 一甲氧基苯氧基）一 1—硝基苯（ 〇4克）Step 2 · 4 — (3 —Carboxy-4-methoxyphenoxy)- 1 nitrobenzene Paper scale applicable to China National Standard (CNS) A4 specification (210 X 297 mm) -47- 1269791 Pi/ B7 V. INSTRUCTIONS (45) » 4 (3-methoxycarbonyl-4-methoxyphenoxy)- 1 -nitrobenzene (1.2 g), Κ〇Η (〇·33 g) Water (5 ml) was added to a solution of EtOAc (45 mL), and the mixture was stirred at room temperature overnight, and then heated under reflux for 4 hours. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in water (50 mL) and made acidic with 1 N H C 1 solution. The resulting mixture was extracted with E t 〇 A c (50 mL). The organic layer was dried (M g S 0 4 ) and concentrated under reduced pressure to give 4 (3-carboxy-4-methoxyphenoxy)-1-nitrobenzene (4 g)

(請先閱讀背面之注意事項再填寫本頁) 步驟3 4 - ( 3 (N—甲基氨基甲醯）一4一甲氧 基苯氧基）一 1—硝基苯： 將S〇C 12 (〇 · 64毫升，8 · 77毫莫耳） 部 ^ n l n n n l J ，t n ϋ Mammm a— 零计^40 争. 經濟部智慧財產局員工消費合作社印製 分一部分地加入含有4 一（ 3 -殘基—4 一甲氧基苯氧基 )一 1 一硝基苯（0 · 50克，1 · 75毫莫耳）的 C Η 2 C 1 2 ( 1 2毫升）溶液中。在回流溫度下’，將所產 生的溶液加熱1 8小時，冷卻至室溫後再於減壓下加以濃 縮。將所產生之黃色固體溶於CH2C 1 2 ( 3毫升）中， 然後以甲胺溶液（2 · 0 Μ，含於T H F中，3 · 5毫升 ，7 · 0 2毫莫耳）一部分一部分地處理所產生的溶液（ 注意：有氣體發生），並將之在室溫下攪拌4小時。以 -48- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 1269791 Α7 Β7 五、發明說明（46 ) 1 N N a〇Η溶液處理所產生的混合物，然後以 c H 2 C 1 2 ( 2 5毫升）萃取之。將有機層乾燥（ N a 2 S 0 後在減壓下加以濃縮以產生4(Please read the notes on the back and fill out this page.) Step 3 4 - ( 3 (N-methylaminoformamidine)- 4-methoxyphenoxy)- 1-nitrobenzene: Will S〇C 12 (〇·64 ml, 8 · 77 mmol) Department ^ nlnnnl J , tn ϋ Mammm a — zero count ^ 40 contend. Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative prints part of the addition to contain 4 one (3 - disabled) Benzyl 4-methoxyphenoxy)-mononitrobenzene (0 · 50 g, 1 · 75 mmol) in a solution of C Η 2 C 1 2 (12 mL). The resulting solution was heated at reflux temperature for 18 hours, cooled to room temperature and then concentrated under reduced pressure. The resulting yellow solid was dissolved in CH 2 C 1 2 (3 mL) and then partially treated with methylamine (2············· The resulting solution (note: gas was generated) was stirred at room temperature for 4 hours. Use -48- This paper scale applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1269791 Α7 Β7 V. Invention description (46) 1 NN a〇Η solution treatment of the resulting mixture, then with c H 2 Extracted by C 1 2 (25 ml). Dry the organic layer (N a 2 S 0 and concentrate under reduced pressure to give 4

(3 - ( N 一甲基氨基甲醯）一4一甲氧基苯氧基）一1一硝基苯 此爲一種黃色固體（〇 . 50克，9 5%)。(3 - (N-Methylaminocarbamidine)-1,4-methoxyphenoxy)-mononitrobenzene This is a yellow solid (50 g, 9 5%).

步驟4 . 4— (3— N —甲基氨基甲酿）一 4 一甲氧基 經濟部智慧財產局員工消費合作社印製 苯氧基）苯胺： 將含有4 一（3 —（N —甲基氨基甲醯）一 4 一甲氧 基苯氧基）—1 一硝基苯（0 · 78克，2 · 60毫莫耳 )和10% Pd/C (〇· 2〇克）的Et〇H (55 毫升）漿液在1大氣壓的H2 (氣球）下攪拌2 · 5天，然 ί戔經由一塞里特®墊加以過濾。將所產生的溶液在減壓下進 行濃縮以產生4 一（3 —（N —甲基氨基甲醯）—4 一甲 氧基苯氧基）苯胺，此爲一種蒼白色固體（〇 . 68克， 96%) ：TLC(〇-l% E t a N / 9 9 * 9 % E t 0 A c ) R f 〇·36。Step 4. 4—(3-N-Methylaminoglycol)-1-4 Methoxy Economics Intellectual Property Office Staff Consumer Cooperative Printed Phenoxy) Aniline: Will contain 4 (3 - (N-methyl) Aminoguanidine)- 4-methoxyphenoxy)-1 mononitrobenzene (0 · 78 g, 2 · 60 mmol) and 10% Pd/C (〇 2 g) EtEH (55 ml) The slurry was stirred at 1 atmosphere of H2 (balloon) for 2 · 5 days, then filtered through a Celite® pad. The resulting solution was concentrated under reduced pressure to give 4-(3-(N-methylaminocarbazide)-4-methoxyphenoxy)phenylamine as a pale solid ( s. , 96%) : TLC (〇-l% E ta N / 9 9 * 9 % E t 0 A c ) R f 〇·36.

A 用於製備含ω -烷基酞醯亞胺之苯胺的一般方法 。5 —（ 4 一胺基苯氧基）一 2 —甲基異吲哚滿 —1，3 —二酮的合成法 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -49- ------Τ-----裝--------訂--------- (請先閱讀背面之注意事項再填寫本頁) 1269791 Δ7 Ά/ Β7 經濟部智慧財產局員工消費合作社印製 五、發明說明（47A General method for the preparation of aniline containing ω-alkyl quinone imine. Synthesis of 5-(4-aminophenoxy)-2-methylisoindan-1,3-dione This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) - 49- ------Τ-----装--------Book--------- (Please read the notes on the back and fill out this page) 1269791 Δ7 Ά/ Β7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description (47

(4 —硝基苯氧基）一 步驟 甲基異吲哚滿 一1 ，3-二酮的合成 將含有5 -（ 4 一硝基苯氧基）-吲哚滿—1 ，3 二酮（A3步驟2 ; 1 · 0克，3 · 52毫莫耳）和 NaH(〇· 13 克，5 · 27 毫莫耳）的 DMF (15 毫升）漿液在室溫下攪拌1小時，然後以甲基碘（0 · 3 毫升，4 · 5 7毫莫耳）處理之。在室溫下將所產生的混 合物攪拌一整夜，然後將之冷卻至 °C，再以水（1 0毫 升）處理之。收集所產生的固體並在減壓下乾燥之以產生 5 (4 一硝基苯氧基）一 2 —甲基異吲哚滿一 1 ，3 二酮，此爲一種亮黃色固體（0 · 87克，83%) TLC (35% Et〇Ac/65% 己烷） R f 〇· 6 1 。(4-Nitrophenoxy) one-step synthesis of methyl isoindole-1,3-dione will contain 5-(4-nitrophenoxy)-indan-1,3dione ( A3 step 2; 1 · 0 g, 3 · 52 mM) and NaH (〇 · 13 g, 5 · 27 mmol) of DMF (15 ml) slurry were stirred at room temperature for 1 hour, then with methyl Iodine (0 · 3 ml, 4 · 5 7 mmol) was treated. The resulting mixture was stirred overnight at room temperature, then cooled to ° C and treated with water (10 mL). The resulting solid was collected and dried under reduced pressure to give 5 (4-nitrophenoxy)-2-methylisoindan-1,3dione as a bright yellow solid (0. Gram, 83%) TLC (35% Et〇Ac/65% hexane) R f 〇· 6 1 .

-------------衣--------訂--------- (請先閱讀背面之注意事項再填寫本頁) 步驟 (4 一胺基苯氧基）一 2 —甲基異吲哚滿 1 ，3 將含硝基苯氧基一 2 -甲基異吲哚滿一 1 ，3 —二酮 (〇·87克，2·78毫莫耳）和10%Pd/C ( 〇-10克）的-6〇11漿液在1大氣壓之112(氣球）下 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -50- A7 1269791 B7____ 五、發明說明（48 ) . 攪拌一整晚。將所產生之混合物經由塞里特®墊加以過濾並 在減壓下加以濃縮。將所產生之黃色固體溶於E t 0 A c (3毫升）中並將之通過S ι〇2 (60% E t 0 A c / 4 0 %己烷）管塞加以過濾以產生5 -（ 4 一胺基苯氧基 )一 2 —甲基異吲哚滿一 1 ，3 —二酮，此爲一種黃色固 體（0·67 克，86%) :TLC(40%------------- Clothing -------- set --------- (Please read the note on the back and then fill out this page) Step (4 Amine Phenoxy group) 2-methylisoindole 1, 3 will contain nitrophenoxy-2-methylisoindan-1,3-dione (〇·87 g, 2.78 m Moer) and 10% Pd/C (〇-10g) -6〇11 slurry at 1 atmosphere of 112 (balloon) This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) - 50- A7 1269791 B7____ V. INSTRUCTIONS (48) . Stir overnight. The resulting mixture was filtered through a Celite® pad and concentrated under reduced pressure. The resulting yellow solid was dissolved in EtOAc (3 mL) and filtered thru EtOAc (EtOAc: EtOAc (EtOAc) 4-monoaminophenoxy)-2-methylisoindan-1,3-dione, a yellow solid (0·67 g, 86%): TLC (40%)

Et〇Ac/6〇％己烷）Rf 0·27。 A 1 0 · 經由將ω -烷氧基羰芳基先驅物質與胺進行反 應來合成ω -氨基甲醯芳基苯胺類的一般方法 。4 — (2 — (Ν — (2 —嗎琳一4 —基乙基 )氨基甲醯）吡陡氧基）苯胺的合成法 〇Et〇Ac/6〇% hexane) Rf 0·27. A 1 0 · A general method for synthesizing ω-carbamoyl anilides by reacting an ω-alkoxycarbonylaryl precursor with an amine. 4 — (2 — (Ν — (2 — morphine-4-ylethyl) carbam) pyridoxoxy) aniline synthesis 〇

步驟1 · 4 —氯基一 2— (Ν— (2 —嗎—4 —基乙基 )氨基甲醯）吡啶的合成 將4 — ( 2 -（胺乙基）嗎啉（2 · 5 5毫升， 1 9 · 4毫莫耳）一滴滴地加入含有4 —氯吡啶一 2 -羧 酸甲酯氫氯酸鹽（方法A 2，步驟2 ; 1 · 0 1克， 4· 86毫莫耳）的THF (20毫升）溶液中，並在回 流溫度下將所產生的溶液加熱2 0小時，將之冷卻至室溫 後，以水（50毫升）處理之。以Et〇Ac (50毫升 )萃取所產生的混合物。將有機層加以乾燥（M g S〇4 ) ------1--------I----訂—------- (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -51 - 1269791 Α7 Β7 五、發明說明（49 ) (請先閱讀背面之注意事項再填寫本頁) 並在減壓下進行濃縮以產生4一氯基一2-（N-（2-嗎啉一 4 一基乙基）氨基甲醯）吡啶，此爲一種黃色油（ 1·25 克，95%):TLC(1〇％ Μ e Ο Η / 9 0% Ε t Ο A c ) R r 〇·5〇。 〇Step 1 · 4 - Synthesis of chloro - 2 - ( Ν - (2 - — - 4 - ylethyl) carbamoyl pyridine) 4 - ( 2 -(Aminoethyl)morpholine (2 · 5 5 ml , 1 9 · 4 mM) Add methyl 4-chloropyridin-2-carboxylate hydrochloride (Method A 2, Step 2; 1 · 0 1 g, 4. 86 mmol) The solution was heated in THF (20 mL) EtOAc (EtOAc)EtOAc. The resulting mixture is dried (M g S〇4 ) ------1--------I------------- (Read first Note on the back page of this page) Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed This paper scale applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) -51 - 1269791 Α7 Β7 V. Invention Description (49 (Please read the notes on the back and fill out this page) and concentrate under reduced pressure to give 4-chloro- 2-(N-(2-morpholino-4-ylethyl)carbamidine)pyridine This is a yellow oil (1·25) , 95%): TLC (1〇% Μ e Ο Η / 9 0% Ε t Ο A c) R r · 5〇 billion billion.

步驟2 . 4— (2 —（Ν —（2 —嗎啉一 4 一基乙基） 氨基甲醯）吡啶氧基）苯胺的合成 將含有4 —胺基苯酚（0 · 49克，4 · 52毫莫耳 )和特一丁氧化鉀（〇 ..5 3克，4 · 75毫莫耳）的 D M F ( 8毫升）溶液在室溫下攪拌2小時，然後接著以 4 —氯基—2 — (Ν — (2 —嗎啉一4 一基乙基）氨基甲 醯）吼啶（1 · 22克，4 · 52毫莫耳）和K2C〇3 ( 經濟部智慧財產局員工消費合作社印製Step 2. 4 - (2 - (Ν - (2 - morpholine - 4 - ylethyl) carbamate) pyridyloxy) aniline will contain 4-aminophenol (0 · 49 g, 4 · 52 Mol) and a solution of potassium monobutoxide (〇.. 5 3 g, 4 · 75 mmol) in DMF (8 ml) were stirred at room temperature for 2 hours, then followed by 4-chloro- 2 - (Ν — (2 —morpholine-4-ylethyl)carbamidine) acridine (1 · 22 g, 4 · 52 mmol) and K2C〇3 (Printed by the Ministry of Economic Affairs, Intellectual Property Office, Staff Cooperatives)

〇，3 1克，2 · 2 6毫莫耳）處理之。將所產生的混合 物在7 5 °C下加熱一整晚，將之冷卻至室溫後，再於 E t 0 A c (25毫升）和飽和的NaCl溶液（25毫 升）之間進行分離。以E t〇A c ( 2 5毫升）將水溶液 層進行反萃取。以飽和的N a C 1溶液（3 X 2 5毫升） 淸洗合倂的有機層並於減壓下進行濃縮。以管柱層析法將 所產生的棕色固體加以純化（5 8克；梯度是從1 〇 〇 % £1〇八（：至2 5% MeOH/75% EtOAc )以產生4 — (2 — (N — (2 —嗎琳一 4 —基乙基）氣 基甲醯）吡啶氧基）苯胺（1·〇克，65%) · τ L C 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -52- 1269791 A7 B7 經濟部智慧財產局員工消費合作社印製 五、發明說明（5(3) (10% M e Ο Η R r 〇 · 3 2 。 % E t 0 A c〇, 3 1 gram, 2 · 2 6 millimoles). The resulting mixture was heated at 75 ° C overnight, cooled to room temperature and then separated between Et.sub.0 A (25 mL) and saturated NaCI (25 mL). The aqueous layer was back extracted with E t 〇 A c (25 ml). The combined organic layer was washed with a saturated NaCI solution (3×2 5 mL) and concentrated under reduced pressure. The resulting brown solid was purified by column chromatography (5 8 g; gradient from 1 〇〇% £1 〇8 (: to 2 5% MeOH/75% EtOAc) to yield 4 - (2 - ( N — (2 —Methylene 4-ethylidene) gas methyl hydrazide) pyridyloxy) aniline (1·〇克, 65%) · τ LC This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -52- 1269791 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 5, Invention Description (5(3) (10% M e Ο Η R r 〇 · 3 2 . % E t 0 A c

A 用於將硝基芳香烴類還原成芳基胺類的一般方 法。4 一（3 -羧基苯氧基）苯胺的合成A general method for the reduction of nitroaromatic hydrocarbons to arylamines. Synthesis of 4-(3-carboxyphenoxy)aniline

將含4 一（ 3 -羧基苯氧基）一 1 一硝基苯（ 5 · 38克，20 · 7毫莫耳）和1〇％ Pd/C ( 〇 · 50克）的Me〇H (120毫升）漿液在H2大氣壓 (氣球）下攪拌2天。將所產生的混合物經由一塞里特@墊 加以過濾再於減壓下進行濃縮以產生4 -（ 3 -羧基苯氧 基）苯胺，此爲一種棕色固體（2· 26克，48%): T L C (10% M e 0 Η / 9 0 % C Η 2 C 1 2 ) R f 0 · 4 4 (劃線）。 A 1 2 · 用於合成含異吲哚滿酮之苯胺的一般方法。 4 一（ 1 一酮基異吲哚滿一 5 —基氧基）苯胺 的合成Me〇H (120) containing 4-(3-carboxyphenoxy)-l-nitrobenzene (5 · 38 g, 20 · 7 mmol) and 1〇% Pd/C (〇·50 g) The milliliter slurry was stirred under H2 atmospheric pressure (balloon) for 2 days. The resulting mixture was filtered through a Celite @ pad and concentrated under reduced pressure to give 4-(3-carboxyphenoxy)aniline as a brown solid (2·26 g, 48%): TLC (10% M e 0 Η / 90% C Η 2 C 1 2 ) R f 0 · 4 4 (line). A 1 2 · General method for the synthesis of aniline containing isoindanone. Synthesis of 4-(1-ketoisoisoindol-5-yloxy)aniline

------；--------------訂--------- (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -53- 1269791 A7 ___ B7 五、發明說明（51) , 步驟1 · 5 -羥基異吲哚一 1 —酮的合成 將鋅粉（4 7 · 6克，7 2 9毫莫耳）一部分一部分 地慢慢加入含5 -羥基酞醯亞胺（1 9 · 8克，1 2 1毫 莫耳）的A c〇Η ( 5 0 0毫升）溶液中，然後，將混合 物在回流溫度下加熱4 0分鐘，趁熱過濾之，並在減壓下 加以濃縮。依相同規模重覆進行反應並以管柱層析法將合 倂的油性剩餘物加以純化（1 · 1公斤S 1〇2 ;梯度從 6 0 % Et〇Ac/4〇％ 己烷至 25% M e Ο Η / 7 5 % E t〇A c )以產生5 —羥基異吲哚滿一1 一酮 (3·77 克·） ：TLC(l〇〇％ Et〇Ac)Rf Ο · 1 7 ； Η P L C ES— MS m / z 15 0(( M + H ) + )。 (請先閱讀背面之注意事項再填寫本頁) • ·ϋ n In n n _1« n 訂----- 步驟2 · 4 — ( 1 —異吲哚酮—5 —基氧基） 基苯的合成 硝 SI,------;--------------Book--------- (Please read the notes on the back and fill out this page) This paper size applies to China Standard (CNS) A4 size (210 X 297 mm) -53- 1269791 A7 ___ B7 V. Description of invention (51), Step 1 · Synthesis of 5-hydroxyisoindole-1-one. Zinc powder (4 7 · 6 g, 7 2 9 mmoles) A portion of the solution of A c〇Η (500 ml) containing 5-hydroxy quinhomine (1 9 · 8 g, 1 2 1 mmol) was slowly added in part. Then, the mixture was heated at reflux temperature for 40 minutes, filtered while hot, and concentrated under reduced pressure. The reaction was repeated on the same scale and the oily residue of the combined hydrazine was purified by column chromatography (1 · 1 kg S 1〇2; gradient from 60% Et〇Ac/4〇% hexane to 25%) M e Ο Η / 7 5 % E t〇A c ) to give 5-hydroxyisoindan-1-one (3·77 g·) : TLC (l〇〇% Et〇Ac)Rf Ο · 1 7 ; Η PLC ES - MS m / z 15 0 (( M + H ) + ). (Please read the notes on the back and then fill out this page) • · In n In nn _1« n Order----- Step 2 · 4 — ( 1 —Isterone-5-yloxy) Benzene Synthetic nitrate SI,

在0 °C下，將5 -羥基異吲哚一 1 —酮（2 · 0克， 經濟部智慧財產局員工消費合作社印製 1 3 · 4毫莫耳）一部分一部分地加入含NaH ( 〇· 3 9克，1 6 . · 1毫莫耳）的D M F漿液中。將所產 生的漿液加溫至室溫並攪拌4 5分鐘，然後，加入4 -氟 基一 1 一硝基苯，再將混合物在7 0 °C下加熱3小時。將 混合物冷卻至0 °C並以水一滴滴地處理之直至形成沈澱物 。收集所產生之固體以產生4 一（ 1 一異吲哚酮一 5 —基 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -54- 1269791 Α7 —___ Β7 經濟部智慧財產局員工消費合作社印製 五、發明說明（52 ) · 氧基）一 1 一硝基苯，此爲一種暗黃色固體（3 · 23克 ’89%) ： T L C (10 0% E t 0 A c ) R f 0 · 3 5。At 0 °C, 5-hydroxyisoindole-1-ketone (2 · 0 g, printed by the Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative 1 3 · 4 mmol) was partially added to NaH-containing (〇· 3 9 grams, 1 6 . · 1 millimolar) in DMF slurry. The resulting slurry was warmed to room temperature and stirred for 45 minutes, then 4-fluoromononitrobenzene was added, and the mixture was heated at 70 ° C for 3 hours. The mixture was cooled to 0 ° C and treated dropwise with water until a precipitate formed. Collect the solids produced to produce 4 (1 -isoxanthone-5 - basic paper scale applicable to China National Standard (CNS) A4 specification (210 X 297 mm) -54 - 1269791 Α7 —___ Β7 Ministry of Economics intellectual property Bureau employee consumption cooperative printing 5, invention description (52) · oxy) 1-nitrobenzene, this is a dark yellow solid (3 · 23 g '89%): TLC (10 0% E t 0 A c ) R f 0 · 3 5.

步驟3 · 4 —（ 1 一酮基異吲哚滿一 5 -基氧基）苯胺 的合成 在Η 2大氣壓（氣球）下，將含4 — ( 1 一異问丨D朵滿一 5 -基氧基）—1 一硝基苯（2 · 克，7 · 8毫莫耳 )和1〇％ Pd/C (0 · 2〇克）的Et〇H(5〇 毫升）漿液攪拌4小時，然後將之經由塞里特@墊過濾、t ° 在減壓下將濾液加以濃縮以產生4 -（ 1 -酮基異啤晚滿 一5—基氧基）苯胺，此爲一種暗黃色固體：TLC( 10 0% E t 0 A c ) R f 〇·15。 A 1 3 . 經由經Ε D C I促成之醯胺形成作用，再接著 進行硝基芳香烴的還原作用來合成ω -氨基甲 醯苯胺類的一般方法 4 一 （ 3 — Ν —甲氧氨基甲醯苯氧基）苯胺的 合成法 ο2νStep 3 · 4 —( 1 -One ketoisoindan-5-yloxy)aniline is synthesized at 大 2 atm (balloon) and will contain 4 — ( 1 异 丨 朵 D full 5 - base Oxy) 1-nitrobenzene (2 · g, 7 · 8 mmol) and 1% Pd / C (0 · 2 g) of Et〇H (5 ml) slurry was stirred for 4 hours, then This was filtered through a Celite @ pad, and the filtrate was concentrated under reduced pressure to give 4 -(1 - keto-pyrene-pentanyl-5-yloxy)aniline as a dark yellow solid: TLC (10 0% E t 0 A c ) R f 〇·15. A 1 3 . General method for the synthesis of ω-carbamoylanilides via the formation of guanamine promoted by ruthenium DCI followed by reduction of nitroaromatic hydrocarbons 4 (3 - Ν-methoxyaminomethyl fluorene benzene Synthesis of oxy)aniline ο2ν

本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） (請先閱讀背面之注意事項再填寫本頁)This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back and fill out this page)

Mr — -55- 1269791 Α7 Β7 五、發明說明（53) * » 步驟1 . 4— (3 —乙氧鑛基苯氧基）—1 一硝基苯的 合成 將含有4 一氟基—1 一硝基苯（16毫升，150毫 莫耳），3 —羥基苯甲酸乙酯（25克，150毫莫耳） 和K2c〇3 (4 1克，3〇〇毫莫耳）之DMF (125 毫升）所構成的混合物在回流溫度下加熱一整晚，再將之 冷卻至室溫並以水（2 5 0毫升）處理之。以E t OA c (3 X 1 5 0毫升）來萃取所產生的混合物。以水（3 X 1 00毫升）和飽和的Na C 1溶液（2x 1 0Q毫升） 依序淸洗合倂的有機層，乾燥之（N a 2 S 0 4 )並在減壓 下濃縮之。以管柱層析法將剩餘物加以純化（1 〇 % Et〇Ac/90%己烷）以產生4 一（3 —乙氧羰基苯 氧基）一 1 一硝基苯，此爲一種油（3 8克）。 (請先閱讀背面之注意事項再填寫本頁) 〇Mr — -55- 1269791 Α7 Β7 V. Inventive Note (53) * » Step 1. 4—(3—Ethoxyphenoxyphenoxy)-1 The synthesis of mononitrobenzene will contain 4 fluoro--1 Nitrobenzene (16 ml, 150 mmol), ethyl 3-hydroxybenzoate (25 g, 150 mmol) and K2c〇3 (4 1 g, 3 mmol) DMF (125 ml) The resulting mixture was heated at reflux temperature overnight, then cooled to room temperature and treated with water (250 mL). The resulting mixture was extracted with E t OA c (3 X 150 ml). The combined organic layers were washed sequentially with water (3×10 mL) and sat. NaCI solution (2×1×········ The residue was purified by column chromatography (1 〇% Et〇Ac/90% hexane) to give 4-(3-ethoxycarbonylphenoxy)-l-nitrobenzene as an oil ( 3 8 grams). (Please read the notes on the back and fill out this page) 〇

經濟部智慧財產局員工消費合作社印製 步驟2· 4-（3-羧基苯氧基）一1一硝基苯的合成 將4 一（3 —乙氧羰基苯氧基）一 1 一硝基苯（ 5·14克，17·9毫莫耳）加入3:1 THF/水 溶液（7 5毫升）中，再將此混合物加以劇烈攪拌並加入 含Li〇H — H2〇（1 · 50克，35 . 8毫莫耳）的水 (3 6毫升）溶液中。將所產生的混合物在5 0 °C下加熱 一整晚，然後將之冷卻至室溫，並於減壓下濃縮之，再以 1 Μ H C 1溶液將ρ Η値調整成2。經由過濾法將所產 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -56- 1269791 Δ7 八/ Β7 經濟部智慧財產局員工消費合作社印制衣 五、發明說明（54) 生的亮黃色固體移除並以己烷淸洗之以產生4 一（ 3 -羧 基苯氧基）—1—硝基苯（4 · 40克，95%)。Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives, Printing Step 2, Synthesis of 4-(3-carboxyphenoxy)-mononitrobenzene, 4-(3-ethoxycarbonylphenoxy)-mononitrobenzene (5·14 g, 17·9 mmol) was added to a 3:1 THF/water solution (75 ml), and the mixture was stirred vigorously and added with Li〇H-H2〇 (1 · 50 g, 35 . 8 mM) in water (36 ml) solution. The resulting mixture was heated at 50 ° C overnight, then cooled to room temperature and concentrated under reduced pressure, and then ρ Η値 was adjusted to 2 with 1 Μ H C 1 solution. Apply the paper size to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) by filtration method -56-1269791 Δ7 八/ Β7 Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperative Printed Clothing V. Invention Description (54 The raw bright yellow solid was removed and washed with hexane to give 4-(3-carboxyphenoxy)-1-nitrobenzene (4.40 g, 95%).

NHMe 步驟3 4 一（ 3 — .（ N —甲基氨基甲醯）苯氧基） 1 -硝基苯的合成 將4 一（3 -羧基苯氧基）一 1 一硝基苯 7 2 克，14.4 毫莫耳），EDCI.HC1 (3·63 克 ，18· 6毫莫耳），Ν —甲基嗎啉（1·6毫升’ 14 · 5毫莫耳）和申胺（2 · 0Μ，於THF中；8毫 升，1 6毫莫耳）溶於C Η 2 C 1 2 ( 4 5毫升）中’並將 此混合物在室溫下攪拌3天，再於減壓下進行濃縮°卩夺乘iJ 餘物溶於E t〇Ac (50毫升）中並以1M HC 1溶 液（5 0毫升）萃取所產生的混合物。以E t 0 A c C 2 x 5 0毫升）反萃取水溶液層。以飽和N a C 1溶液（ 5 0毫升）淸洗合倂的有機層，乾燥（N a 2 S 0 4 )後再1 於減壓下進行濃縮以產生4 一（3 -（N -甲基氨基甲醯 )苯氧基）一 1 一硝基苯，此爲一種油（1 · 89克）°NHMe Step 3 4 Synthesis of a (3-(N-methylaminoformamidine)phenoxy)-1-nitrobenzene 4-(3-carboxyphenoxy)-l-nitrobenzene 7 2 g, 14.4 millimolar), EDCI.HC1 (3·63 g, 18·6 mmol), Ν-methylmorpholine (1.6 ml '14 · 5 mmol) and Shenamine (2 · 0 Μ, In THF; 8 ml, 16 mmol (1 ml) dissolved in C Η 2 C 1 2 (45 ml) and the mixture was stirred at room temperature for 3 days, then concentrated under reduced pressure. The residue obtained by iJ was dissolved in EtOAc (50 mL) and the mixture was extracted with 1M EtOAc (EtOAc). The aqueous layer was back extracted with E t 0 A c C 2 x 50 ml). The organic layer of the combined hydrazine was washed with a saturated NaCI solution (50 mL), dried (N a 2 S 0 4 ) and then concentrated under reduced pressure to give 4-(3-(N-methyl) Myrma) phenoxy)-mononitrobenzene, which is an oil (1 · 89 g) °

NHMe (請先閱讀背面之注意事項再填寫本頁) 訂---- 步驟4 4 一（ 3—（N —甲基氨基甲醯）苯氧基）苯 胺的合成 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -57- 經濟部智慧財產局員工消費合作社印製 1269791 A7 B7 五、發明說明（55) . 將含4 一（3 — (N —甲基氨基甲醯）苯氧基）一1 一硝基苯（1 · 89克，6 · 95毫莫耳）和5% Pd /C (0·24克）的EtOAc (20毫升）漿液在H2 大氣壓（氣球）下攪拌一整晚。將所產生的混合物經過塞 里特®墊加以過濾並在減壓下進行濃縮。經由管柱層析法（ 5 % M e 0 Η / 9 5 % C Η 2 C 1 2 )將剩餘物加以純 化。所產生的油會在真空下固化以產生4 一（ 3 —（ N — 甲基氨基甲醯）苯氧基）苯胺，此爲一種黃色固體（ 0·95 克，56%)。 A 1 4 · 經由E D C I所促成之醯胺形成作用，再接著. 進行硝基芳香烴的還原作用來合成ω -氨基甲 酿苯胺類的一般方法。4 — (3 — (5 —甲基 氨基甲醯）吡啶氧基）苯胺 〇NHMe (Please read the note on the back and fill out this page) Order---- Step 4 4 Synthesis of a (3-(N-methylaminocarbamidine)phenoxy)aniline This paper scale applies to Chinese national standards ( CNS)A4 Specification (210 X 297 mm) -57- Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 1269791 A7 B7 V. Description of Invention (55) . Will contain 4 (3 - (N-methylaminoformamidine) a slurry of phenoxy)-mononitrobenzene (1 · 89 g, 6 · 95 mmol) and 5% Pd / C (0.22 g) in EtOAc (20 mL) at H2 atmosphere (balloon) Stir all night. The resulting mixture was filtered through a pad of Celite® and concentrated under reduced pressure. The residue was purified by column chromatography (5 %M e 0 Η / 9 5 % C Η 2 C 1 2 ). The resulting oil was solidified under vacuum to give 4-(3-(N-methylaminomethylhydrazide)phenoxy)aniline as a yellow solid (0.95 g, 56%). A 1 4 · A general method for the synthesis of ω-aminoanilin by the action of decylamine promoted by E D C I followed by reduction of nitroaromatic hydrocarbons. 4 — (3 — (5-methylaminocarbamidine)pyridinyloxy)aniline 〇

步驟1 · 4 一（3 — (5 —甲氧羰基）吡啶氧基）一 1 -硝基苯的合成 將5 —羥基菸鹼酸甲酯（2 · 0克，13 · 1毫莫耳 )的DMF (10毫升）溶液加入含NaH (〇 · 63克 ，26 · 1毫莫耳）的DMF (20毫升）漿液中。將所 產生的混合物加入含4 一氟基硝基苯（1 · 4毫升， 13 · 1毫莫耳）的DMF (10毫升）溶液中並在7〇 ---------------------訂--------- (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -58- 1269791 A7 B7 五、發明說明（56)Step 1 · 4 Synthesis of a (3-(5-methoxycarbonyl)pyridinyloxy)-1-nitrobenzene methyl 5-hydroxynicotinate (2 · 0 g, 13 · 1 mmol) A solution of DMF (10 ml) was added to a solution of NaH (?·········· The resulting mixture was added to a solution of 4-fluorofluorobenzene (1.4 ml, 13 · 1 mmol) in DMF (10 mL) at 7 〇----------- ----------Book--------- (Please read the note on the back and fill out this page) This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 PCT) -58- 1269791 A7 B7 V. Description of invention (56)

I °c下’將所產生的混合物加熱一整晚，待冷卻至室溫後， 先以Me〇Η (5毫升），再以水（50毫升）處理之。 以E t〇A c ( 1 〇 〇毫升）萃取所產生的混合物。在減 壓下，將有機層進行濃縮。經由管柱層析法（3 〇 % E t〇A c / 7 0 %己烷）來純化剩餘物以產生4 一（ 3 —(5 —甲氧羰基）吡啶氧基）一1—硝基苯（〇 · 6〇 克）。 步驟2 · 4 —（3 —（5 —甲氧羰基）吡啶氧基）苯胺 的合成 在H2大氣壓（氣球）下，將含4 一（3 —（5 —甲氧 鑛基）吡陡氧基）—1 一硝基苯（〇 · 60克，2 . 20 毫莫耳）和 10% Pd/C^3Me〇H/Et〇Ac， 液攪拌7 2小時。將所產生的混合物加以過濾並將濾液在 減壓下加以濃縮。經由管柱層析法（梯度從1 〇 % Et〇Ac/90%己烷至30% EtOAc/70% 己烷至5 0 % E t〇A c / 5 0 %己烷）將剩餘物加以 純化以產生4一（ 3 -（ 5 —甲氧羰基）定氧基）苯胺 (〇· 28 克，6〇％) : 1 H NMR (CDC 13) 5 3.92(s，3H) ，6.71(d，2H)， 6·89(ά，2Η) ，7.73(d，lH)， 8-51(d，lH)，8，8 7 (d，lH)。 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） (請先閱讀背面之注意事項再填寫本頁) -嚓衣 訂i 經濟部智慧財產局員工消費合作社印製 -59- 1269791 A7 B7 五、發明說明（57)The resulting mixture was heated overnight at rt. After cooling to room temperature, it was treated with Me (5 mL) and then water (50 mL). The resulting mixture was extracted with E t 〇 A c (1 〇 〇 ml). The organic layer was concentrated under reduced pressure. The residue was purified by column chromatography (3 〇% E t 〇A c / 70% hexane) to give 4-(3-(5-methoxycarbonyl)pyridinyloxy)-1-nitrobenzene. (〇·6〇克). Step 2 · 4 -(3 -(5-Methoxycarbonyl)pyridinyloxy)aniline is synthesized under H2 atmospheric pressure (balloon), containing 4-(3-(5-methoxyarene)pyroxy) -1 mononitrobenzene (〇·60 g, 2. 20 mmol) and 10% Pd/C^3Me〇H/Et〇Ac, stirred for 72 hours. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (gradient from 1 〇% Et 〇Ac / 90% hexanes to 30% EtOAc / 70% hexanes to 50% EtOAc / 50% hexanes) To give 4-(3-(5-methoxycarbonyl) alkoxy)aniline (〇·28 g, 6〇%): 1 H NMR (CDC 13) 5 3.92 (s, 3H), 6.71 (d, 2H) ), 6·89 (ά, 2Η), 7.73 (d, lH), 8-51 (d, lH), 8, 8 7 (d, lH). This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) (please read the note on the back and fill out this page) - 嚓衣订 i Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing -59- 1269791 A7 B7 V. Description of invention (57)

A 經由親電子性硝化反應，再接著進行還原反應 來合成苯胺。4 一（3 -甲基氨磺醯苯氧基） 苯胺 B「一 ΥA is synthesized by electrophilic nitration followed by reduction to form aniline. 4 one (3 -methylsulfamophenoxy) aniline B "one Υ

NHMe 經濟部智慧財產局員工消費合作社印製 步驟1 · 將甲胺_ 0莫耳濃度，含於THF中；28毫升 ’ 5 6毫莫耳）在°(：下加入含3 -溴苯磺醯氯（2 · 5克 ，11 · 2毫莫耳）的THF (15毫升）中。將所產生 的溶液加溫至室溫並在室溫下攪拌一整夜。將所產生的混 合物在EtOAc(25毫升）和1M HC1溶液（ 25毫升）之間進行分離。以Et〇Ac (2x25毫升 )將水溶液相進行反萃取。將合倂的有機相依序以水（2 X 2 5毫升）和飽和的N a C 1溶液.（2 5毫升）淸洗之 ，乾燥（M g S〇4 )後，在減壓下加以濃縮以產生N —甲 基一 3 —溴基苯磺胺，此爲一種白色固體（2 · 8克’ 9 9%)。 步驟2NHMe Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Print Step 1 · Add methylamine _ 0 molar concentration in THF; 28 ml ' 5 6 mM) at ° (: add 3-bromobenzenesulfonate) Chlorine (2 · 5 g, 11 · 2 mmol) in THF (15 mL) EtOAc. Separation between 25 ml) and 1 M HCl solution (25 ml). The aqueous phase was back-extracted with Et 〇Ac (2 x 25 mL). The organic phase of the hydrazine was sequentially water (2 X 2 5 mL) and saturated. N a C 1 solution (25 ml) was washed, dried (M g S 〇 4 ), and concentrated under reduced pressure to give N-methyl- 3-bromobenzenesulfonamide as a white solid. (2 · 8 grams ' 9 9%). Step 2

N 甲基- 3 -溴基苯磺胺的合成法Synthesis of N-methyl-3-bromobenzenesulfonamide

〇〇

Q、々〇 S、NHMe 4_(3-（N-甲基氨磺醯）苯氧基）苯的 合成 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -60- ------1--------------訂--------- (請先閱讀背面之注意事項再填寫本頁)Synthesis of Q, 々〇S, NHMe 4_(3-(N-methylsulfamophene)phenoxy)benzene This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -60- - -----1--------------Book--------- (Please read the notes on the back and fill out this page)

步驟3 _ 4— (3— (Ν —甲基氨磺醯）苯氧基）一 1 經濟部智慧財產局員工消費合作社印製 1269791 A7 B7 五、發明說明（58) . 將N -甲基一 3 —溴基苯磺胺（2 · 5克，1 0毫莫 耳）加入含苯酚（1·9克，20毫莫耳），K2C〇3( 6 · 0克，40毫莫耳）和Cu I (4克，20毫莫耳） 的D M F ( 2 5毫升）漿液中，並將所產生的混合物在回 流溫度下攪拌一整晚，冷卻至室溫後，將之在E t〇A c (50毫升）和IN HC 1溶液（50毫升）中進行分 離。以E t〇A c ( 2 X 5 0毫升）來反萃取溶液層。將 合倂的有機層依序以水（2 X 5 0毫升）和飽和的 N a C 1溶液（2 5毫升）淸洗，乾燥（M g S〇4 )後， 在減壓下進行濃縮。經由管柱層析法將剩餘的油加以純化 (30% Et〇Ac/7〇％己烷）以產生4—(3— (N —甲基氨磺醯）苯氧基）苯（0·30克）。 〇2ν 一硝基苯的合成 在一10°C 下，將 NaN〇2 (〇 · 0 97 克， 1 · 14毫莫耳）於5分鐘內一部分一部分地加入含4 一 (3 -（N —甲基氨磺醯）苯氧基）苯（〇 · 30克， 1 · 14毫莫耳）的TFA (6毫升）溶液中。將所產生 的溶液在- 1 〇 °C下攪拌1小時，再將之加溫至室溫並在 減壓下加以濃縮。將剩餘物在E t 0 A c ( 1 0毫升）和 水（1 〇毫升）間進行分離。將有機相以水（1 〇毫升） 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） (請先閱讀背面之注意事項再填寫本頁) -n n ϋ n n an 一 口、 n n ·ϋ ·ϋ -61 - 1269791 A7 B7 經濟部智慧財產局員工消費合作社印製 五、發明說明（59) I 和飽和N a C 1溶液（1 〇毫升）依序加以淸洗，乾燥（ Mg S〇4)後，再於減壓下加以濃縮以產生4 一（ 3 -（ N —甲基氨磺醯）苯氧基）一1 一硝基苯（〇 · 20克） 。此物質可直接用於下一步驟而不需進一步純化。 h2nStep 3 _ 4—(3—(Ν-Methylsulfamoxene)phenoxy)-1 Economic Intelligence Bureau Intellectual Property Bureau Staff Consumer Cooperative Printed 1269791 A7 B7 V. Description of Invention (58) . N-Methyl One 3-Bromobenzenesulfonamide (2 · 5 g, 10 mmol) added with phenol (1.9 g, 20 mmol), K2C〇3 (6 · 0 g, 40 mmol) and Cu I (4 g, 20 mmol) in a DMF (25 ml) slurry, and the resulting mixture was stirred at reflux temperature overnight. After cooling to room temperature, it was taken at E t 〇 A c (50 Separate in milliliters and IN HC 1 solution (50 ml). The solution layer was back extracted with E t 〇 A c ( 2 X 50 ml). The combined organic layers were washed successively with water (2×150 mL) and sat. Na············ The remaining oil was purified by column chromatography (30% Et〇Ac / 7〇% hexane) to give 4-(3-(N-methylsulfamophene)phenoxy)benzene (0·30) Gram). Synthesis of 〇2ν-nitrobenzene At a temperature of 10 °C, NaN〇2 (〇·97 g, 1·14 mmol) was partially added to a portion containing 5 in 5 minutes (3 - (N - Methylammonium sulfonate) phenoxy)benzene (〇·30 g, 1 · 14 mmol) in TFA (6 mL). The resulting solution was stirred at -1 ° C for 1 hour, then warmed to room temperature and concentrated under reduced pressure. The residue was separated between E t 0 A c (10 mL) and water (1 mL). The organic phase is water (1 〇 ml). This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back and fill out this page) -nn ϋ nn an sip, nn ·ϋ ·ϋ -61 - 1269791 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed V. Inventive Note (59) I and saturated NaCl1 solution (1 ml) were washed and dried (Mg S After 〇4), it was concentrated under reduced pressure to give 4-(3-(N-methylsulfonium)phenoxy)-mononitrobenzene (20 g). This material was used directly in the next step without further purification. H2n

〇、、&lt;P Π Α ς NHMe u 步驟4· 4—(3一（N一甲基氨磺醯）苯氧基）苯胺 的合成 將含有4 — (3 — (N -甲基氨磺醯）苯氧基）—1 —硝基苯（〇· 30克）和10% Pd/C ( 0 · 030克）的E t〇Ac (20毫升）漿液在H2大氣 壓（氣球）下攪拌一整夜。將所產生的混合物經由塞里特® 墊加以過濾。將濾液在減壓下進行濃縮。將剩餘物經由管 柱層析法（3 0 % E t 0 A c / 7 0 %己烷）加以純化 以產生4 一（ 3 —（N —甲基氨磺醯）苯氧基）苯胺（ 〇〇,, &lt;P Π Α ς NHMe u Step 4· 4—(3-(N-Methylaminosulfonyl)phenoxy)aniline will contain 4 —(3 — (N-methylsulfamoxime) a slurry of phenoxy)-1-nitrobenzene (〇·30 g) and 10% Pd/C (0·030 g) in E t〇Ac (20 ml) was stirred overnight under H 2 atmosphere (balloon) . The resulting mixture was filtered through a Celite® pad. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (30% E t 0 A c / 70% hexane) to yield 4-(3-(N-methylsulfonium)phenoxy)aniline ( 〇

A (請先閱讀背面之.注意事項再填寫本頁) 7〇克） ω —酮類的改良法。4 — (4 一（1— (N -甲氧基）亞胺基乙基）苯氧基）苯胺HC1鹽 HCI Η〇ΝA (please read the back of the book first. Note this page and then fill out this page) 7 gram) ω - improved method of ketones. 4 — (4-(1-(N-methoxy)iminoethyl)phenoxy)aniline HC1 salt HCI Η〇Ν

將鄰一甲基羥基胺HC 1鹽（0 · 65克，7 · 78 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 62- 1269791 Α7 Β7 經濟部智慧財產局員工消費合作社印制π 五、發明說明（60) 毫莫耳，2 · 0當量）加入含有（4 —乙醯苯氧基） 苯胺H C 1鹽（依類似於方法a 1 3 ，步驟4的方式來製 備；1 · 〇克，3 · 8 9毫莫耳）的漿液中（此漿液是經 由將目丨j述化合物加入由E t 〇 Η ( 1 Q毫升）和D比D定（ 1 · 0毫升）所組成之混合物中來製備的）。將所產生之 溶液在回流溫度下加熱3 0分鐘，冷卻至室溫後，再於減 壓下加以濃縮。以水（1 〇毫升）將所產生之固體加以硏 磨並以水淸洗之以產生4 一（4 一（1— (Ν —甲氧基） 亞胺基乙基）苯氧基苯胺HC 1鹽，此爲一種黃色固體（ 〇-85克）：丁乙（：（5〇％ Et〇Ac/50% 石 油醚）0*78；^ NMR (DMSO-de) δ 3.90(s，3H)，5.70(s，3H); HPLC— MS m/z 2 5 7 ( ( M + H ) + )。 A17 · Ν — (ω —甲矽烷氧基烷基）醯胺類。4 一（ 4 一（2 —（N — (2 —二異丙基甲石夕院氧基 )乙基氨基甲醯）吡啶氧基苯胺Will o-methylhydroxylamine HC 1 salt (0 · 65 g, 7 · 78 paper scale applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 62- 1269791 Α7 Β7 Ministry of Economic Affairs Intellectual Property Bureau staff consumption Co-operative printing π V. Description of the invention (60) Millol, 2 · 0 equivalent) Addition of (4-ethenyloxy) aniline HC 1 salt (prepared in a manner similar to method a 1 3 , step 4) ;1 · 〇克, 3 · 8 9 mM) in the slurry (this slurry is added by adding the compound of the target to E t 〇Η (1 Q ml) and D to D (1 · 0 ml) Prepared in the mixture of the components). The resulting solution was heated at reflux temperature for 30 minutes, cooled to room temperature, and concentrated under reduced pressure. The resulting solid was honed with water (1 ml) and rinsed with water to give 4-(4-(1-methoxy-methoxy)iminoethyl)phenoxyaniline HC 1 Salt, this is a yellow solid (〇-85 g): butyl b (: (5〇% Et〇Ac / 50% petroleum ether) 0*78; ^ NMR (DMSO-de) δ 3.90 (s, 3H), 5.70(s,3H); HPLC-MS m/z 2 5 7 ( ( M + H ) + ). A17 · Ν — (ω-Methoxyalkyloxyalkyl) decylamine. 4 (4 (2) —(N — (2 —Diisopropylmethyl sylvestreoxy)ethylaminocarbamidine)pyridinylaniline

步驟1 · 4 —氯基一 N— (2 -三異丙基甲矽烷氧基） 乙基吡啶一 2 -羧醯胺 將三異丙基甲矽烷基氯（1 · 59克，8 · 2毫莫耳 ，1 · 1當量）和咪唑（1 · 12克’ 16 · 4毫莫耳， ---------------------訂--------- (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -63- 1269791 A7 B7 五、發明說明（61 ) &gt; 2 · 2當量）加入含有4 —氯基—N —（2 —羥乙基）吡 啶一 2 -羧醯胺（依類似於方法A 2，步驟3 b的方式來 製備；1 · 5克，7 · 4毫莫耳）的無水DMF (7毫升 )溶液中。在室溫下，將所產生的黃色溶液攪拌3小時， 然後，在減壓下加以濃縮。將剩餘物在水（1 〇毫升）和 E t〇A c ( 1 〇毫升之間進行分離。以e t〇A c ( 3 x 1 〇毫升）萃取水溶液層。將合倂的有機相加以乾燥 (Mg SO 4)並在減壓下進行濃縮以產生4 一氯基一 2 -(N —（ 2 —三異丙基甲矽烷氧基）乙基）吡啶羧醯胺， 此爲一種橘色油（2 . 3 2克，8 8 % )。此物質可直接 用於下一步驟中而不必進一步純化。 (請先閱讀背面之注意事項再填寫本頁)Step 1 · 4 -Chloro-N-(2-triisopropylformamoxy)ethylpyridin-2-carboxycarboxamide Triisopropylcarbamimidyl chloride (1 · 59 g, 8.2 mmol Mohr, 1 · 1 equivalent) and imidazole (1 · 12 g ' 16 · 4 mmol, --------------------- order----- ---- (Please read the note on the back and fill out this page.) This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -63- 1269791 A7 B7 V. Invention description (61 ) &gt ; 2 · 2 equivalents) is added to contain 4-chloro-N-(2-hydroxyethyl)pyridine-2-carboxycarboxamide (prepared in a manner similar to Method A 2, Step 3 b; 1-5 g, 7 · 4 mmoles in anhydrous DMF (7 mL). The resulting yellow solution was stirred at room temperature for 3 hours and then concentrated under reduced pressure. The residue was separated between water (1 mL) and E t〇A c (1 mL). The aqueous layer was extracted with et〇A c (3 x 1 mL). The combined organic phases were dried ( Mg SO 4) and concentrated under reduced pressure to give 4-chloro-di-(N-(2-tris-isopropylamyloxy)ethyl)pyridinecarboxamide as an orange oil ( 2 . 2 2 g, 8 8 %). This material can be used directly in the next step without further purification. (Please read the notes on the back and fill out this page)

經濟部智慧財產局員工消費合作社印製 烷氧基）乙基氨基甲醯）吡啶氧基苯胺 將特一丁氧化鉀（〇 . 67克，6 . 0毫莫耳， 1 · 0當量）一部分一部分地加入含4 一羥基苯胺（ 〇· 70克’ 6 · 〇毫莫耳）的無水DMF (8毫升）溶 液中以引起放熱作用。當此混合物已冷卻至室溫後，將含 4 一氯基一 2 —（N —（2 —二異丙基甲砂院氧基）乙基 )吡啶羧醯胺（2 · 3 2克，6毫莫耳，1當量）的 DMF ( 4毫升）溶液加入其中，再接著加入K2C〇3 ( 〇·42克，3·0毫莫耳，〇·5當量）。將所產生的 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） A7 1269791 ____B7_ 五、發明說明（62 ) ’ 邱分 混合物在8 0 °C下加熱一整晚。然後，再加入額外一 口1 的特—丁氧化鉀（◦ · 34克，3毫莫耳，0 · 5當量） 並將混合物在8 0 °C下再加熱4小時。以冰/水浴將混合 物冷卻至0 °C，然後，將水（約1毫升）慢慢地，一滴滴 地加入其中。以E t〇A c (以1 〇毫升）萃取有機層。 將合倂的有機層以飽和的N a C 1溶液（2 0毫升）加以 淸洗”乾燥（M g S〇4 )後再於減壓下進行濃縮。經由管 柱層析法將棕色油性剩餘物加以純化（S i 0 2 ; 3 〇 %Ministry of Economic Affairs, Intellectual Property Office, Staff and Consumers Cooperative, printing alkoxy)ethylaminopyridinium)pyridyloxyaniline, part of potassium monobutoxide (〇. 67 g, 6.0 mmol, 1 · 0 equivalent) A solution of 4-hydroxyaniline (〇·70 g of '6·〇 mmol) in anhydrous DMF (8 ml) was added to cause an exotherm. When the mixture has cooled to room temperature, it will contain 4-chloro- 2-(N-(2-diisopropylcarbamate)ethyl)pyridinecarboxamide (2 · 3 2 g, 6 Millol, 1 eq. of a solution of DMF (4 mL) was added, followed by K2C 〇3 ( 〇·42 g, 3.0 mM, 〇·5 eq.). The paper size produced will be applied to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). A7 1269791 ____B7_ V. Inventive Note (62) ’ The mixture is heated at 80 ° C for one night. Then, an additional 1 part of potassium tert-butoxide (◦ · 34 g, 3 mmol, 0 · 5 equivalents) was added and the mixture was heated at 80 ° C for an additional 4 hours. The mixture was cooled to 0 ° C in an ice/water bath, and then water (about 1 ml) was slowly added thereto dropwise. The organic layer was extracted with E t 〇 A c (in 1 mL). The combined organic layer was washed with a saturated NaCI1 solution (20 mL), dried (M.sup.sup.4) and then concentrated under reduced pressure. Purified (S i 0 2 ; 3 〇 %

Et〇Ac/70%石油醚）以產生4 一 （4 一 （2 —( N -（ 2 —三異丙基甲矽烷氧基）吡啶氧基苯胺，此爲— 種透明、淡棕色油（0 · 9 9克，3 8 % )。 A 1 8 · 經2 —甲基吡啶類的氧化作用來合成2 — D比B定 羧酸酯4 一（5 — (2 —甲氧鑛基）d比η定氧基 )苯胺的合成法 (請先閱讀背面之注意事項再填寫本頁) -ϋ n n n n n n 一 uv I HI ·ϋ ·ϋ ·ϋEt〇Ac/70% petroleum ether) to give 4 (4-(N-(2-isopropylidene)-pyridyloxy)pyridanilide, which is a transparent, light brown oil (0) · 9 9g, 3 8 % ). A 1 8 · Synthesis of 2-D to B-carboxylic acid ester 4 by the oxidation of 2-methylpyridines (5 - (2-methoxylated) d ratio Synthesis of η oxy) aniline (please read the notes on the back and fill out this page) -ϋ nnnnnn a uv I HI ·ϋ ·ϋ ·ϋ

經濟部智慧財產局員工消費合作社印製 步驟1 · 4 一（ 5 -（ 2 —甲基）吡啶氧基）—1 —硝 基苯 將由5 —羥基一 2 —甲基吡啶（1 0 · 〇克， 91 · 6毫莫耳），1 一氟基—4 —硝基苯（9 · 8毫升 ，91. 6毫莫耳，1· ◦當量），K2C〇3(25克， 183毫莫耳，2·0當量）溶於DMF (1〇〇毫升） 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） :的_ 一 --- A7 1269791 ____B7_____ 五、發明說明（63 ) , 中所組成的混合物在回流下加熱一整晚。將所產生的混合 物冷卻至室溫，以水（2 0 〇毫升）處理之再以 E t〇A c ( 3 X 1 〇 〇毫升）萃取之。將合倂的有機層 依序以水（2 X 1 〇 〇毫升）和飽和的N a C 1溶液（ 1〇0毫升）淸洗之，乾燥（M g S〇4 )後再於減壓下加 以濃縮以產生4 — (5 —（2 -甲基）吼陡氧基）—1 一 硝基苯，此爲一種棕色固體（12. 3克）。Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives, Printing Step 1 · 4 -( 5 -( 2 -methyl)pyridyloxy)-1 -nitrobenzene will be 5-hydroxy-2-methylpyridine (1 0 · gram , 91 · 6 mM), 1 fluoro-4- 4-nitrobenzene (9 · 8 ml, 91.6 mm, 1 ◦ equivalent), K2C 〇 3 (25 g, 183 mmol, 2·0 eq.) dissolved in DMF (1 〇〇 ml) This paper scale is applicable to China National Standard (CNS) A4 specification (210 X 297 mm): _ I--- A7 1269791 ____B7_____ V. Description of invention (63) The mixture consisting of the mixture was heated under reflux overnight. The resulting mixture was cooled to room temperature, treated with water (20 mL) and then extracted with Et.sub. The organic layer of the combined organic layer was washed with water (2 X 1 〇〇 ml) and saturated NaCl1 solution (1 〇 0 ml), dried (M g S〇4) and then decompressed under reduced pressure. Concentrated to give 4-(5-(2-methyl)oximeoxy)-l-nitrobenzene as a brown solid (12.3 g).

〇 步驟2 · 4 — (5 — (2 —甲氧羰基）吡啶氧基）—1 -硝基苯的合成 將由4 — (5 — (2 —甲基）卩比卩疋氧基）一1—硝基 苯（1 · 70克，7 · 39毫莫耳）和二氧化硒（ 2 · 50克，22 · 2毫莫耳，3 · 0當量）溶於吡啶（ 2〇毫升）中所組成的混合物在回流溫度下加熱5小時， 然後再將之冷卻至室溫。將所產生的漿液進行過濾然後在 減壓下加以濃縮。將剩餘物溶於M e Ο Η ( 1 0 0毫升） 中。以濃H C 1溶液（7毫升）來處理該溶液並在回流溫 度下加熱3小時，冷卻至室溫後再於減壓下進行濃縮。將 剩餘物在E t〇A c ( 5 0毫升）和1 N N a〇Η溶液 (50毫升）之間進行分離。以Et〇Ac (2X50毫 升）萃取水溶液層並在將合倂的有機層依序以水（ 2 X 5 0毫升）和飽和的N a C 1溶液（5 0毫升）淸洗 ------1-------------訂--------- (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印制衣 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -66- 1269791 A7 B7 經濟部智慧財產局員工消費合作社印製 五、發明說明（64 ) » 後’乾燥之（M g S〇4 )，再於減壓下進行濃縮。經由管 柱層析法將剩餘物加以純化（S 1〇2 ; 5 〇 % E t〇Ac/50%己烷）以產生4 — (5— （2 —甲氧 羰基）吡啶氧基）一 1—硝基苯（〇 · 7〇克）。〇Step 2 · 4 — (5 — (2 -Methoxycarbonyl)pyridinyloxy)-1-nitrobenzene will be synthesized from 4 — (5 — (2-methyl) fluorenyl) Nitrobenzene (1 · 70 g, 7 · 39 mmol) and selenium dioxide ( 2 · 50 g, 22 · 2 mmol, 3 · 0 equivalent) dissolved in pyridine (2 mL) The mixture was heated at reflux temperature for 5 hours and then cooled to room temperature. The resulting slurry was filtered and concentrated under reduced pressure. The residue was dissolved in Me Ο Η (100 ml). The solution was treated with a concentrated HCI solution (7 mL) and heated at reflux temperature for 3 hr, cooled to room temperature and then concentrated under reduced pressure. The residue was separated between Et, EtOAc (50 mL) and 1N EtOAc (50 mL). The aqueous layer was extracted with Et〇Ac (2×50 mL) and the combined organic layers were washed sequentially with water (2×50 mL) and saturated NaCI1 solution (50 mL)---- -1-------------Book--------- (Please read the notes on the back and fill out this page) Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Cooperatives Paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -66- 1269791 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description (64) » After 'drying' (M g S 〇 4 ), and then concentrated under reduced pressure. The residue was purified by column chromatography (S 1 〇 2; 5 〇 % E t 〇 Ac / 50% hexane) to give 4-(5-(2-methoxycarbonyl)pyridinoxy)-1 - Nitrobenzene (〇·7〇g).

〇Me 步驟3 · 4 -（5— (2 —甲氧鑛基）d比π定氧基）苯胺 的合成 將4 一 （ 5 — （ 2 —甲氧羰基）吼啶氧基）一 ]_ 一硝 基苯（〇.5〇克）和1〇％ Pd/C (〇 · 50克） 溶於由E t〇A c ( 2 0毫升）和Me OH ( 5毫升）所 組成的混合物中，並將此漿液置於Η 2大氣壓（氣球）下一 整晚。將所產生的混合物通過塞里特®墊進行過濾並將濾液 在減壓下加以濃縮。經由管柱層析法將剩餘物加以純化（ S i 0 2 » 7 0 % Et〇Ac/3〇％己院）以產生4 — (5 —（2 —甲氧羰基）吡啶氧基）苯胺（〇 · 40克） A 1 9 * ω —磺醯苯基胺類的合成法。4 一（4 一甲基 磺醯苯氧基）苯胺的合成〇Me Step 3 · 4 -(5-(2-carbomethoxy)d) than π-oxyl) Aniline is synthesized as 4-(5-(2-methoxycarbonyl)acridinyloxy)-] Nitrobenzene (〇.5〇g) and 1〇% Pd/C (〇·50g) were dissolved in a mixture consisting of E t〇A c (20 ml) and Me OH (5 ml), and The slurry was placed at Η 2 atmospheres (balloon) for the entire night. The resulting mixture was filtered through a Celite® pad and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (S i 0 2 » 70% Et〇Ac / 3 〇% hexane) to give 4-(5-(2-methoxycarbonyl)pyridinyloxy)aniline ( 〇· 40 g) A 1 9 * ω - synthesis of sulfonyl phenylamines. Synthesis of 4-(4-methylsulfonylphenoxy)aniline

/Me 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） --------------------訂--------- (請先閱讀背面之注意事項再填寫本頁) -67- 1269791 A7 B7 五、發明說明（65 步驟1 4 一（4 一甲基磺醯苯氧基）—1 一硝基苯：/Me This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -------------------- Order -------- - (Please read the notes on the back and fill out this page) -67- 1269791 A7 B7 V. INSTRUCTIONS (65 Step 1 4 A (4 Methanesulfonylphenoxy)-1 Mononitrobenzene:

將 m - C P B A 7 - 8 % 4 · 0克）在〇 °c下慢 慢地加入含4 一（ 4 一甲硫基苯氧基）一 1 —硝基苯（ 2 · 0克，7 . 7毫莫耳）的CH2C12(75毫升）溶 液中，並將反應混合物在室溫下攪拌5小時。以1 N N a〇Η溶液（2 5毫升）來處理反應混合物。以1 N N a Ο Η溶液（2 5毫升），水（2 5毫升）和飽和的 N a C 1溶液（2 5毫升）依序將有機層進行淸洗，乾燥 之（Mg SO 4)並將之在減壓下進行濃縮以產生4 一（4 一甲基擴醯苯氧基）一 1 一硝基苯，此爲一種固體（ 2 · 1 克）。 步驟2 · 4 — (4 —甲基擴醯苯氧基）一 1 一苯胺：依 類似於方法A 1 8，步驟3中所說明的方式將4 一（ 4 一 基擴醯苯氧基）- 1 -硝基苯還原成苯胺。 (請先閱讀背面之注意事項再填寫本頁)Add m - CPBA 7 - 8 % 4 · 0 g) slowly to 含4c (4-methylthiophenoxy)-1-nitrobenzene (2.0 g, 7. 7) To a solution of CH2C12 (75 mL), mp. The reaction mixture was treated with a 1 N Na solution (25 mL). The organic layer was washed successively with 1 NN a Ο Η solution (25 ml), water (25 ml) and saturated NaCI1 solution (25 mL), and dried (Mg SO 4) Concentration under reduced pressure gave 4-(4-methylmethyl phenoxy)-mononitrobenzene as a solid (2 · 1 g). Step 2 · 4 — (4-Methyl-fluorenated phenoxy)-monophenylene: 4-(4-yl-phenyleneoxy)-in a manner similar to that described in Method A1, Step 3 Reduction of 1-nitrobenzene to aniline. (Please read the notes on the back and fill out this page)

B B 經濟部智慧財產局員工消費合作社印製 步驟 脲先驅產物的合成法 利用C D I從苯胺合成異氰酸酯類的一般方法。 4 一溴基一 3 -（三氟甲基）苯基異氰酸酯的合 成 CF, BrB B Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed Steps Synthesis of urea precursor products General method for synthesizing isocyanates from aniline using C D I. Synthesis of 4-monobromo-3-(trifluoromethyl)phenylisocyanate CF, Br

NH2.HCI 4 —溴基—3 —（三氟甲基）苯胺HC 1鹽的 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐）NH2.HCI 4 —Bromo-3—(trifluoromethyl)aniline HC 1 salt This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm).

-68- 1269791 A7 B7 五、發明說明（66 ) 合成法 在含4 —渙基一 3 —(三氟甲基）苯胺（64克， 267笔旲耳）的Et2〇（5 0 0毫升）溶液中，將 HC1溶液莫耳濃度，在Et2〇中：3〇〇毫升） 滴一滴地加入其中。將所產生的混合物，在室溫下攪拌 1 6小時。接著經由過濾法移除所得到的粉白色沉澱物 再以E t 2〇（5 〇毫升）淸洗之得到4 一溴基一 3 一（ 氟甲基）苯胺He 1鹽（73克，98%)。 CF, Br-68- 1269791 A7 B7 V. INSTRUCTIONS (66) Synthetic method in Et2〇 (500 ml) solution containing 4-mercapto-3-(trifluoromethyl)aniline (64 g, 267 pens) In the middle, the molar concentration of the HC1 solution, in Et 2 :: 3 〇〇 ml), was added dropwise. The resulting mixture was stirred at room temperature for 16 hours. The resulting powdery white precipitate was removed by filtration and washed with EtOAc (5 mL) to afford 4-bromo-tri-(trifluoromethyl)aniline He 1 salt (73 g, 98%) ). CF, Br

NC〇 -------1-----衣 (請先閱讀背面之注音？事項再填寫本頁} 經濟部智慧財產局員工消費合作社印製 步驟2 · 4 —溴基一 3 -（三氟甲基）苯基異氰酸酯 將氯甲酸三氯甲酯一滴滴地加入含4 一溴基一 3 一（ 三氟甲基）苯胺HC1鹽（36 · 8克，133毫莫耳） 的甲苯（2 7 8毫升）中以處理之。將所得的混合物在回 流下加熱1 8小時，並於減壓下濃縮之。將所得到的剩餘 物以甲苯（5 0 0毫升）處理後，再以C Η 2 C 1 2 ( 5 0 0毫升）處理之，並於減壓下加以濃縮。重覆進行以 C Η 2 C 1 2處理/濃縮的步驟一次，將所得的琥珀色的油 置於一 2 0 °C下1 6小時，以得到一種褐色固體4 一溴基 —3 —（三氟甲基）苯基異氰酸酯（35 · 1克，86% )°GC— MS m/z 265(M+)。NC〇-------1-----Clothing (please read the phonetic transcription on the back? Please fill out this page again) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Print Step 2 · 4 —Bromo-based 3 - (Trifluoromethyl)phenylisocyanate Trichloromethyl chloroformate was added dropwise to toluene containing 4-bromomono-3-tris(trifluoromethyl)aniline HC1 salt (36 · 8 g, 133 mmol) (2 7 8 ml) was treated in vacuo. The obtained mixture was heated under reflux for 18 hours and concentrated under reduced pressure. The residue obtained was taken in toluene (500 mL). Treated by C Η 2 C 1 2 (500 mL), and concentrated under reduced pressure. The procedure of C Η 2 C 1 2 treatment/concentration was repeated once, and the obtained amber oil was placed in one. 16 hours at 20 ° C to give a brown solid 4-bromo 3-(trifluoromethyl)phenyl isocyanate (35 · 1 g, 86%) °GC-MS m/z 265 (M+) .

C 脲形成的方法 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -69- 華. 1269791 A7 B7 五、發明說明（67) · c 1 a · 經由將異氰酸酯與苯胺進行反應來合成脲的一 般方法。N —（4 一氯基—3 — （三氟甲基） 苯基）—Ν' — (4 —（2 —（N —甲基氨基 甲醯）一 4 一吼陡氧基）苯基）脲C Urea formation method This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -69- Hua. 1269791 A7 B7 V. Inventive Note (67) · c 1 a · via isocyanate and aniline The general method of reacting to synthesize urea. N —(4-Chloro-3-(trifluoromethyl)phenyl)-Ν' — (4 —(2 —(N —Methylaminomethylhydrazine)-4′吼-stoxy)phenyl)urea

NHMe 於0°C下，在含4 一氯基一 3 — 氟甲基）苯基異 氰酸酯 4 克NHMe at 4 ° C in 4 chloro- 3 -fluoromethyl)phenyl isocyanate 4 g

9毫莫耳）的CH2C (請先閱讀背面之注意事項再填寫本頁) 3 5毫升）溶液中，一滴滴地加進含4 一（ 2 —（N —甲 基氨基甲醯）一 4 一吡啶氧基）苯胺（A2方法，步驟4 :16 · 〇 克，67 · 77 毫莫耳）的 CH2C12(3 5 毫升）懸浮液。將所得的混合物在室溫下攪拌2 2小時後 ，將得到的黃色固體經過濾法移除，以C Η 2 C 1 2 ( 4 一 2 X 3 0毫升）淸洗之，並且在減壓下加以乾燥（大約1 mmHg)以得到Ν — (4 -氯基—3 —（三氟甲基苯基 )—N — （4 一 （2 — (N —甲基氨甲基甲醯） 經濟部智慧財產局員工消費合作社印製 吡啶氧基）苯基）脲，此爲一種白色固體（2 8 · 5克 9 3%) :mp 207-209 °C； 'H-NMR (DMSO-de) 5 2.77(d，J=4.8Hz，3H)， 7 · 1 6 ( m，3 H )， 7.37(d，J = 2.5Hz，lH)， 7.62(m，4H)， -70- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 1269791 A7 B7 五、發明說明（68 ) 8 · 1 1 ( d，J = 2 ·8 . 4 9 ( d，J = 5 . 8*77 ( b r d，lH)，8.99(s，ih)，9.21(s，1H); HPLC ES— MS m/z 4 6 5 ( ( M + H )9 millimoles of CH2C (please read the notes on the back and fill out this page) 3 5 ml) solution, add 4 to 1 (2 - (N-methylaminometh)) 4 Pyridyloxy)aniline (A2 method, step 4:16 · gram, 67 · 77 mmol) of CH 2 C 12 (3 5 mL) suspension. After the resulting mixture was stirred at room temperature for 2 hours, the obtained yellow solid was removed by filtration, washed with C Η 2 C 1 2 ( 4 - 2 X 3 0 ml) and under reduced pressure Dry (about 1 mmHg) to obtain Ν-(4-chloro-3-3-(trifluoromethylphenyl)-N-(4-(2-(N-methylaminomethylformamidine)) Ministry of Economics The property bureau employee consumption cooperative printed pyridyloxy)phenyl)urea, which was a white solid (2 8 · 5 g 9 3%) : mp 207-209 ° C; 'H-NMR (DMSO-de) 5 2.77 (d, J = 4.8 Hz, 3H), 7 · 1 6 ( m, 3 H ), 7.37 (d, J = 2.5 Hz, lH), 7.62 (m, 4H), -70- This paper scale applies to China Standard (CNS) A4 specification (210 X 297 mm) 1269791 A7 B7 V. Description of invention (68) 8 · 1 1 ( d, J = 2 · 8. 4 9 ( d, J = 5 . 8*77 ( brd , lH), 8.99 (s, ih), 9.21 (s, 1H); HPLC ES-MS m/z 4 6 5 ( ( M + H )

Hz HzHz Hz

H HH H

C b 經由將一種異氰酸酯和一種苯胺進行反應來合 成脲的一般方法。N — (4 -溴基—3 -（： 氟甲基）苯基）一— （4 一 （2 — (N_ 甲基氨基甲醯）一4一吡啶氧基）苯基）脲C b is a general method for synthesizing urea by reacting an isocyanate with an aniline. N —(4-bromo-3-(-fluorofluoro)phenyl)-(4-(2-(N-methylaminocarbamidine)-4-pyridyloxy)phenyl)urea

NHMe 經濟部智慧財產局員工消費合作社印制衣 N N Η Η 於〇 °c下，在含4 一溴基一 3 —（三氟甲基）苯基異 氰酸酯（B1方法，步驟2 : 8 · 0克，30 · 1毫莫耳 )的C H 2 C 1 2 ( 8 0毫升）溶液中，一滴滴地加進含4 一（2 — （Ν —甲基氨基甲醯）一 4 一吡啶氧基）苯胺（ Α2方法，步驟4 ; 7 · 0克，28 · 8毫莫耳）的 C Η 2 C 1 2 ( 1 4 0毫升）溶液。將所得的混合物在室溫 下攪拌1 6小時後，再將所得的黃色固體經過濾移除，以 C Η 2 C 1 2 ( 2 X 5 0毫升）淸洗之，並且在減壓下（大 約1 m m H g )於4 0 °C下進行乾燥以得到Ν —（ 4 —溴NHMe Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed NN Η Η under 〇°c, in 4-bromo-3-(trifluoromethyl)phenylisocyanate (B1 method, Step 2: 8 · 0 g , in a solution of CH 2 C 1 2 (80 ml) of 30 · 1 mmol, added dropwise to a 4-(2-(methyl-methylcarbamidine)-tetrapyridyloxy)aniline (Α2 method, step 4; 7 · 0 g, 28 · 8 mmol) C Η 2 C 1 2 (140 ml) solution. After the resulting mixture was stirred at room temperature for 16 hours, the obtained yellow solid was removed by filtration, washed with C Η 2 C 1 2 ( 2 X 50 mL) and under reduced pressure (about 1 mm H g ) is dried at 40 ° C to obtain Ν —( 4 —bromine

基一 3 —（三氟甲基）苯基）一 N —（4 — (2 — (N (請先閱讀背面之注意事項再填寫本頁)Base - 3 - (trifluoromethyl)phenyl) - N - (4 - (2 - (N (please read the back of the note first, then fill out this page)

本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -71 - 經濟部智慧財產局員工消費合作社印製 1269791 A7 B7 五、發明說明（69) , 甲基氨基甲醯）一 4 一吡啶氧基）苯基）脲，此爲一種淡 黃色固體（13-2 克，90%) :mp 2 0 3 -205 °C ； 'H-NMR (DMSO-de) ά 2.77(d，J=4.8Hz，3H)， 7 · 1 6 ( m，3 Η )， 7.37(d，J=2. 5Hz，lH)， 7 · 5 8 ( m，3 H )， 7.77(d，J=8.8Hz，lH)， 8.11(d，J=2.5Hz，lH)， 8.49(d，J = 5.5Hz，lH)， 8 · 7 7 ( b r d，lH)， 8-99(s，lH) ，9-21(s，lH)； HPLC ES— MS m / z 5 0 9 ( ( M + H ) + ) 〇 C 1 c · 經由將一種異氰酸酯和一種苯胺進行反應來合 •成脲的一般方法。N -（4 —氯基—3 -（三 氯甲基）苯基一 N — (2 —甲基一 4— (2 —(N —甲基氨基甲醯）一 4 一吡啶氧基）苯 基）脲 ---------------------訂--------- (請先閱讀背面之注意事項再填寫本頁)This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -71 - Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 1269791 A7 B7 V. Invention Description (69), Methylaminocarbamidine) 4-Pyridinyloxy)phenyl)urea, a pale yellow solid (13-2 g, 90%): mp 2 0 3 - 205 ° C; 'H-NMR (DMSO-de) ά 2.77 (d, J = 4.8 Hz, 3H), 7 · 1 6 ( m, 3 Η ), 7.37 (d, J = 2. 5 Hz, lH), 7 · 5 8 ( m, 3 H ), 7.77 (d, J = 8.8 Hz, lH), 8.11 (d, J = 2.5 Hz, lH), 8.49 (d, J = 5.5 Hz, lH), 8 · 7 7 (brd, lH), 8-99 (s, lH), 9- 21(s,lH); HPLC ES-MS m / z 5 0 9 ((M + H) + ) 〇C 1 c · A general method for the formation of urea by reacting an isocyanate with an aniline. N -(4-Chloro-3-(trichloromethyl)phenyl-N-(2-methyl-4-(2-(N-methylaminocarboxamidine)-4-pyridyloxy)phenyl ) Urea--------------------- Order--------- (Please read the notes on the back and fill out this page)

以Et3N (0 · 16毫升）和4 —氯基一3 —三氟甲 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -72- A7 1269791 B7_ 五、發明說明（70 ) , 基苯基異氰酸酯（0 · 10克，0 · 45毫莫耳）來處理 含2 —甲基一4 — (2 — （N —甲基氨基甲酸一4 一吼口定 氧基）苯胺（A5方法：0 · 11克，0 · 45毫莫耳） 的C Η 2 C 1 2 ( 1毫升）溶液。將所得的褐色水溶液在室 溫下攪拌6天，再以水（5毫升）處理之。將水溶液層以 E t 0 A c ( 3 X 5毫升）進行反萃取。將所得的有機層 加以合倂後進行乾燥（M g S ◦ 4 )並且在減壓下加以濃縮 以得到N — (4 —氯基一3 —（三氟甲基苯基）一 N&gt; — (2 —甲基一 4 — (2 — （N —甲基一氨基甲醯）一4 — 吡啶氧基）苯基）脲，此爲一種褐色油（0 · 1 1克， 〇 . 22 毫莫耳）：iH — NMR (DMS〇一d6) 5 2 . 2 7 ( s，3 Η )， 2.77(d，J = 4.8Hz，3H)， 7.〇3(dd，J = 8- 5，2-6Hz，lH)， 7.11(d，J = 2.9Hz，lH)， 7-15(dd，J = 5.5，2.6，Hz，lH)， 7.38(d，J = 2- 6Hz，lH)， 7 · 6 2 ( a p p d，J = 2- 6Hz，2H)， 7-84(d，J = 8.8Hz，lH)， 8 · 1 2 ( s ^ 1 H ) ，8*17(s，lH)； 8.5〇（d，J = 5.5Hz，lH)， 8.78(q，J = 5.2，1H)， 9.52(s，lH) ； Η P L C ES— MS m / z 479 ( (M + H)+) 。 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） (請先閱讀背面之注意事項再填寫本頁) ------訂---------' 經濟部智慧財產局員工消費合作社印製 -73- 1269791 A7 B7 經濟部智慧財產局員工消費合作社印製 五、發明說明（71)It is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) with Et3N (0 · 16 ml) and 4-chloro- 3 - trifluoromethyl paper. -72- A7 1269791 B7_ V. Invention description (70 ), phenyl isocyanate (0 · 10 g, 0 · 45 mmol) to treat 2-amino- 4-(2-(N-methylcarbamic acid- 4 吼 定 定 oxy) aniline ( A5 method: 0 · 11 g, 0 · 45 mmol of a solution of C Η 2 C 1 2 (1 ml). The obtained brown aqueous solution was stirred at room temperature for 6 days and then treated with water (5 ml) The aqueous layer was back-extracted with E t 0 A c (3 X 5 ml). The obtained organic layer was combined and dried (M g S ◦ 4 ) and concentrated under reduced pressure to give N- ( 4-Chloryl-3-(trifluoromethylphenyl)-N&gt; - (2-methyl-4-yl-(2-(N-methylmonocarbamidine)-4-pyridyloxy)phenyl) Urea, this is a brown oil (0 · 1 1 g, 〇. 22 mmol): iH - NMR (DMS 〇 1 d6) 5 2 . 2 7 ( s, 3 Η ), 2.77 (d, J = 4.8) Hz, 3H), 7.〇3 (dd, J = 8- 5,2-6 Hz, lH), 7.11 (d, J = 2.9 Hz, lH), 7-15 (dd, J = 5.5, 2.6, Hz, lH), 7.38 (d, J = 2- 6 Hz, lH) , 7 · 6 2 (appd, J = 2- 6Hz, 2H), 7-84 (d, J = 8.8Hz, lH), 8 · 1 2 ( s ^ 1 H ) , 8*17(s, lH) ; 8.5 〇 (d, J = 5.5 Hz, lH), 8.78 (q, J = 5.2, 1H), 9.52 (s, lH); Η PLC ES - MS m / z 479 ( (M + H) +). This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back and fill out this page) ------Book ---------' Economy Ministry of Intellectual Property Bureau employee consumption cooperative printing -73- 1269791 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description (71)

C d · 經由將一種異氰酸酯和一種苯胺進行反應來合 成脲的一般方法。N -（4 一氯基一 3—(三 氟甲基）苯基一 N -（4 一氨苯基）脲C d · A general method for synthesizing urea by reacting an isocyanate with an aniline. N -(4-chloro-mono-3-(trifluoromethyl)phenyl-N-(4-monophenyl)urea

NH 2 將對一苯二胺（3 · 32克，30 · 7毫莫耳）一整 份加入含4 一氯基一 3 —（三氟甲基）苯基異氰酸酯.（ 2· 27克，10· 3毫莫耳）的CH2C12(308毫 升）溶液中。將所產生的混合物在室溫下攪拌1小時，以 C Η 2 C 1 2 ( 1 〇 〇毫升）處理之並在減壓的情況下將之 加以濃縮。將所產生的粉紅色固體溶於由E t〇A c ( 1 1 0毫升）和M e〇Η ( 1 5毫升）所組成的混合物中 ，再以0 · 0 5 N H C 1溶液淸洗該透明溶液。在減壓 下將有機層加以濃縮後可產生不純的Ν -（ 4 一氯基- 3 一（二氟甲基）苯基）一 Ν — (4 —胺苯基）脲（ 3.3 克）：TLC(1〇〇％ EtOAc) R f 〇· 7 2 。NH 2 will be added to the monophenyldiamine (3 · 32 g, 30 · 7 mmol) in an integral portion of 4-chloro-tris-(trifluoromethyl)phenyl isocyanate. (2.77 g, 10 · 3 mM) in CH2C12 (308 ml) solution. The resulting mixture was stirred at room temperature for 1 hour, treated with C Η 2 C 1 2 (1 〇 〇 ml) and concentrated under reduced pressure. The resulting pink solid was dissolved in a mixture consisting of E t〇A c (110 ml) and Me 〇Η (15 ml), and the solution was washed with a 0. 0 5 NHC 1 solution. Solution. Concentration of the organic layer under reduced pressure afforded impure Ν-(4-chloro- 3 -(difluoromethyl)phenyl)-indole-(4-aminophenyl)urea (3.3 g): TLC (1% EtOAc) R f 〇· 7 2 .

C 經由將一種異氰酸酯和一種苯胺進行反應來合 成脲的一般方法。N -（4 —氯基一 3 氟甲基）苯基） )脲C A general method for synthesizing urea by reacting an isocyanate with an aniline. N -(4-chloroamino-3-fluoromethyl)phenyl))urea

N 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） (請先閱讀背面之注意事項再填寫本頁) 裴---------訂----- (三 —(4 —乙氧碳基苯基 -74- 1269791 A7 B7 五、發明說明（72N This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back and fill out this page) 裴---------Book----- ( Tri-(4-ethoxyphenylphenyl-74- 1269791 A7 B7 V. Description of invention (72

OEt 於含4 一異氰酸苯甲酸乙酯（3 · 14克，16 · 4 毫莫耳）的CH2C 1 2 ( 3 〇毫升）水溶液中加入4 一氯 基—3 一（三氟甲基）苯胺（3 · 2 1克，16 · 4毫莫 耳），.接著將此水溶液在室溫下攪拌過夜。最後，以 C Η 2 C 1 2 ( 5 0毫升）稀釋所得的漿液’再過濾之，以 得到Ν —（4 一氯一3 —(三氟甲基）苯基）一( 4一乙氧羰基苯基）脲，此爲一種白色固體（5·93克 ,97%) :TLC (40% Et〇Ac/60% 己烷 )R f 〇 · 4 4 0OEt is added to a solution of ethyl 4-isocyanate (3 · 14 g, 16 · 4 mmol) in CH 2 C 1 2 (3 mL) aqueous solution of 4-chloro-3-(trifluoromethyl) Aniline (3 · 21 g, 16 · 4 mmol). This aqueous solution was then stirred at room temperature overnight. Finally, the resulting slurry was diluted with C Η 2 C 1 2 (50 ml) and filtered again to give Ν-(4-chloro-3-(trifluoromethyl)phenyl)-(4-ethoxycarbonyl) Phenyl)urea, which is a white solid (5·93 g, 97%): TLC (40% Et〇Ac/60% hexane) R f 〇· 4 4 0

C 經由一種異氰酸酯和一種苯胺間的反應來合成 脲的一般方法。N — (4 —氯基—3 —（三氟 甲基）苯基）一N/—(3-羧苯基）脲 (請先閱讀背面之注意事項再填寫本頁) -mMMmmm mmaamB mmtt In M·— emmmB i &gt; ϋ__Β an In - 11 =口 s·. 經濟部智慧財產局員工消費合作社印製 CF, C1C A general method for the synthesis of urea via a reaction between an isocyanate and an aniline. N — (4-Chloro-3-(3-trifluoromethyl)phenyl)-N/—(3-carboxyphenyl)urea (please read the back note before filling in this page) -mMMmmm mmaamB mmtt In M ·—emmmB i &gt; ϋ__Β an In - 11 = mouth s·. Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed CF, C1

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Ν Η Η 在含4 一氯基一 3 —（三氟甲基）苯基異氰酸酯（ 1 · 21克，5 · 46毫莫耳）的CH2C I2 (8毫升） 水溶液中加入4 一（ 3 —羧苯氧基）苯胺（A 1方法： 0 · 8 1克，5 · 7 6毫莫耳），將所得的混合物在室溫 下攪拌一整夜。以Me OH ( 8毫升）處理後，再將之攫 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） •75- 1269791 A7 B7 經濟部智慧財產局員工消費合作社印製 五、發明說明（73) &gt; 拌2小時。接著把得到的混合物置於減壓的環境下進行濃 縮。最後，將所得的褐色固體以1 : E t〇A c /己 烷溶液加以碾製以得到一種白色固體的N —（ 4 一氯基-3 —（三氟甲基）苯基）一 -（3 —羧苯基）脲（1 · 2 1 克，7 6 % )。 C .2 a· · 經由將一種苯胺和N，N / —羰基二咪唑進行 反應，再接著加入第二種苯胺來合成脲的一般 方法。N — (2 —甲氧基一 5 —(三氟甲基） 苯基）—— (4 — (2 —（N —甲基氨基 甲醯）一 4 一吡啶氧基）苯基）脲的合成 CR 〇 NHMe ! 在0°C下，於含2 —甲氧基一 5 -（三氟甲基）苯胺 (0 · 1 5克）的無水CH2C 12 (1 5毫升）溶液中加 入C D I ( 〇 · 1 3克）。將所得的水溶液在一小時內加 溫至室溫，攪拌1 6小時，再以4 一（ 2 -（ N —甲基氨 基甲醯）一 4 —吡啶氧基）苯胺（0 · 18克）處理之。 將得到的黃色水溶液在室溫下攪拌7 2小時，再以水（ 125毫升）處理之。接著，用Et〇Ac (2X150 毫升）萃取所得的水溶性混合物。然後’以一飽和的 N a C 1溶液（1 0 0毫升）來淸洗合倂的有機層，乾燥 (M g S〇4 )後在減壓下進行濃縮。以（9 〇 %Ν Η Η Add 4 - (3-carboxyl) to a solution of 4-chloro-tris-(trifluoromethyl)phenylisocyanate (1 · 21 g, 5 · 46 mmol) in CH2C I2 (8 mL) Phenoxy)aniline (A 1 method: 0 · 8 1 g, 5 · 7 6 mmol), and the resulting mixture was stirred at room temperature overnight. After treatment with Me OH (8 ml), it is applied to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). 75- 1269791 A7 B7 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 5 , invention description (73) &gt; mix for 2 hours. The resulting mixture was then concentrated under reduced pressure. Finally, the obtained brown solid was triturated with a 1:E t 〇A c /hexane solution to give N-( 4 - chloro- 3-(trifluoromethyl)phenyl)-- as a white solid. 3 —Carboxyphenyl)urea (1 · 2 1 g, 76 %). C.2 a· · A general method for the synthesis of urea via the reaction of an aniline with N,N / -carbonyldiimidazole followed by the addition of a second aniline. Synthesis of N — (2-methoxy-5-(trifluoromethyl)phenyl)-(4-(2-(N-methylaminoformamidine)-4-pyridyloxy)phenyl)urea CR 〇NHMe ! Add CDI (0·C) to a solution of 2-methoxy-5-(trifluoromethyl)aniline (0.15 g) in anhydrous CH2C12 (15 mL) at 0 °C 1 3 grams). The resulting aqueous solution was warmed to room temperature over one hour, stirred for 16 hours, and treated with 4-(2-(N-methylaminoformamidine)-4-pyridyloxy)aniline (0 · 18 g) It. The resulting aqueous yellow solution was stirred at room temperature for 7 h then treated with water (125 mL). Next, the resulting water-soluble mixture was extracted with Et 〇Ac (2×150 mL). Then, the combined organic layer was washed with a saturated aqueous solution of N a C 1 (100 mL), dried (M g S 〇 4 ) and concentrated under reduced pressure. With (9 〇 %

本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） n (請先閱讀背面之注意事項再填寫本頁) ---—訂---- Φ. 1269791 Α7 Β7 五、發明說明（74) . E t〇A c / 1 0 %己烷）將剩餘物加以硏磨。將所產生 的白色固體經由過濾法加以收集，再以E t〇A c淸洗之 。將濾液在減壓下進行濃縮並經由管柱層析法將剩餘的油 加以純化（梯度從3 3 % E t〇A c / 6 7 %己烷至 50% £七〇八（：/5〇％己烷至1〇〇％ E t〇Ac )以產生N — (2 —甲氧基一5 —三氟甲基） 苯基）·— N/ — (4 -（2 — (N -甲基氨基甲醯）—4 一吡啶氧基）苯基）脲，此爲一種淡褐色固體（0 · 0 9 30%) *TLC(l〇〇% EtOAc)This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) n (Please read the note on the back and fill out this page) -------- Φ. 1269791 Α7 Β7 V. Invention Description (74) . E t〇A c / 1 0 % hexane) The residue is honed. The resulting white solid was collected by filtration and washed with EtOAc. The filtrate was concentrated under reduced pressure and the remaining oil was purified by column chromatography (gradient from 3 3 % E t〇A c / 6 7 % hexane to 50% £ 〇 ( (: /5 〇) % hexane to 1% E t〇Ac) to produce N —(2-methoxy-5-trifluoromethyl)phenyl)·- N/ — (4 -(2 - (N-methyl) Methotrexate) 4-pyridyloxy)phenyl)urea, which is a light brown solid (0·0 9 30%) *TLC (10% EtOAc)

克 R 〇· 6 H — NMR (DMS〇 d 7 6 9 6 d 4 8 H z ，3 H )克 R 〇· 6 H — NMR (DMS〇 d 7 6 9 6 d 4 8 H z , 3 H )

H 7H 7

F •1 — 7·6 及 8·4 — 8·6(ιη，11Η) •75(d，J=4.8Hz，lH)， • 5 5 ( s，1 Η ); AB— MS m/z 461 ( (M + H)+) ϋ ϋ n n in I 1 ϋ 1 n 11 I «ϋ n alai 1 n y.l n i_l I an immmm n I I (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 C 2 b · 經由將一種苯胺與N，N / -羰基二咪唑進行 反應後，接著再加入第二種苯胺來合成脲的一 般方法。對稱的脲爲N，N / —羰基二咪唑反 應步驟的副產品。雙（4 一 （ 2 —（ N —甲基 氨基甲醯）一4一吼陡氧基）苯基）脲的合成F •1 — 7·6 and 8·4 — 8·6(ιη,11Η) •75(d,J=4.8Hz,lH), • 5 5 ( s,1 Η ); AB— MS m/z 461 ( (M + H)+) ϋ ϋ nn in I 1 ϋ 1 n 11 I «ϋ n alai 1 n yl n i_l I an immmm n II (Please read the note on the back and fill out this page) Ministry of Economics Intellectual Property The Bureau of Staff Consumer Cooperatives prints C 2 b · a general method for synthesizing urea by reacting an aniline with N,N / -carbonyldiimidazole followed by the addition of a second aniline. Symmetrical urea is a by-product of the N,N / -carbonyldiimidazole reaction step. Synthesis of bis(4-(2-(N-methylaminocarbamidine)-tetra-indoleoxy)phenyl)urea

MeHNMeHN

NHMe Η Η 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -77- 1269791 A7 ____B7________ 五、發明說明（75 ) · 在〇 °C下，於攪拌中的3 —氨基一 2 —甲氧基喹啉（ 〇· 14克）的無水CH2Cl2(l5晕:升谷液中加入 C D I ( 〇 · 1 3克）。將所得的水溶液在一小時內加溫 至室溫攪拌1 δ小時後，以4 一（ 2 —（ Ν —甲基氨基甲 酿）〜4 一哦陡氧基）苯胺（〇 · 1 8克）處理所產生的 混合物。接著，將所得到的黃色水溶液在室溫下攪拌7 2 小時，，以水（1 2 5毫升）處理後再用E t〇A c ( 2 X 1 5 〇毫升）萃取所得的水溶性混合物。然後，將合倂的 有機層以一種飽和N a C 1水溶液（1 0 0毫升）淸洗後 ’乾燥之（M g S〇4 )並在減壓下加以濃縮，再用（9 0 % E t 0 A c / 1 〇 %己烷）來碾製剩餘物。經由過濾 法收集所得的白色固體。最後，以E t〇A c沖洗之以得 到雙（4 一 （2 — (N —甲基氨基甲醯）一 4 一吡啶氧基 )苯基）脲（〇.〇81 克，44%) :TLC(l〇〇 % E t 0 A c ) R f 0·50; 1H — NMR (DMS〇 一 d6) 5 -------------#裝-------—訂--------- (請先閱讀背面之注音？事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製NHMe Η Η This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) -77- 1269791 A7 ____B7________ V. Description of invention (75) · 3-Amino group in stirring at 〇 °C 2-methoxyquinoline (〇·14g) of anhydrous CH2Cl2 (l5 halo: adding CDI (〇·13g) to the trough solution. The obtained aqueous solution is heated to room temperature for 1 hour and stirred for 1 δ hours. After that, the resulting mixture was treated with 4 (2 -( Ν-methylamino-branched)~4- oh-stoxy)aniline (〇·18 g). Next, the obtained yellow aqueous solution was at room temperature. After stirring for 7 hours, the obtained water-soluble mixture was extracted with E t〇A c ( 2 X 1 5 ml) after treatment with water (1 25 ml). Then, the organic layer of the combined organic layer was saturated. The aqueous solution of N a C 1 (100 ml) was washed and dried (M g S 〇 4 ) and concentrated under reduced pressure, and then used (90% E t 0 A c / 1 〇 % hexane) To grind the residue. The resulting white solid was collected by filtration. Finally, rinsed with E t〇A c to give a double (4 - (2 - (N Methylaminocarbamidine) 4-tetrapyridyloxy)phenyl)urea (〇.〇81 g, 44%): TLC (l〇〇% E t 0 A c ) R f 0·50; 1H — NMR ( DMS〇一d6) 5 -------------#装--------订--------- (Please read the phonetic on the back? This page is printed by the Intellectual Property Office of the Ministry of Economic Affairs.

IImll I- Η M _—- κίν J _—&gt; 〇〇 1 ， c0， ， ， oo d . d d s E /(\ 7— /IV /{\ /IV 6 1 8 5 6 c T i—14 T 00 L 2 7 8 8 8 H 5 5 4 s Η Η Η H 12 4 8 z z z H 6 \)y XXJ Η H 1 2 m z 3 ΊΧ 5IImll I- Η M _—- κίν J _—&gt; 〇〇1 , c0, , , oo d . dds E /(\ 7— /IV /{\ /IV 6 1 8 5 6 c T i—14 T 00 L 2 7 8 8 8 H 5 5 4 s Η Η Η H 12 4 8 zzz H 6 \)y XXJ Η H 1 2 mz 3 ΊΧ 5

H + M -78 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 1269791 A7 B7 五、發明說明（76) . C 2 C · 經由將一種異氰酸酯和一種苯胺進行反應來合 成脲的一般方法。N —（2 —甲氧基一 5 -（ 三氟甲基）苯基—N〃一（4 — (1 ，3 —二 酮基異吲哚滿- 5 -基氧基）苯基）脲的合成H + M -78 - This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1269791 A7 B7 V. Inventive Note (76) . C 2 C · By reacting an isocyanate with an aniline A general method of synthesizing urea. N —(2-methoxy-5-(trifluoromethyl)phenyl-N〃-(4-(1,3-diketoisoindan-5-yloxy)phenyl)urea synthesis

在攪拌中的含2 —甲氧基一 5 —（三氟甲基）苯基異 氰酸酯（0 · 10克，0 · 47毫莫耳）的CH2Cl2( 1 · 5毫升）水溶液中，一*次加入5 -（4 一氨基苯氧基 )異吲哚滿一1 ，3 —二酮（A 3方法，步驟3 ; 0 · 1 2克，0 · 4 7毫莫耳）。將所得的混合物攪拌 1 2小時，再以CH2C 12 ( 1 0毫升）和MeOH (5 毫升）來處理之。接著，再依序以1 N H C 1水溶液（ 1 5毫升），飽和N a C 1水溶液（1 5毫升）來沖洗所 得的混合物並乾燥（M g S〇4 )之。最後，在減壓的情況 下進行濃縮以得一種白色固體的N —（2 —甲氧基一 5 — (三氟甲基）苯基一N/ — (4 — (1 ，3 —二酮基異吲 ΰ朵滿一 5 —基氧基）苯基）脈（〇 · 2克’ 9 6%). T L C (70% Et〇Ac/30% 己烷） R f 〇 · 50 ； 'H-NMR (DMSO-de) 5 3 · 9 5 ( s，3 Η )， 7·31 — 7.10(m，6H)， 本紙張尺度適用中國國家標準（CNS)A4規格（210 χ 297公釐） _ 79 _ (請先閱讀背面之注意事項再填寫本頁) m ·ϋ n tmme tMmm n in n I n l Hi 經濟部智慧財產局員工消費合作社印製 1269791 A7 B7 五、發明說明（77) » 7.57(d，J = 9.3Hz，2H)， 7-80(d，J 二 8·7Ηζ，1Η)， 8 * 5 3 ( b r s，2H)，9.57(s，lH)， 1 1 · 2 7 ( b r s’lH);HPLC ES-MS 472·〇((Μ + Η) +，1〇〇%)。 C 2 d · 經由將一種苯胺與N，N &gt; -羰基二咪唑進行 反應，接著再加入第二種苯胺來合成脲的一般 方法。N — ( 5 —(特丁基）—2 — ( 2，5 —二甲基吡咯基）苯基）—N — —（4 一（2 一（N —甲基氨基甲醯）一 4 一吡啶氧基苯基 )脲的合成 (請先閱讀背面之注意事項再填寫本頁)In a stirred solution of 2-methoxy-5-(trifluoromethyl)phenylisocyanate (0 · 10 g, 0 · 47 mmol) in CH 2 Cl 2 (1.5 ml) 5-(4-Aminophenoxy)isoindole-1,3-dione (A3 method, step 3; 0 · 1 2 g, 0 · 4 7 mmol). The resulting mixture was stirred for 12 h then treated with CH2C12 (10 mL) and MeOH (5 mL). Then, the obtained mixture was washed successively with a 1 N H C 1 aqueous solution (15 ml), saturated aqueous NaCI (1 5 ml) and dried (M g S 〇 4 ). Finally, it was concentrated under reduced pressure to give N-(2-methoxy-5-(trifluoromethyl)phenyl-N/-(4-(1,3-dione) as a white solid. Isoindole-5-yloxy)phenyl) vein (〇·2 g '9 6%). TLC (70% Et〇Ac/30% hexane) R f 〇· 50 ; 'H-NMR (DMSO-de) 5 3 · 9 5 ( s, 3 Η ), 7·31 — 7.10 (m, 6H), This paper scale applies to Chinese National Standard (CNS) A4 specification (210 297 297 mm) _ 79 _ (Please read the notes on the back and fill out this page) m ·ϋ n tmme tMmm n in n I nl Hi Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1269791 A7 B7 V. Inventions (77) » 7.57(d, J = 9.3 Hz, 2H), 7-80 (d, J 2.8 Ηζ, 1 Η), 8 * 5 3 (brs, 2H), 9.57 (s, lH), 1 1 · 2 7 (br s'lH HPLC ES-MS 472·〇((Μ + Η) +, 1〇〇%) C 2 d · by reacting an aniline with N,N &gt;-carbonyldiimidazole, followed by a second General method for the synthesis of urea from aniline. N — ( 5 —(tert-butyl)—2 — ( 2,5 —dimethylpyrrolyl)benzene Synthesis of 4-(2-(N-methylaminocarbamidine)-4-pyridyloxyphenyl)urea (Please read the note on the back and fill out this page)

經濟部智慧財產局員工消費合作社印製 在一攪拌中的含CDI(〇·21克，1·30毫莫 耳）的CH2C 1 2 ( 2毫升）溶液中，一次加入5 —(特 一丁基）—2 — (2，5 —二甲基11比咯基）苯胺（A4方 法，步驟2 : 0 · 3 0克，1 · 2 4毫莫耳）。將所得的 混合物在室溫下攪拌4小時，然後一次加入4 一（ 2 -（ N —甲基氨基甲醯）一 4_吡啶氧基）苯胺（0 · 0 6 5 克，0 · 2 6 7毫莫耳）。接著，將此混合物在3 6 °C下 加熱過夜，冷卻至室溫，再以EtOAc (5毫升）稀釋 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -80- 經濟部智慧財產局員工消費合作社印製 1269791 7 Α7 Β7 五、發明說明（78) 之，最後依次以水（1 5毫升），1 N H C 1溶液（ 1 5毫升）淸洗之，乾燥（M g S〇4 )後，經由矽膠墊來 加以過濾以得到一種黃色固體的N —（ 5 -特一 丁基）一 2 — （2 ，5 —二甲基吡咯基）苯基）一N/— (4—( 2 一（N —甲基氨基甲醯）一 4 一吡啶氧基）苯基）脲（ 〇·033 克，24%) :TLC(40% EtOAc /60%己烷）Rf 〇·24; 1 H NMR (丙酮一d6)5 1.37(s，9H)， 1 · 8 9 ( s，6 Η )， 2.89(d，J=4.8Hz，3H)， 5 · 8 3 ( s，2 H )， 6·87 — 7.2〇（m，6H)， 7-17(dd，lH)， 7·51- 7.58(m，3H)， 8.43(d，J = 5.4Hz，lH)， 8.57(d，J = 2*lHz，lH)， 8 * 8 0 ( b r s，lH) ； Η P L C ES— MS 512 ( (M + H) + ， 1〇〇％)。 C 3 · 利用三光氣來合成二苯脲的組合方法 將用來偶合的苯胺之一，溶解在二氯乙烷（0 · 1〇 Μ )中。將此水溶液（0 · 5毫升）移至含有二氯乙烷（ 1毫升）的8毫升小瓶中，然後加入一種雙（三氯甲基） 碳酸酯水溶液（0 · 12Μ在二氯乙烷中，〇 · 2毫升， --------------------丨訂---------^9— (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -81 - 1269791 經濟部智慧財產局員工消費合作社印製 Α7 Β7 五、發明說明（79) · 0 · 4當量），再加入二異丙基乙胺（〇 · 3 5M在二氯 乙烷中’ 0 · 2毫升，1 · 2當量）。接著，將這個小瓶 子蓋上蓋子，在8 0 °C下加熱5小時。將之冷卻至室溫 1 0小時後，加入第二種苯胺（〇 . 1 〇 Μ在二氯乙烷中 ，〇· 5毫升，1· 〇當量），再加入二異丙基乙胺（ 0.35Μ在二氯乙烷中，〇·2毫升，1.2當量）。 將所得混合物在8 0 °C下加熱4小時，冷卻至室溫並且以 M e〇Η ( 〇 · 5毫升）處理之。最後，將此混合物在減 壓下進行濃縮，所得的最終產品再以逆相Η P L C來純化 〇 C 4 · 經由將一種苯胺與光氣進行反應，再接著加入第 一種本3女來合成服的一'般方法。Ν —（ 2 —甲氧 基一 5—(三氟甲基）苯基）一 N/—（4—( 2 —（Ν —甲基氨基甲醯）一 4 —吡啶氧基）苯 基）脲的合成Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, printed in a stirred solution of CDI (〇·21 g, 1·30 mmol) in CH2C 1 2 (2 mL), one-time addition of 5-(te-butyl) )—2 — (2,5-Dimethyl 11-pyryl)aniline (A4 method, Step 2: 0 · 30 g, 1 · 2 4 mmol). The resulting mixture was stirred at room temperature for 4 hours, then a solution of 4-(2-(N-methylaminoformamidine)-4-pyridyloxy)aniline (0 · 0 6 5 g, 0 · 2 6 7) Millions of ears). Next, the mixture was heated at 3 6 ° C overnight, cooled to room temperature, and diluted with EtOAc (5 mL). The paper size was applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) -80- Economy Ministry of Intellectual Property Bureau employee consumption cooperative printed 1269791 7 Α7 Β7 5, invention description (78), and finally washed with water (15 ml), 1 NHC 1 solution (15 ml), dry (M g S After 〇4), it was filtered through a pad to obtain a yellow solid N-(5-tert-butyl)-2-(2,5-dimethylpyrrolyl)phenyl)-N/- (4) -( 2 -(N-methylaminoformamidine)-tetrapyridyloxy)phenyl)urea (〇·033 g, 24%): TLC (40% EtOAc / 60% hexanes) Rf 〇 24; 1 H NMR (acetone-d6) 5 1.37 (s, 9H), 1 · 8 9 (s, 6 Η ), 2.89 (d, J = 4.8 Hz, 3H), 5 · 8 3 (s, 2 H ), 6·87 — 7.2〇(m,6H), 7-17(dd,lH), 7·51- 7.58(m,3H), 8.43(d,J = 5.4Hz,lH), 8.57(d,J = 2*lHz, lH), 8 * 8 0 (brs, lH); Η PLC ES-MS 512 ( (M + H) + , 1〇〇%). C 3 · Combination method for synthesizing diphenylurea using triphosgene One of the anilines used for coupling is dissolved in dichloroethane (0·1〇 Μ ). This aqueous solution (0.5 ml) was transferred to an 8 ml vial containing dichloroethane (1 mL), then a solution of bis(trichloromethyl)carbonate (0 · 12 Torr in dichloroethane, 〇· 2 ml, --------------------丨定---------^9— (Please read the notes on the back and fill in this Page) This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -81 - 1269791 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed Β7 Β7 V. Invention description (79) · 0 · 4 equivalents Further, diisopropylethylamine (〇·3 5M in dichloroethane '0 · 2 ml, 1.2 · equivalent) was added. Next, the vial was capped and heated at 80 ° C for 5 hours. After cooling to room temperature for 10 hours, a second aniline (〇. 1 〇Μ in dichloroethane, 〇·5 ml, 1·〇 equivalent) was added, followed by diisopropylethylamine (0.35). Μ in dichloroethane, 〇 2 ml, 1.2 equivalents). The resulting mixture was heated at 80 ° C for 4 hours, cooled to room temperature and treated with EtOAc (EtOAc). Finally, the mixture is concentrated under reduced pressure, and the resulting final product is purified by reverse phase Η PLC to purify 〇C 4 · by reacting an aniline with phosgene, and then adding the first 3 females to the synthetic clothes. A 'general approach. Ν —( 2 —Methoxy-5-(trifluoromethyl)phenyl)-N/—(4-( 2 —(Ν-methylaminocarbamidine)-4-pyridyloxy)phenyl)urea Synthesis

在〇°C，攪拌中的含光氣.（1 · 9Μ在甲苯中， 2 ·〇7毫升，〇· 21克，1 · 30毫莫耳）的 C Η 2 C 1 2 ( 2 0毫升）水溶液中，加入無水吡啶（ 〇· 32毫升）’再加入2 —甲氧基一 5 —（三氟甲基） 苯胺（0 · 7 5克）。讓此黃色水溶液加溫至室溫後在此 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公爱） -82- -n n n n -I n I 一口， W·· Μ······· · I (請先閱讀背面之注意事項再^&gt;寫本頁) 經濟部智慧財產局員工消費合作社印製 1269791 Α? — Β7 五、發明說明（8(3) &gt; 同時會產生沉澱物。將這個黃色混合物攪拌1小時後，在 減壓下進行濃縮。將所得的固體先以無水甲苯（2 0毫升 )處理後，再以4 一（2 —（N —甲基氨基甲醯）—4 — 吡啶氧基）苯胺（依照A 2方法來製造，0 · 3克）處理 之。處理後，將所得到的懸浮液在8 0 °C加熱2 0小時， 冷卻至室溫。將所得的混合物以水（1 0 0毫升）稀釋， 並用一種飽和N a H C〇3水溶液（2 - 3毫升）加以鹼化 ，然後以E t〇A c ( 2 X 2 5 0毫升）來萃取這個鹼性 水溶液。將有機層則分別以一種飽和N a C 1水溶液沖洗 後、合倂、乾燥（M g S〇4 )，並且在減壓下濃縮。將所 得的粉紅-褐色剩餘物溶解於M e Ο Η中，然後，吸附至 S i〇2 (100克）上。經管柱層法（300克S i〇2 ;梯度從 1% E t 3 N / 3 3 % Et〇Ac/66%己 烷遞增至1% E t 3 N / 9 9 % £1〇八〇及1% E t 3 N / 2 0 % MeOH/79% EtOAc)，接 下來，在4 5 °C，減壓下濃縮而得一種溫的濃縮的 E t〇A c水溶液，再以己烷（1 0毫升）處理以慢慢的 產生N —（2 —甲氧基一 5 —（三氟甲基）苯基）〜 —(4 — (2 — (N —甲基氨基甲醯）—4 一吡啶氧基） 苯基）脲（0.44 克）：TLC(1% E t 3 0 / 9 9 % EtOAc) R f 0.40。 D · 脲的互變現象 D 1 a · 將ω -氨基苯脲轉變成ω -（芳醯氨基）苯基 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -83- ------1------------丨訂---------^ (請先閱讀背面之注咅？事項再填寫本頁)In 〇 ° C, the phosgene in the stirring. (1 · 9 Μ in toluene, 2 · 〇 7 ml, 〇 · 21 g, 1 · 30 mmol) C Η 2 C 1 2 (20 ml) Aqueous pyridine (〇·32 ml) was added to the aqueous solution and then 2-methoxy-5-(trifluoromethyl)aniline (0·75 g) was added. After the yellow aqueous solution is warmed to room temperature, the Chinese National Standard (CNS) A4 specification (210 X 297 public) is applied to the paper scale. -82- -nnnn -I n I, W·· Μ···· ··· · I (please read the precautions on the back and then ^&gt; write this page) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1269791 Α? — Β7 V. Invention Description (8(3) &gt; The precipitate was stirred for 1 hour, and concentrated under reduced pressure. The obtained solid was treated with anhydrous toluene (20 mL) and then taken to 4-(2-(N-methylaminocarbazide). - 4 - pyridyloxy) aniline (manufactured according to the A 2 method, 0 · 3 g) was treated. After the treatment, the obtained suspension was heated at 80 ° C for 20 hours, and cooled to room temperature. The resulting mixture was diluted with water (100 mL) and basified with a saturated aqueous solution of &lt;RTI ID=0.0&gt;&gt; Alkaline aqueous solution. The organic layer is washed with a saturated aqueous solution of NaCl1, dried, and dried (M g S 〇4), and concentrated under reduced pressure. The obtained pink-brown residue was dissolved in Me Ο ,, and then adsorbed onto S i 〇 2 (100 g). The column layer method (300 g S i 〇2 ; gradient from 1% E t 3 N / 3 3 % Et〇Ac / 66% hexane to 1% E t 3 N / 9 9 % £1〇 〇 and 1% E t 3 N / 2 0 % MeOH/79% EtOAc), then concentrated at 45 ° C under reduced pressure to give a warm concentrated concentrated aqueous solution of EtOAc EtOAc (EtOAc) N —(2-methoxy-5-(trifluoromethyl)phenyl)~—(4 — (2 — (N —methylaminocarbamidine)-4 pyridinoxy)phenyl)urea (0.44 g): TLC (1% E t 3 0 / 9 9 % EtOAc) R f 0.40. D · Urea interconversion D 1 a · Conversion of ω-aminophenylurea to ω -(aryl fluorenylamino)phenyl paper The scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) -83- ------1------------丨--------- ^ (Please read the note on the back? Please fill out this page again)

1269791 A7 __ B7 五、發明說明（81 ) 脲類。N —（4 一氯基一 3 —(三氟甲基）苯 基）一N/— (4 — （3 —甲氧基甲醯苯基） 羧氨基苯基）脲的合成 ^.OMe 〇 在含N —（4 —氯基一 3 —（（三氟甲基）苯基）一 — （4 —氨基苯）脲（Cld方法；〇 · 〇5〇克， 1_52毫莫耳），一甲基異酞酸酯（〇· 25克， 1.38毫莫耳），^^〇3丁.112〇（〇.41克， 3 · 03毫莫耳）和N -甲基嗎啉（〇 · 33毫升， 3 · 03毫莫耳）的DMF (8毫升）溶液中加入 EDCI.HC1 (〇·29 克，1·52 毫莫耳）。將 所得的混合物在室溫下攪拌過夜並以E t ◦ A c ( 2 5毫 升）稀釋後再依序用水（2 5毫升）和一種飽和 N a H C〇3水溶液（2 5毫升）淸洗之。最後將有機層進 行乾燥（N a 2 S〇4 )並且在減壓下加以濃縮。將所得的 固體以一種E t〇A c水溶液（8 0 % E t 0 A c / 2〇％己院）加以碾製以得到N — ( 4 —氯基一 3 —(三 _甲基）苯基）一N — (4— ( 3 —甲氧基甲_苯基） 羧氨基苯基）脲（〇· 27克’43%) :mp 12 1 —122;TLC(8〇％ Et〇Ac/20%己烷） R f 0 · 7 5 ° ----------------------訂---------線 (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 本紙張中國國家標準（CNS)A4規格（210 X 297公釐） -84- 1269791 A7 Β7 五、發明說明（82 )1269791 A7 __ B7 V. Description of invention (81) Urea. Synthesis of N-(4-chloro-3-(trifluoromethyl)phenyl)-N/-(4-(3-methoxymethyl phenyl) carboxyaminophenyl)urea ^.OMe Containing N —(4-chloro-(3-trifluoromethyl)phenyl)-(4-aminophenyl)urea (Cld method; 〇·〇5〇g, 1_52 mmol), monomethyl Isodecanoate (〇·25g, 1.38mmol), ^^〇3丁.112〇(〇.41g, 3 · 03mmol) and N-methylmorpholine (〇·33ml, EDCI.HC1 (〇·29 g, 1.52 mmol) was added to a solution of 3 · 03 mmol) in DMF (8 ml). The resulting mixture was stirred at room temperature overnight and taken to EtOAc EtOAc (25 ml) was diluted and washed with water (25 ml) and a saturated aqueous solution of Na 2 HC 3 (25 mL). The organic layer was dried (N a 2 S 〇 4 ) and Concentration under reduced pressure. The obtained solid was triturated with an aqueous solution of E t〇A c (80% E t 0 A c / 2%%) to obtain N - (4-chloro-3 - ( Tris-methyl)phenyl)-N-(4-(3-methoxymethyl)-phenyl Carboxyaminophenyl)urea (〇·27 g '43%): mp 12 1 —122; TLC (8〇% Et〇Ac/20% hexane) R f 0 · 7 5 ° ------- --------------- Order --------- line (please read the note on the back and then fill out this page) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed version Paper China National Standard (CNS) A4 Specification (210 X 297 mm) -84- 1269791 A7 Β7 V. Invention Description (82)

D b ω 羧苯基脲類轉變成(芳香基氨基甲醯 )苯脲類的轉變。Ν 三氟甲基）苯基）一 (4 一氯基 一 3 —(( Ν —(4 (3 —甲基 氨基甲醯苯基）氨基甲醯苯基）脲的合成 CF&lt;&gt; ηConversion of D b ω carboxyphenylurea to (arylaminocarbamidine) phenylurea. Synthesis of Ν(trifluoromethyl)phenyl)-(4-monochloro- 3 -(( Ν-(4 (3-methylaminomethyl phenyl)) carbamoyl)urea CF&lt;&gt; η

NHMe 經濟部智慧財產局員工消費合作社印製 於0 °C下’在含N —（4 一氯基一 3 —（（三氟甲基 )苯基一 Ν — 一（4一（3 —甲基氨基甲醯苯基）羧氨基 苯基）脲（0 · 14克，〇 · 48毫莫耳），3 -甲基氨 基甲醯苯胺（0.080克，0.53毫莫耳）， Η〇ΒΤ·Η2〇（〇 · 14克，1 · 〇7毫莫耳）和Ν — 甲基嗎啉（0 · 5毫升，1 · 〇7毫莫耳）的DMF (3 毫升）水溶液中加入EDCI .HC1 (〇 · 1〇克， 〇· 5 3毫莫耳），將得到的混合物加熱至室溫並且攪拌 過夜。將所得的混合物先以水（1 〇毫升）處理，再用 E t〇A c ( 2 5毫升）來萃取，然後，在減壓的情況下 濃縮該有機層。最後，將得到的黃色固體溶解於 EtOAc (3毫升）中，再以石夕躍墊加以過濾（I?克 ，梯度從70% E t〇Ac/3〇％己院至10% M e Ο Η / 9 0 % EtOAc)以產生 Ν — (4 3 — ----------------·.-----訂 —-------- (請先閱讀背面之注意事項再填寫本頁) 氯 飯/甲基）苯基）一 Ν — （4 — (3 —甲基氨 基甲醯苯基）脲，此爲一種白色固體（0 · 〇97克， 4 1%) : rn ρ 225 — 2 29 ;TLc (1〇〇% 〕 * ί -* &gt; ί } ί 7 ·*· 5 ΰ 1269791 A7 B7 五、發明說明（83) , E t 0 A c ) R f 0.23。 (請先閱讀背面之注意事項再填寫本頁)NHMe Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative printed at 0 °C 'in the presence of N-(4-chloro-mono-3-((trifluoromethyl)phenyl)--(4-(3-methyl) Carbamate phenyl)carboxyaminophenyl)urea (0 · 14 g, 〇 · 48 mmol), 3-methylcarbamidine aniline (0.080 g, 0.53 mmol), Η〇ΒΤ·Η2〇 (〇·14 g, 1 · 〇7 mmol) and Ν-methylmorpholine (0.5 ml, 1 · 〇7 mmol) in DMF (3 ml) in water. Add EDCI.HC1 (〇· 1 gram, 〇·5 3 mmol, the resulting mixture was warmed to room temperature and stirred overnight. The resulting mixture was treated with water (1 mL) and then EtOAc (25 mL) To extract, then, the organic layer was concentrated under reduced pressure. Finally, the obtained yellow solid was dissolved in EtOAc (3 mL) E t〇Ac/3〇% 己至至10% M e Ο Η / 90% EtOAc) to produce Ν — (4 3 — ----------------·.- ----Book --------- (Please read the note on the back first Fill in this page again) Chlorinated rice / methyl) phenyl) - 4 - (4 - (3 - methylaminoformamidine phenyl) urea, which is a white solid (0 · 〇97 g, 4 1%): Rn ρ 225 — 2 29 ; TLc (1〇〇% 〕 * ί -* &gt; ί } ί 7 ·*· 5 ΰ 1269791 A7 B7 V. Inventive Note (83) , E t 0 A c ) R f 0.23. (Please read the notes on the back and fill out this page)

Die· 使用組合的方法來將ω —羧酸苯基脲轉變成ω 一（芳香基氨基甲醯）苯基脲。Ν -（4 一氯 基一3 —（（三氟甲基）苯基）一 Ν/ — (4 —(Ν — (3 — (Ν —（3 —吡啶基）氨基甲 、 醯）苯基）氨基甲醯）苯基）脲Die· uses a combined method to convert ω-carboxylic acid phenylurea to ω-(arylaminoformamidine)phenylurea. Ν-(4-Chloro-l-((trifluoromethyl)phenyl)-indole/(4—(Ν—(3 —(Ν—(3—pyridyl)aminomethyl, fluorenyl)phenyl) Methotrexate)phenyl)urea

將Ν — (4 -氯基一 3 —（（三氟甲基）苯基）一 — (3 —羧苯基）脲（方法Cl f : 〇 · 〇30克， 0 · 0 6 7毫莫耳）和N —環己基—N—(甲基聚苯乙嫌 )碳二亞胺（55毫克）在1 ，2 -二氯乙烷（1毫升） 的混合物，以3 -氨基吡啶的C Η 2 C 1 2 ( 1 Μ ; 經濟部智慧財產局員工消費合作社印製 〇· 074%毫升，〇 · 074毫莫耳）水溶液來加以處 理。（如果有不溶或混濁的情形，可以加入少量的 D M S 0 )。將所得的混合物在3 6 °C下加熱過夜。接下 來，用T H F ( 1毫升）來處理混濁反應，並且繼續加熱 1 8小時。將由此所得的混合物再以聚（4 一（異氰醯甲 基）苯乙烯）（0.040克）處理之，於36 °C下攪拌 7 2小時後，將之冷卻至室溫並過濾之。最後，將所得的 水溶液經由矽膠（1克）管塞進行過濾，並在減壓的情況 下進行濃縮以得到N —（4 一氯基一 3 —（（三氟甲基） 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -86-Ν —(4-Chloro-1,3-(3-trifluoromethyl)phenyl)-(3-carboxyphenyl)urea (Method Cl f : 〇· 〇 30 g, 0 · 0 6 7 mmol And a mixture of N-cyclohexyl-N-(methylpolyphenylene) carbodiimide (55 mg) in 1,2-dichloroethane (1 ml) with 3 -aminopyridine C Η 2 C 1 2 ( 1 Μ ; Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 〇 · 074% ml, 〇 · 074 mmol) aqueous solution to be treated. (If there is insoluble or turbid, you can add a small amount of DMS 0 The resulting mixture was heated overnight at 3 6 ° C. Next, the turbid reaction was treated with THF (1 mL), and heating was continued for 18 hours. The mixture thus obtained was again poly(4-(isocyanide). After treatment with 醯methyl)styrene) (0.040 g), after stirring at 36 ° C for 72 hours, it was cooled to room temperature and filtered. Finally, the obtained aqueous solution was passed through a silicone gel (1 g) plug. Filtration and concentration under reduced pressure to give N-(4-chloro-1,3-(3-trifluoromethyl) paper Applicable Chinese National Standard (CNS) A4 size (210 X 297 mm) -86-

經濟部智慧財產局員工消費合作社印製 1269791 Α7 Β7 五、發明說明（84) 苯基）一 — (4 — (N — (3 — (N — (3— 吡啶基 )氨基甲醯）苯基）氨基甲醯）苯基）脲（〇 · q24克 ，59%) : T L C ( 7 0 % Et〇Ac/3〇％ 己院 )R f 0 · 1 2。 D 2 * 將6^ -碳院氧基芳基脲類轉變成ω -氨基甲醯芳 .基脲類。Ν— (4 —氯基一 3 —（（三氟甲基） 苯基）一 Ν —（4 一（3 —曱基氨基甲醯苯基） 羧基氨苯基）脲的合成 ^.NHMe 〇 在N—（4一氯基一3—((三氟甲基）苯基）一 -（4 一（3 —碳甲氧苯基）羧基氨苯基）脲（ 0 · 17克，〇 · 34毫莫耳）的樣品中加入甲胺莫 耳濃度，在THF中，1毫升，1·7毫莫耳）。將所得 的混合物在室溫下攪拌過夜’並且在減壓下進行濃縮以得 到白色固體N—(4—氯基一3—（三氟甲基）苯基）一 N &gt; —（ 4 一（ 3 — ·甲基氨基甲醯苯基）羧基氨苯基）脲 :mp 247;TLC(l〇〇% E t 0 A c )Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, Printed 1269791 Α7 Β7 V. Description of Invention (84) Phenyl)-(4 — (N — (3 — (N — (3-)-pyridyl)carbamidine)phenyl) Methotrexate phenyl)urea (〇·q24 g, 59%): TLC (70% Et〇Ac/3〇% hexane) R f 0 · 1 2 . D 2 * converts 6^-carbon-yard oxyaryl ureas into ω-carbamyl aryl ureas. Ν-(4-Chloryl-3-((trifluoromethyl)phenyl)-anthracene-(4-(3-indolylaminocarboxamidinephenyl)carboxyaminophenyl)urea Synthesis ^.NHMe 〇 N-(4-chloro-3-((trifluoromethyl)phenyl)-(4-(3-carbomethoxyphenyl)carboxyaminophenyl)urea (0 · 17 g, 〇 · 34 m Methylamine concentration was added to the sample of Mohr) in THF, 1 mL, 1·7 mmol. The resulting mixture was stirred at room temperature overnight and concentrated under reduced pressure to give a white solid. N-(4-Chloryl-3-(trifluoromethyl)phenyl)-N &gt; -( 4 -( 3 - methylaminomethyl hydrazinophenyl)carboxyaminophenyl)urea: mp 247; TLC (l〇〇% E t 0 A c )

Rf 〇.35&gt;為灿 f?.r 斷彳, D 3 · 將ω -碳烷氧基芳基脲類轉變成ω -羧芳基脲類 。Ν— (4 —氯基—3—（三氟甲基）苯基）一 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） (請先閱讀背面之注意事項再填寫本頁} 訂---------線血 -87- A7 1269791 ______B7 ___- 五、發明說明（85 ) N 一（4 一羧苯基）脲的®成Rf 〇.35&gt; is a can of f?.r, D 3 · converts ω-carbon alkoxy aryl ureas into ω-carboxyaryl ureas. Ν—(4-Chloro-3-(trifluoromethyl)phenyl) is a paper scale applicable to China National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back and fill in the form) Page} Order---------Line blood-87- A7 1269791 ______B7 ___- V. Description of invention (85) N-(4-carboxyphenyl)urea®

在含Ν -（4 一氯基—3—(三氟甲基）苯基）一 N/— （4 —乙氧甲醯苯基）脲（方法Cle ; 5 · 93 克，15 · 3毫莫耳）的Me〇Η (75毫升）漿液中’ 加入ΚΟΗ水溶液（2 . 5Ν，10毫升，23毫莫耳） 。將所得的混合物在回流溫度下加熱1 2小時，然後冷卻 至室溫，再於減壓的情況下進行濃縮。接著用水（5 0毫 升）稀釋剩餘物並以1 N H C 1水溶液處理來將ρ Η値 調整到2至3之間。最後，收集所產生的固體並在減壓下 進行乾燥，以得到Ν — ( 4 —氯基—3 -（（三氟甲基） 苯基）一 Ν&gt;— (4 —羧苯基）脲，此爲一種白色固體（ 5 ·〇 5 克，9 2 % )。 D 4 * 將ω —院氧基酯類轉變成ω -院基醯胺類的一般 方法。Ν— (4 -氯基一 3 —（三氟甲基）苯基 )—— ( (4 — （3 — (5 — （2 —二甲氨 基乙基）氨基甲醯）吡啶基）氧苯基）脲的合成In the case of ruthenium-(4-chloro-3-(trifluoromethyl)phenyl)-N/-(4-ethoxymethyl phenyl)urea (Method Cle; 5 · 93 g, 15 · 3 mmol) Ears of Me〇Η (75 ml) in a slurry of 'added hydrazine solution (2.5 liters, 10 ml, 23 mM). The resulting mixture was heated at reflux temperature for 12 hours, then cooled to room temperature and concentrated under reduced pressure. The residue was then diluted with water (50 mL) and treated with 1 N H C 1 aqueous solution to adjust ρ Η値 to between 2 and 3. Finally, the solid produced is collected and dried under reduced pressure to give bis(4-chloro-3-((trifluoromethyl)phenyl)- hydrazine-(4-carboxyphenyl)urea. This is a white solid (5 · 〇 5 g, 92 %). D 4 * A general method for converting ω-homoyloxyesters into omega-homolinylamines.Ν—(4-Chloro-3 Synthesis of (-(trifluoromethyl)phenyl)-((4 — (3 — (5 — (2-dimethylaminoethyl)aminocarboxamidine)pyridyl)oxyphenyl)urea

步驟1 · Ν— (4 —氯基—3—(三氟甲基）苯基）— 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） ------r--------------訂 —--------線 (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 -88- 1269791 Δ7 Ά/ Β7 經濟部智慧財產局員工消費合作社印製 五、發明說明（86 N ^ ( 苯基）脲 4 — ( 3 —（ 5 -羧基吡啶基）氧 依類似於方法C 1 a的方式，從4 一氯基一 3 —(三 甲基）苯基異氰酸酯和4 一（ 3 — ( 5 -甲氧羰基d比π定 基）氧苯胺（方法A1 4，步驟2)來合成N -（4 —氯 基一 3 —（三氟甲基）苯基）Step 1 · Ν—(4-Chloro-3-(trifluoromethyl)phenyl)—This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) ------r- ------------- order --------- line (please read the note on the back and then fill out this page) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing -88- 1269791 Δ7 Ά/ Β7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description (86 N ^ (phenyl) urea 4 - ( 3 - ( 5 -carboxypyridyl) oxyhydroxide similar to the method C 1 a Synthesis of N-(4) from 4-chloro-3-(trimethyl)phenyl isocyanate and 4(3-(5-methoxycarbonyl d to π-decyl) oxyaniline (Method A1 4, Step 2) -Chloro-3-(trifluoromethyl)phenyl)

N 5—甲氧羰基吡啶基）氧苯基）脲。以K〇Η(〇· 克’ 2 · 5毫莫耳）的水（1毫升）溶液來處理Ν - (4 氛基一 3 —(二藏甲基）苯基） Ν 4 一（5 —甲氧羰基吡啶基）氧苯基）脲（〇 · 26克， 0 · 5 6毫莫耳）的M e Ο Η ( 1 〇毫升）懸浮液。然後 ，在室溫下將之攪拌1小時並將所得的混合物用1 Ν H C 1水溶液來調整ρ Η値至5。接下來經由過濾法移走 沉澱物並且以水沖洗之。將所得固體溶於E t〇Η ( 1〇 毫升），再於減壓下加以濃縮。然後，重覆上述E t〇Η /濃縮步 )苯基） 基）脲（0 步驟 (請先閱讀背面之注意事項再填寫本頁) 二次以得到N —（4 一氯基—3 —（三氟甲基 N —（ （4 一（3 —（5 —殘基吼π定基）氧苯 • 1 8 克，7 1 % )。N 5 —Methoxycarbonylpyridyl)oxyphenyl)urea. Treat Ν with a solution of K〇Η(〇·克 ' 2 · 5 mmol) in water (1 ml) - (4 aryl - 3 - (di-m-methyl) phenyl) Ν 4 - (5 - A A suspension of Me Ο Η (1 〇 ml) of oxycarbonylpyridyl)oxyphenyl)urea (〇·26 g, 0·5 6 mmol). Then, it was stirred at room temperature for 1 hour and the resulting mixture was adjusted to ρ 5 with 1 Ν H C 1 aqueous solution. The precipitate was then removed via filtration and rinsed with water. The obtained solid was dissolved in EtOAc (1 mL) and concentrated. Then, repeat the above E t 〇Η / concentration step) phenyl) ure) urea (0 step (please read the back of the note before filling this page) twice to get N - (4 chloro - 3 - ( Trifluoromethyl N — ((4 - (3 - (5 - residue 吼 π decyl) oxybenzene • 18 g, 71%).

N— (4 —氯基—3—(三氟甲基）苯基）— Ν’一 （ （4 — (3 — (5— (2 —二甲氨基 乙基）氨基甲醯）吡啶基）氧苯基）脲 -89 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） A7 1269791 _______B7____ 五、發明說明（87 ) * 將N —（4 一氯基一 3 —(三氟甲基）苯基）一 一（（4 一（ 3 -（ 5 -羧基吡啶基）氧苯基）脲（ 〇.05〇克，0 .〇11毫莫耳）N，N —二甲基乙二 胺（0·22毫克，0·17毫莫耳）’H〇BT( 〇· 028克，0 . 17毫莫耳）’N —甲基嗎啉（ 〇·〇35克，0 · 28毫莫耳）和EDCI ·Η(：1 ( 0 . 032克，0 · 17毫莫耳）於DMF (2 · 5毫升 )中的混合物在室溫下攪拌過夜。將所得的水溶液在N-(4-Chloryl-3-(trifluoromethyl)phenyl)- Ν'-((4 - (3 - (5-(2-dimethylamino)))) Phenyl)urea-89 - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) A7 1269791 _______B7____ V. Description of invention (87) * Will N - (4 - chloro group - 3 - (three Fluoromethyl)phenyl)-((4-(3-carboxypyridyl)oxyphenyl)urea (〇.05〇克, 0.〇11mmol) N,N-dimethyl Ethylenediamine (0·22 mg, 0·17 mmol) 'H〇BT (〇·028 g, 0.17 mmol) 'N-methylmorpholine (〇·〇 35 g, 0 · 28 Mix the mixture of DMCI and EDCI · Η (: 1 (0. 032 g, 0 · 17 mmol) in DMF (2.5 ml) at room temperature overnight.

Et〇Ac (50毫升）和水（50毫升）之間進行分_ 。接著以水（3 5毫升）沖洗有機層、乾燥（M 2 S 〇 4 } 之，然後在減壓下進行濃縮。最後，將剩餘物溶解於戚/ ^ /滴滴 量的CH2C 12 (大約2毫升）中，再將E t2〇 (三 地加入其中以處理之，可得到N —（ 4 一氯基—3 一 一 氟甲基）苯基）一Ν〃 —（ （4— (3— (5— (2 甲氨基乙基）氨基甲醯）吡啶基）氧苯基）脲的白€ __ d 6 物（〇· 48 克，84%:'Η NMR (DMS〇〆 )5 2-10(s^6H) ^3-26(s^H) ---------------------^--------- (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 3 0 3 9 4 2 0 6 4 6 1 2 • · · · * LCD 7 7 8 8 9Between Et〇Ac (50 ml) and water (50 ml). The organic layer was then washed with water (35 ml), dried (M 2 S 〇 4 } and then concentrated under reduced pressure. Finally, the residue was dissolved in 戚 / ^ / drop of CH 2 C 12 (about 2 In ML), E t2 〇 (addition of three places to treat it, N - ( 4 - chloro - 3 - fluoromethyl) phenyl) - (4 - (3 - ( 5-(2-Methylaminoethyl)carbamidine)pyridyl)oxyphenyl)urea white __d 6 (〇· 48 g, 84%: 'Η NMR (DMS〇〆) 5 2-10 ( s^6H) ^3-26(s^H) ---------------------^--------- (Please read the back Note: Please fill out this page again) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 3 0 3 9 4 2 0 6 4 6 1 2 • · · · * LCD 7 7 8 8 9

本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -90- 1269791 Α7 Β7 五、發明說明（88) , (請先閱讀背面之注意事項再填寫本頁) D 5 · 將N —（ ω -甲矽烷氧基氧烷基）醯胺類去保護 的一般方法。Ν — ( 4 —氯基一 3 —三氟甲 基）本基）—Ν — (4 -（4— (2— (Ν — (2 -羥基）乙基氨基甲醯）吡啶氧基苯基）脲 的合成This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) -90-1269791 Α7 Β7 5. Inventive Note (88), (Please read the note on the back and fill in this page) D 5 · Will A general method for the deprotection of N-(ω-formose oxyoxyalkyl) decylamines. Ν —( 4 —Chloro-3-trifluoromethyl) benzyl) —Ν —(4-(4-(2-hydroxy)ethylaminopyridinium)pyridinyloxyphenyl) Synthesis of urea

在含Ν —（4 —氯基—3 —((三氟甲基）苯基）— 一（4 — (4 — (2 —（Ν —（2 —三異丙基甲矽烷 氧基）乙基氨基甲醯）吡啶氧基苯基）脲（以類似方法 Cla中的方式來製備；〇 · 25克，0 · 37毫莫耳） 的無水T H F溶液中加入四丁銨化氟（1 · 〇莫耳濃度， 經濟部智慧財產局員工消費合作社印製 在丁 H F中；2毫升）。將混合物在室溫下攪拌5分鐘， 以水（1 0毫升）處理之。接著，以E t〇A c ( 3 X 1，〇毫升）來萃取水溶性混合物，將合倂的有機層加以乾 燥（M g S 0 4 )後，再於減壓下加以濃縮，並以管柱層析 法（S i〇2;梯度從1〇〇%己烷至40% Et〇Ac / 6 0 %己烷）將剩餘物加以純化以產生N -（ 4 一氯基 —3 -（（三氟甲基）苯基）——（4 — (4 — (2 一（N -羥基）乙基氨基甲醯）吡啶氧基苯基）脲’此爲 一種白色固體（〇·〇19克，1〇％)。 下面所列的化合物爲列於下列表格中依照上面所詳述 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -91 -Containing Ν-(4-chloro-(3-(trifluoromethyl)phenyl)-(4-(4-(2-(2-(2-(2-(-)--------- Methamido)pyridinyloxyphenyl)urea (prepared in a similar manner as in the process of Cla; 〇·25 g, 0 · 37 mmol) in tetrahydroammonium fluoride (1 · 〇 Mo Ear concentration, printed by the Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative in Ding HF; 2 ml). The mixture was stirred at room temperature for 5 minutes, treated with water (10 ml). Then, with E t〇A c (3 X 1, 〇 ml) to extract the water-soluble mixture, and the combined organic layer was dried (M g S 0 4 ), and then concentrated under reduced pressure, and subjected to column chromatography (S i 〇 2; gradient from 1% hexane to 40% Et〇Ac / 60% hexane) The residue was purified to give N-(4-chloro-3-((trifluoromethyl)phenyl) - (4 - (4 - (2 - (N-hydroxy) ethylaminomethionine) pyridyloxyphenyl) urea 'This is a white solid (〇·〇 19 g, 1%). Compound for column The following table in accordance with the above, this paper detailed scale applicable to Chinese National Standard (CNS) A4 size (210 X 297 mm) -91--

甲基氨基甲醯苯氧基）苯胺反應以得到脲 1269791 五、發明說明（89) 的實驗步驟來合成的化合物： 示範之化合物的合成法 (化合物的特性可以參考表格） 一目1 ·根據A 1 3方法製造4 一（ 3 — N —甲基氨基甲 醯苯氧基）苯胺。根據C 3方法，先將3 一特一丁基苯胺 與雙（二氯甲基）碳酸酯進行反應，接著再與4 一（ 3 一Methylaminopyridinium phenoxy)aniline reaction to obtain urea 1269791 V. Compounds synthesized by the experimental procedure of Invention (89): Synthesis of exemplary compounds (characteristics of compounds can be referred to the table) Monom 1 · According to A 1 3 Method for the preparation of 4-(3-N-methylaminoformamidine phenoxy)aniline. According to the C 3 method, 3-tert-butylaniline is first reacted with bis(dichloromethyl)carbonate, followed by 4 (3)

N 項目2 :根據方法a 1 3，步驟1將4 一氟基一 l —硝基 本和對一羥基乙醯苯進行反應以得到4 一（ 4 一乙醯苯氧 基）一1 一硝基苯。根據方法A1 3，步驟4，將4 一（ 4 一乙醯苯氧基）一 1 一硝基苯還原以得到4一（4_乙 醯苯氧基）苯胺。根據方法C 3，將3 -特一丁基苯胺先 與雙（三氯甲基）碳酸酯進行反應再與4 一（ 4 一乙醯苯 氧基）本I女反應以得到脈。 項目3 :根據方法C 2 d，將3 —特—丁基苯胺以C D I 進行處理’接下來，再以根據方法A 8製造的4 一（ 3 -N -甲基氨基甲醯）一 4 一甲氧基苯氧基）苯胺來處理之 以得到脲。 項目4 :根據方法B1 ，將5 -特一 丁基一 2 —甲氧基苯 胺轉變成5 -特- 丁基- 2 -甲氧基苯基異氰酸酯。將根 據方法A 1 3製造的4— ( 3 - N —甲基氨基甲醯苯氧基 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） ---------------------訂---------線 (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 -92- 1269791 A7 ___：_ B7____ 一 五、發明說明（90 ) · )苯胺’與根據方法c 1 a製得的異氰酸酯進行反應以得 到脲。 項目5 :根據方法C2d，將5 —特一 丁基一 2 -甲氧基 苯胺先與CD I反應，再與根據方法as所製造的4—( 3 — N —甲基氨基甲醯）·— 4 一甲氧基苯氧基）苯胺進行 反應以得到脲。 項目6:根據方法A3來製造5-（4一氨基苯氧基）異 吲哚滿一 1 ，3 -二酮。將根據方法2 d製得的5 -特一 丁基- 2 -甲氧基苯胺先與CD I產生反應，接著再與5 一（4 一氨基苯氧基）異吲哚滿一 1 ，3 一二酮進行反應 以得脲。 項目7 ··根據方法a 1 2來合成4 一（ 1 一酮基異吲哚滿 一 5 -基氧基）苯胺。將根據方法2 d製得的5 —特一丁 基一 2 -甲氧基苯胺先與CD I反應再與4 一（ 1 一酮基 異吲哚滿- 5 -基氧基）苯胺進行反應以得脲。 項目8 ··根據方法A1 3來合成4 一（3 — N —甲基氨基 甲醯苯氧基）苯胺。將根據方法C 2 a所製得的2 —甲氧 基—5 -（三氟甲基）苯胺先與CD I反應，再與4 —( 3 - N -甲基氨基甲醯苯氧基）苯胺進行反應以得脲。 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） (請先閱讀背面之注意事項再填寫本頁)N Item 2: According to the method a 1 3, step 1 is to react 4-fluoro-mono-nitro- and hydroxy-p-hydroxybenzene to obtain 4-(4-ethoxyphenoxy)-l-nitrobenzene. . 4-(4-Ethylphenoxy)-mononitrobenzene is reduced according to Method A1 3, Step 4 to give 4-(4-ethylphenoxy)aniline. According to the method C 3, 3-tert-butylaniline is first reacted with bis(trichloromethyl)carbonate and then reacted with 4-(tetramethyloxy)oxyl to obtain a vein. Item 3: Treatment of 3-tert-butylaniline in CDI according to method C 2 d 'Next, followed by 4-(3-N-methylaminomethylhydrazine)-4A manufactured according to Method A8 Oxyphenoxy)aniline is treated to give urea. Item 4: According to Method B1, 5-tert-butyl-2-methoxyaniline was converted to 5-tert-butyl-2-methoxyphenyl isocyanate. The 4-(3-N-methylaminoformamidine phenoxy) paper manufactured according to Method A1 3 applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) --------- ------------Book---------Line (please read the notes on the back and fill out this page) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed -92- 1269791 A7 ___: _ B7____ 1-5, invention description (90) ·) Aniline' is reacted with an isocyanate prepared according to method c 1 a to obtain urea. Item 5: According to the method C2d, 5-tert-butyl-2-methoxyaniline is first reacted with CD I and then with 4-(3-N-methylaminocarbamidine) manufactured according to the method as. 4-Methoxyphenoxy)aniline is reacted to obtain urea. Item 6: 5-(4-Aminophenoxy)isoindan-1,3-dione was produced according to Method A3. The 5-tert-butyl-2-methoxyaniline prepared according to the method 2 d is first reacted with CD I, and then with 5-(4-aminophenoxy)isoindole 1 , 3 The diketone is reacted to obtain urea. Item 7 · Synthesis of 4-(1-ketoisoindan-5-yloxy)aniline according to Method a 1 2 . The 5-tert-butyl-2-methoxyaniline prepared according to the method 2 d is first reacted with CD I and then reacted with 4 -( 1 -ketoisoindan-5-yloxy)aniline to Get urea. Item 8 · Synthesis of 4-(3-N-methylaminomethanephenoxy)aniline according to Method A1 3 . The 2-methoxy-5-(trifluoromethyl)aniline prepared according to the method C 2 a is first reacted with CD I and then with 4-(3-N-methylaminomethylphenoxy)aniline The reaction is carried out to obtain urea. This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back and fill out this page)

經濟部智慧財產局員工消費合作社印制农 -93- 1269791 A7 B7 經濟部智慧財產局員工消費合作社印製 五、發明說明（91 ) 項目9 ·根據方法a 3 ，步驟2 ，將4 一羥基乙醯苯與2 一氯基一 5 一硝基吡啶進行反應以得4 一（ 4 —乙醯苯氧 基）一 5 -硝基吡啶。根據方法a 8，步驟4，將4 一（ 4 —乙醯本氧基）一 5 —硝基d比d定還原至4 一（4 —乙醯 苯氧基）—5 —氨基吡啶。接下來根據方法b 1 ，將2 _ 甲氧基一 5 — （三氟甲基）苯胺轉變成2 一甲氧基一 5 一 (二氧甲基）苯基異氰酸酯。最後，根據方法C 1 a ，將 異氰酸酯與4 一（4 一乙酸基苯氧基）一 5 -氨基吡啶反 應以產生脲。 項目1 0 :根據方法A 1 3，步驟1 ，將4 —氟基—1 — 硝基苯與對-羥苯乙酮進行反應以得到4 一（ 4 一乙醯苯 氧基）—1 一硝基苯。根據方法A 1 3，步驟4，將4 — (4 一乙醯本氧基）—1 一硝基苯進行還原以產生4 一（ 4 一乙醯苯氧基）苯胺。根據方法C 3 ，先將5 —（三氟 甲基）- 2 —甲氧基丁基苯胺與雙（三氯甲基）碳酸酯進 行反應再與4 一（ 4 -乙醯苯氧基）苯胺反應以得到脲。 項目1 1 :先根據方法A2，步驟3 a來合成4 一氯基一 N -甲基一 2 -吡啶羧醯胺，再將之根據方法A 2，步驟 4來與3 -氨基酚進行反應，但是以DMA C來取代 DMF，如此可得3 —（一 2— (N —甲基氨基甲驢）一 4 一卩比卩定氧基）本脈。根據方法C 4 ’將2 —甲氧基一 5 一（三氟甲基）苯胺與光氣反應，再接著與3 -（一 2 — ------I----- (請先閱讀背面之注意事項再填寫本頁) 訂i&quot;-- 绫·丨 本纸張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -94- 1269791 A7 B7 經 Μ 部 智 慧 財 產 局 員 工 消 費 合 作 社 印 製 五、發明說明（92 N—甲基氨基甲醯）一4-吡啶氧基）苯胺反應以產生 脲 項目1 2 :根據方法A 2，步驟3 b ，將4〜氯吼陡_ 2 -羯酸氣與氣進fl*反應以形成4 一氯基- 2 - 定殘醒胺 。根據方法A 2 ’步驟4 ’將4 —氯基一 2 —吼聢殘醯胺 與3 —氨基酚進行反應’但以D M A C取代D M F，如此 可得3 -（ 2 —热基甲釀一 4 一吼d定氧基）苯胺。根據方 法C2 a ，將2 —甲氧基一 5 —（三氟甲基）苯胺與光氣 進行反應，再與3— ( 2 -氨基甲醯一 4 —吡d定氧基）苯 胺反應以產生脲。 項目1 3 :根據方法A 2 ’步驟3 b來合成4 一氯基一 Ν —甲基—2 -吡啶羧醯胺。根據方法a 2 ，步驟4，將4 一氯基一 N —甲基—2 —吡陡羧醯胺與4 一氨基酣進行反 應，但以D M A C取代D M F，如此可得4 一（ 2 —（ n -甲基氨’基甲醯）—4 —吡啶氧基）苯胺。根據方法 C2a ，將2 —甲氧基—5 —（三氟甲基）苯胺與cDl 進行反應，再接著與4 一（2 -（N -甲基氨基甲醯）〜 4 -吼陡氧基）苯胺反應以得到脲。 項目1 4 :根據方法a 2，步驟3 b ，將4 一氯吡D定—2 一羰醯氯H C 1鹽與氯進行反應以形成4 一氯基〜2 啶羧醯胺。根據方法A 2，步驟4，將4 一氯基 ---------------------訂 —-------- (請先閱讀背面之注意事項再填寫本頁) 吡 吡 2 -95 1269791 經濟部智慧財產局員工消費合作社印制衣 A7 B7 五、發明說明（93) » » 陡殘_胺與4 一氨基酚進行反應，但以〇 M A C取代 D M F以得到4 一（ 2 —氨基甲醯一 4 —吡啶氧基）苯胺 。根據方法C4，將2 —甲氧基一 5 —（三氟甲基）苯胺 與光氣進行反應，再與4 — (2 -氨基甲醯一 4 一吡啶氧 基）苯胺進行反應以得到脲。 項目15 :根據方法C2d，將5—(三氟甲基）一 2 — 甲氧基苯胺先與C D I反應，再與根據方法a 8製得的4 一 （3 — N —甲基氨基甲醯）一 4 一甲氧基苯氧基）苯胺 反應以得到脲。 項目16 ··根據方法A5合成4 一（2 —（N —甲基氨基 甲醯）一 4 一吼D疋氧基）—2 —甲基苯胺。根據方法B1 ，將5 —（二裁甲基）一 2 -甲氧基苯胺轉變成5—(三 氟甲基）-2-甲氧苯基異氰酸酯。接下來，根據方法 Cl c ’將異氰酸酯與4 一（2 —甲基氨基甲醯）一 4 一 吡啶氧基）- 2 —甲基苯胺產生反應以得到脲。 項目17 :根據方法A6合成4 一（2— (N —甲基氨基 甲醯）一 4 一吼B定氧基）—2 一氯苯胺。根據方法b 1將 5 -（三氟甲基）一 2 —甲氧基苯胺變換成5 — （三氟甲 基）一 2 —甲氧苯基 異氰酸鹽。接著根據方法c 1 a ， 5 —（三氟甲基）一 2 —甲氧苯基 異氰酸鹽與4 一（2 一（N —甲基氨基甲醯）—4 一（吡π定基氧）一 2 —氯苯 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -------------裝--------訂--------- I (請先閱讀背面之注意事項再填寫本頁) -96- 1269791 A7 B7 經濟部智慧財產局員工消費合作社印製 五、發明說明（94) ^ 胺反應以得到脲。 項目18 :根據方法A2，步驟4，將5 —氨基一2 —甲 酚與經由根據方法A 2 ，步驟3 b合成的4 —氯基一 N - 甲基一 2 —吡啶羧醯胺反應以得到3 — ( 2 — n —甲基氨 ♦ 基曱醯）—4 一吡啶氧基）一 4〜甲基苯胺。接著根據方 法B1 ，將5 —（三氟甲基）一 2 一甲氧基苯胺轉變成5 一（三氟甲基）一 2 —甲氧苯基異氰酸酯。最後，根據方 法C 1 a讓5 —（三氟甲基）一 2 —甲氧苯基異氰酸酯與 3 — （2 — N —甲基氛基甲醯）一 d比d定氧基）一4 一 甲基苯胺進行反應以得到脲。 項目1 9 .根據方法A 2 ’步驟3 b，將4 一氯批11定—2 一羰醯氯與乙胺反應以得到4 一氯基一 N_乙基一 2 —吡 啶羧醯胺。將此化合物再根據方法A 2，步驟4與4 -氨 基酚反應，以得到4 一（2 —（N —乙基氨基甲醯）一 4 一吡啶氧基）苯胺。接著，根據方法B 1 ，將5 —（三氟 甲基）一 2 —甲氧苯胺變換成5 —(三氟甲基）一 2 —甲 氧苯基異氰酸酯。最後，根據方法Cl a ，將5 —（三氟 甲基）一2 —甲氧苯基異氰酸酯與4— (2 — （N —乙基 氨基甲醯）- 4 -吡啶氧基）苯胺反應以得到脲。 項目20，根據方法A2，步驟4，將4 一氨基—2 -氯 酚與4 -氯基一 N -甲基一 2 -吡啶羧醯胺（根據方法 本纸張尺度適用中國國家標準（CNS)A4規格(210 X 297公釐） 71 ---------------------訂--------- (請先閱讀背面之注意事項再填寫本頁) A7Ministry of Economic Affairs, Intellectual Property Bureau, Staff and Consumer Cooperatives, Printing Agriculture-93- 1269791 A7 B7 Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives, Printing 5, Inventions (91) Item 9 · According to Method a 3, Step 2, 4 hydroxy B The indenebenzene is reacted with 2-chloro-5-nitropyridine to give 4-(4-ethoxyphenoxy)-5-nitropyridine. According to the method a 8, step 4, 4 -( 4 -ethenyloxy)-5 -nitrod d is reduced to 4 -(4-ethoxyphenoxy)-5-aminopyridine. Next, according to the method b 1 , 2 -methoxy-5-(trifluoromethyl)aniline was converted into 2-methoxy-5-(dioxymethyl)phenyl isocyanate. Finally, according to the method C 1 a , the isocyanate is reacted with 4-(4-acetoxyphenoxy)-5-aminopyridine to produce urea. Item 10: According to the method A 1 3, step 1, 4-fluoro-l-nitrobenzene is reacted with p-hydroxyacetophenone to obtain 4 (4-ethyl phenoxy)-1 Base benzene. According to the method A 1 3, step 4, 4-(4-acetamidooxy)-1 mononitrobenzene is reduced to give 4-(4-methoxyphenoxy)aniline. According to the method C 3 , 5-(trifluoromethyl)-2-methoxybutylaniline is first reacted with bis(trichloromethyl) carbonate and then with 4-(4-ethoxyphenoxy)aniline The reaction is carried out to obtain urea. Item 1 1 : First, according to Method A2, Step 3a, 4-chloro-N-methyl-2-pyridine carboxamide is synthesized, and then reacted with 3-aminophenol according to Method A 2, Step 4. However, DMF is replaced by DMA C, so that 3-(2-2-(N-methylaminoformamidine)-4 卩 卩 氧基 氧基 氧基) is obtained. According to the method C 4 ', 2-methoxy-5-(trifluoromethyl)aniline is reacted with phosgene, followed by 3 - (2 - ------I----- Read the notes on the back and fill out this page. Book i&quot;-- 绫·丨本纸标准Applicable to China National Standard (CNS) A4 Specification (210 X 297 mm) -94- 1269791 A7 B7 Economics Department Intellectual Property Bureau Employees' consumption cooperatives printed five, invention instructions (92 N-methylaminoformamidine)- 4-pyridyloxy) aniline reaction to produce urea project 1 2: according to method A 2, step 3 b, 4~ chloranthene steep _ 2 - decanoic acid reacts with gas into fl* to form 4-chloro- 2 - hydrazine. According to the method A 2 'Step 4', the 4-chloro- 2-anthracene residue is reacted with 3-aminophenol, but the DMF is replaced by DMAC, so that 3 - ( 2 - heat-based one-four-one is obtained吼d alkoxy) aniline. According to the method C2 a , 2-methoxy-5-(trifluoromethyl)aniline is reacted with phosgene, and then reacted with 3-(2-aminocarboxamidine-4-pyridoxy)aniline to produce Urea. Item 13: Synthesis of 4-chloro-mono-methyl-2-pyridine carboxamide according to Method A 2 'Step 3 b. According to the method a 2 , step 4, 4-chloro-N-methyl-2-pyridinium carboxamide is reacted with 4-amino hydrazine, but DMF is substituted for DMF, thus obtaining 4 (2 - (n) -Methylamino 'carbamyl)-4-pyridyloxy)aniline. According to the method C2a, 2-methoxy-5-(trifluoromethyl)aniline is reacted with cD1, followed by 4 (2-(N-methylaminocarbamidine)~4-anthraceoxy) The aniline is reacted to obtain urea. Item 14: According to method a 2, step 3 b, 4 -chloropyridinium di- 2 -carbonylonium chloride H C 1 salt is reacted with chlorine to form 4-chloro- 2 -pyridinium carboxamide. According to method A 2, step 4, 4 chloro------------------------------- (please read the back Precautions and then fill out this page) Pipi 2 -95 1269791 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed Clothing A7 B7 V. Inventions (93) » » Steep Residues - Amine reacts with 4-aminophenol, but The MAC is substituted for DMF to give 4-(2-aminocarboxamidine-4-pyridyloxy)aniline. According to the method C4, 2-methoxy-5-(trifluoromethyl)aniline is reacted with phosgene, and then reacted with 4-(2-aminopyridinium-4-pyridyloxy)aniline to obtain urea. Item 15: According to method C2d, 5-(trifluoromethyl)-2-methoxyaniline is first reacted with CDI and then with 4-(3-N-methylaminoformamidine) prepared according to method a8. A 4-methoxyphenoxy)aniline is reacted to obtain a urea. Item 16 · Synthesis of 4-(2-(N-methylaminocarbamazepine)-4-ylindoleoxy)-2-methylaniline according to Method A5. According to the method B1, 5-(dimethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate. Next, an isocyanate is reacted with 4-(2-methylaminoformamidine)-4-pyridyloxy)-2-methylaniline according to the method Cl c ' to obtain a urea. Item 17: Synthesis of 4-(2-(N-methylaminomethylhydrazine)-4 吼B-oxyl)-2 monochloroaniline according to Method A6. 5-(Trifluoromethyl)-2-methoxyaniline was converted to 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method b1. Then according to the method c 1 a , 5-(trifluoromethyl)-2-methoxyphenyl isocyanate and 4-(2-(N-methylaminocarbamidine)-4(pyridinyloxy) A 2-chlorobenzene paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) -------------Installation--------Set--- ------ I (please read the note on the back and fill out this page) -96- 1269791 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed V. Inventions (94) ^ Amine reaction to obtain urea. Item 18: According to Method A2, Step 4, 5-Amino-2- cresol is reacted with 4-chloro-N-methyl-2-pyridine carboxamide synthesized according to Method A 2, Step 3 b to give 3 — ( 2 — n —methylamino ♦ hydrazide — — 4 -pyridyloxy)- 4-methylaniline. Next, according to the method B1, 5-(trifluoromethyl)-2-methoxyaniline is converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate. Finally, according to the method C 1 a, 5-(trifluoromethyl)-2-methoxyphenyl isocyanate is substituted with 3-(2-N-methylmethylcarbamidine)-d-d-oxyl group. The methylaniline is reacted to obtain urea. Item 19. 9. According to the method A 2 'Step 3 b, 4 -chlorobenzene 11 - 2 -carbonylcarbonyl chloride is reacted with ethylamine to give 4-chloro-N-ethyl-2-pyridinium carboxamide. This compound is further reacted with 4-aminophenol according to Method A 2, Step 4 to give 4-(2-(N-ethylaminocarbazide)-4-pyridyloxy)aniline. Next, 5-(trifluoromethyl)-2-methoxyaniline was converted to 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1. Finally, according to the method Cl a , 5-(trifluoromethyl)-2-methoxyphenyl isocyanate is reacted with 4-(2-(N-ethylaminoformamidine)-4-pyridyloxy)aniline to obtain Urea. Item 20, according to method A2, step 4, 4-amino-2-chlorophenol and 4-chloro-N-methyl-2-pyridine carboxamide (according to the method of this paper scale applicable to China National Standard (CNS) A4 size (210 X 297 mm) 71 --------------------- Order --------- (Please read the notes on the back first. Fill in this page) A7

1269791 五、發明說明（95 ：) A2 ，步驟3b合成）進行反應以得4 一（2— N —甲基 氨基甲醯）一 4 一吡啶氧基）一 3 -氯苯胺。根據方法b ’將5 — （三氟甲基）一 2 —甲氧苯胺變換成5 —（H氟 甲基）一2—甲氧苯基異氰酸酯。接著根據方法cia , 將5 —（三氟甲基）一 2 一甲氧苯基異氰酸酯與4〜（2 一（N —甲基氨基甲醯）一 4一吡啶氧基）_3_氯苯胺 進行反應以得到脲。 項目21 :根據方法A19 ，步驟1 ，將4 — (4 一甲硫 基苯氧基）一 1一硝基苯氧化或4 一（ 4 一甲磺醯苯氧基 )一 1 一硝基苯。將此硝基苯再根據方法A 1 9 ，步驟2 還原成4 — (4 一甲磺醯苯氧基）—1—苯胺。接著，根 據方法C 1 a ’將5 —(三氟甲基）一2 —甲氧苯基異氰 酸酯與4 -（甲磺醯苯氧基）—1 一苯胺進行反應以得到 脲0 ----------------------訂--------- (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 ， | οα 4 4 1 驟成 C 步原法 ， 還方 5 苯據 1 基根 Α 硝， 法 I 來 方 1 下 據 I 接 根} ο : 基胺 2 氧苯 2 苯 } 目醯基 項甲氧 脲 •1^ 異辱 基⑴ 苯應 氧反 甲行 - 進 2 胺 _ 苯 \)/ \ϊ/ 基基 4 與 酯 酸 氰 基苯甲氧 氨醯氟苯 I 甲三醯 3 基 C 甲 {氨一基 I I 5 氨 4 3 將 | 將 C ， 3 一 B 5 法 成方 合據 3 根 A 。 法酮 方二 據 I 根 3 0〇 IX 2 | 目哚 項 _ 異基 Nly 甲 基氟 氧三 苯C 基| 氨 5 I 將 4 ， 本紙張尺度適用17 @ @家標準(CNS)A4規格（210 X 297公爱） -98- 1269791 A7 B7 五、發明說明（96) , )一 2 —甲氧苯胺轉變成5 — （三氟甲基）一2 —甲氧苯 基異氰酸酯。接著根據方法C 1 a ，讓5 -（三氟甲基） 一 2 —甲氧苯基異氰酸酯與5 —（ 4 一氨基苯氧基）異吲 哚滿一 1，3 —二酮進行反應以得到脲。 項目2 4 :根據方法A 2，步驟3 b ，將4 —氯吡啶—2 一羰醯氯與二甲胺進行反應，所得的4 —氯基—N，N -二甲基一 2 -吡啶羧醯胺再根據方法A 2 ，步驟4與4 — 氨酚反應而得4 一（2 — (N，N —二甲基氨基甲醯一 4 一吡啶氧基）苯胺。接下來，根據方法B 1 ，將5 -（三 氟甲基）一 2 —甲氧苯胺變換成5 —（三氟甲基）一2 — 甲氧苯基異氰酸酯。最後，根據方法Cl a ，5 —（三氟 甲基）一2 —甲氧苯基異氰酸酯與4 一（2 —（N，N — 二甲基氨基甲醯）- 4 -吡啶氧基）苯胺進行反應以得到 脲。 項目2 5 :根據方法A 1 2來合成4 一（ 1 一酮基異吲哚 滿一 5 -基氧基）苯胺，接下來，再根據方法C2d (先 以CD I處理5 —（三氟甲基）一 2 —甲氧基苯胺，再以 4 一（ 1 一酮基異吲哚滿一 5 -基氧基）苯胺處理之，以 得到脲。 項目2 6 :根據方法A 1 3 ，步辱1 ，將4 —羥苯乙酮與 4 一氟基硝基苯進行反應以得到4 一（ 4 一乙醯苯氧基） 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） ------I----- (請先閱讀背面之注意事項再填寫本頁) 11111 經濟部智慧財產局員工消費合作社印製 1269791 A7 B7 五、發明說明（97) (請先閱讀背面之注意事項再填寫本頁) 硝基苯。接下來，根據方法A 1 3 ，步驟4，將硝基苯還 原成4 一 （4 一乙醯苯氧基）苯胺，再根據方法A16 ， 將4 一（ 4 一乙醯苯氧基）苯胺變換成4 一（ 4 一（ 1 — (N—甲氧基）亞胺乙基）苯氧基苯胺 HC1鹽。根據 方法B1 ，將5 —（三氟甲基）一 2 —甲氧基苯胺轉變成 5 —（三氟甲基）一 2 —甲氧苯基異氰酸酯，最後，根據 方法C 1 a讓（5 —（三氟甲基）一 2 —甲氧苯基異氰酸 酯與4 一（4 一（1 一（N —甲氧）亞胺乙基）苯氧基苯 胺 H C 1鹽進行反應以得到脲。 項目27 :根據方法Α2，步驟3b來合成4 一氯基一 Ν -甲基吡啶羧醯胺。接著根據方法A 2 ，步驟4，將氯吡 啶4 一氨基硫酚進行反應以得到4 一（ 4 一（ 2 -甲基氨 基甲醯）苯硫基）苯胺。經由方法B 1 ，將5 — （三氟甲 基）一 2 —甲氧基苯胺變換成5 — （三氟甲基）一 2 —甲 氧苯基異氰酸酯。最後，根據方法C 1 a ，將5 —（三氟 甲基）一 2 —甲氧苯基異氰酸酯與4 — (4 一 （2 — （N -甲基氨基甲醯）苯硫基）苯胺進行反應以得到脲。 經濟部智慧財產局員工消費合作社印制衣 項目28 :根據方法A9合成5 -（4 一氨基苯氧基）一 2 -甲基異吲哚滿一 1 ，3 —二酮。根據方法B 1 ，將5 -（三氟甲基）一 2 —甲氧苯基異氰酸酯。接著，根據方 法C la ，將5 —(三氟甲基）一 2 —甲氧苯基異氰酸酯 與5 —（4 一氨基苯氧基）一 2 —甲基異吲哚滿一 1 ，3 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -100- 1269791 五、發明說明（98) -二酮進行反應，以得到脲。 (請先閱讀背面之注意事項再填寫本頁)1269791 V. INSTRUCTION DESCRIPTION (95:) A2, step 3b synthesis) The reaction is carried out to give 4-(2-N-methylaminocarbamidine)-4-pyridyloxy)-3-chloroaniline. The 5-(trifluoromethyl)-2-methoxyaniline was converted to 5-(H-fluoromethyl)-2-methoxyphenyl isocyanate according to the method b'. Next, according to the method cia, 5-(trifluoromethyl)-2-methoxyphenyl isocyanate is reacted with 4~(2-(N-methylaminoformamidine)-4-pyridyloxy)_3-chloroaniline To obtain urea. Item 21: Oxidation of 4-(4-methylthiophenoxy)-mononitrobenzene or 4-(4-monosulfonylphenoxy)-mononitrobenzene according to Method A19, Step 1. This nitrobenzene is then reduced to 4-(4-methanesulfonylphenoxy)-1-phenylamine according to Method A1 9 and Step 2. Next, 5-(trifluoromethyl)-2-methoxyphenyl isocyanate is reacted with 4-(methylsulfonylphenoxy)-1 monoaniline according to the method C 1 a ' to obtain urea 0 ---- ------------------Book --------- (Please read the note on the back and then fill out this page) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative System, | οα 4 4 1 The first step is C, and the other is 5 benzene according to 1 base Α nitrate, method I to 1 according to I root} ο : amide 2 oxybenzene 2 benzene} Methionine•1^Insult base (1) Benzene oxygen anti-A line - 2 amine _ benzene \) / \ϊ / base 4 and ester cyanobenzoic acid fluorobenzene I 甲三醯 3 base C A {Amino-based II 5 Ammonia 4 3 will | C, 3 - B 5 method into a combination of 3 A. The ketone side is based on I root 3 0 〇 IX 2 | 目目 _ hetero-based Nly methyl fluorooxytriphenyl C-based | ammonia 5 I will 4, the paper scale applies 17 @ @家标准(CNS)A4 specification ( 210 X 297 gong) -98- 1269791 A7 B7 V. Inventive Note (96) , ) 2- methoxyaniline is converted to 5-(trifluoromethyl)-2-methoxyphenyl isocyanate. Next, according to the method C 1 a , 5-(trifluoromethyl)-2-methoxyphenyl isocyanate is reacted with 5-(4-aminophenoxy)isoindole-1,3-dione to obtain Urea. Item 2 4: According to the method A 2, step 3 b, 4-chloropyridin-2-carboindole chloride is reacted with dimethylamine to obtain 4-chloro-N,N-dimethyl-2-pyridine carboxylate. The guanamine is then reacted according to Method A 2 , Step 4 and 4 - Aminophenol to give 4-(N-N-dimethylaminoformamidine-4-pyridinyloxy)aniline. Next, according to Method B 1 Conversion of 5-(trifluoromethyl)-2-methoxyaniline to 5-(trifluoromethyl)-2-methoxyphenyl isocyanate. Finally, according to the method Cl a , 5-(trifluoromethyl) 2-Hydroxyphenyl isocyanate is reacted with 4-(2-(N,N-dimethylaminoformamidine)-4-pyridyloxy)aniline to give urea. Item 2 5: according to Method A 1 2 Synthesis of 4-(1-ketoisoindolino-5-yloxy)aniline, followed by treatment of 5((trifluoromethyl)-2-methoxyaniline according to Method C2d (CD I) It is then treated with 4-(1-ketoisoindan-5-yloxy)aniline to give urea. Item 2 6: According to Method A 1 3, step 1 , 4 - hydroxyacetophenone and 4 one The reaction of nitrobenzene is carried out to obtain 4-(4-ethyl phenoxy). The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) ------I----- (Please read the notes on the back and fill out this page) 11111 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 1269791 A7 B7 V. Inventions (97) (Please read the notes on the back and fill out this page) Nitrobenzene Next, according to the method A 1 3 , step 4, the nitrobenzene is reduced to 4-(4-ethoxyphenoxy)aniline, and according to the method A16, 4 (tetramethylphenoxy)aniline is added. Conversion to 4-(4-(1-(N-methoxy)iminoethyl)phenoxyaniline HC1 salt. Conversion of 5-(trifluoromethyl)-2-methoxyaniline according to Method B1 To 5-(trifluoromethyl)-2-methoxyphenyl isocyanate, and finally, (5-(trifluoromethyl)-2-methoxyphenyl isocyanate and 4 (4 (1) according to the method C 1 a 1 (N-methoxy)imine ethyl)phenoxyaniline HC 1 salt is reacted to obtain urea. Item 27: According to method Α 2, step 3b To synthesize 4-monochloro-indolyl-methylpyridinecarboxamide. Then, according to the method A 2 , step 4, the chloropyridine 4 -aminothiophenol is reacted to obtain 4 -( 4 -(2-methylaminoformamidine) Phenylthio)aniline The 5-(trifluoromethyl)-2-methoxyaniline was converted to 5-(trifluoromethyl)-2-methoxyphenyl isocyanate via Method B1. Finally, according to the method C 1 a , 5-(trifluoromethyl)-2-methoxyphenyl isocyanate is reacted with 4-(4-(N-methylaminocarbamid)phenylthio)aniline. To obtain urea. Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative, Printing and Garment Project 28: Synthesis of 5-(4-aminophenoxy)-2-methylisoindan-1,3-dione according to Method A9. Method B 1 , 5-(trifluoromethyl)-2-methoxyphenyl isocyanate. Next, according to the method C la , 5-(trifluoromethyl)-2-methoxyphenyl isocyanate is 5-( 4 monoaminophenoxy)-2-methylisoindole 1 , 3 The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) -100- 1269791 V. Description of invention (98) - Diketone is reacted to obtain urea. (Please read the notes on the back and fill out this page)

項目29 :根據方法A2 ，步驟3b來合成4一氯基一N —甲基吼D定竣醯胺。根據方法a 2，步驟4，將氯吡啶與 3 —氨基硫酚進行反應以得到3 — (4 — (2 — (N —甲 基氨基甲醯）本硫基。接著，根據方法B 1 ，將5 —(二 氟甲基）一 2 —甲氧基苯胺變換成5一（三氟甲基）一 2 一甲氧苯基異氰酸酯。最後，根據方法C 1 a ，將5—( 三氟甲基）一2-甲氧苯基異氰酸酯與3一（4一（2-(N -甲基氨基甲醯）苯硫基苯胺進行反應以得到脲。 項目3 0 :根據方法A 2，步驟3 b，將4 —氯吡π定—2 -鑛醯氯與異丙胺進行反應。所得的4 -氯基- Ν -異丙 基一 2 -吡啶殘醯胺再根據方法a 2，步驟4與4 一氨基 酚進行以得到4一（2—(N〜異丙基氨基甲醯）一4一 吡啶氧基）苯胺，接著，根據方法B 1 ，將5 -（三氟甲 經濟部智慧財產局員工消費合作社印製 基）一 2 —甲氧基苯胺轉變成5 — （三氟甲基）一 2 —甲 氧苯基異氰酸酯。最後，根據方法Ci a ，5 一（三氟甲 基）一 2 -甲氧苯基異氰酸酯與4 一（2 — (N —異丙基 氨基甲醯）- 4 -吡啶氧基）苯胺進行反應以得到脲。 項目3 1 :根據方法A 14來合成4 一（3 — (5 —甲氧 羰基）吡陡氧基）苯胺。根據方法B 1 ，將5 —（三氟甲 基）一 2 —甲氧基）苯胺轉變成5 —（三氟甲基）一 2 — 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公爱） -101 - 1269791 Α7 _ Β7 ' &quot; ---. 五、發明說明（99 ) 甲氧苯基異氰酸酯。接著根據方法c 1 a ，將5 一（ Ξ氣 甲基）一 2 —甲氧苯基異氰酸酯與4 一（3 — （5 —甲氧 羰基）吡啶氧基）苯胺反應以得到脲。根據方法D 4，步 驟1 ’將N— (5 —（三氟甲基）—2 —甲氧苯基）〜 N — (4 一（3 —（5 —甲氧羰基吡d定基）氧基）苯基 )脲進行皂化。最後，根據方法D 4，步驟2將相對的酸 與4 一（ 2 —氨乙基）嗎啉進行偶合以得到醯胺。 項目3 2 :根據方法A 14來合成4一（3 —（5 —甲氧 鑛基）吡啶氧基）苯胺。根據方法B 1 ，將5 —（三氟甲 基）一 2 —甲氧基苯胺轉變成5 —(三氟甲基）一2〜甲 氧苯基異氰酸酯。接著，根據方法Cl a ，將5 —（三氟 甲基）一2 —甲氧苯基異氰酸酯與4 一（3 — （5 —甲氧 羰基）吡啶氧基苯胺，產生反應以得到脲。最後，根據方 法D4，步驟1 ，將N — (5 —三氟甲基）一2 —甲氧苯 基）— (4 —（3 —（5 —甲氧羰基吡啶基）氧基 )苯基）脲進行皂化，再根據方法D 4，步驟2將相對的 酸與甲胺進行偶合以得到醯胺。 項目33 ·•根據方法A14來合成4 — (3 —（5 -甲氧 羰基）吡啶氧基）苯胺。根據方法B 1 ，將5 —（三氟甲 基）一 2 —甲氧基苯胺轉變成5 —（三氟甲基）一 2 —甲 氧苯基異氰酸酯。接著，根據方法Cla ，將5 —（三氟 甲基）一 2 —甲氧苯基異氰酸酯與4 一（3 — （5 —甲氧 Γ%先閱讀背面之注意事項再填寫本頁} 裝 ή^τ· 經濟部智慧財產局員工消費合作社印製 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -102- 1269791 A7 ---—_____ B7 _____ 五、發明說明（100) (請先閱讀背面之注意事項再填寫本頁) 鑛基）哦陡氧基）苯胺進行反應以得到脲。最後根據方法 D4 ’步驟1 ，將N — (5 —(三氟甲基）一2 —甲氧苯 基）—N /一（4 一（3 — (5 —甲氧羰基吡啶基）氧基 )本基）脲進行皂化再根據方法D 4，步驟2將相對的酸 與N ’ N —二甲基乙二胺進行偶合以得到醯胺。 項目3 4 :根據方法a 1 1來合成4 一（ 3 -羧基苯氧基 )本胺。根據方法B1 ，將5 -（三氟甲基）一 2 —甲氧 基苯胺轉變成5一 （三氟甲基）一2一甲氧苯基異氰酸酯 。接者，根據方法Cl f ，將4 一（3 —羧基苯氧基）苯 胺與5 —(三氟甲基）—2 一甲氧苯基異氰酸酯進行反應 以ί守到N - (5 — （三氟甲基）一 2 —甲氧苯基）一 N — (3 —羧苯基）脲’最後再根據方法〇 1 ^與3 —氨吡啶 進行偶合。 項目35:根據方法All來合成4—(3-羧基苯氧基 )本胺。根據方法B 1 ，將5 -（三氟甲基）一2 —甲氧 經濟部智慧財產局員工消費合作社印製 基本胺變換成5— （三氟甲基）-2—甲氧苯基異氰酸酯 。接下來，根據方法C 1 f ，將4 一（ 3 -羧基苯氧基） 苯胺與5 —（三氟甲基）- 2 —甲氧苯基異氰酸酯進行反 應’以得到N — (5 —（三氟甲基）—2 —甲氧苯基）一 N -（3 —殘苯基）脲，最後，再根據Die ，將之與N 一（4 一氟苯基）哌哄進行偶合。 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公爱） - 103- A7 1269791 B7___ 五、發明說明（1〇1) » 項目3 6 :根據方法A 1 1來合成4 一（ 3 -羧基苯氧基 )苯胺。根據方法B 1 ，將5 -_ (三氟甲基）一 2 —甲氧 (請先閱讀背面之注意事項再填寫本頁) 基苯肢變換成5 -（二氟甲基）一 2 —甲氧苯基異氰酸酯 。接下來，根據方法C 1 f ，將4 — ( 3 —羧基苯氧基） 苯胺與5 —（三氟甲基）一 2 -甲氧苯基異氰酸酯進行反 應以得到N —（ 5 -（三氟甲基）一2 —甲氧苯基）— N / -（ 3 -羧苯基）脲，最後，再根據方法D 1 c，將 之與4 -氟苯胺進行偶合。 項目3 7 :根據方法A 1 1來合成4 一（ 3 —羧基苯氧基 )苯胺。根據方法B 1 ，將5 —(三氟甲基）一 2 —甲氧 基苯胺變換成5 —（三氟甲基）一 2 —甲氧苯基一異氰酸 酯。接下來，根據方法C 1 f ，將4 一（ 3 —羧基苯胺基 )苯胺與5 -（三氟甲基）一 2 —甲氧苯基異氰酸酯進行 反應以得到N —（5 —（三氟甲基）一2 —甲氧苯基）一 N / -（ 3 —羧苯基）脲，最後再根據D 1 c ，將之與4 一（二甲氨）苯胺進行偶合。 經濟部智慧財產局員工消費合作社印製 項目3 8 :根據方法A 1 1來合成4 一（ 3 —竣基苯氧基 )苯胺。根據方法B1 ，將5 —(三氟甲基）一 2 —甲氧 基苯胺變換成5 -（三氟甲基）- 2 -甲氧苯基異氰酸酯 。接下來，根據方法C 1 f ，將4 一（ 3 —羧基苯氧基）Item 29: Synthesis of 4-chloro-N-methylindole D decylamine according to Method A2, Step 3b. According to the method a 2, step 4, the chloropyridine is reacted with 3-aminothiophenol to obtain 3-(4-(N-methylaminoformamidine) thiol. Next, according to the method B 1 , 5-(Difluoromethyl)-2-methoxyaniline is converted to 5-mono(trifluoromethyl)-2-methoxyphenyl isocyanate. Finally, according to the method C 1 a , 5-(trifluoromethyl) a 2-methoxyphenyl isocyanate is reacted with 3-mono-(4-(N-methylaminoformamidine)phenylthioaniline to give urea. Item 3 0: according to Method A 2, Step 3 b, 4-Chloropyridinium-2-mineral chloride is reacted with isopropylamine. The resulting 4-chloro-indolyl-isopropyl-2-pyridine residue is further subjected to method a 2, step 4 and 4 amino group. Phenol is carried out to obtain 4-(2-(N~isopropylaminoformamidine)-4-pyridyloxy)aniline, and then, according to Method B1, 5-(Trifluoroa Ministry of Economic Affairs Intellectual Property Office Staff Consumption Cooperative Printing base) 2-methoxyaniline is converted to 5-(trifluoromethyl)-2-methoxyphenyl isocyanate. Finally, according to the method Ci a , 5 -(trifluoromethyl) 2-methoxyphenyl isocyanate is reacted with 4-(2-(N-isopropylaminocarboxamidine)-4-pyridyloxy)aniline to give urea. Item 3 1 : Synthesis according to Method A 14 4 ( 3-(5-methoxycarbonyl)pyridoxy)aniline. Conversion of 5-(trifluoromethyl)-2-methoxy)aniline to 5-(trifluoromethyl)- 2 according to Method B1 — The paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 public) -101 - 1269791 Α7 _ Β7 ' &quot; ---. V. Description of invention (99) methoxyphenyl isocyanate. c 1 a , reacting 5 -(helium methyl)-2-methoxyphenyl isocyanate with 4 -(3 -(5-methoxycarbonyl)pyridinyloxy)aniline to give urea. According to method D 4, step 1 'Saponification of N-(5-(trifluoromethyl)-2-methoxyphenyl)~N-(4-(3-(5-methoxycarbonylpyridyl)oxy)phenyl)urea Finally, according to method D 4, step 2, the relative acid is coupled with 4-(2-aminoethyl)morpholine to give the decylamine. Item 3 2: according to method A 1 4 to synthesize 4-(3-(5-methoxyadenyl)pyridinyloxy)aniline. According to method B 1 , 5-(trifluoromethyl)-2-methoxyaniline is converted to 5-(trifluoro) Methyl)- 2~methoxyphenyl isocyanate. Next, according to the method Cl a , 5-(trifluoromethyl)-2-methoxyphenyl isocyanate and 4-(3-(5-methoxycarbonyl)pyridine Oxyaniline produces a reaction to give urea. Finally, according to Method D4, Step 1, N-(5-trifluoromethyl)-2-methoxyphenyl)-(4-(3-(5-methoxycarbonylpyridyl)oxy)phenyl) The urea is saponified and the relative acid is coupled with methylamine according to Method D4, Step 2 to give the decylamine. Item 33 • Synthesis of 4-(3-(5-methoxycarbonyl)pyridinyloxy)aniline according to Method A14. 5-(Trifluoromethyl)-2-methoxyaniline was converted to 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1. Next, according to the method Cla, 5-(trifluoromethyl)-2-methoxyphenyl isocyanate and 4 (3 - (5-methoxyox% first read the back of the note) τ· Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed on this paper scale applicable to China National Standard (CNS) A4 specification (210 X 297 mm) -102- 1269791 A7 ----_____ B7 _____ V. Description of invention (100) (Please read the notes on the back and then fill out this page.) Mine base) Ohstoxy) Aniline is reacted to obtain urea. Finally, according to the method D4 'Step 1, N-(5-(trifluoromethyl)-2-methoxyphenyl)-N/-(4-(3-(5-methoxycarbonylpyridyl)oxy)) The urea is saponified and then coupled with N'N-dimethylethylenediamine according to Method D4, Step 2 to give the decylamine. Item 3 4: Synthesis of 4-(3-carboxyphenoxy)amine according to Method a 1 1 . According to Method B1, 5-(trifluoromethyl)-2-methoxyaniline was converted to 5-mono(trifluoromethyl)-2-methoxyphenyl isocyanate. Further, according to the method Cl f , 4 -(3-carboxyphenoxy)aniline is reacted with 5-(trifluoromethyl)-2-methoxyphenyl isocyanate to maintain N - (5 - (three) Fluoromethyl)-2-methoxyphenyl)-N-(3-carboxyphenyl)urea was finally coupled according to the procedure 〇1^ with 3-aminopyridine. Item 35: Synthesis of 4-(3-carboxyphenoxy)benamine according to Method All. According to the method B 1 , the 5-amine (5-(trifluoromethyl)-2-methoxyphenyl isocyanate is converted into a 5-amine (5-(trifluoromethyl)-2-methoxyphenyl isocyanate). Next, according to the method C 1 f , 4 -(3-carboxyphenoxy)aniline is reacted with 5-(trifluoromethyl)-2-methoxyphenyl isocyanate to obtain N - (5 - (three) Fluoromethyl)-2-methoxyphenyl)-N-(3-residylphenyl)urea, and finally, coupled with N-(4-fluorophenyl)piperidin according to Die. This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public) - 103- A7 1269791 B7___ V. Description of invention (1〇1) » Item 3 6 : Synthesis according to method A 1 1 4 (3) -Carboxyphenoxy)aniline. According to the method B 1 , 5 - (trifluoromethyl)-2-methoxy (please read the back of the note first, then fill in the page). Convert the benzophenone to 5-(difluoromethyl)-2. Oxyphenyl isocyanate. Next, 4-(3-carboxyphenoxy)aniline is reacted with 5-(3-trifluoromethyl)-2-methoxyphenyl isocyanate according to the method C 1 f to give N-(5-(trifluoro) Methyl)-2-methoxyphenyl)-N/-(3-carboxyphenyl)urea, and finally, coupled with 4-fluoroaniline according to Method D1c. Item 3 7: Synthesis of 4-(3-carboxyphenoxy)aniline according to Method A11. According to Method B1, 5-(trifluoromethyl)-2-methoxyaniline was converted to 5-(trifluoromethyl)-2-methoxyphenyl monoisocyanate. Next, according to the method C 1 f , 4-(3-carboxyanilino)aniline is reacted with 5-(trifluoromethyl)-2-methoxyphenyl isocyanate to obtain N—(5 —(trifluoromethyl) Base 2 - methoxyphenyl)-N / -(3-carboxyphenyl)urea, and finally coupled to 4-(dimethylamino)aniline according to D 1 c. Printed by the Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperatives Project 3 8: Synthesis of 4-(3-nonylphenoxy)aniline according to Method A 1 1 . According to Method B1, 5-(trifluoromethyl)-2-methoxyaniline was converted to 5-(trifluoromethyl)-2-methoxyphenyl isocyanate. Next, according to the method C 1 f , 4 (3-carboxyphenoxy)

苯胺與5 —（三氟甲基）- 2 —甲氧苯基異氰酸酯進行反 應以得到N — ( 5 —（三氟甲基）—2 —甲氧苯基）一N 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -104- 1269791 A7 ______— _ B7______五、發明說明（102) 一（3 -殘苯基）脲，最後，再根據方法d 1 c ，將之 與5 —氨基一 2 —甲氧吡啶進行偶合。 羧一 \)y I 基 3 甲 C 氟 - 三 4 ( 成 -合 5 來將 IX ， IX ΊΧ A B 法法 方 '方 據據 根根 ♦ · 〇 9 胺 3 苯 目 項基 基將 甲 ’ 氟 f 三 ^—_ ( C I 法 5 方 成據 換根 變來 胺下 苯接 基。 氧酯 氧甲酸 苯 I 基 2 氰基 異氧 基苯 苯基 氧羧 甲 一 _ N 5 到 與得 胺以 苯應 基· 甲 氟 三 反 行 進 酯 酸 氰 一 異 3 基 (苯 I 氧 4 甲 基 甲 氟 三 2 基 苯 氧 甲 將 C 1-1 D 法 方 據 根 再 後 。 最合 。 偶 脲行 &gt;進 基安 苯5 羧代 一 啉 3 嗎 · *— (請先閱讀背面之注意事項再填寫本頁) 訂- 4 巨 項 成 合 來 IX ΊΧ A 法 方 據 根 基 氧 苯 基 羧 1 B 法 方 據 根 〇 胺 苯 將 基 甲 氟 三 氧 甲 - 2 醋 } 酸基 氰氧 異苯 基基 苯羧 氧 I 甲 3 I ( 2 | I 4 }將 基 ’ 甲 f 氟 1 三 C C法 I 方 5 據 成根 換， 變來 胺下 苯接 基 。 經濟部智慧財產局員工消費合作社印製 I N 3 ( 5 .到 C 一 與得 IN 胺以' 與 苯應 N 之 基 甲 氟 三The aniline is reacted with 5-(trifluoromethyl)-2-methoxyphenyl isocyanate to obtain N-(5-(trifluoromethyl)-2-methoxyphenyl)-N. The paper size is applicable to Chinese national standards. (CNS) A4 size (210 X 297 mm) -104- 1269791 A7 _______ _ B7______ V. Description of invention (102) One (3-residual phenyl) urea, and finally, according to method d 1 c Coupling with 5-amino-2-methoxypyridine. Carboxy-1) y I group 3 A C fluoro-tris 4 (into - 5 to IX, IX ΊΧ AB method French side) according to the roots ♦ · 〇9 amine 3 benzene terminology base A 'fluorine f 三^—_ (The CI method 5 is converted to the base to change the phenyl group. Oxy oxy oxyformate phenyl I group 2 cyanoisooxybenzene phenyloxycarboxymethyl _ N 5 to the amine Benzene-methyl-trifluoro-trans-transesteric acid cyanide-iso-3 group (benzene I Oxygen 4-methylmethylfluorotrisyl-2-phenylphenoxymethyl) will be C 1-1 D according to the roots. The most suitable. &gt;Into Benzene Benzene 5 Carboxymorpholine 3 ??? *- (Please read the notes on the back and fill out this page) Order - 4 Giants come together IX ΊΧ A French base oxyphenyl carboxy 1 B method According to the decylamine phenyl fluorotrimethoxy- 2 vinegar} acid cyanooxyisophenyl phenyl carboxyoxy I methyl 3 I ( 2 | I 4 } will be based on a - f fluoride 1 three CC method I side 5 According to the change of roots, the amines are replaced by benzene. The Ministry of Economic Affairs, the Intellectual Property Bureau, the employee consumption cooperative, printed IN 3 (5. to C, with the IN amine to 'with benzene should N A three fluoro groups

)基 基定 苯i 羧 I 反 行 進 酯 酸 氰 異 基 苯 氧 甲 I 2 基 甲 氟 三 基 苯 氧 甲 I 2 將 C 1-1 D 法 方 據 根 是 後 最 脲 合 0 行 進 畊 哌 基 I 4 甲基與 I 氯之 N I 將 C 4 再 I 將著 3 ， 接 C 3 ， I C 酯 4 法酸 成方氰 合據異 來根成 3 。 換 1 胺變 A 苯胺 法 } 苯 方基 } 據氧基 根苯甲 :氯 1 醯三 4 甲 C 目基 -項氨 3 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -105- 1269791 A7 B7 五、發明說明（103) (3 (N甲基氣基甲醯）苯氧基）苯胺進行反應以 得到脲 (請先閱讀背面之注意事項再填寫本頁) 項目42 :根據方法八2來合成4 — (2—n〜甲基氨基 甲醯一 4 一吼陡氧基）苯胺。接下來，根據方法^ a : 將4 一氯基一 3 -（三氟甲基）苯基異氰酸酯與4 一 -N -甲基热基甲醯—4 - Dttu定氧基）苯胺進行反應以得 到脲。 項目4 3 :根據方法a 2，步驟3 b ，將4 一氯吡啶—2 一羰醯氯HC 1鹽與氨反應以形成4 一氯基一2一吡啶羧 醯胺。接下來’根據方法A 2，步驟4，將4 一氯基一 2 一吡啶羧醯胺與4 一氨基酚反應以得到4 一（ 2 一（氨基 甲醯一 4 一批D定氧基）苯胺反應，最後根據方法^ i a ， 將4 一氯基一 3 —（三氟甲基）苯基異氰酸酯與4 一（2 -氨基甲醯- 4 -吡啶氧基）苯胺進行反應以得到脲。 經濟部智慧財產局員工消費合作社印製 項目4 4 :根據方法A 2，步驟3 b ，將4 一氯吡啶—2 一羰醯氯HC 1鹽與氨進行反應以得到4 一氯基一 2 —吡 D定羧醯胺。接下來，根據方法A 2，步驟4，將4 一氯基 一 2 -吡啶羧醯胺與3 -氨基酚進行反應以得到3 —（ 2 -氨基甲醯- 4 -吡啶氧基）苯胺。最後’根據方法 C 1 a ，將4 一氯基一 3 -（三氟甲基）苯基異氰酸酯與 3 -（ 2 -氨基甲醯一 4 一吡啶氧基）苯胺進行反應以得 本纸張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） _ ^ - A7 1269791 五、發明說明（1〇4) 到脲。 項目4 5 :根據方法A2 ，步驟33來合成4〜畲货Benzyl benzene i carboxy I counter-transesteric acid cyanyl phenoxy methoxyl 2 2 fluorotriyl phenoxymethyl I 2 C 1-1 D radix is the most urethral 0 I 4 methyl and I chloride NI will be C 4 and then I will be 3, followed by C 3 , IC ester 4 acid to form cyanide according to the different roots into 3 . Change 1 Amine to A aniline method} Phenyl group} Oxygen Benzene: Chlorine 1 醯3 4 A C-based-term ammonia 3 This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) ) -105- 1269791 A7 B7 V. INSTRUCTIONS (103) (3 (N-methyl carbamoyl) phenoxy) aniline is reacted to obtain urea (please read the back note before refilling this page) Item 42 : 4-(2-n~methylaminocarbamidine-4 oxonoxy)aniline was synthesized according to Method VIII. Next, according to the method ^ a : 4 - chloro-tris-(trifluoromethyl) phenyl isocyanate is reacted with 4 -N-methylcarbylmethyl 4- 4 - Dttu oxy) aniline to obtain Urea. Item 4 3: According to Method a 2, Step 3 b, 4-chloropyridine-2 carbonyl chloride HC 1 salt is reacted with ammonia to form 4-chloro-2-pyridylcarboxamide. Next, according to the method A 2, step 4, 4 -chloro-2-pyridinium carboxamide is reacted with 4 - aminophenol to obtain 4 - (1 - (aminocarbamate - 4 batch D-oxy) aniline The reaction is finally carried out by reacting 4-chloro-3-mono(trifluoromethyl)phenylisocyanate with 4-(2-aminopyridin-4-pyridyloxy)aniline according to the method ia to obtain urea. Intellectual Property Office Staff Consumer Cooperative Print Project 4 4: According to Method A 2, Step 3 b, 4 chloropyridine-2 carbonyl chloride HC 1 salt is reacted with ammonia to obtain 4 monochloro-2-pyridyl D Carboxylamidine. Next, according to Method A 2, Step 4, 4-chloro-2-dipyridinium carboxamide is reacted with 3-aminophenol to obtain 3-(2-aminoformamidine-4-pyridinium oxide). Aniline. Finally, according to the method C 1 a , 4-chloro-3-tris(trifluoromethyl)phenylisocyanate is reacted with 3-(2-carbamidine-4-pyridyloxy)aniline to obtain This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) _ ^ - A7 1269791 V. Description of invention (1〇4) Urea Item 45: The method of synthesis of 4 ~ She cargo A2, Step 33

斜基-N 一甲基一 2 一吡啶羧醯胺，再根據方法A 2 ，步 囉4，將 之與3-氨基酚進行反應以得到3一（2—、 甲基氨 基甲醯）一 4 一吡啶氧基）苯胺。接著，根據方 — 达 C 1 a ，將4 一氯基—3 —（三氟甲基）苯基異氰酸酯與 2 —（N -甲基氨基甲醯）—4 一吡啶氧基）苯胺進行 應以得到脲。 7 ^ C請先閱讀背面之注意事項再填寫本頁〕 項目4 6 :根據方法a 3來合成5 (4 氨基苯氧_ ) 異吲哚滿一 1 ，3 —二酮。根據方法c 1 a ，將4 一 3—(三氟甲基）苯基異氰酸酯與5 -（4 一氨墓苯 基）異吲哚滿一 1 ，3 -二酮反應以得到脲。 氧 經濟部智慧財產局員工消費合作社印製 項目47 :根據方法A5來合成4— (2 — (N —甲墓氨 基甲醯）—4 一吡啶氧基）一 2 —甲基苯胺。根據方法 C 1 c ’將4 一氯基一 3 -（二氟甲基）苯基異氰酸酯與 5 -（ 4 一氨基苯氧基）異吲哚滿進行反應以得到脲。 項目48 :根據方法A1 5來合成4 — (3 — N —甲基氨 磺醯）苯氧基苯胺。根據方法C 1 a ，將4 一氯基一 3 -(三氟甲基）苯基異氰酸酯與4 一（ 3 - N —甲基氨磺醯 )苯氧基）苯胺進行反應以得到脲。 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -107· 1269791 A7 ---B7_ 五、發明說明（105) 項目4 9 .根據方法A6來合成4 - (2 -（N —甲基氨 基甲醯）一 4 一吡啶氧基）一 2 一氯苯胺。根據方法 C 1 a ’將4 一氯基一 3 一（三氟甲基）苯基異氰酸酯與 4— (2— (N —甲基氨基甲醯）—4 —吡啶氧基）一2 -氯苯胺進行反應以得到脲。 項目50 :根據方法A2，步驟4，將5 —氨基一 2 -甲 酚與經由根據方法A 2，步驟3 b所合成的4 一氯基一 N 一甲基一 2 —吡啶羧醯胺反應以得到3 — ( 2 一（ N —甲 基氨基甲醯）一 4 一吡啶氧基）一 4一甲基苯胺。根據方 法C 1 a ，將4 一氯基一 3 —(三氟甲基）苯基異氰酸酯 與3— (2 — (N —甲基氨基甲醯）—4 一 d比π定氧基）一 4 一甲基苯胺進行反應以得到脲。 項目5 1 :根據方法A 2，步驟3 b ，將4 一氯吡啶一 2 一碳_氯與乙胺反應，再將所得的4 一氯基一 N —乙基一 2 -吡啶羧醯胺，根據方法A 2，步驟4與4 一氨基酚進 行反應以得到4 一（ 2 — ( N —乙基氨基甲醯）一 4 一 _ D定氧基）苯胺。最後根據方法C 1 a ，將4 一氯基一 3 — (三氟甲基）苯基異氰酸酯與4— (2 —（N —乙基氨基 甲醯）一 4 —吡啶氧基）苯胺反應以產生脲。 項目5 2 :根據方法A 2，步驟4，將4 一氨基一 2 —氯 酚與根據方法A 2，步驟3 b所合成的4 一氯基一 N 一甲 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 裝--- (請先閱讀背面之注意事項再填寫本頁) 訂·- 經濟部智慧財產局員工消費合作社印製 -108- A7 1269791 ____B7 五、發明說明（) % » 基一 2 —吡啶羧醯胺進行反應以得到4 — ( 2 — ( N _甲 基氨基甲醯）一 4 一吡啶氧基）一 3 -氯苯胺。最後，根 據方法C l a ，將4 一氣基一 3 —（三氟甲基）苯基異氰 酸酯與4 一（2 — （N —甲基氨基甲醯）一4 一吡啶氧基 )一3-氯苯胺反應以產生脲。 項目5 3 :根據方法A19 ，步驟1 ，將4 — (4 —甲硫 基苯氧基）一1一硝基苯進行氧化以產生4一（4一甲磺 醯本氧基）一 1 一硝基苯。根據方法A 1 9 ，步驟2，將 硝基加以速原以得到4 一（ 4 —甲擴醯苯氧基）—1 一苯 胺。根據方法C 1 a ，將4 —氯基一 3 三氟甲基）苯 基異氰酸酯與4 一（4 一甲磺醯苯氧基）一苯胺進行 反應以得到脲。 (請先閱讀背面之注意事項再填寫本頁)Andryl-N-methyl-2-dipyridylcarboxamide, which is then reacted with 3-aminophenol according to Method A 2 , Step 4 to give 3-(2-methylaminomethylhydrazine)-4 Monopyridyloxy)aniline. Next, according to the formula C 1 a , 4-chloro-3-(trifluoromethyl)phenyl isocyanate is reacted with 2-(N-methylaminoformamidine)-4-pyridyloxy)aniline. Urea is obtained. 7 ^ C Please read the notes on the back and fill out this page. Item 4 6 : According to method a 3 to synthesize 5 (4 aminophenoxy _ ) isoindole 1 , 3 - diketone. According to the method c 1 a , 4-tris(trifluoromethyl)phenylisocyanate is reacted with 5-(4-aminotodenyl)isoindole-1,3-dione to give urea. Oxygen Ministry of Economic Affairs, Intellectual Property Office, Staff Consumption Cooperative Printed Item 47: Synthesis of 4-(2 - (N-methyl-todenine)- 4-pyridyloxy)- 2-methylaniline according to Method A5. 4-Chloryl-3-(difluoromethyl)phenylisocyanate is reacted with 5-(4-aminophenoxy)isoindole according to the method C 1 c ' to give a urea. Item 48: Synthesis of 4-(3-N-methylaminosulfonyl)phenoxyaniline according to Method A1 5 . According to the method C 1 a , 4-chloro-3-(trifluoromethyl)phenylisocyanate is reacted with 4-(3-N-methylsulfamophenoxy)phenoxy)aniline to give a urea. This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -107· 1269791 A7 ---B7_ V. Invention description (105) Item 4 9. Synthesize according to Method A6 4 - (2 -( N-methylaminocarbamidine) 4-tetrapyridyloxy)-2-chloroaniline. 4-Chloro-tri-(trifluoromethyl)phenylisocyanate and 4-(2-(N-methylaminoformamidine)-4-pyridyloxy)-2-chloroaniline according to Method C 1 a ' The reaction is carried out to obtain urea. Item 50: According to Process A2, Step 4, 5-Amino-2- 2-cresol is reacted with 4-chloro-N-methyl-2-pyridine carboxamide synthesized according to Method A 2, Step 3 b There is obtained 3-(2-(N-methylaminoformamidine)-tetrapyridyloxy)-tetramethylaniline. According to the method C 1 a , 4-chloro-tris-(trifluoromethyl)phenylisocyanate and 3-(2-(N-methylaminoformamidine)-4-d to π-oxyl group)-4 Monomethylaniline is reacted to obtain urea. Item 5 1 : According to the method A 2, step 3 b , 4 -chloropyridine- 2 -carbon-chloride is reacted with ethylamine, and the obtained 4-chloro-N-ethyl-2-pyridine carboxamide is obtained. According to Method A 2, Step 4 is reacted with 4-aminophenol to give 4-(2-(N-ethylaminocarbamidine)-4-D-oxy)aniline. Finally, according to the method C 1 a , 4-chloro-3-trifluoromethylphenyl isocyanate is reacted with 4-(2-(N-ethylaminocarbamidine)-4-pyridyloxy)aniline to produce Urea. Item 5 2: According to Method A 2, Step 4, 4-amino-2-chlorophenol is applied to the Chinese National Standard (CNS) according to the method of Method A 2, Step 3 b. A4 size (210 X 297 mm) Pack--- (Please read the note on the back and fill out this page) Order ·- Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed -108- A7 1269791 ____B7 V. Invention Description () % » The base 2-pyridine carboxamide is reacted to give 4-(2-(N-methylaminoformamidine)-tetrapyridyloxy)-3-chloroaniline. Finally, according to the method C la , 4-mono-l-(trifluoromethyl)phenylisocyanate and 4-(2-(N-methylaminoformamidine)-4-pyridyloxy)-chloroaniline The reaction produces urea. Item 5 3: Oxidation of 4-(4-methylthiophenoxy)-mononitrobenzene according to Method A19, Step 1, to give 4-(4-methanesulfonyloxy)- 1 -nitrate Base benzene. According to the method A 1 9 , step 2, the nitro group is subjected to a pyrogen to obtain 4-(4-methylaminophenoxy)-1 phenylamine. According to the method C 1 a , 4-chloro-3-trifluoromethyl)phenyl isocyanate is reacted with 4-(4-methanesulfonylphenoxy)monophenylamine to give a urea. (Please read the notes on the back and fill out this page)

項目5 4 :根據方法A 步驟 ，將4 一溴苯 經濟部智慧財產局員工消費合作社印製 與甲fee進ί 了反應以得到N —甲基- 4 一溴苯;g黃月安 法A 1 5 ’步驟2 ，將N —甲基一 4 一溴苯磺胺與 偶合以得到4 一（4 — (N —甲基氨磺)苯氧基 接下來，根據方法A 1 5，步驟3 ，將4 ― 甲基氨磺醯）苯氧基）苯變換成4一（4〜 磺醯）苯氧基）一 1 一硝基苯。根據方法A ^ ，將4 一（4一 （N —甲基氨磺醯）苯氧基） 苯還原成4 — (4 一 N —甲基氨磺醯）苯基氧 後，根據方法Cla ，將4 —氯基一 3〜 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 4〜 N〜 5， 〜1 )苯 氣甲 磺醯氯 根據方 酚進行 )苯。 (N〜 甲基氨 步驟4 〜硝基 月安。最 基）苯 A7 1269791 B7______ 五、發明說明（彳07) 基異氰酸酯與4 一（ 3— N -甲基氨磺醯）苯氧基苯胺進 行反應以得到脲。 (請先閱讀背面之注意事項再填寫本頁) 項目5 5 :根據方法A 1 8，步驟1 ，將5 -羥基—2 - 甲基吡啶與1 一氟基一 4 一硝基苯進行偶合以得到4 一（ 5 —（ 2 —甲基）吡啶氧基）一 1 一硝基苯。藉由羧酸將 甲基吡啶氧化後再根據方法A 1 8 ，步驟2將其酯化以得 到4 一（ 5 —（ 2 —甲氧羰基）吡啶氧基）一1 一硝基苯 。接下來，根據方法A 1 8，步驟3將硝基苯進行還原以 得到4 一（ 5 — ( 2 —甲氧羰基）吡啶氧基苯胺，最後’ 根據方法C 1 a ，將苯胺與4 —氯基—3 —(三氟甲基） 苯基異氰酸酯進行反應以得到脲。 項目5 6 :根據方法A 1 8，步驟1 ，將5 -羥基一 2 - 經濟部智慧財產局員工消費合作社印製 甲基吡啶與1 一氟基一 4 一硝基苯進行偶合以得到4 一（ 5 —（2 —甲基）吼[1定氧基）一 1—硝基苯。藉由羧酸將 甲基吡啶氧化，再根據方法A 1 8，步驟2將其酯化以得 到4 一（5 —（2 —甲氧羰基）吡啶氧基）一1 一硝基苯 。接下來，根據方法A 1 8，步驟3 ，將硝基苯還原成4 一（5 — 2 —甲氧羯基）吡d定氧基）苯胺。根據方法 C 1 a ’將苯胺與4 一氯基一 3 —（三氟甲基）苯基異氰 酸酯進行反應以得N— (4 -氯基一 3 —（三氟甲基）苯 基）一 N — (4 -（2 —(甲氧羰基）—5 —吡啶氧基） 苯基）脲。最後，根據方法D 2，將甲酯與甲胺進行反應 本纸張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -110- 1269791 a7 B7 五、發明說明（108) 以得到Ν — （4 一氯基一 3 -（三氟甲基）苯基）一 一 （4— (2 — （Ν —甲基氨基甲醯）一5 —吡啶氧基） 苯基）脲。 項目57 :根據方法Cld製造Ν — (4 —氯基—3 -（ 三氟甲基）苯基一 N / -（4 一氨苯基）脲。根據方法 D1 a·，將N — (4 —氯基一 3 —(三氟甲基）苯基一 N &gt; — ( 4 -氨苯基）脲與異酞酸一甲酯進行偶合以得到 脲。 項目58 :根據方法Cld製造N — (4 —氯基—3 —( 三氟甲基）苯基一 N &gt; -（ 4 一氨苯基）脲。接下來根據 方法Dla ，將N -（4 —氯基一 3 —(三氟甲基）苯基 )一 N / -（ 4 一氨苯基）脲與異酞酸—甲酯進行偶合以 得到N —（4 —氯基一 3 —（三氟甲基）苯基一 N，一（ 4 一（3 -甲氧羰基苯基）羧氨苯基）脲。最後，根據方 法D2 ’將N — (4 —氯基一 3 —(二每甲基）苯基一N /一（4 一（3 -甲氧羰基苯基）羧氨苯基）脲與甲胺進 行反應以得到相對的甲胺。 項目5 9 :根據方法A 2，步驟3 b ，將4 一氯吡啶一 2 一羰醯氯與二甲胺進行反應，以得到4 一氯基一 N，N -二甲基一 2 —吡啶羧醯胺再根據方法A 2 ，步驟4，將之 與4 一氨基酉分進行反應以得到4— (2— (N，N —二甲 本纸張尺度適用中國國家標準（CNS)A4規格（210 x 297公釐） 裝—— (請先閱讀背面之注意事項再填寫本頁) 訂： 經濟部智慧財產局員工消費合作社印製 -111 - A7 1269791 _______ B7 ___ 五、發明說明（109) . 基氨基甲醯）一 4 一吡啶氧基）苯胺。最後，根據方法 C 1 a ，將4 一氯基一 3 —（三氟甲基）苯基異氰酸酯與 4 一 （2 — （N，N —二甲基氨基甲醯）一4 一吼陡氧基 )苯胺反應以得到脲。 項目6 0 :根據方法A1 3 ，步驟1 ，將4 一羥基乙醯苯 與4 一氟基硝基苯反應而得4 一（4 一乙醯苯氧基）硝基 苯。接下來，根據方法1 3，步驟4，將硝基苯還原成4 一（4 一乙醣苯氧基）苯胺。再根據方法A1 6 ，將其變 換成4 一（4 — (1— (N —甲氧基）亞胺乙基）苯氧基 苯胺H C 1鹽。最後，根據方法c 1 a ，將4 一（三氟甲基）苯基異氰酸酯與4 一（4 一乙醯苯氧基） 苯胺反應以得到脲。 裝·— (請先閱讀背面之注意事項再填寫本頁) 基一 3 項目 ••根據方法A 1 3，步驟2來合成4 一（ 3 羧 ，步驟3將4 經濟部智慧財產局員工消費合作社印製Item 5 4: According to the method A, the 4 bromobenzene Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperatives printed and reacted with a Fee to obtain N-methyl-4-bromobenzene; g Huangyuean A 1 5 ' Step 2: coupling N-methyl-4-bromobenzenesulfonamide to obtain 4-(4-(N-methylsulfinyl)phenoxy group. Next, according to Method A 1 5, Step 3, 4 - A The sulfazone phenoxy)benzene is converted into a 4-(4~sulfonyl)phenoxy)-mononitrobenzene. According to the method A ^, after the reduction of 4-(4-(methyl-aminosulfonium)phenoxy)benzene to 4-(4-N-methylsulfamophene)phenyloxy, according to the method Cla, 4 —Chloro-A-3~ This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 4~N~5, ~1) Benzene gas sulfonium chloride according to phenolic phenol). (N~methylammonium step 4~nitro-nitroan. Most basic) benzene A7 1269791 B7______ V. INSTRUCTION DESCRIPTION (彳07) The base isocyanate is reacted with 4-(3-N-methylsulfamophene)phenoxyaniline The reaction is carried out to obtain urea. (Please read the notes on the back and then fill out this page) Item 5 5: According to Method A 1 8 , Step 1, couple 5 - hydroxy-2-methylpyridine with 1 - fluoro- 4 - nitrobenzene 4-(5-(2-methyl)pyridinyloxy)-mononitrobenzene was obtained. The methylpyridine is oxidized by a carboxylic acid and then esterified according to Method A 18 and Step 2 to give 4-(5-(2-methoxycarbonyl)pyridinyloxy)-1-nitrobenzene. Next, the nitrobenzene is reduced according to the method A 18.8, step 3 to obtain 4(5-(2-methoxycarbonyl)pyridinylaniline, and finally 'According to the method C1a, the aniline and the 4-chloro group Benzyl-3-(trifluoromethyl)phenylisocyanate is reacted to obtain urea. Item 5 6 : According to Method A 1 8 , Step 1, 5 - Hydroxy - 2 - Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed The base pyridine is coupled with 1-fluoro-based 4-nitrobenzene to give 4-(5-(2-methyl)anthracene [1 oxy)-1-nitrobenzene. Methylpyridine by carboxylic acid Oxidation, followed by esterification according to Method A 18, Step 2 to give 4-(5-(2-methoxycarbonyl)pyridinyloxy)-l-nitrobenzene. Next, according to Method A 18. 3. Reduction of nitrobenzene to 4-(5-2 methoxyindolyl)pyroxy)aniline. The aniline is reacted with 4-monochloro-3-(trifluoromethyl)phenylisocyanate according to the method C 1 a ' to obtain N-(4-chloro-3-tris(trifluoromethyl)phenyl)-N. —(4-(2-(methoxycarbonyl)-5-pyridinyloxy)phenyl)urea. Finally, according to the method D 2, the methyl ester and methylamine are reacted. The paper scale is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) -110-1269791 a7 B7 5. The invention description (108) Ν — (4-Chloro-tris-(trifluoromethyl)phenyl)-one (4-(2-(indolyl)methylpyridinium)-5-pyridyloxy)phenyl)urea. Item 57: Ν-(4-Chloro-3-(trifluoromethyl)phenyl-N/-(4-aminophenyl)urea is produced according to the method Cld. According to the method D1 a·, N — (4 — Chloro-3-trifluoromethylphenyl-N-gt;-(4-aminophenyl)urea is coupled with monomethyl isononanoate to give urea. Item 58: N- (4) according to the method Cld -Chloro-3-(trifluoromethyl)phenyl-N&gt;-(4-monophenylphenyl)urea. Next, according to the method Dla, N-(4-chloro-1,3-(trifluoromethyl) Phenyl)-N/-(4-monophenylphenyl)urea is coupled with isononanoic acid-methyl ester to give N-(4-chloroamino-3-(trifluoromethyl)phenyl-N, one ( 4-(3-methoxycarbonylphenyl)carboxyaminophenyl)urea. Finally, according to the method D2', N-(4-chloroyl-3-(di-methyl)phenyl-N/one (4 one (3-Methoxycarbonylphenyl)carboxyaminophenyl)urea is reacted with methylamine to give the corresponding methylamine. Item 5: According to Method A 2, Step 3 b, 4-chloropyridine-2-oxoindene Chlorine reacts with dimethylamine to give 4-chloro-N,N- Methyl-2-pyridine carboxamide is then reacted with 4-amino oxime according to method A 2 , step 4 to obtain 4-(2-(N, N-dimethyl benzoic paper scale applicable to Chinese national standard) (CNS) A4 size (210 x 297 mm) Packing - (Please read the note on the back and fill out this page) Order: Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed -111 - A7 1269791 _______ B7 ___ V. Description of the invention (109). Aminoguanidine)-tetrapyridyloxy)aniline. Finally, according to the method C 1 a , 4-chloro-3-mono(trifluoromethyl)phenylisocyanate is used together with 4 (2) - (N,N-dimethylaminoformamidine) - 4 - decyloxy) aniline to give urea. Item 60: According to Method A1 3, Step 1, 4 hydroxyethyl benzene and 4 fluoro The nitrobenzene is reacted to give 4-(4-ethoxyphenoxy)nitrobenzene. Next, according to Method 13 and Step 4, the nitrobenzene is reduced to 4 (4-ethylene phenoxy) Aniline. According to method A1 6 , it is converted into 4-(4-(N-methoxy)iminoethyl)phenoxyaniline HC. 1. Salt. Finally, according to the method c 1 a , 4 -(trifluoromethyl)phenylisocyanate is reacted with 4 -(tetramethylphenoxy)aniline to obtain urea. Packing - (Please read the back Note: Please fill out this page again.) Base 1 Project •• According to Method A 1 3, Step 2 to synthesize 4 (3 Carboxy, Step 3 will be printed by 4 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative

基苯氧基）一 1 一硝基苯。根據方法A —(3 —羧苯氧基）一 1—硝基苯與4 一（2 -氨乙基） 嗎啉進行偶合以得到4 — ( 3 — ( N -（ 2 —嗎啉基乙基 )氨基甲醯）苯氧基）一 1 一硝基苯。接下來，根據方、法 A 1 3，步驟4將4 — ( 3 — ( N〜（2 —嗎啉基乙基） 氨基甲薩）苯氧基）一 1—硝基苯還原成4 一（3 — 一（2 -嗎啉基乙基）氨基甲醯）苯氧基）苯胺。最後根 據方法C 1 a ’將4 —氯基—3 —（三氟甲基）苯基異气 酸酯與4 — (3 —（N— (2 —嗎啉基乙基）氨基甲酶） 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -112- 1269791Phenoxy group) 1-nitrobenzene. Coupling according to the method A-(3-carboxyphenoxy)-l-nitrobenzene with 4-(2-aminoethyl)morpholine to give 4-(3 - (N-(2-morpholinoethyl) Carbamate) phenoxy)-1-nitrobenzene. Next, according to the method, the method A 1 3, step 4, 4 - ( 3 - ( N ~ (2 - morpholinoethyl) aminometha) phenoxy) 1-nitrobenzene is reduced to 4 ( 3 — mono(2-morpholinylethyl)carbamidine)phenoxy)aniline. Finally, according to the method C 1 a ', 4-chloro-3-(trifluoromethyl)phenyl isocyanate and 4-(3-(N-(2-morpholinylethyl)carbamate) The paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) -112- 1269791

苯氧基）苯胺反應以得到脲。 經濟部智慧財產局員工消費合作社印製 項目6 2 :根據方法A1 3，步驟2來合成4 一（3〜竣 基苯氧基）—1 一硝基苯。然後根據方法A 1 3，步驟3 將4〜（3 —羧基苯氧基）—1—硝基苯與1一（2〜胺 乙基）六氫吡啶進行偶合以產生4—(3—(N〜（2〜 六氯哏啶基乙基）氨基甲醯）苯氧基）一1一硝基苯。根 據方法A1 3 ，步驟4將4— (3— (N— (2 —六氮哦 11 疋基乙基）氨基甲醯）苯氧基）一 1 —硝基苯還原成 (3〜（N—（2—六氫吡啶基乙基）氨基甲醯）苯氧基 )苯胺。根據方法Cla ，將4一氯基一3—（三氟甲基 )苯基異氰酸酯與4 一（3 -（N -（2 —六氫吡啶基乙 基）氨基甲醯）苯氧基）苯胺進行反應以產生脲。 項目63 :根據方法A13 ，步驟2來合成4 一（3 -羧 基苯氧基）一 1 一硝基苯。根據方法A1 3，步驟3將4 一（3 -羧基苯氧基）一 1 -硝基苯與四氫糠胺進行偶合 以產生4 一（ 3 — （N —四氫呋喃基甲基）氨基甲醯）苯 氧基）苯胺。根據方法Cla ，將4 —氯基—3 一（三氟 甲基）苯基異氰酸酯與4 一（3 一（N 一四氫呋喃基甲基 )氨基甲醯）苯氧基）苯胺進行反應以產生脲。 項目64 :根據方法A1 3，步驟2來合成4 — (3 -羧 基苯氧基）一 1 一硝基苯。根據方法A 1 3，步驟3將4 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -------------裝--------訂· (請先閱讀背面之注意事項再填寫本頁} -113- 1269791 A7 B7 五、發明說明（111) ' 1 一（3 -羧基苯氧基）一 1—硝基苯與2 —胺甲基—1 — (請先閱讀背面之注意事項再填寫本頁) 乙基吡咯烷進行偶合以產生4 一（ 3 — ( N - (( 1 —甲 基吡咯烷基）甲基）氨基甲醯）苯氧基）—1—硝基苯。 根據方法A 1 3 ，步驟4，將4〜（3 — ( N — ( ( 1 — 甲基吡咯烷基）甲基）氨基甲醯）苯氧基）_1_硝基苯 還原成4 — (3 —（N —（ （1〜甲基吡咯烷基）甲基） 氣基甲醯）苯氧基）苯胺。根據方法C 1 a ，將4 一氯基 一 3 —（三氟甲基）苯基異氰酸酯與4 一（3— (N —（ (1 一甲基吡咯烷基）甲基）氨基甲醯）苯氧基）苯胺進 行反應以產生脲。 項目6 5 :依方法2 ’步驟3 b的說明來合成4 一氯基一 N -甲基吡啶羧醯胺。根據方法a 2，步驟4將氯吡啶與 4 一胺基苯硫酚進行反應以產生4 一（4 一（2— (N — 甲基氨基甲醯）苯硫基）苯胺。根據方法C 1 a ，將4 一 氯基—3 -（三氟甲基）苯基異氰酸酯與4 一（4 一（2 -（N -甲基氨基甲醯）苯硫基）苯胺進行反應以產生脲 〇 經濟部智慧財產局員工消費合作社印製 項目6 6 ·根據方法A 2 ’步驟3 b ，將4 —氯吼π定一 2 -羰醯氯與異丙胺進行反應。根據方法A 2，步驟4將所 產生的4 一氯基一 N —異丙基一 2 —吡啶羧醯胺與4 一胺 基酚進行反應以產生4一（2-（N-異丙基氨基甲醯） 一 4 一吡啶氧基）苯胺。根據方法C 1 a ，將4 一氯基— 本纸張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） ， -114 - 1269791 A7 氣甲基）苯基異氰酸酯與4 — (2 —（N -異丙 五、發明說明（112) 3 基氨基甲醯） , 〜4〜吡啶氧基）苯胺進行反應以產生脲 項目6 (三氟 方法D N / — 7 ： 甲基 3將 4 一氯基一 脲。根 基）苯 據方 基〜 苯胺進行偶 苯基一 N &gt; 苯基）脲。 根據方法C 1 e來合成N -（4 一氯基一 3 — )苯基一 N__ (4 一乙氧羰基苯基）脲。根據 N— (4 —氯基一 3 —（三氟甲基）苯基一 〜乙氧羰基苯基）脲進行皂化以產生N —（4 (二氟甲基）苯基一 N / -（ 4 一羧苯基） 法Dlb ，將N — (4-氯基一3 —(三氟甲 N 一（4-羧苯基）脲與3-甲基氨基甲酸 合以產生N -（4 一氯基一 3 —（三氟甲基） 一 （4一 （3 —甲基氨基甲醯苯基）氨基甲醯 (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 項目6 8 :根據方法A 9來合成5 一（ 4 一胺基苯氧基） 一 2 -甲基異吲哚滿一 ][，3 一二酮。根據方法◦丄a ， 將4 一氯基一 3 —（三氟甲基）苯基異氰酸酯與5一（4 一胺基苯氧基）—2 —甲基異吲哚滿一 1 ，3 一二酮進行 反應以產生脲。 項目6 9 ··依方法A 2 ’步驟3 b中的說明來合成4 一氯 基一 N -甲基吼π疋竣酸fl女。根據方法a 2將氯d比n定與3 — 胺基苯硫酚進行反應以產生3 —（4 一（2 —（N —甲基 氨基甲醯）苯硫基）苯胺。根據方法C 1 a ，將4 一氯基 本纸張尺度適用中國國家標準（CNS)A4規格（210 x 297公爱） -115- 1269791 A7The phenoxy)aniline is reacted to give urea. Printed by the Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperatives Project 6 2: According to Method A1 3, Step 2 to synthesize 4-(3~nonylphenoxy)-1 mononitrobenzene. Then, according to Method A 1 3, Step 3, 4~(3-carboxyphenoxy)-1-nitrobenzene is coupled with 1-(2-aminoethyl)hexahydropyridine to give 4-(3-(N) ~(2~ Hexachloroacridinylethyl)carbamidine)phenoxy)-mononitrobenzene. According to Method A1 3, Step 4 reduces 4-(3-(N-(2-hexanitro- 11-decylethyl)aminocarboxamidine)phenoxy)-1-nitrobenzene to (3~(N- (2-Hexidopyridylethyl)aminocarboxamidine)phenoxy)aniline. According to the method Cla, 4-chloro-3-trifluoromethylphenyl isocyanate is reacted with 4-(3-(N-(2-hexahydropyridylethyl)carbamidine)phenoxy)aniline The reaction produces urea. Item 63: Synthesis of 4-(3-carboxyphenoxy)-mononitrobenzene according to Method A13, Step 2. Coupling of 4-(3-carboxyphenoxy)-l-nitrobenzene with tetrahydrofurfurylamine according to Method A1 3, Step 3 to give 4-(3-(N-tetrahydrofurylmethyl)carbamidine) Phenoxy)aniline. 4-Chloro-3-(trifluoromethyl)phenylisocyanate was reacted with 4-(3-(N-tetrahydrofurylmethyl)carbamidine)phenoxy)aniline according to Method C1a to give the urea. Item 64: 4-(3-Carboxyphenoxy)-mononitrobenzene was synthesized according to Method A1 3, Step 2. According to method A 1 3, step 3 applies 4 paper scales to China National Standard (CNS) A4 specification (210 X 297 mm) ------------- -Settings (Please read the notes on the back and fill out this page again) -113- 1269791 A7 B7 V. INSTRUCTIONS (111) '1 -(3-Carboxyphenoxy)-1-nitrobenzene and 2-amine Methyl-1—(Please read the notes on the back and fill out this page) Ethylpyrrolidine is coupled to give 4(3 - (N - ((1 -methylpyrrolidinyl)methyl))carbamidine Phenoxy)-1-nitrobenzene. According to Method A 1 3 , Step 4, 4~(3 - (N - ((1 -methylpyrrolidinyl)methyl)carbamidine)phenoxy _1_Nitrobenzene is reduced to 4 —(3 —(N —((1~methylpyrrolidinyl)methyl))carbyl)phenoxy)aniline. According to method C 1 a , 4 chlorine The base 3-(trifluoromethyl)phenylisocyanate is reacted with 4-(3-(N-((1-methylpyrrolidinyl)methyl)aminocarboxamidine)phenoxy)aniline to produce urea. Item 6 5: According to the description of Method 2 'Step 3 b 4 monochloro-N-methylpyridinecarboxamide. According to method a 2, step 4, chloropyridine is reacted with 4-aminothiophenol to produce 4-(4-(N-methylamino) Formyl) phenylthio)aniline. According to method C 1 a , 4-chloro-3-(trifluoromethyl)phenylisocyanate is 4-(4-(N-methylaminoformamidine) The reaction of phenylthio)aniline to produce urea 〇 〇 〇 〇 智慧 智慧 员工 员工 员工 员工 员工 员工 员工 6 6 · · · · · · · · · · · 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据 根据The reaction is carried out. According to Method A 2, Step 4, the resulting 4-chloro-N-isopropyl-2-pyridine carboxamide is reacted with 4-aminophenol to produce 4-(N-N-iso Propylaminoformamidine) 4-tetrapyridyloxy)aniline. According to method C 1 a , 4 chloro-based paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm), -114 - 1269791 A7 gas methyl) phenyl isocyanate with 4 - (2 - (N-isopropyl five, invention description (112) 3-aminocarbamidine), ~4~pyridyloxy) The amine is reacted to produce urea item 6 (trifluoro method DN / - 7 : methyl 3 will be 4-chloro-urea. base) benzene according to the aryl group ~ aniline to be phenyl-N &gt; phenyl) urea. Method C 1 e to synthesize N -(4 -chloro-3-yl)phenyl-N__(4-ethoxycarbonylphenyl)urea. Saponification according to N-(4-chloro-3-mono(trifluoromethyl)phenyl-ethoxycarbonylphenyl)urea to give N-(4(difluoromethyl)phenyl-N / -( 4 Monocarboxyl) method Dlb, combining N-(4-chloro-1,3-(3-trifluoromethyl-(4-carboxyphenyl)urea) with 3-methylcarbamate to give N-(4-chloro group A 3-(trifluoromethyl)-(4-(3-methylaminoformamidophenyl)carbamidine (please read the notes on the back and fill out this page) Printed by the Intellectual Property Office of the Ministry of Economic Affairs Item 6 8 : Synthesis of 5-(4-aminophenoxy)-2-methylisoindan][,3-dione according to Method A9. According to the method ◦丄a, 4-chloro group A 3-(trifluoromethyl)phenylisocyanate is reacted with 5-(4-aminophenoxy)-2-methylisoindan-1,3-dione to produce urea. Item 6 9 · • Synthesis of 4-chloro-N-methylindolinic acid fl according to the description in Method A 2 'Step 3 b. According to Method a 2, the ratio of chlorine d to n is determined by 3-aminothiophenol Reaction to produce 3 - (4 a (2 - ( N-methylcarbamidine)phenylthio)aniline. According to method C 1 a , 4 chloro-based paper scale applies to Chinese National Standard (CNS) A4 specification (210 x 297 public) -115-1269791 A7

五、發明說明（113) 氟甲基）苯基異氰酸酯與3 一（4 一（2 -（ 基氨基甲醯）苯硫基）苯胺進行反應以產生脲。 目7〇 :根據方法10來合成4 — (2 — (N -（2 -_ # ~ 4 一基乙基）氨基甲醯）吡啶氧基）苯胺。根據方 a ’將4_氯基—3 一（三氟甲基）苯基異氰酸酯 與4— (2 —（N —（2 —嗎啉—4 —基乙基）氨基甲醯 &gt; # D定氧基）苯胺進行反應以產生脲。 I、目7 1 :根據方法a 1 4來合成4 — ( 3 —（ 5 —甲氧 羯基）吡啶氧基）苯胺。根據方法C . 1 a ，將4 一氯基一 3 — （三氟甲基）一 2 —甲氧苯基異氰酸酯與4 一 （3 — (5 -甲氧羰基）吡啶氧基）苯胺進行反應以產生脲。根 據方法D4，步驟1將N —（4 一氯基一 3 -（三氟甲基 )苯基）一 N&gt; — (4 —（3 —（5 —甲氧羰基吡啶基） 氧基）氧基）苯基）脲進行巷化並將該相對應的酸與4 -(2 —胺乙基）嗎啉進行偶合以產生醯胺。 項目72 :根據方法A14來合成4 — (3 -（5 —甲氧 羰基）吡啶氧基）苯胺。根據方法C 1 a將4 一氯基一 3 一（三氟甲基）苯基異氰酸酯與4 一（3 -（5 —甲氧羰 基）吡啶氧基）苯胺進行反應來產生脲。根據方法D 4， 步驟1將N — (5 —（二菊/甲基）一2 —甲氧苯基）一 N，—（4 一（3 —（5 —甲氧羰基吡啶基）氧基）苯基 (請先閱讀背面之注意事項再填寫本頁) 裝 訂· 經濟部智慧財產局員工消費合作社印製 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -116- 1269791 A7 _ _B7____ 五、發明說明（11， )脲進行皂化，並將該相對應的酸根據方法D 4，步驟2 與甲胺進行偶合以產生醯胺。 (請先閱讀背面之注意事項再填寫本頁) 項目73 :根據方法A14來合成4 — (3 —（5 -甲氧 羰基）吡啶氧基）苯胺。根據方法C 1 a將4 一氯基—3 一（三氟甲基）苯基異氰酸酯與4 一（3 —（5 —甲氧鑛 基）吡啶氧基）苯胺進行反應以產生脲。根據方法D 4， 步驟1將N —（5—(三氟甲基）一 2 —甲氧苯基）- 一（4 一（3 —（5 —甲氧羰基吡啶基）氧基）苯基 )脲進行皂化’並將該相對應的酸根據方法4，步驟2與 N，N —二甲基乙二胺進行偶合以產生醯胺。 經濟部智慧財產局員工消費合作社印製 項目7 4 :根據方法A 2，步驟3 b將4 —氯吡啶—2 — 鑛醯氯HC 1鹽與2 -羥基乙胺進行反應以形成4 -氯基 —N -（2 -三異丙基甲矽烷氧基）乙基吡啶一 2 -羧醯 胺。根據A1 7 ’先將4 —氯基一 N — (2 —三異丙基甲 砂烷氧基）乙基吡啶- 2 -羧醯胺與三異丙基甲矽烷基化 氯進行反應再與4 一胺基酚反應以形成4 一（ 4 一（ 2 — (N —（ 2 —三異丙基甲矽烷氧基）乙基氨基甲醯）吡啶 氧基苯胺。根據方法C la ，將4 一氯基一 3 —（三氟甲 基）本基異気酸醋與4 — (4 一（2 -（N — (2 —三里 丙基甲5夕院氧基）乙基氨基甲醯）吡啶氧基苯胺進行反應 以產生N — (4〜氯基—3 一（（三氟甲基）苯基）一 — (4 —（4〜（2 — (N -（2 —三異丙基甲矽烷 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公爱） -117- A7 1269791 ______B7 __ 五、發明說明（115) » 氧基）乙基氨基甲醯）吡啶氧基苯基）脲。 (請先閱讀背面之注意事項再填寫本頁) 項目7 5 :根據方法A 1 1來合成4 一（ 3 一羧基苯氧基 )苯S女。根據方法Cl f將4〜氯基一 3—(三氟甲基） 苯基異氰酸酯與4 一（3 -（5 -甲氧羰基）吡啶氧基） 苯胺進行反應以產生脲，再將此脲根據方法D 1 c與3 -胺乙基六氫吡畊進行偶合。 項目7 6 :根據方法A 1 1來合成4 一（ 3 -羧基苯氧基 )苯胺。根據方法Clf將4一氯基一3—（三氟甲基） 苯基異氰酸酯與4 -（ 3 -羧基苯氧基）苯胺進行反應以 產生脲，再將此脲根據方法D 1 c與N -（ 4 一乙醯苯基 )六氫吡畊進行偶合。 項目7 7 :根據方法A 1 1來合成4— (3 —羧基苯氧基 )苯胺。根據方法Clf將4一氯基一3—（三氟甲基） 苯基異氰酸酯與4 -（ 3 -羧基苯氧基）苯胺進行反應以 產生脲，再將此脲與4 -氟苯胺根據方法D 1 c進行偶合 經濟部智慧財產局員工消費合作社印製 項目78 :根據方法Al 1來合成4 一（3 —羧基苯氧基 )。根據方法C 1 f將4 —氯基一 3—(三氟甲基）苯基 異氰酸酯與4 一（ 3 一羧基苯氧基）苯胺進行反應以產生 脲，並將此脲根據方法D 1 c與4 一（二甲胺）苯胺進行 本纸張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -118- 1269791 A7 B7 五、發明說明（11e) , 偶合。 (請先閱讀背面之注意事項再填寫本頁) 項目7 9 :根據方法A 1 1來合成4 一（3 —羧基苯氧基 )苯胺。根據方法C1f將4一氯基一3-（三氟甲基） 苯基異氰酸酯與4 -（ 3 -羧基苯氧基）苯胺進行反應以 產生脲，並根據方法D 1 c ，將之與N -苯基乙二胺進行 偶合。· 項目8 0 :根據方法A 1 1來合成4 一（3 -羧基苯氧基 )苯胺。根據方法C 1 a將4 一氯基一 3 -（二氟甲基） 苯基異氰酸酯與4 -（ 3 -羧基苯氧基）苯胺進行反應以 產生脲，再根據方法D 1 c將之與2 -甲氧基乙胺進行偶 合。 經濟部智慧財產局員工消費合作社印製 項目8 1 :根據方法All來合成4 一（3 -羧基苯氧基 )苯胺。根據方法C 1 f將4 一氯基一3 —（三氟甲基） 苯基異氰酸酯與4 -（ 3 -羧基苯氧基）苯胺進行反應以 產生脲，再根據方法D 1 c將之與5 -胺基一 2 —甲氧基 吡啶進行偶合。 項目8 2 :根據方法A 1 1來合成4 一（3 -羧基苯氧基 )苯胺。根據方法C 1 f將4 一氯基一 3 —（三氟甲基） 苯基異氰酸酯與4-（3-羧基苯氧基）苯胺進行反應， 並根據方法D 1 c將之與4 -嗎啉苯胺進行偶合。 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -119- 1269791 A7 _______B7__ 五、發明說明（1彳7) ' 1 項目8 3 :根據方法A 1 1來合成4 一（3 —羧基苯氧基 (請先閱讀背面之注意事項再填寫本頁) )苯胺。根據方法Cl f將4 一氯基—3—（三氟甲基） 苯基異氰酸酯與4 -（ 3 -羧基苯氧基）苯胺進行反應以 產生脲，並根據方法D 1 c將之與N —（ 2 -吡啶基）六 氫吡畊進行偶合。 項目8 4 ·根據方法a 2 ’步驟3 b ’將4 一氯吼π定一 2 一羰醯氯HC1鹽與2一羥基乙胺進行反應以形成4一氯 基—Ν —（2 —三異丙基甲矽烷氧基）乙基吡啶一 2 一竣 醯胺。根據方法Α1 7，先將4 一氯基一 Ν -（2 -三異 丙基甲砂;t兀氧基）乙基吼η定一 2 —羧醯胺與三異丙基甲石夕 烷氧基化氯進行反應，再繼續與4 -胺基酚進行反應。根 據方法C 1 a ，將4 一氯基一 3 —(三氟甲基）苯基異氰 酸酯與4 一（4 — (2 -（N — (2 —三異丙基甲矽烷氧 基）乙基氨基甲醯）吡啶氧基苯胺進行反應以產生N 一（ 4 —氯基一 3 —((三氟甲基）苯基）—n — —（4一（ 經濟部智慧財產局員工消費合作社印製 4 一（2 一（N〜（2 -三異丙基甲矽烷氧基）乙基氨基 甲醯）吡啶氧基苯基）脲。根據方法D 5，將脲進行去保 護以產生N —（4 一氯基—3 —（（三氟甲基）苯基）〜 — (4 — (4一（2 — (N — (2 —羥基）乙基氨基 甲醯）吡啶氧基苯基）脲。 項目85 ··根據方法A2來合成4一（2 —（N —甲基氨V. INSTRUCTION INSTRUCTION (113) Fluoromethyl)phenylisocyanate is reacted with 3-(4-(ylaminocarbamid)phenylthio)aniline to produce urea. Item 7: Synthesis according to Method 10 —(2 —(N -(2 -_# ~ 4-ylethyl)carbamidine)pyridinoxy)aniline. 4-Chloro-3-(trifluoromethyl)phenylisocyanate according to the square a ' The reaction is carried out with 4-(2-(2-(2-morpholine-4-ylethyl)carbamidine&gt;# D-oxy)aniline to produce urea. I, item 71: according to method a 1 4 To synthesize 4-(3-(5-methoxyindolyl)pyridinyloxy)aniline. According to Method C. 1 a , 4-chloro-3-(trifluoromethyl)-2-methoxyphenyl isocyanate Reaction with 4-(3-(5-methoxycarbonyl)pyridinyloxy)aniline to produce urea. According to Method D4, Step 1 will be N-(4-chloro-3-mono(trifluoromethyl)phenyl) a N&gt; - (4 -(3 -(5-methoxycarbonylpyridinyl)oxy)oxy)phenyl)urea is channeled and the corresponding acid is 4-(2-aminoethyl)? The morpholine is coupled to produce Amine. Item 72: Synthesis of 4-(3-(5-methoxycarbonyl)pyridinyloxy)aniline according to Method A14. 4-Chloro-tri-(trifluoromethyl)phenylisocyanate according to Method C1a Reaction with 4-(3-(5-methoxycarbonyl)pyridinyloxy)aniline to produce urea. According to Method D4, Step 1 will be N-(5-(di-Chrysanthemum/methyl)-2-methoxybenzene Base)-N,-(4-(5-(5-methoxycarbonylpyridinyl)oxy)phenyl (please read the back of the note first and then fill out this page) Binding · Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) -116-1269791 A7 _ _B7____ V. Invention Description (11, ) Urea is saponified, and the corresponding acid is according to Method D 4 , Step 2 is coupled with methylamine to produce indoleamine. (Please read the notes on the back and fill out this page.) Item 73: Synthesis of 4-(3-(5-methoxycarbonyl)pyridinyloxy) according to Method A14 Aniline. According to the method C 1 a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate and 4 3-(5-Methoxytriyl)pyridinyloxy)aniline is reacted to produce urea. According to Method D 4, Step 1 is N-(5-(trifluoromethyl)-2-methoxyphenyl)- (4 -(5-(5-methoxycarbonylpyridyl)oxy)phenyl)urea is saponified' and the corresponding acid is subjected to Method 4, Step 2 and N,N-dimethylethylenediamine Coupling to produce a guanamine. Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed Project 7 4: According to Method A 2, Step 3 b, 4-chloropyridine-2-mineral chloride HC 1 salt is reacted with 2-hydroxyethylamine to form 4-chloro group —N —(2-Triisopropylformamoxy)ethylpyridine-2-carboxycarbamide. According to A1 7 ', 4-chloro-N-(2-triisopropylsilyloxy)ethylpyridin-2-carboxycarboxamide is reacted with triisopropylformamidine alkyl chloride to react with 4 The monoaminophenol is reacted to form 4-(4-(2-distributyl)-pyridyloxy)ethylaminopyridinium)pyridinylaniline. According to the method Cla, 4-chloro Benzyl 3-(trifluoromethyl)-n-isophthalic acid vinegar with 4 - (4 -(2 -(N - (2 -tripropylmethyl) 5 etheneoxy)ethylaminopyridinium)pyridinyloxy The aniline is reacted to produce N-(4~chloro-3-3-((trifluoromethyl)phenyl)-(4-(4~(2 - (N-(2-)-isopropylidene) paper The scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 public) -117- A7 1269791 ______B7 __ V. Description of invention (115) » Oxy)ethylaminopyridinium)pyridyloxyphenyl)urea. Please read the precautions on the back and fill out this page. Item 7 5: Synthesis of 4-(3-carboxyphenoxy)benzene S according to Method A 1 1. According to the method Cl f 4~Chloro- 3 - ( Trifluoromethyl) The phenyl isocyanate is reacted with 4-(3-(5-methoxycarbonyl)pyridinyloxy)aniline to produce urea, which is then coupled with 3-Aminoethylhexahydropyrazine according to Method D1c. 7 6 : Synthesis of 4-(3-carboxyphenoxy)aniline according to Method A 1 1. 4-Chloro-3-(trifluoromethyl)phenylisocyanate and 4-(3-carboxybenzene) according to Method Clf The oxy)aniline is reacted to produce urea, which is then coupled according to the method D 1 c with N -( 4 -ethyl phenyl)hexahydropyrrol. Item 7 7 : Synthesis according to Method A 1 1 (3-Carboxyphenoxy)aniline. 4-Chloro-3-(trifluoromethyl)phenylisocyanate is reacted with 4-(3-carboxyphenoxy)aniline according to the method Clf to produce urea, and then This urea is reacted with 4-fluoroaniline according to method D 1 c. Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Print Project 78: Synthesis of 4-(3-carboxyphenoxy) according to Method Al 1 . According to Method C 1 f 4-Chloryl-3-(trifluoromethyl)phenylisocyanate is reacted with 4-(3-monocarboxyphenoxy)aniline to produce urea And this urea is used according to the method D 1 c and 4 (dimethylamine) aniline. This paper scale is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) -118-1269791 A7 B7 V. Invention Description (11e) , Coupling. (Please read the notes on the back and fill out this page.) Item 7 9: Synthesis of 4-(3-carboxyphenoxy)aniline according to Method A 1 1 . 4-Chloro-3-(trifluoromethyl)phenylisocyanate is reacted with 4-(3-carboxyphenoxy)aniline according to method C1f to produce urea, and according to method D 1 c , it is combined with N - Phenylethylenediamine is coupled. • Item 80: Synthesis of 4-(3-carboxyphenoxy)aniline according to Method A 1 1 . 4-Chloro-3-(difluoromethyl)phenylisocyanate is reacted with 4-(3-carboxyphenoxy)aniline according to method C 1 a to produce urea, which is then reacted according to method D 1 c -Methoxyethylamine is coupled. Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives Project 8 1 : Synthesis of 4-(3-carboxyphenoxy)aniline according to Method All. 4-Chloryl-3-(trifluoromethyl)phenylisocyanate is reacted with 4-(3-carboxyphenoxy)aniline according to method C 1 f to produce urea, which is then reacted according to method D 1 c - Amino-2-methoxypyridine is coupled. Item 8 2: Synthesis of 4-(3-carboxyphenoxy)aniline according to Method A 1 1 . 4-Chloryl-3-(trifluoromethyl)phenylisocyanate is reacted with 4-(3-carboxyphenoxy)aniline according to Method C 1 f and is combined with 4-morpholine according to Method D 1 c The aniline is coupled. This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -119-1269791 A7 _______B7__ V. Description of invention (1彳7) ' 1 Item 8 3 : Synthesize 4 according to method A 1 1 3-Carboxyphenoxy (please read the precautions on the back and fill out this page)) Aniline. 4-Chloro-3-(trifluoromethyl)phenylisocyanate is reacted with 4-(3-carboxyphenoxy)aniline according to the method Clf to produce urea, and is reacted with N according to the method D 1 c. (2-Pyridinyl) hexahydropyrazine for coupling. Item 8 4 · According to method a 2 'Step 3 b '4 4 -Chloropurine π 2 -Carbohydrazide HC1 salt is reacted with 2 -hydroxyethylamine to form 4-chloro-indole - (2 - triiso) Propylmethyl alkoxy) ethyl pyridine mono-2-amine. According to the method Α17, first, 4-chloro-indenyl-(2-triisopropylmethicin; t兀oxy)ethyl 吼η is determined to be a 2-carboguanamine and triisopropylmethyl oxalate The chlorine is reacted and the reaction with 4-aminophenol is continued. According to the method C 1 a , 4-chloro-3-(trifluoromethyl)phenylisocyanate and 4-(4-(2-(2-isopropyl-2-decyloxy)ethylamino) A pyridinium pyridyloxyaniline is reacted to produce N-(4-chloro-1,3-((trifluoromethyl)phenyl)-n-(4) (Ministry of Commerce, Intellectual Property Office, Consumer Cooperatives, Printed 4 One (2~(N~(2-triisopropylcarbamoyloxy)ethylaminopyridinium)pyridyloxyphenyl)urea. According to Method D5, the urea is deprotected to produce N-(4 Chloro-3-((trifluoromethyl)phenyl)~(4-(4-(2-(2-hydroxy)ethylaminopyridinyl)pyridyloxyphenyl)urea. Item 85 ··According to Method A2 to synthesize 4-(2-(N-methylamide)

1269791 A7 --- B7 五、發明說明（”8) . 基甲醯）—4 一吡啶氧基）苯胺。根據方法B 1來將4 一 溴基一 3 —(三氟甲基）苯胺轉變成4 一溴基一 3 -（三 氟甲基）苯基異氰酸酯。根據C la ’將4 —溴基一 3 — (—'親甲基）苯基異氨酸醋與4 一（2 —（N —甲基氨基 甲醯）- 4 -吡啶氧基）苯胺進行反應以產生脲。 項目86 :根據方法A6來合成4 — (2 —（N —甲基氨 基甲醯）-4 一吡啶氧基）一 2 —氯苯胺。根據方法B 1 ’將4 一溴基一 3 —（三氟甲基）苯胺轉變成4 一溴基一 3 -（三氟甲基）苯基異氰酸酯。根據方法c 1 a ，將4 一溴基一 3 —（三氟甲基）苯基異氰酸酯與4 — (2 —（ N-甲基氨基曱醯）一 4 一吡啶氧基）一 2 —氯苯胺進行 反應以產生脲。 項目8 7 :根據方法A 2，步驟4，將根據方法A 2，步 驟3 b所合成的4 一氯基一 N -甲基一 2 -吼d定竣醒胺與 4 一胺基一 2 —氯酚進行反應以產生4 一（2 -（N —甲 基氨基甲醯）一4一吡啶氧基）一3-氯苯胺。根據方法 B1 ，將4 一溴基一 3 -（三氟甲基）苯胺轉變成4 一溴 基一 3 —(三氟甲基）苯基異氰酸酯。根據方法c ；[ a ， 將4 一溴基一 3 —（三氟甲基）苯基異氰酸酯與4 一（2 —(N -甲基氨基甲醯）一 4 一吡啶氧基）〜3 —氯苯胺 進行反應以產生脲。 項目8 8 :根據方法a 2，步驟3 b ，將4〜氯D[i π定一2 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公爱） 裝—— (請先閱讀背面之注意事項再填寫本頁) 訂： 經濟部智慧財產局員工消費合作社印製 -121 1269791 A7 B7 五、發明說明（119) » 一羰醯氯與乙胺進行反應。根據方法A 2，步驟4，將所 產生的4 一氯基一 N —乙基一吡啶羧醯胺與4〜胺基酚進 行反應以產生4 一 （2 —（N -乙基氨基甲醯）一 4 一吼 陡氧基）苯胺。根據方法B 1 ，將4 一溴基一 3 -（三氟 甲基）苯胺轉變成4 一溴基一 3 —（三氟甲基）苯基異氰 酸酯。根據方法C 1 a ，將4 一溴基一 3 — ( 氟甲基） 苯基異氰酸酯與4 一（2 -（N —乙基氨基甲酶）—4一 吡啶氧基）苯胺進行反應以產生脲。 項目8 9 :根據方法A2，步驟3 a來合成4〜氯基—N 一甲基一 2 -吡啶羧醯胺，然後，再根據方法a 2，步驟 4將它與3 —胺基酚進行反應以形成3 —（2〜（N 一甲 基氨基甲醯）一 4 一吡啶氧基）苯胺。根據方法b 1 ，將 4 —溴基一 3 —（三氟甲基）苯胺轉變成4 一溴基一 3 — (三氟甲基）苯基異氰酸酯。根據方法C 1 a ，將4 一溴 基—3 —（三氟甲基）苯基異氰酸酯與3 — (2 —（N- 甲基氨基甲醯）一 4 -吡啶氧基）苯胺進行反應以產生脲 〇 項目9 0 :根據方法A 2，步驟4，將5 -胺基一2 -甲 基酚與4 一氯基一N —甲基—2 —吡啶羧醯胺（已根據方 法A2 ’步驟3b來合成）進行反應以進行3 — (2 - N 一甲基氨基甲醯）一 4 一吡啶氧基）一 4 —甲基苯胺。根 據方法B1，將4一溴基一3—(三氟甲基）苯胺轉變成 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -------------裝--- (請先閱讀背面之注意事項再填寫本頁) 訂： 經濟部智慧財產局員工消費合作社印製 -122- 1269791 A7 B7 五、發明說明（120) 4 一溴基一 3_ (三氟甲基）苯基異氰酸酯。根據c丄a ，將4-溴基- 3一（三氟甲基）$基異氰酸酯與3_ ( 2 - (N 一甲基氨基甲醯）-4 -吡啶氧基）—4_甲基 苯胺進行反應以產生脲 項目9 1 :根據方法A 2 ’步驟3 b，將4 —氯吡啶—2 一羰醯氯與二甲胺進行反應。根據方法A2，步驟4，將1269791 A7 --- B7 V. INSTRUCTIONS ("8) . 基 醯) - 4 - pyridyloxy) aniline. Conversion of 4-bromo-tris-(trifluoromethyl)aniline to method B 1 4-monobromo-tris-(trifluoromethyl)phenylisocyanate. According to C la ', 4-bromo-mono-3-(-'-methyl)phenyl isocyanine vinegar and 4 one (2 - (N -Methylcarbamidine)-4-pyridyloxy)aniline was reacted to produce urea. Item 86: Synthesis of 4-(2-(N-methylaminocarbamidine)-4-pyridinyloxy) according to Method A6 2-Chloroaniline. Conversion of 4-bromo-tris-(trifluoromethyl)aniline to 4-bromo-tris-(trifluoromethyl)phenylisocyanate according to method B 1 '. According to method c 1 a Reacting 4-bromo-3-trifluoromethylphenyl isocyanate with 4-(2-(N-methylaminopurine)-4-pyridyloxy)-2-chloroaniline to produce urea Item 8 7 : According to the method A 2, step 4, the 4-chloro-N-methyl- 2 - fluorene synthesized according to the method A 2, the step 3 b is determined to be an amine and a 4-amino group. Chlorophenol The reaction is carried out to give 4-(2-(N-methylaminoformamidine)-4-pyridyloxy)-3-chloroaniline. According to Method B1, 4-bromo-tris-(trifluoromethyl)aniline is converted. To 4-bromo-mono-3-(trifluoromethyl)phenylisocyanate. According to method c; [a, 4-bromo-tris-(trifluoromethyl)phenylisocyanate with 4 (2 - (N) -Methylaminoguanidine)-tetra-pyridyloxy)~3-chloroaniline is reacted to produce urea. Item 8 8: According to method a 2, step 3 b, 4~chloro D[i π is set to 2 Paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public) installation - (Please read the note on the back and fill out this page) Order: Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing -121 1269791 A7 B7 V. INSTRUCTIONS (119) » Reaction of monocarbonyl chloride with ethylamine. According to method A 2, step 4, the resulting 4-chloro-N-ethyl-pyridinium carboxamide and 4-amino group are obtained. The phenol is reacted to produce 4-(2-(N-ethylaminocarbamidine)-tetra-anthranoxy)aniline. According to Method B1, 4-bromo Conversion of 3-yl-(trifluoromethyl)aniline to 4-bromo-tris-(trifluoromethyl)phenylisocyanate. According to method C 1 a , 4-bromo-3-(fluoromethyl)benzene The isocyanate is reacted with 4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)aniline to produce urea. Item 8 9: Synthesis of 4~Chloro-N according to Method A2, Step 3a Monomethyl-2-pyridine carboxamide, and then reacted with 3-aminophenol according to method a 2, step 4 to form 3-(2~(N-methylaminocarbamidine)-4 Pyridyloxy) aniline. According to the method b 1 , 4-bromomono-3-(trifluoromethyl)aniline was converted to 4-bromomono-3-(trifluoromethyl)phenylisocyanate. According to the method C 1 a , 4-bromo-3-trifluoromethylphenyl isocyanate is reacted with 3-(2-(methylaminocarbamidine)-4-pyridyloxy)aniline to produce Urea oxime item 90: According to method A 2, step 4, 5-amino-2-methylphenol and 4-chloro-N-methyl-2-pyridine carboxamide (already according to method A2 'step 3b To carry out the reaction, 3-(2-N-methylaminoformamidine)-tetrapyridyloxy)-4-methylaniline was carried out. According to Method B1, 4-Bromyl-3-(trifluoromethyl)aniline is converted to paper scale for Chinese National Standard (CNS) A4 specification (210 X 297 mm) ----------- -- Pack --- (Please read the note on the back and fill out this page) Order: Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed -122- 1269791 A7 B7 V. Invention Description (120) 4 Monobromo-A-3_ (Trifluoromethyl)phenyl isocyanate. According to c丄a, 4-bromo-3-tris(trifluoromethyl)$-isocyanate was reacted with 3_(2-(N-methylaminocarbamidine)-4-pyridyloxy)-4-methylaniline Reaction to produce urea item 91: According to method A 2 'step 3 b, 4-chloropyridine-2-carbonylcarbonyl chloride is reacted with dimethylamine. According to method A2, step 4, will

所產生的4 —氯基—N，N 2 -吡啶羧醯胺與 4 一胺基酚進行反應以產生4〜（2〜（N，N —二甲基 氨基甲醯）一 4 一吡啶氧基）苯胺。根據方法B丄，將4 溴基一 3 氟甲基）苯胺轉變成4 一溴基一 3 氟甲基）苯基異氰酸酯。根據方法c;La ，將4 一溴基 3 —（三氟甲基）苯基異氰酸酯與4— (2 —（N，N 二甲基氨基甲釀）-4-吼啶氧基）苯胺進行反應以產 生脲 (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 項目9 2 : 依方法A2 ，步驟3b中的說明來合成4一氯基一n -甲基吡陡殘醯胺。根據方法A 2，步驟4，將氯吡D定與 4 一胺基苯硫酌進行反應以產生4 一（4 一（2 —（N -甲基氨基甲醯）苯硫基）苯胺。根據方法B 1 ，將4 一溴 基一 3 — 氟甲基）苯胺轉變成4 一溴基一 3 氟 甲基）苯基異氰酸酯。根據方法C 1 a ，將4 一溴基一 3 一（二氟甲基）苯基異氰酸酯與4 一（4 — (2 — (N — 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -123· A7 1269791 -_B7___ 五、發明說明（121) a 甲基氨基甲醯）苯硫基）苯胺進行反應以產生脲。 (請先閱讀背面之注意事項再填寫本頁) 項目9 3 :依方法A 2 ，步驟3 b中的說明來合成4 —氯 基一 N -甲基D[t n定羧醯胺。根據方法a 2 ，步驟4將氯口比 D定與3 -胺基苯硫酚進行反應以產生3 一（4 一（2一（ N —甲基氨基甲醯）苯硫基）苯胺。根據方法B 1 ，將4 一溴基一 3 -（三氟甲基）苯胺轉變成4 —溴基一 3 -（ 三氟甲基）苯基異氰酸酯。根據方法C 1 a ，將4 一溴基 一 3〜（三氟甲基）苯基異氰酸酯與3 一（4 一（2一（ 甲基氨基甲醯）苯硫基）苯胺進行反應以產生脲。 項目94 :根據方法A10來合成4 一（2 —（N— (2 一嗎啉一 4 一基乙基）氨基甲醯）吡啶氧基。根據方法 B1 ，將4 一溴基一3 —（三氟甲基）苯胺轉變成4 一溴 基一 3 —（三氟甲基）苯基異氰酸酯。根據方法Cia ， 將4 一溴基一 3 -（三氟甲基）苯基異氰酸酯與4 一（2 —(N - （ 2 —嗎啉—4 —基乙基）氨基甲醯）吡啶氧基 )苯胺進行反應以產生脲。 經濟部智慧財產局員工消費合作社印製 項目9 5 :將4— (2 —（N —甲基氨基甲艦）一 4 一 d比 啶氧基）苯胺根據方法A 2的說明來加以合成。根據a 7 來合成4 —氯基一 2 —甲氧基一 5 —（三氟甲基）苯胺。 根據方法B1來將4 一氯基一 2 —甲氧基一5 —（三氟甲 基）苯胺轉變成4 一氯基一 2 -甲氧基一 5 —（三氟甲基 -124- 本纸張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 1269791 A7 B7 五、發明說明（122) .The resulting 4-chloro-N,N 2 -pyridinecarboxamide is reacted with 4-aminophenol to produce 4~(2~(N,N-dimethylaminoformamidine)-tetrapyridyloxy )aniline. According to Method B, 4 bromo-3-fluoromethyl)aniline is converted to 4-bromomono-3-fluoromethyl)phenylisocyanate. Reaction of 4-bromo 3-(trifluoromethyl)phenylisocyanate with 4-(2-(N,N-dimethylaminomethyl)-4-acridinyloxy)aniline according to Method c;La To produce urea (please read the note on the back and then fill out this page) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed Project 9 2 : Synthesize 4-chloro-n-methyl according to the method in Method A2, Step 3b Pyridoxamine. According to the method A 2, step 4, the chloropyrrolidine D is reacted with the 4-aminophenylsulfuric acid to produce 4-(4-(N-methylaminomethylguanidinium)phenylthio)aniline. B 1 , 4 -Bromo-3-trifluoromethyl)aniline is converted to 4-monobromo-3-fluoromethyl)phenyl isocyanate. According to the method C 1 a , 4 - bromo-3-tris(difluoromethyl)phenyl isocyanate is 4 (4 - (2 - (N - this paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) -123· A7 1269791 -_B7___ V. INSTRUCTIONS (121) a Methylaminopyridinium phenylthio)aniline is reacted to produce urea. (Please read the notes on the back and fill out this page) 9 3 : Synthesis of 4-chloro-N-methyl D[tn-carboxycarboxamide according to the method in Method A 2 , Step 3 b. According to Method a 2 , Step 4 is to determine the ratio of Chlorine to D to 3 - Amine The thiophenol is reacted to produce 3-(4-(N-methylaminoformamidine)phenylthio)aniline. According to Method B1, 4-bromo-3-(trifluoromethyl) Conversion of aniline to 4-bromo-mono-3-(trifluoromethyl)phenylisocyanate. According to method C 1 a , 4-bromo- 3~(trifluoromethyl)phenylisocyanate is combined with 3 (4) 2-(Methylaminoformamidine)phenylthio)aniline was reacted to produce urea. Item 94: Synthesis according to Method A10 4 (2 -(N-(2)-morpholine-4 Ethyl)carbamidine)pyridyloxy. According to method B1, 4-bromo-3-trifluoromethylaniline is converted to 4-bromo-3-trifluoromethylphenylisocyanate. Method Cia, 4-monobromo-3-trifluoromethylphenylisocyanate and 4-(2-(N-(2-morpholine-4-ylethyl)carbamidine)pyridinyloxyaniline The reaction is carried out to produce urea. Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing project 9 5: 4 - (2 - (N - methylaminocarb) - 4 - d-pyridyloxy) aniline according to method A 2 The synthesis is carried out according to the synthesis of 4-chloro- 2-methoxy-5-(trifluoromethyl)aniline according to a 7. According to the method B1, 4-chloro- 2-methoxy-5-( Conversion of trifluoromethyl)aniline to 4 monochloro-2-methoxy-5-(trifluoromethyl-124- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1269791 A7 B7 V. Description of invention (122).

)苯基異氰酸酯。根據方法c 1 a •，將4 一氯基一 2 -甲 氧基〜5 —（三氟甲基）苯基異氰酸酯與4 一（2— (N 一甲基氨基甲醯）一 4 -吡啶氧基）苯胺進行反應以產生. 脲。 項目96 :根據方法A 6來合成4 一（2 -（N —甲基氨 基甲M) — 4 一吡啶氧基）一 2 —氯苯胺。根據方法A7 來合成4 一氯基一 2 —甲氧基一 6 —(三氟甲基）苯胺。 根據方法B1 ，將4 —氯基一 2 —甲氧基_5—（三氟甲 基）苯胺轉變成4 —氯基一 2 -甲氧基一 5—(三氟甲基 )苯基異氰酸酯。根據方法C la ，將4 —氯基一 2 -甲 氧基一 5 —（三氟甲基）苯基異氰酸酯與4 一—（N 一甲基氨基甲醯）一 4 —吡啶氧基）一 2 —氯苯胺進行反 應以產生脲。 項目9 7 ··根據方法A 2，步驟4，將4 —胺基一 2 -氯 酚與4 一氯基一 N -甲基一 2吡啶羧醯胺（已根據方法 A2 ’步驟3來合成）進行反應以產生4 一—（N — 甲基氨基甲醯）—4 一吡啶氧基3 -氯苯胺。根據方 法A7來合成4 一氯基一2 —甲氧基一 5 —（三氟甲基） 本S女。根據方法B 1 ，將4 一氯基一 2 —甲氧基一 5 —（ 三氟甲基）苯胺轉變成4 一氯基一 2 —甲氧基一 5 —（三 氟甲基）苯基異氰酸酯。根據方法C 1 a ，將4 一氯基一 2 —甲氧基一 5 —（三氟甲基）苯基異氰酸酯與4一（2 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） _裝--- (請先閱讀背面之注意事項再填寫本頁) 訂： 經濟部智慧財產局員工消費合作社印製 -125- 1269791 A7 B7 五、發明說明（123) —(N —甲基氨基甲醯）一4 一吡啶氧基）—3 —氯苯胺 進行反應以產生脲。 項目98 :根據方法A2，步驟3a來合成4 —氯基一 N 一甲基一 2 —吡啶羧醯胺，再根據方法A 2 ，步驟4來將 之與3 -胺基酚進行反應以形成3 -（2 -（N -甲基氨 基甲醯）一 4 一吼陡氧基）苯胺。根據方法A 7來合成4 一氯基一 2 —甲氧基一 5 -（三氟甲基）苯胺。根據方法 B1 ，將4 一氯基一 2 —甲氧基一 5 —（三氟甲基）苯胺 轉變成4 一氯基一 2 —甲氧基一 5 -（三氟甲基）苯基異 氰酸酯。根據方法Cl a ，將4 一氯基一 2 -甲氧基一 5 一（三氟甲基）異氰酸酯與3 —（2 —（N —甲基氨基甲 醯）一 4 一吡啶氧基）苯胺進行反應以產生脲。 項目9 9 :根據方法A 2，步驟3 b ，將4 —氯吡啶一 2 -羰醯氯與乙胺進行反應。根據方法A 2，步驟4，將所 產生的4 一氯基一 N —乙基一 2 -吡啶羧醯胺與4 一胺基 酚進行反應以產生4 一（2— (N -乙基氨基甲醯）一 4 一吡啶氧基）苯胺。根據方法A 7來合成4 一氯基一 2 -甲氧基一 5 —（三氟甲基）苯胺。根據方法B1 ，將4 一 氯基一 2 —甲氧基一 5 —（三氟甲基）苯胺轉變成4 一氯 基一 2 -甲氧基一 5 —（三氟甲基）苯基異氰酸酯。根據 方法C la ，將4 一氯基一2 —甲氧基一 5 — （三氟甲基 )苯基異氰酸酯與4一（2—（N—乙基氨基甲醯）一4 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） ί裝—— (請先閱讀背面之注意事項再填寫本頁) · 經濟部智慧財產局員工消費合作社印製 -126- 1269791 A7 B7 五、發明說明（124) -吼D定氧基）苯胺進行反應以產生脲。 (請先閱讀背面之注意事項再填寫本頁) 項目1 0 0 :根據方法A 2 ，步驟3 b ，將4 一氯吡啶一 2 -鑛醯氯與二乙胺進行反應。根據方法a 2，步驟4， 將所產生的4 —氯基一 N，N -二甲基一 2 —吡啶羧醯胺 與4 一胺基酚進行反應以產生4 一（2 — (N，N —二甲 基氨基甲醯）一 4 一吡啶氧基）苯胺。根據方法a 7來合 成4 一氯基一 2 —甲氧基—5 —(三氟甲基苯胺。根據 方法B1 ,將.4 —氯基—2 —甲氧基—5 —(三氟甲基） 苯胺轉變成4 一氯基一 2 -甲氧基一 5 —（三氟甲基）苯 基異氰酸酯。根據方法Cl a ，將4 一氯基一 2 —甲氧基 —5—（三氟甲基）苯基異氰酸酯與4一（2一（N，n 一一甲基氨基甲醯）-4-吡啶氧基）苯胺進行反應以產 生脲。 項目1 0 1 :根據方法A 2，步驟3 a來合成4 —氯基一 經濟部智慧財產局員工消費合作社印製 N 一甲基—2 —吡啶羧醯胺，再根據方法A 2 ，步驟4將 之與3 肢基酣進fT反應以形成3 - 2〜（n —甲基氨基 甲醯）一 4 一吡啶氧基）苯胺。依方法a丄中的說明來合 成2—胺基一3—甲氧基萘。根據方法C3 ，先將2—胺 基 3 -甲氧基奈與雙（二氯甲基）碳酸酯進行反應，再 與3 — (2 —（N —甲基氨基甲醯）〜4 一吡啶氧基）苯 胺反應以形成脲。 項目102 :根據方法A2來合成4 — (2一 一甲基 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -127« A7 1269791 B7 五、發明說明（125) » 氨基甲醯）一 4 一吡啶氧基）苯胺。根據方法A 4來合成 5 一特一 丁基一 2 —（2 ，5 -二甲基吡咯基）苯胺。根 (請先閱讀背面之注意事項再填寫本頁) 據方法C2d，先將5 —特—丁基一 2—（2 ，5 —二甲 基吡略基）苯胺與CDI進行反應，再與4一（2-（N 一甲基氨基甲醯）- 4 -吡啶氧基）苯胺進行反應以產生 脲。 ’ 項目1 0 3 :根據方法A2，步驟3 b來合成4 一氯基一 N —甲基一 2 —吡啶羧醯胺。根據方法a 2 ，步驟4，利 用DMAC來取代DMF，將4 一氯基—N —甲基一2 — 吡啶羧醯胺與4 一胺基酚進行反應以產生4 -； ( 2 -（ N 一甲基氣基甲釀）一 4 一哦π定氧基）苯胺。根據方法 C2b ，先將3 —胺基一 2 —甲氧基喹啉與CD I反應， 再與4 一（2 — （N —甲基氨基甲醯）一 4 一吡啶氧基） 苯胺反應以產生雙（4 一（2 —（N —甲基氨基甲醯）一 4 一吡啶氧基）苯基）脲。 經濟部智慧財產局員工消費合作社印製 下表中所列者爲已根據上述詳細之實驗步驟來合成的 化合物。 表格 下列表1 - 6所列之化合物係根據上述的一般方法來 合成，且較詳細之示範步驟係列於上述項目中，其特性則 顯示於表中。 -128- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） A7 1269791 _ B7_ 五、發明說明（126) 表1. 3-特-丁苯基尿素類Phenyl isocyanate. According to the method c 1 a •, 4-chloro- 2-methoxy-5-(trifluoromethyl)phenylisocyanate and 4-(2-(N-methylaminoformamidine)-4-pyridyloxy The aniline is reacted to produce a urea. Item 96: Synthesis of 4-(2-(N-methylaminomethyl)-4-pyridyloxy)-2-chloroaniline according to Method A6. 4-Chloro-2-methoxy- 6-(trifluoromethyl)aniline was synthesized according to Method A7. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was converted to 4-chloro-2-carbo-5-(trifluoromethyl)phenylisocyanate according to Method B1. 4-Chloro-2-2-methoxy-5-(trifluoromethyl)phenylisocyanate and 4-(N-methylaminocarbamidine)-4-pyridyloxy)-2 according to the method C la - Chloroaniline is reacted to produce urea. Item 9 7 · According to Method A 2, Step 4, 4-amino-2-chlorophenol and 4-chloro-N-methyl-2-pyridine carboxamide (synthesized according to Method A2 'Step 3) The reaction is carried out to give 4-(N-methylaminocarbamidine)-4-pyridyloxy-3-chloroaniline. According to the method A7, 4-chloro- 2-methoxy-5-(trifluoromethyl)-S female was synthesized. Conversion of 4-chloro-2-methoxy-5-(trifluoromethyl)aniline to 4-chloro-2-carbo-5-(trifluoromethyl)phenyl isocyanate according to Method B1 . According to the method C 1 a , 4-chloro- 2-methoxy-5-(trifluoromethyl)phenylisocyanate is used with 4 (2 paper scales applicable to the Chinese National Standard (CNS) A4 specification (210 X 297) )) _装--- (Please read the note on the back and fill out this page) Order: Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed -125- 1269791 A7 B7 V. Invention Description (123) —(N — Methyl carbamate) 4-tetrapyridyloxy)-3-chloroaniline is reacted to produce urea. Item 98: Synthesis of 4-chloro-N-methyl-2-pyridine carboxamide according to Method A2, Step 3a, and reacting with 3-aminophenol according to Method A 2 , Step 4 to form 3 -(2-(N-methylaminocarbamidine)-4 oxonoxy)aniline. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was synthesized according to Method A7. According to the method B1, 4-chloro-2-carbo-5-(trifluoromethyl)aniline was converted into 4-chloro-2-carbo-5-(trifluoromethyl)phenylisocyanate. 4-Chloro-2-methoxy-5-(trifluoromethyl)isocyanate is treated with 3-(2-(N-methylaminoformamidine)-4-pyridyloxy)aniline according to the procedure Cl a The reaction produces urea. Item 9 9: 4-Chloropyridine-2-oxoindole chloride was reacted with ethylamine according to Method A 2, Step 3 b. According to Method A 2, Step 4, the resulting 4-chloro-N-ethyl-2-pyridine carboxamide is reacted with 4-aminophenol to produce 4-(2-(N-ethylamino)醯) 4-tetrapyridyloxy)aniline. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was synthesized according to Method A7. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was converted to 4-chloro-2-carbo-5-(trifluoromethyl)phenyl isocyanate according to Method B1. According to the method C la , 4 - chloro 2- methoxy 5- 5 - (trifluoromethyl ) phenyl isocyanate and 4 - (2-(N-ethylaminocarbamidine) - 4 paper scales are applicable to China. National Standard (CNS) A4 Specification (210 X 297 mm) ί Installed - (Please read the note on the back and fill out this page) · Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed -126- 1269791 A7 B7 V. DESCRIPTION OF THE INVENTION (124) - 吼D-oxyl) aniline is reacted to produce urea. (Please read the precautions on the back and fill out this page.) Item 1 0 0: According to Method A 2 , Step 3 b , 4 -Chloropyridine 2- 2 -mine chloride is reacted with diethylamine. According to method a 2, step 4, the resulting 4-chloro-N,N-dimethyl-2-pyridine carboxamide is reacted with 4-aminophenol to produce 4 (2 - (N, N) - dimethylaminoformamidine) 4-tetrapyridyloxy)aniline. 4-Chloro-2-methoxy-5-(trifluoromethylaniline) was synthesized according to Method a7. According to Method B1, .4-chloroyl-2-methoxy-5-(trifluoromethyl) Conversion of aniline to 4-chloro-2-carbo-5-(trifluoromethyl)phenyl isocyanate. 4-Chloro-2-methoxy-5-(trifluoromethyl) according to Method Cl a Phenyl isocyanate is reacted with 4-(2-(N,n-monomethylaminoformamidine)-4-pyridinyloxy)aniline to produce urea. Item 1 0 1 : according to Method A 2, Step 3 a To synthesize 4-chloro-I-Ministry of Commerce, Intellectual Property Office, Staff Consumer Cooperative, to print N-methyl-2-pyridine carboxamide, and then react with 3 limbs into fT according to Method A 2 and Step 4 to form 3 - 2~(n-methylaminoformamidine)-tetrapyridyloxy)aniline. 2-Amino-3-methoxynaphthalene is synthesized according to the description in Method a. According to the method C3, 2-amino-3-methoxynaphthalene is first reacted with bis(dichloromethyl)carbonate, and then 3-(2-(N-methylaminocarbamidine)~4-pyridinyloxy The aniline reacts to form urea. Item 102: Synthesis according to Method A2 4 - (2 -1 methyl paper size applicable to China National Standard (CNS) A4 specification (210 X 297 mm) -127 « A7 1269791 B7 V. Description of invention (125) » Amino醯) 4-tetrapyridyloxy)aniline. According to the method A 4, 5-tert-butyl-2-(2,5-dimethylpyrrolyl)aniline was synthesized. Root (please read the note on the back and then fill out this page) According to the method C2d, first react 5-te-butyl-2-(2,5-dimethylpyrrolidyl)aniline with CDI, and then with 4 Mono(2-(N-methylaminoformamidine)-4-pyridyloxy)aniline is reacted to produce urea. Item 1 0 3: Synthesis of 4-chloro-N-methyl-2-pyridine carboxamide according to Method A2, Step 3b. According to method a 2 , step 4, DMF is substituted for DMF, and 4-chloro-N-methyl-2-pyridine carboxamide is reacted with 4-aminophenol to produce 4 -; ( 2 -( N Methyl gas based brewing) A 4 哦 π 定 oxy) aniline. According to the method C2b, 3-amino-2-methoxyquinoline is first reacted with CD I, and then reacted with 4-(2-(N-methylaminocarbamidine)-4-pyridyloxy)aniline to produce Bis(4-(2-N-methylaminoformamidine)-tetrapyridyloxy)phenyl)urea. Printed by the Intellectual Property Office of the Ministry of Economic Affairs, the Consumer Cooperatives. The following table lists the compounds that have been synthesized according to the detailed experimental procedures described above. Tables The compounds listed in Tables 1 - 6 below were synthesized according to the general methods described above, and a more detailed demonstration of the series of steps in the above items, the characteristics of which are shown in the table. -128- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) A7 1269791 _ B7_ V. Description of invention (126) Table 1. 3-tert-Butylphenyl urea

經濟部智慧財產局員工消費合作社印製 項 g R mp (°C) HPLC (分） TLC Rf TLC 溶劑系統 質譜儀 (來源） 合成 方法 1 〇\ y-NH ^&gt;〇-〇 Me 0.22 50% EtOAc /50% 己烷 418 (M+H)+ (HPLC) ES-MS) A13 C3 2 0.58 50% EtOAc /50% 己烷 403 (M+H)+ (HPLC ES-MS) A13 C3 3 〇\ V-NH 133- 135 0.68 100% EtOAc 448 (M+H)+ (FAB) A8 C2d (請先閱讀背面之注意事項再填寫本頁) I裝 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -129- 1269791 A7 B7 五、發明說明（127) 表2. 5-特-丁基-2-甲氧苯基尿素類 R、_Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed item g R mp (°C) HPLC (minutes) TLC Rf TLC Solvent System Mass Spectrometer (Source) Synthetic Method 1 〇\ y-NH ^&gt;〇-〇Me 0.22 50% EtOAc / 50% hexanes 418 (M+H) + (EtOAc) EtOAc (EtOAc) EtOAc (EtOAc) V-NH 133- 135 0.68 100% EtOAc 448 (M+H)+ (FAB) A8 C2d (Please read the note on the back and fill out this page) I Paper size is applicable to China National Standard (CNS) A4 specification ( 210 X 297 mm) -129- 1269791 A7 B7 V. Description of invention (127) Table 2. 5-tert-Butyl-2-methoxyphenyl urea R, _

1.J1.J

〇Me 項 巨〇Me item

R mp (°C) HPLC (分） TLC Rf TLC 溶劑系統 質譜儀 (來源） 合成 方法 4 5.93R mp (°C) HPLC (minutes) TLC Rf TLC Solvent System Mass Spectrometer (Source) Synthesis Method 4 5.93

448 (M+H)+ (HPLC) ES-MS) A13 B1 Cla (請先閱讀背面之注意事項再填寫本頁)448 (M+H)+ (HPLC) ES-MS) A13 B1 Cla (please read the notes on the back and fill out this page)

120- 122 0.67 100%120- 122 0.67 100%

EtOAc 478 (M+H)+ (FAB) A8 C2d 經濟部智慧財產局員工消費合作社印製 6 7 0.40EtOAc 478 (M+H)+ (FAB) A8 C2d Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 6 7 0.40

50% EtOAc /50% 己烷 460 (M+H)+ (HPLC ES-MS) A3 C2d 0.7950% EtOAc / 50% hexane 460 (M+H) + (HPLC ES-MS) A3 C2d 0.79

本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -130- A7 1269791 B7_ 五、發明說明（128) 表3. 5-(三氟甲基)j甲氧苯基尿素This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -130- A7 1269791 B7_ V. Description of invention (128) Table 3. 5-(Trifluoromethyl)j-methoxyphenyl urea

經濟部智慧財產局員工消費合作社印製 項 R mp (°C) HPLC 份） TLC Rf TLC 溶劑系統 質譜儀 (來源） 合成 方法 8 〇\ V-NH 令會 250 (分解) 460 (M+H)+ (FAB) A13 C2a 9 206- 208 0.54 10% MeOH /90% CH2CI2 446 (M+H)+ (HPLC ES-MS) A3步驟 2， A8步驟 4， Bl, Cla 10 0.33 50% EtOAc /50% 石油醚 445 (M+H)+ (HPLC ES-MS) A13 C3 11 0心 0.20 2% EbN 99% EtOAc 447 (MeOH +H)+ (HPLC ES-MS) A2 C4 (請先閱讀背面之注意事項再填寫本頁) -i^w --------訂·--------· 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -131 - A7 1269791Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed by R mp (°C) HPLC) TLC Rf TLC Solvent System Mass Spectrometer (Source) Synthetic Method 8 〇\ V-NH Order 250 (Decomposition) 460 (M+H) + (FAB) A13 C2a 9 206- 208 0.54 10% MeOH /90% CH2CI2 446 (M+H)+ (HPLC ES-MS) A3 Step 2, A8 Step 4, Bl, Cla 10 0.33 50% EtOAc /50% Petroleum ether 445 (M+H)+ (HPLC ES-MS) A13 C3 11 0 heart 0.20 2% EbN 99% EtOAc 447 (MeOH + H) + (HPLC ES-MS) A2 C4 (Please read the back note first) Fill in this page again) -i^w --------Book·-------· This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -131 - A7 1269791

B 五、發明說明（129) 經濟部智慧財產局員工消費合作社印製B V. Description of invention (129) Printed by the Consumers' Cooperative of the Intellectual Property Office of the Ministry of Economic Affairs

(請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -132- 1269791 A7 B7 五、發明說明（130) 經濟部智慧財產局員工消費合作社印製 19 〇\ V-NH 194- 196 0.31 5% MeOH /45% EtOAc /50% 石油醚 475 (M+H)+ (HPLC ES-MS) A2 B1 Cla 20 〇\ Cl V-NH 214- 216 0.25 5% MeOH /45% EtOAc /50% 石油醚 495 (M+H)+ (HPLC ES-MS) A2 Cla 21 -Qr°-QrK, 208- 210 0.30 50% EtOAc /50% 己烷 481 (M+H)+ (HPLC ES-MS) A19 C2a 22 〇 )^nh2 188 -190 0.30 70% EtOAc /50% 己烷 447 (M+H)+ (HPLC ES-MS) A15， 步驟4， Cla 23 VNH 〇 0.50 70% EtOAc /30% 己烷 472 (M+H)+ (FAB) A3 B1 Cla 24 〇 Me 203- 205 0.13 100% EtOAc 479 (M+H)+ (HPLC ES-MS) A2 B1 Cla (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -133- 1269791 A7 _ B7五、發明說明（131) 25(Please read the notes on the back and fill out this page.) This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) -132- 1269791 A7 B7 V. Description of Invention (130) Ministry of Economic Affairs Intellectual Property Office Employee Consumption Cooperative Printed 19 〇\ V-NH 194- 196 0.31 5% MeOH /45% EtOAc /50% petroleum ether 475 (M+H)+ (HPLC ES-MS) A2 B1 Cla 20 〇\ Cl V-NH 214- 216 0.25 5% MeOH /45% EtOAc /50% petroleum ether 495 (M+H) + (HPLC ES-MS) A2 Cla 21 -Qr°-QrK, 208- 210 0.30 50% EtOAc /50% hexane 481 (M+H)+ (HPLC ES-MS) A19 C2a 22 〇)^nh2 188 -190 0.30 70% EtOAc / 50% hexane 447 (M+H) + (HPLC ES-MS) A15, Step 4, Cla 23 VNH 〇0.50 70% EtOAc / 30% hexanes 472 (M+H) + (FAB) A3 B1 Cla 24 〇Me 203- 205 0.13 100% EtOAc 479 (M+H)+ (HPLC ES-MS) A2 B1 Cla (Please read the note on the back and fill out this page) This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) -133- 1269791 A7 _ B7 V. Invention Description (131) 25

0.09 75% EtOAc /25% 己烷 458 (M+H)+ (HPLC ES-MS) A12 C2d 260.09 75% EtOAc / 25% hexanes 458 (M+H) + (HPLC ES-MS) A12 C2d 26

Me〇Me〇

169- 171 0.67 50% EtOAc /50% 石油醚 474 (M+H)+ (HPLC ES-MS) A13 步驟1， A13步驟 4， A16， B1 Cla ------------嫌裝—— (請先閱讀背面之注意事項再填寫本頁) 27169- 171 0.67 50% EtOAc /50% petroleum ether 474 (M+H)+ (HPLC ES-MS) A13 Step 1, A13 Step 4, A16, B1 Cla ------------ Packing - (Please read the notes on the back and fill out this page) 27

218- 219 0.40 50% EtOAc /50% 石油醚 477 (M+H)+ (HPLC ES-MS) A2步驟 3b， A2步驟 4， Bl， Cla 訂 28218- 219 0.40 50% EtOAc /50% petroleum ether 477 (M+H)+ (HPLC ES-MS) A2 Step 3b, A2 Step 4, Bl, Cla Order 28

212- 214 0.30 40% EtOAc /60% 己烷 A9 B1 Cla 經濟部智慧財產局員工消費合作社印製 29212- 214 0.30 40% EtOAc /60% Hexane A9 B1 Cla Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 29

〇 s〇 s

e H.M N 0.33 50% EtOAc /50% 石油醚 474 (M+H)+ (HPLC ES-MS) A2步驟 3b， A2步驟 4， Bl， Cla 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -134- 1269791 A7 B7 五、發明說明（132)e HM N 0.33 50% EtOAc /50% petroleum ether 474 (M+H)+ (HPLC ES-MS) A2 Step 3b, A2 Step 4, Bl, Cla This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) -134- 1269791 A7 B7 V. Description of invention (132)

CH2CI2 D4 ------------裝----- (請先閱讀背面之注意事項再填寫本頁) 33CH2CI2 D4 ------------ Pack----- (Please read the notes on the back and fill out this page) 33

N-Mq 217- 219 0.07 訂 10% MeOH / CH2CI2 A14 B1 Cla D4N-Mq 217- 219 0.07 Order 10% MeOH / CH2CI2 A14 B1 Cla D4

本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -135- 1269791 A/ B7 五、發明說明（133) 經濟部智慧財產局員工消費合作社印製 36 F— _ 0.77 70% EtOAc /30% 己烷 All B1 Clf Die 37 Me &gt;=0 0.58 70% EtOAc /30% 己烷 All B1 Clf Die 38 MeO—f ~\-NH 0.58 70% EtOAc /30% 己烷 All B1 Clf Die 39 V_/ 0.17 70% EtOAc /30% 己烷 All B1 Clf Die 40 香4 0.21 70% EtOAc /30% 己烷 All B1 Clf Die (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS)A4規格（210 χ 297公釐） -136- A7 1269791 B7_ 五、發明說明（134) 表4. 3-(三氟甲基)-4-氯苯基尿素類This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -135-1269791 A/ B7 V. Invention Description (133) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 36 F — _ 0.77 70% EtOAc / 30% Hexane All B1 Clf Die 37 Me &gt; = 0.58 70% EtOAc / 30% Hexane All B1 Clf Die 38 MeO-f ~\-NH 0.58 70% EtOAc / 30% Hexane All B1 Clf Die 39 V_/ 0.17 70% EtOAc /30% Hexane All B1 Clf Die 40 Fragrance 4 0.21 70% EtOAc / 30% Hexane All B1 Clf Die (Please read the note on the back and fill out this page) This paper size applies to China National Standard (CNS) A4 Specification (210 297 297 mm) -136- A7 1269791 B7_ V. Description of Invention (134) Table 4. 3-(Trifluoromethyl)-4-chlorophenylurea

經濟部智慧財產局員工消費合作社印製 項 巨 R mp (°C) HPLC (分） TLC Rf TLC 溶劑系統 質譜儀 (來源） 合成 方法 41 V-NH Me 163- 165 0.08 50% EtOAc/ 50% 石油醚 446 (M+H)+ (HPLC ES-MS) A13 C3 42 〇\ V-NH -〇 WMe 215 0.06 50% EtOAc/ 50% 石油醚 465 (M+H)+ (HPLC ES-MS) A2 Cla 43 〇\ V-nh2 0.10 50% EtOAc/ 50% 石油醚 451 (M+H)+ (HPLC ES-MS) A2 Cla 44 -Q J叫 °Λ_^Ν 0.25 30% EtOAc/ 70% 石油醚 451 (M+H)+ (HPLC ES-MS) A2 Cla (請先閱讀背面之注意事項再填寫本頁) 裝 -137- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 1269791 A7 B7 五、發明說明（135) 經濟部智慧財產局員工消費合作社印製 45 0心 0.31 30% EtOAc/ 70% 石油醚 465 (M+H)+ (HPLC ES-MS) A2 Cla 46 -〇。分。. VNH 〇 176- 179 0.23 40% EtOAc/ 60% 己烷 476 (M+H)+ (FAB) A3 Cla 47 Me VNH 谷# 0.29 5% MeOH/ 45% EtOAc/ .50% 石油醚 478 (M+H)+ (HPLC ES-MS) A5 Clc 48 〇-S?NH 206- 209 A15 Cla 49 〇\ Cl V-NH Me 147- 151 0.22 50% EtOAc/ 50% 石油醚 499 (M+H)+ (HPLC ES-MS) A6 Cla 50 —V-NH /=&lt; Me 〇七N 0.54 100% EtOAc 479 (M+H)+ (HPLC ES-MS) A2 Cla (請先閱讀背面之注意事項再填寫本頁) 裝 訂： 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -138- 1269791 A7 B7 五、發明說明（136) 經濟部智慧財產局員工消費合作社印製 51 〇\ V-NH 普θ Β 187- 189 0.33 5% MeOH/ 45% EtOAc/ 50% 石油醚 479 (M+H)+ (HPLC ES-MS) A2 Cla 52 〇\ Cl V-NH 各會 219 0.18 5% MeOH/ 45% EtOAc/ 50% 石油醚 499 (M+H)+ (HPLC ES-MS) A2 Cla 53 246- 248 0.30 50% EtOAc/ 50% 己烷 485 (M+H)+ (HPLC ES-MS) A19, Cla 54 Me 196- 200 0.30 70% EtOAc/ 30% 己烷 502 (M+H)+ (HPLC ES-MS) A15 Cla 55 228- 230 0.30 30% EtOAc/ 70% CH2CI2 466 (M+H)+ (HPLC ES-MS) 56 普 Me 238- 245 (請先閱讀背面之注意事項再填寫本頁) 裝—— 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -139- 1269791 A7 B7 五、發明說明（137) 經濟部智慧財產局員工消費合作社印製 57 221- 222 0.75 80% EtOAc/ 20% 己烷 492 (M+H)+ (FAB) Cld Dla 58 〇\ V-NH 247 0.35 100% EtOAc Cld Dla D2 59 〇、Me &gt;-N； 198- 200 0.09 100% EtOAc 479 (M+H)+ (HPLC ES-MS) A2 Cla 60 Me〇 158- 160 0.64 50% EtOAc/ 50% 石油醚 61 V-nh 195- 197 0.39 10% MeOH/ CH2CI2 A13 Cla 62 〇\ V-NH 170- 172 0.52 10% MeOH/ CH2CI2 A13 Cla 63 〇\ 168- 171 0.39 10% MeOH/ CH2CI2 A13 Cla 64 0 Etv V-NH 普 176- 177 0.35 10% MeOH/ CH2CI2 A13 Cla (請先閱讀背面之注意事項再填寫本頁) 裝 -l^J« — — — III. .参 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -140- 1269791 ^ Β7 五、發明說明（138) 經濟部智慧財產局員工消費合作社印製 65 〇 V-NH -o^-oMe ΠΟ- 133 487 (M+H)+ (HPLC ES-MS) A2 B1 Cla 66 〇\ V-NH 155 A2 Cla 67 〇\ y-NH 侈WMe 225- 229 0.23 100% EtOAc Cle D3 Dlb 68 \^NMe 〇 234- 236 0.29 40% EtOAc/ 60% 己烷 A9 Cla 69 s-v^N 0.48 50% EtOAc/ 50% 石油醚 481 (M+H)+ (HPLC ES-MS) 70 〇\ V-NH 0.46 50% MeOH/ 95% CH2CI2 564 (M+H)+ (HPLC ES-MS) A10 Cla 71 〇 V-NH 199- 201 0.50 10% MeOH/ CH2CI2 A14 Cla D4 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 裝—— (請先閱讀背面之注意事項再填寫本頁) -141 - 1269791 A7 B7 五、發明說明（139) 經濟部智慧財產局員工消費合作社印製 72 〇 V-NH 235- 237 0.55 10% MeOH/ CH2CI2 A14 Cla D4 73 V-NH —\ 7一〇一(\ /) N - Me N Me 200- 201 0.21 50% MeOH/ CH2CI2 A14 Cla D4 74 〇 V-NH 〇Si(Pr-〇3 145- 148 75 (~Vnh 0.12 70% EtOAc/ 30% 己烷 527 (M+H)+ (HPLC ES-MS) All Clf Die 76 0 Me—^ Μ 〇 0.18 70% EtOAc/ 30% 己烷 All Clf Die 77 F—/ V-NH W_}^〇 0.74 70% EtOAc/ 30% 己烷 All Clf Die 78 Me 0.58 70% EtOAc/ 30% . 己烷 All Clf Die (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS)A4規格（210 χ 297公釐） -142- 1269791 A7 B7 五、發明說明（14°) 經濟部智慧財產局員工消費合作社印製 79 V-NH -〇°-〇 0.47 70% EtOAc/ 30% 己烷 569 (M+H)+ (HPLC ES-MS) All Clf Die 80 〇\ V-NH -〇-°-〇 ^〇Me 0.18 70% EtOAc/ 30% 己烷 508 (M+H)+ (HPLC ES-MS) All Clf Die 81 齡^&gt;&gt;〇 0.58 70% EtOAc/ 30% 己烷 557 (M+H)+ (HPLC ES-MS) All Clf Die 82 0 ~VN— \——/ \=/ \=：Q 音θ 0.37 70% EtOAc/ 30% 己烷 611 (M+H)+ (HPLC ES-MS) All Clf Die 83 Q 〇 0.19 70% EtOAc/ 30% 己烷 All Clf Die 84 ^Vnh 、。h 179- 183 A2 All Cla D5 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） (請先閱讀背面之注意事項再填寫本頁) · m n n ·Βϋ n ϋ— In h 口' I ·ϋ_— &gt;ϋ ϋ_3 n ϋ m n 1 鲁！ -143- A7 1269791 B7 五、發明說明（141) 表5. 3-(三氟甲基&gt;4-溴苯基尿素Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed by Giant R mp (°C) HPLC (Minutes) TLC Rf TLC Solvent System Mass Spectrometer (Source) Synthetic Method 41 V-NH Me 163- 165 0.08 50% EtOAc / 50% Petroleum Ether 446 (M+H)+ (HPLC ES-MS) A13 C3 42 〇\V-NH-〇WMe 215 0.06 50% EtOAc/ 50% petroleum ether 465 (M+H)+ (HPLC ES-MS) A2 Cla 43 〇 \ V-nh2 0.10 50% EtOAc / 50% petroleum ether 451 (M+H) + (HPLC ES-MS) A2 Cla 44 -QJ Λ°Λ^^ 0.25 30% EtOAc/ 70% petroleum ether 451 (M +H)+ (HPLC ES-MS) A2 Cla (Please read the note on the back and fill out this page) 装-137- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1269791 A7 B7 V. INSTRUCTIONS (135) Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 45 0 hearts 0.31 30% EtOAc/ 70% petroleum ether 465 (M+H)+ (HPLC ES-MS) A2 Cla 46 -〇. Minute. VNH 〇176- 179 0.23 40% EtOAc / 60% Hexane 476 (M+H) + (FAB) A3 Cla 47 Me VNH Valley # 0.29 5% MeOH / 45% EtOAc / .50% petroleum ether 478 (M+ H)+ (HPLC ES-MS) A5 Clc 48 〇-S?NH 206- 209 A15 Cla 49 〇\ Cl V-NH Me 147- 151 0.22 50% EtOAc/ 50% petroleum ether 499 (M+H)+ ( HPLC ES-MS) A6 Cla 50 —V-NH /=&lt; Me 〇7N 0.54 100% EtOAc 479 (M+H)+ (HPLC ES-MS) A2 Cla (Please read the notes on the back and fill out this Page) Binding: This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -138-1269791 A7 B7 V. Invention Description (136) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 51 〇\ V -NH θθ Β 187- 189 0.33 5% MeOH / 45% EtOAc / 50% petroleum ether 479 (M+H) + (HPLC ES-MS) A2 Cla 52 〇\ Cl V-NH Each meeting 219 0.18 5% MeOH / 45% EtOAc / 50% petroleum ether 499 (M+H) + (HPLC ES-MS) A2 Cla 53 246- 248 0.30 50% EtOAc / 50% hexane 485 (M+H) + (HPLC ES-MS) A19, Cla 54 Me 196-200 0.30 70% EtOAc / 30% hexanes 502 (M+H) + (HPLC ES-MS) A15 Cla 55 228-230 0.30 30% EtOAc / 70% CH2CI2 466 (M +H)+ (HPLC ES-MS) 56 General Me 238- 245 (Please read the note on the back and fill out this page) Packing - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) ) -139- 1269791 A7 B7 V. INSTRUCTIONS (137) Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 57 221- 222 0.75 80% EtOAc/ 20% Hexane 492 (M+H)+ (FAB) Cld Dla 58 〇 \ V-NH 247 0.35 100% EtOAc Cld Dla D2 59 〇,Me &gt;-N; 198-200 0.09 100% EtOAc 479 (M+H)+ (HPLC ES-MS) A2 Cla 60 Me〇158- 160 0.64 50% EtOAc/50% petroleum ether 61 V-nh 195-197 0.39 10% MeOH/CH2CI2 A13 Cla 62 〇\V-NH 170- 172 0.52 10% MeOH/CH2CI2 A13 Cla 63 〇\ 168- 171 0.39 10% MeOH/ CH2CI2 A13 Cla 64 0 Etv V-NH 176- 177 0.35 10% MeOH/ CH2CI2 A13 Cla (Please read the note on the back and fill out this page) Install -l^J« — — — III. . Paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -140-1265791 ^ Β7 V. Invention description (138) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative print 65 V-NH -o^-oMe ΠΟ- 133 487 (M+H)+ (HPLC ES-MS) A2 B1 Cla 66 〇\ V-NH 155 A2 Cla 67 〇\ y-NH Extra WMe 225- 229 0.23 100% EtOAc Cle D3 Dlb 68 \^NMe 〇 234- 236 0.29 40% EtOAc / 60% hexane A9 Cla 69 sv^N 0.48 50% EtOAc / 50% petroleum ether 481 (M+H)+ (HPLC ES-MS) 70 〇\ V-NH 0.46 50% MeOH/ 95% CH2CI2 564 (M+H)+ (HPLC ES-MS) A10 Cla 71 〇V-NH 199- 201 0.50 10% MeOH/ CH2CI2 A14 Cla D4 Paper size for China National Standard (CNS) A4 Specification (210 X 297 mm) Packing - (Please read the note on the back and fill out this page) -141 - 1269791 A7 B7 V. Description of Invention (139) Ministry of Economic Affairs Intellectual Property Office Staff Consumption Co-operative printing 72 〇V-NH 235- 237 0.55 10% MeOH/ CH2CI2 A14 Cla D4 73 V-NH —\ 7 〇 ( (\ /) N - Me N Me 200- 201 0.21 50% MeOH/ CH2CI2 A14 Cla D4 74 〇V-NH 〇Si(Pr-〇3 145- 148 75 (~Vnh 0.12 70% EtOAc/ 30% hexane 527 (M+H)+ (HPLC ES-MS) All Clf Die 76 0 Me-^ Μ 〇 0.18 70% EtOAc / 30% Hexane All Clf Die 77 F—/ V-NH W_}^〇0.74 70% E tOAc/ 30% Hexane All Clf Die 78 Me 0.58 70% EtOAc/ 30% . Hexane All Clf Die (Please read the note on the back and fill out this page) This paper size applies to the Chinese National Standard (CNS) A4 specification ( 210 χ 297 mm) -142- 1269791 A7 B7 V. Description of Invention (14°) Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 79 V-NH -〇°-〇0.47 70% EtOAc/ 30% Hexane 569 ( M+H)+ (HPLC ES-MS) All Clf Die 80 〇\ V-NH -〇-°-〇^〇Me 0.18 70% EtOAc/ 30% Hexane 508 (M+H)+ (HPLC ES-MS ) All Clf Die 81 Age^&gt;&gt;〇0.58 70% EtOAc/ 30% Hexane 557 (M+H)+ (HPLC ES-MS) All Clf Die 82 0 ~VN— \——/ \=/ \ =:Q θ θ 0.37 70% EtOAc / 30% Hexane 611 (M+H) + (HPLC ES-MS) All Clf Die 83 Q 〇 0.19 70% EtOAc / 30% hexanes All Clf Die 84 ^Vnh. h 179- 183 A2 All Cla D5 This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back and fill out this page) · mnn ·Βϋ n ϋ — In h ' I ·ϋ_— &gt;ϋ ϋ_3 n ϋ mn 1 Lu! -143- A7 1269791 B7 V. INSTRUCTIONS (141) Table 5. 3-(Trifluoromethyl) 4-bromophenylurea

經濟部智慧財產局員工消費合作社印製 項 g R mp (°C) HPLC (分） TLC Rf TLC 溶劑系統 質譜儀 (來源） 合成 方法 85 〇\ V-NH 186- 187 0.13 50% EtOAc/ 50% 石油醚 509 (M+H)+ (HPLC ES-MS) A2 B1 Cla 86 〇\ Cl V-NH ..-b-o-O Me 150- 152 0.31 50% EtOAc/ 50% 石油醚 545 (M+H)+ (HPLC ES-MS) A6 B1 Cla 87 〇\ CI V-NH 217- 219 0.16 50% EtOAc/ 50% 石油醚 545 (M+H)+ (HPLC ES-MS) A2 B1 Cla 88 〇\ V-NH 183- 184 0.31 50% EtOAc/ 50% 石油醚 525 (M+H)+ (HPLC ES-MS) A2 B1 Cla 89 °-\^N 0.21 50% EtOAc/ 50% 石油醚 511 (M+H)+ (HPLC ES-MS) A2 B1 Cla ------------·裝--------訂 (請先閱讀背面之注意事項再填寫本頁) ·%· 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -144- 1269791 A7 B7 五、發明說明（142) 經濟部智慧財產局員工消費合作社印製 90 —&lt;^~V-Me V-NH 0.28 50% 525 A2 Me °Λ_^Ν EtOAc/ 50% (M+H)+ (HPLC B1 Cla 石油醚 ES-MS) 91 〇、 Me V-N 214- 0.28 50% 522 A2 216 EtOAc/ 50% (M+H)+ (HPLC B1 Cla 石油醚 ES-MS) 92 〇\ &gt;-nh 0.47 50% 527 A2步驟 普 EtOAc/ 50% (M+H)+ (HPLC 3b， A2步驟 石油醚 ES-MS) 4， Bl， Cla 93 —V-NH 0.46 50% 527 A2步驟 W /=&lt; ， s心 EtOAc/ 50% (M+H)+ (HPLC 3b， A2步驟 石油醚 ES-MS) 4， Bl， Cla 94 〇 &gt;~NH i 145- 0.41 50% A10 -〇〇Λ &gt;Λ; 150 MeOH/ B1 \=/ _U / 〉 ^-0 i 95% Cla CH2CI2 ------------裝---I (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -145- 1269791 A7 B7 五、發明說明（143) 表6. 5-(三氟甲基&gt;4-氯基-2-甲氧苯基尿素Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed item g R mp (°C) HPLC (minutes) TLC Rf TLC Solvent System Mass Spectrometer (Source) Synthetic Method 85 〇 \ V-NH 186- 187 0.13 50% EtOAc / 50% Petroleum ether 509 (M+H)+ (HPLC ES-MS) A2 B1 Cla 86 〇\ Cl V-NH ..-boO Me 150- 152 0.31 50% EtOAc/ 50% petroleum ether 545 (M+H)+ ( HPLC ES-MS) A6 B1 Cla 87 〇\ CI V-NH 217- 219 0.16 50% EtOAc/ 50% petroleum ether 545 (M+H)+ (HPLC ES-MS) A2 B1 Cla 88 〇\ V-NH 183 - 184 0.31 50% EtOAc / 50% petroleum ether 525 (M+H) + (HPLC ES-MS) A2 B1 Cla 89 °-\^N 0.21 50% EtOAc / 50% petroleum ether 511 (M+H)+ HPLC ES-MS) A2 B1 Cla ------------·装--------Book (please read the notes on the back and fill out this page) ·%· The paper size Applicable to China National Standard (CNS) A4 Specification (210 X 297 mm) -144- 1269791 A7 B7 V. Invention Description (142) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 90 —&lt;^~V-Me V- NH 0.28 50% 525 A2 Me °Λ_^Ν EtOAc/ 50% (M+H)+ (HPLC B1 Cla petroleum ether ES-MS) 91 〇, Me VN 214- 0.28 50% 522 A2 216 EtOAc / 50% (M+H) + (HPLC B1 Cla petroleum ether ES-MS) 92 〇\ &gt;-nh 0.47 50% 527 A2 Step EtOAc/ 50% (M+H)+ (HPLC 3b, A2 Step Petroleum Ether ES-MS) 4, Bl, Cla 93 —V-NH 0.46 50% 527 A2 Step W /=&lt;, s EtOAc/ 50% (M+H)+ (HPLC 3b, A2 Step Petroleum Ether ES -MS) 4, Bl, Cla 94 〇&gt;~NH i 145- 0.41 50% A10 -〇〇Λ &gt;Λ; 150 MeOH/ B1 \=/ _U / 〉 ^-0 i 95% Cla CH2CI2 --- ---------Install---I (Please read the note on the back and fill out this page) This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -145- 1269791 A7 B7 V. INSTRUCTIONS (143) Table 6. 5-(Trifluoromethyl)- 4-chloro-2-methoxyphenylurea

經濟部智慧財產局員工消費合作社印製 項 巨 R • mp (°C) HPLC (分） TLC Rf TLC 溶劑系統 質譜儀 (來源） 合成 方法 95 〇 V-NH 140- 144 0.29 5% MeOH/ 45% EtOAc/ 50% 石油醚 495 (M+H)+ (HPLC ES-MS) A2 A7 B1 Cla 96 〇\ Cl &gt;-NH 244- 245 0.39 5% MeOH/ 45% EtOAc/ 50% 石油醚 529 (M+H)+ (HPLC ES-MS) A6 A7 B1 Cla 97 ———〇\ Cl V-NH 220- 221 0.25 5% MeOH/ 45% EtOAc/ 50% 石油醚 529 (M+H)+ (HPLC ES-MS) A2 A7 B1 Cla 98 -〇 Vnh 0.27 5% MeOH/ 45% EtOAc/ 50% 石油醚 495 (M+H)+ (HPLC ES-MS) A2 A7 B1 Cla 99 〇\ V-NH 音 ~d，Et 180- 181 0.52 5% MeOH/ 45% EtOAc/ 50% 石油醚 509 (M+H)+ (HPLC ES-MS) A2 A7 B1 Cla 100 V-NH -O〇^ Pr&quot; 162- 165 A2 A7 B1 Cla 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） ------------裝--- (請先閱讀背面之注意事項再填寫本頁) 訂.- -146- A7 1269791 B7_ 五、發明說明（144) 表7. 額外的尿素類 經濟部智慧財產局員工消費合作社印製 項 巨 R mp (°C) HPLC (分） TLC Rr TLC 溶劑系統 質譜儀 (來源） 合成 方法 101 〇Me H H _____________________________ 162- 165 A1 A2 C3 102 1 Η Η Mev-Me 0.10 50% EtGAc/ 50% 己烷 442 (M+H)+ (HPLC ES-MS) A2 A4 C2d 103 叉 ΗΝ ΝΗ 0 ^ 0 〇 NH-Me Me~NH 125- 130 0.24 40% EtOAc/ 60% 己烷 512 (M+H)+ (FAB) A2 C2b (請先閱讀背面之注意事項再填寫本頁) 裝 «. 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -147- 1269791 Α7 Β7 五、發明說明（145) Μ述實施例可以經由將前述實施例中所使用之操作條 件及/或反應物加以取代後重覆進行而得到類似的成功。 由前述說明，內行人士可以很容易地確認本發明之必 須特徵且在不背離其精神和範圍的情況下將本發明做一些 改變和修正以適應不用的用途和狀況。 -----I-----·裝 (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed by Giant R • mp (°C) HPLC (minutes) TLC Rf TLC Solvent System Mass Spectrometer (Source) Synthetic Method 95 〇V-NH 140- 144 0.29 5% MeOH / 45% EtOAc / 50% petroleum ether 495 (M+H) + (HPLC ES-MS) A2 A7 B1 Cla 96 〇\Cl &gt;-NH 244- 245 0.39 5% MeOH / 45% EtOAc / 50% petroleum ether 529 (M +H)+ (HPLC ES-MS) A6 A7 B1 Cla 97 ———〇\ Cl V-NH 220- 221 0.25 5% MeOH/ 45% EtOAc/ 50% petroleum ether 529 (M+H)+ (HPLC ES -MS) A2 A7 B1 Cla 98 -〇Vnh 0.27 5% MeOH / 45% EtOAc / 50% petroleum ether 495 (M+H)+ (HPLC ES-MS) A2 A7 B1 Cla 99 〇\ V-NH tone ~d , Et 180- 181 0.52 5% MeOH / 45% EtOAc / 50% petroleum ether 509 (M+H) + (HPLC ES-MS) A2 A7 B1 Cla 100 V-NH -O〇^ Pr&quot; 162- 165 A2 A7 B1 Cla This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) ------------ Pack--- (Please read the back note and fill out this page) Order.- -146- A7 1269791 B7_ V. INSTRUCTIONS (144) Table 7. Additional Urea Economics Department Intellectual Property Office Staff Consumer Cooperative Printed Giant R mp (°C) HPLC (minutes) TLC Rr TLC Solvent System Mass Spectrometer (Source) Synthetic Method 101 〇Me HH _____________________________ 162- 165 A1 A2 C3 102 1 Η Η Mev-Me 0.10 50% EtGAc/ 50% Hexane 442 (M+H)+ (HPLC ES-MS) A2 A4 C2d 103 fork ΝΗ 0 ^ 0 〇NH-Me Me~NH 125- 130 0.24 40% EtOAc/ 60% hexane 512 (M+H)+ ( FAB) A2 C2b (Please read the note on the back and fill out this page) Loading «. This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -147- 1269791 Α7 Β7 V. Invention description ( 145) The above-described examples can be similarly succeeded by substituting the operating conditions and/or reactants used in the foregoing examples and repeating them. From the foregoing description, it will be readily appreciated by those skilled in the art that the present invention may be modified and modified to adapt to the use and condition without departing from the spirit and scope of the invention. -----I-----·Installation (Please read the notes on the back and fill out this page) Printed by the Intellectual Property Office of the Ministry of Economic Affairs

本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -148-This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -148-

Claims (1)

A8 ί Β8 C8 DS 1269791 六、申請專利範圍 附件2A : 第89 1 00575號專利申請案 中文申請專利範圍替換本 (請先閨讀背*之注意事項再填寫本頁) 民國94年8月26日修正 1 · 一*種式（I )所示之化合物 A - D - B ( I ) 或：^:藥學上可接受的鹽’其中 D 晏一 NH— C (〇）一 NH —， A晏如下式之經取代部分： —L 一 Μ — L 1， · 其中 L爲選自： (i )苯基，其可經選自下列之取代基取代：鹵素，C i —C 5烷基’經鹵素取代之C i 一 C 5烷基，及C i 一 C 2 烷氧基；或 (i i )吡啶基，其可經選自下列之取代基取代··鹵素， 一 C5烷基，該鹵素取代之匚：—C5烷基，及C! — 經濟部智慧財產局員工消費合作社印製 C 5烷氧基； L 1包含一經取代之環形部分，選自下列： (i )苯基，其經選自一 C (〇）R c及 c ( 0 ) N R a R b中之取代基取代，且可經1或2個 選自下列中之取代基取代：R 7，0 R 7及鹵素，其中R 7 爲鹵素，c 1 一 C 5烷基或經鹵素取代之C ! 一 C 5烷基； (i i )吡啶基，其經選自—C (〇）R c及 本紙張尺度逍用中國國家.標準（CNS)A4洗格（210X297公釐） 1269791 A8 B8 C8 D8 六、申請專利範圍 一 C (〇）N R a R h中之取代基取代.，且可經1至2個 選自下列中之取代基取代：R 7，〇R 7及鹵素，其中R 7 爲鹵素，C i 一 C 5烷基或經鹵素取代之C 2 - C 5烷基； 及A8 ί Β8 C8 DS 1269791 VI. Patent Application Scope Attachment 2A: Patent Application No. 89 1 00575 Replacing the Chinese Patent Application Scope (please read the back note* and fill out this page again) August 26, 1994 Amendment 1 · A compound of formula (I): A - D - B ( I ) or: ^: pharmaceutically acceptable salt 'where D 晏 -NH - C (〇) - NH -, A 晏Substituted moiety: -L - Μ - L 1, wherein L is selected from: (i) phenyl which may be substituted with a substituent selected from the group consisting of halogen, C i -C 5 alkyl' via halogen Substituting a C i -C 5 alkyl group, and a C i -C 2 alkoxy group; or (ii) a pyridyl group which may be substituted with a substituent selected from the group consisting of halogen, a C5 alkyl group, which is substituted by the halogen匚: —C5 alkyl, and C! — Ministry of Economic Affairs Intellectual Property Office employee consumption cooperative printed C 5 alkoxy; L 1 contains a substituted ring portion selected from the following: (i) phenyl selected from Substituted by a substituent in C(〇)R c and c( 0 ) NR a R b and may be substituted by 1 or 2 substituents selected from the group consisting of R 7,0 R And halogen, wherein R 7 is halogen, c 1 -C 5 alkyl or C + -C 5 alkyl substituted by halogen; (ii) pyridyl group selected from -C (〇)R c and the paper The standard is (China Standard) (CNS) A4 washing (210X297 mm) 1269791 A8 B8 C8 D8 VI. The patent application range C (〇) NR a R h is replaced by a substituent, and can be 1 to 2 Substituted by a substituent selected from the group consisting of R 7, 〇R 7 and halogen, wherein R 7 is halogen, C i -C 5 alkyl or C 2 -C 5 alkyl substituted by halogen; ^一!— (·請先聞讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 其中R8爲氨或Ci — C5院基； . R e爲選自下列： a )氫， b) C! — C5烷基，其可經鹵素，羥基或Cl—C3 烷氧基取代， c) 苯基，其可經鹵素，羥基，Ci—Cs烷基，Ci 一 C 3烷氧基或C F 3取代， d )吡啶基，其可經鹵素，羥基，C i 一 C 5烷基， C〗一 C 4烷氧基或C F 3取代，及 e )六氫吡畊基，其可經鹵素，羥基，c i 一 C 5烷 基’ Ci-Ca烷氧基，CF3或苯基（其可經鹵素或 一 C (〇）C Η 3取代）取代； R a與R b各獨立選自下列中： a )氫， b ) C ! — C 5烷基，其可經C F 3，嗎啉基，C ζ - 訂 ^9. 本纸浪尺度適用中國國家標準（CNS ) A4洗格（2I0X29?公釐） -2 - 1269791 Λ8 B8 C8 D8 ________________ 一 六、申讀專利範圍 C 3烷氧基，丨贼啶基，四氫呋喃基，C i 一 C 3烷基吡咯B定 基，一NH —苯基，羥基，鹵素，〜〇s i(Ci — C5院 基）3或二（C 1 — C 4院基）胺基取代， c )苯基，其可經鹵素，二（Cl 一 Cl烷基）胺基 ，嗎啉基，-六氫吡啡（苯基）（其苯基可經鹵素或 一 C (〇）C Η 3取代），一六氫吡_ (吡啶基），羥基 ，Ci— C5 垸基，CF3，Ci— c3 燒基或—ΝΗ —苯 基取代，及 d )吡啶基，其可經一 C i 一 c 4燒氧基，—六氫吡 哄（苯基）（其苯基可經鹵素或一C (〇.）CH3取代） ，一六氫吡畊（吡啶基），羥基，鹵素，C i — C 5烷基 ，（：F3，二（Ci — Ca烷基）胺基，嗎啉基或—NH — 苯基取代； Μ爲選自下列中之1或2個橋接基團： —〇 一，一S —，一 C (〇）一及一 ΝΗ-; Β爲選自下列： (i )苯基，其可經獨立選自下列中之取代基取代： a )鹵素， b) Ci — 〇5丈兀基’其可經齒素或〜〇R7取代，宜 中R7爲氫或Ci—Cs烷基， c ) C i 一 C 4烷氧基，其可經鹵素取代， d)苯基或—〇 -苯基，其可經—C(0)NHCH3 ，C : — C 5院基，齒素或一 〇 R 7取代’其中R 7爲氫或 C 1 一 C 5烷基， 本紙張尺度適用中國國家·標準（CNS ) A4見格（210X297公釐） --------Jt—丨 (·請先閨讀背面之注*事項再填寫本頁) 訂 經濟部智慧財產局員工消費合作社印製 -3- 79 9 6 2 8 8 8 8 ABCD 六、申請專利範圍 e )吡咯基或吡啶基，其可經C r 一 C 5烷基，鹵素 或一〇R ^取代，其中R ’爲氫或C 1 _ C 5院基，或 (i i )萘基，其可經獨立選自下列中之取代基取代 a )鹵素， 1) ) C 1 — C 5院基，其可經鹵素或一〇R 7取代，其 中R7爲氫或Ci— c5烷基，及 c ) C ! 一 C 4烷氧基，其可經鹵素取代。 2 ·如申請專利範圍第1項的化合物，其中該直接連 接至D的B和L的1哀形構造並不是在 ''鄰〃的位置被 —〇Η所取代。 3 ·如申請專利範圍第1項的化合物，其中該直接連 接至D的Β和L的環形構造並不是在 ''鄰〃的位置被一個 帶有可離子化之氫及具有1 0或更小之p K a的部分所取 代。 4 ·如申請專利範圍第1項的化合物，其中B爲： (i )苯基，其可經獨立選自下列中之取代基取代： a )鹵素， b) C!—c5烷基，其可經鹵素或一〇R7取代，其 中R7爲氫或Ci 一 C5烷基，及 c ) C i 一 c 4烷氧基，其可經鹵素取代。 5 ·如申請專利範圍第1項的化合物，其中B爲： (i )苯基，其可經獨立選自下列中之取代基取代： C 1 ，F ’第三丁基，CF3及一〇CH3。 本纸張尺度適用中囯國家·標準（CNS ) A4現格（210X297公釐） — (請先閎讀背έ之注意事¾再填寫本頁) 订 經濟部智慧財產局員工消費合作社印製 -4-^一!—(·Please read the notes on the back and fill out this page.) The Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs prints R8 for ammonia or Ci-C5. The R e is selected from the following: a) Hydrogen, b) C! - C5 alkyl, which may be substituted by halogen, hydroxy or Cl-C3 alkoxy, c) phenyl which may be halogen, hydroxy, Ci-Cs alkyl, Ci-C3 alkoxy Substituting or CF 3 substituted, d) pyridyl, which may be substituted by halogen, hydroxy, C i -C 5 alkyl, C 1,4-C 4 alkoxy or CF 3 , and e) hexahydropyrrole, which may Substituted by halogen, hydroxy, ci-C 5 alkyl ' Ci-Ca alkoxy, CF 3 or phenyl (which may be substituted by halogen or a C (〇) C Η 3 ); R a and R b are each independently selected from In the following: a) hydrogen, b) C ! - C 5 alkyl, which can be CF 3, morpholinyl, C ζ - order ^9. This paper wave scale applies Chinese National Standard (CNS) A4 wash grid (2I0X29 ?mm) -2 - 1269791 Λ8 B8 C8 D8 ________________ 1-6, the scope of the patent application C 3 alkoxy, oxime pyridine, tetrahydrofuranyl, C i -C 3 alkylpyrrole B group, an NH phenyl group , hydroxy, halogen , 〇 si (Ci - C5, based on the base) 3 or two (C 1 - C 4 -based) amine-substituted, c) phenyl, which can be halogen, di(Cl-Cl alkyl)amine, Orolinyl, hexahydropyridinyl (phenyl) (the phenyl group may be substituted by halogen or a C(〇)C Η 3), hexahydropyridyl (pyridyl), hydroxy, Ci-C5 fluorenyl, CF3 , Ci—c3 alkyl or —ΝΗ—phenyl substituted, and d) pyridyl, which may be alkoxy, hexahydropyridinium (phenyl) via a C i -c 4 (the phenyl group may be halogen or a C (〇.)CH3 substituted), hexahydropyrazine (pyridyl), hydroxy, halogen, C i - C 5 alkyl, (: F3, di(Ci - Ca alkyl) amine, morpholinyl Or -NH - phenyl substituted; Μ is one or two bridging groups selected from the group consisting of: - 〇, s, -, C, 一, and ΝΗ -; Β is selected from the following: a phenyl group which may be substituted with a substituent independently selected from the group consisting of: a) halogen, b) Ci - 〇5 兀 兀 '' which may be substituted by dentate or 〇R7, preferably R7 is hydrogen or Ci- Cs alkyl, c) C i - C 4 alkoxy, which may be substituted by halogen, d Phenyl or hydrazine-phenyl, which may be substituted by -C(0)NHCH3, C: -C 5 , dentate or 〇R 7 'where R 7 is hydrogen or C 1 -C 5 alkyl This paper scale applies to China National Standards (CNS) A4 (210X297 mm) --------Jt-丨(·Please read the note on the back* and fill out this page) Intellectual Property Office Staff Consumer Cooperative Printed -3- 79 9 6 2 8 8 8 8 ABCD VI. Patent Application E) Pyrrolyl or pyridyl group, which can be Cr-C5 alkyl, halogen or 〇R ^ Substituted, wherein R' is hydrogen or C1_C5, or (ii) naphthyl, which may be substituted with a substituent independently selected from the group consisting of a) halogen, 1)) C1 - C5, It may be substituted by halogen or a hydrazine, wherein R7 is hydrogen or Ci-c5 alkyl, and c) C!-C4 alkoxy, which may be substituted by halogen. 2. A compound as claimed in claim 1, wherein the 1 sacred structure of B and L directly linked to D is not replaced by 〇Η at the position of the ''o'. 3. A compound as claimed in claim 1, wherein the ring structure of Β and L directly attached to D is not at a position of ''orthoquinone' and is one with ionizable hydrogen and having 10 or less The part of p k a is replaced. 4. A compound as claimed in claim 1, wherein B is: (i) a phenyl group which may be substituted with a substituent independently selected from the group consisting of: a) halogen, b) C!-c5 alkyl, which may Substituted by halogen or a fluorene R7 wherein R7 is hydrogen or Ci-C5 alkyl, and c) C i - c 4 alkoxy, which may be substituted by halogen. 5. A compound as claimed in claim 1 wherein B is: (i) a phenyl group which may be substituted with a substituent independently selected from the group consisting of: C 1 , F 't-butyl, CF 3 and mono-CH 3 . This paper scale applies to China National Standards (CNS) A4 (210X297 mm) — (please read the notes on the back 3⁄4 and then fill out this page) Order Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed-4 - 一園 範⑧于請中 ABCDOne Park Fan 8 is in the middle of the ABCD •如ΐ請專利範圍第1項的化合物，其中L爲， (1 )笨基，其可經獨立選自下列中之取代基取代 c 1，FhH3，或 丄Ί · (1 1 )吼啶基，其可經選自下列中之取代_取代： C 1，F 及 c Η 3。 7 ·如申請專利範圍第6項的化合物，其中L爲： (1 )苯基，其可經獨立選自下列中之取代基取代： C 1 ’ F 及 C Η 3，或 (1 1 )吡啶基，其可經選自下列中之取代基取代： C 1 ’ F 及 c η 3。 ， 8 ·如申請專利範圍第1項的化合物，其中L 1爲： (1 )苯基，其經一 C ( 0 ) N R a R b取代，且可 糸二1或2個選自下列中之取代基取代：R 7，0 R 7及鹵 素’其中R7爲氫，Ci 一 C5烷基或經鹵素取代之Ci — C 5院基。 ^-- (請先閎讀背面之注意事項再填寫本頁) 訂 基 啶 中 其 物 合 化 的 項 IX 第 圍 範 利 專 請 甲 如 批 是 經濟部智慧財產局員工消費合作社印製 基 啶 吼 中 其 物 合 化 的 項 5 第 圍 ★PB AyB— 利 專 請 串 如 是 是 1—一 L 中 其 物 合 化 的 項 4 第 圍 範 利 專 請 串 如 一—I 基 啶¾ IX 基 啶 吼 中 其 物 合 化 的 項 8 第 圍 範 利 專 請 串 如 中 其 物 合 化 的 項 6 第 圔 範 利 專 請 甲 如 是 是 本纸張尺度適用中國國家標準（CNS ) A4現格（210X297公釐） -5 - 1269791 A8 B8 C8 D8 六、申請專利範圍 吡啶基。 1 4 ·如申請專利範圍第7項的化合物，其中L 1是 吡啶基。 1 5 ·如申請專利範圍第1 1項的化合物，其中Μ爲 —0 — ° 1 6 ·如申請專利範圍第1 2項的化合物，其中Μ爲 —0 — ° 1 7 ·如申請專利範圍第1 3項的化合物，其中Μ爲 — 〇 一〇 1 8 ·如申請專利範圍第1 4項的化合物，其中Μ爲 —〇一° 1 9 ·如申請專利範圍第9項的化合物，其中L 1額 外地經一或二個選自如下群體之取代基取代：鹵素，C ! 一 C 5烷基，及經鹵素取代之c 1 — C 5烷基。 2 0 ·如申請專利範圍第1 1項的化合物，其中L 1 額外地經一或二個選自如下群體之取代基取代：鹵素， C 1 一 C 5烷基，及經鹵素取代之c 1 一 C 5烷基。 2 1 ·如申請專利範圍第1 2項的化合物，其中L 1 額外地經一或二個選自如下群體之取代基取代：鹵素， C 1 一 C 5烷基，及經鹵素取代之C i 一 C 5烷基。 2 2 ·如申請專利範圍第1 3項的化合物，其中L 1 額外地經一或二個選自如下群體之取代基取代：鹵素， C 1 — C 5烷基，及經鹵素取代之C 1 — C 5烷基。 2 3 ·如申請專利範圍第1 4項的化合物，其中L 1 本纸乐尺度逍用中國國家禚準（CNS ) A4現格（210X 297公釐） --------,# ! (請先閨讀背面之注意事¾再填寫本頁) 訂 經濟部智慧財產局員工消費合作社印製 -6- [269791 A8 B8 C8 D8 々、申請專利範圍 額外地經一或二個選自如下群體之取代基取代：鹵素， c 1 一 C 5院基，及經鹵素取代之C 1 一 C 5焼基。 2 4 ·如申請專利範圍第1 8項的化合物，其中L 額外地經一或二個選自如下群體之取代基取代·鹵素， c i — C 5烷基’及經鹵素取代之c i 一 C 5烷其 、 &amp;枝基。 2 5 ·如申請專利範圍第1項的化合物， 一 其中乙 經一 C (〇）R c所取代。 裹 2 6 .如申請專利範圍第i項的化合物，其中 經一C (〇）N R a R b所取代 2 7 ·如申請專利範圍第1 〇項的化合物， 經一 C (〇）N R a R b所取代，其中R a和R b 立地爲氫，Ci— C5烷基或Ci — C3烷氧基。 2 8 ·如申請專利範圍第1 1項的化合物， 經一 C(〇）NRaRb取代，其中Ra與Rb各獨 c 1一 C5院基或C 1 — C3烷氧基。 2 9 ·如申請專利範圍第1 2項的化合物， 乙1 儳 先辑讀背面之注意事硕丟填寫本頁) 其中 裹各 自獨 其中乙1 从馬氣， 訂 經 C(〇)NRaRb取代，其中與Rb各獨立 其中 經濟部智慧財產局員工消費合作社印製 Cl 一 c5烷基或Ci — c3烷氧基。 3 0 ·如申請專利範圍第1 3項的化合物， 爲氣， άφ. 經 &lt;3(〇^1^1^取代，其中]^與1^各獨立 C 1 一 C5院基或Cl 一 C3院氧基。 3 1 ·如申請專利範圍第1 4項的化合物， 其中 經一C (〇）N R a R b取代，其中R a與R 1)各竭&amp; Ci 一 C5烷基或Ci— C3烷氧基。 其中 本纸張尺度適用中國國家.標準（CNS ) ( 210Χ297公釐） [269791 A8 B8 C8 D8 申請專利範圍 •如申請專利範圍第1項的化·合物，具_ # (I ) A - D - B ( I )， 或其藥學上可接受的鹽，其中 D 是一N Η - C (〇）一 N Η —， Α是如下式：一 L— M—L1， 其中L是苯基，其可經獨立選自下列之取代基取代：_素 ’ C 1 — C 5院基’經鹵素取代之C 1 一 C 5院基，及C 一 C 5烷氧基； L 1包含一經一 C (〇）N R a R b取代之吡啶基，且 可經1或2個選自下列中之取代基取代：.R 7 〇R 7及 -------- (請先間讀背面之注意事項再填寫本頁) 鹵 素，其中爲氫，Ci 一 Cs院基或經鹵素取代之c 一 C 5烷基 Ra與Rb各獨立選自下列中： a 氫 訂 b C C 5烷基，其可經c F 嗎啉基 C 經濟部智慧財產局員工消費合作社印製 C 3院氧基，_ D定基，四氫咲喃基，C 1 一 C 3院基批略陡 基’ 一NH —苯基，羥基，鹵素，一〇s i(Ci — C5烷 基）3或二（C i 一 C 4烷基）胺基取代， c )苯基，其可經鹵素，二（Ci — C4烷基）胺基 ’嗎啉基’-六氫吡畊（苯基）（其苯基可經鹵素或 一 C (〇）C Η 3取代），一六氫吡畊（吡υ定基），經基 ，豳素，C!— C5烷基，CF3，Ci—Cs烷基或 一 NH —苯基取代，及 d )吼啶基，其可經一 C ! 一 C 4烷氧基，一六氫毗 鲁· 本紙張尺度適用中國國家择準（CNS ) A4洗格（210X297公釐） -8 - [269791 A8 B8 C8 D8 ¥、申請專利範圍 哄（苯基）（其苯基可經鹵素或一 C (〇）CH3取代） ’一六氮吡畊（吡啶基），羥基，鹵素，c】一 c 5烷基 ’ C F 3，二（C i 一 C 4烷基）胺基’嗎啉基或 苯基取代； Μ舄選自下列之1或2個橋接基團： N Η 〇 -s — ，一C(〇）及一 ΝΗ B爲苯基，其可經獨立選自下列中之取代基取代： a )鹵素， b) Ci—Cs烷基，其可經鹵素或一〇R7取代，其 中尺7爲氫或（：1一（：5烷基，及 · C ) C i 一 C 4烷氧基，其可經鹵素取代。 3 3 ·如申請專利範圍第3 2項的化合物，具有式（ D — B 或其藥學上可接受的鹽，其中 D 是一 NH-C (〇）一 NH A是如下式 -- (請先閏讀背面之注意事項再填寫本頁) ^9. 璉濟部智慧財產局員X消費合作社印製 其中L是苯基， L 1包含一經一 C (〇）N R a R b取代之吡啶基，且 可經1或2個，選自下列之取代基取代： R7，〇R7及鹵素，其中R7爲氫 或經鹵素取代之C ! 一 C 5烷基， R a與r b各獨立選自下列中： C C 5烷基 本紙汝尺度適用中國國家择準（〇^)八4見格（210父297公釐） -9- 1269791• A compound of claim 1 wherein L is a (1) stupid group which may be substituted with a substituent independently selected from the group consisting of c 1, FhH3, or 丄Ί · (1 1 ) acridinyl. , which may be substituted by a substituent selected from the group consisting of C 1, F and c Η 3. 7. A compound according to claim 6 wherein L is: (1) a phenyl group which may be substituted with a substituent independently selected from the group consisting of: C 1 'F and C Η 3, or (1 1 ) pyridine a group which may be substituted with a substituent selected from the group consisting of C 1 'F and c η 3 . 8. The compound of claim 1, wherein L 1 is: (1) a phenyl group substituted by a C ( 0 ) NR a R b and which may be one or two selected from the group consisting of Substituent substitution: R 7, 0 R 7 and halogen 'where R 7 is hydrogen, Ci - C 5 alkyl or Ci - C 5 substituted by halogen. ^-- (Please read the note on the back and fill out this page) IX of the substance in the base of the pyridine IX. Fan Li specializes in the approval of the Ministry of Economic Affairs, the Intellectual Property Bureau, the employee consumption cooperative, the printing of the base. Item 5 of the 吼 第 第 ★ ★ 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 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 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 P P P P P P P P P P P P P P P P P P P P P P Item 8 of the materialization of the article, the second paragraph of the Fan Li special string of items such as the integration of the elements of the sixth paragraph Fan Li special request A if this paper scale applies the Chinese National Standard (CNS) A4 grid (210X297 public PCT) -5 - 1269791 A8 B8 C8 D8 VI. Patented range Pyridyl. A compound according to claim 7, wherein L 1 is a pyridyl group. 1 5 · The compound of claim 1 of the patent scope, wherein Μ is -0 - ° 1 6 · The compound of claim 12, wherein Μ is -0 - ° 1 7 · as claimed a compound of the formula 1, wherein Μ is - 〇 〇 8 8 · 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 · It is additionally substituted with one or two substituents selected from the group consisting of halogen, C.-C5 alkyl, and halogen-substituted c1-C5 alkyl. A compound according to claim 11 wherein L 1 is additionally substituted with one or two substituents selected from the group consisting of halogen, C 1 -C 5 alkyl, and halogen substituted c 1 A C 5 alkyl group. A compound according to claim 12, wherein L 1 is additionally substituted with one or two substituents selected from the group consisting of halogen, C 1 -C 5 alkyl, and halogen substituted C i A C 5 alkyl group. 2 2 · A compound according to claim 13 wherein L 1 is additionally substituted with one or two substituents selected from the group consisting of halogen, C 1 -C 5 alkyl, and halogen substituted C 1 — C 5 alkyl. 2 3 · If you apply for the compound of the 14th patent range, the L 1 paper size is 中国 China National Standard (CNS) A4 (210X 297 mm) --------, # ! (Please read the note on the back first and then fill out this page.) Ordering the Ministry of Economic Affairs, Intellectual Property Bureau, Staff and Consumer Cooperatives, Printing -6- [269791 A8 B8 C8 D8 々, the scope of application for patents is additionally selected from one or two Substituent substituents of the group: halogen, c 1 -C 5 moieties, and C 1 -C 5 fluorenyl substituted by halogen. 2 4 · A compound according to claim 18, wherein L is additionally substituted with one or two substituents selected from the group consisting of halogen, ci - C 5 alkyl ' and halogen substituted ci - C 5 Alkanes, &amp; 2 5 · If the compound of claim 1 is a compound, one of which is substituted by a C (〇) R c . Wrap 2 6 . The compound of claim i, wherein the compound is replaced by a C (〇)NR a R b 2 · a compound of the first aspect of the patent application, via a C (〇) NR a R Substituted by b, wherein R a and R b are hydrogen, Ci—C5 alkyl or Ci—C3 alkoxy. 2 8 · The compound of claim 11 is substituted by a C(〇)NRaRb wherein Ra and Rb are each a c 1 -C5 or a C 1 -C 3 alkoxy group. 2 9 ·If you apply for the compound of the 12th item of the patent scope, B1 儳 辑 辑 辑 辑 硕 硕 硕 填写 填写 填写 填写 填写 填写 填写 填写 填写 填写 填写 填写 填写 填写 填写 填写 填写 填写 填写 填写 填写 填写 填写 填写 填写 填写 填写 填写 填写 填写 填写Among them, Rb is independent of the Ministry of Economic Affairs, the Intellectual Property Office, and the employee consumption cooperative, which prints Cl-c5 alkyl or Ci-c3 alkoxy. 3 0 · If the compound of claim 13th is in the patent, it is gas, άφ. By &lt;3(〇^1^1^, where ^^ and 1^ each independently C 1 -C5 yard or Cl -C3 a compound according to claim 14 of the patent, wherein is substituted by a C (〇)NR a R b wherein R a and R 1) are each &amp; Ci-C5 alkyl or Ci- C3 alkoxy group. The paper size is applicable to the Chinese National Standard (CNS) (210Χ297 mm) [269791 A8 B8 C8 D8 Patent Application Range • For example, the compound of the patent application scope 1 has _ # (I ) A - D - B ( I ), or a pharmaceutically acceptable salt thereof, wherein D is N Η - C (〇)-N Η —, Α is as follows: L-M-L1, wherein L is phenyl, Substituted by a substituent independently selected from the group consisting of: a C 1 - C 5 - a C 1 -C 5 alkoxy group substituted by a halogen, and a C 1 C 5 alkoxy group; 〇) NR a R b substituted pyridyl group, and may be substituted by 1 or 2 substituents selected from the group consisting of: R 7 〇R 7 and --- (please read the back of the note first) Matters refill this page) Halogen, which is hydrogen, Ci-Cs or halogen-substituted c-C5 alkyl Ra and Rb are each independently selected from the following: a Hydrogen b CC 5 alkyl, which can be c F morpholino C Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed C 3 hospital oxygen, _ D-based, tetrahydrofuranyl, C 1 - C 3 hospital base slightly steep base '-NH-phenyl, Hydroxyl group, Halogen, mono-si (Ci-C5 alkyl) 3 or di(C i -C 4 alkyl)amino substituted, c) phenyl, which can be halogen, di(Ci-C4 alkyl)amine' Lolinyl '-hexahydropyrazine (phenyl) (its phenyl group may be substituted by halogen or a C(〇)C Η 3), hexahydropyrrolidine (pyridinyl), trans-base, alizarin, C! - C5 alkyl, CF3, Ci-Cs alkyl or a NH-phenyl substitution, and d) acridinyl, which may be applied via a C!-C4 alkoxy group, a hexahydropyrazine paper scale China National Selection (CNS) A4 Washing (210X297 mm) -8 - [269791 A8 B8 C8 D8 ¥, the scope of patent application 哄 (phenyl) (the phenyl group can be replaced by halogen or a C (〇) CH3) 'Hexazapirin (pyridyl), hydroxy, halogen, c)-c 5 alkyl 'CF 3, bis(C i -C 4 alkyl)amino 'morpholinyl or phenyl substituted; From one or two of the following bridging groups: N Η 〇-s — , one C (〇) and one ΝΗ B is a phenyl group which may be substituted with a substituent independently selected from the group consisting of: a) halogen, b) Ci-Cs alkyl, which can be taken via halogen or a hydrazine Generation, wherein the ruler 7 is hydrogen or (: 1 - (: 5 alkyl, and · C) C i - C 4 alkoxy, which may be substituted by halogen. 3 3 · A compound according to claim 3, having the formula (D-B or a pharmaceutically acceptable salt thereof, wherein D is an NH-C (〇)-NH A is as follows-- Note on the back side and fill in this page) ^9. The Ministry of Intellectual Property of the Ministry of Finance X Consumer Cooperative printed that L is a phenyl group, and L 1 contains a pyridyl group substituted by a C (〇)NR a R b , and It may be substituted by 1 or 2 substituents selected from the group consisting of R7, 〇R7 and halogen, wherein R7 is hydrogen or halogen substituted C!-C5 alkyl, and R a and rb are each independently selected from the following: CC 5 alkyl paper 汝 scale for China's national selection (〇 ^) eight 4 see grid (210 father 297 mm) -9- 1269791 經濟部智慧財產局員工消費合作社印製 六、申請專利範圍 a )氫， b ) C ! — C 5烷基，其可經C ρ 3，嗎啉基，C 1 一 C 3烷氧基，哌啶基，四氫呋喃基，c ! 一 c 3烷基吡咯11 定 基’ 一N Η —苯基，羥基，鹵素，〜〇s i ( C 1 — C 5烷 基）3或二（C i 一 C 4烷基）胺基取代， c )苯基，其可經鹵素，二（c i 一 C 4烷基）胺基 ’嗎啉基，-六氫吡哄（苯基）（其苯基可經鹵素或 一 C (〇）c Η 3取代），一六氫D比π井（D比陡基），經基 ，鹵素，Ci—Cs烷基，CFs，Ci—Cs烷基或 —NH —苯基取代，及 . d )吡啶基，其可經一 c i 一 C 4烷氧基，—六氫吡 畊（苯基）（其苯基可經鹵素或一 C(〇)CH3取代） ，—六氫卩比卩井（吼卩定基），經基，鹵素，C 1 一 C 5院基 ，CF3，二（Ci — Cd烷基）胺基，嗎啉基或—NH -苯基取代； Μ爲一〇一， Β爲苯基，其可經獨立選自下列中之取代基取代·· a )鹵素， b) Ci— C5烷基，其可經鹵素或一〇r7取代，其 中R 爲氣或Ci 一 Cs院基，及 c ) C i 一 C 4烷氧基，其可經鹵素取代。 3 4 ·如申請專利範圍第3 2項的化合物，其中該直 接連接至D的B和L的環形構造並不是在、、鄰〃的位置被 一〇Η所取代。 本纸張尺度適用中國國家禚準（CNS ) Α4見格（2】0X297公釐） 广诘先滅讀，背之注意事¾再填寫本頁) 訂 άφ. -10- 8 8 8 8 ABCD 1269791 六、申請專利範圍 3 5 ·如申請專利範圍第3 2項的化合物，其中該直 接連接至D的b和l的環形構造並不是在、、鄰〃的位置被 一個帶有可離子化之氫及具有1 0或更小之P K a的部分 所取代。 3 6 ·如申請專利範圍第3 3項的化合物，其中該直 接連接至D的b和l的環形構造並不是在 '、鄰〃的位置被 一〇Η所取代。 3 7 ·如申請專利範圍第3 3項的化合物，其中該直 接連接至D的Β和L的環形構造並不是在 '、鄰〃的位置被 一個帶有可離子化之氫及具有1 〇或更小之p K a的部分 所取代。 3 8 ·如申請專利範圍第3 2項的化合物，其中用於 B和L的取代基以及用於l 1之額外取代基係選自如下群 體· Ci — C5院基，CF3，鹵素及Cl 一 C5院氧基。 3 9 ·如申請專利範圍第3 3項中的化合物，其中用 於B和L的取代基，以及用於l 1之額外取代基係選自如 下群體：Ci—c5烷基，CF3，鹵素及C! — C5烷氧 基° 4 〇 ·如申請專利範圍第1項的化合物，它是一種選 自如下群體之式（I )所示化合物的藥學上可接受的鹽： a )由式（I )化合物和選自如下群體之有機酸或無 機酸所形成的鹼式鹽：氫氯酸、氫溴酸、硫酸、磷酸、甲 礦酸、三氟磺酸、苯磺酸、對一甲苯磺酸、1 一萘磺酸、 2 —萘磺酸、醋酸、三氟醋酸、蘋果酸、酒石酸、檸檬酸 本紙張尺度適用中國國家.標準（CNS ) A4洗格（210X297公釐） — (·請先閱讀背面之注意事項再填寫本頁) 訂 經濟部智慧財產局員工消費合作社印製 -11 - 8 8 8 8 ABCD 1269791 六、申請專利範圍 、乳酸、草酸、琥珀酸、反一丁烯二酸、順一丁烯二酸、 苯甲酸、水楊酸、苯乙酸、及扁桃酸；和 b )有機鹼或無機鹼的酸式鹽。 4 1 .如申請專利範圍第2 7項的化合物，其爲一種 藥學上可接受的鹽，且爲由式（I )化合物和選自如下群 體之有機酸和無機酸所形成的鹼式鹽：氫氯酸、氫溴酸、 硫酸、磷酸、甲磺酸、三氟磺酸、苯磺酸、對一甲苯磺酸 、1一萘磺酸、2-萘磺酸、醋酸、三氟醋酸、蘋果酸、 酒石酸、檸檬酸、乳酸、草酸、琥珀酸、反一丁烯二酸、 順一丁烯二酸、苯甲酸、水楊酸、苯乙酸、.及扁桃酸。 4 2 ·如申請專利範圍第3 2項的化合物，它是一種 藥學上可接受的鹽，且爲由式（I )化合物和選自如下群 體之有機酸和無機酸所形成的鹼式鹽：氫氯酸、氫溴酸、 硫酸、磷酸、甲磺酸、三氟磺酸、苯磺酸、對一甲苯磺酸 、1 一萘磺酸、2 -萘磺酸、醋酸、三氟醋酸、蘋果酸、 酒石酸、檸檬酸、乳酸、草酸、琥珀酸、反一丁烯二酸、 順一丁烯二酸、苯甲酸、水楊酸、苯乙酸、及扁桃酸。 4 3 ·如申請專利範圍第3 3項的化合物，它是一種 藥學上可接受的鹽，且是由式（I )化合物和選自如下群 體之有機酸和無機酸所形成的鹼式鹽：氫氯酸、氫溴酸、 硫酸、甲磺酸、三氟磺酸、苯磺酸、對一甲苯磺酸、1 — 萘磺酸、2 -萘磺酸、醋酸、三氟醋酸、蘋果酸、酒石酸 、檸檬酸、乳酸、草酸、琥珀酸、反-丁烯二酸、順〜丁 烯二酸、苯甲酸、水楊酸、苯乙酸、及扁桃酸。 本纸張尺度適用中國國家標準（CNS ) A4現格（210X297公变 1 &quot; &quot;&quot; -12- ---------^— (請先閨讀背面之注意事項再填寫本頁) 訂 άφ, 經濟部智慧財產局員工消費合作社印製 269791 Αδ Β8 a D8 4 4 生長 合物 藥學 該式 義者 該式 義者 該式 義者 申請專利範圍 種用來治療由r a ί催化酶所促成之癌細胞 的藥學組成物，它包含了如申請專利範圍第1項的化 或如申請專利範圍第1項中式（I )所示之化合物的 上可接受的鹽，及一種生理學上可接受的載體。 4 5 ·如申請專利範圍第4 4項的藥學組成物，其中 (I )所示之化合物爲如申請專利範圍第2 7項中所定 0 4 6 ·如申請專利範圍第4 4項的藥學組成物，其中 (I )所示之化合物爲如申請專利範圍第3 2項中所定 〇 4 7 ·如申請專利範圍第4 4項的藥學組成物，其中 (I )所示之化合物爲如申請專利範圍第3 3項中所定 〇 4 8 ·如申請專利範圍第1項的化合物，其爲選自如 (請先閨讀背面之注意事頊再填寫本頁) 經濟部智慧財產局員工消費合作社印製 下群體的化合物： 3 -特丁基苯脲類： Ν -（3 —特—丁基苯）一 Ν' 一（甲基氨基甲醯）苯氧基）苯脲和 (4 一 （3 — （Ν Ν (3 —特一 丁基苯）一 Ν (4 — ( 4 —乙醯 苯氧基）苯脲； 5 —特一 丁基一 2 -甲氧基苯脲類： Ν— (5 —特—丁基一2 —甲氧苯基）一Ν — —（4 一（1 ，3 —二酮基異吲哚滿一 5 -基氧基）苯基）脲； 本纸乐尺度速用中國國家·標準（CNS ) A4C格（2】0Χ 297公釐） -13- ABCD 1269791 六、申請專利範圍 N - ( 5 -特—丁基一 2 —甲氧苯基）—N ^ - ( 4 一（1 一酮基異吲哚滿一 5 —基氧基）苯基）脲； (請先閲讀背面之注意事項再填寫本頁) N — （5 —特一 丁基一 2 —甲氧苯基）一N/— (4 一 （4 一甲氧基一 3 — （ N —甲基氨基甲醯）苯氧基）苯 基）脲和 N — （ 5 —特一丁基一2 —甲氧苯基）一N — -（ 4 一（3—（N—甲基氨基甲醯）苯氧基）苯基）脲； 2 —甲氧基一 5 —（三氟甲基）苯脲類： N — （2 —甲氧基一 5 — （三氟甲基）苯基）—N， —(3 —（ 2 —氨基甲酿一4一吼[1定氧基）苯基）脲， N — （2 —甲氧基一 5 — （三氟甲基）苯基）一 一 （3 — (2 — (N —甲基氨基甲醯）一 4 一吡啶氧基） 苯基）脲， N— (2 —甲氧基一5 — （三氟甲基）苯基）一 N&quot; 一（4 一（ 2 —氨基甲醯一 4 一吼卩定氧基）苯基）脲， N — （2 —甲氧基一 5 —(三氟甲基）苯基）一N&gt; 經濟部智慧財產局員工消f合作社印製 一 （4— (2— (N —甲基氨基甲醯）一 4 一 d比υ定氧基） 苯基）脲， N — （2 —甲氧基一5 — （三氟甲基）苯基）一 一 （4 一 （2 — （N —甲基氨基甲醯一 4 一吡啶硫基）苯 基）脲， N — （2 —甲氧基一 5 —(三氟甲基）苯基）一 N， —(2 —氯基一4 — (2 — （N —甲基氨基甲酸）（4 — 本纸張尺度適用中國國家.標準（CNTS ) A4現格（21〇X：297公釐） -14- 7996 2 ABCD 六、申請專利範圍 吡啶氧基）苯基）脲和 N — （2 —甲氧基一5 — （三氟甲基）苯基）— (請先閏讀背面之注意事項再填寫本頁) 一 （3 —氯基—4 — (2 - （N —甲基氨基甲醯）（4一 吡啶氧基））苯基）脲； 4 一氯基一3 -（三氟甲基）苯脲類： N—（4一氯基一3-（二氟甲基）苯基）一N/-(3 —（2 -氨基甲醯一 4 —吡啶氧基）苯基）脲， N — （4 一氯基一 3 —（三氟甲基）苯基）一 Ν' — (3—（2—(Ν—甲基氨基甲醯一4一吡啶氧基）苯基 )脲， Ν —（4 一氯基一3—(三氟甲基）苯基）一 Ν' — (4 一（ 2 —氨基甲醯一 4 一吡啶氧基）苯基）脲，和 Ν — （4 —氯基一 3—(三氟甲基）苯基）—Ν' — (4 一 （2 — （Ν —甲基氨基甲醯）（4 一吡啶氧基）苯 基）脈； 經濟部智慧財產局員工消費合作社印製 -15- 79962 ABCD 六、申請專利範圍 (請先閱讀背面之注意事項再填寫本頁) N — ( 4 —溴基一 3 -（二_甲基）苯基）—N / — (3 — （ 2 — ( N —甲基氨基甲醯）一4 一吡啶硫基）） 苯基）脲， N —（4 一溴基—3 —(三氟甲基）苯基）—丨\[/ — (2 —氯基一 4 一 （2 — (N -甲基氨基甲醯）（4 一哦 啶氧基））苯基）脲和 N— (4 —漠基一3 —（二氟甲基）苯基）—Ν' — (3 —氯基一4 一 （2 — (Ν —甲基氨基甲醯）（4 一吡 啶氧基））苯基）脲；和 2 —甲氧基一 4 一氯基一 5 - （三氟甲基）苯脲類： Ν —（2 —甲氧基一 4 一氯基一 5 — （三氟甲基）苯 基）一 Ν/— (3 — （2 — （Ν -甲基氨基甲醯）一 4 一 毗啶氧基）苯基）脲， Ν —（2 —甲氧基一4 一氯基一 5 — （三氟甲基）苯 基）一Ν/ — (4 — (2 —（Ν —甲基氨基甲醯）一 4 一 吡啶氧基）苯基）脲， Ν — （2 —甲氧基一4 一氯基一 5 —（三氟甲基）苯 經濟部智慧財產局員工消費合作社印製 基）一 Ν — (2 —氯基一 4 一 （2 — （Ν —甲基氨基甲 醯）（4 一吡啶氧基））苯基）脲和 Ν — (2 —甲氧基—4 一氯基—5 —（三氟甲基）苯 基）一 Ν/— (3 —氯基一 4 一 （2 — （Ν —甲基氨基甲 醯）（4 一吡啶氧基））苯基）脲。 4 9 ·如申請專利範圍第3 4項的化合物，它是一種 藥學上可接受的鹽，且爲由式（I )化合物和選自如下群 本纸張尺度適用中國國家.標準（CNS) Α4規格（2!0Χ 297公釐） -16- 1269791 A8 B8 C8 D8 六、申請專利範圍 (.請先¾•讀背面之注意事¾再填寫本頁) 體之有機酸和無機酸所形成的鹼式鹽：氫氯酸、氫溴酸、 硫酸、磷酸、甲磺酸、三氟磺酸、苯磺酸、對-甲苯磺酸 、1 一萘磺酸、2 -萘磺酸、醋酸、三氟醋酸、蘋果酸、 酒石酸、檸檬酸、乳酸、草酸、琥珀酸、反一丁烯二酸、 順一丁烯二酸、苯甲酸、水楊酸、苯乙酸、及扁桃酸。 5 0 ·如申請專利範圍第1項的化合物，其中經取代 結構L之取代基爲選自下列：甲基，三氟甲基，乙基，正 丙基，正丁基，正戊基，異丙基，第三丁基，甲氧基，乙 氧基，丙氧基，Cl，Br及F。 5 1 ·如申請專利範圍第5 0項的化合物，其中經取 代結構B和L之取代基爲選自下列：甲基，三氟甲基，乙 基，正丙基，正丁基，正戊基，異丙基，第三丁基，第二 丁基’異丁基，甲氧基，乙氧基，丙氧基，Cl ，Br及 F 〇 5 2 · —種用來治療癌細胞生長之藥學組成物，包含 如申請專利範圍第1項的化合物或其藥學上可接受的鹽， 及一種生理學上可接受的載體。 經濟部智慧財產局員工消費合作社印製 5 3 ·如申請專利範圍第5 2項之用來治療癌細胞生 長之藥學組成物，包含N —（4 —氯一 3 —（三氟甲基） 苯基）一(4 —（2 —氨基甲醯—4 —吡啶氧基） 苯基）脲或其藥學上可接受的鹽。 5 4 ·如申請專利範圍第5 2項之用來治療癌細胞生 長之藥學組成物，包含N —（4 一氯一 3 -（三氟甲基） 苯基）一N，一 （4 一（2 —（N —甲基氨基甲醯）一4 本纸張尺度適用中國國家標準（cns ) A4洗格（2丨公釐） -17- 9 97 6 2 ABCD 經濟部智慧財產局員工消費合作社印製 六、申請專利範圍 一卩比U定氧基）苯基）脲或其藥學上可接受的鹽。 5 5 .如申請專利範圍第5 2項之用來治療癌細胞生 長之藥學組成物’其中藥學上可接受的鹽爲：選自如下群 體之有機酸和無機酸的鹼式鹽：氫氯酸、氫溴酸、硫酸、 磷酸、甲磺酸、三氟磺酸、苯磺酸、對一甲苯磺酸、1 -萘磺酸、2 —萘磺酸、醋酸、三氟醋酸、蘋果酸、酒石酸 、檸檬酸、乳酸、草酸、琥珀酸、反—丁烯二酸、順一丁 烯二酸、苯甲酸、水楊酸、苯乙酸、及扁桃酸。 5 6 .如申請專利範圍第5 2項之用來治療癌細胞生 長之藥學組成物’其中藥學上可接受的鹽爲 N— (4 —氯一 3 —(三氟甲基）苯基）一 N/ —( 4一（2—氨基甲醯一4一吡啶氧基）苯基）脲之甲苯磺 酸鹽。 5 7 .如申請專利範圍第5 2項之用來治療癌細胞生 長之藥學組成物，其中藥學上可接受的鹽爲 N— (4 —氯一 3 —(三氟甲基）苯基）一 ( 4一（2—(N—甲基氨基甲醯）一4一吡啶氧基）苯基 )脲之甲苯磺酸鹽。 5 8 .如申請專利範圍第4 1項的化合物，其爲一種 藥學上可接受的鹽，且爲N-（4一氯一3—(三氟甲基 )苯基）一 — (4 — 2 —（N —甲基氨基甲醯）一 4 一吡啶氧基）苯基）脲之甲苯磺酸鹽。 5 9 ·如申請專利範圍第4 4項的用來治療由r a f 催化酶所促成之癌細胞生長的藥學組成物，其含有如申請 本紙張尺度適用中國國家.標準（CNS ) ( 210X297公釐） (請先聞讀背面之注意事^再填寫本頁)Printed by the Intellectual Property Office of the Ministry of Economic Affairs, the Consumer Cooperatives. VI. Application for patents a) Hydrogen, b) C! - C 5 alkyl, which can pass C ρ 3 , morpholinyl, C 1 -C 3 alkoxy, piperazine Pyridyl, tetrahydrofuranyl, c ! a c 3 alkylpyrrole 11 definite '-N Η phenyl, hydroxy, halogen, ~ 〇 si (C 1 - C 5 alkyl) 3 or di (C i - C 4 alkane Substituted with an amine group, c) a phenyl group which may be halogen, a di(ci-C 4 alkyl)amino group, a morpholinyl group, a hexahydropyridinium (phenyl group) (the phenyl group may be halogen or a C (〇)c Η 3 substituted), one hexahydro D is more than π well (D is more steep), substituted by a base, halogen, Ci-Cs alkyl, CFs, Ci-Cs alkyl or -NH-phenyl, And d) a pyridyl group which may be substituted by a ci-C 4 alkoxy group, hexahydropyrazine (phenyl) (the phenyl group may be substituted by halogen or a C(〇)CH3), hexahydroindole ratio卩井(吼卩定基), thiol-based, halogen, C 1 -C 5 -based, CF3, bis(Ci-Cd alkyl)amine, morpholinyl or -NH-phenyl substituted; , Β is a phenyl group, which can be independently selected from the following Substituent ·· a) halogen, b) Ci-C5 alkyl, which may be substituted by halogen or mono-r7, wherein R is a gas or Ci-Cs, and c) C i - C 4 alkoxy, Can be substituted by halogen. The compound of claim 3, wherein the ring structure of B and L directly connected to D is not replaced by a fluorene at the position of the orthoquinone. This paper scale applies to China National Standard (CNS) Α4 见4 (2) 0X297 mm) 诘 诘 灭 , , , , , 诘 诘 诘 ά ά ά ά ά ά ά ά ά ά ά ά ά ά ά ά. -10- 8 8 8 8 ABCD 1269791 6. Patent application scope 3 5 · A compound of claim 32, wherein the ring structure of b and l directly connected to D is not an ionizable hydrogen at the position of the orthoquinone And a portion having a PK a of 10 or less is substituted. 3 6 · A compound of claim 3, wherein the ring structure of b and l directly connected to D is not replaced by a fluorene at the position of '. 3 7 · A compound of claim 3, wherein the ring structure of Β and L directly attached to D is not at the position of ', orthoquinone, with an ionizable hydrogen and having 1 〇 or The smaller part of p K a is replaced. 3 8 · A compound according to claim 3, wherein the substituents for B and L and the additional substituents for l are selected from the group consisting of Ci - C5, CF3, halogen and Cl C5 hospital oxygen. 39. The compound of claim 3, wherein the substituents for B and L, and the additional substituents for l are selected from the group consisting of Ci-c5 alkyl, CF3, halogen and C! - C5 alkoxy group 4 〇 · A compound of claim 1 which is a pharmaceutically acceptable salt of a compound of formula (I) selected from the group consisting of: a) from formula (I) a compound and a basic salt formed from an organic or inorganic acid selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, mineralic acid, trifluorosulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid 1, 1-naphthalenesulfonic acid, 2-naphthalenesulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid. The paper scale is applicable to China. Standard (CNS) A4 washing (210X297 mm) — (·Please first Read the notes on the back and fill out this page. Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives -11 - 8 8 8 8 ABCD 1269791 6. Patent application scope, lactic acid, oxalic acid, succinic acid, anti-monoic acid, Citric acid, benzoic acid, salicylic acid, phenylacetic acid, and Peach acid; and b) an organic or inorganic base acid salt. A compound according to claim 27, which is a pharmaceutically acceptable salt and which is a basic salt formed from a compound of the formula (I) and an organic acid and an inorganic acid selected from the group consisting of: Hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, trifluorosulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 1-naphthalenesulfonic acid, 2-naphthalenesulfonic acid, acetic acid, trifluoroacetic acid, apple Acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, trans-maleic acid, cis-monocarboxylic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid. 4 2 · A compound of claim 3, which is a pharmaceutically acceptable salt and which is a basic salt formed from a compound of formula (I) and an organic acid and a mineral acid selected from the group consisting of: Hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, trifluorosulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 1-naphthalenesulfonic acid, 2-naphthalenesulfonic acid, acetic acid, trifluoroacetic acid, apple Acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, trans-maleic acid, cis-monocarboxylic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid. 4 3 · A compound of claim 3, which is a pharmaceutically acceptable salt and which is a basic salt formed from a compound of formula (I) and an organic acid and a mineral acid selected from the group consisting of: Hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, trifluorosulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 1-naphthalenesulfonic acid, 2-naphthalenesulfonic acid, acetic acid, trifluoroacetic acid, malic acid, Tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, trans-butenedioic acid, cis-butenedioic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid. This paper scale applies to the Chinese National Standard (CNS) A4 (210X297 public change 1 &quot;&quot;&quot; -12- ---------^- (please read the notes on the back and fill in This page) ά φ, Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 269791 Αδ Β8 a D8 4 4 growth compound pharmacy A pharmaceutical composition of a cancer cell promoted by an enzyme, which comprises an acceptable salt of a compound as shown in the first aspect of the patent application or a compound of the formula (I) in the first aspect of the patent application, and a physiological An acceptable carrier. 4 5 . The pharmaceutical composition of claim 4, wherein the compound represented by (I) is as defined in Item 27 of the patent application scope. a pharmaceutical composition according to Item 4, wherein the compound represented by (I) is a pharmaceutical composition as defined in Item 3 of the patent application, and the pharmaceutical composition is as shown in (4). The compound is as specified in item 3 of the patent application scope. 4 8 · If you apply for the compound of the first paragraph of the patent scope, it is selected from the group (please read the back note first and then fill out this page). The Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed the group of compounds: 3 - special Butyl phenylureas: Ν -(3 - tex-butyl benzene) mono-'-(methylaminoformamidine)phenoxy)phenylurea and (4 one (3 - (Ν Ν (3 - special one) Benzene) Ν (4 - ( 4 - ethoxyphenoxy) phenylurea; 5 - tert-butyl 2- 2 - methoxy phenylurea: Ν - (5 - tex-butyl 2- methoxy Phenyl)-indole-(4-(1,3-diketoisoindolyl-5-yloxy)phenyl)urea; This paper is used in China National Standards (CNS) A4C ( 2]0Χ 297 mm) -13- ABCD 1269791 6. Patent application scope N - (5-tert-butyl-2-methoxyphenyl)-N ^ - ( 4 -(1-ketoisoindane) 5-5-yloxy)phenyl)urea; (Please read the back of the precautions and fill out this page) N — (5 —Te-butyl- 2 -methoxyphenyl)-N/—(4 one ( 4-methoxy-3 (N-methylaminoformamidine)phenoxy)phenyl)urea and N-(5-t-butyl-2-methoxyphenyl)-N--(4-(3-(N-methyl) Aminomethyl)phenoxy)phenyl)urea; 2-methoxy-5-(trifluoromethyl)phenylurea: N —(2-methoxy-5-(trifluoromethyl)phenyl )—N, —(3 —( 2 —amino-branched 4-tetrahydro[1-oxy)phenyl)urea, N —(2-methoxy-5-(trifluoromethyl)phenyl)- One (3 - (2 - (N-methylaminoformamidine)-tetrapyridyloxy)phenyl)urea, N-(2-methoxy-5-(trifluoromethyl)phenyl)-N&quot One (4-(2-aminocarboxamidine-4-yloxy)phenyl)urea, N-(2-methoxy-5-(trifluoromethyl)phenyl)-N&gt; Ministry of Economic Affairs The Intellectual Property Office staff eliminates the co-production of a (4-(2-(N-methylaminocarbamidine)--4-d-butoxy)phenyl)urea, N-(2-methoxy-5) —(trifluoromethyl)phenyl)-one (4 one (2 - (N-methyl) Carbenium-4-pyridylthio)phenyl)urea, N —(2-methoxy-5-(trifluoromethyl)phenyl)-N, —(2-chloroyl-4) (2 — (N-methylcarbamic acid) (4 - This paper scale applies to China. Standard (CNTS) A4 grid (21〇X: 297 mm) -14- 7996 2 ABCD VI. Patent pending range pyridyloxy) Phenyl)urea and N-(2-methoxy-5-(trifluoromethyl)phenyl)- (please read the back of the note first and then fill out this page) one (3 - chloro - 4 - ( 2-(N-methylaminocarbamidine)(4-pyridyloxy))phenyl)urea; 4 monochloro-3-trifluoromethyl)phenylurea: N-(4-chlorol-3) -(Difluoromethyl)phenyl)-N/-(3-(2-aminocarbazin-4-ylpyridyloxy)phenyl)urea, N — (4-chloro-3-yl-(trifluoromethyl) Phenyl)- Ν' — (3-(2-(Ν-methylaminocarbamidine-4-pyridyloxy)phenyl)urea, Ν-(4-chloro- 3-(trifluoromethyl) Phenyl)-anthracene - (4-(2-aminocarboxamidine-4-pyridinyloxy) Phenyl)urea, and hydrazine - (4-chloro-mono-3-(trifluoromethyl)phenyl)-hydrazide'- (4-(2 - (Ν-methylaminocarbamidine)) (4-pyridyloxy) Phenyl) pulse; Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing -15- 79962 ABCD VI. Application for patent scope (please read the note on the back and fill out this page) N — ( 4 —Bromo-based 3 - ( Di-methyl)phenyl)-N / (3 - ( 2 - ( N - methylaminocarbamidine) - 4 -pyridylthio)) phenyl)urea, N - (4 - bromo - 3 - (trifluoromethyl)phenyl)-oxime\[/ - (2-chloro-indenyl-4-(2-(N-methylaminoformamidine)(4-oxalyloxy))phenyl)urea and N — (4 —Molydi-3 —(difluoromethyl)phenyl)—Ν′ — (3 —Chloro-l- 4-(2-(Ν-methylaminocarbamidine)(4-pyridyloxy)) Phenyl)urea; and 2-methoxy-4-tetrachloro-5-(trifluoromethyl)phenylurea: Ν-(2-methoxy-4-isochloro-5-(trifluoromethyl) Phenyl) Ν / - (3 - (2 - (Ν - methylamino) Methyl hydrazide) -4-cyclohexyloxy)phenyl)urea, hydrazine - (2-methoxy-4-isochloro-5-(trifluoromethyl)phenyl) hydrazine / — (4 - (2 —(Ν —methylaminocarbamidine)-4-pyridyloxy)phenyl)urea, Ν —(2-methoxy-4-monochloro-5-(trifluoromethyl)benzene Ministry of Economic Affairs Intellectual Property Office Employees' consumption cooperatives printed on the basis of a group - (2 - chloro-based 4-(2-(Ν-methylaminocarbamidine) (4-pyridyloxy))phenyl)urea and hydrazine - (2-methoxy —4-chloro-(5-(trifluoromethyl)phenyl)-indole-(3-chloro-indenyl- 4-(2-(indole-methylaminoformamidine)(4-pyridyloxy)) Phenyl) urea. 4 9 · A compound of claim 34, which is a pharmaceutically acceptable salt, and which is a compound of formula (I) and is selected from the following group of papers for use in China. Standard (CNS) Α 4 Specifications (2!0Χ 297 mm) -16- 1269791 A8 B8 C8 D8 VI. Patent application scope (.Please read the following 3⁄4•Read the back of the matter 3⁄4 and fill in this page) The alkali formed by the organic acid and inorganic acid Salt: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, trifluorosulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 1-naphthalenesulfonic acid, 2-naphthalenesulfonic acid, acetic acid, trifluoro Acetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, trans-maleic acid, cis-monocarboxylic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid. The compound according to claim 1, wherein the substituent of the substituted structure L is selected from the group consisting of methyl, trifluoromethyl, ethyl, n-propyl, n-butyl, n-pentyl, and iso Propyl, tert-butyl, methoxy, ethoxy, propoxy, Cl, Br and F. 5 1 · A compound according to claim 50, wherein the substituents of the substituted structures B and L are selected from the group consisting of methyl, trifluoromethyl, ethyl, n-propyl, n-butyl, n-pentyl Base, isopropyl, tert-butyl, t-butyl 'isobutyl, methoxy, ethoxy, propoxy, Cl, Br and F 〇 5 2 · - used to treat cancer cell growth A pharmaceutical composition comprising a compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof, and a physiologically acceptable carrier. Printed by the Intellectual Property Office of the Ministry of Economic Affairs, Employees' Consumption Cooperatives 5 · The pharmaceutical composition for the treatment of cancer cell growth, including N-(4-chloro-3-(3-trifluoromethyl)benzene A (4-(2-aminocarbazin-4-pyridyloxy)phenyl)urea or a pharmaceutically acceptable salt thereof. 5 4 · A pharmaceutical composition for treating cancer cell growth according to the scope of claim 5, comprising N-(4-chloro-3-(-trifluoromethyl)phenyl)-N, one (4 one ( 2 —(N —Methylaminocarbamidine)—4 This paper scale applies to Chinese National Standards (cns) A4 Washing (2丨公) -17- 9 97 6 2 ABCD Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperatives System 6, the scope of application of the patent is more than U-oxy) phenyl) urea or a pharmaceutically acceptable salt thereof. 5 5. The pharmaceutical composition for treating cancer cell growth according to the scope of claim 5, wherein the pharmaceutically acceptable salt is: a basic salt of an organic acid and an inorganic acid selected from the group consisting of: hydrochloric acid , hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, trifluorosulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 1-naphthalenesulfonic acid, 2-naphthalenesulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid , citric acid, lactic acid, oxalic acid, succinic acid, trans-butenedioic acid, cis-monocarboxylic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid. 5 6. A pharmaceutical composition for treating cancer cell growth as claimed in claim 52, wherein the pharmaceutically acceptable salt is N-(4-chloro-3-(3-trifluoromethyl)phenyl) a tosylate salt of N/(4-(2-carbamid-4-pyridyloxy)phenyl)urea. 5 7. The pharmaceutical composition for treating cancer cell growth according to claim 52, wherein the pharmaceutically acceptable salt is N-(4-chloro-3-(trifluoromethyl)phenyl)- (Toluenesulfonate of 4-(2-(N-methylaminocarbamidine)-tetrapyridyloxy)phenyl)urea. 5 8. A compound according to claim 41, which is a pharmaceutically acceptable salt and which is N-(4-chloro-3-(trifluoromethyl)phenyl)-(4-2) - (N-methylaminoformamidine)-tetrapyridyloxy)phenyl)urea tosylate. 5 9 · The pharmaceutical composition for treating the growth of cancer cells promoted by the raf catalytic enzyme according to the patent application No. 4 4, which is applicable to the Chinese National Standard (CNS) (210×297 mm) as applied for the paper scale. (Please read the notes on the back first and then fill out this page) -18- ABCD 1269791 六、申請專利範圍 專利範圍第1項中所定義式（I )化合物的藥學上可接受 的鹽’其爲N —（4 一氯一 3 —(三氟甲基）苯基）一 n / — ( 4 — 2 — （ N —甲基氨基甲醯）一 4 —吡啶氧基） 苯基）脲之甲苯磺酸鹽。 (請先¾•讀背面之注意事vfx:填寫本頁) 經濟部智慧財產局員工消費合作社印製 本纸張尺度適用中國國家.標準（CNS ) A4洗格（210X297公釐） -19--18- ABCD 1269791 6. Pharmacologically acceptable salt of the compound of formula (I) as defined in claim 1 of the patent scope of the patent scope, which is N-(4-chloro-3-(trifluoromethyl)phenyl a tosylate of n / (4 - 2 - (N - methylaminoformamidine) - 4 - pyridinyloxy) phenyl) urea. (Please read the following on the back of the vfx: fill out this page) Printed by the Ministry of Economic Affairs, Intellectual Property Office, Staff and Consumer Cooperatives This paper scale applies to China. Standard (CNS) A4 Wash (210X297 mm) -19-
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